A multi-element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials.

A multi-element inductively coupled plasma-mass spectrometry (ICP-MS) survey method has been demonstrated as an alternative to the antiquated 'heavy metals limit test' prescribed by United States Pharmacopoeia (USP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP), for drug substances, intermediates, and raw materials. The survey method is simple, fast, sensitive, semi-quantitative to quantitative, and includes all the elements which can be analyzed by atomic spectroscopy.

Metabolism of xilobam in laboratory animals and man.

1. Biotransformation and excretion of xilobam (Xm) were studied after single oral doses of Xm-14C in mouse, rat, dog and man. 2. Following oral administration of Xm-14C, recoveries of total 14C (0-24 h) in urine were > or = 78% of the dose in all species. 3. Xm and a total of 11 metabolites have been isolated and identified, which accounted for 30, 65, 21 and 49% of the total 14C in the urine samples from mouse, rat, dog and man, respectively. 4. Xm was sequentially oxidized at the pyrrolidine ring to form 5'-OH Xm and 5'-oxo Xm. Both metabolites were isolated from human plasma accounting for 61% of the radioactivity in the sample. 5'-OH Xm was also identified as a major in vitro metabolite in the 9000g supernatant from a rat liver homogenate preparation. 5. 5'-OH Xm was isolated from the urine of all species except rats. However, oxidation products of 5'-oxo Xm were also present. Oxidation at the phenyl (ph) ring and at the phCH3 group produced the corresponding 4-OHph and phCH2OH metabolites. Subsequent water addition at the 2-position of the pyrrolidine ring followed by cleavage and/or cyclization of the above metabolites resulted in six additional urinary metabolites.

Isolation and characterization of the major equilibrium product of FK-520.

The existence of an isomeric form in equilibrium with the major component of FK-520 in polar solutions has been demonstrated. This minor component has been isolated in high yield and purity by a novel crystallization strategy and preparative HPLC. The equilibrium product was characterized by NMR and MS.

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).

Substances derived from 4-de-N-methylfortimicin B.

The preparation of 4-de-N-methylfortimicin A analogs as well as the preparation of 4-de-N-methyl-4-N-(beta-aminoethyl)-4-N-ethylfortimicin B is reported. It was shown that the 4-N-methyl group in fortimicin analogs is essential for antibacterial activity since neither the 4-de-N-methylfortimicin A nor the 4-de-N-methyl-4-N-(beta-aminoethyl)-4-N-ethylfortimicin B exhibited useful biological activity.

Modification of the 5' position of purine nucleosides. 2. Synthesis and some cardiovascular properties of adenosine-5'-(N-substituted)carboxamides.

We have shown previously that the esters of adenosine-5'-carboxylic acid (10) represent a new class of potent nontoxic coronary vasodilators. For example, the ethyl ester (12), which is active by an intraduodenal or intravenous route in dogs, causes a large increase in coronary sinus PO2 and coronary blood flow. Because of the pronounced vasoactive properties of the esters of adenosine-5'-carboxylic acid, a systematic study of the corresponding amides (14--50) was undertaken. In addition, several other analogues containing the N1-oxide function (51--52) or 2',3' substituents (3--9, 53--54) were studied.

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.

Spectinomycin modification. IV. 7-deoxy-4(R)-dihydrospectinomycin.

7-Deoxy-4(R)-dihydrospectinomycin (7) has been prepared and its structure firmly established by proton magnetic resonance and high resolution mass spectrometry. This spectinomycin analog is devoid of antibiotic activity.

The structures of the m-chloroperbenzoic acid oxidation products of 8,9-anhydroerythromycins A- and B-6,9-hemiacetal and of (8S)-8-hydroxyerythromycin B.

13C-NMR studies have confirmed the structures of (8S)-8-hydroxyerythromycins A- and B-6,9;9,11-acetal proposed by KROWICKI and ZAMOJSKI2,3) for the products of the m-chloroperbenzoic acid oxidation of 8,9-anhydroerythromycins A- and B-6,9-hemiacetal. The preparations of (8S)-8-methylthiomethoxy- and (8S)-8-methoxyerythromycin B-6,9;9,11-acetals are described. The latter are stable in aqueous acetic acid under conditions which convert (8S)-8-hydroxyerythromycin B-6,9;9,11-acetal into (8S)-8-hydroxyerythromycin B.

Biotransformation of lankamycin, darcanolide, and 11-acetyllankolide by a blocked mutant of the erythromcyin producing organism Streptomyces erythreus.

The biotransformation of lankamycin and congeners darcanolide and 11-acetylankolide by a blocked mutant of the erythromycin-producing organism Streptomyces erythreus, which cannot synthesize erythromycin without supplementation with erythromycin precursors, was investigated. Darcanolide and 11-acetyllankolide were converted into the corresponding 15-deoxy-15-oxo derivatives. Lankamycin was transformed to 15-deoxy-15-oxolankamycin, 4''-deacetyl-15-deoxy-15-oxolankamycin and 3'-de-O-methylankamycin. None of the derivatives possessed high antimicrobial activity.

Fortimicins A and B, new aminoglycoside antibiotics. III. Structural identification.

The structures of fortimicins A and B have been determined by PMR, CMR, mass spectra and CD combined with chemical degradations. Both antibiotics are pseudodisaccharides and incorporate a novel aminocyclitol, fortamine. In contrast to the diaminocyclitol moieties of known aminoglycosides, fortamine is a 1,4-diamine, contains both N- and O-methyl groups and possesses chiro stereochemistry. Both antibiotics are glycosides of 6-epi-purpurosamine B, but fortimicin A differs from fortimicin B by being a glycyl amide.

A new aminoglycoside antibiotic complex--the seldomycins. III. The structures of seldomycin factors 1 and 2+.

The structures of seldomycin factors 1 and 2 have been determined by consideration of chemical degradation and spectral properties. Factor 1, also known as XK-88-1, is shown to be 6-O-(2-amino-2-deoxy-alpha-D-xylopyranosyl) paromamine (1) and factor 2, also known as XK-88-2, is shown to be 4'-deoxy-neamine (2). Mass spectral evidence has been obtained that suggests the most probable structure for seldomycin factor 3, also known as XK-88-3, is 6'-amino-6'-deoxyseldomycin factor 1 (12).

Spectinomycin modification. II. 7-EPI-sectinomycin.

7-Epi-spectinomycin (9) and 7-epi-4(R)-dihydrospectinomycin (10) have been prepared and their structure firmly established by proton magnetic resonance. Both of these spectinomycin analogs are devoid of antibiotic activity.

A new antibiotic XK-62-2. III The structure of XK-62-2, a new gentamicin C complex antibiotic.

The structure of XK-62-2 has been firmly established to be 6'-N-methylgentamicin C1a (3) by application of spectroscopic methods in conjunction with chemical degradation. The data obtained in every case are completely consistent with the proposed structure.