埃索美拉唑镁的合成

2-羟甲基-3,5-二甲基-4-硝基吡啶经氯化亚砜氯化后得2-氯甲基-3,5-二甲基-4-硝基吡啶盐酸盐(3),3与5-甲氧基-2-巯基苯并咪唑缩合得5-甲氧基-2[(3,5-二甲基-4-硝基-2-吡啶基)甲硫基]-1H苯并咪唑(4),4经不对称氧化得5-甲氧基-2-[[(3,5-二甲基-4-硝基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(5),5再通过甲氧基化后得埃索美拉唑钠(6),最后6与氯化镁反应得埃索美拉唑镁,总收率约73.6％(以2-羟甲基-3,5-二甲基-4-硝基吡啶计).     

奥美拉唑产品中二种杂质的制备

为对奥美拉唑产品中的杂质进行定量控制,以2-巯基-5-甲氧基-IH-苯并咪唑和2-氯甲基-3,5-二甲基-4-甲氧基吡啶经缩合、氧化制得2个奥美拉唑杂质--5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基)甲磺酰基]-1H-苯并咪唑和5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基-1-氧化物)甲磺酰基]-1H-苯并咪唑,并经核磁共振和质谱确证结构.     

H~+、K~+-ATP酶抑制剂Pantoprazole Sodium

合成反应是由3-甲氧基-2-甲基-4硝基吡啶-N-氧化物(Ⅰ)或4-氯-3-甲氧基-2-甲基吡啶-N-氧化物(Ⅱ)在热的甲醇中和甲醇钠反应产生3,4-二甲氧基-2-甲基吡啶-N-氧化物(Ⅲ),Ⅲ在90℃酸酐中异构化,并用NaOH水解转化为2-羟甲基-3,4-二甲氧基吡啶(Ⅳ),Ⅳ和SOCl_2在CH_2Cl_2起反应生成相应的2-氯甲基-3,4-二甲氧基吡啶鎓盐(Ⅴ);Ⅴ和5-二氟甲氧基-2-巯基苯并咪唑(Ⅵ),在热甲醇中通过NaOH缩合产生5-(二氟甲氧基)-2[[(3,4-二甲氧基-2-吡啶     

S-泮托拉唑钠的合成工艺改进

用2-甲基-3、4-二甲氧基吡啶为原料,经氯化亚砜氯化后得2-氯甲基-3、4-二甲氧基吡啶盐酸盐,再和5-二氟甲氧基-2-硫基-1H-苯并咪唑进行缩合反应,再经不对称氧化得S-泮托拉唑,再经氢氧化钠成盐后得S-泮托拉唑钠。     

奥美拉唑杂质的合成

目的研究奥美拉唑杂质:2-[(5-甲氧基-1 H-苯并咪唑-2-亚磺酰基)甲基]-3,5-二甲基-4-羟基吡啶的合成方法。方法以2-氯甲基-4-甲氧基-3,5-二甲基吡啶盐酸盐(CMML)为原料,通过脱甲基、缩合、氧化三步反应制得2-[(5-甲氧基-1 H-苯并咪唑-2-亚磺酰基)甲基]-3,5]二甲基-4-羟基吡啶。结果合成的目标化合物经核磁共振氢谱、核磁共振碳谱及质谱确证。结论该合成通过三步得到目标化合物,收率约为23%。     

泰妥拉唑的合成

2,3-二氨基-6-甲氧基吡啶和乙氧基荒酸钾经闭环得到5-甲氧基-1H-咪唑并[4，5-自]吡啶-2-硫醇，再与2-氯甲基-3,5-二甲基-4-甲氧基吡啶缩合后氧化得到抗溃疡药泰妥拉唑，总收率48％。     

艾司奥美拉唑钠两种砜类杂质的一锅法合成研究

目的合成艾司奥美拉唑钠两个砜杂质,加强其质量控制。方法以2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐和2-巯基-5-甲氧基苯并咪唑为起始原料,通过一锅法同时合成艾司奥美拉唑钠的两个砜类杂质:5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]磺酰基]-1H-苯并咪唑(收率为49%)和5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-1-氧代-2-吡啶基)甲基]磺酰基]-1H-苯并咪唑(收率为46%),总收率为95%。结果与结论两个杂质的结构经质谱、核磁共振氢谱确证,纯度均高于99.8%,可作为艾司奥美拉唑钠原料药和制剂研究质量控制的标准品。本工艺采用一锅法同时合成两种砜类杂质,该法操作简单、条件温和、纯度高、收率高、成本低。     

罗氟司特的合成

3,4-二羟基苯甲醛与二氟一氯甲烷醚化得到3-羟基-4-二氟甲氧基苯甲醛,与氯甲基环丙烷醚化得到3-环丙基甲氧基-4-二氟甲氧基苯甲醛,再经氧化、氯代后与4-氨基-3,5-二氯吡啶反应,制得慢性阻塞性肺病治疗药罗氟司特,总收率约23％.     

奥美拉唑磺酰化物的制备

目的:提供一种制备奥美拉唑磺酰化物的简单方法.方法:2-巯基-5-甲氧基苯并咪唑和2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐经缩合、氧化可制得奥美拉唑.奥美拉唑再用高锰酸钾氧化可得到奥美拉唑磺酰化物,产品经IR、1H-NMR、MS、UV确证结构.结果与结论:本方法步骤简单,条件温和,后处理方便,所得奥美拉唑磺酰化物纯度达99%以上.     

泮托拉唑钠的合成

以2-氯甲基-3,4-二甲氧基吡啶盐酸盐和5-二氟甲氧基-2-巯基-1H-苯并咪唑为原料,用二氯甲烷和水作溶剂,经相转移催化缩合反应、用次氨酸钠氧化、成盐反应三步"一锅法"制得泮托拉唑钠,总收率约75%。     

Oxidation of 5-hydroxypyrimidine nucleosides to 5-hydroxyhydantoin and its alpha-hydroxy-ketone isomer

The reaction of hydroxyl radicals with 2'-deoxycytidine (dCyd), as well as the decomposition of dCyd radical cations, leads to a complex mixture of oxidation products in aqueous aerated solutions. The oxidation of dCyd gives products with a relatively low oxidation potential that are highly susceptible to further oxidation, including 5-hydroxy-2'-deoxycytidine (5-oh-dCyd) and 5-hydroxy-2'-deoxyuridine (5-oh-dUrd). Previously, we showed that the oxidation of 2'-deoxyuridine (dUrd) involves the formation of dialuric acid and isodialuric acid intermediates, followed by ring contraction to N1-(2-deoxy-beta-D-erythro-pentofuranosyl)-5-hydroxyhydantoin (5-oh-dHyd). In this work, we have examined the oxidation of 5-oh-dCyd and 5-oh-dUrd in greater detail. The oxidation of these substrates by Br2 led to a similar profile of intermediate and stable products indicating that the dialuric and isodialuric acid derivatives of dCyd largely undergo deamination before they transform into 5-oh-dHyd. Analysis of the final mixture of oxidation products by HPLC revealed the formation of two novel products. On the basis of NMR and MS, these products were identified as the diastereomers of N1-(2-deoxy-beta-D-erythro-pentofuranosyl)-5-hydroxyimidazolidine-2,5-dione (iso-4-oh-dHyd). These products arise from alpha-hydroxy-ketone isomerization of 5-oh-dHyd. The isomerization of 5-oh-dHyd to iso-4-oh-dHyd was reversible, and each diastereomer produced a specific diastereomer of the other structural isomer. The rate of isomerization was accelerated in going from pH 5 to pH 9, whereas all isomers decomposed at higher pH. In contrast, interconversion between each pair of diastereomers was minor. Thus, we conclude that the oxidation of 5-oh-dCyd or 5-oh-dUrd gives a mixture of four isomers of 5-oh-dHyd and iso-4-oh-dHyd as final products. The biological consequences of dCyd oxidation may ultimately depend on the effects of these products.     

Determination of cytochrome P450 enzymes involved in the metabolism of (-)-terpinen-4-ol by human liver microsomes

The in vitro metabolism of (-)-terpinen-4-ol was examined in human liver microsomes and recombinant enzymes. The biotransformation of (-)-terpinen-4-ol was investigated by gas chromatography-mass spectrometry. (-)-Terpinen-4-ol was found to be oxidized to (-)-(1S,2R,4R)-1,2-epoxy-p-menthan-4-ol, major metabolic product by human liver microsomal P450 enzymes. The formation of metabolites of (-)-terpinen-4-ol was determined by relative abundance of mass fragments and retention times on GC. CYP2A6 in human liver microsomes was a major enzyme involved in the oxidation of (-)-terpinen-4-ol by human liver microsomes, based on the following lines of evidence. First, of 11 recombinant human P450 enzymes tested, CYP2A6 had the highest activity for oxidation of (-)-terpinen-4-ol. Second, oxidation of (-)-terpinen-4-ol was inhibited by (+)-menthofuran. Finally, there was a good correlation between CYP2A6 maker activity and (-)-terpinen-4-ol oxidation activities in liver microsomes of 10 human samples. Kinetic analysis showed that the V(max)/K(m) values for (-)-(1S,2R,4R)-1,2-epoxy-p-menthan-4-ol catalysed by liver microsomes of human sample HH-18 was 2.49 μL/min/nmol. Human recombinant CYP2A6 catalysed (-)-(1S,2R,4R)-1,2-epoxy-p-menthan-4-ol with V(max) values of 13.9 nmol/min/nmol P450 and apparent K(m) values of 91 μM.     

Doxazosin treatment and peroxidation of low-density lipoprotein among male hypertensive subjects: in vitro and ex vivo studies.

Doxazosin is an antihypertensive drug that gives rise to 6- and 7-hydroxydoxazosin during hepatic metabolism. The structures of the hydroxymetabolites suggest that they may possess antioxidative properties. The aim of the present study was to examine whether doxazosin and 6- and 7-hydroxydoxazosin were able to scavenge free radicals and whether these compounds might protect low-density lipoprotein (LDL) against in vitro and ex vivo oxidation. Both 6- and 7-hydroxydoxazosin showed radical scavenging capacity as assessed by measuring scavenging of 1,1-diphenyl-2-picrylhydrazyl radicals. In vitro incubation with 10 microM 6- and 7-hydroxydoxazosin significantly reduced human mononuclear cell-mediated oxidation of LDL, measured as the formation of lipid peroxides and the relative electrophoretic mobility of LDL (to 10 and 6% of the control, respectively). Furthermore, formation of conjugated dienes in LDL during Cu2+-induced oxidation was significantly reduced in the presence of 5 microM 6- and 7-hydroxydoxazosin (to 28% of tmax [time to maximum] of control). However, treatment of hypertensive patients with increasing doses of doxazosin (from 1 to 8 mg/day) for 8 weeks altered neither Cu2+-catalyzed, 2,2'azobis-(2-amidinopropane hydrochloride)-initiated, nor cell-mediated oxidation of patient LDL ex vivo. Furthermore, the total antioxidative capacity of plasma was unaffected by treatment. In conclusion, the present study shows that 6- and 7-hydroxydoxazosin have radical scavenging properties and protect LDL against in vitro oxidation. However, treatment of hypertensive male subjects with increasing doses of doxazosin for 8 weeks did not affect ex vivo oxidation of LDL.     

Reactivity of peroxynitrite versus simultaneous generation of (*)NO and O(2)(*)(-) toward NADH

The oxidation of NADH by peroxynitrite takes place indirectly via the radical intermediates formed during the self-decomposition of peroxynitrite, i.e., (*)OH and (*)NO(2), and the oxidation yield exceeds 29% at relatively high NADH concentrations. The efficiency of oxidation of NADH by peroxynitrite is hardly affected by the presence of bicarbonate at physiological pH, and is remarkably increased when authentic peroxynitrite is replaced by low and equal fluxes of (*)NO and O(2)(*)(-). We determined the rate constants for the reactions of NADH with (*)OH, CO(3)(*)(-), and (*)NO(2) to be (2. 0 +/- 0.2) x 10(10), (1.4 +/- 0.3) x 10(9), and (4.0 +/- 2.0) x 10(3) M(-)(1) s(-)(1), respectively. We show that the reaction of NADH with (*)OH in aerated solution does not form O(2)(*)(-), whereas the other one-electron oxidants oxidize NADH to NAD(*), which in turn very efficiently reduces oxygen to O(2)(*)(-). These results suggest that at physiological pH the oxidation of NADH by peroxynitrite in the absence or presence of bicarbonate occurs mainly through the reactions of NADH with (*)OH or CO(3)(*)(-), which are formed in about equal yields. The oxidation of NADH by continuous generation of (*)NO and O(2)(*)(-) proceeds via a chain mechanism, and therefore, the oxidation yield increases upon decreasing the flux of the radicals, and is higher than that obtained with authentic peroxynitrite.     

Oxidation of carbovir, a carbocyclic nucleoside, by rat liver cytosolic enzymes. Enantioselectivity and enantiomeric inhibition.

Previous metabolism studies of (-)-cis-carbovir (1'R-cis-2-amino-1,9-dihydro-9-[4'S-hydroxymethyl-2-cyclopenten-1- yl]-6H- purin-6-one), an antiviral agent, have shown that the major route of metabolism of carbovir in the rat is oxidation of the methylene hydroxyl group of the cyclopentadiene ring to form the corresponding 4'-carboxylic acid metabolite. We have determined that rat hepatic alcohol dehydrogenase and aldehyde dehydrogenase are responsible for this biotransformation through sequential oxidation of the alcohol through the aldehyde to the carboxylic acid. The results of incubations of racemic (+/-)-cis-carbovir with rat liver cytosol showed that this oxidation occurs enantioselectively favoring the (+)-enantiomer by a factor of 6- to 7-fold. We have proven that alcohol dehydrogenase contributes to the enantioselectivity of the overall oxidation process, but were unable to determine whether or not any contribution is made by aldehyde dehydrogenase. Parallel incubations conducted with the separate enantiomers revealed that the concentration required to achieve a half-maximal rate for the oxidation of the (+)-enantiomer (0.27 mM) was one-fifth that required for the (-)-enantiomer (1.36 mM). Results from enantiomeric inhibition studies showed that (+)-carbovir inhibited the oxidation of (-)-carbovir. In contrast, (-)-carbovir did not inhibit the oxidation of (+)-carbovir.     

Inhibition of human low density lipoprotein and high density lipoprotein oxidation by oligostilbenes from rhubarb

The objective of the present study was to elucidate the beneficial properties of ampelopsine B (1) and epsilon-Viniferin (2), two oligostilbenes isolated from rhubarb, toward cardiovascular disease by protecting human lipoproteins against lipid peroxidation. In low density lipoprotein (LDL) oxidation, both 1 and 2 exert an inhibitory activity against Cu(2+)-, 2,2'-azobis-(2-amidinopropane) hydrochloride (AAPH)-induced, as exhibited by prolongation of lag time from 52 to 118 and 136 min, respectively, and also increasing the lag time 38 to 105 and 128 min in high density lipoprotein (HDL) oxidation for 1 and 2, respectively, at the concentration of 3.0 microM. In generation of thiobarbituric acid reactive substances (TBARS), compounds 1 and 2 inhibited LDL oxidation mediated by either catalytic Cu(2+) or thermo-labile radical initiator (AAPH) in a dose-dependent manner with IC(50) values of 3.6 and 6.0 microM for 1, and 1.7 and 3.2 microM for 2, respectively. In addition, compounds 1-2 also showed strong ability to protect HDL oxidation induced by both Cu(2+) and AAPH with low IC(50) values. The results suggest that oligostilbenes 1-2 may have a role in preventing lipoprotein oxidation.     

Activation of the carcinogen N-hydroxy-N-(2-fluorenyl)benzamide via chemical and enzymatic oxidations. Comparison to oxidations of the structural analogue N-hydroxy-N-(2-fluorenyl)acetamide.

Chemical or enzymatic oxidations of the carcinogen N-hydroxy-N-(2- fluorenyl)benzamide (N-OH-2-FBA) were investigated under the conditions facilitating one-electron oxidation or oxidative cleavage of N-hydroxy-N-(2-fluorenyl)acetamide (N-OH-2-FAA). HPLC methods were developed for separation and quantitation of the above hydroxamic acids and their respective oxidation products. To identify the products of oxidation of N-OH-2-FBA, N-(benzoyloxy)-2-FBA (N-BzO-2-FBA) was synthesized and shown to undergo ortho rearrangement to 1- and 3-BzO-2-FBA. Oxidation of N-OH-2-FBA (4.88 mM) with alkaline K3Fe(CN)6 in benzene was complete and yielded equimolar amounts of 2-nitrosofluorene (2-NOF) and the ester (chiefly N-BzO-2-FBA), indicative of one-electron oxidation to nitroxyl free radical which undergoes bimolecular dismutation. However, one-electron oxidation of N-OH-2-FBA (30 or 10 microM) by horseradish peroxidase/H2O2 at pH 7 or myeloperoxidase/H2O2 at pH 6.5 yielded only approximately 10% as much product as N-OH-2-FAA (30 microM). The addition of 0.1 mM Br- +/- 0.1 M Cl- at pH 4 to 6.5 increased 2-NOF formation in MPO/H2O2-catalyzed oxidations. Simulations of these oxidations with HOCl/Cl- or HOBr/Br- showed that the latter was more efficient, converting N-OH-2-FAA almost completely and less than or equal to 62% of N-OH-2-FBA to 2-NOF. The amounts of the ester (N- and o-BzO-2-FBA), which by itself did not contribute to 2-NOF formation or significant substrate regeneration, indicated that approximately 10% of 2-NOF originated from one-electron oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of fatty acid oxidation by phosphodiesterase III inhibitors in rat myocytes.

In order to study the regulation of fatty acid oxidation in the heart, the effects of some phosphodiesterase III inhibitors, such as enoximone and milrinone, on the oxidation of [1-14C]palmitic acid, [1-14C]octanoic acid, and [2-14C]pyruvate were studied in adult rat myocytes. Enoximone and milrinone, at a concentration of 0.25 mM, increased palmitate oxidation significantly, by 70 and 40%, respectively. Also, enoximone increased octanoate oxidation by 45%. In contrast, pyruvate oxidation was decreased by 60% by enoximone. To investigate the effects of enoximone or milrinone on the pathway of fatty acid oxidation, their effects on the oxidation of either [1-14C]palmitoyl-CoA or [1-14C]palmitoylcarnitine were studied with rat heart homogenates. Neither enoximone nor milrinone had any effects on the oxidation of these compounds. Compounds known to elevate intracellular [Ca2+] or cyclic AMP, such as the calcium ionophore A23187, ionomycin, dibutyryl cyclic AMP, or isoproterenol, had no effect on palmitate oxidation. Enoximone, at a concentration of 0.25 mM, increased palmitate uptake by 40% in rat myocytes. These results suggest that enoximone and milrinone increase fatty acid oxidation in myocytes by increasing their cellular transport, and they also show the usefulness of these compounds as a tool to study the regulation of this vital pathway in heart.     

Electrooxidation of cetirizine dihydrochloride with a glassy carbon electrode

The electrochemical oxidation of cetirizine dihydrochloride (CTZH) at different pHs and concentrations using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) with a glassy carbon (GC) electrode was studied. This study indicated that CTZH was susceptible to oxidation. The statistical analysis proved that the CV and DPV methods were reproducible and selective for the determination of CTZH. The results showed that voltammetric determination of CTZH could be made in the concentration ranges of 2 x 10(-5) M - 1 x 10(-4) M by CV and 2 x 10(-5) M - 1 x 10(-4) M by DPV with a GC electrode. The oxidation process was found to be irreversible over the pH range studied (2-10) and was shown to be mainly diffusion controlled. The determination of CTZH was performed in phosphate buffers covering the pH range of 2-10. No satisfactory results were obtained in 0.5 M H2SO4 solution. With both of the methods used the best results were obtained in phosphate buffer of pH 8. Application of the suggested methods to pharmaceutical formulations is presented and compared with the first derivative spectrophotometric method. No interference was observed from common pharmaceutical adjuvants.     

Studies on anticoccidial agents. 11. Synthesis and anticoccidial activity of nitropyridinecarboxamides and derivatives.

Of the nine nitropyridinecarboxamides, which are isomers of 5-nitronicotinamide, a potent anticoccidial agent, 2-nitropyridine-3, -4, -5-, or 6-carboxamides and 3-nitropyridine-4- or 6-carboxamides were prepared from the corresponding acids via the esters of the acid chlorides. 3-Nitropyridine-2-carboxamide was obtained from 2-methyl-3-nitropyridine by oxidation with SeO2, oximation, dehydration with Ac2O, and hydrolysis with H2SO4. 4-Nitropyridine-2-carboxamide was prepared from 2-cyano-4-nitropyridine by hydrolysis, and the 3-carboxamide analogue was obtained from 4-amino-3-cyanopyridine by oxidation with H2O2 and fuming H2SO4. Of these compounds 2-nitro- and 3-nitro- but not 4-nitropyridinecarboxamides were found to be active against Eimeria tenella. N-Substituted analogues of 2-nitro- and 3-nitropyridine carboxamides were also prepared in a conventional manner and optimal anticoccidial activity was attained with 2-nitroisonicotinamide and its N-alkanoyl, N-aromatic, and N-heterocyclic acyl derivatives.