4-Benzyloxy-2,3,5-morpholintrione und 3-Benzyloxy-2,4-oxazolidindione aus N-Benzyloxyglykolamiden und Oxalylchlorid

4-(Benzyloxy)morpholine-2,3,5-triones and 3-(Benzyloxy)oxazolidine-2,4-diones from N-(Benzyloxy)glycolamides and Oxalyl Chloride The reaction of N-(benzyloxy)-2-hydroxycarboxamides 1 with oxalyl chloride produces, depending on the substituents at C-2, either 4-(benzyloxy)morpholine-2,3,5-triones 5 and 3-(benzyloxy)oxazolidine-2,4-diones 3 or exclusively heterocycles of type 5 . Hydrogenolysis of 5 gives N-hydroxyimides 8 .     

Synthese und Eigenschaften 4-unsubstituierter und 4-monosubstituierter Perhydro-1,5,2-dioxazin-3,6-dione

Synthesis and Properties of 4-Unsubstituted and 4-Monosubstituted Perhydro-1,5,2-dioxazine-3,6-diones The reaction of N-alkyl(aralkyl)glycolohydroxamic acids 2 with 1,1′-carbonyldiimidazole produces either perhydro-1,5,2-dioxazine-3,6-diones 3 , linear acylation products of type 1 or phenylglyoxylamides 4 . The formation of 3, 1 and 4 depends on the nature of the substituents at C-2 and the reaction conditions. In the presence of hydrazines 6 the heterocycles 3 are transformed into 3-aminooxazolidine-2,4-diones 8 .     

Mehrcyclische Azine mit Heteroatomen in 1- und 3-Stellung. 41. Mitt. Synthese heterocyclischer Immunmodulatoren. 3. Mitt.: Darstellung von N-1-substituierten 3-(2-Mercaptoethyl)chinazolin-2,4(1H,3H)-dionen über Bis[2-(2-amino-benzoylamino)ethyl]disulfane und Prüfung auf immunstimulatorische Wirksamkeit

Synthesis of N-1-Substituted 3-(2-Mercaptoethyl)quinazoline-2,4(1H,3H)-diones via Bis[2-(2-amino-benzoylamino)ethyl]sulfanes and Test for Immuno-Stimulating Activity A 3-step synthesis, starting from substituted isatoic anhydride was used to prepare substituted 3-(2-mercaptoethyl)quinazoline-2,4(1H,3H)-diones 4 . Reaction of 1 with cystamine afforded bis[2-(2-amino-benzoylamino)ethyl]disulfanes 2 . Reaction of 2 with ethyl chloroformate and subsequent reduction of the heterocyclic disulfanes 3 gave mercaptoethylquinazoline-2,4-diones 4a – f . N-1 methyl and benzyl substituted derivatives 4b and 4c , respectively, show immuno-show immuno-stimulating activity in various tests.     

Zur Reaktion von Quadratsäuredimethylester mit N,N-disubstituierten Hydrazin-Derivaten

The Reaction of Squaric Acid Dimethyl Ester with N,N-Disubstituted Hydrazines Reaction of 3,4-dimethoxy-3-cyclobutene-1,2-dione (2) with N,N-disubstituted hydrazines yields 3,4-bishydrazino-3-cyclobutene-1,2-diones 3 , which are converted into 3-amino-4-hydrazino-3-cyclobutene-1,2-diones 6 with N-N splitting by refluxing in ethanol.     

Synthese und Eigenschaften von 3-Alkoxy-3,4-dihydro-2H-1,3-benzothiazin-2,4-dionen

Synthesis and Properties of 3-Alkoxy-3,4-dihydro-2H-1,3-benzothiazine-2,4-diones The reaction of 2-mercaptobenzoic acid, 1,1′-carbonyldiimidazole and O-alkylhydroxylamine affords 3-alkoxy-3,4-dihydro-2H-1,3-benzothiazine-2,4-diones 3 . Acid catalyzed methanolysis of the tetrahydropyranyloxy group in 3d gives the cyclic N-hydroxy imide 3e , which can be easily acylated with benzoyl chloride or 4-tolylisocyanate giving rise to the benzothiazine derivatives 3f and 3g .     

Untersuchungen in der Reihe der N1-Hydroxyamidine: Synthesen und Umsetzungen mit Isocyanaten und 1,1′-Carbonyl-diimidazol

N¹-Hydroxyamidines: Syntheses and Reactions with Isocyanates and 1,1′-Carbonyldiimidazole Reactions of N²-unsubstituted N¹-hydroxyamidines 3, 4 with isocyanates lead to open-chain products. Ring closure to 7 does not occur. Treatment with 1,1′-carbonyldiimidazole yields the cyclic products 8, 9 . Formamidine derivatives with N²-substitution give the 1-amidinoimidazoles 17 , which can be regarded as addition products of carbodiimides 16 and imidazole.     

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.     

Manuifolin Q,an unusual 4-aryl-substituted isoflavan from Maackia tenuifolia

Manuifolin Q (1), an unusual 4-aryl-substituted isoflavan, was isolated from the roots of Maackia tenuifolia. Its absolute configuration was determined as (3R,4R)-3,4-trans-7,2′-dihydroxy-4′-methoxy-4-[(2,4-dihydroxy-5-(1,1-dimethyl-2-propenyl)]-phenyl-isoflavan, on the basis of spectroscopic analysis.     

Untersuchungen an 1,3-Thiazinen, 14. Mitt. Neue und bekannte Möglichkeiten zur Darstellung von N-monosubstituierten 3-Carbamoylmercaptopropionsäuren und deren Cyclisierung zu Tetrahydro-1,3-thiazin-2,4-dionen – ein Vergleich

1,3-Thiazines, XIV: Comparison of New and Known Methods for the Preparation of N-Monosubstituted 3-(Carbamoylmercapto)propionic Acids and their Cyclisation to Tetrahydro-1,3-thiazine-2,4-diones Three newly developed synthetic methods for N-monosubstituted 3-carbamoylmercapto propionic acids 2 have been compared with known methods concerning scope and yield. Method C - addition of 3-mercapto propionic acid methyl ester to isocyanates followed by acid hydrolysis to 2 proved best. With phosphorus pentoxide/p-toluene sulfonic acid/toluene higher yields of the tetrahydro-1,3-thiazine-2,4-diones 12 could be achieved from the acids 2 than by known methods.     

Untersuchungen an 1,3-Thiazinen, 32. Mitt.1) Oxidationen an Thiourethanen, 6. Mitt.2). 3-Amino-5,6-dihydro-2H-1,3-thiazin-2,4(3H)-dione,neuartige cyclische Thiolcarbazate

1,3-Thiazines, XXXII¹⁾; Oxidations of Thiourethanes, VI²⁾: 3-Amino-5,6-dihydro-2H-1,3-thiazine-2,4(3H)-diones, Novel Cyclic Thiolcarbazates 3-Amino-5,6-dihydro-2H-1,3-thiazine-2,4(3H)-diones 2 were synthesized by oxidative desulfurisation of the 2-thioxo analogues 1 or by cyclisation of the 3-(carbazoylthio)-propionic acids 4 . Some of the compounds are biologically active.     

Hypoglycaemic activity of 1,1'-biadamantylaryl sulphonylureas

Replacement of the 1-adamantyl group with a 1,1′-biadamantyl group in the N-adamant-1-yl-N'-arylsulphonylureas leads to compounds having the same or a doubled hypoglycaemic activity. The new biadamantyl derivatives exert a delayed onset of action compared with that of the corresponding adamantane derivatives. The most promising, 3,3′-di(N'-p-toluenesulphonylureido)-1,1′-biadamantyl (Compd No. 1) and 3,3′-di(N'-p-methoxybenzenesulphonylureido)-1,1′-biadamantyl (Compd No. 3) are only slightly toxic and appear not to have other pharmacological activity.     

Studies on the genotoxicity of dipyridyl and biphenyl derivatives using Salmonella typhimurium

Paraquat (1,1′-dimethyl-4,4′-bipyridinum dichloride) is a widely used herbicide, and the high incidence of preneoplastic lesion on the skins of the workers in a Paraquat manufactory indicates the potential genotoxicity of this compound and its derivatives. Paraquat is made from 4,4′-dipyridyl by methylation. During the course of synthesis of 4,4′-dipyridyl, several by-products such as 2,2′-, 2,3′-, 3,3′-, and 2,4′-dipyridyls are formed. Some investigators have claimed that the genotoxicity of Paraquat preparation might be due to the presence of these by-products, but detailed experimental evidence is lacking. In this article, a systematic study on the mutagenicity of these compounds, we show these compounds to be moderately mutagenic in the presence of S9 mix. Both Paraquat and 4,4′-dipyridyl are less active in these mutagenicity assays. Biphenyl derivatives are similar to dipyridyls in chemical configuration. Furthermore, two generally known carcinogens, 2-acetylaminofluorene and benzidine, are biphenyl derivatives. Several related compounds including N-acetoxy-2-acetylamino-fluorene, 2 nitrofluorene, and the newly synthesized compounds N-nitroso-N,N′-diacetyl-benzidine, N-nitrosophenacetin, and N-nitroso-2-acetylaminofluorene were tested for their mutagenicities in the Salmonella system. The results indicate that N-nitroso-biphenyl derivatives are direct mutagens. This finding strongly suggests that nitrosation might play an important role in the activation of certain amines and amides in the living organisms.     

1,5-Benzodiazepine, 1. Mitt.: Racemate und Enantiomere von 3,3-Dialkyl-1,5-benzodiazepin-2,4-dionen: Synthese,Konfiguration und enantiomere Reinheit

1,5-Benzodiazepines, I: Racemates und Enantiomers of 3,3-Dialkyl-1,5-benzodiazepine-2,4-diones: Synthesis, Configuration, and Enantiomeric Purity The syntheses of the rac. and the enantiomeric 3,3-dialkyl-1,5-benzodiazepine-2,4-diones 1 - 3 were performed as shown in Scheme 5, starting from 4- resp. 5-chloro-2-nitro-N-methylaniline ( 10/11 ) and the rac. or enantiomeric dialkylcyanoacetic acid chlorides 6a/6b . The enantiomers of ethylmethylcyanoacetic acid ( 5a ) are known. From butylmethylcyanoacetic acid ( 5b ) the (S)-(-)-enantiomer was obtained using codeine as resolving agent. By ring closure of 14/15 the benzodiazepines 16/17 were obtained, but the main products were the benzimidazoles 18/19 . The yield of 16/17 could be increased to 62–80 % when the conditions of the reaction were modified. The N-phenylation of 16/17 according to a modified Ullmann reaction gave the rac. and the enantiomeric 1,5-benzodiazepines 1 - 3 in high yields. - The absol. configurations of the new enantiomeric compounds are compiled in Tab. 1. The enantiomeric purities (e/e) of the 1,5-benzodiazepines 1 und 3 and of all intermediates are > 95 %. The enantiomeric purities of (R)-(-)-2 and the corresponding intermediates were not determined.     

1,2,3,4-Tetrahydrophthalazine, 3. Mitt. 2,4-Dialkyl-2,3,4,5,7,12-hexahydro-1H-(1,2,5)triazepin[1,2-b]phthalazin-1,5-dione

1,2,3,4-Tetrahydrophthalazines, III: 2,4-Dialkyl-2,3,4,5,7,12-hexahydro-1H-[1,2,5]triazepino[1,2-b]phthalazine-1,5-diones A series of 3-substituted 2,4-dialkyl-2,3,4,5,7,12-hexahydro-1H-[1,2,5]triazepino[1,2-b]phthalazine-1,5-diones was obtained by condensation of 2,3-bis-(2-bromoacyl)-1,2,3,4-tetrahydrophthalazines with primary amines.     

Characterization of the Diastereoisomers of Nicotine-1′-N-Oxide,a Metabolite of Nicotine,and Other Possible Oxidation Products by Nuclear Magnetic Resonance Spectroscopy

Abstract

1. R,S-cis and S,S-trans(methyl/pyridyl) diastereoisomeric mixtures of nicotine-1′-N-oxide and nicotine-1,1′-di-N-oxide, nicotine-1-N-oxide and S-(-)-cotinine were synthesized from S-(-)-nicotine and characterized by descending paper chromatography and n.m.r. spectroscopy.

2. Both nicotine-1,1′-di-N-oxide and nicotine-1-N-oxide predominated as the S,S-trans diastereoisomers; the percentage of R,S-cis nicotine-1,1′-di-N-oxide formed depended on the route of synthesis employed. The possible mechanism of N-oxide formation is discussed.     

Untersuchungen an 1,3-Thiazinen, 33. Mitt.1) Oxidationen an Thiourethanen, 7. Mitt.2). Oxidative Desulfurierung von Dithiourethanen durch salpetrige Säure und Salpetersäure

1,3-Thiazines, XXXIII¹⁾; Oxidations of Carbamothioates, VII²⁾: Oxidative Desulfurisation of Carbamodithioates by Nitrous and Nitric Acid Carbamodithioates, mainly 2-thioxo-tetrahydro-4H-1,3-thiazin-4-ones 1 , were converted to carbamothioates, mainly 5,6-dihydro-2H-1,3-thiazin-2,4(3H)-diones 2 , by nitrous and nitric acid. With cone. nitric acid additional nitration of phenyl substituents was achieved.     

Einführung schwefelhaltiger Substituenten in 6-Amino-4-methyl-salicylsäureester

Introduction of Sulfur Containing Substituents into 6-Amino-4-methylsalicylates The reaction of the azasulfonium salt 2 , formed by the addition of N-chlorosuccinimide to dimethyl sulfide, with methyl 4-methyl-6-(propylamino)salicylate ( 1 ) affords the sulfonium betaine 4 . With nitric acid 4 is converted into [2-hydroxy-3-methoxycarbonyl-6-methyl-4-(propylamino)-phenyl](dimethyl)sulfonium nitrate ( 5 ). With Raneynickel, methyl 4-methyl-3-methylthio-4-(propylamino)salicylate ( 6 ) is formed. The reaction of methyl 4-methyl-6-morpholinosalicylate ( 7 ) with the methylsulfinyl carbanion leads to the formation of 2′-hydroxy-4′-methyl-2-methylsulfinyl-6′-morpholino-acetophenone ( 9 ), which upon heating with trifluoroacetic acid undergoes cyclisation to give 6-methyl-2-methylthio-4-morpholino-3(2H)-benzofuranone ( 8 ).     

Synthesis and antifungal properties of N-[(1,1′-biphenyl)-4-ylmethyl]-1H-imidazol-1-amine derivatives

In the course of a study on 1H-imidazol-1-amine derivatives as antifungal agents, we found that N-[(1,1′-biphenyl)-4-ylmethyl]-N-[(2,4-dichlorophenyl)methyl]-1H-imidazol-1-amine (1a) exhibited promising activities. In order to explore more in detail the structure–activity relationship of this new class of antifungal agents, we report now the synthesis and the biological activity of new analogues (1b–k) of compound 1a. The synthesis was performed using N-[(1,1′-biphenyl)-4-ylmethyl]-1H-imidazol-1-amine as starting material which was reacted with the proper arylmethyl halide. Most of the newly synthesized imidazolamines exhibited both fungal growth inhibition activity and cellular selectivity.     

Untersuchungen an 1,3-Thiazinen, 37. Mitt. Umsetzungen NH-acider Tetrahydro-1,3-thiazinderivate mit Sulfensäure- und Sulfonsäurechloriden

Investigations on 1.3-Thiazines, XXXVII; Reactions of NH-acidic Tetrahydro-1.3-thiazine Derivatives with Sulfenic and Sulfonic Acid Chlorides N-sulfenyl derivatives were obtained from 5,6-dihydro-2H-1,3-thiazine-2.4(3H)-diones 1 and sulfenic acid chlorides in the presence of triethylamine or from the sodium salts of 1, 3. 2-Thioxo-tetrahydro-4H-1,3-thiazine-4-ones 4 were on the other hand sulfenylated at sulfur to 5 which was easily cleaved hydrolytically to 1 . N-Sulfonylation was only achieved with methane sulfonyl chloride to yield 13.     

An Improved Synthesis of the Antiulcer Drug Ranitidine from N-[2-[[[5-(hydroxymethyl)-2-furanyl]-methyl]-thio]-ethyl]-N′-methyl-2-nitro-1,1-ethenediamine

An improved synthesis of the antiulcer drug ranitidine from N-[2-[[[5-(hydroxymethyl)-2-furanyl]-methyl]-thio]-ethyl]-N′-methyl-2-nitro-1,1-ethenediamine is reported.