Nitramine, 12. Mitt. Fluormethyl- und Azidomethyl-alkylnitramine

Nitramines, XII: N-Fluoromethyl- and N-Azidomethyl-N-alkylnitramines The N-chloromethyl-N-alkylnitramines 1 react with potassium fluoride and 18-crown-6 to give the unstable N-fluoromethyl-N-alkylnitramines 2 . With sodium azide the stable N-azidomethyl-N-alkylnitramines 3 are formed. With alkynes the latter cyclize to yield 1,2,3-triazoles, the structures of which were studied.     

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.     

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.     

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) .     

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.     

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).     

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 .     

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 .     

N-Hydroxy-N-arylacetamides. III: Mechanism of haemoglobin oxidation by N-hydroxy-4-chloroacetanilide in erythrocytes in vitro

1. N-Hydroxy-4-chloroacetanilide(N-hydroxy-4ClAA) was the most active, and N-hydroxy-2-acetylaminofluorene(N-hydroxy-2AAF) the least active compound among six N-hydroxy-N-arylacetamides, in forming ferrihaemoglobin(HbFe³⁺) in bovine erythrocytes in the presence of 11 mM glucose.

2. N-Hydroxy-4ClAA oxidized 25 equiv. of HbFe²⁺, both in the presence and absence of glucose or lactate. Therefore, its catalytic properties did not depend on metabolic regeneration by the NADPH- or NADH-dependent erythrocyte reductases.

3. In contrast, N-hydroxy-4-chloroaniline(N-hydroxy-4ClA) oxidized 760 equiv. of HbFe²⁺ in the presence of glucose, but only 81 equiv. of HbFe²⁺ in the presence of lactate. These results indicate that the catalytic activity depended on the metabolic regeneration from 4-chloronitrosobenzene(4-CINOB) by NADPH-dependent erythrocyte reductases.

4. A relationship was established between HbFe³⁺ concn. and the concn. of N-hydroxy-4ClA and 4-CINOB(determined together), 4-chloroacetanilide(4-ClAA) and 4-chloroaniline(4-CIA), indicating co-oxidation of N-hydroxy-4ClAA and oxyhaemoglobin in erythrocytes and partial reduction of the newly formed 4-CINOB to 4-CIA.

5. In rat blood in vitro incubated with N-hydroxy-4CIAA, 4-CINOB concn. increased with increasing HbFe³⁺ concn., indicating that 4-CINOB was formed by co-oxidation of oxyhaemoglobin and N-hydroxy-4CIAA, and not by enzymic N-deacetylation.     

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.     

Metabolism of promethazine in vitro. Identification of N-oxidized products

1. Incubation of promethazine (Ia) and desmethylpromethazine (Ib) with 9000g supernatant fractions of rabbit liver homogenate resulted in formation of N-dealkylated, N-oxygenated and ring-hydroxylated products.

2. The N-oxidation products identified by t.l.c. and mass spectra using synthetic reference products are promethazine-N-oxide (IX) and the nitrone (VIII), which is believed to be formed chemically and metabolically from the metabolite N-hydroxydesmethylpromethazine (VII).     

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.     

H n.m.r. spectrum from the flexible N-terminal segment of Streptomyces subtilisin inhibitor

The ¹H n.m.r. spectrum of Streptomyces subtilisin inhibitor shows a limited number of unusually sharp signals at room temperature. Some of these signals are assigned uniquely to protons of the side chains of the N-terminal segment, Aspl-Ala2-Pro3-Ser4-Ala5-Leu6-Tyr7-based on experiments of spin decoupling, pH titration, and enzymatic cleavage of the protein. Quantitative examination of these signals indicates that the N-terminal end of this protein is heterogeneous in that the protein contains a considerable fraction whose sequence starts with Ala2 rather than with Asp1. The pK_a values for the amino groups of Asp1 and Ala2 exposed at the N-terminus are determined to be 8.9 ± 0.4 and 9.0 ± 0.1, respectively. Furthermore, examination of the line-widths of the methyl proton resonances of Ala2 and Ala5 residues indicates that the N-terminal peptide segment is free and undergoes rapid segmental motions in the order of 10^?9s.     

Prodrugs of Peptides. 11. Chemical and Enzymatic Hydrolysis Kinetics of N-Acyloxymethyl Derivatives of a Peptide-like Bond

Various carboxylic acid esters of the N-hydroxymethyl derivative of N-benzyloxycarbonylglycine benzylamide, used as a peptide-like model, were prepared and their decomposition kinetics studied in aqueous solution and in human plasma solutions. These N-acyloxymethylamide derivatives were found to undergo a facile decomposition by a pH-independent process in the pH range 4–8.5, the half-lives being 1–11hr at 37°C. The cause of this limited stability was suggested to be due to the occurrence of an elimination-addition mechanism involving a reactive N-acyliminium ion intermediate. In alkaline solutions (pH > 10) the derivatives showed a normal ester stability. The ester group in the N-acyloxymethyl derivatives was readily hydrolyzed by plasma enzymes to yield the N-hydroxymethyl amide, which subsequently decomposed to the parent amide. The results obtained suggest that N-acyloxymethylation of a peptide bond may be a useful prodrug approach to obtain derivatives with varying lipophilicities and a ready ability to undergo conversion to the parent peptide in vivo. However, the stability of the derivatives in aqueous solutions is limited.     

Detoxication of N-Oxygenated Arylamines in Erythrocytes. an Overview

1. Reactive N-oxygenated arylamines, namely, N-hydroxyarylamines and nitroso-arenes, are toxic, mutagenic, carcinogenic and allergenic.

2. Erythrocytes are a very sensitive target for these compounds, but little is known of the detoxication capacity of these cells.

3. This overview considers the most important reactions of p-substituted N-oxygenated arylamines in red cells, namely, (i) ferrihaemoglobin formation by N-hydroxyarylamines with concomitant co-oxidation to nitrosoarenes; (ii) compartmentation of nitrosobenzenes by ligation to deoxyhaemoglobin, (iii) reactions of nitrosobenzene with glutathione, (iv) adduct formation of nitrosobenzenes with thiol groups of haemoglobin.

4. To predict the metabolic fate of N-oxygenated arylamines in red cells, the respective kinetic parameters of reactions (i) to (iv) have been determined, and indicate good linear free energy correlations (pH7.4, 37°C). These data may help to estimate the detoxication capacity of erythrocytes in vivo.     

Untersuchungen an 1,3-Thiazinen, 31. Mitt. 3-Carbazoylthio-propionsäuren aus Hydrazinderivaten,Carbonylsulfid und β-Propiolactonen

1,3-Thiazines XXXI¹⁾: 3-(Hydrazinocarbonylthio)propionic Acids from Hydrazine Derivatives, Carbon Oxide Sulfide and β-Propiolactones Hydrazine, N-mono- and N,N-disubstituted hydrazines, N-aminoheterocycles and N-4-phenylthio-semicarbazide were reacted with carbon oxide sulfide and triethylamine to yield the unstable hydrazinecarbothioates 3 , which were 2-ethoxycarbonylated with β-propiolactones to give the novel pharmacologically active (hydrazinocarbonylthio)propionic acids 4 .     

Imidazolsynthesen, 10. Mitt. Zur selektiven Synthese N-substituierter Imidazol-4-äthanole

Selective Synthesis of N-Substituted Imidazole-4-ethanols The synthesis of N-substituted methoxyethylimidazoles 5 , 6 from aldehydes 1 , 1-hydroxy-4-methoxy-2-butanone ( 2 ), primary amines 3 , and ammonia ( 4 ), using the Weidenhagen cyclisation, yields mixtures in which, according to gc analysis, the 1,4-isomers 5 prevail. Ether cleavage with HI gives the N-substituted imidazole-4-ethanols 8 .     

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.     

Synthese von 9-Fluorenalkanaminen, 3. Mitt. Stickstoffalkylierte und -acylierte 2-(9H-Fluoren-9-yl)-2-propanamine

Synthesis of (9-Fluorenylalkan)amines, III: N-Alkylated or N-Acylated 2-(9H-Fluoren-9-yl)-2-propanamines The synthesis of N-alkylated or N-acylated derivatives of the fluorene 3a is described. Compound 3b can be prepared via 1b and 2b , but 3c – 3f have to be synthesised by direct alkylation or acylation of 3a . The reaction of 8 with basic agents yields the stable derivative 9 .     

Cyclic analogues of bradykinin.

N ^α-L-Arg-cyclo[(Nε-L-Lys¹, Gly⁶)-bradykinin] (ACLGB) and cyclo-ε-kallidin (CK) have been prepared by solution procedure. ACLGB synthesis involves the coupling of Z-Arg(Z₂)-OPfp with a partly deblocked cyclopeptide. During the preparation of CK, a linear precursor with a glycine residue at the C-terminal end was used to suppress the side reactions. Cyclization was attained by reacting DCC and N-hydroxysuccinimide in DMF solution, the resulting mixture was submitted to preparative chromatography. The synthesis was terminated by deblocking the protected cyclopeptides by hydrogenation. ACLGB and CK exhibit a prolonged hypotensive activity.