Polyamide salt, preparation method therefor and use thereof

Abstract

Provided are a polyamide salt, a preparation method therefor and a use thereof. Provided are a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound or a salt of a stereoisomer thereof, a preparation method therefor, a use thereof, a pharmaceutical composition comprising a therapeutically effective amount of the salt, and a use thereof in preparation of a medication for preventing and / or treating κ-opioid receptor-mediated related diseases.

Description

A polyamide salt, preparation method and application thereof

[0001] This application claims priority to Chinese patent application No. 202311226591X filed on September 22, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention belongs to the technical field of drug synthesis, and particularly relates to a polyamide salt and a preparation method and application thereof. Background Art

[0003] Opioid receptors are an important class of G protein-coupled receptors that serve as binding targets for endogenous opioid peptides and opioid drugs. Activated opioid receptors regulate the nervous system's immune and endocrine systems. Opioid drugs are currently the most potent and commonly used central nervous system analgesics. Opioid receptors in the central nervous system include μ, δ, and κ receptors.

[0004] The κ-opioid receptor (KOR) is composed of 380 amino acids and is expressed in sensory neurons, dorsal root ganglion cells, and primary afferent neuron terminals. It participates in important physiological activities such as pain perception, neuroendocrine function, emotional behavior, and cognition.

[0005] KOR agonists have promising applications as drugs in the pharmaceutical industry. For example, CN108290926A discloses a class of phenylpropionamide derivatives that can act as KOR agonists, and CN101627049A also discloses a class of synthetic peptide amides that can act as KOR agonists. Among them, the compound D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH (development code CR845) has been approved for marketing in Europe and the United States.

[0006] Summary of the Invention

[0007] International patent application PCT / CN2023 / 083063 describes a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound represented by formula (A) (hereinafter referred to as "Compound A"), the structure of which is shown below. All contents of International patent application PCT / CN2023 / 083063 are incorporated herein by reference.

[0008] The inventors have found that the free form of Compound A is extremely unstable and unsuitable for industrial production and storage. The technical problem to be solved by the present invention is to provide a polyamide salt, a preparation method and application thereof, specifically a salt form of Compound A or its stereoisomers, a preparation method and application thereof.

[0009] In one aspect, the present invention provides an acid salt of Compound A or a stereoisomer thereof.

[0010] In another aspect, the present invention provides a method for preparing an acid salt of Compound A or a stereoisomer thereof.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of Compound A or an acid salt of its stereoisomers, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0012] On the other hand, the present invention provides a use of an acid salt of Compound A or its stereoisomer or a pharmaceutical composition comprising the same in the preparation of a drug, wherein the drug is preferably a drug for preventing and / or treating diseases mediated by κ opioid receptors.

[0013] The acetate of Compound A and the hydrochloride of Compound A of the present invention have excellent physical and chemical properties, such as good solubility in a variety of solvents, and exhibit high stability in stability tests such as high temperature, light, oxidation, and accelerated tests. These properties give the acetate of Compound A and the hydrochloride of Compound A of the present invention significant advantages in formulation development and production processes, ensuring the effectiveness and consistency of the drug while improving its feasibility and reliability in clinical applications. These properties are of great significance for the stability and effectiveness of the drug in long-term storage, transportation, and actual use. DETAILED DESCRIPTION

[0014] definition

[0015] Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" all express the same meaning, that is, X can be any one or more of A, B, C.

[0016] An "amino protecting group" refers to an easily removable group introduced onto an amino group in order to maintain the amino group unchanged during reactions at other sites of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), p-nitrobenzenesulfonyl, tert-butylsulfinyl, trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, or p-methoxybenzyl.

[0017] "Room temperature" refers to a temperature between 10°C and 40°C. In some embodiments, "room temperature" refers to a temperature between 15°C and 30°C; in other embodiments, "room temperature" refers to a temperature between 18°C ​​and 25°C.

[0018] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and that the description includes instances where the cycloalkyl is substituted with alkyl and instances where the cycloalkyl is not substituted with alkyl.

[0019] A "pharmaceutical composition" refers to a composition containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers, diluents, or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0020] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0021] "Amorphous," "amorphous form," or "amorphous form" refers to a substance whose particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity. This is characterized by a diffuse, non-peaked X-ray powder diffraction pattern. Amorphous is a specialized physical form of solid matter, and its locally ordered structure suggests a close relationship to crystalline forms.

[0022] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0023] Unless otherwise specified, the "%" mentioned herein when describing the content refers to mass percentage.

[0024] In the present invention, the mechanism of the "acid radical conversion" process is different from the traditional mechanism of producing weak acids from strong acids. The "acid radical conversion" of the present invention is mainly achieved through anion exchange resin. The anion exchange resin has the ability to adsorb and exchange anions in the solution. Under normal circumstances, the anion exchange resin contains strong basic groups, and the positively charged groups on it can be adsorbed and combined with the anions in the solution, thereby realizing anion exchange. Under the combined action of electrostatic attraction and concentration gradient diffusion force, the anions on the anion exchange resin are replaced. In the implementation process of the present invention, in the method for "acid radical conversion" of preparing the acetate salt of compound A, the model of the anion exchange resin used is 205*7 acetic acid type resin.

[0025] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is specifically disclosed, where "+ / -" means plus or minus.

[0026] As mentioned above, since compound A is extremely unstable in its free state and easily deteriorates after being released, it is not suitable for industrial production and storage. Therefore, the present invention aims to provide a salt of compound A.

[0027] In some embodiments, the acid salt of Compound A of the present invention has good physicochemical properties. In some embodiments, the salt of Compound A of the present invention has good solubility in a variety of solvents. In some embodiments, the salt of Compound A of the present invention has high purity. In some embodiments, the salt of Compound A of the present invention has high stability, for example, under conditions of high temperature, light, oxidation, high humidity, etc., the HPLC purity changes little. In some embodiments, the salt of Compound A of the present invention can meet the pharmaceutical requirements of production, transportation and storage, and can be adapted to industrial production. In some embodiments, the salt of Compound A of the present invention has one or more of the above-mentioned beneficial effects.

[0028] In one aspect, the present invention provides an acid salt of Compound A or a stereoisomer thereof.

[0029] In some embodiments, the acid salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, lactate, citrate, tartrate, aspartate, glutamate, benzoate, citrate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, or a combination thereof.

[0030] In some embodiments, the acid salt is formate, trifluoroacetate, phosphate, citrate, benzoate, lactate, hydrochloride, or acetate, preferably hydrochloride or acetate.

[0031] In some embodiments, the acid salt is a hydrochloride salt.

[0032] In some embodiments, the acid salt is acetate.

[0033] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:0.4 to 1:4, preferably 1:0.4 to 0.6 (e.g., 1:0.5), 1:0.8 to 1.2 (e.g., 1:1), 1:1.4 to 1.6 (e.g., 1:1.5), 1:1.8 to 2.2 (e.g., 1:2), 1:2.4 to 2.6 (e.g., 1:2.5) or 1:2.8 to 3.2 (e.g., 1:3), preferably 1:0.8 to 1.2 (e.g., 1:1), 1:1.8 to 2.2 (e.g., 1:2) or 1:2.8 to 3.2 (e.g., 1:3).

[0034] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:0.5 to 1:4; preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:0.5 to 3; more preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:0.5 to 2.5; further preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:0.5 to 2; further preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:0.5 to 1.5; even further preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:0.5 to 1. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:0.5.

[0035] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1 to 1:4; preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1 to 3; more preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1 to 2.5; further preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1 to 2; further preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1 to 1.5. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.

[0036] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:1.5 to 1:4; preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:1.5 to 3; more preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:1.5 to 2.5; further preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:1.5 to 2. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:1.5.

[0037] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:2 to 1:4; preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:2 to 3; more preferably, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:2 to 2.5. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (radical) is 1:2.

[0038] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1 to 2. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1.1 to 1.9. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1.2 to 1.9. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1.3 to 1.8. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1.4 to 1.7. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1.1. In some specific embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (anion) is 1:1.2. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.3. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.4. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.5. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.6. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.7. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.8. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:1.9. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acid (root) is 1:2.

[0039] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the formic acid molecule is 1:0.8-1.2, 1:1.8-2.2 or 1:2.8-3.2, preferably 1:1.8-1.2, for example, about 1:1.

[0040] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the trifluoroacetic acid molecule is 1:0.8-1.2, 1:1.8-2.2 or 1:2.8-3.2, preferably 1:1.8-2.2, for example about 1:2.

[0041] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the acetic acid molecule is 1:0.8-1.2, 1:1.8-2.2 or 1:2.8-3.2, preferably 1:1-2, 1:0.8-1.2, for example, about 1:2, 1:1.

[0042] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to hydrogen chloride molecules is 1:0.8-1.2, 1:1.8-2.2 or 1:2.8-3.2, preferably 1:1.8-2.2, for example, about 1:2.

[0043] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the hydrogen chloride molecule is 1:0.5 to 2; preferably, the molar ratio of the compound of formula A or its stereoisomer to the hydrogen chloride molecule is 1:1 to 2. In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the hydrogen chloride molecule is 1:2.

[0044] In some embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:0.5-2; preferably, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1-2; more preferably, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.4-1.7. In some specific embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1. In some specific embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.1. In some specific embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.2. In some specific embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.3. In some specific embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.4. In some specific embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.5. In some embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.6. In some embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.7. In some embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.8. In some embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:1.9. In some embodiments, the molar ratio of the compound of Formula A or its stereoisomer to the acetic acid molecule is 1:2.

[0045] In another aspect, the present invention provides an acetate salt of a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound represented by formula (I) or a stereoisomer thereof.

[0046] On the other hand, the present invention provides an acetate salt of a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound represented by formula (I-1) or a stereoisomer thereof.

[0047] On the other hand, the present invention provides an acetate salt of a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound represented by formula (I-2) or a stereoisomer thereof.

[0048] On the other hand, the present invention provides an acetate salt of a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound represented by formula (I-3) or a stereoisomer thereof.

[0049] On the other hand, the present invention provides an acetate salt of a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound represented by formula (I-4) or a stereoisomer thereof.

[0050] In another aspect, the present invention provides a tetrahydro-2H-pyran-4-yl(1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl)carbamate compound represented by formula (II) or the hydrochloride salt of a stereoisomer thereof.

[0051] In some embodiments, the acid salt is a non-solvate or a solvate, wherein the solvent is selected from one or more of water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene or toluene.

[0052] In some embodiments, the acid salt is a non-solvate or a solvate, wherein the solvent is selected from water and methyl acetate.

[0053] In some embodiments, the molar ratio of the compound of formula A or its stereoisomer to the solvent is 1:0.4 to 1:4, preferably 1:0.4 to 0.6 (e.g., 1:0.5), 1:0.8 to 1.2 (e.g., 1:1), 1:1.4 to 1.6 (e.g., 1:1.5), 1:1.8 to 2.2 (e.g., 1:2), 1:2.4 to 2.6 (e.g., 1:2.5) or 1:2.8 to 3.2 (e.g., 1:3); more preferably 1:0.8 to 1.2 (e.g., 1:1), 1:1.8 to 2.2 (e.g., 1:2) or 1:2.8 to 3.2 (e.g., 1:3); further preferably 1:1, 1:2 or 1:3.

[0054] In some embodiments, the acid salt is a non-solvate.

[0055] In some embodiments, the acid salt is anhydrous.

[0056] In some embodiments, the acid salt is in a crystalline or amorphous form.

[0057] On the other hand, the present invention also relates to a method for preparing the acid salt of the compound represented by formula A or its stereoisomer.

[0058] In some embodiments, the method for preparing the acid salt of Compound A comprises the step of reacting Compound A with an acid to form a salt.

[0059] In some specific embodiments, the method for preparing the formate salt of Compound A comprises contacting Compound A with formic acid to cause a salt-forming reaction, thereby obtaining the formate salt of Compound A.

[0060] In some specific embodiments, the method for preparing the hydrochloride of Compound A comprises contacting Compound A with hydrochloric acid to cause a salt-forming reaction to obtain the hydrochloride of Compound A.

[0061] In some specific embodiments, the method for preparing the trifluoroacetic acid salt of Compound A comprises contacting Compound A with trifluoroacetic acid to cause a salt-forming reaction to obtain the trifluoroacetic acid salt of Compound A.

[0062] In some specific embodiments, the method for preparing the acetate salt of Compound A comprises contacting Compound A with acetic acid to cause a salt-forming reaction to obtain the acetate salt of Compound A.

[0063] In some embodiments, the method for preparing the acid salt of Compound A comprises contacting Compound A protected by an amino protecting group with an acid (eg, a strong acid), and then reacting Compound A with the acid to form a salt after removing the amino protecting group under acidic conditions.

[0064] In some embodiments, the method for preparing the acid salt of compound A comprises contacting the compound represented by formula (A) or a stereoisomer thereof protected by an amino protecting group (such as Boc) with an acid X to remove the amino protecting group (such as Boc), and then reacting with the acid X to form a salt to obtain the X acid salt of the compound represented by formula (A) or a stereoisomer thereof, wherein the acid X has the property of removing the amino protecting group (such as Boc).

[0065] In some embodiments, the acid X includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid.

[0066] In some specific embodiments, the method for preparing the formate salt of compound A comprises contacting the compound of formula (A) or its stereoisomer protected by an amino protecting group (such as Boc) with formic acid to remove the amino protecting group (such as Boc) and then reacting with formic acid to form a salt to obtain the formate salt of the compound of formula (A) or its stereoisomer.

[0067] In some specific embodiments, the method for preparing the hydrochloride of compound A comprises contacting the compound represented by formula (A) or its stereoisomer protected by an amino protecting group (such as Boc) with hydrochloric acid to remove the amino protecting group (such as Boc) and then reacting with hydrochloric acid to form a salt to obtain the hydrochloride of the compound represented by formula (A) or its stereoisomer.

[0068] In some specific embodiments, the method for preparing the trifluoroacetate salt of compound A comprises contacting the compound represented by formula (A) or its stereoisomer protected by an amino protecting group (such as Boc) with trifluoroacetic acid to remove the amino protecting group (such as Boc) and then reacting with trifluoroacetic acid to form a salt to obtain the trifluoroacetate salt of the compound represented by formula (A) or its stereoisomer.

[0069] The aforementioned amino-protecting group-protected compound of formula (A) or its stereoisomer refers to a compound of formula (A) or its stereoisomer having an easily removable group introduced into the amino group thereof so that the amino group remains unchanged when reacting at other sites. Non-limiting examples of such amino-protecting groups include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), p-nitrobenzenesulfonyl, tert-butylsulfinyl, trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, or p-methoxybenzyl.

[0070] In some embodiments, the method for preparing the acid salt of Compound A adopts an acid radical conversion method, that is, converting one acid salt of Compound A into another acid salt.

[0071] In some embodiments, the acid radical conversion method comprises converting a strong acid salt of Compound A into a weak acid salt.

[0072] In some embodiments, the method for preparing an acid salt of compound A or a stereoisomer thereof comprises contacting a Y acid salt of the compound represented by formula A or a stereoisomer thereof with a Z acid to perform acid radical conversion to generate a Z acid salt of the compound represented by formula A or a stereoisomer thereof; wherein the Y acid is an acid having stronger acidity than the Z acid.

[0073] In some embodiments, the method for preparing the acetate salt of Compound A or its stereoisomer comprises contacting a γ-acid salt of the compound represented by Formula A or its stereoisomer with acetic acid to perform acid radical conversion to produce the acetate salt of the compound represented by Formula A or its stereoisomer, wherein the γ-acid is an acid stronger than acetic acid. The γ-acid includes but is not limited to trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoroacetic acid, phosphoric acid, and formic acid; preferably, the γ-acid is one or more of hydrochloric acid, trifluoroacetic acid, or formic acid.

[0074] In some embodiments, the hydrochloride salt of Compound A is contacted with acetic acid to produce the acetate salt of Compound A.

[0075] In some embodiments, the trifluoroacetic acid salt of Compound A is contacted with acetic acid to produce the acetate salt of Compound A.

[0076] In some embodiments, the formate salt of Compound A is contacted with acetic acid to produce the acetate salt of Compound A.

[0077] In some embodiments, the acid radical conversion method comprises eluting the yttrium salt of Compound A through high performance liquid chromatography with an eluent containing acetic acid, concentrating, and drying to obtain the acetate salt of Compound A. In some embodiments, the acid radical conversion method comprises treating the yttrium salt of Compound A with an alkali-free treatment and then adding acetic acid dropwise to obtain the acetate salt of Compound A. In some embodiments, the acid radical conversion method comprises treating the yttrium salt of Compound A with an acetate-type ion exchange resin to obtain the acetate salt of Compound A. The yttrium acid is an acid stronger than acetic acid. The yttrium acid includes but is not limited to trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoroacetic acid, phosphoric acid, or formic acid; preferably, the yttrium acid is hydrochloric acid, trifluoroacetic acid, or formic acid.

[0078] In some embodiments, the acid radical conversion method comprises eluting the trifluoroacetate of Compound A through high performance liquid chromatography with an eluent containing acetic acid, concentrating, and drying to obtain the acetate of Compound A. In some embodiments, the acid radical conversion method comprises treating the trifluoroacetate of Compound A with an alkali and then dropwise adding acetic acid to obtain the acetate of Compound A. In some embodiments, the acid radical conversion method comprises treating the trifluoroacetate of Compound A with an acetic acid-type ion exchange resin to obtain the acetate of Compound A.

[0079] In some embodiments, the acid radical conversion method comprises eluting the formate of Compound A through high performance liquid chromatography with an eluent containing acetic acid, followed by concentration and drying to obtain the acetate of Compound A. In some embodiments, the acid radical conversion method comprises treating the formate of Compound A with an alkali and then dropwise adding acetic acid to obtain the acetate of Compound A. In some embodiments, the acid radical conversion method comprises treating the formate of Compound A with an acetic acid-type ion exchange resin to obtain the acetate of Compound A.

[0080] In some embodiments, the acid radical conversion method comprises eluting the hydrochloride of Compound A through high performance liquid chromatography with an eluent containing acetic acid, concentrating, and drying to obtain the acetate of Compound A. In some embodiments, the acid radical conversion method comprises treating the hydrochloride of Compound A with alkali and then dropwise adding acetic acid to obtain the acetate of Compound A. In some embodiments, the acid radical conversion method comprises treating the hydrochloride of Compound A with an acetic acid-type ion exchange resin to obtain the acetate of Compound A.

[0081] In some embodiments, the method for preparing the acetate salt of compound A or its stereoisomer comprises: adding a y acid salt of compound A or its stereoisomer and 205*7 acetate-type ion exchange resin to water, stirring to ensure complete conversion of the acid radical, filtering, and freeze-drying the resulting filtrate at a temperature of (-45°C) to (20-25°C) for 60-75 hours to obtain the acetate salt of compound A or its stereoisomer; the y acid includes but is not limited to trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoroacetic acid, phosphoric acid or formic acid; preferably, the y acid is hydrochloric acid, trifluoroacetic acid or formic acid.

[0082] In some embodiments, the method for preparing the acetate salt of compound A or its stereoisomer as shown in formula (I-2) comprises: adding Y acid salt of compound A or its stereoisomer and 205×7 acetate type ion exchange resin to water, stirring to ensure that the acid radical is completely converted, filtering, and freeze-drying the obtained filtrate at a temperature of (-45°C) to (25°C) for 70 to 75 hours to obtain the acetate salt of compound A or its stereoisomer as shown in formula (I-2); preferably, the freezing temperature is (-45°C) to (25°C). )-(25°C), the freezing time is 70-73h; more preferably, the freezing temperature is (-45°C)-(25°C), the freezing time is 71-73h; further preferably, the freezing temperature is (-45°C)-(25°C), the freezing time is 72h; the Y acid includes but is not limited to trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoroacetic acid, phosphoric acid or formic acid; preferably, the Y acid is hydrochloric acid, trifluoroacetic acid or formic acid. In some embodiments, the method for preparing the acetate salt of compound A or its stereoisomer shown in formula (I-3) comprises: adding a y acid salt of compound A or its stereoisomer and 205×7 acetate-type ion exchange resin to water, stirring to ensure complete conversion of the acid radical, filtering, and freeze-drying the resulting filtrate at a temperature of (-45°C)-(20°C) for 67-70 hours to obtain the acetate salt of compound A or its stereoisomer shown in formula (I-3); preferably, the freezing temperature is (-45°C)-(25°C) and the freezing time is 68-70 hours; more preferably, the freezing temperature is (-45°C)-(25°C) and the freezing time is 69 hours; the y acid includes but is not limited to trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoroacetic acid, phosphoric acid or formic acid; preferably, the y acid is hydrochloric acid, trifluoroacetic acid or formic acid.

[0083] In some embodiments, the method for preparing the acetate salt of compound A or its stereoisomer represented by formula (I-4) comprises: adding a y acid salt of compound A or its stereoisomer and 205×7 acetate-type ion exchange resin to water, stirring to ensure complete conversion of the acid radical, filtering, and freeze-drying the resulting filtrate at a temperature of (-45°C)-(20°C) for 63 to 66 hours to obtain the acetate salt of compound A or its stereoisomer represented by formula (I-4); preferably, the freezing temperature is (-45°C)-(20°C) and the freezing time is 64 to 66 hours; more preferably, the freezing temperature is (-45°C)-(20°C) and the freezing time is 65 to 66 hours; the y acid includes but is not limited to trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoroacetic acid, phosphoric acid or formic acid; preferably, the y acid is hydrochloric acid, trifluoroacetic acid or formic acid.

[0084] The present invention can obtain acetates of compound A containing compound A and acetic acid in different molar ratios by strictly controlling the freezing temperature and freeze-drying time; in particular, acetates of compound A containing compound A and acetic acid in a molar ratio of 1:1 to 2 can be obtained.

[0085] This method of converting the strong acid salt of compound A into a weak acid to obtain the weak acid salt of compound A is also applicable to the preparation of other weak acid salts of compound A, which cannot directly remove the amino protecting group (such as Boc) on compound A.

[0086] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the acid salts described above, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0087] In some embodiments, the composition comprises a therapeutically effective dose of any acid salt as described above, and a buffer system. In some embodiments, the buffer system is an acetic acid-acetate (e.g., sodium salt) buffer system, a phosphoric acid-phosphate (e.g., sodium salt) buffer system, or a tartaric acid-tartrate (e.g., sodium salt) buffer system. In some embodiments, the buffer system is an acetic acid-sodium acetate buffer system.

[0088] The present invention further relates to the use of an acid salt of any of the compounds described above, or a pharmaceutical composition thereof, in preparing a drug.

[0089] In some embodiments of the present invention, the drug is a drug for preventing and / or treating kappa opioid receptor-mediated diseases.

[0090] In further embodiments of the present invention, the kappa opioid receptor-mediated related diseases are selected from one or more of pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma, preferably pain.

[0091] In further embodiments of the present invention, the pain is selected from one or more of neuropathic pain, truncal pain, visceral pain, cutaneous pain, arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, indigestion, post-surgical pain, post-medical treatment pain, eye pain, otitis pain, breakthrough cancer pain, and pain associated with GI disorders.

[0092] Example

[0093] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content of the present invention's teachings, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the application's appended claims.

[0094] The reagents or instruments used in this application, if the manufacturer is not indicated, are all conventional products that can be obtained commercially. Specifically, compounds 1-3 were purchased from Nanjing Komer Biopharmaceutical Co., Ltd. Wherein, "FA" refers to formic acid. "TFA" refers to trifluoroacetic acid. "EtOAc" refers to ethyl acetate. "MeOH" refers to methanol. "DMF" refers to N,N-dimethylformamide. "DIPEA" refers to N,N-diisopropylethylamine. "HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. "MeCN" refers to acetonitrile. "DCM" refers to dichloromethane.

[0095] Example 1 (Formate of Compound A)

[0096] 1.1 Synthesis of Compound 1-1

[0097] Benzyl 4-aminopiperidine-1-carboxylate (500 mg, 2.134 mmol, 1 eq.) was dissolved in toluene (5 mL), and diphosgene (260 uL, 1.314 mmol, 0.62 eq.) was added. The mixture was stirred at 90°C for 3 h, followed by the dropwise addition of tetrahydropyran-4-ol (205 uL, 2.007 mmol, 0.94 eq.). The resulting mixture was stirred at 90°C under a nitrogen atmosphere overnight, cooled to room temperature, poured into ice water, and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed twice with saturated aqueous NaCl (2 x 15 ml), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 1-1. The crude product of compound 1-1 was used directly in the next step without further purification.

[0098] 1.2 Synthesis of compound 1-2

[0099] Compound 1-1 (433 mg, 1.195 mmol, 1 eq.) and Pd / C (100 mg, w / t, 10%) were added to methanol (10 mL, 246.99 mmol, 206.73 eq.). The mixture was stirred overnight at room temperature under a hydrogen atmosphere, then filtered and the resulting filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to obtain a crude product of compound 1-2 (448 mg). The crude product of compound 1-2 was used directly in the next step without further purification.

[0100] 1.3 Synthesis of Compounds 1-4

[0101] Under nitrogen at room temperature, compound 1-2 (113 mg, 0.495 mmol, 1.5 eq.) was dissolved in DMF (10 mL). Compound 1-3 (248.79 mg, 0.330 mmol, 1 eq.) was added and stirred. DIPEA (85.30 mg, 0.660 mmol, 2 eq.) and HATU (188.21 mg, 0.495 mmol, 1.5 eq.) were then added and stirred overnight. The mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaCl (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by HPLC to obtain compound 1-4 (104 mg, 32.69% yield, 99% purity). The purification conditions were as follows: mobile phase, MeCN-H2O; elution time: 10 min; elution gradient: 10% (MeCN) to 50% (MeCN); detection wavelength: UV 254 nm.

[0102] 1.4 Synthesis of Compound A Formate

[0103] Under nitrogen at room temperature, compound 1-4 (104 mg, 0.108 mmol, 1 eq.) and TFA (4 mL) were added to DCM (16 mL). After stirring for 3 h, the mixture was concentrated under reduced pressure. 25 mL of ice water was added to the residue, and the pH was adjusted to 7-8 by dropwise addition of saturated aqueous sodium bicarbonate. The mixture was then extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with saturated aqueous NaCl (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and the residue concentrated. The residue was purified by HPLC, and the resulting aqueous phase was lyophilized in a freeze-drying oven to obtain the formate salt of compound A (19.7 mg, 22.73% yield, 95.0% purity). The following conditions were used: mobile phase: MeCN-H2O (0.1% FA), elution time: 10 min; elution gradient: 10% (MeCN) to 50% (MeCN); detection wavelength: UV 254 nm. LC-MS (ES, m / z) = 764 [M+H] + .

[0104] 1H NMR(400MHz,D2O)δ8.36(s,1H),7.26(h,J=6.6Hz,6H),7.13(t,J=7.1Hz,4H),4 .65(s,2H),4.59–4.47(m,1H),4.26–4.03(m,2H),3.96–3.76(m,4H),3.56(d,J= 10.2Hz,3H),3.22(q,J=13.7Hz,1H),3.02–2.75(m,7H),1.86(s,4H),1.60(dt,J =15.1,7.7Hz,6H),1.46(d,J=6.3Hz,3H),1.38–1.11(m,4H),0.91–0.70(m,6H).

[0105] Example 2 (Trifluoroacetate salt of Compound A)

[0106] At room temperature under nitrogen, compound 1-4 (104 mg, 0.108 mmol, 1 eq.) and TFA (4 mL) were added to DCM (16 mL) and stirred for 3 h. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was dispersed in DCM (2 mL) and stirred at room temperature for 2 h. MBTE (6 mL) was added dropwise to precipitate a solid, which was then filtered. The resulting filter cake was dried in a vacuum oven to obtain the trifluoroacetic acid salt of compound A (87.47 mg, 81.64% yield, 98% purity). LC-MS (ES, m / z) = 764 [M+H] + .

[0107] 1H NMR (400MHz, DMSO-d6) δ8.81(d,J=8.1Hz,1H),8.41(d,J=8.0Hz,1H),8.12(t,J=6.1Hz,1H),8.06(s,2H),7.84(d,J=7. 3Hz,2H),7.33–7.20(m,10H),4.81–4.59(m,3H),4.37(dd,J=12.0,6.2Hz,1H),4.17(dd,J=24.9,13.1Hz,1H),4.02(s,1 H),3.90–3.72(m,3H),3.41(t,J=10.8Hz,4H),3.10(ddd,J=17.0,12.1,4.2Hz,3H),2.94(dd,J=14.4,7.9Hz,1H),2.87– 2.64(m,4H),1.90–1.70(m,4H),1.53(ddt,J=26.5,21.0,10.0Hz,8H),1.36–1.18(m,4H),0.90(dd,J=16.7,5.9Hz,6H).

[0108] Example 3 (Preparation of the hydrochloride salt of compound A)

[0109] At room temperature and under nitrogen, compound 1-4 (100 mg, 0.104 mmol, 1 eq.) was added to HCl / ethyl acetate (2 M, 5 mL) and stirred for 3 h in an ice bath. The precipitated solid was filtered. The resulting filter cake was dried to obtain the hydrochloride salt of compound A (Formula (II)) (79.1 mg, 88.04% yield, 99% purity). LC-MS (ES, m / z) = 764 [M+H] + .

[0110] 1 H NMR (400MHz, DMSO-d6) δ9.07(t,J=6.7Hz,1H),8.54(d,J=7.9Hz,1H),8.14(d,J=10.8Hz,6H),7.41(d,J=7.5Hz,2H),7.32–7. 19(m,8H),4.76–4.58(m,3H),4.42–4.29(m,1H),4.17(t,J=16.2Hz,1H),4.03(d,J=6.8Hz,1H),3.81(t,J=12.4Hz,3H),3.54 (s,1H),3.42(dd,J=6.7,3.0Hz,1H),3.22(dd,J=14.4,4.6Hz,1H),3.18–3.05(m,2H),2.96(dd,J=14.2,7.6Hz,1H),2.90–2. 81(m,1H),2.75(q,J=9.6,8.3Hz,2H),1.88–1.64(m,5H),1.53(dp,J=30.6,7.3Hz,8H),1.37–1.14(m,4H),1.03–0.70(m,6H).

[0111] The method for determining the number of HCl in the hydrochloride of compound A is as follows:

[0112] Take 0.3g of the hydrochloride salt of Compound A obtained by the above experimental steps, dissolve it in 20ml of water, add 3-5 drops of potassium chromate indicator and shake well. Slowly add silver nitrate titrant (0.05mol / L) dropwise, shaking while adding. When the solution changes from yellow to light brick red, it is the titration endpoint. A total of 14.70ml of silver nitrate titrant is used. Each 1ml of silver nitrate titrant (0.05mol / L) is equivalent to 1.772mg of Cl. The final hydrochloric acid mass percentage is determined to be 8.8%; n 化合物A :n HCl=(100-8.8) / 763.46:8.8 / 36.5=0.1195:0.2411=1: 2.02≈1:2.

[0113] Example 4 (Preparation of Acetate Salt of Compound A)

[0114] At room temperature and under a nitrogen atmosphere, the trifluoroacetic acid salt of Compound A obtained in Example 2 (75 mg, 0.077 mmol, 1 eq.) and 205×7 acetate ion exchange resin (211 mg, 0.77 mmol, 10 eq.) were added to purified water (5 mL), stirred for 5 hours, and then filtered. The resulting aqueous phase was lyophilized in a freeze-drying oven and freeze-dried at a temperature of -45-25°C for 72 hours to obtain the acetate salt of Compound A represented by formula (I-2) (54.6 mg, yield 83.61%, purity 99%). LC-MS (ES, m / z) = 764 [M+H] + .

[0115] 1 HNMR(400MHz,CD3OD)δ7.25(ddd,J=32.5,17.2,7.3Hz,10H),4.87–4.74(m,2H),4.65 (dd,J=9.0,5.2Hz,1H),4.45–4.27(m,2H),4.01(d,J=13.9Hz,1H),3.93–3.83(m,2H) ,3.73–3.51(m,4H),3.29–3.11(m,2H),3.03–2.81(m,5H),2.67(dd,J=13.7,8.3Hz,1 H),1.93(s,7H),1.81–1.53(m,9H),1.52–1.28(m,4H),0.97(dd,J=14.5,6.0Hz,6H).

[0116] Example 5 (Preparation of Acetate Salt of Compound A)

[0117] At room temperature and under a nitrogen atmosphere, the hydrochloride salt of compound A (8.0 g, 9.56 mmol, 1 eq.) obtained by the method described in Example 3 and 205×7 acetate ion exchange resin (26.21 g, 95.6 mmol, 10 eq.) were added to purified water (40 mL), stirred for 10 hours, and then filtered. The resulting aqueous phase was lyophilized in a freeze-drying oven and freeze-dried at a temperature of -45-20°C for 66 hours to obtain the acetate salt of compound A (6.92 mg, yield 83.57%, purity 99%). LC-MS (ES, m / z) = 764 [M+H]+ .

[0118] 1 H NMR (400MHz, CD3OD) δ7.39–7.28(m,10H),7.23(t,J=7.3Hz,1H),4.84–4.70(m,3H),4.47–4.27(m,2H),4. 18(dd,J=9.0,4.8Hz,1H),4.03–3.85(m,3H),3.69(d,J=6.1Hz,1H),3.55(t,J=10.3Hz,2H),3.42–3.31(m, 2H),3.25(dd,J=14.5,5.3Hz,2H),3.11–2.92(m,5H),2.92–2.75(m,1H),1.93(d,J=13.7Hz,4H),1.69(dtd ,J=33.5,18.3,16.2,7.8Hz,10H),1.50(d,J=8.9Hz,2H),1.47–1.33(m,2H),0.98(dd,J=15.8,6.0Hz,6H).

[0119] Example 6 (Preparation of Acetate Salt of Compound A)

[0120] At room temperature and under a nitrogen atmosphere, the hydrochloride salt of compound A (8.0 g, 9.56 mmol, 1 eq.) obtained by the method described in Example 3 and 205×7 acetate ion exchange resin (26.21 g, 95.6 mmol, 10 eq.) were added to purified water (40 mL), stirred for 10 hours, and then filtered. The resulting aqueous phase was lyophilized in a freeze-drying oven and freeze-dried at a temperature of -45-20°C for 69 hours to obtain the acetate salt of compound A (6.78 g, yield 83.09%, purity 99%). LC-MS (ES, m / z) = 764 [M+H] + .

[0121] 1H NMR (400MHz, CD3OD) δ7.41–7.15(m,10H),4.89–4.62(m,5H),4.48–4.26(m ,2H),4.15–3.86(m,4H),3.69(d,J=11.1Hz,1H),3.55(t,J=10.3Hz,2H),3 .33(s,1H),3.25(td,J=15.0,5.2Hz,3H),3.02–2.77(m,5H),2.10–1.85(m ,4H),1.82–1.55(m,9H),1.52–1.30(m,4H),0.98(dd,J=14.7,6.2Hz,6H).

[0122] Example 7 (Preparation of Acetate Salt of Compound A)

[0123] At room temperature and under a nitrogen atmosphere, the hydrochloride salt of compound A (8.0 g, 9.56 mmol, 1 eq.) obtained by the method described in Example 3 and 205×7 acetate ion exchange resin (26.21 g, 95.6 mmol, 10 eq.) were added to water (40 mL), stirred for 10 hours, and then filtered. Acetic acid (1.74 g, 28.68 mmol, 3 eq.) was added to the filtrate, stirred until uniform, and the resulting aqueous phase was lyophilized in a freeze-drying oven at a freezing temperature of -45-20°C for 69 hours to obtain the acetate salt of compound A (7.21 g, yield 85.94%, purity 99%).

[0124] The obtained acetate salt of compound A represented by formula (I-5) (5.0 g) was freeze-dried at a freezing temperature of 20°C for 36 hours to obtain acetate salt of compound A represented by formula (I-3) (4.75 g, yield 97.74%, purity 99%).

[0125] The acetate salt (3.0 g) of compound A represented by formula (I-3) was freeze-dried at 25°C for 36 h to obtain the acetate salt of compound A represented by formula (I-6) (2.89 g, yield 98.97%, purity 99%).

[0126] Example 8 (Preparation of Acetate Salt of Compound A)

[0127] The acetate salt of compound A represented by formula (I-3) obtained by the method described in Example 6 (5.0 g) was freeze-dried at a freezing temperature of 20°C for 36 hours to obtain the acetate salt of compound A represented by formula (I-7) (4.88 g, yield 97.99%, purity 99%).

[0128] The obtained acetate salt of compound A represented by formula (I-7) (3.0 g) was freeze-dried at a freezing temperature of 25°C for 36 hours to obtain acetate salt of compound A represented by formula (I-8) (2.92 g, yield 98.98%, purity 99%).

[0129] Example 7 Method for Determining the Number of Acetic Acids in Acetate Salt of Compound A

[0130] The detection conditions of high performance liquid chromatography (HPLC) are as follows:

[0131] Filler: octadecylsilane bonded silica gel; Mobile phase A: phosphoric acid solution (V 磷酸 :V 水 =0.7ml:1000ml; adjust pH to 3.0 with sodium hydroxide solution (0.42%); mobile phase B: methanol; column temperature: 35°C; detection wavelength: 210nm; flow rate: 1.2ml / min; injection volume: 10μl; elution gradient is as follows:

[0132] Preparation of the sample solution to be tested: Take the acetate of compound A represented by formula (I-2), formula (I-4) and formula (I-3) in Example 4, Example 5 and Example 6 respectively, and use diluent (V 流动相A :V 流动相B =95:5) and ultrasonically dissolved and diluted to form the sample solution to be tested (1 mg / ml).

[0133] Preparation of reference solution: dilute glacial acetic acid with diluent (V 流动相A :V 流动相B =95:5) and diluted to prepare a reference solution (1 mg / ml).

[0134] Inject the reference solution (10 μl) and each sample solution (10 μl) into the liquid chromatograph and record the chromatogram. According to the calculation formula: as well as Get the percentage of acetic acid in the sample to be tested; where R f A is the correction factor obtained from the reference solution; 样 is the main peak area of ​​the sample to be tested; V 供 is the volume of the sample solution to be tested (ml); m 供 is the weight of the sample to be tested (mg). Then according to the calculation formula: n 化合物A :n CH3COOH =(100-acetic acid content) / 763.46:acetic acid content / 60.05, to obtain the molar ratio of compound A to acetic acid in the sample to be tested.

[0135] The test results are as follows:

[0136] Physical and chemical properties research

[0137] The inventors further studied the physicochemical properties of the salt forms of the corresponding compounds. The preparation and characterization of the specific salt forms disclosed in this application do not limit the scope of protection of the present invention. Those skilled in the art can, based on the present disclosure, obtain more salt forms of the compounds of the present invention through conventional salt-forming methods, and these salt forms are all protected by the present invention.

[0138] 1. Physicochemical properties of compound A salt

[0139] 1.1 Experimental Purpose

[0140] The physicochemical properties of the salt form of compound A were investigated.

[0141] 1.2 Experimental methods

[0142] 1.2.1 pH determination

[0143] Take an appropriate amount of sample, weigh it accurately, dissolve it in water and dilute it to make a solution containing approximately 10 mg per 1 ml, and determine it according to the law (General Rules 0631 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0144] 1.2.2 Specific rotation determination

[0145] Take an appropriate amount of sample, weigh it accurately, dissolve it in methanol and dilute it to make a solution containing about 10 mg per 1 ml, and measure it according to the law (measurement temperature 25°C, and the rest is in accordance with the general rules 0621 of the fourth part of the Chinese Pharmacopoeia 2020 edition).

[0146] 1.2.3 Moisture determination

[0147] Take a sample and determine it according to the moisture determination method (Method 0832, General Rules of Part IV, 2020 Edition of the Chinese Pharmacopoeia).

[0148] 1.2.4 Determination of acetic acid content

[0149] Take an appropriate amount of sample (acetate), accurately weigh it, dissolve it in diluent [mobile phase A (General Chapter 0872) - methanol (95:5)], and quantitatively dilute it to a solution containing approximately 1 mg per 1 ml, which serves as the test solution. Determine the amount of acetic acid in synthetic peptides according to the method for the determination of acetic acid in synthetic peptides (General Chapter 0872, Part IV, Chinese Pharmacopoeia 2020 Edition).

[0150] 1.3 Experimental Results

[0151] The results are shown in the following table:

[0152] Table 1.3 Physicochemical properties of compound A salt Note: “ / ” means not detected.

[0153] 2. Solubility test of compound A salt

[0154] 2.1 Experimental Purpose

[0155] The solubility of the salt form of Compound A in various solvents was investigated.

[0156] 2.2 Experimental methods

[0157] Weigh the sample and grind it into fine powder. Place it in a certain volume of solvent at 25℃±2℃, and shake it vigorously for 30 seconds every 5 minutes. Observe the dissolution within 30 minutes. If there are no visible solute particles or droplets, it is considered to be completely dissolved.

[0158] 2.3 Experimental results:

[0159] The results are shown in the following table:

[0160] Table 2.3 Solubility of different salt forms of compound A Note: "Soluble" means that 1g (ml) of solute can be dissolved in 1 to less than 10ml of solvent; "Slightly soluble" means that 1g (ml) of solute can be dissolved in 100 to less than 1000ml of solvent; "Almost insoluble or insoluble" means that 1g (ml) of solute cannot be completely dissolved in 10000ml of solvent.

[0161] From the above data, it can be seen that the acetate of Compound A and the hydrochloride of Compound A represented by formula (II) are readily soluble in water, methanol, and ethanol, while Compound A is almost insoluble in water and slightly soluble in methanol and ethanol.

[0162] Considering that the acetate of compound A represented by formula (I-2), the acetate of compound A represented by formula (I-3), the acetate of compound A represented by formula (I-4), the acetate of compound A represented by formula (I-5), the acetate of compound A represented by formula (I-6), the acetate of compound A represented by formula (I-7), and the acetate of compound A represented by formula (I-8) all exhibit the same or similar stability in stability tests such as high temperature, light, oxidation, and accelerated tests, only one of the acetates is selected as a representative for testing in the following stability tests.

[0163] 3. Stability test under high temperature and light conditions

[0164] Compound A, the hydrochloride of compound A represented by formula (II), and the acetate of compound A represented by formula (I-4) were respectively placed under the following experimental conditions:

[0165] (1) High temperature conditions: open, temperature is 40℃;

[0166] (2) Lighting conditions: Cool white fluorescent lamp and near-ultraviolet lamp are present simultaneously, open, room temperature, illumination is 5000lx±500lx, and the intensity of near-ultraviolet lamp is 90μW / cm 2 ;

[0167] Compound A, the hydrochloride of compound A represented by formula (II), and the acetate of compound A represented by formula (I-4) were placed under each of the above test conditions for 30 days, and samples were taken on the 5th, 10th, and 30th days, and the percentage content of compound A, the maximum single impurity, and the total impurities were detected by high performance liquid chromatography (HPLC).

[0168] The HPLC detection conditions are as follows:

[0169] The detection conditions of high performance liquid chromatography (HPLC) were as follows: filler: octadecylsilane bonded silica gel; mobile phase A: potassium dihydrogen phosphate aqueous solution (0.02 mol / L, containing 0.1% triethylamine, pH adjusted to 3.0 with phosphoric acid) and acetonitrile, wherein V 磷酸二氢钾溶液 :V 乙腈 =90:10; Mobile phase B: potassium dihydrogen phosphate aqueous solution (0.02 mol / L, containing 0.1% triethylamine, pH adjusted to 3.0 with phosphoric acid) and acetonitrile, wherein V 磷酸二氢钾溶液 :V 乙腈 =30:70; column temperature: 40°C; detection wavelength: 210 nm; flow rate: 1.0 ml / min; injection volume: 10 μl; elution gradient as shown in Table 3.1;

[0170] Table 3.1 Elution gradient

[0171] The stability test results are shown in Table 3.2 below;

[0172] Table 3.2 Stability test data under high temperature and light conditions

[0173] As shown in Table 3.2, under the conditions of (high temperature 40°C, 30 days) and (light exposure for 30 days), the acetate of compound A represented by formula (I-4) and the hydrochloride of compound A represented by formula (II) both have superior stability compared to compound A. In particular, under the condition of 30 days of light exposure, the maximum single impurity content of compound A is 30 times that of the acetate of compound A represented by formula (I-4) and 18 times that of the hydrochloride of compound A represented by formula (II); the total impurity content of compound A is 8.8 times that of the acetate of compound A represented by formula (I-4) and 3 times that of the hydrochloride of compound A represented by formula (II).

[0174] 4. Stability test under accelerated conditions

[0175] Compound A, the hydrochloride salt of Compound A represented by Formula (II), and the acetate salt of Compound A represented by Formula (I-2) were each ultrasonically dissolved in a 20% methanol solution and diluted to a concentration of 0.5 mg / ml. The resulting solutions of Compound A (0.5 mg / ml), the hydrochloride salt of Compound A represented by Formula (II) (0.5 mg / ml), and the acetate salt of Compound A represented by Formula (I-2) (0.5 mg / ml) were placed in simulated commercial packaging (pharmaceutical low-density polyethylene bags) and subjected to an accelerated test for 6 months at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5%. Samples were collected at the first, second, third, and sixth months, and the percentages of Compound A, the largest single impurity, and total impurities were determined by high-performance liquid chromatography (HPLC).

[0176] The HPLC detection conditions are as follows:

[0177] The detection conditions of high performance liquid chromatography (HPLC) were as follows: filler: octadecylsilane bonded silica gel; mobile phase A: potassium dihydrogen phosphate aqueous solution (0.02 mol / L, containing 0.1% triethylamine, pH adjusted to 3.0 with phosphoric acid) and acetonitrile, wherein V 磷酸二氢钾溶液 :V 乙腈 =90:10; Mobile phase B: potassium dihydrogen phosphate aqueous solution (0.02 mol / L, containing 0.1% triethylamine, pH adjusted to 3.0 with phosphoric acid) and acetonitrile, wherein V 磷酸二氢钾溶液 :V 乙腈 =30:70; column temperature: 40°C; detection wavelength: 210 nm; flow rate: 1.0 ml / min; injection volume: 10 μl; elution gradient as shown in Table 4.1;

[0178] Table 4.1 Elution gradient

[0179] The results of the accelerated test are shown in Table 4.2 below;

[0180] Table 4.2 Stability test data under accelerated conditions

[0181] Table 4.2 shows that in a 6-month accelerated test at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5% RH, the acetate salt of Compound A represented by Formula (I-2) and the hydrochloride salt of Compound A represented by Formula (II) exhibited superior stability compared to Compound A. At 2 months of the accelerated test, the maximum single impurity content of Compound A was 38.9 times that of the acetate salt of Compound A represented by Formula (I-2) and 58.3 times that of the hydrochloride salt of Compound A represented by Formula (II); the total impurity content of Compound A was 14.4 times that of the acetate salt of Compound A represented by Formula (I-2) and 27.6 times that of the hydrochloride salt of Compound A represented by Formula (II).

[0182] 5. Stability test under oxidative conditions

[0183] To a 20 ml volumetric flask containing Compound A (10 mg), the hydrochloride salt of Compound A represented by Formula (II) (10 mg), and the acetate salt of Compound A represented by Formula (I-3) (10 mg), a 10% hydrogen peroxide solution (2 ml) was added. The mixture was allowed to stand at room temperature for 2 h. A 20% methanol solution was then added and ultrasonically dissolved, diluted to the mark, and shaken to obtain test solutions of Compound A, the hydrochloride salt of Compound A represented by Formula (II), and the acetate salt of Compound A represented by Formula (I-3), respectively. A blank control solution containing no oxidizing agent, hydrogen peroxide solution, was also prepared. The percentage of Compound A, the largest single impurity, and the total impurities in each test solution was determined by high-performance liquid chromatography (HPLC).

[0184] The HPLC detection conditions are as follows:

[0185] The detection conditions of high performance liquid chromatography (HPLC) were as follows: filler: octadecylsilane bonded silica gel; mobile phase A: potassium dihydrogen phosphate aqueous solution (0.02 mol / L, containing 0.1% triethylamine, pH adjusted to 3.0 with phosphoric acid) and acetonitrile, wherein V 磷酸二氢钾溶液 :V 乙腈 =90:10; Mobile phase B: potassium dihydrogen phosphate aqueous solution (0.02 mol / L, containing 0.1% triethylamine, pH adjusted to 3.0 with phosphoric acid) and acetonitrile, wherein V 磷酸二氢钾溶液 :V 乙腈 =30:70; column temperature: 40°C; detection wavelength: 210 nm; flow rate: 1.0 ml / min; injection volume: 10 μl; elution gradient as shown in Table 5.1;

[0186] Table 5.1 Elution gradient

[0187] The results of the stability test under oxidizing conditions are shown in Table 5.2 below;

[0188] Table 5.2 Stability test data under oxidative conditions

[0189] As shown in Table 5.2, under the oxidative conditions of hydrogen peroxide, the stability of the acetate salt of compound A represented by formula (I-3) and the hydrochloride salt of compound A represented by formula (II) are both superior to that of compound A. The maximum single impurity and total impurity contents of compound A are significantly higher than those of the acetate salt of compound A represented by formula (I-3) and the hydrochloride salt of compound A represented by formula (II).

[0190] Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes may be made to the present invention without departing from the spirit and scope of the invention, and these modifications and changes are also encompassed within the scope of the invention.

Claims

1. A tetrahydro-2H-pyran-4-yl (1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl) carbamate compound represented by formula (A) or an acid salt of a stereoisomer thereof 2. The acid salt according to claim 1, characterized in that The acid salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, lactate, citrate, tartrate, aspartate, glutamate, benzoate, citrate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof.

3. The acid salt according to claim 1 or 2, characterized in that The acid salt is formate, trifluoroacetate, phosphate, citrate, benzoate, lactate, hydrochloride or acetate, preferably hydrochloride or acetate.

4. The acid salt according to any one of claims 1 to 3, characterized in that The acid salt is hydrochloride.

5. The acid salt according to any one of claims 1 to 3, characterized in that The acid salt is acetate.

6. The acid salt according to any one of claims 1 to 5, characterized in that The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:0.4 to 1:4, preferably 1:0.4 to 0.6, 1:0.8 to 1.2, 1:1.4 to 1.6, 1:1.8 to 2.2, 1:2.4 to 2.6 or 1:2.8 to 3.2, preferably 1:0.8 to 1.2, 1:1.8 to 2.2 or 1:2.8 to 3.2, preferably 1:1, 1:2 or 1:

3.

7. The acid salt according to any one of claims 1 to 6, characterized in that The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1-2.

8. The acid salt according to any one of claims 1 to 7, characterized in that The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.1; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.2; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.3; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.4; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.5; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.6; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.7; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.8; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:1.9; or The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:

2.

9. The acid salt according to any one of claims 1 to 8, characterized in that The molar ratio of the compound of formula (A) or its stereoisomer to the acid radical is 1:

2.

10. A tetrahydro-2H-pyran-4-yl (1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl) carbamate compound represented by formula (I) or an acetate salt of a stereoisomer thereof 11. A tetrahydro-2H-pyran-4-yl (1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidin-4-yl) carbamate compound represented by formula (II) or a hydrochloride of a stereoisomer thereof 12. A method for preparing a compound represented by formula (A) or an acid salt of a stereoisomer thereof, characterized in that: The method comprises contacting a compound represented by formula (A) or a stereoisomer thereof protected by an amino protecting group (such as Boc) with an X acid to obtain an X acid salt of the compound represented by formula (A) or a stereoisomer thereof; wherein the X acid is capable of removing the amino protecting group (such as Boc).

13. The method for preparing the compound represented by formula (A) or the acid salt of its stereoisomer according to claim 12, characterized in that: The X acid includes, but is not limited to, one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid.

14. A method for preparing the hydrochloride of the compound represented by formula (A) or its stereoisomer, characterized in that: The method comprises contacting a compound represented by formula (A) or a stereoisomer thereof protected by an amino protecting group (such as Boc) with hydrochloric acid to obtain a hydrochloride of the compound represented by formula (A) or a stereoisomer thereof.

15. A method for preparing a compound represented by formula (A) or an acid salt of a stereoisomer thereof, characterized in that: The Y acid salt of the compound represented by formula (A) or its stereoisomer is contacted with Z acid to carry out acid radical conversion to generate Z acid salt of the compound represented by formula (A) or its stereoisomer; wherein the Y acid is an acid stronger than the Z acid.

16. A method for preparing the acetate of the compound represented by formula (A) or its stereoisomer, characterized in that: The Y acid salt of the compound represented by formula (A) or its stereoisomer is contacted with acetic acid to carry out acid radical conversion to generate the acetate salt of the compound represented by formula (A) or its stereoisomer, wherein the Y acid is an acid stronger than acetic acid.

17. The method for preparing the acetate salt of the compound represented by formula (A) or its stereoisomer according to claim 16, characterized in that: The Y acid includes, but is not limited to, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid, phosphoric acid or formic acid; preferably, the Y acid is hydrochloric acid, trifluoroacetic acid or formic acid.

18. The method for preparing the acetate salt of the compound represented by formula (A) or its stereoisomer according to claim 16 or 17, characterized in that: contacting the compound represented by formula (A) or the hydrochloride of its stereoisomer with acetic acid to generate the acetate of compound A; or contacting the trifluoroacetate of the compound represented by formula (A) or its stereoisomer with acetic acid to generate the acetate of compound A; or The compound represented by formula (A) or its stereoisomer formate is contacted with acetic acid to produce the acetate of compound A.

19. A pharmaceutical composition comprising a therapeutically effective dose of the acid salt of any one of claims 1 to 11, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. The composition according to claim 19, comprising a therapeutically effective dose of the acid salt of any one of claims 1 to 11, and an acetic acid-acetate buffer system, a phosphoric acid-phosphate buffer system or a tartaric acid-tartrate buffer system.

21. Use of an acid salt according to any one of claims 1 to 11, or a pharmaceutical composition according to claims 19 to 20 in the preparation of a medicament, wherein the medicament is preferably a medicament for preventing and / or treating diseases mediated by kappa opioid receptors, preferably, the diseases mediated by kappa opioid receptors are selected from one or more of pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma, preferably pain; preferably, the pain is selected from one or more of neuropathic pain, trunk pain, visceral pain, skin pain, arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, postoperative pain, post-medical treatment pain, eye pain, otitis pain, explosive cancer pain and pain associated with GI disorders.

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