Thromboxane synthetase inhibitors and antihypertensive agents. 4. N-[(1H-imidazol-1-yl)alkyl] derivatives of quinazoline-2,4(1H,3H)-diones, quinazolin-4(3H)-ones, and 1,2,3-benzotriazin-4(3H)-ones.

The quinazolinedione, quinazolinone, and 1,2,3-benzotriazinone title compounds were prepared as analogues of N-[(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-diones which were the subject of a previous report from our laboratories. These compounds were evaluated as thromboxane (TX) synthetase inhibitors and as antihypertensive agents. While each series of compounds had activity both as TX synthetase inhibitors and as antihypertensives, the best compounds were N-[(1H-imidazol-1-yl)alkyl]quinazoline-2,4(1H,3H]-diones (V). In general these compounds were all selective enzyme inhibitors at least equipotent with the standard dazoxiben. These compounds were also very active antihypertensive agents as determined in SHR. The SAR is discussed for both types of activity. Compound 20a was further evaluated for TX formation inhibiting properties in several other platelet types both in vitro and ex vivo and is between 100 and 1000 times more potent than dazoxiben.

Derivatives of 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine as central nervous system agents.

Four 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepines were prepared and evaluated as central nervous system agents. All were active psychotropic agents as determined by animal screening tests. The most interesting compound, 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, showed dual activity as an antidepressant against tetrabenazine depression and as a neuroleptic as measured by protection vs. amphetamine lethality in grouped mice.

Derivatives of 1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione as anxiolytic agents.

A study of the pharmacological properties of pyrrolo[2,1-c][1,4]benzodiazepine derivatives led to the choice of (+)-1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolol[2,1-c][1,4]benzodiazepine-5,11)10H)-dione as a candidate for anxiolytic evaluation in a limited clinical trial in man. Metabolism studies in laboratory animals have pointed to rapid hydroxylation, possibly in the 3 and 11a positions. A series of compouds containing methyl groups in one or more of these positions has been prepared in an effort to block metabolism and thereby obtain more active or longer acting compounds. All of these derivatives were less active than the parent compound.

Thromboxane synthetase inhibitors and antihypertensive agents. 2. N-[(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-diones and N-[(1H-1,2,4-triazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-diones as unique antihypertensive agents.

A series of N-[(1H-heteroaryl)alkyl]-1H-isoindole-1,3(2H)-diones were prepared as part of a continuing investigation into the biological properties of compounds that were both thromboxane synthetase inhibitors and potential antihypertensive agents. The most active thromboxane synthetase inhibition was found for the title imidazole derivatives wherein a hexyl or octyl chain separated the heterocyclic ends of the molecule (5,6) or with substitution on the isoindole portion of the molecule (18, 19, 21, 22, 25, 26). Compounds with shorter alkyl chain separations had good antihypertensive effects (1-5, 8-10, 19-22, 27-30). Butyl derivative 3 was chosen for further evaluation as a potential antihypertensive agent with thromboxane synthetase inhibitory properties.

Thromboxane synthetase inhibitors and antihypertensive agents. 1. N-[(1H-imidazol-1-yl)alkyl]aryl amides and N-[(1H-1,2,4-triazol-1-yl)alkyl]aryl amides.

The title compounds were prepared to investigate their potential as thromboxane synthetase inhibitors as well as antihypertensive agents. Imidazoles VIII and triazoles X were prepared to examine the effects of aromatic substitution, chain length, and heterocycle substitution upon biological activity. Imidazoles VIII and triazoles X were thromboxane synthetase inhibitors that did not inhibit prostacyclin formation. The most interesting thromboxane synthetase inhibitors prepared were 4-chloro-, 4-(trifluoromethyl)-, and 4-bromobenzamide derivatives of (1H-imidazol-1-yl)alkylamines with C5-C8 alkyl chains separating the heterocycle from the amide moiety, while the most active antihypertensive agents were 3- or 4-chloro-, -bromo, or -(trifluoromethyl)benzamides with C3 alkyl chains. The best thromboxane synthetase inhibitors in this study were up to 10 times more potent than the standard, dazoxiben (UK 37,248).

Thromboxane synthetase inhibitors and antihypertensive agents. 3. N-[(1H-imidazol-1-yl)alkyl]heteroaryl amides as potent enzyme inhibitors.

The title compounds were prepared as the heterocyclic analogues of thromboxane (TX) synthetase inhibitors and antihypertensive agents previously reported from our laboratories. These compounds were at least as active TX synthetase inhibitors as their benzene isosteres with the indole derivatives 50-55 having the most potent enzyme inhibiting activity measured to date in our laboratories. The best compound, 54, is more than 200-fold more potent than the standard, dazoxiben. In contrast, the antihypertensive activity of these series of compounds was no better than their benzene counterparts and is far lower than the isoindoledione derivatives prepared in a related series. The structure-activity relationship results from this study were similar to our previous observations and include the fact that the amide moiety effectively replaces a carboxylic acid for potent TX synthetase inhibition and that a four to six methylene unit separation (approximately 8.5 A) between amide and imidazole moieties achieves maximal activity.

Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines.

The synthesis of a series of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines (VIII) is reported. Some of these derivatives show activity in tests predictive of anxiolytic activity [(a) protection against pentylenetetrazole-induced convulsions; (b) thirsty rat conflict procedure]. They also represent a new class of compound which inhibits [3H]diazepam binding. Structure--activity correlations, as well as the ability of structures VIII to inhibit [3H]diazepam binding (in vitro), are discussed.