Search

A series of [(3-aryl-1,2-benzisoxazol-6-yl)oxy]acetic acids was synthesized and tested for diuretic activity in saline-loaded mice and in conscious, water-loaded dogs. The structural requirements for good diuretic activity in both mice and dogs were found to be very specific. In summary, the compounds with the best diuretic activity (13i, 13q, and 13ff) were substituted with a 2-fluorophenyl group at the 3 position and chlorine or bromine at the 7 position. Compound 13ff, [(7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]acetic acid (HP 522), was found to be moderately uricosuric in chimpanzees and was selected for further development.

1,2,3,4-Tetrahydrobenzo[c]-1,5-naphthyridine (5a) was prepared by a novel synthetic route involving the rearrangement of (±)-(Z)-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10(2H,5H)-dione oxime to afford 1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one, which was reduced to 5a. The cholinomimetic activity observed with 5a prompted the synthesis and biological evaluation of additional analogues.

A series of 2-phenyl- and 2-amino-4-aryl-4,5-dihydro-3H-1,3-benzodiazepines was prepared and submitted for broad biological screening, including evaluation for potential antihypertensive activity. Compound 4a [(+/-)-4,5-dihydro-2,4-diphenyl-3-methyl-3H-1,3-benzodiazepine hydrochloride] was the most active member of the series in the spontaneously hypertensive rat (SHR) model, producing a 56 mmHg decrease in systolic blood pressure at an oral screening dose of 50 mg/kg. The synthesis of 4a analogues containing nuclear substituents in the 4-phenyl moiety resulted in a marked decrease of antihypertensive activity. It was not possible to improve on the antihypertensive properties of 4a through further synthetic modifications.

Antidepressant-like activity, as evidenced by marked inhibition of tetrabenazine-induced ptosis, was previously reported for (+/-)-4,5-dihydro-4-phenyl-3H-1,3-benzodiazepine derivatives. Since optimal antitetrabenazine activity was associated with (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine (9k, HRP 543) and the 2-ethyl-3-methyl analogue (10k), the synthesis and evaluation of nuclear-substituted derivatives of these two compounds was also investigated. The initial synthesis involved Friedel-Crafts acylation of substituted benzenes with 2-nitrophenylacetyl chloride to afford 1-aryl-2-(2-nitrophenyl)ethanones 2, which were converted in five steps to (+/-)-alpha-aryl-N-methyl-2-nitrobenzeneethanamines 7. Greater flexibility with respect to the introduction of nuclear substituents was achieved by conversion of 2-nitrotoluene derivatives to 2 via acylation of intermediate beta-(dimethylamino)-2-nitrostyrenes with various aroyl chlorides and hydrolysis. Reductive amination of 2 with methylamine and sodium cyanoborohydride afforded 7 directly and significantly reduced the number of synthetic steps. Reduction of 7a-j to diamines 8a-j and cyclization with appropriate ortho esters gave nuclear-substituted analogues of 9k and 10k. Marked antitetrabenazine activity was associated with many of these compounds. Significant enhancement of activity with respect to the unsubstituted analogues 9k and 10k was not observed, with the exception of 9c which appeared to be slightly more potent than 9k.

A series of (+/-)-4,5-dihydro-4-phenyl-3H-1,3-benzodiazepines and (+/-)-4,5-dihydro-4-phenyl-1H-1,3-benzodiazepines was synthesized as part of a program to develop novel psychotropics. Of these compounds, (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine (10a, HRP 543) emerged as a potential antidepressant. In in vivo mouse tests (inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity) which are predictive of antidepressant-like activity, 10a is comparable to amitriptyline. The similarity is also maintained in vitro, as both 10a and amitriptyline inhibit norepinephrine and serotonin uptake into rat brain synaptosomes. No significant inhibition of rat brain monoamine oxidase A or B was found with 10a, nor did the compound potentiate tryptamine-induced seizures. On chronic administration, the number of cortical beta-adrenergic receptor sites was similarly reduced by 10a and desipramine. The anticholinergic activity of clinically useful antidepressants, such as amitriptyline, is a proposed cause of side effects which reduce patient compliance. In contrast to the tricyclics, 10a apparently lacks anticholinergic activity, as evidenced in vitro by negligible displacement of [3H]quinuclidinyl benzylate from rat brain muscarinic receptors and in vivo by insignificant antagonism of the cholinergic stimulation produced by physostigmine or oxotremorine. These data suggest that 10a may be clinically useful as a novel nontricyclic antidepressant which is devoid of anticholinergic side-effect liability. Further evaluation of 10a in nonrodent species is in progress.

The indazole, benzisothiazole, and benzisothiazole 1,1-dioxide analogues of [[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]acetic acid were synthesized and tested for diuretic activity in saline-loaded mice. Each analogue was found to be less active than the parent benzisoxazole: the diuretic activity followed the order O greater than S greater than N = SO2 in regard to the heteroatom in the 1-position of the ring.

4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (6) was previously reported as a potent antiinflammatory-analgesic agent characterized by an impressive therapeutic ratio in comparison with indomethacin. With the goal of finding compounds that might display even more favorable therapeutic ratios and/or enhanced antiinflammatory/analgesic properties in comparison to 6, we synthesized 4-(4,10-dihydro-10-oxothieno [3,2-c][1]-benzoxepin-8-yl) butanol (4b) and -butyric acid (5a) and a series of related derivatives. All compounds were evaluated for potential analgesic activity in the phenylquinone-induced writhing (PQW) assay, for antiinflammatory activity in the carrageenan-induced paw edema (CPE) model and, where warranted, for gastric irritation (GI) liability. Of the compounds investigated, 4b (HP 573) displays moderate analgesic-like activity in PQW, is approximately half as potent as indomethacin or 6 as an antiinflammatory agent in the CPE, and is characterized by an extremely low propensity to induce GI as reflected by comparison of the therapeutic ratios (GI ED50/CPE ED50: 4b greater than 46, 6 = 9.9, indomethacin = 0.4). Compound 4b was selected for clinical evaluation.

4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (6) was previously reported as a potent antiinflammatory-analgesic agent characterized by an impressive therapeutic ratio in comparison with indomethacin. With the goal of finding compounds that might display even more favorable therapeutic ratios and/or enhanced antiinflammatory/analgesic properties in comparison to 6, we synthesized 4-(4,10-dihydro-10-oxothieno [3,2-c][1]-benzoxepin-8-yl) butanol (4b) and -butyric acid (5a) and a series of related derivatives. All compounds were evaluated for potential analgesic activity in the phenylquinone-induced writhing (PQW) assay, for antiinflammatory activity in the carrageenan-induced paw edema (CPE) model and, where warranted, for gastric irritation (GI) liability. Of the compounds investigated, 4b (HP 573) displays moderate analgesic-like activity in PQW, is approximately half as potent as indomethacin or 6 as an antiinflammatory agent in the CPE, and is characterized by an extremely low propensity to induce GI as reflected by comparison of the therapeutic ratios (GI ED50/CPE ED50: 4b greater than 46, 6 = 9.9, indomethacin = 0.4). Compound 4b was selected for clinical evaluation.