卡培他滨的新合成路线

目的 合成抗肿瘤药卡培他滨。方法 以D-核糖为起始原料,经1-位甲基苷化、2,3-位亚异丙基保护、5-位对甲苯磺酰化、碘代、自由基法脱碘和乙酰化得中间体1,2,3-三-O-乙酰基-5-脱氧-&;#61538;-D-呋喃核糖(7),7与硅烷基保护的5-氟胞嘧啶糖苷化、碱基N-4位酰化、脱除糖基上的保护基制得卡培他滨。 结果与结论 总收率17.9%,目标化合物结构经1H-NMR、MS谱确证。新路线的还原步骤采用了价廉易得的次磷酸/偶氮二异丁腈体系,可避免金属氢化物的使用,反应时间较短,收率高,利于工业化的开展。     

5-氧-烯丙基-2,3,4-三-氧-苄基-D-核糖醇的合成工艺改进

目的合成5-氧-烯丙基-2,3,4-三-氧-苄基-D-核糖醇。方法以D-核糖为原料,经甲苷化、苄基化、水解、肟保护、烯丙基化、脱肟、还原7步反应得到5-氧-烯丙基-2,3,4-三-氧-苄基-D-核糖醇。结果与讨论总收率55%,目标产物结构经核磁共振氢谱确认。该合成路线步骤少,绿色环保,适合工业化生产。     

1，3，5-三-甲酰基-2-去氧-2-氟-β-D-核糖的合成

目的 合成1，3，5-三-苯甲酰基-2-去氧-2-氟-β-D-核糖。方法以D-核糖为起始原料，经甲基化、苯甲酰化、溴代脱溴、乙酰化、重排、活化、氟代7步反应，合成目标化合物。结果产物的总收率14．1％，结构经熔点和核磁共振确认。结论所选合成路线减少了反应步骤，改善了反应条件，提高了反应收率。     

卡培他滨的合成

D-核糖经缩酮化、酯化、还原、水解和酰化反应制得1,2,3-三-O-乙酰基-5-脱氧-β-D-呋喃核糖(7),7与5-氟胞嘧啶进行Silyl反应,再与氯甲酸正戊酯进行酰胺化,最后水解去除乙酰基得到卡培他滨,总收率约21%。     

1,3,5-三-苯甲酰基-2-去氧-2-氟-β-D-核糖的合成

目的合成1,3,5-三-苯甲酰基-2-去氧-2-氟-β-D-核糖。方法以D-核糖为起始原料,经甲基化、苯甲酰化、溴代脱溴、乙酰化、重排、活化、氟代7步反应,合成目标化合物。结果产物的总收率14.1%,结构经熔点和核磁共振确认。结论所选合成路线减少了反应步骤,改善了反应条件,提高了反应收率。     

8-氧-叔丁基二甲基硅烷基-4,5-氧-羰基-3-去氧-β-D-甘露-2-辛酮糖甲酸酯烯丙基苷的合成

目的 研究8-氧-叔丁基二甲基硅烷基-4,5-氧-羰基-3-去氧-β-D-甘露-2-辛酮糖甲酸酯烯丙基苷的合成.方法 以草酰乙酸和D-阿拉伯糖为原料,通过cornforth反应、乙酰化、甲酯化、烯醇化、脱乙酰基、硅基化、碳酸酯化等7步反应制备目标化合物.结果与结论 与文献谱图进行对照,确证目标化合物的结构,7步反应的总收率为22％,化合物的立体选择性较高,方法操作简单、易于实施,为含(2-7)苷键结构的Kdo寡糖制备奠定了基础.     

1,2,3-三-O-乙酰基-5-脱氧-D-呋喃核糖的制备

1,2,3-三-O-乙酰基-5-脱氧-D-呋喃核糖(1)是合成核苷类抗肿瘤药卡培他滨(capecitabine)和去氧氟尿苷(doxifluridine)的重要中间体[1].     

1-脱氮腺苷的改良合成法

腺苷类似物1-脱氮腺苷(1)具有广泛的生物活性,有抑制血小板凝聚和腺苷脱氨酶的作用。本文介绍1的新合成方法。合成路线如方程式所示。化合物2与硝酸-三氟醋酸混合物反应生成7-硝基咪唑并[4.5-6]吡啶4-氧化物(3)。和PCl_3处理3,生成脱氧衍生物4。在催化量的SnCl_4作用下,4再与等摩尔的1,2,3,5-四-O-乙酰基-β- D映喃核糖(TAR)进行反应,得到7-硝基-3-(2,3,5-三-O-乙酰基-β-D-呋喃核糖)-3H咪唑并[4,5-b]吡啶(5),收率82%。在化合物5的甲醇溶液中通入氨气,脱去保护基,生成化合物6,收率86%。用Pd/C加压氢化,     

N-(4-甲基-香豆素-7-基)-Nα-叔丁氧羰基-Nω-乙酰基赖氨酰胺(MAL)的合成

目的:改进N-(4-甲基-7-香豆素-7-基)-Nα-(叔丁氧羰基)-Nω-乙酰基赖氨酰胺(MAL)的合成方法.方法:以间氨基酚为原料,经氨基保护、环合、脱保护、活化缩合等5步反应得目标化合物MAL.结果:改进后的合成方法简便、反应条件温和,且提高了产率.目标化合物结构经UV,IR,1H-NMR,MS-ESI分析确证.结论:该方法原料易得、操作简便,总收率31.8%.     

佛波酯磷脂酰－L－丝氨酸（PEPS）中间体的合成工艺改进

目的改进佛波酯磷脂酰-L-丝氨酸（PEPS）的中间体3-苄基-2-（8-叔丁基二苯基硅氧辛酰基）-1-三苯甲基-Sn-甘油（9）和N-叔丁氧羰基-L-丝氨酸二苯甲酯（11）的合成工艺。方法以D-甘露醇为原料，经丙叉基保护、氧化-还原、苄基保护、脱丙叉保护、选择性保护、酯化、羧基还原、硅烷基保护合成化合物9；以L-丝氨酸为原料，经氨基、羧基保护合成化合物11。结果与结论目标化合物的结构经。H-NMR谱确证，改进后的工艺，缩短了合成路线，简化了柱色谱分离、纯化步骤，具有原料易得，操作简便，成本低廉的优点。     

卡培他滨的合成工艺研究

目的:改进抗肿瘤药物卡培他滨的合成工艺。方法:5-氟胞嘧啶经硅烷化保护后与1,2,3-三-O-乙酰基-β-D-呋喃核糖缩合反应,得到2,3-二-O-乙酰基-5′-脱氧-5-氟胞苷,后者与氯甲酸正戊酯酰胺化反应后经过甲醇钠/甲醇体系脱保护得到卡培他滨,重点考察了硅烷化保护剂以及不同碱性体系对脱保护反应的影响。结果:采用以上工艺,四步反应合成了卡培他滨并通过~1H-NMR和MS确认。结论:成功改进了卡培他滨的合成工艺,提高了收率,质量可控,适合工业化生产。     

Assessment of Drug–drug Interaction and Optimization in Capecitabine and Irinotecan Combination Regimen using a Physiologically Based Pharmacokinetic Model

Capecitabine and irinotecan (CPT-11) combination regimen (XELIRI) is used for colorectal cancer treatment. Capecitabine is metabolized to 5-fluorouracil (5-FU) by three enzymes, including carboxylesterase (CES). CES can also convert CPT-11 to 7-ethyl-10-hydroxycamptotecin (SN-38). CES is involved in the metabolic activation of both capecitabine and CPT-11, and it is possible that drug–drug interactions occur in XELIRI. Here, a physiologically based pharmacokinetic (PBPK) model was developed to evaluate drug–drug interactions. Capecitabine (180 mg/kg) and CPT-11 (180 mg/m²) were administered to rats, and blood (250 μL) was collected from the jugular vein nine times after administration. Metabolic enzyme activities and K_i values were calculated through in vitro experiments. The plasma concentration of 5-FU in XELIRI was significantly decreased compared to capecitabine monotherapy, and metabolism of capecitabine by CES was inhibited by CPT-11. A PBPK model was developed based on the in vivo and in vitro results. Furthermore, a PBPK model-based simulation was performed with the capecitabin dose ranging from 0 to 1000mol/kg in XELIRI, and it was found that an approximately 1.7-fold dosage of capecitabine was required in XELIRI for comparable 5-FU exposure with capecitabine monotherapy. PBPK model-based simulation will contribute to the optimization of colorectal cancer chemotherapy using XELIRI.     

肿瘤患者个体差异对卡培他滨药物代谢动力学影响

目的:研究个体差异(性别、年龄、体表面积及体质量)对肿瘤患者体内卡培他滨的药代动力学的影响,为临床合理使用卡培他滨提供依据。方法:选取76例不同类型肿瘤患者为研究对象,餐后口服卡培他滨片0.6 g(0.15 g,4片)后进行多点采集血样,HPLC-MS/MS检测受试者给药后血浆中的卡培他滨及其活性代谢物5-氟尿嘧啶(5-FU)的血药浓度,Phoenix WinNonlin7.0软件计算卡培他滨和5-FU的药动学参数AUC 0-∞和C max,研究性别、年龄、体表面积及体质量与卡培他滨及5-FU药动学的相关性。结果:男性卡培他滨C max比女性高49%,卡培他滨AUC 0-∞及5-FU的C max和AUC 0-∞值在性别之间没有区别。受试者年龄(26~65岁)与卡培他滨C max负相关(P<0.05),而与卡培他滨AUC 0-∞及5-FU的AUC 0-∞和C max无相关性;不同体表面积(1.28~2.01 m 2)患者卡培他滨的AUC 0-∞和C max值无明显差异,而5-FU的AUC 0-∞和C max随着体表面积的增加而减少。不同体质量(45.0~83.0 kg)患者体内卡培他滨的AUC 0-∞和C max的值无明显差异,但5-FU的AUC 0-∞和C max差异具有统计学意义(P<0.05)。结论:现有研究对象结果显示不同的个体差异因素对于卡培他滨的药动学影响不同。其中,性别和年龄主要影响卡培他滨吸收,而体表面积和体质量是卡培他滨的代谢过程主要影响因素。     

Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: comparison of the simulated 5-FU exposures in the tumour tissue between human and xenograft model.

The nonlinear pharmacokinetics of capecitabine, a triple prodrug of 5-FU preferentially activated in tumour tissues, was investigated in human cancer xenograft models. A physiologically based pharmacokinetic (PBPK) model integrating the activation process of capecitabine to 5-FU and 5-FU elimination was constructed to describe the concentration/time profiles of capecitabine and its three metabolites, including 5-FU, in blood and organs. All the biochemical parameters (enzyme kinetic parameters, plasma protein binding and tissue binding of capecitabine and its metabolites) integrated in this model were measured in vitro. The simulated curves for the blood and tumour concentrations of capecitabine and its metabolites can basically describe the observed values. A simple prodrug of 5-FU, doxifluridine, is known to be activated to 5-FU to some extent in the gastrointestinal (GI) tract, causing diarrhoea, which is the dose limiting side effect of doxifluridine. Consequently, the therapeutic index (the ratio of 5-FU AUC in the tumour to that in GI) after the administration of effective dose capecitabine was predicted by this PBPK model and found to be five times and 3000 times greater than that of doxifluridine and 5-FU, respectively. This was compatible with the previous result for the difference in the ratio of the toxic dose to the minimum effective dose between capecitabine and doxifluridine, suggesting that 5-FU preferentially accumulates in tumour tissue after oral administration of capecitabine compared with the other drugs (doxifluridine and 5-FU). The 5-FU AUC in tumour tissue of human cancer xenograft models at the minimum effective dose was comparable with those estimated for humans at the clinical dose. In addition, the predicted therapeutic indices at the respective doses were correlated well between humans and mice (xenograft model). These results suggest that the 5-FU AUC in human tumour tissue at its clinically effective dose can be predicted based on the PBPK model inasmuch as the 5-FU AUC in a human cancer xenograft model at its effective dose may be measured or simulated.     

Clinical pharmacokinetics of capecitabine

Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps. After oral administration of 1250 mg/m2, capecitabine is rapidly and extensively absorbed from the gastrointestinal tract [with a time to reach peak concentration (tmax) of 2 hours and peak plasma drug concentration (Cmax) of 3 to 4 mg/L] and has a relatively short elimination half-life (t(1/2)) [0.55 to 0.89 h]. Recovery of drug-related material in urine and faeces is nearly 100%. Plasma concentrations of the cytotoxic moiety fluorouracil are very low [with a Cmax of 0.22 to 0.31 mg/L and area under the concentration-time curve (AUC) of 0.461 to 0.698 mg x h/L]. The apparent t(1/2) of fluorouracil after capecitabine administration is similar to that of the parent compound. Comparison of fluorouracil concentrations in primary colorectal tumour and adjacent healthy tissues after capecitabine administration demonstrates that capecitabine is preferentially activated to fluorouracil in colorectal tumour, with the average concentration of fluorouracil being 3.2-fold higher than in adjacent healthy tissue (p = 0.002). This tissue concentration differential does not hold for liver metastasis, although concentrations of fluorouracil in liver metastases are sufficient for antitumour activity to occur. The tumour-preferential activation of capecitabine to fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phosphorylase, key enzymes in the conversion process. As with other cytotoxic drugs, the interpatient variability of the pharmacokinetic parameters of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine and fluorouracil, is high (27 to 89%) and is likely to be primarily due to variability in the activity of the enzymes involved in capecitabine metabolism. Capecitabine and the fluorouracil precursors 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine do not accumulate significantly in plasma after repeated administration. Plasma concentrations of fluorouracil increase by 10 to 60% during long term administration, but this time-dependency is assumed to be not clinically relevant. A potential drug interaction of capecitabine with warfarin has been observed. There is no evidence of pharmacokinetic interactions between capecitabine and leucovorin, docetaxel or paclitaxel.     

熊果酸氨基酸偶联物的合成及保肝活性

目的 设计合成熊果酸 28 位氨基酸偶联物并测定其保肝活性。方法 以熊果酸为起始原料,首先将 3 位羟基进行酯保护,28 位羧基与保护的氨基酸反应,然后脱保护基,得到偶联物。利用肝细胞培养和小鼠急性肝损伤 CCl₄、ConA 筛选模型分别测定偶联物的体外、体内保肝活性。结果与结论 得到 3 个未见报道的化合物,其结构经核磁共振谱和质谱确定。水溶性测定结果显示 3 个偶联物的水溶性很低,保肝试验结果显示 3 个偶联物无明显的保肝活性。     

Irinotecan and capecitabine as second-line treatment after failure for first-line infusional 24-h 5-fluorouracil/folinic acid in advanced colorectal cancer: a phase II study

The efficacy of combination therapy with irinotecan and capecitabine has been demonstrated for the first-line treatment of metastatic colorectal cancer (MCRC). The aim of this trial was to evaluate the efficacy and safety of this combination in MCRC as second-line treatment after failure of 24-h infusional 5-fluorouracil (5-FU24h) and folinic acid (FA). Patients pre-treated with 5-FU24h/FA were recruited at two institutions to receive 6 x weekly irinotecan 70 mg/m2 and capecitabine (1000 mg/m2 b.i.d. days 1-14 and 22-35). Courses were repeated on day 50. In elderly patients (>65 years) a 20% dose reduction of both drugs was scheduled. Twenty-eight patients [M/F 20/8; median age 65 years (range 44-79); median ECOG score 1] were enrolled. The most frequent sites of metastases were liver, n=20, lymph nodes and lungs, n=10, respectively. Half of the patients had two or more metastatic sites. A total of 71 treatment courses (median 2, range 1-8) were administered. Main toxicities [worst per patient (%); CTC grade 1/2/3/4] were: anaemias 18/14/-/-; leukocytopenia 11/21/-/-; thrombocytopenia 11/-/-/-; diarrhea 18/36/21/-; nausea/vomiting 43/29/4/-; mucositis 4/11/-/-; alopecia 7/25/-/-; hand-foot syndrome 7/21/-/-; fatigue 14/14/-/-; renal insufficiency (caused by diarrhea and exsiccosis) -/-/-/7. Dose intensity in the first course was [median/mean (%)]: irinotecan 92/83; capecitabine 88/82. Twenty-three patients are evaluable for response analysis (five did not complete the first course): three patients showed partial remissions (13%) and 11 patients had stable disease (48%). Median time to progression was 3.0 months for the total population (range 1.4-17.3) and 6.5 months for responders (partial response plus no change). Seventy-four percent of the patients received a third-line therapy. Overall survival was 15.7 months calculated from the start of study treatment. Second-line therapy with irinotecan and capecitabine yielded a tumor control in 61% of patients with MCRC. Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan.     

Discovery and development of novel anticancer drug capecitabine

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three enzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.     

Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial

Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.