阿卡波糖 | 56180-94-0

• 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 - 有机氧化合物
• 中文名称: 阿卡波糖
• 中文别名: 阿卡糖；O-4,6-双脱氧-4[[(1S,4R,5S,6S)4,5,6-三羟基-3-(羟基甲基)-2-环己烯]氨基]-(-D-吡喃 葡糖基(1→4)-O-)-D-吡喃葡糖基(1→4)-D-吡喃葡萄糖；阿卡波糖水合物
• 英文名称: acarbose
• 英文别名: acarboze；acrabose；O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-α-D-glucopyranosyl-(1→4)-O-α-D-glucopyranosyl-(1→4)-D-glucopyranose；D-glucose；Glucobay；ACB；(2R,3R,4R,5R)-4-[(2R,3R,4R,5S,6R)-5-[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino]oxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2,3,5,6-tetrahydroxyhexanal
• CAS: 56180-94-0
• 化学式: C₂₅H₄₃NO₁₈
• 分子量: 645.612
• InChiKey: CEMXHAPUFJOOSV-XGWNLRGSSA-N

物化性质

• 熔点：
  165-170°C
• 比旋光度：
  D18 +165° (c = 0.4 in water)
• 沸点：
  675.05°C (rough estimate)
• 密度：
  1.4278 (rough estimate)
• 溶解度：
  极易溶于水，溶于甲醇，几乎不溶于二氯甲烷。
• LogP：
  -7.935 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -8.8
• 重原子数：
  44
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  329
• 氢给体数：
  14
• 氢受体数：
  19

ADMET

代谢

阿卡波糖在胃肠道内被广泛代谢，主要由肠道细菌代谢，其次是由消化酶代谢，至少转化为13种已知的代谢物。大约三分之一的这些代谢物被吸收进入血液循环，随后通过肾脏排出体外。主要的代谢物似乎是4-甲基pyrogallol的甲基、硫酸盐和葡萄糖苷酸结合物。只有一种代谢物——由阿卡波糖分解出一个葡萄糖分子产生——被确定具有α-葡萄糖苷酶抑制活性。

Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity.

来源:DrugBank

代谢

阿卡波糖仅在消化道内代谢，主要由肠道细菌以及消化酶进行。至少已经通过色谱法从尿液中分离出13种代谢物。主要的代谢物被鉴定为4-甲基pyrogallol衍生物（即硫酸盐、甲基和葡萄糖苷酸结合物）。一种代谢物（通过从阿卡波糖上断裂一个葡萄糖分子形成）也具有α-葡萄糖苷酶抑制活性。这种代谢物与从尿液中回收的母化合物一起，占总给药剂量的不到2%。

Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. ... At least 13 metabolites have been separated chromatographically from urine specimens. The major metabolites have been identified as 4-methylpyrogallol derivatives (i.e., sulfate, methyl, and glucuronide conjugates). One metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-glucosidase inhibitory activity. This metabolite, together with the parent compound, recovered from the urine, accounts for less than 2% of the total administered dose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在几项大型临床试验中，与安慰剂相比，阿卡波糖治疗（2%至5%）导致血清酶水平升高超过正常上限3倍的情况更为常见，但所有升高均为无症状，并在停止治疗后迅速恢复正常。这些研究没有报告临床上明显的肝损伤病例。然而，在获得批准并广泛临床使用后，至少有十几例临床上明显的肝损伤与阿卡波糖使用有关。肝损伤通常在开始治疗后的2到8个月内出现，并伴有血清酶升高的肝细胞模式，血清ALT水平显著升高，提示急性病毒性肝炎。免疫过敏特征和自身抗体形成并不典型。虽然大多数病例病情较轻，但有些病例伴有明显黄疸，并有死亡病例报告给赞助商。没有将慢性肝损伤或消失胆管综合征与阿卡波糖使用联系起来的病例，大多数药物引起的肝损伤和急性肝衰竭的大型病例系列也没有发现由阿卡波糖引起的病例。在几个实例中进行了再次挑战，并导致发病时间缩短。

In several large clinical trials, serum enzyme elevations above 3 times the upper limit of normal were more common with acarbose therapy (2% to 5%) than with placebo, but all elevations were asymptomatic and resolved rapidly with stopping therapy. These studies reported no instances of clinically apparent liver injury. Subsequent to approval and with wide clinical use, however, at least a dozen instances of clinically apparent liver injury have been linked to acarbose use. The liver injury typically arises 2 to 8 months after starting therapy and is associated with a hepatocellular pattern of serum enzyme elevations with marked increases in serum ALT levels, suggestive of acute viral hepatitis. Immunoallergic features and autoantibody formation are not typical. While most cases are mild, some are associated with marked jaundice and cases with a fatal outcome have been reported to the sponsor. No cases of chronic liver injury or vanishing bile duct syndrome have been linked to acarbose use, and most large series of cases of drug induced liver injury and acute liver failure have not identified cases due to acarbose. Rechallenge has been carried out in several instances and resulted in recurrence with a shortening of the time to onset.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

母乳喂养期间使用的总结：由于少于2%的阿卡波糖剂量从母亲胃肠道被吸收，因此药物通过母乳传给婴儿的可能性很小。[1] ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Because less than 2% of a dose of acarbose is absorbed from the mother's gastrointestinal tract, it is unlikely that any drug reaches the infant through breastmilk.[1] ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

...报告了地高辛和阿卡波糖之间可能存在相互作用。在这些报告中，地高辛的吸收被阿卡波糖的联合给药显著降低。阿卡波糖的降糖作用源于其对α-葡萄糖苷酶的可逆和竞争性抑制，该酶水解后来作为葡萄糖分子吸收的低聚糖。阿卡波糖仅在小肠中发挥作用，大部分以原形出现在粪便中。地高辛是一种用于治疗心力衰竭和/或慢性房颤的知名药物。阿卡波糖延迟人类对蔗糖和淀粉的消化；因此，随后会出现胃肠道转运的干扰，导致稀便。因此，阿卡波糖的联合给药可能会增加胃肠道运动，降低地高辛的吸收。阿卡波糖还可能在吸收前干扰地高辛的水解，从而改变相应基因的释放，从而影响地高辛实验室测试的可靠性。这些病例报告表明，地高辛的吸收被阿卡波糖的给药降低。...

... A possible interaction between digoxin and acarbose was reported. In these reports, absorption of digoxin was decreased dramatically by coadministration of acarbose. The hypoglycemic action of acarbose stems from the reversible and competitive inhibition of alpha-glucosidase that hydrolyzes oligosaccharides absorbed later as glucose molecules. Acarbose functions exclusively in intestine, and most of it appears unchanged in feces. Digoxin is a well-known medication used in the treatment of heart failure and/or chronic atrial fibrillation. Acarbose delays the digestion of sucrose and starch in humans; as a result, a disturbance of gastrointestinal transit, causing loose stools, follows. Therefore, it is possible that gastrointestinal motility is increased, and absorption of digoxin decreased, by coadministration with acarbose. It is also possible that acarbose interferes with the hydrolysis of digoxin before its absorption, resulting in alteration in the release of the corresponding genine and thus affecting the reliability of the digoxin laboratory test. These case reports indicate that the absorption of digoxin is decreased by the administration of acarbose. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一项单中心、安慰剂对照的临床研究中，测试了含有氢氧化镁和氢氧化铝的抗酸剂（Maalox 70；10毫升）对口服降糖药阿卡波糖（Glucobay 100，Bay g 5421，CAS 56180；100毫克）药效动力学的影响，研究对象为24名健康男性志愿者。药物单独使用或联合使用，并与安慰剂进行比较。志愿者被随机分配到四个不同的治疗组。连续4天的每日用药为1片安慰剂片，或1片含100毫克阿卡波糖的片剂，或1片含100毫克阿卡波糖加10毫升抗酸悬浮液，或1片安慰剂片加10毫升抗酸悬浮液，不同治疗之间有6-10天的洗脱期。疗效评估基于服用75克蔗糖后餐后血糖和血清胰岛素水平，测量最大浓度和“曲线下面积”（0-4小时）。没有发现抗酸剂对阿卡波糖降低血糖和胰岛素作用的影响。因此，阿卡波糖与所测试的抗酸剂之间似乎没有显著相互作用。与所测试的抗酸剂类似的抗酸剂在与阿卡波糖联合使用时不需要被归类为禁忌症。

In a single-centre, placebo-controlled, clinical study, the influence of an antacid containing magnesium hydroxide and aluminium hydroxide (Maalox 70; 10 mL) on the pharmacodynamics of the oral antidiabetic drug acarbose (Glucobay 100, Bay g 5421, CAS 56180; 100 mg) was tested in 24 healthy male volunteers. The drugs were given alone or in combination and were compared with placebo. Volunteers were randomized into four different treatment groups. The daily medication over 4 days was 1 x 1 placebo tablet, or 1 x 1 tablet containing 100 mg acarbose, or 1 x 1 tablet containing 100 mg acarbose plus 10 mL antacid suspension, or 1 x 1 placebo tablet plus 10 ml antacid suspension, interrupted by wash-out phases of 6-10 days between successive treatments. Efficacy was assessed on the basis of postprandial blood glucose and serum insulin levels after administration of 75 g sucrose, and was measured as maximal concentrations and 'area under the curve' (0-4 hr). No influence of the antacid on the blood glucose and insulin-lowering effect of acarbose could be detected. Hence, there does not appear to be a significant interaction between acarbose and the antacid tested. Antacids similar to that tested do not need to be classified as a contraindication when used in combination with acarbose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

为了探究阿卡波糖治疗是否改变共同给药的罗格列酮的药代动力学（PK）。十六名健康志愿者（24-59岁）在第1天接受了单次8毫克的罗格列酮剂量，随后在接下来的7天中重复给予阿卡波糖[100毫克，每日三次（随餐）]。在阿卡波糖每日三次给药的最后一天（第8天），将单次剂量的罗格列酮与阿卡波糖的早晨剂量一起给予。比较了第1天和第8天罗格列酮给药后的PK曲线，并计算了点估计（PE）和相关95%置信区间（CI）。罗格列酮的吸收（以峰浓度Cmax和达峰时间Tmax衡量）不受阿卡波糖的影响。从时间零到无穷大的浓度-时间曲线下面积[AUC(0-∞)]在罗格列酮和阿卡波糖联合给药时平均降低了12%（95% CI -21%, -2%），并伴随着终末消除半衰期大约减少了1小时（23%）（4.9小时对比3.8小时）。这种AUC(0-∞)的小幅减少似乎是由于罗格列酮的系统清除率改变，而不是吸收的变化。观察到的AUC(0-∞)和半衰期的变化不太可能是临床相关的。罗格列酮和阿卡波糖的联合给药被良好耐受。以治疗剂量给予的阿卡波糖对罗格列酮的药代动力学有轻微但临床上不显著的影响。

To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-hr (23%) reduction in terminal elimination half-life (4.9 hr versus 3.8 hr). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and half-life are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

阿卡波糖的口服生物利用度极低，口服给药的母药小于1-2%达到系统循环。尽管如此，大约35%的放射性总量从口服给药的放射性标记阿卡波糖剂量中到达系统循环，血浆放射性峰值在给药后14-24小时出现——这种延迟可能是代谢物吸收的反映，而不是母药吸收。由于阿卡波糖旨在肠道内发挥作用，其极低的口服生物利用度在治疗上是可取的。

The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约一半的口服给药剂量在给药后96小时内通过粪便排出。吸收到系统循环中的少量药物物质（大约占口服给药剂量的34%）主要通过肾脏排出，这表明如果母药更容易被吸收，肾脏排泄将是一个重要的消除途径 - 这一点进一步得到了支持数据，大约89%的静脉给药剂量以活性药物的形式在48小时内通过尿液排出（相比之下，口服给药后排出量不到2%）。

Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours.

来源:DrugBank

吸收、分配和排泄

在一项针对6名健康男性的研究中，服用阿卡波糖的口服剂量中不到2%被吸收为活性药物，而大约35%的总放射性来自14C标记的口服剂量被吸收。平均来说，口服剂量的51%在摄入后96小时内以未吸收的药物相关放射性物质形式从粪便中排出。因为阿卡波糖在胃肠道的局部作用，这种亲本化合物的低系统生物利用度在治疗上是可取的。

In a study of 6 healthy men, less than 2% of an oral dose of acarbose was absorbed as active drug, while approximately 35% of total radioactivity from a 14C-labeled oral dose was absorbed. An average of 51% of an oral dose was excreted in the feces as unabsorbed drug-related radioactivity within 96 hours of ingestion. Because acarbose acts locally within the gastrointestinal tract, this low systemic bioavailability of parent compound is therapeutically desired.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康志愿者口服14C标记的阿卡波糖后，放射性物质的血浆浓度峰值在给药后14-24小时达到，而活性药物的血浆浓度峰值在大约1小时达到。阿卡波糖相关放射性物质的延迟吸收反映了由肠道细菌或肠道酶水解形成的代谢物的吸收。

Following oral dosing of healthy volunteers with 14C-labeled acarbose, peak plasma concentrations of radioactivity were attained 14-24 hours after dosing, while peak plasma concentrations of active drug were attained at approximately 1 hour. The delayed absorption of acarbose-related radioactivity reflects the absorption of metabolites that may be formed by either intestinal bacteria or intestinal enzymatic hydrolysis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿卡波糖仅在胃肠道内代谢，主要由肠道细菌以及消化酶进行。其中一部分代谢物（约占总剂量的34%）被吸收并随后通过尿液排出。

Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. A fraction of these metabolites (approximately 34% of the dose) was absorbed and subsequently excreted in the urine.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  1
• 海关编码：
  29400090
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H315,H319,H335

制备方法与用途

阿卡波糖简介

阿卡波糖（Acarbose）是一种C7N-氨基环醇类的假性四糖物质，通过与α-葡萄糖苷酶发生竞争性抑制作用而广泛应用于Ⅱ型糖尿病的治疗。它能够有效降低餐后高血糖。

临床应用

阿卡波糖是从放线菌培养液中分离得到的一种复杂低聚糖，是临床上常用的一线口服降糖药。其主要通过与肠黏膜α-葡萄糖苷酶结合，抑制该酶的活性，从而减缓食物中淀粉、蔗糖、乳糖、麦芽糖、糊精等碳水化合物的降解速度。这延缓了葡萄糖的吸收，达到降低餐后血糖的目的，并间接改善空腹血糖水平，减轻尿糖现象。此外，阿卡波糖还能减轻体重、降低血压和甘油三酯水平，长期服用可降低心血管疾病的风险，适用于以碳水化合物为主要食物成分或餐后血糖升高的2型糖尿病患者。

副反应

常见胃肠道功能紊乱症状，包括腹胀、腹泻和腹痛。这些症状是由于糖类在小肠内分解及吸收障碍，在结肠内由细菌作用于未被吸收的糖类而产生。罕见情况下，阿卡波糖可能会引起肝细胞性肝损伤，伴有黄疸和转氨酶升高，停药后可缓解。此外，过敏反应和皮肤反应也少见。

制备

阿卡波糖的生物合成途径可以概括为以下三个过程：

1. 氨基环醇的合成：7-P-景天庚糖逐步通过一系列酶促反应生成NDP-1-epi-valienol-7-phosphate。
2. 4-氨基-4,6-二脱氧葡萄糖的合成：D-1-磷酸葡萄糖经过核苷酸化、脱水和转氨基等步骤，最终生成dTDP-4-氨基-4,6-双脱氧葡萄糖。
3. 阿卡波糖的合成：NDP-1-epi-valienol-7-phosphate与dTDP-4-氨基-4,6-双脱氧葡萄糖在糖基转移酶的作用下发生糖基转移反应，生成dTDP-acarvicose-7-phosphate。随后，dTDP-acarvicose-7-phosphate再与麦芽糖分子结合，生成acarbose-7-phosphate。菌体在胞内完成acarbose-7-phosphate的合成后，还需通过转运蛋白AcbWXY/GacWXY将该物质跨膜转运至胞外，并发生去磷酸化作用最终生成阿卡波糖。

化学性质

无定形粉末。 [α]D18 +165°（C=0.4，水）。

用途

阿卡波糖是一种低聚糖，可逆地抑制小肠粘膜刷状缘上的α-糖苷酶活性，缓慢降低消化复杂多糖及蔗糖的速度，从而延缓葡萄糖的吸收。它常用于胰岛素依赖型和非胰岛素依赖型糖尿病的治疗。

类别与毒性

类别：有毒物品
毒性分级：低毒
急性毒性：口服-大鼠 LD50: 24000 毫克/公斤；口服 - 小鼠 LD50: 24000 毫克/公斤
可燃性危险特性：可燃；加热分解释放有毒氮氧化物烟雾。
储运特性：库房通风低温干燥。
灭火剂：干粉、泡沫、砂土和水。

反应信息

• 作为试剂：
  描述：

  对硝基苯-α-D-葡萄糖吡喃苷 在 baker's yeast α-glucosidase 、 水 、 阿卡波糖 作用下， 生成 a-无水葡萄糖酯 、 对硝基苯酚
  参考文献：
  名称：

  (Z)-3-Butylidenephthalide from Ligusticum porteri, an α-Glucosidase Inhibitor

  摘要：

  An extract from the roots of Ligusticum porteri, orally administered to groups of normal and diabetic mice, showed significant hypoglycemic and antihyperglycemic effects. Experimental type-II DM was achieved by treating mice with streptozotocin 15 min after an injection of beta-nicotinamide adenine dinucleotide. (Z)-6,6',7,3'alpha-Diligustilide (1), (Z)ligustilide (2), 3-(Z)-butylidenephthalide (3), myristicin (4), and ferulic acid (5) were isolated from the active extract. When tested In Vivo, compounds 1-3 showed antihyperglycemic activity, with 3 being the most active. Compound 3 (56.2 mg/kg) decreased blood glucose levels in NAD-STZ-diabetic mice after an oral sucrose load, suggesting that its antihyperglycemic effect is due to inhibition of alpha-glucosidase at the intestinal level. Furthermore, 3 inhibited the activity of yeast-a-glucosidase (IC(50) 2.35 mM) in a noncompetitive fashion with a K(i) of 4.86 mM; Docking analysis predicted that 3 binds to the enzyme in a pocket close to the catalytic site, but different from that for acarbose, with a K(i) of 11.48 mM. Compounds 1 and 2 did not affect a-glucosidase In Vivo, but altered glucose absorption by a mechanism yet to be determined. The stimulatory effect of 5 on insulin secretion, present in high amounts in the extract, has been demonstrated in previous investigations. The present study provides scientific support of the use of L. porteri in Mexican folk medicine for the treatment of diabetes.

  DOI：

  10.1021/np100447a

文献信息

• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES QUI LUI SONT ASSOCIÉS
  申请人：ARENA PHARM INC

  公开号：WO2012135570A1

  公开（公告）日：2012-10-04

  The present invention relates to compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as a single agent or in combination with one or more pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, or an alpha-glucosidase inhibitor, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing a blood incretin level; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及式(Ia)化合物以及药用可接受的盐、溶剂化物和水合物，它们作为单一药剂或与一个或多个药物制剂如DPP-IV抑制剂、双胍类药物或α-葡萄糖苷酶抑制剂联合使用，在例如治疗以下疾病中有用：GPR119受体相关疾病；通过增加血液中肠促胰岛素水平而改善的状况；代谢相关疾病；2型糖尿病；肥胖；及其相关并发症。
• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR GPR119 ET TRAITEMENT DES TROUBLES QUI LUI SONT LIÉS
  申请人：ARENA PHARM INC

  公开号：WO2012040279A1

  公开（公告）日：2012-03-29

  The present invention relates to the GPR119 receptor agonists:3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide; -fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide; and 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as a single pharmaceutical agent or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及GPR119受体激动剂：3-氟-4-(5-氟-6-(4-(3-(2-氟丙基)-1,2,4-噁二唑-5-基)哌啶-1-基)嘧啶-4-基氨基)-N,N-二甲基苯甲酰胺；-氟-4-(5-氟-6-(4-(3-(2-氟丙基)-1,2,4-噁二唑-5-基)哌啶-1-基)嘧啶-4-基氨基)-N-甲基苯甲酰胺；以及3-氟-4-(5-氟-6-(4-(3-(2-氟丙基)-1,2,4-噁二唑-5-基)哌啶-1-基)嘧啶-4-基氨基)苯甲酰胺，以及其药学上可接受的盐、溶剂化合物和水合物，这些化合物可用作单一药物代理或与一个或多个额外的药物代理结合使用，例如DPP-IV抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、噻唑烷二酮类药物或抗糖尿病肽类似物，用于治疗例如从以下选择的疾病：GPR119受体相关疾病；通过增加胰高血糖素分泌而改善的疾病；通过增加血液中胰高血糖素水平而改善的疾病；低骨密度症状；神经系统疾病；代谢相关疾病；2型糖尿病；肥胖症；以及相关并发症的治疗。
• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES ASSOCIÉS
  申请人：ARENA PHARM INC

  公开号：WO2013055910A1

  公开（公告）日：2013-04-18

  The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof,that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及式(I)的化合物及其药学上可接受的盐、溶剂化合物、水合物和N-氧化物，这些化合物可作为单一药物代理或与一个或多个额外的药物代理结合使用，例如DPP-IV的抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、噻嗪二酮类药物或抗糖尿病肽类似物，用于治疗例如从以下选择的疾病中选择的疾病：GPR119受体相关疾病；通过增加促胰高血糖素分泌而改善的状况；通过增加血液促胰高血糖素水平而改善的状况；低骨量状况；神经系统疾病；与代谢相关的疾病；2型糖尿病；肥胖症；以及相关并发症。
• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR DE GPR119 ET TRAITEMENT DE TROUBLES ASSOCIÉS
  申请人：ARENA PHARM INC

  公开号：WO2011127051A1

  公开（公告）日：2011-10-13

  The present invention relates to compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as a single agent or in combination with one or more additional pharmacetical agents, such as, an inhibitor of DPP-IV, a biguanide, an SGLT2 inhibitor, or an alpha-glucosidase inhibitor, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing a blood incretin level; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及式(Ia)的化合物及其药学上可接受的盐、溶剂和水合物，这些化合物可作为单一药剂或与一个或多个额外的药剂（如DPP-IV抑制剂、双胍类药物、SGLT2抑制剂或α-葡萄糖苷酶抑制剂）结合使用，在治疗中发挥作用，例如治疗选择自：GPR119受体相关疾病；通过增加血液胰高血糖素水平改善的病症；与代谢相关的疾病；2型糖尿病；肥胖；以及相关并发症。
• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES ASSOCIÉS À CELUI-CI
  申请人：ARENA PHARM INC

  公开号：WO2012170702A1

  公开（公告）日：2012-12-13

  The present invention relates to compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof, that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及具有式(Ia)的化合物以及其药学上可接受的盐、溶剂合物、水合物和N-氧化物，这些化合物可用作单一药物代理或与一个或多个额外的药物代理结合使用，例如DPP-IV的抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、麦格利那类药物、噻唑烷二酮或抗糖尿病肽类似物，在治疗中使用，例如选择自以下疾病的一种：GPR119受体相关疾病；通过增加肠高血糖素分泌改善的情况；通过增加血液高血糖素水平改善的情况；低骨量特征的情况；神经系统疾病；代谢相关疾病；2型糖尿病；肥胖及相关并发症。