κ-opioid receptor agonists and their uses

Abstract

The present invention belongs to the field of biopharmaceuticals and provides a κ-opioid receptor agonist having the following formula, its stereoisomers, and pharmaceutically acceptable salts thereof. The κ-opioid receptor agonist has high selectivity for the κ-opioid receptor, its activity is 3 to 15 times that of diferikephalin, and has high pharmacological activity, and can be used for the treatment, prevention and / or remission of pruritus, and / or analgesia. D-Phe-AA1-AA2-D-Lys-4-aminopiperidine-4-carboxamide-AA3-AA4-AA5 [Formula I].

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202310371594.6, filed with the China National Intellectual Property Office on 10 April 2023, with the title of the invention "Long-acting K-opioid receptor agonist," and to Chinese Patent Application No. 202410112984.6, filed with the China National Intellectual Property Office on 26 January 2024, with the title of the invention "Long-acting K-opioid receptor agonist," all of which are incorporated herein by reference in whole.

[0002] This invention belongs to the field of biopharmaceutical technology and specifically relates to a highly selective κ-opioid receptor agonist and its uses. [Background technology]

[0003] Opioid drugs exert their physiological effects primarily by binding to three known classical opioid receptors (μ, δ, and κ). All three of these receptors belong to the G protein-coupled receptor family and are mainly distributed in the central nervous system, but are also present in many peripheral tissues.

[0004] The most classic of these drugs is morphine, which exerts its analgesic effect primarily through the action of μ-opioid receptors. Clinically used analgesics also include other μ-opioid receptor drugs, such as traditional opioids represented by dihydromorphinone and fentanyl. However, long-term use of μ-opioid receptor drugs can cause many side effects, including tolerance, dependence, respiratory depression, and adverse effects on gastrointestinal motility, which can lead to increased healthcare costs and affect the patient's recovery period. On the other hand, non-opioid injections such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) have reduced analgesic effects, so their scope of application and dosage are limited. Furthermore, acetaminophen can induce liver damage, and NSAIDs can cause various gastrointestinal disorders, among other specific side effects.

[0005] κ-opioid receptors are present in the brain, spinal cord, central nervous system terminals, peripheral nerve terminals, somatic and visceral primary sensory afferent nerve cell bodies, and immune cells. Studies have shown that κ-opioid receptor agonists can be used to target K-opioid receptors for the treatment of pain and the prevention of various diseases and symptoms, such as the treatment of pain including hyperalgesia, application to eye problems and eye pain, and application to the treatment of uremia and opioid-induced pruritus.

[0006] Difelikefalin (trade name: KORSUVA) is a first-in-class, highly selective κ-opioid receptor (KOR) complete agonist that can inhibit the activity of peripheral neurons causing pruritus, but does not show significant activity to other receptors (including μ- or δ-opioid receptors), ion channels, or transporters. Unlike small molecule KOR agonists, Korsuva is a small molecule synthetic peptide that activates KORs expressed primarily in peripheral neurons (PNS) and immune cells. The U.S. FDA approved difelikefalin for the treatment of moderate to severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). In several different Phase II or Phase III studies, difelikefalin demonstrated antipruritic and analgesic effects, as well as suppression of postoperative pain (IV formulation in laparoscopic hysterectomy, abdominal wall hernia and bunion resection).

[0007] The present invention aims to discover novel and highly active κ-opioid receptor agonists. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] One object of the present invention is to provide a peptide compound that is a novel and highly active κ-opioid receptor agonist having high selectivity for κ-opioid receptors. Another object of the present invention is to provide a pharmaceutical composition. A further object of the present invention is to provide uses for the compound and pharmaceutical composition. [Means for solving the problem]

[0009] The objective of this invention is achieved through the following technical solutions.

[0010] In the first aspect, the present invention provides a κ-opioid receptor agonist having the following formula I, its stereoisomers, and pharmaceutically acceptable salts thereof: [Formula I] D-Phe-AA1-AA2-D-Lys-4-aminopiperidine-4-carboxamide-AA3-AA4-AA5 Here, AA1 is a modified or unmodified D-Phe, or a modified or unmodified D-Tyr. AA2 is D-Leu or D-cyclopropylalanine; AA3 is -(PEG m1 (CH2) m2 CO) m3 -, (AA6) m4 Either it is or does not exist (where m1 is an integer from 1 to 10, m2 is an integer from 1 to 5, m3 is an integer from 1 to 5, m4 is an integer from 1 to 5, and AA6 is AEEA, Gly, D-type or L-type Ala, D-type or L-type Leu, D-type or L-type Phe, D-type or L-type Ser, D-type or L-type Thr, D-type or L-type Tyr, D-type or L-type Asp, D-type or L-type Glu, D-type or L-type Gln, D-type or L-type Lys, D-type or L-type Arg, or D-type or L-type His); AA4 is (AA7) nEither it exists or it does not exist (where n is an integer from 1 to 10, and AA7 is a D-type or L-type Lys, a D-type or L-type Dap, a D-type or L-type Dab, a D-type or L-type Orn, a D-type or L-type Dah, or a D-type or L-type Dao); AA5 is either OH or NH2.

[0011] Preferably, AA1 is a modified D-Phe selected from the group consisting of D-Phe(2-F), D-Phe(4-F), D-Phe(2-Cl), D-Phe(4-Cl), D-Phe(2-Br), D-Phe(4-Br), D-Phe(2-I), D-Phe(4-I), D-Phe(4-Me), D-Phe(4-Et), D-Phe(4-Ipr), D-Phe(4-NH2), D-Phe(4-NHCH3), D-Phe(4-NHCH2CH3), D-Phe(4-NHCH(CH3)2), D-Phe(4-N(CH3)2), and D-Phe(4-N(CH3)CH2CH3).

[0012] Preferably, AA1 is a modified D-Tyr selected from the group consisting of D-Tyr(Me), D-Tyr(Et), D-Tyr(CH2CF3), and D-Tyr(Ipr).

[0013] Furthermore, the κ-opioid receptor agonist has a structure represented by formula II, and includes its stereoisomer and its pharmaceutically acceptable salts: [Formula II] D-Phe-AA1-AA2-D-Lys-4-aminopiperidine-4-carboxamide-R-(AA8) p -NH2(OH)

[0014] Unless otherwise specified, "-NH2(OH)" in the structural formula of this invention represents either -NH2 or -OH.

[0015] Here, AA1 is a modified D-Phe or modified D-Tyr, and the specific modification method is as described above. AA2 is D-Leu or D-cyclopropylalanine, R is -PEG m1 CH2CO-, -AEEA n1 -, or -Gly n2 is present as - or is absent (where m1 is specifically an integer of 1 to 5 selected from the group consisting of 1, 2, 3, 4, 5, n1 is specifically an integer of 1 to 5 selected from the group consisting of 1, 2, 3, 4, 5, and n2 is specifically an integer of 1 to 5 selected from the group consisting of 1, 2, 3, 4, 5), AA8 is Lys or D-Lys, p is specifically an integer of 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and when p is 0, AA8 is absent.

[0016] In any one embodiment of the present invention, the κ-opioid receptor agonist is a compound having a structure represented by Formula III, its stereoisomer, and its pharmaceutically acceptable salt: [Formula III] D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-R1-(AA8) p1 -NH2(OH) where D-Tyr(X) is a modified D-Tyr selected from the group consisting of D-Tyr(Me), D-Tyr(Et), D-Tyr(CH2CF3), and D-Tyr(Ipr); R1 is -PEG k1 CH2CO or -Gly n2 is present as - or is absent (where k1 is specifically an integer of 1 to 5 selected from the group consisting of 1, 2, 3, 4, 5, and n2 is specifically an integer of 1 to 5 selected from the group consisting of 1, 2, 3, 4, 5); AA8 is Lys or D-Lys; p1 is specifically an integer of 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and when p2 is 0, AA8 is absent.

[0017] In any embodiment of the present invention, the κ-opioid receptor agonist is a compound having the structure represented by formula IV, its stereoisomer, and a pharmaceutically acceptable salt thereof: [Formula IV] D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-R2-(AA8) p2 -NH2(OH) In the formula, D-Tyr(X) is a modified D-Tyr selected from the group consisting of D-Tyr(Me), D-Tyr(Et), and D-Tyr(Ipr); R2 is -PEG k2 It may or may not exist as CH2CO- (wherein k2 is specifically an integer from 1 to 5 selected from the group consisting of 1, 2, 3, 4, and 5, and in the most preferred embodiment of the present invention, k2 is 1, 2, or 3); AA8 is Lys or D-Lys; p3 is specifically an integer from 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. If p3 is 0, then AA8 does not exist. In the most preferred embodiment of the present invention, p3 is 0 or 1.

[0018] In any embodiment of the present invention, the κ-opioid receptor agonist is a compound having the structure represented by formula V, its stereoisomer, and a pharmaceutically acceptable salt thereof: [Formula V] D-Phe-D-Phe(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-(AA8) p3 -NH2(OH) In the formula, D-Phe(X) is a modified D-Phe selected from the group consisting of D-Phe(2-F), D-Phe(4-F), D-Phe(2-Cl), D-Phe(4-Cl), D-Phe(2-Br), D-Phe(4-Br), D-Phe(2-I), D-Phe(4-I), D-Phe(4-Me), D-Phe(4-Et), D-Phe(4-Ipr), and D-Phe(4-NH2); AA8 is Lys or D-Lys; p3 is specifically an integer from 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. If p3 is 0, then AA8 does not exist. In the most preferred embodiment of the present invention, p3 is 0 or 1.

[0019] More preferably, the κ-opioid receptor agonist has one or more structures selected from the group consisting of 1) to 10) below: 1) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxylic acid-NH2(OH) 2) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-NH2(OH) 3) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-(AA8) q -NH2(OH) 4) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-PEG k1 CH2CO-AA8-NH2(OH) 5) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-Gly n2 -AA8-NH2(OH) 6) D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-NH2(OH) 7) D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-AA8-NH2(OH) 8) D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-PEG k2 CH2CO-AA8-NH2(OH) 9) D-Phe-D-Phe(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-NH2(OH) 10) D-Phe-D-Phe(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-AA8-NH2(OH) In the above structural formula, AA8 is either Lys or D-Lys; In equation 1), D-Tyr(X) is D-Tyr(Et); In equations 2) and 3), D-Tyr(X) is D-Tyr(Me), D-Tyr(Et), D-Tyr(CH2CF3), or D-Tyr(Ipr), and q is 1, 2, 3, 4, 5, or 6; In equations 4) to 8), D-Tyr(X) is D-Tyr(Et), k1 is 1, 2, 3, 4, or 5, n2 is 1, 2, 3, 4, or 5, and k2 is 1, 2, or 3; In formula 9), D-Phe(X) is D-Phe(4-F), D-Phe(4-Cl), D-Phe(4-Br), or D-Phe(4-I); In formula 10), D-Phe(X) is D-Phe(4-F), D-Phe(4-Cl), D-Phe(4-Br), D-Phe(4-I), D-Phe(4-Me), D-Phe(4-Et), D-Phe(4-Ipr), or D-Phe(4-NH2).

[0020] In a second aspect, the present invention provides a pharmaceutical composition comprising a κ-opioid receptor agonist according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Furthermore, the pharmaceutical composition further comprises its pharmaceutically acceptable carrier.

[0021] In a third aspect, the present invention provides the use of the κ-opioid receptor agonist, its stereoisomer, its pharmaceutically acceptable salt, and / or the pharmaceutical composition in the manufacture of a pharmaceutical product used for the prevention and / or relief and / or analgesia of pruritus.

[0022] The κ-opioid receptor agonist according to the present invention exhibits high selectivity for κ-opioid receptors, its activity is 3 to 15 times greater than that of commercially available diferikephalin drugs, and it has high pharmacological activity, making it suitable for the treatment or prevention and / or remission of pruritus and / or analgesia. [Modes for carrying out the invention]

[0023] In this invention, the term "stereoisomer" refers to a compound that has the same chemical structure but differs in the spatial arrangement of its atoms or groups. Stereoiomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and atropisomers.

[0024] In this invention, "pharmaceutical composition" refers to a composition used for the treatment of a disease or for in vitro cell culture experiments. When used for the treatment of a disease, the term "pharmaceutical composition" usually refers to a unit dose and can be prepared by any method well known in the pharmaceutical field. All such methods include the step of combining an active ingredient with one or more adjuvants constituting auxiliary components.

[0025] In this invention, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or with the mammals it treats. Preferably, in this invention, "pharmaceutically acceptable" means that it is approved by a federal regulatory agency or a national government, or is listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in animals, particularly humans.

[0026] Specifically, the term “pharmaceutically acceptable adjuvant” may include any solvent, solid excipient, diluent, liquid excipient, etc., suitable for a particular target dosage form. Except for cases where conventional adjuvants are incompatible with the κ-opioid receptor agonists according to the present invention, such as resulting undesirable biological effects or interactions with other components in the pharmaceutically acceptable composition that occur in a harmful manner, the uses of such adjuvants are also considered within the scope of this disclosure.

[0027] The technical solutions in embodiments of the present invention are described below clearly and completely. It should not be understood that the embodiments described herein are only a part of, and not all, embodiments of the present invention. All other embodiments that can be obtained by those skilled in the art without expending work commensurate with inventive step based on embodiments of the present invention are also included within the scope of the present invention.

[0028] In this invention, the terms “reduction,” “improvement,” and “alleviation” can be used interchangeably herein. These terms refer to obtaining a beneficial or desired outcome, including but not limited to therapeutic benefits. “Therapeutic benefit” means the elimination or improvement of the potential disorder being treated, where the therapeutic benefit is obtained by observing improvement in the subject by eliminating or improving one or more physiological symptoms associated with the potential disorder, even though the subject may still be suffering from the potential disorder.

[0029] The present invention discloses κ-opioid receptor agonists and their uses, and those skilled in the art can implement the invention by appropriately adjusting the relevant parameters with reference to the contents of this specification. Although the methods according to the present invention have been described through preferred embodiments, it will be apparent to those interested that the techniques of the present invention can be carried out and applied by modifying or appropriately changing and combining the compounds and methods for producing them described herein without departing from the content, spirit, and scope of the invention.

[0030] Table 1 below shows the Japanese names corresponding to the English abbreviations used in this invention. [Table 1] [Examples]

[0031] [Example 1] Preparation of the compound The preparation method involves using a polypeptide solid-phase synthesis method to prepare a peptide resin, acid-hydrolyzing the peptide resin to obtain a crude product, and finally purifying the crude product to obtain a pure product. Here, the step of preparing the peptide resin by polypeptide solid-phase synthesis involves sequentially linking the corresponding protected amino acids in the following sequence onto a carrier resin by coupling solid-phase synthesis to prepare the peptide resin.

[0032] In the above preparation method, the amount of Fmoc-protective amino acid used is 1.2 to 6 times the total number of moles of resin added, preferably 2.5 to 3.5 times.

[0033] In the above preparation method, the substitution value of the carrier resin is a resin with a concentration of 0.3 to 1.5 mmol / g, preferably a resin with a concentration of 0.6 to 1.0 mmol / g.

[0034] In a preferred embodiment of the present invention, the coupling solid-phase synthesis method involves removing the Fmoc protecting group from the protected amino acid-resin obtained in the previous step, and then coupling it with the next protected amino acid. The deprotection time for removing the Fmoc protection is 10 to 60 minutes, preferably 15 to 25 minutes. The coupling reaction time is 60 to 300 minutes, preferably 100 to 140 minutes.

[0035] The coupling reaction described above requires the addition of a condensation reagent. The condensation reagent is one selected from DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, or O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, preferably N,N-diisopropylcarbodiimide. The molar amount of the condensation reagent used is 1.2 to 6 times the total number of moles of amino groups in the amino resin, preferably 2.5 to 3.5 times.

[0036] The coupling reaction described above requires the addition of an activating reagent. The activating reagent is 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, preferably 1-hydroxybenzotriazole. The amount of activating reagent used is 1.2 to 6 times the total number of moles of amino groups in the amino resin, preferably 2.5 to 3.5 times.

[0037] In a preferred embodiment of the present invention, the reagent used to remove the Fmoc protection is a mixed solution of PIP / DMF (piperidine / N,N-dimethylformamide). This mixed solution contains 10-30%(V) piperidine. The amount of reagent used to remove the Fmoc protection is 5-15 mL per gram of amino resin, preferably 8-12 mL per gram of amino resin.

[0038] More preferably, the acid decomposition agent used in the acid decomposition of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1,2-ethanedithiol (EDT), and water. The mixed solvent consists of 80-95% TFA, 1-10% EDT, and the remainder being water, by volume.

[0039] More preferably, the mixed solvent consists of 89-91% TFA, 4-6% EDT, and the remainder being water by volume. Most preferably, the mixed solvent consists of 90% TFA, 5% EDT, and the remainder being water by volume.

[0040] The amount of acid decomposing agent required is 4 to 15 mL per gram of peptide resin, preferably 7 to 10 mL per gram of peptide resin.

[0041] The decomposition time using the aforementioned acid decomposing agent is 1 to 6 hours, preferably 3 to 4 hours, under room temperature conditions. Furthermore, the crude product is purified by high-performance liquid chromatography and freeze-dried to obtain the pure product.

[0042] 1. Synthesis of peptide resins A peptide resin was prepared by sequentially linking protective amino acids corresponding to the sequence to a carrier resin via Fmoc deprotection and coupling reactions. (1) Linking of the first protective amino acid in the main chain

[0043] 0.03 mol of the first protective amino acid and 0.03 mol of HOBt were dissolved in an appropriate amount of DMF. 0.03 mol of DIC was slowly added to the protective amino acid DMF solution while stirring, and the mixture was reacted at room temperature with stirring for 30 minutes to obtain an activated protective amino acid solution, which was prepared for use in the next step.

[0044] 0.01 mol of carrier resin (substitution value approximately 0.4 mmol / g) was deprotected with a 20% PIP / DMF solution for 25 minutes, washed, filtered, and Fmoc was removed to obtain the resin.

[0045] The activated first protective amino acid solution was added to the resin from which Fmoc had been removed, and the coupling reaction was carried out for 60 to 300 minutes. The mixture was then filtered and washed to obtain a resin containing one protective amino acid. (2) Linking of other protective amino acids

[0046] Using the same method as the one for linking the first protective amino acid described above, the corresponding other protective amino acids described above were linked in sequence to obtain a peptide-containing resin. 2. Preparation of the crude product

[0047] The peptide resin described above was added to a cleavage reagent in a volume ratio of TFA:water:EDT = 95:5:5 (10 mL / g of cleavage reagent in the resin), stirred well, and reacted at room temperature with stirring for 3 hours. The reaction mixture was filtered through a sand core funnel, the filtrate was collected, the resin was washed three times with a small amount of TFA, the filtrates were combined, concentrated under reduced pressure, and precipitated with anhydrous diethyl ether. The precipitate was precipitated three times with anhydrous diethyl ether, vacuum dried, and a whitish powder was obtained. 3. Preparation of the pure product

[0048] The concentrated solution of the crude product described above was filtered through a 0.45 μm mixed microporous membrane to purify it and prepare it for use in subsequent steps. For purification, high-performance liquid chromatography was used, with a 10 μm reversed-phase C18 as the purification chromatography packing. A 0.1% TFA / aqueous solution - 0.1% TFA / acetonitrile solution was used as the mobile phase system, and a 30 mm × 250 mm chromatography column was set to a flow rate of 20 mL / min. Gradient elution was used, and purification was performed by cyclic sample loading. The crude product solution was injected into the chromatography column, eluted with the mobile phase, the main peak was collected, and after evaporating the acetonitrile, a purified intermediate concentrate was obtained.

[0049] The purified intermediate concentrate was filtered through a 0.45 μm filter membrane and prepared for use in subsequent steps. Salt exchange was performed by high-performance liquid chromatography, with a mobile phase system of 1% acetic acid / aqueous solution-acetonitrile, a 10 μm reverse-phase C18 chromatography packing for purification, and a flow rate of 20 mL / min on a 30 mm × 250 mm chromatography column (the flow rate can be adjusted accordingly depending on the specifications of the chromatography column). Using gradient elution and cyclic sample loading, the sample was injected into the chromatography column, eluted with the mobile phase, a chromatograph was collected, the change in absorbance was observed, the main peak of the salt exchange was collected, the purity of the liquid phase was detected, the main peak solution of the salt exchange was combined, concentrated under reduced pressure to obtain a pure aqueous acetic acid solution, and freeze-dried to obtain the pure product.

[0050] The compounds synthesized using the above method are shown in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0051] [Example 2] Measurement of κ receptor agonist activity 1.Measurement method Gi-coupled human potassium opioid receptor (OPRK1), when stimulated by a specific opioid receptor agonist, can inhibit the intracellular adenylyl cyclase pathway and reduce cAMP levels. Since forskolin promotes cAMP release in cell lines that highly express opioid receptors, stimulating cell lines stably transfected with opioid receptors allows for the measurement of the inhibitory effect of the test compound on forskolin-induced cAMP release, thereby detecting the activity of the test compound. Relative light units (RLU) from cells after stimulation at each dose were measured using homogeneous time-resolved fluorescence (HTRF) to determine the EC of the agonist. 50 The following was calculated. This activity measurement method is currently widely used both domestically and internationally to measure the activity of opioid receptor agonists.

[0052] Using the CHO-K1 cell line, which stably expresses opioid receptors, stably transfected cells were stimulated with different concentrations of agonists (stimulated with a constant concentration of forskolin). The EC of the agonists was determined by measuring the relative luminescence units of cells stimulated at each dose. 50 They sought it. 2.Measurement results

[0053] The measurement results are shown in Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0054] From the experimental results described above, it became clear that the compounds according to the present invention have much higher activity than diferikephalin, and that compounds 1 to 142 in the examples have 3 to 15 times the activity of diferikephalin.

[0055] It should be noted that the above embodiments are provided solely to illustrate the technical solutions of the present invention, but do not limit the invention. While the present invention has been described in detail with reference to the above embodiments, those skilled in the art will understand that the technical solutions described in the above embodiments can be modified, or some or all of their technical features can be replaced with equivalents. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions described in the embodiments of the present invention.

Claims

1. A κ-opioid receptor agonist having the following formula I, its stereoisomer, and its pharmaceutically acceptable salt: [Formula I] D-Phe-AA1-AA2-D-Lys-4-aminopiperidine-4-carboxamide-AA3-AA4-AA5 [In formula I, AA1 is a modified or unmodified D-Phe, or a modified or unmodified D-Tyr; AA2 is D-Leu or D-cyclopropylalanine; AA3 is -(PEG ｍ１ (CH ２ ) ｍ２ CO) ｍ３ -, (AA6) ｍ４ or does not exist (where m １ is an integer from 1 to 10, m ２ is an integer from 1 to 5, m ３ is an integer from 1 to 5, m ４ is an integer from 1 to 5, and AA6 is AEEA, Gly, D- or L-Ala, D- or L-Leu, D- or L-Phe, D- or L-Ser, D- or L-Thr, D- or L-Tyr, D- or L-Asp, D- or L-Glu, D- or L-Gln, D- or L-Lys, D- or L-Arg, or D- or L-His); AA4 is (AA7) ｎ Either it exists or does not exist (where n is an integer from 1 to 10, and AA7 is a D-type or L-type Lys, a D-type or L-type Dap, a D-type or L-type Dab, a D-type or L-type Orn, a D-type or L-type Dah, or a D-type or L-type Dao); AA5 is OH or NH ２ It is.

2. AA1 is D-Phe (2-F), D-Phe (4-F), D-Phe (2-Cl), D-Phe (4-Cl), D-Phe (2-Br), D-Phe (4-B r), D-Phe (2-I), D-Phe (4-I), D-Phe (4-Me), D-Phe (4-Et), D-Phe (4-Ipr), D-Phe (4-NH ２ ), D-Phe (4-NHCH ３ ), D-Phe (4-NHCH ２ CH ３ ), D-Phe(4-NHCH(CH ３ ) ２ ), D-Phe(4-N(CH ３ ) ２ ), and D-Phe(4-N(CH ３ )CH ２ CH ３ The κ-opioid receptor agonist according to claim 1, characterized in that it is a modified D-Phe selected from the group consisting of ), or a modified D-Tyr selected from the group consisting of D-Tyr(Me), D-Tyr(Et), and D-Tyr(Ipr), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof.

3. The κ-opioid receptor agonist according to claim 2, characterized by having a structure represented by the following formula II, its stereoisomer, and a pharmaceutically acceptable salt thereof: [Formula II] D-Phe-AA1-AA2-D-Lys-4-aminopiperidine-4-carboxamide-R-(AA8) ｐ -NH ２ (OH) [In formula II, AA1 is modified D-Phe or modified D-Tyr; AA2 is D-Leu or D-cyclopropylalanine; R stands for PEG ｍ１ CH ２ CO-, -AEEA ｎ１ - or -Gly ｎ２ - exists as, or does not exist (however, m １ n1 is an integer from 1 to 5 specifically selected from the group consisting of 1, 2, 3, 4, and 5, and n1 is an integer from 1 to 5 specifically selected from the group consisting of 1, 2, 3, 4, and 5, and n ２ (Specifically, these are integers from 1 to 5 selected from the group consisting of 1, 2, 3, 4, and 5); AA8 is Lys or D-Lys; p is specifically an integer from 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; If p is 0, then AA8 does not exist.

4. The κ-opioid receptor agonist according to claim 3, characterized by having a structure represented by the following formula III, its stereoisomer, and its pharmaceutically acceptable salt: [Formula III] D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-R １ - (AA8) ｐ１ -NH ２ (OH) [In formula III, D-Tyr (X) is D-Tyr (Me), D-Tyr (Et), D-Tyr (CH ２ CF ３ It is a modified D-Tyr selected from the group consisting of ), and D-Tyr(Ipr); R １ Ha-PEG ｋ１ CH ２ CO- or -Gly ｎ２ - exists as, or does not exist (however, k １ Specifically, n is an integer from 1 to 5 selected from the group consisting of 1, 2, 3, 4, and 5. ２ (Specifically, these are integers from 1 to 5 selected from the group consisting of 1, 2, 3, 4, and 5); AA8 is Lys or D-Lys; p １ Specifically, is an integer from 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; p ２ If it is 0, then AA8 does not exist.

5. The κ-opioid receptor agonist according to claim 3, characterized by having a structure represented by the following formula IV, its stereoisomer, and its pharmaceutically acceptable salt: [Formula IV] D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-R ２ - (AA8) ｐ２ -NH ２ (OH) [In formula IV, D-Tyr(X) is a modified D-Tyr selected from the group consisting of D-Tyr(Me), D-Tyr(Et), and D-Tyr(Ipr); R ２ Ha-PEG ｋ２ CH ２ It exists as CO- or does not exist (however, k ２ Specifically, k is an integer from 1 to 5 selected from the group consisting of 1, 2, 3, 4, and 5, and in the most preferred embodiment of the present invention, the k ２ (The numbers are 1, 2, and 3); AA8 is Lys or D-Lys; p ３ Specifically, is an integer from 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; p ３ If it is 0, then AA8 does not exist.

6. The κ-opioid receptor agonist according to claim 3, characterized by having a structure represented by the following formula V, its stereoisomer, and its pharmaceutically acceptable salt: [Formula V] D-Phe-D-Phe(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-(AA8) ｐ３ -NH ２ (OH) [In formula V, D-Phe (X) is D-Phe (2-F), D-Phe (4-F), D-Phe (2-Cl), D-Phe (4-Cl), D-Phe (2-Br), D-Phe (4-Br), D-Phe (2-I), D-Phe (4-I), D-Phe (4-Me), D-Phe (4-Et), D-Phe (4-Ipr), and D-Phe (4-NH ２ It is a modified D-Phe selected from the group consisting of; AA8 is Lys, or D-Lys; p ３ Specifically, is an integer from 0 to 6 selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; p ３ If it is 0, then AA8 does not exist.

7. A κ-opioid receptor agonist according to any one of claims 1 to 6, characterized by having one or more structures selected from the group consisting of 1) to 10) below, its stereoisomer, and a pharmaceutically acceptable salt thereof: 1) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxylic acid-NH ２ (OH) 2) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-NH ２ (OH) 3) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-(AA8) ｑ -NH ２ (OH) 4) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-PEG ｋ１ CH ２ CO-AA8-NH ２ (OH) 5) D-Phe-D-Tyr(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-Gly ｎ２ -AA8-NH ２ (OH) 6) D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-NH ２ (OH) 7) D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-AA8-NH ２ (OH) 8) D-Phe-D-Tyr(X)-D-cyclopropylalanine-D-Lys-4-aminopiperidine-4-carboxamide-PEG ｋ２ CH ２ CO-AA8-NH ２ (OH) 9) D-Phe-D-Phe(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-NH ２ (OH) 10) D-Phe-D-Phe(X)-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-AA8-NH ２ (OH) [In the above structural formula, AA8 is Lys or D-Lys; In equation 1), D-Tyr(X) is D-Tyr(Et); In formulas 2) to 3), D-Tyr (X) is D-Tyr (Me), D-Tyr (Et), D-Tyr (CH ２ CF ３ ), or D-Tyr(Ipr), where q is 1, 2, 3, 4, 5, or 6; In equations 4) to 8), D-Tyr(X) is D-Tyr(Et), and k １ is 1, 2, 3, 4, or 5, and n ２ is 1, 2, 3, 4, or 5, and k ２ is 1, 2, or 3; In formula 9), D-Phe (X) is D-Phe (4-F), D-Phe (4-Cl), D-Phe (4-Br), or D-Phe (4-I); In formula (10), D-Phe(X) is D-Phe(4-F), D-Phe(4-Cl), D-Phe(4-Br), D-Phe(4-I), D-Phe(4-Me), D-Phe(4-Et), D-Phe(4-Ipr), or D-Phe(4-NH ２ ).

8. A pharmaceutical composition characterized by comprising a κ-opioid receptor agonist according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, further comprising the pharmaceutically acceptable carrier.

10. Use of a κ-opioid receptor agonist according to any one of claims 1 to 7, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition according to any one of claims 8 to 9 in the manufacture of a pharmaceutical product used for the prevention and / or relief and / or analgesia of pruritus.

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