Patent EP-1530574-B1 (EP)
Inventor: LUECKING ULRICH
IPC: A61K31/506
Filed: 2003-08-05
Granted: 2006-11-22
Abstract: Pyrimidine derivatives (I), having the 2- and 4-positions linked by a nitrogen-containing chain forming a fused macrocyclic ring, are new.  Macrocyclic pyrimidine derivatives of formula (I) and their isomers, diastereomers, enantiomers and salts are new; A = arylene or heteroarylene; B = direct bond; or 1-12C alkylene, 2-12C alkenylene, 2-12C alkynylene, arylene or heteroarylene (all optionally substituted (os) by one or more of OH, halo, CN, NO2, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, aryl, heteroaryl, -(CH2)p-aryl, -(CH2)p-heteroaryl, -phenyl-(CH2)p-R10, -(CH2)p-PO3(R10)2, NR8R9, NR8COR9, NR8CSR9, NR8SOR9, NR8SO2R9, NR8CONR8R9, NR8COOR9, NR8C(=NH)NR9R10, NR8CSNR9R10, NR8SONR9R10, NR8SO2NR9R10, COR8, CSR8, SOR8, SO2R8, SO2NR8R9, SO3R8, COOR8, CONR8R9, CSNR8R9, SR8 or CR8(OH)-R9); X, Y = O, S, NR11, NR11O, ONR11, CR6R7, CO, CS, SO, SO2, COO, S(O)O, OS(O), SO2O, OSO2, CONR8, NR8CO, OCONR8, NR8COO, CSNR8, NR8CS, OCSNR8, NR8CSO, SONR8, NR8SO, SO2NR8, NR8SO2, NR8CONR9, NR8CSNR9, NR8SONR9 or NR8SO2NR9; R1, R5 = H, OH, halo, CN. NO2, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, aryl, heteroaryl, -(CH2)p-aryl, -(CH2)p-heteroaryl, -phenyl-(CH2)p-R10, -(CH2)p-PO3(R10)2, NR8R9, NR8COR9, NR8CSR9, NR8SOR9, NR8SO2R9, NR8CONR8R9, NR8COOR9, NR8C(=NH)NR9R10, NR8CSNR9R10, NR8SONR9R10, NR8SO2NR9R10, COR8, CSR8, SOR8, SO2R8, SO2NR8R9, SO3R8, COOR8, CONR8R9, CSNR8R9, SR8 or CR8(OH)-R9); or 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, cycloalkyl, aryl or heteroaryl, all substituted by one or more of OH, alkoxy, halo, phenyl or NR3R4; R2 = H or 1-10C alkyl; R3  =  H, halo, NO2, CN, 1-10C alkyl, 1-10C haloalkyl, 2-10C alkenyl, 2-10C alkynyl, cycloalkyl, OH, alkoxy, alkylthio, NH2, -NH-(CH2)p-cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, mono- or dialkylamino, alkylsulfinyl, alkylsulfonyl, 1-6C alkanoyl, CONR8R9, COR10, acetoxyalkyl, COOH, aryl, heteroaryl, -(CH2)p-aryl, -(CH2)p-heteroaryl, -phenyl-(CH2)p-R10, -(CH2)pPO3(R10)2 or NR8R9; or 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, cycloalkyl, aryl or heteroaryl, all substituted by one or more of OH, alkoxy, halo, alkylthio, NH2, CN, alkyl, -NH-(CH2)p-cycloalkyl, cycloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, mono- or dialkylamino, alkylsulfinyl, alkylsulfonyl, 1-6C alkanoyl, CONR8R9, COR10, acetoxyalkyl, COOH, aryl, heteroaryl, -(CH2)p-aryl, -(CH2)p-heteroaryl, -phenyl-(CH2)p-R10, -(CH2)pPO3(R10)2 or NR8R9; R4 = H, halo or 1-4C alkyl; R6-R11 = H; or 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, cycloalkyl, aryl or heteroaryl (all os by one or more of OH, 1-12C alkoxy, halo, alkylthio, NH2, CN, alkyl, -NH-(CH2)p-cycloalkyl, cycloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, mono- or dialkylamino, alkylsulfinyl, alkylsulfonyl, 1-6C alkanoyl, CONR8R9, COR10, acetoxyalkyl, COOH, aryl, heteroaryl, -(CH2)p-aryl, -(CH2)p-heteroaryl, -phenyl-(CH2)p-R10, -(CH2)pPO3(R10)2 or NR8R9;  m = 0-8; n, p = 0-6; Provided that in R1, R3 and R5 - R11 the phenyl, cycloalkyl, aryl, heteroaryl, -(CH2)p-aryl and -(CH2)p-heteroaryl groups are os by one or more of halo, OH, alkyl, alkoxy, CF3 or CF3, the cycloalkyl and 1-10C alkyl groups are optionally interrupted by one or more N, O and/or S and the cycloalkyl rings are os by one or more =O and optionally contain one or more double bonds; unless specified otherwise alkyl moieties have 1-6C, alkenyl or alkynyl moieties 2-6C, cycloalkyl moieties 3-10C, aryl or arylene moieties 3-12C and heteroaryl or heteroarylene moieties 3-18C. Independent claims are also included for: (1) the preparation of (I); and (2) acyclic pyrimidine derivatives of formulae (II) and (III) as intermediates for (I). D' = NH2 or NO2; q = 1-12; U = OH or -NH-COO-CH2Ph; W' = OH or COOH.