CXCR3 antagonists

Details CXCR3 antagonists CXCR3 antagonists

2002-06-06

2004-09-21

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S264110, C544S253000, C544S279000, C544S298000, C544S319000, C544S330000

Reexamination Certificate

active

06794379

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+
])
1
, 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).
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)) termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated heterotrimeric 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,
72:415425 (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 I-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 represents an attractive avenue into the development of new therapeutic agents. Such compounds are provided herein.
SUMMARY OF THE INVENTION
The present invention provides compounds which are useful in the treatment or prevention 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 compounds provided herein have the general formula (I):
wherein X represents a bond, —C(O)—, —C(R
5
)(R
6
)—, —C(R
5
)═, —S(O)—, —S(O)
2
— or —N═; Z represents a bond, —N═, —O—, —S—, —N(R
17
)— or —C(R
7
)═, with the proviso that X and Z are not both a bond; L represents a bond, C(O)—(C
1
-C
8
)alkylene, (C
1
-C
8
)alkylene or (C
2
-C
8
)heteroalkylene; Q represents a bond, (C
1
-C
8
)alkylene, (C
2
-C
8
)heteroalkylene, —C(O)—, —OC(O)—, —N(R
8
)C(O)—, —CH
2
CO—, —CH
2
SO— or —CH
2
SO
2
—, and optionally L and Q can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 3 heteroatoms. The symbols R
1
and R
2
independently represent H, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, aryl or heteroaryl, or optionally are combined to form a 3 to 8-membered ring having from 0 to 2 heteroatoms as ring vertices, and optionally R
2
and L can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms. The symbol R
3
represents hydroxy, (C
1
-C
8
)alkoxy, amino, (C
1
-C
8
)alkylamino, di(C
1
-C
8
)alkylamino, (C
2
-C
8
)heteroalkyl, (C
3
-C
9
)heterocyclyl, (C
1
-C
8
)acylamino, amidino, guanidino, ureido, cyano, heteroaryl, —CONR
9
R
10
or —CO
2
R
11
. The symbol R
4
represents (C
1
-C
20
)alkyl, (C
2
-C
20
)heteroalkyl, heteroaryl, aryl, heteroaryl(C
1
-C
6
)alkyl, heteroaryl(C
2
-C
6
)heteroalkyl, aryl(C
1
-C
6
)alkyl or aryl(C
2
-C
6
)heteroalkyl. The symbols R
5
and R
6
independently represent H, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, heteroaryl or aryl, or optionally R
5
and R
6
are combined to form a 3- to 7-membered ring. The symbols R
7
and R
8
independently represent H, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, heteroaryl or aryl. The symbols R
9
, R
10
and R
11
each independently represent H, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, heteroaryl, aryl, heteroaryl(C
1
-C
6
)alkyl, heteroaryl(C
2
-C
8
)heteroalkyl, aryl(C
1
-C
8
)alkyl or aryl(C
2
-C
8
)heteroalkyl.
Turning next to the ring vertices, Y
1
, Y
2
, Y
3
and Y
4
, the symbols Y
1
and Y
2
independently represent —C(R
12
)═, —N═, —O—, —S—, or —N(R
13
)—. The symbol Y
3
represents N or C wherein the carbon atom shares a double bond with either Z or Y
4
; and Y
4
represents —N(R

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