Patent ID: 6559162
Filing Date: 2003-05-06
Classification: A61P,C07D

Abstract:
A compound of formula I, whereinthe wavy bond represents optional endo- or exo-stereochemistry; one of R1 and R2 represents R1a and the other represents a fragment of the formula Ia, R1a represents C1-12 alkyl (optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het1, â€”C(O)R7a, â€”OR7b, â€”N(R8)R7c, â€”C(O)XR9, â€”C(O)N(R10)R7d and â€”S(O)2R11), Het2, â€”C(O)R7a, â€”C(O)XR9, â€”C(O)N(R10)R7d or â€”S(O)2R11; R7a to R7d independently represent, at each occurrence when used herein, H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from â€”OH, C1-6 alkoxy, halo, cyano, nitro, aryl, Het3 and â€”NHC(O)R12), aryl or Het4, or R7d, together with R10, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups); R12 represents H, C1-4 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, cyano, aryl and â€”NHC(O)R13) or aryl; R13 represents H, C1-4 alkyl or aryl; R8 represents H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from â€”OH, halo, cyano, nitro and aryl), aryl, â€”C(O)R14a or â€”C(O)OR14b; R14a and R14b represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from â€”OH, halo, cyano, nitro and aryl) or aryl, or R14a represents H; X represents O or S; R9 represents, at each occurrence when used herein, C1-12 alkyl (optionally substituted and/or terminated by one or more substituents selected from â€”OH, halo, cyano, nitro, aryl, C1-6 alkoxy, â€”SO2R15 and Het5); R15 represents C1-6 alkyl or aryl; R10 represents, at each occurrence when used herein, H, C1-12 alkyl, C1-6 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from â€”OH, halo, cyano, nitro, C1-4 alkyl and C1-4 alkoxy), â€”D-aryl, â€”D-aryloxy, â€”D-Het6, â€”Dâ€”N(H)C(O)R16a, â€”Dâ€”S(O)2R17a, â€”Dâ€”C(O)R16b, â€”Dâ€”C(O)OR17b, â€”Dâ€”C(O)N(R16c)R16d, or R10, together with R7d, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups); R16a to R16d independently represent H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from â€”OH, halo, cyano, nitro and aryl), aryl, or R16c and R16d together represent C3-6, alkylene; R17a and R17b independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from â€”OH, halo, cyano, nitro and aryl) or aryl; D represents a direct bond or C1-6 alkylene; R11 represents, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from is â€”OH, halo, cyano, nitro and aryl), aryl or Het7; R4 represents H, halo, C1-6 alkyl, â€”OR18, â€”Eâ€”N(R19)R20 or, together with R5, represents &boxH;O; R5 represents H, C1-6 alkyl or, together with R4, represents &boxH;O; R18 represents H, C1-6 alkyl, â€”E-aryl, â€”Eâ€”Het8, â€”C(O)R21a, â€”C(O)OR21b or â€”C(O)N(R22a)R22b; R19 represents H, C1-6 alkyl, â€”E-aryl, â€”Eâ€”Het8, â€”C(O)R21a, â€”C(O)OR21b, â€”S(O)2R21c, â€”[C(O)]pN(R22a)R22b or â€”C(NH)NH2; R20 represents H, C1-6 alkyl, â€”E-aryl or â€”C(O)R21d; R21a to R21d independently represent, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het9), aryl, Het10, or R21a and R21d independently represent H; R22a and R22b independently represent, at each occurrence when used herein, H or C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het11), aryl, Het12, or together represent C3-6 alkylene, optionally interrupted by an O atom; E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene; p represents 1 or 2; Het1 to Het12 independently represent, at each occurrence when used herein, five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from â€”OH, oxo, halo, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, aryl, aryloxy, â€”N(R23a)R23b, â€”C(O)R23c, â€”C(O)OR23d, â€”C(O)N(R23e)R23f, â€”N(R23g)C(O)R23h and â€”N(R23i)S(O)2R23j; R23a to R23j independently represent C1-6 alkyl, aryl or R23a to R23i independently represent H; A represents a direct bond, â€”Jâ€”, â€”Jâ€”N(R24)â€” or â€”Jâ€”Oâ€” (in which latter two groups, N(R24)â€” or Oâ€” is attached to the carbon atom bearing R4 and R5); B represents â€”Zâ€”, â€”Zâ€”N(R25)â€”, â€”N(R25)â€”Zâ€”, â€”Zâ€”S(O)nâ€”, â€”Zâ€”Oâ€” (in which latter two groups, Z is attached to the carbon atom bearing R4 and R5), â€”N(R25)C(O)Oâ€”Zâ€”, (in which latter group, â€”N(R25) is attached to the carbon atom bearing R9 and R10) or â€”C(O)N(R25)â€” (in which latter group, â€”C(O) is attached to the carbon atom bearing R4 and R5); J represents C1-6 alkylene optionally substituted by one or more substituents selected from â€”OH, halo and amino; Z represents a direct bond or C1-4 alkylene; R24 and R25 independently represent H or C1-6 alkyl; G represents CH or N; R6 represents one or more optional substituents selected from â€”OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by â€”N(H)C(O)OR26a), C1-6 alkoxy, â€”N(R27a)R27b, â€”C(O)R27c, â€”C(O)OR27d, â€”C(O)N(R27e)R27f, â€”N(R27g)C(O)R27h, â€”N(R27i)C(O)N(R27j)R27k, â€”N(R27m)S(O)2R26b, â€”S(O)nR26c, and/or â€”OS(O)2R26d; R26a to R26d independently represent C1-6 alkyl; R27a to R27m independently represent H or C1-6 alkyl; n represents, at each occurrence, 0, 1 or 2; and Ra to Rh and R3 independently represent H or C1-4 alkyl; wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; or a pharmaceutically acceptable derivative thereof; provided that (a) when A represents â€”Jâ€”N(R24)â€” or â€”Jâ€”Oâ€”, then: (i) J does not represent C1 alkylene; and (ii) B does not represent â€”N(R25)â€”, â€”N(R25)â€”Zâ€” (in which latter group N(R25) is attached to the carbon atom bearing R4 and R5), â€”S(O)nâ€”, â€”Oâ€” or â€”N(R25)C(O)Oâ€”Zâ€” when R4 and R5 do not together represent &boxH;O; (b) when R4 represents â€”OR18 or â€”N(R19)(R20), then: (i) A does not represent â€”Jâ€”N(R24)â€” or â€”Jâ€”Oâ€”; and (ii) B does not represent â€”N(R25)â€”, â€”N(R25)â€”Zâ€” (in which latter group N(R25) is attached to the carbon atom bearing R4 and R5), â€”S(O)nâ€”, â€”Oâ€” or â€”N(R25)C(O)Oâ€”Zâ€”; (c) when A represents a direct bond, then R4 and R5 do not together represent &boxH;O; and (d) the compound is not: (Â±) (8&bgr;)-4-amino-5-chloro-2-methoxy-N-(3-benzyl-3-azabicyclo[3.2.1]oct-8-yl)benzamide; (S)-N-(3-benzyl-3-azabicyclo[3.2.1]oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide; or (S)-N-(3-benzyl-3-azabicyclo[3.2.1]oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide hydrochloride.