[Pharmacological studies of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivatives (450191-S) (I). Behavioral analysis].

The behavioral effects of 450191-S and its metabolites were investigated in mice, rats, cats and rhesus monkeys, and they were compared with those of related benzodiazepines (BDZ) such as diazepam and nitrazepam. Oral administration of 450191-S consistently caused sedation without excitability in mice and rats, and it was only 1/2 to 1/266 as potent as the BDZ in producing motor incoordination as assessed by traction, rotarod performance and inclined screen tests in mice, induced much less ataxia in cats and monkeys, and inhibited respiration in anesthetized cats. The locomotor activities of mice and rats measured by Animex and the open field test were not affected by 450191-S, but rearing and preening decreased with 450191-S as with the BDZ. 450191-S was equipotent with nitrazepam and 2 to 6 times more potent than diazepam and estazolam in potentiating chlorprothixene-induced hypnosis and thiopental-Na-induced anesthesia. These effects were not different with successive 14-day administration of 450191-S. Anti-pentylenetetrazol, picrotoxin and bicuculline convulsions of 450191-S had the same potency as nitrazepam, but caused much less anti-electroshock convulsion than the BDZ. 450191-S had potent antianxiety activity as observed by anti-aggressive and anti-conflict activities and had almost the same effect as diazepam on operant behavior. The metabolites M-1, M-2, M-A and M-3 showed approximately the same potency as 450191-S in inducing anesthetic potentiation and antianxiety activity, but they were much more potent in causing disturbance of the somatic functions. These results indicate that 450191-S possesses inhibitory effects on the central nervous system, including a potent sleep-inducing effect, and is characterized by markedly weak muscle relaxant activity and motor incoordination.

Amino acid amide derivatives of 2-[3-(aminomethyl)-4H-1,2,4-triazol-4-yl]benzophenones, a novel class of annelated peptidoaminobenzophenones.

A series of the title compounds was prepared via condensation of the 3-(aminomethyl)triazolylbenzophenone (5) with N-protected amino acids, followed by deprotection, amination of the 3-[(chloroacetamido)methyl]triazolylbenzophenone (6a,b), or reduction of the relevant azide derivative (6c). Some of the title compounds were also derived directly from the quinazolines 3 or 4 by acid-induced rearrangement, followed by deprotection. These new amino acid amide derivatives of the triazolylbenzophenones (2) were evaluated for central nervous system (CNS) activity. Members of this class of compounds exhibited a high level of CNS activities. For example, 2',5-dichloro-2-[3-[(glycylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone (2c) was as active as triazolam, with an ED50 of 0.58 mg/kg (mice, po), against antifighting activity in the foot shock-induced fighting test. Other triazolylbenzophenone derivatives (2a-f) showed similar pharmacological activities.

Novel peptidoaminobenzophenones, terminal N-substituted peptidoaminobenzophenones, and N-(acylglycyl)aminobenzophenones as open-ring derivatives of benzodiazepines.

Peptidoaminobenzophenones (1), terminal N-substituted peptidoaminobenzophenones (14), and acylglycylaminobenzophenones (16) were prepared as a novel series of ring-opened derivatives of 1,4-benzodiazepine. Z-Gly- and Z-Ala-N-methylaminobenzophenones (4) were treated with HBr-HOAc to give Gly- and Ala-N-methylaminobenzophenone hydrobromides (8). Reaction of 8 with chloroacetyl chloride in dimethylformamide (DMF) or hexamethylphosphoramide (HMPA) gave chloracetamide (13), which was allowed to react with various amines to afford a number of terminal N-substituted derivatives (14). Reaction of 8 with various acyl halides in HMPA or DMF gave a number of acylglycyl-N-methylaminobenzophenones (16). Peptidoaminobenzophenones (1) were also prepared by several convenient methods. Many of these compounds exhibited high CNS activity in animals when given orally. In antianxiety activity the potency of some compounds is equal to or higher than that of diazepam.

Pharmacology of 2-o-chlororbenzoyl-4-chloro-N-methyl-N alpha-glycylglycinanilide hydrate (45-0088-S), a compound with benzodiazepine-like properties.

2-o-Chlorobenzoyl-4-chloro-N-methyl-N alpha-glycylglycinanilide hydrate (45-0088-S), a dipeptido-aminobenzophenone compound, inhibited pentetrazole-induced convulsion and suppressed electroshock-induced fighting behavior in mice, reduced conflict behavior in rats and monkeys, and induced muscle relaxation in cats at lower doses than did diazepam. This pharmacological profile suggests that 45-0088-S can be an active, water-soluble antianxiety agent in man.

Peptidoaminobenzophenones, a novel class of ring-opened derivatives of 1,4-benzoidazepines.

A series of noval peptidoaminobenzophenones has been prepared via several routes and was evaluated for CNS activity. The structure--activity relationships in the series are discussed. In general, dipeptido-N-methylaminobenzophenones showed higher activities than the corresponding NH derivatives. Some compounds had very high activities in antipentylenetetrazole and antifighting tests in mice when orally administered. Very weak toxicity was also found in these compounds. Water solubility of the peptidoaminobenzophenones and their salts were tested. Possible in these compounds. Water solubility of the peptidoaminobenzophenones and their salts were tested. Possible in vivo conversion of peptidoaminobenzophenone by enzymatic cleavage of the terminal amino acid, followed by chemical cyclization to 1,4-benzodiazepine, is also discussed. Such novel open-ring derivatives of 1,4-benzodiazepine may serve as useful CNS agents.

The pharmacology of 20681-S and 20682-S, 6-oxo-N-cyclopropylmethylmorphinans, as narcotic antagonist analgesics.

It has been demonstrated that L-3hydroxy-6-oxo-N-cyclopropylmethylmorphinan methansulfonate (20681-S) and L-3,14-dihydroxy-6-oxo-N-cyclopropylmethylmorphinan methansulfonate (20682-S), have antinociceptive and narcotic antagonistic properties. In the rodent antinociceptive test, the action of 20681-S was more potent and of longer duration than that of morphine and of cyclazocine after subcutaneous or oral administration. The antinociceptive effect of 20682-S ranked between that of morphine and that of pentazocine in the mouse acetic acid-writhing test. Both compounds possessed potent narcotic antagonistic activities, 20682-S being more active than naloxone and oxilorphan and 20681-S being equipotent with cyclazocine. The latent side effects (respiratory depression and fall in blood pressure) and the acute toxicity of 20681-S and 20682-S, were less than those of reference narcotic antagonists or of narcotic antagonist analgesics.