萘丁美酮的简便合成

萘丁美酮化学名为4-(6-甲氧基-2-萘基-2-丁酮(1)是非留体消炎镇痛解热药。对肠胃道刺激性较轻,易于耐受。从2-溴-6-甲氧基萘开始,与3-丁烯-2-醇(2)或3-丁烯-2-酮(甲基乙烯酮,3)在钯催化下进行偶合分别以1步法或2步法得到成品1。与2反应时选用催化剂为(ph_3P)_3PdCl~2或ph_3P加Pd(OAc)_2,另加NaHCO_3在1-甲基-2-吡咯烷酮(NMP)中140℃反应5小时,1的收率分别为65和60%。不饱和醇4可能为中间体,经异构化而生成1。与3反应时催化剂为(ph_3P)_2PdCl_2,在NMP中加压130℃反应3小时,得收率90%     

1-[2-(2,4-二氟苯基)-2,3-环氧丙基]-1H-1,2,4-三唑甲烷磺酸盐的合成

1- [2 - ( 2 ,4-二氟苯基 ) - 2 ,3-环氧丙基 ]- 1 H- 1 ,2 ,4-三唑甲烷磺酸盐 ( 1 )是合成氟康唑等抗真菌药物的关键中间体。文献 [1]以间二氟苯 ( 2 )为原料 ,与氯乙酰氯反应生成 α-氯 - 2 ,4-二氟苯乙酮 ( 3) ,3在甲苯中与三唑反应生成 2 ,4-二氟 - α- ( 1 H- 1 ,2 ,4-三唑 - 1 -基 )苯乙酮 ( 4 ) ,4与 ylid试剂碘化三甲基硫盐反应形成环氧化物 ,再与甲磺酸成盐得到 1。此法第 2步和第 3步收率均很低 ,分别为 8.7%和2 1 .84% ,成品生产成本较高。本文参照文献 [2 ]的相转移催化三唑烷基化方法 ,以 TEBA为相转移催化剂 ,K2 CO3 为…     

马来酸桂哌齐特的合成

目的 改进马来酸桂哌齐特的合成方法。方法 以四氢吡咯为原料,与氯乙酰氯酰化得到中间体N-(2-氯乙酰基)四氢吡咯(1);以(E)-3,4,5-三甲氧基肉桂酸为原料,与特戊酰氯成混合酸酐后再与无水哌嗪进行单酰化反应制得中间体(E)-1-(3,4,5-三甲氧基)肉桂酰基哌嗪(2);中间体1与中间体2发生烃化反应制备桂哌齐特游离碱(3),3与马来酸成盐得目标化合物。结果与结论 以(E)-3,4,5-三甲氧基肉桂酸计,经3步反应合成了马来酸桂哌齐特,总收率为68.88%,其结构经1H-NMR、MS谱确证。     

盐酸贝那普利的合成

以L-苹果酸为手性源,经成酐活化、傅-克反应、常压氢化和酯化反应制得(S)-2-羟基-4-苯基丁酸乙酯(8),8经甲磺酰化活化后经与丙酸钾反应和水解制得构型反转的(R)-2-羟基4-苯基丁酸乙酯(3).3经磺酰化活化后与(3S)-3-氨基-2,3,4,5-四氢-2-氧代-1H-1-苯并氮(革)-1-乙酸叔丁酯(2)反应后水解、成盐制得盐酸贝那普利,总收率约32％.     

N—（2—氨乙基）吗啉合成工艺的改进

N- ( 2 -氨乙基 )吗啉 ( 1 )是医药中间体及有机合成原料 ,主要合成方法有 3种 :( 1 )氨法 [1] ,由二乙二醇与氨反应制得 ,收率为 34.5 % ;( 2 )乙二胺法 [2 ] ,由 2 ,2′-二氯二乙醚和乙二胺反应制得 ,收率为 5 1 .0 % ;( 3)乙醇胺法 [3 ] ,以乙醇胺为原料 ,先制得溴乙胺氢溴酸盐 ,再与吗啉反应 ,总收率为61 .7%方法 ( 3)利用苯水共沸技术提高了溴乙胺氢溴酸盐的收率 ,与吗啉的缩合反应在乙醚中进行 [4 ] ,但由于吗啉溶于乙醚 ,而溴乙胺难溶 ,二者在溶剂中相溶性差。我们在重复文献操作时发现 ,过量吗啉可使溴乙胺的氨基游离并自身缩合 ,…     

盐酸曲唑酮的合成

间氯苯胺与二乙醇胺和氢溴酸反应得到1-(3-氯苯基)哌嗪二氢溴酸盐,再经烷基化得1-(3-氯苯基)-4-(3-氯丙基)哌嗪单盐酸盐(4);另由邻氯吡啶与氨基脲盐酸盐反应制得1,2,4-三唑并[4,3-a]吡啶-3(2H)-酮(7)。4和7经缩合、成盐得到盐酸曲唑酮,总收率为30.4%(以间氯苯胺计)。     

富马酸卢帕他定的合成

以烟酸乙酯(4)和间氯苯乙腈(5)为原料,经克莱森缩合、酸水解脱羧反应,得2-(3-氯苯基)-1-(吡啶-3-基)-1-乙酮(6)。6与水合肼经黄鸣龙还原反应,得3-(3-氯苯乙基)吡啶(7),7在钨酸钠催化下经过氧化氢氧化后,再经Reissert-Henze吡啶氰基化反应,得3-(3-氯苯乙基)-2-氰基吡啶(8),水解后闭环得8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮(3),再与1-[(5-甲基吡啶-3-基)甲基]-4-哌啶酮(12)经McMurry偶联反应,并与富马酸成盐,得到富马酸卢帕他定(1),总收率28.0%(以4计),纯度99.7%。该路线避免格氏试剂的使用,且环合反应使用“一锅法”,操作方便,适合工业化生产。     

盐酸度洛西汀的合成

以2-乙酰噻吩、N-甲基苄胺和多聚甲醛为原料,经Mannich反应、硼氢化钠还原、与1-氟萘经O-烷基化反应制得(±)-N-苄基-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-1-丙胺,脱苄基后经L-二苯甲酰酒石酸拆分得到( )-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-1-丙胺-L-二苯甲酰酒石酸盐,用氢氧化钠游离后与盐酸成盐得到盐酸度洛西汀,总收率为13.5%。     

瑞格列奈关键中间体(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺的合成

目的研究合成非磺酰脲类促胰岛素分泌剂瑞格列奈的关键中间体(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺的合成工艺。方法以邻氟苯甲醛(1)为起始原料,首先与盐酸羟胺反应生成邻氟苯甲醛肟(2),再经脱水生成邻氟苯腈(3),然后与哌啶进行胺解反应生成邻哌啶基苯腈(4),再与溴代异丁基镁进行格氏反应生成亚胺衍生物(5),最后经硼氢化钠还原生成消旋伯胺(6),经与N-乙酰-L-谷氨酸成盐、拆分、氢氧化钠水解得到目标产物S-(6)。结果以邻氟苯甲醛为起始原料,经6步反应合成了(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺,总收率达15.4%,目标产物结构经ESI-MS、1H-NMR确证。结论本合成方法原料易得,反应条件温和,适合大规模制备。     

内皮素-3对犬肺动静脉的作用

阐明内皮素 3(ET 3)对肺动静脉的作用机理 .利用犬离体肺动静脉条 ,观察其张力改变 .结果可见 :①ET 3(1～ 30 μmol·L- 1)引起肺动脉舒张 (低浓度 )和收缩 (高浓度 )双向反应 ,ETB 受体激动剂IRL162 0 (1～ 30 μmol·L- 1)只引起舒张反应 ;去内皮 ,ETB 受体阻断剂IRL10 38(1μmol·L- 1)或左旋硝基精氨酸 (L NA ,10 μmol·L- 1)均使ET 3或IRL162 0所致舒张反应减弱或消失 ,ETA 受体阻断剂BQ12 3(10 μmol·L- 1)则使ET 3所致收缩反应翻转为舒张反应 ;②同浓度的ET 3和IRL162 0只引起肺静脉浓度依赖性收缩反应 ;BQ12 3可使ET 3所致收缩反应减弱 ,IRL10 38可使IRL162 0所致收缩反应减弱 ;③在BQ12 3预处理条件下给予第二剂ET 3(30 μmol·L- 1) ,肺静脉表现为舒张反应 ,吲哚美辛 (1μmol·L- 1)可使其舒张反应减弱 .本研究表明 :①存在于肺动脉平滑肌上的ETA 受体参与血管的收缩反应 ,肺动脉内皮上的ETB 受体通过释放NO参与舒张反应 ;②肺静脉平滑肌上的ETA 和ETB 受体均参与收缩反应 ,但ETB 受体所致收缩反应易脱敏 ;③在肺静脉平滑肌上可能还存在非ETA/非ETB 受体 ,通过释放舒张性PG物质参与舒张反应 .     

Inhibition of phenol sulfotransferase (SULT1A1) by quercetin in human adult and foetal livers

1. Quercetin is one of the most abundant flavonoids in edible vegetables, fruit and wine. The aim was to study the type of inhibition of SULT1A1 by quercetin in the human adult and foetal livers. 2. The activity of SULT1A1 was measured with 4 microM 4-nitrophenol and 0.4 microM 3'-phosphoadenosine-5'-phosphosulphate-[(35)S], and its mean (+/-SD) and median were 769 +/- 311 and 740 pmol min(-1) mg(-1), respectively (adult liver, n = 10), and 185 +/- 98 and 201 pmol min(-1) mg(-1), respectively (foetal liver, n = 8, p < 0.0001). 3. In non-inhibited samples, K(m) for SULT1A1 (mean +/- SD) was 0.31 +/- 0.14 microM (adult liver) and 0.49 +/- 0.17 microM (foetal liver, n.s.). V(max) for SULT1A1 (mean +/- SD) was 885 +/- 135 pmol min(-1) mg(-1) (adult liver) and 267 +/- 93 pmol min(-1) mg(-1) (foetal liver, p = 0.007). 4. The IC(50) of quercetin for SULT1A1 was measured in three samples of adult and foetal livers and was 13 +/- 2.1 and 12 +/- 1.4 nM, respectively. 5. The type of inhibition was mixed non-competitive in adult and foetal livers and K(i) was 4.7 +/- 2.5 nM (adult liver) and 4.8 +/- 1.6 nM (foetal liver). 6. In the adult liver, the intrinsic clearance (mean +/- SD) was 3.3 +/- 1.5 ml min(-1) mg(-1) (non-inhibited samples), 0.9 +/- 0.4 ml min(-1) mg(-1) (12.5 nM quercetin) and 0.5 +/- 0.06 ml min(-1) mg(-1) (25 nM quercetin). In the foetal liver, the intrinsic clearance (mean +/- SD) was 0.5 +/- 0.2 ml min(-1) mg(-1) (non-inhibited samples), 0.12 +/- 0.01 ml min(-1) mg(-1) (12.5 nM quercetin) and 0.2 +/- 0.09 ml min(-1) mg(-1) (25 nM quercetin). 7. In conclusion, quercetin is a potent inhibitor of human adult and foetal liver SULT1A1. It reduces the sulphation rate and intrinsic clearance of 4-nitrophenol in both human adult and foetal livers. This suggests that quercetin may inhibit the sulfation rate of those drugs sulphated by SULT1A1. The inhibition of SULT1A1 is complex and not due solely to competition at the catalytic site of SULT1A1.     

在大鼠肝微粒体中反式曲马朵代谢及反式氧去甲基曲马朵生成的立体选择性(英文)

目的:研究反式曲马朵[(±)一trans-T]代谢及反式氧去甲基曲马朵(M1)生成的立体选择性,方法:(±)-trans-T及其对映体分别与大鼠肝微粒体孵育,高效毛细管电泳法测定孵育液中(±)-trans-T及M1对映体的浓度。结果:以(±)-trans-T单一对映体为底物孵育时,(+)-trans-T的代谢速率较低,(+)-M1生成有较低的V_(max)和CL_(int).以(±)-trans-T消旋体为底物孵育时,(±)-trans-T对映体的代谢速率及(±)-M1对映体的生成速率不同程度地减慢。右美沙芬、普罗帕酮和氟西汀既能抑制(±)-trans-T的代谢,又能抑制M1的生成;普罗帕酮和氟西汀能增强(±)-trans-T代谢及M1生成的立体选择性,右美沙芬仅使M1生成的立体选择性增强。结论:在大鼠肝微粒体中,(±)-trans-T代谢及M1生成有立体选择;(±)-trans-T对映体间存在相互作用。右美沙芬、普罗帕酮及氟西汀对它们的立体选择性产生不同的影响。     

(9S)-9-(2-hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one, a selective and orally active neuropeptide Y Y5 receptor antagonist

(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ((S)-1) was identified as a selective and orally active neuropeptide Y Y5 receptor antagonist. The structure-activity relationship for this structural class was investigated and showed that limited substitution on the phenyl ring was tolerated and that modification of the 4,4-dimethyl group of the cyclohexenone and the 3,3-dimethyl group of the xanthenone parts slightly improved potency. The plasma concentration-time profile after oral administration of (S)-1 in Sprague-Dawley (SD) rats showed significant in vivo racemization of (S)-1 and that (S)-1 is cleared much more quickly than (R)-1. The duration of (S)-1 in SD rats after oral administration of (RS)-1 racemate was twice as long as that following oral administration of (S)-1. The C max values of (S)-1 after administration of (S)-1 and (RS)-1 were comparable, and the brain to plasma ratio for (S)-1 was 0.34 in SD rats. In our acute D-Trp (34)NPY-induced food intake model, both (S)-1 and (RS)-1 showed potent and dose-dependent efficacy. Therefore, the use of (RS)-1 is suitable for studies that require sustained plasma exposure of (S)-1.     

Developmental toxic effects of N-ethyl-2-pyrrolidone administered orally to rats

The developmental toxicity of N-ethyl-2-pyrrolidone (NEP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given NEP at doses of 0 (distilled water), 50, 250, 500 and 750 mg kg(-1) day(-1), by gavage (5 ml kg(-1)), on gestational days (GD) 6-20. Maternal toxicity, as evidenced by reduction in body weight gain and food consumption, was observed in all NEP groups at the beginning of treatment (GD 6-9). The incidence of resorptions was significantly increased at 500 mg kg(-1) day(-1), and reached 83% at 750 mg kg(-1) day(-1). There was a dose-related decrease in fetal weight, which was significantly lower than control at 250 mg kg(-1) day(-1) and higher doses. The incidence of malformed fetuses per litter and the number of litters with malformed fetuses were significantly increased at 500 and 750 mg kg(-1) day(-1). Malformations mainly consisted of edema, anal atresia with absent tail, cardiovascular defects and fused cervical arches. Ossification of skull bones and sternebrae was significantly reduced at 500 and 750 mg kg(-1) day(-1). The incidence of supernumerary ribs was significantly elevated at 250 mg kg(-1) day(-1) and higher doses. In conclusion, NEP administered by gavage is embryotoxic and teratogenic at maternal toxic doses.     

内皮素对慢性低氧大鼠肺动脉平滑肌细胞膜钾通道活性的影响

目的观察内皮素(ET-1)对慢性低氧大鼠肺动脉平滑肌细胞(PASMCs)膜电压门控钾通道(K_V)活性的影响。方法将12只Wistar大鼠随机分为对照组和慢性低氧组，每组6只。用全细胞膜片钳记录方法研究ET-1对两组大鼠PASMCs膜电位(E_m)、膜电容(C_m)及电压门控钾电流(IK_V)的影响。结果ET-1可引起两组大鼠PASMCs去极化，且对两组大鼠IK_V均有明显的浓度依赖性抑制作用。在慢性低氧组，高浓度ET-1对IK_V的抑制作用强于对照组。结论低氧并未改变ET-1引起PASMCs去极化及浓度依赖性抑制IK_V的特性，且慢性低氧可能改变了PASMCs对ET-1的敏感性，内皮素和低氧对PASMCs IK_V的抑制作用有协同性。     

Human adult and foetal liver sulphotransferases: inhibition by mefenamic acid and salicylic acid

1. The aim was to see whether mefenamic acid and salicylic acid had different inhibition profiles for SULT1A1 (substrate: 4-nitrophenol) and SULT1A3 (dopamine) activities and on (-)-salbutamol and minoxidil sulphation rates in the human adult and mid-gestational foetal livers. 2. The activity (pmolmin(-1) mg(-1) of SULT1A1 was 662 +/- 78 (adult) and 246 +/- 159 (foetus; p = 0.003) and that of SULT1A3 was 24 +/- 4 (adult) and 121 +/- 90 (foetus; p = 0.030). The rate (pmol min(-1) mg(-1)) of (-)-salbutamol sulphation was 109 +/- 27 (adult) and 117 +/- 34 (foetus; p = (0.144) and that of minoxidil sulphation was 202 +/- 38 (adult) and 108 +/- 44 (foetus; p = 0.001). 3. With mefenamic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 0.2 +/- 0.004 (adult) and 0.01 +/- 0.002 (foetus; p = 0.001); for SULT1A3 it was 76 +/- 6 (adult) and 77 +/- 13 (foetus; p = 0.889); for the rate of ( )-salbutamol sulphation it was 0.07 +/- 0.005 (adult) and not determinable (foetus) and for minoxidil sulphation it was 1.6 +/- 0.7 (adult) and 0.15 +/- 0.04 (foetus; p = 0.076). 4. With salicylic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 30 +/- 2 (adult) and 25 +/- 1 (foetus; p = 0.011); for SULT1A3 it was 690 +/- 36 (adult) and 570 +/- 16 (foetus; p = 0.229); for the rate of ( )-salbutamol sulphation it was 93 +/- 11 (adult) and 344 +/- 42 (foetus; p = 0.010); with minoxidil as substrate, the IC50 was not determinable. 5. In summary, SULT1A1, SULT1A3 and the sulphotransferases towards (-)-salbutamol and minoxidil had measurable activities in the mid-gestational human foetal liver. Mefenamic acid was a more potent inhibitor than salicylic acid of both human adult and foetal liver SULT1A1 and SULT1A3 activities. Foetal liver SULT1A1 was more susceptible than adult liver SULT1A1 to inhibition by mefenamic acid and salicylic acid. These results are consistent with the view that sulphotransferases develop early in the human foetal liver and drugs may inhibit their activities.     

消旋11-去甲胡桐素A的合成方法改进及其药理学评价

本文发展一个实用改进方法以合成具有抗人免疫缺陷病毒(HIV-1)的天然产物的类似物11-去甲胡桐素A［(±)-1］，方法改进包括以间苯三酚为起始原料与正丁酰乙酸乙酯在饱和氯化氢甲醇存在下，经过Pechmann反应生成5，7-双羟基-4-正丙基香豆素(3)，再与巴豆酸用多聚磷酸作溶剂及催化剂进行酰化，同时分子内环合得到收率为70%关键中间体苯并二氢吡喃酮(4)，并与缩醛1，1-二乙氧基-3-甲基-2-丁烯用微波辅助催化得到苯并吡喃(6)， 最后用Luche还原以CeCl₃·7H₂O作催化剂， 在低温下经NaBH₄选择性还原化合物(6)得到目标产物即消旋11-去甲胡桐素A (±)-1。上述4步反应总收率32%， 比原方法提高1倍。体外研究表明(±)-1对HIV-1(野株)及耐药株均有明显抑制逆转录酶和P24抗原的活性， (±)-1在细胞培养内分别与作用机制不同的3种治疗艾滋病药物(AZT、 T-20、 Indinavir)都有明显的协同作用。小鼠急性毒性， (±)-1的LD₅₀灌胃给药为735.65 mg·kg^-1， 腹腔给药为525.10 mg·kg^-1。小鼠灌胃给与(±)-1血浆峰浓度(C_max)与药时曲线面积AUC_0-∞分别为0.54 μg·mL^-1及1.08 (μg·mL^-1)·h。为了初步观察(±)-1的体内药效，采用血清药理学方法，小鼠腹腔注射1次(±)-1或临床有效对照药奈韦拉平，30 min和60 min后血清有相似的抑制HIV-1逆转录酶活性。实验结果提示去甲11-胡桐素A值得进一步研究。     

7-OH-flavone is sulfated in the human liver and duodenum,whereas 5-OH-flavone and 3-OH-flavone are potent inhibitors of SULT1A1 activity and 7-OH-flavone sulfation rate

1. The aim of this investigation was to see whether 7-OH-flavone, 5-OH-flavone and 3-OH-flavone, which are present in edible vegetables, fruit and wine, are substrates or inhibitors of human liver and duodenum sulfotransferase. 2. An assay was set up to study the sulfation of 7-OH-flavone, and using this assay, it was observed that 7-OH-flavone was sulfated and the rate of sulfation (mean +/- SD) was 324 +/- 87 pmol min(-1) mg(-1) (liver) and 584 +/- 164 pmol min(-1) mg(-1) (duodenum; p < 0.0001). 3. 7-OH-flavone sulfotransferase followed Michaelis-Menten kinetics and the K(m) (mean +/- SD) was 0.2 +/- 0.04 microM (liver) and 1.1 +/- 0.3 microM (duodenum; p = 0.008). V(max) (mean +/- SD) was 392 +/- 134 pmol min(-1) mg(-1) (liver) and 815 +/- 233 pmol min(-1) mg(-1) (duodenum; p = 0.016). 4. 5-OH-flavone and 3-OH-flavone were not sulfated and were inhibitors of human liver and duodenum SULT1A1 activity and 7-OH-flavone sulfation rate. 5. The IC50 of 5-OH-flavone for SULT1A1 was 0.3 +/- 0.06 microM (liver) and 0.3 +/- 0.1 microM (duodenum; n.s.) and those of 3-OH-flavone were 1.0 +/- 0.1 microM (liver) and 1.6 +/- 0.03 microM (duodenum; p = 0.0006). 6. There was inhibition of 7-OH-flavone sulfation rate by 5-OH-flavone and 3-OH-flavone. The IC(50) of 5-OH-flavone for the sulfation rate of 7-OH-flavone was 3.5 +/- 0.5 microM (liver) and 69 +/- 18 microM (duodenum; p < 0.0001) and for 3-OH-flavone it was 18 +/- 3.4 microM (liver) and 213 +/- 47 microM (duodenum; p < 0.0001). 7. The position of the hydroxy group confers to the molecules of OH-flavones the quality of substrate or inhibitor of sulfotransferase.     

Developmental toxicity study with triethylene glycol given by gavage to CD rats and CD-1 mice

Triethylene glycol (TEG) is a liquid industrial chemical with a potential for human exposure. The likelihood for developmental toxicity was investigated in two species. Timed-pregnant CD rats and CD-1 mice were dosed daily by gavage with undiluted TEG over gestational days (gd) 5-15 at 0.0 (water control), 1126, 5630 or 11,260 mg kg(-1) day(-1) with rats and 0.0, 563, 5630 or 11,260 mg kg(-1) day(-1) with mice. They were examined daily, and gestational body weights and food and water consumption measured throughout gestation. At necropsy on gd 21 (rats) or gd 18 (mice) dams were examined for body, gravid uterine, liver and kidney weights, and implantation sites. Maternal kidneys were examined histologically. Fetuses were weighed, sex determined, and examined for external, soft tissue and skeletal variations and malformations. Rat dams had reduced body weights, body weight gains, and food consumption, and increased water consumption and relative kidney weights at 11,260 mg kg(-1) day(-1). They also had reduced body weight and increased water consumption at 5630 mg kg(-1) day(-1). Mice had clinical signs and increased relative kidney weight at 11,260 mg kg(-1) day(-1). Renal histology was normal in both species. Neither species had treatment-related effects on corpora lutea or implantations. Fetal body weights were reduced at 11,260 mg kg(-1) day(-1) (both species) and 5630 mg kg(-1) day(-1) (mice). In rat fetuses there was a pattern of delayed ossification in the thoracic region at 11,260 mg kg(-1) day(-1). Mouse fetuses had delayed ossification in the frontal and supraoccipital bones, cervical region, hindlimb proximal phalanges and reduced caudal segments at 11,260 mg kg(-1) day(-1), and in the skull bones at 5630 mg kg(-1) day(-1). These patterns of delayed ossification are consistent with reduced fetal body weights. No biologically significant embryotoxicity or teratogenicity was observed at any dosage in either species. The NOEL for TEG given by gavage over the period of organogenesis was 1126 mg kg(-1) day(-1) in the rat and 5630 mg kg(-1) day(-1) in the mouse for maternal toxicity, and 5630 mg kg(-1) day(-1) (rat) and 563 mg kg(-1) day(-1) (mouse) for developmental toxicology.     

Structural identification and characterization of potential impurities of pantoprazole sodium

Six impurities in pantoprazole sodium bulk drug substance were detected by a simple high performance liquid chromatographic method (HPLC) whose area percentage ranged from approximately 0.05 to 0.34%. Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the molecular weight of the impurities. A thorough study was undertaken to characterize these impurities. These impurities were synthesized, subsequently characterized and were co-injected with the sample containing impurities and found the retention time match of the spiked impurities. Based on their spectral data (IR, NMR and MS), these impurities were characterized as; 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (Impurity-I); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (Impurity-II); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-1-oxide-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (Impurity-III); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1-((3,4-dimethoxy-2-pyridinyl)methyl)-1H-benzimidazole (Impurity-IV); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-((3,4-dimethoxy-2-pyridinyl)methyl)-1H-benzimidazole (Impurity-V); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-1-oxide-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (Impurity-VI). The formation of these impurities was proposed. The structure of the Impurity-II was unambiguously confirmed by single crystal X-ray diffraction (XRD) studies.