头孢替唑钠的合成工艺研究

目的 改进头孢替唑钠的合成工艺。 方法 以7-氨基头孢烷酸 （7-ACA）为起始原料,与1H-四氮唑乙酸-1,3,4-噻二唑-2-硫酯（2）反应得中间体7-（1H-四氮唑乙酰氨基）头孢烷酸（3）,以甲磺酸为催化剂,3与2-巯基-1,3,4-噻二唑经亲核取代反应制得头孢替唑酸（4）,4与碳酸氢钠反应得到目标化合物。结果与结论 目标化合物的结构经¹H-NMR 和 HR-MS 确证,改进后的合成工艺操作简便,总收率达69.6%,降低了成本,有利于工业化生产。     

利拉利汀

利拉利汀(linagliptin)是德国勃林格殷格翰制药公司(Boehringer Ingelheim Pharmaceuticals Inc.)开发的口服降糖药物,于2011年5月2日经美国 FDA 批准上市,商品名为 Tradjenta 。本品为片剂,与饮食和锻炼结合用于改善2型糖尿病患者的血糖控制能力。利拉利汀的中文化学名称：8-[(3R)-3-氨基-1-哌啶基]-7-(2-丁炔基)-3,7-二氢-3-甲基-1-[(4-甲基-2-喹唑啉基)甲基]-1H-嘌呤-2,6-二酮;英文化学名称：8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione;分子式：C₂₅H₂₈N₈O₂;分子量：472.54;CAS登记号：668270-12-0。     

盐酸鲁拉西酮

盐酸鲁拉西酮（lurasidone hydrochloride,商品名为 Latuda）是由日本住友制药公司开发的具有双重作用的新型抗精神病药物。它对 5-HT_2A 受体和多巴胺 D₂ 受体均具有高度亲和力。对精神病人的阳性和阴性症状均具有显著疗效。该药于2010年10月28日经美国食品药品管理局（FDA）批准在美国上市。 盐酸鲁拉西酮的中文化学名称：(3aR, 4S , 7R, 7aS ) -2-[ (1R, 2R ) -2-[ 4-(1, 2-苯并异噻唑-3-基)哌嗪-1-基甲基] 环己基甲基]六氢-1H-4, 7-甲基异吲哚-1, 3-二酮盐酸盐;英文化学名称:（3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride;分子式：C₂₈H₃₆N₄O₂S; 相对分子量：492.26;CAS 登记号：367514-88-3。     

Crizotinib

Crizotinib是由辉瑞公司开发的，主要用于治疗通过 FDA 批准的检测方法诊断为间变性淋巴瘤激酶（ALK）阳性的局部晚期或转移的非小细胞肺癌 (NSCLC)，它是目前惟一个治疗该类疾病的药物。crizotinib于2011年8月26日获得美国 FDA 批准上市。该药为胶囊剂，商品名为Xalkori。 Crizotinib 的中文化学名称：3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-[1-(4-哌啶基)-1H-吡唑-4-基]-2-吡啶胺；英文化学名称：(R)-3-[1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-5-(1-piperidin-4-yl- 1H-pyrazol-4-yl)-pyridin-2-ylamine；分子式：C₂₁H₂₂Cl₂FN₅O；分子量：450.34；CAS登记号：877399-52-5。     

艾曲波帕(eltrombopag olamine)

英国葛兰素史克公司开发的造血新药艾曲波帕（eltrombopag olamine,商品名为 Promacta）于2008年11月获得FDA批准在美国上市,用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜（ITP）患者的血小板减少。艾曲波帕的中文化学名称：3’-{(2Z)-2-[1-(3,4-二甲苯基)-3-甲基-5-氧代-1,5-二氢-4H-吡唑-4-亚基]肼基}-2’-羟基-3-联苯基甲酸-2-氨基乙醇盐（1:2）;英文化学名称：3’-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4- ylidene]hydrazino}-2’-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol（1:2）;分子式: C₂₅H₂₂N₄O₄;相对分子质量：564.65;CAS登记号：496775-61-2。     

抗肿瘤药物 linifanib 的合成

目的 合成抗肿瘤药物 linifanib 并优化其工艺。方法 以 2,6-二氟苯甲腈为原料经取代、重氮化、环合等 4 步反应制得关键中间体3-氨基-4-碘吲唑（5）;以对氟硝基苯为原料经 Suzuki 偶联、还原、缩合反应得到关键中间体1-(2-氟-5-甲基苯基)-3-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环硼乙烷-2-基)苯基]脲（10）;中间体 5 与 10 经 Suzuki 偶联反应制得抗肿瘤药 linifanib。结果 目标化合物的结构经¹H-NMR 谱和质谱确证,总收率为39.4%。结论 与文献报道的工艺比较, 新工艺成本低廉,操作简单,反应时间缩短,有利于工业化生产。     

(S)-1-(N-烯丙氧羰基)亚胺乙基-3-巯基吡咯烷的合成

目的 合成帕尼培南关键中间体 (S)-1-( N-烯丙氧羰基)亚胺乙基-3-巯基吡咯烷。方法 以氯甲酸烯丙酯为酰化剂,与盐酸乙脒进行 N-酰化反应得到 1-亚胺乙基氨基甲酸烯丙酯,该化合物与 3-R-羟基吡咯烷进行缩合,再经甲磺酰化、S_N2 取代、水解共 5 步反应得到目标化合物。结果与结论 该合成路线中使用新型保护基烯丙氧羰基替代传统的保护基—对硝基苄氧羰基,目标化合物的结构经 ¹H-NMR、MS 谱确证,总收率为 41.6%,各步反应操作简便,条件温和,有利于工业化生产。     

泰比培南酯的合成工艺研究

目的 研究新型碳青霉烯类抗生素泰比培南酯的合成工艺。方法 以 (4R,5S,6S)-3-二苯基磷酰氧基-6-[(1R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸对硝基苄酯和3-巯基-1-(1,3-噻唑啉-2-基)氮杂环丁烷盐酸盐为起始原料,经过缩合、氢化、亲核取代3步反应,得到目标产物。结果与结论 目标化合物及中间体的结构经熔点、IR、MS、¹H-NMR和¹³C-NMR 谱确证。该合成工艺反应步骤少、操作简便、收率高、产品纯度高,有利于工业化生产。     

8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物的设计、合成及抗真菌活性研究

目的 设计、合成一系列 8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物,测定其体外抗真菌活性。方法 以邻氟苯胺为起始原料,经与丙烯酸加成、在多聚磷酸（PPA）中环合制得中间体8-氟-2,3-二氢喹啉-4(1H)-酮;该中间体与各种 N⁴-取代的氨基脲缩合得到目标化合物。采用二倍浓度稀释法测试各目标化合物的体外抗真菌活性,实验选用 8 种临床上常用的致病真菌为测试菌株,以氟康唑、伊曲康唑为阳性对照药。结果与结论 16 个 8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物均未见文献报道,其结构经¹H-NMR、MS 谱确证;活性测试结果表明,合成的多个目标化合物对测试真菌表现出较好的体外抑菌活性,尤其是对红色毛藓菌的活性均好于阳性对照药。     

阿卡他定

阿卡他定(alcaftadine)是Vistakon制药公司开发的一种新型组胺H₁受体拮抗剂。于2010年7月获美国FDA批准上市,商品名为 Lastacaft。该药为滴眼液,用于2岁以上人群过敏性结膜炎相关性眼部瘙痒的治疗。 阿卡他定的中文化学名称：11-(1-甲基-4-哌啶亚基)-6, 11-二氢-5H-咪唑[2, 1-b][3]苯并氮杂卓-3-甲醛;英文化学名称：11-(1-methyl-4-piperidinylidene)-6, 11-dihydro-5H-imidazo[2, 1-b][3]benzazepine- 3-carbaldehyde;分子式：C₁₉H₂₁N₃O;分子量：307.39;CAS登记号：147084-10-4。     

In vitro effect of sanguinarine alkaloid on binding of [3H]candesartan to the human angiotensin AT1 receptor

The type of interaction of 5-methyl-2,3,7,8-bis(methylenedioxy)benzo[c]phenanthridinium (sanguinarine), an alkaloid isolated from the root of Bocconia frutescens L., with the human angiotensin AT(1) receptor was evaluated in both intact cells and membrane binding of [3H](2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-benzimidazoline-7-carboxylic acid) ([3H]candesartan). The results indicate that the inhibition of [3H]candesartan binding by sanguinarine is independent of cell viability, since the alkaloid inhibited at a similar extent radioligand binding on both intact Chinese hamster ovary (CHO) cells transfected with the human angiotensin AT(1) receptor (hAT(1)) and their cell membranes (K(i)=0.14 and 1.10 microM, respectively). The unsuccessful recovery of [3H]candesartan binding after washing sanguinarine off the cells suggested a nearly irreversible or slow reversible interaction. Saturation binding studies showed a substantial reduction of the B(max) without affecting the K(d). In addition, the presence of 2-n-butyl-4chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole (losartan) could not prevent sanguinarine inhibition of [3H]candesartan binding neither. The present findings indicate that sanguinarine interacts with the receptor in a slow, nearly irreversible and noncompetitive manner.     

抗肿瘤药物neratinib的合成

目的合成抗癌药neratinib。方法以2-氯-4-硝基苯酚和2-氯甲基吡啶为起始原料,经醚化、硝基还原得到3-氯-4-（吡啶-2-甲氧基）苯胺,3-氯-4-（吡啶-2-甲氧基）苯胺与3-氰基-6-乙酰氨基-7-乙氧基-4-氯喹啉反应得到3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉,3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉去乙酰保护基后,与（E）-4-二甲氨基-2-丁烯酰氯经酰化反应得到ner-atinib。结果与结论目标物neratinib的总收率为56.0%,其结构经核磁共振氢谱、质谱确证。     

Insurmountable angiotensin AT1 receptor antagonists: the role of tight antagonist binding.

Angiotensin II increased the inositol phosphates production (EC50 = 3.4+/-0.7 nM) in Chinese hamster ovary (CHO) cells expressing the cloned human angiotensin AT1 receptor (CHO-AT1 cells). Coincubation with angiotensin AT1 receptor antagonists produced parallel rightward shifts of the concentration-response curve without affecting the maximal response. The potency order is 2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-benz imidazoline-7-carboxylic acid (candesartan) > 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole-5-carboxylic acid (EXP3174) > 2-n-butyl-4-spirocyclopentane-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl)methyl]2-imidazolin-5-one (irbesartan)> of 2-n-butyl-4-chloro-5-hydroxymethyl-1-(2'-(1H-tetrazol-5-yl)bipheny l-4-yl)methyl]imidazole (losartan). Additionally, preincubation with these antagonists depressed the maximal response, i.e., 95%, 70%, 30% of the control response for candesartan, EXP3174 and irbesartan and not detectable for losartan. Increasing the antagonist concentration or prolonging the preincubation time did not affect this depression. Furthermore, these values remained constant for candesartan and EXP3174, when the angiotensin II incubation time varied between 1 and 5 min. Our data indicate that antagonist-receptor complexes are divided into a fast reversible/surmountable population and a tight binding/insurmountable population at the very onset of the incubation with angiotensin II.     

Design,synthesis and pharmacological analysis of 5-[4′-(substituted-methyl)[1,1′-biphenyl]-2-yl]-1<Emphasis Type="Italic">H</Emphasis>-tetrazoles

In the present paper 5-[4′-({4-[(4-aryloxy)methyl]-1H-1,2,3-triazol-1-yl}methyl)[1,1′-biphenyl]-2-yl]-1H-tetrazoles (5a–g) and [2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-substituted-1-carbodithioates (11h–q) have been designed and synthesized. These compounds were subjected to docking (against AT₁ receptor protein enzyme in complex with Lisinopril), in vitro angiotensin converting enzyme inhibition, anti-proliferative, anti-inflammatory screening (through egg albumin denaturation inhibition and red blood cell membrane stabilization assay) and finally anti-fungal activity analyses. Some of the compounds have shown significant pharmacological properties.     

Binding of the antagonist [3H]candesartan to angiotensin II AT1 receptor-transfected [correction of tranfected] Chinese hamster ovary cells

Binding of the non-peptide angiotensin II AT1 antagonist [3H](2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]- H-benzimidazoline-7-carboxylic acid ([3H]candesartan) to human angiotensin II AT1 receptor-transfected Chinese hamster ovary (CHO-AT1) cells was inhibited to the same extent by angiotensin II and non-peptide angiotensin II AT1 antagonists. No binding was observed in control CHO-K1 cells. Dissociation was slow (k(-1) = 0.0010+/-0.0001 min(-1)) after removal of the free [3H]candesartan but increased 5-fold upon addition of supramaximal concentrations of angiotensin II AT1 antagonists. Angiotensin II responses recovered equally slow from candesartan-pretreatment. When washed and further incubated, these angiotensin II responses also recovered more rapidly in the presence of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphen yl-4-yl)methyl]imidazole (losartan), indicating that unlabelled ligands prevented reassociation. [3 H]candesartan saturation binding experiments required a long time to reach equilibrium. Therefore, the equilibrium dissociation constant (Kd = 51+/-8 pM) was calculated from the association and dissociation rate constants. Our findings indicate that the insurmountable nature of candesartan in functional studies is related to its slow dissociation from the receptor.     

Identification and characterization of potential impurities of valsartan,AT1 receptor antagonist

Five impurities (related substances) were detected during the impurity profile study of an antihypertensive drug substance, valsartan. A simple gradient high performance liquid chromatographic method (HPLC) and liquid chromatography–mass spectrometry (LC–MS) were used for the detection. Based on the spectral data (IR, NMR and MS) followed by synthesis, these impurities were characterized as (S)-N-(1-carboxy-2-methylprop-1-yl)-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine (impurity I); (S)-N-(1-carboxy-2-methylprop-1-yl)-N-(5-phenylthio)pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine (impurity II); (S)-N-(1-carboxy-2-methylprop-1-yl)-N-(5-phenyl)pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine (impurity III); (S)-N-(1-carboxy-2-methylprop-1-yl)-N-4-pentenoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine (impurity IV); (S)-N-(1-carboxy-2-methylprop-1-yl)-N-(5-hydroxy)pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine (impurity V).     

Effect of peptide and nonpeptide antagonists of angiotensin II receptors on noradrenaline release in hypothalamus of rats with angiotensin II-induced increase of water intake

Angiotensin II (Ang II) administered intracerebroventriculary (icv) at a dose that induces drinking behavior in rats significantly increased K⁺-stimulated release of [³H] noradrenaline (NA) in hypothalamus without affecting basal [³H] NA release. The observed difference between the effects of Ang II on basal and K⁺-stimulated [³H]NA release may possibly be due to the fact that peptides are released after increased neuronal activity. It can be suggested that Ang II is important primarily in pathological states and that NA plays a substantial role in the brain Ang II-induced drinking response. The imidazolic nonpeptidic compound 2-n-butyl-4-chloro-5-hydroxymethyl-1-{[2-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl}imidazole potassium salt (DuP 753, losartan), its active metabolite 2-n-butyl-4-chloro-1-{[2-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl}imidazole-5-carboxylic acid (EXP 3174) and peptide Ang II analogue, sarmesin, antagonized the Ang II-induced effect on [³H]NA release, in spite of the differences in their chemical structures. Thus, the drugs tested inhibited K⁺-stimulated [³H]NA release in hypothalamus, acting via the angiotensin (AT) 1 receptor subtype. We could not reject the possibility of a non-receptor mechanism of action for DuP 753, EXP 3174 and sarmesin. This research allows us to suggest a neurochemical mechanism for the modulatory role of these drugs on the NA-ergic system. The Ang II receptor antagonists studied may become important therapeutic agents, which act preferentially on pathologically activated systems. These agents may be of use for the prevention of excessive ingestion of water in some neuropsychotic diseases.     

Isolation and Characterisation of Degradation Impurities in the Cefazolin Sodium Drug Substance

Two unknown impurities were detected in the cefazolin sodium bulk drug substance using gradient reversed-phase high-performance liquid chromategraphy (HPLC). These impurities were isolated by preparative HPLC and characterized by using spectroscopic techniques like LC-MS, LC-MS/MS, 1D, 2D NMR, and FT-IR. Based on the spectral data, the impurities have been characterized as N-(2,2-dihydroxyethyl)-2-(1H-tetrazol-1-yl)acetamide (Impurity-I) and 2-{carboxy[(1H-tetrazol-1-ylacetyl)amino]methyl}-5-methylidene-5,6-dihydro-2H-1,3-thiazine-4-carboxylic acid (Impurity-II). The structures of these impurities were also established unambiguously by co-injection into HPLC to confirm the retention time. To the best of our knowledge, these two impurities were not reported elsewhere.     

Reversible and syntopic interaction between angiotensin receptor antagonists on Chinese hamster ovary cells expressing human angiotensin II type 1 receptors

Evidence for a competitive type of interaction between angiotensin II type 1 (AT(1)) antagonists on Chinese hamster ovary cells expressing the human AT(1) receptor (CHO-AT(1)) was obtained by analyzing the binding of [(3)H]-2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H- ben zimidazoline-7-carboxylic acid ([(3)H]candesartan) and by measuring the AT-induced production of inositol phosphates. The AT(1) antagonists candesartan, 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]+ ++imid azole-5-carboxylic acid (EXP3174), or 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl- 4-yl)methyl]imidazole (losartan) produced a concentration-dependent increase in the apparent K(d) values of [(3)H]candesartan in saturation binding experiments, while the B(max) values were unchanged. Furthermore, the dissociation rate of the radioligand initiated by 1 microM unlabelled candesartan was not changed in the presence of 10 microM losartan, 10 microM EXP3174, or 10 microM irbesartan (2-n-butyl-4-spirocyclopentane-1-[(2'-(1H-tetrazol-5-yl)b iph enyl-4-yl) methyl]2-imidazolin-5-one)). Preincubation of the CHO-AT(1) cells with candesartan, EXP3174, and irbesartan caused a reduction in the maximal AT-induced inositol mono-, bis-, and trisphosphate production. This insurmountable effect was reversed in the presence of 1 microM losartan. In line with this finding, the insurmountable antagonist concentration-inhibition curves at 10 microM AT were shifted to the right in the presence of losartan. For candesartan this effect was concentration-dependent, yielding a pK(B) value for losartan of 7.7, which is similar to the pK(B) from previously obtained AT concentration-response curves. Finally, the dissociation rate of candesartan, EXP3174, irbesartan, and losartan was determined by measuring the recovery of AT responses after antagonist pretreatment and washing of the cells with medium containing 1 microM losartan to prevent re-association of the insurmountable antagonists. In addition, similar kinetic data were obtained from the slowing of the [(3)H]candesartan association rate to antagonist preincubated cells.     

Pharmacological and Pharmacokinetic Evaluation of EXP3312, an Orally-active Non-peptide Angiotensin II-Receptor Antagonist

EXP3312, 2-n-propyl-4-chloro-l-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylaldehyde, is a non-peptide angiotensin II (AII) AT₁-receptor antagonist. In the rabbit isolated aorta EXP3312 inhibited the contractile response to AII competitively with a pA₂ value of 8.24. In renal hypertensive rats EXP3312 reduced blood pressure with intravenous and oral ED30 values of 0.19 and 0.14 mg kg^?1, respectively. It also reduced blood pressure in frusemide-treated dogs when administered orally at 1 and 3 mg kg^?1. In rats and dogs, the absolute oral bioavailability of EXP3312 averaged 60 and 28%, respectively. When EXP3312 was administered intravenously to rats and dogs the plasma elimination half-lives were 1.20 and 2.52 h, respectively. In rats and dogs EXP3312 was metabolized to an active metabolite M1, 2-n-propyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. M1 is about ten times more potent than EXP3312 in renal hypertensive rats; the intravenous ED30 value was 0.02 mg kg^?1. Because high plasma levels of M1 were found in rats after oral administration of EXP3312, it is likely that M1 contributes to the long duration of the antihypertensive effects of EXP3312 in renal hypertensive rats. The results show that EXP3312 is a potent, orally active, competitive and selective AT₁-receptor antagonist and a potent antihypertensive agent; it is likely to be therapeutically useful in the treatment of hypertension and congestive heart failure.