Chirale 3-Aminopropanole, 2. Mitt. N-Alkylierungsprodukte

Chiral 3-Aminopropanols, II: N-Alkylated Products From the racem. and optically active 3-aminopropanols 1a-1d the N-monomethyl compounds 3 are obtained via the urethanes 2 . Methylation of 1a-1d according to Eschweiler-Clarke or reaction with formaldehyde/NaBH₃CN yield the N-dimethyl compounds 4 . With acetone/NaBH₄ 1a-1d react to give the N-isopropyl compounds 6 .     

Reaktionen von N-Alkoxycycliminiumsalzen, 9. Mitt. Nucleophile Substitutionsreaktionen an halogensubstituierten N-Methoxypyridiniumsalzen

Reactions of N-Alkoxycycliminium Salts, IX: Nucleophilic Substitutions of Halogeno-N-methoxypyridinium Salts The chloro-N-methoxypyridinium compounds 2a and 2c react with nucleophiles by substitution of the halogen atom. With pyridine derivatives, 2a yields the N-(2-pyridyl)pyridinium compounds 7 . With aromatic amines, the 1:1 products 16 or the 1:2 products 13 are formed, depending on the basicity of the amine. The 2-pyridoniminium or 6-amino-2-pyridoniminium structure of 16 or 13 follows from electronic and NMR spectra. In contrast, 2b undergoes base induced ring cleavage yielding the derivatives 21 and 22 of glutaconic dialdehyde with all-trans configuration.     

β-Substituierte Enamine, 12. Mitt. N-Aryl-2-nitro- und N-Aryl-2-chlor-2-nitro-enamine

β-Substituted Enamines, XII. N-Aryl-2-nitro- and N-Aryl-2-chloro-2-nitroenamines 1-Chloro-1-nitroacetone ( 4 ), obtained from sulfuryl chloride and nitroacetone ( 2 ), is a stable compound. In the presence of alkali it forms 1-chloro-1-isonitrosoacetone ( 9 ). With diazomethane it reacts to give 1 -chloro-1-methoxyiminoacetone ( 8 ). By aniline 4 is cleaved with the formation of acetanilide and chloronitromethane. In the presence of titanium tetrachloride, however, condensation to 1-chloro-1-nitro-2-phenylaminopropene ( 3a ) is achieved. The condensation of nitroacetone ( 2 ) with primary aromatic amines via β-nitroenamines 1 and subsequent chlorination with N-chlorosuccinimide also leads to N-aryl-2-chloro-2-nitroenamines 3 .     

Derivatives of 2-Amino-1,2,3,4-Tetrahydronaphthalene,X. Syntheses of N-Alkyl- and -Dialkylaminoalkanoyl Derivatives of trans-2-Amino-3-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydro-naphthalene

By reacting trans-2-amino-3-hydroxy-5,8-dimethoxytetraline (1) with chloroacetyl chloride, the amide 2 was obtained. With primary and secondary amines 2 gives the N-alkyl- and N-dialkylaminoacetyl derivatives 3a-i. Compound 3c possesses antiarrhythmic activity.     

Dietary Administration of Asimina triloba. (Paw Paw) Extract Increases Tumor Latency in N.-Methyl-N.-nitrosourea–Treated Rats

Abstract

The paw paw tree, Asimina triloba. (L.) Dunal (Annonaceae), contains more than 50 bioactive components, primarily annonaceous acetogenins. Some therapeutic activities have been associated with this material, but the potential to mediate a cancer chemopreventive effect has not been reported. In this study, a standardized extract from the twigs, in which bullatacin, asimicin, and trilobacin represent the most potent and major bioactive acetogenins, was tested in the N.-methyl-N.-nitrosourea–induced mammary carcinogenesis model. With Sprague-Dawley rats given a diet containing paw paw extract (1250 and 2500 mg/kg diet; based on maximum tolerated dose studies), mammary tumor latency was increased from 55 to 66 days. However, mammary tumor incidence and multiplicity were not affected by extract consumption.     

Isosteric conversion of protein carboxyl groups into carboxamide groups. I. Examination of alkyl and aryl esters as model compounds

With a view to substituting protein carboxyl groups by carboxamide groups the properties of a number of model compounds have been examined. The methyl ester of acetylglycine can be 97% converted into amide in 7 M ammonium acetate/ 7 M ammonia in 10 min. Amidation of the N-ethylsalicylamide ester of benzoyl-glycine, prepared by reaction with N-ethylbenzisoxazolium fluoroborate (EBI), is 100% complete in 2 M ammonium acetate/ammonia, pH 9.2, within 1 min; no rearrangement into imide occurred at all. Under the conditions of protein modification (0.1 M EBI, pH 4.2, 0°) acetyltyrosinamide is 13% converted into a compound, presumably containing the N-ethylsalicylimidate group, exhibiting an absorption maximum at 309 nm (e = 3300). This compound decomposes in ammonium acetate/ammonia, pH 9.1, within 1 min. Nα-acetylhistidinamide is not converted at all. Reaction with aminogroups can either be avoided by protection of these groups or be analyzed by spectroscopy of the amidine produced. Spectral data required for analysis have been measured for N-ethylsalicylamide (Λ^max295 nm, e = 3200 at pH 6, Λ_max324 nm, e = 5100 at pH 10, pK 8.15), for O-acetyl-N-ethylsalicylamide (e = 1200 at 250 nm, e = 180 at 280 nm) and for O-diethylsalicylamidine (Δ_max277nm, e = 2330 at pH 6, Λ_max302 nm, e = 3230 at pH 10, pK 7.90).     

Derivatization to stabilize some aliphatic primary hydroxylamines for g.l.c. analysis

By appropriate choice of trimethylsilylating and trifluoroacetylating reagents and organic solvents for extraction, stable derivatives of aliphatic primary hydroxylamines metabolites, N-hydroxyphentermine, N-hydroxychlorphentermine, N-hydroxymexiletene, N-hydroxy-phenethylamine, N-hydroxyamphetamine, and N-hydroxy-3,4-dimethoxyamphetamine, were obtained and examined by g.l.c. analysis without decomposition and without interference from the parent drug or other metabolic products.     

N-Oxide Formation and Related Reactions in Drug Metabolism

Abstract

1. Tertiary amine drugs are converted into dealkylated and N-oxide metabolites by liver microsomal enzymes. The two reactions are catalyzed by NADPH-dependent microsomal electron transfer chains; the first involving NADPH-cytochrome c reductase and cytochrome P-450, the latter a different flavo-protein and no cytochrome P-450. The individual rates are highly dependent on the animal species and experimental conditions.

2. N-oxides can be further metabolized by dealkylation and/or by reduction. However, N-oxides are not obligatory intermediates in the dealkylation of tertiary amines. Rather, two alternative pathways are open to these compounds: C-oxygenation and N-oxygenation.

3. With imipramine and imipramine-N-oxide as substrates it could be shown that tertiary amine dealkylation and N-oxidation are catalyzed by microsomal enzymes only, whereas N-oxide dealkylation and reduction occur only in extra-microsomal compartments. With isotope trapping experiments the simultaneous occurrence of all four reactions could be demonstrated in NADPH-fortified liver homogenate, and the individual reaction rates could be determined. Experiments with liver slices, perfused livers and whole animals suggest a similar kinetic situation whereby N-oxide formation may well be a major pathway.     

Untersuchungen an 1,3-Thiazinen, 25. Mitt. Transacylierende N-Acyl-tetrahydro- und N-Acyl-dihydro-1,3-thiazin-derivate

1,3-Thiazines, XXV: Transacylating Derivatives of N-Acyltetrahydro- and N-Acyldihydro-1,3-thiazine Novel N-acyl-2-thioxo-3,4-dihydro-1,3-thiazine-4-ones 4 and N-acyl-tetrahydro-1,3-thiazine-2,4-diones 7 were preparee by acylation of the N-unsubstituted 1,3-thiazine derivatives 3 and 6 with acid chlorides. Their characteristics are compared with those of known N-acylthiazine derivatives.     

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.     

Nitramine, 19. Mitt. Zur Stabilität von Dialkylnitraminen

Nitroamines, XIX: The Stability of Dialkylnitroamines Dialkylnitroamines are sensitive to bases and give aldehydes, primary amines and nitrite ions. After treating the N-benzyl-N-methylnitroamines 1–3 with lithium diisopropylamide we succeeded in isolating the aldimines 4–6 . From N-benzyl-N-(cyanomethyl)nitroamine (7) (cyanomethylimino)benzaldehyde (9) was obtained, and N-benzyl-N-(ethoxycarbonylmethyl)nitroamine (8) reacted with sodium hydride to yield [(ethoxycarbonylmethyl)imino]benzaldehyde (10) .     

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.     

The in vitro N-oxygenation of N-tert.alkyl-substituted benzamidine

Studies of the N-Oxygenation of N-(tert.Alkyl)benzamidines in vitro N-tert.Butyl- and N-tert.octylbenzamidine ( 1a and b ) and their potential N-oxygenated metabolites, the amidoximes 2a and b , have been synthesized and characterized. N-tert.Butylbenzamidine 1a is N-oxygenated to the amidoxime 2a by aerobic incubation with non-induced microsomal fractions of rabbit liver homogenates and NADPH. This transformation supports the hypothesis that benzamidines undergo N-oxygenation by the cytochrome P-450 enzyme system when N-dealkylation is not possible (absence of hydrogen atoms in α-position to the amidine nitrogen atoms).     

Ringschlußreaktionen mit N-(Chlormethyl)carbimidoylchloriden, 2. Mitt. Umsetzungsprodukte mit N,N′-Dimethylthioharnstoff

Heterocyclisation Reactions with N-(Chloromethyl)carboximidoyl Chlorides, II: Reaction with N, N′-Dimethylthiourea N-(Chloromethyl)benzimidoyl chloride ( 1 ) and N, N′-dimethylthiourea ( 2 ) react to form the three isomeric triazine and thiadiazine derivatives 6 , 7 and 8 , which were separated by layer chromatography. Their structures were determined by ¹³C-NMR spectroscopy. The thiadiazine derivative 11 was isolated as a by-product. A mechanism is proposed for its formation.     

Antimykotische Wirkstoffe, 10. Mitt. N′-Substituierte N-(1-Adamantyl)harnstoffe

Antimycotic Agents, X: N′-Substituted N-(1-Adamantyl)ureas By nucleophilic addition of 1-aminoadamantane (1) to isocyanates 2 the N′-substituted N-(1-adamantyl)ureas 3 are obtainable. Amenable to this reaction are aliphatic and alicyclic as well as aromatic isocyanates.     

N-Hydroxy-N-arylacetamides. II: Molecular aspects of ferrihaemoglobin formation by N-hydroxy-N-arylacetamides and arylhydroxylamines in the rat

1. Ferrihaemoglobin(HbFe³⁺) formation in rats after i.p. injection of 6 N-hydroxy-N-arylacetamides has shown that N-hydroxy-4-chloroacetanilide(N-hydroxy-4CIAA) was the most active and N-hydroxy-2-acetylaminofluorene(N-hydroxy-2AAF) the least active compound tested. As N-hydroxy-N-arylacetamides were thought to produce HbFe³⁺ only after enzymic N-deacetylation, the corresponding arylhydroxylamines were also tested for HbFe³⁺-forming activity and were found to be more active, N-hydroxy-4-chloroaniline(N-hydroxy-4CIA) being one of the most active and N-hydroxy-2-aminofluorene(N-hydroxy-2AF) the least active compound tested.

2. N-Hydroxy-4-chloroacetanilide given i.p. to rats more rapidly invaded the blood and produced larger amounts of ferrihaemoglobin than did N-hydroxy-2-acetylaminofluorene, due to differences in their availability in plasma.

3. Injection of 50mg/kg of N-hydroxy-4-chloroacetanilide gave similar concn of HbFe³⁺ and 4-chloronitrosobenzene(4-CINOB) as injections of 8?mg/kg of N-hydroxy-4-chloroaniline, indicating that the arylhydroxylamine, after N-deacetylation, was the active molecule in vivo.

4. The concn of 4-chloronitrosobenzene declined faster than HbFe³⁺ concn. 4-Chloronitrosobenzene therefore is a further example of a ‘hit-and-run’ chemical.

5. Inhibition by the microsomal carboxylesterase inhibitor, bis(4-nitrophenyl)phosphate(BNPP), indicated that ferrihaemoglobin formation by 4-chloroacetanilide, but not by N-hydroxy-4-chloroacetanilide, depends on the enzymic activity of hepatic microsomal carboxylesterases.     

Diffusion of homologous N-alkyl-N-[2-(2,2-diphenyl-2-hydroxyacetyloxy)ethyl]-N,N-dimethyl-ammonium bromides through lipid membranes (author's transl)

Diffusion of Homologous N-Alkyl-N-[2-(2,2.diphenyl-2-hydroxyacetyloxy)ethyl]-N,N-dimethyl. ammonium Bromides through Lipid Membranes The diffusion of homologous N-Alkyl-N-[2-(2,2-diphenyl-2-hydroxyacetyloxy)ethyl]-N,N-dimethylammonium bromides through porous filters of cellulose nitrate soaked with n-octanol is studied. With hydrophilic compounds the diffusion through the lipid membranes is rate determining and thus a function of the membrane/water partition coefficient. The diffusion of lipophilic compounds however is independent of the partition coefficient, the rate-determining step is the diffusion through the stationary water layers. These results are consistent with the diffusion kinetics of the same compounds in the three-phase model water/n-octanol/water.     

Barbitursäurederivate, 25. Mitt. Chirale N-Alkyl-norhexobarbitale

Chiral N-Alkylnorhexobarbitals Syntheses of the racemates and the enantiomers of the N-alkylnorhexobarbitals 2a --c are reported. The stereospecific condensations of disubstituted cyanoacetates with highly alkylated ureas proceed in the same direction as with N-methylurea.     

Heterocyclische Spirocyclohexadienone, 3. Mitt.

Heterocyclic Spirocyclohexadienones, III With N-methyl-naphthylamine 3-substituted 2-naphthol derivatives give the corresponding spirocyclohexadienones in good yields; 9-phenanthrol also proceeds analogously. 4-Substituted 1-naphthols react similarly but the spiroketones thus obtained are more labile and are formed in minor yields. From the behaviour of spirocyclohexadienones with protonic acids, carbonyl reagents and complex hydrides a reaction mechanism is deduced.     

Untersuchungen an 1,3-Thiazinen, 26. Mitt. Neuartige N-Carbamoyl- und Thiocarbamoyl-2-thioxo-1,3-thiazinderivate

1,3-Thiazines, XXVI: Novel N-Carbamoyl- and Thiocarbamoyl-2-thioxo-1,3-thiazine Derivatives The N-unsubstituted 1,3-thiazine derivatives 1–3 were transformed into the N-carbamoyl- or N-thiocarbamoyl-1,3-thiazine derivatives 5–9 by carbamic acid chlorides or thiocarbamic acid chlorides in the presence of triethylamine or sodium hydride.