Pyridazino:pyrrolo:isoquinoline deriv. anti:proliferative agents - used as non-selective cation channel blockers for inhibiting calcium flow into cells, and as antitumour agents

摘要

The use of -amino-pyridazino (4;,5;:3,4) pyrrolo (2,1-a) isoquinolines of formula (I) or their salts with acids, bases or complex formers is claimed for prodn. of medicaments with antiproliferative activity. In (I), R1, R2 = H, 3-7C cycloalkyl, 2-5C alkenyl; phenyl (opt. substd. by 1 or 2 of halogen and OMe); propargyl or 1-5C opt. unsatd. alkyl (opt. substd. by OH, 1-4C alkoxy, halogen, mono- or di- (1-2C alkyl)-amino, 2-4C acylamino, 3-7C cycloalkyl, phenyl (itself opt. substd. by one or more of halogen, 1-2C alkyl, 1-2C alkoxy, mono- or di-(1-2C alkyl)- amino, NH2, 2-3C acylamino or alkylsulphonylamino), furyl, thienyl or 5- or 6-membered N-heterocyclyl (opt contg. a further O or S heteroatom and opt. substd. by 1-4C alkyl); or NR1R2 = 3-7 membered ring, opt. contg. a further O or N heteroatom and opt. substd. by phenyl-(1-4) alkyl (opt. ring-substd. by 1 or 2 of halogen and OMe); if R1 = H, R2 may also = NH2, di-(1-2C alkyl)- amino, acetonylamino, 2-3C acylamino, 1-3C alkylsulphonyl, (1-3C) alkoxycarbonyl, -N=C(Me)2 or a 5- or 6-membered heterocycle contg. N and opt. a further N, O or S heteroatom; R3-R5 = H or 1-4C alkyl; R7, R8 = OH, 1-4C alkoxy, or 1-4C alkylthio; R6, R9 = H, 1-4C alkoxy, 1-4C alkylthio or NR10R11; R10 = H or 1-4C alkyl; R11 = H or 1-4C alkyl (opt. substd. by OH, OMe or furfuryl). USE/ADVANTAGE - (I) block calcium ion flow into cells via non-selective cation channels (NCC), as shown by inhibition of thapsigargin-stimulated Ca flow through NCC. (I) inhibit cell proliferation and tumour growth, which are dependent on cytoplasmic C concn. In tests against proliferation of various human tumour cell lines, (I) show 5-100 times stronger activity then verapamil, typically having IC50 ca. 1 mcg/ml. (I) are used as antitumour agents by oral or parenteral admin. Unit dose is 0.1-500 mg p.o. or 0.05-150 mg i.v. (I) are known cardioprotective and neuroprotective agents; see DE3500941, DE3525048 and EP-252299.