SYNTHESIS AND EVALUATION OF 4-AMINO-SUBSTITUTED 7-METHOXY (AND 7-HYDROXY)-11-METHYL (AND 5,11-DIMETHYL)-10H-PYRIDO [2,3-B] CARBAZOLES AND 4-AMINO-SUBSTITUTED 11-METHYL (AND 5,11-DIMETHYL)-10H-PYRIDO[3',4' 4,5]PYRROLO [3,2-G] QUINOLINES, 2 NEW SERIES RELATED TO ANTITUMOR ELLIPTICINE DERIVATIVES/

2-Acetyl-4-chloro-3-lithiopyridine ethylene glycol ketal (6b) was reac ted with 3-formyl-5-methoxy-1-methyl-indole (9) and 3-formyl-1-methyl- 1H-pyrrolo [3,2-c] pyridine (12), giving the corresponding expected al cohols. Reduction of these intermediates with triethylsilane trifluoro acetic acid and subsequent cyclodehydration then led to 4-chloro-7-met hoxy-10,11-dimethyl-10H-pyrido [2,3-b] carbazole (8a) and the correspo nding 7-aza-analog (8b). The synthesis of 4-chloro-11-methyl (and 5,11 -dimethyl)-10-unsubstituted derivatives of these two series was perfor med through an independent pathway, involving condensation of convenie ntly substituted 2-amino carbazoles (17) and 7-amino-5H-pyrido [4,3-b] indoles (18) with 5-(ethoxymethylene)-2,2-dimethyl-1, ,3-dioxane-4,6- dione, thermal cyclization of the resulting compounds with concomitant decarboxylation to the corresponding tetracyclic fused-4-quinolone sy stems and final chlorination with phosphorus oxychloride. Nucleophilic substitution of various 4-chloro derivatives was then easily performe d in an excess of the required dialkylamino alkylamines at reflux and 4-amino substituted-7-hydroxy-10H-pyrido [2,3-b] carbazoles (25d-e) we re obtained from 7-methoxy precursors (25a-b), by demethylation with b oron tribromide in methylene chloride at -65 degrees C or with boiling 47% hydrobromic acid. Cytotoxicity determination of all new aminosubs tituted derivatives and in vivo antitumor evaluation of the most activ e compounds clearly show that these two series of ellipticine analogs closely related to highly active products are devoid of antitumor prop erties in two experimental models shown to be sensitive to ellipticine s The place of the pyridinic nitrogen atom in these series has thus be en demonstrated to play a crucial role in antitumor activity.