Alkylierungs-, Arylierungs- und Acylierungsreaktionen von 4,5-Dihydro-2H-3-benzothiepin-1-on und seinem Sulfon

Alkylation, Arylation and Acylation Reactions of 4,5-Dihydro-2H-3-benzothiepin-1-one and its Sulfone After deprotonation of the CH acidic methylene group in position 2, 4,5-dihydro-2H-3-benzothiepin-1-one ( 1a ) and its sulfone 1b were reacted with methyl iodide, ethyl bromide, n-butyl bromide, benzyl bromide, 1-fluoro-2,4-dinitrobenzene, benzoyl chloride, methyl chloroformate, diethylcarbamoyl chloride, esters of chloroacetic acid, chloroacetonitrile, chloromethoxymethane or 2-dialkylaminoethyl chloride. Depending on the nature of the electrophile, mono- or di-substitution at C-2 or O-substitution to yield enol ethers take place.     

芳氧乙基季銨盐的制备

为了寄生虫病的实驗治疗,制备了一系列β-芳氧乙基季銨盐。带有各种不同取代基团的苯酚与二甲基或二乙基β-氯乙基胺在丙酮溶液中于无水碳酸鉀的作用下縮合,成为相应β-芳氧乙基二甲基或二乙基胺,后者也可由各該苯酚先与过量溴化乙烯縮合成1-芳氧基-2-溴乙烷,再与二甲胺或二乙胺作用制成。这些胺化合物再与碘甲烷、溴化苄或溴化对硝基苄共热,便成相应β-芳氧乙基季銨盐。对硝基苯基β-溴乙基硫醚与三甲胺縮合,生成对硝基苯巯乙基三甲基季銨盐。     

Zur Thermolyse von Mannich-Basen aus β-Ketosulfoxiden,Benzaldehyd und sekundären Aminen

Thermolysis of Mannich Bases from β-Ketosulfoxides, Benzaldehyde and Secondary Amines By condensation of ω-(methylsulfinyl)acetophenone (1) with benzaldehyde and secondary amines stable Mannich bases 2 are obtained as mixtures of four diastereomeric forms according to the presence of three chiral centers. Amine elimination above 180°C leads to a single E-diastereomer of 2-methylsulfinyl-1,3-diphenylpropenone (3) as indicated by the ¹H and ¹³C-NMR spectra.     

Synthesis of NCA [carbonyl‐11C]amides by direct reaction of in situ generated [11C]carboxymagnesium halides with amines under microwave‐enhanced conditions

No‐carrier‐added (NCA) aromatic and aliphatic [carbonyl‐¹¹C]amides were rapidly (<5 min) synthesized in one pot in useful radiochemical yields (20–65%, decay‐corrected) by directly coupling amines with NCA [¹¹C]carboxyhyphenmagnesium halides generated in situ from Grignard reagents and cyclotron‐produced [¹¹C]carbon dioxide. In this system cyclohexylcarboxymagnesium chloride ( 1b ) is more reactive than 4‐fluorophenylcarboxymagnesium bromide ( 2b ) and primary amines (e.g. aniline, aminopyridines) far more reactive than secondary amines (e.g. 2‐(methylamino)pyridine). The scope of the reaction was widened considerably by the application of microwaves, which allowed reactions to be carried out at much higher temperature than the boiling point of the solvent (i.e. tetrahydrofuran, b.p. 67°C). Copyright © 2003 John Wiley & Sons, Ltd.     

新类型酸性色素定量胺类化合物的研究:羊毛罂粟蓝测定胺类药物

前报报道了自70种色素中研究选出测定胺类的两种色素之一:二甲苯蓝(XC)⁽¹⁾,本文报道另一种色素:羊毛罂粟蓝(EG)。经研究得出:EG对亲脂性较大的胺,苯乙托品(Ⅰ)⁽²⁾的检出限为15ng/ml,苯乃辛(Ⅱ)⁽²⁾为20 ng/ml,其吸收系数(E_{1cm^1%)(Ⅰ为36.89×10²,Ⅱ为24.36×10²)为溴百里酚蓝(BTIJ)的4.6～5.9倍。EG—胺配合物的氯仿液呈绿蓝色,λmax635.5nm。测定时色素浓度应为2×10^-3mol/L。检量线在0～7(Ⅰ)与0～10(Ⅱ)μg/ml为直线。EG—胺配合物的分子比在EG浓度为2×10^-3mol/L时,EG:Ⅱ=1:1;2×10^-4mol/L时则为0.5:1。Ⅰ则在EG浓度不同时分子比基本不变,为1.3:1。用EG测定Ⅰ或Ⅱ0.2μg/ml时,CV在±5%以内;2.5,5.0,10.0μg/ml时为±1～2%。EG与XC一样,为文献上尚未用来测定胺类的新类型酸性色素,属同一类,其基本构造为:}     

Increased acetone exhalation induced by metabolites of halogenated C1 and C2 compounds

Rats were exposed, in a closed desiccator jar chamber, to concentrations of various halogenated C₁ and C₂ compounds at which the metabolizing capacities were saturated (V _max conditions). Within the exposure period of 50 h concentrations of the xenobiotic and of exhaled acetone were monitored in the gas phase of the system. The quantitative extent of acetone exhalation was dependent on the individual compound examined. Acetone exhalation was stimulated in presence of vinyl chloride, vinyl bromide, vinyl fluoride, vinylidene fluoride, cis-and trans-1,2-di-chloroethylene, trichloroethylene, perchloroethylene, methylene chloride, chloroform, carbon tetrachloride and 1,1,2-trichloroethane. No stimulation of acetone exhalation occured with 1,1,1-trichloroethane and with the reference hydrocarbon n-hexane. Also, acetone exhalation was evoked by infusions of either fluoroacetate or chloroacetate, two anticipated or proven metabolites of some haloethylenes; the infusion rates of which were based on calculations of the metabolic rates of vinylidene fluoride and of vinyl chloride, respectively.     

Cadmium exposure increases susceptibility to testicular autoimmunity in mice

Cadmium, one of various environmental toxicants, is known to suppress systemic immunity and to injure the testicular capillary endothelia with resultant necrosis of testicular tissues in mice and rats treated with high doses. Recently, it also became evident that cadmium can affect the integrity of the blood–testis barrier (BTB), the endocrine function of Leydig cells, apoptosis of germ cells and systemic immunity, even on treatment with a low dose that does not induce spermatogenic disturbance. Experimental autoimmune orchitis (EAO), i.e., an organ‐specific autoimmunity of the testis, can be induced by repeated immunization with testicular antigens, and its pathology is characterized by lymphocytic inflammation and spermatogenic disturbance. In the present study, we investigated the morphological and functional changes of testes in mice treated with a low dose of cadmium chloride (CdCl₂) and also examined its toxicity as to susceptibility to EAO. The results showed that exposure to 3 mg CdCl₂ kg^?1 body weight did not affect the spermatogenic state. However, the BTB at the tubuli recti and the rete testis, but not the seminiferous tubules, was slightly weakened, and intra‐testicular mRNA expression of interleukin (IL)‐6, tumor necrosis factor‐α and IL‐1β was significantly increased by the CdCl₂ treatment. Furthermore, immunization with testicular antigens after the CdCl₂ exposure significantly augmented the EAO severity. Therefore, exposure to a low dose of CdCl₂ induces no significant disturbance of spermatogenesis, however, it does change the immunological microcircumstances in the testis, resulting in increased susceptibility to testicular autoimmunity. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of a deuterium‐labelled standard of bufotenine (5‐HO‐DMT)

The Batcho–Leimgruber strategy was employed to synthesize 3‐(2‐dimethylamino‐[²H₄]‐ethyl)‐1H‐indol‐5‐ol (bufotenine, 5‐HO‐DMT) ( 8 ) from commercial 3‐methyl‐4‐nitro‐phenol ( 1 ), benzyl bromide and N,N–dimethylformamide–dimethylacetal. Compound 4 was synthesized from compound 3 using the Batcho–Leimgruber strategy in the presence of Raney nickel and hydrazine hydrate. Compound 4 was treated with oxalyl chloride, dimethylamine and lithium aluminum [²H₄]‐hydride to yield [2‐(5‐benzyloxy‐1H‐indol‐3‐yl)‐[²H₄]‐ethyl]‐dimethyl‐amine ( 7 ). The benzyl ether in compound 7 was cleaved by hydrogenolysis to give bufotenine 8 . Copyright © 2007 John Wiley & Sons, Ltd.     

Zur Tautomerie von O-Acyl- und O-Alkylidenpropandinitril-Gruppen in Trihalotropolonen und Dithiotropolonen

Tautomerism of O-Acyl and O-Alkylidenpropanedinitrile Groups in Trihalotropolones and Dithiotropolones The thallium(I)-trihalotropolonates 4 react with benzoyl chloride ( 5 ) or (1-chlorobenzylidene)propanedinitrile ( 7 ) to form the O-benzoyl-trihalotropolones 6 or the O-(benzylidenepropanedinitrile)trihalotropolones 8. Both of them show a rapid migration of the O-substituents between the oxygen atoms with very similar ΔG^# and k₂₅ values obtained from NMR spectra. Alkylation of sodium dithiotropolonate ( 10 ) gives rise to the thermolabile dithiotropolone ethers 12 , which decompose on heating before undergoing a thio-Claisen rearrangement. O-Thiobenzoyl-tropolone ( 18 ) has been prepared from tropolone ( 13 ) and thiobenzoyl chloride ( 15 ) or from sodium tropolonate ( 19 ) and dithiobenzoic acid anhydride ( 20 ). 18 too shows a rapid migration of the thiobenzoyl group.     

胆甾醇衍生的几种含硫化合物的合成

1.由3β-溴代-△⁵-胆甾烯与β-氨基乙醇反应,分离得到三种产物:3β-(2′-羟乙基氨基)-△⁵-胆甾烯;3α-(2′-羟乙基氨基)-△⁵-胆甾烯与6-(2′-羟乙基氨基)-3:5-环胆甾烷。2.3β-(2′-羟乙基氨基)-△⁵-胆甾烯经亚硫酰氯作用后,与异硫脲反应可获得3β(2′-异硫脲代乙氨基)-△⁵-胆甾烯。继续水解得3β-(2′-巯乙基氨基)-△⁵-胆甾烯。它们可分别视为N取代的半胱胺或β-氨乙基异硫脲的衍生物。3.由3β-巯基-△⁵-胆甾烯与β-溴代乙胺作用,制得3β-(2′-氨乙基巯基)-△⁵-胆甾烯。后者可视为S取代的半胱胺衍生物。3β-(3′-邻苯二甲酰亚胺丙基代巯基)-△⁵-胆甾烯与3β-(3′,4′,5′-三甲氧基苯甲酰巯基)-△⁵-胆甾烯也由类似方法合成。     

Micromethod for the determination of bupivacaine in maternal and foetal blood during obstetric analgesia

A method for the determination of bupivacaine in maternal and foetal blood during obstetric analgesia is described. The drug and the internal standard, 1-pentyl-2-(2,6-xylylcarbamoyl)-piperidine, are initially extracted into methylene chloride. Perchloric acid is added to retain bupivacaine and the standard as Perchlorates in the organic phase accomplishing a selective separation from less hydrophobic amines. Bupivacaine and the standard are then re-extracted into sulphuric acid, followed by a purification with methylene chloride. The aqueous extract is finally made alkaline and the compounds extracted into 10 μl methylene chloride. This extract is analysed by gas chromatography using a 3% OV-17 column. The standard deviation of the method at therapeutic concentrations is about 10% and the lowest level which can be determined with reasonable accuracy is 15 ng ml^?1.     

Pyridazin-Analoga biologisch aktiver Verbindungen, 2. Mitt. 4-Aryl-pyridazino[4,5-d]pyridazine mit cyclischem Amin-Substituenten an C-1

Pyridazine Analogues of Biologically Active Compounds, II: 4-Arylpyridazino[4,5-d]pyridazines with Cyclic Amine Substituents at C-1 Preparation of the title compounds 6a-f by treatment of the 1-chloro-4-arylpyridazino[4,5-d]pyridazines 4a,b with various cyclic amines is described. The compounds 4a,b are obtained in satisfying yields by reaction of 4-arylpyridazino[4,5-d]pyridazin-1(2H)-ones with POCl₃ in the presence of pyridine. Some of the new compounds show diuretic activity.     

Carbon‐14 labeling of Saxagliptin (BMS‐477118)

An efficient synthesis of carbon‐14‐labeled Saxagliptin (BMS‐477118) is described. Initial synthesis of the key radiolabeled intermediate (S)‐N‐Boc‐2‐(3′‐hydroxyadamantyl)glycine 2a utilized adamantanemethanol in a 10‐step sequence. To shorten the sequence, 1‐adamantylzinc bromide was reacted with ethyl [1, 2‐¹⁴C]oxalyl chloride catalyzed by [1,1′‐bis(diphenylphosphino)ferrocene]dichloropalladium (II). In five steps, 2b was synthesized in an overall yield of 20% based on ethyl [1, 2‐¹⁴C]oxalyl chloride. Compound 2b was subsequently converted to [¹⁴C] BMS‐477118 in a short sequence. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthese und zentrale Wirkungen von 4-hydroxy-(alkyl)- und 4-amino-(alkyl)-substituierten 2,6-Epoxy-3-benzoxocinen

Synthesis and Central Effects of 4-Hydroxy-(alkyl)- and 4-Amino-(alkyl)-Substituted 2,6-Epoxy-3-benzoxocines The tricyclic hemiacetal 1 is transformed with amines to the N/O-acetals 3 and 10 , with nitromethane to the 4-nitromethyl derivative 13 , and with the Wittig reagents 15a and 15b to the 2-benzopyrans 16 and 19 . Reduction and methylation of 13 yield the tertiary amine 4; through three steps the secondary amine 18 and the tertiary amine 5 are prepared from 16 and 19 , respectively. The 1,3-dioxane ring of all these 2,6-epoxy-3-benzoxocine derivatives exists in the chair conformation with an equatorial C-4 substituent. After application of the amines 5 , 11c , and 18 mice do not show any symptoms of central activity; weak CNS-effects are observed with the alcohols 1 and 2 . For the tertiary amine 4 , which causes considerable central effects (Straub-tail-phenomenon, convulsions, etc.), an ED₅₀ of 78 mg/kg is determined in the mouse “writhing”-test.     

Use of tetrabutylammonium salts of amino acids in peptide synthesis

Tetrabutylammonium (TBA) salts of amino acids and peptides have increased solubility, as compared with that of alkali metals salts, in organic solvents. We have compared the reaction rates for tripeptide formation in methylene chloride from Boc-Gly-Phe activated with various phenols, N-oxysuccinimide and azide, and TBA-salt of tryptophan, as well as Trp-OCH₃. H-Trp-O^? TBA⁺ as an amino component significantly accelerates the rate of reaction. Although a significant degree of racemization has been found, the use of TBA-salt of amino acids and peptides is justified in many cases due to high conversion rates.     

Agonist binding at alpha2-adrenoceptors of human platelets using 3H-UK-14,304: regulation by Gpp(NH)p and cations

Summary The agonist/₂-adrenoceptor interactions at human platelet membranes have been examined in radioligand binding studies with the full agonist ligand ³H-UK-14,304 [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] and the antagonist ligand ³H-yohimbine. From association kinetics of different concentrations of ³H-UK-14,304 (0.75–8.1 nmol/l) a K _D-value of 2.37 nmol/l in agreement with the high-affinity KD-value (K _DH = 1.60 ± 0.15 nmol/1) obtained from equilibrium binding studies was derived. In the presence of Gpp(NH)p about 6% of specific radioligand binding was observed in the association reaction. Addition of Gpp(NH)p at equilibrium resulted in a rapid loss (t _1/2 < 1 min) of 80% of bound radioligand. Dissociation after addition of an excess of phentolamine (10 mol/l) showed a biphasic time course independent of the radioligand concentration with the proportions of /15 of rapidly (t _/12 < 2 min) and /45 of slowly dissociating ligand (k–1 = 0.033±0.004 min^–1). Application of a sequential binding model resulted in K _D-values from this approach also in agreement with K _DH from equilibrium binding studies. The rank order of potency for different agonists and antagonists to compete for binding with ³H-UK-14,304 indicated an ₂-adrenoceptor interaction: (–)adrenaline > clonidine > (–)noradrenaline > (–)isoprenaline and yohimbine = rauwolscine > phentolamine > prazosin >- corynanthine > timolol respectively. The analysis of competition isotherms of UK-14,304 versus ³H-yohimbine (Hill-coefficient = 0.59 ± 0.03) showed that the agonist binds to two affinity states of the ₂-adrenoceptor, with high (K _DH = 1.77 ± 0.50 nmol/l) and low affinity (K _DL = 71.2 ± 11.6 nmol/l) respectively. From these experiments a fraction of 56.9%±2.1% of the total number of ₂-adrenoceptors (B _max = 198.4 ± 8.0 fmol/mg of protein) in the high-affinity state was calculated. Similar results were obtained from ³H-UK-14,304 saturation isotherms according to a two-state binding model (K _DH = 1.60±0.15 nmol/l; K _DL = 66.2±10.7 nmol/l; B _maxH = 57.6% ± 2.3%). Adrenoceptor agonists competed for specific binding of ³H-UK 14,304 and ³H-yohimbine in a manner that suggests that the ³H-UK-14,304 (3.5 nmol/l) labeled sites represent predominantly the agonist induced or stabilized high-affinity state of the ₂-adrenoceptor. Adrenoceptor antagonists had equal affinities irrespective of the receptor states labeled by the agonist or antagonist radioligand. A loss of the high-affinity binding capacity (B _maxH) of the agonist due to the presence of Gpp(NH)p was delineated from ³H-UK-14,304 saturation isotherms. An IC₅₀-value of 0.181 ± 0.007 mol/l for this Gpp(NH)p-effect was calculated. Divalent cations such as magnesium and manganese (10 mmol/l) increased specific binding of ³H-UK-14,304 by a factor of 3, without any influence on binding of the antagonist ³H-yohimbine. In contrast, sodium chloride strikingly decreased high-affinity binding of the agonist radioligand (IC₅₀ = 41.9 ± 3.7 mmol/l). Unlike Gpp(NH)p, sodium chloride (> 30 mmol/l) additionally promoted a marked decrease of the affinity of UK-14,304 at the low-affinity binding component. In contrast to the effects on agonist binding, sodium chloride concentrations of 30 to 300 mmol/l increased the binding affinity of the antagonist ³H-yohimbine about 2-fold. The sodium substitute N-methyl-D-glucamine was without effect on binding of ³H-UK-14,304 indicating that the influence of sodium chloride on binding properties was not due to changes in osmolarity. In conclusion these results suggest that ³H-UK-14,304 labels preferentially the agonist induced or stabilized high-affinity state (_2H) of the platelet ₂-adrenoceptor.Abbreviations UK 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline - Gpp(NH)p guanylyl-imidodiphosphate - EDTA ethylene dinitrilo tetraacetic acid Preliminary data were presented at the Joint Meeting of the Belgian, Dutch and German Pharmacological and Toxicological Societies at Aachen, FRG, September 23–26, 1985 (Schloos et al. 1985)This report is part of the thesis to be presented by J. Schloos in partial fulfillment of the requirements for a Doctor of Natural Science degree Send offprint requests to J. Schloos at the above address     

3-[p-ω-取代氨基烃氧基)-苯甲酰]-吲哚衍生物的合成

本文根据某些吲哚化合物具有抗生育活性,结合多数非甾体抗生育化合物联有碱性醚链的结构特征,设计并合成了以吲哚为母核的四种类型化合物(Ⅰ_1～7,Ⅱ_1～7,Ⅲ_1～7,Ⅳ₁)22个,并验证了三个熔点与文献报道不符的关键中间体。对小白鼠的初步药理试验表明:所合成的化合物均无抗着床作用;Ⅱ₁,Ⅱ₂,Ⅱ₄和Ⅱ₅有明显的镇痛作用;Ⅲ₂和Ⅲ₃则有较强的抗电休克作用。     

4-Sulfobenzyl ester – an anionic protecting group for peptide synthesis

The preparation of the 4-sulfobenzyl esters of 18 amino acid derivatives is described. This carboxyl protecting group was introduced according to Hubbuch et al. (1980). The caesium or dicyclohexylammonium salts of N-terminal protected amino acids were reacted with 4-(bromomethyl)benzenesulfonate (1). After N-terminal deblocking, the amino acid-4-sulfobenzyl esters were isolated as zwitterions. The protecting group was removable by catalytic hydrogenation and by saponification. The 4-sulfobenzyl esters could be easily converted to amides and hydrazides. They were stable to 2 M hydrogen bromide in acetic acid as well as to a 10-fold excess of trifluoromethane sulfonic acid in trifluoro-acetic acid. The behaviours of ⁺H₂-Gly-Phe-Leu-OBzl-SO^-₃ and the corresponding methyl, benzyl and 4-nitrobenzyl esters were compared under various conditions.     

Herstellung und Reaktionsverhalten eines schwefelverbrückten Bischinolons

Synthesis and Properties of a Sulfur-bridged Bisquinolone Starting with the tosylated enaminone 5 , the novel quinolone derivatives 3, 8, 9 , and 10 were formed by reactions with acetic acid, sulfuryl chloride, and thionyl bromide, respectively. Alkylation of the sulfur-bridged bisquinolone 8 yields the N-substituted quinolones 11 and 12 . Dehydratisation of 8 leads to the novel heterocyclic system 13 . Reaction of 8 with POCI₃ affords the 4-chloroquinoline derivative 14 , from which the sulfoxide 15 can be obtained. The quinoline 14 reacts with thiourea to give the isothiuronium salt 16 . Compound 16 is converted into the dithiino bisquinoline 18 either by heating or via the thione 17 by H₂S elimination.     

Binding of3H-desipramine to the neuronal noradrenaline carrier of rat phaeochromocytoma cells (PC-12 cells)

Summary The specific (i.e., nisoxetine-sensitive) binding of³H-desipramine was studied in purified plasma membranes of PC-12 cells (rat phaeochromocytoma cells).³H-desipramine bound reversibly and with high affinity (K _D=4.5 nmol/l) to a single, non-interacting site (Hill coefficient=1.04); the maximal number of binding sites (B _max) was 19.6 pmol/mg protein.Like the uptake of noradrenaline (by uptake₁), the binding of³H-desipramine was dependent on both sodium and chloride. The stimulation of binding by chloride and sodium was characterized by a Hill coefficient of about 1 and 2, respectively. Both, chloride and sodium, slowed the rate of dissociation of bound³H-desipramine. Increasing concentrations of sodium decreased theK _D of³H-desipramine binding without altering theB _max.The binding of³H-desipramine was inhibited by tricyclic antidepressants and other noradrenaline uptake blockers. There was a highly significant correlation between the potencies of a series of drugs for the inhibition of³H-desipramine binding and for the inhibition of³H-noradrenanne uptake into intact PC-12 cells. Both, binding of³H-desipramine and uptake of³H-noradrenaline, were stereoselectively inhibited by the enantiomers of cocaine and oxaprotiline. However, for most of the substrates of uptake₁ the IC₅₀ for inhibition of³H-desipramine binding was much higher than that for inhibition of³H-noradrenaline uptake. Nevertheless, noradrenaline competitively inhibited³H-desipramine binding and unmasked dissociation of bound³H-desipramine. Thus,³H-desipramine probably binds to the substrate recognition site.From theB _max of³H-desipramine binding to PC-12 membranes and from theV _max of³H-noradrenaline uptake into PC-12 cells, a duration of about 400 ms for the transport cycle for a single noradrenaline molecule was calculated. In addition, from theB _max the maximum number of³H-desipramine binding sites (carriers) for a single PC-12 cell was calculated to be 55,000.A part of this study was presented at the IUPAHR 9th International Congress of Pharmacology (Bönisch et al. 1984)This study was supported by the Deutsche Forschungsgemeinschaft (Bo 521 and SFB 176)