FURTHER STUDIES WITH HYDRALAZINE-14C·HCl (H-14C) AND METABOLITES

Israili, Zafar H.; Dayton, Peter G.; Segal, Jack L.; Leifer, C E; O’Malley, K; J, Gilbert; McNay, J. L.

doi:10.1016/b978-0-08-021308-8.51418-6

Cited by 3 publications

(1 citation statement)

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“…33 Tropisetron (Navoban), marketed by Novartis, is an antiemetic agent used as an analgesic in fibromyalgia (Figure 1 ). 34…”

Section: Table 1 Optimization Of the Reaction Condition...mentioning

confidence: 99%

A New Method for the Synthesis of 1-Methyl-1H-indole-3-carboxylate Derivatives, Employing Copper(II)

Akbari¹,

Faryabi²

2023

Synthesis

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We report an efficient method for synthesizing 1-methyl-1H-indole-3-carboxylates with cross-dehydrogenative coupling. However, the coupling reactions are a way to functionalize the α carbon of an iminium from tertiary amines. The synthesis of 1-methyl-1H-indole-3-carboxylate from N,N-dimethylaniline with bromoacetates has not been reported. In the present work, we describe a novel route for synthesizing 1-methyl-1H-indole-3-carboxylate with N,N-dimethylaniline with a wide range of phenyl bromoacetate derivatives. The features such as simple procedure and good to excellent yields (69-90%), make this method a highly efficient procedure for the preparation of indole derivatives using Cu(OAc)2·H2O as a catalyst in the presence of tert-butyl hydroperoxide.

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“…33 Tropisetron (Navoban), marketed by Novartis, is an antiemetic agent used as an analgesic in fibromyalgia (Figure 1 ). 34…”

Section: Table 1 Optimization Of the Reaction Condition...mentioning

confidence: 99%

A New Method for the Synthesis of 1-Methyl-1H-indole-3-carboxylate Derivatives, Employing Copper(II)

Akbari¹,

Faryabi²

2023

Synthesis

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Studies on hydralazine

Talseth

1976

Eur J Clin Pharmacol

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The bioavailability of orally administered hydralazine was assessed in 4 healthy subjects after separate administration of a single oral or intravenous dose (0.3 mg-kg-1). Comparison of the areas under the serum concentration-time curves showed that 26-55% of the oral dose was available to the systemic circulation as unchanged drug. The 0-24 h excretion of the drug in urine was rapid: 11.4-14.1% of the dose after intravenous administration, and 2.0-3.6% after an oral dose. Acetylation of hydralazine leads to formation of 3-methyl-s-triazolo-3,4, aphthalazine (MTP) and a gas-liquid-chromatographic method for its measurement in urine was developed. After oral and intravenous administration, 0.8-1.2% and 1.4-2.3% of the dose, respectively, were recovered within 24 hours from urine as MTP. After oral administration there was a relative increase in the amount of MTP in every subject, which indicates route-dependent metabolism. The lower bioavailability of oral hydralazine could be explained in terms of first-pass metabolism.

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Pharmacokinetics of hydralazine and its acid-labile hydrazone metabolites in relation to acetylator phenotype

Shen

Hosler

Schroder

et al. 1980

Journal of Pharmacokinetics and Biopharmaceutics

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The pharmacokinetics of hydralazine (H) and its acid-labile hydrazone metabolites were compared in rapid and slow acetylators. Following a 20-mg intravenous infusion, the elimination half-life (t 1/2 beta) and the apparent volume of distribution of H did not differ between the two groups. Plasma clearance estimates approached hepatic blood flow. When a single 100-mg dose of H was given orally, the area under the plasma concentration-time curve (AUC) and a systemic availability (theta) in slow acetylators were, on the average, twice as high as in the rapid acetylators, indicating a difference in the extent of first-pass metabolism of the drug. Furthermore, the observed theta in the slow individuals exceeded theoretical predictions. Hence saturation of first-pass metabolism of H is suggested, and a nonlinear relationship between AUC and oral dose of H was indeed observed in the three subjects studied with two doses. The half-life of decline of the acid-labile metabolites was similar to the t 1/2 beta of H. The AUCs for metabolies were 4--12 times larger than for the parent drug. However, the ratio between the metabolite AUC and drug AUC did not differ irrespective of routes of administration or the acetylator status.

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FURTHER STUDIES WITH HYDRALAZINE-14C·HCl (H-14C) AND METABOLITES

Cited by 3 publications

References 0 publications

A New Method for the Synthesis of 1-Methyl-1H-indole-3-carboxylate Derivatives, Employing Copper(II)

A New Method for the Synthesis of 1-Methyl-1H-indole-3-carboxylate Derivatives, Employing Copper(II)

Studies on hydralazine

Pharmacokinetics of hydralazine and its acid-labile hydrazone metabolites in relation to acetylator phenotype

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