Immunosuppressive imidazole derivatives and their combination preparations with tacrolimus or cyclosporins

A method for increasing graft survival time in a transplantation subject having a graft comprising:

• administering to said subject:
• a compound (a) that is a compound possessing an inhibitory activity on the production of nitric oxide and
• compound (b) that is a tricyclic macrolide or a salt, solvate or hydrate thereof,
• in an amount and for a time and under conditions effective to increase graft survival time,
• wherein said tricyclic macrolide has the following structure:
• wherein
• each of the adjacent pairs R1 and R2, R3 and R4, and R5 and R6 are independently
• (a) two adjacent hydrogen atoms, but R2 may also be an alkyl group,
• (b) or may form a bond between the carbon atoms to which they are attached,
• R7 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group or together with R1 is an oxo group;
• R8 and R9 are independently a hydrogen atom or hydroxy group;
• R10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group;
• X is an oxo group;
• a hydrogen atom and a hydroxy group;
• two hydrogen atoms;
• or a group represented by the formula —CH2O—;
• Y is an oxo group;
• a hydrogen atom and a hydroxyl group;
• two hydrogen atoms;
• or a group represented by the formula N—NR11R12 or N—OR13;
• R11 and R12 are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
• R13, R14, R15, R16, R17, R18, R19, R22 and R23 are independently a hydrogen atom or an alkyl group;
• R24 is a ring system that may contain one or more heteroatoms and may be substituted;
• n is an integer of 1 or 2;
• wherein in addition to the above definitions,
• Y, R10 and R23 together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula —CH2Se(C6H5), and an alkyl substituted by one or more hydroxy groups,
• wherein compound (a) is not compound (b).