Synthese und analgetische Aktivität von 4′.5′-Dimethoxy-3.7-imino-1.2-benzocycloocten-Derivaten

Synthesis and Analgetic Activity of Derivatives of 4′.5′-Dimethoxy-3.7-imino-1.2-benzocyclooctene The synthesis of derivatives of 4′.5′-dimethoxy-3.7-imino-1.2-benzocyclooctene an isomer of 6.7-benzomorphan, is described. The tail flick test for analgetic activity of the hydrochlorides of compounds 15, 16, 20 and 21 shows weak effects of compounds 15, 16 and 21 .     

Synthese eines Biscumarinyläthan-Derivates aus 2,4,3′,5′-Tetrahydroxy-diphenyläthan. 1. Mitt. über Biscumarinyläthane und Biscumarinyläthene

Synthesis of a Biscoumarinylethane Derivative 2,4,3′,5′-Tetrahydroxy-diphenylethane ( 2a ) forms in ethyl acetoacetate/sulfuric acid a biscoumarinylethane-derivative, which can be described as a result of its chemical and spectroscopic properties as 1-[4-methyl-7-hydroxy-coumarinyl-(6)]-2-[4-methyl-5-hydroxy-coumarinyl-(7)]ethane ( 1a ). The synthesis of the biscoumarinylethene derivative 3 from 2,4,3′,5′-tetrahydroxystilbene ( 1a ) or 1,2-dibromo-1-[2,4-diacetoxyphenyl]-2-[3,5-diacetoxyphenyl]-ethane ( 11 ) was not successful.     

Contribution of a significant first‐pass effect of dimethyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylene dioxybiphenyl‐2,2′‐dicarboxylate in the liver to its poor bioavailability in rats

Objectives The objective of this study was to investigate the mechanism responsible for the poor oral bioavailability of dimethyl-4′,4′-dimethoxy-5,6,5′,6′-dimethylene dioxy-biphenyl-2,2′-dicarboxylate (DDB), a hepatoprotective agent, in rats. Methods DDB was intravenously administered to rats at doses of 0.2-1 mg/kg. To determine the hepatic first-pass effect in rats, DDB (1 mg/kg) was administered via the pyloric vein and the femoral vein. Direct measurement of intestinal permeability was attempted using Caco-2 cell monolayers and rat intestinal epithelium. Key findings A moment analysis indicated that the volume of distribution and clearance remained unchanged with the magnitude of the dose, indicating that DDB exhibited linear pharmacokinetics. When the area under the curve for DDB after administration to the pyloric vein was compared with that after femoral vein administration, the ratio (F_H) was found to be 0.294, indicating a significant first-pass effect for DDB. The permeability of DDB was high in the rat intestine (1.78 ± 0.229 × 10⁻⁵ cm/s) and in Caco-2 cell monolayers (6.8 ± 0.70 × 10⁻⁵ cm/s), suggesting that DDB, in soluble form, was readily permeable across the intestinal epithelium. Conclusions These observations indicated that despite the fact that DDB was readily permeable to the intestinal epithelium, a significant first-pass metabolism was associated with its pharmacokinetics in rats.     

Rac‐ and R‐(+)‐[4,4′,5,5′‐2H4]‐2‐(1′‐[2′′,6′′‐dichlorophenoxy]‐ethyl)‐Δ2‐imidazoline (lofexidine)

The synthesis of the d₄‐forms of rac‐ and R‐lofexidine was accomplished. Two methods are described; one method is a two‐step synthesis of rac‐d₄‐lofexidine from 2‐chloropropionitrile, the second method is a three‐step preparation of R‐d₄‐lofexidine in absolute enantiomeric purity from S‐methyl lactate. The commercial availability of R‐methyl lactate makes this latter enantioselective synthesis applicable also to the synthesis of S‐d₄‐ lofexidine. These procedures also conserve the utilization of the relatively expensive [1,1′,2,2′‐²H₄]ethylene diamine precursor. The availability of S‐ and R‐d₄‐lofexidines will enable pharmacokinetic studies to be carried out to determine if differential in vivo metabolism of the two enantiomers of lofexidine occurs. Copyright © 2009 John Wiley & Sons, Ltd.     

Radiosynthesis of the fluorinated sucrose analogue, 1′‐[18F]fluoro‐1′‐deoxysucrose

Fluorinated and deoxysucrose analogues have been proven useful in probing the substrate specificity and roles of sucrose processing enzymes and transporters in plants. To synthesize an ¹⁸F‐labeled fluorodeoxysucrose analogue suitable for in vivo studies, an acyl‐protected, disaccharide‐based radiofluorination precursor (sucrose 1′‐O‐trifluoromethanesulfonyl‐2,3,4,6,3′,4′,6′‐hepta‐O‐acetate; 2) was prepared by regioselective mono‐deacetylation of sucrose octaacetate using a commercial esterase enzyme followed by conversion of the resultant sucrose heptaacetate to the corresponding triflate. Reaction of this triflate precursor with [¹⁸F]fluoride followed by base hydrolysis to remove the acetate groups and HPLC purification gave 1′‐[¹⁸F]fluoro‐1′‐deoxysucrose (4) in an overall synthesis time of 80 min and with a median decay corrected yield of 26% (n = 4). This study demonstrates the use of an enzymatic approach to aid the synthesis of a regiospecific radiofluorination precursor starting from the readily available fully acetylated sugar, thus avoiding the need for a complex classical carbohydrate protection strategy to individually protect each hydroxyl group in the molecule. Copyright © 2012 John Wiley & Sons, Ltd.     

Mammatumorhemmende Antiöstrogene vom Typ des 3,3′-Dihydroxy-α,β-dialkylstilbens

Mammary Tumor Inhibiting Antiestrogens of the 3,3′-Dihydroxy-α,β-dialkylstilbene Type. The trans-3,3′-dihydroxy-α,β-dialkylstilbenes 1, 3–5 are antiestrogens with a marked effect on the DMBA-induced hormone dependent mammary carcinoma of the SD-rat (especially 3 and 4 ). They are synthesized by reaction of (3-methoxyphenyl)diazoalkanes c with SO₂ to give 1,1-dioxo-2,5-dialkyl-2,5-bis-(3-methoxyphenyl)-Δ³-1,3,4-thiadiazolines d . Thermal decomposition yields the 3,3′-dimethoxy-α,β-dialkylstilbenes e which are then subjected to ether cleavage.     

Synthesen von Flavon-2′-carbonsäuren und Chromono-(2′,3′-3,4)-isocumarin-derivaten

Synthesis of Flavone-2′-carboxylic Acids and Chromonoisocoumarines When we tried to synthesize 1,2-bischromonylbenzene derivatives from phthalic acid and o-hydroxy-acetophenone derivatives by Baker-Venkataraman-rearrangement flavone-2′-carboxylic acid derivatives are obtained in one step. This is a simple way to get flavone-2′ carboxylic acids and chromonoisocoumarines.     

Synthesis of tritium‐labelled 3′‐azido‐3′‐deoxythymidine

New approaches to the synthesis of 3′‐azido‐3′‐deoxythymidine labelled with tritium in the heterocyclic base have been developed. With this aim, enzymatic transribosylation with [³H]thymine using the enzyme preparation from rat liver and a three‐step chemical synthesis with use of the tritium labelled precursor were studies. The enzyme preparation did not catalyse the transfer of the 3′‐azido‐3′‐deoxyribosyl fragment to the [³H]thymine residue. 5′‐O‐Benzoyl‐2,3′‐anhydrothymidine was taken as a precursor for the tritium labelling by the chemical methods. The resulting [³H]3′‐azido‐3′‐deoxythymidine was obtained with a specific radioactivity of 18.3 Ci/mmol, the tritium is located in the C‐6 position of the thymine residue. Copyright © 2003 John Wiley & Sons, Ltd.     

Reaktionen von 7-Diphenylmethylen-bis-benzo- 2H-pyrano[4,3-b:3′,4′-e]-4H-pyran-6,8-dion

Reactions of 7-Diphenylmethylene-bis-benzo-2H-pyrano[4,3-b:3′,4′ e]4H-pyran-6,8-dione The title compound is cleaved with nucleophilic reagents to the coumarinyl-butenone 3a or to the biscoumarinyl-ethene-derivatives 4a or 4b . 3a reacts with acetic anhydride or diazomethane to the pyrano-coumarines 6c or 6d ; the coumarinyl-chromonyl-ethene 7 was obtained with dimethylformamide acetal.     

Synthesis of 3′‐deoxy‐3′‐[18F]fluoro‐1‐β‐D‐xylofuranosyluracil ([18F]‐FMXU) for PET

The synthesis of a pyrimidine analog, 3′‐deoxy‐3′‐[¹⁸F]‐fluoro‐1‐β‐D ‐xylofuranosyluracil ([¹⁸F]‐FMXU) is reported. 5‐Methyluridine 1 was converted to its di‐methoxytrityl derivatives 2 and 3 as a mixture. After separation the 2′,5′‐di‐methoxytrityluridine 2 was converted to its 3′‐triflate 4 followed by derivatization to the respective N³‐t‐Boc product 5 . The triflate 5 was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6 , which by acid hydrolysis yielded compound 7 . The crude preparation was purified by HPLC to obtain the desired product [¹⁸F]‐FMXU. The radiochemical yields were 25–40% decay corrected (d. c.) with an average of 33% in four runs. Radiochemical purity was >99% and specific activity was >74 GBq/µmol at the end of synthesis (EOS). The synthesis time was 67–75 min from the end of bombardment (EOB). Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and In‐vitro Activity of 4′‐Modified Analogues of ddA as Potent Anti‐HIV Agents

This paper reports the synthesis of novel 4′‐hydrophobic pocket deoxythreosyl C‐nucleosides. The key threose‐like intermediates 9 and 14 were constructed from acyclic ketone derivatives, respectively. The antiviral activities of the synthesized compounds against the HIV‐1, HSV‐1, HSV‐2, and HCMV viruses were evaluated. The 9‐deaza‐adenine derivatives 10 and 20 showed good anti‐HIV activity without exhibiting significant cytotoxicity.     

Synthesis of all‐trans‐[10′‐3H]‐8′‐apo‐β‐carotenoic acid

The enzyme, 15,15′‐β‐carotene dioxygenase (BCDOX), facilitates the oxidation of β‐carotene to yield retinal. This is a remarkable process in which one of 11 double bonds in β‐carotene is selectively oxidized. To further probe the mechanistic aspects of BCDOX, the synthesis of all‐trans‐[10′‐³H]‐8′‐apo‐β‐carotenoic acid is reported. This compound will be used as a photoaffinity labeling reagent to probe the β‐carotene binding pocket within BCDOX. The synthesis outlines a simple and efficient route for the incorporation of tritium at the 10′ olefinic carbon of 8′‐apo‐β‐carotenoic acid. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [1,2,4]triazolo[3′,4′:3,4][1,2,4]triazino[5,6-b]indole,tetrazolo[5′,1′:3,4][1,2,4]triazino[5,6-b]indole and their Derivatives

Reactions of 5-ethyl 5H-1,2,4-triazino|5,6-b|indol-3-thione ( 1 ) with various reagents have been studied. 1 and hydrazine hydrate in anhydrous ethanol gave 5-ethyl-3-hydrazino-5H-1,2,4-triazino|5,6-b|indole ( 2 ). This compound was condensed with formic acid and acetic acid to give 10-ethyl-10H-|1,2,4|triazolo|3′,4′:3,4||1,2,4|triazino|5,6-b|indole ( 4 , R=H) and 10-ethyl-1 -methyl-10H-|1,2,4|triazolo-|3′,4′:3,4‖ 1,2,4|triazino|5,6-b|indole ( 4 , R = CH₃), respectively. Treatment of 2 with nitrous acid gave 10-ethyl-10H-tetrazolo|5′,1′:3,4‖ 1,2,4|triazino|5,6-b|indole ( 7 ). Interaction of 2 with acetylacetone in alcoholic KOH gave the pyrazole 8 , whereas reaction of 2 with ethyl acetoacetate in anhydrous ethanol led to the expected hydrazone 9 , which on reflux with alcoholic KOH gives 1-(5-ethyl-5H-1,2,4-triazino| 5,6-b|indol-3-yl)-3-methyl-2-pyrazolin-5-one 10 . Treatment of 2 with ethyl chloroformate gives 11 , which can be converted to 10-ethyl-2,10-dihydro-1H-|1,2,4|triazolo|3′,4′:3,4|triazino|5,6-b|-indol-1-one 12 by fusion.     

The synthesis of [3,4,1′‐13C3]genistein

A facile synthesis is described for [3,4,1′‐¹³C₃]genistein for use as an internal standard in isoflavone analysis by mass spectrometric methods. Ethyl 4‐hydroxy[1‐¹³C]benzoate was first prepared from the reaction of diethyl [2‐¹³C]malonate and 4H‐pyran‐4‐one. Two further ¹³C atoms were incorporated using potassium [¹³C]cyanide as the source to give 4′‐benzyloxy‐[1,2,1′‐¹³C₃]phenylacetonitrile. [3,4,1′‐¹³C₃]Genistein was then constructed through coupling of the isotopically labelled phenylacetonitrile with phloroglucinol under Hoesch conditions, followed by formylation and cyclization. Copyright © 2007 John Wiley & Sons, Ltd.     

1,4-Dioxo-2,3-diazachinolizidin und 1,3-Dioxo-2-aza-(2′-amino)-indolizidin

1,4-Dioxo-2,3-diazaquinolizidine and 1,3-Dioxo-2-aza-(2′-amino)-indolizidine The synthesis of 1,4-dioxo-2,3-diazaquinolizidine (1) was successful a) by heating of diethyl piperidyl-1,2-dicarboxylate (3) with anhydrous hydrazine in presence of sodium ethoxide and b) by reaction of picolinic acid hydrazide with ethyl chloroformate to 4 , which was hydrogenated to 7 and condensed in presence of sodium ethoxide to 1 . 1,4-Dioxo-2,3-diaza-(2′,3′-diphenyl)-quinolizidine (9) was obtained from diethyl piperidyl-1,2-dicarboxylate (3) and hydrazobenzene. 3 and hydrazine gave 1,3-dioxo-2-aza-(2′-amino)-indolizidine (12) .     

Fully automated synthesis and purification of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[18F]fluorobenzamido]ethylpiperazine

We have developed an efficient synthesis method for the rapid and high‐yield automated synthesis of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[¹⁸F]fluorobenzamido]ethylpiperazine (p‐[¹⁸F]MPPF). No‐carrier‐added [¹⁸F]F^? was trapped on a small QMA cartridge and eluted with 70% MeCN(aq) (0.4 mL) containing Kryptofix 222 (2.3 mg) and K₂CO₃ (0.7 mg). The nucleophilic [¹⁸F]fluorination was performed with 3 mg of the nitro‐precursor in DMSO (0.4 mL) at 190 °C for 20 min, followed by the preparative HPLC purification (column: COSMOSIL Cholester, Nacalai Tesque, Kyoto, Japan; mobile phase: MeCN/25 mm AcONH₄/AcOH = 200/300/0.15; flow rate: 6.0 mL/min) to afford p‐[¹⁸F]MPPF (retention time = 9.5 min). p‐[¹⁸F]MPPF was obtained automatically with a radiochemical yield of 38.6 ± 5.0% (decay corrected, n = 5), a specific activity of 214.3 ± 21.1 GBq/µmol, and a radiochemical purity of >99% within a total synthesis time of about 55 min. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis,characterization, and monoamine transporter activity of the new psychoactive substance 3′,4′‐methylenedioxy‐4‐methylaminorex (MDMAR)

The recent occurrence of deaths associated with the psychostimulant cis‐4,4′‐dimethylaminorex (4,4′‐DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4‐methylenedioxy‐4‐methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis‐ and trans‐MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis‐isomer (90%). Exposure of the cis‐isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans‐isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non‐selective monoamine releasing agent (+)‐3,4‐methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis‐ and trans‐4,4′‐DMAR, were assessed under identical conditions. cis‐MDMAR, trans‐MDMAR, cis‐4,4′‐DMAR and trans‐4,4′‐DMAR were more potent than MDMA in their ability to function as efficacious substrate‐type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis‐4,4′‐DMAR, cis‐MDMAR and trans‐MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans‐4,4′‐DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring‐substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side‐effects after high dose exposure. Copyright © 2014 John Wiley & Sons, Ltd.     

Pharmacophoric features for a very potent 5‐spirofluorenehydantoin inhibitor of cancer efflux pump ABCB1, based on X‐ray analysis

In order to extend knowledge about pharmacophoric features responsible for ABCB1 inhibitory properties of imidazolidin‐2,4‐dione derivatives, 1′‐[4‐(4‐(o‐methoxyphenyl)‐piperazin‐1‐yl)butyl]‐3′‐methyl‐spiro(fluoren‐9,5′‐imidazolidine)‐2′,4′‐dione ( 3 ) and its salt ( 4 ) with rhodanine‐3‐acetic acid ( RA ) were prepared and investigated by X‐ray diffraction method, as well as their efflux modulating effects in cancer cells (mouse T‐lymphoma), cytotoxic and antiproliferative activities were evaluated in vitro. The molecular geometry, intermolecular interactions, and crystal packing of base and acid forms of 3 were analyzed to see, if conformational changes influence the biological activities. The geometry of 2‐methoxyphenylpiperazine and 5‐spirofluorenehydantoin moieties was compared with other crystal structures containing these fragments. Our results indicated a very potent inhibitory action on ABCB1 pump, and significant cytotoxic and antiproliferative properties of 3 in T‐lymphoma, even more potent in the case of multidrug resistance cells. Furthermore, the compound 3 converted into the salt 4 of inactive acid ( RA ) has maintained both, the efflux pump inhibitory and antiproliferative activities, showing strong synergism with doxorubicin. A comparison of geometry of 3 in both crystal structures ( 3 and 4 ) shows a significant difference in the arrangement of piperazine ring with respect to the aliphatic linker.     

Synthesis and biological evaluation of a lipophilic,fluorine‐18‐labeled 5‐ethynyl‐2′‐deoxyuridine derivative

The synthesis and preliminary biological evaluation of a lipophilic, fluorine‐18‐labeled 5‐ethynyl‐2′‐deoxyuridine derivative [¹⁸F]‐ 3 is described. Initially, 5‐ethynyl‐2′‐deoxyuridine 5 was synthesized by coupling trimethylsilyl protected acetylene to 5‐iodo‐2′‐deoxyuridine 4 , followed by deprotection in alkaline conditions. Compound 5 was then reacted with 4‐(4′‐iodophenyl)phenol to give 5‐[4(4′‐hydroxyphenyl)phenyl]ethynyl‐2′‐deoxyuridine 6 . Compound 6 was reacted with BrCH₂CHF as alkylating agent to give stable or radiolabeled 3 . The crude products were purified using reversed phase‐high performance liquid chromatography to obtain compound 3 and [¹⁸F]‐ 3 in 33 and 7.4% yield (decay corrected), respectively. The synthesis time to obtain pure [¹⁸F]‐ 3 was about 60 min (starting from BrCH₂CHF). The specific radioactivity of the tracer was between 74 and 222 GBq/µmol. The log P_7.4 of [¹⁸F]‐ 3 was found to be 2.4. However, biodistribution study in normal mice showed low uptake of the tracer in the brain. The affinity of compounds 6 and 3 for varicella‐zoster virus thymidine kinase enzyme (VZV‐TK) was examined in vitro and the results revealed that the fluorinated analog 3 has a poor affinity for the enzyme in contrast to the phenol precursor 6 . Copyright © 2007 John Wiley & Sons, Ltd.     

Bequeme Synthese von Bis-3′-0-(5-ethyl-2′-desoxyuridin)-sulfoxid (KK-Ro 258)

Convenient Synthesis of Bis-3′-0-(5-ethyl-2′-deoxyuridine) Sulfoxide (KK-Ro 258) The title compound 4 was prepared by treating 5′-0-trityl-5-ethyl-2′-deoxyuridine with thionyl chloride in a mixture of dichloromethane and pyridine. The trityl group was removed by standard procedures.