Cer(IV)oxidationen von β-Aminoketonen, 8. Mitt.: Synthese von im Piperidinteil verschieden substituierten 1,2,3,4-Tetrahydroisochinolinen

Cerium(IV) Oxidations of β-Aminoketones, VIII¹⁾: Synthesis of 1,2,3,4-Tetrahydroisoquinolines with Differently Substituted Piperidine Parts 1- and 3-Alkyl- and/or aryl substituted tetrahydroisoquinolines are obtained by oxidative cyclisation of N-benzyl-β-aminoketones with cerium(IV) sulphate. In nearly all cases formation of mixtures of diastereomeres is observed. If the ketone function is replaced with COOR-, CN-, CHO and NO₂-groups no cyclisation occurs under standard reaction conditions. The products of hydrolysis, N-benzyl-N-methylaminopropionic acid, and of oxidation in benzylic position, benzaldehyde and benzoic acid, are mainly formed during the reaction. The oxidation of the N-benzylaminopropionaldehydacetal 1k yields the isoquinolinedione 4k .     

Cer(IV)-Oxidationen von β-Aminoketonen. 3. Mitt.: Ein Syntheseweg zu 4-spirosubstituierten 1,2,3,4-Tetrahydroisochinolinen

Cerium(IV) Oxidations of β-Aminoketones. Part III: A Pathway to 4-Spiro-Substituted 1,2,3,4-Tetrahydroisoquinolines Substituted 2′-methyl-2′,3′-dihydro-1′H-spiro[cycloalkan-1,4′-isoquinolin]-2-ones and -[chroman-3,4′-isoquinolin]-4-ones are synthesized by cerium(IV) oxidation of (N-benzyl-N-methylamino)methylcycloalkan-1-ones or corresponding substituted chromanones.     

Absorption,Excretion and Metabolism of a New Dihydropyridine Diester Cerebral Vasodilator in Rats and Dogs

1. After oral administration of [¹⁴C]dihydropyridine diester, the plasma concn. of radioactivity was similar in rats and dogs, reaching a maximum at 0·5 to 1?h and decreasing with a half life of about 3·5 h. The plasma concn. of unmetabolized drug in dogs was 10 times higher than in rats. Radioactivity in rat tissue was high in liver, kidney and lung after both oral and intravenous administration.

2. In both species, 66–72% of radioactivity was excreted in faeces and 23–29% in urine in 48?h, regardless of the route of administration. Biliary excretion in rats after oral dosage amounted to 65%.

3. Eight metabolites were identified from urine of dogs and rats. They were derived from one or several of the following pathways: I, debenzylation of the N-benzyl-N-methylaminoethyl side chain; II, reduction of the 3-nitro group on the phenyl substituent; III, oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine; IV, oxidative removal of the N-benzyl-N-methylamino group yielding a carboxylic acid; V, hydrolysis of the N-benzyl-N-methylamino-ethyl ester to the corresponding carboxylic acid; VI, hydroxylation of the 2-methyl group of the 1,4-dihydropyridine ring to hydroxymethyl.     

A procedure for the analysis of S-benzyl-N-acetylcysteine and S-(o-methylbenzyl)-N-acetylcysteine in human urine

1. Analytical methods for mercapturic acids, the end-products of gluthathione metabolism of the industrial solvents toluene and o-xylene (i.e., S-benzyl-N-acetylcysteine and S-(o-methylbenzyl)-N-acetylcysteine), added to human urine have been developed.

2. The sensitivity is 2ng/μl (R.S.D. = ±13%) and 1 ng/μl (R.S.D.= ±6.4%) urine for S-benzyl-N-acetylcysteine and S-(o-methylbenzyl)-N-acetylcysteine, respectively, when using the h.p.l.c. method.

3. The corresponding sensitivities for the g.l.c.-mass spectrometric method are 0.5 and 0.3 ng/μl urine, respectively.     

Identification of the in vitro N-oxidized metabolites of (+)- and (−)-N-benzylamphetamine

This study has identified (+)- and (-)-N-benzyl-N-hydroxyamphetamine as metabolites after incubation of both (+)- and (-)-N-benzylamphetamine with fortified rabbit liver homogenates. The isomeric hydroxylamine metabolites were identified using the techniques of g.l.c., t.l.c. and combined g.l.c.-mass spectrometry (ms) and by comparison with results from reference samples. An additional novel metabolic product was identified after incubation of N-benzylamphetamine which had properties consistent with that of N-benzyl-amphetamine nitrone.     

Zur Reaktion von 2-Hydroxycarbohydroxamsäuren mit Benzaldehyddimethylacetal

The Reaction of 2-Hydroxycarbohydroxamic Acids with Benzaldehyde Dimethylacetal The reaction of 2-hydroxycarbohydroxamic acids 1 with benzaldehyde dimethylacetal produces O-(2-hydroxyalkanoyl)benzaldoximes 6 in moderate yields. Compounds 6 are considered to arise from the rearrangement of transient N-acyl nitrones. N-Benzyloxy-2-(hydroxy)diphenylacetamide (10) reacts with benzaldehyde dimethylacetal to yield the 4-oxazolidone 11 , wich is converted by catalytic hydrogenation into 3-hydroxy-2,5,5-triphenyloxazolidin-4-one (7a) .     

Improved Preparation of α,N-Diphenylnitrones and N-Benzyl-N-Phenylhydroxylamines by direct Oxidation of Secondary Anilines

A simple and rapid method for the oxidation of secondary anilines to α,N-diphenylnitrones and the subsequent reduction to secondary N-benzyl-N-phenylhydroxylamines is described.     

N-Monomethylierung des Tetrandrins

N-Monomethylation of Tetrandrine With methyl iodide, tetrandrine forms the isomeric tetrandrinium salts 2 and 3 at a ratio of 4 : 1. Pure 3 is obtained via N'-benzyl-N-methyltetrandrinium diiodide. Deviations from data reported in the literature are discussed.     

Inhibition of cyclic AMP phosphodiesterase by 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)] ethyl ester 5-methyl ester hydrochloride (YC-93), a potent vasodilator.

A new, potent vasodilator (YC-93), 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methyl amino)] ethyl ester 5-methyl ester hydrochloride, competitively inhibited cyclic adenosine 3′,5′-monophosphate (cyclic AMP) phosphodiesterase in the 105,000 g supernatant solutions from canine basilar, carotid, coronary and femoral arteries. The inhibition constant (K_i) of YC-93 for these enzyme preparations was in the range of 2.0–4.3 μM at substrate concentrations near the low K_m (about 1 μM for each enzyme preparation), and was 4.0–12 μM at substrate concentrations near the high K_m (50–70 μM). The potency of YC-93 for inhibition of coronary phosphodiesterase at 1 μM cyclic AMP and 50 μM cyclic AMP was much greater than that of papaverine and 3-isobutyl-l-methyl xanthine (IBMX). Commercially available cyclic AMP phosphodiesterase purified from beef heart was also strongly inhibited by YC-93 in a competitive manner and its K_i value was 2.0 μM in the wide range of substrate concentrations tested. Studies on the structure-activity relationship using low K_m phosphodiesterase from canine coronary artery and high K_m phosphodiesterase from beef heart, demonstrated that 3,5-diethoxycarbonyl-1,4-dihydro-2, 4,6-collidine, the simplest 1,4-dihydropyridine derivative (tested in the present studies) resulted in slightly less inhibition than papaverine, and the inhibitory potency of the former compound was greatly increased mainly by two structural modifications. Firstly, addition of a nitrophenyl group at position 4 of the 1,4-dihydropyridine ring, secondly, the replacement of ethylester at position 3 of the 1,4-dihydro-pyridine ring by N-benzyl-N-methylaminoethyl ester. A few dihydropyridine derivatives together with YC-93 were the most potent inhibitors of cyclic AMP phosphodiesterase among the compounds tested. The finding that the level of cyclic AMP in canine arterial strips was increased by 64 per cent (P < 0.01) even after 1 min exposure to 1 μM YC-93 supports the possibility of at least a partial involvement of phosphodiesterase inhibition in vasodilation by the drug.     

Metabolism in the rat of a model xenobiotic plant metabolite S-benzyl-N-malonyl-L-cysteine

1. The metabolism of a model xenobiotic plant metabolite S-benzyl-N-malonyl-L-cysteine (BMC) administered to rat at 10?mg/kg has been studied using a combination of radio-t.l.c. and?h.p.l.c.

2. The major route of excretion for the administered ¹⁴C was via the urine (79% in 3 days).

3. The major metabolite was hippuric acid. The extent of biotransformation of BMC indicated the lability of the N-malonyl bond whose hydrolytic removal initiated a metabolic sequence which involved the action of C-S lyase to produce benzyl thiol.

4. A comparison of the findings from this study with those from experiments with N-acetyl-S-benzyl-L-cysteine and S-benzyl-L-cysteine is made to support the metabolic pathway proposed.     

Degradation reactions of oral antidiabetics. 1. Reactions of arylsulfonylurea compounds with carboxylic acid anhydrides

Degradation of Oral Antidiabetics, 1: Reactions of Arylsulfonylureas with Carboxylic Acid Anhydrides The arylsulfonylureas 1a–h were reacted with carboxylic acid anhydrides in pyridine. By acetic anhydride, compounds 1 were cleaved rapidly to the N-(arylsulfonyl)acetamides 2 and N-alkylacetamides 3 . In contrast, phthalic anhydride prompted a slow reaction yielding mixtures of N-(arylsulfonyl)phthalimides 9 , arylsulfonamides 10 and N-alkylphthalimides 11 . The ratio of the products formed depends on the reaction time. In the presence of catalytic amounts of DMAP, only 10 and 11 were obtained. Depending on the structure of compounds 1 , treatment with succinic anhydride led to succinic diamides 17 , arylsulfonamides 10 and N-alkyl-succinimides 18 , or N-(arylsulfonyl)succinimides 19 .     

Comparative pharmacokinetics of nicardipine hydrochloride,a new vasodilator,in various species

1. The pharmacokinetics of a new potent vasodilator, 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nicardipine hydrochloride), were studied after oral and i.v. dosage to rats, dogs, monkeys and humans.

2. The plasma half-life and volume of distribution in humans after i.v. administration did not change with dosage in clinical range. In rats and dogs these parameters increased with higher doses, probably because of the potent vasodilative effect of the drug.

3. The plasma clearance in dogs and humans was not affected by dosage, but in rats tended to increase slightly with higher doses.

4. Systemic availability after oral administration was low in spite of excellent absorption, indicating a marked first-pass effect. Increased systemic availability with increased dose indicates that the metabolic activity of the liver may become partly saturated with the drug or its metabolites.

5. Disappearance of the drug from the plasma after i.v. administration was fastest in rats > dogs ≈ monkeys > humans. The terminal half-life of the drug after i.v. administration to humans was about 1?h.     

Synthesis of some biologically active substituted thiazole and thiazoline-amino acid derivatives

Synthesis of a series of N-(2-acetylaminothiazole-5-sulphonyl) amino acids (II–VI) and some of their corresponding methyl esters (VII–XI) is described. Coupling of N-tosyl- or N-phthalylamino acid with 2-amino-2-thiazoline using the DCC method furnishes 2-(N-tosyl- or N-phthalylamino acyl)amino-2-thiazolines (XII–XXI). Hydrazinolysis of 2-(N-Pht-L-Phe or N-Pht-L-Ala)amino-2-thiazoline in ethanol afforded 2-(L-Phe or L-Ala) amino-2-thiazoline (XXII and XXIII) respectively. Synthesis of the dipeptide 2-(N-Tos-L-Val-L-Leu) amino-2-thiazoline (XXIV) has been achieved employing the azide method. Sixteen thiazole- and thiazoline-amino acid derivatives were found to be active against a number of microorganisms.     

N-Arylacyl- und N-Arylalkyl-Derivate von 2-Amino-1-butanol mit zwei Chiralitätszentren

N-Arylacyl and N-Arylalkyl Derivatives of 2-Amino-1-butanol with Two Chiral Centers Syntheses of all optical isomers of 2-(N-(2-phenylbutyryl)amino]-1-butanols 1a–d and 2-[N-methyl-N-(2-phenylbutyryl)amino]-1-butanols 2a–d are reported. Reduction of the amides leads to the amines 3a–d and 4a– d . Each of these compounds has two chiral centers, for which the absolute configurations are established.     

Derivate des 2-Amino-1,2,3,4-tetrahydro-naphthalins, 5. Mitt. Synthese des trans-2-Amino-3,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalins und seiner N-substituierten Derivate

Derivatives of 2-Amino-1,2,3,4-tetrahydronaphthalene, V: Syntheses of trans-2-Amino-3,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene and N-Substituted Derivatives. The trans-aminoalcohol 14 was synthesized by ammonolysis of 5,8-dimethoxy-2,3-epoxytetraline (I) . The hydrochloride of 14 was further demethylated and trans-2-amino-3,5,8-trihydroxy-tetraline hydrobromide (14a ) was obtained. Similarly the hydrobromides of the 3,5,8-trihydroxy-analogues 1a–13a were obtained from the N-substituted trans-2-amino-3-hydroxy-5,8-dimethoxytetraline hydrochlorides 1–13 .     

A comparison of aralkylamines and aralkylguanidines as antagonists of adrenergic neurone blockade

Structure-activity relationships have been studied for aralkylamines and aralkylguanidines which restore the responses of the nictitating membranes to nerve stimulation in anaesthetised cats given sympathetic blocking drugs. This reversing action was largely specific for adrenergic neurone blockade; blockade of sympathetic ganglia or of α-adrenergic receptors was unaffected. (+)-Amphetamine was the most active amine and N-benzyl-N-methylguanidine was the most active guanidine. In mice, ptosis resulting from adrenergic neurone blockade was much more readily prevented or abolished by the aralkylamines and aralkylguanidines than was ptosis caused by other types of sympathetic blocking agent. The most potent antagonist of ptosis was N-(2-phenylcyclopropyl)guanidine which was about ten times as active as amphetamine. The relative antagonistic potencies of 2 amines and 8 guanidines were virtually identical for all types of adrenergic neurone blocking drug, regardless of whether or not they cause noradrenaline depletion. The prevention of guanethidine-induced ptosis was always accompanied by some reduction in the extent of heart-noradrenaline depletion, but the minimum dose of antagonist required to prevent ptosis completely was always lower than that required to eliminate depletion.     

Isosteric conversion of protein carboxyl groups into carboxamide groups. II. Application to lysozyme

For isosteric conversion of carboxyl groups of proteins into amide groups, ammonolysis of protein esters under mild conditions was attempted. Ammonolysis of methyl esters of lysozyme and bovine serum albumin proved to be incomplete. Highly reactive N-ethylsalicylamide esters of guanylated lysozyme were therefore prepared by subjecting the protein to reaction with N-ethylbenz-isoxazolium ion at pH 4.2, 0°. Per molecule, 5–7 ester groups were introduced, with concomitant decrease of activity of 80–90%. Only 0.3 tyrosine was modified. On hydrolysis at pH 9.2 the activity was completely restored. At pH 7.9 three classes of ester groups could be distinguished: one group of high rate of hydrolysis (k₁ = 1.5 min^-1), three groups of intermediate rate (k₂ = 0.13 min^-1) and two groups of low rate (k³ = 0.018 min^-1). The intermediate rate approximated the rate of hydrolysis of the model compound benzoylglycine N-ethyl-salicylamide ester (k = 0.15 min^-1). Ammonolysis at pH 9.2 in 2.0 M ammonia/ ammonium acetate provided complete conversion of the ester groups into amide groups without restoration of activity, confirming the essentiality of certain carboxyl groups. In particular, rearrangement of the ester groups into relatively stable imide groups by O–N acyl migration was found to be completely absent. When native lysozyme was esterified with N-ethylbenzisoxazolium ion the activity did not completely return on hydrolysis.     

Heterocyclische 12-π- und 14-π-Systeme, 21. Mitt. Zum Reaktionsverhalten von 2-Äthyl-3-formyl-5-methylbenzofuran

Heterocyclic 12-π and 14-πSystems, XXI: Reactions of 2-Ethyl-3-formyl-5-methylbenzofurane 2-Ethyl-5-methyl-benzo[b]furane (1) reacts with Vilsmeier reagent to yield 2-ethyl-3-formyl-5-methylbenzo[b]furane (2) which reacts with N-nucleophiles to give compounds 3a–3c . With C-nucleophiles derivatives 4a–4g are obtained.     

Structure and Properties of Cyclic Polymethylene Ureas,III. Synthesis and Biological Activity of Some Mannich Bases of Tetrahydro-2-(1H)-Pyrimidinone

Some N-mono- 2a–e and N,N-bis(aminomethyl) derivatives 3a–b of tetrahydro-2-(1H)-pyrimidinone 1a and tetrahydro-2(1H)-pyrimidinethione 1e are obtained by the Mannich reaction of 1a or 1e with formaldehyde and secondary amines. The compounds show a marked antiviral activity.     

The Recognition of a Diarylimine as a Metabonate Produced During Incubation of N-Benzyl-4-chloroaniline with Hepatic Microsomal Preparations

Abstract— Evidence is presented for the formation of N-benzylidene-4-chloroaniline as a metabonate during the metabolism of N-benzyl-4-chloroaniline. Control studies suggest that the diarylimine is formed as a chemical artifact from the debenzylation products (benzaldehyde and 4-chloroaniline). This novel observation indicates a possible pathway to amide formation from N-benzylanilines via diarylimines as intermediates.