Nicotinamide riboside derivative and application thereof

Abstract

The invention relates to nicotinamide riboside derivatives as shown in a formula (I), and isotope forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphic substances thereof. The invention also discloses a preparation method of the compound and application of the compound in preparation of medicines for preventing and / or treating metabolic syndrome diseases.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a nicotinamide riboside derivative, a pharmaceutical composition and use thereof in preparing a medicament for preventing and / or treating metabolic syndrome diseases. Background Art

[0002] Metabolic syndrome (MetS) is a clinical syndrome characterized by insulin resistance and the coexistence of multiple metabolic abnormalities. Its main manifestations include obesity (especially central obesity), impaired glucose metabolism, hypertension, and dyslipidemia. Obesity, a core component of MetS, is essentially a chronic imbalance between energy intake and energy expenditure. When subcutaneous fat storage capacity reaches saturation, excess lipids are ectopically deposited in internal organs such as the liver, muscles, and vascular system, leading to multiple pathological processes such as non-alcoholic fatty liver disease (NAFLD), atherosclerotic cardiovascular disease (ASCVD), and insulin resistance. These pathological changes not only accelerate the progression of obesity but also further drive the development and progression of MetS, creating a vicious cycle. Patients with MetS have a significantly higher risk of developing type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and non-alcoholic steatohepatitis (NASH) than the general population. Furthermore, metabolic abnormalities may be closely associated with the development and progression of numerous other diseases, such as hyperuricemia, chronic kidney disease, and certain types of cancer. The occurrence of these diseases not only seriously reduces the quality of life of patients, but also significantly shortens their life expectancy, bringing a heavy burden to patients and their families.

[0003] Currently, the treatment and management of metabolic syndrome primarily encompasses lifestyle interventions (specifically, diet and exercise), pharmacotherapy (such as antidiabetic, antihypertensive, and lipid-lowering medications), and metabolic surgery (e.g., gastric bypass surgery). Lifestyle interventions, as a first-line treatment, hold a fundamental and crucial position. However, in practice, patients often struggle to adhere to these interventions over the long term due to various factors, resulting in poor compliance. While metabolic surgery has demonstrated significant success in improving metabolic syndrome, it carries certain surgical risks and potential postoperative complications, which to some extent limit its widespread application. Therefore, pharmacotherapy plays an important complementary role in the comprehensive management of metabolic syndrome. In particular, medications that combine weight loss with metabolic improvement, such as glucagon-like peptide-1 (GLP-1) receptor agonists (including semaglutide and liraglutide), have garnered significant attention and recognition. These medications not only effectively reduce weight by delaying gastric emptying and enhancing satiety, but also stimulate insulin secretion in a glucose-dependent manner, thereby improving glycemic control. However, most GLP-1 drugs currently used in clinical practice require subcutaneous injection. Although the research and development of oral preparations has made certain progress, it still faces many challenges, which to some extent limits the widespread application of such drugs.

[0004] Given the complex pathophysiology of metabolic syndrome and its significant impact on multiple systems, future research should focus on multi-target combination therapies. Through comprehensive and in-depth research, we aim to more effectively improve the pathological processes of insulin resistance, inflammatory responses, and lipid metabolism disorders, thereby providing more comprehensive and effective treatment strategies for the prevention and treatment of metabolic syndrome. Summary of the Invention

[0005] To solve the above problems, the present invention provides a nicotinamide riboside derivative that can be used to prepare a drug for preventing and / or treating metabolic syndrome.

[0006] Specifically, the present invention provides the following technical solutions:

[0007] In a first aspect, the present invention provides a nicotinamide riboside derivative represented by formula (I) or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs.

[0008]

[0009] in,

[0010] R1 is selected from one of H, -C(O)R4, -C(O)2R4, and -C(O)NHR4;

[0011] R2 is selected from one of H, -C(O)R5, -C(O)2R5, and -C(O)NHR5;

[0012] R3 is selected from one of H, -C(O)R6, -C(O)2R6, and -C(O)NHR6;

[0013] R4, R5, R6 are each independently selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, The substituents in the substituted C1-C8 alkyl, substituted C3-C8 cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are selected from one or more of the following groups: halogen, -OH, -NH2, -OMe, -CN, and -NO2;

[0014] At least one of R1, R2, and R3 is not H, and at least one of R1, R2, and R3 contains the following structural fragment:

[0015] n is 0 or 1;

[0016] R7 is H or a side chain group of an α-amino acid, and the α-amino acid includes alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, asparagine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0017] The general structural formula of the above-mentioned α-amino acids is R-CH(NH2)-COOH, wherein the side chain group of the α-amino acid is the group R in the general structural formula, for example, the group R in alanine is a methyl group, and the group R in benzoic acid is a benzyl group.

[0018] Further, R1 is -C(O)R4, R4 is R2 and R3 are both hydrogen.

[0019] Furthermore, the compound is a compound represented by the following structural formula 1 and formula 2:

[0020]

[0021] Furthermore, the pharmaceutically acceptable salt is a salt composed of the nicotinamide riboside derivative and an inorganic anion or an organic anion; wherein the inorganic anion includes a halogen ion, a perchlorate ion, a sulfate ion, a hydrogen sulfate ion, a nitrate ion, a phosphate ion, and an acid phosphate ion; and the organic anion includes a formate ion, an acetate ion, a trifluoroacetate ion, a propionate ion, a pyruvate ion, a glycolate ion, an oxalate ion, a malonate ion, a succinate ion, a glutarate ion, a fumarate ion, a maleate ion, a lactate ion, a malate ion, a citrate ion, a tartaric acid ion, a methanesulfonate ion, an ethanesulfonate ion, a benzenesulfonate ion, a salicylate ion, a p-toluenesulfonate ion, and an ascorbic acid ion.

[0022] A second aspect of the present invention provides a pharmaceutical composition comprising the nicotinamide riboside derivative of formula (I) according to the first aspect, or one or more of its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs.

[0023] Furthermore, in the pharmaceutical composition, the nicotinamide riboside derivative represented by any one of the above formula (I) or its isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs are used in combination with other drugs.

[0024] In a third aspect, the present invention provides a use of the nicotinamide riboside derivative of formula (I) according to the first aspect, or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs, or the pharmaceutical composition according to the second aspect, in the preparation of a medicament for preventing and / or treating metabolic syndrome.

[0025] Furthermore, the metabolic syndrome diseases include but are not limited to obesity, diabetes, non-alcoholic fatty liver disease, hypertension, hyperlipidemia, and may also be other metabolic syndrome diseases.

[0026] Furthermore, the drug is used to reduce the activity levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase in serum.

[0027] Furthermore, the drug is used to lower blood sugar levels.

[0028] Furthermore, the drug is used to increase the concentration of nicotinamide adenine dinucleotide in the liver and bones.

[0029] Furthermore, the drug further comprises one or more of a pharmaceutically acceptable carrier, an excipient, and a diluent; preferably, the pharmaceutically acceptable carrier comprises microspheres, nanoparticles, and liposomes.

[0030] Furthermore, the dosage form of the drug includes but is not limited to injection, lyophilized powder for injection, suspension, implant I, embolic agent, capsule, tablet, pill and oral solution.

[0031] Furthermore, when the dosage form of the drug is a solid dosage form for oral administration (e.g., capsules, tablets, pills, powders, granules, etc.), the nicotinamide riboside derivative represented by formula (I) or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs or the pharmaceutical composition as an active ingredient can be mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate; and / or, mixed with one or more of the following ingredients: (1) fillers or solubilizers, such as starch, lactose, sucrose, Sugar, glucose, mannitol and silicic acid, etc.; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrants, such as agar, calcium carbonate, potato starch, tapioca starch, alginic acid, silicate, sodium carbonate, etc.; (5) dispersants, such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate, etc.; (8) adsorbents, such as kaolin, etc.; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc.

[0032] Furthermore, when the solid dosage form is a tablet, pill, capsule, or granule, it may be coated or microencapsulated with an enteric coating material and / or other materials known in the art. The release of the active ingredient in such a solid dosage form can be delayed in a certain portion of the digestive tract. Materials that can be used to encapsulate the components include polymeric substances and waxes. If desired, the active ingredient may also be microencapsulated with one or more of the above-mentioned excipients.

[0033] Furthermore, when the dosage form of the drug is a liquid dosage form for oral administration (e.g., an emulsion, solution, suspension, syrup, tincture, etc.), in addition to the active ingredient (the nicotinamide riboside derivative represented by formula (I) or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorphic form, or the pharmaceutical composition), the liquid dosage form may also contain an inert diluent commonly used in the art, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly one or more of cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil. In addition to these inert diluents, the liquid dosage form of the present invention may also include conventional adjuvants, such as pharmaceutically acceptable wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0034] Furthermore, the suspending agent includes one or more of ethoxylated stearyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitol, microcrystalline cellulose, and agar.

[0035] Furthermore, the dosage form of the drug can also be a dosage form for parenteral injection, including but not limited to sterile aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, sterile powders for reconstitution into sterile injectable solutions and dispersions, etc.

[0036] Furthermore, the dosage form of the drug may be a dosage form for topical administration, including but not limited to ointments, powders, suppositories, drops, sprays, inhalants, etc. In addition to the active ingredient, the dosage form for topical administration may further comprise a pharmaceutically acceptable carrier, preservative, buffer, etc., and may contain a propellant if necessary.

[0037] As used herein, the following definitions and terms shall apply unless otherwise indicated.

[0038] "R" and "S" as terms for describing isomers are descriptors of the stereochemical configuration of an asymmetrically substituted carbon atom. Designation of an asymmetrically substituted carbon atom as "R" or "S" is accomplished by applying the Cahn-Ingold-Prelog priority rules, which are well known to those skilled in the art and are described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (IUPAC) Rules of Organic Nomenclature.

[0039] The term C used here i-j For example, "C1-C8 alkyl" means that the alkyl unit has any number of carbon atoms between 1 and 8.

[0040] As used herein, "alkyl" refers to a fully saturated straight-chain or branched alkane group. Non-limiting examples of exemplary C1-C8 alkyl groups include methyl (abbreviated as Me), ethyl, n-propyl, isopropyl, n-butyl, pentyl, heptyl, etc. In addition, the term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, such as cyclopentanyl, cyclohexyl, etc. "Heterocycle" is a non-aromatic heterocycle containing at least one heteroatom, including but not limited to O, S, N, etc., such as tetrahydrofuran, piperidine, etc.

[0041] As used herein, "aryl" refers to a valent group formed by losing a hydrogen atom from an aromatic ring structure in an aromatic hydrocarbon molecule, including but not limited to phenyl, 1-naphthyl, 2-naphthyl, etc. "Heteroaryl" refers to an aryl group containing one or more heteroatoms, including but not limited to O, S, N, etc., such as pyridine, furan, thiophene, etc.

[0042] Unless otherwise indicated, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0043] By means of the above technical solution, the present invention has at least the following advantages:

[0044] The present invention provides a class of nicotinamide riboside derivatives. In mice with non-alcoholic fatty liver disease treated with these compounds, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels are significantly reduced. These compounds can also significantly reduce blood glucose levels in mice with induced fatty liver disease after oral administration of glucose, and can rapidly and effectively increase the concentration of nicotinamide adenine dinucleotide in the liver and bone tissue of mice. Compared with nicotinamide riboside, these compounds exhibit high biological activity and good stability, and have good application prospects in the preparation of drugs for preventing and / or treating metabolic syndrome. DETAILED DESCRIPTION

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0046] The present invention will be further described below with reference to specific examples so that those skilled in the art may better understand and implement the present invention, but the examples are not intended to limit the present invention. Unless otherwise indicated, all reagents used were purchased from commercial suppliers and used without further purification. The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as MS, NMR, etc. The abbreviations used are those conventional in the art.

[0047] In the following examples of this application, the synthesis method of the reaction intermediates used is as follows:

[0048] Intermediate a-1: ((R)-3-hydroxybutyryl)-L-phenylalanine (BHB-Phe) was prepared according to the method described in the literature (Ref.: Aβ-hydroxybutyrate shunt pathway generates anti-obesity ketonemetabolites. https: / / doi.org / 10.1016 / j.cell.2024.10.032.).

[0049]

[0050] Reaction Scheme 1

[0051] MS-ESI (m / z): 252.14 [M+1] + .

[0052] Example 1

[0053] Compound 1 is prepared from compound I-1 and compound I-2 according to the synthesis method shown in the following reaction scheme 2:

[0054]

[0055] Reaction Scheme 2

[0056] The specific preparation process is as follows:

[0057] (1) Preparation of Intermediate I-3: N,N'-carbonyldiimidazole (CDI, 270 mg, 1.64 mmol) dissolved in anhydrous THF (5 mL) was added to a dry round-bottom flask containing ((S)-2-hydroxypropionyl)-L-phenylalanine (compound I-1, Lac-Phe, 389 mg, 1.64 mmol). The mixture was vigorously stirred overnight under N2. NRH (Intermediate I-2, 0.84 g, 3.29 mmol) dissolved in anhydrous DMF (10 mL) was added to the mixture. The DMF was then removed under high vacuum, and the solid was dissolved in EtOAc (20 mL) and washed with brine (3×10 mL). The organic layer was concentrated to obtain a light yellow compound. The target compound, Intermediate I-3 (304 mg, 39%) was obtained by chromatography.

[0058] MS-ESI (m / z): 476.17 [M+1] + .

[0059] (2) Hexachloroacetone (1.63 mL, 8.85 mmol) and EtOAc (2 mL) were added to intermediate I-3 (286 mg, 0.6 mmol), followed by stirring at room temperature overnight. The solution was then concentrated under high vacuum and the sample was purified by silica gel column chromatography to obtain the target compound 1 (163 mg, 57%).

[0060] MS-ESI (m / z): 474.17 [M] +.

[0061] 1 H NMR(400MHz,MeOD-d4)δ:9.59(s,1H),9.32(d,J=6.0Hz,1H),9.04(d,J=7.8H z,1H),8.23-8.17(m,1H),7.29(5H,m),6.02(d,J=6.0Hz,1H),5.37(d,J=4.8 Hz,1H),4.69(m,1H),4.44-4.40(m,2H),4.25(s,1H),4.04-4.02(m,1H),3.8 8-3.80(m,1H),3.79-3.74(m,1H),3.72-3.66(m,1H),1.14(d,J=6.8Hz,3H).

[0062] Example 2

[0063] Compound 2 was prepared from intermediate a-1 and compound I-2 according to the synthesis method in Example 1:

[0064]

[0065] The product was characterized and the results are as follows:

[0066] MS-ESI (m / z): 488.23[M] + .

[0067] 1 HNMR(400MHz, DMSO-d6)δ:9.53(s,1H),9.30(d,J=6.2Hz,1H),9.02(d,J=7.6Hz,1H),8.22(m,1H),7.26(m,5H),6.00(d,J=6.2Hz,1H), 5.35(d,J=5.0Hz,1H),4.67(m,1H),4.42(m,1H),4.25(s,1H),4.01(m,3H),3.19(m,1H),2.95(m,1H),2.28(m,2H),1.16-1.06(m,3H).

[0068] Test Example 1

[0069] The effects of compounds 1 and 2 synthesized in the above examples on the activity levels of three liver enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), in the serum of mice with non-alcoholic fatty liver disease were tested, using one or two combinations of compounds NR-Cl, I-1, and compound a-1 as reference compounds, wherein:

[0070] The structure of compound NR-Cl is:

[0071] The structure of compound I-1 is:

[0072] The structure of compound a-1 is:

[0073] The specific test operations are as follows:

[0074] Male C57BL / 6 mice were obtained from Shanghai Slake Laboratory Animal Co., Ltd. From 7 days before the experiment until the entire experiment, the animals were housed in a laminar flow cleanroom with a strictly controlled temperature of (22 ± 3)°C, a relative humidity of 40%–80%, and good ventilation. The animals were housed in polycarbonate cages, three per cage, under a circadian lighting schedule of 12 h light / 12 h dark. After acclimatization, C57BL / 6 mice were randomly divided into the following 7 groups (n=6 / group): normal control group (PBS + basal diet), model control group (PBS + high-fat diet), reference compound A group (NR-Cl, 100 mg / kg + high-fat diet), reference compound B group (compound a-1 (48.0 mg / kg) + NR-Cl (52.0 mg / kg) + high-fat diet), reference compound C group (compound I-1 (46.6 mg / kg) + NR-Cl (53.4 mg / kg) + high-fat diet), compound 1 group (compound 1 (100 mg / kg) + high-fat diet), and compound 2 group (compound 2 (100 mg / kg) + high-fat diet). The details are as follows:

[0075] Construction of non-alcoholic fatty liver disease mouse model: Except for the mice in the normal control group, the mice in other groups were fed with a methionine / choline-deficient (MCD) high-fat diet for four weeks to establish the non-alcoholic fatty liver disease (NAFLD) animal model. All groups had free access to water.

[0076] Four weeks after MCD diet induction, drug intervention began: the normal control group and the model control group were gavage-administered with a saline solution containing 7.1% DMSO; the reference compound A group (NR-Cl, 100 mg / kg), the reference compound B group (compound a-1 (48.0 mg / kg) + NR-Cl (52.0 mg / kg)), the reference compound C group (compound I-1 (46.6 mg / kg) + NR-Cl (53.4 mg / kg)), the compound 1 group (compound 1, 100 mg / kg), and the compound 2 group (compound 2, 100 mg / kg) were treated accordingly. Twelve hours after drug administration, blood was collected into anticoagulant-free blood collection tubes, centrifuged at 6000 g for 15 minutes at 4°C, and serum was separated and transferred to fresh tubes for later use. Serum activities of three liver enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), were measured using a Thermofisher Indiko automated biochemical analyzer. The test results are shown in Table 1 below:

[0077] Table 1 Plasma concentrations of ALT, AST and ALP liver enzymes in different groups of mice

[0078] experimental group Compound ALT(U / L) AST(U / L) ALP(U / L) Normal control group / 45.4 103.9 190.7 Model control group PBS 461.2 432.7 244.7 Reference compound group A NR-Cl 310.5 258.6 173.3 Reference compound group B a-1+NR-Cl 214.6 148.9 132.5 Reference compound group C I-1+NR-Cl 193.6 162.1 143.6 Compound 1 Compound 1 127.3 93.5 108.6 Compound Group 2 Compound 2 134.3 101.8 125.9

[0079] As shown in Table 1, the levels of ALT, AST and ALP in the serum of mice increased significantly after MCD treatment. After drug intervention, compared with the reference compound A group fed only by compound NR-Cl and the reference compound C group fed by compound I-1 + NR-Cl (molar ratio of 1: 1), the ALT, AST and ALP levels in the serum of mice in the compound 1 group fed by compound 1 decreased more significantly; and the ALT, AST and ALP levels in the serum of mice in the compound 2 group decreased more significantly compared to the reference compound A group and the reference compound B group. It can be seen that compared to compound NR-Cl or a mixture of compound NR-Cl and compound I-1 / compound a-1 in a molar ratio of 1: 1, the compounds 1 and 2 provided by the present invention have a significantly better effect on reducing the levels of ALT, AST and ALP liver enzymes in the serum of mice with non-alcoholic fatty liver disease.

[0080] Test Example 2

[0081] The effects of Compounds 1 and 2 synthesized in the above Examples on the blood glucose levels of mice with induced fatty liver disease after oral administration of glucose in Test Example 1 were tested. One or a combination of the above Compounds NR-Cl, I-1, and Compound a-1 was used as a reference compound. The specific test procedures were as follows:

[0082] The establishment of the non-alcoholic fatty liver disease mouse model was consistent with that in Test Example 1.

[0083] Mice were fed an MCD diet for four weeks and then began receiving oral gavage from the fifth week of the experiment: the normal control group and the model control group (PBS group) were given a saline solution containing 7.1% DMSO via oral gavage; the reference compound A group (NR-Cl, 100 mg / kg), the reference compound B group (compound a-1 (48.0 mg / kg) + NR-Cl (52.0 mk / kg)), the reference compound C group (compound I-1 (46.6 mg / kg) + NR-Cl (53.4 mk / kg)), the compound 1 group (compound 1 (100 mg / kg)), and the compound 2 group (compound 2 (100 mg / kg)) were given the corresponding treatments. After five weeks of treatment, all experimental animals underwent an oral glucose tolerance test (OGTT). The specific operation process is as follows: After the animals are fasted for 12 hours, the baseline (0 minute) blood glucose level is first measured; then a 2g / kg glucose load is orally administered, and the blood glucose concentration is measured at three time points: 30 minutes, 60 minutes, and 120 minutes after administration using the Accu-Chek Performa blood glucose monitoring system. The measurement results are shown in Table 2 below:

[0084] Table 2 Oral glucose tolerance test after administration of different compounds

[0085] experimental group Compound Blood glucose 120 minutes after loading (mmol / l) Normal control group / 3.58 Model control group PBS 5.31 Reference compound group A NR-Cl 4.16 Reference compound group B a-1+NR-Cl 3.79 Reference compound group C I-1+NR-Cl 3.92 Compound 1 Compound 1 3.47 Compound Group 2 Compound 2 3.20

[0086] As shown in Table 2, compared with the normal control group, the blood glucose levels of mice treated with MCD were significantly increased after oral administration of glucose. After five weeks of treatment with different compounds, the blood glucose levels of mice 120 minutes after oral glucose load were significantly lower than those of the model control group, and the blood glucose levels of mice in the compound 1 and 2 treatment groups were the lowest.

[0087] Test Example 3

[0088] Compounds 1 and 2 synthesized in the examples were used as precursors of nicotinamide mononucleotide (NMN). The effects of treatment with different compounds on nicotinamide adenine dinucleotide (NAD+) levels in skeletal muscle and liver tissue of mice with induced fatty liver disease were tested. One or a combination of the above-mentioned compounds NR-Cl, I-1, and compound a-1 was used as a reference compound. The specific experimental procedures were as follows:

[0089] The establishment and treatment of the non-alcoholic fatty liver disease mouse model were consistent with those in Test Example 2. NAD+ levels in skeletal muscle and liver tissues of the treated mice were measured. Liver and skeletal muscle tissues were collected 0, 4, 8, and 24 hours after the last dose, and nicotinamide adenine dinucleotide (NAD+) concentrations in different tissues were analyzed. Tissue samples were processed as follows:

[0090] Liver sample processing: The mouse liver was completely dissected, and the surface blood was thoroughly rinsed with normal saline. After aseptically absorbing the residual water, the liver was immediately stored at -70℃ for subsequent NAD+ concentration analysis.

[0091] Skeletal muscle sample processing: The soleus skeletal muscle tissue was precisely separated and the attached gastrocnemius tissue was removed. After rinsing with normal saline to remove contaminants, the surface liquid was aseptically aspirated and the sample was quickly transferred to a -70°C environment for cryopreservation as a backup sample for NAD+ concentration analysis.

[0092] After thawing samples for analysis, tissue was homogenized and extracted as follows:

[0093] Tissue homogenization procedure:

[0094] 1. Add 5×(tissue weight×5) mL 0.1 M ZnSO4 to all tubes.

[0095] 2. Add 5×(tissue weight×5) mL of methanol to all tubes.

[0096] 3. Homogenize each sample until it becomes completely liquid.

[0097] 4. Vortex each sample. Tissue Extraction Procedure: a. On ice, aliquot 20 μL of standard, blank control, and blank matrix into a 96-well plate. b. Aliquot 20 μL of sample into each sample well. c. Add 100 μL of alprazolam dissolved in 80:20 methanol:water (volume ratio) to each well, except for the blank, which contains 100 μL of blank methanol:water (volume ratio 80:20). d. Cover the plate and vortex the samples. Centrifuge at 3300 rpm for 10 minutes.

[0098] 5. Transfer 80 μL of supernatant to a clean 96-well plate.

[0099] 6. Add 80 μL of LC-MS water to all wells.

[0100] 7. Cover and vortex. Determine tissue NAD+ concentration by LC / MS. The conditions are as follows: Column: C18 reversed-phase column (2.1×100 mm, 3.5 μm), Mobile phase: acetonitrile / water gradient elution system containing 0.1% formic acid, Flow rate: 0.3 mL / min, Column temperature: 35°C, Mass spectrometry conditions: Electrospray ionization (ESI) positive mode, Peak area integration using Xcalibur software.

[0101] The average NAD+ concentrations in the liver and bone tissues of mice treated with different compounds are shown in Table 3 below:

[0102] Table 3 NAD+ concentrations in liver and bone tissues of mice after administration of different compounds

[0103]

[0104] As can be seen from Table 3, compared with the normal control group, the NAD+ concentration in the liver and bones of mice treated with MCD was significantly reduced, and the NAD+ concentration in the liver and bones of mice treated with different compounds was significantly increased. Among them, the NAD+ concentration in the liver of mice after the last administration of compounds 1 and 2 was not less than 0.94μmol / g, and the NAD+ concentration in the bones was not less than 0.58μmol / g after 4 hours, which were significantly higher than those in other groups. Moreover, the high NAD+ concentration was still maintained 24 hours after drug administration, showing high biological activity and good stability.

[0105] In summary, the nicotinamide riboside derivatives provided by the present invention can effectively reduce the levels of alanine aminotransferase (ALT), AST, and ALP in the serum of mice with non-alcoholic fatty liver disease, and can significantly reduce the blood glucose levels of mice with induced fatty liver disease after oral administration of glucose. They can also quickly and effectively increase the concentration of nicotinamide adenine dinucleotide in the liver and bone tissue of mice. Compared with nicotinamide riboside, they exhibit higher biological activity and have good application prospects in the preparation of drugs for the prevention and / or treatment of metabolic syndrome diseases.

[0106] The above embodiments are merely preferred embodiments for the purpose of fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are within the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

Claims

1. A nicotinamide riboside derivative of formula (I) or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs, in, R1 is selected from one of H, -C(O)R4, -C(O)2R4, and -C(O)NHR4; R2 is selected from one of H, -C(O)R5, -C(O)2R5, and -C(O)NHR5; R3 is selected from one of H, -C(O)R6, -C(O)2R6, and -C(O)NHR6; R4, R5, R6 are each independently selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, The substituents in the substituted C1-C8 alkyl, substituted C3-C8 cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are selected from one or more of the following groups: halogen, -OH, -NH2, -OMe, -CN, and -NO2; At least one of R1, R2, and R3 is not H, and at least one of R1, R2, and R3 contains the following structural fragment: n is 0 or 1; R7 is H or a side chain group of an α-amino acid, and the α-amino acid includes alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, asparagine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

2. The nicotinamide riboside derivative of formula (I) according to claim 1, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorphic form, wherein: R1 is -C(O)R4, R4 is R2 and R3 are both hydrogen.

3. The nicotinamide riboside derivative of formula (I) according to claim 1, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorphic form, wherein: The compound is a compound represented by structural formula 1 or structural formula 2:

4. The nicotinamide riboside derivative of formula (I) according to any one of claims 1 to 3, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph. The pharmaceutically acceptable salt is a salt formed by the nicotinamide riboside derivative and an inorganic anion or an organic anion; wherein, The inorganic anions include halogen ions, perchlorate ions, sulfate ions, hydrogen sulfate ions, nitrate ions, phosphate ions, and acid phosphate ions; The organic anions include formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartaric acid, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbic acid.

5. A pharmaceutical composition, characterized in that The nicotinamide riboside derivative of formula (I) according to any one of claims 1 to 4 or one or more of its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs.

6. Use of a nicotinamide riboside derivative of formula (I) according to any one of claims 1 to 4, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or the pharmaceutical composition according to claim 5, in the preparation of a medicament for preventing and / or treating metabolic syndrome.

7. The use according to claim 6, characterized in that The metabolic syndrome diseases include obesity, diabetes, non-alcoholic fatty liver disease, hypertension, and hyperlipidemia.

8. The use according to claim 6, characterized in that The drug further comprises one or more pharmaceutically acceptable carriers, excipients, and diluents.

9. The use according to claim 8, characterized in that The carriers include microspheres, nanoparticles and liposomes.

10. The use according to any one of claims 6 to 9, characterized in that: The dosage forms of the drug include injection, freeze-dried powder for injection, suspension, implant, embolic agent, capsule, tablet, pill and oral solution.

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