Salts of Carebastine and their uses

Abstract

The present invention relates to the field of pharmaceutical chemistry, and discloses a salt of carebastine and its use, which solves the problems of the prior art, such as poor solid form of carebastine, many impurities, instability, difficulty in purification, difficulty in mass synthesis, and inapplicability to medicinal use. The salt of carebastine of the present invention includes, but is not limited to, acid salts or base salts, particularly potassium salt, sodium salt, methanesulfonate salt and p-toluenesulfonate salt. The salt of carebastine of the present invention is used in the preparation of drugs for histamine H1 receptor antagonists. The salt of carebastine of the present invention has the characteristics of easy purification, high stability, simple process, easy industrial production, and good hygroscopicity and convenient storage. And the salt of the present invention can enter the body quickly and exert its medicinal effect, has good oral absorption, and is superior to ebastine in both safety and individual variation, and is a promising anti-allergic disease drug for development.

Description

[Technical field]

[0001] This application claims priority to a patent for invention entitled "Salt of Carebastine and Use Thereof" filed on May 6, 2022, with patent number CN202210486129.2, which is incorporated herein by reference.

[0002] Technical Field The present invention relates to the field of medicinal chemistry, in particular to salts and uses of carebastine. [Background technology]

[0003] Allergic disease (anaphylactia), also known as anaphylaxis, refers to a disease that causes an allergic or metamorphic reaction due to contact with an allergen. Currently, the most common allergic diseases in clinical practice mainly include allergic rhinitis, asthma, urticaria, atopic dermatitis, allergic ophthalmic conjunctivitis, and allergic gastrointestinal disease. An allergic reaction is a reaction that causes tissue damage or functional disorders when an immunized organism is stimulated by the same antigen again. In recent years, the incidence rate of allergic diseases in China has been on the rise, approaching 40%. Taking allergic rhinitis as an example, it is the disease with the highest incidence rate, and according to incomplete statistics, the number of people suffering from the disease worldwide has exceeded 500 million so far. Allergic rhinitis is mainly seen as nasal congestion, nasal itching, runny nose, sneezing, etc. If allergic diseases occur repeatedly for a long period of time, and are not prevented or treated in a timely manner, it may affect the quality of life of patients, such as sleep, social life, and work.

[0004] Histamine H1 receptor antagonists are drugs commonly used in the prevention and treatment of allergic diseases, and are divided into three generations according to their development process. The first generation, such as chlorpheniramine, promethazine, diphenhydramine, and cyproheptadine, have a short duration of action and have central nervous system depressant and sedative effects, but they have side effects such as drowsiness, epilepsy, skin rash, and allergic shock. The second generation, such as loratadine, cetirizine, ebastine, astemizole, and terfenadine, have a long duration of action and no sedative effects. Among them, astemizole and terfenadine have been found to prolong the QTc interval and, in a very small number of cases, cause arrhythmia under excessive or other specific conditions, so that their approval has now been revoked by the regulatory authorities. The third generation is represented by mizolastine, desloratadine, and levocetirizine. Among them, mizolastine has a unique dual action of antihistamine and resistance to other inflammatory mediators. Desloratadine is an active metabolite of loratadine, which has resolved the issue of large individual differences in loratadine. Levocetirizine is a single isomer of cetirizine.

[0005] Ebastine tablets are second-generation histamine H1 receptor antagonists, and are strong, long-acting, and highly selective histamine H1 receptor blocking agents. They have no antagonistic effect on acetylcholine receptors in the central nervous system, selectively block histamine H1 receptors, and have no sedative effect. They are used to treat various allergic diseases, such as urticaria, allergic rhinitis, eczema, dermatitis, prurigo, and skin pruritus. After oral administration, ebastine is rapidly absorbed and is metabolized in large part by a strong hepatic transit effect. It is metabolized mainly by two pathways. In one pathway, it is dealkylated by the action of CYP3A enzyme to produce dealkylated ebastine metabolites. In the other pathway, it is metabolized by the action of CYP2J2 enzyme to produce hydroxyebastine metabolites, which are further oxidized by CYP2J2 and CYP3A4 enzymes to produce the acidic metabolite carebastine. Neither ebastine nor its metabolite, kalestatin, enters the central nervous system and has no adverse central nervous system or anticholinergic effects.

[0006] QTc interval prolongation associated with ebastine treatment has not yet been reported or documented. Thus, the use of ebastine once daily offers an effective and well-tolerated alternative to other second-generation antihistamines currently used in the frontline treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. Compared with first-generation H1 receptor antagonists, ebastine did not obviously cause cardiac and psychomotor abnormalities. However, after oral administration, the onset of effect of ebastine is 1-4 hours, making it unsuitable for the emergency treatment of acute allergic diseases such as acute urticaria, asthma, etc.

[0007] Currently, the only histamine H1 receptor antagonists that are clinically effective and fast are levocetirizine and cetirizine. Levocetirizine and cetirizine are more easily absorbed into the central nervous system than ebastine, and clinically cause drowsiness and headache. Therefore, clinically, there is a strong demand for histamine H1 receptor antagonists that are non-sedative and fast-acting, and can be applied to patients with acute allergic diseases such as acute urticaria and asthma.

[0008] Carebastine is the in vivo active metabolite of ebastine and its structural formula is shown in Formula I.

[0009] [ka]

[0010] Like ebastine, carebastine has a strong selective antagonistic effect on histamine H1 receptors, can inhibit the release of histamine, and has a weak antagonistic effect on H1 receptors in the central nervous system and anticholinergic effect. By directly administering carebastine, the problem of the slow onset of effect when ebastine is orally administered can be effectively solved. However, carebastine does not have a good solid form, and as a result, carebastine cannot meet pharmaceutical requirements. That is, a preparation with a poor solid form cannot be used stably, is difficult to purify, cannot be mass-produced, cannot be quality-controlled, and is not pharmacologic acceptable, so that carebastine is not currently available on the market as a drug. Summary of the Invention

[0011] One of the objects of the present invention is to provide a salt of carebastine that solves the problems of the prior art, such as poor solid form of carebastine, high impurity content, instability, difficulty in purification, difficulty in mass synthesis, and inapplicability for medicinal purposes.

[0012] A second object of the present invention is to provide uses of salts of carebastine.

[0013] A third object of the present invention is to provide a composition comprising a salt of carebastine.

[0014] In order to achieve the above object, the present invention adopts the following technical solutions.

[0015] In one embodiment, the present invention provides a pharma- ceutically acceptable salt of carebastine, which is an acid salt formed from carebastine and an acid, or a base salt formed from carebastine and a base.

[0016] In some embodiments of the invention, the acid salt is an inorganic acid salt or an organic acid salt.

[0017] Furthermore, the inorganic acid salt is selected from sulfates, hydrogen sulfates, nitrates, hydrobromides, hydroiodides, carbonates, hydrogen carbonates, sulfites, bisulfites, pyrosulfates, monohydrogen phosphates, dihydrogen phosphates, perchlorates, persulfates, hemisulfates, bisulfates, thiocyanates, phosphates, pyrophosphates, and metaphosphates.

[0018] Further, the organic acid salts include formates, acetates, propionates, butyrates, benzoates, malonates, succinates, pyruvates, methanesulfonates, ethanesulfonates, propanesulfonates, citrates, 4-nitrobenzoates, benzenesulfonates, p-toluenesulfonates, malates, propiolates, 2-butynoates, 2-hydroxy-ethanesulfonates, vinyl acetates, tartrates, L-tartrates, fumarates, isethionates, maleates, lactates, and lactobionates. , pamoate, salicylate, galactaric acid, glucoheptonic acid, mandelate, 1,2-ethanedisulfonate, oxalate, trifluoroacetate, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1,4-dioxide, hexyne-1,6-dioxide, hydroxyacetate, alginate, ascorbate, erythorbate, aspartate, L-aspartate, glutamate, L-glutamate, 2-phenoxybenzoate, 2-(4-hydroxybenzoate), ... Dibenzoyl)benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorinated benzoate, camphorate, itaconate, camphorsulfonate, levocamphorsulfonate, toluate, dinitrobenzoate, sulfamate, lactobionate, galacturonic acid, cyclopentylpropionate, dodecyl sulfate, acrylate, cyclopentanepropionate, glycerolinate, methoxybenzoate, digluconate, gluconate, heptanoate, hexabenzoate Acetate, 2-hydroxy-ethanesulfonate, trimethylacetate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectinate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, neopentylate, picrate, stearate, 2,The salt is selected from 2-dichloroacetate, acylated amino acid salt, alginate, 4-acetaminobenzenesulfonate, decanoate, cholate, octylate, nonanoate, cyclamate, phthalate, cysteine ​​hydrochloride, sorbate, pamoate, mucate, glycine hydrochloride, naphthalenedisulfonate, xylenesulfonate, cystine dihydrochloride, undecanoate, polyvinylsulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyvinylsulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and pentanoate.

[0019] In some embodiments of the invention, the organic acid salt is selected from methanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenedisulfonate, naphthalene-1-sulfonate, or naphthalene-2-sulfonate.

[0020] Furthermore, the organic acid salt is selected from methanesulfonate, benzenesulfonate, or p-toluenesulfonate.

[0021] In some embodiments of the invention, the alkali salt is selected from an alkali metal salt, a substituted or unsubstituted ammonium salt, an amine salt, a basic amino acid salt, or a substituted or unsubstituted pyridine salt.

[0022] Furthermore, the metal alkali salt is selected from the group consisting of lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, iron salts, and zinc salts, and is preferably the potassium salt or the sodium salt.

[0023] Furthermore, the substituted or unsubstituted ammonium salt is selected from an ammonium salt, a tetramethylammonium salt, a tetraethylammonium salt, or a choline salt.

[0024] Furthermore, the amine salt is selected from methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, isopropylamine salt, tert-butylamine salt, diisopropylamine salt, 2-ethylaminoethoxide, trometamol salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, piperidine salt, piperazine salt, morpholine salt, meglumine salt, N-methylglucosamine salt, dimethylglucosamine salt, ethylglucosamine salt, dicyclohexylamine salt, 1,6-hexanediamine salt, galactosamine salt, glucosamine salt, trihydroxymethylaminomethane salt, aminopropylene glycol salt, 1-amino-2,3,4-butane trialkoxide, and sericin salt.

[0025] Furthermore, the basic amino acid salt is selected from a lysine salt, an arginine salt, an L-arginine salt, a histidine salt, an L-histidine salt, a sarcosine salt, an L-lysine salt, or an ornithine salt.

[0026] Furthermore, the substituted or unsubstituted pyridine salt is selected from a pyridine salt, a methylpyridine salt, an ethylpyridine salt, or a propylpyridine salt.

[0027] In some embodiments of the present invention, the salt of carebastine is a single salt or a double salt, in which the molar ratio of carebastine to the salt-forming group in the single salt is 1:1 to 2:1, and in which the molar ratio of carebastine to the salt-forming group in the double salt is 1:4 to 4:1.

[0028] Further, in some embodiments, the salt of carebastine is selected from the following:

[0029] [ka]

[0030] Meanwhile, the present invention provides a method for preparing a salt of carebastine described in any one of the above, comprising the step of heating and reacting 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid with an acid or a base under organic solvent conditions to form a salt.

[0031] Furthermore, the acid includes organic acids or inorganic acids, preferably, the organic acids include, but are not limited to, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or naphthalene-2-sulfonic acid.

[0032] Furthermore, the base includes a metal base, preferably, the metal base includes, but is not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, or magnesium hydroxide.

[0033] Further, the organic solvent includes, but is not limited to, alcohols, esters, or nitriles. Preferably, the alcohols include, but are not limited to, methanol, ethanol, or isopropanol, the esters include, but are not limited to, ethyl acetate, and the nitriles include, but are not limited to, acetonitrile.

[0034] Furthermore, the heating temperature is selected from the range of 30 to 100°C, and preferably 50 to 60°C.

[0035] In a third aspect, the present invention provides a pharmaceutical composition of a salt of carebastine according to any one of the above, further comprising a pharma- ceutically acceptable carrier.

[0036] The above-mentioned "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which an active ingredient is administered, and which, within the scope of reasonable medical judgment, is suitable for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0037] In a fourth aspect, the present invention provides a use of a salt of carebastine according to any one of the above in the preparation of a histamine H1 receptor antagonist.

[0038] Furthermore, the above uses include the use of a salt of carebastine described in any one of the above in the manufacture of a medicament for treating and / or preventing an allergic disease.

[0039] Furthermore, the allergic disease is an acute allergic disease.

[0040] Furthermore, the allergic disease is selected from urticaria, allergic rhinitis, eczema, dermatitis, and skin pruritus.

[0041] More preferably, the acute allergic disease is selected from acute urticaria or acute allergic rhinitis.

[0042] In the present invention, the names represented by the English abbreviations are as follows:

[0043] DMAC: Acetamide

[0044] EA: Ethyl acetate

[0045] DMSO: Dimethyl sulfoxide

[0046] CMC-Na: sodium carboxymethylcellulose.

[0047] Effect of the Invention The present invention has the following advantageous effects compared to the prior art.

[0048] The carebastine salt of the present invention is a white powdery solid, has a good medicinal solid form, and has high purity and stability. Carebastine is an active metabolite of ebastine, and after entering the body, it exerts its medicinal effect without going through enzyme metabolism, and has a fast time to exert its medicinal effect, which can avoid safety risks due to individual differences in administration caused by genetic polymorphism of the enzyme, and life-threatening risks due to persistent allergy caused by ineffectiveness. The carebastine salt of the present invention can provide a new option for clinical allergy patients.

[0049] Carebastine is an acid-base amphoteric compound. The applicant has conducted a large number of experiments and thoroughly studied salts of carebastine, and found that the salts that carebastine can form are limited, and the purity and stability of the acid salts are superior to those of the base salts, for example, the purity and stability of the p-toluenesulfonic acid salt are superior to those of the potassium salt. However, the inventor has found that the hygroscopicity of the carebastine acid salt is very high, but the potassium salt and the p-toluenesulfonic acid salt of the present invention have better hygroscopicity.

[0050] On the other hand, the p-toluenesulfonate salt of the present invention is not as soluble as free carebastine, but in a pharmacokinetic study on rats, it was surprisingly found that both p-toluenesulfonate and potassium salt of carebastine have better pharmacokinetic properties than ebastine and free carebastine when administered at the same molar ratio. For example, in the AUC comparison, the AUC of carebastine in the body for the p-toluenesulfonate group and potassium salt group of carebastine was obviously greater than that of the ebastine group and free carebastine group, and the T of the generated carebastine was significantly greater than that of the ebastine group and free carebastine group. max Ebastine T max This means that the onset of efficacy of the carebastine salt of the present invention is faster and has better pharmacokinetic properties when administered at the same molar ratio. In addition, according to a study of acute toxicity in mice, the acute toxicity of both the p-toluenesulfonate and potassium salt of carebastine is lower than that of ebastine. [Brief description of the drawings]

[0051] [Figure 1] HPLC chromatogram of carebastine (free state) on day 0.

[0052] [Diagram 2] This is an HPLC chromatogram of carebastine (free state) after irradiation with light (12 days).

[0053] [Diagram 3] HPLC chromatogram of carebastine p-toluenesulfonate on day 0.

[0054] [Figure 4] HPLC chromatogram of carebastine p-toluenesulfonate after irradiation with light (12 days). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] The present invention will be described in more detail below with reference to examples and experimental examples. The examples and experimental examples of the present invention are only intended to explain the technical solution of the present invention and are not intended to limit the present invention. Any equivalent substitutions in the field of the present invention made based on the disclosure of the present invention are within the scope of protection of the present invention.

[0056] The structure of the compound was determined by nuclear magnetic resonance ( 1 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0057] The liquid chromatograph mass spectrometer (LC-MS) was an Agilent G6120B (used with a liquid-phase Agilent 1260). 1 1 H NMR) was performed using a Bruker AVANCE-400 or Bruker AVANCE-800. 1 1 H NMR shifts (δ) are given in parts per million (ppm), the internal standard is tetramethylsilane (TMS), and the chemical shifts are scaled at 10 -6 It is expressed in units of (ppm).

[0058] The term "room temperature" in the present invention means a temperature between 10°C and 30°C.

[0059] Example 1: Preparation of potassium 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionate (carebastine potassium salt)

[0060] [ka]

[0061] Step 1: Preparation of methyl 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionate

[0062] [ka]

[0063] 4-(diphenylmethoxy)piperidine hydrochloride (473 mg, 1.77 mmol), DMAC (4.5 ml), K3PO4 (1.13 g, 5.3 mmol), and KI (29 mg, 0.177 mmol) were added to a 25 ml one-neck flask, stirred, and heated to 100°C. 2-[4-(4-chloro-1-butyryl)phenyl]-2-methylpropionate methyl (600 mg, 2.12 mmol) was weighed and dissolved in 1 ml of DMAC, and the reaction solution was slowly added dropwise and reacted for 4 to 6 hours while maintaining the temperature, and the completion of the reaction of the raw materials was detected by TLC. The temperature was lowered to room temperature, and isopropyl acetate and water were added, and the mixture was stirred and separated. The aqueous phase was extracted with isopropyl acetate, and the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 500 mg of the target product, with a yield of 45% and a purity of 97.3%.

[0064] ESI-MS: m / z = 514.3 (M+H) + .

[0065] 1H NMR (400 MHz, CDCl3) δ: 7.93 (d, J=8.3Hz, 2H), 7.47 (m, 4H), 7.42 (d, J=8.3Hz, 2H), 7.30 (m, 4H), 7.18 (m, 2H), 3.64 (s, 3H),2.98 (m, 4H), 2.42-2.40 (m, 4H), 1.96 (m, 4H), 1.62 (s, 6H), 1.42 (m, 4H).

[0066] Step 2: Preparation of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid (carebastine)

[0067] [ka]

[0068] In a 25ml three-neck flask, (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl-2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)-butyryl)phenyl)-2-methylpropionate methyl (320mg, 0.62mmol), 1.5ml methanol, and 2ml 10% NaOH were added, heated to 60℃, and reacted for 2 hours, and the reaction completion of the raw material was detected by TLC. After the reaction was completed, it was cooled to room temperature, concentrated and dried, EA was added, and hydrochloric acid was added to adjust the pH to 2-3, separated, washed with water once, and the organic phase was dried, concentrated and dried to obtain 300mg of the target product. The yield was 95% and the purity was 95.0%.

[0069] ESI-MS: m / z = 500.3 (M+H) + .

[0070] 1H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57-7.24 (m,12H), 5.48 (s,1H),3.73 (m, 1H), 3.05-3.02 (m, 2H), 2.77-2.66 (m, 6H), 2.20-2.07 (m, 2H), 2.00-1.81 (m,4H), 1.58 (s, 6H).

[0071] Step 3: Preparation of potassium 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionate (carebastine potassium salt)

[0072] [ka]

[0073] A 25 ml three-neck flask was charged with 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid (499 mg, 1 mmol) and 3.5 ml of acetonitrile, and the mixture was heated to 60° C., potassium hydroxide (56 mg, 1 mmol) was added, and the mixture was stirred and cooled to cause precipitation of a white solid. The solid was filtered and dried to obtain 500 mg of carebastine potassium salt with a yield of 90% and a purity of 98.67%.

[0074] ESI-MS: m / z = 500.3 (M+H) + .

[0075] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57-7.24 (m,12H), 5.48 (s,1H),3.73 (m, 1H), 3.05-3.02 (m, 2H), 2.77-2.66 (m, 6H), 2.20-2.07 (m, 2H), 2.00-1.81 (m,4H), 1.58 (s, 6H).

[0076] Example 2: Preparation of sodium 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionate (carebastine sodium salt)

[0077] [ka]

[0078] The preparation method of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid in this embodiment is the same as that in Example 1.

[0079] A 25 ml three-neck flask was charged with 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid (499 mg, 1 mmol) and 3.5 ml of acetonitrile, heated to 60° C., sodium hydroxide (40 mg, 1 mmol) was added and stirred for 1 hour, concentrated and dried, methyl tert-butyl ether was added and stirred, filtered and dried to obtain 458 mg of carebastine sodium salt with a yield of 85% and a purity of 96.98%.

[0080] ESI-MS: m / z = 500.3 (M+H) + .

[0081] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57-7.24 (m,12H), 5.48 (s,1H),3.73 (m, 1H), 3.05-3.02 (m, 2H), 2.77-2.66 (m, 6H), 2.20-2.07 (m, 2H), 2.00-1.81 (m,4H), 1.58 (s, 6H).

[0082] Example 3: Preparation of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid p-toluenesulfonate (carebastine p-toluenesulfonate)

[0083] [ka]

[0084] The preparation method of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid in this embodiment is the same as that in Example 1.

[0085] A 25 ml three-neck flask was charged with 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid (500 mg, 0.1 mmol) and 1 ml of isopropanol, and the mixture was heated to 60° C., p-toluenesulfonic acid (172 mg, 1 mmol) was added and stirred, and the temperature was lowered to precipitate a white solid, which was filtered and dried to obtain 585 mg of carebastine p-toluenesulfonate with a yield of 87% and a purity of 99.99%.

[0086] ESI-MS: m / z = 500.3 (M+H) + .

[0087] 1 H NMR (400 MHz, CDCl3) δ:7.94 (d, 2H), 7.49 (dd, 4H), 7.36 (dt, 8H), 7.29-7.21 (m, 2H), 7.11 (d, 2H), 5.48 (s,1H),3.73 (m, 1H), 3.05-3.02 (m, 2H), 2.77-2.66 (m, 6H), 2.41(s,3H),2.20-2.07 (m, 2H), 2.00-1.81 (m,4H), 1.58 (s, 6H).

[0088] Example 4: Preparation of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid methanesulfonate (carebastine methanesulfonate)

[0089] [ka]

[0090] The preparation method of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid in this embodiment is the same as that in Example 1.

[0091] A 25 ml three-neck flask was charged with 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid (499 mg, 1 mmol) and 3.5 ml of EA, heated to 60° C., methanesulfonic acid (96 mg, 1 mmol) was added and stirred for 1 hour, concentrated and dried, methyl tert-butyl ether was added and stirred, filtered, and dried to obtain 482 mg of carebastine methanesulfonate as a white solid, with a yield of 81% and a purity of 96.81%.

[0092] ESI-MS: m / z = 500.3 (M+H) + .

[0093] 1 H NMR (400 MHz, CDCl3) δ: δ:7.75-7.63 (m, 2H), 7.57-7.24 (m,12H), 5.48 (s,1H),3.73 (m, 1H), 3.29(s,3H),3.09 (s, 1H),3.05-3.02 (m, 2H), 2.77-2.66 (m, 6H), 2.20-2.07 (m, 2H), 2.00-1.81 (m,4H), 1.58 (s, 6H).

[0094] Example 5: Preparation of Carebastine p-Toluenesulfonate

[0095] [ka]

[0096] A 25 ml three-neck flask was charged with 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid (500 mg, 0.1 mmol) and 1 ml of isopropanol, heated to 80° C., p-toluenesulfonic acid (172 mg, 1 mmol) was added, and the mixture was stirred to react completely. The temperature was lowered, the mixture was crystallized, filtered, and dried to obtain 565 mg of carebastine p-toluenesulfonate with a yield of 84% and a purity of 97.91%.

[0097] ESI-MS: m / z = 500.3(M+H)+.

[0098] 1 H NMR (400 MHz, CDCl3) δ:7.94 (d, 2H), 7.49 (dd, 4H), 7.36 (dt, 8H), 7.29-7.21 (m, 2H), 7.11 (d, 2H), 5.48 (s,1H),3.73 (m, 1H), 3.05-3.02 (m, 2H), 2.77-2.66 (m, 6H), 2.41(s,3H),2.20-2.07 (m, 2H), 2.00-1.81 (m,4H), 1.58 (s, 6H).

[0099] In each experimental example of the present invention, "Ebastine (Comparative Example 1 group, purchased)" means that the experimental sample used in the corresponding group is commercially purchased ebastine (Comparative Example 1), and "Carebastine p-toluenesulfonate (Example 3 group)" means that the experimental sample used in the corresponding group is carebastine p-toluenesulfonate prepared in Example 3. Similar descriptions should be interpreted in the same way.

[0100] Experimental Example 1: Histamine shock experiment in guinea pigs

[0101] 1. Experimental Sample Ebastine (Comparative Example Group 1, purchased), carebastine potassium salt (Example Group 1), carebastine sodium salt (Example Group 2), carebastine p-toluenesulfonate (Example Group 3), carebastine methanesulfonate (Example Group 4).

[0102] 2. Experimental Method Sixty guinea pigs weighing about 220g were randomly divided into six groups: blank control group, Example 1 group, Example 2 group, Example 3 group, Example 4 group, and ebastine group. Except for the blank control group, the remaining groups were intragastrically administered with the corresponding drug at a dose equivalent to 1.00mg / kg ebastine, and the blank group was administered with an equal volume of 0.5% CMC-Na solution. The drug administration volume was 10ml / kg in each group. One hour after drug administration, 2ml / kg of 0.125wt.% histamine phosphate saline solution was intravenously injected into the lateral side of the hind foot of the guinea pig. After completing the injection within 10 seconds, the time was immediately measured with a stopwatch, and the animals were observed to show accelerated breathing and a latent period of convulsive falling.

[0103] 3. Experimental Results

[0104] [Table 1]

[0105] Comparison with blank control group: p<0.01 Comparison with ebastine group (Comparative Example 1 group): ▲ p<0.01

[0106] The compounds of the examples and ebastine significantly prolonged the respiratory acceleration latency and convulsion latency of guinea pigs sensitized by histamine after intravenous injection of histamine (p<0.01) compared with the blank control group, and no animal death was observed. The compounds of the examples 1, 2, 3, and 4 groups significantly prolonged the respiratory acceleration latency and convulsion latency of guinea pigs compared with the ebastine administration group (p<0.01).

[0107] Experimental example 2: Pharmacokinetics experiment in rats

[0108] 1. Experimental Sample Ebastine (Comparative Example Group 1), Carebastine (Comparative Example Group 2), Carebastine potassium salt (Example Group 1), Carebastine p-toluenesulfonate (Example Group 3).

[0109] 2. Experimental Method

[0110] Twenty-four SD rats weighing approximately 180-200g were randomly divided into four groups, each with six rats, half male and half female. The corresponding drugs were administered orally and intragastrically. The rats were fasted for 12 hours before drug administration, but water intake was not restricted. In each group, the drug was administered at a molar equivalent to 10mg / kg ebastine. The groups and doses are as follows:

[0111] Comparative Example 1 Group: Ebastine, 10 mg / kg,

[0112] Comparative Example 2 Group: Carebastine, 10.63 mg / kg,

[0113] Example 1 group: Carebastine potassium salt, 11.11 mg / kg,

[0114] Example Group 3: carebastine p-toluenesulfonate, 14.39 mg / kg.

[0115] Sample preparation: All samples were prepared on a normal stage in the preparation room. Using DMSO as a solvent, ebastine, carebastine, and solutions prepared in Examples 1 and 3 were prepared to be 1.00 mg / mL. As rat administration solutions, a 10 mg / mL ebastine solution, a 10 mg / mL carebastine solution, an 11.11 mg / kg solution in Example 1, and a 14.39 mg / mL solution in Example 3 were each prepared in a 0.5% CMC-Na solution.

[0116] Blank blood samples were collected before dosing, and blood samples were collected at the following time points after dosing: 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, and 24 hours. Approximately 0.5 mL of blood was collected and placed in EDTA-K2 tubes, and plasma was centrifuged and stored at -80°C. A liquid chromatography-tandem mass spectrometry system (LC-MS / MS) was used to detect and analyze the prototype and metabolites of carebastine in plasma samples, and pharmacokinetic parameters were calculated.

[0117] 3. Experimental Results

[0118] After single-dose administration of Example 1, Example 3, ebastine and carebastine compounds to SD rats, the content of prototypes in the ebastine group was less than 3ng / mL, which meant that ebastine could be rapidly metabolized after entering the body.

[0119] After single administration of the compounds of Example 1, Example 3, ebastine and carebastine to SD rats, the average pharmacokinetic parameters of carebastine produced by metabolism in each group are shown in the following table.

[0120] [Table 2]

[0121] As can be seen from the above table, after the compounds of Example 1 and Example 3 were orally administered to rats, the AUC last was significantly superior to the ebastine group and the carebastine group, but the peak time T max was smaller than that of the ebastine group and the carebastine group. This means that the examples 1 and 3 of the present invention can enter the body quickly and inhibit histamine H1 receptors. They have potential for clinical treatment of patients with acute allergic diseases such as acute urticaria.

[0122] In addition, during the pharmacokinetic study in rats, the AUC and C of three female rats in the ebastine group were max AUC and C for three male rats max It was found that there was a smaller and more obvious difference. This means that after ebastine administration, SD rats showed gender difference in ebastine. Meanwhile, the compound of the present invention example did not show gender difference.

[0123] As a result, when administered at equimolar doses, the compounds of the examples of the present invention had a shorter time to peak (T max ) is rapid, in particular the compound of Example 3 is very fast in its onset of effect and shows no gender difference, which has potential for clinical treatment of patients with acute allergic diseases such as acute urticaria, and can reduce individual dosing differences.

[0124] Experimental example 3: Acute toxicity study in mice

[0125] 1. Experimental Sample Ebastine (Comparative Example 1), Carebastine potassium salt, Carebastine p-toluenesulfonate.

[0126] 2. Experimental Method

[0127] Seventy healthy adult KM mice weighing 18-22 g were randomly divided into seven groups: a blank control group, a high dose group of Example 1, a low dose group of Example 1, a high dose group of Example 3, a low dose group of Example 3, a high dose group of ebastine, and a low dose group of ebastine. Each group was half male and half female.

[0128] The high dose group of Example 1, the high dose group of Example 3, and the high dose group of ebastine were administered at the same molar dose, 5.38 g / kg, 6.72 g / kg, and 5 g / kg, respectively. The low dose group of Example 1, the low dose group of Example 3, and the low dose group of ebastine were administered at the same molar dose, 2.69 g / kg, 3.36 g / kg, and 2.5 g / kg, respectively. All drugs were administered intragastrically. The blank group was administered an equal volume of 0.5% CMC-Na solution. All animals were fasted for 12 hours before drug administration, but drinking water was not restricted.

[0129] After drug administration, the mice were continuously kept and observed for 14 days, and the mice were observed and recorded daily for toxic reactions (e.g., death, etc.). After the observation period ended, all surviving animals were dissected and each organ was roughly observed for significant lesions.

[0130] 3. Experimental Results

[0131] After a single intragastric administration of low doses of the compounds of Examples 1 and 3 and ebastine, no obvious abnormalities were found in all animals at all observation stages, and no obvious abnormalities were found in most observations after animal necropsy, with MDT>2.5g / kg.After a single intragastric administration of high doses of the compounds of Examples 1 and 3 and ebastine, the mortality rate of ebastine group was higher than that of Examples 1 and 3, indicating that the compounds of Examples 1 and 3 of the present invention are safer than ebastine.

[0132] [Table 3]

[0133] Experimental example 4: Stability study

[0134] 1. Experimental Sample Carebastine (Comparative Example 2, Comparative Example 2'), Carebastine potassium salt (Example 1), Carebastine p-toluenesulfonate (Example 3, Example 5).

[0135] 2. Experimental Method

[0136] As samples, three portions each of carebastine (Comparative Example 2), carebastine purified product (Comparative Example 2'), carebastine potassium salt (Example 1), carebastine p-toluenesulfonate (Example 3), and carebastine p-toluenesulfonate (Example 5) were placed in weighing bottles. Each group of samples was exposed to high temperature (60°C), high humidity (RH 80%), and light irradiation (5000 Lux). After 12 days, samples were taken and detection was performed. The above-mentioned Carebastine purified product Comparative Example 2' was produced by subjecting Comparative Example 2 to column chromatography using ordinary technical means in this field.

[0137] The detection method is as follows. An appropriate amount of each sample was taken, precisely weighed, dissolved in acetonitrile, and quantitatively diluted to a solution containing approximately 0.08 mg per ml. Each sample solution was injected into the liquid chromatograph using high performance liquid chromatography with octadecylsilane-bonded silica gel as the packing, water-acetonitrile (1:1) as the mobile phase, a detection wavelength of 256 nm, a column temperature of 35°C, and a sample injection volume of 10 ul, and the chromatogram was recorded.

[0138] 3. Experimental Results

[0139] As can be seen from the results in the table below, carebastine p-toluenesulfonate was stable under conditions of high temperature, high humidity, and light irradiation, and carebastine potassium salt was slightly less stable under light irradiation than carebastine p-toluenesulfonate, but free carebastine (Comparative Example 2) was unstable under light irradiation, with an increase in impurities and a clear decrease in purity. Figures 1 to 4 also show HLPC chromatograms of free carebastine (Comparative Example 2) and carebastine p-toluenesulfonate exposed to light for 0 days and 12 days. This proves that carebastine (free state) is decomposed significantly by light irradiation, has stability problems, and generates a large amount of impurities exceeding 0.1%, making it unsuitable as a pharmaceutical product.

[0140] [Table 4]

[0141] Experimental Example 5: Examination of Hygroscopicity

[0142] 1. Experimental Sample Carebastine (Comparative Example 2), Carebastine hydrochloride (Comparative Example 3), Carebastine potassium salt (Example 1), Carebastine p-toluenesulfonate (Example 3). However, carebastine hydrochloride can be prepared by referring to the description in Patent US6340761, and has a purity of 99% or more.

[0143] 2. Experimental Method

[0144] (1) Prepare a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and, on the day before the experiment, place it in an appropriate constant temperature dryer at 25°C ± 1°C (with a saturated solution of ammonium chloride or ammonium sulfate placed at the bottom) or in an artificial humidity chamber (set temperature 25°C ± 1°C, relative humidity 80% ± 2%) and accurately weigh the weight (m1).

[0145] (2) An appropriate amount of sample was taken and placed in the weighing bottle so that the thickness of the sample was generally about 1 mm, and the weight (m2) was precisely measured.

[0146] (3) The weighing bottle was opened and left with the cap under the above constant temperature and humidity conditions for 24 hours.

[0147] (4) The cap of the weighing bottle was closed and the weight (m3) was accurately measured.

[0148] (5) Weight increase rate = (m3-m2) / (m2-m1)×100%

[0149] 3. Experimental Results

[0150] The results of hygroscopicity are shown in the table below. The results show that the carebastine potassium salt and carebastine p-toluenesulfonate of the present invention have superior hygroscopicity to the free carebastine and carebastine hydrochloride.

[0151] [Table 5]

[0152] The results are as defined by the Pharmacopoeia: "hygroscopic" indicates a weight gain of less than 15% but equal to or greater than 2%, "extremely hygroscopic" indicates a weight gain of more than 15%, "not hygroscopic or slightly hygroscopic" indicates a weight gain of less than 0.2%, and "slightly hygroscopic" indicates a weight gain of less than 2% but equal to or greater than 0.2%.

[0153] Experimental Example 6: Solubility test

[0154] 1. Experimental Sample Carebastine (Comparative Example 2), Carebastine p-toluenesulfonate (Example 3).

[0155] 2. Experimental Method

[0156] Hydrochloric acid solution of pH 1.2: 7.65 ml of hydrochloric acid was taken, diluted to 1000 ml with water, and shaken uniformly to obtain the solution.

[0157] Phosphate buffer solution of pH 4.5: 3.40278 g of KH2PO4 was weighed out, dissolved in water, diluted to 500 ml, and shaken to obtain a homogenous solution.

[0158] Phosphate buffer solution of pH 6.8: 3.40353 g of KH2PO4 and 0.4428 g of sodium hydroxide were weighed out, dissolved in water, diluted to 500 ml, and shaken to obtain a homogenous solution.

[0159] Appropriate amounts of the compounds of Example 3 and Comparative Example 2 were placed in Erlenmeyer flasks containing 50 ml of water, 50 ml of a hydrochloric acid solution of pH 1.2, 50 ml of a phosphate buffer solution of pH 4.5, and 50 ml of a phosphate buffer solution of pH 6.8, respectively, to make the solutions supersaturated, and insoluble matter was clearly observed.

[0160] The Erlenmeyer flask was placed in a thermostatic water bath at 37°C and a shaking speed of 120 rpm. Sampling was performed at 24, 48, and 72 hours, and the samples were detected by liquid chromatography.

[0161] 3. Experimental Results

[0162] [Table 6]

[0163] As shown in the above table, in all test media, the solubility of Example 3 was lower than that of Comparative Example 2 at different times. However, the compound of Example 3 showed better pharmacokinetic properties in rat pharmacokinetic experiments.

[0164] The above example is merely one of the preferred embodiments of the present invention, and does not limit the scope of protection of the present invention. However, any substantially meaningless changes or modifications made in the design concept and spirit of the subject of the present invention, as long as the technical problems solved are still consistent with the present invention, should be included in the scope of protection of the present invention.

Claims

1. A salt of carebastine, which is an acid salt formed from carebastine and an acid, or a base salt formed from carebastine and a base.

2. The salt of carebastine according to claim 1, characterized in that the acid salt comprises an inorganic acid salt or an organic acid salt, preferably the organic acid salt is selected from methanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenedisulfonate, naphthalene-1-sulfonate, or naphthalene-2-sulfonate.

3. The salt of carebastine according to claim 2, wherein the acid salt is selected from the group consisting of a methanesulfonate, a benzenesulfonate, and a p-toluenesulfonate.

4. The salt of carebastine according to claim 1, characterized in that the base salt comprises an alkali metal salt, a substituted or unsubstituted ammonium salt, an amine salt, a basic amino acid salt, or a substituted or unsubstituted pyridine salt, preferably selected from a lithium salt, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, an aluminum salt, an iron salt, or a zinc salt.

5. The salt of carebastine according to claim 4, characterized in that the base salt is selected from the potassium salt or the sodium salt.

6. The salt of carebastine according to any one of claims 1 to 5, characterized in that the salt of carebastine is a single salt or a double salt, the molar ratio of carebastine to a salt-forming group in the single salt being 1:1 to 2:1, and the molar ratio of carebastine to a salt-forming group in the double salt being 1:4 to 4:

1.

7. The salt of carebastine according to any one of claims 1 to 6, characterized in that the salt of carebastine is selected from the following: 【Chemistry 1】

8. 8. A method for preparing the salt of carebastine according to any one of claims 1 to 7, comprising the step of reacting 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butyryl)phenyl)-2-methylpropionic acid with an acid or a base by heating under an organic solvent condition to form a salt.

9. A pharmaceutical composition comprising the salt of carebastine according to any one of claims 1 to 7, further comprising a pharma- ceutically acceptable carrier.

10. Preferably, the use includes use in the preparation of a medicament for treating and / or preventing an allergic disease, More preferably, the allergic disease is an acute allergic disease, More preferably, the allergic disease is selected from urticaria, allergic rhinitis, eczema, dermatitis, or skin pruritus; Even more preferably, the use of the salt of carebastine according to any one of claims 1 to 7 in the preparation of a medicament of a histamine H1 receptor antagonist, wherein said acute allergic disease is acute urticaria or acute allergic rhinitis.

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