Inhibitors of IMPDH enzyme
AssigneeVertex Pharmaceuticals Incorporated
InventorsDavid M. Armistead, Michael C. Badia, Guy W. Bemis, Randy S. Bethiel, Catharine A. Frank, Perry M. Novak, Steven M. Ronkin, Jeffrey O. Saunders
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Abstract
The present invention relates to a novel class of compounds which are IMPDH inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMPDH enzyme activity and consequently, may be advantageously used as agents for immunosuppression. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.
Claims21
A compound of the formula:
- ##STR50## wherein:
- E is oxygen;
- G and G' are independently selected from the group consisting of R.sup.6 and (CH.sub.2).sub.n --Y;
- D is selected from the group consisting of C(O), C(S) and S(O).sub.2 ;
- B is phenylene;
- B' is phenyl;
- wherein each of B and B' optionally comprises up to 3 substituents, wherein:
- the first of said substituents, if present, is selected from R.sup.1, R.sup.2, R.sup.4 or R.sup.5,
- the second of said substituents, if present, is selected from R.sup.1 or R.sup.4, and
- the third of said substituents, if present, is R.sup.1 ;
- wherein:
- each R.sup.1 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R.sup.6 or (CH.sub.2).sub.n --Y;
- wherein n is 0, 1 or 2;
- and
- Y is selected from halogen, CN, NO.sub.2, CF.sub.3, OCF.sub.3, OH, SR.sup.6, S(O) R.sup.6, SO.sub.2 R.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2, NR.sup.6 R.sup.8, COOH, COOR.sup.6 or OR.sup.6 ;
- each R.sup.2 is independently selected from (C.sub.1 -C.sub.4)-straight or branched alkyl, or (C.sub.2 -C.sub.4)-straight or branched alkenyl or alkynyl;
- and each R.sup.2 optionally comprises up to 2 substituents, wherein:
- the first of said substituents, if present, is selected from R.sup.1, R.sup.4 and R.sup.5, and
- the second of said substituents, if present, is R.sup.1 ;
- each R.sup.4 is independently selected from OR.sup.5, OC(O)R.sup.6, OC(O)R.sup.5, OC(O)OR.sup.6, OC(O)OR.sup.5, OC(O)N(R.sup.6).sub.2, OP(O)(OR.sup.6).sub.2, SR.sup.6, SR.sup.5, S(O)R.sup.6, S(O)R.sup.5, SO.sub.2 R.sup.6, SO.sub.2 R.sup.5, SO.sub.2 N(R.sup.6).sub.2, SO.sub.2 NR.sup.5 R.sup.6, SO.sub.3 R.sup.6, C(O)R.sup.5, C(O)OR.sup.5, C(O)R.sup.6, C(O)OR.sup.6, NC(O)C(O)R.sup.6, NC(O)C(O)R.sup.5, NC(O)C(O)OR.sup.6, NC(O)C(O)N(R.sup.6).sub.2, C(O)N(R.sup.6).sub.2, C(O)N(OR.sup.6)R.sup.6, C(O)N(OR.sup.6)R.sup.5, C(NOR.sup.6)R.sup.6, C(NOR.sup.6)R.sup.5, N(R.sup.6).sub.2, NR.sup.6 C(O)R.sup.1, NR.sup.6 C(O)R.sup.6, NR.sup.6 C(O)R.sup.5, NR.sup.6 C(O)OR.sup.6, NR.sup.6 C(O)OR.sup.5, NR.sup.6 C(O)N(R.sup.6).sub.2, NR.sup.6 C(O)NR.sup.5 R.sup.6, NR.sup.6 SO.sub.2 R.sup.6, NR.sup.6 SO.sub.2 R.sup.5, NR.sup.6 SO.sub.2 N (R.sup.6).sub.2, NR.sup.6 SO.sub.2 NR.sup.5 R.sup.6, N(OR.sup.6)R.sup.6, N(OR.sup.6)R.sup.5, P(O)(OR.sup.6)N(R.sup.6).sub.2, and P(O)(OR.sup.6).sub.2 ;
- each R.sup.5 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, or S, and wherein a CH.sub.2 adjacent to said N, O or S maybe substituted with C(O);
- and each R.sup.5 optionally comprises up to 3 substituents, each of which, if present, is R.sup.1 ;
- each R.sup.6 is independently selected from H, (C1-C4)-straight or branched alkyl, or (C2-C4)-straight or branched alkenyl;
- and each R.sup.6 optionally substituted with R7;
- R.sup.7 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, or S, and wherein a CH.sub.2 adjacent to said N, O or S maybe substituted with C(O);
- and each R.sup.7 optionally comprises up to 2 substituents independently chosen from H, (C.sub.1 -C.sub.4)-straight or branched alkyl, or (C.sub.2 -C.sub.4) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH.sub.2).sub.n --Z;
- wherein n is 0, 1 or 2;
- and
- wherein if B is unsubstituted phenyl and all of said substituents present are on B' are R.sup.1, then at least one of said R.sup.1 substituents is not chloro, bromo or iodo;
- and wherein B and B' are not simultaneously unsubstituted phenyl.
Dependencies are inferred from the claim text.