Indoline analogues of idazoxan: potent alpha 2-antagonists and alpha 1-agonists.

The synthesis and alpha-adrenergic activity of a series of substituted 2-imidazolinylindolines are described. Substitution in the indoline ring generated compounds with a spectrum of adrenoceptor antagonist/agonist profiles that proved sensitive to both the nature and position of the substituent. Many of the derivatives possess greater presynaptic antagonist potency than the corresponding benzodioxan 1, dihydrobenzofuran 2, and indan 3 analogues; however, this alpha 2-antagonism is often accompanied by alpha 1-agonist activity. It was not possible to separate alpha 2-antagonist from alpha 1-agonist properties in this series. Compounds of most interest proved to be the N-ethyl 6, 5-chloro-N-methyl 18, and 5-chloro-N-ethyl 23 derivatives, all being potent alpha 2-antagonists and alpha 1-agonists. Substitution at the 4- and 7-position of the indoline ring generally gave compounds with nonselective agonist properties.

Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 1. Hydrazines.

The synthesis and anticonvulsant activity of a series of 2-aryl-5-hydrazino-1,3,4-thiadiazoles are described. The combination of preferred aromatic substituents in the 2-position coupled with alkyl substitution on the hydrazine moiety led to a number of potent compounds lacking sedation, ataxia, or lethality. 5-(2-Biphenylyl)-2-(1-methylhydrazino)-1,3,4-thiadiazole (4m) represents a new class of anticonvulsant agent and compares favorably with the standard drugs phenytoin, phenobarbital, and carbamazepine.

Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 2. Aminoalkyl derivatives.

This paper describes the synthesis and pharmacological evaluation of a number evaluation of a number of substituted 1,3,4-thiadiazoles. The first member of the series, 2-(aminomethyl)-5-(2-biphenylyl)-1,3,4-thiadiazole (7) was found to possess potent anticonvulsant properties in rats and mice and compared favorably with the standard anticonvulsant drugs phenytoin, phenobarbital, and carbamazepine in a number of test situations. The potency of compound 7 was maintained on alkylation of the side-chain nitrogen atom; however, aryl substitution or chain lengthening caused a drop in potency. Replacement of the 2-biphenylyl group by phenyl or benzyl also lead to inactive compounds.

Alpha-adrenoreceptor reagents. 4. Resolution of some potent selective prejunctional alpha 2-adrenoreceptor antagonists.

The resolution of three 2-substituted derivatives of idazoxan is described. The enantiomers show large separations in activity in a variety of in vitro and in vivo tests, and the active isomers are all potent and selective antagonists at the alpha 2-adrenoreceptor. The significance of these results in relation to those published on the enantiomers of idazoxan and to those on optically active alpha 2-adrenoreceptor agonists is discussed.

Effect of methoxy substitution on the adrenergic activity of three structurally related alpha 2-adrenoreceptor antagonists.

We have recently reported the synthesis and alpha 2-antagonist activity of the methoxy derivative 2 [2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline] and described the enhanced potency of this compound over the parent 1,4-benzodioxan, idazoxan, in reversing the inhibition caused by alpha 2-adrenoreceptor agonists of the electrically induced twitch in the rat or mouse vas deferens. It was of interest to us to discover whether a similar substitution in the structurally related alpha 2-adrenoreceptor antagonists piperoxan, prosympal, and fenmetazole would similarly enhance potency. We subsequently discovered that this was not so and potency was decreased markedly. In particular, that of the methoxy derivative of piperoxan was ca. 220 times less than the parent structure.

Alpha-adrenoreceptor reagents. 3. Synthesis of some 2-substituted 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists.

The synthesis and pharmacological activity of a series of 2-substituted derivatives of the selective alpha 2-adrenoreceptor antagonist idazoxan (RX 781094) is described. Substitution in this position by alkyl, alkenyl, cycloalkenyl, and alkoxy groups in many cases gives compounds whose potencies and selectivities are significantly greater than those of the parent compound.

Substituted 5H-dibenz[b,g]-1,4-oxazocines and related amino acids with antiinflammatory activity.

During an investigation of the antiinflammatory properties of a number of tetracyclic derivatives of 6,8-dichlorodibenz[b,f]oxepin-10(11H)-one, the ring-expanded 1,3-dichloro-5H-dibenz[b,g]-1,4-oxazocine (9) was prepared and found to be considerable pharmacological interest. It was subsequently found that the corresponding ring-opened amino acid 66, a close analogue of the antiinflammatory agent fenclofenac, also possessed significant antiinflammatory activity, superior both to the dibenzoxazocine and to fenclofenac. These findings prompted extensive synthetic programs in both areas, and a number of derivatives in the amino acid series showed potencies considerably in excess of the standard compound. These phenylacetic acids, however, were significantly more ulcerogenic than fenclofenac whereas the corresponding dibenzoxazocines showed few signs of ulcerogenicity at doses up to 1 g/kg.

Substituted (2-phenoxyphenyl)acetic acids with antiinflammatory activity. 2.

A number of polychlorinated (phenoxyphenyl)acetic acids were prepared as close structural analogues of the antiinflammatory compound fenclofenac, [2-(2,4-dichlorophenoxy)phenyl]acetic acid. Increased potency was shown in several of these compounds, in particular, [2-(2,3,5,6-tetrachlorophenoxy) phenyl]acetic acid (8), which was 40 times more potent than fenclofenac in the adjuvant-induced arthritis screen. In further tests it was found to be equipotent with indomethacin but with a much reduced incidence of acute toxicity (LD50 and ulcerogenicity). On chronic dosing, however, serious toxicity problems arose (including anemia, neutrophilia, and severe peritonitis), and this led to the abandonment of further work on the compound. Three further analogues were prepared containing NH, S, and SO moieties bridging the phenyl rings. Although the NH compound bore a very close structural resemblance both to the above O-linked compound and the potent antiinflammatory drug diclofenac, [2-[(2,6-dichlorophenyl)imino]phenyl]acetic acid, it showed low activity in primary screens. Similarly, neither the S- or SO-bridged analogues had potencies that approached that of 8.

2-Amino-2-deoxygalacturonic acid in lipopolysaccharides from Pseudomonas aerugimosa.

2-Amino-2-deoxygalacturonic acid was identified as a component of the lipopolysaccharide from Pseudomonas aeruginosa N.C.T.C. 8505. The compound probably occurs in the region of polysaccharide responsible for O-antigenic specificity.