Benzothiopyranoindazoles, a new class of chromophore modified anthracenedione anticancer agents. Synthesis and activity against murine leukemias.

The synthesis of the benzothiopyranoindazoles, a new class of chromophore modified anthracenediones related to mitoxantrone, is described. In this structural class the quinone moiety, which is believed to be responsible for the cardiotoxicity of the anthracyclines, has been designed out. The synthesis of the benzothiopyranoindazoles was carried out by a multistep sequence from requisite 1-chloro-4-nitro-9H-thioxanthen-9-one precursors. Reaction with a monoalkylhydrazine gave a 5-nitrobenzothiopyranoindazole adduct, which was catalytically reduced to a corresponding C-5 anilino intermediate. Alkylation of 7 with a requisite X(CH2)nNR1R2 (X = Cl, Br; R1, R2 = H, alkyl, acyl; n = 2,3) provided target "two-armed" benzothiopyranoindazoles or A-ring methoxy and/or side chain acyl intermediates, which could be converted to 3 by appropriate deprotection methodologies. Alternatively, certain target compounds 3 were synthesized by reaction of 7 with appropriately functionalized glycine precursors under Schotten-Bauman or BOP chloride condensation conditions to provide C-5 acylamino intermediates, followed by Red-Al reduction and deprotection steps. Described also is the synthesis of selected benzothiopyranoindazole congeners with proximal acylamino side chains at C-5 and B-ring sulfone functionality at S-6. Potent activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-9) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by (a) a basic side chain at N-2 and a dibasic side chain at C-5 with primary or secondary distal amine substitution, (b) certain patterns of A-ring hydroxylation with 8-OH and 9-OH most favorable, and (c) sulfide oxidation state at S-6. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional broad-spectrum in vivo anticancer activity, selected compounds in this series have been chosen for development toward clinical trials.

N2-1H-benzimidazol-2-yl-N4-phenyl-2,4-pyrimidinediamines and N2-1H-benzimidazol-2-yl-5,6,7,8-tetrahydro-N4-phenyl-2,4-quinazolinediamines as potential antifilarial agents.

A series of N2-1H-benzimidazol-2-yl-N4-phenyl-2,4-pyrimidinediamines and N2-1H-benzimidazol-2-yl-5,6,7,8-tetrahydro-N4-phenyl-2,4-quinazolinediamines (XI) was synthesized for antifilarial evaluation. Condensation of the requisite beta-keto ester (VI) with N-cyanoguanidine afforded 2-pyrimidinylcyanamides (VIIa,b) and (5,6,7,8-tetrahydro-4-hydroxy-2-quinazolinyl)cyanamide (VIIc). Reaction of VII with a substituted o-phenylenediamine gave 2-(1H-benzimidazol-2-ylamino)-4-pyrimidinols and 2-[(5,6-dichloro-1H-benzimidazol-2-yl)amino]-5,6,7, 8-tetrahydro-4-quinazolinol (IX). Chlorination with phosphoryl chloride, followed by condensation with the appropriate substituted benzenamine, gave the desired N2-1H-benzimidazol-2-yl-N4-phenyl-2,4-pyrimidinediamines and N2-1H-benzimidazol-2-yl-5,6,7,8-tetrahydro-N4-phenyl-2,4-quinazolinediamines (XI). None of these compounds possessed antifilarial activity against Litomosoides carinii or Brugia pahangi infections in jirds.

The metabolism of [14C]-debrisoquine in man.

1 The synthesis of [14C]-debrisoquine hydrochloride and 4-hydroxy-debrisoquine sulphate is described. 2 The metabolic fate and excretion profile in both urine and faeces of 14C-labelled debrisoquine was studied in five healthy human subjects. 3 Investigations showed that the drug is well-absorbed after a single oral dose of 32 mg and quantitatively eliminated from the body within three days. 4 4-Hydroxy-debrisoquine is the major metabolite of debrisoquine, although significant amounts of 5-,6-, 7- and 8-hydroxy-debrisoquine are also formed. 5 Electron-capture gas chromatography is a useful method for measuring debrisoquine and its five hydroxylated metabolites in urine at the pg level.