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Piperidine derivatives useful as ccr5 antagonistsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Lymphokine, InterleukinPiperidine derivatives useful as ccr5 antagonists description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080095740, Piperidine derivatives useful as ccr5 antagonists. Brief Patent Description - Full Patent Description - Patent Application Claims
PRIORITY APPLICATION [0001] This application is a divisional of U.S. application Ser. No. 10/738,907, filed Dec. 17, 2003, which claims the benefit of U.S. provisional Application Ser. No. 60/434,306, filed Dec. 18, 2002, both of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] The present invention relates to piperidine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compound of this invention, and methods of treatment using the inventive compounds. The invention also relates to the use of a combination of the compound of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of the compound of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis. BACKGROUND OF INVENTION [0003] The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned. While recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus. [0004] It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists. [0005] CCR5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies. Inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease. WO 02/791194 discloses other piperidine derivatives useful as CCR5 antagonists. [0006] Other piperidine derivatives, which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease, are disclosed in U.S. Pat. Nos. 5,883,096, 6,037,352, 5,889,006, 5,952,349, and 5,977,138. [0007] A-M. Vandamme et al., Antiviral Chemistry & Chemotherapy, 9:187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy ("HAART"). HAART involves various combinations of nucleoside reverse transcriptase inhibitors ("NNRTI"), non-nucleoside reverse transcriptase inhibitors ("NNRTI") and HIV protease inhibitors ("PI"). In compliant drug-naive patients, HAART is effective in reducing mortality and the progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority. SUMMARY OF THE INVENTION [0008] The present invention provides a novel class of compounds as antagonists of the CCR5 receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, and methods of treatment, prevention or amelioration of one or more diseases associated with the CCR5 receptor. [0009] One aspect of the invention relates to a compound having the general structure shown in Formula I: or a pharmaceutically acceptable salt or solvate thereof; wherein: [0010] n is 0, 1, 2, 3 or 4; [0011] s is 0, 1, 2, 3 or 4; [0012] t is 1, 2, 3 or 4 with the provisos that [0013] i) when n is 0 and s is 2, then t is 1, 3 or 4; and [0014] ii) when n is 0 and t is 2, then s is 0, 1, 3 or 4; [0015] X and Z can be the same or different with each being independently N or CH; [0016] R.sup.1 is H, alkyd, aralkyl, --S(O.sub.2)alkyl, --S(O.sub.2)aryl, --C(O)alkyl, --C(O)aryl, -alkyl-aryl-R.sup.8, -alkyl-heteroaryl-R.sup.8, --S(O.sub.2)cycloalkyl, --S(O.sub.2)-aryl-R.sup.8, --C(O)cycloalkyl, --C(O)-aryl-R.sup.8, --C(O)NR.sup.20R.sup.21 or --S(O.sub.2)NR.sup.20R.sup.21; [0017] R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 can be the same or different each being independently H or alkyl; [0018] R.sup.3 is H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl or heteroaryl; [0019] or R.sup.2 and R.sup.3 taken together are .dbd.N(O-alkyl), .dbd.N(OH), .dbd.N--N(R.sup.20R.sup.21) or .dbd.CH(alkyl) provided that when one or both of X and Z is N, R.sup.2 and R.sup.3 together are not .dbd.CH(alkyl); [0020] R.sup.8 is aryl, heteroaryl, fluorenyl; and diphenylmethyl, heteroaryl-N-- wherein each R.sup.10 is the same or different and independently selected from --CH.sub.3 or halogen, Y is N or N(.fwdarw.O) and each of said aryl, fluorenyl, diphenyl and heteroaryl is substituted or optionally independently substituted with 1 to 4 substituents which substituents can be the same or different each being independently selected from the group consisting of R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15; Continue reading about Piperidine derivatives useful as ccr5 antagonists... 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