磷酸西格列汀的合成工艺改进

目的改进磷酸西格列汀的合成方法。方法以2,4,5-三氟苯乙酸为原料,经缩合、水解得到3-氧代-(2,4,5-三氟苯基)丁酸甲酯,该甲酯与手性苯乙胺反应,经硼氢化钠还原,再经缩合、脱保护、成盐得到磷酸西格列汀。结果与结论提供了一条简捷高效且适合工业化生产磷酸西格列汀的工艺路线,7步反应的总收率为39.5%。关键还原步骤以廉价的硼氢化钠为还原剂,使本工艺避免了使用有毒、昂贵试剂,符合绿色化学的原则。     

安立生坦的合成工艺改进研究

目的对安立生坦合成工艺的改进进行研究。方法以二苯甲酮为起始原料,经过缩合、醇解、水解、拆分和取代反应合成安立生坦。醇解采用盐酸进行反应,采用拆分剂盐酸盐和碱试剂通过"一锅法"进行拆分。结果优化了醇解和拆分反应,避免了高毒性物质的产生;优化后,安立生坦的质量分数为99.7%,光学纯度达99.8%,工艺的总收率为30.0%。结论安立生坦的合成工艺改进后操作性好,条件温和,避免产生基因毒性和其他高毒性物质,成本较低,更适于药品的工业化生产。     

6-(4-氨基苯基)-5-甲基-4,5-二氢-3(2H)-哒嗪酮的拆分及左西孟旦的合成

目的合成治疗急性心衰新药左西孟旦。方法以乙酰苯胺为原料 ,经Friedel Crafts酰化反应、Mannich反应、氰化、水解、环合反应制得 6 (4 氨基苯基 ) 5 甲基 4,5 二氢 3 (2H) 哒嗪酮 ,并对该化合物的拆分条件进行了探索和优化。拆分后的左旋体经两步反应制得左西孟旦。结果与结论拆分一步收率较文献大大提高 ,达 5 4 9%。合成左西孟旦总收率为 1 8 4%。     

超临界流体萃取拆分手性外消旋伪麻黄碱

目的用超临界CO₂流体萃取技术拆分伪麻黄碱异构体。方法用单通路法,毛细管电泳分析。将消旋伪麻黄碱转化为非对映体盐,用超临界二氧化碳作为萃取溶剂,可从反应混合物中选择性萃取出伪麻黄碱的一个异构体,达到拆分伪麻黄碱的目的。结果酒石酸是伪麻黄碱良好的拆分剂,半摩尔法形成非对映体盐以超临界二氧化碳流体萃取拆分,一次萃取产物e.e.值可达100%。结论对拆分剂及非对映体盐进行分子构键的计算结果表明拆分剂与被拆分物质成盐的反应规律为R构型优先与S构型反应,理论预测与拆分结果基本吻合。     

罗通定的合成工艺改进

目的改进天然产物L-四氢巴马汀(罗通定)的合成工艺,并对四氢巴马汀右旋体进行回收再利用。方法以黄藤素为起始原料,经还原、拆分和碱化3步反应得到目标化合物罗通定;并将四氢巴马汀右旋体经碱化、氧化后制成碘化黄藤素,可重复制备罗通定。主要对还原剂及还原反应条件、拆分剂及拆分条件进行了改进,并对四氢巴马汀右旋体的回收工艺进行了优化。结果与结论目标产物的结构经1H-NMR、13C-NMR、IR、高分辨质谱、X-射线粉末衍射等确证,一次拆分总收率可达36.4%(以黄藤素计),四氢巴马汀右旋体的回收率可达85%。目标化合物经HPLC检测含量为99.9%。改进后的合成工艺反应步骤少、操作简便、条件温和、原料价廉易得,产物收率及纯度均较高,适合工业化生产。     

苯磺顺阿曲库铵合成工艺的优化

目的 对苯磺顺阿曲库铵合成工艺的优化 方法 以3,4-二甲氧基苯乙胺和3,4-二甲氧基苯乙酸为原料,依次经酰化、脱水环化及还原制得四氢罂粟碱。采用半量拆分法,以D-(+)-二对甲基苯甲酰酒石酸为拆分剂,进行拆分,得到R-四氢罂粟碱,经过麦克加成,氮甲基化反应得苯磺酸阿曲库铵。 结果 目标产物结构通过质谱法、核磁共振氢谱、碳谱和DEPT谱对结构进行了确证,产物的纯度经 HPLC检测为99.18 %,总产率为24.79%。结论 优化后的工艺反应条件温和、操作简便,反应产率高,为工业化生产提供了信息和依据。     

苯磺酸左旋氨氯地平手性拆分工艺研究

目的研究苯磺酸左旋氨氯地平的手性拆分工艺。方法以D-酒石酸为拆分剂,以二甲基亚砜(DMSO)为溶剂,对消旋氨氯地平进行拆分,研究了溶剂水分、溶剂用量、反应温度和拆分剂用量等因素对苯磺酸左旋氨氯地平的收率和光学纯度的影响。结果通过平行实验找到了最佳工艺条件:当二甲基亚砜水分≤0.3%,二甲基亚砜的用量为:二甲基亚砜(mL)/消旋氨氯地平(g)=7∶1,反应温度20³0℃,D-酒石酸用量为:D-酒石酸(mol)/消旋氨氯地平(mol)=0.25∶1时,反应产物具有较高的收率和光学纯度。结论此工艺操作简便,收率较高,适合工业化生产。     

合成罗哌卡因中间体S型N-(2,6-二甲苯基)-2-哌啶甲酰胺拆分工艺改进

目的:探讨合成罗哌卡因的关键中间体S型N-(2,6-二甲苯基)-2-哌啶甲酰胺(Pipecoloxylidide)的拆分和消旋新方法,以提高S型Pipecoloxylidide收率。方法:新工艺将拆分后从母液里回收的R型和S型Pipecoloxylidide混合物与偶氮二异丁腈(引发剂)、巯基乙酸乙酯在惰性溶剂甲苯中混合,于80℃进行消旋反应,并再次拆分得到S型Pipecoloxylidide以循环利用。结果:S型Pipecoloxylidide的收率由原工艺的30%左右提高到60%左右,经过拆分后的光学纯度值可达100%。结论:改进后的工艺能耗低(反应温度由原工艺的130℃以上降为80℃),条件温和,减少了副反应发生,工艺操作简单,能有效提高产品收率和纯度。     

(S)-和(R)-盐酸氟西汀的合成

目的:研究光学活性盐酸氟西汀的合成工艺。方法:以苯乙酮为起始原料,经Mannich反应、还原、醚化3步反应合成外消旋氟西汀游离碱。外消旋体用L-( )-扁桃酸和D-(-)-扁桃酸反复交替拆分,分别得到了(S)-和(R)-型的盐酸氟西汀。结果:合成外消旋氟西汀游离碱的总收率为26.4%。拆分收率为42%。结论:该方法缩短了反应路线,操作简便,收率提高,适于工业生产。     

利拉鲁肽与西格列汀分别联合二甲双胍治疗2型糖尿病效果观察

目的：比较在二甲双胍基础上加用利拉鲁肽与西格列汀治疗2型糖尿病（ T2DM）对血糖控制的疗效。方法将2012年11月-2014年1月收治的34例 T2DM 患者随机分为西格列汀组16例和利拉鲁肽组18例,西格列汀组给予西格列汀联合二甲双胍治疗,利拉鲁肽组给予利拉鲁肽联合二甲双胍治疗,两组均治疗16周。观察两组治疗前、后体质量指数（BMI）、空腹血糖（FBG）及餐后2 h血糖（2 h PBG）、糖化血红蛋白（HbA1c）变化情况。结果治疗16周后两组 BMI、FBG 及2 h PBG、HbA1c 较治疗前均降低,且利拉鲁肽组 BMI 和 FBG 较西格列汀组明显降低（P〈0.05,P〈0.01）。两组均无低血糖发生,利拉鲁肽组发生胃肠道反应3例,西格列汀组发生1例,均自行缓解。结论西格列汀或利拉鲁肽联合盐酸二甲双胍均可有效降低糖尿病患者 BMI及血糖,但利拉鲁肽能更加明显的降低FBG及 BMI。     

A randomized clinical trial of the safety and efficacy of sitagliptin in patients with type 2 diabetes mellitus inadequately controlled by acarbose alone

Objective: To evaluate the safety and efficacy of sitagliptin when added to the treatment of patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on acarbose monotherapy.

Research design and methods: This was a multicenter, randomized, placebo-controlled, double-blind clinical trial. Patients (N?=?381) with T2DM and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥?7.0% and ≤10.0%) on acarbose monotherapy (at least 50?mg three times daily) were randomized in a 1:1 ratio to receive the addition of sitagliptin 100?mg or matching placebo once daily for 24 weeks.

Main outcome measures: Changes from baseline in HbA1c and fasting plasma glucose (FPG) at Week 24.

Results: The mean baseline HbA1c in randomized patients was 8.1%. At Week 24, the placebo-controlled, least squares mean changes from baseline (95% confidence interval) in HbA1c and FPG in the sitagliptin group were ?0.62% and ?0.8?mmol/L (p?p?Conclusions: Sitagliptin was generally well tolerated and provided statistically superior and clinically meaningful improvements in glycemic control after 24 weeks of treatment compared to placebo when added to treatment of patients with inadequate glycemic control on acarbose monotherapy.

Clinicaltrials.gov: NCT01177384.     

Comparing postprandial efficacy in type 2 diabetic patients receiving mitiglinide and sitagliptin by using continuous glucose monitoring: a pilot study

Objective: To compare postprandial efficacy in type 2 diabetic patients given mitiglinide and sitagliptin, both of which are known to improve postprandial hyperglycemia, by using continuous glucose monitoring (CGM).

Methods: Eleven patients with type 2 diabetes were given mitiglinide 10 mg three times a daily or sitagliptin 50 mg once a day for 1 month and were hospitalized for 4 days and evaluated by CGM. On discharge, they were crossed over to the other regimen for 1 month of treatment/4 days of evaluation. The CGM data were used to compare each parameter for glycemic variability.

Results: The patients were 60 ± 10 (mean ± SD) years old, and had HbA1c value 7.3 ± 0.9%. The pre-meal glucose levels before lunch were significantly lower with mitiglinide than with sitagliptin (116 ± 26/131 ± 34 mg/dl, p = 0.022). The AUC measuring over 140 mg/dl 3 h after breakfast (mitiglinide 4812 ± 4219/sitagliptin 7807 ± 6391 mg/dl·min, p = 0.042) and lunch (mitiglinide 5658 ± 5856/sitagliptin 8492 ± 7161, p = 0.050) was significantly lower with mitiglinide than with sitagliptin.

Conclusions: A CGM-based comparison showed that mitiglinide and sitagliptin were different in their glucose-lowering effects, where mitiglinide significantly improved hyperglycemia after breakfast and lunch, and significantly lowered pre-meal glucose levels before lunch, compared to sitagliptin.     

Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone

Importance of the field: Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Areas covered in this review: To date, clinical trials conducted in type 2 diabetes patients have used combinations of sitagliptin (100 mg/day) and pioglitazone (30 – 45 mg/day) as separate tablets. These trials have shown that the combinations offer additive efficacy in reducing blood glucose when given as initial antidiabetic therapy and as add-on therapy when pioglitazone alone fails to maintain glycemic control.

What the reader will gain: Initial therapy with a combination of sitagliptin (100 mg/day) and pioglitazone (30 mg/day) reduced HbA1c by > 2% starting from a baseline > 9%. Adding sitagliptin (50 – 100 mg/day) to patients inadequately controlled on pioglitazone reduced HbA1c by 0.7 – 1.4% from a baseline of 8 – 8.5%. The combination did not increase the risk of hypoglycemia and produced similar or slightly more weight gain than pioglitazone alone when introduced as initial antidiabetic therapy.

Take home message: The combination of sitagliptin and pioglitazone was well tolerated in these trials, and would appear to be suited to a fixed-dose single-tablet combination for once-daily administration.     

Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes

ABSTRACT

Objective: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions.

Methods: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50?mg b.i.d.) with metformin (1000?mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50?mg sitagliptin twice daily and placebo to metformin twice daily; 1000?mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50?mg of sitagliptin twice daily and 1000?mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations–time curve over the dosing interval (AUC_{0–12 h}), maximum observed plasma concentrations (C_max), and time of occurrence of maximum observed plasma concentrations (T_max). Renal clearance was also determined for sitagliptin.

Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC_{0–12 h} geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC_{0–12 h} GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics.

Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.     

Once-daily sitagliptin,a dipeptidyl peptidase-4 inhibitor,for the treatment of patients with type 2 diabetes

ABSTRACT

Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP?4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100?mg daily was evaluated as a once-daily (100?mg once-daily) or twice-daily (50?mg twice-daily) dosing regimen.

Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA_1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100?mg once-daily, or sitagliptin 50?mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.

Results: Mean baseline HbA_1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤?7%. After 12 weeks, treatment with all doses of sitagliptin significantly (?p < 0.05) reduced HbA_1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2?mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly (?p < 0.05) reduced by –14.0 to –22.6?mg/dL with all doses of sitagliptin relative to placebo. HOMA?β was significantly (?p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA?IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100?mg once-daily and 50?mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100?mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study.

Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100?mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.     

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT

Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A_1c ≥?8.0% and ≤?11.0%) type 2 diabetes mellitus (T2DM).

Research design and methods: This was a multi­national, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥?6?weeks of stable metformin monotherapy (≥?1500?mg/day), patients were randomized to either the addition of sitagliptin 100?mg once daily or placebo to ongoing metformin for 30?weeks.

Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A_1c (HbA_1c) measured after 18?weeks of sitagliptin treatment. Key secondary end­points included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA_1c at 30 weeks. The proportion of patients meeting the goal of HbA_1c <?7.0% was also analyzed.

Results: Sitagliptin significantly reduced HbA_1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA_1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA_1c <?7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not signif­icantly increase the risk of hypoglycemia or gastro­intestinal adverse events.

Conclusions: Addition of sitagliptin 100?mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Trial registration: ClinicalTrials.gov identifier: NCT00337610.     

Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide

ABSTRACT

Objective: To estimate risk and relative risk (RR) of acute pancreatitis among patients using incretin-based diabetes therapies (exenatide or sitagliptin) compared to patients treated with agents with established safety profiles (metformin or glyburide).

Research design and methods: The study population was derived from a large US commercial health insurance transaction database using an active drug safety surveillance system (i3 Aperio^*). This analysis is based on data from June 2005 through June 2008. Cohorts of exenatide and sitagliptin initiators were each matched to an equal number of metformin or glyburide (met/gly) initiators using propensity scores to reduce confounding in the comparison of outcomes during follow-up. Patients with claims suggesting pancreatic disease in the 6 months prior to cohort entry were excluded.

Main outcome measure: Claims for hospitalizations associated with a primary diagnosis of acute pancreatitis (ICD-9 577.0).

Results: There were 27?996 exenatide initiators and 16?276 sitagliptin initiators and approximately equal numbers of matched comparators. During follow-up of up to 1 year, acute pancreatitis occurred among 0.13% of patients treated with exenatide and 0.12% of patients treated with sitagliptin. The risk of acute pancreatitis was comparable for initiators of exenatide (RR 1.0; 95% confidence interval (CI) 0.6–1.7) and sitagliptin (RR 1.0; 95% CI 0.5–2.0) relative to the comparison cohorts.

Conclusions: These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.     

Effects of sitagliptin or mitiglinide as an add-on to acarbose on daily blood glucose fluctuations measured by 72 h subcutaneous continuous glucose monitoring in Japanese patients with type 2 diabetes: a prospective randomized study

Objective: Postprandial hyperglycemia and blood glucose fluctuations increase the risk of macroangiopathy in patients with type 2 diabetes mellitus (T2DM). However, few studies have examined the effects of oral hypoglycemic drugs on blood glucose fluctuations in daily life.

Methods: Twenty-nine T2DM patients treated with acarbose were randomized to receive either sitagliptin (14 patients) or mitiglinide (15 patients) together with acarbose for 4 weeks. Patients were then switched to a combination of 10 mg mitiglinide and 0.2 mg voglibose for 4 weeks. All patients wore a continuous glucose monitoring (CGM) device for 5 – 7 days in week 3 of each treatment period.

Results: The percentage of blood glucose levels in the hyperglycemic range, blood glucose indices derived from 24-h CGM profiles and the glycemic parameters (HbA1c, glycated albumin and fasting plasma glucose) were significantly improved by adding sitagliptin or mitiglinide to ongoing acarbose therapy. These parameters also tended to improve in the mitiglinide/voglibose combination period.

Conclusion: Daily blood glucose fluctuations were significantly improved by adding sitagliptin or mitiglinide to acarbose, and improved after switching to the mitiglinide/voglibose combination. Larger controlled studies are needed to verify the effects of adding sitagliptin or mitiglinide to acarbose on glucose fluctuations.     

A randomized,double-blind,placebo-controlled trial evaluating sitagliptin action on insulin resistance parameters and β-cell function

Aim: To evaluate the impact on glycemic control, insulin secretion and on insulin resistance of a sitagliptin + metformin combination compared to metformin monotherapy in type 2 diabetic, naïve to treatment, patients.

Materials and methods: A total of 178 Caucasian type 2 diabetic patients were randomized to take sitagliptin 100 mg once a day or placebo in addition to previously taken metformin, for 12 months. The authors evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, retinol binding protein-4 (RBP-4), visfatin, and chemerin. Before and 12 months after the addition of sitagliptin, patients underwent tests to assess insulin sensitivity and insulin secretion.

Results: Sitagliptin + metformin gave a better decrease of glycemic control, HOMA-IR and glucagon levels compared to placebo + metformin; sitagliptin + metformin also better increased HOMA-β and all β-cell measurements recorded after the clamp. Regarding adipocytokines, sitagliptin + metformin better reduced RBP-4, visfatin and chemerin levels, compared to placebo + metformin.

Conclusion: When metformin alone is not enough to reach an adequate glycemic control, sitagliptin can be a valid option, because of its effects in reducing insulin resistance and in preserving β-cell function.