Antihistamine compounds and preparation methods and uses thereof

Abstract

The present invention relates to an antihistamine compound, a preparation method and use thereof. Specifically, it relates to an antihistamine compound having a structure of formula I and a pharmaceutically acceptable salt thereof and a preparation method thereof, a pharmaceutical composition having the antihistamine compound having a structure of formula I and a pharmaceutically acceptable salt thereof as an active ingredient and use thereof in treating seasonal and perennial allergic rhinitis, allergic conjunctivitis, urticaria and the like.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and more specifically, relates to an antihistamine compound, a preparation method thereof and use thereof in the medical field. Background Art

[0002] Allergic diseases are major diseases that affect human health. The development and acquisition of antiallergic drugs with stronger efficacy and lower adverse reactions has always been one of the research focuses of drug workers around the world. H1 receptor antagonists are the main drugs for the clinical treatment of allergic diseases. Structure-activity relationship studies have shown that H1 receptor antagonists are generally composed of an aromatic ring region, a connecting segment and a basic amine region. According to their structural types, they can be roughly divided into ethylenediamines, aminoalkyl ethers, propylamines and tricyclic drugs. The main adverse reactions of H1 receptor antagonists in clinical application are concentrated in two aspects: central inhibition and cardiac toxicity. The former is because the H1 receptor antagonist molecules are highly lipid-soluble and can easily pass through the blood-cerebrospinal fluid barrier, thus causing sedative and hypnotic effects. The latter is because some H1 receptor antagonists can inhibit the delayed rectifier potassium current potassium ion channel on human myocardial cells, leading to a prolonged QT interval on the electrocardiogram, and at the same time inducing torsades de pointes (TdP), which can cause fatal arrhythmias. Among them, the H1 receptor antagonists astemizole and terferadine have been withdrawn from the market due to cardiotoxicity issues.

[0003] Although many tricyclic antihistamine derivatives have been synthesized, including ketotifen, which has good activity. However, as the research progresses, its side effects gradually emerge. The biggest side effect of ketotifen fumarate is central nervous system inhibitory effects such as drowsiness or fatigue. This side effect is more obvious in adults and is one of the main reasons for the restriction of clinical use. Its drowsiness or fatigue can reduce the quality of life of asthma and childhood asthma patients. Therefore, it is of great research value to modify the structure of ketotifen and then screen out new drugs with stronger antihistamine activity and lower toxic side effects. Summary of the invention

[0004] One object of the present invention is to provide an antihistamine compound and a pharmaceutically acceptable salt thereof.

[0005] Another object of the present invention is to provide a method for preparing the compound.

[0006] Another object of the present invention is to provide the medical use of such compounds, which are generally useful for treating seasonal and perennial allergic rhinitis, allergic conjunctivitis, urticaria and the like.

[0007] Another object of the present invention is to disclose a pharmaceutical composition containing the compound and its pharmaceutically acceptable salt as the main active ingredient.

[0008] Now in combination with the purpose of the present invention, the content of the present invention is elaborated in detail.

[0009] The present invention specifically relates to compounds having the structure of formula I and pharmaceutically acceptable salts thereof;

[0010]

[0011] Wherein, X1 is H, alkali metal, amino acid, meglumine, choline; X2 is H, alkali metal, amino acid, meglumine, choline; n1 is an integer of 1-5; n2 is an integer of 0-3.

[0012] The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof, wherein the compound is selected from the following:

[0013]

[0014]

[0015]

[0016]

[0017]

[0018]

[0019] Comparative compound 1: Hydroxyhexyl loratadine

[0020]

[0021] Comparative compound 2: Hydroxypentyl loratadine

[0022]

[0023] Comparative compound 3: Hydroxybutyric acid loratadine

[0024]

[0025] Comparative compound 4: Hydroxypropyl loratadine

[0026]

[0027] Comparative compound 5: Hydroxyethyl desloratadine

[0028]

[0029] Comparative compound 6: Ketotifen

[0030]

[0031] Comparative compound 7: Rupatifene

[0032] The present invention also provides the use of the compound of formula I, a pharmaceutically acceptable salt or a pharmaceutical composition comprising the compound, for treating seasonal and perennial allergic rhinitis, allergic conjunctivitis, urticaria and other diseases.

[0033] The preparation of the compound of formula I is as follows:

[0034]

[0035] Wherein, X1, X2 and n are defined as above.

[0036] Among them, the synthesis of M1 has been reported in the literature, and those skilled in the art can prepare it according to the reported method.

[0037] M1 is dissolved in a non-protonic solvent such as dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine or toluene, and a solution of a halogenated alcohol and a corresponding organic solvent is added dropwise, and an organic base or inorganic base such as triethylamine, pyridine, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide is used as an acid-binding agent, and the reaction is carried out at -5 to 60°C to obtain compound I. The molar ratio of M1 to the halogenated alcohol is 1:(1-10).

[0038] M1 or compound I is dissolved in a non-protonic solvent such as dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine or toluene, and a solution of chlorobromoalkane and a corresponding organic solvent is added dropwise, and an organic base or inorganic base such as triethylamine, pyridine, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide is used as an acid binding agent, and the reaction is carried out at -5 to 60°C to obtain compound II. The molar ratio of M1 or compound I to chlorobromoalkane is 1:(1-10).

[0039] The above-obtained product compound II is dissolved in acetonitrile, acetone, methanol, ethanol or tetrahydrofuran, triethylamine is added and stirred evenly, phosphoric acid is added dropwise, and the reaction is carried out at 25-80°C to obtain compound III.

[0040] The above-obtained product compound III is dissolved in acetonitrile, acetone, methanol, ethanol or tetrahydrofuran, and sodium hydroxide or potassium hydroxide or choline hydroxide or arginine or proline is added, and the reaction is carried out at 25-80°C to obtain compound IV, i.e., a pharmaceutically acceptable salt.

[0041] The compounds of the present invention are used in the form of pharmaceutical preparations, and the administration route can be parenteral (such as intravenous, intramuscular) and oral administration.

[0042] The pharmaceutical composition of the compounds of this invention is prepared as follows: using standard and conventional technology, the compounds of this invention are combined with acceptable solid or liquid carriers in pharmaceutics, and are arbitrarily combined with acceptable adjuvants and excipients in pharmaceutics to be prepared into microparticles or microspheres. Solid dosage forms include tablets, dispersible particles, capsules, sustained-release tablets, sustained-release pellets, etc. Solid carriers can be at least one material, which can serve as diluents, flavoring agents, solubilizers, lubricants, suspending agents, adhesives, disintegrants and wrappers. Inert solid carriers include magnesium phosphate, magnesium stearate, sucrose, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulose materials such as methylcellulose, microcrystalline cellulose, low melting point paraffin, polyethylene glycol, mannitol, cocoa butter, etc. Liquid dosage forms include solvents, suspensions such as injections, powders, etc.

[0043] The amount of active ingredient (compound of the present invention) contained in the pharmaceutical composition and unit dosage form can be specifically used according to the patient's condition and the doctor's diagnosis. The amount or concentration of the compound used is adjusted within a wide range. Usually, the amount of the active compound ranges from 0.5% to 90% (weight) of the composition. Another preferred range is 0.5 to 70%. DETAILED DESCRIPTION

[0044] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited thereto.

[0045] Preparation Example

[0046] Example 1: Preparation of Intermediate 1

[0047]

[0048] Add 100 ml of tetrahydrofuran, 10 g of M1, 43.80 g of bromochloromethane and 3.38 g of sodium hydroxide to the reaction bottle, slowly raise the temperature to 60°C, stir for 6 h, filter the reaction solution after the reaction is completed, and evaporate the filtrate to remove the solvent under reduced pressure to obtain 9.11 g of intermediate 1 with a yield of 78.3%.

[0049] Example 2: Preparation of Intermediate 2

[0050]

[0051] Intermediate 2 was prepared by the same method as that of Intermediate 1 in Example 1, except that chlorobromomethane was replaced by chlorobromoethane, and other materials remained unchanged.

[0052] Example 3: Preparation of Intermediate 3

[0053]

[0054] Intermediate 3 was prepared by the same method as that of Intermediate 1 in Example 1, except that chlorobromomethane was replaced by 1,3-chlorobromopropane, and other materials remained unchanged.

[0055] Example 4: Preparation of Intermediate 4

[0056]

[0057] Intermediate 4 was prepared by the same method as that of Intermediate 1 in Example 1, except that chlorobromomethane was replaced by 1,4-chlorobromobutane, and other materials remained unchanged.

[0058] Example 5: Preparation of Intermediate 5

[0059]

[0060] Intermediate 5 was prepared by the same method as that of Intermediate 1 in Example 1, except that chlorobromomethane was replaced by 1,5-chlorobromopentane, and other materials remained unchanged.

[0061] Example 6: Preparation of Intermediate 6

[0062]

[0063] Intermediate 6 was prepared by the same method as that of Intermediate 1 in Example 1, except that chlorobromomethane was replaced by 1-chloroethanol, and other materials remained unchanged.

[0064] Example 7: Preparation of Intermediate 7

[0065]

[0066] Intermediate 7 was prepared by the same method as that of Intermediate 1 in Example 1, except that bromochloromethane was replaced by 1-chloropropanol, and other materials remained unchanged.

[0067] Example 8: Preparation of Intermediate 8

[0068]

[0069] Intermediate 8 was prepared by the same method as that of Intermediate 1 in Example 1, except that chlorobromomethane was replaced by 1-chlorobutanol, and other materials remained unchanged.

[0070] Example 9: Preparation of Intermediate 9

[0071]

[0072] Intermediate 9 was prepared by the same method as that of Intermediate 1 in Example 1, except that chlorobromomethane was replaced by 1-chloropentanol, and other materials remained unchanged.

[0073] Example 10: Preparation of Intermediate 10

[0074]

[0075] Intermediate 10 was prepared by the same method as that of Intermediate 1 in Example 1, except that M1 was replaced by Intermediate 6, and other materials remained unchanged.

[0076] Example 11: Preparation of Intermediate 11

[0077]

[0078] Intermediate 11 was prepared by the same method as Intermediate 1 in Example 1, except that M1 was replaced by Intermediate 7, and other materials remained unchanged.

[0079] Example 12: Preparation of Intermediate 12

[0080]

[0081] Intermediate 12 was prepared by the same method as Intermediate 1 in Example 1, except that M1 was replaced by Intermediate 8, and other materials remained unchanged.

[0082] Example 13: Preparation of Intermediate 13

[0083]

[0084] Intermediate 13 was prepared by the same method as Intermediate 1 in Example 1, except that M1 was replaced by Intermediate 9, and other materials remained unchanged.

[0085] Example 14: Preparation of Compound III-1

[0086]

[0087] Take 30ml of acetonitrile and place it in a reaction bottle, add 7.34g of triethylamine and 8.38g of phosphoric acid, stir and heat to 60℃ to dissolve, slowly add 10g of intermediate 1, keep warm at 60℃ for 6 hours after the addition is complete, after stopping, evaporate the solvent under reduced pressure at 60℃, evaporate to dryness, add 20ml of water and stir, slowly add concentrated hydrochloric acid dropwise to adjust the pH to 1.5, add 50ml (25ml×2 times) of ethyl acetate to extract the water layer, remove the water layer, and then evaporate the ethyl acetate under reduced pressure at 50℃ to obtain 9.1g of compound III-1, with a yield of 77.1%.

[0088] Example 15: Preparation of Compound III-2

[0089]

[0090] Compound III-2 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 2, and other materials remained unchanged.

[0091] Example 16: Preparation of Compound III-3

[0092]

[0093] Compound III-3 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 3, and other materials remained unchanged.

[0094] Example 17: Preparation of Compound III-4

[0095]

[0096] Compound III-4 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 4, and other materials remained unchanged.

[0097] Example 18: Preparation of Compound III-5

[0098]

[0099] Compound III-5 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 5, and other materials remained unchanged.

[0100] Example 19: Preparation of Compound III-6

[0101]

[0102] Compound III-6 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 10, and other materials remained unchanged.

[0103] Example 20: Preparation of Compound III-7

[0104]

[0105] Compound III-7 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 11, and other materials remained unchanged.

[0106] Example 21: Preparation of Compound III-8

[0107]

[0108] Compound III-8 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 12, and other materials remained unchanged.

[0109] Example 22: Preparation of Compound III-9

[0110]

[0111] Compound III-9 was prepared by the same method as compound III-1 in Example 14, except that intermediate 1 was replaced by intermediate 13, and other materials remained unchanged.

[0112] Example 23: Preparation of Compound IV-1

[0113]

[0114] Take 10 g of compound III-1 and add it to a reaction bottle, then add 50 ml of ethanol, heat to 50°C and stir to dissolve, add 1.97 g of sodium hydroxide and stir to dissolve, keep warm and stir for 20 minutes, filter, cool the filtrate to 0-5°C, keep warm for 4 hours to crystallize, filter, and air dry the filter cake to obtain 9.5 g of compound IV-1, with a yield of 85.7%.

[0115] Example 24: Preparation of Compound IV-2

[0116]

[0117] Compound IV-2 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-2, sodium hydroxide was replaced by potassium hydroxide, and other materials remained unchanged.

[0118] Example 25: Preparation of Compound IV-3

[0119]

[0120] Compound IV-3 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-3, sodium hydroxide was replaced by choline hydroxide, and other materials remained unchanged.

[0121] Example 26: Preparation of Compound IV-4

[0122]

[0123] Compound IV-4 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-4, and other materials remained unchanged.

[0124] Example 27: Preparation of Compound IV-5

[0125]

[0126] Compound IV-5 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-5, and other materials remained unchanged.

[0127] Example 28: Preparation of Compound IV-6

[0128]

[0129] Compound IV-6 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-6, sodium hydroxide was replaced by arginine, and other materials remained unchanged.

[0130] Example 29: Preparation of Compound IV-7

[0131]

[0132] Compound IV-7 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-7, and other materials remained unchanged.

[0133] Example 30: Preparation of Compound IV-8

[0134]

[0135] Compound IV-8 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-8, and other materials remained unchanged.

[0136] Example 31: Preparation of Compound IV-9

[0137]

[0138] Compound IV-9 was prepared by the same method as compound IV-1 in Example 23, except that compound III-1 was replaced by III-9, and other materials remained unchanged.

[0139] Physical and chemical properties investigation

[0140] Example 32: Dissolution study of the compounds of the present invention

[0141] The solubility of the compound of the present invention and the comparative compound in water, methanol and isopropanol was tested respectively. The test results are shown in Table 1 below.

[0142] Table 1: Solubility test results

[0143] Compound water Methanol Isopropyl alcohol Ⅲ-1 20mg / ml 35mg / ml 24mg / ml Ⅲ-2 20mg / ml 35mg / ml 24mg / ml Ⅲ-3 20mg / ml 35mg / ml 24mg / ml Ⅲ-4 20mg / ml 35mg / ml 24mg / ml Ⅲ-5 20mg / ml 38mg / ml 24mg / ml Ⅲ-6 20mg / ml 38mg / ml 24mg / ml Ⅲ-7 20mg / ml 38mg / ml 24mg / ml Ⅲ-8 20mg / ml 38mg / ml 24mg / ml Ⅲ-9 20mg / ml 38mg / ml 24mg / ml Ⅳ-1 488mg / ml 35mg / ml 1mg / ml Ⅳ-2 348mg / ml 35mg / ml 1mg / ml Ⅳ-3 404m / ml 38mg / ml 1mg / ml Ⅳ-4 476m / ml 35mg / ml 1mg / ml Ⅳ-5 478mg / ml 35mg / ml 1mg / ml Ⅳ-6 289mg / ml 28mg / ml 2mg / ml Ⅳ-7 466mg / ml 35mg / ml 2mg / ml Ⅳ-8 470mg / ml 35mg / ml 2mg / ml Ⅳ-9 473mg / ml 35mg / ml 2mg / ml Ketotifen Almost insoluble 30mg / ml 20mg / ml Rupatifene Almost insoluble 30mg / ml 20mg / ml Hydroxyethyl Desloratadine Almost insoluble 27mg / ml 21mg / ml Hydroxypropyl loratadine Almost insoluble 24mg / ml 26mg / ml Loratadine Hydroxybutyrate Almost insoluble 22mg / ml 28mg / ml Hydroxypropyl Loratadine Almost insoluble 19mg / ml 29mg / ml Hydroxyhexyl loratadine Almost insoluble 15mg / ml 32mg / ml

[0144] The results show that the solubility of the compound of the present invention in water is better than that of ketotifen, rupatifene and hydroxyethyl desloratadine series compounds, especially the sodium salt is more soluble in water and is more suitable for preparing intravenous administration preparations. The solubility of the compound of the present invention in methanol and isopropanol is comparable to that of the comparative compound.

[0145] Efficacy studies

[0146] Example 33: Antiasthmatic effect of the compounds of the present invention on histamine-induced asthmatic guinea pigs

[0147] A guinea pig was taken and placed in a plexiglass bell jar, and a saline histamine solution (0.8 mg / mL) was ultrasonically sprayed into the guinea pig for 40 seconds. The time when the guinea pig developed asthma was recorded, and the time of convulsion and fall was taken as the incubation period. Guinea pigs with a latency period exceeding 180 seconds were not selected. The selected 125 guinea pigs were randomly divided into 25 groups, 5 in each group: a normal control group, a ketotifen group (1 mg / kg), a rupatifene group (1 mg / kg), a hydroxyethyl desloratadine group (1 mg / kg), a hydroxypropyl desloratadine group (1 mg / kg), a hydroxybutyl desloratadine group (1 mg / kg), a hydroxypentyl desloratadine group (1 mg / kg), a hydroxyhexyl desloratadine group (1 mg / kg), and a group of the compound of the present invention (1 mg / kg). The mice were intragastrically administered with 2 mL / kg bw. 60 min after administration, the mice were placed in glass bell jars and sprayed with histamine hydrochloride solution under the same conditions as in the pre-selection. The latency of asthma onset was recorded. If asthma did not occur within 8 min, it was counted as 8 min. The results were processed statistically.

[0148] The results are shown in Table 2

[0149] Table 2 shows the results of the test compounds' antagonistic effects on histamine ( n=5)

[0150]

[0151]

[0152] The test results show that the compound of the present invention has a significantly longer latent period after drug administration than the normal control group, ketotifen group, rupatifene group and hydroxyethyl desloratadine series group, indicating that the compound of the present invention is superior to the control group and the normal group in inhibiting asthma.

[0153] Example 34: Effect on the muscle tone of isolated ileal smooth muscle of guinea pigs

[0154] The guinea pig was knocked unconscious with a wooden stick, and the abdomen was immediately opened to separate the ileum of about 15 cm in length. The contents of the intestinal segment were washed with Tyrode's solution and placed in Tyrode's solution at 37°C for standby use, while oxygen was supplied. The experimental intestinal tube (length 1 cm) was cut and placed in 20 ml Tyrode's solution at 37°C, with continuous oxygen supply. One end was fixed on the ventilation hook, and the other end was connected and fixed on the muscle tension transducer and led to the computer interface. The muscle tension value of the ileal smooth muscle was recorded with the BL system, and the experiment was carried out after the intestinal segment contraction was stable.

[0155] After the ileum contraction curve stabilizes, record the tension value before adding the drug, then add the drug or DMSO respectively, and record the average tension value of the ileum contraction curve at this point 5 minutes later. Repeat the operation 8 times. Calculate the spasmolysis percentage according to the following formula.

[0156]

[0157] The results are shown in Table 3:

[0158] Table 3 shows the results of the test compounds' antagonistic effects on histamine ( n=8)

[0159]

[0160]

[0161] After the ileal peristalsis curve stabilizes, record the tension value before adding the compound, then add 0.05 mL of histamine. When the maximum contraction is reached, add 0.05 mL of different compounds or DMSO respectively, observe and record the average tension value when adding histamine and 3 minutes after adding the compound. Repeat the operation 8 times to calculate the percentage of antispasmodic effect.

[0162]

[0163] The results are shown in Table 4

[0164] Table 4 shows the results of the test compounds' antagonistic effects on histamine ( n=8)

[0165]

[0166]

[0167] The test results show that compared with the ketotifen group, rupatifene and hydroxyethyldesloratadine series groups, the compound of the present invention has better antihistamine activity.

[0168] Preparation

[0169] Example 35: Preparation of oral solution

[0170] prescription:

[0171]

[0172] Preparation method: Take 500 ml of water for injection, add sucrose and stir to dissolve; take 0.6 g of compound IV-2 and add it to the solution and stir to dissolve, then take citric acid and ethyl 4-hydroxybenzoate and add them to the solution and stir to dissolve, add water to 1000 ml, filter, divide into packages, and sterilize at 105°C for 30 minutes to obtain the product.

[0173] Example 36: Preparation of lyophilized formulation

[0174] prescription:

[0175]

[0176] Preparation method: Take 700 ml of water for injection, add compound IV-4 and stir to dissolve, then take glucose and add it to the solution and stir to dissolve, adjust the pH of the solution to 8-9 with hydrochloric acid, filter, pour into a 7 ml vial, add half a stopper, place in a freeze dryer, freeze dry, press the stopper, and roll the cap.

[0177] Example 37: Preparation of tablets

[0178] prescription:

[0179]

[0180]

[0181] Preparation method: Take the prescribed amount of starch, microcrystalline cellulose and compound III-2, mix them evenly; use 4% povidone K30 solution to make the materials into a soft material, use a 20-mesh screen to granulate, dry at 40-50°C until the moisture content is qualified, pass through a 20-mesh screen to granulate, add the prescribed amount of magnesium stearate, finally mix, measure the intermediate content, and determine the tablet weight; tablet press.

[0182] Stability studies

[0183] Example 38: Stability study of the compounds of the present invention

[0184] The compound of the present invention was placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months, and samples were taken to determine properties, related substances and contents. The results are shown in Table 5 below.

[0185] Table 5: Accelerated stability test results of the compounds of the present invention

[0186]

[0187]

[0188] The results show that the compounds of the present invention have good stability under accelerated conditions, especially the sodium salt compound has significantly better stability than other compounds.

Claims

1. An antihistamine compound or a pharmaceutically acceptable salt thereof, the structure of which is shown in Formula I: in, X1 is H, an alkali metal or choline; X2 is H, an alkali metal or choline; n1 is an integer of 1-5; n2 is an integer of 1-3.

2. The antihistamine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salts include salts formed with inorganic salts or organic bases.

3. The antihistamine compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The organic base is selected from choline hydroxide, meglumine or diisopropylethylamine.

4. The antihistamine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salts include metal salts or salts formed with basic amino acids.

5. The antihistamine compound or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: The metal salt is selected from alkali metal salts and alkaline earth metal salts, the alkali metal salt is selected from sodium salts or potassium salts, the alkaline earth metal salt is selected from calcium salts, magnesium salts or barium salts, and the basic amino acid is selected from lysine and arginine.

6. An antihistamine compound or a pharmaceutically acceptable salt thereof, characterized in that Selected from the following compounds:

7. A pharmaceutical composition comprising a therapeutic amount of the antihistamine compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. Use of the antihistamine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of antiallergic drugs.

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