Lysinomicin, a new aminoglycoside antibiotic. II. Structure and stereochemistry.

The structure of lysinomicin, a new aminocyclitol antibiotic, was established as 3-epi-2'-N-(L-beta-lysyl)-4',5'-didehydro-6'-de-C-methylfortimi cin B (1) on the basis of spectral evidence and chemical degradation of the antibiotic. In the course of the degradation of 1, three additional compounds with interesting biological properties were obtained: 3-epi-2'-N-(L-beta-lysyl)-6'-de-C-methylfortimicin B (4), 3-epi-4',5'-didehydro-6'-de-C-methylfortimicin B (6) and 3-epi-6'-de-C-methylfortimicin B (7).

Semi-automated preparation of a 11C-labelled antibiotic--[N-methyl-11C]erythromycin A lactobionate.

A fast semi-automated method is described for labeling the antibiotic, erythromycin A (1), with the short-lived positron-emitting radionuclide, 11C (t 1/2 = 20.4 min), in order to permit the non-invasive study of its tissue uptake in vivo. Labelling was achieved by the fast reductive methylation of N-demethylerythromycin A (2) with [11C]formaldehyde, itself prepared from cyclotron-produced [11C]-carbon dioxide. Rapid chemical and radiochemical purification of the [N-methyl-11C]erythromycin A (3) were achieved by HPLC and verified by TLC with autoradiography. The purified material was formulated for human i.v. injection as a sterile apyrogenic solution of the lactobionate salt. The preparation takes 42 min from the end of radionuclide production and from [11C]carbon dioxide produces [N-methyl-C11]erythromycin A lactobionate in 1-12% radiochemical yield, corrected for radioactive decay.

6'-N-methylfortimicins A and B and 6',6'-di-N-methylfortimicins A and B.

Selective 6'-N-alkylation of 1,2'-di-N-benzyloxycarbonylfortimicin B was effected by both catalytic and chemical reductive alkylation in the presence of aldehydes. These facile selective 6'-N-alkylations were used as the basis of the preparations of the 6',6'-di-N-methylfortimicins A and B, and the 6'-N-methylfortimicins A and B. Of these new 6'-N-methylated fortimicins, only 6'-N-methylfortimicin A has appreciable antibacterial activity, which was about half that of fortimicin A.

4-N-Aminoacylfortimicins E.

The conversion of fortimicin E, a minor metabolite from the Micromonospora olivoasterospora fermentation which also produces fortimicin A and fortimicin B, to four 4-N-aminoacylfortimicins E was accomplished. The new 4-N-aminoacylfortimicins E showed only weak antimicrobial activity against several Gram-negative and Gram-positive microorganisms.

2,5-Bis(3,4-dimethoxybenzyl)cyclopentylamine, a peripheral dopamine blocking agent.

2,5-Bis(3,4-dimethoxybenzyl)cyclopentylamine hydrochloride has been synthesized. The intermediate 2,5-bis-(3,4-dimethoxybenzyl)cyclopentanone was formed in 91.8% yield using a sodium methoxide catalyzed aldol condensation and catalytic reduction. The oxime of this ketone was catalytically hydrogenated to the amine which was converted to the hydrochloride (76%). The amine hydrochloride was found to be an effective antagonist to the low-dose hypotensive effect of dopamine; the half-life of this effect was 18 min. At dopamine doses of 3 mg/kg in the atropinized and phenoxybenzamine treated dog, the ED50 for blockade was 4--5 mumol/kg. In direct contrast to its peripheral dopamine blocking activity, the compound potentiates apomorphine-induced stereotypy.

Local anesthetic activity and acute toxicity of N-substituted 1,2,3,4-tetrahydro-1- and 2-naphthylamines.

Seven N-substituted 1,2,3,4-tetrahydro-1- and three 2-naphthylamines were prepared and tested for local anesthetic activity in the rabbit corneal reflex test and the mouse sciatic nerve block test. At 0.1 and 1%, three 1-alkylamino compounds had durations of action comparable to that of tetracaine in the rabbit corneal reflex test and were considerably more potent than lidocaine. The other four 1-alkylamino derivatives were inactive or at best minimally active. The durations of action of 1% concentrations of the three 2-alkylamino compounds were equivalent to that of 1% lidocaine in the corneal reflex test. In the mouse sciatic nerve block test, the three active 1-alkylamino compounds were considerably longer acting than either tetracaine or lidocaine. Three 1-alkylamino and the three 2-alkylamino compounds showed toxicity equal to or greater than lidocaine, while two 1-alkylamino and two 2-alkylamino compounds showed toxicity equal to or greater than tetracaine by the intraperitoneal route in mice. N-Heptyl-1,2,3,4-tetrahydro-6-methoxy-1-naphthylamine methanesulfonate was the most promising local anesthetic in these series.

Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains.

Ten new delta6a,10a-THC analogs with arylalkyl side chains, one with a dimethylaminoalkyl side chain, and six heterocyclic delta6a,10a-THC analogs [8-substituted 5,5-dimethyl-10-hydroxy-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzo-pyrano[4,3-c]pyridines] were prepared. They showed pharmacological activity as analgesics, tranquilizers, antihypertensives, and hypnotics and as antisecretory, antiulcer, and antidiarrheal agents. The most potent compounds had either a 1-methyl-4-(4-fluorophenyl)butyl or a 1,2-dimethyl-4-(4-fluorophenyl)butyl side chain.