A gemfibrozil deuterium derivative, and a preparation method and application thereof

Abstract

The application discloses a gemfibrozil deuterated derivative as shown in formula (I) and a preparation method and application thereof, and belongs to the field of organic and pharmaceutical synthesis. The method has simple preparation process and low cost. The gemfibrozil deuterated derivative synthesized by the method has the advantages of high purity and high deuterium substitution rate. The application also discloses application of the gemfibrozil deuterated derivative in treatment of hyperlipidemia. The gemfibrozil deuterated derivative has significantly improved pharmacological effect and significantly reduced toxic metabolites.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, particularly to the field of organic synthesis technology, and especially to a gemfibrozil deuterated derivative, its preparation method, and its application. Background Technology

[0002] Hyperlipidemia is a major cause of cardiovascular and cerebrovascular diseases, posing a significant threat and high incidence rate, and is a silent killer endangering human life and health. Gemfibrozil, a clofibrate derivative lipid regulator, is an important lipid-lowering drug that reduces blood cholesterol and triglyceride levels. Launched in the United States in 1982, gemfibrozil overcame the severe hepatotoxicity of previous lipid-lowering drugs while retaining its effectiveness. It can prevent arteriosclerosis, help reduce the incidence of myocardial infarction, and has a hypoglycemic effect. It is well absorbed by the gastrointestinal tract after oral administration and can be taken long-term. Furthermore, recent studies suggest that gemfibrozil may be a promising treatment for Alzheimer's disease. However, gemfibrozil poses a potential carcinogenic risk to humans, and its use is strictly limited. Metabolic studies have shown that under the action of human metabolic enzymes, the benzylic methyl group of the gemfibrozil molecule is oxidized, thereby losing its drug activity and triggering the production of carcinogenic substances.

[0003] Due to the superior stability of CD bonds compared to CH bonds, deuterated drugs exhibit relatively slower metabolism and prolonged half-life in vivo, offering benefits such as reduced dosage and side effects in clinical applications. Consequently, deuterated drugs have become a research hotspot in new drug development. With the advancement of C-H bond activation reactions, transition metal-catalyzed hydrogen isotope exchange reactions have been widely applied to the synthesis of deuterated drugs, but these typically require expensive transition metal catalysts or ligands with complex structures. Currently, there are no reports of directly achieving selective deuteration of gemfibrozil via hydrogen isotope exchange reactions. Cellular and animal experiments demonstrate that deuterated methyl gemfibrozil can significantly reduce the metabolic rate and decrease the formation of toxic adducts, exhibiting a clear advantage over the original gemfibrozil. Therefore, developing new processes to synthesize deuterated gemfibrozil derivatives and further advancing the therapeutic application of deuterated gemfibrozil in hyperlipidemia and Alzheimer's disease is of great significance.

[0004] This invention uses gemfibrozil as a starting material to synthesize deuterated gemfibrozil derivatives. The raw materials are readily available, the yield is high, and the process is simple, making it suitable for industrial production. Summary of the Invention

[0005] The purpose of this invention is to provide a deuterated gemfibrozil derivative, its preparation method, and its application, which can overcome the rapid metabolism of gemfibrozil, reduce the generation of toxic metabolites, and fill the research gap in deuterated gemfibrozil derivatives.

[0006] This invention provides a deuterated gemfibrozil derivative having a structure as shown in formula (I):

[0007]

[0008] Wherein, R1 and R2 are independently methyl (-CH3) or deuterated methyl (-CD3), etc., at least one of which is -CD3; R3 is selected from H and alkyl groups;

[0009] Preferably, R1 is selected from methyl or deuterated methyl;

[0010] R2 is selected from deuterated methyl;

[0011] R3 is selected from hydrogen or methyl.

[0012] Furthermore, the gemfibrozil deuterated derivative comprises the following structure:

[0013]

[0014] The present invention also provides a method for preparing the deuterated derivative of gemfibrozil shown in Formula I1. The method is as follows: under the presence of a solvent, using an alkali metal as a catalyst, and under heating conditions, gemfibrozil and a deuterium source reagent undergo a hydrogen-deuterium exchange reaction to prepare the deuterated derivative of gemfibrozil shown in Formula I1.

[0015] The reaction route of the gemfibrozil deuterated derivative shown in Formula I1 is as follows:

[0016]

[0017] The catalyst is any one or more of bis(trimethylsilyl)aminopotassium, bis(trimethylsilyl)aminocesium, potassium tert-butoxide, etc.; preferably, it is bis(trimethylsilyl)aminocesium.

[0018] The amount of catalyst used is 50%-150% of the molar amount of gemfibrozil; preferably, it is 150%.

[0019] The solvent is any one or a combination of aromatic hydrocarbons, alkanes or ether solvents; preferably, it is benzene or tetrahydrofuran.

[0020] The deuterium source reagent is any one or a combination thereof, such as deuterium gas or deuterated dimethyl sulfoxide; preferably, it is deuterium gas.

[0021] The pressure of the deuterium gas is 1-50 bar; preferably, it is 4 bar.

[0022] The reaction temperature is 60℃-120℃; preferably, it is 80℃.

[0023] The reaction time is 12-96 hours; preferably, it is 24 hours.

[0024] This invention also provides a method for preparing the deuterated gemfibrozil derivative shown in Formula I2, the reaction route of which is as follows:

[0025]

[0026] The preparation method includes the following steps:

[0027] In step (1), 5-bromo-2-methylphenol (II) and tert-butyldimethylchlorosilane were reacted under alkaline conditions in the presence of a solvent to prepare compound III;

[0028] In step (2), compound III and deuterated iodomethane are reacted under alkaline conditions to prepare compound IV;

[0029] Step (3): Compound IV is deprotected under alkaline conditions to obtain compound V;

[0030] In step (4), compound V and compound VI react, followed by hydrolysis, to prepare gemfibrozil deuterated derivative (I2).

[0031] In step (1), the solvent is selected from any one or more of N,N-dimethylformamide, tetrahydrofuran, dichloromethane, etc.; preferably, it is N,N-dimethylformamide.

[0032] In step (1), the alkali is one or more of n-butyllithium, tert-butyllithium, etc.; preferably, it is n-butyllithium.

[0033] In step (1), the molar ratio of 5-bromo-2-methylphenol (II), tert-butyldimethylchlorosilane and base is 1:1.2:2.0 to 1:2.0:3.0; preferably, it is 1:1.2:2.5.

[0034] In step (1), the reaction time is 2 hours to 16 hours; preferably, it is 2 hours.

[0035] In step (1), the reaction temperature is 25℃~50℃; preferably, it is room temperature.

[0036] In step (2), the alkali used is one or more of n-butyllithium, tert-butyllithium, etc.; preferably, it is n-butyllithium.

[0037] In step (2), the molar ratio of compound III, deuterated iodomethane and base is 1:1.1:1.1 to 1:3.0:2.0; preferably, it is 1:1.1:1.1.

[0038] In step (2), the reaction time is 8 to 24 hours; preferably, it is 16 hours.

[0039] In step (2), the reaction temperature is -78℃ to 35℃; preferably, it is -78℃.

[0040] In step (3), the alkali is cesium fluoride, etc.

[0041] In step (3), the molar ratio of compound IV to the base is 1:1 to 1:1.5; preferably, it is 1:1.2.

[0042] In step (3), the reaction time is 6 hours to 36 hours; preferably, it is 12 hours.

[0043] In step (3), the reaction temperature is 25℃-50℃; preferably, it is room temperature.

[0044] In step (4), the molar ratio of compound V to compound VI is 1:1 to 1:1.5; preferably, it is 1:1.1.

[0045] In step (4), the reaction time is 6 hours to 36 hours; preferably, it is 16 hours.

[0046] In step (4), the temperature of both the reaction and the hydrolysis reaction is 25℃-80℃; preferably, it is 70℃.

[0047] This invention also provides a method for preparing the gemfibrozil esterified deuterated derivative shown in Formula I3, the reaction route of which is as follows:

[0048]

[0049] The method for preparing the gemfibrozil-esterified deuterated derivative shown in Formula I3 includes the following reaction steps:

[0050] The gemfibrozil deuterated derivative shown in Formula I1 was dissolved in a solvent, and alkali and iodomethane were added to prepare the gemfibrozil esterified deuterated derivative (I3).

[0051] The solvent is selected from one or more of DCM, tetrahydrofuran, benzene, dimethyl sulfoxide, etc.; preferably, it is DCM.

[0052] The alkali is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; preferably, it is potassium carbonate.

[0053] The molar ratio of compound I1 to iodomethane is 1:1.1 to 1:3.0, preferably 1:2.

[0054] The molar ratio of compound I1 to the base is 1:1.1 to 1:3.0, preferably 1:1.5.

[0055] The reaction time is 6 to 24 hours; preferably, it is 12 hours.

[0056] The reaction temperature is 25℃~50℃; preferably, it is room temperature.

[0057] This invention also provides a method for preparing the gemfibrozil esterified deuterated derivative shown in Formula I4, the reaction route of which is as follows:

[0058]

[0059] The preparation method of the gemfibrozil-esterified deuterated derivative shown in Formula I4 includes the following reaction steps:

[0060] The gemfibrozil deuterated derivative shown in I2 was dissolved in a solvent, and a base and iodomethane were added to prepare the gemfibrozil esterified deuterated derivative shown in Formula I4.

[0061] The solvent is selected from one or more of DCM, tetrahydrofuran, benzene, dimethyl sulfoxide, etc.; preferably, it is DCM.

[0062] The alkali is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; preferably, it is potassium carbonate.

[0063] The molar ratio of compound I2 to iodomethane is 1:1.1 to 1:3.0, preferably 1:1.

[0064] The molar ratio of compound I2 to the base is 1:1.1 to 1:3.0, preferably 1:1.

[0065] The reaction time is 6 to 24 hours; preferably, it is 12 hours.

[0066] The reaction temperature is 25℃~50℃; preferably, it is room temperature.

[0067] The present invention also provides a pharmaceutical / pharmaceutical composition comprising a gemfibrozil deuterated derivative as described above and a pharmaceutically acceptable carrier.

[0068] Preferably, the pharmaceutically acceptable carrier refers to a carrier that, when properly administered to animals or humans, does not produce adverse, allergic, or other adverse reactions. Pharmaceutically acceptable carriers include, but are not limited to: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium methylcellulose, ethylcellulose, and methylcellulose; tragacanth gum powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tween; wetting agents such as sodium lauryl sulfate; colorants; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic salt solutions; and phosphate buffers, etc. These substances are used as needed to help stabilize the formulation or to improve its activity or bioavailability or to produce an acceptable taste or smell when taken orally.

[0069] Specifically, the drug / drug composition may also contain physiologically compatible excipients, including buffers, diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, adsorbents, lubricants, etc.

[0070] Specifically, the drug / drug composition can be formulated into injections, sterile powders for injection, tablets, pills, capsules, lozenges, liniments, powders, granules, syrups, solutions, tinctures, aerosols, powder inhalers, or suppositories, etc. All of the above dosage forms of the drug / drug composition can be prepared according to conventional methods in the pharmaceutical field.

[0071] Specifically, the drug / drug composition can be introduced into the body, such as into muscles, intradermal tissues, subcutaneous tissues, veins, or mucous membranes, via injection, spray, nasal drops, eye drops, penetration, absorption, or physical or chemical mediated methods; or it can be introduced into the body after being mixed with or encapsulated by other substances. Preferably, it is administered by injection. The drug / drug composition can also be used in combination with other treatment methods, including surgery, radiotherapy, chemotherapy, and targeted therapy.

[0072] Furthermore, the drug / drug composition can be used alone and / or in combination with drugs such as clofibrate, acilimus, lovastatin, pravastatin, etc., to treat hyperlipidemia.

[0073] The present invention also provides the use of the gemfibrozil deuterated derivative or the drug / drug composition thereof in the preparation of drugs for treating hyperlipidemia, diabetes, Alzheimer's disease, and antitumor diseases.

[0074] In one specific embodiment, the reaction formula of the preparation method is one of the following reaction formulas:

[0075] Reaction Formula 1:

[0076]

[0077] Reaction 2:

[0078]

[0079] Reaction 3:

[0080]

[0081] Reaction Formula 4:

[0082]

[0083] This invention describes the preparation route of gemfibrozil deuterated derivatives and synthesizes four gemfibrozil deuterated derivatives.

[0084] The beneficial effects of this invention include: This invention uniquely proposes a method for synthesizing bis-deuterated methyl gemfibrozil using gemfibrozil as a starting material through a heating reaction under an alkali metal catalyst and a deuterium source. This invention can directly prepare deuterated gemfibrozil derivatives in one step, eliminating the traditional multi-step synthesis steps, simplifying the process, and making it suitable for industrial production. The deuterated gemfibrozil derivatives prepared using the method provided by this invention have high purity, high yield, and stable chemical properties; they can be used to prepare pharmaceutical compositions, slow down drug metabolism, reduce toxic metabolites, and are used for the efficient treatment of hyperlipidemia. Attached Figure Description

[0085] Figure 1 For gemfibrozil deuterated derivative (I1) 1 H NMR spectrum;

[0086] Figure 2 For gemfibrozil deuterated derivative (I1) 13 C NMR spectrum;

[0087] Figure 3 Gemfibrozil esterified deuterated derivative (I3) 1 H NMR spectrum

[0088] Figure 4 Gemfibrozil esterified deuterated derivative (I4) 1 H NMR spectrum;

[0089] Figure 5 It is a metabolite of gemfibrozil and gemfibrozil deuterated derivative I1 in human liver microsomes;

[0090] Figure 6It is a metabolite of gemfibrozil and gemfibrozil deuterated derivative I1 in human liver S9;

[0091] Figure 7 Safety evaluation of gemfibrozil deuterated derivative I1;

[0092] Figure 8 The PPARα agonist effect of gemfibrozil deuterated derivatives I1-I4. Detailed Implementation

[0093] The present invention will be further described in detail below with reference to the specific embodiments and accompanying drawings. Except for the contents specifically mentioned below, the processes, conditions, and experimental methods for implementing the present invention are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations.

[0094] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0095] The following specific embodiments are intended to further illustrate the content of the present invention, rather than to limit the scope of protection of the claims of the present invention.

[0096] This invention discloses a gemfibrozil deuterated derivative, its preparation method, and its applications, belonging to the fields of organic and pharmaceutical synthesis. This invention relates to compounds represented by structural formula (I) and their pharmaceutically acceptable salts: R1 and R2 are either methyl (-CH3) or deuterated methyl (-CD3), with at least one being -CD3. The preparation method and pharmaceutical uses of the deuterated gemfibrozil are specifically disclosed. This invention features a simple and low-cost process. The deuterated gemfibrozil derivative synthesized using this invention exhibits high purity and a high deuteration rate. This invention also relates to the application of the described deuterated gemfibrozil derivative, which significantly enhances pharmacological activity and significantly reduces toxic metabolites.

[0097] Example 1

[0098] Under an inert atmosphere, gemfibrozil (CAS: 25812-30-0, 0.3 mmol, 0.0751 g), benzene (1.0 mL), and bis(trimethylsilylamino)cesium (150 mol%, 0.1320 g) were added sequentially to a 30 mL autoclave. The autoclave was sealed and purged with deuterium gas at 4 bar, and the reaction was carried out at 80 °C for 24 hours. The reaction solution was separated by column chromatography to obtain 96% yield of the gemfibrozil bis(deuterated) methyl derivative; the product was subjected to NMR analysis. 1 HNMR, 13 C10 NMR analysis showed a deuteration rate of 99%. The NMR data are as follows: 1HNMR(400MHz, CDCl3)δ7.00(d,J=7.6Hz,1H),6.66(d,J=7.6Hz,1H),6.61(s,1H),4.07-3.82(m,2H),2 .30-2.27(m,0.04H,99%labeled),2.16-2.13(m,0.04H,99%labeled),1.93-1.67(m,4H),1.26(s,6H). 13 C NMR (101MHz, CDCl3) δ 184.7, 157.1, 136.5, 130.4, 123.7, 120.9, 112.1, 68.1, 42.1, 37.0, 25.3, 25.1, 21.2-20.5 (m, labeled, 1C), 15.9-14.7 (m, labeled, 1C). The structural formula is shown below:

[0099]

[0100] Example 2

[0101] Under an inert atmosphere, gemfibrozil (CAS: 25812-30-0, 0.3 mmol, 0.0751 g), tetrahydrofuran (1.0 mL), and bis(trimethylsilylamino)potassium (150 mol%, 0.0898 g) were added sequentially to a 30 mL autoclave. The autoclave was sealed, purged with 6 bar deuterium gas, and heated at 100 °C for 24 hours. The reaction mixture was separated by column chromatography to obtain 98% yield of the gemfibrozil bis(deuterated) methyl derivative; the product was subjected to NMR analysis. 1 H NMR, 13 C10 NMR analysis showed a deuteration rate of 99%. The structural formula is shown below:

[0102]

[0103] Example 3

[0104] Under inert atmosphere, gemfibrozil (CAS: 25812-30-0, 0.3 mmol, 0.0751 g), tetrahydrofuran (1.0 mL), and bis(trimethylsilylamino)potassium (250 mol%, 0.1496 g) were added sequentially to a 30 mL autoclave. The autoclave was sealed and purged with deuterium gas at 4 bar, and the reaction was carried out at 80 °C for 48 hours. The reaction solution was separated by column chromatography to obtain 95% yield of the gemfibrozil bis(deuterated) methyl derivative; the product was subjected to NMR. 1 H NMR, 13 C10 NMR analysis showed a deuteration rate of 99%. The structural formula is shown below:

[0105]

[0106] Example 4

[0107] Under an inert atmosphere, gemfibrozil (CAS: 25812-30-0, 0.3 mmol, 0.0751 g), deuterated dimethyl sulfoxide (2.0 mL), and potassium tert-butoxide (250 mol%) were added sequentially to a 30 mL reaction tube. The reaction tube was sealed and the reaction was heated at 100 °C for 36 hours. The reaction solution was separated by column chromatography to obtain a 93% yield of the gemfibrozil bis-deuterated methyl derivative; the product was subjected to NMR analysis. 1 H NMR, 13 C10 NMR analysis showed a deuteration rate of 99%. The structural formula is shown below:

[0108]

[0109] Example 5

[0110] The synthetic route for gemfibrozil deuterated derivative I2 in this invention is shown below, specifically including the following preparation steps:

[0111]

[0112] Step (1) Synthesis of Compound III: 5-bromo-2-methylphenol (II, 3.0 g, 16.04 mmol), imidazole (2.73 g, 40.0 mmol), and DMF (30 mL) were added to a 100 mL flask. Tert-butyldimethylchlorosilane (2.9 g, 19.25 mmol) was added with stirring, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain 4.76 g of Compound III, which was directly used in the next step of the reaction.

[0113] Step (2) Synthesis of Compound IV: Compound III (1.0 g, 3.32 mmol) was dissolved in dry tetrahydrofuran (20 mL). The reaction temperature was controlled at -78 °C. Under a nitrogen atmosphere, n-butyllithium (3.65 mmol, 2.4 M) was slowly added dropwise, and the mixture was stirred at low temperature for 30 minutes. Then, deuterated iodomethane (529.10 mg, 3.65 mmol) was added dropwise, and the mixture was slowly restored to room temperature. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the organic phase was extracted and separated to obtain 0.71 g of compound IV, which was directly used in the next step of the reaction.

[0114] Step (3) Synthesis of compound V: Compound IV (0.71 g, 3.0 mmol) was dissolved in tetrahydrofuran, cesium fluoride (0.55 g, 3.6 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, saturated ammonium chloride aqueous solution was added to quench the reaction. The organic phase was extracted and separated with dichloromethane to obtain 0.31 g of compound V.

[0115] Step (4) Synthesis of Compound I2: Compound V (20 mg) and Compound VI (39 mg) were dissolved in DMF, and NaH (25.4 mg, 60 wt%) was added. The mixture was heated and stirred at 70 °C for 16 hours. After the reaction was complete, the organic phase was extracted and separated to obtain 23.9 mg of the product.

[0116] NMR data: 1 HNMR(400MHz, CDCl3)δ7.01(d,J=7.6Hz,1H),6.67(d,J=7.2Hz,1H),6.62(s,1H),4.02-3.8 3(m,2H),2.30-2.27(m,0.02H,99%labeled),2.15(s,3H),1.93-1.66(m,4H),1.26(s,6H).

[0117] Example 6

[0118] The synthetic route for gemfibrozil-esterified deuterated derivative I3 in this invention is shown below, specifically including the following preparation steps:

[0119]

[0120] In a 10 mL reaction flask, the gemfibrozil deuterated derivative I1 (1.0 mmol, 256.37 mg) prepared in Examples 1-4 of this invention was dissolved in 2 mL of dichloromethane, and K2CO3 (1.5 mmol, 207.31 mg) was slowly added. The mixture was stirred at room temperature for 30 minutes. Subsequently, CH3I (2.0 mmol, 283.88 mg) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was complete, the reaction solution was separated by column chromatography to obtain gemfibrozil esterified deuterated derivative I3 in 75% yield; the product was subjected to NMR. 1 HNMR testing showed a deuteration rate of 99%.

[0121] NMR data: 1 H NMR (400MHz, CDCl3) δ7.00 (d, J = 7.2Hz, 1H), 6.71-6.63 (m, 1H), 6.60 (s, 1H), 4.00-3.84(m,2H),3.66(s,3H),2.15(s,3H),1.79-1.67(m,4H),1.22(s,6H).

[0122] Example 7

[0123] The synthetic route for gemfibrozil-esterified deuterated derivative I3 in this invention is shown below, specifically including the following preparation steps:

[0124]

[0125] In a 10 mL reaction flask, the gemfibrozil deuterated derivative I1 (1.0 mmol, 256.37 mg) prepared in Examples 1-4 of this invention was dissolved in 2 mL of tetrahydrofuran, and KOH (1.2 mmol) was slowly added. The mixture was stirred at room temperature for 30 minutes. Then, CH3I (1.5 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was complete, the reaction solution was separated by column chromatography to obtain 80% yield of the gemfibrozil esterified deuterated derivative I3; the product was subjected to NMR analysis. 1 H NMR testing showed a deuteration rate of 99%.

[0126] Example 8

[0127] The synthetic route for gemfibrozil-esterified deuterated derivative I4 in this invention is shown below, specifically including the following preparation steps:

[0128]

[0129] In a 5 mL reaction flask, 0.5 mmol (126.68 mg) of the gemfibrozil deuterated derivative I2 prepared in Example 5 of this invention was dissolved in 1 mL of dichloromethane. K2CO3 (1.0 mmol (138.21 mg) was slowly added, and the mixture was stirred at room temperature for 30 minutes. Then, CH3I (1.0 mmol (141.94 mg) was added, and the reaction was continued at room temperature for 12 hours. After the reaction was complete, the reaction solution was separated by column chromatography to obtain 68% yield of the gemfibrozil esterified deuterated derivative I4; the product was subjected to NMR analysis. 1 HNMR testing showed a deuteration rate of 99%.

[0130] NMR data: 1 H NMR (400MHz, CDCl3) δ7.00 (d, J = 7.6Hz, 1H), 6.70-6.63 (m, 1H), 6.61 (s, 1H), 4.00-3.85 (m, 2H), 3.67 (s, 3H), 1.81-1.67 (m, 4H), 1.22 (s, 6H).

[0131] Example 9

[0132] The synthetic route for gemfibrozil-esterified deuterated derivative I4 in this invention is shown below, specifically including the following preparation steps:

[0133]

[0134] In a 5 mL reaction flask, the gemfibrozil deuterated derivative I2 (0.5 mmol, 126.68 mg) prepared in Example 5 of this invention was dissolved in 1 mL of tetrahydrofuran, and KOH (1.0 mmol) was slowly added. The mixture was stirred at room temperature for 10 minutes. Then, CH3I (2.0 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was complete, the reaction solution was separated by column chromatography to obtain the gemfibrozil esterified deuterated derivative I4 in 78% yield; the product was subjected to NMR analysis. 1 H NMR testing showed a deuteration rate of 99%.

[0135] Example 10

[0136] Identification of gemfibrozil and the deuterated derivative I1 metabolites of gemfibrozil prepared in Examples 1-4 of this invention

[0137] Experimental materials: human liver microsomes, midazolam, phosphate buffer, magnesium chloride, NADP+, glucose-6-phosphate, glucose-6-phosphate dehydrogenase, glutathione, acetonitrile.

[0138] Experimental steps:

[0139] High-resolution mass spectrometry was used to detect gemfibrozil and gemfibrozil deuterated derivative I1 metabolites using an in vitro liver microsomal incubation system.

[0140] a. The 200 μL in vitro metabolic reaction system contained phosphate buffer at pH 7.4, 4 mM magnesium chloride, 1 mM NADP+, 10 mM glucose-6-phosphate, 1 unit / ml glucose-6-phosphate dehydrogenase, 5 mM glutathione, a final concentration of liver microsomal protein of 0.2 mg / ml, and a final concentration of gemfibrozil or gemfibrozil deuterated derivative I1 of 10 μM.

[0141] b. After reacting at 37°C for 60 minutes, add 100 μl of acetonitrile to terminate the reaction;

[0142] c. Centrifuge at 20,000g for 30 minutes, collect the supernatant, and perform mass spectrometry analysis to quantitatively detect the metabolites.

[0143] Experimental results:

[0144] like Figure 5 As shown, gemfibrozil can produce two hydroxylated products, with hydroxylation sites on the benzene ring and the methyl group, respectively. After hydroxylation on the benzene ring, quinone metabolites are readily produced, which can bind to glutathione, potentially causing intracellular glutathione depletion and leading to cell necrosis or apoptosis. In contrast, the deuterated gemfibrozil derivative I1 prepared in Examples 1-4 of this invention can also produce the same hydroxylated products, but it is not readily bound to glutathione, suggesting that its toxicity may be reduced.

[0145] Example 11

[0146] Identification of gemfibrozil and the deuterated derivative I1 metabolites of gemfibrozil prepared in Examples 1-4 of this invention

[0147] Experimental materials: human liver S9, midazolam, Tris-HCl buffer, magnesium chloride, NADPH, PAPS, glutathione, acetonitrile.

[0148] Experimental steps:

[0149] High-resolution mass spectrometry was used to detect gemfibrozil and gemfibrozil deuterated derivative I1 metabolites using a human liver S9 in vitro incubation system.

[0150] a. The 200 μL in vitro metabolic reaction system contained Tris-HCl buffer at pH 7.4, 1 mM NADPH, 4 mM PAPS, 5 mM glutathione, a final concentration of human liver S9 protein of 1 mg / ml, and a final concentration of gemfibrozil or gemfibrozil deuterated derivative I1 of 10 μM.

[0151] b. After reacting at 37°C for 60 minutes, add 100 μl of acetonitrile to terminate the reaction;

[0152] c. Centrifuge at 20,000g for 30 minutes, collect the supernatant, and perform mass spectrometry analysis to quantitatively detect the metabolites.

[0153] Experimental results:

[0154] like Figure 6 As shown, the two hydroxylated products of gemfibrozil can be further metabolized by sulfonate transferase (SULT) to generate two sulfonated products, one of which can bind to glutathione. Although the deuterated gemfibrozil derivative I1 prepared in Example 1 of this invention can also produce the same sulfonated product, it does not bind to glutathione, suggesting that its toxicity may be reduced.

[0155] Example 12

[0156] Safety evaluation of gemfibrozil deuterated derivative I1 prepared in Example 1 of this invention

[0157] [Experimental Materials]: Gemfibrozil deuterated derivative I1

[0158] Experimental steps:

[0159] Animals that passed quarantine were weighed and randomly divided into a negative control group and a test substance group ①, with 10 animals in each group, half male and half female. Animals in the negative control group were administered 20 mL / kg of the solvent by gavage daily, while mice in the test substance group ① were administered the corresponding test substance suspension (specifically, a solution of deuterated gemfibrozil prepared with CMC-Na as the solvent) by gavage at a dose of 200 mg / kg, once daily for 14 consecutive days.

[0160] Experimental results:

[0161] like Figure 7 As shown, the gemfibrozil deuterated derivative I1 prepared in Example 1 of this invention has good safety and hypoglycemic effect.

[0162] Example 13

[0163] Evaluation of the agonistic properties of gemfibrozil and its deuterated derivative PPARα

[0164] Experimental materials: Gemfibrozil, deuterated gemfibrozil derivative I1 prepared in Examples 1-4 of this invention, deuterated gemfibrozil derivative I2 prepared in Example 5 of this invention, esterified deuterated gemfibrozil derivative I3 prepared in Examples 6-7 of this invention, and esterified deuterated gemfibrozil derivative I4 prepared in Example 8 of this invention.

[0165] Experimental steps:

[0166] Cells containing the luciferase reporter gene of PPARα were constructed, and the agonistic effects of gemfibrozil, deuterated gemfibrozil derivative I1, deuterated gemfibrozil derivative I2, deuterated gemfibrozil esterified derivative I3, and deuterated gemfibrozil esterified derivative I4 on PPARα were screened at concentrations of 100 and 200 μM. 4 The cells were seeded at a density of 100 cells / well in a 96-well plate. After 24 hours, the supernatant was aspirated and different concentrations of drug-containing culture medium were added. After another 24 hours, fluorescein detection reagent was added for detection.

[0167] Experimental results:

[0168] like Figure 8 As shown, deuterated gemfibrozil derivatives I1 (bis-deuterated gemfibrozil), I2 (mono-deuterated gemfibrozil), I3 (bis-deuterated gemfibrozil ester), and I4 (mono-deuterated gemfibrozil ester) exhibit PPARα activating activity in a concentration gradient-dependent manner. This result confirms that the deuterated gemfibrozil derivatives retain the core function of gemfibrozil (PPARα activating), indicating that deuteration does not disrupt its pharmacophore structure and that the deuterated derivatives possess biological activity.

[0169] In Examples 10 and 11 of this invention, the deuterated gemfibrozil derivatives exhibit better metabolic stability in human liver microparticles and human liver S9. This indicates that the deuterated gemfibrozil derivatives of this invention have better pharmacokinetic stability and in vivo activity in humans, making them suitable for subsequent drug development.

[0170] The deuterated gemfibrozil derivatives described in this invention possess the characteristics of gemfibrozil, but are superior in terms of biological activity, safety, and efficacy. They can replace gemfibrozil in the application fields of gemfibrozil. Therefore, the deuterated gemfibrozil derivatives described in this invention can be used in the pharmaceutical field.

[0171] The synthesized gemfibrozil deuterated derivatives (I1-I2) have high deuteration rates and high purity, which can meet the requirements for analysis and detection, prolonging drug action time, and reducing the formation of toxic metabolites.

[0172] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of this invention are included in this invention and are protected by the appended claims.

[0173] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0174] As used in this invention, the term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention but does not exclude other aspects.

[0175] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0176] Although embodiments of the present description have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the present description, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A gemfibrozil deuterated derivative, characterized in that, The gemfibrozil deuterated derivative has the following structure: 。 2. A method for preparing a deuterated gemfibrozil derivative of formula I2, characterized in that, The preparation method includes the following steps: Step (1): Compound III is prepared by reacting 5-bromo-2-methylphenol II and tert-butyldimethylchlorosilane under alkaline conditions in the presence of a solvent; the solvent is any one or more of N,N-dimethylformamide, tetrahydrofuran, and dichloromethane; the molar ratio of 5-bromo-2-methylphenol II, tert-butyldimethylchlorosilane, and base is 1:1.2:2.0 to 1:2.0:3.0; the base is one or two of n-butyllithium and imidazole; the reaction temperature is 25℃ to 50℃; the reaction time is 2 hours to 16 hours. In step (2), compound III and deuterated iodomethane are reacted under alkaline conditions to prepare compound IV; the molar ratio of compound III, deuterated iodomethane and base is 1:1.1:1.1 to 1:3.0:2.0; the base is one or both of n-butyllithium and tert-butyllithium; the reaction temperature is -78℃ to 35℃; the reaction time is 8 hours to 24 hours. Step (3): Compound IV is deprotected under alkaline conditions to obtain compound V; the base is cesium fluoride; the molar ratio of compound IV to base is 1:1 to 1:5; the reaction temperature is 25℃-50℃; the reaction time is 6 hours-36 hours. Step (4): Compound V and Compound VI react, followed by hydrolysis, to prepare the deuterated gemfibrozil derivative of Formula I2; the molar ratio of Compound V to Compound VI is 1:1 to 1:1.5; the reaction temperature is 25℃-80℃; the reaction time is 6 hours-36 hours; the reaction route of the deuterated gemfibrozil derivative of Formula I2 is as follows: 。 3. A pharmaceutical composition, characterized in that, It comprises the gemfibrozil deuterated derivative of claim 1, and further comprises a pharmaceutically acceptable carrier.

4. The application of gemfibrozil deuterated derivative I1 in the preparation of drugs for treating hypoglycemia, characterized in that, The structure of the gemfibrozil deuterated derivative I1 is as follows: 。

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