ABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Pyridines/chemical synthesis , Animals , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Lewis Lung/drug therapy , Cell Survival/drug effects , DNA, Neoplasm/drug effects , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Humans , Leukemia P388/drug therapy , Melanoma, Experimental/drug therapy , Mice , Pyridines/pharmacology , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Carboxylic Acids/chemical synthesis , Psychotropic Drugs/chemical synthesis , Pyrimidines/chemical synthesis , 5-Hydroxytryptophan/pharmacology , Aggression/drug effects , Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/pharmacology , Animals , Apomorphine/pharmacology , Carboxylic Acids/pharmacology , Carboxylic Acids/toxicity , Dopamine Agonists/pharmacology , Drug Interactions , Female , Hexobarbital/pharmacology , Hypnotics and Sedatives/pharmacology , Lethal Dose 50 , Magnetic Resonance Spectroscopy , Male , Mice , Motor Activity/drug effects , Pain Measurement/drug effects , Psychotropic Drugs/pharmacology , Psychotropic Drugs/toxicity , Pyrimidines/pharmacology , Pyrimidines/toxicity , Rats , Rats, Wistar , Reaction Time/drug effects , Reserpine/antagonists & inhibitors , Sleep/drug effects , Stereotyped Behavior/drug effectsABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Carbazoles/chemical synthesis , Ellipticines/chemical synthesis , Adenocarcinoma/pathology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Carbazoles/pharmacology , Cell Survival/drug effects , Colonic Neoplasms/pathology , Ellipticines/pharmacology , Leukemia L1210/pathology , Mice , Neoplasm Transplantation , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Reserpine/antagonists & inhibitors , Serotonin Antagonists/chemical synthesis , 5-Hydroxytryptophan/antagonists & inhibitors , Aggression/drug effects , Animals , Anticonvulsants/pharmacology , Female , Hexobarbital/antagonists & inhibitors , Male , Mice , Motor Activity/drug effects , Pain Measurement/drug effects , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/toxicity , Pyrimidines/pharmacology , Pyrimidines/toxicity , Rats , Rats, Wistar , Serotonin Antagonists/pharmacology , Serotonin Antagonists/toxicity , Stereotyped Behavior/drug effectsABSTRACT
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.
Subject(s)
Analgesics/chemical synthesis , Anticonvulsants/chemical synthesis , Antihypertensive Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Pyrimidines/chemical synthesis , Triazoles/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Magnetic Resonance Spectroscopy , Pyrimidines/pharmacology , Sarcoma 180/drug therapy , Triazoles/pharmacologyABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents , Pyrazines/chemical synthesis , Pyrimidinones/chemical synthesis , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Central Nervous System/drug effects , Pyrazines/pharmacology , Pyrimidinones/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Orotic Acid/analogs & derivatives , Animals , Chemical Phenomena , Chemistry , Lethal Dose 50 , Male , Mice , Orotic Acid/chemical synthesis , Orotic Acid/pharmacology , Rats , Rats, Inbred StrainsABSTRACT
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.
