Chinon-Amin-Reaktionen, 4. Mitt. 2,3,4-Trihydro-benzo[f]chinoxalin-6-one

Quinone Amine Reactions, IV: 2,3,4-Trihydrobenzo[f]quinoxalin-6-ones 1,4-Naphthoquinones 2 react with ethylenediamine (3) to yield 5-substituted 2,3,4-trihydrobenzo[f]-quinoxalin-6-ones 7 . The analogous reactions with N-acetylethylenediamine (12) indicate that amino-1,4-naphthoquinones 6 are intermediates but not 1,4-naphthoquinoneimines 4 . Compounds 6 result from addition-enolization-oxidation or addition-elimination mechanism. Both mechanisms are found to occur in the reaction of 2-bromo-1,4-naphthoquinone (2e) with 3 .     

Zur Umsetzung von N-benzylsubstituierten Piperidoncarbonsäureestern mit Cer(IV)-sulfat

The Reaction of N-Benzyl-3-(methoxycarbonyl)-4-piperidones with Cerium(IV) Sulfate After oxidation reactions of N-benzyl-3-(methoxycarbonyl)-4-piperidones 1 with cerium(IV) sulfate the following heterocycles can be isolated: substituted hydrogenated 2,6-methano-2-benzazocin-5-ones 2 , 1,4,5,6-tetrahydro-3-(methoxycarbonyl)pyridin-4-ones 3 and 3-(methoxycarbonyl)pyridin-4-ones 4 . The structures of these compounds were determined by spectroscopic methods.     

Nachweis der Inversion bei der Umsetzung optisch aktiver 1-(0-Hydroxymethyl-benzyl)-N-methyl-1,2,3,4-tetrahydroisochinoline zu 3-Phenylisochromanen

Conversion of 1-[2-(Hydroxymethyl)benzyl]-N-methyl-1,2,3,4-tetrahydroisoquinolines to 3-Phenylisochromans: Evidence of Inversion. Optically active 1-[2-(hydroxymethyl)benzyl]-N-methyl-1,2,3,4-tetrahydroisoquinolines react with ethyl chloroformate (CAE) to yield optically active 3-phenylisochromans. Oxidation to the 3-phenylisochroman-1-ones and degradation with ozone to malic acid demonstrate an inversion in the course of the CAE reaction.     

2-Amino-2′-[18F]fluorobenzhydrols,intermediates for the synthesis of [2′-18F]-1,4-benzodiazepine-2-ones

A method for synthesizing ¹⁸F-labelled 2-amino-2′-fluorobenzhydrols under nocarrier-added conditions for use as radiolabelled intermediates in the synthesis of[2′-¹⁸F]-1,4-benzodiazepine-2-ones is presented. Anilinodichloroborane reagents were formed by the reaction of boron trichloride with 4-chloro-N-methylaniline, 6a , 4-nitro-N-methylaniline, 6b , 4-nitro-N-ethylaniline, 6c , and 4-chloro-N-(2,2,2-trifluoroethyl)aniline, 6d . 2-[¹⁸F]Fluorobenzaldehyde, 5 , synthesized in 55–70% yields by the nucleophilic aromatic substitution of 2-nitrobenzaldehyde with the Kryptofix/K⁺ complex of [¹⁸F]F⁻, was subsequently reacted with the anilinodichloroborane coupling reagents with aromatic substitution occurring ortho to the amino group. The resulting 2-amino-2′-[¹⁸F]fluorobenzhydrols, 7a - 7d , were produced in conversions of 60–95% with reaction time ⩽ 10 min at room temperature or 60°C, depending on the aniline used. The total synthesis time, including evaporation of the target water, was 60–65 min. The total radiochemical conversions were of the order of 50–65% for 7a - 7c and 35–45% for 7d , decay-corrected and based on [¹⁸F]F⁻.     

Photochemische Abbauwege des Amino- und Hydroxyphenazons in Aceton

Photodegradation of Amino- and Hydroxyphenazone in Acetone The photochemical degradation of aminophenazone in acetone leads to 2-[1-(methylimino) ethyl]-4-oxopent-2-enoic anilide (7) , 6-methyl-2-[1-(methylimino)ethyl]-4-oxohepta-2,5-dienoic anilide (9) , N, N,-dimethyl-N′-phenyl oxamide (10) and N,N-dimethyl-N′-phenylurea (11) . In addition to the last two products, oxanilide and N-methyl-N′-phenyl oxamide are obtained, when the irradiation is carried out in acetonitrile. 6-Methyl-2-[1-(methylimino)ethyl]-4-oxohepta-2,5-dienoic anilide, oxanilide and N-methyl-N′-phenyl oxamide are formed as a result of hydroxyphenazone photolysis in acetone. The degradation mechanism is discussed.     

3-Alkoxy-1.2.3-oxathiazolidin-4-on-2-oxide und 1-Alkoxy-indolin-2-one aus N-Alkoxyglykolamiden und Thionylchlorid oder 1.1′-Thionyldiimidazol

3-Alkoxy-1.2.3-oxathiazolidin-4-one-2-oxides and 1-Alkoxyindolin-2-ones from N-Alkoxyglycolamides and Thionyl Chloride or 1.1′-Thionyldiimidazole The reaction of N-alkoxyglycolamides 1 with thionyl chloride or 1.1′-thionyldiimidazole is shown to produce, dependending on the substituents at C-2 in 1 , either 3-alkoxy-1.2.3-oxathiazolidin-4-one-2-oxides 4 or 1-alkoxy-3-arylindolin-2-ones 6 .     

1,3-Bis(pyridin-2-ylthio)propan-2-one,Bis(thieno[2,3-b]pyridin-2-yl)-ketone und 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-one

1,3-Bis(pyridin-2-ylthio)propan-2-ones, Bis(thieno[2,3-b]pyridin-2-yl)ketones and 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-ones Reaction of 1a-d with 1,3-dichloroacetone gives the bissulphides 2a-d . Base catalyzed cyclization of 2a-d affords heterocyclically substituted ketones 3a-e . Treatment of 3a and 3b in conc. H₃PO₄ leads to the bispyridothienopyridines 5a and 5b .     

Synthesis and Antitumor Activity of Novel Dibutyltin Carboxylates of Aminoglucosyl Derivatives

In this study, di‐n‐butyltin(IV) oxide was reacted with the amino glucose analog, cis‐4‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl)imido]‐4‐oxo‐2‐butenoic acid ( 1a ) and o‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl) carbamoyl] benzoic acid ( 2a ) to give the complexes bis‐{cis‐4‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl)imido‐4‐oxo‐2‐butenoic acid]‐di‐n‐butyltin} carboxylate ( 1 ) and bis‐{o‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl) carbamoyl‐benzoic acid]‐di‐n‐butyltin}carboxylate ( 2 ). These two compounds were then characterized by IR, NMR and MS. In vitro tests showed that both compounds have high cytotoxicity in four tumor cell lines (P388, HL‐60, A549 and BEL‐7402). Clonogenic assays demonstrated that both compounds 1 and 2 have hematopoietic cell toxicity at 10^?6 m .     

Synthese und Eigenschaften 6-substituierter 4-Alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-one

Synthesis and Properties of 6-Substituted 4-Alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones Reactions of the N-alkoxy-2-(2-thienyl)glycolamides 1B with dicyclohexylcarbodiimide yield the 4-alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones 2b . Acid catalyzed methanolysis of the tetrahydropyranyl group in 2B, Bk results in the formation of the bicyclic lactams 5 .     

Syntheses of some norcholanylisoquinoline derivatives.

N-Phenethyl- and N-[2-(3′,4′-dimethoxyphenyl)ethyl]amides 5-8 of cholanic acid and 3α-acetoxy-cholanic acid were subjected to the Bischler-Napieralski reaction to yield the respective 3′,4′-di-hydroisoquinolines, 9-12. Reaction of 5 also yielded N,N-bis(phenethyl)cholanamidine 13 . The 3′,4′-dihydroisoquinoline 11 was converted to the tetrahydro derivative 14 and to the aromatic compounds 15 and 16 .     

Synthese von 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-onen und 6,11-Dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-on

Synthesis of 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-ones and 6,11-Dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one The title compounds 4 and 6 were prepared by Fischer indole synthesis. 4a is substituted in 10-position by reaction with bromine in glacial acetic acid. A fast ring inversion is observed for the azepine ring in 4 and 6 .     

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.     

Bifunktionelle Elektrophile zur Darstellung [c]-heteroanellierter Chinazolinon-Derivate: 2-Isocyanatocyclohex-1-encarbonsäurenitril,ergänzend zu 2-Isocyanatobenzonitril

2-Isocyanatocyclohex-1-ene-carbonitrile and 2-Isocyanatobenzonitrile as Bifunctional Electrophiles in the Synthesis of [c]-Heteroanellated Quinazoline Derivatives. N′-substituted N-(2-cyanophenyl)ureas afford [1,2,4]triazolo[1,5-c]- and imidazo[1,2-c]-quinazolin-5(6H)-ones. 2-Isocyanatocyclohex-1-ene-carbonitrile as starting compound leads to the 7,8,9,10-saturated structural analogues.     

Human moricizine metabolism. I. Isolation and identification of metabolites in human urine

1. Using synthetic standards and or spectral data, seven moricizine metabolites were structurally identified in human urine. Two novel metabolites were identified as phenothiazine-2-carbamic acid and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate. Two novel human moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine, a previously identified dog metabolite, and 2-aminophenothiazine, a previously identified rat metabolite, were also identified. Three additional human metabolites, phenothiazine-2-carbamic acid ethyl ester sulphoxide (P2CAEES), moricizine sulphoxide, and ethyl {10-[N-(2′-hydroxyethyl)3-aminopropionyl] phenothiazin-2-yl} carbamate, all previously described in the literature, were observed. 2. Both 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3- aminopropionyl) phenothiazin-2-yl] carbamate, and possibly ethyl {10-[N-(2′-hydroxyethyl)3-aminopropionyl]phenothiazin-2-yl} carbamate, possess the structural characteristics thought to be necessary for class 1 antiarrhythmic activity.     

3-Acyl-pyrano [2,3-b]indol-4-one

3-Acylpyrano[2,3-b]indol-4-ones The mixture which is obtained by treating 1-methyloxindole ( 1 ) with phosgene reacts with the alkali salts of the 1,3-dicarbonyl compounds 10a - 10d to yield the 3-acylpyrano[2,3-b]indol-4-ones 11a - 11d . Reactions with the salts of 1, 3-dimethylbarbituric acid and of 1 lead to the pyrone derivatives 12 and 13 , respectively.     

Substituted adamantylphthalimides: Synthesis,antiviral and antiproliferative activity

In this study, three groups of adamantylphthalimides, bearing different substituents at the phthalimide moiety, N-(4′-R²)phthalimidoadamantanes ( 1 – 7 ), 3-[N-(4′-R²)phthalimido]-1-adamantanols ( 8 – 10 ), and 3-[N-(4′-R²)phthalimido]adamantane-1-carboxylic acids ( 11 – 15 ), were synthesized and screened against tumor cells and viruses. The most potent compounds are not substituted at the adamantane and bear an OH or NH₂ substituent at the phthalimide (compounds 3 and 5 ). The antiproliferative activities of compounds 3 and 5 are in the micromolar range, much higher than the one of thalidomide. A minor antiviral activity against cytomegalovirus and varicella-zoster virus was found for compounds 3 and 5 , but these compounds lacked selectivity. The results presented are important for the rational design of the next-generation compounds with anticancer and antiviral activities.     

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-a]pyrimidone-(6) aus 2-Acetoacetylamino-imidazo[2,1-b]-1,3,4-thiadiazolen

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones by Cyclisation of 2-(Acetoacetylamino)-imidazo[2,1-b]-1,3,4-thiadiazoles The 2-acetoacetylamino-6-methyl- (or -aryl) imidazo[2,1-b]-1,3,4-thiadiazoles 1, 2a–f cyclise on heating in polyphosphoric acid (PPA) to yield the tricyclic 2,8-dimethyl- or 2-aryl-8-methyl-imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones 3, 4a–f . Only 4c inhibits the growth of vaccinia viruses. The other compounds have no antiviral activity.     

Untersuchungen an 1,3-Dicarbonyl-Verbindungen, 23. Mitt. 3-Acyl-4-oxo-4H-[1]benzothieno[3,2-b]pyrane

1,3-Dicarbonyl Compounds, XXIII: 3-Acyl-4H-[1]benzothieno[3,2-b]pyran-4-ones Syntheses of the 3-acylpyrones 6 and 8 from the 1,3-dicarbonyl compound 1 and reactions of the products are reported.     

In vitro and in vivo evaluation of radiolabeled methyl N-[5-(3′-halobenzoyl)-1H-benzimidazol-2-yl]carbamate for cancer radiotherapy

The role of theranostics in cancer management is growing so is the selection of vectors used to deliver these modalities to cancer cells. We describe biological evaluation of a novel theranostic agent targeted to microtubules. Methyl N-[5-(3′-[¹³¹I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate ( 1 ) and methyl N-[5-(3′-[¹²⁵I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate ( 2 ) were synthesized from a common precursor 3′-stannylated derivative ( 4 ). Antiproliferative effects and radiotoxicity of ¹³¹I-labeled β-particle emitting 1 were examined in vitro in human neuroblastoma and glioblastoma cells lines. The therapeutic potential of 1 was also examined in a subcutaneous mouse model of human glioblastoma U-87 MG. Compound 1 at the extracellular radioactive concentration of 0.35 MBq/mL, easily achievable in vivo, kills >90% of neuroblastoma cells and >60% glioblastoma cells as measured in a clonogenic assay. D₁₀ doses established for 1 indicate that as few as 3,000 decays are sufficient to kill 90% of BE(2)-C cells. Even U-87 MG cells, the least sensitive of the tested cell lines, require <20,000 decays of intracellular ¹³¹I to reduce number of clonogenic cells by 90%. Biodistribution studies of 2 delivered either intratumorally or intraperitoneally show a similar tissue distribution for both routes of the drug administration. The whole body clearance half-lives were on average 6 hr. Intratumor administration of 1 produces significant tumor growth delay. After a single dose of 8.4 ± 0.3 MBq of compound 1 , the tumor doubling times were 3.2 ± 0.1 and 7.9 ± 0.6 days in control and treated mice, respectively. Methyl N-[5-(3′-radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates have properties compatible with a theranostic approach to cancer management.     

Acetylenchemie, 3. Mitt. Ein einfacher Zugang zum Flindersin via Phasen-Transfer-Reaktion

Acetylene Chemistry, III: A Simple Approach to Flindersine by Phase-Transfer Reaction Reaction of 4-hydroxyquinolin-2-one (4) with 3-chloro-3-methylbut-1-yne by phase-transfer catalysis affords flindersine (3) and 2,3-dihydro-3,3-dimethyl-2-methylenefuro[3,2-c]quinolin-4-one (5) , whereas indolin-2-one (4g) yields N-(1′,1′-dimethylprop-2-yn-1-yl)indolin-2-one (19) . The reaction mechanism is discussed and studied by varying the reaction conditions.