Immunosuppressive compounds
AssigneeVertex Pharmaceuticals Incorporated
InventorsDavid M. Armistead, Joshua S. Boger, Harold V. Meyers, Jeffrey O. Saunders, Roger D. Tung
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Abstract
This invention relates to a novel class of immunosuppressive compounds having an affinity for the FK-506 binding protein (FKBP). Once bound to this protein, the immunosuppressive compounds inhibit the prolyl peptidyl cis-trans isomerase (rotamase) activity of the FKBP and inhibit T cell activation. As such, the compounds of this invention can be used as immunosuppressive drugs to prevent or significantly reduce graft rejection in bone marrow and organ transplantations and for use in the treatment of a wide variety of autoimmune diseases in humans and other mammals.
Claims8
A method of suppressing graft rejection in an individual, comprising the step of administering to the individual a composition comprising an immunosuppressant compound that binds to FK-506 binding protein and having a molecular weight below 750 atomic mass units in an amount effective to reduce or eliminate an immune response, in a physiologically acceptable vehicle,
- wherein the immunosuppressant compound is represented by the formula:
- ##STR7## and pharmaceutically acceptable salts thereof, wherein A in O, NH, or N-(C1-C4 alkyl);
- wherein B is hydrogen, CHL--Ar, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl or Ar substituted (C1-C6)-alkyl or (C2-C6)-alkenyl, or ##STR8## wherein L and Q are independently hydrogen, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl;
- wherein T is Ar or substituted cyclohexyl with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl or O-(C2-C4)-alkenyl and carbonyl;
- wherein Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, CF.sub.3, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl, O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl, O-benzyl, O-phenyl, amino and phenyl;
- wherein D is U;
- E is either oxygen or CH-U, provided that if D is hydrogen, then E is CH-U or if E is oxygen then D is not hydrogen;
- wherein U is hydrogen, O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl, 2-indolyl, 3-indolyl, (C1-C4)-alkyl-Ar, (C2-C4)-alkenyl-Ar or Ar;
- wherein J is hydrogen or C1 or C2 alkyl;
- K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl;
- and
- wherein the stereochemistry at carbon position 1 is S.
A method of preventing or significantly reducing autoimmune response in a mammal, comprising the step of administering to the mammal a composition comprising an immunosuppressant compound that binds to FK-506 binding protein and having a molecular weight below 750 atomic mass units in an amount effective to reduce or eliminate an immune response, in a physiologically acceptable vehicle,
- wherein the immunosuppressant compound is represented by the formula:
- ##STR9## and pharmaceutically acceptable salts thereof, wherein A in O, NH, or N-(C1-C4 alkyl);
- wherein B is hydrogen, CHL--Ar, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl or Ar substituted (C1-C6)-alkyl or (C2-C6)-alkenyl, or ##STR10## wherein L and Q are independently hydrogen, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl;
- wherein T is Ar or substituted cyclohexyl with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl or O-(C2-C4)-alkenyl and carbonyl;
- wherein Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, CF.sub.3, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl, O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl, O-benzyl, O-phenyl, amino and phenyl;
- wherein D is U;
- E is either oxygen or CH-U, provided that if D is hydrogen, then E is CH-U or if E is oxygen then D is not hydrogen;
- wherein U is hydrogen, O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl, 2-indolyl, 3-indolyl, (C1-C4)-alkyl-Ar or (C2-C4)-alkenyl-Ar or Ar;
- wherein J is hydrogen or C1 or C2 alkyl;
- K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl;
- and
- wherein the stereochemistry at carbon position 1 is S.
Dependencies are inferred from the claim text.