Artemisinin derivatives, their production methods and uses

Abstract

Disclosed are artemisinin derivatives, a method for producing the same, and uses thereof. The structural formula of the artemisinin derivative is represented by Formula I. The compound has appropriate solubility, is relatively stable under storage conditions, and according to pharmacokinetic experiments, artemisinin is detected in eye tissues, and is distributed in the cornea, conjunctiva, and aqueous humor, and it has been shown that it can reach a high drug concentration, and it is an excellent artemisinin prodrug. The compound of Formula I has remarkable absorbability, shows high absorbability of drug concentration in eye tissues, and has a significantly better inhibitory effect on neovascularization in a burn model than artemisinin. It is manufactured into liquid preparations such as eye drops and injection solutions, and can be used to treat eye tissue diseases. 【Chemical 1】 TIFF2025518413000019.tif43170

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to artemisinin derivatives, a method for producing the same, and uses thereof.

Background Art

[0002] Artemisinin is the drug with the highest therapeutic effect against malaria. The combination therapy mainly based on artemisinin drugs is currently the most effective and important means for the treatment of malaria. However, with the progress of recent research, more and more other effects of artemisinin, such as anti-tumor, treatment of pulmonary hypertension, anti-diabetes, embryotoxicity, anti-fungal, immunomodulation, etc., have been discovered and applied in research.

[0003] Malaria is an insect-borne infectious disease, which is caused by the bite of a female Anopheles mosquito infected with the malaria parasite. If it attacks multiple times over a long period, symptoms such as splenomegaly and anemia will occur. The reason why malaria can be treated to a certain extent is the action of artemisinin. The peroxide bond in the artemisinin structure has oxidizing properties and is an essential group for anti-malaria. As the mechanism of action, free radicals produced by artemisinin in the body bind to malaria proteins, changing the cell membrane structure of the malaria parasite. When free radicals bind to malaria proteins, the double membrane of mitochondria expands and finally detaches, destroying the cell structure and function of the malaria parasite, and chromatin in the cell nucleus is also affected to a certain extent. On the other hand, amino acids are the basic substances that make up proteins. When artemisinin acts, the absorption of isoleucine by the malaria parasite decreases, and the synthesis of worm body proteins is inhibited. Artesunate not only kills pathogenic worms, but also has anti-schistosomiasis, anti-toxoplasma infection treatment, anti-Pneumocystis carinii, anti-coccidium and other effects. Clinical trials have proved that artemisinin and its derivatives have no particularly significant side effects during the process of treating malaria.

[0004] In recent years, artemisinin has been found to have a certain effect on the treatment of age-related macular degeneration and fundus diseases. However, due to the physicochemical properties of artemisinin, such as instability, easy oxidation, and poor solubility in water, it is difficult to apply it in the form of liquid preparations, especially eye drops. Both artemisinin and artesunate are poorly soluble in water and difficult to be absorbed by eye tissues. Therefore, it is necessary to search for artemisinin derivatives with appropriate solubility and can be absorbed by eye tissues.

Summary of the Invention

Problems to be Solved by the Invention

[0005] The object of the present invention is to provide a compound represented by formula I or a pharmaceutically acceptable salt thereof, which is an excellent artemisinin derivative.

Means for Solving the Problems

[0006] To achieve the above object, the following technical means are used.

[0007] A compound represented by formula I or a pharmaceutically acceptable salt thereof.

Chemical Formula

[0008] Furthermore, the compound represented by formula I may be a compound represented by formula II,

Chemical Formula

[0009] Furthermore, X - is an acid anion formed when an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, HBr, HI, citric acid, fumaric acid, succinic acid, acetic acid, nitric acid, hydrogen sulfate, lactic acid, methanesulfonic acid, and benzenesulfonic acid ionizes.

[0010] In the present invention, a pharmaceutically acceptable salt of the compound represented by Formula I is a salt that is suitable for contact with tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reactions, etc. within the scope of reliable medical judgment, and that has a reasonable benefit / risk ratio.

[0011] Preferably, the pharmaceutically acceptable salt of the compound represented by Formula I is citrate, trans-2-butenedioate, salicylate, L-tartrate, fumarate, hydrochloride, acetate, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, oxalate, lactate, lysinate or aspartate.

[0012] The present invention further provides a method for producing the compound represented by the above Formula I.

[0013] The method for producing the compound represented by Formula I according to the present invention 1) A step of dissolving 3-dimethylamino-1-alkyl alcohol in acetonitrile, dropping methyl iodide, and reacting with stirring to obtain a quaternary ammonium salt intermediate; 2) A step of dispersing dihydroartemisinin in dichloromethane, sequentially adding the quaternary ammonium salt intermediate and a catalytic amount of boron trifluoride etherate, and reacting to obtain the compound represented by Formula (I).

[0014] The alkyl in 3-dimethylamino-1-alkyl alcohol may be propyl, butyl, etc.

[0015] The mass ratio of dimethylamino-alkyl alcohol to methyl iodide is 1:3 to 5, and the mass ratio of dihydroartemisinin to the quaternary ammonium salt intermediate is 1:1 to 2.

[0016] Preferably, the reaction temperature of the above reaction is 20°C to 45°C, and the reaction time of the above reaction is 2 h (hours) to 6 h.

[0017] The present invention further provides the use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing and / or treating eye tissue diseases.

[0018] The present invention also provides the use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof in the manufacture of an inhibitor for preventing and / or treating corneal neovascularization.

[0019] The present invention provides a drug or drug composition for preventing and / or treating eye tissue diseases, comprising the compound represented by the above formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0020] The drug may be introduced into a living body such as muscle, intradermal, subcutaneous, vein, mucosal tissue, etc. by injection, injection, nasal drop, eye drop, penetration, absorption, physical or chemical methods, or may be introduced into the living body after being mixed or coated with other substances.

[0021] Preferably, the eye tissue disease is eye tissue inflammation or eye tissue macular degeneration.

[0022] Preferably, the pharmaceutically acceptable carrier comprises at least one of a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, a surfactant, an adsorbent carrier, and a lubricant.

[0023] Preferably, the dosage form of the drug or drug composition is a liquid preparation. Preferably, the liquid preparation is an eye drop or an injection solution. Preferably, the pH of the eye drop is 5.5 to 6.5.

Advantages of the Invention

[0024] The advantageous effects are as follows. The compound represented by the formula I of the present invention has appropriate solubility, is relatively stable under storage conditions, is an excellent artemisinin prodrug, and the compound of the formula I of the present invention has significant absorption advantages and can be manufactured into liquid preparations such as eye drops and injection solutions to treat eye tissue diseases.

Brief Description of the Drawings

[0025]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0026] Hereinafter, the present invention will be further described with reference to specific examples, but the present invention is not limited to the following examples. Unless otherwise specified, the above methods are all conventional methods. Unless otherwise specified, the above raw materials are all publicly available.

[0027] Example 1: Synthesis of SZY1905-P30

Chemical formula

[0028] Add 10 g of quaternary ammonium salt intermediate I and 8.0 g of dihydroartemisinin to a 100 ml one-necked flask in sequence, add 100 ml of dichloromethane, stir to disperse, add a catalytic amount of boron trifluoride ether solution dropwise. After the addition is complete, the supernatant solution gradually turns dark red, stir at room temperature for 2 h and monitor by TLC until the reaction of the raw materials is complete. Wash the reaction solution successively with saturated ammonium chloride and saturated sodium chloride, rotary dry the organic phase under reduced pressure to obtain 10.8 g of SZY1905-P30 crude product. Purify the crude product by column chromatography using dichloromethane:methanol (1:0 to 30:1) to obtain 1.4 g of foamy solid SZY1905-P30.

[0029] 1 1H NMR in CDCl3 δ: 5.4 (s, 1H), 5.3 (m, 1H), 5.0 (m, 1H), 4.6 - 4.4 (m, 2H), 3.7 - 3.4 (m, 12H), 1.9 - 1.8 (m, 3H), 1.6 - 1.3 (m, 12H), 1.1 (m, 3H), 0.8 (m, 3H). LC - MS: m / z = 384.3 (M + 1).

[0030] Example 2: Synthesis of SZY1905-P31

Chemical formula

[0031] Add 2.0 g of the quaternary ammonium salt intermediate II and 2.0 g of dihydroartemisinin to a 100 - ml single - necked flask in sequence, add 40 ml of dichloromethane, stir to disperse, add a catalytic amount of boron trifluoride etherate dropwise. After the addition is complete, the supernatant solution gradually turns dark red, stir at room temperature for 2 h and monitor by TLC until the reaction of the raw materials is complete. Wash the reaction solution successively with saturated ammonium chloride and saturated sodium chloride, rotary - dry the organic phase under reduced pressure to obtain 2.5 g of the SZY1905 - P31 crude product. Purify the crude product by column chromatography using dichloromethane:methanol (1:0 to 30:1) to obtain 300 mg of the foamy solid SZY1905 - P31.

[0032] 11H NMR in CDCl3 δ: 5.4 (s, 1H), 5.0 (m, 1H), 3.8 (m, 1H), 3.6 - 3.5 (m, 4H), 3.3 (m, 10H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 - 1.8 (m, 4H), 1.6 - 1.3 (m, 11H), 1.1 (m, 3H), 0.8 (m, 3H). LC-MS: m / z = 398.1.0 (M+1).

[0033] Example 3: Synthesis of maleate compound [Chemical formula] Add 1 g of SZY1905-P30 to a 100 ml single-necked flask, add 20 ml of ethanol, stir to dissolve, add dropwise 3 mL of an ethanol solution of 0.32 g of maleic acid. After the addition is complete, cool the temperature to 0 °C in an ice-water bath. A white solid gradually precipitates. Stir at 0 °C for 2 h, then perform suction filtration to obtain 0.8 g of the maleate compound.

[0034] 1 1H NMR in d6-DMSO δ: 6.2 (s, 2H), 5.5 (s, 1H), 5.3 (d, 1H), 3.6 - 3.5 (m, 2H), 3.3 (m, 1H), 2.9 (s, 6H) 2.2 - 2.0 (m, 4H), 1.9 - 1.8 (m, 5H), 1.7 - 1.3 (m, 9H), 1.2 (m, 3H), 0.9 (m, 3H). LC-MS: m / z = 384.3 (M+1).

[0035] Similarly, replace maleic acid with other organic acids to obtain other organic acid salts according to the above method.

[0036] Example 3: Solubility test at different pH values First, use phosphoric acid and NaOH to prepare a series of solutions with pH = 5 - 8, and the preparation method is shown in Table 1. TIFF2025518413000007.tif48170The solubilities of SZY1905-P30 and SZY1905-P31 at different pH values are shown in Table 2. TIFF2025518413000008.tif61170

[0037] Example 4: Stability Test at Different pH Values 1. Stability of SZY1905-P30 at Different pH Values Weighed 10 mg of the sample, added 10 ml of aqueous solutions with different pH values, dissolved it by ultrasonic wave, filtered it, and then performed HPLC test. The results are shown in Table 3. TIFF2025518413000009.tif73170

[0038] 2. Stability of SZY1905-P31 at Different pH Values Weighed 10 mg of the sample, added 10 ml of aqueous solutions with different pH values, dissolved it by ultrasonic wave, filtered it, and then performed HPLC test. The results are shown in Table 4. TIFF2025518413000010.tif73170

[0039] Example 5: Synthesis of Sulfate Compound of SZY1905-P30 TIFF2025518413000011.tif46170 Added 3.5 g of SZY1905-P30 to a 100 ml single-necked flask, added 35 ml of ethanol, stirred and dissolved it, cooled it down in an ice-water bath, dropped 1.1 g of 30% sodium hydroxide solution, stirred for 10 min (minutes), then dropped 2.8 mL of 3N H2SO4 ethanol solution. A white solid gradually precipitated, stirred at 0 °C for 2 h, and suction filtered to obtain 1.6 g of SZY1905-P30 sulfate compound.

[0040] 1 H NMR d6-DMSO δ: 5.8 (s, 1H), 5.5 (d, 1H), 3.6 - 3.4 (m, 2H), 3.3 (m, 1H), 3.0 (s, 9H), 2.6 - 2.2 (m, 5H), 2.2 - 1.8 (m, 4H), 1.7 - 1.4 (m, 9H), 1.2 (m, 3H), 0.9 (m, 3H). LC-MS: m / z = 384.3.

[0041] Similarly, artemisinin quaternary ammonium propyl ether iodate (SZY1905-P30) is replaced with artemisinin quaternary ammonium butyl ether iodate (SZY1905-P31), and a sulfate compound of SZY1905-P31 is obtained according to the above method.

[0042] Similarly, other salts of SZY1905-P30 and SZY1905-P31 can also be obtained.

[0043] Comparative Example 1: Synthesis of hydrochloride compound of SZY1905-P32

Chemical formula

[0044] 2.3 g of SZY1905-P32 is added to a 100 ml single-necked flask, 20 ml of ethanol is added and stirred to dissolve, cooled in an ice water bath, 2.5 mL of 3N HCl ethanol solution is added dropwise. After the addition is completed, white solid gradually precipitates, stirred at 0 °C for 2 h, suction filtered to obtain 1.8 g of hydrochloride compound of SZY1905-P32.

[0045] 1 H NMR d6-DMSO δ: 5.4 (s, 1H), 5.0 (d, 1H), 3.9 - 3.5 (m, 4H), 3.3 (m, 2H), 2.5 - 2.1 (m, 5H), 1.9 - 1.8 (m, 3H), 1.6 - 1.1 (m, 9H), 1.0 (m, 3H), 0.9 (m, 3H). LC-MS: m / z = 342.2 (M+1).

[0046] Example 6: Effect of Alkaline Thermal Burn on Corneal Neovascularization in New Zealand Rabbits I. Experimental Purpose To observe the effects of eye drops of 1% SZY1905-P30, 1% SZY1905-P31, and 1% SZY1905-P32 on corneal neovascularization in New Zealand rabbits with alkaline thermal burn.

[0047] II. Experimental Materials, Instruments, and Experimental Animals 1. Experimental Materials 0.5% Tetracaine Hydrochloride (Sun Yat-sen University Zhongshan Ophthalmic Center, 20220113), Tobramycin and Dexamethasone Sodium Phosphate Eye Drops (Sun Yat-sen University Zhongshan Ophthalmic Center, 20211217), Chloral Hydrate Solution (Sun Yat-sen University Zhongshan Ophthalmic Center, 20220224), 1.0 mol / L NaOH Solution, Filter Paper, Stopwatch, Fluorescein Sodium Eye Drops (Sun Yat-sen University Zhongshan Ophthalmic Center), 0.9% Sodium Chloride Injection (Guangdong Yixiang Pharmaceutical Co., Ltd., 210926202), 50 ml Syringe, 1 ml Syringe.

[0048] 2. Experimental Instruments Digital Slit Lamp Microscope BX-900 (Switzerland, Haag-Streit Gruppe), Electronic Scale.

[0049] 3. 1% SZY1905-P30 (22030201, 5.0 ml / bottle), 1% SZY1905-P30 (22030202, 5.0 ml / bottle), 1% SZY1905-P32 (22031501, 5.0 ml / bottle)

[0050] 4. Experimental Animals Healthy New Zealand rabbits are purchased from Huadong Xinhua Experimental Animal Farm in Huadu District, Guangzhou. Exclude anterior eye lesions by slit lamp examination. The age is 2.0 - 2.5 months and the body weight is 2.2 kg - 2.9 kg.

[0051] III. Experimental Procedure 1. Weighing of experimental animals: Weigh and record the body weight of experimental animals using an electronic scale. TIFF2025518413000013.tif93170

[0052] 2. Experimental animal modeling For 24 New Zealand rabbits, first anesthetize them by intravenous injection of chloral hydrate solution, with the dosage being approximately 0.5 ml / kg. Next, instill 0.5% tetracaine hydrochloride to anesthetize the ocular surface. Then, soak a piece of filter paper with a diameter of approximately 8 mm in 1 mol / L NaOH solution for 1 minute to saturate it, place it on the center of the cornea for 1 minute, immediately wash the cornea and conjunctival sac repeatedly with 0.9% sodium chloride injection for 1 minute after removing the filter paper, and then instill tobramycin - dexamethasone - sodium phosphate eye drops.

[0053] 3. Administration to experimental animals After modeling, divide the 24 animals into four groups: the modeling group, the SZY1905 - P30 eye drop group, the SZY1905 - P31 eye drop group, and the 1% SZY1905 - P32 eye drop group. Administer the drug three times a day, two drops each time. Here, the modeling group is not administered with the drug. TIFF2025518413000014.tif42170

[0054] 4. Photography using a digital slit lamp Before modeling and on the first day after modeling (day 0 of administration), the seventh day after modeling (day 6 of administration), and the fourteenth day after modeling (day 13 of administration), take pictures using a digital slit lamp, stain the cornea with sodium fluorescein, and observe and take pictures with a slit lamp microscope.

[0055] IV. Experimental results The New Zealand rabbit numbered 157 died suddenly due to respiratory distress on the fifth day after modeling. There were 5 animals (101, 108, 109, 156, 161) remaining in the 1% SZY1905 - P32 eye drop group, and subsequent experiments were conducted on 10 eyes.

[0056] (I) Ocular inflammatory conditions Number of eyes of New Zealand rabbits with conjunctival congestion, corneal edema, angiogenesis, and fluorescein staining on the first day after modeling TIFF2025518413000015.tif54170Number of eyes of New Zealand rabbits with conjunctival congestion, corneal edema, angiogenesis, and fluorescein staining on the seventh day after modeling TIFF2025518413000016.tif54170Number of eyes of New Zealand rabbits with conjunctival congestion, corneal edema, angiogenesis, and fluorescein staining on the fourteenth day after modeling TIFF2025518413000017.tif48170

[0057] (2) Scoring of fluorescein staining Scoring criteria: 0 ---- No staining of corneal epithelium 1 ---- Less than 30 staining points on corneal epithelium 2 ---- Staining points on corneal epithelium less than half of corneal area 3 ---- Staining points on corneal epithelium larger than half of corneal area or large - area sheet - like staining occurs

[0058] (3) Scoring of angiogenesis 0 ---- No new blood vessels are generated in the cornea 1 ---- A small amount of new blood vessels are generated in the cornea 2 ---- A large amount of new blood vessels are generated in the cornea 3 ---- The cornea is covered with new blood vessels

[0059] Examples of fluorescein staining for each treatment group in Example 6 are shown in, for example, Fig. 1. Examples of angiogenesis for each treatment group in Example 6 are shown in Fig. 2. As can be seen from the figures, some New Zealand rabbits after alkali burns began to generate a small amount of new blood vessels from the 7th day after modeling. Compared with the New Zealand rabbits in which angiogenesis occurred in the four groups, the SZY1905-P30 administration group and the SZY1905-P31 group could delay the generation of new blood vessels and were significantly superior to the SZY1905-P32 eye drop group. It can be concluded that the new blood vessels of the New Zealand rabbits in the SZY1905-P32 eye drop group spread throughout the cornea.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In Formula I, n is an integer from 1 to 15.)

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 3 or 4.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the compound represented by formula I is citrate, trans-2-butenedioate, salicylate, L-tartrate, fumarate, sodium salt, potassium salt, calcium salt, hydrochloride, acetate, nitrate, sulfate, hydrogensulfate, phosphate, hydrogenphosphate, acetate, oxalate, lactate, lysine salt, or aspartate salt.

4. 1) dissolving 3-dimethylamino-1-alkyl alcohol in acetonitrile, adding methyl iodide dropwise and reacting with stirring to obtain a quaternary ammonium salt intermediate; 2) dispersing dihydroartemisinin in dichloromethane, and sequentially adding a quaternary ammonium salt intermediate and a catalytic amount of boron trifluoride etherate to react with each other to obtain the compound represented by formula (I).

5. 10. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating an ocular tissue disease.

6. The use according to claim 5, wherein the ocular tissue disease is ocular tissue inflammation or ocular tissue macular degeneration.

7. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the manufacture of an inhibitor for preventing and / or treating corneal neovascularization.

8. A drug or drug composition for preventing and / or treating an ocular tissue disease, comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

9. The use according to claim 8, wherein the ocular tissue disease is ocular tissue inflammation or ocular tissue macular degeneration.

10. An inhibitor for preventing and / or treating corneal neovascularization, wherein the active ingredient comprises a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

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