| Bridged bicyclic amine derivatives useful as ccr-3 receptor antagonists -> Monitor Keywords |
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  Bridged bicyclic amine derivatives useful as ccr-3 receptor antagonistsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of One Nitrogen And Six Carbons, Polycyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos, Ring Nitrogen Of The Seven-membered Hetero Ring Is Shared By An Additional Cyclo Of The Polycyclo Ring System, Two Of The Cyclos Share At Least Three Ring Members (i.e., Bridged)The Patent Description & Claims data below is from USPTO Patent Application 20060189596. Brief Patent Description - Full Patent Description - Patent Application Claims
PRIORITY [0001] This application claims priority from U.S. Ser. No. 60/450,380, filed 27 Feb. 2003, incorporated herein by reference in full. FIELD OF THE INVENTION [0002] The invention relates to certain bridged bicyclic amine derivatives that are CCR-3 receptor antagonists, as well as pharmaceutical compositions containing them and methods for their use. BACKGROUND INFORMATION [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. 323:1033-39 (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, 15:127-33 (1994), Rot, A. M. et al., J. Exp. Med. 176:1489-95 (1992) and Ponath, P. D. et al., J. Clin. Invest., 97(3):604-12 (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 has been observed at the site of administration of eotaxin, whether by intradermal or intraperitoneal injection or aerosol inhalation (see Griffith-Johnson, D. A. et al., supra; Jose, P. J. et al., supra; Rothenberg, M. E. et al., J. Exp. Med. 181:1211 (1995), and Ponath, P. D., supra). [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 and IL-3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects in patients such as glaucoma, osteoporosis, and growth retardation (see Hanania, N. A. et al., J. Allergy and Clin. Immunol., 96:571-79 (1995) and Saha, M. T. et al., Acta Paediatrica, 86(2):138-42 (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., 183:2437-48 (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., 99(2):178-84 (1997)). U.S. Pat. Nos. 6,140,344 and 6,166,015 issued to Applicant herein and EP application EP903349, published Mar. 24, 1999 disclose CCR-3 antagonists that inhibit eosinophilic recruitment by chemokine such as eotaxin. SUMMARY OF THE INVENTION [0006] The present invention is directed to bridged cyclic amine derivatives useful as CCR3 receptor antagonists 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. [0007] In a first aspect, this invention provides a compound of Formula (I): wherein: [0008] T is where R.sup.6 is taken together with one of R.sup.7 and R.sup.8 to form a bridge of one to two bridgehead carbon atoms, and the other of R.sup.7 and R.sup.8 is selected from hydrogen and R.sup.9; [0009] Ar and Ar.sup.1 are, independently of each other, aryl or heteroaryl; [0010] F is alkylene, alkenylene, or a bond; [0011] E is selected from --C(.dbd.O)N(R.sup.10)--, --SO.sub.2N(R.sup.10)--, --N(R.sup.11)C(.dbd.O)N(R.sup.10)--, --N(R.sup.11)SO.sub.2N(R.sup.10)--, --N(R.sup.11)C(.dbd.S)N(R.sup.10)--, --N(R.sup.11)C(.dbd.O)--, --N(R.sup.11)SO.sub.2--, --N(R.sup.12)C(.dbd.O)CH(R.sup.13)--, and CH(R.sup.13)C(.dbd.O)N(R.sup.12)--, where: [0012] R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are, independently of each other, hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(.dbd.O)-Z, where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy; [0013] or alternatively, R.sup.12 and R.sup.13 may be taken together with the nitrogen and carbon atoms to which they are attached, respectively, to form a heterocyclyl or heteroaryl ring optionally substituted with up to two groups selected from R.sup.14; [0014] R.sup.3 and R.sup.4 are, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, -(alkylene)-C(.dbd.O)-Z.sup.1, or -(alkylene)-C(.dbd.O).sub.2Z.sup.1, where Z.sup.1 is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy; [0015] R.sup.5 is hydrogen or alkyl; [0016] Q is --C(.dbd.O)-- or C.sub.1-2alkylene; [0017] R.sup.9 is attached to any available carbon atom of ring T and is selected from lower alkyl, hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, or a lower alkyl substituted with one of hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy; [0018] R.sup.14 is selected from lower alkyl, hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, and a lower alkyl substituted with one of hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy; [0019] m is 0 or 1; and [0020] n is 0 to 4; and prodrugs, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. [0021] The invention also relates to pharmaceutical compositions containing compounds of Formula (I), above, and methods of treating CCR-3 receptor mediated diseases, such as asthma, by administration of a therapeutically-effective amount of a compound of Formula (I), to a patient in need of treatment thereof. DETAILED DESCRIPTION OF THE INVENTION Definitions Continue reading... Full patent description for Bridged bicyclic amine derivatives useful as ccr-3 receptor antagonists Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Bridged bicyclic amine derivatives useful as ccr-3 receptor antagonists patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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