Methotrexate derivatives useful for treating cancer and arthritis.

Abstract

The present invention provides novel derivs. I [X = OH, NH2; Z = (CH2)n; n = 1, 2; R1 = alkenyl, alkynyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, arylalkyl, C5-10-alkyl; R2 = H, C1-8-alkyl, CF3, OCF3, alkoxy, alkenyl, aralkyl, (heteroaryl)alkyl, alkynyl, CHO COMe, halogen (with the proviso that R1 = C5-10-alkyl, when R2 = H)], or a pharmaceutically acceptable ester, amide, salt or solvate, of MTX. Thus, [4-(pteridin-6-ylmethyl)amino]benzamide deriv. II was prepd. from 4-H2N-3-MeC6H4CO2H, via amidation with L-Glutamic acid di-Et ester hydrochloride, N-alkylation with HC≡CCH2Br, N-alkylation with 6-(Bromomethyl)pteridine-2,4-diamine and sapon. The novel derivs. have increased selectivity, inhibit the activity of Her2, EGFR, or B-Raf to a greater degree than MTX, and display greater antiproliferative activity than MTX. Pteridine II was tested for peptide inhibitory activity [IC50 = 0.9 μM vs. Her2; IC50 = 5 μM vs. B-Raf; IC50 = 5 μM vs. EGFR; IC50 = 3.8 μM vs. pyruvate carboxylase; IC50 = 2 μM vs. propionyl-CoA carboxylase subunit α ; IC50 = 3.5 μM vs. Propionyl-CoA carboxylase subunit β; IC50 = 10 nM vs. dihydrofolate reductase] and antiproliferative activity [IC50 = >4 vs. SR lymphoma; IC50 = >2 vs. OVCAR8 ovarian carcinoma; IC50 = >1 vs. NCI-H460 lung cancer; IC50 = >1 vs. MCF-7 mammary adenocarcinoma; IC50 = >6 vs. HT29 colon cancer; IC50 = >4 vs. SK-mel 5 skin melanoma; IC50 = >1 vs. PC-3 carcinoma]. Also provided are pharmaceutical compns. contg. the novel derivs., to methods of prepn. of such derivs., to methods of inhibiting the biol. activity of polypeptides, methods of inhibiting cell proliferation, and the use of the novel compds. in therapy, particularly for the treatment of neoplastic, hyperproliferative, and immune disorders, including cancer, arthritis, and psoriasis. [on SciFinder(R)]