CN115043904A - Long-acting K opioid receptor agonist - Google Patents

Long-acting K opioid receptor agonist Download PDF

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CN115043904A
CN115043904A CN202110252205.9A CN202110252205A CN115043904A CN 115043904 A CN115043904 A CN 115043904A CN 202110252205 A CN202110252205 A CN 202110252205A CN 115043904 A CN115043904 A CN 115043904A
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fmoc
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lys
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CN115043904B (en
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周述靓
王鹏
邓岚
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Chengdu Aoda Biotechnology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The invention relates to the field of medicine synthesis, and discloses a long-acting K opioid receptor agonist. The long-acting K opioid receptor agonist is used for preparing a pharmaceutical composition for treating diseases, and the pharmaceutical composition is used for relieving moderate-to-severe pruritus of a patient and postoperative analgesia.

Description

Long-acting K opioid receptor agonist
Technical Field
The invention relates to a long-acting K opioid receptor agonist and application thereof.
Background
Opioids exert their physiological effects primarily through binding to the three known classical opioid receptors, μ, δ and κ. These three receptors are members of the G protein-coupled receptor family, are distributed primarily in the central nervous system, and are also present in many peripheral tissues.
The most classical drug is morphine, which exerts analgesic effect mainly through the action of mu opioid receptors, and clinically commonly used analgesic drugs also include other mu opioid receptor drugs, such as traditional opioid drugs represented by hydromorphone and fentanyl. However, mu opioid receptor drugs can cause a variety of side effects after long-term use, such as tolerance, dependence, and respiratory depression, as well as gastrointestinal motility, which not only increases the cost of treatment, but also affects the patient's recovery cycle. Some non-opioid injections, such as acetaminophen and non-steroidal anti-inflammatory drugs, have poor analgesic effect, so that the application range and dosage of the non-opioid injections are limited; in addition, there are some side effects, such as acetaminophen increases liver toxicity, and non-steroidal anti-inflammatory drugs cause various gastrointestinal diseases.
Studies have found that using kappa opioid receptor agonists, kappa opioid receptors can be targeted for intervention to treat pain and prevent a wide variety of diseases and conditions. Such as pain for hyperalgesia, ocular disorders and pain, uremia and pruritus caused by opiates.
Difelikefatin, a kappa opioid receptor agonist, selectively targets peripheral kappa opioid receptors to relieve itch and for post-operative analgesia, has entered the three-phase clinical trial phase, and patients have poor patient compliance due to the short in vivo half-life of Difelikefatin, which requires daily subcutaneous administration. The invention aims to provide long-acting kappa opioid receptor agonist for patients, reduce the administration frequency and improve the administration compliance of the patients.
Disclosure of Invention
The invention provides a long-acting K opioid receptor agonist and application thereof.
To achieve the above object, the present invention provides, in a first aspect, a compound of structure I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug based on the compound, or any mixture thereof.
D-Phe-D-Phe-D-Leu-D-Lys (R1) -4-aminopiperidine-4-carboxamide-AA 1-AA2(R2) -AA3
Structure I
AA1 in Structure I is (PEG) m1 (CH 2 ) m2 CO) m3 -, or is absent;
wherein: m1 is an integer from 1 to 10;
m2 is an integer from 1 to 5;
m3 is an integer from 1 to 5;
AA2 in structure I is Lys, or Dah, or Orn, or Dab, or Dap;
AA3 in Structure I is NH 2 Or is OH;
r1 in structure I is-CH 2 CH 2 B(OH) 2 Or is-CH 2 CH(Ph,B(OH) 2 ) Or is-CH 2 CH (Ring)Hexyl radical, B (OH) 2 ) Or is-CH 2 Ph(p-B(OH) 2 ) Or is-CH 2 Ph(m-B(OH) 2 ) Or is-CH 2 Ph(o-B(OH) 2 ) Or is-CH (CH) 3 )Ph(p-B(OH) 2 ) Or is-CH (CH) 3 )Ph(m-B(OH) 2 ) Or is-CH (CH) 3 )Ph(o-B(OH) 2 ) Or is-CH 2 CO piperidine (4-B (OH) 2 ) Or is absent;
r2 in structure I is HO 2 C(CH 2 )n 1 CO-(γGlu) n2 -(PEG n3 (CH 2 ) n4 CO) n5 -；
Wherein: n1 is an integer from 10 to 20;
n2 is an integer from 1 to 5;
n3 is an integer from 1 to 30;
n4 is an integer from 1 to 5;
n5 is an integer from 1 to 5.
The long-acting K opioid receptor agonist comprises pharmaceutically acceptable salts, solvates, chelates or non-covalent complexes, prodrugs based on the compound, or any mixture of the above forms.
The invention also provides pharmaceutical compositions comprising a compound according to the invention and the use of a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for the treatment of a disease.
Further, the pharmaceutical composition is used for relieving moderate to severe pruritus and for postoperative analgesia.
More of the present invention will be described in detail below or some of it can be appreciated in embodiments of the invention.
Unless otherwise indicated, the amounts of the various ingredients, reaction conditions, and the like used herein are to be construed in any case to mean "about". Accordingly, unless expressly stated otherwise, all numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in the respective experimental conditions.
Herein, when a chemical structural formula and a chemical name of a compound are ambiguous or ambiguous, the compound is exactly defined by the chemical structural formula. The compounds described herein may contain one or more chiral centers, and/or double bonds and the like, and stereoisomers, including isomers of double bonds (e.g., geometric isomers), optical enantiomers, or diastereomers, may also be present. Accordingly, any chemical structure within the scope of the description, whether partial or complete, including similar structures as described above, includes all possible enantiomers and diastereomers of the compound, including any stereoisomer alone (e.g., pure geometric isomers, pure enantiomers, or pure diastereomers), as well as any mixture of such stereoisomers. Mixtures of these racemates and stereoisomers may also be further resolved into the enantiomers or stereoisomers of their constituent members by those skilled in the art using non-stop separation techniques or methods of chiral molecular synthesis.
The compounds of formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds. In the above case, a single enantiomer or diastereomer, such as an optical isomer, can be obtained by asymmetric synthesis or racemate resolution. Resolution of the racemates can be accomplished by various methods, such as conventional recrystallization from resolution-assisting reagents, or by chromatographic methods. In addition, the compounds of formula I also include cis and/or trans isomers with double bonds.
The compounds of the present invention include, but are not limited to, the compounds of formula I and all of their pharmaceutically acceptable different forms. The pharmaceutically acceptable different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above and any mixtures of these forms.
Detailed Description
The invention discloses a long-acting K opioid receptor agonist and application thereof, and a person skilled in the art can realize the long-acting K opioid receptor agonist by appropriately improving related parameters by referring to the content. It is specifically noted that all such substitutions and modifications will be apparent to those skilled in the art and are intended to be included herein. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the compounds and processes described herein, as well as other changes and combinations of the foregoing, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention. The Chinese names corresponding to the English abbreviations related in the invention are shown in the following table:
english abbreviation Name of Chinese English abbreviation Name of Chinese
Fmoc 9-fluorenylmethoxycarbonyl group Boc Boc-acyl
D-Phe Phenylalanine D-Leu D-leucine
D-Lys D-lysine Dap 2, 3-diaminoPropionic acid mesilate
Lys Lysine AEEA 2- (2- (2-aminoethoxy) ethoxy) acetic acid
Dab 2, 4-diaminobutyric acid Dah 2, 7-Diaminoheptanoic acid
EXAMPLE 1 preparation of Compound 1
D-Phe-D-Phe-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-Lys (AEEA-AEEA-gamma Glu-18 alkanedioic acid) -NH 2
The preparation method comprises the following steps: preparing peptide resin by adopting a solid-phase polypeptide synthesis method, carrying out acidolysis on the peptide resin to obtain a crude product, and finally purifying the crude product to obtain a pure product; the step of preparing the peptide resin by the solid-phase polypeptide synthesis method is to sequentially insert corresponding protective amino acids in the following sequences on a carrier resin by the solid-phase coupling synthesis method to prepare the peptide resin:
in the preparation method, the dosage of the Fmoc-protected amino acid is 1.2-6 times of the total mole number of charged resin; preferably 2.5 to 3.5 times.
In the preparation method, the substitution value of the carrier resin is 0.3-1.5 mmol/g resin, and the preferable substitution value is 0.6-1.0 mmol/g resin.
In a preferred embodiment of the present invention, the solid-phase coupling synthesis method comprises: and (3) after the Fmoc protecting group of the protected amino acid-resin obtained in the previous step is removed, carrying out coupling reaction with the next protected amino acid. The deprotection time for removing Fmoc protection is 10-60 minutes, and preferably 15-25 minutes. The coupling reaction time is 60-300 minutes, and preferably 100-140 minutes.
The coupling reaction needs to add a condensation reagent, and the condensation reagent is selected from one of DIC (N, N-diisopropyl carbodiimide), N, N-dicyclohexylcarbodiimide, benzotriazole-1-yl-oxy tripyrrolidinophosphonium hexafluorophosphate, 2- (7-aza-1H-benzotriazole-1-yl) -1,1,3, 3-tetramethylurea hexafluorophosphate, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate or O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate; n, N-diisopropylcarbodiimide is preferred. The molar consumption of the condensation reagent is 1.2-6 times of the total molar number of amino groups in the amino resin, and preferably 2.5-3.5 times.
The coupling reaction needs to add an activating reagent, wherein the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, and 1-hydroxybenzotriazole is preferred. The amount of the activating agent is 1.2 to 6 times, preferably 2.5 to 3.5 times of the total mole of the amino groups in the amino resin.
As a preferable scheme of the invention, the reagent for removing Fmoc protection is PIP/DMF (piperidine/N, N-dimethylformamide) mixed solution, and the piperidine content in the mixed solution is 10-30% (V). The dosage of the Fmoc protection removing reagent is 5-15 mL per gram of amino resin, and preferably 8-12 mL per gram of amino resin.
Preferably, the peptide resin is subjected to acidolysis, resin removal and side chain protecting group removal, and then oxidative cyclization to obtain a crude product:
more preferably, the acidolysis agent used in the acidolysis of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1, 2-Ethanedithiol (EDT) and water, and the volume ratio of the mixed solvent is as follows: 80-95% of TFA, 1-10% of EDT and the balance of water.
More preferably, the volume ratio of the mixed solvent is: 89-91% of TFA, 4-6% of EDT and the balance of water. Optimally, the volume ratio of the mixed solvent is as follows: TFA 90%, EDT 5%, balance water.
The dosage of the acidolysis agent is 4-15 mL of acidolysis agent required by each gram of peptide resin; preferably, 7-10 mL of acidolysis agent is required per gram of peptide resin.
The time for using the acidolysis agent for cracking is 1-6 hours at room temperature, and preferably 3-4 hours.
The oxidizing agent used in the oxidative cyclization is iodine or H 2 O 2 Or DMSO, preferably iodine. The oxidant is added in a titration mode, and the oxidant is stopped adding when the oxidation end point is reached.
Further, the crude product is purified by high performance liquid chromatography and freeze-dried to obtain a pure product.
1. Synthesis of peptide resins
Rink Amide BHHA resin is used as carrier resin, and is coupled with protected amino acid shown in the following table in sequence through Fmoc protection removal and coupling reaction to prepare peptide resin. The protected amino acids used in this example correspond to the protected amino acids shown below:
the peptide sequence n ═ Protected amino acids
1 Fmoc-Lys(Alloc)
2 Fmoc-4-aminopiperidine-4-carboxylic acid
3 Fmoc-D-Lys(Boc)
4 Fmoc-D-Leu
5 Fmoc-D-Phe
6 Boc-D-Phe
Side chain-1 Fmoc-AEEA
Side chain-2 Fmoc-AEEA
Side chain-3 Fmoc-γGlu-OtBu
Side chain-4 Octadecanedioic acid mono-tert-butyl ester
(1) 1 st protected amino acid inserted into main chain
Dissolving 0.03mol of the 1 st protected amino acid and 0.03mol of HOBt in a proper amount of DMF; and slowly adding 0.03mol of DIC into the protected amino acid DMF solution under stirring, and reacting for 30 minutes under stirring at room temperature to obtain an activated protected amino acid solution for later use.
0.01mol of Rink amide MBHA resin (substitution value about 0.4mmol/g) is taken out, deprotected for 25 min by using 20% PIP/DMF solution, washed and filtered to obtain Fmoc-removed resin.
And adding the activated 1 st protected amino acid solution into the Fmoc-removed resin, performing coupling reaction for 60-300 minutes, and filtering and washing to obtain the resin containing 1 protected amino acid.
(2) Other protected amino acids incorporated into the backbone
And sequentially inoculating other corresponding protected amino acids to the main chain by the same method for inoculating the 1 st protected amino acid to the main chain to obtain the resin containing the main chain amino acid.
(3) Side chain insertion of the 1 st protected amino acid
Dissolving 0.03mol of the 1 st protected amino acid of the side chain and 0.03mol of HOBt in a proper amount of DMF; and adding 0.03mol DIC slowly into the protected amino acid DMF solution under stirring, and reacting for 30 minutes under stirring at room temperature to obtain the activated protected amino acid solution.
Taking 2.5mmol of tetratriphenylphosphine palladium and 25mmol of phenylsilane, dissolving with a proper amount of dichloromethane, deprotecting for 4 hours, filtering and washing to obtain a resin without Alloc for later use.
Adding the activated side chain 1 st protected amino acid solution into the Alloc-removed resin, performing coupling reaction for 60-300 minutes, filtering and washing to obtain the side chain 1 st protected amino acid-containing resin.
(4) By introducing other protected amino acids into side chains
And sequentially inoculating the protected amino acid and the mono-protected fatty acid corresponding to the side chain by adopting the same method for inoculating the 1 st protected amino acid into the main chain to obtain the peptide resin.
2. Preparation of crude product
Adding a cleavage reagent (10 mL of cleavage reagent/g of resin) with a volume ratio of TFA: water: EDT (95: 5), uniformly stirring, stirring at room temperature for reaction for 3 hours, filtering a reaction mixture by using a sand core funnel, collecting a filtrate, washing the resin with a small amount of TFA for 3 times, combining the filtrates, concentrating under reduced pressure, adding anhydrous ether for precipitation, washing the precipitate with anhydrous ether for 3 times, and drying to obtain the white-like powder.
Dissolving the obtained white-like powder by using 30% acetic acid solution to prepare a solution of about 3mg/ml, dropwise adding an iodine/ethanol saturated solution under stirring until complete cyclization, and concentrating under reduced pressure at 35-40 ℃ to obtain a crude product concentrated solution.
3. Preparation of the pure product
Filtering the crude concentrated solution with 0.45 μm mixed microporous membrane, and purifying;
purifying by high performance liquid chromatography, wherein the chromatographic packing for purification is 10 μm reversed phase C18, the mobile phase system is 0.1% TFA/water solution-0.1% TFA/acetonitrile solution, the flow rate of a 30mm by 250mm chromatographic column is 20mL/min, eluting by a gradient system, circularly sampling for purification, sampling the crude product solution in the chromatographic column, starting the mobile phase for elution, collecting the main peak, and evaporating acetonitrile to obtain a purified intermediate concentrated solution;
filtering the purified intermediate concentrated solution with 0.45 μm filter membrane for use, and performing salt exchange by high performance liquid chromatography with 1% acetic acid/water solution-acetonitrile as mobile phase system, 10 μm reversed phase C18 as purification chromatographic filler, and 20mL/min of 30 mm/250 mm chromatographic column flow rate (corresponding flow rate can be adjusted according to chromatographic columns of different specifications); the method comprises the steps of adopting a gradient elution and circulation loading method, loading a sample into a chromatographic column, starting mobile phase elution, collecting a map, observing the change of the absorbance, collecting a main salt exchange peak, detecting the purity by using an analysis liquid phase, combining main salt exchange peak solutions, concentrating under reduced pressure to obtain a pure acetic acid aqueous solution, and freeze-drying to obtain 5.3g of a pure product, wherein the purity is 98.3%, the total yield is 34.8%, and the molecular weight is 1521.9 (100% M + H).
EXAMPLE 2 preparation of Compound 2
D-Phe-D-Phe-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-AEEA-
Lys (AEEA-AEEA-gamma Glu-18 alkanedioic acid) -NH 2
The procedure is as in example 1, using the protected amino acids as in the following table:
the peptide sequence n ═ Protected amino acids
1 Fmoc-Lys(Alloc)
2 Fmoc-AEEA
3 Fmoc-4-aminopiperidine-4-carboxylic acid
4 Fmoc-D-Lys(Alloc)
5 Fmoc-D-Leu
6 Fmoc-D-Phe
7 Boc-D-Phe
Side chain-1 Fmoc-AEEA
Side chain-2 Fmoc-AEEA
Side chain-3 Fmoc-γGlu-OtBu
Side chain-4 Octadecanedioic acid mono-tert-butyl ester
4.9g of pure product is obtained, the purity is 98.5 percent, and the total yield is 29.4 percent. The molecular weight was 1667.1 (100% M + H).
EXAMPLE 3 preparation of Compound 3
D-Phe-D-Phe-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide PEG 5 CH 2 CO-
Lys (AEEA-AEEA-gamma Glu-18 alkanedioic acid) -NH 2
The procedure is as in example 1, using the protected amino acids as follows:
the peptide sequence n ═ Protected amino acids
1 Fmoc-Lys(Alloc)
2 Fmoc-PEG 5 CH 2 COOH
3 Fmoc-4-aminopiperidine-4-carboxylic acid
4 Fmoc-D-Lys(Alloc)
5 Fmoc-D-Leu
6 Fmoc-D-Phe
7 Boc-D-Phe
Side chain-1 Fmoc-AEEA
Side chain-2 Fmoc-AEEA
Side chain-3 Fmoc-γGlu-OtBu
Side chain-4 Octadecanedioic acid mono-tert-butyl ester
5.2g of pure product is obtained, the purity is 98.4 percent, and the total yield is 28.9 percent. The molecular weight was 1799.2 (100% M + H).
EXAMPLE 4 preparation of Compound 4
D-Phe-D-Phe-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-Lys (PEG) 5 CH 2 CO-gamma Glu-20 alkanedioic acid) -NH 2
The procedure is as in example 1, using the protected amino acids as follows:
the peptide sequence n ═ Protected amino acids
1 Fmoc-Lys(Alloc)
2 Fmoc-4-aminopiperidine-4-carboxylic acid
3 Fmoc-D-Lys(Boc)
4 Fmoc-D-Leu
5 Fmoc-D-Phe
6 Boc-D-Phe
Side chain-1 Fmoc-PEG 5 CH 2 COOH
Side chain-2 Fmoc-γGlu-OtBu
Side chain-3 Octadecanedioic acid mono-tert-butyl ester
5.5g of pure product is obtained, the purity is 97.7 percent, and the total yield is 35.8 percent. The molecular weight was 1536.9 (100% M + H).
EXAMPLE 5 preparation of Compound 5
D-Phe-D-Phe-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-AEEA-
Lys(PEG 5 CH 2 CO-gamma Glu-20 alkanedioic acid) -NH 2
The procedure is as in example 1, using the protected amino acids as in the following table:
the peptide sequence n ═ Protected amino acids
1 Fmoc-Lys(Alloc)
2 Fmoc-AEEA
3 Fmoc-4-aminopiperidine-4-carboxylic acid
4 Fmoc-D-Lys(Alloc)
5 Fmoc-D-Leu
6 Fmoc-D-Phe
7 Boc-D-Phe
Side chain-1 Fmoc-PEG 5 CH 2 COOH
Side chain-2 Fmoc-γGlu-OtBu
Side chain-3 Octadecanedioic acid mono-tert-butyl ester
5.1g of pure product is obtained, the purity is 98.9 percent, and the total yield is 30.3 percent. The molecular weight was 1682.1 (100% M + H).
EXAMPLE 6 preparation of Compound 6
D-Phe-D-Phe-D-Leu-D-Lys-4-aminopiperidine-4-carboxamide-PEG 5 CH 2 CO-
Lys(PEG 5 CH 2 CO-gamma Glu-20 alkanedioic acid) -NH 2
The procedure is as in example 1, using the protected amino acids as follows:
the peptide sequence n ═ Protected amino acids
1 Fmoc-Lys(Alloc)
2 Fmoc-PEG 5 CH 2 COOH
3 Fmoc-4-aminopiperidine-4-carboxylic acid
4 Fmoc-D-Lys(Alloc)
5 Fmoc-D-Leu
6 Fmoc-D-Phe
7 Boc-D-Phe
Side chain-1 Fmoc-PEG 5 CH 2 COOH
Side chain-2 Fmoc-γGlu-OtBu
Side chain-3 Octadecanedioic acid mono-tert-butyl ester
5.6g of pure product is obtained, the purity is 98.3 percent, and the total yield is 30.9 percent. The molecular weight was 1814.2 (100% M + H).
EXAMPLE 7 determination of analgesic Activity
SD rats are used for subcutaneous single administration, the dosage is 0.025mg/kg, the animals are subjected to intraperitoneal injection of 0.3% acetic acid solution 2ml/kg 4 hours after administration, the animals are allowed to rest for 10min, the analgesic activity of the compound is evaluated by observing and recording the writhing frequency of writhing of each group of rats within 20min of each time point, the observation time points are 4h, 24h and 48h after administration, and the experimental results are as follows:
number of wriggling in rat
Figure BDA0002966516910000101
EXAMPLE 8 determination of anti-itching Activity
Mice were injected intrathecally with morphine to induce itching, and the test samples were observed for their effect of regulating itching, using C57/BL6 mice.
4 hours, 24 hours and 48 hours after subcutaneous administration of test samples, mice were intrathecally injected with 1nmol morphine in a volume of 5 μ l, mice in each group were observed and recorded for mouse scratching reaction for 40min, and the number of scratching of mice was recorded, wherein 1 scratching is defined as 1 or continuous multiple scratching in which the hindpaw lifts the body or face, and the hindpaw falls to the ground or bites and is licked to represent the end of this scratching, or the forepaw scratches the body or face 1 or continuous multiple scratching, and the hindpaw falls to the ground or is licked. The test results are as follows:
number of scratching mice (4h)
Figure BDA0002966516910000111
EXAMPLE 8 determination of Primary pharmacokinetic Properties
SD rats are used for subcutaneous single administration with the dose of 0.1mg/kg, and orbital veins of the rats are respectively bled before administration (0h) and after administration for 1h, 2h, 3h, 4h, 8h, 24h, 48h, 96h and 144h, and plasma samples are separated by centrifugation.
Plasma concentrations of the corresponding compounds in plasma samples of SD rats were measured by LC-MS, and the half-lives of the compounds in SD rats administered Subcutaneously (SC) are shown in the following table:
compound (I) t 1/2 (h)
Compound 1 9.8
Compound 2 8.7

Claims (4)

1. A long-acting K opioid receptor agonist having the structural formula i:
D-Phe-D-Phe-D-Leu-D-Lys (R1) -4-aminopiperidine-4-carboxamide-AA 1-AA2(R2) -AA3
Structure I
AA1 in Structure I is (PEG) m1 (CH 2 ) m2 CO) m3 -, or is absent;
wherein: m1 is an integer from 1 to 10;
m2 is an integer from 1 to 5;
m3 is an integer from 1 to 5;
AA2 in structure I is Lys, or Dah, or Orn, or Dab, or Dap;
AA3 in Structure I is NH 2 Or is OH;
r1 in structure I is-CH 2 CH 2 B(OH) 2 Or is-CH 2 CH(Ph,B(OH) 2 ) Or is-CH 2 CH (cyclohexyl, B (OH) 2 ) Or is-CH 2 Ph(p-B(OH) 2 ) Or is-CH 2 Ph(m-B(OH) 2 ) Or is-CH 2 Ph(o-B(OH) 2 ) Or is-CH (CH) 3 )Ph(p-B(OH) 2 ) Or is-CH (CH) 3 )Ph(m-B(OH) 2 ) Or is-CH (CH) 3 )Ph(o-B(OH) 2 ) Or is-CH 2 CO piperidine (4-B (OH) 2 ) Or is absent;
r2 in structure I is HO 2 C(CH 2 )n 1 CO-(γGlu) n2 -(PEG n3 (CH 2 ) n4 CO) n5 -；
Wherein: n1 is an integer from 10 to 20;
n2 is an integer from 1 to 5;
n3 is an integer from 1 to 30;
n4 is an integer from 1 to 5;
n5 is an integer from 1 to 5.
2. The long-acting K opioid receptor agonist of claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex of the analog, a prodrug based on the compound, or a mixture of any of the foregoing.
3. The long-acting K opioid receptor agonist of claims 1 and 2 for use in the preparation of a pharmaceutical composition for the treatment of a disease.
4. The pharmaceutical composition according to claim 3, for alleviating moderate to severe itching in a patient and for post-operative analgesia.
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