K. D. Berlin

Complete 1H and 13C NMR Spectral Assignment of δ-Cadinene, a Bicyclic Sesquiterpene Hydrocarbon

δ‐Cadinene from cade oil and ylang‐ylang essential oil was independently analyzed by two research groups employing 2D NMR spectroscopy to effect the complete assignment of 1H and 13C spectra and to confirm the previously reported structure of δ‐cadinene.

Metabolism and metabolite pharmacokinetics of BRB-I-28, a class Ib antiarrhythmic agent

SummaryThe metabolism of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane), a novel class Ib antiarrhythmic agent, was characterized in vivo in dogs and rats and in vitro with rat liver microsomal preparations containing a NADPH-generating system. In dogs, rats and the in vitro hepatic microsomal oxidation system, BRB-I-28 was extensively metabolized to form 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane-3-oxide (I), a major metabolite. The metabolite I was produced via S-oxidation, presumably by the hepatic P-450 system. Formation of a minor metabolite, 7-benzoyl-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzylic site was also identified in rats. Following intravenous and oral administration of BRB-I-28 to dogs, the plasma concentration of major metabolite I could be best described by a 1-compartmental model. The plasma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of the parent BRB-1-28, respectively, suggesting that BRB-I-28 was metabolized significantly by the first pass effect following oral administration. Extensive metabolism of BRB-I-28 to form metabolites I and II, which have demonstrated much lower antiarrhythmic activities, further supports previously observed pharmacodynamic and pharmacokinetic findings.

CARBON-13 NMR STUDIES OF 1-PHENYL-4-PHOSPHORINANONE AND DERIVATIVES. SINGLE CRYSTAL X-RAY DIFFRACTION ANALYSIS OF 1-PHENYL-4-PHOSPHORINANONE 1-OXIDE AND 1-SULFIDE

Abstract The 13C nmr spectral analysis has been recorded for the title compounds in DCC13, and all data appear to be in a accord with chair forms. Single crystal x-ray diffraction analysis of 1-phenyl-4-phosphorinanone 1-oxide and the corresponding sulfide revealed flattened chair forms in the solid state. Neither the solution data nor the x-ray data provided any evidence for a twist form for either compound as has been suggested for the carbon counterpart, namely, cyclohexane-1,4-dione.

The acute and subchronic toxicity of BRB-I-28, a novel class Ib antiarrhythmic agent, in CD-1 mice.

The acute and subchronic toxic effects of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane HCl), a novel class Ib antiarrhythmic agent, were investigated in male and female mice. The estimated oral LD(50) for BRB-I-28 was 128 mg/kg (male mice) and 131 mg/kg (female mice). In subchronic oral studies, four groups of mice (15/sex/group/dose) were fed daily with diets containing BRB-I-28 for 90 consecutive days. The equivalent daily doses were approximately 0, 16, 32, 76 (male) and 0, 18, 37, 89 mg/kg (female). All mice survived. Food consumption per day was decreased, but water consumption per day was increased (in a non-dose-dependent manner). However, both mean body weight and mean body weight gain were not significantly changed as were true for hematological and clinical chemistry profiles, except for serum Na(+) concentration (male) and serum K(+) concentration in male and female mice (high dose levels). Hepatocellular necrosis occurred in male and female mice (in a dose-dependent fashion). Renal cortical vacuoles and myocardial necrosis with low numbers of lymphocytic infiltrations were present in female mice (middle and high doses). Lesions in the liver, kidney and heart were mild with (very small) changes in serum biochemical values. These data suggest that BRB-I-28 has limited toxic potential, and coupled with low proarrhythmic and other desirable cardiovascular effects, makes BRB-I-28 worthy of further development.

CARBON-PHOSPHORUS HETEROCYCLES. SYNTHESIS OF SUBSTITUTED 2,3,4,5-TETRAHYDRO-5-OXO-2,2-DIPHENYL-1H-2-BENZOPHOSPHEPINIUM SALTS VIA INTRAMOLECULAR ACYLATION WITH 115% POLYPHOSPHORIC ACID

Abstract Intramolecular acylation involving three ω-carboxyalkylphosphonium salts 1a-c has been achieved in the presence of 115% polyphosphoric acid (PPA) to yield the heretofore unknown 2,3,4,5-tetrahydro-5-oxo-2,2-diphenyl-1H-2-benzo-phosphepinium salts 2a-c. The open-chain precursors were easily prepared by quaternization of the corresponding tertiary arylmethyl-substituted phosphines with 3-chloropropanoic acid. Cyclization of the carboxy-substituted salts was accomplished at 200°C with PPA in modest yields (37–64%). A mechanism reminiscent of a classic electrophilic acylation process was tentatively proposed. An x-ray crystallographic analysis of a single crystal of 2a showed the phosphepin ring to exist in a twisted-chair conformation.

SYNTHESIS OF TRICYCLIC AND TETRACYCLIC THIAZOLOIMIDAZOLE ACETIC ACIDS

Ausgehend von den Ketonen (I) werden die Thiocyanate (V) hergestellt, die zu den Thiazoloirnidazolen (VI) cyclisiert werden.

The structure of methyl 2-chloro-8-oxo-6H,8H-[1]benzopyrano[4',3':4,5]imidazo[2,1-b][1,3]thiazine-10-carboxylate

C 15HgC1N204S, M r = 348.76, orthorhombic, Pbca, a = 7.1732 (6), b = 13.872 (1), c = * To whom all correspondence should be addressed. 0108-2701/87/091723-04501.50 28.627 (2) A, V = 2848.6 (4) A 3, Z = 8, Dx= 1.627gcm -3, CuKfi, 2 = 1 . 5 4 1 8 A , p = 3 8 . 0 c m -1, F(000) -1424, T = 298 K, R = 0.049 for 2913 reflections. The molecule consists of a chlorophenyl, a pyran,

7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonane 3-oxide

The molecular geometry of a major metabolite, C14H19NOS, of a potent anti-arrhythmic drug, 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane (BRB-I-28), has been determined by X-ray diffraction. The 3,7-dihetero bicyclic system of the sulfoxide molecule adopts a chair--chair conformation like that of the HCLO4 salt of the BRB-I-28 molecule. The S...N contact distance of 2.863(2)A in the present molecule is significantly shorter than that found in the crystal structure of its precursor [3.038(4)A]. The overall molecule possesses pseudo-mirror symmetry.