Immunosuppressive compounds
OwnerDavid M. Armistead, Joshua S. Boger +3inventors
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.
Claims18
An immunosuppressant compound represented by the formula:
- ##STR7## and pharmaceutically acceptable salts thereof;
- wherein B is 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 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;
- 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 O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl;
- wherein J is hydrogen or C1 or C2 alkyl;
- wherein K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl;
- wherein D is not identical to --O--B;
- and
- wherein the stereochemistry at carbon position 1 is R or S;
- provided that
- when J is hydrogen;
- D is methoxy or ethoxy;
- and B is methyl or ethyl then K is not methyl;
- and
- when J is hydrogen;
- D is methoxy and B is n-butyl, then K is not methyl.
An immunosuppressant compound represented by the formula:
- ##STR9## and pharmaceutically acceptable salts thereof;
- wherein the stereochemistry at position 1 is R or S;
- wherein B is benzyl or ethyl or tert-butyl;
- wherein D is methoxy;
- wherein J is methyl, benzyl or ethyl;
- and
- wherein K is hydrogen, methyl or isopropyl;
- provided that when B is ethyl;
- and K is hydrogen then J is not methyl.
An immunosuppressant compound selected from the group consisting of:
- N-Methyloxalyl-N-methylglycine benzyl ester, (S)-N-Methyloxalyl-N-methylalanine benzyl ester (S)-N-Methyloxalyl-N-methylvaline benzyl ester, N-Methyloxalyl-N-benzylglycine ethyl ester and (S)-N-Methyloxalyl-N-ethylalanine tert-butyl ester.
A composition comprising an immunosuppressive amount of a compound in a physiologically acceptable vehicle, said compound being represented by the formula:
- ##STR10## and pharmaceutically acceptable salts thereof;
- wherein B is 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 alkenyl, or ##STR11## 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;
- 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 O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl;.
- wherein J is hydrogen or C1 or C2 alkyl;
- wherein K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl;
- and
- wherein the stereochemistry at carbon position 1 is R or S.
A method for suppressing an immune response in a mammal, comprising the step of administering to said mammal a composition comprising an immunosuppressant compound having an affinity for FK-506 binding protein and a molecular weight below about 750 amu, wherein said compound is represented by the formula:
- ##STR12## and pharmaceutically acceptable salts thereof, wherein B is 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 alkenyl, or ##STR13## 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;
- 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 O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl;
- wherein J is hydrogen or C1 or C2 alkyl;
- wherein K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl;
- and
- wherein the stereochemistry at carbon position 1 is R or S.
A method for preventing or significantly reducing graft rejection in a bone marrow or organ transplant in a mammal, comprising the step of administering to said mammal a composition comprising an immunosuppressant compound having an affinity for FK-506 binding protein and a molecular weight below about 750 amu, wherein said compound is represented by the formula:
- ##STR14## and pharmaceutically acceptable salts thereof, wherein B is 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 alkenyl, or ##STR15## 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;
- 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 O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl;
- wherein J is hydrogen or C1 or C2 alkyl;
- wherein K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl;
- and
- wherein the stereochemistry at carbon position 1 is R or S.
A method for preventing or significantly reducing an autoimmune response in a mammal, comprising the step of administering to said mammal a composition comprising an immunosuppressant compound having an affinity for FK-506 binding protein and a molecular weight below about 750 amu, wherein said compound is represented by the formula:
- ##STR16## and pharmaceutically acceptable salts thereof, wherein B is 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 alkenyl, or ##STR17## 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;
- 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 O-(C1-C4)-straight or branched alkyl or O-(C2-C4)-straight or branched alkenyl;
- wherein J is hydrogen or C1 or C2 alkyl;
- wherein K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl;
- and
- wherein the stereochemistry at carbon position 1 is R or S.
Dependencies are inferred from the claim text.