WO2022022472A1 - 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 PDF

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WO2022022472A1
WO2022022472A1 PCT/CN2021/108490 CN2021108490W WO2022022472A1 WO 2022022472 A1 WO2022022472 A1 WO 2022022472A1 CN 2021108490 W CN2021108490 W CN 2021108490W WO 2022022472 A1 WO2022022472 A1 WO 2022022472A1
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高志玲
黄强
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高志玲
黄强
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Definitions

  • the present invention relates to the use of nicotinamide riboside aryl formate compounds and compositions thereof in food supplements for increasing the level of coenzyme I (NAD) in the human body or medicines for treating diseases related to the level of coenzyme I,
  • NAD coenzyme I
  • Coenzyme I the chemical name is nicotinamide adenine dinucleotide or nicotinic acid diphosphate, exists in two states of oxidized (NAD+) and reduced (NADH) in mammals, and is an important part of human redox reactions.
  • coenzyme At the same time, it is the only substrate for coenzyme I consuming enzymes (such as NAD+-dependent ADP ribosyltransferase), which can facilitate the decomposition of coenzyme I (NAD+) into ADP ribose and nicotinamide (Nam) as a substrate. perform different physiological functions in cells.
  • Cyclic ADP ribose synthase (cADPR synthases) cyclic ribose polymerase (cADP synthase): it is composed of a pair of extracellular enzymes, called lymphocyte antigens CD38 and CD157, which use NAD as a substrate to generate cyclic ADP Ribose, an important calcium signaling messenger, is physiologically important in calcium homeostasis maintenance and immune response;
  • SIRT1-SIRT7 histone deacetylases, with 7 different isoforms (SIRT1-SIRT7), which are involved in cell stress resistance, energy metabolism, cell apoptosis It plays an important role in the process of death and aging.
  • SIRT1 regulates the acetylation state of histones under the participation of coenzyme I (NAD), which is important for enhancing cardiac tolerance to oxidative stress. It plays an important role in regulating myocardial energy metabolism and anti-aging.
  • the concentration of coenzyme I (NAD) in mammals is stable and maintains the normal functions of various cells.
  • the concentration of coenzyme I (NAD) in the body determines the process and degree of cellular senescence, and a decrease in the concentration will accelerate the process of cellular senescence (Imai, S. Cell Biochem Biophys, 2009, 53, 65).
  • NAD levels decrease significantly, the natural aging process occurs, and at the same time, aging-related diseases occur one after another.
  • NAD levels and liver cancer (Cancer Cell 2014, 26, 826), diabetes (Scientific Reports 2016, 6, 26933), AIDS (Clinical Infectious Diseases 2003, 36, 453), hepatitis B (Arch Virol. 2015, 2712), muscular dystrophy (Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019; 0:1), obesity (Am.J.Clin.Nutr.2018,108,343), Parkinson’s disease (Cell Reports 2018,23,2976), heart failure (Circulation.2018,137, 2256), metabolic diseases (J.Biomedical Science 2019, 26, 34), aging (GeroScience 2019, 41, 419), Alzheimer’s disease (PNAS, 2018, E1876), hypertension (Nature Communications 2018, 9, 1286), etc. treatment related.
  • nicotinamide mononucleic acid NAD
  • NR nicotinamide riboside
  • the NAD level in the body can be increased, the body can be rejuvenated, and the occurrence of senile diseases or the degree of disease occurrence can be reduced.
  • Nicotinamide riboside chloride has been widely used as NAD supplement after safety evaluation (Human and Experimental Toxicology, 2016, 1-12) and certain clinical trials (Nature Communications 2016, 7, 12948), and nicotinamide nucleic acid is also widely used Use, however, less security assessments.
  • NR appears to be a natural precursor of NAD, it may represent only a small amount, if any, of NAD biosynthesis due to the apparent lack of NR in dietary sources.
  • NRs contain high-energy glycosidic bonds, which are spontaneously unstable in aqueous solutions, yielding nicotinamide and ribose breakdown products. This spontaneous reaction occurs over the course of hours or days depending on the specific environmental conditions, but it makes it difficult to maintain any naturally occurring NR in food sources.
  • NR can be difficult to isolate from natural sources, so it is usually produced by chemical synthesis.
  • NR chloride prepared by Todd and coworkers is a mixture of glycosidic linkage alpha and beta anomers (approximately 1:4 ratio).
  • NR chloride is a hygroscopic amorphous material.
  • the bioavailability of nicotinamide riboside may be limited by the conditions of different modes of administration. Therefore, there is a need for nicotinamide riboside analogs with improved bioavailability and optimal tissue selectivity. There is a need for NAD enhancers that are bioavailable, stable and effective for NAD elevation in desired tissues.
  • the nicotinamide riboside benzoate OTf was prepared in CN106715455A, and this triflate may be genotoxic.
  • nicotinamide riboside benzoate OTf is used as an intermediate for preparing hydrogenated nicotinamide riboside benzoate.
  • the biological test results in this patent document show that the fatty acid ester of nicotinamide riboside or its hydride can release free nicotinamide riboside substantially completely after incubation in rat plasma for 30 minutes.
  • hydrogenated nicotinamide riboside tribenzoate did not release free nicotinamide riboside after 30 min incubation in rat plasma.
  • mice The results of animal experiments also showed that the fatty acid ester hydride of nicotinamide riboside can significantly increase the level of nicotinamide riboside after 2 hours and 6 hours of gavage in mice, for example, hydrogenated nicotinamide riboside tri-normal
  • the plasma nicotinamide riboside concentration in mice reached 39800 2 hours after butyrate administration, while the nicotinamide riboside concentration in mice plasma 2 hours after hydrogenated nicotinamide riboside tribenzoate administration Only 7000, equivalent to 17% of the amount of nicotinamide riboside produced by fatty acid ester derivatives.
  • test results in the patent document CN106715455 indicate that hydrogenated nicotinamide riboside tribenzoate has no application value as a synthetic precursor of nicotinamide riboside or coenzyme I (NAD) in vivo.
  • Gamboa Landa et al. disclose the preparation method of nicotinamide riboside chloride, synthesizing nicotinamide riboside chloride from nicotinamide riboside tribenzoate chloride as an intermediate, and the yield is as low as 57% (WO2019122084A1), and The reaction needs to be carried out at -32 ⁇ C for 96 hours, and the conditions are very harsh, and it is difficult to achieve in general industrial conditions.
  • Patent document WO 2019/006262A1 discloses that the two-step yield of Riboside Acetate for preparing NR is only 27%. Therefore, the production cost of NR is high.
  • US Patent Document US 9877981 discloses that ribose fatty acid ester intermediate (IM-1) is converted into 1-chloride intermediate (IM-2) and then reacted with nicotinamide to generate nicotinamide riboside triacetate (IM- 3), the obtained ⁇ , ⁇ epimer ratio is 4:6, and the stereoselectivity is poor.
  • the NR obtained by directly condensing IM-1 with nicotinamide and then deprotecting it contains 13% ⁇ epimer by-product (Beilstein J.Org.Chem.2019,15,401).
  • the by-product of ⁇ epimer needs to be separated and purified by activated carbon column chromatography, and the purification and post-treatment are complicated and are not suitable for industrial production.
  • the product produced by the reaction of nucleoside fatty acid ester and nicotinamide disclosed in the patent document CN106715455 is basically an oily substance (foam), and none of the by-product ⁇ -isomers can be removed by simple methods, such as recrystallization. Therefore, such compounds are not easy to be industrially produced.
  • a nicotinamide riboside triarylcarboxylate compound represented by formula (I) or a nicotinamide riboside triarylcarboxylate compound represented by formula (I) and optional edible or
  • each Ar is the same or different, and each independently represents an aryl group optionally substituted by one or more substituents, and the substituents on each Ar are independently selected from halogen, cyano, -R ', -OR', -SR', -NR'R", -COR', -CONR'R", and -COOR';
  • Each R' and R" is independently selected from the group consisting of: hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, and aryl or substituted aryl
  • the substituents on the alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups are one or more, each independently selected from: halogen, cyano, alkyl, and alkoxy; optional
  • Each R' and R" is independently selected from the group consisting of: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl, sec-butyl, n-pentyl, cyclic propyl, cyclobutyl, or cyclopentyl, trifluoromethyl, amino, or methoxycarbonyl
  • X - is an acid anion of an organic acid or an inorganic acid
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid
  • the organic acid includes formic acid , ascorbic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, gluconic acid, tartaric acid, glucuronic acid , carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, p-bromobenzenesulfonic acid, glutamic acid, salicylic acid, or pamoic acid; optionally, X is a halogen
  • the compound of formula (I) has the structure shown in formula (II),
  • the R on each benzene ring is independently hydrogen, or the same as the definition of the substituent on Ar above; optionally, the number of R on each benzene ring is 1, 2 or 3, and each R is the same or different ;
  • X- is as defined above as X- .
  • the "halogen” is selected from fluorine, chlorine, bromine, and iodine.
  • the "alkyl” in the “alkyl” and “alkoxy” is each independently a C 1 -C 20 straight or branched chain alkyl, optionally, selected from: methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, and n-pentyl.
  • alkenyl is a straight or branched chain C2 - C6 alkenyl.
  • alkynyl is a straight or branched chain C2 - C6 alkynyl.
  • cycloalkyl is a C 3 -C 10 monocyclic or bicyclic cycloalkyl.
  • the "aryl” is a 6-10-membered aryl group; it can be a phenyl group or a naphthyl group.
  • each Ar is the same or different, and is independently selected from:
  • the compound of formula (I) is a compound represented by the following formula (II-1),
  • the compound represented by the formula (II-1) is in an amorphous form or a crystalline form.
  • the crystal form of the compound represented by the formula (II-1) is crystal form A or crystal form B.
  • XRPD X-ray diffraction
  • the dosage form of the food supplement or drug is an oral formulation
  • the oral formulation is a solid formulation
  • the solid formulation includes tablets, powders, granules, and capsules.
  • the pH value is neutral or acidic, optionally, the pH value is 1-7, and optionally the pH value is 4-7.
  • the diseases associated with coenzyme I level include: liver cancer, diabetes, AIDS, hepatitis B, muscular dystrophy, obesity, Parkinson's disease, heart failure, metabolic disease, aging, Alzheimer's disease, hypertension Wait. Animal experiments have shown that taking supplements to increase NAD levels has the effect of treating or improving these diseases.
  • the nicotinamide riboside triarylcarboxylate compound represented by the formula (I) can be prepared by the following synthetic route.
  • an edible or pharmaceutical composition which comprises the nicotinamide riboside triarylcarboxylate compound represented by the above formula (I) and optional edible or pharmaceutical excipients.
  • the nicotinamide riboside triarylcarboxylate compound represented by the formula (I) or its composition can be used alone or in combination with one or more other food supplements or drugs, and these food supplements include Resveratrol and/or pterostilbene.
  • SIRT1 is an NAD+ (nicotinamide adenosine dinucleotide)-dependent deacetylase. It participates in various cellular biological functions mainly through the deacetylation of various non-histone and histone proteins.
  • Resveratrol a polyphenolic natural product found to have various physiological benefits, is a SIRT1 agonist (Curr. Med. Chem. 19, 1663–1681 (2012).).
  • Pterostilbene a natural analogue of resveratrol, is also a SIRT1 agonist in addition to its significant antioxidant effects. Because of the methylation of its two hydroxyl groups, its lipophilicity and bioavailability are greatly improved.
  • the edible or pharmaceutical adjuvants contained in the composition are conventional adjuvants in the art.
  • a method for increasing the level of coenzyme I in a human body or treating a disease associated with the level of coenzyme I comprising administering to a person in need thereof an effective amount of formula (I) for increasing the level of coenzyme I in the human body or treating a disease associated with the level of coenzyme I
  • formula (I) for increasing the level of coenzyme I in the human body or treating a disease associated with the level of coenzyme I
  • the nicotinamide riboside triarylcarboxylate compound can effectively release nicotinamide riboside in the body and greatly increase the average level of NAD. For example, within 24 hours after gavage of the compound of formula (II-1) in mice, the average level of NAD increased by 80% compared with the blank control, and the highest was 2.1 times (see Table 4 below). Therefore, the nicotinamide riboside triarylcarboxylate compound can be used as a precursor for new NAD synthesis, as a food supplement or as a drug for treating NAD level-related diseases, for increasing the NAD level in the body, improving human health, or Treatment of diseases caused by reduced NAD.
  • nicotinamide riboside triarylcarboxylate compounds the stereoselectivity of beta epimer is nearly 100%, and the target product with high purity (97%) can be obtained by simple recrystallization, and the yield is high.
  • nicotinamide riboside tribenzoate chloride was produced from tribenzoyl-1-ethyl ester catalyzed by SnCl in 87% yield (WO2019/122084A1), compared to NR disclosed in WO 2019/006262 , the production cost of compound II-1 is significantly lower than that of NR, which is more suitable for industrial scale application.
  • Figure 1 XRPD pattern of Compound II-1 Amorphous.
  • D-ribose 1 (5 g, 33.3 mmol) was added to methanol (30 mL), under nitrogen protection, 0.5 mL of concentrated sulfuric acid was added dropwise at 0°C, and then reacted at room temperature overnight, sodium carbonate was added to adjust the pH to 7-8, filtered, The filtrate was spin-dried to obtain 6.3 g of compound 2 as a pale yellow oil, which was directly used in the next reaction.
  • the compound 2 obtained above was dissolved in pyridine (40 mL), and under nitrogen protection, benzoyl chloride (24 mL) was added dropwise at 0°C. After the dropwise addition, the mixture was warmed to room temperature and reacted overnight. A large amount of pyridine was removed by rotary evaporation, and dissolved in DCM. The pH of the sulfuric acid solution/L was adjusted to 5-6, and the layers were separated. The organic phase was washed with water, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 3, which was directly used in next reaction.
  • Intermediate 2 reacts with selected substituted benzoyl chloride to generate intermediate a, which is then converted into intermediate b, which is condensed with nicotinamide 5 under SnCl catalysis to generate corresponding target derivative I as shown in the following table (wherein X - is Cl - ):
  • Preparation and Dosing Accurately weigh an appropriate amount of the test product and mix it with an appropriate volume of water to obtain a clear solution or uniform suspension. Animal rats were dosed within 4 hours after preparation of the formulation. Dosage formulations were administered by oral gavage in accordance with facility standard operating procedures. The dose volume will be determined by the body weight of the animals collected on the morning of dosing.
  • Liver treatment Liver tissue was collected at each time point, washed twice with pre-cooled deionized water, and dried with filter paper. Liver tissue was immediately homogenized with 10 times the volume of methanol-water solution (1:2, v/v), and immediately after homogenization, a portion of liver tissue homogenate (such as 200uL homogenate) was used for analysis, and precipitated on wet ice After samples, the supernatant was taken by centrifugation and stored in a refrigerator at -70 ⁇ 10°C until LC-MS/MS analysis. Take 800uL of the remaining liver homogenate as a spare.
  • Rats were given compound II-1 (all doses were 0.636 mmol/kg, 383.5 mg/kg) and NR (185 mg/kg, 0.636 mmol/kg), respectively, at 0.25, 0.5, 1, 2, 4 , 8, 12, 15, 19, 24h time points to obtain rat liver samples, according to the above method, use LC-MS/MS test to determine the in vivo NAD concentrations of the above compounds in the liver respectively (see Table 4).
  • compound II-1 can be used as a new precursor for NAD synthesis in vivo, as a food supplement or as a drug for the treatment of related diseases, to increase the level of NAD in the body, improve human health, or treat diseases caused by NAD reduction. .
  • the preparation of compound II-1 is simpler, the cost is significantly reduced, and the compound II-1 has obvious practical advantages.
  • Compound II-1 can only be stored in a solid state.
  • the pH of the preparation is controlled at neutral or slightly acidic (pH 1-7), preferably pH 4-7.
  • the set preparations are prepared according to the preparation process regulations for clinical use.

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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

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 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 Endocrinol Metab,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 Reports 2016,6,26933)、艾滋病(Clinical Infectious Diseases 2003,36,453)、乙型肝炎(Arch Virol.2015,2712)、肌肉萎缩症(Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration,2019；0:1)、肥胖(Am.J.Clin.Nutr.2018,108,343)、帕金森病(Cell Reports 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-32□C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，
Figure PCTCN2021108490-appb-000001
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，
Figure PCTCN2021108490-appb-000002
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C 1-C 20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C 2-C 6烯基。
可选地，所述“炔基”为直链或支链C 2-C 6炔基。
可选地，所述“环烷基”为C 3-C 10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：
Figure PCTCN2021108490-appb-000003
可选地，所述式(I)化合物为下式(II-1)所示的化合物，
Figure PCTCN2021108490-appb-000004
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，
Figure PCTCN2021108490-appb-000005
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。
Figure PCTCN2021108490-appb-000006
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SnCl 4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WO 2019/006262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：
Figure PCTCN2021108490-appb-000007
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,CDCl 3)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SnCl 4(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
Figure PCTCN2021108490-appb-000008
Figure PCTCN2021108490-appb-000009
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。
Figure PCTCN2021108490-appb-000010
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SnCl 4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
Figure PCTCN2021108490-appb-000011
Figure PCTCN2021108490-appb-000012
Figure PCTCN2021108490-appb-000013
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
Figure PCTCN2021108490-appb-000014
Figure PCTCN2021108490-appb-000015
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，
    Figure PCTCN2021108490-appb-100001
    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，
    Figure PCTCN2021108490-appb-100002
    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C 1-C 20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C 2-C 6烯基；
    可选地，所述“炔基”为直链或支链C 2-C 6炔基；
    可选地，所述“环烷基”为C 3-C 10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：
    Figure PCTCN2021108490-appb-100003
    Figure PCTCN2021108490-appb-100004
  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，
    Figure PCTCN2021108490-appb-100005
  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，
    Figure PCTCN2021108490-appb-100006
    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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