Derivative of artemisinin and preparation method and application thereof

Abstract

The invention discloses an artemisinin derivative as well as a preparation method and application thereof. The structural formula of the artemisinin derivative is as shown in formula I in the specification. The compound has proper solubility and is relatively stable under storage conditions, pharmacokinetic experiments show that artemisinin can be detected in eye tissues, and artemisinin is distributed in cornea, conjunctiva and aqueous humor to achieve higher drug concentration and is an excellent artemisinin prodrug, and the compound in the formula I has remarkable absorbability and can be used for preparing the artemisinin prodrug. The artemisinin prepared by the preparation method has good drug concentration in eye tissues, has obviously better angiogenesis inhibition effect in a burn model than artemisinin, can be prepared into liquid preparations such as eye drops and injection, and is used for treating eye tissue diseases. # imgabs0 #

Description

A derivative of artemisinin and its preparation method and application Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to an artemisinin derivative and a preparation method and application thereof. Background Art

[0002] Combination therapy, primarily based on artemisinin, is the most effective treatment for drug-resistant malaria and remains the most effective and important treatment for malaria. However, with the deepening of research in recent years, more and more other effects of artemisinin have been discovered and applied, including anti-tumor, treatment of pulmonary hypertension, anti-diabetes, embryotoxicity, antifungal, and immunomodulatory effects.

[0003] Malaria is an insect-borne disease caused by the bite of an infected anemone, Plasmodium. Repeated attacks over a long period of time can result in hepatosplenomegaly, accompanied by anemia and other symptoms. Artemisinin has been crucial to the limited treatment of malaria. The peroxide bond in artemisinin's structure is oxidative, making it an essential group for antimalarial activity. Its mechanism of action is that free radicals generated by artemisinin bind to plasmodium proteins, altering the structure of the parasite's cell membrane. These free radicals cause the mitochondrial double membrane to rupture and eventually detach, disrupting the parasite's cellular structure and function. This also affects the chromatin within the nucleus. Amino acids are the building blocks of protein. Artemisinin reduces the absorption of isoleucine by the parasite, hindering protein synthesis. Artemisia annua not only kills parasites but also has anti-schistosomal effects, therapeutic effects against toxoplasmosis, effects against Pneumocystis carinii, and anticoccidial effects. Clinical trials have shown that artemisinin and its derivatives do not have particularly obvious side effects in the treatment of malaria.

[0004] In recent years, artemisinin has been found to be effective in treating retinal macular degeneration and fundus diseases. However, due to its physical and chemical properties, artemisinin is unstable, easily oxidized, and poorly soluble in water. Therefore, it is difficult to use in liquid preparations, especially eye drops. Both artemisinin and artesunate are poorly soluble in water and poorly absorbed by ocular tissue. Therefore, it is very necessary to find an artemisinin derivative with moderate solubility that can be absorbed into ocular tissue.

[0005] Summary of the Invention

[0006] 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.

[0007] To achieve the above objectives, the following technical solutions are adopted:

[0008] The compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] In Formula I, n can be an integer of 1-15, such as 2, 3, or 4.

[0011] Furthermore, the compound represented by formula I may be a compound represented by formula II:

[0012]

[0013] In formula II, n can be an integer of 1-15, such as 2, 3, or 4; X - Represents anions.

[0014] Furthermore, the X - The acid anions are selected from the group consisting of 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 toluenesulfonic acid.

[0015] The pharmaceutically acceptable salts of the compounds of Formula I described in the present invention refer to salts that are suitable for contact with the tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable effect / risk ratio within the scope of sound medical judgment.

[0016] Preferably, the pharmaceutically acceptable salt of the compound represented by Formula I is citrate, fumarate, salicylate, L-tartrate, fumarate, hydrochloride, acetate, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, oxalate, lactate, lysine or aspartate.

[0017] The present invention also provides a method for preparing the compound represented by the above formula I.

[0018] The method for preparing the compound represented by formula I provided by the present invention comprises the following steps:

[0019] 1) dissolving 3-dimethylamino-1-alkyl alcohol in acetonitrile, adding iodomethane dropwise and stirring to react, to obtain a quaternary ammonium salt intermediate;

[0020] 2) Dispersing dihydroartemisinin in dichloromethane, adding a quaternary ammonium salt intermediate and a catalytic amount of boron trifluoride etherate in sequence, and reacting to obtain the compound represented by formula (I).

[0021] The alkyl group in the 3-dimethylamino-1-alkyl alcohol may be propyl, butyl, or the like.

[0022] The mass ratio of the dimethylamino-alkyl alcohol to methyl iodide is 1:3-5; the mass ratio of dihydroartemisinin to the quaternary ammonium salt intermediate is 1:1-2.

[0023] Preferably, the reaction temperature is 20-45° C., and the reaction time is 2-6 h.

[0024] The present invention also provides use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating eye tissue diseases.

[0025] The present invention also provides use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of an inhibitor for preventing and / or treating corneal neovascularization.

[0026] The present invention provides a medicine or pharmaceutical composition for preventing and / or treating eye tissue diseases, comprising the compound represented by formula I as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0027] The drug can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, or mucosal tissues by injection, spraying, nasal drops, eye drops, penetration, absorption, physical or chemical mediation; or introduced into the body after being mixed or encapsulated with other substances.

[0028] Preferably, the eye tissue disease is eye tissue inflammation or eye tissue macular degeneration.

[0029] Preferably, the pharmaceutically acceptable carrier includes at least one of a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, a surfactant, an adsorption carrier and a lubricant.

[0030] Preferably, the drug or pharmaceutical composition is in the form of a liquid preparation; preferably, the liquid preparation is an eye drop or an injection. Preferably, the pH value of the eye drop is 5.5-6.5.

[0031] Beneficial effects: The compound represented by formula I of the present invention has suitable solubility and is relatively stable under storage conditions. It is an excellent artemisinin prodrug. The compound represented by formula I of the present invention has significant absorption advantages and can be prepared into liquid preparations, such as eye drops, injections, etc., for the treatment of eye tissue diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG1 is a diagram illustrating the fluorescent staining of each treatment group in Example 6;

[0033] FIG2 is a diagram illustrating the angiogenesis of each treatment in Example 6. DETAILED DESCRIPTION

[0034] The present invention is further described below with reference to specific examples, but the present invention is not limited to the following examples. The methods described are conventional methods unless otherwise specified. The raw materials described can be obtained from public commercial channels unless otherwise specified.

[0035] Example 1: Synthesis of SZY1905-P30

[0036]

[0037] To a 100ml single-necked flask, add 5g of 3-dimethylamino-1-propanol and 100ml of acetonitrile, stirring to dissolve. Add 20.7g of iodomethane dropwise. Stir at room temperature for 2h after addition. Monitor the reaction by TLC to confirm completion. Add 100ml of tertiary methyl ether dropwise to the reaction solution. A white solid precipitates in the solution, which is filtered to yield 10.4g of quaternary ammonium salt intermediate I.

[0038] To a 100ml single-necked flask, 10g of quaternary ammonium salt intermediate I and 8.0g of dihydroartemisinin were added sequentially. 100ml of dichloromethane was added with stirring and dispersion, and a catalytic amount of boron trifluoride in ether was added dropwise. Upon completion of the addition, the clear solution gradually turned deep red. Stir at room temperature for 2 hours, and TLC confirmed the completion of the reaction. The reaction solution was washed sequentially with saturated ammonium chloride and saturated sodium chloride. The organic phase was evaporated to dryness under reduced pressure to obtain 10.8g of crude SZY1905-P30. This crude product was purified by column chromatography using dichloromethane:methanol (1:0-30:1) to obtain 1.4g of SZY1905-P30 as a foamy solid.

[0039] 1HNMR CDCl3δ: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).

[0040] LC-MS: m / z=384.3 (M+1).

[0041] Example 2: Synthesis of SZY1905-P31

[0042]

[0043] To a 100ml single-necked flask, add 1g of 3-dimethylamino-1-butanol and 20ml of acetonitrile, stirring to dissolve. Add 3.64g of iodomethane dropwise. Stir at room temperature for 2h after addition. Monitor the reaction by TLC to confirm completion. Add 20ml of tert-methyl ether dropwise to the reaction solution. A white solid precipitates in the solution, which is filtered to yield 2.0g of quaternary ammonium salt intermediate II.

[0044] To a 100ml single-necked flask, 2.0g of quaternary ammonium salt intermediate II and 2.0g of dihydroartemisinin were added sequentially. 40ml of dichloromethane was added with stirring and dispersion. A catalytic amount of boron trifluoride etherate was added dropwise. Upon completion of the addition, the clear solution gradually turned deep red. Stir at room temperature for 2 hours. TLC confirmed the completion of the reaction. The reaction solution was washed sequentially with saturated ammonium chloride and saturated sodium chloride. The organic phase was evaporated to dryness under reduced pressure to obtain 2.5g of crude SZY1905-P31. This crude product was purified by column chromatography using dichloromethane:methanol (1:0-30:1) to obtain 300mg of SZY1905-P31 as a foamy solid.

[0045] 1HNMR CDCl3δ: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).

[0046] LC-MS: m / z=398.1.0 (M+1).

[0047] Example 3: Synthesis of maleate compounds

[0048]

[0049] 1 g of SZY1905-P30 was added to a 100 ml single-necked flask, and 20 ml of ethanol was added and stirred to dissolve. 3 mL of ethanol solution of 0.32 g of maleic acid was added dropwise. After the addition, the mixture was cooled to 0°C in an ice-water bath. A white solid gradually precipitated. The mixture was stirred at 0°C for 2 h and filtered to obtain 0.8 g of a maleate compound.

[0050] 1HNMR d6-DMSOδ: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).

[0051] LC-MS: m / z=384.3 (M+1).

[0052] Similarly, other organic acid salts can be obtained by replacing maleic acid with other organic acids according to the above method.

[0053] Example 3: Solubility test at different pH values

[0054] First, phosphoric acid and NaOH were used to prepare a series of solutions with a pH of 5-8. The preparation method is shown in Table 1.

[0055] Table 1 Preparation methods of solutions with different pH values

[0056] Preparation method: Purified water, pH = 5.0, diluted with phosphoric acid aqueous solution, pH = 6.0, diluted with phosphoric acid aqueous solution, pH = 7.0, KH2PO4 and NaOH buffer solution, pH = 8.0, KH2PO4 and NaOH buffer solution

[0057] The solubility of SZY1905-P30 and SZY1905-P31 at different pH values ​​is shown in Table 2.

[0058] Table 2 Solubility of SZY1905-P30 and SZY1905-P31 at different pH values ​​at 25°C (room temperature)

[0059] pH valueSZY1905-P30(mg / ml)SZY1905-P31(mg / ml)Purified water>10>105.0>1>16.0>1>17.0>1>18.0>1>1

[0060] Example 4: Stability test at different pH values

[0061] 1. Stability of SZY1905-P30 at different pH

[0062] 10 mg of sample was weighed, added into 10 ml of aqueous solution with different pH values, dissolved by ultrasonication, filtered and then tested by HPLC. The results are shown in Table 3.

[0063] Table 3 Stability of SZY1905-P30 at different pH

[0064] 0 day (%) 8 day (%) 20 day (%) 30 day (%) Purified water 97.09 96.91 97.04 97.28 pH = 5.0 97.23 96.90 97.01 97.25 pH = 6.0 97.24 96.95 96.81 97.23 pH = 7.0 97.34 97.09 96.97 97.26 pH = 8.0 97.22 97.13 96.98 97.13

[0065] 2. Stability of SZY1905-P31 at different pH

[0066] 10 mg of sample was weighed, added into 10 ml of aqueous solution with different pH values, dissolved by ultrasonic, filtered and then tested by HPLC. The results are shown in Table 4.

[0067] Table 4 Stability of SZY1905-P31 at different pH

[0068] 0 day (%) 8 day (%) 20 day (%) 30 day (%) Purified water 98.05 97.68 97.35 97.46 pH = 5.0 98.11 97.69 97.38 97.48 pH = 6.0 98.16 97.64 97.39 97.48 pH = 7.0 98.26 97.85 97.57 97.58 pH = 8.0 98.14 97.64 97.33 97.49

[0069] Example 5: Synthesis of SZY1905-P30 sulfate compound

[0070]

[0071] 3.5 g of SZY1905-P30 was added to a 100 ml single-necked flask, and 35 ml of ethanol was added and stirred to dissolve. The mixture was cooled in an ice-water bath, and 1.1 g of 30% sodium hydroxide solution was added dropwise. After stirring for 10 min, 2.8 mL of 3N H2SO4 ethanol solution was added dropwise. A white solid gradually precipitated. The mixture was stirred at 0°C for 2 h and filtered to obtain 1.6 g of SZY1905-P30 sulfate compound.

[0072] 1HNMR d6-DMSOδ: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).

[0073] LC-MS: m / z=384.3.

[0074] Similarly, artemisinin quaternary ammonium propyl ether iodide (SZY1905-P30) was replaced with artemisinin quaternary ammonium butyl ether iodide (SZY1905-P31), and the sulfate compound of SZY1905-P31 was obtained according to the above method.

[0075] Similarly, other salts of SZY1905-P30 and SZY1905-P31 can also be obtained.

[0076] Comparative Example 1: Synthesis of the hydrochloride compound of SZY1905-P32

[0077]

[0078] To a 100ml single-necked flask, 3.0g of 3-amino-1-propanol and 6.0g of dihydroartemisinin were added sequentially. 40ml of dichloromethane was added with stirring and dispersion. A catalytic amount of boron trifluoride etherate was added dropwise. Upon completion of the addition, the clear solution gradually turned deep red. Stir at room temperature for 2h. TLC confirmed the completion of the reaction. The reaction solution was washed sequentially with saturated ammonium chloride and saturated sodium chloride. The organic phase was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using dichloromethane:methanol (1:0-10:1) to obtain 2.3g of foamy SZY1905-P32.

[0079] 2.3 g of SZY1905-P32 was added to a 100 ml single-necked flask, and 20 ml of ethanol was added and stirred to dissolve. The mixture was cooled in an ice-water bath, and 2.5 ml of 3N HCl ethanol solution was added dropwise. After the addition, a white solid gradually precipitated. The mixture was stirred at 0°C for 2 h and filtered to obtain 1.8 g of SZY1905-P32 hydrochloride compound.

[0080] 1HNMR d6-DMSOδ: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).

[0081] LC-MS: m / z=342.2 (M+1).

[0082] Example 6: Effect of Alkali Burn on Corneal Neovascularization in New Zealand Rabbits

[0083] 1. Experimental Purpose

[0084] The effects of 1% SZY1905-P30, 1% SZY1905-P31, and 1% SZY1905-P32 eye drops on corneal neovascularization in New Zealand rabbits with alkali burns were observed.

[0085] 2. Experimental Materials, Instruments, and Experimental Animals

[0086] 1. Experimental Materials

[0087] 0.5% tetracaine hydrochloride (Affiliated Eye Hospital of Sun Yat-sen University; 20220113); tobramycin dexamethasone sodium phosphate eye drops (Affiliated Eye Hospital of Sun Yat-sen University; 20211217); chloral hydrate solution (Affiliated Eye Hospital of Sun Yat-sen University; 20220224); 1.0 mol / L NaOH solution; filter paper; stopwatch; fluorescein sodium eye drops (Affiliated Eye Hospital of Sun Yat-sen University); 0.9% sodium chloride injection (Guangdong Yixiang Pharmaceutical Co., Ltd., 210926202); 50 ml syringe; 1 ml syringe.

[0088] 2. Experimental Instruments

[0089] Digital slit lamp microscope BX-900 (Haag-Streit Gruppe, Switzerland) and electronic scale.

[0090] 3. 1% SZY1905-P30 (22030201; 5.0 ml / vial); 1% SZY1905-P30 (22030202; 5.0 ml / vial); 1% SZY1905-P32 (22031501; 5.0 ml / vial)

[0091] 4. Experimental Animals

[0092] Healthy New Zealand rabbits were purchased from Xinhua Experimental Animal Farm in Huadong, Huadu District, Guangzhou. Slit lamp examination was performed to exclude preganglionic ocular lesions. They were 2.0–2.5 months old and weighed 2.2–2.9 kg.

[0093] 3. Experimental Process

[0094] 1. Weighing of experimental animals: Weigh the weight of experimental animals with an electronic scale and record

[0095] No. Weight (kg) No. Weight (kg) 7 12.6117 2.67 32.2118 2.88 6 2.414 32.48 7 2.3145 2.98 9 2.4147 2.49 32.4148 2.79 4 2.415 12.89 7 2.3156 2.710 12.2157 2.6108 2.716 12.8109 2.716 6 2.7110 2.3168 2.9

[0096] 2. Experimental Animal Modeling

[0097] Twenty-four New Zealand rabbits were anesthetized with an intravenous injection of chloral hydrate solution at a dose of approximately 0.5 ml / kg. The ocular surface was then anesthetized with 0.5% tetracaine hydrochloride eye drops. A piece of filter paper approximately 8 mm in diameter was then soaked in a 1 mol / L sodium hydroxide solution for 1 minute until saturated. The paper was then placed in the center of the cornea for 1 minute. The filter paper was removed, and the cornea and conjunctival sac were immediately and repeatedly irrigated with 0.9% sodium chloride injection for 1 minute. Tobramycin and dexamethasone sodium phosphate eye drops were then administered.

[0098] 3. Drug administration to experimental animals

[0099] After modeling, 24 animals were divided into four groups: modeling group; SZY1905-P30 eye drop group; SZY1905-P31 eye drop group; and 1% SZY1905-P32 eye drop group. Drugs were administered three times daily, two drops each time. The modeling group received no medication.

[0100] Group number Modeling group 71, 73, 110, 117, 118, 143 SZY1905-P30 eye drops group 86, 89, 93, 145, 148, 166 SZY1905-P31 eye drops group 87, 94, 97, 147, 151, 168 SZY1905-P32 eye drops group 101, 108, 109, 156, 157, 161

[0101] 4. Digital slit lamp photography

[0102] Photos were taken with a digital slit lamp before modeling, on the first day after modeling (drug administration day 0), on the seventh day after modeling (drug administration day 6), and on the fourteenth day after modeling (drug administration day 13). The cornea was stained with sodium fluorescein and observed and photographed under a slit lamp microscope.

[0103] 4. Experimental Results

[0104] New Zealand rabbit No. 157 died unexpectedly due to shortness of breath on the 5th day after modeling. There were 5 animals (101, 108, 109, 156, and 161) left in the 1% SZY1905-P32 eye drop group, and 10 eyes were used for subsequent experiments.

[0105] (1) Eye inflammation

[0106] Number of New Zealand rabbit eyes with conjunctival congestion, corneal edema, neovascularization and fluorescein staining on the first day of modeling

[0107]

[0108] Number of New Zealand rabbit eyes with conjunctival congestion, corneal edema, neovascularization and fluorescein staining on the 7th day of modeling

[0109]

[0110] Number of New Zealand rabbit eyes with conjunctival congestion, corneal edema, neovascularization and fluorescein staining on the 14th day of modeling

[0111]

[0112] (2) Fluorescein staining scoring

[0113] Scoring criteria:

[0114] 0————No staining of corneal epithelium

[0115] 1————There are fewer than 30 corneal epithelial pigmentation spots

[0116] 2————The corneal epithelial pigmentation is less than half of the corneal area

[0117] 3————The corneal epithelial pigmentation is larger than half of the corneal area, or there is a large area of ​​flaky pigmentation

[0118] (III) Neovascularization score

[0119] 0————No neovascularization of the cornea

[0120] 1————A small amount of new blood vessels are formed in the cornea

[0121] 2————There is a lot of new blood vessels in the cornea

[0122] 3————The cornea is full of new blood vessels

[0123] Figure 1 shows an example of fluorescein staining for each treatment group in Example 6, and Figure 2 shows an example of angiogenesis for each treatment in Example 6. As shown in the figure, after alkali burn, some New Zealand rabbits began to develop a small amount of new blood vessels on the seventh day after modeling. Comparison of the New Zealand rabbits with new blood vessels in the four groups shows that the SZY1905-P30 and SZY1905-P31 groups were able to delay the rapid formation of new blood vessels, and their performance was significantly better than that of the SZY1905-P32 eye drop group. In the New Zealand rabbits in the SZY1905-P32 eye drop group, new blood vessels had spread throughout the cornea.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: In Formula I, n is an integer of 1-15.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The n is 3 or 4.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt of the compound represented by Formula I is citrate, fumarate, salicylate, L-tartrate, fumarate, sodium salt, potassium salt, calcium salt, hydrochloride, acetate, nitrate, sulfate, bisulfate, phosphate, hydrogenphosphate, acetate, oxalate, lactate, lysine salt or aspartate salt.

4. A method for preparing the compound according to any one of claims 1 to 3, comprising the steps of: 1) dissolving 3-dimethylamino-1-alkyl alcohol in acetonitrile, adding iodomethane dropwise and stirring to react, to obtain a quaternary ammonium salt intermediate; 2) Dispersing dihydroartemisinin in dichloromethane, adding a quaternary ammonium salt intermediate and a catalytic amount of boron trifluoride etherate in sequence, and reacting to obtain the compound represented by formula (I).

5. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating eye tissue diseases.

6. The use according to claim 5, characterized in that: The eye tissue disease is eye tissue inflammation or eye tissue macular degeneration.

7. Use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of an inhibitor for preventing and / or treating corneal neovascularization.

8. A medicament or pharmaceutical composition for preventing and / or treating eye tissue diseases, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

9. The use according to claim 8, characterized in that: The eye tissue disease is eye tissue inflammation or eye tissue macular degeneration.

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

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