Chemokine receptor antagonists

Details Chemokine receptor antagonists Chemokine receptor antagonists

2000-04-25

2001-11-13

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S256000, C514S259500, C544S238000, C544S311000, C544S283000, C544S287000

Reexamination Certificate

active

06316449

ABSTRACT:

BACKGROUND OF THE INVENTION
U.S. Pat. No. 3,139,428 teaches compounds of formula
wherein R
1
is hydrogen, methyl, or R
3
; R
2
is hydrogen, keto, hydroxyl or a radical of the formula —OR
4
in which R
4
is the acyl radical of an aliphatic carboxylic acid containing 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, valeryl, hexanoyl and the like, benzoyl or benzoyl substituted with 1, 2, or 3 lower alkyl, halo or lower alkoxy groups, for example p-methylbenzoyl, m-methylbenzoyl, o-methylbenzoyl, 3,4-dimethylbenzoyl, p-chlorobenzoyl, p-fluorobenzoyl, o-bromobenzoyl, m-chlorobenzoyl, 2,4-dichlorobenzoyl, p-methoxybenzoyl, 3,4,5-trimethoxybenzoyl, 3,4-dimethoxybenzoyl and the like; and R
3
is ═CHR
5
or —CH
2
R
6
in which R
5
is lower alkyl, furyl, phenyl, phenyl lower alkyl such as benzyl, phenethyl, phenylpropyl and the like, phenyl lower alkenyl such as cinnamyl, phenylpropenyl, phenylbutenyl and the like, methylenedioxyphenyl, or phenyl nuclearly substituted with 1 or 2 halo, lower alkyl, lower alkoxy or nitro groups such as p-chlorophenyl, 3,4-dichlorophenyl, m-methylphenyl, o-bromophenyl, p-ethylphenyl, p-fluorophenyl, p-methoxyphenyl, o-methoxyphenyl, m-butoxyphenyl, p-nitrophenyl, 3,4-dinitrophenyl, 2,4-dinitrophenyl, o-nitrophenyl, m-nitrophenyl and the like, and R
6
is lower alkyl, furyl, phenyl, phenyl lower alkyl, methylenedioxyphenyl, or phenyl nuclearly substituted with 1 or 2 halo, lower alkyl, lower alkoxy or amino groups. The compounds are disclosed as useful as intermediates and as anti-inflammatory agents.
U.S. Pat. No. 3,291,800 teaches compounds of formula
wherein R
1
represents lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, aryl such as phenyl or aralkyl such as benzyl; R
2
represents hydrogen, lower alkyl such as methyl, ethyl, propyl, isopropyl and the like, lower alkoxy such as methoxy or ethoxy or acetyl; R
3
represents hydrogen or lower alkyl and R
4
represents hydrogen hydroxy or keto and to the nontoxic pharmaceutically acceptable acid addition and quaternary ammonium salts thereof. The compounds are disclosed as having pharmacological activity as analgesics, tranquilizers, and anti-inflammatory agents.
These patents are hereby incorporated by reference.
Migration of leukocytes from blood vessels into diseased tissues is important to the initiation of normal disease-fighting inflammatory responses. But this process, known as leukocyte recruitment, is also involved in the onset and progression of debilitating and life-threatening inflammatory and autoimmune diseases. The pathology of these diseases results from the attack of the body's immune system defenses on normal tissues. Thus, blocking leukocyte recruitment to target tissues in inflammatory and autoimmune disease would be a highly effective therapeutic intervention. The leukocyte cell classes that participate in cellular immune responses include lymphocytes, monocytes, neutrophils, eosinophils and basophils. In many cases, lymphocytes are the leukocyte class that initiates, coordinates, and maintains chronic inflammatory responses, and thus are generally the most important class of cells to block from entering inflammatory sites. Lymphocytes attract monocytes to the site, which, collectively with lymphocytes, are responsible for much of the actual tissue damage that occurs in inflammatory disease. Infiltration of lymphocytes and/or monocytes is responsible for a wide range of chronic, autoimmune diseases, and also organ transplant rejection. These diseases include, but are not limited to, rheumatoid arthritis, atherosclerosis, psoriasis, chronic contact dermatitis, inflammatory bowel disease, multiple sclerosis, sarcoidosis, idiopathic pulmonary fibrosis, dermatomyositis, skin pemphigoid and related diseases, (e.g.,
pemphigus vulgaris, p. foliacious, p. erythematosis
), glomerulonephritides, vasculitides, hepatitis, diabetes, allograft rejection, and graft-versus-host disease.
This process, by which leukocytes leave the bloodstream and accumulate at inflammatory sites, and initiate disease, takes place in at least three distinct steps which have been described as (1) rolling, (2) activation/firm adhesion and (3) transendothelial migration (Springer T. A.,
Nature
1990;346:425-433; Lawrence and Springer,
Cell
1991;65:859-873; Butcher E. C.,
Cell
1991;67:1033-1036). The second step is mediated at a molecular level by chemoattractant receptors. Chemoattractant receptors on the surface of leukocytes bind chemoattractant cytokines secreted by cells at the site of damage or infection. Receptor binding activates leukocytes, increases the adhesiveness of the adhesion molecules that mediate transendothelial migration, and promotes directed migration of the cells toward the source of the chemoattractant cytokine.
A recent discovery is the existence of a large family (>20 members) of structurally homologous chemoattractant cytokines, approximately 8 to 10 kD in size. These molecules share the ability to stimulate directed cell migration (chemotaxis) and have been collectively called “chemokines,” a contraction of chemotactic cytokines. Each chemokine contains four cysteine residues (C) and two internal disulfide bonds. Chemokines can be grouped into two subfamilies, based on whether the two amino terminal cysteine residues are immediately adjacent (C—C family) or separated by one amino acid (C—X—C family). These differences correlate with the organization of the two subfamilies into separate gene clusters. Within each gene cluster, the chemokines typically show sequence similarities between 25% to 60%.
The chemokines of the C—X—C subfamily, such as interleukin-8, are produced by a wide range of cell types and act predominantly on neutrophils as mediators of acute inflammation. Chemokines of the C—C subfamily are also produced by a wide variety of cell types. These molecules act predominantly on subsets of mononuclear inflammatory cells. Currently there are at least six C—C chemokines with known chemotactic activity for human monocytes and/or T cells, including MCP-1, MCP-2, MCP-3, MIP-1&agr;, MIP-1&bgr;, and RANTES. This suggests there may be a high degree of redundancy in chemoattractant pathways. In addition, most C—C chemokines are chemotactic for more than one cell type. For examples, RANTES (regulated on activation, normal T cell expressed and secreted) acts on memory CD4
+
T cells, eosinophils, and monocytes. Monocyte chemoattractant protein-1 (MCP-1), another C—C chemokine, acts on monocytes, activated “memory” T cells and on basophils. MCP-1 is also a potent secretogogue of inflammatory mediators for monocytes and basophils.
Five C—C chemokine receptors have recently been characterized (CCRR1-5 or CCR1-CCR5), and all of these belong to the seven transmembrane spanning G protein-coupled receptor family. Each of these receptors mediates the binding and signaling of more than one chemokine. For example, the CCR1 receptor binds both MIP-1&agr; and RANTES. There are 2 receptors which bind MCP-1, CCR2 (with alternately spliced forms, 2A and 2B) and CCR4. CCR2 is also known to mediate binding and signaling of MCP-3. The CCR4 receptor binds and signals, in addition to MCP-1, with RANTES and MIP-1&agr;. Which of these is responsible for the MCP-1 mediated recruitment of monocytes and T cells is not known.
In agreement with the observation that lymphocyte emigration into inflammatory sites is usually accompanied by emigration of monocytes, MCP-1 is expressed at sites of antigen challenge and autoimmune disease. However, analyses of human inflammatory lesions with antibodies to other chemokines show RANTES, MIP-1I, MIP-1&thgr; and MCP-3 to be present as well. Injection of MCP-1 into skin sites in mice provokes only a mild monocytic infiltrate or no infiltrate at all (Ernst C. A. et al.,
J. Immunol
. 1994;152:3541-3544). Whether these results reflect redundant and complex recruitment pathways has not been resolved. MCP-1 and MCP-3 may play a role in allergic hypersensitivity disease. This is suggested by the observation that MCP-1

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