A salt of carisoprodol and its uses

Abstract

The present invention discloses a salt of carisoprodol and its uses, relating to the field of pharmaceutical chemistry, and solving the problems in the prior art such as poor solid form of carisoprodol, many impurities, instability, difficult purification, difficult scale-up synthesis, and inapplicability to medicine. The carisoprodol salt of the present invention includes but is not limited to acid salts or base salts, especially including potassium salt, sodium salt, methanesulfonate and p-toluenesulfonate. The salt of carisoprodol of the present invention has the use in preparing drugs for histamine H1 receptor antagonists. The carisoprodol salt of the present invention has the characteristics of easy purification, high stability, simple process and easy industrial production, and has good hygroscopicity characteristics, which is convenient for storage; at the same time, the salt of the present invention can quickly enter the body to exert a pharmacological effect, has good oral absorption, and its safety and individual differences are superior to ebastine, and it is a promising drug for treating allergic diseases.

Description

[0001] This application claims the priority of the invention patent with the title "A Salt of Carisoprodol and Its Use" and the patent number CN202210486129.2, which was filed on May 6, 2022, and is hereby incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to the technical field of pharmaceutical chemistry, and particularly to a salt of carisoprodol and its use. Background Art

[0003] Allergic diseases, also known as allergic reactions, refer to diseases caused by contact with sensitizing substances that trigger allergic or allergic reactions. Currently, common allergic diseases clinically mainly include allergic rhinitis, asthma, urticaria, atopic dermatitis, allergic conjunctivitis, and allergic gastrointestinal diseases, etc. An allergic reaction refers to a reaction of tissue damage or functional disorder that occurs when an immunized organism is re-exposed to the same antigenic stimulus. In recent years, the incidence of allergic diseases in China has been showing a continuous upward trend, and the incidence of allergic diseases in China is close to 40%. Taking allergic rhinitis as an example, allergic rhinitis is the disease with the highest incidence. As of now, the incomplete statistics show that the number of patients worldwide has exceeded 500 million. Allergic rhinitis is mainly manifested as nasal congestion, nasal itching, runny nose, sneezing, etc. The symptoms of allergic diseases occur repeatedly in the long term. If not prevented or intervened in time, it may affect the patient's quality of life such as sleep, social interaction, and work.

[0004] Histamine H1 receptor antagonists are a common type of drug for the prevention and treatment of allergic diseases. From the perspective of the development process, they are mainly divided into three generations. The first generation includes chlorpheniramine, promethazine, diphenhydramine, and cyproheptadine. These drugs have a short action time and simultaneously have central inhibition and sedative effects, showing adverse reactions such as drowsiness, epilepsy, rash, and anaphylactic shock. The second generation includes loratadine, cetirizine, ebastine, astemizole, and terfenadine, which have a long-acting and non-sedative effect; among them, astemizole and terfenadine have been found to prolong the QTc interval and, in rare cases, cause arrhythmia under overdose or other specific conditions, and now the regulatory agencies have revoked the approval for them. The third generation is represented by mizolastine, desloratadine, and levocetirizine. Among them, mizolastine has a unique dual effect of antihistamine and anti-other inflammatory mediators; desloratadine is the active metabolite of loratadine, which solves the problem of large individual differences of loratadine; levocetirizine is the single isomer of cetirizine.

[0005] Ebastine tablets belong to the second-generation histamine H1 receptor antagonists. It is a potent, long-acting, and highly selective histamine H1 receptor blocker, and has no antagonistic effect on cholinergic receptors in the central nervous system. It can selectively block histamine H1 receptors without sedative effects, and is used to treat various allergic diseases: urticaria, allergic rhinitis, eczema, dermatitis, prurigo, cutaneous pruritus, etc. After oral administration, ebastine is rapidly absorbed and mostly metabolized by strong hepatic first-pass effects. It mainly undergoes two metabolic routes. One is dealkylation under the action of CYP3A enzyme to generate dealkylated ebastine metabolites; the other metabolic route is to generate hydroxyebastine metabolites under the action of CYP2J2 enzyme, and hydroxyebastine is further oxidized by CYP2J2 and CYP3A4 enzymes to generate an acidic metabolite Carebastine. Neither ebastine nor its metabolite Carebastine enters the central nervous system, and has no adverse central nervous effects and anticholinergic effects.

[0006] It has not been reported, and there is no evidence indicating QTc interval prolongation related to ebastine treatment. Therefore, once-daily ebastine provides an effective and well-tolerated alternative to other second-generation antihistamines currently used for the first-line treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. Compared with the first-generation H1 receptor antagonists, no obvious abnormalities in the heart and psychomotor system have been seen with ebastine. However, since the oral onset time of ebastine is 1 - 4 hours, it is not suitable for the emergency treatment of acute allergic diseases such as acute urticaria and asthma.

[0007] Currently, the histamine H1 receptor antagonists with relatively fast onset in clinical practice are only levocetirizine and cetirizine. Levocetirizine and cetirizine are more likely to enter the central nervous system compared with ebastine, and show drowsiness and headache clinically. Therefore, there is an urgent clinical need for a non-sedative and fast-acting histamine H1 receptor antagonist that can be used for patients with acute allergic diseases such as acute urticaria and asthma patients.

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

[0009] .

[0010] Like ebastine, Carebastine has a strong selective antagonistic effect on histamine H1 receptors, can inhibit histamine release, and has weak H1 receptor antagonistic and anticholinergic effects on the central nervous system. Using Carebastine directly as a drug can effectively solve the problem of slow oral onset time of ebastine. However, Carebastine does not have a good solid form, resulting in Carebastine not meeting the pharmaceutical requirements: poor solid form preparations cannot be used stably, are not easy to purify, cannot be scaled up for production, have uncontrollable quality, and are not suitable for medicinal use. Therefore, there is currently no marketed drug of Carebastine. Summary of the Invention

[0011] One of the objectives of the present invention is to provide a salt of carisoprodol, so as to solve the problems in the prior art, such as poor solid form of carisoprodol, many impurities, instability, difficulty in purification, difficulty in scale-up synthesis, and inapplicability to medicine.

[0012] Another objective of the present invention is to provide a use of the salt of carisoprodol.

[0013] The third objective of the present invention is to provide a composition containing the salt of carisoprodol.

[0014] To achieve the above objectives, the technical solutions adopted by the present invention are as follows:

[0015] On the one hand, the present invention provides a pharmaceutically acceptable salt of carisoprodol, which is an acid salt formed by carisoprodol and an acid, or a base salt formed by carisoprodol and a base.

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

[0017] Furthermore, the above inorganic acid salts are selected from sulfate, bisulfate, nitrate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, bisulfate, thiocyanate, phosphate, pyrophosphate or metaphosphate.

[0018] Further, the above-mentioned organic acid salts are selected from formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, methanesulfonate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, malate, propiolate, 2-butynoate, 2-hydroxy-ethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, hydroxyethyl sulfonate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1,2-ethanedisulfonate, oxalate, trifluoroacetate, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, glycolate, alginate, ascorbate, isoascorbate, aspartate, L-aspartate, glutamate, L-glutamate, 2-phenoxybenzoate, 2-(4-hydroxybenzoyl)benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, levocamphorsulfonate, methylbenzoate, dinitrobenzoate, aminosulfonate, lacturonate, galacturonate, cyclopentanepropionate, dodecyl sulfate, acrylate, cyclopentanepropionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, pivalate, 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, pivalate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salt, alginate, 4-acetamidobenzenesulfonate, caprate, cholate, caprylate, pelargonate, cyclamate, phthalate, cysteine hydrochloride, sorbate, pamoate, mucate, glycine hydrochloride, naphthalenedisulfonate, xylenesulfonate, cystine dihydrochloride, undecanoate, polyvinylsulfonate, sulfosalicylic acid salt, phenylbutyrate, 4-hydroxybutyrate, polyvinyl sulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or valerate.

[0019] In some embodiments of the present invention, the above-mentioned organic acid salts are selected from methanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenedisulfonate, naphthalene-1-sulfonate or naphthalene-2-sulfonate.

[0020] Further, the above-mentioned organic acid salts are selected from methanesulfonate, benzenesulfonate or p-toluenesulfonate.

[0021] In some embodiments of the present invention, the above-mentioned alkali salts are selected from alkali metal salts, substituted or unsubstituted ammonium salts, amine salts, basic amino acid salts, or substituted or unsubstituted pyridinium salts.

[0022] Further, the above-mentioned metal alkali salts are selected from lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, iron salts, or zinc salts; preferably potassium salts or sodium salts.

[0023] Further, the above-mentioned substituted or unsubstituted ammonium salts are selected from ammonium salts, tetramethylammonium salts, tetraethylammonium salts, or choline salts.

[0024] Further, the above-mentioned amine salts are selected from methylamine salts, dimethylamine salts, trimethylamine salts, ethylamine salts, diethylamine salts, triethylamine salts, isopropylamine salts, tert-butylamine salts, diisopropylamine salts, 2-ethylaminoethanol salts, tromethamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, piperidine salts, piperazine salts, morpholine salts, glucosamine salts, N-methylglucosamine salts, dimethylglucosamine salts, ethylglucosamine salts, dicyclohexylamine salts, 1,6-hexanediamine salts, galactosamine salts, glucosamine salts, tris(hydroxymethyl)aminomethane salts, aminopropanediol salts, 1-amino-2,3,4-butanetriol salts, or serinol salts.

[0025] Further, the above-mentioned basic amino acid salts are selected from lysine salts, arginine salts, L-arginine salts, histidine salts, L-histidine salts, sarcosine salts, L-lysine salts, or ornithine salts.

[0026] Further, the above-mentioned substituted or unsubstituted pyridinium salts are selected from pyridinium salts, methylpyridinium salts, ethylpyridinium salts, or propylpyridinium salts.

[0027] In some embodiments of the present invention, the salt of carisoprodol is a single salt or a double salt. In the single salt, the molar ratio of carisoprodol to the salt radical is 1:1 to 2:1, and in the double salt, the molar ratio of carisoprodol to the salt radical is 1:4 to 4:1.

[0028] Further, in some embodiments, the salts of carisoprodol are selected from:

[0029] , , , , , , or .

[0030] On the other hand, the present invention provides a method for preparing the salt of carisoprodol as described in any one of the above, comprising the following steps: reacting 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid with an acid or a base under heating conditions in an organic solvent to form a salt.

[0031] Further, the above-mentioned acid includes organic acid or inorganic acid; preferably, the organic acid includes but is not limited to p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or naphthalene-2-sulfonic acid.

[0032] Further, the above-mentioned base includes metal base; preferably, the metal base includes but is not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide.

[0033] Further, the above-mentioned 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; the nitriles include but are not limited to acetonitrile.

[0034] Further, the temperature of the above-mentioned heating is selected from 30~100 °C; preferably 50~60 °C.

[0035] In the third aspect, the present invention provides a pharmaceutical composition of any one of the above-mentioned salts of carisoprodol, and the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0036] The above-mentioned "pharmaceutically acceptable carrier": refers to a diluent, adjuvant, excipient or vehicle administered together with the active ingredient, and is suitable for contacting human and / or other animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit / risk ratio.

[0037] In the fourth aspect, the present invention provides the use of any one of the above-mentioned salts of carisoprodol in the preparation of a histamine H1 receptor antagonist.

[0038] Further, the above-mentioned use includes the use of any one of the above-mentioned salts of carisoprodol in the preparation of a drug for treating and / or preventing allergic diseases.

[0039] Further, the above-mentioned allergic disease is an acute allergic disease.

[0040] Further, the above-mentioned allergic diseases are selected from urticaria, allergic rhinitis, eczema, dermatitis or pruritus.

[0041] More preferably, the above-mentioned acute allergic diseases are selected from acute urticaria or acute allergic rhinitis.

[0042] The names represented by the Chinese and English abbreviations in the present invention are:

[0043] DMAC: acetamide

[0044] EA: ethyl acetate

[0045] DMSO: dimethyl sulfoxide

[0046] CMC-Na: sodium carboxymethyl cellulose.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The carisoprodol salt of the present invention is a white powdery solid, having a good pharmaceutical solid form, high purity and stability. Carisoprodol is an active metabolite of ebastine, which can produce a pharmacodynamic effect without enzymatic metabolism after entering the body, with a fast onset time, avoiding the safety risks caused by individual medication differences due to the gene polymorphism of enzymes and the life-threatening risks of persistent allergies caused by ineffectiveness. The carisoprodol salt of the present invention provides a new option for clinical allergic patients.

[0049] Carisoprodol is an amphoteric compound. After a large number of experiments, the applicant systematically studied the salts of carisoprodol and found that the salts that carisoprodol can form are limited, and the purity and stability of the acid salts are better than those of the base salts. For example, the purity and stability of the p-toluenesulfonate are better than those of the potassium salt. However, the inventor of the present invention found that the carisoprodol acid salt has relatively serious hygroscopicity. In contrast, the potassium salt and p-toluenesulfonate of the present invention have better hygroscopicity characteristics.

[0050] On the other hand, the solubility of the p-toluenesulfonate of the present invention is lower than that of free carisoprodol. However, from the pharmacokinetic study of rats, the applicant surprisingly found that when administered at the same molar dose, both the carisoprodol p-toluenesulfonate and the potassium salt have better pharmacokinetic properties than ebastine and free carisoprodol. For example, in terms of AUC comparison, the AUC of carisoprodol in the body of the carisoprodol p-toluenesulfonate group and the potassium salt group is significantly greater than that of the ebastine group and the free carisoprodol group, and the T max of the generated carisoprodol is less than the T max of ebastine, indicating that the carisoprodol salt of the present invention has a faster onset and better pharmacokinetic properties when administered at the same molar dose. In addition, the acute toxicity study of mice found that the acute toxicities of both the carisoprodol p-toluenesulfonate and the potassium salt are lower than that of ebastine. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Appendix Figure 1 is the HPLC chart of carisoprodol (free form) on day 0;

[0052] Appendix Figure 2 is the HPLC chart of carisoprodol (free form) under light (12 days);

[0053] Appendix Figure 3 is the HPLC chart of carisoprodol p-toluenesulfonate on day 0;

[0054] Appendix Figure 4 is the HPLC chart of carisoprodol p-toluenesulfonate under light (12 days). DETAILED DESCRIPTION OF THE INVENTION

[0055] The present invention will be further described in detail below in combination with examples and experimental examples. The examples and experimental examples of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the present invention. Any equivalent substitution in the art made in accordance with the content disclosed in the present invention belongs to the protection scope of the present invention.

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

[0057] The liquid chromatography - mass spectrometer (LC~MS) was Agilent G6120B (used in conjunction with liquid phase Agilent 1260); the nuclear magnetic resonance spectrometer ( 1 HNMR) was Bruker AVANCE~400 or Bruker AVANCE~800. The nuclear magnetic resonance ( 1 H NMR) chemical shift ( δ ) was given in parts per million (ppm), with tetramethylsilane (TMS) as the internal standard, and the chemical shift was given in units of 10 ~6 (ppm).

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

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

[0060]

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

[0062]

[0063] Add 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) to a 25 ml single-necked flask, stir and heat to 100 °C. Weigh methyl 2-[4-(4-chloro-1-butanoyl)phenyl]-2-methylpropionate (600 mg, 2.12 mmol) and dissolve it in 1 ml of DMAC, slowly add it dropwise to the reaction solution, keep the temperature for reaction for 4 - 6 h, and detect by TLC until the raw materials are completely reacted. Cool to room temperature, add isopropyl acetate and water, stir and separate the layers. Extract the aqueous phase with isopropyl acetate again, combine the organic phases, wash twice with water, dry over anhydrous sodium sulfate, filter, concentrate, and pass through a silica gel column to obtain 500 mg of the title product, with a yield of 45% and a purity of 97.3%.

[0064] ESI-MS: m / z = 514.3(M+H) + 。

[0065] 1 H 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)butanoyl)phenyl)-2-methylpropanoic acid (Carisoprodol)

[0067]

[0068] Add methyl 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate (320 mg, 0.62 mmol), 1.5 ml of methanol, and 2 ml of 10% NaOH to a 25 ml three-necked flask, heat to 60 °C and react for 2 h until the raw materials are completely reacted as monitored by TLC. After the reaction is completed, cool to room temperature, concentrate to dryness, add EA, adjust the pH to 2 - 3 with hydrochloric acid, separate the layers, wash with water once, dry the organic phase, and concentrate to dryness to obtain 300 mg of the title product. Yield: 95%, purity 95.0%.

[0069] ESI-MS: m / z = 500.3(M+H) + 。

[0070] 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).

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

[0072]

[0073] Add 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid (499 mg, 1 mmol) and 3.5 ml of acetonitrile to a 25 ml three-necked flask. Heat to 60 °C, add potassium hydroxide (56 mg, 1 mmol), stir, cool down, precipitate white solid, filter, and dry to obtain 500 mg of Carisoprodol 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)butanoyl)phenyl)-2-methylpropionate (Carisoprodol sodium salt)

[0077]

[0078] In this example, the preparation method of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid is the same as that in Example 1.

[0079] Add 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid (499 mg, 1 mmol) and 3.5 ml of acetonitrile to a 25 ml three-necked flask. Heat to 60 °C, add sodium hydroxide (40 mg, 1 mmol), stir for 1 h, concentrate to dryness, add methyl tert-butyl ether and stir, filter, and dry to obtain 458 mg of Carisoprodol sodium salt, with a yield of 85% and a purity of 96.98%.

[0080] ESI-MS: m / z = 500.3(M+H) + 。

[0081] 1 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).

[0082] Example 3: Preparation of 2-(4-(4-(4-(Diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid p-toluenesulfonate (Carisoprodol p-toluenesulfonate)

[0083]

[0084] In this example, the preparation method of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid is the same as that in Example 1.

[0085] Add 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid (500 mg, 0.1 mmol) and 1 ml of isopropanol to a 25 ml three-necked flask, heat to 60 °C, add p-toluenesulfonic acid (172 mg, 1 mmol), stir, cool down, precipitate white solid, filter, and dry to obtain 585 mg of Carisoprodol p-toluenesulfonate, with a yield of 87% and a purity of 99.99%.

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

[0087] 1 1H 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)butanoyl)phenyl)-2-methylpropanoic acid mesylate (carisoprodol mesylate)

[0089]

[0090] In this example, the preparation method of 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid is the same as that in Example 1.

[0091] Add 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid (499 mg, 1 mmol) and 3.5 ml of EA to a 25 ml three-necked flask, heat to 60 °C, add methanesulfonic acid (96 mg, 1 mmol), stir for 1 h, concentrate to dryness, add methyl tert-butyl ether and stir, filter, and dry to obtain a white solid, 482 mg of carisoprodol mesylate, with a yield of 81% and a purity of 96.81%.

[0092] ESI-MS: m / z = 500.3(M+H) + 。

[0093] 1 1H 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 carisoprodol p-toluenesulfonate

[0095]

[0096] Add 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid (500 mg, 0.1 mmol) and 1 ml of isopropanol to a 25 ml three-necked flask, heat to 80 °C, add p-toluenesulfonic acid (172 mg, 1 mmol), stir until the reaction is complete, cool down, crystallize, filter, and dry to obtain 565 mg of carisoprodol p-toluenesulfonate, with a yield of 84% and a purity of 97.91%.

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

[0098] 1 1H 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] Note: In each test example of the present invention, "ebastine (control group 1, purchased)" means that the test sample used in this group is commercially available ebastine (control group 1); "carisoprodol tosylate (Example 3 group)" means that the test sample used in this group is carisoprodol tosylate prepared in Example 3; similar records are interpreted similarly.

[0100] Test Example 1: Histamine-induced guinea pig shock test

[0101] 1. Test samples: ebastine (control group 1, purchased), carisoprodol potassium salt (Example 1 group), carisoprodol sodium salt (Example 2 group), carisoprodol tosylate (Example 3 group), carisoprodol mesylate (Example 4 group).

[0102] 2. Test method: Take 60 guinea pigs, weighing about 220 g, and randomly divide them into 6 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 other groups were administered the corresponding drugs by gavage according to the equimolar dose conversion of 1.00 mg / kg of ebastine. The blank group was given an equal volume of 0.5% CMC-Na solution, and the dosing volume was 10 ml / kg for all groups. One hour after administration, a 2 ml / kg of 0.125 wt.% histamine phosphate saline solution was injected into the lateral vein of the hind paw of the guinea pigs. After the injection was completed within 10 s, a stopwatch was immediately used to time, and the latency of increased respiration and convulsion and collapse of the animals was observed.

[0103] 3. Test results:

[0104]

[0105] Compared with the blank control group: ∗ p < 0.01; compared with the ebastine group (control group 1): ▲ p < 0.01.

[0106] Compared with the blank control group, after intravenous injection of histamine, both the compound of the example and ebastine significantly prolonged the latency of increased respiration and the convulsion latency in guinea pigs sensitized to histamine (p < 0.01), and no animal death occurred; compared with the ebastine administration group, the compounds in groups 1, 2, 3, and 4 of the example prolonged the latency of increased respiration and the convulsion latency in guinea pigs more significantly (p < 0.01).

[0107] Test Example 2: Pharmacokinetics Test in Rats

[0108] 1. Test samples: Ebastine (Group of Comparative Example 1), Carisoprodol (Group of Comparative Example 2), Potassium Carisoprodol (Group of Example 1), p-Toluenesulfonic Acid Carisoprodol (Group of Example 3).

[0109] 2. Test method:

[0110] Take 24 SD rats, weighing about 180 - 200 g, randomly divide them into 4 groups, with 6 rats in each group, half male and half female, and orally administer the corresponding drugs by gavage. The rats are fasted for 12 h before drug administration and can drink water freely. Each group is administered an equimolar dose of ebastine at 10 mg / kg. The groups and doses are as follows:

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

[0112] Group of Comparative Example 2: Carisoprodol, 10.63 mg / kg;

[0113] Group of Example 1: Potassium Carisoprodol, 11.11 mg / kg;

[0114] Group of Example 3: p-Toluenesulfonic Acid Carisoprodol, 14.39 mg / kg.

[0115] Preparation of test substances: The preparation of test substances is carried out on a conventional workbench in the preparation room. Use DMSO as the solvent to prepare stock solutions of 1.00 mg / mL of ebastine, carisoprodol, Example 1, and Example 3 respectively. The rat administration solutions are prepared into 10 mg / mL of ebastine solution, 10 mg / mL of carisoprodol solution, 11.11 mg / kg of Example 1 solution, and 14.39 mg / mL of Example 3 solution with 0.5% CMC-Na solution respectively.

[0116] Collect blank blood before drug administration, and collect blood at the predetermined time points after drug administration: 0.25 h, 0.5 h, 0.75 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 24 h. Collect about 0.5 mL of blood, place it in an EDTA-K2 tube, centrifuge to separate plasma, and store it at -80 °C. Use a liquid chromatography-mass spectrometry (LC-MS / MS) analysis system to detect and analyze the prototype and metabolite carisoprodol in plasma samples, and calculate pharmacokinetic parameters.

[0117] 3. Test results:

[0118] After a single administration of the compounds of Example 1, Example 3, ebastine, and carisoprodol to SD rats, the content of the prototype in the ebastine group was lower than 3 ng / mL, indicating that ebastine can be rapidly metabolized after entering the body.

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

[0120] .

[0121] As can be seen from the above table, after oral administration of the compounds of Example 1 group and Example 3 group to rats, the amount of carisoprodol AUC in the plasma of rats in Example 1 group and Example 3 group last was significantly better than that of the ebastine group and the carisoprodol group; however, the time to peak concentration T of carisoprodol in Example 1 group and Example 3 group max was less than that of the ebastine group and the carisoprodol group, indicating that the compounds of Example 1 group and Example 3 group of the present invention can quickly enter the body, inhibit the histamine H1 receptor, and have the potential for the treatment of clinically acute allergic disease patients such as acute urticaria.

[0122] In addition, during the rat pharmacokinetic study, it was also found that the AUC and C of 3 female rats in the ebastine group max were less than those of 3 male rats AUC and C max , showing an obvious difference, indicating that after administration of ebastine, in SD rats, ebastine showed gender differences. However, the compounds of the examples of the present invention did not show gender differences.

[0123] The results showed that under the condition of equimolar dose administration, the time to peak concentration (T max ) of the compounds of the examples of the present invention was faster than that of ebastine. Especially for the compound of Example 3, the onset was very fast, and there was no gender difference, having the potential for the treatment of clinically acute allergic disease patients such as acute urticaria, and can reduce individual medication differences.

[0124] Test Example 3: Acute toxicity study of mice

[0125] 1. Test samples: Ebastine (Comparative Example 1), potassium carisoprodol, p-toluenesulfonate carisoprodol.

[0126] 2. Test method:

[0127] 70 healthy adult KM mice, weighing 18 - 22 g, with an equal number of males and females, were randomly divided into 7 groups: blank control group, high-dose group of Example 1, low-dose group of Example 1, high-dose group of Example 3, low-dose group of Example 3, high-dose group of ebastine, and low-dose group of ebastine.

[0128] The high-dose groups of Example 1, Example 3, and the high-dose group of ebastine were administered at the same molar dose, which were 5.38 g / kg, 6.72 g / kg, and 5 g / kg respectively; the low-dose groups of Example 1, Example 3, and the low-dose group of ebastine were administered at the same molar dose, which were 2.69 g / kg, 3.36 g / kg, and 2.5 g / kg respectively; all drugs were administered by gavage. The blank group was given an equal volume of 0.5% CMC-Na solution. All animals were fasted for 12 h before dosing and were not deprived of water.

[0129] After dosing, the animals were continuously raised and observed for 14 days. The toxic reactions (such as death) of the mice were observed and recorded every day. After the observation period ended, all surviving animals were dissected, and the major organs were grossly observed for any obvious lesions.

[0130] 3. Test results:

[0131] After a single gavage administration of low doses of the compounds of Example 1, Example 3, and ebastine, no obvious abnormalities were observed in all animals during the entire observation period. No obvious abnormalities were found during gross dissection of the animals, and MDT > 2.5 g / kg. After a single gavage administration of high doses of the compounds of Example 1, Example 3, and ebastine, the mortality rate in the ebastine group was higher than that in the groups of Example 1 and Example 3, indicating that the compounds of Example 1 and Example 3 of the present invention have higher safety compared with ebastine.

[0132] 。

[0133] Test Example 4: Stability study

[0134] 1. Test samples: Carisoprodol (Comparative Example 2, Comparative Example 2'), Carisoprodol potassium salt (Example 1), Carisoprodol p-toluenesulfonate (Example 3, Example 5).

[0135] 2. Test method:

[0136] Weigh 3 portions each of the samples Carisoprodol (Comparative Example 2), purified Carisoprodol (Comparative Example 2'), Carisoprodol potassium salt (Example 1), Carisoprodol p-toluenesulfonate (Example 3), and Carisoprodol p-toluenesulfonate (Example 5) and place them in weighing bottles respectively. Each group of samples was placed under the conditions of high temperature (60 °C), high humidity (RH80%), and light (5000 Lux). Samples were taken for testing after 12 days. Note: The purified Carisoprodol of Comparative Example 2' can be prepared by column chromatography of Comparative Example 2 by conventional technical means in the art.

[0137] Detection method: Take an appropriate amount of each sample, weigh accurately, dissolve with acetonitrile and quantitatively dilute to a solution containing about 0.08 mg per 1 ml. Use high performance liquid chromatography with octadecylsilane chemically bonded silica gel as the filler, water-acetonitrile (1:1) as the mobile phase, detection wavelength of 256 nm, column temperature of 35 °C, injection volume of 10 μl; Inject each sample solution into the liquid chromatograph and record the chromatogram.

[0138] 3. Test results:

[0139] As shown in the results in the following table, carisoprodol tosylate is stable under high temperature, high humidity and light conditions. Compared with carisoprodol potassium salt and carisoprodol tosylate, the stability of carisoprodol potassium salt decreases slightly under light, but free carisoprodol (Comparative Example 2) is very unstable under light conditions, with an increase in impurities and a significant decrease in purity. Attached Figures 1 to 4 Also shown are the HLPC charts of free carisoprodol (Comparative Example 2) and carisoprodol tosylate under 0-day and 12-day light, proving that carisoprodol (free form) degrades more under light, has stability problems, and produces more impurities greater than 0.1%, which is not suitable for medicinal use.

[0140] 。

[0141] Test Example 5: Hygroscopicity study

[0142] 1. Test samples: Carisoprodol (Comparative Example 2), Carisoprodol Hydrochloride (Comparative Example 3), Carisoprodol Potassium Salt (Example 1), Carisoprodol Tosylate (Example 3). The preparation of carisoprodol hydrochloride refers to the description in Patent US6340761 with a purity of over 99%.

[0143] 2. Test method:

[0144] (1) Take a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm), place it in a suitable constant temperature dryer at 25 °C ± 1 °C (ammonium chloride or ammonium sulfate saturated solution placed at the bottom) or an artificial climate chamber (set temperature 25 °C ± 1 °C, relative humidity 80% ± 2%) one day before the test, and weigh accurately (m1);

[0145] (2) Take an appropriate amount of the test substance, spread it evenly in the above-mentioned weighing bottle, and the thickness of the test substance is generally about 1 mm, and weigh accurately (m2);

[0146] (3) Open the weighing bottle and place it together with the bottle cap under the above-mentioned constant temperature and humidity conditions for 24 h;

[0147] (4) Cover the weighing bottle lid and weigh accurately (m3);

[0148] (5)Percentage of weight gain = (m3 - m2) / (m2 - m1) × 100%.

[0149] 3. Test results:

[0150] The hygroscopicity results are shown in the following table: The results indicate that the potassium salt of carisoprodol and carisoprodol p-toluenesulfonate of the present invention have better hygroscopicity characteristics than free carisoprodol and carisoprodol hydrochloride.

[0151] .

[0152] According to the pharmacopoeia definition, the above results are as follows: "Hygroscopic" means that the hygroscopic weight gain is less than 15% but not less than 2%; "Highly hygroscopic" means that the hygroscopic weight gain is not less than 15%; "Non-hygroscopic or almost non-hygroscopic" means that the hygroscopic weight gain is less than 0.2%; "Slightly hygroscopic" means that the hygroscopic weight gain is less than 2% but not less than 0.2%.

[0153] Test Example 6: Solubility test

[0154] 1. Test samples: Carisoprodol (Comparative Example 2), Carisoprodol p-toluenesulfonate (Example 3).

[0155] 2. Test method:

[0156] pH 1.2 hydrochloric acid solution: Take 7.65 ml of hydrochloric acid, dilute it with water to 1000 ml, and shake well to obtain it.

[0157] pH 4.5 phosphate buffer solution: Weigh 3.40278 g of KH2PO4, dissolve it in water and dilute it to 500 ml, and shake well to obtain it.

[0158] pH 6.8 phosphate buffer solution: Weigh 3.40353 g of KH2PO4 and 0.4428 g of sodium hydroxide, dissolve them in water and dilute it to 500 ml, and shake well to obtain it.

[0159] Take appropriate amounts of the compounds of Example 3 and Comparative Example 2 and place them into conical flasks containing 50 ml of water, 50 ml of pH 1.2 hydrochloric acid solution, 50 ml of pH 4.5 phosphate buffer solution, and 50 ml of pH 6.8 phosphate buffer solution respectively, so that the solution is in a supersaturated state and insoluble substances can be clearly seen.

[0160] Place the conical flasks in a water bath at a constant temperature of 37 °C, with an oscillation rate of 120 revolutions / min. Sampling is carried out at 24 h, 48 h, and 72 h respectively, and detected by a liquid chromatograph.

[0161] 3. Test results:

[0162]

[0163] The results are shown in the above table: among all the tested media, at different times, the solubility of Example 3 is lower than that of Comparative Example 2. However, the compounds of Example 3 all showed better pharmacokinetic properties in the rat pharmacokinetic experiments.

[0164] The above embodiments are only one of the preferred embodiments of the present invention and should not be used to limit the protection scope of the present invention. Any modification or polishing that has no substantial meaning made on the main design concept and spirit of the present invention, as long as the technical problems solved are still consistent with those of the present invention, should be included in the protection scope of the present invention.

Claims

1. A salt of carisoprodol, characterized in that, The salt is p-toluenesulfonate or potassium salt.

2. The salt of carisoprodol according to claim 1, characterized in that, The salt of carisoprodol is a single salt or a double salt. The molar ratio of carisoprodol to the salt radical in the single salt is 1:1 to 2:1, and the molar ratio of carisoprodol to the salt radical in the double salt is 1:4 to 4:

1.

3. The salt of carisoprodol according to claim 1, characterized in that, The salt of carisoprodol is selected from: or 。 4. A method for preparing the salt of carisoprodol according to any one of claims 1 to 3, characterized in that, The preparation method comprises the following steps: 2-(4-(4-(4-(diphenylmethoxy)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoic acid reacts with an acid or a base under the condition of an organic solvent by heating to form a salt; the acid is selected from p-toluenesulfonic acid, and the base is selected from potassium hydroxide.

5. The preparation method according to claim 4, characterized in that, The organic solvent is selected from alcohols, esters or nitriles.

6. The preparation method according to claim 4, characterized in that, The organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate or acetonitrile.

7. The preparation method according to claim 4, characterized in that, The heating temperature is 30-100 °C.

8. The preparation method according to claim 6, characterized in that, The heating temperature is 50-60 °C or 80 °C.

9. A pharmaceutical composition comprising the salt of carisoprodol according to any one of claims 1 to 3, characterized in that, The pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

10. Use of the salt of carisoprodol according to any one of claims 1 to 3 in the preparation of a drug for histamine H1 receptor antagonists.

11. Use of the salt of carisoprodol according to any one of claims 1 to 3 in the preparation of a drug for treating and / or preventing allergic diseases.

12. The use according to claim 11, characterized in that, The allergic disease is an acute allergic disease.

13. The use according to claim 12, characterized in that, The acute allergic disease is acute urticaria or acute allergic rhinitis.

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