Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-25
2003-05-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S287000, C544S290000, C514S287000
Reexamination Certificate
active
06559160
ABSTRACT:
BACKGROUND OF THE INVENTION
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall,
Cytokine,
3:165-183 (1991), Schall, et al.,
Curr. Opin. Immunol.,
6:865-873 (1994) and Murphy,
Rev. Immun.,
12:593-633 (1994)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca
2+
])
i
, granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
There are four classes of chemokines, CXC (&agr;), CC (&bgr;), C(&ggr;), and CX
3
C (&dgr;), depending on whether the first two cysteines are separated by a single amino acid (C—X—C), are adjacent (C—C), have a missing cysteine pair (C), or are separated by three amino acids (CXC
3
). The &agr;-chemokines, such as interleukin-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-1) are chemotactic primarily for neutrophils and lymphocytes, whereas &bgr;-chemokines, such as RANTES, MIP-1&agr;, MIP-1&bgr;, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al.,
Nature,
381:661-666 (1996)). The C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al.,
Science,
266:1395-1399 (1994)) while the CX
3
C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al.,
Nature,
385:640-644 (1997).
The chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk,
Trends Pharm. Sci.,
15:159-165 (1994)) which are termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least twelve human chemokine receptors that bind or respond to &bgr;-chemokines with the following characteristic pattern: CCR1 (or “CKR-1” or “CC-CKR-1”) MIP-1&agr;, MIP-1&bgr;, MCP-3, RANTES (Ben-Barruch, et al.,
J. Biol. Chem.,
270:22123-22128 (1995); Neote, et al.,
Cell,
72:415-425 (1993)); CCR2A and CCR2B (or “CKR-2A”/“CKR-2A” or “CC-CKR-2A”/“CC-CKR2A”) MCP-1, MCP-3, MCP-4; CCR3 (or “CKR-3” or “CC-CKR-3”) eotaxin, RANTES, MCP; (Ponath, et al.,
J. Exp. Med.,
183:2437-2448 (1996)); CCR4 (or “CKR-4” or “CC-CKR-4”) TARC, MDC (Imai, et al.,.
J. Biol. Chem.,
273:1764-1768 (1998)); CCR5 (or “CKR-5” or “CC-CKR-5”) MIP-1 &agr;, RANTES, MIP-1 &bgr; (Sanson, et al.,
Biochemistry,
35:3362-3367 (1996)); CCR6 MIP-3 alpha (Greaves, et al.,
J. Exp. Med.,
186:837-844 (1997)); CCR7 MIP-3 beta and 6Ckine (Campbell, et al.,
J. Cell. Biol.,
141:1053-1059(1998)); CCR8 1-309, HHV8 vMIP-I, HHV-8 vMIP-II, MCV vMCC-I (Dairaghi, et al.,
J. Biol. Chem.,
274:21569-21574 (1999)); CCR9 Teck (Zaballos, et al.,
J. Immunol.,
162:5671-5675 (1999)), D6 MIP-1 beta, RANTES, and MCP-3 (Nibbs, et al.,
J. Biol. Chem.,
272:32078-32083 (1997)), and the Duffy blood-group antigen RANTES, MCP-1 (Chaudhun, et al.,
J. Biol. Chem.,
269:7835-7838 (1994)).
Chemokine receptors, such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX
3
CR1, and XCR1 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
The CXCR3 chemokine receptor is expressed primarily in T lymphocytes, and its functional activity can be measured by cytosolic calcium elevation or chemotaxis. The receptor was previously referred to as GPR9 or CKR-L2. Its chromosomal location is unusual among the chemokine receptors in being localized to Xq13. Ligands that have been identified that are selective and of high affinity are the CXC chemokines, IP10, MIG and ITAC.
The highly selective expression of CXCR3 makes it an ideal target for intervention to interrupt inappropriate T cell trafficking. The clinical indications for such intervention are in T-cell mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Inappropriate T-cell infiltration also occurs in psoriasis and other pathogenic skin inflammation conditions, although the diseases may not be true autoimmune disorders. In this regard, up-regulation of IP-10 expression in keratinocytes is a common feature in cutaneous immunopathologies. Inhibition of CXCR3 can be beneficial in reducing rejection in organ transplantation. Ectopic expression of CXCR3 in certain tumors, especially subsets of B cell malignancies indicate that selective inhibitors of CXCR3 will have value in tumor immunotherapy, particularly attenuation of metastasis.
In view of the clinical importance of CXCR3, the identification of compounds that modulate CXCR3 function represent an attractive avenue into the development of new therapeutic agents. Such compounds are the provided herein.
SUMMARY OF THE INVENTION
The present invention is directed to compounds which are modulators of CXCR3 chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of diseases in which CXCR3 chemokine receptors are involved.
More particularly, the compounds provided herein have the general formula:
in which Ar represents a substituted or unsubstituted aryl or heteroaryl group; the symbol R
1
represents a substituted or unsubstituted (C
5
-C
5
)alkyl group; the symbol R
2
represents a substituted or unsubstituted (C
1
-C
8
)alkyl group; the subscript n is an integer of from 0 to 4, and each R
3
independently represents an aryl substituent, preferably selected from halogen, hydroxy, (C
1
-C
8
)alkyl, (C
1
-C
8
)alkoxy, nitro, cyano, amino, and mono- or di-alkylamino; X is CH or N; Y is a substituted or unsubstituted (C
2
-C
8
)alkylene or (C
2
-C
8
)heteroalkylene; and Z is —NR
4
R
5
, in which R
4
and R
5
are independently hydrogen or (C
1
-C
8
)alkyl.
DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C
1
-C
10
means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as “heteroalkyl.” Alkyl groups which are limited to hydrocarbon groups are termed “homoalkyl”.
The term
Dairaghi Daniel J.
McMaster Brian E.
Schall Thomas J.
Chemocentryx, Inc.
Habte Kahsay
Shah Mukund J.
Townsend and Townsend / and Crew LLP
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