Anti-histamine compound, its preparation method and use

Abstract

The present invention relates to antihistamine compounds, a method for preparing the same, and uses thereof. Specifically, it relates to an antihistamine compound having a structure of formula I, and a pharmaceutically acceptable salt thereof, a method for preparing the same, a pharmaceutical composition containing the antihistamine compound having a structure of formula I and a pharmaceutically acceptable salt thereof as an active ingredient, and their use in the treatment of diseases such as seasonal and perennial allergic rhinitis, allergic conjunctivitis, and urticaria.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and more specifically, relates to an antihistamine compound, a method for preparing the same, and their use in the field of medicine.

[0002] This application claims the priority of a Chinese patent application filed with the China National Intellectual Property Administration on July 21, 2022, with an application number of 202210874033.3 and an invention title of "Antihistamine Compound, Preparation Method and Use Thereof", and all its contents are incorporated herein by reference.

Background Art

[0003] Allergic diseases are major diseases affecting human health. The development and availability of anti-allergy drugs with stronger effects and fewer side effects have always been one of the key research focuses for pharmaceutical professionals worldwide. H1 receptor antagonists are the main drugs for the clinical treatment of allergic diseases. As a result of studying the structure-activity relationship, it has been shown that H1 receptor antagonists generally consist of an aromatic ring region, a connecting section, and an alkaline amine region. According to the type of their structure, they can be roughly divided into ethylenes, aminoalkyl ethers, propylamines, and tricyclic drugs. The main side effects during the clinical application of H1 receptor antagonists are central depression and cardiotoxicity. The former is because the H1 receptor antagonist molecule has high lipid solubility and can easily pass through the blood-brain barrier, causing sedation and hypnosis. The latter is because certain H1 receptor antagonists may inhibit the delayed rectifier potassium current potassium ion channel in human cardiomyocytes. As a result, the QT interval of the electrocardiogram is prolonged, inducing torsades de pointes (TdP) and causing lethal arrhythmia. Astemizole and terfenadine, which are H1 receptor antagonists, were withdrawn from the market due to cardiotoxicity problems.

[0004] Although many tricyclic antihistamine derivatives have been synthesized, among them is desloratadine with high activity. However, as research has deepened, its side effects have gradually become apparent. At low concentrations, due to the similar affinity of desloratadine for M-type cholinergic receptors and histamine H receptors, symptoms such as fatigue, dry mouth, dizziness, and headache are inevitably generated. Also, there is a possibility of sedative effects in patients without blood-brain barrier resistance. In addition, desloratadine has a certain inhibitory effect on potassium channels at high concentrations, which may thereby affect the cardiovascular system. Therefore, modifying the structure of desloratadine to screen for new drugs with more potent antihistamine activity, better physical and chemical properties, and better stability has great research value.

Summary of the Invention

Problems to be Solved by the Invention

[0005] One object of the present invention is to provide an antihistamine compound and a pharmaceutically acceptable salt thereof.

[0006] Another object of the present invention is to provide a method for preparing such a compound.

[0007] A further object of the present invention is to provide the pharmaceutical use of a compound for treating diseases such as seasonal / perennial allergic rhinitis, allergic conjunctivitis, and urticaria.

[0008] Yet another object of the present invention is to disclose a pharmaceutical composition containing such a compound and a pharmaceutically acceptable salt thereof as the main active ingredient.

Means for Solving the Problems

[0009] Hereinafter, in combination with the objects of the present invention, the content of the present invention will be described in detail.

[0010] Specifically, the present invention relates to a compound having the structure of formula I and a pharmaceutically acceptable salt thereof. JPEG2025519828000001.jpg65170(Here, R1 is a halogen, X1 is H, an alkali metal, an amino acid, meglumine, or choline, X2 is H, an alkali metal, an amino acid, meglumine, or choline, n1 is an integer from 1 to 5, and n2 is an integer from 1 to 3.)

[0011] The present invention provides a compound of formula I and a pharmaceutically acceptable salt thereof, selected from the following. JPEG2025519828000002.jpg164170JPEG2025519828000003.jpg214170JPEG2025519828000004.jpg240170JPEG2025519828000005.jpg230170JPEG2025519828000006.jpg226170JPEG2025519828000007.jpg222170JPEG2025519828000008.jpg99170

[0012] The present invention also provides for treating diseases such as seasonal and perennial allergic rhinitis, allergic conjunctivitis, and urticaria using a pharmaceutical composition comprising a compound of formula I, a pharmaceutically acceptable salt, or such a substance.

[0013] The preparation of the compound of formula I is as follows. JPEG2025519828000009.jpg200170(Here, the definitions of R1, X1, X2, and n are as described above.) The synthesis of M1 has been reported in the literature and can be carried out by those skilled in the art according to the reported methods.

[0014] Dissolve M1 in an aprotic solvent such as dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine, or toluene, dropwise add a solution of halohydrin or its corresponding organic solvent, and react at -5 to 60 °C using 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 as an acid binder to prepare Compound I. The molar ratio of M1 to halohydrin is 1:(1 to 10).

[0015] Dissolve M1 or Compound I in an aprotic solvent such as dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine, or toluene, dropwise add a solution of chlorobromoalkane or its corresponding organic solvent, and react at -5 to 60 °C using 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 as an acid binder to prepare Compound II. The molar ratio of M1 or Compound I to chlorobromoalkane is 1:(1 to 10).

[0016] Dissolve Compound II, the product obtained above, in acetonitrile, acetone, methanol, ethanol, or tetrahydrofuran, add triethylamine and stir uniformly, dropwise add phosphoric acid, and react at 25 to 80 °C to prepare Compound III.

[0017] Dissolve Compound III, the product obtained above, in acetonitrile, acetone, methanol, ethanol, or tetrahydrofuran, add sodium hydroxide, or potassium hydroxide, or choline hydroxide, or arginine, or proline, and react at 25 to 80 °C to prepare Compound IV, which is a pharmaceutically acceptable salt.

[0018] The compounds of the present invention are used in the form of pharmaceutical preparations, and the administration route thereof may be either a parenteral route (for example, intravenous or intramuscular administration) or oral administration.

[0019] The pharmaceutical composition of the compound of the present invention is prepared as follows. By standard and conventional techniques, the compound of the present invention is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally a pharmaceutically acceptable adjuvant and excipient, to prepare microparticles or microspheres. Solid dosage forms include tablets, granular dispersions, capsules, sustained-release tablets, sustained-release pellets, and the like. The solid carrier may be at least one substance that can function as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, disintegrant, and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, talc, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic substances such as methylcellulose, microcrystalline cellulose, low melting point paraffin, polyethylene glycol, mannitol, cocoa butter, and the like. Liquid dosage forms include solvents, suspensions such as injections, powders, and the like.

[0020] The amount of the active ingredient (the compound of the present invention) contained in the pharmaceutical composition and unit dosage form can be specifically applied according to the patient's condition and the doctor's diagnosis, and the amount or concentration of the compound used can be adjusted within a wide range. Usually, the range of the amount of the active compound is 0.5% to 90% by weight of the composition. Another preferred range is 0.5 to 70%.

Mode for Carrying Out the Invention

[0021] Hereinafter, the present invention will be further described with reference to specific examples, which do not limit the present invention. Preparation Example

[0022] Example 1: Preparation of Intermediate 1 100 ml of tetrahydrofuran, 10 g of M1, 33.3 g of chlorobromomethane, and 2.57 g of sodium hydroxide were added to a reaction flask, and the temperature was slowly raised to 60 °C and stirred for 6 h to react. After the reaction was completed, the reaction solution was filtered, and the solvent was evaporated under reduced pressure from the filtrate to obtain 8.67 g of Intermediate 1 (yield 75%).

[0023] Example 2: Preparation of Intermediate 2 Intermediate 2 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but M1 was changed to M2, and other materials were the same.

[0024] Example 3: Preparation of Intermediate 3 Intermediate 3 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but M1 was changed to M3, and other materials were the same.

[0025] Example 4: Preparation of Intermediate 4 Intermediate 4 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to chloro-bromoethane, and other materials were the same.

[0026] Example 5: Preparation of Intermediate 5 Intermediate 5 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to chloro-bromoethane, M1 was changed to M2, and other materials were the same.

[0027] Example 6: Preparation of Intermediate 6 Intermediate 6 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to chloro-bromoethane, M1 was changed to M3, and other materials were the same.

[0028] Example 7: Preparation of Intermediate 7 JPEG2025519828000016.jpg46170 Intermediate 7 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,3-chlorobromopropane, and other materials remained the same.

[0029] Example 8: Preparation of Intermediate 8 JPEG2025519828000017.jpg48170 Intermediate 8 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,3-chlorobromopropane, M1 was changed to M2, and other materials remained the same.

[0030] Example 9: Preparation of Intermediate 9 JPEG2025519828000018.jpg50170 Intermediate 9 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,3-chlorobromopropane, M1 was changed to M3, and other materials remained the same.

[0031] Example 10: Preparation of Intermediate 10 JPEG2025519828000019.jpg45170 Intermediate 10 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,4-chlorobromobutane, and other materials remained the same.

[0032] Example 11: Preparation of Intermediate 11 JPEG2025519828000020.jpg48170 Intermediate 11 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,4-chlorobromobutane, M1 was changed to M2, and other materials remained the same.

[0033] Example 12: Preparation of Intermediate 12 Intermediate 12 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,4-chlorobromobutane, M1 was changed to M3, and other materials remained the same.

[0034] Example 13: Preparation of Intermediate 13 Intermediate 13 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,5-chlorobromopentane, and other materials remained the same.

[0035] Example 14: Preparation of Intermediate 14 Intermediate 14 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,5-chlorobromopentane, M1 was changed to M2, and other materials remained the same.

[0036] Example 15: Preparation of Intermediate 15 Intermediate 15 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1,5-chlorobromopentane, M1 was changed to M3, and other materials remained the same.

[0037] Example 16: Preparation of Intermediate 16 Intermediate 16 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane was changed to 1-chloroethanol, and other materials remained the same.

[0038] Example 17: Preparation of Intermediate 17 Intermediate 17 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, except that chlorobromomethane It was changed to 1-chloropropanol, and the other materials remained the same.

[0039] Example 18: Preparation of Intermediate 18 Intermediate 18 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to 1-chlorobutanol, and the other materials remained the same.

[0040] Example 19: Preparation of Intermediate 19 Intermediate 19 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to 1-chloropentanol, and the other materials remained the same.

[0041] Example 20: Preparation of Intermediate 20 Intermediate 20 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but M1 was changed to Intermediate 16, and the other materials remained the same.

[0042] Example 21: Preparation of Intermediate 21 Intermediate 21 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but M1 was changed to Intermediate 17, and the other materials remained the same.

[0043] Example 22: Preparation of Intermediate 22 Intermediate 22 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but M1 was changed to Intermediate 18, and the other materials remained the same.

[0044] Example 23: Preparation of Intermediate 23 Intermediate 23 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but M1 was changed to Intermediate 19, and the other materials remained the same.

[0045] Example 24: Preparation of Compound III-1 Put 30 ml of acetonitrile into a reaction flask, add 7.0 g of triethylamine and 8.0 g of phosphoric acid, stir and heat to 60 °C for dissolution. Slowly add Intermediate 1. After the addition is complete, keep the temperature at 60 °C for 6 hours. After the reaction is stopped, evaporate the solvent under reduced pressure at 60 °C. After the solvent is completely evaporated, add 20 ml of water and stir. Slowly dropwise add concentrated hydrochloric acid to adjust the pH to 1.5. Add 50 ml (25 ml × 2 times) of ethyl acetate to extract the aqueous layer and remove the aqueous layer. Then, evaporate ethyl acetate under reduced pressure at 50 °C to obtain 9.8 g of Compound III-1 (yield 83.7%).

[0046] Example 25: Preparation of Compound III-2 Compound III-2 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 2 and other materials remained the same.

[0047] Example 26: Preparation of Compound III-3 Compound III-3 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 3 and other materials remained the same.

[0048] Example 27: Preparation of Compound III-4 Compound III-4 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 4 and other materials remained the same.

[0049] Example 28: Preparation of Compound III-5 Compound III-5 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 5 and other materials remained the same. The file name is JPEG2025519828000037.jpg with a size of 56170.

[0050] Example 29: Preparation of Compound III-6 Compound III-6 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 6 and other materials remained the same. The file name is JPEG2025519828000038.jpg with a size of 60170.

[0051] Example 30: Preparation of Compound III-7 Compound III-7 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 7 and other materials remained the same. The file name is JPEG2025519828000039.jpg with a size of 57170.

[0052] Example 31: Preparation of Compound III-8 Compound III-8 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 8 and other materials remained the same. The file name is JPEG2025519828000040.jpg with a size of 54170.

[0053] Example 32: Preparation of Compound III-9 Compound III-9 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 9 and other materials remained the same. The file name is JPEG2025519828000041.jpg with a size of 57170.

[0054] Example 33: Preparation of Compound III-10 Compound III-10 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 10 and other materials remained the same. The file name is JPEG2025519828000042.jpg with a size of 49170.

[0055] Example 34: Preparation of Compound III-11 Compound III-11 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 11, and other materials remained the same. The file JPEG2025519828000043.jpg has 52170 pixels.

[0056] Example 35: Preparation of Compound III-12 Compound III-12 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 12, and other materials remained the same. The file JPEG2025519828000044.jpg has 53170 pixels.

[0057] Example 36: Preparation of Compound III-13 Compound III-13 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 13, and other materials remained the same. The file JPEG2025519828000045.jpg has 49170 pixels.

[0058] Example 37: Preparation of Compound III-14 Compound III-14 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 14, and other materials remained the same. The file JPEG2025519828000046.jpg has 49170 pixels.

[0059] Example 38: Preparation of Compound III-15 Compound III-15 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 15, and other materials remained the same. The file JPEG2025519828000047.jpg has 49170 pixels.

[0060] Example 39: Preparation of Compound III-16 Compound III-16 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, but Intermediate 1 was changed to Intermediate 20, and other materials remained the same. The file JPEG2025519828000048.jpg has 47170 pixels.

[0061] Example 40: Preparation of Compound III-17 JPEG2025519828000049.jpg47170 Compound III-17 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 21 and other materials remained the same.

[0062] Example 41: Preparation of Compound III-18 JPEG2025519828000050.jpg48170 Compound III-18 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 22 and other materials remained the same.

[0063] Example 42: Preparation of Compound III-19 JPEG2025519828000051.jpg43170 Compound III-19 was prepared in the same manner as the preparation method of Compound III-1 in Example 24, except that Intermediate 1 was changed to Intermediate 23 and other materials remained the same.

[0064] Example 43: Preparation of Compound IV-1 JPEG2025519828000052.jpg51170 10 g of Compound III-1 was added to a reaction flask, followed by 50 ml of ethanol. The mixture was heated to 50 °C, stirred and dissolved. 1.91 g of sodium hydroxide was added and stirred until dissolved. The mixture was stirred for 20 minutes while maintaining the temperature, then filtered. The filtrate was cooled to 0 - 5 °C and crystallized for 4 hours while maintaining the temperature. It was then filtered, and the filter cake was dried by blowing air to obtain 9.9 g of Compound IV-1 (yield 89.7%). Example 44: Preparation of Compound IV-2 JPEG2025519828000053.jpg54170 Compound IV-2 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, except that Compound III-1 was changed to Compound III-4, sodium hydroxide was changed to potassium hydroxide, and other materials remained the same.

[0065] Example 45: Preparation of Compound IV-3 Compound IV-3 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, except that Compound III-1 was changed to Compound III-7, sodium hydroxide was changed to choline hydroxide, and other materials remained the same.

[0066] Example 46: Preparation of Compound IV-4 Compound IV-4 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, except that Compound III-1 was changed to Compound III-10 and other materials remained the same.

[0067] Example 47: Preparation of Compound IV-5 Compound IV-5 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, except that Compound III-1 was changed to Compound III-10, sodium hydroxide was changed to choline hydroxide, and other materials remained the same.

[0068] Example 48: Preparation of Compound IV-6 Compound IV-6 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, except that Compound III-1 was changed to Compound III-13, sodium hydroxide was changed to choline hydroxide, and other materials remained the same.

[0069] Example 49: Preparation of Compound IV-7 Compound IV-7 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, except that Compound III-1 was changed to Compound III-13, sodium hydroxide was changed to choline hydroxide, and other materials remained the same.

[0070] Example 50: Preparation of Compound IV-8 Compound IV-8 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, but Compound III-1 was changed to Compound III-16, sodium hydroxide was changed to arginine, and other materials remained the same.

[0071] Example 51: Preparation of Compound IV-9 Compound IV-9 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, but Compound III-1 was changed to Compound III-17, and other materials remained the same.

[0072] Example 52: Preparation of Compound IV-10 Compound IV-10 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, but Compound III-1 was changed to Compound III-18, and other materials remained the same.

[0073] Example 53: Preparation of Compound IV-11 Compound IV-11 was prepared in the same manner as the preparation method of Compound IV-1 in Example 43, but Compound III-1 was changed to Compound III-19, and other materials remained the same. Investigation of Physical and Chemical Properties

[0074] Example 54: Investigation of the Solubility of the Compounds of the Present Invention The solubilities of the compounds of the present invention and the comparative compounds in water, methanol, and isopropyl alcohol were tested respectively. JPEG2025519828000063.jpg53170 Comparative Compound 1: Hydroxyhexyldesloratadine JPEG2025519828000064.jpg49170 Comparative Compound 2: Hydroxypentyldesloratadine JPEG2025519828000065.jpg54170 Comparative Compound 3: Hydroxybutyldesloratadine JPEG2025519828000066.jpg54170 Comparative Compound 4: Hydroxypropyl desloratadine JPEG2025519828000067.jpg56170 Comparative Compound 5: Hydroxyethyl desloratadine JPEG2025519828000068.jpg52170 Comparative Compound 6: Desloratadine. The test results are shown in Table 1 below.

[0075] (Table 1) Test results of solubility JPEG2025519828000069.jpg214170

[0076] The results show that the solubility of the compounds of the present invention in water is better than that of the compounds of the desloratadine and hydroxyethyl desloratadine series. In particular, its sodium salt has a higher solubility in water and is more suitable for the preparation of intravenous administration preparations. The compounds of the present invention have shown solubility equivalent to that of desloratadine in methanol and isopropyl alcohol. Pharmacodynamic study

[0077] Example 55: Anti-asthmatic effect of the compounds of the present invention on histamine-induced asthma guinea pigs Guinea pigs were taken, placed in bell jars made of polymethyl methacrylate, and a histamine hydrochloride solution (0.8 mg / mL) was sprayed for 40 seconds by ultrasonic atomization. The time when the guinea pigs developed asthma was recorded. Using the time of convulsions and falling as the latent period, guinea pigs with a latent period exceeding 180 s were not selected. The 185 selected guinea pigs were randomly divided into the following 37 groups of 5 each: normal control group, desloratadine group (1 mg / kg), hydroxyethyl desloratadine group (1 mg / kg), hydroxypropyl desloratadine group (1 mg / kg), hydroxybutyl desloratadine group (1 mg / kg), hydroxypentyl desloratadine group (1 mg / kg), hydroxyhexyl desloratadine group (1 mg / kg), and the compound group of the present invention (1 mg / kg). The guinea pigs were force-fed orally at 2 mL / kg bw. Sixty minutes after administration, each guinea pig was placed in a glass bell jar, and a histamine hydrochloride solution was sprayed according to the same conditions as in the pre-selection. The latent period of asthma was recorded. If asthma did not develop even after 8 minutes, it was recorded as 8 minutes, and the results were statistically processed.

[0078] The results are shown in Table 2.

[0079] (Table 2) Results of the histamine antagonistic effect of the test compounds (x￣±s, n = 5) JPEG2025519828000070.jpg208170

[0080] The test results showed that the latent period after administration of the compound of the present invention was significantly longer than that of the normal control group, desloratadine group, and hydroxyethyl desloratadine series groups, indicating that the compound of the present invention inhibits asthma better than the control group and the normal group. Example 56: Effect on the muscle tension of the excised ileum smooth muscle of guinea pigs

[0081] The guinea pigs were anesthetized with a wooden stick, and immediately their abdomens were opened to excise the ileum about 15 cm in length. The contents of the intestinal part were washed with Tyrode's solution and placed in Tyrode's solution at a constant temperature of 37°C while supplying oxygen simultaneously. An experimental intestinal tube (1 cm in length) was cut and placed in 20 ml of Tyrode's solution at a constant temperature of 37°C, and oxygen supply was continued. One end of the intestinal tube was fixed to a ventilation hook, and the other end was connected to and fixed to a muscle tension transducer and led to a computer interface. The muscle tension value of the ileal smooth muscle was recorded using a BL system, and the experiment was carried out after the contraction of the intestinal part was stabilized.

[0082] When the ileal contraction curve was stable, the muscle tension value before adding the drug was recorded, the drug or DMSO was added respectively, and the average muscle tension value of the ileal contraction curve at this time was recorded 5 minutes later. Eight parallel operations were performed. The spasmolytic percentage was calculated according to the following formula. Spasmolytic percentage = (Muscle tension before adding the test compound - Muscle tension after adding the test compound) / Muscle tension before adding the test compound × 100% The results are shown in Table 3.

[0083] (Table 3) Results of the histamine antagonistic effect of the test compound (x￣±s, n = 8) JPEG2025519828000071.jpg199170

[0084] When the ileal peristalsis curve was stable, the tension value was recorded before adding the compound. 0.05 mL of histamine was added, and when the maximum contraction was reached, 0.05 mL of different compounds or DMSO was added one by one. The average tension value 3 minutes after adding histamine and the compound was observed and recorded. Eight parallel operations were performed to calculate the spasmolytic percentage. Spasmolytic percentage = (Tension after adding histamine - Tension after adding the test compound) / Tension after adding histamine × 100% The results are shown in Table 4.

[0085] (Table 4) Results of the histamine antagonistic effect of the test compound (x￣±s, n = 8) The test results of JPEG2025519828000072.jpg194127 show that the compound of the present invention has higher antihistamine activity compared to the desloratadine group and the hydroxyethyl desloratadine series group. Preparation of Formulations

[0086] Example 57: Preparation of Oral Solution Prescription: Preparation method of JPEG2025519828000073.jpg28170: Sucrose was added to 500 ml of water for injection and stirred until dissolved. 6 g of Compound IV-1 was added to the solution and stirred until dissolved. Citric acid and ethyl 4-hydroxybenzoate were added to the solution and stirred until dissolved. Water was added up to 1000 ml, filtered, individually packaged, and sterilized at 105 °C for 30 minutes.

[0087] Example 58: Preparation of Freeze-Dried Preparation Prescription: Preparation method of JPEG2025519828000074.jpg23170: Compound IV-4 was added to 700 ml of water for injection and stirred until dissolved. Glucose was added to the solution and stirred until dissolved. The pH of the solution was adjusted to 8 - 9 with hydrochloric acid, filtered, filled into 7-ml vials, half-capped, placed in a freeze dryer, freeze-dried, stoppered, and capped.

[0088] Example 59: Preparation of Tablets Prescription: Preparation method of JPEG2025519828000075.jpg32170: The prescribed amount of starch, microcrystalline cellulose, and Compound III-12 were uniformly mixed. The material was made into a soft mass using a 4% povidone K30 solution, granulated through a 20-mesh sieve, dried at 40 - 50 °C to a predetermined moisture content, screened through a 20-mesh sieve for sizing, the prescribed amount of magnesium stearate was added, finally mixed, the intermediate content was measured, the tablet weight was measured, and then tabletted. Study on Stability

[0089] Example 60: Investigation on the Stability of the Compound of the Present Invention The results of leaving the compound of the present invention under the conditions of a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months and measuring the properties, related substances and contents are shown.

[0090] (Table 5) Results of the accelerated stability test of the compound of the present invention JPEG2025519828000076.jpg231170

[0091] The results show that the compound of the present invention has good stability under accelerated conditions, and in particular, the stability of the sodium salt compound is significantly superior to that of other compounds.

Claims

1. An antihistamine compound and a pharmaceutically acceptable salt thereof, wherein the structure is represented by Formula I. (Here, R １ is a halogen, X １ is H, an alkali metal, an amino acid, meglumine, or choline, and X 2 is H, an alkali metal, an amino acid, meglumine, or choline, n1 is an integer from 1 to 5, and n2 is an integer from 1 to 3.)

2. The pharmaceutically acceptable salt includes a salt formed with an inorganic base or an organic base. The antihistamine compound and the pharmaceutically acceptable salt thereof according to Claim 1, characterized in that.

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

4. The pharmaceutically acceptable salt includes a metal salt or / and a basic amino acid salt. The antihistamine compound and the pharmaceutically acceptable salt thereof according to Claim 1, characterized in that.

5. 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. The basic amino acid salt is selected from lysine salts and arginine salts. The antihistamine compound and the pharmaceutically acceptable salt thereof according to Claim 4, characterized in that.

6. The antihistamine compound and the pharmaceutically acceptable salt thereof are selected from the following compounds. The antihistamine compound and the pharmaceutically acceptable salt thereof according to Claim 1, characterized in that.

7. A pharmaceutical composition comprising a therapeutically effective amount of the antihistamine compound and / or the pharmaceutically acceptable salt thereof according to any one of Claims 1 to 6, and other pharmaceutically acceptable auxiliary materials.

8. Use of the antihistamine compound or the pharmaceutically acceptable salt thereof according to any one of Claims 1 to 6 in the preparation of an anti-allergy drug.

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