Synthese von 3-methylendisubstituierten 2-Oxo-tetrahydrofuranen und ihre Umlagerung zu den 5,6-Dihydro-2H-pyran-2-onen

Synthesis of 3-Methylene-2-oxotetrahydrofurans and their Rearrangement to 5,6-Dihydro-2H-pyran-2-ones . The synthesis of the 3-methylene-2-oxotetrahydrofurans 5a–g and 6–8 from the α-ketolactons 1a,b by Knoevenagel reaction with 2a–f, 3 and 4 in the presence of TiCl₄/pyridine, piperidine acetate/β-alanine and β-alanine is described. Ring opening and hydrolysis of 5a–d, 5f and 6 gives the 5,6-dihydro-2H-pyran-2-ones 9a–f .     

Untersuchungen an 1,3-Dicarbonylverbindungen, 14. Mitt. 4-Oxo-4H-[1]benzofuro[3,2-b]pyrane und 4-Oxo-4H[1]benzothieno-[3,2-b]pyrane

1,3-Dicarbonyl Compounds, XIV: 4-Oxo-4H-[1]benzofuro[3,2-b]pyranes and 4-Oxo-4H-[1]benzothieno[3,2-b]pyranes The 1,3-dicarbonyl compounds 1 condense with dialkyl oxalates to form the 1,3,5,6-tetracarbonyl compounds 2 , which hydrolize under mildly alkaline conditions to give the ketocarboxylic acids 3 . Compounds 2 and 3 cyclize on heating with alcohols, saturated with HCl, to yield the alkyl 4-pyrone-2-carboxylates 4 . The acids 5 , obtained from 4 , decarboxylate on heating with quinoline/copper to give the heterocycles 6 . Compound 6b is also obtained from 1b by reaction with N,N-dimethylformamide dimethyl acetal (DMFDMA) and treatment with acid of the product 8b , whereas 1a and DMFDMA give the derivative 7a . Compounds 4 were characterized in the form of their amides 10 . The pyrylium salts 11 were obtained from 6 by reaction with dimethyl sulfate/HClO₄. Compounds 4 and 6 are converted to the thiocarbonyl compounds 12 and 13 by reaction with P₄S₁₀. Condensation of 2 with triethyl orthoformate/acetic anhydride yields the alkyl 4-pyrone-3-ketocarboxylates 14 . Compound 15b , formed by hydrolysis from 14b, afforded the 4-pyrone-3-carboxylic acid 16b by oxidative decarbonylation.     

2-Thiocarbamoyl- und 2-Methylendithioderivate von 4,5-Dihydro-2H-3-benzothiepin-1-on und seinem Sulfon

2-Thiocarbamoyl and 2-Methylenedithio Derivatives of 4,5-Dihydro-2H-3-benzothiepin-1-one and its Sulfone Reactions of the carbanions of 4,5-dihydro-2H-3-benzothiepin-1-one (3a) and its sulfone 3b with isothiocyanates afford the 2-aryl- and 2-alkyl-thiocarbamoyl derivatives 4 . According to spectroscopic findings these derivatives are Z-isomers of the chelated enol forms 5 . Upon thermolysis they are converted with the elimination of a primary amine into the 1,3-dithietane derivatives 8 . The reaction of thiophosgene with 3a also affords 8a , whereas with 3b the thiocarbonate 12 is formed. - With carbon disulfide the carbanions of 3a and 3b undergo reactions that lead to mono- or di-anions of type 2 or 1 . These can be alkylated to give the ketene mercaptals 13–15 , the dithioesters 7 and the 1,3-dithietane derivatives 8 . Compound 3a reacts with dimethyl trithiocarbonate to yield the dithioester 7a , whereas with S,S-dimethyl dithiocarbonate the thiolester 6a is obtained. According to spectroscopic findings these products are chelates of the enol forms 10 and 11 , respectively.     

Chemical synthesis and biological activities of 5-deazaaminopterin analogues bearing substituent(s) at the 5- and/or 7-position(s)

Condensation of cyanothioacetamide (4) with ethyl alpha-(ethoxymethylene)acetoacetate (5b), ethyl 4-ethoxy-2-(ethoxymethylene)-3-oxobutanoate (5c), ethyl 2-(ethoxymethylene)-3-oxo-4-phenylpropanoate (5d) afforded exclusively the corresponding 6-substituted pyridines (6b-d). Cyclization of 4 with 3-carbethoxybutane-2,4-dione (5e) gave 3-cyano-5-(ethoxycarbonyl)-4,6-dimethylpyridine-2(1H)-thione (6e), whereas reaction of 4 with 3-carbethoxy-1-phenylpropane-1,3-dione (5f) yielded two products, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-phenylpyridine-2(1H)-thione (6f) and the 6-methyl-4-phenyl isomer 6g. The structural assignments for 6f and 6g are made on the basis of 1H and 13C NMR spectral analyses of the 2-(methylthio)nicotinates (7f,g) prepared from 6f and 6g by treatment with MeI/K2CO3. Nicotinates 7b,d-g were converted into their corresponding 2,4-diaminopyrido[2,3-d]pyrimidines 12b,d-g in five steps, via reduction, protection, oxidation, condensation with guanidine, and deprotection. The 7-mono- and 5,7-disubstituted-5-deazaaminopterins (1b,d-g) were prepared from the respective pyrido[2,3-d]pyrimidines 12b,d-g. Preliminary biological studies showed that 7-methyl and 5,7-dimethyl analogues (1b and 1e) were less active than methotrexate against human leukemic HL-60 and murine L-1210 cells in tissue culture. Compound 1e produced an ILS of 71% at 100 mg/kg per day X 5 (ip) in BDF mice inoculated ip with 10(6) L-1210 cells.     

Synthesis of Some Novel 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles as Potent Anti-Inflammatory Agents

A series of 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles 4a–j were obtained via multiple step synthesis sequence beginning with the hydroxybenzophenones (1a–g). Hydroxybenzophenones on reaction with chloroacetonitrile affords [(2-benzoyl) phenoxy] acetonitrile (2a–g), which reacts with H₂S/NH₄OH and yields [(2-benzoyl) phenoxy] acetothiamide (3a–g), which on treatment with phenacylbromides affords 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles (4a–j). All the newly synthesized compounds were evaluated for their anti-inflammatory activity and were compared with standard drugs. Of the compounds studied, (4g), compounds with chloro substituents showed more potent activity than the standard drug phenyl butazone at all doses tested.     

Verzweigtkettig substituierte Trifluormethylpyrimidine

Trifluoromethylpyrimidines Carrying Branched Chain Substituents The reaction conditions used in the condensation of O-methylisourea sulfate (1a) with the β-diketones 2a–2c to produce the pyrimidine derivatives 3a–3c may also be applied to the β-diketones 2d–2g to synthesize the pyrimidine derivatives 3g, 3i, 3k, and 3m which carry a branched chain substituent in 4-position. The 2-(methylthio)pyrimidines 3d, 3e, 3f, 3h, 3j, 3l, and 3n arise from the reactions of S-methylisothiourea sulfate (1b) with 2a–2g. Reactions of 1a or 1b with 7,7-dimethyl-1,1,1,2,2,3,3-heptafluoro-4,6-octanedione (4) yield the addition products 5a and 5b.     

Synthesis, reactions and biological activity of some new thieno[2,3-f]-1,3-benzodioxoles.

The reaction of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) with some aromatic or heterocyclic amines gave the corresponding 6-(aryl or heterocyclyl) carbamoyl-7-chlorothieno [2,3-f]-1,3-benzodioxoles (3a-c, 4a, b and 5). Compound 2 was also reacted with potassium thiocyanate, ethanol or sodium azide to afford the isothiocyanto compound 6, the ester 7 and the acid azide 9, respectively. Hydrazinolysis of 7 gave the carbohydrazide 8. The compounds 6, 8 and 9 were used as precursors in the synthesis of the target heterocycles, 7-chlorothieno[2,3-f]-1,3-benzodioxoles substituted with a variety of moieties at position-6 (10-15, 17, 19-26, 28-31). Also, 2-methyl-1,3-dixolo[5,6][1]benzothieno[2,3-c]quinolin- 6(5 H)-one (33) was prepared. The antibacterial and antifungal activities of some selected compounds were also reported.     

Acenaphthen-5,6-dicarbonsäure-imid-derivate

Derivatives of 2H-Indeno[6,7,1-def]isoquinoline The synthesis of the derivatives 1a–1i of 1,3,6,7-tetrahydro-2H-indeno[6,7,1-def]isoquinoline-1,3-dione is reported. It was impossible to oxidize these compounds to the 1,3-dihydro derivatives 2a–2i . The carbocyclic analogue, 7-methoxy-5H-cyclopenta[ed]phenalen-5-one (5) , reacts with 2,4-dinitrophenylhydrazine to yield the hydrazone 6 .     

3-Substituierte 2-Phenylindole: Synthese und biologische Eigenschaften

3-Substituted 2-Phenylindoles: Synthesis and Biological Properties Knoevenagel-reaction of indol-3-carbaldehydes 5a,b and 7a,b with nitromethane leads to the nitroethenes 12 and 14 , the analogous reaction with malodinitrile to the methylidenemalonic acid dinitriles 16 .- Michael-addition of nitromethane at 12 and 14 affords the 1,3-dinitropropanes 13 and 15 , reduction of 16 the methylmalonic acid dinitriles 17 .- Reaction of indoles 3 with n-BuLi/phenylsulfonylchloride leads to the 3-chloroindoles 18 , reaction with NaH/ethyliodide, ether cleavage and acylation to derivatives 19 .- Compounds 7–11, 14–17 , and 19 show affinity to the estrogen receptor. Compounds 7b, 9–11, 17b , and 19b inhibit the growth of MCF-7-and MDA-MB-231 cells. IC₀-values are determined and structure-activity relationships are discussed.     

Untersuchungen zur 6-Hydroxyindol-Bildung bei der Nenitzescu-Reaktion, 3. Mitt.1): Synthese und oxidative Cyclisierung von 3-(4-Hydroxyphenyl)-4-amino-3-penten-2-onen

Investigations on the Formation of 6-Hydroxyindole in the Nenitzescu Reaction, III: 3-Phenyl-4-amino-3-penten-2-ones 8a-g are synthesized from phenylacetone 5 and the 1,3-diketones 6a,b . Oxidative cyclisation of 8b to 9a,b is performed with Pb(OAc)₄. This proves that cyclization of quinol-intermediate 3 within the Nenitzescu reaction can yield 4 . Formation of an intramolecular CT-complex leading to 4 from 3 and to 9a,b from 7 is discussed.     

Über die Reaktionsprodukte der jodometrischen Gehaltsbestimmung von Ascaridol

On the Products of the Iodometric Assay of Ascaridol At least 15 products are formed in the iodometric assay of ascaridol ( 10 ) when carried out according to DAB 7. Seven of these products ( 1a, b, 2a, b, 3, 4, 14 ) arise from the reaction of 10 with hydrochloric acid. As reported earlier by Böhme et al., the reduction of 10 by iodide gives cis-2-p-menthene diol ( 11 ), which either is converted by acid into the isomeric menthenediols 5, 6 and 8 and their monoacetates or reacts with iodide by a reductive 1,4-elimination to form 1,3-p-menthadiene ( 12 ). The diols 5 , 6 and 8 are dehydrated to p-cymol, which is oxidized in part to 8-hydroxy-p-cymol ( 14 ). Compound 12 is oxidized to 3-p-menthene-8-ol or forms the dimeric compounds 16 , 17 and 18 by reaction with 14 .     

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⁻.     

Zur Stereochemie der 3-Oxo-5-phenyl-1-cyclopentancarbonsäuren, 9. Mitt. Synthese kernfluorierter stereomerer 3-Oxo-5-phenyl-1-cyclopentancarbonsäuren

Stereochemistry of 3-Oxo-5-phenylcyclopentanecarboxylic Acids, IX: Synthesis of Stereoisomeric 5-(Fluorophenyl)-3-oxocyclopentanecarboxylic Acids The stereoselective synthesis of the cis- and trans 5-(fluorophenyl)-3-oxocyclopentanecarboxylic acids 5a-d/6a-d by combined Michael and Dieckmann reaction from trimethyl ethanetricarboxylate and the fluorinated methyl cinnamates 1a-d is described. Acidic and basic degradation of the trimethyl 5-phenyl-3-oxocyclopentane-1,1,t-4-tricarboxylates 2a–d proceeds via the 5-phenyl-c-1-methoxycarbonyl-3-oxocyclopentane-t-1-carboxylic acids 3a–d and the 5-phenyl-3-oxocyclopentane-1,1-dicarboxylic acids 4a–d . The structures were determined by diazomethane esterification of 5a–d to 7a–d , 6a–d to 8a–d , 3a–d and 4a–d to 9a–d .     

Antimykotische Wirkstoffe,Mitt. Chlor-(1-piperazinyl)-1,3,5-triazine

Antimycotic Agents, XXII: Chloro-(1-piperazinyl)-1,3,5-triazines Reactions of cyanuric chloride (1) with the piperazine dervatives 2a–c a –20 to 10°C yield the dichloro-(1-piperazinyl)-1,3,5-triazines 3a–c . At the elevated reaction temperature of 40°C, the 2-chloro-4,6-bis(piperazinyl) 1,3,5-triazines 5a–b arise from 1 and the piperazine dervatives 4a–b . The differently substituted chloro-1,3,5-triazines (9) are formed by successive reactions of 1 with two different cyclic secondary amines ( 6 and 8 ). The ¹H-NMR spectra of compounds 3,5 , and 9 exhibit two signal groups bet ween 2.4 and 4.0 ppm which are characteristic of piperazine rings. Some of the newly developed compounds possess strong antimycotic activity e. g. 3c being active against Trichophyton mentagrophytes, trichophyton rubrum, and Microsporum conis. Also, anthelminthic, trichomonacidal insect growth regulatory and nootropic activities are shown by the new compounds.     

New thiazolyl-pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

A new series of N-substituted pyrazoline derivatives 6a–g , 7a–g , 8a–g , and 9a–g was synthetized by reaction of hydrazine derivatives and chalcone–thiazole hybrids bearing nitrogen mustard 5a–g . The chalcones 5a–g were obtained by Claisen–Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a–g . These new compounds 6/7/8/9a–g were screened for their antifungal activity against Cryptococcus neoformans, with IC₅₀ values of 3.9–7.8 µg/ml for the N-3,5-dichlorophenyl pyrazolines 9e – g . Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl ( 6a,b ) and N-formyl pyrazolines ( 7a , 7b , 7c , and 7g ) showed inhibitory activity against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-intermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g , 8f , and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC₅₀ values of 11.80, 6.46, and 4.98 μM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent.     

Benzimidazoliumsalze durch nucleophile aromatische Substitution

Benzimidazolium Salts by Nucleophilic Aromatic Substitution Condensation of the N,N′-dimethylbenzamidines 5 or their lithium salts 6 with o-nitrophenyl substituted aryl fluorides leads to the benzamidines 7 . These cyclise on heating up to 100–150° by nucleophilic aromatic substitution to form the benzimidazolium nitrites 9 . The 1,3-dimethyl-2-phenyl-5-nitrobenzimidazolium nitrite 9a is hydrolysed by methanolic potassium hydroxide to yield N-methyl-N-(2-methylamino-5-nitrophenyl)benzamide ( 11 ). The sodium salt of 11 reforms 9a on treatment with nitrosyl tetrafluoroborate. The ring closure 7 → 9 is also deduced from the ¹H-NMR and ¹³C-NMR spectra. The successful cyclisation of the benzamidines 7 depends on two N,N′-alkyl groups and one N-(2-nitrophenyl) group. With N-ethyl-N′-methylbenzamidine it has been shown that the reversible 1,3-shift of an N-(2,4-dinitrophenyl) group is more rapid than the irreversible ring closure to form a benzimidazolium salt (e. g. 19 ? 20 ); with an N-(2-nitrophenyl) group the rates of the 1,3-shift and of the ring closure are of a comparable order of magnitude (e. g. 23?24 → 25).     

Synthesis of (S)-3,4-Diaminobutanenitriles as Precursors for 3-Amino-GABA Derivatives

Starting from natural asparagine ( 1 ) a synthesis of the protected (S)-3,4-diaminobutanenitriles 5 and 8a – c via the β-homoserine derivative 2 is described. The amino function in position 4 was introduced by Mitsunobu-coupling or by reductive amination when a strange deformylation of the amino aldehyde 7 was observed as a side reaction. The Mitsunobu-product 5 was converted into the dibenzylamine substituted GABA 6b which was investigated for its affinity at the GABA-A receptor.     

Synthesis of some new s-alkylated 1,2,4-triazoles, their mannich bases and their biological activities

A series of 1‐(4‐methoxyphenyl)‐2‐[5‐{(biphenyl‐4‐yloxy)methyl}4‐(substituted phenyl)‐3‐mercapto‐(4H)‐1,2,4‐triazol‐3‐ylthio)] ethanones (6a–6s) and 4‐(substituted phenyl)‐3‐(morpholin/pyrrolidin‐4‐ylmethylthio)‐5‐(4‐phenylphenoxymethyl)‐4H‐1,2,4‐triazoles (7a–7e) were synthesized in order to obtain new compounds with potent anti‐inflammatory and analgesic activity with insignificant ulceration. Among the synthesized compounds, ( 6c), (6e), (6g) and (6l) from triazole series and ( 7b) and (7e) from Mannich base series were found to exhibit significant anti‐inflammatory activity with 59.69, 59.69, 64.69, 79.84, 54.54, 79.69% and 52.55, 57.50, 72.52, 83.03, 60.06, 84.08% inhibition of paw edema at 3 h and 5 h respectively, in comparison to the standard drug ibuprofen ( 7 8.93 and 82.58% at 3 h and 5 h). The active compounds were further tested for their analgesic activity and gastric ulceration study. Compounds 6g, 7b and 7e exhibited significant analgesic activity with reaction time ( 3.60, 3.22, 3.88 s ) respectively at 60 min. without causing any gastric irritation. These compounds were also screened for their in vitro antimicrobial activity, Compounds 6f, 6g, 6h, 6l, 6o, 6p, 7a, 7b and 7c showed significant zone of inhibition against various antimicrobial stains. It is concluded that the compounds 6g, 7b and 7e possess a good spectrum of activities. Compound 7e may be considered potent for development of better anti‐inflammatory agent. The antimicrobial activity revealed that most of the compounds showed moderate to significant activity. Compounds containing nitro, chloro, bromo and fluoro group showing better activity. All the compounds from 7a, 7b and 7e were active against gram positive bacteria (S. aureus).     

Adenosine deaminase inhibitors. Synthesis and biological evaluation of (+/-)-3,6,7,8-tetrahydro-3-[(2-hydroxyethoxy)methyl]imidazo[4,5-d] [1,3]diazepin-8-ol and some selected C-5 homologues of pentostatin

The synthesis of several analogues of (8R)-3-(2-deoxy-beta-D-erythro- pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin, 1a) is described. Ring closure of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride (3) with triethyl orthoacetate or triethyl orthopropionate gave the C-5 methyl and ethyl ketoaglycons, 6,7-dihydro-5-methylimidazo[4,5-d][1,3]diazepin-8(3H)-one (4b) and 5-ethyl-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (4c), respectively. Stannic chloride catalyzed condensation of the pertrimethylsilyl derivatives of 4b and 4c with a protected glycosyl halide afforded anomeric mixtures of ketonucleosides 3-(2-deoxy-3,5-di-O-p-toluoyl-beta- and -alpha-D-erythro-pentofuranosyl)-6,7-dihydro-5-methylimidazo[4,5-d] [1,3]diazepin-8(3H)-one (5b and 6b) and 3-(2-deoxy-3,5-di-O-p-toluoyl)-beta- and -alpha-D-erythro-pentofuranosyl)-5-ethyl-6,7-dihydroimidazo[4,5-d]- [1,3]diazepin-8(3H)-one (5c and 6c), respectively. Subsequent separation of the anomers, followed by deprotection and reduction of 5b, 6b, and 5c, afforded the respective 8R and 8S isomers. Stannic chloride catalyzed condensation of pertrimethylsilyl ketoaglycon 4a with 2-(chloromethoxy)-1-(p-toluoyloxy) ethane to give ketonucleoside 6,7-dihydro-3-[[2-(p-toluoyloxy)ethoxy] methyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one (9a) was followed by deprotection to 6,7-dihydro-3[(2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3] diazepin-8(3H)-one (9b) and then reduction to the racemic acyclic pentostatin analogue (+/-)-3,6,7,8-tetrahydro-3-[ (2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3]diazepin-8-ol (2). Ki values for the in vitro adenosine deaminase (EC 3.5.4.4; type I; calf intestinal mucosa) inhibitory activities of 1b, 1c, and 2 were determined to be 1.6 X 10(-8), 1.5 X 10(-6), and 9.8 X 10(-8) M, respectively. When compounds 2 and 9b were tested in combination with vidarabine against herpes simplex virus, type 1, in an HEp-2 plaque reduction assay, only compound 2 was able to potentiate the antiviral activity of vidarabine.     

Synthese und pharmakologische Prüfung von 2- und 3-substituierten Pyrano[2,3-b]indolonen

Synthesis and Pharmacological Test of 2- and 3-Substituted Pyrano[2,3-b]indolones . The condensation of oxindole (3a) with ethyl 2-methylacetoacetate (6b) leads to the propionyloxindole 4 . With the acetal esters 6f, 6g and 6h and the cyclic β-ketoesters 12, 13 and 14 the reaction results in the 3-acyloxindoles 7f, 7c , and 7d or 7h and 15a, 15b, 15c . These can be cyclised to the 2- and 3-substituted pyrano[2,3-b]indolones 16a–16c and 17a–17c .