Synthesis of N-(methoxycarbonylthienylmethyl)thioureas and evaluation of their interaction with inducible and neuronal nitric oxide synthase.

Two isomeric N-(methoxycarbonylthienylmethyl)thioureas were synthesised by a sequence of radical bromination of methylthiophenecarboxylic esters, substitution with trifluoroacetamide anion, deprotection, formation of the corresponding isothiocyanates and addition of ammonia. The interaction of these new thiophene-based thioureas with inducible and neuronal nitric oxide synthase was evaluated. These novel thienylmethyl-thioureas stimulated the activity of inducible Nitric Oxide Synthase (iNOS).

Formic acid catalysed rearrangement of 5beta-methyldihydrothevinols (= 3,6-dimethoxy-5,17-dimethyl-4,5-epoxy-6,14-ethanomorphinan-7-methanols): synthesis of new doubly bridged morphinan derivatives.

We recently showed that substitution of a 5beta-methyl group allows the isolation of 14-alkenyldihydrocodeinones from the action of hot formic acid on certain dihydrothevinols. It has now been shown that, in those dihydrothevinols which are converted to stable side chain olefins by such treatment, introduction of a 5beta-methyl group results in the formation of new doubly bridged morphinan derivatives in addition to the dihydrocodeinones or olefins. The new morphinans have low affinities for opioid receptors.

Time-dependence and preliminary SAR studies in inhibition of nitric oxide synthase isoforms by homologues of thiocitrulline.

Treatment of N(alpha)-Cbz-N(epsilon)-(2-hydroxyethylaminothiocarbonyl)-L-lysine N-(2-hydroxyethyl)amide with boiling hydrochloric acid gave N(epsilon)-(4,5-dihydrothiazol-2-yl)-L-lysine. This was a weak and non-isoform selective inhibitor of NOS, whereas N(epsilon)-aminothiocarbonyl-L-lysine and its methyl ester were potent, with IC(50)=13 and 18 microM, respectively, against human iNOS and IC(50)=3 and 8 microM, respectively, against rat nNOS. Time dependence was observed for inhibition of nNOS by the ester.

Synthesis of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas and evaluation as modulators of the isoforms of nitric oxide synthase.

Inhibition of the isoforms of nitric oxide synthase (NOS) has important applications in therapy of several diseases, including cancer. Using 1400 W [N-(3-aminomethylbenzyl)acetamidine], thiocitrulline and N(delta)-(4,5-dihydrothiazol-2-yl)ornithine as lead compounds, series of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas were designed as inhibitors of NOS. Ring-substituted benzyl and phenyl isothiocyanates were synthesised by condensation of the corresponding amines with thiophosgene and addition of ammonia gave the corresponding thioureas in high yields. The substituted 2-amino-4,5-dihydrothiazoles were approached by two routes. Treatment of simple benzylamines with 2-methylthio-4,5-dihydrothiazole at 180 degrees C afforded the corresponding 2-benzylamino-4,5-dihydrothiazoles. For less nucleophilic amines and those carrying more thermally labile substituents, the 4,5-dihydrothiazoles were approached by acid-catalysed cyclisation of N-(2-hydroxyethyl)thioureas. This cyclisation was shown to proceed by an S(N)2-like process. Modest inhibitory activity was shown by most of the thioureas and 4,5-dihydrothiazoles, with N-(3-aminomethylphenyl)thiourea (IC(50)=13 microM vs rat neuronal NOS and IC(50)=23 microM vs rat inducible NOS) and 2-(3-aminomethylphenylamino)-4,5-dihydrothiazole (IC(50)=13 microM vs rat neuronal NOS and IC(50)=19 microM vs human inducible NOS) being the most potent. Several thioureas and 4,5-dihydrothiazoles were found to stimulate the activity of human inducible NOS in a time-dependent manner.