Preparation of arylmorpholines as inhibitors of DNA-dependent protein kinase and methods to potentiate cancer treatment.

Abstract

Compds. that inhibit DNA-dependent protein kinase, I [n = 0-4; X = (un)substituted 4-7 membered aliph. ring contg. 0-3 heteroatoms consisting of N, O and S (X = morpholinyl preferred); Z = independently N or CR3; R3 = independently H, halo, CHO, alkoxy, etc.; R1 = H, (un)substituted alkyl, cycloalkyl, CO, NO2, etc.; R2 = H, (un)substituted alkyl, carbamoyl, alkoxy, sulfamyl, etc.; with provision when X = morpholinyl, R2 and R4 and R3 = H at each occurrence, then R1 is different from COMe, phenylalkene, and NO2; and with the provision that when X = morpholinyl, R4 = H and Z = N at each occurrence, then R1 and R2 when taken together is different from triazole], were prepd. and compns. of I with other antineoplastic agents are claimed for use in cancer treatment therapy. Thus, II was prepd. in 23% yield via formylation of 3-(4-morpholinyl)phenol. II demonstrated an IC50 value of 400 nM in DNA-PK assay. Preliminary results of animal tumor model studies indicate II enhanced the tumoristatic effect of total body irradn. (using 100-500 rad γ-radiation, II delayed tumor growth 1.2 to 1.8-fold relative to animals receiving radiation only). [on SciFinder(R)]