US 7,592,350 B2
Polycyclic compounds as potent alpha2-adrenoceptor antagonists
David Din Belle, Espoo (Finland); Reija Jokela, Helsinki (Finland); Arto Tolvanen, Espoo (Finland); Antti Haapalinna, Turku (Finland); Arto Karjalainen, Espoo (Finland); Jukka Sallinen, Turku (Finland); and Jari Ratilainen, Kulho (Finland)
Assigned to Orion Corporation, Espoo (Finland)
Appl. No. 10/510,019
PCT Filed Apr. 03, 2003, PCT No. PCT/FI03/00255
§ 371(c)(1), (2), (4) Date May 31, 2005,
PCT Pub. No. WO03/082866, PCT Pub. Date Oct. 09, 2003.
Claims priority of provisional application 60/369347, filed on Apr. 03, 2002.
Claims priority of application No. 20020642 (FI), filed on Apr. 03, 2002.
Prior Publication US 2006/0094740 A1, May 04, 2006
Prior Publication US 2007/0293527 A9, Dec. 20, 2007
Int. Cl. A61K 31/4355 (2006.01); C07D 491/12 (2006.01)
U.S. Cl. 514—285  [546/62; 546/47; 514/280] 8 Claims
 
1. A compound of formula IA:

OG Complex Work Unit Drawing
wherein,
X is O or S;
Z is —CHR8—;
R1 is chosen from hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, halo(C1-C6)alkyl, (C1-C6)alkoxy-CO—, CN, NO2, NH2, mono- or di(C1-C6)alkylamino, and carboxyl;
R3 is chosen from hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C4cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, aryloxy, aryl(C1-C6)alkoxy, aryloxy(C1-C6)alkyl, aryl(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, NH2, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl-CO—, (C1-C6)alkyl-CO—O—, (C1-C6)alkyl-CO—O—(C1-C6)alkyl, (C1-C6)alkoxy-CO—, (C1-C6)alkoxy-CO—(C1-C6)alkyl, (C1-C6)alkoxy-CO—(C1-C6)alkoxy(C1-C6)alkyl, carbamoyl, mono- or di(C1-C6)alkylcarbamoyl, carboxyl and (C1-C6)alkyl-S—(C1-C6) alkyl,
wherein the (C3-C7)cycloalkyl or aryl group is unsubstituted or is substituted with 1 or 2 substituents each independently chosen from hydroxy, (C1-C6)alkyl, halogen, (C1-C6) alkoxy, NH2, CN and NO2, or one of R3 or R4 and R6 together form a bond between the ring atoms to which they are attached;
R4 is chosen from hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)alkoxy(C1-C6)alkyl;
R5 is chosen from H, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, aryloxy, aryl(C1-C6)alkoxy, aryloxy(C1-C6)alkyl, aryl(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkyl-CO—O—, (C1-C6)alkyl-CO—O—(C1-C6)alkyl, (C1-C6)alkoxy-CO—(C1-C6)alkoxy(C1-C6)alkyl, carbamoyl, mono- or di(C1-C6)alkylcarbamoyl, carboxyl and (C1-C6)alkyl-S—(C1-C6)alkyl,
wherein the (C3-C7)cycloalkyl or aryl is unsubstituted or is substituted with 1 or 2 substituents each independently chosen from hydroxy, (C1-C6)alkyl, halogen, (C1-C6)alkoxy, NH2, CN and NO2, or R4 and R5 form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered saturated carbocyclic ring substituted with 1, 2, or 3 substituents, R9,
wherein R9 are each independently chosen from hydroxy, (C1-C6)alkyl, halogen, NH2, NO2, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, carboxyl, (C1-C6)alkyl-CO—, (C1-C6)alkyl-CO—O—, (C1-C6)alkoxy-CO—, (C1-C6)alkoxy-CO—(C1-C6)alkyl, carbamoyl mono- or di(C1-C6)alkylcarbamoyl and oxo;
R6 is chosen from H, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)alkoxy(C1-C6)alkyl, or R6 forms a bond between the ring atom to which it is attached and the ring atom to which R7 is attached;
R7 is chosen from H, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)alkoxy(C1-C6)alkyl;
R8 is H, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)alkoxy(C1-C6)alkyl;
R15 is chosen from H, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl-CO—, (C1-C6)alkyl-CO—O—(C1-C6)alkyl, (C1-C6)alkoxy-CO—, (C1-C6)alkoxy-CO—(C1-C6)alkyl, (C1-C6)alkoxy-CO—(C1-C6)alkoxy(C1-C6)alkyl, carbamoyl, mono- or di(C1-C6)alkylcarbamoyl and carboxyl;
R16 is chosen from H and (C1-C6)alkyl; and
m is 0 to 2;
or a pharmaceutically acceptable salt or ester thereof.