Long-acting K-opioid receptor agonist

Description

1 / 15 Long-acting K-opioid receptor agonist

[0001] This application claims priority over Chinese Patent Application No. 202310371590.8, filed with the National Intellectual Property Administration of China on April 10, 2023, and entitled “LONG-ACTING KOPIOID RECEPTOR AGONIST”, which is incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure relates to a long-acting opioid K receptor agonist and uses thereof. BACKGROUND

[0003] Opioid drugs exert physiological effects primarily through binding to three classic opioid receptors known as μ, δ, and κ. These three receptors are all members of the G protein-coupled receptor family, are primarily distributed in the central nervous system, and also exist in many peripheral tissues.

[0004] The most classic of these drugs is morphine, which exerts an analgesic effect primarily through the μ-opioid receptor. Clinically common analgesic medications also include other μ-opioid receptor drugs, such as traditional opioid medications as represented or dihydromorphone and fentanyl. However, long-term use of μ-opioid receptor drugs can lead to multiple side effects, such as tolerance, dependence, hypoventilation, effects on gastrointestinal motility, and the like, which not only increase treatment costs but also affect patient recovery periods.Due to their weak analgesic effects, some non-opioid injections, such as acetaminophen and non-steroidal anti-inflammatory drugs, have limited ranges and dosages of application; additionally, they also have certain side effects, for example, acetaminophen increases liver toxicity, and non-steroidal anti-inflammatory drugs can cause various gastrointestinal disorders. Petition 870250091662, dated 07 / 10 / 2025, page 10 / 74 2 / 15

[0005] Research has found that, using K-type opioid receptor agonists, the K-type opioid receptor can be used as an intervention target to treat pain and prevent a wide variety of diseases and conditions, for example, pain treatment including hyperalgesia, use in eye disorders and eye pain, treatment of pruritus caused by uremia and opioids, and the like.

[0006] Difelicefalin, a K-opioid receptor agonist that selectively targets peripheral K-opioid receptors to relieve pruritus and is used for postoperative analgesia, has already entered phase III clinical trials. Due to the fact that Difelicefalin has a short half-life in vivo, patients require daily subcutaneous administration, resulting in poor patient adherence. The present disclosure aims to provide a long-acting K-opioid receptor agonist to reduce the frequency of administration and improve patient adherence. SUMMARY

[0007] The present disclosure provides a long-acting opioid K receptor agonist and uses thereof.

[0008] To achieve the aforementioned purposes, the present disclosure first provides a compound as represented by structural formula I, as well as a pharmaceutically acceptable salt, a solvate, a chelate, or a non-covalent complex thereof, a prodrug based on the compound, or any mixture of the foregoing forms: D-Phe-AA1-AA2-D-Lys-4-amino-4-piperidinecarboxylic acid-AA3-AA4(R)-AA5 structural formula I

[0009] AA1 in structural formula I is D-Tyr(Me) or D-Tyr(Et), or D-Tyr(Ipr) or D-Phe(2-F), or D-Phe(4-F), or D-Phe(2-Cl), or D-Phe(4-Cl), or D-Phe(2-Br), or D-Phe(4-Br), or D-Phe(2-I), or D-Phe(4-I) or D-Phe(4-N(CH3)CH2CH3);

[0010] AA2 in structural formula I is D-Leu or D-cyclopropylalanine; Petition 870250091662, dated 07 / 10 / 2025, p. 11 / 74 3 / 15

[0011] AA3 in structural formula I is (PEGm1(CH2)m2CO)m3-, or (AA6)mi, or is absent, where:

[0012] m1 is an integer in the range of 1 to 10;

[0013] m2 is an integer in the range of 1 to 5;

[0014] m3 is an integer in the range of 1 to 5; and

[0015] AA6 is Gly, or D-Ala, or L-Ala, or D-Leu, or L-Leu, or D-Phe, or L-Phe, or D-Ser, or L-Ser, or D-Thr, or L-Thr, or D-Tyr, or L-Tyr, or D-Asp, or L-Asp, or D-Glu, or L-Glu, or D-Gln, or L-Gln, or D-Lys, or L-Lys, or D-Arg, or L-Arg, or D-His or L-His;

[0016] AA4 in structural formula I is (AA7)n or is absent, where:

[0017] n is an integer in the range of 1 to 10; and

[0018] AA7 is D-Lys, or L-Lys, or D-Dap, or L-Dap, or D-Dab, or L-Dab, or DOrn, or L-Orn, or D-Dah, or L-Dah, or D-Dao or L-Dao;

[0019] AA5 in structural formula I is OH or NH2; and

[0020] R in structural formula I is HO2C(CH2)n1CO-(AA8)n2(PEGn3(CH2)n4CO)n5-, or HO2C(CH2)n1CO-(AA8)n2-(AA9)n6-, where:

[0021] n1 is an integer in the range of 10 to 20;

[0022] n2 is an integer in the range of 1 to 5;

[0023] n3 is an integer in the range of 1 to 30;

[0024] n4 is an integer in the range of 1 to 5;

[0025] n5 is an integer in the range of 1 to 5;

[0026] n6 is an integer in the range of 1 to 10;

[0027] AA8 is yGIu, or εLys, or β-Ala, or γ-aminobutyric acid or 5-Ava; and

[0028] AA9 is Ala, or Gly, or Leu, or Phe, or Ser, or Thr, or Tyr, or Asp, or Glu, or Gln, or Lys, or D-Lys, or Arg or His.

[0029] The long-acting K-opioid receptor agonist provided in the present disclosure includes a pharmaceutically acceptable salt, a solvate, a chelate or a non-covalent complex thereof, a prodrug based on the compound or any mixture of the foregoing forms.

[0030] The present disclosure also provides a pharmaceutical composition Petition 870250091662, dated 07 / 10 / 2025, page 12 / 74 4 / 15 comprising a compound according to the present disclosure and a use of the pharmaceutical composition in the manufacture of a medicament to treat a disease.

[0031] Additionally, the pharmaceutical composition is used to relieve moderate to severe itching and for postoperative analgesia.

[0032] Further content involved in the present disclosure is described in detail below. Some of the content may be covered by combining the examples in the present disclosure.

[0033] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions and the like used in the present disclosure are to be understood as being modified in all cases by the term about or “approximately”. Consequently, unless otherwise indicated, the numerical parameters cited in the following description and claims are approximations that may differ due to differences in standard error found in their respective experimental conditions.

[0034] In the present disclosure, if there is a discrepancy or ambiguity between a chemical structure and a chemical name for a compound, the chemical structure shall prevail in defining the compound. The compounds described herein may contain one or more chiral centers and / or double bonds and the like, and may therefore exist as stereoisomers, including double-bond isomers (such as geometric isomers), enantiomers, or diastereomers. Consequently, any chemical structure within the scope of this disclosure that contains such similar structures in part or in whole is intended to encompass all possible enantiomers and diastereomers of the compound. This includes any simple stereoisomer (such as a simple geometric isomer, a simple enantiomer, or a simple diastereomer) as well as any mixture of these isomers.Mixtures of these racemates and stereoisomers can be further resolved into their constituent enantiomers or stereoisomers by a person skilled in the art. Petition 870250091662, dated 07 / 10 / 2025, page 13 / 74 5 / 15 technique using various separation techniques or chiral synthesis methods.

[0035] The compounds as represented by structural formula I include, but are not limited to, optical isomers, racemates, and / or other mixtures of these compounds. In such cases, a simple enantiomer or diastereomer, including an optically active isomer, can be obtained by asymmetric synthesis or by racemate resolution. Racemate resolution can be performed by various methods, such as conventional recrystallization using a resolving agent or by chromatographic methods. Additionally, the compounds as represented by structural formula I also include cis- and / or trans-isomers with double bonds.

[0036] The compounds of the present disclosure include, but are not limited to, the compounds as represented by structural formula I and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above substances, and any mixtures of the foregoing forms. DETAILED DESCRIPTION

[0037] The present disclosure provides a long-acting K-opioid receptor agonist and uses thereof. A person skilled in the art may, by reference to the contents of this disclosure, appropriately modify the relevant parameters to practice the present disclosure. It should be particularly noted that all similar substitutions and modifications obvious to a person skilled in the art are intended to be included in the present disclosure. Although the methods of the present disclosure have been described by preferred examples, it will be evident to those skilled in the art that appropriate modifications, or variations and combinations, may be made to the compounds and methods of preparation described herein without departing from the content, spirit, and scope of the present disclosure to realize and apply the technology of the present disclosure. The full names corresponding to the English abbreviations used in the present disclosure are Petition 870250091662, dated 07 / 10 / 2025, page 14 / 74 6 / 15 shown in the table below: Table 1 English Abbreviations Full Name English Abbreviations Full Name Fmoc 9-fluorenylmethyloxycarbonyl OtBu tert-butoxy tBu tert-butyl Boc tert-butoxycarbonyl Trt trityl Pbf (2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)sulfonyl Ala alanine Leu leucine Arg arginine Lys lysine Asn asparagine Phe phenylalanine Asp aspartic acid Pro proline Cys cysteine ​​Ser serine Gln glutamine Thr threonine Glu glutamic acid Trp tryptophan Gly glycine Tyr tyrosine His histidine Val valine Ile isoleucine Dab 2,4-diaminobutyric acid 5-Ava 5-aminovaleric acid Orn ornithine Aib aminoisobutyric acid Dah acid 2,7-diaminoheptanoic acid Dap 2,3diaminopropionic acid Dao 2,8-diaminooctanoic acid Petition 870250091662, dated 07 / 10 / 2025, page 15 / 74 7 / 15 Ada 2-aminoadipic acid Apm 2-aminopimelic acid Asu 2-aminosuberic acid

[0038] Example 1: preparation of compounds

[0039] The preparation method is solid-phase polypeptide synthesis, which comprises: preparing a peptide resin by solid-phase polypeptide synthesis, cleaving the peptide resin with an acid to obtain a crude product, and finally purifying the crude product to obtain a pure product. In which, the step of preparing the peptide resin by solid-phase polypeptide synthesis involves sequentially coupling the corresponding protected amino acids of the following sequence onto a carrier resin via a solid-phase coupling synthesis method to prepare the peptide resin:

[0040] In the preparation method mentioned above, the Fmoc-protected amino acid is used in an amount of 1.2 to 6 times the total molar amount of the resin, preferably 2.5 to 3.5 times.

[0041] In the preparation method mentioned above, the carrier resin has a substitution value of 0.3 to 1.5 mmol / g resin, preferably 0.6 to 1.0 mmol / g resin.

[0042] In a preferred embodiment of the disclosure, the solid-phase coupling synthesis method is as follows: the protecting group Fmoc is removed from the protected amino acid resin obtained from the previous step, followed by a coupling reaction with the next protected amino acid. The deprotection step of removing the Fmoc group lasted from 10 to 60 min, preferably 15 to 25 min. The coupling reaction lasted from 60 to 300 min, preferably 100 to 140 min.

[0043] The coupling reaction requires the addition of a condensing reagent. The condensing reagent is selected from the group that Petition 870250091662, dated 07 / 10 / 2025, page 16 / 74 8 / 15 consists of DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, N,N,N',N'-tetramethyluronium benzotriazol hexafluorophosphate, and O-(benzotriazol)N,N,N',N-tetramethyluronium tetrafluoroborate. N,N-diisopropylcarbodiimide is preferred. The condensation reagent is used in a molar amount of 1.2 to 6 times the total molar amount of amino groups in the amino resin, preferably 2.5 to 3.5 times.

[0044] The coupling reaction requires the addition of an activating agent. The activating agent is selected from the group consisting of 1-hydroxybenzotriazole and N-hydroxy-7-azabenzotriazole, preferably 1-hydroxybenzotriazole. The activating agent is used in an amount of 1.2 to 6 times the total molar quantity of amino groups in the amino resin, preferably 2.5 to 3.5 times.

[0045] In a preferred embodiment of the present disclosure, the reagent for removing the Fmoc protecting group is a mixed solution of PIP / DMF (piperidine / N,N-dimethylformamide), wherein the mixed solution contains 10% to 30% (V) piperidine. The amount of Fmoc deprotecting reagent used is 5 to 15 ml per gram of amino resin, preferably 8 to 12 ml per gram of amino resin.

[0046] More preferably, the acidolysis agent used in the acidolysis step of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1,2-ethanedithiol (EDT) and water, wherein the mixed solvent has a volume ratio of: 80% to 95% TFA, 1% to 10% EDT, with the remainder being water.

[0047] Even more preferably, the mixed solvent has a volume ratio of: 89% to 91% TFA, 4% to 6% EDT, with the remainder being water. Most preferably, the mixed solvent has a volume ratio of: 90% TFA, 5% EDT, with the remainder being water.

[0048] The acidolysis agent is used in an amount of 4 to 15 ml per Petition 870250091662, dated 07 / 10 / 2025, page 17 / 74 9 / 15 gram of peptide resin; preferably, 7 to 10 ml per gram of peptide resin.

[0049] The cleavage step using the acidolysis agent lasts 1 to 6 h, preferably 3 to 4 h, at room temperature.

[0050] Additionally, the crude product is purified by high-performance liquid chromatography and then lyophilized to obtain the pure product.

[0051] 1. Peptide resin synthesis

[0052] The peptide resin was prepared by taking a carrier resin and sequentially coupling the corresponding protected amino acids of the sequence via Fmoc coupling and deprotection reactions:

[0053] (1) Coupling of the first protected amino acid of the main chain

[0054] 0.03 mol of the first protected amino acid and 0.03 mol of HOBt were dissolved in an appropriate amount of DMF. Separately, 0.03 mol of DIC was slowly added to the DMF solution of the protected amino acid with stirring. The reaction was carried out at room temperature with stirring for 30 min to obtain an activated protected amino acid solution, which was reserved for later use.

[0055] 0.01 mol of Rink amide MBHA resin (substitution value was approximately 0.4 mmol / g) was taken and deprotected by treatment with a 20% PIP / DMF solution for 25 min. The Fmoc-deprotected resin was obtained after washing and filtration.

[0056] The activated protected amino acid solution was added to the unprotected resin by Fmoc, and the coupling reaction was carried out for 60 to 300 min. The resin containing a protected amino acid was obtained after filtration and washing.

[0057] (2) Coupling of other amino acids protected from the main chain

[0058] Using the same method as for coupling the first amino acid of the main chain, the other corresponding protected amino acids of the main chain were sequentially coupled to obtain a resin containing the main chain amino acids. Petition 870250091662, dated 07 / 10 / 2025, page 18 / 74 10 / 15

[0059] (3) Coupling of the first protected amino acid from the side chain

[0060] 0.03 mol of the first side-chain protected amino acid and 0.03 mol of HOBt were dissolved in an appropriate amount of DMF. Separately, 0.03 mol of DIC was slowly added to the DMF solution of the protected amino acid with stirring. The reaction was carried out at room temperature with stirring for 30 min to obtain an activated protected amino acid solution.

[0061] 2.5 mmol of tetrakis(triphenylphosphine)palladium(0) and 25 mmol of phenylsilane were dissolved in an appropriate amount of dichloromethane, and a deprotection reaction was carried out for 4 h. The Alloc-deprotected resin was obtained after filtration and washing, which was reserved for later use.

[0062] The solution of the first protected amino acid side chain was added to the Alloc-unprotected resin, and the coupling reaction was carried out for 60 to 300 min. The resin containing the first protected amino acid side chain was obtained after filtration and washing.

[0063] (4) Coupling of other side-chain protected amino acids

[0064] Using the same method as for coupling the first protected amino acid of the main chain, the corresponding protected amino acids and monoprotected fatty acids of the side chain were sequentially coupled to obtain the peptide resin.

[0065] 2. Preparation of the raw product

[0066] The peptide resin obtained above was treated with a cleavage reagent (10 ml of cleavage reagent per gram of resin) with a TFA:water:EDT volume ratio of 95:5:5. The mixture was stirred uniformly and allowed to react at room temperature for 3 h. The reaction mixture was filtered through a frit funnel, and the filtrate was collected. The resin was washed three times with a small amount of TFA. The filtrates were combined and concentrated under reduced pressure. Anhydrous diethyl ether was added, and a precipitate was produced. The precipitate was washed three times with anhydrous diethyl ether and then dried under vacuum to produce a whitish powder. Petition 870250091662, dated 07 / 10 / 2025, page 19 / 74 11 / 15

[0067] 3. Preparation of the pure product

[0068] The crude product concentrate obtained above was purified by filtration through a mixed microporous filter membrane of 0.45 μm and reserved for later use.

[0069] Purification was performed using high-performance liquid chromatography. The chromatographic packing material for purification was 10 μm of reversed-phase C18 material, and the mobile phase system consisted of 0.1% TFA / water and 0.1% TFA / acetonitrile. For a 30 mm*250 mm chromatography column, the flow rate was 20 ml / min. A gradient elution and cyclic loading purification was used. The crude product solution was loaded onto the column, and the mobile phase was initiated for elution. The main peak was collected, and after removing acetonitrile by evaporation, a purified intermediate concentrate was obtained.

[0070] The purified intermediate concentrate was filtered through a 0.45 μm membrane and reserved for later use. Salt exchange was performed using high-performance liquid chromatography. The mobile phase system was 1% acetic acid / water-acetonitrile, and the chromatographic packing material for purification was 10 μm of C18 reversed-phase material. For a 30 mm*250 mm chromatography column, the flow rate was 20 ml / min (the flow rate can be adjusted according to different chromatography column specifications). A gradient elution and cyclic loading method was used. The sample was loaded onto the column, the mobile phase was initiated for elution, and chromatograms were collected. Changes in absorbance were observed, and the main peak of the salt exchange was collected. Purity was verified by analytical liquid chromatography.The fractions containing the main peak of salt exchange were combined, concentrated under reduced pressure to obtain an aqueous solution of purified product in acetic acid, and then lyophilized to obtain the pure product.

[0071] Using the method described above, the following compounds were synthesized: Petition 870250091662, dated 07 / 10 / 2025, page 20 / 74 12 / 15 Table 2 Compound 1 D-Phe-D-Tyr(Et)-D-Leu-D-Lys-4-aminopiperidine-4- carboxamide-Lys(PEG4CH2CO-γGlu-octadecanodioic acid)NH2 Compound 2 D-Phe-D-Tyr(Et)-D-Leu-D-4-Lys-D-4-aminopiperidine carboxamide-PEG1CH2CO-Lys(PEG4CH2CO-γGlu-octadecanodioic acid)-NH2 Compound 3 D-Phe-D-Tyr(Et)-D-Leu-D-Lys-4-aminopiperidine-4carboxamide-AEEA-Lys(PEG4CH2CO-γGlu-CO octadecanodioic acid)-NH2 Compound 4 D-Phe-D-Tyr(Et)-D-Leu-D-Lys-4-aminopiperidine-4carboxamide-PEG4CH2CO-Lys(PEG4CH2CO-γGlu-octadecanodioic acid)-NH2 Compound 5 D-Phe-D-Tyr(Me)-D-Leu-D-Lys-4-aminopiperidine-4carboxamide-AEEA-Lys(PEG4CH2CO-γGlu-octadecanodioic acid)-NH2 Compound 6 D-Phe-D-Phe(4-Cl)-D-Leu-D-Lys-4-aminopiperidine-4carboxamide-AEEA-Lys(PEG4CH2CO-γGlu-octadecanodioic acid)-NH2 Compound 7 D-Phe-D-Phe(4-F)-D-Leu-D-Lys-4-aminopiperidine-4carboxamide-AEEA-Lys(PEG4CH2CO-γGlu-octadecanodioic acid)-NH2 Compound 8 D-Phe-D-Tyr(Et)-D-Leu-D-Lys-4-aminopiperidine-4carboxamide-AEEA-Lys(PEG3CH2CO-γGlu-octadecanodioic acid)-NH2 Compound 9D-Phe-D-Tyr(Et)-D-Leu-D-Lys-4-aminopiperidine-4carboxamide-AEEA-Lys(PEG5CH2CO-γGlu-octadecanedioic acid)-NH2 Compound D-Phe-D-Tyr(Et)-D-Leu-D-Lys-4-aminopiperidine-4- Petition 870250091662, dated 07 / 10 / 2025, p. 21 / 74 13 / 15 10 carboxamide-Gly-Lys(PEG4CH2CO-γGlu-octadecanedioic acid)-NH2 Compound 12 D-Phe-D-Tyr(Et)-D-Cyclopropylalanine-D-Lys-4-aminopiperidine4-carboxamide-AEEA-Lys(PEG4CH2CO-γGlu-octadecanedioic acid)-NH2

[0072] Example 2: determination of agonist activity

[0073] 1. Determination Method

[0074] The human Gi-coupled opioid receptor kappa-1 (OPRK1), upon stimulation with its specific opioid receptor agonists, can inhibit the intracellular adenylate cyclase pathway and decrease cAMP levels. Forskolin can stimulate cAMP release in cell lines that highly express opioid receptors. By stimulating cell lines stably transfected with opioid receptors, the inhibitory effect of a test compound on forskolin-stimulated cAMP release can be measured to determine the compound's activity. The relative light units (RLU) of the cells after stimulation with different doses were measured via the homogeneous time-resolved fluorescence (HTRF) technique, and the EC50 of the agonist was subsequently calculated. This method of activity determination is a commonly used method currently used to determine the activities of opioid receptor agonists both domestically and internationally.

[0075] A CHO-K1 cell line that stably expresses opioid receptors was used. The stably transfected cells were stimulated with various concentrations of agonists (under stimulation with a certain concentration of forskolin). The relative light units of the cells after stimulation with different doses were measured, from which the value Petition 870250091662, dated 07 / 10 / 2025, page 22 / 74 14 / 15 The EC50 of the agonist was subsequently obtained by calculation.

[0076] 2. Determination results

[0077] The results of the determination are presented in the table below: Table 3 Compounds Result of EC50 Activity Determination (pmol) % of Relative Activity Difelicefalin 652.6 100% Compound 1 4628.4 15.6% Compound 2 3471.3 20.7% Compound 3 3021.3 23.8% Compound 4 4183.3 17.2% Compound 5 5305.7 13.6% Compound 6 5879.3 12.2% Compound 7 6869.5 10.5% Compound 8 4078.8 17.7% Compound 9 4379.9 16.4% Compound 10 4763.5 15.1% Compound 11 4265.4 16.9% Compound 12 4729.0 15.2%

[0078] Example 3: Determination of preliminary pharmacokinetic properties

[0079] The compound with the best activity was selected for determination of its preliminary pharmacokinetic properties. Two male Macaca fascicularis were used as experimental animals. Subcutaneous administration was performed at a dose of 0.1 mg / kg. Venous blood samples were collected before administration (0 h) and at 1 h, 2 h, 3 h, 4 h, 8 h, Petition 870250091662, dated 07 / 10 / 2025, page 23 / 74 15 / 15 h, 18 h, 24 h, 48 h, 96 h, 144 h and 168 h post-administration. Plasma samples were separated by centrifugation. The plasma concentration of the compound in the plasma samples was determined using liquid chromatography-mass spectrometry. The half-life of the compound after subcutaneous (SC) administration is shown in the table below: Table 4 Compound t1 / 2 (h) Compound 3 55.1

[0080] The foregoing constitutes merely preferred embodiments of the present disclosure. It should be noted that, for a person of ordinary skill in the art, various improvements and modifications may be made without departing from the principles of the present disclosure, and such improvements and modifications should also be regarded as falling within the scope of protection of the present disclosure. Petition 870250091662, dated 07 / 10 / 2025, page 24 / 74

Claims

1 / 2 CLAIMS 1. Long-acting K-opioid receptor agonist characterized by having a structural formula I: D-Phe-AA1-AA2-D-Lys-4-aminopiperidine-4-carboxylic acid-AA3-AA4(R)AA5 structural formula I AA1 in structural formula I is D-Tyr(Me) or D-Tyr(Et), or D-Tyr(Ipr) or DPhe(2-F), or D-Phe(4-F), or D-Phe(2-Cl), or D-Phe(4-Cl), or D-Phe(2-Br), or DPhe(4-Br), or D-Phe(2-I), or D-Phe(4-I), or D-Phe(4-Me), or D-Phe(4-Et), or DPhe(4-Ipr), or D-Phe(4-NH2), or D-Phe(4-NHCH3), or D-Phe(4-NHCH2CH3), or D-Phe(4-NHCH(CH3)2), or D-Phe(4-N(CH3)2) or D-Phe(4-N(CH3)CH2CH3); AA2 in structural formula I is D-Leu or D-cyclopropylalanine; AA3 in structural formula I is (PEGm1(CH2)m2CO)m3-, or (AA6)m1, or is absent, where: m1 is an integer in the range of 1 to 10; m2 is an integer in the range of 1 to 5; m3 is an integer in the range of 1 to 5;and AA6 is Gly, or D-Ala, or L-Ala, or D-Leu, or L-Leu, or D-Phe, or L-Phe, or D-Ser, or L-Ser, or D-Thr, or L-Thr, or D-Tyr, or L-Tyr, or D-Asp, or L-Asp, or D-Glu, or L-Glu, or D-Gln, or L-Gln, or D-Lys, or L-Lys, or D-Arg, or L-Arg, or D-His or L-His; AA4 in structural formula I is (AA7)n or is absent, where: n is an integer in the range of 1 to 10; and AA7 is D-Lys, or L-Lys, or D-Dap, or L-Dap, or D-Dab, or L-Dab, or D-Orn, or L-Orn, or D-Dah, or L-Dah, or D-Dao or L-Dao; AA5 in structural formula I is OH or NH2; and R in structural formula I is HO2C(CH2)mCO-(AA8)n2-(PEGn3(CH2)n4CO)n5-, or HO2C(CH2)n1CO-(AA8)n2-(AA9)n6-, where: Petition 870250091662, dated 07 / 10 / 2025, page 25 / 74 2 / 2 n1 is an integer in the range of 10 to 20; n2 is an integer in the range of 1 to 5; n3 is an integer in the range of 1 to 30; n4 is an integer in the range of 1 to 5; n5 is an integer in the range of 1 to 5; n6 is an integer in the range of 1 to 10;AA8 is γGIu, or εLys, or β-Ala, or γ-aminobutyric acid or 5-Ava; and AA9 is Ala, or Gly, or Leu, or Phe, or Ser, or Thr, or Tyr, or Asp, or Glu, or Gln, or Lys, or D-Lys, or Arg or His.; 2. Long-acting opioid K receptor agonist according to claim 1, characterized by including a pharmaceutically acceptable salt, a solvate, a chelate, or a non-covalent complex thereof, a prodrug based on the compound, or any mixture of the foregoing forms.

3. Long-acting opioid K receptor agonist, according to claim 1 or 2, characterized by being for use in the manufacture of a pharmaceutical composition to treat a disease.

4. Long-acting opioid K receptor agonist, according to claim 3, characterized in that the pharmaceutical composition is used to relieve moderate to severe pruritus in a patient and for postoperative analgesia.

5. Pharmaceutical composition characterized by comprising a long-acting opioid K receptor agonist as defined in any one of claims 1 to 4.

6. Use of the long-acting K-opioid receptor agonist as defined in any one of claims 1 to 4, or of the pharmaceutical composition as defined in claim 5, characterized in being in the manufacture of a medicament for relieving moderate to severe pruritus in a patient and for postoperative analgesia. Petition 870250091662, dated 10 / 07 / 2025, p. 26 / 74