Pteridine derivatives as immunosuppressants, their preparation, pharmaceutical compositions, and use in therapy.

Abstract

The invention relates to substituted pteridine derivs. of formula I, which are useful as immunosuppressive agents, and as such are useful in the treatment in transplant rejection and/or in the treatment of certain inflammatory diseases. In compds. I, R1 is (un)substituted piperazin-1-yl or (un)substituted homopiperazin-1-yl; R2 is (un)substituted aryl; R3 is hydrogen; and R4 is selected from H, halo, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo-C1-7 alkyl, carboxy-C1-7 alkyl, carboxyaryl, aryloxy, amino, alkylamino, arylamino, etc.; including pharmaceutically acceptable salts, stereoisomers, N-oxides, solvates, and dihydro and tetrahydro derivs. thereof. The invention also relates to the prepn. of I, pharmaceutical compns. comprising at least one compd. I as an active agent, optionally including one or more addnl. biol. active agents, as well as to the use of the compns. for preventing or treating immune disorders, transplant rejection, cardiovascular disorders, allergic conditions, CNS disorders, TNF-α related disorders, viral diseases, inflammatory bowel diseases, and cell proliferative disorders. Nitrosation of 2,6-diamino-4-hydroxypyrimidine followed by redn. and heterocyclization with 3,4-dimethoxyphenylglyoxal monoxime (prepn. from 3,4-dimethoxyacetophenone is given) gave pterine II, which underwent N-acetylation and condensation with 1,2,4-triazole to give triazolylpteridine III. Compd. III was substituted with piperazine, acylated with phenoxyacetyl chloride, and deprotected to give piperazinylpteridine IV. The compds. of the invention express immunosuppression in a mixed lymphocyte reaction (MLR) assay and a TNF-α assay, with compd. IV expressing IC50 values of 3.8 nM and 80 nM, resp. [on SciFinder(R)]