雷尼司他 | 147254-64-6

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 雷尼司他
• 英文名称: ranirestat
• 英文别名: (R)-(-)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone；R-(-)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro[1,2-a]pyrrolopyridine-4-spiro-3'-pyrrolidine-1,2',3'5'-tetraone；AS-3201；(R)-2-(4-bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3'-pyrrolidine]-1,2',3,5'-tetrone；(3R)-2'-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4'(1'H)-pyrrolo[1,2-a]pyrazine]-1',2,3',5(2H')-tetraone；(3R)-2'-[(4-bromo-2-fluorophenyl)methyl]spiro[pyrrolidine-3,4'-pyrrolo[1,2-a]pyrazine]-1',2,3',5-tetrone
• CAS: 147254-64-6
• 化学式: C₁₇H₁₁BrFN₃O₄
• 分子量: 420.194
• InChiKey: QCVNMNYRNIMDKV-QGZVFWFLSA-N

物化性质

• 熔点：
  192-193℃
• 沸点：
  702.7±60.0 °C(Predicted)
• 密度：
  1.83

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  88.5
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 储存条件：
  2-8℃

制备方法与用途

生物活性

Ranirestat (AS-3201) 是一种有效的、口服活性的醛糖还原酶 (AR) 抑制剂，对大鼠晶状体 AR 和重组人 AR 的 IC50 分别为 11 nM 和 15 nM，对于重组人 AR 的 Ki 为 0.38 nM。Ranirestat 可用于糖尿病感觉运动性多发性神经病的研究，并且对糖尿病视网膜具有神经保护作用。

靶点

• IC50: 11 nM (大鼠晶状体醛糖还原酶) 和 15 nM (重组人醛糖还原酶)
• Ki: 0.38 nM (重组人醛糖还原酶)

体外研究

Ranirestat 浓度依赖性地抑制高浓度（500 mg/dl）葡萄糖条件下培养的大鼠红细胞和坐骨神经中山梨醇的累积。Ranirestat 抑制山梨醇累积的效力在大鼠红细胞和坐骨神经之间相似，IC50 值分别为 0.010 μM 和 0.041 μM。

体内研究

口服给予 Ranirestat (0.03-1.0 mg/kg；每天一次；连续三周；雄性 STD-Wistar 大鼠) 后，剂量依赖性地降低了大鼠坐骨神经中升高的山梨醇和果糖水平，而不影响血液中的葡萄糖水平。Ranirestat 还以剂量依赖性的方式改善了 STZ 引起的运动神经传导速度（MNCV）下降。

• 动物模型: 雄性 STD-Wistar 大鼠 (约 12 周龄；体重 260-290 g)，腹腔注射链脲佐菌素 (STZ)
• 剂量: 0.03 mg/kg、0.1 mg/kg、0.3 mg/kg、1 mg/kg
• 给药方式: 口服，每天一次，连续三周
• 结果: 剂量依赖性地降低了大鼠坐骨神经中升高的山梨醇和果糖水平，而不影响血液中的葡萄糖水平。

反应信息

• 作为反应物：
  描述：

  uridine diphosphoglucuronic acid 、 雷尼司他 在 human liver microsomes 、 magnesium chloride 作用下， 以 various solvents 为溶剂， 反应 20.0h， 生成 AS-3201 N-glucuronide
  参考文献：
  名称：

  UDP-葡糖醛酸糖基转移酶2B亚家族对人肝微粒体中醛糖还原酶抑制剂（AS-3201）的尿苷二磷酸糖的选择性缀合。

  摘要：

  N-葡萄糖苷化被认为是人类巴比妥类药物的主要代谢反应。但是，尚未弄清参与该N-葡萄糖苷化的酶。因此，为弄清参与人肝微粒体中N-葡萄糖苷化的酶，我们使用醛糖还原酶抑制剂AS-3201作为底物，研究了重组UDP-葡萄糖醛酸糖基转移酶（UGT）中的N-葡萄糖基转移酶活性。发现AS-3201在人肝微粒体中被生物转化为N-葡萄糖苷和N-葡萄糖醛酸苷。N-葡萄糖基转移酶活性可通过多种UGT亚型（UGT1A1，UGT1A3，UGT1A4，UGT2B4，UGT2B7和UGT2B15）检测到。相比之下，使用UGT1A（UGT1A1，UGT1A3，UGT1A4和UGT1A9）观察到相同底物的N-葡萄糖醛酸转移酶活性，但未观察到UGT2B亚型。然后，我们确定了每个重组UGT的相对活性因子，并估计了每个UGT亚型对人肝微粒体中N-葡萄糖苷化的贡献。结果表明，UGT2B亚型主要促进人肝微粒体中AS-3201的N-葡

  DOI：

  10.1016/j.bcp.2003.11.010
• 作为产物：
  描述：

  (R)-2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide 在 palladium on activated charcoal 氢气 、 溶剂黄146 、 三乙胺 作用下， 以 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 25.0~70.0 ℃ 、101.33 kPa 条件下， 反应 33.5h， 生成 雷尼司他
  参考文献：
  名称：

  Novel, Highly Potent Aldose Reductase Inhibitors:  (R)-(−)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 4-spiro-3‘-pyrrolidine-1,2‘,3,5‘-tetrone (AS-3201) and Its Congeners

  摘要：

  A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo- [1,2-a][1,2a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)enantiomer 44 (SX-3202): From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single-crystal X-ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.

  DOI：

  10.1021/jm9802968

文献信息

• Process for production of 2,5 dioxopyrrolidine 3 carboxylate
  申请人：Tanaka Daisuke

  公开号：US20110190497A1

  公开（公告）日：2011-08-04

  The present invention provides a novel intermediate which enable to prepare tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives such as Ranirestat being promising therapeutic agents for diabetic complications in a short process and in an economically advantageous and safe manner, and a process for preparing the same. That is, the present invention provides a process for preparing a compound of the following formula (I) wherein R 1 is an amino group protected with a protecting group, etc., and R 2 is a lower alkyl group, etc., comprising the following steps (1) and (2): (1) a step of converting a cyano group in a compound of the following formula (II) wherein n and m are each independently 0 or 1; provided when n is 0 and m is 1, then R 2 and R 3 are the same or different protecting groups for a carboxyl group; and when n is 1 and m is 0, then R 2 and R 3 are the same protecting groups for a carboxyl group; and R 1 is as defined above, into a carbamoyl group in the presence of divalent palladium compound(s), primary amide(s) and water; and (2) a step of cyclizing the product obtained in the step (1).

  本发明提供了一种新型的中间体，能够以简短的过程、经济上可行且安全的方式制备四氢吡咯[1,2-a]吡嗪-4-螺-3'-吡咯烷衍生物，例如Ranirestat，这是一种对糖尿病并发症有治疗前景的药物，以及一种制备该中间体的方法。即，本发明提供了一种制备如下公式(I)化合物的方法，其中R1是带有保护基团的氨基，R2是低级烷基等，包括以下步骤(1)和(2)：(1)将如下公式(II)化合物中的腈基转换为氨基甲酰基的步骤，其中n和m各自独立地为0或1；当n为0且m为1时，R2和R3是相同的或不同的羧基保护基团；当n为1且m为0时，R2和R3是羧基的相同保护基团；R1如上所述，该步骤中存在二价钯化合物、一级酰胺和水；(2)将步骤(1)中得到的产物环化的步骤。
• 3-HYDRAZINO-2,5-DIOXOPYRROLIDINE-3-CARBOXYLATES, PROCESS FOR PRODUCTION OF THE SAME, AND USE OF THE SAME
  申请人：Tanaka Daisuke

  公开号：US20090253917A1

  公开（公告）日：2009-10-08

  The present invention provides 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates of the formula (I): wherein R 1 is a C 1-6 alkyl group, etc., R 2 is a hydrogen atom or a COOR 3 group, wherein R 3 is a tert-C 4-6 alkyl group, a 2,2,2-trichloroethyl group or a benzyl group in which the benzene ring moiety may be optionally substituted by one or two atoms or groups independently selected from the group consisting of a halogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy group, a cyano group and a nitro group, and a salt thereof, which are useful as a novel intermediate for preparing tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives such as Ranirestat being promising therapeutic agents for diabetic complications in a short process and in an economically advantageous and safe manner, and the process for preparing the same.

  本发明提供了3-肼基-2,5-二氧吡咯烷-3-羧酸酯的公式(I)： 其中R1是C1-6烷基等，R2是氢原子或COOR3基团，其中R3是叔C4-6烷基，2,2,2-三氯乙基或苯甲基，其中苯环部分可以任选地被一个或两个独立地选自由卤素原子、C1-4烷基、C1-4烷氧基、腈基和硝基组成的组的原子或基团所取代，以及其盐，这些盐是有用的，因为它们可以用作以经济上可行且安全的方式，以较短的工艺过程来制备四氢吡咯[1,2-a]吡嗪-4-螺-3'-吡咯烷衍生物，如Ranirestat，后者是治疗糖尿病并发症的有希望的治疗剂，以及制备该化合物的工艺。
• A Concise Enantioselective Synthesis of (−)-Ranirestat
  作者：Barry M. Trost、Maksim Osipov、Guangbin Dong

  DOI：10.1021/ol100167w

  日期：2010.3.19

  A concise, enantioselective synthesis of the potent aldose reductase inhibitor ranirestat (1) is reported. The synthesis was accomplished employing inexpensive, commercially available starting materials. A palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) of malonate 4 was utilized as a key transformation to construct the tetrasubstituted chiral center in the target.

  报道了有效醛糖还原酶抑制剂雷尼司他 ( 1 )的简明、对映选择性合成。合成是使用廉价的、可商购的起始材料完成的。钯催化的丙二酸4 的不对称烯丙基烷基化 (Pd-AAA)被用作构建目标中四取代手性中心的关键转化。
• En Route to an Efficient Catalytic Asymmetric Synthesis of AS-3201
  作者：Tomoyuki Mashiko、Keiichi Hara、Daisuke Tanaka、Yuji Fujiwara、Naoya Kumagai、Masakatsu Shibasaki

  DOI：10.1021/ja0752585

  日期：2007.9.1

  A catalytic asymmetric synthesis of AS-3201 via catalytic asymmetric amination with a novel lanthanum−amide complex is described. The amination reaction proceeded efficiently with as little as 1 mol % of catalyst loading, allowing for an efficient access to the key intermediate for the synthesis of AS-3201, a potent aldose reductase inhibitor.

  描述了通过催化不对称胺化与新型镧-酰胺复合物催化不对称合成 AS-3201。胺化反应在低至 1 mol% 的催化剂负载下有效进行，从而可以有效地获得合成 ​​AS-3201（一种有效的醛糖还原酶抑制剂）的关键中间体。
• PROCESS FOR PRODUCING OPTICALLY ACTIVE SUCCINIMIDE DERIVATIVES AND INTERMEDIATES THEREOF
  申请人：Kyowa Hakko Bio Co., Ltd.

  公开号：US20140099681A1

  公开（公告）日：2014-04-10

  A process for producing optically active succinimide derivatives as key intermediates of (3R)-2′-(4-bromo-2-fluorobenzyl)spiropyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine}-1′,2,3′,5(2′H)-tetraone, which comprises the following reaction steps.

  生产(3R)-2′-(4-溴-2-氟苯基)螺吡咯啉-3,4′(1′H)-吡咯并[1,2-a]吡嗪}-1′,2,3′,5(2′H)-四酮的光学活性琥珀酰亚胺衍生物作为关键中间体的方法，包括以下反应步骤。