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  Ccr-3 receptor antagonistsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Nitrogen Containing Other Than Solely As A Nitrogen In An Inorganic Ion Of An Addition Salt, A Nitro Or A Nitroso Doai, Ureas (i.e., N-c(=o)-n), Benzene Ring ContainingThe Patent Description & Claims data below is from USPTO Patent Application 20060167105. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE [0001] This application is a division of copending U.S. Ser. No. 10/242,610, filed Sep. 12, 2002, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/318,992, filed Sep. 13, 2001, both incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] The invention relates to certain 1,2-diaminocyclopentane derivatives that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use, and methods and intermediates useful for preparing them. BACKGROUND OF THE INVENTION [0003] Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema and parasitic infections ((see Bousquet, J. et al., N. Eng. J. Med. 323: 1033-1039 (1990) and Kay, A. B. and Corrigan, C. J., Br. Med. Bull. 48:51-64 (1992)). In asthma, eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators. Chemokines such as RANTES, eotaxin and MCP-3 are known to activate eosinophils ((see Baggiolini, M. and Dahinden, C. A., Immunol. Today. 15:127-133 (1994), Rot, A. M. et al., J. Exp. Med. 176, 1489-1495 (1992) and Ponath, P. D. et al., J. Clin. Invest., Vol. 97, #3, 604-612 (1996)). However, unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic for eosinophils ((see Griffith-Johnson, D. A. et al., Biochem. Biophy. Res. Commun. 197:1167 (1993) and Jose, P. J. et al., Biochem. Biophy. Res. Commun. 207, 788 (1994)). Specific eosinophil accumulation was observed at the site of administration of eotaxin whether by intradermal or intraperitoneal injection or aerosol inhalation ((see Griffith-Johnson, D. A. et al., Biochem. Biophy. Res. Commun. 197:1167 (1993); Jose, P. J. et al., J. Exp. Med. 179, 881-887 (1994); Rothenberg, M. E. et al., J. Exp. Med. 181, 1211 (1995) and Ponath, P. D., J. Clin. Invest., Vol. 97, #3, 604-612 (1996)). [0004] Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma ((R. P. Schleimer et al., Am. Rev. Respir. Dis., 141, 559 (1990)). The glucocorticoids are believed to inhibit IL-5, IL-3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in the patients ((see Hanania, N. A. et al., J. Allergy and Clin. Immunol., Vol. 96, 571-579 (1995) and Saha, M. T. et al., Acta Paediatrica, Vol. 86, #2, 138-142 (1997)). It is therefore desirable to have an alternative means of treating eosinophil related diseases without incurring these undesirable side effects. [0005] Recently, the CCR-3 receptor was identified as a major chemokine receptor that eosinophils use for their response to eotaxin, RANTES and MCP-3. When transfected into a murine pre-.beta. lymphoma line, CCR-3 bound eotaxin, RANTES and MCP-3 conferred chemotactic responses on these cells to eotaxin, RANTES and MCP-3 ((see Ponath, P. D. et al., J. Exp. Med. 183, 2437-2448 (1996)). The CCR-3 receptor is expressed on the surface of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly selective for eotaxin. Studies have shown that pretreatment of eosinophils with an anti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 ((see Heath, H. et al., J. Clin. Invest., Vol. 99, #2, 178-184 (1997)). Applicants' issued U.S. patents U.S. Pat. Nos. 6,140,344 and 6,166,015 and published EP application EP903349, published Mar. 24, 1999 disclose CCR-3 antagonists that inhibit eosinophilic recruitment by chemokine such as eotaxin. [0006] Therefore, blocking the ability of the CCR-3 receptor to bind RANTES, MCP-3 and eotaxin and thereby preventing the recruitment of eosinophils should provide for the treatment of eosinophil-mediated inflammatory diseases. SUMMARY OF THE INVENTION [0007] The present invention concerns novel 1,2-diaminocyclopentane derivatives which are capable of inhibiting the binding of eotaxin to the CCR-3 receptor and thereby provide a means of combating eosinophil induced diseases, such as asthma. [0008] In a first aspect, this invention provides a compound of Formula (I): wherein: [0009] R.sub.1 is hydrogen or alkyl; [0010] R.sub.2 is arylalkyl; [0011] R.sub.3 is hydrogen, alkyl, acyl, aryl, or arylalkyl; [0012] R.sub.4 is -W-X-Y-Z; [0013] W is absent or alkylene; [0014] X is absent, carbonyl, oxy, --S(O).sub.n--, or --N(R.sub.a)--; [0015] Y is arylene or heteroarylene; and [0016] Z is hydrogen, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, or heteroarylalkyl; [0017] R.sub.a is hydrogen, alkyl, acyl, aryl, arylalkyl, alkoxycarbonyl, or benzyloxycarbonyl and [0018] n is 0, 1, or 2; [0019] or a salt thereof. [0020] In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Continue reading... 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