CN101128433A - 作为钙蛋白酶抑制剂的异喹啉衍生物 - Google Patents
作为钙蛋白酶抑制剂的异喹啉衍生物 Download PDFInfo
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- CN101128433A CN101128433A CNA2005800481674A CN200580048167A CN101128433A CN 101128433 A CN101128433 A CN 101128433A CN A2005800481674 A CNA2005800481674 A CN A2005800481674A CN 200580048167 A CN200580048167 A CN 200580048167A CN 101128433 A CN101128433 A CN 101128433A
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- Prior art keywords
- butyl
- isoquinoline
- sec
- dihydro
- subunit
- Prior art date
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Abstract
本发明涉及具有钙蛋白酶抑制剂活性的在3-位用仲丁基取代的部分还原的异喹啉衍生化合物。本发明化合物包括衍生于(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸和(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸的酯或酰胺。具有式Ⅰ或Ⅱ的化合物可用于预防或治疗变性疾病。
Description
发明领域
本发明处于具有治疗活性的酶抑制剂,更具体地讲是钙蛋白酶抑制剂的领域中。
现有技术
钙蛋白酶或Ca2+-活化的中性蛋白酶(CANP,E.C.3.4.22.17)为具有非常活性的代谢作用的半胱氨酸蛋白酶家族。尽管它们的天然底物还没有清楚地确定,这些酶催化多种参与信号转导、细胞骨架重建、细胞周期调节和细胞凋亡的蛋白水解(Adv.Pharmacol.1996,37,117)。在哺乳动物中,钙蛋白酶家族包括几种组织特异性同工型和两种普遍存在的同工酶:μ-钙蛋白酶(或者钙蛋白酶I)和m-钙蛋白酶(或者钙蛋白酶II),体外激活它们分别需要微摩尔和毫摩尔量的Ca2+。采用X-射线衍射的结构研究已经显示每一种同工型由呈现木瓜蛋白酶型的半胱氨酸蛋白酶结构域的大的亚单位(~80kDa)和对每一种同工酶常见的小的亚单位(~30kDa)组成。每一种亚单位的C-末端具有能够结合Ca2+的结构域(钙调素型结构域)(FEBS Lett.2001,501,111)。
当细胞内Ca2+浓度增加时可发生的钙蛋白酶的过度激活涉及多种疾病,例如脑和心脏局部缺血、脑发作(cerebral ictus)、阿尔茨海默病、帕金森病、亨廷顿病、肌肉萎缩症(muscular distrophy)、白内障、脱髓鞘疾病(例如多发性硬化症)以及其它的变性疾病(Pathophysiology 1999,6,91;Brain Res.Rev.2003,42,169)。
钙蛋白酶选择性抑制剂的主要应用为作为神经保护剂药物。在与神经保护有关的治疗领域中,迄今已采用各种策略。已使用作用于膜去极化和Ca2+进入细胞、或者防止自由基产生(抗氧剂)、或者作为神经递质作用的拮抗剂的药物(J.Clinical Neurosci.2002,9,4)。大量注意已集中到能阻断谷氨酸的NMDA受体的药物,然而,阻断兴奋性氨基酸离子型受体不是预防兴奋性神经毒性作用的理想方法,因为这些药物具有拟精神病副作用(Pharmacol.Ther.1999,81,163;Neurobiol.Disease 2003,12,82)。取得神经保护作用的令人感兴趣的供选方法是阻断被生理静默的“受体后”细胞现象,换言之,寻找通过兴奋性神经毒剂诱导的分解代谢级联的选择性阻断剂。当作用于在神经变性期间激活的代谢途径时,这些具有细胞内作用的潜在的药物有预见地允许更有效和选择性的神经保护剂作用。
钙蛋白酶的过度激活需要Ca2+的细胞内浓度持续增加,并且该酶在静止细胞中是潜伏的[换言之,具有“正常的”Ca2+水平]。因此,钙蛋白酶的抑制作用呈现为神经变性疾病的合适治疗方法。和拮抗谷氨酸和天冬氨酸的NMDA受体的情况一样,根据其特征,钙蛋白酶的抑制作用在人治疗中会比它们在病理过程中激活前阻断代谢过程可预见地具有更少的副作用,由于钙蛋白酶在“正常”生理条件下不被激活,并且兴奋性氨基酸的作用对神经系统的正常功能是必需的。
此外,除了它在某些生理过程的作用以外,强力和选择性钙蛋白酶抑制剂作为研究该蛋白酶作用机制的工具是非常有用的。
另外,不同取代的异喹啉衍生物已经用作具有不同生物活性范围的药效团(US-5576435;Eur.J.Pharmacology.2004,501,111)。而且,氨基酸和相关化合物例如氨基羰基化合物具有不同生物学性质范围(J.Med.Chem.2002,45,4762;Bioorg.Med.Chem.Lett.2000,10,1497)。
已描述可逆和不可逆钙蛋白酶抑制剂(Trends Mol.Medicine 2001,7,355;US-6103720;WO-9641638、US5541290;ES-200301125;ES-200401104;Bioorg.Med.Chem.Lett.2004,14,2753;Chemistry&Biodiversity 2004,1,442)。这些抑制剂最常见的结构特征是它们为肽或者具有少量氨基酸(2-6)的拟肽(peptidomimetics),疏水性并且具有一些亲电官能团,其中可提及的是α-酮膦酸酯、α-酮次磷酸酯、α-酮膦氧化物、α-酮酯、α-酮酸、α-酮酰胺、三氟甲基酮、醛、甲基锍盐、环氧化物等。这些化合物显然作用于钙蛋白酶的木瓜蛋白酶型结构域,这导致相对低的选择性,因此它们经常也是其它半胱氨酸蛋白酶(例如,木瓜蛋白酶)并且甚至是丝氨酸蛋白酶的抑制剂。而且,这些化合物为肽衍生物的事实意味着在一些情况下它们具有某些不合乎需要的药理性质,例如通过细胞膜无效转运或者通过肽酶降解。部分由于这些缺陷,尚未发现具有治疗用途的钙蛋白酶抑制剂。
我们小组最近制备了多种特征为异喹啉衍生物的钙蛋白酶抑制剂(Adv.Synth.Catal.2002,344,855)。然而,使这些异喹啉衍生物具有作为钙蛋白酶抑制剂的活性需要存在肽链(例证性实例为化合物1和2,我们通常从种属上将它们称作肽-杂环杂化物),并且如通过化合物1和2的IC50值显示的那样,生物活性高度依赖肽片段的长度。然而,我们的初步结果指明其中不含肽链的异喹啉的简单衍生物不是钙蛋白酶抑制剂,如对化合物3阐明的那样。
作为钙蛋白酶抑制剂的异喹啉衍生物的深入研究使我们发现当异喹啉环3-位的取代基为仲丁基时,钙蛋白酶的抑制活性显著增加,并且肽链的存在对得到这样的生物活性不是绝对必需的。肽链的存在在该类型的化合物中不是必需的的事实显著增加它作为酶抑制剂的有用的治疗潜力:期待这些不含任何肽链的异喹啉衍生物代谢更稳定并且它们的细胞转运比肽-杂环杂化物更有效。
发明概述
本发明涉及具有钙蛋白酶抑制剂活性的衍生于部分还原的异喹啉的化合物。一种本发明化合物为衍生于(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸和(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸的酯或酰胺,包括其在异喹啉片断4-位的取代基为与氨基酸有关的结构(包括氨基羰基化合物的片断)的化合物,其通过羰基亚甲基键合于异喹啉片断。
描述
本发明涉及一种化合物,其特征为具有在3-位用仲丁基取代的部分还原的异喹啉结构和具有以下式I或II,
其中:
基团X一般地为氧(O)或硫(S),
星号(*)一般地表示构型(R)或(S)的立构中心(stereogenic centre),
基团R1独立地选自:
-NH2,
-NHR4,其中R4表示烷基、芳基、氨基酸衍生物或肽衍生物,
-NR5R6,其中R5和R6独立地选自烷基、芳基、氨基酸衍生物、肽衍生物,并且基团R5和R6形成环状系统,
-OH,
-OR7,其中R7表示烷基或芳基;
基团R2和R3为相同或不同的并且独立地选自基团O(氧)、NH或NR8,其中R8表示烷基或芳基
Z选自
-具有2-8个碳原子的烷基,
-芳基,
-芳基烷基,
-独立地包含1-3个氧原子和2-10个碳原子的烷氧基链,
-衍生于氨基酸或肽的片断。
以下为优选的化合物:
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(7),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(8),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸异丙基酯(9),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸1-丁基酯(10),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸苄基酯(11),
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-烯基酯(12),
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-炔基酯(13),
(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(S,S,S,S,Z,Z)-4-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-苄基酯(14),
(S,S,Z)-N-苄基-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(15),
(S,S,Z)-N-(3-乙酰基-苯基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(16),
(S,S,Z)-N-(2’-氨基-联苯-2-基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(17),
(S,S,S,S,Z,Z)-2,2’-双-[(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰基氨基]联苯(18),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰基氨基]-联苯-2-基氨基甲酰基}-2-甲基-丙基)-氨基甲酸(S,S,S,Z)-9H-芴(fuorene)-9-基甲基酯(19),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-苯基-乙基)-氨基甲酸(S,S,S,Z)-9H-芴-9-基甲基酯(20),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-甲基-丁基)-氨基甲酸(S,S,S,S,Z)-9H-芴-9-基甲基酯(21),
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-丁酰胺(22),
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-苯基-丙酰胺(23),
(S,S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-戊酰胺(24),
(S,S,S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酸甲酯(25),
(S,S,S,S,S,S,S,S,Z)-2-(2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酰氨基)-3-甲基-戊酸甲酯(26),
(S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-丁酰氨基}-3-苯基-丙酸甲酯(27),
(S,S,Z)-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(28),
(S,S,Z)-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(29),和
(S,S,S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酸甲酯(30),
和任何它们的异构体。
以下合成中间体也是尤其优选的本发明化合物:
(S,S)-3-甲基-2-(2-碘代苯甲酰氨基)-戊酸甲酯(4),
(S,S)-N-[(1-羟基甲基-2-甲基)-丁基]-2-碘代-苯甲酰胺(5),和
(S,S,E)-5-甲基-4-(2-碘代苯甲酰氨基)-2-庚烯酸甲酯(6),
和任何它们的异构体。
采用本领域专家已知的有机合成中的标准方法(ChemicalApproaches to the Synthesis of Peptides and Proteins,CRC Press,BocaRaton,1997;Comprehensive Organic Synthesis.Pergamon Press,1991;Synlett 2000,509;Adv.Synth.Catal.2001,343,360;Topics CurrentChemistry 1999,204,127;Bull.Soc.Chim.Belg.1978,87,229)实施合成本发明通式I和II的化合物。作为例证性实例,尽管不受限制,已经自(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(III)的相应异构体或自(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(IV)的相应异构体开始制备在本专利中描述的化合物。以下表示使用也为本发明目的的以下化合物作为中间体合成化合物III和IV,
(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(A)的任何异构体,
5-甲基-4-(2-碘代苯甲酰氨基)-2-庚烯酸甲酯(B)的任何异构体,
N-[(1-羟基甲基-2-甲基)-丁基]-2-碘代-苯甲酰胺(C)的任何异构体,
和
2-(2-碘代苯甲酰氨基)-3-甲基-戊酸甲酯(D)的任何异构体。
由于存在于化合物I和II中的主要官能团(如由取代基R1、R2和R3表示的那样)为酰胺或酯,在制备类型I和II化合物中的基本反应为作为亲电试剂的酸或酸衍生物与作为亲核试剂的胺或醇之间的酰化反应。式I和II化合物的合成策略取决于基团R1、R2和R3的结构,并且也取决于这些基团是相同还是不同的。构成本发明目的的类型I和II化合物的一种特殊类型为类型V化合物,其中存在氨基酸链、肽和相关化合物,通过乙酰基亚甲基连接于异喹啉片断。这些化合物通过有机合成中常见的并且是本领域专家已知的转化采用合适的氨基酸衍生物、肽和相关化合物制备。
用于合成式I和II化合物的醇、胺、氨基酸、肽和它们的衍生物是市售的或者通过有机合成中的标准方法制备。在一些情况中,尤其是对于系列D-非天然氨基酸和相关化合物,已经使用采用酶酰基转移酶作为生物催化剂的生物催化方法(Tetrahedron:Asymmetry1998,9,1951-1965)。
当肽已经用作化合物I和II合成中的亲核或亲电试剂时,它们的合成已经通过氨基酸和肽化学中的标准方法实施。叔丁氧基羰基(Boc)、苄氧基羰基(Cbz)和芴基甲氧基羰基(Fmoc)已经用作氨基的保护;羧基已经被保护为脂族酯(甲基、乙基或苄基)。用于合成用作亲核试剂的这些肽的偶合反应已经采用标准方法进行:通过活化羰基为酰氯,或者通过形成活性酯(例如五氟苯基),或者通过混合酸酐,或者通过“原位”活化羰基(通过用碳二亚胺和1-羟基苯并三唑的组合处理酸或相关方法)(Chemical Approaches to the Synthesis of Peptidesand Proteins,CRC Press,Boca Raton,1997)。
本发明化合物的基本特征是它们为钙蛋白酶抑制剂。存在钙蛋白酶的多种同工型,它们在结构上彼此非常相似并且就已知而言具有相同的作用机制。两种最丰富的是微钙蛋白酶(micro-calpain)(或者钙蛋白酶I)和毫钙蛋白酶(milli-calpain)(或者钙蛋白酶II),它们在体外试验中在对于活化必要的Ca2+浓度方面有差异。因为酶的两种同工型彼此非常相似,在文献的许多实例中已经发现钙蛋白酶抑制剂为两种同工酶的抑制剂(Adv.Synth.Catal.2002,344,855)。所以,在本发明中,当我们提到钙蛋白酶时,我们指两种同工型(或者同工酶),它们被包括在钙蛋白酶的定义中。因此,本发明的另一个目的是式I或II化合物作为钙蛋白酶抑制剂的用途。
根据IC50值定量抑制钙蛋白酶的能力,IC50值被定义为减少酶的催化活性达一半的抑制剂的浓度。IC50值越低,抑制剂越有效。一些本发明化合物对钙蛋白酶I的抑制作用结果(生理观察点的最大相关性)显示在表1和图1中。给定钙蛋白酶II(也称作毫钙蛋白酶)需要更大量的Ca2+用于活化,它不可能具有这样的相关生理作用,因为这样的Ca2+浓度将在毫钙蛋白酶可变得活化前引起细胞死亡。由于这个原因,对钙蛋白酶I已经进行抑制作用试验,尽管它们可对钙蛋白酶II外推。
表1.构成本发明目的的化合物对钙蛋白酶抑制作用的代表性结果
化合物 | IC50 |
7 | 25nM |
11 | 124μM |
12 | 85μM |
13 | 59μM |
14 | 5μM |
15 | 140μM |
16 | 130μM |
17 | 86nM |
18 | 742nM |
19 | 100μM |
20 | 48μM |
21 | 5μM |
22 | 17μM |
23 | 7μM |
24 | 50μM |
25 | 447nM |
26 | 159nM |
27 | 626nM |
28 | 38μM |
一些在图1中表示的化合物是非常有效的钙蛋白酶抑制剂并且它们可用于设计具有治疗应用的化合物。由于已经发现钙蛋白酶过度活化与多种变性疾病有关,本发明另外的目的是式I或II化合物用于治疗或预防变性疾病和用于制备用于预防或治疗变性疾病的药物的用途,尤其是当变性疾病选自脑局部缺血、心脏局部缺血、脑发作、阿尔茨海默病、帕金森病、亨廷顿病、肌肉萎缩症、白内障和脱髓鞘病时,并且尤其是如果脱髓鞘病为多发性硬化时(Pathophysiology 1999,6,91;Brain Res.Rev.2003,42,169)。
附图简述
图1显示对构成本发明目的的(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸的衍生物和(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸的衍生物和它们作为钙蛋白酶I抑制剂的生物活性的研究结果。
实施例
作为例证性实例,尽管不受限制,给出了一些式I或II异喹啉衍生物的试验方法和光谱与分析数据,还包括它们的生物活性试验。
实施例1
(S,S)-3-甲基-2-(2-碘代苯甲酰氨基)-戊酸甲酯(4)的合成
向L-异亮氨酸甲酯盐酸盐(13.07g,72.0mmol)在THF(300mL)和H2O(300mL)中的溶液中加入K2CO3(39.80g,288mmol)。使混合物冷却至0℃并在搅拌5分钟后,加入2-碘代苯甲酰氯(19.18g,72.0mmol)。在0℃下搅拌混合物30分钟并然后缓慢达到室温过夜。除去THF并用EtOAc(3×50mL)提取水相。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,自EtOAc/己烷重结晶纯化,得到4(16.76;62%)。白色固体。
m.p.:67-70℃
[α]D=+9.2(c=1.0,CHCl3).
IR(KBr)v:3436,3294,2964,1743,1644,1585,1525,1463,1201,1015cm-1.
1H-NMR(300MHz,CDCl3)δ:7.87(m,1H,H-C(3’));7.41(m,2H,H-C(5’)),H-C(6’);7.11(m,1H,H-C(4’));6.33(broad d,J=8.1,1H,NH);4.83(dd,J=8.1,4.6,1H,H-C(2));3.78(s,H,CO2Me),2.06(m,1H,H-C(3));1.52(m,1H,Ha-C(4));1.29(m,1H,Hb-C(4));1.03(d,J=6.8,3H,Me-C(3));0.97(t,J=7.6,3H,H-C(5))ppm.
13C-NMR(50MHz,CDCl3)δ:171.9(CO2Me);168.7(CONH);141.7(C(1’));139.9(C(3’));131.2(C(4’));128.3,128.0(C(5’)),(C(6’));92.2(C(2’));56.7(C(2));52.1(CO2Me);38.0(C(3));25.2(C(4));15.6(Me-C(3));11.6(C(5))ppm.
MS(ES+)m/e:376([M+H]+),398([M+Na]+),773([2M+H]+).
EA:C14H18INO3的理论值:C 44.82,H 4.84,N 3.73。
实测值:C 45.12,H 5.10,N 4.00。
实施例2
(S,S)-N-[(1-羟基甲基-2-甲基)-丁基]-2-碘代-苯甲酰胺(5)的合成
向4(8.44g,22.5mmol)在THF(50mL)中的于-10℃下的溶液中加入LiBH4(1.47g,67.5mmol)。紧接着然后缓慢加入MeOH(45mL),在-10℃下搅拌混合物10分钟并然后使之达到室温。之后,加入H2O,真空除去THF并用EtOAc(3×50mL)提取水相。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,经柱层析法纯化,先后使用己烷/EtOAc(1∶1-1.9)和EtOAc作为洗脱剂,得到5(6.6g;85%收率)。白色固体。
m.p.:125-126℃
[α]D=-27.8(c=1.0,CHCl3).
IR(KBr)v:3410,3295,1628,1544,1076,cm-1.
1H-NMR(400MHz,CDCl3,构象异构体M和m的混合物,4∶1)δ:7.81(m,0.7H,H-C(3’),M);7.72(m,0.3H,H-C(3’),m);7.50-7.31(m,2H,H-C(5’)H-C(6’),M+m);7.10-7.04(m,1H,H-C(4’),M+m);6.42(d,J=8.1,0.2H,NH,m);6.06(broad d,J=8.1,0.8H,NH,M);3.99-3.85(m,1H,H-C(2),M+m);3.85-3.72(m,2H,H-C(1),M+m);2.88(broad t,J=5.4,0.2H,OH,m);2.62(broad t,J=5.4,0.8H,OH,M);1.80-1.50(m,2H,H-C(4),M+m);1.28-1.14(m,1H,H-C(3),M+m);0.97(d,J=6.8,3H,Me-C(3));0.92(t,J=7.5,3H,H-C(5))ppm.
13C-NMR(50MHz,CDCl3)δ:170.0(CONH);142.7(C(1’));139.7(C(3’));131.1(C(4’));128.5,128.1(C(5’),(C(6’));92.3(C(2’));36.2(C(1));56.4(C(2));35.5(C(3));25.6(C(4));15.6(Me-C(3));11.3(C(5))ppm.
Ms(ES+)m/e:348([M+H]+),370([M+Na]+),717([2M+Na]+).
EA:C13H18INO2的理论值:C 44.97,H 5.23,N 4.03。
实测值:C 45.11,H 5.26,N 4.18。
实施例3
(S,S,E)-5-甲基-4-(2-碘代苯甲酰氨基)-2-庚烯酸甲酯(6)的合成
向在-78℃下的用相同溶剂(12mL)稀释的2M草酰氯在无水CH2Cl2(10.33mL,20.8mmol)中的市售溶液中滴加无水DMSO(2.9mL,41.0mmol)在无水CH2Cl2(30mL)中的溶液。在-78℃下搅拌混合物30分钟,之后通过套管滴加醇5(4.44g,12.8mmol)在无水CH2Cl2(25mL)中的溶液。在-78℃下搅拌混合物1小时并然后滴加Et3N(10.26ml,74.0mmol)。在-78℃下搅拌约1小时后,当醛氧化完成时(tlc),加入Ph3P=CHCO2Me(6.0g,19.0mmol)并然后使反应物缓慢达到室温过夜。最后,真空除去溶剂,得到粗产物,经柱层析法纯化,使用己烷/EtOAc作为洗脱剂(4∶1-1.1),得到不饱和N-苯甲酰氨基酯6的E异构体(4.1g;80%收率)。白色固体。
m.p.:124-125℃
[α]D=+1.7(c=1.0,CHCl3).
IR(KBr)v:3347,3275,2958,1721,1640,1531cm-1.
1H-NMR(300MHz,CDCl3)δ:7.85(d,J=7.8,1H,H-C(3’));7.37(m,2H,H-C(5’),H-C(6’));7.10(m,1H,H-C(4’));6.92(dd,J=15.8,5.9,1H,H-C(3));6.05(dd,J=15.8,1.7,1H,H-C(2));5.93(broad d,J=8.8,1H,NH);4.79(m,1H,H-C(4));3.72(s,3H,CO2Me);1.79(m,1H,H-C(5));1.54(m,1H,Ha-C(6));1.22(m,1H,Hb-C(6));0.97(m,6H,Me-C(5),H-C(7))ppm.
13C-NMR(50MHz,CDCl3)δ:168.7(CONH);166.5(CO2Me);145.9(C(3));142.0(C(1’));139.9(C(3’));131.2(C(4’));128.3,128.2(C(5’),C(6’));122.0(C(2));92.1(C(2’));54.8(C(4));51.7(CO2Me);38.7(C(5));25.4(C(6));15.4(Me-C(5));11.6(C(7))ppm.
MS(ES+)m/e;402([M+H]+),424([M+Na]+),803([2M+H]+),825([2M+Na]+).
EA:C16H20INO3的理论值:C 47.89,H 5.02,N 3.49。
实测值:C 48.11,H 5.13,N 3.61。
实施例4
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(7)的合成
将酯6(4.17g,10.4mmol)、Pd(OAc)2(80mg,0.035mmol)、Ph3P(288mg,1.08mmol)和Et3N(3.2mg,20.6mmol)在无水CH3CN(250mL)中的混合物在氩气下伴随剧烈搅拌回流3天。然后使混合物达到室温,随后加入H2O(250mL)并用CHCl3(3×50mL)提取。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,经柱层析法纯化,使用己烷/EtOAc(4∶1-2∶3)作为洗脱剂,得到化合物7(2.4g;85%收率)。白色无定形固体。
[α]D=-365.8(c=0.5,CHCl3).
IR(KBr)v:3434,1715,1669,1568,1195,1167,774cm-1.
1H-NMR(500MHz,CDCl3)δ:8.13(m,1H,H-C(8’));7.57(m,3H,H-C(5’),H-C(6’),H-C(7’));6.60(broad d,J=3.4,1H,NH);6.34(s,1H,H-C(2));5.45(m,1H,H-C(3’));3.77(s,3H,CO2Me);1.61(m,1H,H-C(1”));1.45(m,1H,Ha-C(2”));1.15(m,1H,Hb-C(2”));0.87(d,J=6.8,3H,Me-C(1”));0.81(t,J=7.6,3H,H-C(3”))ppm.
13C-NMR(50MHz,CDCl3)δ:165.4(CONH);164.0(CO2Me);150.7(C(4’));135.3(C(4a’));132.7,130.5(C(5)or C(6’)or C(7’));128.4(C(8a’);127.9(C(8’));123.8(C(5’)or(C(6’)or C(7’));116.4(C(2));55.8(C(3’));51.5(CO2Me);41.5(C(1”));24.4(C(2”));15.1(Me-C(1’));11.0(C(3”))ppm.
MS(ES+)m/e:274([M+H]+),296([M+Na]+),547([2M+H]+),569([2M+Na]+).
EA:C16H19NO3的理论值:C 70.31,H 7.01,N 5.12。
实测值:C 70.15,H 7.02,N 5.04。
实施例5
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(8)的合成
向7(273mg,1.0mmol)在THF-H2O的1∶1混合物(10mL)中的于室温下的溶液中加入LiOH(83.9mg,2.0,mmol)在H2O(2mL)中的溶液。在室温下搅拌混合物过夜并然后用5%HCl酸化至pH=2。真空除去THF并用EtOAc(3×50mL)提取水相。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,经EtOAc/己烷重结晶纯化,得到为白色固体的酸8(140mg,54%收率)。
m.p.:215-216℃(伴随预先软化)
[α]D=-333.8(c=0.49,DMF).
IR(KBr)v:3435,2966,1674,1306cm-1.
1H-NMR(300MHz,DMSO-d6)δ:12.46(broad s,1H,CO2H);8.60(d,J=4.9,1H,NH);7.91(dd,J=7.3,1.5,1H,H-C(8’));7.75(dd,J=7.9,1.3,1H,H-C(5’));7.64-7.53(m,2H,H-C(6’),H-C(7’));6.36(s,1H,H-C(2));5.24(dd,J=7.7,4.9,1H,H-C(3’));1.47(m,1H,Ha-C(2”));1.45(m,1H,H-C(1”));1.16(m,1H,Hb-C(2”));0.74(m,6H,Me-C(1”),H-C(3”))ppm.
13C-NMR(50MHz,DMSO-d6)δ;166.7(CONH);162.5(CO2H);149.1(C(4’));135.1(C(4a’));132.6,130.3(C(6’),C(7’));128.7(C(8a’);127.0(C(8’));124.4(C(5’));117.6(C2));53.9(C(3’));41.2(C(1”));24.3(C(2”));15.0,10.9(Me-C(1’),C(3”))ppm.
MS(ES+)m/e:260([M+H]+),282([M+Na]+),519([2M+H]+),541([2M+Na]+).
EA:C16H17NO3的理论值:C 69.48,H 6.61,N 5.40。
实测值:C 69.25,H 7.00,N 5.41。
实施例6
酸8与醇和二醇的反应(通用方法I)
酸8的酯的合成
向酸8(100mg,0.38mmol)在无水CH2Cl2(2.5mL)中的于0℃下的混悬液中滴加SOCl2(0.28mL,3.8mmol)。搅拌混合物直到达到室温并然后加热回流约1小时。然后减压除去溶剂,得到油,使其溶于无水CH2Cl2(2.5mL)中,向其中加入在氩气下的溶于无水CH2Cl2(2.5mL)中的相应的醇(0.76mmol对于一元醇和0.15mmol对于二元醇)。然后用CH2Cl2(50mL)稀释反应物并用饱和NaHCO3水溶液(3x50mL)提取。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,经柱层析法纯化,使用己烷/EtOAc(4∶1-1∶1)作为洗脱剂。以下指出的产率指由两个反应(形成酰氯和合成酯)组成的全部过程。
实施例7
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸异丙基酯(9)的合成
按照通用方法I,得到为无色油的化合物9(81mg,71%收率)。
[α]D=-341.8(c=0.25,CHCl3).
IR(KBr)v:3429,2968,2876,1708,1672,1372,1181,1107,775cm-1.
1H-NMR(400MHz,CDCl3)δ:8.09(m,1H,H-C(8’));7.55(m,3H,H-C(5’),H-C(6’),H-C(7’));6.97(broad s,1H,NH);6.28(s,1H,H-C(2));5.44(dd,J=4.5,2.4,1H,H-C(3’));5.07(sep,J=6.21H,CHMe2);1.58(m,1H,H-C(1”));1.43(m,1H,Ha-C(2”));1.28(d,J=6.2,3H,CO2CHMe2);1.26(d,J=6.2,3H,CO2CHMe2);1.15(m,1H,Hb-C(2”));0.86(d,J=6.8,3H,Me-C(1”));0.78(t,J=7.4,3H,H-C(3”))ppm.
13C-NMR(50MHz,CDCl3)δ:165.0(CONH);164.0(CO2CHMe2);149.8(C(4’));135.5(C(4a’));132.6,130.4(C(5’)or C(6’)or C(7’));128.4(C(8a’);127.9(C(8’));123.8(C(5’)or(C(6’)or C(7’));117.5(C(2));67.8(CO2CHMe2);55.8(C(3’));41.5(C(1”));24.4(C(2”));21.9(CO2CHMe2);15.1(Me-C(1’));11.0(C(3”))ppm.
MS(ES+)m/e:302([M+H]+),324([M+Na]+),603([2M+H]+),625([2M+Na]+).
实施例8
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸1-丁基酯(10)的合成
按照通用方法I,得到为白色固体的化合物10(82mg,69%收率)。
m.p.:110-112℃
[α]D=-316.6(c=0.5,CHCl3).
IR(KBr)v:3467,3311,2927,1707,1667,1599,1186,770cm-1.
1H-NMR(300MHz,CDCl3)δ:8.14(m,1H,H-C(8’));7.59(m,3H,H-C(5’),H-C(6’),H-C(7’));6.48(broad s,1H,NH);6.35(s,1H,H-C(2));5.46(dd,J=6.8,3.4,1H,H-C(3’));4.18(t,J=6.7,2H,CO2CH2CH2CH2CH3);1.73-1.59(m,3H,H-C(1”)CO2CH2CH2CH2CH3);1.50-1.42(m,3H,Ha-C(2”),CO2CH2CH2CH2CH3);1.18(m,1H,Hb-C(2”));0.96(t,J=7.4,CO2CH2CH2CH2CH3);0.88(d,J=6.8,3H,Me-C(1”));0.82(t,J=7.2,H,H-C(3”))ppm.
13C-NMR(50MHz,CDCl3)δ:165.6(CONH);164.7(CO2CH2CH2CH2CH3);150.2(C(4’));135.5(C(4a’));132.8,130.5(C(5’)or C(6’)or C(7’));128.1(C(8a’);126.9(C(8’));123.9(C(5’)or(C(6’)or C(7’));117.0(C(2));64.4(CO2CH2CH2CH2CH3);55.9(C(3’));41.5(C(1”));39.6(CO2CH2CH2CH2CH3);24.4(C(2”));19.2(CO2CH2CH2CH2CH3);15.1(Me-C(1’));13.7(CO2CH2CH2CH2CH3);11.0(C(3”))ppm.
MS(ES+)m/e:316([M+H]+),338([M+Na]+),631([2M+H]+),653([2M+Na]+).
实施例9
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸苄基酯(11)的合成
按照通用方法I,得到为白色固体的化合物11(69mg,50%收率)。
m.p.:53-54℃
[α]D=-178.5(c=0.005,CHCl3).
IR(KBr)v:3435,2927,1710,1669,1159,1028,767,695cm-1.
1H-NMR(300MHz,CDCl3)δ:8.14(m,1H,H-C(8’));7.56(m,3H,H-C(5’),H-C(6’),H-C(7’));7.39(m,5H,CO2CH2Ph);6.86(broad d,J=4.3,1H,NH);6.40(s,1H,H-C(2));5.46(dd,J=7.1,4.3,1H,H-C(3’));5.22(s,2H,CO2CH2Ph);1.61(m,1H,H-C(1”));1.44(m,1H,Ha-C(2”));1.14(m,1H,Hb-C(2”));0.87(d,J=6.8,3H,Me-C(1”));0.81(t,J=7.3,3H,H-C(3”))ppm.
13C-NMR(50MHz,CDCl3)δ:165.2(CONH);163.8(CO2CHPh);150.9(C(4’));135.6C(4a’));135.4(C(Ph));132.7,130.6(C(5’)or C(6’)or C(7’));128.6,128.5,128.4,128.3,128.1(7C,C(8’)C(8a’),(C(Ph)));123.9(C(5’)or(C(6’)or C(7’));116.5(C(2));66.3(CO2CHPh);55.9(C(3’));41.5(C(1”));24.4(C(2”));15.1(Me-C(1’));11.1(C(3”))ppm.
MS(ES+)m/e:350([M+H]+),372([M+Na]+),699([2M+H]+),721([2M+Na]+).
实施例10
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-烯基酯(12)的合成
按照通用方法I,得到为白色固体的化合物12(35mg,41%收率)。
m.p.:79-81℃
[α]D=-404.2(c=0.12,CHCl3).
IR(KBr)v:3429,2964,2927,1714,1671,1273,1157,773cm-1.
1H-NMR(300MHz,CDCl3)δ:8.14(m,2H,H-C(8’));7.56(m,6H,H-C(5’),H-C(6’),H-C(7’));6.67(broad d,J=4.6,2H,NH);6.34(s,2H,H-C(2));5.84(t,J=4.1,2H,CH=CH);5.46;(dd,J=7.1,4.6,2H,C(3’));4.81(t,J=4.1,4H,CO2CH2CH=CHCH2CO2);1.59(m,1H,H-C(1”));1.44(m,2H,Ha-C(2”));1.16(m,2H,Hb-C(2”));0.87(d,J=6.8,6H,Me-C(1”));0.80(t,J=7.4,6H,H-C3”))ppm.
13C-NMR(50MHz,CDCl3)δ:165.1(CONH);163.8(CO2CH2CH=CHCH2CO2);151.2(C(4’));135.3(C(4a’));132.6,130.7(C(5’)or C(6’)or C(7’));128.4,128.2,128.1(C(8’),C(8a’)C(CH=CH));123.8(C(5’)or C(6’)or C(7’));116.2(C(2));59.9(CO2CH2CH=CHCH2CO2);55.9(C(3’));41.5(C(1”));24.5(C(2”));15.1(Me-C(1’));11.0(C(3”))ppm.
MS(ES+)m/e:571([M+H]+),593([M+Na]+),1141([2M+H]+),1163([2M+Na]+).
实施例11
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-炔基酯(13)的合成
按照通用方法I,得到为白色固体的化合物13(44mg,52%收率)。
m.p.:85-87℃
[α]D=-447.2(c=0.14CHCl3).
IR(KBr)v:3434,2963,2927,1718,1669,1378,1273,1152,771cm-1.
1H-NMR(300MHz,CDCl3)δ:8.12(m,2H,H-C(8’));7.55(m,6H,H-C(5’),H-C(6’),H-C(7’));6.67(broad d,J=4.5,2H,NH);6.35(s,2H,H-C(2));5.41(dd,J=7.3,4.5,2H,C(3’));4.82(s,4H,CO2CH2C≡CCH2CO2);1.59(m,2H,H-C(1”));1.42(m,2H,Ha-C(2”));1.15(m,2H,Hb-C(2”));0.85(d,J=6.8,6H,Me-C(1”);0.77(t,J=7.3,6H,H-C3”))ppm.
13C-NMR(75MHz,CDCl3)δ;164.5(CONH);163.7(CO2CH2C≡CCH2CO2);152.1(C(4’));135.1(C(4a’));132.8,130.9(C(5’)or C(6’)or C(7’));128.4(C(8a’)),128.1(C(8’));123.9(C(5’)or(C(6’)or C(7’));115.6(C(2));80.8(CO2CH2C≡CCH2CO2);56.1(C(3’));52.1(CO2CH2C≡CCH2CO2);41.6(C(1”));24.4(C(2”));15.1(Me-C(1’));11.1(C(3”))ppm.
MS(ES+)m/e:569([M+H]+),591([M+Na]+),1137([2M+H]+),1159([2M+Na]+).
实施例12
(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(S,S,S,S,Z,Z)-4-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-苄基酯(14)的合成
按照通用方法I,得到为白色固体的化合物14(25mg,27%收率)。
m.p.:213-215℃
[α]D=-391.0(c=0.22,CHCl3).
IR(KBr)v:3422,2927,1712,1671,1379,1275,1158,775cm-1.
1H-NMR(300MHz,CDCl3)δ:8.14(m,2H,H-C(8’));7.57(m,6H,H-C(5’),H-C(6’),H-C(7’));7.43(s,4H,CO2CH2PhCH2CO2);6.40(s,2H,H-C(2));6.25(broad d,J=4.7,2H,NH);5.45(dd,J=7.1,4.7,2H,H-C(3’));5.23(s,2H,CO2CH2PhCH2CO2);5.22(s,2H,CO2CH2PhCH2CO2);1.61(m,2H,H-C(1”));1.44(m,2H,Ha-C(2”));1.17(m,2H,Hb-C(2”));0.87(d,J=6.8,6H,Me-C(1”));0.81(t,J=7.3,6H,H-C3”))ppm.
13C-NMR(75MHz,CDCl3)δ:165.1(CONH);163.9(CO2CH2PhCH2CO2);151.3(C(4’));135.9(C(Ph));135.3(C(4a’));132.7,130.6(C(5’)or C(6’)orC(7’));128.5(6C,C(8a’),C(Ph));128.0(C(8’));123.8(C(5’)or C(6’)orC(7’));116.3(C(2));65.8(CO2CH2PhCH2CO2);55.9(C(3’));41.5(C(1”));24.4(C(2”));15.1(Me-C(1’));11.0(C(3”))ppm.
MS(ES+)m/e:621([M+H]+),643([M+Na]+),1241([2M+H]+),1264([2M+Na]+).
实施例13
酸8与胺和二胺反应(通用方法II)
酸8的酰胺的合成
向酸8(100mg,0.38mmol)在无水CH2Cl2(2.5mL)中的于0℃下的混悬液中滴加SOCl2(0.28mL,3.8mmol)。搅拌混合物直到达到室温并然后加热回流约1小时。然后减压除去溶剂,得到深色的油,使其溶于无水CH2Cl2(2.5mL)中,向其中加入在氩气下的溶于无水CH2Cl2(2.5mL)中的相应的胺(0.57mmol的单胺或0.17mmol的二胺)。然后加入Et3N(0.1mL,0.76mmol)并在室温下搅拌过夜。然后用CH2Cl2(50mL)稀释反应物并用5%HCl水溶液(3×50mL)和饱和NaHCO3水溶液(3×50mL)顺序提取。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,经柱层析法纯化,使用己烷/EtOAc(7∶3-1∶1)作为洗脱剂。
实施例14
(S,S,Z)-N-苄基-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(15)的合成
按照通用方法II,得到为白色固体的化合物15(119mg,90%收率)。
m.p.:90-94℃
[α]D=-315.1(c=0.25,CH3OH).
IR(KBr)v:3435,2963,2927,1651,1523,1450cm-1.
1H-NMR(300MHz,CDCl3)δ:8.10(m,1H,H-C(8’));7.49(m,3H,H-C(5’),H-C(6’),H-C(7’));7.32(s,5H,CONHCH2Ph);6.20(broad s,J=4.5,1H,NH);6.17(s,1H,H-C(2));6.02(m,1H,CONHCH2Ph);5.65(dd,J=7.3,4.5,2H,H-C(3’));4.53(m,2H,CONHCH2Ph);1.63(m,1H,H-C(1”));1.45(m,1H,Ha-C(2”));1.19(m,1H,Hb-C(2”));0.89(d,J=6.8,3H,Me-C(1”));0.81(t,J=7.3,3H,H-C(3”))ppm.
13C-NMR(75MHz,CDCl3)δ:164.7(CONHCH2Ph);163.9(CONH);147.1(C(4a’));137.9(C(4’));135.9(C(Ph));132.7,129.9(C(5’)or C(6’)or C(7’));128.8,128.4,127.9,127.7(7C,C(8’),C(8a’),C(Ph));123.5(C(5’)or C(6’)orC(7’));119.2(C(2));55.6(C(3’));43.7(CONHCH2Ph);41.3(C(1”));24.6(C(2”));15.2(Me-C(1’));11.1(C(3”))ppm.
MS(ES+)m/e:349([M+H]+),371([M+Na]+),697([2M+H]+),719([2M+Na]+).
实施例15
(S,S,Z)-N-(3-乙酰基-苯基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(16)的合成
按照通用方法II,得到为白色固体的化合物16(112mg,79%收率)。
m.p.:147-151℃
[α]D=-333.5(c=0.26,CH3OH).
IR(KBr)v:3413,3435,2964,2927,1673,1656,1549,1484,1167,688cm-1.
1H-NMR(500MHz,50℃,CDCl3)δ:8.33(broad s,1H,CONHAr);8.10(m,2H,H-C(8’)H-Ar);7.98(d,J=7.3,1H,H-Ar);7.66(d,J=7.8,1H H-Ar);7.46(m,4H,H-C(5’),H-C(6’),H-C(7’),H-Ar);6.51(broad s,1H,NH);6.35(s,1H,H-C(2));5.60(dd,J=7.3,4.8,2H,H-C(3’));2.57(s,3H,ArCOCH3);1.63(m,1H,H-C(1”));1.47(m,1H,Ha-C(2”));1.15(m,1H,Hb-C(2”));0.90(d,J=6.8,3H,Me-C(1”));0.80(t,J=7.3,3H,H-C(3”))ppm.
13C-NMR(75MHz,CDCl3)δ:198.3(ArCOCH3);164.5,163.3(CONH);148.2(C(4a’));138.8(C(4’));135.9,132.8,130.2,128.2,127.8(C(Ph),C(5’)orC(6’)or C(7’),C(8’));129.(3C(8a’));124.4,123.9(C(2),C(Ph));55.6(C(3’));41.3(C(1”));29.7(ArCOCH3);24.7(C(2”));15.2(Me-C(1’));11.2(C(3”))ppm.
MS(ES+)m/e:377([M+H]+),399([M+Na]+),753([2M+H]+),775([2M+Na]+).
实施例16
(S,S,Z)-N-(2’-氨基-联苯-2-基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(17)的合成
按照通用方法II,得到为白色固体的化合物17(121mg,75%收率)。
[α]D=-312.6(c=0.33,CH3OH).
IR(KBr)v:3436,1661,1515,1439,1299,1161,749cm-1.
1H-NMR(300MHz,30℃,CDCl3,构象异构体M和m的混合物,1∶1)δ:8.24(m,2H,H-Ar,M+m);8.08(m,2H,H-C(8’),M+m);8.00(broad s,1H,CONHAr,M);7.95(broad s,1H,CONHAr,m);7.54-7.39(m,8H,H-C(5’),H-C(6’),H-C(7’),H-Ar,M+m);7.29-7.22(m,6H,H-Ar,M+m);7.19-7.09(m,2H,H-Ar,M+m);6.92-6.82(m,4H,H-A r,M+m);6.38(broad s,1H,NH,M);6.38(m,1H,NH,m);6.10(s,1H,H-C(2),M);6.06(s,1H,H-C(2),m);5.59(m,1H,H-C(3’),M);5.33(m,1H,H-C(3’),m);3.97(s,2H,ArNH2,M+m);1.59(m,1H,H-C(1”),M+m);1.41(m,1H,Ha-C(2”)M+m);1.13(m,1H,Hb-C(2”),M+m);0.85(d,J=4.2,3H,Me-C(1”),M);0.83(d,J=4.2,3H,Me-C(1”),m);0.77(t,J=7.3,3H,H-C(3”))ppm.
1H-NMR(300MHz,DMSO-d6)δ;9.32(broad s,1H,CONHAr);8.48(broadd,J=4.6,1H,NH);7.87(m,1H,H-C(8’));7.70(d,1H,H-C(5’));7.58(m,3H,H-C(6’),H-C(7’),H-C(2));7.37(m,1H,H-Ar)7.25(m,2H,H-Ar);7.06(m,1H,H-Ar);6.92(m,1H,H-Ar);6.78(m,1H,H-Ar);6.64(m,1H,H-Ar);6.56(m,1H,H-Ar);5.43(m,1H,H-C(3’));4.63(s,2H,ArNH2);1.35(m,2H,Ha-C(2”),H-C(1”));1.21(m,1H,Hb-C(2”));0.73(m,6H,Me-C(1”),H-C(3”))ppm.
13C-NMR(300MHz,CDCl3,构象异构体M和m的混合物,1∶1)δ:163.9,163.8,163.2(CONH,M+m);147.5,147.1,150.9,137.8,135.9,132.7,130.0,128.8,128.0,127.9,127.8(19C,C(4),(C(4a’),(C(5’),C(6’),C(7’),C(8’),C(8a’),C(Ph),M+m);125.2,125.1(C(Ar),M+m);123.8,123.7(C(5’)or C(6’)or C(7’),M+m);122.5,122.3(C(Ar),M+m);120.3,120.1,119.7,119.4,(C(2),C(Ar),M+m);115.9(C(Ar))55.9,55.6(C(3’),M+m);41.4(C(1”));24.6(C(2”));15.2(Me-C(1’));11.2(C(3”))ppm.
MS(ES+)m/e:426([M+H]+),753([2M+H]+),851([2M+H]+),874([2M+H+Na]+).
实施例17
(S,S,S,S,Z,Z)-2,2’-双-[(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]联苯(18)的合成
按照通用方法II,得到为白色固体的化合物18(154mg,61%收率)。
m.p.:177-180C
[α]D=-395.0(c=0.25,CH3OH).
IR(KBr)v:3435,2963,1656,1521,1302,1161,753cm-1.
1H-NMR(300MHz,CDCl3,构象异构体M和m的混合物,1∶1)δ:8.10(m,2H,CONH-Bif,M+m);8.06(m,1H,H-C(8’),M);8.01(m,1H,H-C(8’),m);7.52-7.16(m,14H,H-C(5’),H-C(6’),H-C(7’),H-Bif,M+m);6.61(broad d,1H,NH-L-Biq,M);6.36(d,J=4.4,1H,NH-L-Biq,m);6.07(s,1H,H-C(2),M);6.02(s,1H,H-C(2),m);5.55(m,1H,H-C(3’),M);5.37(m,1H,H-C(3’),m);1.61-1.52(m,1H,H-C(1”),M+m);1.38(m,1H,Ha-C(2”),M+m);1.12(m,1H,Hb-C(2”),M+m);0.86-0.71(m,12H,Me-C(1”),H-C(3”),M+m)ppm.[缩略词Biq用于异喹啉衍化的基团,缩略词Bif用于联苯衍生物]
MS(ES+)m/e:667([M+H]+),689([M+Na]+),1356([2M+H+Na]+).
实施例18
胺17与氨基酸衍生物的反应(通用方法III)
肽-杂环-联苯杂化物的合成
向相应的N-Fmoc-氨基酸(0.31mmol)在无水CH2Cl2(2.0mL)中的于0℃下的混悬液中滴加SOCl2(0.23mL,3.1mmol)。搅拌混合物直到达到室温并然后加热回流约1小时。然后减压除去溶剂,得到白色固体,使其溶于无水CH2Cl2(2.0mL)中,向其中加入在氩气下溶于无水CH2Cl2(2.0mL)中的胺17(200mg,0.47mmol)。然后加入Et3N(80μL,0.62mmol)并在室温下搅拌过夜。然后用CH2Cl2(50mL)稀释反应物并用NaHCO3水溶液(3×50mL)和饱和5%HCl水溶液(3x50mL)顺序提取。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,经柱层析法纯化,使用己烷/EtOAc(3∶2-1∶1)作为洗脱剂。
实施例19
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-甲基-丙基)-氨基甲酸(S,S,S,Z)-9H-芴-9-基甲基酯(19)的合成
按照通用方法III,得到为白色固体的化合物19(172mg,73%收率)。
m.p.:133-135℃
[α]D=-188.0(c=0.25,CH2Cl2).
IR(KBr)v:3408,2963,1663,1519,1450,1299,1232,758,739cm-1.
1H-NMR(300MHz,323K,CDCl3,构象异构体M和m的混合物,1∶1)δ:8.14-7.93(m,2H,H-Ar,M+m);7.75-7.70(m,1H,H-Ar,M+m);7.57-7.12(m,19H,H-Ar,CONH-Bif-CONH,M+m);6.18(d,J=4.4,0.5H,NH-L-Biq,M);6.12(d,J=4.4,0.5H,NH-L-Biq,m);6.03(s,0.5H,H-C(2)M);5.98(s,0.5H,H-C(2),m);5.45(m,0.5H,H-C(3’)M);5.36(s,0.5H,H-C(3’),m);5.04(broad s,1H,NH-Fmoc,M+m);4.42-4.26(m,2H,CH2-Fmoc,M+m),4.17-4.09(m,1H,CHα-L-Val,M+m),3.87(m,0.5H,CH-Fmoc,M),3.81(m,0.5H,CH-Fmoc,m),1.96(m,1H,CHβ-L-Val,M+m),1.54(m,1H,H-C(1”),M+m);1.40(m,1H,Ha-C(2”),M+m);1.10(m,1H,Hb-C(2”),M+m);0.89-0.73(m,12H,Me-C(1”),H-C(3”),Me2 of L-Val,M+m)ppm.
1H-NMR(300MHz,353K,DMSO-d6)δ:8.93(broad s,1H,CONHBif);8.75(broad s,1H,CONHBif);8.14-6.94(m,22H,H-C(5’)H-C(6’),H-C(7’),H-C(8’),H-Ar);6.43(s,1H,H-C(2));5.34(m,1H,H-C(3’));4.32-4.15(m,3H,CH2-Fmoc,CH-Fmoc);3.84(m,1H,CHα-L-Val);1.91(m,1H,CHβ-L-Val);1.38(m,2H,Ha-C(2”),H-C(1”));1.09(m,1H,Hb-C(2”));0.86-0.66(m,12H,Me-C(1”),H-C(3”),Me2 of L-Val)ppm.
MS(ES+)m/e:747([M+H]+),770([M+Na]+),1515([2M+H+Na]+).
实施例20
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-苯基-乙基)-氨基甲酸(S,S,S,Z)-9H-芴-9-基甲基酯(20)的合成
按照通用方法III,得到为白色固体的化合物20(109mg,45%收率)。
m.p.:108-110℃
[α]D=-181.0(c=0.23,CH2Cl2).
IR(KBr)v:3409,2956,1659,1519,1450,1247,1161,1046,758,739cm-1.
1H-NMR(300MHz,313K,CDCl3,构象异构体M和m的混合物,1.5∶1)δ:8.14-7.99(m,2H,H-Ar,M+m);7.88-7.65(m,3H,H-Ar,M+m);7.48-7.01(m,20H,H-Ar,M+m);6.72(d,J=4.4,0.6H,NH-L-Biq,M);6.52(d,J=4.4,0.4H,NH-L-Biq,m);6.05(s,0.6H,H-C(2),M);5.98(s,0.4H,H-C(2),m);5.46(m,0.4H,H-C(3’)m);5.37(s,0.4H,H-C(3’),M);5.27(broad s,0.6H,NH-Fmoc,M);5.02(broad s,0.4H,NH-Fmoc,m);4.38-4.06(m,4H,CH2-Fmoc,CH-Fmoc,CHα-L-Phe,M+m),3.21(m,1H,CHβ-L-Phe,M),2.84(m,1H,CHβ-L-Phe,m);1.61(m,1H,H-C(1”),M+m);1.41(m,1H,Ha-C(2”),M+m);1.13(m,1H,Hb-C(2”),M+m);0.80(d,2H,J=6.8,Me-C(1”),M);0.80(d,0.5H,J=6.8,Me-C(1”),m);0.74(t,3H,J=7.8,H-C(3”),M+m)ppm.
MS(ES+)m/e:795([M+H]+),818([M+Na]+),1612([2M+H+Na]+).
实施例21
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-甲基-丁基)-氨基甲酸(S,S,S,S,Z)-9H-芴-9-基甲基酯(21)的合成
按照通用方法III,得到为白色固体的化合物21(101mg,58%收率)。
m.p.:116-120℃
[α]D=-155.1(c=0.12,CHCl3).
IR(KBr)v:3406,3282,2963,2920,1662,1516,1450,1233,757,740cm-1.
1H-NMR(300MHz,318K,CDCl3,构象异构体M和m的混合物,1∶1)δ:8.12-7.01(m,22H,H-Ar,CONH-Bif-CONH,M+m);6.33(broad s,0.5H,NH-L-Biq,M);6.27(broad s,0.5H,NH-L-Biq,m);6.05(s,0.5H,H-C(2)M);5.99(s,0.5H,H-C(2),m);5.47(m,0.5H,H-C(3’)M);5.34(s,0.5H,H-C(3’),m);5.23(broad s,1H,NH-Fmoc,M+m);4.44-3.88(m,4H,CH2-Fmoc,CH-Fmoc,CHα-L-IIe,M+m),1.86(m,0.5H,CHβ-L-IIe,M);1.72(m,0.5H,CHβ-L-IIe,m),1.54(m,1H,H-C(1”),M+m);1.40(m,1H,Ha-C(2”),M+m);1.14(m,1H,Hb-C(2”),CHb-L-IIe,M+m);0.88-0.70(m,12H,Me-C(1”),H-C(3”),[CH-CH3]of L-IIe,[CH2-CH3]of L-IIe,M+m)ppm.
MS(ES+)m/e:761([M+H]+),783([M+Na]+),1522([2M+H]+),1545([2M+Na]+).
实施例22
N-Fmoc基团的脱保护(通用方法IV)
在氩气下,向相应保护的N-Fmoc化合物(0.09mmol)在0.3mL无水DMF中的于0℃下的溶液中加入哌啶(70μL)。然后使混合物达到室温反应2小时。一旦已经除去溶剂,得到粗产物,经柱层析法纯化,使用己烷/EtOAc(1∶1-1∶9)作为洗脱剂。
实施例23
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-丁酰胺(22)的合成
按照通用方法IV,得到为白色固体的化合物22(12mg,24%收率)。
m.p.:110-113℃
[α]D=-35.9(c=0.07,CHCl3).
IR(KBr)v:3434,2956,1660,1521,14369,1165,753cm-1.
1H-NMR(500MHz,313K,CDCl3,构象异构体M和m的混合物,1∶1)δ:9.31(broad s,0.5H,CONH-Bif-CONH,M);9.28(broad s,0.5H,CONH-Bif-CONH,m);8.38(broad s,0.5H,CONH-Bif-CONH,M);8.28(broad s,0.5H,CONH-Bif-CONH,m);8.09(m,1H,H-C(8’),M);8.19(m,1H,H-C(8’),m);7.45(m,6H,H-Ar.H-Bif M+m);7.23(m,5H,H-Ar.H-Bif M+m);6.25(d,J=4.5,0.5H,NH-L-Biq,M);6.18(d,J=4.5,0.5H,NH-L-Biq,m);6.03(s,0.5H,H-C(2)M);5.99(s,0.5H,H-C(2),m);5.52(m,0.5H,H-C(3’)M+m);3.47(m,1H,NH2,M);3.29(m,1H,NH2,m);3.23(d,J=3.4,0.5H,CHα-L-Val,M);3.15(d,J=3.4,0.5H,CHα-L-Val,m),2.24(m,1H,CHβ-L-Val,M+m);1.61(m,1H,H-C(1”),M+m);1.52(m,1H,Ha-C(2”),M+m);1.18(m,1H,Hb-C(2”),M+m);0.91-0.63(m,12H,Me-C(1”),H-C(3”),Me2 of L-Val,M+m)ppm.
MS(ES+)m/e:525([M+H]+),547([M+Na]+),1049([2M+H]+),1072([2M+Na]+).
实施例24
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-苯基-丙酰胺(23)的合成
按照通用方法IV,得到为白色固体的化合物23(32mg,61%收率)。
m.p.:107-110℃
[α]D=-231.0(c=0.06,CH2Cl2).
IR(KBr)v:3435,1658,1519,1436,1161,753cm-1.
1H-NMR(500MHz,CDCl3,构象异构体M和m的混合物,2.5∶1)δ:9.36(broad s,0.7H,CONH-Bif-CONH,M);9.32(broad s,0.3H,CONH-Bif-CONH,m);8.40-8.05(m,3H,H-C(8’),CONH-Bif-CONH,M+m);7.53-7.44(m,6H,H-Ar,H-Bif,M+m);7.43-7.13(m,5H,H-Ar,H-Bif,M+m);6.49(m,1H,NH-L-Biq,M+m);6.07(s,0.7H,H-C(2)M);6.06(s,0.3H,H-C(2),m);5.51(m,1H,H-C(3’)M+m);3.55(m,1H,CHα-L-Phe,M+m);3.18(m,1H,CHβ-L-Phe,M);2.49(m,1H,CHβ-L-Phe,m);1.59(m,1H,H-C(1”),M+m);1.50(m,1H,Ha-C(2”),M+m);1.16(m,1H,Hb-C(2”),M+m);0.90-0.70(m,6H,Me-C(1”),H-C(3”),M+m)ppm.
实施例25
(S,S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-戊酰胺(24)的合成
按照通用方法IV,得到为白色固体的化合物24(34mg,71%收率)。
m.p.:93-96℃
[α]D=-215.6(c=0.09,MeOH).
IR(KBr)v:3413,2962,2920,1666,1580,1521,1436,1302,1164,755cm-1.
1H-NMR(400MHz,CDCl3,构象异构体M和m的混合物,1∶1)δ:9.41(broad s,0.5H,CONH-Bif-CONH,M);9.38(broad s,0.5H,CONH-Bif-CONH,m);8.32(broad s,0.5H,CONH-Bif-CONH,M);8.22(broad s,0.5H,CONH-Bif-CONH,m);8.13(m,0.5H,H-C(8’),M);8.03(m,0.5H,H-C(8’),m);7.46-7.35(m,6H,H-Ar,H-Bif,M+m);7.24-7.09(m,5H,H-Ar,H-Bif,M+m);6.77(d,J=4.4,0.5H,NH-L-Biq,M+m);6.70(d,J=4.4,0.5H,NH-L-Biq,M+m);6.04(s,0.5H,H-C(2),M);6.02(s,0.5H,H-C(2),m);5.48(m,1H,H-C(3’)M+m);3.26(m,J=3.4,0.5H,CHα-L-IIe,M);3.17(m,J=3.4,0.5H,CHα-L-IIe,m);1.96(m,1H,CHβ-L-IIe,M);1.88(m,1H,CHβ-L-IIe,m);1.58(m,1H,H-C(1”),M+m);1.52(m,1H,Ha-C(2”),M+m);1.14(m,1H,Hb-C(2”),M+m);0.89-0.74(m,12H,Me-C(1”),H-C(3”),[CH-CH3]of L-IIe,[CH2-CH3]of L-IIe,M+m)ppm.
实施例26
肽-异喹啉杂化物的合成(通用方法V)
向酸8(150mg,0.58mmol)在无水DMF中的溶液中顺序加入相应的肽(作为三氟乙酸盐)(0.70mmol)、1-羟基苯并三唑(HOBT,92mg,0.70mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,134.4mg,0.70mmol)和4-(二甲基氨基)吡啶(DMAP,7mg,0.058mmol)。在室温下搅拌混合物过夜。然后真空除去有机溶剂并经柱层析法纯化粗产物,得到相应的肽-异喹啉杂化物。
实施例27
(S,S,S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酸甲酯(25)的合成
按照通用方法V,自肽CF3CO2 -+H-L-IIe-L-IIe-OCH3开始,并经层析法(己烷-EtOAc 4∶1-3∶2的混合物)纯化后,得到为白色固体的化合物25(232mg,80%收率)。
IR(KBr)v:3436,2965,1743,1652,1544cm-1.
1H-NMR(300MHz,CDCl3,)δ:8.26(m,J=5.1,1H,NH-L-Iiq);7.96(m,1H-C(8’));7.38-7.21(m,5H H-C(5’),H-C(6’),H-C(7’),NH-L-IIe[1],NH-L-IIe[2]);6.09(s,1H,olefinic H);5.57(dd,J=7.2,5.1,1H,H-C(3’));4.68(m,1H,CHα-L-IIe[2]);4.43(dd,J=7.6,5.1,1H,CHα-L-IIe[1]);3.72(s,3H,CO2Me);1.93-1.79(m,3H,[Me-CH-Et]of L-Iiq;CHβ-L-IIe[1],CHβ-L-IIe[2]);1.66-1.08(m,6H,[Me-CH-CH2CH3]of L-Iiq,[Me-CH-CH2CH3]of L-Iiq,[CH-CH3]of L-IIe[1],[CH-CH3]of L-IIe[2],[CH2CH3]of L-IIe[1],[CH2CH3]of L-IIe[2]ppm.
13C-NMR(50MHz,CDCl3)δ:172.0,171.9(CO2Me,CONH-L-IIe[2]);164.8,164.5(=C-CONH,CONH-L-Iiq),147.5(C(4’)),136.0(C(4a’)),132.4,129.5,123.6(C(5’),C(6’),C(7’),128.3(C(8a’));127.5(C(8));119.2(olefinic CH);57.3(CHα-L-IIe[2]);56.9(CHα-L-IIe[1]);54.9(C(3’));51.9(CO2Me);41.3,38.3,37.1([Me-CH-Et]of L-Iiq;CHβ-L-IIe[1],CHβ-L-IIe[2]);25.1,24.9(3C[Me-CH-CH2CH3]of L-Iiq,CH2-L-IIe[1],CH2of L-IIe[2]);15.4,15.3,15.0,11.4,11.2((6C[Me-CH-CH2CH3]of L-Iiq,[Me-CH-CH2CH3]of L-Iiq,[CH-CH3]of L-IIe[1]),[CH-CH3]of L-IIe[2],CH2-CH3]of L-IIe[1],[CH2-CH3]of L-IIe[2])ppm.MS(ES+)m/e:500([M+H]+),522([M+Na]+),999([2M+H]+),1021([2M+Na]+).
实施例28
(S,S,S,S,S,S,S,S,Z)-2-(2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酰氨基)-3-甲基-戊酸甲酯(26)的合成
按照通用方法V,自肽CF3CO2 -+H-L-IIe-L-IIe-OCH3开始,并经层析法(己烷-EtOAc 1∶4-1∶9的混合物)纯化后,得到为白色固体的化合物26(234mg,66%收率)。
m.p.:151-154℃
[α]D=-100.9(c=0.33,MeOH).
IR(KBr)v:3302,2965,1739,1650,1529,1207cm-1.
1H-NMR(300MHz,(D6)DMSO)δ:8.49(d,J=4.5,1H,NH-L-Biq);8.25(d,J=8.5,1H NH-L-IIe[3]);8.14(d,J=7.3,1H NH-L-IIe[1]);7.99(d,J=8.7,1H NH-L-IIe[2]);7.88(dd,J=7.3,0.8,1H,H-C(8’));7.66-7.58(m,2H H-C(5’),H-C(6’),H-C(7’);7.50(td,J=7.6,0.9,1H,H-C(7’));6.70(s,1H,olefinic H);5.47(dd,J=7.3,4.5,1H,H-C(3’));4.35(t,J=8.5,1H,CHα-L-IIe[3]);4.24(t,J=8.7,1H,CHα-L-IIe[2]);4.17(t,J=7.3,1H,CHα-L-IIe[1]);3.58(s,3H,CO2Me);1.84-1.62(m,3H,CHβ-L-IIe[1],CHβ-L-IIe[2],CHβ-LIIe[3]);1.52-0.91(m,9H,[Me-CH-Et]of L-Biq,[Me-CH-CH2CH3]of L-Biq,CH2-L-IIe[1],CH2-L-IIe[2],CH2-L-IIe[3]);0.90-0.68(m,24H,[Me-CH-CH2CH3]of L-Biq,[Me-CH-CH2CH3]of L-Biq,[CH-CH3]of L-IIe[1],[CH-CH3]of L-IIe[2],[CH-CH3]of L-IIe[3],[CH2-CH3]of L-IIe[1],[CH2-CH3]of L-IIe[2][CH2-CH3]of L-IIe[3])ppm.
13C-NMR(50MHz,(D6)DMSO)δ:171.7,171.2,170.7(CONH-L-IIe[1],CONH-L-IIe[2],=CH-CONH);164.6,162.6(CONH-L-Biq,CO2Me);144.0(C(4’)),136.0(C(4a’)),132.4(C(5’)or C(6’);129.5(C(7’),128.6(C(8a’));126.9(C(8’));123.7(C(5’)or C(6’);120.3(olefinic CH);56.5,56.4,56.2(CHα-L-IIe[1],CHα-L-IIe[2],CHα-L-IIe[3]);54.6C(3’));51.5(CO2Me);41.3[Me-CH-Et]of L-Biq);36.8,36.5,35.9(CHβ-L-IIe[1],CHβ-L-IIe[2],CHβ-L-IIe[3]);24.6,24.2(4C[Me-CH-CH2CH3]of L-Biq,CH2-L-IIe[1],CH2-L-IIe[2],CH2-L-IIe[3]);15.3,15.2,15.0,14.9,11.0,10.9,10.8(8C[Me-CH-CH2CH3]of L-Biq,[Me-CH-CH2CH3]of L-Biq,[CH-CH3]of L-IIe[1],[CH-CH3]of L-IIe[2],[CH-CH3]of L-IIe[3],[CH2-CH3]of L-IIe[1],[CH2-CH3]of L-IIe[2][CH2-CH3]of L-IIe[3])ppm.
MS(ES+)m/e:613([M+H]+),635([M+Na]+),1226([2M+H]+),1247([2M+Na]+).
实施例29
(S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-丁酰氨基)-3-苯基-丙酸甲酯(27)的合成
按照通用方法V,自肽CF3CO2 -+H-L-VaI-L-Phe-OCH3开始,并经层析法(己烷-EtOAc 3∶2-2∶3的混合物)纯化后,得到为白色固体的化合物27(217mg,72%收率)。
m.p.:174-176℃
[α]D=-129.0(c=0.5CHCl3).
IR(KBr)v:3436,2964,1743,1655,1538cm-1.
1H-NMR(400MHz,CDCl3)δ:8.24(d,J=4.6,1H,NH-L-Biq);7.96(dd,J=7.6,1.4,1H,H-C(8’));7.37-7.03(m,10H,H-C(5’),H-C(6’),H-C(7’),NH-L-IIe,NH-L-Phe,aromatic of L-Phe);6.06(s,1H,olefinic H);5.57(dd,J=9.1,4.9,1H,H-C(3’));4.74(dd,J=14.0,6.3,1H,CHα-L-Phe);4.48(dd,J=9.1,6.6,CHα-L-Val);3.66(s,3H,CO2Me);2.91(dd,J=14.0,6.3,2H,CHβ-L-Phe);2.11(m,1H,CHx-L-Val);1.57-1.48(m,2H,[Me-CH-CH2CH3]of L-Biq,);1.17-1.09(m,1H,[Me-CH-CH2CH3]of L-Biq);1.00(d,J=6.7,3H,Me2 of L-Val);0.96(d,J=6.7,3H,Me2 of L-Val);0.85(d,J=6.7,3H,[Me-CH-CH2CH3]of L-Biq);0.80(t,J=7.3,3H,[Me-CH-CH2CH3]of L-Biq)ppm.
13C-NMR(50MHz,CDCl3)δ:1712.0,171.5(CONH-L-Val,CO2Me);164.9,164.6(=CH-CONH,CONH-L-Biq);147.2(C(4’)),135.9,135.7,132.5,129.6,129.2,128.5,128.3,127.4,127.0,123.6(12C,C(4a’),(C(5’),C(6’),C(7’),C(8a’),C(8’),aromatic C of L-Phe):119.1(olefinic CH);58.3(CHα-L-Phe);55.0(C(3’));53.3(CHα-L-Val);52.1(CO2Me);41.3[Me-CH-CH2CH3]of L-Biq),37.5(CHβ-L-Phe);31.6(CHβ-L-Val);24.7([Me-CH-CH2CH3]of L-Biq,19.2,18.2(Me2 of L-Val);15.1([Me-CH-CH2CH3]of L-Biq);11.3([Me-CH-CH2CH3]of L-Biq)ppm.
MS(ES+)m/e:520([M+H]+),542([M+Na]+),1039([2M+H]+),1061([2M+Na]+).
实施例30
(S,S,Z)-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(28)的合成
向异喹啉酮7(273mg,1.0mmol)在无水甲苯(9.0mL)中的溶液中加入Lawesson氏试剂([2,4-双(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂环丁烷-2,4-二硫化物])(445mg,1.1mmol)并使混合物回流约1小时。然后使混合物达到室温并真空除去溶剂,得到粗产物,经柱层析法纯化,使用己烷/EtOAc(19∶1-7∶3)作为洗脱剂,得到263mg(91%收率)为黄色固体的27。
m.p.:50-53℃
[α]D=-754.2(c=0.5,CHCl3).
IR(KBr)v:3436,3432,3170,2665,1713,1637,1368,1215,1195,1172,1013,772cm-1.
1H-NMR(300MHz,50℃,CDCl3)δ:8.58(broad s,1H,NH);8.58(dd,J=7.5,1.7,1H,H-C(8’));7.55-7.43(m,3H,H-C(5’),H-C(6’),H-C(7’)),6.31(s,1H,H-C(2));5.48(dd,J=7.8,5.1,1H,H-C(3’));3.75(s,3H,CO2Me);1.66(m,1H,H-C(1”));1.49(m,1H,Ha-C(2”));1.19(m,1H,Hb-C(2”));0.86-0.79(m,6H,Me-C(1”),H-C(3”))ppm.
13C-NMR(50MHz,CDCl3)δ:191.4(CSNH);165.8(CO2Me);149.6(C(4’));133.1(C(4a’));132.3,131.0(C(5’)or C(6’)or C(7’));130.8(C(8a’));130.5(C(8’));123.7(C(5’)or C(6’)or C(7’));117.1C(2));57.7(C(3’));51.7(CO2Me);40.8(C(1”));24.9(C(2”));14.9,10.9(Me-C(1’))C(3”))ppm.
MS(ES+)m/e:290([M+H]+),312([M+Na]+),601([2M+Na]+).
实施例31
(S,S,Z)-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(29)的合成
向硫代内酰胺27(231.2mg,0.8mmol)在THF-H2O的1∶1混合物(8nL)中的于室温下的溶液中加入LiOH(1.6mmol)在H2O(1.6mL)中的溶液。在室温下搅拌混合物过夜并然后用5%HCl酸化至pH=2。真空除去THF并用EtOAc(3×50mL)提取水相。用盐水洗涤有机相并经MgSO4干燥。一旦已经真空除去溶剂,得到粗产物,经EtOAc/己烷重结晶纯化,得到为黄色固体的酸28(211mg,96%收率)。
m.p.:193-196℃
[α]D=-600.5(c=0.5,CH3OH).
IR(KBr)v:3449,3210,2963,1674,1281,1254,1219,776cm-1.
1H-NMR(300MHz,DMSO-d6)δ:12.77(broad s,1H,CO2H);11.03(d,J=4.9,1NH);8.39(dd,J=7.6,1H,H-C(8’));7.72-7.53(m,3H,H-C(5’),H-C(6’),H-C(7’)),6.39(s,1H,H-C(2));5.33(dd,J=8.2,4.9,1H,H-C(3’));1.56-1.46(m,1H,Ha-C(2”));1.44-1.38(m,1H,H-C(1’));1.19-1.06(m,1H,Hb-C(2”));0.78(t,J=7.5,3H,Me-C(1”));0.81(d,J=6.9,3H,H-C(3”))ppm.
13C-NMR(50MHz,DMSO-d6)δ:189.3(CSNH);166.6(CO2H);147.8(C(4’));133.1(C(4a’));131.1(2C,C(5’)or C(6’)or C(7’));130.6(C(8a’));130.1(C(8’));124.4(C(5’)or C(6’)or C(7’));118.8(C(2));55.7(C(3’));40.9(C(1”));24.8(C(2”));14.9(Me-C(1’));10.9(C(3”))ppm.
MS(ES+)m/e:276([M+H]+),298([M+Na]+),573([2M+Na]+).
实施例32
(S,S,S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酸甲酯(30)的合成
按照通用方法V,自酸29和肽CF3CO2 -+H-L-IIe-L-IIe-OCH3开始得到化合物。经层析法纯化,使用己烷/EtOAc的混合物(4∶1-3∶2)洗脱,以得到为油的30(257mg,86%收率)。
m.p.:178-181℃
[α]D=-366.0(c=0.25,CHCl3).
IR(KBr)v:3435,2964,1739,1631,1525,1212cm-1.
1H-NMR(300MHz,(D6)DMSO)δ:10.96(d,J=4.9,1H,NH-L-Biq);8.38-8.28(m,3H NH-I-IIe[1]),NH-L-IIe[2],H-C(8’));7.65-7.48(m,3H H-C(5’),H-C(6’),H-C(7’);6.72(s,1H,olefinic H);5.61-5.56(m,1H,H-C(3’));4.39(t,J=8.1,1H,CHα-L-IIe[2]);4.16(t,J=7.1,1H,CHα-L-IIe[1]);3.59(s,3H,CO2Me);1.86-1.68(m,2H,CHβ-L-IIe[1],CHβ-L-IIe[2]);1,54-0.98(m,7H,[Me-CH-Et]of L-Biq,[Me-CH-CH2CH3]of L-Biq,CH2-L-IIe[1],CH2-L-IIe[2]);0.86-0.65(m,18H,[Me-CH-CH2CH3]of L-Biq,[Me-CH-CH2CH3]of L-Biq,[CH-CH3]of L-IIe[1],[CH-CH3]of L-IIe[2],[CH2-CH3]of L-IIe[1][CH2-CH3]ofL-IIe[2]).
13C-NMR(50MHz,(D6)DMSO)δ:189.2(CSNH);171.7,171.3(CO2Me,CONH-L-IIe[2]);164.5(=C-CONH);142.9(C(4’)),132.8,130.9,123.8(C(5’),C(6’),C(7’));131.4(C(8’));130.6(C(8a’));129.4(C(4a’));121.5(olefinic CH);56.5(CHα-L-IIe[2]);56.1(CHα-L-IIe[1]);55.0(C(3’));51.5(CO2Me);40.3,36.8,35.9[Me-CH-Et]of L-Biq,CHβ-L-IIe[1],CHβ-L-IIe[2]);24.9,24.7,24.2([Me-CH-CH2CH3]of L-Biq,CH2-L-IIe[1],CH2-L-IIe[2]);15.3,15.1,14.7,11.1,10.8(6C[Me-CH-CH2CH3]of L-Biq,[Me-CH-CH2CH3]of L-Biq,[CH-CH3]ofL-IIe[1],[CH-CH3]of L-IIe[2],[CH2-CH3]of L-IIe[1],[CH2-CH3]of L-IIe[2]).
MS(ES+)m/e:516([M+H]+),583([M+Na]+),1031([2M+H]+),1053([2M+Na]+).
实施例33
酶活性试验:钙蛋白酶的抑制
根据IC50值定量钙蛋白酶抑制能力,IC50值定义为减少酶催化活性一半时的抑制剂浓度。IC50值越低,抑制剂越有效。一些本发明化合物对钙蛋白酶I的抑制结果(生理观察点的最大相关性)显示在表1和图1中。
表1构成本发明目的的化合物对钙蛋白酶抑制作用的代表性结果
化合物 | IC50 |
7 | 25nM |
11 | 124μM |
12 | 85μM |
13 | 59μM |
14 | 5μM |
15 | 140μM |
16 | 130μM |
17 | 86nM |
18 | 742nM |
19 | 100μM |
20 | 48μM |
21 | 5μM |
22 | 17μM |
23 | 7μM |
24 | 50μM |
25 | 447nM |
26 | 159nM |
27 | 626nM |
28 | 38μM |
采用Spectrofluor Tecan Corp93382荧光分光光度计经分光荧光测定法进行实验,在485nM下激发和在530nM下测量。BODIPY-FL(Molecular Probes)标记的酪蛋白用作底物,得自猪红细胞的钙蛋白酶I(Calbiochem,Cat No208712)用作酶。冻干的底物为得自MolecularProbes(reference#E-6638)的蛋白酶试验试剂盒EnzChekgreenfluorescence组分A;组分B,称作20X消化缓冲液,含有13mL的200mM Tris-HCl,pH 7.8和2mM叠氮化钠。所采用的市售钙蛋白酶I具有在1mL水溶液中1mg的浓度(溶液为20mM咪唑-HCl,pH6.8,1mM EDTA,1mM EGTA,5mM β-巯基乙醇,含30%甘油)。
消化缓冲液(消化溶液)的制备
将2.5mL的20X消化缓冲液(得自Molecular Probes的试剂盒组分B)用水稀释至总体积50mL。
底物溶液(酪蛋白溶液)的制备
使200μg的冻干底物(得自Molecular Probes的试剂盒组分A)
溶于200μL的磷酸盐水缓冲液中。将该溶液倾析到量瓶中并用消化溶液稀释至总体积40mL。
钙蛋白酶溶液(钙蛋白酶溶液)的制备
用消化溶液将20μL的钙蛋白酶市售溶液稀释至总体积200μL。
抑制剂溶液(抑制剂溶液)的制备
将抑制剂溶于DMSO中。在介于10nM-200μM的7种不同浓度下试验每一种抑制剂。
酶活性实验
测量荧光随时间的变化得到所有数据。使用多单元装置和Eppendorf多通道吸管允许在最多可达64个实验中测量荧光变化。由此可见,在相同的测量装置中进行对照实验和含不同浓度抑制剂的实验。全部实验进行两次。
对照实验
将180μL的酪蛋白溶液和5μL的钙蛋白酶溶液混合进行对照实验。通过加入10μL的CaCl2在水中的50μM溶液引发反应,并且自加入Ca2+(时间=0)时刻起测量荧光并持续250-300秒(在20个动力学周期期间测量)。荧光的变化(ΔF)表示为与时间(t)的关系。为试验DMSO对酶活性的影响,加入DMSO(以含有抑制剂的实验所使用的量)进行另外的对照实验,得到与对照实验相同的结果。
抑制剂存在下的酶活性
将180μL的酪蛋白溶液、5μL的钙蛋白酶溶液和5μL的抑制剂溶液(具有不同浓度)混合在一起。通过加入10μL的CaCl2在水中的50μM溶液引发反应,并且自加入Ca2+(时间=0)时刻起测量荧光并且持续250-300秒(在20个动力学周期期间测量)。荧光的变化(ΔF)表示为与时间(t)的关系,并且得到每一实验的ΔF/t值。
IC50的测定
对每一种抑制剂,ΔF/t值表示为与抑制剂浓度(c)的关系,自c=0至最多可达c=200μM。数据被拟合为直线并且自方程式确定IC50值(作为引起酶具有一半活性时的抑制剂浓度)。
缩写
以下指出的是所使用缩写的含义:
-CANP:钙活化的中性蛋白酶
-DMF:N,N-二甲基甲酰胺
-DMSO:二甲基亚砜
-EA:元素分析
-EDTA:乙二胺四乙酸
-EGTA:亚乙基双(氧亚乙基次氮基)四乙酸
-EtOAc:乙酸乙酯
-ES:电喷雾
-MS:质谱
-IR:红外
-m.p.:熔点
-NMDA:N-甲基-D-天冬氨酸
-THF:四氢呋喃
-tlc:薄层层析法
-Tris:三(羟基甲基)氨基甲烷
1H-NMR:质子核磁共振
13C-NMR:碳-13核磁共振
Claims (15)
1.一种化合物,其特征为具有在3-位用仲丁基取代的部分还原的异喹啉结构和具有以下式I或II,
其中:
基团X一般地为氧(O)或硫(S),
星号(*)一般地表示构型(R)或(S)的立构中心,
基团R1独立地选自:
-NH2,
-NHR4,其中R4表示烷基、芳基、氨基酸衍生物或肽衍生物,
-NR5R6,其中R5和R6独立地选自烷基、芳基、氨基酸衍生物、肽衍生物,并且基团R5和R6形成环状系统,
-OH,
-OR7,其中R7表示烷基或芳基;
基团R2和R3为相同或不同的并且独立地选自基团O(氧)、NH或NR8,其中R8表示烷基或芳基,
Z选自
具有2-8个碳原子的烷基,
芳基,
芳基烷基,
独立地包含1-3个氧原子和2-10个碳原子的烷氧基链,
衍生于氨基酸或肽的片断。
2.权利要求1的化合物,其特征为选自:
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(7),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(8),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸异丙基酯(9),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸1-丁基酯(10),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸苄基酯(11),
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-烯基酯(12),
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-炔基酯(13),
(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(S,S,S,S,Z,Z)-4-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-苄基酯(14),
(S,S,Z)-N-苄基-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(15),
(S,S,Z)-N-(3-乙酰基-苯基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(16),
(S,S,Z)-N-(2’-氨基-联苯-2-基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(17),
(S,S,S,S,Z,Z)-2,2’-双-[(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]联苯(18),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-甲基-丙基)-氨基甲酸(S,S,S,Z)-9H-芴-9-基甲基酯(19),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-苯基-乙基)-氨基甲酸(S,S,S,Z)-9H-芴-9-基甲基酯(20),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-甲基-丁基)-氨基甲酸(S,S,S,S,Z)-9H-芴-9-基甲基酯(21),
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-丁酰胺(22),
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-苯基-丙酰胺(23),
(S,S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-戊酰胺(24),
(S,S,S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酸甲酯(25),
(S,S,S,S,S,S,S,S,Z)-2-(2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酰氨基)-3-甲基-戊酸甲酯(26),
(S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-丁酰氨基}-3-苯基-丙酸甲酯(27),
(S,S,Z)-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(28),
(S,S,Z)-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(29),
和
(S,S,S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酸甲酯(30),
和任何它们的异构体。
3.一种合成权利要求1的式I或II化合物的方法,其特征为将作为(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸的任何异构体的中间体化合物转化为酰胺或酯。
4.一种合成权利要求1的式I或II化合物的方法,其特征为将作为乙酸(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-甲基酯的任何异构体的中间体化合物通过水解转化。
5.一种合成权利要求1的式I或II化合物的方法,其特征为将作为4-(2-碘代苯甲酰氨基)-5-甲基-2-庚烯酸甲酯的任何异构体的中间体化合物转化为异喹啉衍生物。
6.一种化合物,所述化合物为4-(2-碘代苯甲酰氨基)-5-甲基-2-庚烯酸甲酯的任何异构体。
7.一种合成权利要求1的式I或II化合物的方法,其特征为将作为N-[(1-羟基甲基-2-甲基)-丁基]-2-碘代-苯甲酰胺的任何异构体的中间体化合物转化为α,β-不饱和酯。
8.一种化合物,所述化合物为N-[(1-羟基甲基-2-甲基)-丁基]-2-碘代-苯甲酰胺的任何异构体。
9.一种合成权利要求1的式I或II化合物的方法,其特征为将作为2-(2-碘代苯甲酰氨基)-3-甲基-戊酸甲酯的任何异构体的中间体化合物还原为醇。
10.一种化合物,所述化合物为2-(2-碘代苯甲酰氨基)-3-甲基-戊酸甲酯的任何异构体。
11.权利要求1的化合物作为钙蛋白酶抑制剂的用途,其特征为所述化合物具有在3-位用仲丁基取代的部分还原的异喹啉结构和具有以下式I或II,
其中:
基团X一般地为氧(O)或硫(S),
星号(*)一般地表示构型(R)或(S)的立构中心,
基团R1独立地选自:
-NH2,
-NHR4,其中R4表示烷基、芳基、氨基酸衍生物或肽衍生物,
-NR5R6,其中R5和R6独立地选自烷基、芳基、氨基酸衍生物、肽衍生物,并且基团R5和R6形成环状系统,
-OH,
-OR7,其中R7表示烷基或芳基;
基团R2和R3为相同或不同的并且独立地选自基团O(氧)、NH或NR8,其中R8表示烷基或芳基,
Z选自
具有2-8个碳原子的烷基,
芳基,
芳基烷基,
独立地包含1-3个氧原子和2-10个碳原子的烷氧基链,
衍生于氨基酸或肽的片断。
12.权利要求11的化合物作为钙蛋白酶抑制剂的用途,其特征为所述化合物具有式I或II并且选自:
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(7),
(S,S,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸苄基酯(11),
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-烯基酯(12),
4-[2-3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-乙酸(S,S,S,S,Z,Z)-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-丁-2-炔基酯(13),
(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸(S,S,S,S,Z,Z)-4-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氧基]-苄基酯(14),
(S,S,Z)-N-苄基-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(15),
(S,S,Z)-N-(3-乙酰基-苯基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(16),
(S,S,Z)-N-(2’-氨基-联苯-2-基)-2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰胺(17),
(S,S,S,S,Z,Z)-2,2’-双-[(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]联苯(18),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-甲基-丙基)-氨基甲酸(S,S,S,Z)-9H-芴-9-基甲基酯(19),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-苯基-乙基)-氨基甲酸(S,S,S,Z)-9H-芴-9-基甲基酯(20),
(1-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基氨基甲酰基}-2-甲基-丁基)-氨基甲酸(S,S,S,S,Z)-9H-芴-9-基甲基酯(21),
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-丁酰胺(22),
(S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-苯基-丙酰胺(23),
(S,S,S,S,Z)-2-氨基-N-{2’-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-联苯-2-基}-3-甲基-戊酰胺(24),
(S,S,S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酸甲酯(25),
(S,S,S,S,S,S,S,S,Z)-2-(2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-戊酰氨基}-3-甲基-戊酰氨基)-3-甲基-戊酸甲酯(26),
(S,S,S,S,Z)-2-{2-[2-(3-仲丁基-1-氧代-2,3-二氢-1H-异喹啉-4-亚基)-乙酰氨基]-3-甲基-丁酰氨基}-3-苯基-丙酸甲酯(27),
和
(S,S,Z)-(3-仲丁基-1-硫代-2,3-二氢-1H-异喹啉-4-亚基)-乙酸甲酯(28)。
13.权利要求11和12的具有式I或II的钙蛋白酶抑制剂化合物用于制备用于预防或治疗变性疾病的药物的用途。
14.权利要求13的具有式I或II的钙蛋白酶抑制剂化合物的用途,其中变性疾病为脑局部缺血、心脏局部缺血、脑发作、阿尔茨海默病、帕金森病、亨廷顿病、肌肉萎缩症、白内障和脱髓鞘病。
15.权利要求14的具有式I或II的钙蛋白酶抑制剂化合物的用途,其中脱髓鞘变性疾病为多发性硬化。
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ESP200402995 | 2004-12-16 | ||
ES200402995A ES2255848B1 (es) | 2004-12-16 | 2004-12-16 | Derivados de isoquinolina como inhibidores de calpaina. |
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EP (1) | EP1829864A4 (zh) |
JP (1) | JP2008524170A (zh) |
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ES2531621T3 (es) * | 2005-07-22 | 2015-03-18 | Mochida Pharmaceutical Co., Ltd. | Derivado de heterociclidenacetamida novedoso |
PE20081692A1 (es) | 2007-01-24 | 2008-12-18 | Mochida Pharm Co Ltd | Nuevo derivado de heterocicliden acetamida |
WO2012018638A2 (en) | 2010-07-26 | 2012-02-09 | Biomatrica, Inc. | Compositions for stabilizing dna, rna and proteins in blood and other biological samples during shipping and storage at ambient temperatures |
US9845489B2 (en) | 2010-07-26 | 2017-12-19 | Biomatrica, Inc. | Compositions for stabilizing DNA, RNA and proteins in saliva and other biological samples during shipping and storage at ambient temperatures |
EP2934572A4 (en) | 2012-12-20 | 2016-11-23 | Biomatrica Inc | FORMULATIONS AND METHODS FOR STABILIZING PCR REAGENTS |
EP3632208A1 (en) | 2013-06-13 | 2020-04-08 | Biomatrica, INC. | Cell stabilization |
EP3154338B1 (en) | 2014-06-10 | 2020-01-29 | Biomatrica, INC. | Stabilization of thrombocytes at ambient temperatures |
EP4242628A3 (en) | 2015-12-08 | 2023-11-08 | Biomatrica, INC. | Reduction of erythrocyte sedimentation rate |
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US5470978A (en) * | 1992-11-18 | 1995-11-28 | Eli Lilly And Company | Process and intermediates for the preparation of excitatory amino acid receptor antagonists |
US5541290A (en) * | 1993-06-24 | 1996-07-30 | Harbeson; Scott L. | Optically pure calpain inhibitor compounds |
EP0840614A1 (en) | 1995-06-13 | 1998-05-13 | Sanofi Winthrop, Inc. | Calpain inhibitors for the treatment of neurodegenerative diseases |
RU2190599C2 (ru) * | 1996-12-11 | 2002-10-10 | Басф Акциенгезельшафт | Новые кетобензамиды |
ES2219187B1 (es) | 2003-05-14 | 2006-02-16 | Consejo Sup. Investig. Cientificas | Inhibidores de calpaina. |
ES2243131B1 (es) | 2004-05-07 | 2007-02-01 | Consejo Sup. Investig. Cientificas | Tiamidas derivadas de bifenilo como inhibidores de calpaina. |
-
2004
- 2004-12-16 ES ES200402995A patent/ES2255848B1/es not_active Withdrawn - After Issue
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2005
- 2005-12-05 CN CNA2005800481674A patent/CN101128433A/zh active Pending
- 2005-12-05 EP EP05825225A patent/EP1829864A4/en not_active Withdrawn
- 2005-12-05 US US11/793,011 patent/US7932266B2/en not_active Expired - Fee Related
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US20080090862A1 (en) | 2008-04-17 |
WO2006064075A1 (es) | 2006-06-22 |
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ES2255848B1 (es) | 2007-07-01 |
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EP1829864A1 (en) | 2007-09-05 |
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