Deuterated lamiterone medicine as well as preparation method and application thereof

Abstract

The invention discloses a deuterated lamiterone medicine as well as a preparation method and application thereof, and relates to the technical field of lamiterone, the preparation method comprises the following steps: firstly weighing deuterated propionic acid, and then adding dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain white turbid liquid; dropwise adding the mixed solution into the white turbid liquid, stirring and reacting overnight, adding water for quenching, extracting twice by using dichloromethane, washing by using a saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating to obtain a crude product; performing column chromatography separation on the crude product, concentrating and drying to obtain a deuterated lamiterone medicine; according to the deuterated lamiterone medicine as well as the preparation method and the application thereof, hydrogen atoms at key positions in lamiterone molecules are replaced with deuterium atoms, so that the metabolic rate of deuterated lamiterone is reduced, the half-life period of deuterated lamiterone is prolonged, and the sleep time of a patient is prolonged.

Description

Technical Field

[0001] The present invention relates to lamivudine technology, and in particular to a deuterated lamivudine drug and a preparation method and application thereof. Background Art

[0002] Rame l teon (also known as ramelteon, trade name Rozerem) is the world's first melatonin receptor agonist used to treat insomnia. It is used to treat insomnia patients who have difficulty falling asleep. Rame l teon produces the therapeutic effect of treating insomnia by acting on melatonin receptors MT1 and MT2. It is superior to traditional hypnotic drugs in terms of adverse reactions and addiction.

[0003] However, the elimination half-life of lamivudine is short, which means that lamivudine cannot significantly maintain the patient's sleep, limiting its effect in maintaining sleep. This means that the patient may have difficulty falling asleep again after waking up at night, thus affecting the patient's sleep quality and overall rest effect. Summary of the invention

[0004] The purpose of the present invention is to provide a deuterated lamivudine drug and a preparation method and application thereof, so as to solve the problem that the elimination half-life of lamivudine in the prior art is short and cannot significantly maintain the patient's sleep.

[0005] In order to achieve the above object, the present invention provides the following technical solution: a deuterated lamivudine drug, wherein the deuterated lamivudine drug is a compound of formula I:

[0006]

[0007] A method for preparing a deuterated lamitidone drug, comprising:

[0008] S1. First, weigh deuterated propionic acid, then add dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, and stir for 30 minutes to obtain a white suspension;

[0009] S2, adding the mixed solution dropwise to the white suspension, stirring the reaction overnight, adding water to quench, then extracting twice with dichloromethane, combining the organic layers of the two extractions, washing the combined organic layer with saturated brine, drying with anhydrous sodium sulfate after washing, and concentrating after drying to obtain a crude product;

[0010] S3. The crude product is separated by column chromatography to obtain a pure product, and the pure product is concentrated and dried to obtain a deuterated lamitidone drug.

[0011] Furthermore, the mixed solution in S2 is prepared by dissolving primary amine hydrochloride and N,N-diisopropylethylamine in dichloromethane.

[0012] Furthermore, the reaction temperature of the stirring reaction in S2 overnight is 20-25°C.

[0013] Furthermore, the eluent for column chromatography separation in S3 is a mixed solution of methanol and dichloromethane.

[0014] Furthermore, the volume ratio of methanol to dichloromethane in the mixed solution of methanol and dichloromethane is 1:30.

[0015] A use of the deuterated lamitidone drug in the preparation of hypnotic drugs.

[0016] A use of a deuterated lamitidone drug in the preparation of melatonin receptor MT1 and MT2 agonists.

[0017] A use of the deuterated lamitidone drug prepared by the preparation method in the preparation of hypnotic drugs.

[0018] A use of the deuterated lamitidone drug prepared by the preparation method in the preparation of melatonin receptor MT1 and MT2 agonists.

[0019] Compared with the prior art, the present invention provides a deuterated lamivudine drug and a preparation method and application thereof. The present invention replaces hydrogen atoms at key positions in the lamivudine molecule with deuterium atoms, and utilizes the characteristics that the zero point energy of the carbon-deuterium bond is lower than the zero point energy of the carbon-hydrogen bond and the bond energy of the carbon-deuterium bond is stronger than the bond energy of the carbon-hydrogen bond, so as to achieve the purpose of reducing the metabolic rate of deuterated lamivudine and prolonging the half-life of deuterated lamivudine, so that the therapeutic effect of deuterated lamivudine is stronger than that of lamivudine, and it helps to prolong the sleep time (i.e., maintain sleep), and at the same time avoids the generation of "next morning residual effect", that is, the side effects such as still feeling sleepy, drowsy, and inattention the next morning after taking certain sleeping pills, thereby ensuring that the user's normal activities and quality of life during the day are not affected;

[0020] The preparation method of deuterated lamitidone has simple steps and easy-to-master operation flow, and does not require complex equipment or difficult technical requirements, which effectively lowers the production threshold; its raw materials are easily available and the cost is controllable, making the entire production process more economical and efficient; this combination of simplicity and economy lays a solid foundation for large-scale industrial production, ensuring that the product can be supplied to the market at a stable and competitive price to meet a wide range of needs;

[0021] The deuterated lamitidone drug of the present invention can be used as a melatonin receptor MT1 and MT2 agonist for preparing hypnotic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can also be obtained based on these drawings.

[0023] Figure 1 The carbon nuclear magnetic resonance spectrum of the deuterated lamidepone molecule provided in the embodiment of the present invention;

[0024] Figure 2 A hydrogen nuclear magnetic resonance spectrum of the deuterated lamidepone molecule provided in an embodiment of the present invention;

[0025] Figure 3 A schematic diagram of the structure of the main raw materials and the final product of the preparation method provided in an embodiment of the present invention;

[0026] Figure 4 This is an infrared spectrum of the deuterated lamitidone molecule provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0027] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.

[0028] Embodiment 1:

[0029] See also Figure 1-Figure 2 , a deuterated lamivudine drug, the deuterated lamivudine drug is a compound of formula I:

[0030]

[0031] The specific implementation method is that by replacing the hydrogen atoms at key positions in the lamivudine molecule with deuterium atoms, the zero point energy of the carbon-deuterium bond is lower than the carbon-hydrogen bond and the carbon-deuterium bond energy is stronger than the carbon-hydrogen bond. The metabolic rate of deuterated lamivudine in the body can be significantly reduced. This change not only prolongs the half-life of the drug in the blood, but also enhances its efficacy, so that deuterated lamivudine has better therapeutic performance than undeuterated lamivudine. In addition, due to the slowed metabolic rate of deuterated lamivudine, patients can obtain a more lasting sleep maintenance effect, which is particularly important for people who need to improve sleep quality. At the same time, this method helps to reduce or avoid the "next morning residual effect", that is, taking certain sleeping pills the next morning still feels sleepy, drowsy, inattentive and other side effects, thereby ensuring that the user's normal activities and quality of life during the day are not affected.

[0032] Deuterated lamivudine slows down the metabolism of the drug in the body, allowing its concentration in the blood to remain longer, thereby prolonging the drug's duration of action and helping to improve the drug's bioavailability. For patients who have long relied on sleeping pills, this improvement means they can achieve the same therapeutic effect with a lower dose of the drug, reducing the potential risk of drug accumulation.

[0033] In addition, deuterated lamivudine has a prolonged effect, which is particularly beneficial for patients who need to continuously improve their sleep quality. It can provide stable sleep support at night, helping patients better enter the deep sleep stage, thereby improving overall sleep quality. For those whose daily life and work are affected by insomnia, improving overall sleep quality is very important.

[0034] More importantly, deuterated lamivudine can also help reduce or avoid the "next morning residual effect". Many traditional sleeping pills, while helping patients fall asleep, often leave obvious side effects the next morning, such as drowsiness, grogginess, headaches, and inattention. These side effects not only affect patients' daily lives, but may also have an adverse effect on their work performance. Deuterated lamivudine effectively avoids these problems through its unique metabolic characteristics, allowing patients to quickly regain wakefulness and maintain a good mental state after waking up.

[0035] The deuterated lamitidone drug can be used as a melatonin receptor MT1 and MT2 agonist for preparing hypnotic drugs.

[0036] Embodiment 2:

[0037] See also Figure 3 This embodiment provides a technical solution based on the first embodiment: a method for preparing a deuterated lamitidone drug, comprising:

[0038] S1. First, weigh deuterated propionic acid, then add dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, and stir for 30 minutes to obtain a white suspension;

[0039] S2, adding the mixed solution dropwise to the white suspension, stirring the reaction overnight, adding water to quench, then extracting twice with dichloromethane, combining the organic layers of the two extractions, washing the combined organic layer with saturated brine, drying with anhydrous sodium sulfate after washing, and concentrating after drying to obtain a crude product;

[0040] S3. The crude product is separated by column chromatography to obtain a pure product, and the pure product is concentrated and dried to obtain a deuterated lamitidone drug.

[0041] The specific implementation method is to accurately weigh 0.2g of deuterated propionic acid and place it in a dry and clean reaction bottle. Add 10 ml of dichloromethane as a solvent to the reaction bottle, slowly add 0.71g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 0.50g of 1-hydroxybenzotriazole (HOBT) at room temperature. These two compounds act as condensing agents to promote the formation of amide bonds. Start a magnetic stirrer and continue stirring for 30 minutes. The solution gradually turns into a white suspension to obtain a white suspension.

[0042] Prepare a mixed solution: weigh 0.63 g of primary amine hydrochloride and 6.78 g of N,N-diisopropylethylamine (DI EA), and dissolve them in 32 mL of dichloromethane to obtain a mixed solution;

[0043] The mixed solution was slowly and evenly added to the above white suspension through a constant pressure dropping funnel, and the reaction was stirred at 25°C overnight. The next day, the reaction progress was monitored by thin layer chromatography (TLC), and methanol / dichloromethane = 1:10 was used as the developing solvent. The final results showed that a new spot appeared above the primary amine position, indicating that the expected compound had been successfully generated.

[0044] To terminate the reaction, an appropriate amount of distilled water was added to the solution reacting overnight for quenching. Then, dichloromethane was used for extraction twice, and all organic phases were combined and washed with saturated brine; then, the organic layer was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure on a rotary evaporator to a smaller volume to obtain a crude product.

[0045] The last step is to further purify the crude product through column chromatography technology. The crude product is separated by column chromatography, and the eluent is prepared with methanol / dichloromethane in a ratio of 1:30. The target component flowing out of the column is collected as the pure product. After the pure product is concentrated and vacuum dried again, 0.1g of deuterated lamidepone drug with higher purity and 0.3g of deuterated lamidepone drug with lower purity are finally obtained. The deuterated lamidepone drug with lower purity can be further purified by column chromatography technology again to obtain deuterated lamidepone drug with higher purity.

[0046] The deuterated lamitidone drug can be used as a melatonin receptor MT1 and MT2 agonist for preparing hypnotic drugs.

[0047] Embodiment three:

[0048] See also Figure 3 This embodiment provides a technical solution based on the first or second embodiment: a method for preparing a deuterated lamitidone drug, comprising the following steps:

[0049] Accurately weigh 0.2 g of deuterated propionic acid and place it in a dry and clean reaction bottle. Add 10 ml of dichloromethane as a solvent to the reaction bottle, and slowly add 0.71 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 0.50 g of 1-hydroxybenzotriazole (HOBT) at room temperature. These two compounds act as condensing agents to promote the formation of amide bonds. Start a magnetic stirrer and continue stirring for 30 minutes. The solution gradually turns into a white suspension to obtain a white suspension.

[0050] Prepare a mixed solution: weigh 0.63 g of primary amine hydrochloride and 6.78 g of N,N-diisopropylethylamine (DI EA), and dissolve them in 32 mL of dichloromethane to obtain a mixed solution;

[0051] The mixed solution was slowly and evenly added dropwise to the above white suspension through a constant pressure dropping funnel, and the reaction was stirred at 20°C overnight. The next day, the reaction progress was monitored by thin layer chromatography (TLC), and methanol / dichloromethane = 1:10 was used as the developing solvent. The final results showed that a new spot appeared above the primary amine position, indicating that the expected compound had been successfully generated.

[0052] To terminate the reaction, an appropriate amount of distilled water was added to the solution reacting overnight for quenching. Then, dichloromethane was used for extraction twice, and all organic phases were combined and washed with saturated brine; then, the organic layer was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure on a rotary evaporator to a smaller volume to obtain a crude product.

[0053] The last step is to further purify the crude product by column chromatography technology, and perform column chromatography separation on the crude product and 0.3g of the deuterated lamidepone drug with lower purity obtained in Example 2, and prepare the eluent with methanol / dichloromethane in a ratio of 1:30, collect the target component flowing out of the column as the pure product, and finally obtain 0.67g of deuterated lamidepone drug with higher purity after concentrating and vacuum drying the pure product again. The deuterated lamidepone drug can be used as a melatonin receptor MT1 and MT2 agonist for the preparation of hypnotic drugs.

[0054] Embodiment 4:

[0055] See also Figure 1-Figure 2 and Figure 4 This embodiment provides a technical solution based on the second embodiment: the prepared deuterated lamivudine drug is subjected to relevant characterization.

[0056] 1. Use nuclear magnetic resonance to detect the chemical environment and distribution of hydrogen atoms and the carbon skeleton structure in the deuterated lamivudine molecule.

[0057] Nuclear magnetic resonance spectrometer (NMR) is an instrument that uses the nuclear magnetic resonance phenomenon to analyze the structure of matter. The nuclear magnetic resonance spectrometer is based on the energy level splitting phenomenon of atomic nuclei in a strong magnetic field. The atomic nuclei of certain elements (such as hydrogen) 1 H and carbon 13 C) Absorbs electromagnetic radiation of a specific frequency in a magnetic field, causing transitions between different energy levels and generating NMR signals. The location and intensity of these signals can provide information about the molecular structure.

[0058] Tetramethylsilane (TMS) is a commonly used internal standard substance with a chemical shift set to 0 ppm; in NMR spectra, the signal of TMS is used as a reference point to determine the chemical shifts of other signals.

[0059] The specific detection process is: the deuterated lamidepone sample is dissolved in DMSO-d6, and the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum are tested by Bruker AVANCE II I nuclear magnetic resonance spectrometer (400MHz) with the signal of TMS as 0ppm, and finally the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the deuterated lamidepone molecule are obtained. The results are as follows:

[0060] 1 H NMR (δ. (ppm)): 7.77 (1H, t broad), 6.89 (1H, d), 6.52 (1H, d), 4.51 (1H, m), 4.42 (1H, m), 3.1 (5H, m), 2.79 (1H, m), 2.67 (1H, m), 2.18 (1H, m), 1.92 (1H, m), 1.73 (1H, m), 1.45 (1H, m), 0.98 (3H, s).

[0061] 13 C NMR (δ.(ppm)): 172.7, 158.9, 143.3, 135.1, 122.9, 122.3, 106.7, 70.6, 41.5, 39.8, 36.9, 32.9, 31.3, 30.1, 27.8, 9.8.

[0062] 2. The structural characteristics of deuterated lamivudine molecules were detected by infrared spectrometry.

[0063] Infrared spectrometer is an instrument that uses infrared spectroscopy to analyze substances. It can provide information about chemical bonds and functional groups in molecules. When chemical bonds in molecules (such as CH, OH, C=O, etc.) are irradiated with infrared light, if the frequency of the infrared light matches the vibration frequency of the chemical bonds, the chemical bonds will absorb the light energy, resulting in the transition of the molecular vibration energy level. This absorption is manifested as an absorption peak of a specific wavelength on the infrared spectrum. Each functional group has its characteristic absorption frequency. For specific test results, please refer to Figure 4 .

[0064] The above description is only by way of illustration of certain exemplary embodiments of the present invention. It is undoubted that those skilled in the art can modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the above drawings and descriptions are illustrative in nature and should not be construed as limiting the scope of protection of the claims of the present invention.

Claims

1. A deuterated lamivudine drug, characterized in that: The deuterated lamitidone drug is a compound of formula I:

2. A method for preparing a deuterated lamivudine drug, characterized in that: include: S1. First, weigh deuterated propionic acid, then add dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, and stir for 30 minutes to obtain a white suspension; S2, adding the mixed solution dropwise to the white suspension, stirring the reaction overnight, adding water to quench, then extracting twice with dichloromethane, combining the organic layers of the two extractions, washing the combined organic layer with saturated brine, drying with anhydrous sodium sulfate after washing, and concentrating after drying to obtain a crude product; S3. The crude product is separated by column chromatography to obtain a pure product, and the pure product is concentrated and dried to obtain a deuterated lamitidone drug.

3. The method for preparing a deuterated lamidepone drug according to claim 2, characterized in that: S2 The mixed solution is prepared by dissolving primary amine hydrochloride and N,N-diisopropylethylamine in dichloromethane.

4. The method for preparing a deuterated lamidepone drug according to claim 2, characterized in that: The reaction temperature of S2 for stirring the reaction overnight is 20-25°C.

5. The method for preparing a deuterated lamidepone drug according to claim 2, characterized in that: S3: The eluent for column chromatography separation is a mixed solution of methanol and dichloromethane.

6. The method for preparing a deuterated lamidepone drug according to claim 5, characterized in that: The volume ratio of methanol to dichloromethane in the mixed solution of methanol and dichloromethane is 1:

30.

7. Use of the deuterated lamitidone drug according to claim 1 in the preparation of hypnotic drugs.

8. Use of the deuterated lamitidone drug according to claim 1 in the preparation of melatonin receptor MT1 and MT2 agonists.

9. Use of the deuterated lamidepone drug prepared by the preparation method according to any one of claims 2 to 6 in the preparation of hypnotic drugs.

10. Use of the deuterated lamitidone drug prepared by the preparation method according to any one of claims 2 to 6 in the preparation of melatonin receptor MT1 and MT2 agonists.

Images