二甲双胍 | 657-24-9

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 胰腺激素及其它调节血糖药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 二甲双胍
• 中文别名: 甲福明；1,1-二甲基双胍；双甲胍
• 英文名称: dimethylbiguanide
• 英文别名: metformin；Met；[¹⁴C]-metformin；1,1-dimethylbiguanide；glucophage；1-carbamimidamido-N,N'-dimethylmethanimidamide；1,1-dimethylbiguanide hydrochloride；N,N-dimethyl biguanide；2-Carbamimidoyl-1,1-dimethylguanidine；2-carbamimidoyl-1,1-dimethylguanidine
• CAS: 657-24-9
• 化学式: C₄H₁₁N₅
• mdl: MFCD00242652
• 分子量: 129.165
• InChiKey: XZWYZXLIPXDOLR-UHFFFAOYSA-N

物化性质

• 熔点：
  199-200 °C
• 沸点：
  229.23°C (rough estimate)
• 密度：
  1.0743 (rough estimate)
• 溶解度：
  乙腈（少量溶解）、酸水溶液（少量溶解）、二氯甲烷（少量溶解）
• 物理描述：
  Solid
• 蒸汽压力：
  7.58X10-5 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Metformin hydrochloride/
• 分解：
  Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), hydrogen chloride gas. /Metformin hydrochloride/

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  9
• 可旋转键数：
  2
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  91.5
• 氢给体数：
  3
• 氢受体数：
  1

ADMET

代谢

使用单剂量二甲双胍对正常受试者进行的静脉研究显示，二甲双胍以原药形式在尿液中排泄，不经过肝脏代谢（在人类中未发现代谢物）或胆汁排泄。

Intravenous studies using a single dose of metformin in normal subjects show that metformin is excreted as unchanged drug in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

来源:DrugBank

代谢

Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the drug have been identified in humans. 二甲双胍不会在肝脏或胃肠道代谢，也不会通过胆汁排泄；在人体中没有发现该药物的代谢物。

Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the drug have been identified in humans.

来源:Hazardous Substances Data Bank (HSDB)

代谢

二甲双胍不经过代谢。 消除途径：正常受试者中的静脉单次给药研究表明，二甲双胍以原形通过尿液排出，不经过肝脏代谢（在人类中未发现代谢物）也不通过胆汁排泄。在大约24小时内，约90%的药物在肾功能健康的人体内被消除。二甲双胍的肾清除率大约是肌酐清除率的3.5倍，这表明肾小管分泌是二甲双胍消除的主要方式。 半衰期：6.2小时。作用持续时间为8-12小时。

Metformin is not metabolized. Route of Elimination: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Approximately 90% of the drug is eliminated in 24 hours in those with healthy renal function. Renal clearance of metformin is approximately 3.5 times that of creatinine clearance, indicating the tubular secretion is the primary mode of metformin elimination. Half Life: 6.2 hours. Duration of action is 8-12 hours.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

识别和使用：二甲双胍是一种降血糖药，但不是降血糖剂。它不会导致胰腺释放胰岛素，也不会导致低血糖，即使在大量服用时也不会。人类接触和毒性：二甲双胍被认为通过抑制肝脏产生葡萄糖并增加外周组织对胰岛素的敏感性来发挥作用。它不刺激胰岛素分泌，这解释了为何不会出现低血糖。二甲双胍还对血浆脂质浓度有益，并促进体重减轻。在肾功能损害的患者中可能会发生二甲双胍的积累，这种积累偶尔可能导致乳酸酸中毒，这是一种严重、可能致命的代谢性疾病。乳酸酸中毒构成医疗紧急情况，需要立即住院治疗；乳酸酸中毒的特点是血液乳酸浓度升高、血液pH降低、电解质紊乱伴阴离子间隙增加，以及乳酸/丙酮酸比例增加。乳酸酸中毒还可能与多种病理生理状况相关，包括糖尿病，以及在任何存在实质性组织低灌注和低氧血症的情况下发生。据报道，大约50%的二甲双胍相关乳酸酸中毒的病例是致命的。在包括人淋巴细胞检测在内的体外测试系统中，没有观察到致突变性或染色体损伤的证据。动物研究：在一项为期104周的雄性和雌性大鼠服用二甲双胍盐酸盐的研究中，剂量达到每天900 mg/kg，或在一项为期91周的雄性和雌性小鼠服用二甲双胍盐酸盐的研究中，剂量达到每天1500 mg/kg，没有观察到致癌潜力的证据。二甲双胍（MF）的防癌效果已在小鼠、大鼠和仓鼠中进行了研究。在大多数情况下，二甲双胍治疗导致致癌作用的抑制。在大鼠服用二甲双胍盐酸盐600 mg/kg每天后，没有观察到生育能力受损的证据。在给予大鼠和家兔二甲双胍盐酸盐600 mg/kg每天进行的繁殖研究中，没有发现致畸性。在体内小鼠微核试验或体外测试系统中，包括微生物（Ames试验）和哺乳动物（小鼠淋巴瘤）检测，没有观察到致突变性或染色体损伤的证据。用二甲双胍预处理大鼠小脑颗粒神经元大大增强了细胞对谷氨酸诱导的神经毒性的存活能力。在喂食高脂肪饮食的老年雄性小鼠中，补充二甲双胍6个月后，二甲双胍减少了体脂组成并减弱了高脂肪饮食引起的运动功能下降。在莫里斯水迷宫测试海马依赖性记忆功能的表现显示，二甲双胍预防了高脂肪饮食导致的空间参考记忆受损。生态毒性研究：成年胖头鱼（Pimephales promelas）慢性暴露于二甲双胍4周，剂量为40微克/升。二甲双胍治疗诱导了雄性鱼卵蛋白卵黄素信使核糖核酸（mRNA）的显著上调，这是内分泌干扰的迹象。

IDENTIFICATION AND USE: Metformin is antihyperglycemic, not hypoglycemic agent. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. HUMAN EXPOSURE AND TOXICITY: Metformin is believed to work by inhibiting hepatic glucose production and increasing the sensitivity of peripheral tissue to insulin. It does not stimulate insulin secretion, which explains the absence of hypoglycemia. Metformin also has beneficial effects on the plasma lipid concentrations and promotes weight loss. Accumulation of metformin may occur in patients with renal impairment, and such accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic disease. Lactic acidosis constitutes a medical emergency requiring immediate hospitalization and treatment; lactic acidosis is characterized by elevated blood lactate concentrations, decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. Lactic acidosis also may occur in association with a variety of pathophysiologic conditions, including diabetes mellitus, and whenever substantial tissue hypoperfusion and hypoxemia exist. Approximately 50% of cases of metformin-associated lactic acidosis have been reported to be fatal. No evidence of mutagenicity or chromosomal damage was observed in in vitro test systems, including human lymphocytes assay. ANIMAL STUDIES: No evidence of carcinogenic potential was seen in a 104-week study in male and female rats receiving metformin hydrochloride dosages up to and including 900 mg/kg daily or in a 91-week study in male and female mice receiving metformin hydrochloride at dosages up to and including 1500 mg/kg daily. Cancer preventive effect of metformin (MF) has been studied in mice, rats and hamsters. In the majority of cases metformin treatment leads to inhibition of carcinogenesis. No evidence of impaired fertility was observed in rats following administration of metformin hydrochloride dosages of 600 mg/kg daily. Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily have not revealed teratogenicity. No evidence of mutagenicity or chromosomal damage was observed in vivo in a micronucleus test in mice or in in vitro test systems, including microbial (Ames test) and mammalian (mouse lymphoma) assays. Pretreatment of rat cerebellar granule neurons with metformin greatly enhanced cell viability against glutamate-induced neurotoxicity. In aged male mice fed high-fat diet supplemented with metformin for 6 months, metformin decreased body fat composition and attenuated declines in motor function induced by a high fat diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the high fat diet. ECOTOXICITY STUDIES: Adult fathead minnows (Pimephales promelas) were chronically exposed to metformin for 4 wk, at 40 ug/L. Metformin treatment induced significant up-regulation of messenger ribonucleic acid (mRNA) encoding the egg-protein vitellogenin in male fish, an indication of endocrine disruption.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

二甲双胍的作用机制与其他口服降糖药类别不同。二甲双胍通过减少肝脏产生的葡萄糖、减少肠道对葡萄糖的吸收以及通过增加外周葡萄糖的摄取和利用来提高胰岛素敏感性，从而降低血糖水平。这些效果是由二甲双胍最初激活腺苷酸活化蛋白激酶（AMPK）介导的，这是一种在胰岛素信号传导、全身能量平衡以及葡萄糖和脂肪代谢中发挥重要作用的肝脏酶。激活AMPK是二甲双胍抑制肝细胞产生葡萄糖所需的作用。增加外周葡萄糖的利用可能是由于胰岛素与胰岛素受体的结合改善。二甲双胍给药还会增加骨骼肌中的AMPK活性。已知AMPK会导致GLUT4转移到质膜上，从而实现不依赖胰岛素的葡萄糖摄取。罕见副作用乳酸性酸中毒被认为是由肝脏摄取血清乳酸减少引起的，血清乳酸是糖异生的一个底物。对于那些肾功能健康的人来说，轻微的过量 simply cleared。然而，那些严重肾功能损害的人可能会积聚临床上显著的血清乳酸水平。可能诱发乳酸性酸中毒的其他状况包括严重肝病和急性/失代偿性心力衰竭。

Metformin's mechanisms of action differ from other classes of oral antihyperglycemic agents. Metformin decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the initial activation by metformin of AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. Metformin administration also increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. The rare side effect, lactic acidosis, is thought to be caused by decreased liver uptake of serum lactate, one of the substrates of gluconeogenesis. In those with healthy renal function, the slight excess is simply cleared. However, those with severe renal impairment may accumulate clinically significant serum lactic acid levels. Other conditions that may precipitate lactic acidosis include severe hepatic disease and acute/decompensated heart failure.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

极少数（少于1%）患者在二甲双胍治疗期间出现轻微酶水平升高。实际上，二甲双胍可能实际上会降低患有脂肪肝疾病患者的升高的转氨酶水平。临床上明显的二甲双胍引起的肝损伤非常罕见，尽管这种药物已经广泛使用了数十年，但在文献中描述的案例不到十几例。肝损伤通常在服用1到8周后出现，典型症状包括虚弱和疲劳，随后出现黄疸。已经描述了各种肝细胞损伤和胆汁淤积性损伤的组合，许多情况是混合性的。过敏表现不典型，但已经描述过皮疹、发热和嗜酸性粒细胞增多。自身抗体的形成也不典型。由于这种药物通常与其他降糖药物联合使用，许多降糖药物也会导致肝损伤，因此很难确定损伤是否是由二甲双胍或其他药物引起的。损伤的时间点可能是最具特征性的，损伤出现在开始使用药物后不久，而不是在长期治疗期间。停止使用二甲双胍后，恢复通常很快。

Minor enzyme elevations have been reported to occur during metformin therapy in less than 1% of patients. Indeed, metformin may actually lower elevated aminotransferase levels in patients with fatty liver disease. Clinically apparent liver injury from metformin is very rare, fewer than a dozen cases having been described in the literature despite widespread use of this agent for several decades. The liver injury usually appears after 1 to 8 weeks, typically with symptoms of weakness and fatigue followed by jaundice. Various combinations of hepatocellular and cholestatic injury have been described, and many have been mixed. Allergic manifestations are not typical but rash, fever and eosinophilia have been described. Autoantibody formation is also not typical. Because this agent is usually given in combination with other hypoglycemic agents, many of which also cause liver injury, it can be difficult to establish whether the injury is due to metformin or another agent. The timing of injury is perhaps most characteristic, the injury arising soon after the agent is started and not during long term therapy. Recovery is usually rapid after metformin is stopped.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：二甲双胍

Compound:metformin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

常规片剂吸收：在空腹状态下给予的二甲双胍500毫克片剂的绝对生物利用度约为50%-60%。单次剂量临床研究使用口服二甲双胍剂量500至1500毫克和850至2550毫克表明，随着二甲双胍剂量的增加，剂量比例性不足，归因于吸收减少而非消除变化。在二甲双胍的常规临床剂量和给药方案下，稳态血浆浓度在24-48小时内达到，通常测量值小于1 μg/mL。 缓释片剂吸收：单次口服二甲双胍缓释片后，Cmax达到中位值7小时，范围在4至8小时之间。峰血浆水平测量结果比相同剂量的常规二甲双胍低约20%，然而，两种形式的吸收程度（通过曲线下面积-AUC测量）相似。 食物的影响：食物减少了二甲双胍的吸收，表现为与空腹状态下给药相比，随餐摄入850毫克二甲双胍片剂后的平均峰血浆浓度（Cmax）降低了约40%，血浆浓度-时间曲线下的面积（AUC）降低了25%，达到峰血浆浓度的时间（Tmax）增加了35分钟。尽管食物会使二甲双胍缓释片的吸收程度（通过曲线下面积-AUC测量）增加约50%，但食物对二甲双胍的Cmax和Tmax没有影响。高脂肪和低脂肪餐对缓释二甲双胍的药代动力学具有相似的影响。

**Regular tablet absorption** The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an increase in metformin dose, attributed to decreased absorption rather than changes in elimination. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are achieved within 24-48 hours and are normally measured at <1 μg/mL. **Extended-release tablet absorption** After a single oral dose of metformin extended-release, Cmax is reached with a median value of 7 hours and a range of between 4 and 8 hours. Peak plasma levels are measured to be about 20% lower compared to the same dose of regular metformin, however, the extent of absorption of both forms (as measured by area under the curve - AUC), are similar. **Effect of food** Food reduces the absorption of metformin, as demonstrated by about a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute increase in time to peak plasma concentration (Tmax) after ingestion of an 850 mg tablet of metformin taken with food, compared to the same dose administered during fasting. Though the extent of metformin absorption (measured by the area under the curve - AUC) from the metformin extended-release tablet is increased by about 50% when given with food, no effect of food on Cmax and Tmax of metformin is observed. High and low-fat meals exert similar effects on the pharmacokinetics of extended-release metformin.

来源:DrugBank

吸收、分配和排泄

• 消除途径

这种药物主要通过肾脏排出。二甲双胍的肾清除率大约是肌酐清除率的3.5倍，这表明肾小管分泌是二甲双胍消除的主要途径。口服给药后，大约90%被吸收的二甲双胍在摄入后24小时内通过肾脏排出。

This drug is substantially excreted by the kidney. Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eliminated by the kidneys within the first 24 hours post-ingestion.

来源:DrugBank

吸收、分配和排泄

• 分布容积

单次口服850毫克二甲双胍后，二甲双胍的表观分布容积(V/F)平均为654 ± 358升。

The apparent volume of distribution (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 L.

来源:DrugBank

吸收、分配和排泄

• 清除

肾脏清除率大约是肌酐清除率的3.5倍，这表明肾小管分泌是二甲双胍消除的主要途径。口服给药后，大约90%的吸收药物在最初的24小时内通过肾脏途径消除。

Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours.

来源:DrugBank

吸收、分配和排泄

二甲双胍从胃肠道缓慢且不完全吸收，主要从小肠吸收；吸收在6小时内完成。在空腹条件下，二甲双胍氢氯酸盐的绝对口服生物利用度报告约为50-60%，剂量为0.5-1.5克；药物与肠壁的结合可能解释了吸收的药物量（通过未改变药物的尿液和粪便排泄确定）与某些研究中生物利用的量之间的差异。在单次给药研究中，使用二甲双胍氢氯酸盐常规片剂，剂量为0.5-1.5克或0.85-2.55克，血浆二甲双胍浓度并未随着剂量的增加而成比例增加，这表明存在一个活跃的饱和吸收过程。同样，在使用缓释片剂（Glumetza）的单次给药研究中，剂量为0.5-2.5克，血浆二甲双胍浓度也未随着剂量的增加而成比例增加。在给予二甲双胍氢氯酸盐缓释片剂（Glucophage XR）后达到稳态时，AUC和峰浓度在0.5-2克的范围内并不与剂量成比例。然而，来自动物研究和人类肠细胞培养的有限数据表明，二甲双胍在小肠中的跨上皮转移可能通过一个被动的、非饱和的机制发生，可能涉及细胞旁路。在使用另一种二甲双胍氢氯酸盐缓释片剂（Fortamet）的几项研究中，使用剂量为1-2.5克，二甲双胍的暴露与剂量相关。

Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours. The absolute oral bioavailability of the drug under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g; binding of the drug to the intestinal wall may explain the difference between the amount of drug absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies. In single-dose studies with metformin hydrochloride conventional tablets doses of 0.5-1.5 g or 0.85-2.55 g, plasma metformin concentrations did not increase in proportion to increasing doses, suggesting an active saturable absorption process. Similarly, in single-dose studies with an extended-release tablet preparation (Glumetza) at doses of 0.5-2.5 g, plasma metformin concentrations did not increase in proportion to increasing doses. At steady state after administration of a metformin hydrochloride extended-release tablet preparation (Glucophage XR), the AUC and peak plasma concentrations were not dose proportional within the range of 0.5-2 g. However, limited data from studies in animals and in human intestinal cell cultures suggest that transepithelial transfer of metformin in the intestine may occur through a passive, nonsaturable mechanism, possibly involving a paracellular route. In several studies with another metformin hydrochloride extended-release tablet preparation (Fortamet) using doses of 1-2.5 g, metformin exposure was dose-related.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  应存放在室温、避光且充满惰性气体的环境中。

制备方法与用途

二甲双胍 简介

二甲双胍是治疗2型糖尿病的一线首选和全程用药。它通过增加肌肉、脂肪等外周组织对胰岛素的敏感性，增加葡萄糖的摄取和利用，促进无氧酵解，抑制肝糖原异生作用，减少肝糖输出，并抑制肠壁细胞摄取葡萄糖来降低空腹和餐后高血糖。此外，二甲双胍还有减重作用，能抑制胆固醇生物合成和贮存，降低甘油三酯和总胆固醇水平，改善血管内皮功能，增加血流量。它特别适用于肥胖或超重的2型糖尿病患者，并有助于预防心血管疾病。

用法与用量

口服：开始时每次0.25g，每日3次，餐时或餐后服用。一周后根据病情调整剂量至每次0.5g，每日3次。每日总量不宜超过1.5g，以免引起血糖过低。

不良反应

常见胃肠道反应包括恶心、呕吐、口中金属味及腹泻；可使血乳酸水平升高，并导致乳酸性酸中毒；充血性心力衰竭、肝肾功能不全患者使用时应谨慎，孕妇慎用。糖尿病并发酮症酸中毒或急性感染时禁用。

调整剂量注意事项

在调整药物剂量过程中要防止低血糖、昏迷及酸中毒的发生。与双香豆素类合用可增加出血倾向；本品可能增强加压素的升压作用。若同时服用含醇饮料，可能会引起腹痛、乳酸性酸血症和体温过低。

适应症

二甲双胍通过其降糖机制及特点贯穿于糖尿病的预防、治疗及其并发症防治中：

1. 糖尿病预防：可用于糖尿病二级与三级预防。对存在糖尿病高危因素者，应首先调整生活方式；若效果不佳并逐步升高至“糖尿病前期”，可以使用二甲双胍延缓和预防糖尿病发展。
2. 起始治疗：作为首选降糖药物之一，一旦确诊为2型糖尿病，除非有用药禁忌或不耐受情况，建议首选二甲双胍。
3. 长期治疗：国内外指南共识中均将二甲双胍定位为首选并贯穿全程的药物。除非单药疗效欠佳，否则不应轻易换用其他降糖药物。
4. 防治并发症：其具有降低三酰甘油、保护血管内皮的作用，能有效抗动脉粥样硬化、减少冠心病发生率，并对心血管事件及高血压风险有一定益处。

二甲双胍不仅有助于控制血糖水平，还能带来多种额外的健康获益。在使用过程中，请根据医嘱合理用药并注意监测可能出现的各种不良反应。

反应信息

• 作为反应物：
  描述：

  二甲双胍 在 月桂酸 作用下， 以 丙酮 为溶剂， 以75%的产率得到metformin laurate
  参考文献：
  名称：

  [EN] COMPOSITIONS AND DOSAGE FORMS FOR ENHANCED ABSORPTION OF METFORMIN
  [FR] COMPOSITIONS ET FORMES POSOLOGIQUES POUR UNE ABSORPTION AMELIOREE DE METFORMINE

  摘要：

  描述了由二甲双胍和传输基团（如脂肪酸）组成的复合物。该复合物在胃肠道中具有增强的吸收，特别是在下消化道。该复合物以及使用该复合物制备的组合物和剂型，使药物在十至二十四小时内通过身体吸收，从而实现二甲双胍的一日一次剂量形式。

  公开号：

  WO2005041923A1
• 作为产物：
  描述：

  N1,N1-dimethyl-S-phenyl-N4-thiohydroxybiguanidine 在 human serum 作用下， 生成 二甲双胍
  参考文献：
  名称：

  [EN] NOVEL PRODRUGS OF METFORMIN
  [FR] NOUVEAUX PROMÉDICAMENTS DE LA METFORMINE

  摘要：

  本发明涉及新型二甲双胍前药，其药用盐，含有前药的药物组合物，以及使用前药的方法。具体而言，本发明涉及将含硫的前体连接到二甲双胍上，形成新型可逆生物硫酰基胍（N-S）二甲双胍前药，其具有改善的口服吸收性能，从而提高生物利用度。

  公开号：

  WO2010100337A1
• 作为试剂：
  描述：

  碘苯 、 木榴油 在 copper(l) iodide 、 potassium carbonate 、 二甲双胍 作用下， 以 乙腈 为溶剂， 反应 15.17h， 以75%的产率得到2-甲氧基苯基苯醚
  参考文献：
  名称：

  原位生成的CuI /二甲双胍复合物是C–N和C–O交叉偶联反应的新型高效催化剂

  摘要：

  在N / O-芳基化反应中，原位生成的铜（I）和双胍，即二甲双胍的络合物是一种高效的均相催化剂。使用这种铜催化剂，还可以实现取代苯酚与各种芳基碘化物和溴化物的O-芳基化反应，从而以良好或优异的DMF收率得到二芳基醚。这种非均相铜催化剂还促进了咪唑与乙腈中各种芳基卤化物（Cl，Br，I）的N-芳基化反应。

  DOI：

  10.1016/j.tetlet.2013.10.039

文献信息

• Iridium Supported on Phosphorus‐Doped Porous Organic Polymers: Active and Recyclable Catalyst for Acceptorless Dehydrogenation and Borrowing Hydrogen Reaction
  作者：Wei Yao、Zheng‐Chao Duan、Yilin Zhang、Xinxin Sang、Xiao‐Feng Xia、Dawei Wang

  DOI：10.1002/adsc.201900929

  日期：2019.12.17

  catalyst, which was thoroughly characterized by means of EDS, SEM, TEM, XRD, XPS, and FT‐IR, revealed excellent catalytic activity for the reaction of diphenyl phosphinamide with benzyl alcohols through borrowing hydrogen strategy and acceptorless dehydrogenation with wide functional group tolerance. Moreover, this POP−Ir catalyst could be simply recovered and reused for at least five times without a significant

  铱掺杂磷的多孔有机聚合物（POP-Ir）是通过将简单的铱通过配位键固定在多孔有机聚合物的骨架上而开发的。该POP-Ir催化剂通过EDS，SEM，TEM，XRD，XPS和FT-IR进行了彻底表征，通过借用氢策略和无受体的广泛脱氢反应，显示出对二苯基膦酰胺与苄醇反应的出色催化活性。功能组耐受性。此外，这种POP-Ir催化剂可以简单地回收和再利用至少五次，而不会显着降低活性，并显示出可观的应用前景。对该机制进行了研究，以进一步了解该POP-Ir催化体系和转化。全面的，
• Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties
  作者：Mohammed A. Seleem、Ahmed M. Disouky、Haroon Mohammad、Tamer M. Abdelghany、Ahmed S. Mancy、Sammar A. Bayoumi、Ahmed Elshafeey、Ahmed El-Morsy、Mohamed N. Seleem、Abdelrahman S. Mayhoub

  DOI：10.1021/acs.jmedchem.6b00233

  日期：2016.5.26

  first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue 17 was identified as the most potent analogue constructed thus far. The corresponding amine 8 was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the n-butyl group with cyclic bioisosteres revealed

  合成了一系列第二代2-（1-（2-（4-丁基苯基）-4-甲基噻唑-5-基）亚乙基）氨基胍（1）的类似物，并针对耐甲氧西林的金黄色葡萄球菌（MRSA）进行了测试。 。设计这些化合物的目的是改善药代动力学性质。通过用环状的不可水解的嘧啶环取代第一代成员的可快速水解的席夫碱部分来实现该主要目的。含酰肼的类似物17被确定为迄今为止构建的最有效的类似物。相应的胺8活跃度降低了8倍。最后，将含氮侧链并入芳族体系中完全消除了抗菌特性。用环状生物等排体取代正丁基可显示出环己烯基类似物29，该化合物在体外抗MRSA效能方面表现出显着改善。增大或减小环的尺寸会使抗菌活性变差。化合物17表现出优异的体外和体内药代动力学特性，提供了令人信服的证据证明这种特定的类似物是值得进一步分析的良好候选药物。
• 一种磷酰胺衍生物及制备方法和用途
  申请人：四川海思科制药有限公司

  公开号：CN109305989B

  公开（公告）日：2021-02-26

  本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐，以及在制备用于预防或治疗糖尿病、抗肿瘤、多动运动障碍、运动神经元疾病、脑保护、与中枢神经系统相关疾病、免疫抑制、器官组织或细胞异体抑制排斥反应、免疫调节和/或炎性疾病、惊厥、癫痫或脑卒中药物中的应用，通式(I)化合物的结构为Q‑L‑R1，其基团定义与说明书定义一致。
• COMPOSITIONS FOR THE TREATMENT OF DIABETES AND PRE-DIABETES
  申请人：Kandula Mahesh

  公开号：US20140357680A1

  公开（公告）日：2014-12-04

  The invention relates to the compositions of formula I or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprises a salt of metformin and the methods for treating or preventing metabolic syndrome, prediabetes and diabetes may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of diabetes mellitus, obesity, lipid disorders, hypertriglyceridemia, hyperglycemia, hyperinsulinemia and insulin resistance.

  该发明涉及公式I或其药用可接受的多型体、溶剂化合物、对映体、立体异构体及其水合物的组合物。药物组合物包括二甲双胍的盐，并且用于治疗或预防代谢综合征、糖尿病前期和糖尿病的方法可以制备为口服、颊下、直肠、局部、经皮、经粘膜、静脉、肠道给药、糖浆或注射。这些组合物可用于治疗糖尿病、肥胖、脂质紊乱、高三酰甘油血症、高血糖、高胰岛素血症和胰岛素抵抗。
• [EN] COMPOSITIONS AND METHODS FOR THE TREATMENT OF DIABETES AND PRE-DIABETES<br/>[FR] COMPOSITIONS ET PROCÉDÉS DE TRAITEMENT DU DIABÈTE ET DU PRÉ-DIABÈTE
  申请人：KANDULA MAHESH

  公开号：WO2014195961A1

  公开（公告）日：2014-12-11

  The invention relates to the compositions of formula I or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprises a salt of metformin and the methods for treating or preventing metabolic syndrome, prediabetes and diabetes may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of diabetes mellitus, obesity, lipid disorders, hypertriglyceridemia, hyperglycemia, hyperinsulinemia and insulin resistance.

  该发明涉及公式I或其药用可接受的多型体、溶剂合物、对映体、立体异构体及其水合物的组合物。药物组合物包括二甲双胍的盐，并且用于治疗或预防代谢综合征、糖尿病前期和糖尿病的方法可以制备为口服、颊内、直肠、局部、经皮、经粘膜、静脉、肠道给药、糖浆或注射剂。这种组合物可用于治疗糖尿病、肥胖、脂质紊乱、高三酰甘油血症、高血糖、高胰岛素血症和胰岛素抵抗。