Reactions of morphine derivatives with phenyliodo(III)diacetate (PIDA): synthesis of new morphine analogues.

The reactions of morphine and its derivatives with phenyliodo(III)diacetate (PIDA) have been studied. This methodology has not been introduced to morphine alkaloids, despite the fact that such a strategy would ensure dearomatization of the electrophilic aromatic ring of morphine derivatives leading to nucleophilic ortho-quinoidal structures with potential pharmacological interest. The products, formed in regio- and diastereoselective or diastereospecific reactions, carry mixed-acetal or 1,3-dioxolane moieties. At low concentrations 6a has mu-opioid agonist character but in higher concentrations showed a non receptorial antagonist effect on isolated mouse vas deferens.

[Synthesis and analytical characterization of the dansyl derivatives of 6,14-ethenomorphinans]. / 6,14-Etenomorfinánok danzil-származékainak szintézise és analitikai jellemzése.

The synthesis of the dansyl derivatives of the pharmacologically important 6,14-ethenomorphinans has not been reported. The authors realized the preparation of the dansyl derivatives (2a-i) of some 20-alkyl(aralkyl)-orvinols (1a-i). The authors unequivocally proved the structure of the parent compounds, and their dansyl derivatives. The authors also investigated certain analitical characteristics (thin-layer chromatography, UV-spectral data and reversed-phase HPLC purity tests) for the detection if necessary of these compound in biological fluid. Namely, due to the fluorescent properties of the dansyl derivatives, the sensitivity and selectivity of the analytical determinations of the parent compounds are significantly enhanced.

New nepenthone and thevinone derivatives.

The diastereoselective reaction of thevinone (2a) and nepenthone (2c) and their dihydro derivatives (2b and d) with Grignard reagents afforded new N-substituted (20S)- and (20R)-phenyl-6,14-ethenomorphinan derivatives (6a-y). The Grignard reaction of the N-substituted-N-demethyl derivatives 4a-f and 4m-r with methylmagnesium iodide resulted in the (20R)-phenyl tertiary alcohols 5a-f and 5m-r, respectively, but the conversion of 4g-1 and that of the N-substituted-dihydrothevinone derivatives with phenylmagnesium bromide afforded the (20S)-phenyl derivatives 5g-l and 5s-y, respectively. The N-cyclopropylmethyl-, N-beta-phenylethyl-, and N-propyl derivatives were prepared by the 3-O-demethylation of compounds 5. For the synthesis of the N-allyl-, N-dimethylallyl-, and N-propargyl compounds 2a-d were reacted with the corresponding Grignard reagent, and treatment of the products with cyanogen bromide gave the cyanamides 8a-d. These latter compounds were transformed into 10a, b,d, whose alkylation led to the target derivatives 6d-f, j-l, p-r, and w-y. The biochemical investigation of these substances showed that the affinities to the delta-opioid receptors were high, but the selectivity was low. In two cases (6c and 11d) a mu-opioid receptor specificity was observed.

Influence of spatial orientation of the C-6-OH group in ring C of morphine derivatives on opioid activity.

The effect of epimerization on agonist and antagonist activities of morphine and dihydromorphine, and those of their N-allyl, -propyl and -cyclopropylmethyl derivatives, were studied in rat tail flick, hot plate and mice hot plate and in isolated guinea-pig ileum assays, respectively. Using the rat tail flick, hot plate and mice hot plate tests, isomorphine and dihydroisomorphine were observed to produce dose-dependent, naloxone-reversible agonist (antinociceptive) actions, in a similar dose range as their parent molecules (relative potencies: 0.6-1.9). Also, these compounds produced agonist activities in isolated tissue preparations in a naloxone-reversible manner. While the N-substituted derivatives of isomorphine and dihydroisomorphine failed to produce antinociceptive activities in the rat tail flick test, they proved to be strong agonists in the guinea-pig ileum experiments, although the Ke values of naloxone were 5-6 times higher against these compounds than against their N-CH3 counterparts. Both the agonist and antagonist activities of the N-cyclopropylmethyl derivatives were found to be most potent in the guinea-pig ileum. The epimerization of morphine and dihydromorphine and their N-substituted derivatives evoked only slight changes in opioid activities in vitro. In vivo, merely the allyl substitution on nitrogen influenced the antagonist activities of epimer pairs. In contrast, substantial changes in opioid profile were observed when N-methyl was replaced by allyl-, propyl- or cyclopropylmethyl. Changes performed this way evoked, on the one hand, an enhancement of the affinities of compounds to mu-receptors, with simultaneous loss of intrinsic efficacy at these receptors, and, on the other hand, promoted the appearance of an agonist profile on a distinct (kappa) opioid receptor.

Synthesis of 7 beta-(4-oxo-3,4-dihydrothieno[2,3-d] pyrimidyl-2-thioacetamido)cephalosporanic acid derivatives.

Synthesis of new cephalosporins possessing thieno [2,3-d]pyrimidine is described in the present paper. Potassium salts of 2-thio-4-oxo-3,4-dihydrothieno [2,3-d]pyrimidines, which gave then 2-carboxymethylmercapto-4-oxo-3,4-dihydrothieno [2,3-d]pyrimidines, were prepared from 2-amino-3-carbethoxythiophene derivatives. These compounds were allowed to react with 7-aminocephalosporamic acid (ACA) benzhydryl esters or with 7 beta-chloroacetamidocephalosporanic acid derivatives to obtain new cephalosporins. Antibacterial activities of these new cephalosporins are summarized in the present paper as well.

The pharmacology of N-substituted azidomorphines.

N-allylnorazidomorphine (NAM), N-allyl-14-hydroxynorazidomorphine (NOAM), N-cyclopropylmethylnorazidomorphine (CAM) and N-cyclopropylmethyl-14-hydroxynorazidomorphine (COAM) were synthetized and their pharmacological effect in comparison to naloxone and naltrexone were analyzed. While naloxone and naltrexone are pure antagonists at all points, the N-substituted norazidomorphines were found to be more potent antagonists than naloxone in some of the tests and extremely potent pure agonists in others. Using CAM for routine work we differentiated between opiate A-receptors which are stimulated and opiate B-receptors which are antagonized by CAM. Opiate A-receptors were found to be involved in the behavioral disturbances (inhibition of conditioned avoidance responses, characteristic EEG changes, elimination of slow wave and paradoxical sleep, etc.) caused by the opiates. The guinea-pig ileum and mouse vas deferens are the suitable isolated organs for testing A-receptors. Opiate B-receptors are responsible for the analgesic, antitussive, cataleptic, respiratory depressant and hypotensive effects of the opiates. The isolated nictitating membrane of the cat is an appropriate model for testing the B-receptors. The hypothesis is proposed that A-receptors relate to cholinergic and B-receptors to adrenergic mechanisms; the N-substituted norazidomorphines are tools for the analysis of the two kinds of opiate receptors.

The metabolism of azidomorphine in the rat.

The metabolism of [7,8-3H]azidomorphine and the in vivo stability of the azidogroup in azidomorphine and 14-hydroxyazidomorphine was studied. Asidomorphine conjugates with glucuronic acid, and is N-demethylated by rat liver microsomes. Detection by means of infrared spectroscopy proved that the azidroup in azidomorphine and 14-hydroxyazidomorphine strongly resists biotransformation in the rat.

The pharmacology of 14-hydroxyazidomorphine.

6-Deoxy-6-dihydroazido-14-hydroxyisomorphine (14-hydroxyazidomorphine) was synthesized, its analgesic potency in mice and rats, its antitussive effect in rats and its dependence liability in mice, rats and monkeys were studied. Azidomorphine the 14-nonhydroxylated parent molecule, morphine, hydromorphone and oxymorphone were used for comparison. 14-Hdroxyazidomorphine proved to be as potent an analgesic as azidomorphine, even more potent as an antitussive, and showed the same low tolerance and dependence capacity. It was 11-6 times less toxic than azidomorphine in mice and 6-5 times less toxic in rats.