1-[2-(N-甲基-N-取代苄基)氨基-2-(2,4-二氟苯基)乙基]-1H-1,2,4-三唑类化合物的合成及抗真菌活性

目的:1-[2-(N-甲基-N-取代苄基)氨基-2-(2,4-二氟苯基) 乙基]-1H-1,2 ,4-三唑类化合物的合成及抗真菌活性研究。方法:通过付-克反应、三唑烷基化、酮亚胺还原和Leuckart 反应,得到关键中间体,然后通过N-烷基化反应制得目标化合物,并用二倍稀释法测定了体外抑菌活性。结果:合成了23 个1-[2-(N-甲基-N-取代苄基) 氨基-2-(2,4-二氟苯基)乙基]-1H-1 ,2,4-三唑类化合物,均为首次报道。所有目标化合物对8 种致病真菌均有不同程度的抗真菌活性。大部分化合物对Candida.albicans 和Candida.parapsilosis 的抗菌活性明显高于布替萘芬,其中1 ,2 ,6 ,13,14 ,19 对Candida.albicans 的抗菌活性是益康唑的8～32 倍,2,13 对Cryptococcu.neoformans 的抗菌活性是布替萘芬的4～8 倍,是益康唑64 ～128 倍。所有化合物对Microsporum .canis 的抗菌活性均高于或相当于益康唑。结论:其中一些化合物显示了较强抗真菌的活性,值得进一步研究。     

Synthese und Eigenschaften von 4-Alkoxy-5-imino-1,4-thiazinan-3-onen

Synthesis and Properties of 4-Alkoxy-5-imino-1,4-thiazinan-3-ones 2-(Cyanomethylthio)-2,2-diphenylacetic acid ( 5a ) reacts with alkoxyamines 2 and dicyclohexylcarbodiimide via the not isolated N-alkoxyamides 6a,b to yield the 4-alkoxy-5-imino-1,4-thiazinan-3-ones 7a,b . Reactions of the mono- and unsubstituted acids 5b,c with 2a–c afford primarily the N-alkoxyamides 6c–f , which undergo cyclisation to 7Ac–f in the presence of hydrogen chloride. Treatment of 7Ad,Af with sodium carbonate leads to the unstable bases 7d,f , which are converted to 8 with isocyanates. During the hydrolysis of 7Ad in hot ethanol, ring cleavage is observed leading to the diamide 9 , whereas 7Ab is transformed under the same conditions to 4-benzyloxy-2, 2-diphenyl-1,4-thiazinan-3,5-dione ( 10 )     

Versuche zur photochemischen Synthese ephedrinähnlicher Verbindungen,IV Darstellung von N-primären 2-Aminocyclopropanolen-(1) und deren Isomerisierung

Photochemical Synthesis of Ephedrine-Type Compounds, IV: Synthesis of N-Primary 2-Aminocyclopropan-1-ols and Their Isomerization UV irradiation of N-primary 3-aminopropiophenones leads to dehydrogenation or fragmentation, but not to cyclization of the substrates. However, N-primary 2-aminocyclopropan-1-ol hydrochlorides are obtained by hydrogenolytic debenzylation of photochemically prepared 2-(benzylamino)cyclopropan-1-ols. N-Primary 2-aminocyclopropan-1-ols undergo isomerization to 3-aminoketones, when treated with alkali.     

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 .     

Use of triphenylmethyl (trityl) amino protecting group in the synthesis of ketomethylene analogues of peptides

The Grignard reagents of 2-(2-bromoethyl)-1,3-dioxane and 2-(2-bromoethyl)-1,3-dioxolane readily reacted with the 2-thiopyridyl ester of N-triphenylmethyl-l -leucine to give the ketone adducts 2-[3-oxo-4(S)-(triphenylmethyl) amino-6-methylheptyl]-1,3-dioxane (8a) and 2-[3-oxo-4(S)-(triphenylmethyl) amino-6-methylheptyl]-1,3-dioxolane (8b) in near quantitative yield. When 1 equiv. of the Grignard reagent of 2-(2-bromoethyl)-1,3 dioxane was used, the desired ketone adduct 8a was formed slowly but quantitatively. In contrast, when 2 equiv. of the Grignard reagent were used, the formation of ketone 8a was instantaneous. The triphenylmethyl protecting group was easily removed from 8a using dilute acid to give the amino ketone 2-[3-oxo-4(S)-amino-6-methylheptyl]-1,3-dioxane oxalate salt (9). This material served as a useful intermediate in the synthesis of the ketomethylene analogues of the peptides, Z-Pro-Leu-Gly-OH and Leu-Gly-Val-Phe-OCH₃.     

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.     

Polycarbonylverbindungen, 19. Mitt. Synthese und Solvolysereaktionen tosylsubstituierter Quadratsäurebisamidine

Polycarbonyl Compounds, IXX: Synthesis and Solvolysis Reactions of N-Tosyl Squaric Acid Bisamidines N-Tosyl squaric acid bisamidines were synthesized by the reaction of squaric acid 1,2- and 1,3-diamides 5 and 6 or of their thio analogues 9 and 10 with excess p-tosyl isocyanate ( 4 ). Hydrolysis, sulfhydrolysis and aminolysis of the products are described.     

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 .     

Synthese und Pharmakologie von substituierten N-Benzyliden-Derivaten

Synthesis and Pharmacology of N-Benzylidene Derivatives A series of new derivatives of N-(benzylidene)anthranilic acid and 4-(benzylideneamino)benzoic acid have been synthesized and tested for their pharmacologic activities in animals. Marked anti-inflammatory, hypotensive and analgesic activities were observed. Some compounds also decrease the motorial activity. An attempt has been made to evaluate structure-activity relationships in this series.     

Synthesis of glycosylated tuftsins and tuftsin-containing IgG fragment undecapeptide

Syntheses are described of two new tuftsin derivatives containing a 2-acetamido-2-deoxy-D-galac-topyranosyl unit α- or β-glycosidically linked to the threonine's hydroxy side chain function and of the glycosylated undecapeptide corresponding to the tuftsin region of the heavy chain of IgG (amino acid sequence 289–299). The glycosylated tuftsins were synthesized by the solution procedure. Fmoc-[Gal NAc(Ac)₃α]Thr-OH and Fmoc-[GalNAc(Ac)₃β]Thr-OH were allowed to react with H-Lys(Z)-Pro-Arg(NO₂)-OBzl by the mixed anhydride procedure and the resulting glycosylated tetrapeptides were fully deblocked by catalytic hydrogenation followed by treatment with potassium cyanide, purified by ion exchange chromatography and characterized by analytical HPLC, elemental and amino acid analyses, optical rotation, and proton NMR spectroscopy. Synthesis of the glycosylated undecapeptide was achieved by the continuous flow solid phase procedure on 4-hydroxymethylphenoxyacetyl-norleucyl derivatized Kieselguhr-supported resin. Fmoc-amino acid symmetrical anhydrides or pentafluorophenyl esters, in the presence of N-hydroxybenzotriazole, were used as the acylating agents. To mimic the native sequence of the tuftsin region at the Fc-domain of immunoglobulin G a 2-acetam～do-2-deoxy-β-D-glucopyranosyl unit was N-glycosidically linked to the amide side chain of Asn 297. The glycosylated asparagine residue was introduced as N²-fluorenylmethyloxycarbonyl-N⁴-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopy-ranosyl)-asparagine pentafluorophenyl ester. After cleavage from the resin the glycopeptide was deprotect-ed, purified by ion exchange chromatography, and characterized by analytical HPLC, amino acid analysis, high voltage electrophoresis, and proton NMR. The conformational features of the glyco-undecapeptide were determined by circular dichroism measurements both in water and in 98% trifluoroethanol. Results of biological assays will be published elsewhere.     

Bequeme Darstellung von reinen N-Methylalkylaminen durch Zink/Salzsäure-Reduktion von 1,3,5-Tris(alkyl)-hexahydro-1,3,5-triazinen

Convenient Synthesis of Pure N-Methylalkanamines by Reduction with Zn/Hydrochloric Acid of 1,3,5-Trialkyl(hexahydro)1,3,5-triazines N-Methylalkanamines are available by reduction of 1,3,5-trialkyl(hexahydro)-1,3,5-triazines with Zn/hydrochloric acid at ?5° using a drop-in procedure. The purity (GLC) is in the range of 95%.     

Barbitursäurederivate, 30. Mitt. Synthese racem. und optisch aktiver basisch substituierter Barbitursäuren

Derivatives of Barbituric Acid, XXX: Synthesis of Racemic and Optically Active Barbituric Acids Carrying Basic Substituents Monoalkylated malonates were condensed with N-monosubstituted ureas to yield the 5-monosubstituted barbituric acids 1 , which were reacted to the 5-bromobarbituric acids 2 . From 2 the barbituric acids 3–5 having basic substituents were obtained by nucleophilic substitution with N-bases. From the 27 racemates obtained, 17 were resolved into the enantiomers with camphersulfonic acid.     

Synthesis of modified tuftsins containing monosaccharides or monosaccharide derivatives

Synthesis of some modified tuftsins is described in which a monosaccharide or a monosaccharide derivative was incorporated in the molecule. Acylation of H-Thr-Lys(Z)-Pro-Arg(NO₂)-OBzl with D(+)-gluco-1,5-lactone followed by catalytic hydrogenation gave Nα-gluconyl-tuftsin. Glycosylation of the carboxyl function of the C-terminal arginine has been achieved by reacting, through the mixed anhydride procedure, Boc-Thr-Lys(Z)-Pro-OH with 2-deoxy-2-(N^G-nitroargininamido)-D-glucopyranose followed by catalytic hydrogenation and trifluoroacetic acid treatment. O-Glucosyl-tuftsin has been prepared by reacting o-nitrophenyl N-benzyloxycarbonyl-O-[(α + β)2,3,4,6-tetra-O-benzyl-D-grucopyranosyl]-threoninate with H-Lys(Z)-Pro-Arg(NO₂)-OBzl in the presence of 1-hydroxybenzotriazole. Flash chromatography on silica gel allowed a partial separation of the diastereoisomers, one of which has been isolated in a reasonable yield. The single diasteroisomer and the α + β anomeric mixture were separately deblocked by catalytic hydrogenation and purified by RP-HPLC.     

Dibenz[b,f]azepines,Part 7[1]: Synthesis of New,Potentially CNS Active Dibenz[b,f]azepine Derivatives

Reactions of 5-carboxamido-5H-dibenz[b,f]azepines ( 1a–1d ) with glyoxylic acid methylester methyl hemiacetal (GMHA) led to 5-(carboxamido-N-α-hydroxy-acetic acid methyl ester)-5H-dibenz[b,f]azepines ( 2a–2d ). The reactions with glycols yielded the oligoethylene glycol derivatives ( 3,4 ). The new compounds were screened as anticonvulsants and/or antidepressants (AD).     

Derivate des 2-Amino-1,2,3,4-tetrahydronaphthalins,III. Synthese einiger N'-substituierter N-(trans-3-Hydroxy-1,2,3,4-tetrahydro-2-naphthyl)-piperazine

Derivatives of 2-Amino-1,2,3,4-tetrahydronaphthalene, III: Synthesis of Some N'-Substituted N-(trans-3-Hydroxy-1,2,3,4-tetrahydro-2-naphthyl)piperazines The synthesis of the N'-substituted N-(trans-3-hydroxy-1,2,3,4-tetrahydro-2-naphthyl)piperazines 2 – 5 and of trans-2-morpholino-3-hydroxy-1,2,3,4-tetrahydronaphthalene ( 6 ), starting from 2,3-epoxytetralins 1 , is reported. The new Mannich bases 3 show hypotensive and antiarrhythmic activities.     

Darstellung von N-Imidomethyl-N-sulfonylmethyl-anilin-Derivaten

Synthesis of N-Imidomethyl-N-sulfonylmethylaniline Derivatives. The title compounds 2 are formed by condensation of N-imidomethylaniline derivatives 1 with formaldehyde and sulfinic acid 3 .     

Effects of some derivatives of 2-aminotetralin on dopamine-sensitive adenylate cyclase and on the binding of (3H)haloperidol to neuroleptic receptors in the rat striatum

Putative dopamine agonists from a series of 2-aminotetralin derivatives were assessed for their ability to stimulate dopamine-sensitive adenylate cyclase and to inhibit the binding of [³H]haloperidol to neuroleptic receptors in the rat striatum. Comparisons were made to the ability of these agents to stimulate motor function on intrastriatal injection (stereotyped biting/hyperactivity) or peripheral administration (stereotyped biting). Of the two primary amines, 2-amino-5,6-dihydroxytetralin and 2-amino-6,7-dihydroxytetralin, the 6,7-dihydroxy compound was found to be 20 times more potent than the corresponding 5,6 derivative to stimulate adenylate cyclase. The activities of a series of mono- and di-alkylated substitutes of the two primary amines (methyl, ethyl, propyl, butyl) were determined. Of particular interest, and in contrast with the primary amines, 2-(N,N-dipropyl)amino-5,6-dihydroxytetralin was shown to be twice as potent as the corresponding 6,7-derivative. Of the compounds which were shown to stimulate adenylate cyclase, little difference was found in their activities. In the second assay procedure, inhibition of [³H]haloperidol binding, 2-(N,N-dipropyl)amino-5,6-dihydroxytetralin was the most active compound studied (a hundred times activity of dopamine). Similarly to observations with adenylate cyclase, the 6,7- derivative was the more active of the primary amines (times ten) whilst the 5,6- derivative was the more active of the N,N-dipropylcompounds (times three). General comparisons could be made between the biochemical findings and behavioural observations: those agents most active to induce dopamine-like motor effects on subcutaneous or intrastriatal injection were generally effective to stimulate adenylate cyclase and to inhibit [³H]haloperidol binding, whilst compounds inactive behaviourally were also inactive in vitro [2-(amino)-5,6-dimethoxytetralin and 2-(N, N-dimethyl)amino-5,6-dimethoxytetralin]. However, an absolute correlation between in vivo and in vitro potency could not be found. The most important observation of the present studies is the potency of 2-(N,N-dipropyl)amino-5,6-dihydroxytetralin in the [³H]haloperidol binding assay which indicates that this 2-aminotetralin derivative may be a useful tool in future studies on dopamine receptors.     

Massenspektrometrische Untersuchungen an Edukten für die Synthese H2-aktiver Substanzen

Mess Spectrometry of Reactants for the Synthesis of H₂-Active Compounds 4-[(2-Aminoethoxy)methyl]-5-methylimidazole ( l ), the imidazoles 2-5 with N-substituted ethylenediamine structures and the imidazolecarboxamides 6–8 were investigated by electron impact mass spectrometry. The mechanisms of the competing bond fissions and of the rearrangements are explained. The neighbouring group effects of the various functional groups and their influences on the main fragmentation paths are described.     

DNA-binding compounds – synthesis and intercalating properties of a peptide-diamino diacridine

A novel diacridine has been prepared in which two acridines are linked by a flexible peptide chain composed of γ-aminobutyric acid, tyrosine, lysine and glycine. Synthesis of N-(9-acridinyl)-4-aminobutanoyl-tyrosyl-lysyl-lysyl-glycyl)-N′-(9-acridinyl)-1,3-diaminopropane (VII) was achieved in 8% overall yield by a solution phase stepwise procedure. This compound binds to DNA by intercalation of both chromophores with at least a 140-fold enhancement of affinity compared to 9-aminoacridine.     

Synthese und Eigenschaften des 3-Hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]chinazolin-2-carbonitrils

Synthesis and Properties of 3-Hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]quinazoline-2-carbonitrile Anthranilic acid reacts with 2-chloro-5-cyano-4-hydroxypyrid-6-one (3) in glacial acetic acid to yield 3-hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]quinazoline-2-carbonitrile (4) . When the reaction is carried out in DMF under Ullmann conditions, 2-(dimethylamino)-5-cyano-4-hydroxypyrid-6-one (5) forms as a by-product. The methylation of 3 with diazomethane affords 2-chloro-5-cyano-2-methoxy-N-methylpyrid-6-one (9) and 2-chloro-5-cynao-4,6-dimethoxypyridine (10) . Under similar conditions compound 4 undergoes an esterifying ring cleavage to furnish methyl 2-(5-cyano-4,6-dimethoxypyrid-2-ylamino)benzoate (7) .