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Ccr5 Antagonists Useful for Treating Aids Ccr5 Antagonisten Verwendbar Für Die Behandlung Von Aids Antagonistes De Ccr5 Utiles Dans Le Traitement Du Sida

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Ccr5 Antagonists Useful for Treating Aids Ccr5 Antagonisten Verwendbar Für Die Behandlung Von Aids Antagonistes De Ccr5 Utiles Dans Le Traitement Du Sida Europäisches Patentamt *EP001373256B1* (19) European Patent Office Office européen des brevets (11) EP 1 373 256 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07D 403/06, C07D 417/14, of the grant of the patent: C07D 401/14, A61K 31/506, 06.07.2005 Bulletin 2005/27 A61P 31/18 (21) Application number: 02725381.4 (86) International application number: PCT/US2002/009491 (22) Date of filing: 27.03.2002 (87) International publication number: WO 2002/079194 (10.10.2002 Gazette 2002/41) (54) CCR5 ANTAGONISTS USEFUL FOR TREATING AIDS CCR5 ANTAGONISTEN VERWENDBAR FÜR DIE BEHANDLUNG VON AIDS ANTAGONISTES DE CCR5 UTILES DANS LE TRAITEMENT DU SIDA (84) Designated Contracting States: (74) Representative: Ritter, Stephen David et al AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Mathys & Squire MC NL PT SE TR 120 Holborn Designated Extension States: London EC1N 2SQ (GB) AL LT LV MK RO SI (56) References cited: (30) Priority: 29.03.2001 US 279938 P EP-A- 1 013 276 WO-A-00/66558 WO-A-00/66559 (43) Date of publication of application: 02.01.2004 Bulletin 2004/01 • J. R. TAGAT ET. AL.: "Piperazine Based CCR5 Antagonists as HIV-1 Inhihbitors. I. 2(S)-Merhyl (60) Divisional application: Piperazine as a Key Pharmacophore Element" 05009882.1 BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 16, 2001, pages 2143-6, (73) Proprietor: Schering Corporation XP001098809 Kenilworth, NJ 07033-0530 (US) Remarks: (72) Inventor: MILLER, Michael, W. The file contains technical information submitted Westfield, NJ 07090 (US) after the application was filed and not included in this specification Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 373 256 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 373 256 B1 Description BACKGROUND 5 [0001] The present invention relates to piperidine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. The invention also relates to the use of a combination of a CCR5 antagonist 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 a CCR-5 antagonist of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft 10 v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, aller- gies or multiple sclerosis. [0002] The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and 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. 15 [0003] 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 coreceptor 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 path- ogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the 20 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. [0004] CCR-5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheu- matoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and 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 25 inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease. [0005] Piperidine derivatives which are muscarinic antagonists useful in the treatment o cognitive disorders such as Alzheimer's disease are disclosed in US patents 5,883,096: 6,037,352; 5,889,006; 5,952,349; and 5,977,138. [0006] Piperidine and piperazine derivatives useful in the treatment of AIDS are disclosed in WO 00/66559 and WO 00/66558. 30 [0007] A-M. Vandamme et al., Antiviral Chemistry & Chemotherapy, 9:187-203 (1998) disclose current clinical treat- ments 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 ("NRTI"), non-nucleoside reverse transcriptase inhibitors ("NNRTI") and HIV protease inhibitors ("PI"). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies 35 do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug ther- apies to provide better HIV-1 treatment remains a priority. SUMMARY OF THE INVENTION 40 [0008] The present invention relates to compounds useful as CCR5 antagonist represented by the structural formula I 45 50 or a pharmaceutically acceptable salt or isomer thereof, wherein: Q, X and Z are independently selected from the group consisting of CH and N, provided that one or both of Q and 55 Z is N; 4 5 6 7 R, R , R , R and R are independently selected from the group consisting of H and (C1-C6)alkyl; 1 9 9 R is H, (C1-C6)alkyl, fluoro-(C1-C6)alkyl-, R -aryl(C1-C6)alkyl-, R -heteroaryl-(C1-C6)alkyl-, (C1-C6)alkyl-SO2-, 9 9 22 23 (C3-C6)cycloalkyl-SO2-, fluoro-(C1-C6)alkyl-SO2-, R -aryl-SO2-, R -heteroaryl-SO2-, N(R )(R )-SO2-, (C1-C6) 2 EP 1 373 256 B1 9 9 alkyl-C(O)-, (C3-C6)cycloalkyl-C(O)-, fluoro-(C1-C6)alkyl-C(O)-, R -aryl-C(O)-, NH-(C1-C6)alkyl-C(O)- or R -ar- yl-NH-C(O)-; 2 3 R isHor(C1-C6)alkyl, and R is H, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-, (C3-C10)-cycloalkyl-, (C3-C10)cy- 9 9 9 9 cloalkyl(C1-C6)alkyl-, R -aryl, R -aryl(C1-C6)-alkyl-, R -heteroaryl, or R -heteroaryl(C1-C6)alkyl-, provided that 5 both X and Z are not each N; 2 3 10 11 12 or R and R together are =O, =NOR , =N-NR R or =CH(C1-C6)alkyl, provided that when one or both of X and 2 3 Z is N, R and R together are not =CH(C1-C6)alkyl; 3 9 9 and when X and Z are each CH, R can also be (C1-C6)alkoxy, R -aryloxy, R -heteroaryloxy, (C1-C6)alkyl-C(O) 13 13 O-, (C1-C6)alkyl-NH-C(O)O-, N((C1-C6)alkyl)2-C(O)O-, (C1-C6)alkyl-C(O)-NR -, (C1-C6)alkyl-O-C(O)-NR -, 10 13 13 (C1-C6)alkyl-NH-C(O)-NR - or N((C1-C6)alkyl)2-C(O)-NR -; R8 is (R14,R15,R16)-substituted phenyl, (R14,R15,R16)-substituted pyridyl, (R14,R15,R16)-substituted pyridyl N-ox- ide, or (R14,R15,R16)-substituted pyrimidyl; 9 R is 1, 2 or 3 substituents independently selected from the group consisting of H, halogen, (C1-C6)alkyl, (C1-C6) 22 23 alkoxy, -CF3, -OCF3, CH3C(O)-, -CN, CH3SO2-, CF3SO2- and -N(R )(R ); 15 10 R is H, (C1-C6)alkyl, fluoro(C1-C6)alkyl-, (C3-C10)cycloalkyl(C1-C6)alkyl-, hydroxy(C2-C6)alkyl-, (C1-C6)alkyl- 22 23 O-(C2-C6)alkyl-, (C1-C6)alkyl-O-C(O)-(C1-C6)alkyl- or N(R )(R )-C(O)-(C1-C6)alkyl-; 11 12 R and R are independently selected from the group consisting of H, (C1-C6)alkyl and (C3-C10)cycloalkyl, or 11 12 R and R together are C2-C6 alkylene and form a ring with the nitrogen to which they are attached; 14 15 22 23 R and R are independently selected from the group consisting of (C1-C6)alkyl, halogen, -NR R , -OH, -CF3, 20 -OCH3, -O-acyl and -OCF3; 16 14 24 R is R , hydrogen, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CH=NOR , pyridyl, pyridyl N-oxide, pyrimidinyl, 24 25 26 pyrazinyl, -N(R )CONR R , -NHCONH(chloro-(C1-C6)alkyl), -NHCONH((C3-C10)cycloalkyl(C1-C6)alkyl), -NH- 22 23 CO(C1-C6)alkyl, -NHCOCF3, -NHSO2N(R )(R ), -NHSO2(C1-C6)alkyl, -N(SO2CF3)2, -NHCO2-(C1-C6)alkyl, 27 27 27 22 C3-C10 cycloalkyl, -SR , -SOR ,-SO2R ,-SO2NH(R ), -OSO2(C1-C6)alkyl, -OSO2CF3, hydroxy(C1-C6)alkyl-, 25 24 25 24 -CON R R , -CON(CH2CH2OCH3)2, -OCONH(C1-C6)alkyl, -CO2R , -Si(CH3)3 or -B(OC(CH3)2)2; 17 22 23 19 R is (C1-C6)alkyl, -N(R )(R ) or R -phenyl; 13 18 22 23 24 25 26 R ,R ,R ,R ,R ,R and R are independently selected from the group consisting of H and (C1-C6)alkyl; 19 25 R is 1, 2 or 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, -CF3,-CO2R , -CN, (C1-C6)alkoxy and halogen; 30 20 21 20 21 R and R are independently selected from the group consisting of H and (C1-C6)alkyl, or R and R together with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; and 27 R is (C1-C6)alkyl or phenyl.
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