Synthesis and evaluation of 9-hydroxy-5-methyl-(and 5,6-dimethyl)-6H-pyrido[4,3-b]carbazole-1-N- [(dialkylamino)alkyl]carboxamides, a new promising series of antitumor olivacine derivatives.

Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)-olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy-1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 degrees C or 9-methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 degrees C. Biological testing of the newly obtained 1-carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.

Synthesis and properties of 7-methyl-5-oxo-1,5-dihydro-8-[1,2,4]-triazolo [4,3-c]pyrimidinecarboxylic acid derivatives.

The synthesis of the new triazolo[4,3-c]pyrimidines is described, starting from derivatives of 5-carboxy-2-hydroxy-4-hydrazino-6-methylpyrimidine. The 4-methyl-2,3-dihydropyrazolo[3,4-d]pyrimidine-3,6-dione was also obtained. Some of triazolo[4,3-c]pyrimidines tested for biological activity were found inactive.

Synthesis and biological properties of some 5-aminoorotic acid derivatives.

2,4-Dihydroxy-5-benzoylaminopyrimidine-6-carboxylic acid 1 in the reaction with SOCI2 gave 1-benzoyl-2-oxo-4,6-dihyroxyazetino [3.2-d] pyrimidine 2 which reacted with aliphatic and aromatic amines in ethanol to give appropriate amides 4a-4h of 1 and ethyl 2,4-dihydroxy-5-benzolaminopyrimidine-6-carboxylate 5. Compounds 4d-4g and 8 were centrally active and showed a promising anti-inflammatory and analgesic activity.

Synthesis of 2,4-disubstituted 5-aminopyrimidine-6-carboxylic acids derivatives part I.

5-Benzoyloaminoorotic acid in a reaction with POCl3 forms 2,4-dichloro-5-benzylo-aminopyrimidine-6-carboxylic acid lactam 3, which heated with aliphatic and aromatic amines gives corresponding amides 6-11. These compounds don't show any antiinflammatory or antivirus activity.

Synthesis of perhydropyrazino [1,2-c] pyrimidine derivatives.

The reaction of 1-benzoyl-2-oxo-4,6-dihydroxyazetino-[3,2-d] pyrimidine (III) with diethanolamine affords the amide (IV). Heating of the last with SOCl2 yields 2-beta-chloroethyl-8-hydroxy-9-benzoylamino-perhydropyrazino [1,2-c] pyrimidine-1,6-dione (VI). Reaction of compound (VI) with different amines gives the respective 2-beta-aminosubstituted derivatives (VII-XIII). Some of the obtained compounds showed central activity.

Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part II.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-20 were synthesized and evaluated for their pharmacological activity. Compounds 11-14, 17-19 showed antiaggressive effect, compounds 5, 8, 9, 11, 12 and 19 displayed antiserotonin activity while compound 14 exerted antireserpine action.

Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part III.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-13 were synthesized and evaluated for their pharmacological activity. Compounds 5, 7, 9, 10 and 12 showed antiaggressive effect, compounds 6 and 10 showed synergism with hexobarbital while compound 6 exerted analgesic activity.

Synthesis and biological evaluation of 6-(9-hydroxy-5-methyl (and 5,6-dimethyl)-6H-pyrido[4,3-b]carbazol-1-yl)picolinic amides as new olivacine derivatives.

Starting from 2-(6-methoxy-1-methylcarbazol-2-yl)ethylamine and diethyl-2,6-pyridine dicarboxylate, the title compounds were obtained through five or six steps. The new compounds retained significant cytotoxicity towards various tumor cell lines, but in vivo studies on murine P388 leukemia, B16 melanoma and Lewis lung carcinoma showed a lowered antitumor activity with respect to that of the related olivacine lead compound 1.