CA2252465C — Urea derivatives as inhibitors of impdh enzyme

USPTO Abstract

The present invention relates to a novel class of compounds which are IMPDH inhibitors, the compound having the formula: wherein: B is phenylene D is selected from C(O), C(S), and S(O)2; G and G' are independently selected from R1 and H; E is O or S; and B' is phenyl; wherein: B and B' each optionally comprise up to 3 substituents, wherein: the first of said substituents, if present, is selected from R1, R2, R4 and R5, the second of said substituents, if present, is selected from R1 and R4, and the third of said substituents, if present, is R1; and wherein: each R1 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R6 and (CH2)n-Y; wherein n is 0, 1 or 2; and Y is selected from halogen, CN, NO2, CF3, OCF3, OH, SR6, S(O) R6, S02R6, NH2, NHR6, N(R6) 2, NR6R8, COOH, COOR6 and OR6; each R2 is independently selected from (C1-C4)-straight or branched alkyl, and (C2-C4)-straight or branched alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, wherein; the first of said substituents, if present, is selected from R1, R4 and R5, and the second of said substituents, if present, is R1; R3 is selected from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of said N, O, and S heteroatoms is optionally substituted with C(O); and each R3 optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from R1, R2, R4 and R5, the second of said substituents, it present, is selected from R1 and R4, and the third of said subatituents, if present, is R1; each R4 is independently selected from OR5, OC (O) R6, OC (O) R5, OC (O) OR6, OC (O) OR5, OC (O) N(R6) 2, OP (O) (OR6) 2, SR6, SR5, S(O) R6, S(O) R5, SO2R6, S02R5, SO2N (R6) 2, SO2NR5R6, S03R6, C(O) R5, C(O) OR5, C(O) R6, C(O) OR6, NC (O) C(O) R6, NC (O) C(O) R5, NC (O) C(O) OR6, NC (O) C N(R6) 2, C(O) N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R5, C(NOR6)R6, C(NOR6)R5, N(R6)2, NR6C(O)R1, NR6C(O)R6, NR6C(O) R5, NR6C(O) OR6, NR6C (O) OR5, NR6, C(O) N(R6)2, NR6C(O)NR5R6, NR6SO2R6, NR6SO2R5, NR6, SO2N (R6) 2, NR6SO2NR5R6, N(OR6) R6, N(OR6) R5, P(O)(OR6) N(R6) 2, and P(O) (OR6) 2; each R5 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to said N, O or S may be substituted with C(O); and each R5 optionally comprises up to 3 substituents, each of which, if present, is R1; each R6 is independently selected from H, (C1-C4) -straight or branched alkyl, and (C2-C4) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7; R7 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to said N, O or S may be substituted with C(O); and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C4) -straight or branched alkyl, or (C2-C4) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, and (CH2)n-Z; wherein n is 0, 1 or 2; and Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S (C1-C4) -alkyl, SO (C1-C4) -alkyl, SO2 (C1-C4)-alkyl, NH2, NH (C1-C4) -alkyl, N ( (C1-C4) -alkyl) 2, N ( (C1-C4) -alkyl) R8, COOH, C(O) O(C1-C4) -alkyl and O(C1-C4) -alkyl; and R8 is an amino protecting group; and wherein if B is unsubstituted phenyl and all of said substituents present are on B1 are R2, then at least one of said R1 substituents is not chloro, bromo or iodo; and wherein B and B' are not simultaneously unsubstituted phenyl. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMFDH enzyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.