CN114053292A - 烟酰胺核苷芳甲酸酯类化合物及其组合物的用途以及化合物晶型 - Google Patents
烟酰胺核苷芳甲酸酯类化合物及其组合物的用途以及化合物晶型 Download PDFInfo
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- CN114053292A CN114053292A CN202010764469.8A CN202010764469A CN114053292A CN 114053292 A CN114053292 A CN 114053292A CN 202010764469 A CN202010764469 A CN 202010764469A CN 114053292 A CN114053292 A CN 114053292A
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- nicotinamide riboside
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- -1 Nicotinamide nucleoside aryl formate compound Chemical class 0.000 title claims abstract description 22
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Abstract
烟酰胺核苷三芳甲酸酯类化合物及其组合物用于提高人体内辅酶I(NAD)水平，改善健康状况或治疗相关疾病的用途，以及晶体形式的式(II‑1)化合物。所述烟酰胺核苷三芳甲酸酯类化合物的结构如式(I)所示。作为NAD的合成前体，与烟酰胺核苷比较，所述烟酰胺核苷三芳甲酸酯类化合物不但能有效地提高人体内NAD的水平，而且其制备更容易，成本显著降低，具有显著工业化应用优势。
Description
技术领域
本发明涉及烟酰胺核苷芳甲酸酯类化合物及其组合物在提高人体内辅酶I(NAD)水平的食品补充剂或治疗与辅酶I水平相关疾病的药物中的用途，
背景技术
辅酶I(NAD)，化学名为烟酰胺腺嘌呤二核甘酸或二磷酸烟苷，在哺乳动物体内存在氧化型(NAD+)和还原型(NADH)两种状态，是人体氧化还原反应中重要的辅酶。同时，它是辅酶I消耗酶(如NAD+依赖型ADP核糖基转移酶)的唯一底物，这类酶能利于辅酶I(NAD+)为底物分解成ADP核糖和烟酰胺(Nam)，在不同细胞中发挥不同生理功能。这类酶在体内主要有三种(Dolle，C.，et al.FEBS J，2013.280，3530；Garten，A.，et al.Trends EndocrinolMetab，2009，20，130)：
(1)ADP核糖基转移酶或聚核糖基聚合酶(PARP)：这类酶参与DNA修复、基因表达、细胞周期进展、细胞存活、染色体重建和基因稳定性等；
(2)环ADP核糖合成酶(cADPR synthases)环核糖聚合酶(cADP合酶)：它是由一对细胞外酶组成，称为淋巴细胞抗原CD38和CD157，它们以NAD为底物生成环ADP核糖(重要的钙信号(calcium signaling)信使)，在钙稳态维持方面和免疫应答方面具有重要生理意义；
(3)III蛋白型赖氨酸去乙酰化酶Sirtuins：它们是一类组蛋白去乙酰化酶，有7种不同的亚型(SIRT1-SIRT7)，在细胞抗逆性、能量代谢、细胞凋亡和衰老过程中具有重要作用。大量研究表明Sirtuins对代谢平衡的调节将直接影响到与代谢相关的各种疾病，如SIRT1在利于辅酶I(NAD)的参与下调节组蛋白的乙酰化状态，对增强心脏耐受氧化应激反应、调节心肌能量代谢及抗衰老等起着重要作用。
在健康状态下，哺乳动物体内辅酶I(NAD)浓度稳定，维持各项细胞正常功能。体内的辅酶I(NAD)浓度决定了细胞衰老的过程和程度，浓度下降会加速了细胞衰老过程(Imai，S.Cell Biochem Biophys，2009，53，65)。随着年龄增加，NAD水平显著降低，发生自然衰老过程，同时，与年老相关的疾病相继发生。
NAD水平与肝癌(Cancer Cell 2014，26，826)、糖尿病(Scientific Reports2016，6，26933)、艾滋病(Clinical Infectious Diseases 2003，36，453)、乙型肝炎(ArchVirol.2015，2712)、肌肉萎缩症(Amyotrophic Lateral Sclerosis and FrontotemporalDegeneration，2019；0∶1)、肥胖(Am.J.Clin.Nutr.2018，108，343)、帕金森病(CellReports 2018，23，2976)、心力衰竭(Circulation.2018，137，2256)、代谢疾病(J.Biomedical Science 2019，26，34)、衰老(GeroScience 2019，41，419)、阿兹海默症(PNAS，2018，E1876)、高血压(Nature Communications 2018，9，1286)等的治疗有关。
通过补充体内NAD或其合成前体烟酰胺单核酸(NMN)或烟酰胺核苷(NR)，可以提高体内NAD水平，使机体年轻化，减少老年疾病的发生或降低疾病发生的程度。烟酰胺核苷氯化物经过安全评价(Human and Experimental Toxicology，2016，1-12)和一定的临床试验(Nature Communications 2016，7，12948)，广泛用作NAD补充剂，而烟酰胺核酸也被大量使用，但是，安全评估较少。
根据专利文献CN106715455A中的报道，尽管NR似乎是NAD的天然前体，但由于在膳食来源中明显缺乏NR，其可能仅代表了少量(如果有的话)的NAD生物合成。NR含有高能糖苷键，其在水溶液中自发不稳定，产生烟酰胺和核糖分解产物。这种自发反应根据具体的环境条件以数小时或数天的过程发生，但它使得难以在食物来源中保持任何天然存在的NR。NR可能很难从天然来源分离，因此通常是通过化学合成产生。由Todd及其同事制备的NR氯化物为糖苷键α和β端基差向异构体(约1∶4的比例)的混合物。NR氯化物为吸湿性的无定形物。烟酰胺核苷生物利用度可能受到不同给药方式条件的限制。因此，需要具有改善的生物利用度和最佳的组织选择性的烟酰胺核苷类似物。需要生物可利用的、稳定和在所需的组织中对NAD提高是有效的NAD增强剂。
CN106715455A中制备了烟酰胺核苷苯甲酸酯OTf，而这种三氟甲磺酸酯可能有基因毒性。CN106715455A中将烟酰胺核苷苯甲酸酯OTf作为中间体用于制备氢化烟酰胺核苷苯甲酸酯。该专利文献中的生物试验结果表明，烟酰胺核苷的脂肪酸酯或其氢化物在大鼠血浆中孵化30分钟后，都能基本完全地释放出游离的烟酰胺核苷。相反，氢化烟酰胺核苷三苯甲酸酯在大鼠血浆中孵化30分钟后，没有释放出游离烟酰胺核苷。动物实验结果也表明，烟酰胺核苷的脂肪酸酯氢化物分别给小鼠灌胃2小时和6小时后，都能大幅度提高烟酰胺核苷的水平，例如，氢化烟酰胺核苷三正丁酸酯在给药2小时后，小鼠血浆中的烟酰胺核苷浓度达到39800，而氢化烟酰胺核苷三苯甲酸酯给药2小时后，小鼠血浆中的烟酰胺核苷浓度只有7000，相当于脂肪酸酯衍生物产生的烟酰胺核苷量的17％。因此，专利文献CN106715455中的试验结果表明氢化烟酰胺核苷三苯甲酸酯没有作为体内烟酰胺核苷或者辅酶I(NAD)的合成前体的应用价值。
Gamboa Landa等披露了烟酰胺核苷氯化物的制备方法，由烟酰胺核苷三苯甲酸酯氯化物作为中间体合成烟酰胺核苷氯化物，收率低，为57％(WO2019122084A1)，而且反应需要在-32C进行96小时，条件十分苛刻，一般工业条件难以实现。专利文献WO 2019/006262A1中公开了核糖四乙酸酯(Riboside Acetate)制备NR的二步收率仅为27％。因此，NR的生产成本高。
美国专利文献US 9877981中公开了由核糖脂肪酸酯中间体(IM-1)转化为1-氯化物中间体(IM-2)后与烟酰胺反应生成烟酰胺核苷三乙酸酯(IM-3)，所得α、β差向异构体比例为4∶6，立体选择性较差。而IM-1直接与烟酰胺缩合后再脱保护基得到的NR含有13％的α差向异构体副产物(Beilstein J.Org.Chem.2019，15，401)。α差向异构体副产物需要经过活性炭柱层析分离纯化，纯化、后处理复杂，不适合工业化生产。专利文献CN106715455中公开的核苷脂肪酸酯与烟酰胺反应生成的产物基本是油状物(泡沫状物)，其中的副产物α-异构体都不能通过简单方法，如重结晶方法除去。因此，这类化合物不易进行工业化生产。
发明内容
鉴于此，一方面，提供式(I)所示的烟酰胺核苷三芳甲酸酯类化合物、或者含有所述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物和任选的食用或药用辅料的组合物在制备提高人体内辅酶I水平的食品补充剂或治疗与辅酶I水平相关疾病的药物中的用途，
式(I)中，各个Ar相同或不同，各自独立地表示任选被一个或多个取代基取代的芳基，所述各个Ar上的取代基各自独立地选自卤素、氰基、-R′、-OR′、-SR′、-NR′R″、-COR′、-CONR′R″、和-COOR′；
各个R′和R″各自独立地选自：氢、烷基或取代烷基、烯基或取代烯基、炔基或取代炔基、环烷基或取代环烷基、和芳基或取代芳基；所述烷基、烯基、炔基、环烷基、芳基上的取代基为一个或多个，各自独立地选自：卤素、氰基、烷基、和烷氧基；可选地，各个R′和R″各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、环丙基、环丁基、或环戊基、三氟甲基、氨基、或甲氧羰基；
X-为有机酸或无机酸的酸根负离子，可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、或碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、或双羟萘酸；可选地，X为卤素负离子。
可选地，所述式(I)化合物具有式(II)所示的结构，
其中，各个苯环上的R各自独立地为氢，或者与上述Ar上的取代基定义相同；可选地，各个苯环上的R的个数为1个、2个或3个，且各个R相同或不同；X-的定义与上述X-定义相同。
可选地，所述“卤素”选自氟、氯、溴、和碘。
可选地，所述“烷基”和“烷氧基”中的“烷基”各自独立地为C1-C20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、和正戊基。
可选地，所述“烯基”为直链或支链C2-C6烯基。
可选地，所述“炔基”为直链或支链C2-C6炔基。
可选地，所述“环烷基”为C3-C10单环或双环环烷基。
可选地，所述“芳基”为6-10元芳基；可选为苯基或萘基。
可选地，上述式(I)中，各个Ar相同或不同，各自独立地选自：
可选地，所述式(I)化合物为下式(II-1)所示的化合物，
可选地，所述式(II-1)所示的化合物为无定形形式或晶体形式。
可选地，所述式(II-1)所示化合物的无定形形式使用Cu-Ka，r＝1.54178A辐射时，具有如图1所示的粉末X射线衍射图谱。
可选地，所述式(II-1)所示化合物的晶体形式为晶型A或晶型B，所述晶型A使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(°)：7.51，11.93，15.14，15.91，22.02，23.43，24.09，25.39，26.51，26.93，29.00，29.27，29.70，30.66，32.62，34.37和38.62处有特征峰，可选地，具有如图2所示的衍射图谱。
所述晶型B使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(°)：6.47，9.00，12.90，20.00，22.10，23.50，24.19，25.49，25.91，26.59和30.76处有特征峰，可选地，具有如图3所示的衍射图谱。
可选地，所述食品补充剂或药物的剂型为口服制剂，可选地，所述口服制剂为固体制剂，可选地，所述固体制剂包括片剂、粉剂、粒剂、胶囊。
可选地，所述口服制剂处于溶液或分散液状态时pH值为中性或酸性，可选的，pH值为1-7，可选地pH值为4-7。
可选地，所述与辅酶I水平相关疾病包括：肝癌、糖尿病、艾滋病、乙型肝炎、肌肉萎缩症、肥胖、帕金森病、心力衰竭、代谢疾病、衰老、阿兹海默症、高血压等。动物实验在证明，服用补充剂提高NAD水平有治疗或改善这些疾病的效果。
另一方面，提供无定形、晶型A或晶型B形式的式(II-1)所示的化合物，
所述无定形形式使用Cu-Ka，r＝1.54178A辐射时，具有如图1所示的粉末X射线衍射图谱；所述晶型A使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(°)：7.51，11.93，15.14，15.91，22.02，23.43，24.09，25.39，26.51，26.93，29.00，29.27，29.70，30.66，32.62，34.37和38.62处有特征峰，可选地，具有如图2所示的衍射图谱；所述晶型B使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(°)：6.47，9.00，12.90，20.00，22.10，23.50，24.19，25.49，25.91，26.59和30.76处有特征峰，可选地，具有如图3所示的衍射图谱。
所述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物可以通过以下合成路线制备。
其中Ar和X-的定义如上所述。
另一方面，还提供一种食用或药用组合物，所述组合物含有上述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物和任选的食用或药用辅料。
另一方面，所述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物或其组合物可以单独使用或者与一种或多种其它食物补充剂或药物联用，这些食物补充剂包括白藜芦醇(Resveratrol)和/或紫檀芪(pterostilbene)。
SIRT1是一种NAD+(烟酰胺腺苷二核苷酸)依赖的脱乙酰化酶。它主要通过对多种非组蛋白和组蛋白的去乙酰化作用，参与多种细胞生物学功能。白藜芦醇(Resveratrol)是一种多酚类天然产物，被发现有多种生理益处，是一种SIRT1激动剂(Curr.Med.Chem.19，1663-1681(2012).)。紫檀芪(pterostilbene)是白藜芦醇的天然类似物，除了具有显著的抗氧化作用外，也是SIRT1激动剂。因为它的两个羟基的甲基化，大大提高了它的亲脂性和生物利用度。考虑到NR提高NAD水平，有利于所有7种Sirtuins，加上白藜芦醇和紫檀芪作为Sirt1的激动剂，预期NR与白藜芦醇和/或紫檀芪的联合使用产生协同作用。联合用药的临床试验取得了预想的效果(npj Aging and Mechanism of Disease 2017，0，17)。
所述组合物中所含的食用或药用辅料为本领域的常规辅料。
另一方面，还提供提高人体内辅酶I水平或治疗与辅酶I水平相关疾病的方法，包括向需要的人给予提高人体内辅酶I水平或治疗与辅酶I水平相关疾病有效量的式(I)所示的烟酰胺核苷三芳甲酸酯类化合物、或者含有所述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物和任选的食用或药用辅料的组合物。
有益效果
所述烟酰胺核苷三芳甲酸酯类化合物能在体内有效地释放烟酰胺核苷，大幅提高NAD平均水平。例如，小鼠灌胃式(II-1)化合物后24小时内，NAD平均水平较空白对照提高了80％，最高达到2.1倍(见下表4)。因此，所述烟酰胺核苷三芳甲酸酯类化合物可以作为新的NAD合成的前体，作为食品补充剂或治疗NAD水平相关疾病的药物，用于提高体内的NAD水平，改善人类健康状况，或治疗因NAD降低引起的疾病。
烟酰胺核苷三芳甲酸酯类化合物的合成中β差向异构体的立体选择性近100％，简单重结晶就能得到高纯度(97％)的目标产物，并且收率高。例如，由三苯甲酰基-1-乙酯在SnCl4催化下生产烟酰胺核苷三苯甲酸酯氯化物，收率87％(WO2019/122084A1)，相比WO2019/006262中公开的NR，化合物II-1的生产成本较NR的显著降低，更适合工业上规模化应用。
附图说明
图1：化合物II-1无定形的XRPD图谱。
图2：化合物II-1晶型A的XRPD图谱。
图3：化合物II-1晶型B的XRPD图谱。
具体实施方式
以下通过具体实施方式对本发明作进一步的详细描述。应当理解的是，此处所描述的具体实施方式仅用于示例性地对本发明进行说明，并不用于限制本发明的范围。
实施例1化合物的制备
1、制备无定形形式的化合物II-1：
将D-核糖1(5g，33.3mmol)加入甲醇(30mL)，在氮气保护下，0℃下滴加0.5mL浓硫酸，然后室温反应过夜，加入碳酸钠固体调pH至7～8，过滤，滤液旋干，得到6.3g淡黄色油状物化合物2，直接用于下一步反应。
将上述所得化合物2溶于吡啶(40mL)，在氮气保护下，0℃下滴加苯甲酰氯(24mL)，滴加完毕升至室温反应过夜，旋蒸除去大量吡啶，用DCM溶解，1.5mol/L的硫酸溶液调pH至5～6，分液，有机相分别用水洗，饱和碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，得到化合物3粗品，直接用于下一步反应。
将化合物3中加入冰醋酸(50mL)，乙酸酐(15mL)，在氮气保护下，0℃下滴加浓硫酸(0.5mL)，室温反应过夜，加入冰水(200mL)搅拌，有大量固体析出，过滤，用乙醇重结晶两次得到白色固体4(5g，30％)。1H NMR(400MHz，CDCl3)δ8.11-8.05(m，2H)，8.04-7.97(m，2H)，7.93-7.84(m，2H)，7.68-7.49(m，3H)，7.42(q，J＝8.1Hz，4H)，7.33(t，J＝7.8Hz，2H)，6.43(s，1H)，5.91(dd，J＝6.7，5.0Hz，1H)，5.79(d，J＝4.9Hz，1H)，4.78(dt，J＝9.0，3.4Hz，2H)，4.52(dd，J＝8.1，5.1Hz，1H)，2.00(s，3H)。
将化合物4(5.04g，10mmol，1.0eq)和烟酰胺5(1.83g，15mmol，1.5eq)加入乙腈(30mL)，将SnCl4(5.21g，20mmol，2.0eq)溶于DCM(20mL)中，氮气在保护下，0℃下滴加至反应体系中，滴加完毕后升至室温反应过夜，0℃下滴加饱和碳酸氢钠溶液淬灭反应，调pH至5～6，硅藻土过滤，滤饼用DCM洗，滤液萃取，有机相用饱和食盐水洗2次，无水硫酸钠干燥，过滤，浓缩，然后加入DCM(10mL)溶解，室温下滴加MTBE(50mL)，有粘稠物析出，打浆2h，变为白色粉末状固体，过滤，滤饼用MTBE洗，固体然后再用DCM∶MTBE＝1∶3重结晶，得到白色固体化合物II-1(5.03g，83％)。HPLC分析表明为单一β-构型产物，H-NMR图谱也证明为单一β-构型产物。1H NMR(400MHz，DMSO)δ9.75(s，1H)，9.47(d，J＝6.2Hz，1H)，9.14(d，J＝8.0Hz，1H)，8.82(s，1H)，8.41-8.30(m，1H)，8.21(s，1H)，7.97(dd，J＝29.6，7.4Hz，6H)，7.69(dt，J＝8.6，4.3Hz，3H)，7.51(dt，J＝16.8，6.3Hz，6H)，7.04(d，J＝3.5Hz，1H)，6.12(dd，J＝5.6，3.8Hz，1H)，6.03(t，J＝5.9Hz，1H)，5.18(dd，J＝9.1，4.8Hz，1H)，4.91(qd，J＝12.6，4.2Hz，2H).；m/z(ESI)[M-Cl+H]+＝567.3。
上述所得固体为无定形，使用Cu-Ka辐射，r＝1.54178A，化合物II-1的粉末X射线衍射图如图1所示。
2、制备晶型A形式的化合物II-1
(1)称取适量的无定形原料，溶解于甲醇、水或者氯仿中配置室温下饱和溶液，37℃搅拌48h，缓慢挥去溶剂，得到类白色固体晶型A。
(2)称取20mg无定形原料药，加入二元溶剂2ml(乙醇∶环己烷＝1∶4)，震荡48h，挥去溶剂，得到类白色固体晶型A。
(3)称取20mg无定形原料药，加入二元溶剂2ml(乙醇∶4-甲基-2-戊酮＝1∶4)，震荡48h，挥去溶剂，得到类白色固体晶型A。
(4)称取20mg无定形原料药，加入二元溶剂2ml(乙腈∶环己烷＝1∶4)，震荡48h，挥去溶剂，得到类白色固体晶型A。
使用Cu-Ka辐射，r＝1.54178A，化合物II-1的晶型A的X射线衍射图如图2所示。
晶型A的XRPD衍射峰数据如表1所示。
表1
| 2-Theta | d | I％ |
| 7.51 | 11.7619 | 14.2 |
| 11.927 | 7.4139 | 16.8 |
| 15.139 | 5.8476 | 32.6 |
| 15.914 | 5.5645 | 41.8 |
| 22.02 | 4.0333 | 75 |
| 23.433 | 3.7932 | 20.4 |
| 24.09 | 3.6911 | 100 |
| 25.392 | 3.5049 | 54.8 |
| 26.506 | 3.3599 | 90.5 |
| 26.929 | 3.3082 | 57.4 |
| 28.999 | 3.0765 | 25 |
| 29.266 | 3.049 | 52.5 |
| 29.701 | 3.0054 | 57.2 |
| 30.659 | 2.9137 | 51 |
| 32.616 | 2.7432 | 17.3 |
| 34.368 | 2.6072 | 15.1 |
| 38.621 | 2.3293 | 30 |
3、制备晶型B形式的化合物II-1
称取约50mg的无定形原料，加入2ml正丙醇或异丙醇，37℃震荡48h，缓慢挥去溶剂，得到类白色固体晶型B。
使用Cu-Ka辐射，r＝1.54178A，化合物II-1的晶型B的X射线衍射图如图3所示。
晶型B的XRPD衍射峰数据如表2所示。
表2
4、制备其他烟酰胺核苷三芳甲酸酯类化合物
参照化合物II-1的制备方法，制备下列化合物。
中间体2与选定的取代苯甲酰氯反应生成中间体a，进而转化成中间体b，其在SnCl4催化下与烟酰胺5缩合生成相应的目标衍生物I如下表(其中X-是Cl-)：
表3
实施例2药代动力学试验
1、制剂配制和剂量给药：将适量的供试品精确称重，并与适当体积的水混合，获得清晰的溶液或均匀的悬浮液。在制备制剂后4小时内给动物大鼠给药。剂量制剂按照设施标准操作规程通过口服管饲进行给药。剂量体积将由给药当天早上收集的动物体重决定。
2、肝脏处理：每个时间点采集肝组织，用预冷去离子水洗两次，滤纸吸干水分。肝组织立即采用10倍体积的甲醇-水溶液(1∶2，v/v)匀浆，匀浆完立即取一分部肝组织匀浆液(如200uL匀浆液)用于分析，在湿冰上沉淀样品之后，离心取上清，于-70±10℃冰箱贮存，直至LC-MS/MS分析。剩余肝匀浆液取800uL作为备用。
大鼠分别灌胃服用化合物II-1(给药剂量均为0.636mmol/kg，383.5mg/kg)和NR(185mg/kg，0.636mmol/kg)，分别在0.25、0.5、1、2、4、8、12、15，19，24h时间点取得大鼠肝脏样品，按照上述方法，用LC-MS/MS测试，分别测定上述化合物的体内NAD在肝脏中的浓度(见表4)。
表4.大鼠灌胃化合物II-1(0.636mmol/kg)后肝脏NAD的参数
大鼠灌胃化合物II-1后在24小时内，NAD水平较空白对照组平均提高了80％。最大值是对照组的2.1倍。与NR产生的总NAD相当。但是，NR产生NAD的峰值更高，其余时间较低，而化合物II-1的NAD增加更平稳。因此，化合物II-1完全可以作为新的体内NAD合成的前体，作为食品补充剂或治疗相关疾病的药物，用于提高体内的NAD水平，改善人类健康状况，或治疗因NAD降低引起的疾病。化合物II-1制备更简便，成本显著降低，具有明显的实用优势。
实施例3化合物II-1稳定性试验
化合物II-1在pH＝1的盐酸水溶液中，1h内基本没变，5h后有10％分解，过夜后有30％分解，两天后有48％分解。
化合物II-1在pH＝7的水溶液中，刚配好未分解，5h后有4％分解，过夜后有19％分解，两天后有36％分解
化合物II-1在pH＝8的饱和碳酸氢钠溶液中，配好后检测完全分解。
因此，化合物II-1只能在固体状态下保存。制剂制备时的pH控制在中性或偏酸性(pH1-7)，优选pH4-7。
实施例4联合应用
1.紫檀芪和化合物II-1联合组成：
紫檀芪 化合物II-1
25mg-50mg 250mg-500mg
50mg-100mg 500mg-1500mg
2.口服制剂的制备：
根据设定的紫檀芪和化合物II-1的用量，加上适量辅料，按照制剂工艺规程制备得到设定的制剂供临床使用。
Claims (10)
1.式(I)所示的烟酰胺核苷三芳甲酸酯类化合物、或者含有所述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物和任选的食用或药用辅料的组合物在制备提高人体内辅酶I水平的食品补充剂或治疗与辅酶I水平相关疾病的药物中的用途，
式(I)中，各个Ar相同或不同，各自独立地表示任选被一个或多个取代基取代的芳基，所述各个Ar上的取代基各自独立地选自卤素、氰基、-R′、-OR′、-SR′、-NR′R″、-COR′、-CONR′R″、和-COOR′；
各个R′和R″各自独立地选自：氢、烷基或取代烷基、烯基或取代烯基、炔基或取代炔基、环烷基或取代环烷基、和芳基或取代芳基；所述烷基、烯基、炔基、环烷基、芳基上的取代基为一个或多个，各自独立地选自：卤素、氰基、烷基、和烷氧基；可选地，各个R′和R″各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、环丙基、环丁基、或环戊基、三氟甲基、氨基、或甲氧羰基；
X-为有机酸或无机酸的酸根负离子，可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、或碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、或双羟萘酸；可选地，X为卤素负离子。
2.根据权利要求1所述的用途，其中所述式(I)化合物具有式(II)所示的结构，
其中，各个苯环上的R各自独立地为氢，或者与权利要求1中Ar上的取代基定义相同；可选地，各个苯环上的R的个数为1个、2个或3个，且各个R相同或不同；X-的定义与权利要求1中的X-定义相同。
3.根据权利要求1或2所述的用途，其中，所述“卤素”选自氟、氯、溴、和碘；
可选地，所述“烷基”和“烷氧基”中的“烷基”各自独立地为C1-C20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、和正戊基；
可选地，所述“烯基”为直链或支链C2-C6烯基；
可选地，所述“炔基”为直链或支链C2-C6炔基；
可选地，所述“环烷基”为C3-C10单环或双环环烷基；
可选地，所述“芳基”为6-10元芳基；可选为苯基或萘基。
4.根据权利要求1所述的用途，其中各个Ar相同或不同，各自独立地选自：
5.根据权利要求1所述的用途，其中，所述式(I)化合物为下式(II-1)所示的化合物，
6.根据权利要求5所述的用途，其中，所述式(II-1)所示的化合物为无定形形式或晶体形式；可选地，所述式(II-1)所示化合物的无定形形式使用Cu-Ka，r＝1.54178A辐射时，具有如图1所示的粉末X射线衍射图谱；可选地，所述式(II-1)所示化合物的晶体形式为晶型A或晶型B，所述晶型A使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(°)：7.51，11.93，15.14，15.91，22.02，23.43，24.09，25.39，26.51，26.93，29.00，29.27，29.70，30.66，32.62，34.37和38.62处有特征峰，可选地，具有如图2所示的衍射图谱；所述晶型B使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(。)：6.47，9.00，12.90，20.00，22.10，23.50，24.19，25.49，25.91，26.59和30.76处有特征峰，可选地，具有如图3所示的衍射图谱。
7.根据权利要求1-6任一项所述的用途，其中所述食品补充剂或药物的剂型为口服制剂，可选地，所述口服制剂为固体制剂，可选地，所述固体制剂包括片剂、粉剂、粒剂、胶囊；可选地，所述口服制剂处于溶液或分散液状态时pH值为中性或酸性，可选的，pH值为1-7，可选地pH值为4-7。
8.根据权利要求1-7任一项所述的用途，其中所述与辅酶I水平相关疾病包括：肝癌、糖尿病、艾滋病、乙型肝炎、肌肉萎缩症、肥胖、帕金森病、心力衰竭、代谢疾病、衰老、阿兹海默症、或高血压。
9.根据权利要求1-8任一项所述的用途，其中所述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物、或者含有所述式(I)所示的烟酰胺核苷三芳甲酸酯类化合物和任选的食用或药用辅料的组合物与一种或多种其它食物补充剂或药物联合使用；可选地，与白藜芦醇和/或紫檀芪联用。
10.无定形、晶型A或晶型B形式的式(II-1)所示的化合物，
所述无定形形式使用Cu-Ka，r＝1.54178A辐射时，具有如图1所示的粉末X射线衍射图谱；所述晶型A使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(°)：7.51，11.93，15.14，15.91，22.02，23.43，24.09，25.39，26.51，26.93，29.00，29.27，29.70，30.66，32.62，34.37和38.62处有特征峰，可选地，具有如图2所示的衍射图谱；所述晶型B使用Cu-Ka，r＝1.54178A辐射时，其X-射线衍射(XRPD)在2θ(°)：6.47，9.00，12.90，20.00，22.10，23.50，24.19，25.49，25.91，26.59和30.76处有特征峰，可选地，具有如图3所示的衍射图谱。
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