Antihistamine compounds, methods for preparing them, and their 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 antihistamine compounds, methods 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. Depending on the type of its structure, it 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, resulting in an extended QT interval on the electrocardiogram, inducing torsades de pointes (TdP), and causing lethal arrhythmia. The H1 receptor antagonists astemizole and terfenadine were withdrawn from the market due to cardiotoxicity problems.

[0004] Many tricyclic antihistamine derivatives have been synthesized, including the highly active desloratadine. However, as research has progressed, its side effects have gradually become apparent. At low concentrations, desloratadine's affinity for M-type choline receptors is similar to that of histamine H receptors, inevitably causing symptoms such as fatigue, dry mouth, dizziness, and headache. It may also have a sedative effect in patients with impaired blood-brain barrier resistance. Furthermore, at high concentrations, desloratadine exhibits a certain inhibitory effect on potassium channels, which may affect the cardiovascular system. Therefore, modifying the structure of desloratadine to select new drugs with stronger antihistamine activity, superior physical and chemical properties, and better stability is of great research value. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] One object of the present invention is to provide antihistamine compounds and pharmaceutically acceptable salts thereof.

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

[0007] A further object of the present invention is to provide pharmaceutical uses of compounds that typically treat diseases such as seasonal and perennial allergic rhinitis, allergic conjunctivitis, and urticaria.

[0008] A further object of the present invention is to disclose pharmaceutical compositions having such compounds and pharmaceutically acceptable salts thereof as the main active ingredients. [Means for solving the problem]

[0009] The contents of the present invention will be described in detail below, combining the objectives of the present invention.

[0010] The present invention specifically relates to compounds having a structure of formula I and pharmaceutically acceptable salts thereof. JPEG0007894170000001.jpg65170 (where R1 is a halogen, X1 is H, alkali metal, amino acid, meglumine, or choline, X2 is H, alkali metal, amino acid, meglumine, or choline, n1 is an integer between 1 and 5, and n2 is an integer between 1 and 3.)

[0011] The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof, selected from the following. JPEG0007894170000002.jpg164170JPEG0007894170000003.jpg214170JPEG0007894170000004.jpg240170JPEG0007894170 000005.jpg230170JPEG0007894170000006.jpg226170JPEG0007894170000007.jpg222170JPEG0007894170000008.jpg99170

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

[0013] The preparation of compound I is as follows: JPEG0007894170000009.jpg200170 (Here, the definitions of R1, X1, X2, and n are as described above.) The synthesis of M1 is described in the literature report, and a person skilled in the art can carry it out according to the reported method.

[0014] Compound I is prepared by dissolving M1 in an aprotic solvent such as dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine, or toluene, adding a solution of halohydrin or its corresponding organic solvent dropwise, and reacting it at -5 to 60°C with an organic 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 at -5 to 60°C. The molar ratio of M1 to halohydrin is 1:(1 to 10).

[0015] Compound II is prepared by dissolving M1 or compound I in an aprotic solvent such as dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine, or toluene, adding a dropwise solution of chlorobromoalkane or its corresponding organic solvent, and reacting it at -5 to 60°C with an organic 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 at -5 to 60°C. The molar ratio of M1 or compound I to chlorobromoalkane is 1:(1 to 10).

[0016] Compound II, obtained as a product of the above, is dissolved in acetonitrile, acetone, methanol, ethanol, or tetrahydrofuran, triethylamine is added and the mixture is stirred uniformly, phosphoric acid is added dropwise, and the mixture is reacted at 25-80°C to prepare Compound III.

[0017] Compound III, the product obtained above, is dissolved in acetonitrile, acetone, methanol, ethanol, or tetrahydrofuran, and sodium hydroxide, potassium hydroxide, choline hydroxide, arginine, or proline is added. The mixture is reacted at 25-80°C to prepare Compound IV, a pharmaceutically acceptable salt.

[0018] The compounds of the present invention are used in the form of pharmaceutical formulations, and the route of administration may be parenteral (e.g., intravenous or intramuscular administration) or oral administration.

[0019] Pharmaceutical compositions of the compounds of the present invention are prepared as follows. By standard and prior art, the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally pharmaceutically acceptable excipients and additives to prepare fine particles or microspheres. Solid dosage forms include tablets, granular dispersants, capsules, sustained-release tablets, sustained-release pellets, etc. The solid carrier may be at least one substance that can function as a diluent, flavoring agent, solubilizer, 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, methylcellulose and other cellulosic substances, microcrystalline cellulose, low-melting-point paraffin, polyethylene glycol, mannitol, cocoa butter, etc. Liquid dosage forms include solvents, suspensions such as injections, powders, etc.

[0020] The amount of the active ingredient (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 physician's diagnosis, and the amount or concentration of the compound used can be adjusted within a wide range. Typically, 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%. [Modes for carrying out the invention]

[0021] The present invention will be further described below with reference to specific examples, but these examples are not intended to limit the present invention. Preparation Examples

[0022] Example 1: Preparation of Intermediate 1 JPEG0007894170000010.jpg55170 Add 100 ml of tetrahydrofuran, 10 g of M1, 33.3 g of chlorobromomethane, and 2.57 g of sodium hydroxide to a reaction flask, slowly heat up to 60 °C, stir and react for 6 h. After the reaction is completed, filter the reaction solution, evaporate the solvent from the filtrate under reduced pressure to obtain 8.67 g of Intermediate 1 (yield 75%).

[0023] Example 2: Preparation of Intermediate 2 JPEG0007894170000011.jpg55170 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 remained the same.

[0024] Example 3: Preparation of Intermediate 3 JPEG0007894170000012.jpg52170 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 remained the same.

[0025] Example 4: Preparation of Intermediate 4 JPEG0007894170000013.jpg53170 Intermediate 4 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to chlorobromoethane, and other materials remained the same.

[0026] Example 5: Preparation of Intermediate 5 JPEG0007894170000014.jpg55170 Intermediate 5 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to chlorobromoethane, M1 was changed to M2, and other materials remained the same.

[0027] Example 六: Preparation of Intermediate 6 JPEG0007894170000015.jpg58170 Intermediate 6 was prepared in the same manner as the preparation method of Intermediate 1 in Example 1, but chlorobromomethane was changed to chlorobromoethane, M1 was changed to M3, and other materials remained the same.

[0028] Example 7: Preparation of Intermediate 7 JPEG0007894170000016.jpg46170 Intermediate 7 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed one of the ingredients to 1,3-chlorobromopropane, while keeping the other ingredients the same.

[0029] Example 8: Preparation of Intermediate 8 JPEG0007894170000017.jpg48170 Intermediate 8 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed M1 to M2 and kept the other materials the same.

[0030] Example 9: Preparation of Intermediate 9 JPEG0007894170000018.jpg50170 Intermediate 9 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed M1 to M3 and kept the other materials the same.

[0031] Example 10: Preparation of intermediate 10 JPEG0007894170000019.jpg45170 Intermediate 10 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed one ingredient to 1,4-chlorobromobutane, while keeping the other ingredients the same.

[0032] Example 11: Preparation of intermediate 11 JPEG0007894170000020.jpg48170 Intermediate 11 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed M1 to M2 and kept the other materials the same.

[0033] Example 12: Preparation of intermediate 12 JPEG0007894170000021.jpg45170 Intermediate 12 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed M1 to M3 and kept the other materials the same.

[0034] Example 13: Preparation of intermediate 13 JPEG0007894170000022.jpg47170 Intermediate 13 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed one of the ingredients to 1,5-chlorobromopentane, while keeping the other ingredients the same.

[0035] Example 14: Preparation of intermediate 14 JPEG0007894170000023.jpg53170 Intermediate 14 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed M1 to M2 and kept the other materials the same.

[0036] Example 15: Preparation of intermediate 15 JPEG0007894170000024.jpg45170 Intermediate 15 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed M1 to M3 and kept the other materials the same.

[0037] Example 16: Preparation of intermediate 16 JPEG0007894170000025.jpg53170 Intermediate 16 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed one ingredient to 1-chloroethanol, while keeping the other ingredients the same.

[0038] Example 17: Preparation of intermediate 17 JPEG0007894170000026.jpg50170 Intermediate 17 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed one ingredient to 1-chloropropanol, while keeping the other ingredients the same.

[0039] Example 18: Preparation of Intermediate 18 JPEG0007894170000027.jpg55170 Intermediate 18 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed one ingredient to 1-chlorobutanol, while keeping the other ingredients the same.

[0040] Example 19: Preparation of intermediate 19 JPEG0007894170000028.jpg46170 Intermediate 19 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but chlorobromomethane was not produced. We changed one ingredient to 1-chloropentanol, while keeping the other ingredients the same.

[0041] Example 20: Preparation of intermediate 20 JPEG0007894170000029.jpg48170 Intermediate 20 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but M1 was changed to intermediate 16, and the other materials were kept the same.

[0042] Example 21: Preparation of intermediate 21 JPEG0007894170000030.jpg45170 Intermediate 21 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but M1 was changed to intermediate 17, and the other materials were the same.

[0043] Example 22: Preparation of intermediate 22 JPEG0007894170000031.jpg52170 Intermediate 22 was prepared in the same manner as intermediate 1 in Example 1, but M1 was changed to intermediate 18, and the other materials were the same.

[0044] Example 23: Preparation of intermediate 23 JPEG0007894170000032.jpg45170 Intermediate 23 was prepared in the same manner as the preparation method for intermediate 1 in Example 1, but M1 was changed to intermediate 19, and the other materials were kept the same.

[0045] Example 24: Preparation of Compound III-1 JPEG0007894170000033.jpg56170 Place 30 ml of acetonitrile in a reaction flask, add 7.0 g of triethylamine and 8.0 g of phosphoric acid, stir, and heat to 60°C to dissolve. Slowly add intermediate 1, and after the addition is complete, keep warm at 60°C for 6 hours. After the stop, evaporate the solvent under reduced pressure at 60°C until the solvent is completely evaporated. Then add 20 ml of water and stir, slowly add concentrated hydrochloric acid dropwise to adjust the pH to 1.5, add 50 ml of ethyl acetate (25 ml x 2 times) to extract the aqueous layer, remove the aqueous layer, and then evaporate the ethyl acetate under reduced pressure at 50°C to obtain compound III-1 9.8 g (yield 83.7%).

[0046] Example 25: Preparation of Compound III-2 JPEG0007894170000034.jpg56170 Compound III-2 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 2, and the other materials were the same.

[0047] Example 26: Preparation of Compound III-3 JPEG0007894170000035.jpg56170 Compound III-3 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 3, and the other materials were the same.

[0048] Example 27: Preparation of Compound III-4 JPEG0007894170000036.jpg59170 Compound III-4 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 4, and the other materials were the same.

[0049] Example 28: Preparation of Compound III-5 JPEG0007894170000037.jpg56170 Compound III-5 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 5, and the other materials were the same.

[0050] Example 29: Preparation of Compound III-6 JPEG0007894170000038.jpg60170 Compound III-6 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 6, and the other materials were the same.

[0051] Example 30: Preparation of Compound III-7 JPEG0007894170000039.jpg57170 Compound III-7 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 7, and the other materials were the same.

[0052] Example 31: Preparation of Compound III-8 JPEG0007894170000040.jpg54170 Compound III-8 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 8, and the other materials were the same.

[0053] Example 32: Preparation of Compound III-9 JPEG0007894170000041.jpg57170 Compound III-9 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 9, and the other materials were the same.

[0054] Example 33: Preparation of Compound III-10 JPEG0007894170000042.jpg49170 Compound III-10 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 10, and the other materials were the same.

[0055] Example 34: Preparation of Compound III-11 JPEG0007894170000043.jpg52170 Compound III-11 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 11, and the other materials were the same.

[0056] Example 35: Preparation of Compound III-12 JPEG0007894170000044.jpg53170 Compound III-12 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 12, and the other materials were the same.

[0057] Example 36: Preparation of Compound III-13 JPEG0007894170000045.jpg49170 Compound III-13 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 13, and the other materials were the same.

[0058] Example 37: Preparation of Compound III-14 JPEG0007894170000046.jpg49170 Compound III-14 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 14, and the other materials were the same.

[0059] Example 38: Preparation of Compound III-15 JPEG0007894170000047.jpg49170 Compound III-15 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 15, and the other materials were the same.

[0060] Example 39: Preparation of Compound III-16 JPEG0007894170000048.jpg47170 Compound III-16 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 20, and the other materials were the same.

[0061] Example 40: Preparation of Compound III-17 JPEG0007894170000049.jpg47170 Compound III-17 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 21, and the other materials were the same.

[0062] Example 41: Preparation of Compound III-18 JPEG0007894170000050.jpg48170 Compound III-18 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 22, and the other materials were the same.

[0063] Example 42: Preparation of Compound III-19 JPEG0007894170000051.jpg43170 Compound III-19 was prepared in the same manner as the preparation method for Compound III-1 in Example 24, but intermediate 1 was changed to intermediate 23, and the other materials were kept the same.

[0064] Example 43: Preparation of Compound IV-1 JPEG0007894170000052.jpg51170 Add 10g of compound III-1 to the reaction flask, then add 50ml of ethanol, heat to 50°C and stir to dissolve, add 1.91g of sodium hydroxide and stir to dissolve, stir for 20 minutes while maintaining the temperature, filter, cool the filtrate to 0-5°C, maintain the temperature and crystallize for 4 hours, filter, and air dry the filtered cake to obtain 9.9g of compound IV-1 (yield 89.7%). Example 44: Preparation of Compound IV-2 JPEG0007894170000053.jpg54170 Compound IV-2 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-4, sodium hydroxide was changed to potassium hydroxide, and the other materials were the same.

[0065] Example 45: Preparation of Compound IV-3 JPEG0007894170000054.jpg48170 Compound IV-3 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-7, sodium hydroxide was changed to choline hydroxide, and the other materials were the same.

[0066] Example 46: Preparation of Compound IV-4 JPEG0007894170000055.jpg51170 Compound IV-4 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-10, and the other materials were the same.

[0067] Example 47: Preparation of Compound IV-5 JPEG0007894170000056.jpg49170 Compound IV-5 was prepared in the same manner as the preparation method for Compound IV-1 in Example 43, but Compound III-1 was changed to Compound III-10, sodium hydroxide was changed to choline hydroxide, and the other materials were the same.

[0068] Example 48: Preparation of Compound IV-6 JPEG0007894170000057.jpg47170 Compound IV-6 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-13, sodium hydroxide was changed to choline hydroxide, and the other materials were the same.

[0069] Example 49: Preparation of Compound IV-7 JPEG0007894170000058.jpg44170 Compound IV-7 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-13, sodium hydroxide was changed to choline hydroxide, and the other materials were the same.

[0070] Example 50: Preparation of Compound IV-8 JPEG0007894170000059.jpg46170 Compound IV-8 was prepared in the same manner as the preparation method for Compound IV-1 in Example 43, but Compound III-1 was changed to Compound III-16, sodium hydroxide was changed to arginine, and the other materials were the same.

[0071] Example 51: Preparation of Compound IV-9 JPEG0007894170000060.jpg44170 Compound IV-9 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-17, and the other materials were the same.

[0072] Example 52: Preparation of Compound IV-10 JPEG0007894170000061.jpg44170 Compound IV-10 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-18, and the other materials were the same.

[0073] Example 53: Preparation of Compound IV-11 JPEG0007894170000062.jpg38170 Compound IV-11 was prepared in the same manner as the preparation method for compound IV-1 in Example 43, but compound III-1 was changed to compound III-19, and the other materials were the same. Investigation of physical and chemical properties

[0074] Example 54: Investigation of the solubility of the compound of the present invention The solubility of the compound of the present invention and comparative compounds in water, methanol, and isopropyl alcohol was tested, respectively. JPEG0007894170000063.jpg53170 Comparison compound 1: Hydroxyhexyl desloratadine JPEG0007894170000064.jpg49170 Comparison compound 2: Hydroxypentyl desloratadine JPEG0007894170000065.jpg54170 Comparative compound 3: Hydroxybutyldesloratadine JPEG0007894170000066.jpg54170 Comparative compound 4: Hydroxypropyl desloratadine JPEG0007894170000067.jpg56170 Comparative compound 5: Hydroxyethyl desloratadine JPEG0007894170000068.jpg52170 Comparative compound 6: Desloratadine. The test results are shown in Table 1 below.

[0075] (Table 1) Solubility test results JPEG0007894170000069.jpg214170

[0076] The results show that the solubility of the compounds of the present invention in water is better than that of desloratadine and hydroxyethyl desloratadine series compounds, and in particular, its sodium salt has higher solubility in water, making it more suitable for the preparation of intravenous formulations. This indicates that the compounds of the present invention have solubility in methanol and isopropyl alcohol equivalent to that of desloratadine. Drug efficacy research

[0077] Example 55: Anti-asthmatic effect of the compound of the present invention on histamine-induced asthma guinea pigs Guinea pigs were taken, placed in polymethyl methacrylate bell jars, and histamine hydrochloride solution (0.8 mg / mL) was sprayed for 40 seconds using ultrasonic atomization. The time it took for the guinea pigs to develop asthma was recorded. The incubation period was defined as the time of convulsions and falls, and guinea pigs with an incubation period exceeding 180 seconds 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 of the present invention group (1 mg / kg). Guinea pigs were orally administered 2 mL / kg bw, and 60 minutes after administration, each guinea pig was placed in a glass bell jar and sprayed with histamine hydrochloride solution under the same conditions as pre-selection. The incubation period for asthma was recorded, and if asthma did not develop after 8 minutes or more, it was recorded as 8 minutes. The results were then statistically analyzed.

[0078] The results are shown in Table 2.

[0079] (Table 2) Results of histamine antagonism by the test compound (x ± s, n = 5) JPEG0007894170000070.jpg208170

[0080] The test results showed that the incubation period after administration of the compound of the present invention was significantly longer than that of the normal control group, the desloratadine group, and the hydroxyethyl desloratadine series group, indicating that the compound of the present invention inhibits asthma more effectively than the control group and the normal group. Example 56: Effect of isolated ileal smooth muscle of guinea pig on muscle tone

[0081] A guinea pig was stunned with a stick, its abdomen was immediately opened, and a section of the ileum approximately 15 cm long was extracted. The contents of the intestinal section were washed with Tyrod's solution and placed in a Tyrod's solution at a constant temperature of 37°C, while simultaneously supplying oxygen. A 1 cm long experimental intestinal tract was cut and placed in 20 ml of Tyrod's solution at a constant temperature of 37°C, with continuous oxygen supply. One end of the intestinal tract was secured to a ventilation hook, and the other end was connected to a muscle tone transducer and secured, then pulled to a computer interface. The muscle tone of the ileal smooth muscle was recorded using a BL system, and the experiment was conducted after the contraction of the intestinal section stabilized.

[0082] Once the ileal contraction curve stabilized, the muscle tone value before drug addition was recorded. Then, the drug or DMSO was added, and the average muscle tone value of the ileal contraction curve at that point was recorded 5 minutes later. Eight parallel operations were performed. The antispasmodic percentage was calculated according to the following formula. Antispasmodic effect percentage = (Muscle tone before adding the test compound - Muscle tone after adding the test compound) / Muscle tone before adding the test compound × 100% The results are shown in Table 3.

[0083] (Table 3) Results of histamine antagonism by the test compound (x ± s, n = 8) JPEG0007894170000071.jpg199170

[0084] Once the ileal peristalsis curve stabilized, the tension level was recorded before adding the compound. 0.05 mL of histamine was added, and once maximal contraction was reached, 0.05 mL each of a different compound or DMSO was added. The average tension level was observed and recorded 3 minutes after the addition of histamine and the compound. Eight parallel operations were performed, and the antispasmodic percentage was calculated. Antispasmodic percentage = (Stress after histamine addition - Stress after test compound addition) / Stress after histamine addition × 100% The results are shown in Table 4.

[0085] (Table 4) Results of histamine antagonism by the test compound (x ± s, n = 8) The test results 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 pharmaceutical products

[0086] Example 57: Preparation of oral solution Prescription: Preparation method: Add sucrose to 500 ml of sterile water for injection and stir to dissolve. Add 6 g of compound IV-1 to the solution and stir to dissolve. Add citric acid and ethyl 4-hydroxybenzoate to the solution and stir to dissolve. Add water to 1000 ml, filter, individually package, and sterilize at 105°C for 30 minutes to obtain the product.

[0087] Example 58: Preparation of lyophilized formulation Prescription: JPEG0007894170000074.jpg23170 Preparation method: Add compound IV-4 to 700 ml of sterile water for injection, stir to dissolve, add glucose to the solution, stir to dissolve, adjust the pH of the solution to 8-9 with hydrochloric acid, filter, fill into 7 ml vials, attach half of the stopper, place in a freeze-drying oven, freeze-dry, stopper, and cap.

[0088] Example 59: Preparation of tablets Prescription: Preparation method: The prescribed amounts of starch, microcrystalline cellulose, and compound III-12 were homogeneously mixed. The material was softened with a 4% povidone K30 solution, granulated using a 20-mesh sieve, dried at 40-50°C to the specified moisture content, sieved again using a 20-mesh sieve to granulate, the prescribed amount of magnesium stearate was added, and finally mixed. The intermediate content was measured, the weight of the tablets was measured, and the tablets were compressed. Stability research

[0089] Example 60: Investigation of the stability of the compound of the present invention The compound of the present invention was left for 6 months under conditions of 40°C ± 2°C and 75% ± 5% relative humidity, and the results of measuring its properties, related substances, and content are shown below.

[0090] (Table 5) Results of accelerated stability tests of the compound of the present invention JPEG0007894170000076.jpg231170

[0091] The results indicate that the compounds of the present invention have good stability under accelerated conditions, and in particular, the stability of the sodium salt compounds is significantly better than that of the other compounds.

Claims

1. An antihistamine compound whose structure is represented by formula I, and a pharmaceutically acceptable salt thereof. (Here, R １ is a halogen, X １ H is an alkali metal, choline, and X 2 (where n1 is an integer from 1 to 5, and n2 is an integer from 1 to 3.)

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

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

5. The antihistamine compound and 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 salt or potassium salt, the alkaline earth metal salt is selected from calcium salt, magnesium salt or barium salt, and the basic amino acid salt is selected from lysine salt and arginine salt.

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

7. A pharmaceutical composition comprising a therapeutic amount of an antihistamine compound and / or a pharmaceutically acceptable salt thereof according to any one of claims l to 6, and other pharmaceutically acceptable auxiliary materials.

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

9. An antihistamine compound and a pharmaceutically acceptable salt thereof, characterized by being selected from the following compounds.

10. A pharmaceutical composition comprising a therapeutic amount of the antihistamine compound and / or a pharmaceutically acceptable salt thereof according to claim 9, and other pharmaceutically acceptable auxiliary materials.

11. The use of the antihistamine compound or a pharmaceutically acceptable salt thereof according to claim 9 in the preparation of an antiallergic drug.

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