Novel quinolizidine salicylamide influenza fusion inhibitors.

A novel series of quinolizidine salicylamides was synthesized as specific inhibitors of the H1 subtype of influenza A viruses. These inhibitors inhibit the pH-induced fusion process, thereby blocking viral entry into host cells. Compound 16 was the most active inhibitor in this series with an EC50 of 0.25 microg/mL in plaque reduction assay. The synthesis and the SAR of these compounds are discussed.

New hydrazone derivatives of adriamycin and their immunoconjugates--a correlation between acid stability and cytotoxicity.

New N-substituted hydrazine linkers were synthesized and their hydrazone derivatives of adriamycin were prepared. These functionalized adriamycin derivatives were conjugated with a monoclonal antibody, 5E9. The release rate of adriamycin from the hydrazones and from some of the conjugates was studied, and their relationship to the IC50's of the conjugate against 5E9-positive Daudi cells was investigated.

Substituted benzamides. 1. Potential nondopaminergic antagonists of chemotherapy-induced nausea and emesis.

A series of new substituted benzamides has been synthesized and evaluated for dopamine antagonist activity and for antagonism of cisplatin-induced emesis in the dog and in the ferret. It was found that modification of the 2-methoxy substituent of metoclopramide was detrimental to dopaminergic D2 antagonism but not necessarily to antagonism of cisplatin-induced emesis. A number of analogues having a beta-keto, beta-hydroxy, beta-methoxy, beta-imino, or beta-unsaturated alkyloxy substituent instead of methoxy have shown equal or superior protection from emesis to that of metoclopramide. At the same time these compounds were found to be free of dopaminergic D2 antagonism in both in vitro ([3H]spiperone binding) and in vivo tests (rat catalepsy, antagonism of apomorphine-induced stereotypy in the rat, and apomorphine-induced emesis in the dog).

Disposition of parenteral butorphanol in man.

The metabolism and elimination of 3H-butorphanol (levo-3, 14-dihydroxy-N-(cyclobutylmethyl)[15-3H]morhinan) tartrate were determined in man after therapeutic im (2 mg) and iv (1 mg) doses. As judged from urinary excretion of radioactivity, the im dose was completely absorbed. Butorphanol was rapidly distributed to tissues, had a plasma half-life of about 3 hr, and was extensively metabolized prior to elimination. The major route of elimination was renal, with fecal excretion being a minor route. Hydroxybutorphanol [3, 14-dihydroxy-N-(trans-3'-hydroxycyclobutylmethyl)morphinan] was isolated and identified as a major urinary metabolite and was also present in the plasma. The disposition of butorphanol is compared and contrasted to the disposition of morphine and pentazocine.

Analgesics and narcotic antagonists in the benzomorphan and 8-oxamorphinan series. 5.

3-Methoxy-8-oxamorphinans 9 have been prepared from the corresponding 5-allyl-9alpha-hydroxy-2'-methoxy-2-methyl-6,7-benzomorphans 7. The former compounds were transformed to the 3-hydroxy-8-oxamorphinans 6, a class of potent analgesics and analgesic-antagonists. In ring C of the morphinan nucleus substitution of 8-CH2 with oxygen enhanced both analgesic and antagonist activities, while replacement of hydrogen with a methyl group at C-14 in these compounds enhanced antagonist activity and decreased analgesic activity. Tetrahydrofuranobenzomorphans 3 and 3-hydroxy-8-oxaisomorphinans 4 displayed lower levels of activity. Structural requirements for antagonist activity are discussed.