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WO2019134510A1 - Composé de sel d'ammonium quaternaire de peptide court et son utilisation - Google Patents

Composé de sel d'ammonium quaternaire de peptide court et son utilisation Download PDF

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Publication number
WO2019134510A1
WO2019134510A1 PCT/CN2018/121939 CN2018121939W WO2019134510A1 WO 2019134510 A1 WO2019134510 A1 WO 2019134510A1 CN 2018121939 W CN2018121939 W CN 2018121939W WO 2019134510 A1 WO2019134510 A1 WO 2019134510A1
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Prior art keywords
compound
group
pain
pharmaceutically acceptable
salt
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Chinese (zh)
Inventor
蔡家强
田强
赵明亮
吴雷
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to CN201880071083.XA priority Critical patent/CN111315758B/zh
Publication of WO2019134510A1 publication Critical patent/WO2019134510A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the present invention relates to the field of medicine, and in particular to a short peptide quaternary ammonium salt compound, a pharmaceutical composition comprising the same, and use thereof for preventing or treating a disease associated with kappa opioid receptor.
  • Opioid receptors are widely present in the central nervous system and the peripheral nervous system.
  • Traditional opioid receptor agonists such as morphine and its derivatives, are the most effective drugs for the treatment of chronic arthritis, inflammatory neuralgia, postoperative pain, and moderate to severe pain caused by various cancers.
  • systemic administration of traditional opioid analgesics can cause side effects such as respiratory depression, drug addiction, constipation, nausea, confusion, and tolerance.
  • ⁇ opioid receptor agonists do not cause respiratory depression and constipation, and studies have shown that they are less addictive (Clark C, Halfpenny P, Hill R et al, J .Med.Chem., 1988, 31 831-836).
  • Direct administration of a low dose of a kappa opioid receptor agonist to the affected area does not produce a systemic response, thereby avoiding undesirable symptoms such as calming and anxiety.
  • Peripheral administration of opioid receptor agonists does not have any analgesic effect under normal conditions in the body. In the presence of inflammation or tissue damage, peripheral opioid receptor function is enhanced and analgesia is exerted after administration of the opioid receptor agonist. Effect (Persson T, Calafat J, Janssen H et al, Biochem. Biophys. Res. Commun., 2002, 291, 844-854).
  • the body is also less susceptible to tolerance to kappa opioid receptor agonists (Stein A, Helmke K, Szopko C et al, Dtsch. Med. Wienschr., 1996, 121, 255).
  • the first generation of kappa opioid receptor agonists can be administered to the brain after oral administration of these drugs.
  • the above-mentioned drugs have less side effects than morphine at the effective dose, they are stopped from further development due to side effects such as agitation and hallucination.
  • Second-generation kappa opioid receptor agonists (such as Asimadoline) have similar chemical structures to first-generation ⁇ opioid receptor agonists, but have higher peripheral selectivity (Barber A, Bartoszyk G, Bender H et al, Br. J. Pharmacol. 1994, 113, 1317-1327).
  • CN101627049B discloses a class of synthetic peptides having a polyamide structure which acts as a ligand for a kappa opioid receptor.
  • the inventors of the present application have surprisingly obtained a new class of short peptide quaternary ammonium salt compounds through intensive research and creative labor.
  • These novel short peptide quaternary ammonium salt compounds not only have excellent kappa opioid receptor agonistic efficacy (right The high affinity of the kappa opioid receptor) also has a very large hydrophilic capacity and thus a smaller penetration of the blood-brain barrier and a lower ability to enter the brain.
  • an aspect of the present invention provides a short peptide quaternary ammonium salt compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt comprising a structure of formula (I):
  • R a and R b are each independently selected from the group consisting of H, hydrazine, halogen, hydroxy, C 1-6 alkoxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -CONH a group of C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 6-10 aryl and 5-10 membered heteroaryl; preferably H, hydrazine;
  • n are each independently selected from 0, 1, 2, 3, 4, 5;
  • p is any integer from 0 to 6; preferably any integer from 2 to 4;
  • R c and R d are each independently selected from the group consisting of H, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, C 1-6 alkoxy, fluorenyl, C 1-6 alkyl fluorenyl, Substituent substitution of amino, -CONH 2 , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably H, ⁇ , C 1-6 An alkyl group, more preferably H, hydrazine, C 1-4 alkyl;
  • R x , R y , R z are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 1-6 alkoxyalkyl, PEG, oxygen anion
  • the above C 1-6 alkyl group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group, C 1-6 alkoxyalkyl group, PEG may also be optionally subjected to one or more hydroxyl groups, C 1- 6 alkoxy, amino, alkylamino, decyl, decyl, azide, halogen, carboxylic acid, ester, amide, sulfonic acid, sulfonamide, phosphoric acid, phosphate, phosphoramide, phosphoramidate, C 6-10 aryl, 5-10 membered heteroaryl substituted; preferably R x , R y , R z are each independently selected from C 1-6 alkyl; more preferably R x , R
  • any two of R x , R y and R z are ring-bonded to the nitrogen atom to which they are attached, said ring being a 4-8 membered heterocyclic ring;
  • R e can be selected from:
  • R e is
  • R e can be selected from:
  • R e is
  • the salt is selected from pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, Bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexamethanesulfonate, ethanedisulfonate, ethanesulfonate, formate, Fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide/iodide, isethionate, milk Acid salt, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, whey Acid salt, oxalate, palmitate
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite thereof, a prodrug thereof, or A pharmaceutically acceptable salt or ester and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.
  • Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical combination of the invention
  • Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical combination of the invention
  • a substance for preventing or treating a disease associated with a kappa opioid receptor A substance for preventing or treating a disease associated with a kappa opioid receptor.
  • Another aspect of the invention provides a method of preventing or treating a disease associated with a kappa opioid receptor comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a stereoisomer thereof, A polymorph, a solvate, or a metabolite thereof, a prodrug or a pharmaceutically acceptable salt or ester or a pharmaceutical composition of the invention.
  • the disease associated with the kappa opioid receptor is selected from the group consisting of pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma; preferably, said The pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain, and skin pain; preferably, the pain is selected from the group consisting of arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, medical treatment Post-treatment pain, eye pain, otitis pain, cancer pain, and pain associated with gastrointestinal disorders.
  • Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention
  • the agent is for increasing a level or activity of a kappa opioid receptor in a cell
  • the cell is a cell line or a cell from a subject; preferably, it is for use in vivo In the method; preferably, it is used in an in vitro method.
  • Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention
  • the cell is a cell line or a cell from a subject; preferably, it is used in an in vivo method; preferably, it is used In vitro methods.
  • Another aspect of the invention provides a method of increasing the level or activity of a kappa opioid receptor in a cell comprising administering to said cell an effective amount of a compound of the invention, or a stereoisomer, polymorph thereof Or a pharmaceutically acceptable salt or ester thereof or a pharmaceutical composition of the invention; preferably, the cell is a cell line or a cell from a subject; preferably, The method is carried out in vivo; preferably, the method is carried out in vitro.
  • short peptide quaternary ammonium salt compound refers to a compound, a stereoisomer, a polymorph, a solvate thereof, or a metabolite thereof, a prodrug thereof, or a compound according to any one of the formulae herein.
  • the short peptide quaternary ammonium salt compound preferably contains one or more amide bonds formed by condensation of the same or different L-amino acid or D-amino acid.
  • alkyl is defined as a saturated aliphatic hydrocarbon group, and the saturated aliphatic hydrocarbon includes straight-chain and branched saturated aliphatic hydrocarbon groups. In some embodiments, an alkyl group has from 1 to 6, such as from 1 to 4 carbon atoms.
  • C1-6 alkyl refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl); in some embodiments, the C 1-6 alkyl is optionally 1 or more (such as 1 Up to 3) suitable substituents such as halogen (wherein the group is referred to as "halogenated C 1-6 alkyl” or "C 1-6 haloalkyl", such as CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 , etc.).
  • C 1-4 alkyl refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl) , sec-butyl or tert-butyl).
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptane).
  • the cycloalkyl group described herein has 3 to 15 carbon atoms.
  • C 3-10 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group of 3 to 10 ring-forming carbon atoms. (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl); in some embodiments, the C 3-10 cycloalkyl is optionally 1 or more (such as 1 to 3) substituted substituents, such as methyl substituted cyclopropyl.
  • the 3-10 membered heterocyclic group is a group having 3 to 10 ring-forming carbon atoms and a hetero atom, and includes, for example, but not limited to, an oxiranyl group, an aziridine group, or an azetidinyl group ( Azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridyl Oryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • alkoxy refers to an alkyl-O- group.
  • C 1-6 alkoxy group means a linear or branched aliphatic saturated hydrocarbon group having an alkyl moiety as the above-mentioned "C 1-6 alkyl group”, and examples thereof include a methoxy group and an ethoxy group.
  • Preferred is a C 1-4 alkoxy group.
  • alkylalkyl refers to a radical to which a sulfur atom is attached to an alkyl group, and refers to an alkyl-S- group.
  • the "C 1-6 alkyl fluorenyl group” means a group in which the above C 1-6 alkyl group is bonded to a sulfur atom, and may, for example, be a decyl group, an ethylthio group, a propylthio group or an isopropylthio group. It is preferably a C 1-4 alkyl fluorenyl group.
  • alkoxyalkyl refers to an alkyl-O-alkyl group
  • C1-6 alkoxyalkyl refers to an alkyl moiety as described above for " C1-6
  • the linear or branched aliphatic saturated alkoxy group of the group may be the same or different from the alkyl group bonded to the O atom.
  • Examples of the C 1-6 alkoxyalkyl group are CH 3 OCH 2 -, CH 3 (CH 2 ) 3 O CH 2 CH 2 -, CH 3 OCH(CH 3 )- and the like.
  • PEG polyethylene glycol having HO-(CH 2 CH 2 O) m -, or CH 3 (CH 2 ) m O-(CH 2 CH 2 O) m - structure Group.
  • alkylamino refers to a chemical group having an alkyl-NH- structure.
  • ester group refers to a chemical group having a -COORE structure, wherein RE is selected from alkyl, heteroalkyl, heterocycloalkyl, cycloalkyl, aryl, and heteroaryl groups as described herein. base.
  • sulfonamido refers to "N-sulfonamido” or "S-sulfonamido”;
  • aryl refers to an all-carbon monocyclic or polycyclic aromatic group having a conjugated pi-electron system.
  • C6-10 aryl means an aromatic group containing from 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • heteroaryl refers to a monocyclic or polycyclic aromatic group containing one or more of the same or different heteroatoms, such as oxygen, nitrogen or sulfur; further, A heteroaryl group means a monocyclic, bicyclic or tricyclic aromatic group having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 Or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different, such as oxygen, nitrogen or sulfur; and the heteroaryl group may be benzofused Group.
  • the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl , thiadiazolyl, and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof.
  • heteroaryl group having 5 to 10 ring atoms and comprising at least one hetero atom which may be the same or different, such as oxygen, nitrogen or sulfur; and the heteroaryl group may be benzene And a fused group.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • Ph refers to a phenyl group.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on a specified atom are replaced by a choice of the specified group, provided that the specified atom is not exceeded in the current situation.
  • the lower normal valence and the substitution form a substantially stable compound. Combinations of substituents and/or variables are permissible only if such combinations form a substantially stable compound.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a compound, group or substituent described herein is described as: "optionally" substituted with a specified group or group of atoms, it is meant that the compound, group or substituent may (1) be unsubstituted or ( 2) Substituted by the specified group or atomic group.
  • the compounds of the invention may also comprise one or more (e.g., one, two, three or four) isotopic substitutions.
  • H can be in any isotopic form, including 1H, 2 H (D or ⁇ ) and 3 H (T or ⁇ );
  • C can be in any isotopic form, including 12 C, 13 C and 14 C;
  • any isotopic form including 16 O and 18 O;
  • stereoisomer denotes an isomer formed as a result of the presence of at least one asymmetric center in the compound.
  • compounds having one or more (eg, one, two, three, or four) asymmetric centers which can produce racemates, racemic mixtures, single enantiomers, diastereoisomers The mixture of the constructs and the individual diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which, after administration to a patient in need thereof, are capable of The compounds of the invention or their metabolites or residues are provided directly or indirectly.
  • a compound of the invention it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonic acid Salt, methanesulfonate, methyl sulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, Phosp
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.
  • the pharmaceutically acceptable salt is selected from the group consisting of formates, acetates, hydrochlorides, and trifluoroacetates.
  • esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention. compound of.
  • the compounds of the invention may also be esters per se.
  • the compounds of the invention may exist in the form of solvates and hydrates, and the amount of solvent or water may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention.
  • the invention further includes within its scope prodrugs of the compounds of the invention.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound.
  • the term “administering” for use in the methods of treatment of the invention shall include the treatment of various diseases or conditions with a prodrug form of one or more of the claimed compounds, but The prodrug form is converted to the above compound in vivo after administration to the individual.
  • “Design of Prodrug” ed. H. Bundgaard, Elsevier, 1985, a conventional method of selecting and preparing suitable prodrug derivatives is described.
  • any process for preparing a compound of the invention it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention.
  • This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • Protecting groups which are incorporated herein by reference.
  • the protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the invention provides a compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is Salt of the structure of formula (I):
  • R a and R b are each independently selected from the group consisting of H, hydrazine, halogen, hydroxy, C 1-6 alkoxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -CONH a group substitution of a C 3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group;
  • n are each independently selected from 0, 1, 2, 3, 4, 5;
  • p is any integer from 0 to 6;
  • R c and R d are each independently selected from the group consisting of H, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, C 1-6 alkoxy, fluorenyl, C 1-6 alkyl fluorenyl, a group substitution of an amino group, a -CONH 2 , a C 3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C 6-10 aryl group, and a 5-10 membered heteroaryl group;
  • R x , R y , R z are each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 1-6 alkoxyalkyl, PEG, oxygen anion
  • the above C 1-6 alkyl group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group, C 1-6 alkoxyalkyl group, PEG may also be optionally subjected to one or more hydroxyl groups, C 1- 6 alkoxy, amino, alkylamino, decyl, decyl, azide, halogen, carboxylic acid, ester, amide, sulfonic acid, sulfonamide, phosphoric acid, phosphate, phosphoramide, phosphoramidate, C 6-10 aryl, 5-10 membered heteroaryl substituted;
  • any two of R x , R y and R z are ring-bonded to the nitrogen atom to which they are attached, said ring being a 4-8 membered heterocyclic ring;
  • R e can be selected from:
  • R e can be selected from:
  • the salt is selected from pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, Bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexamethanesulfonate, ethanedisulfonate, ethanesulfonate, formate, Fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide/iodide, isethionate, milk Acid salt, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, whey Acid salt, oxalate, palmitate
  • R a and R b are each independently selected from the group consisting of H, hydrazine, halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl; more preferably, R a and R b are each independently selected from H and hydrazine.
  • R c and R d are each independently selected from the group consisting of H, hydrazine, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, 3- a group of a 10-membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; more preferably, R c and R d are each independently selected from the group consisting of H, hydrazine, and C 1-6 alkyl; Further preferred are H, hydrazine, and C 1-4 alkyl groups.
  • R c and R d are each independently selected from H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably, R c Or R d is isopropyl. More preferably, R c and R d are H and isopropyl, respectively.
  • R x , R y , R z are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 1-6 alkoxyalkyl, PEG, oxygen anion; more preferably, R x , R y , R z are each independently selected from C 1-6 alkyl; more preferably R x , R y , R z are each independently It is selected from a C 1-4 alkyl group. More preferably, R x , R y , and R z are a methyl group.
  • R e is selected from the group consisting of
  • R e is
  • R e is selected from:
  • R e is
  • the salt is selected from pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof include, but are not limited to, acetate, hydrochloride, trifluoroacetate.
  • the compound or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein
  • the compound is a salt containing the structure of formula II:
  • R x , R y , R z , R e , p are as defined above.
  • the compound or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein
  • the compound is a salt containing the structure of formula II-1:
  • the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof wherein
  • the compound is an acetate, hydrochloride and trifluoroacetate salt containing the structure of formula II-1.
  • the compound or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein
  • the compound is a salt containing the structure of formula II-2:
  • the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof wherein
  • the compound is an acetate, hydrochloride and trifluoroacetate salt containing the structure of formula II-2.
  • the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof wherein
  • the compound is a salt containing the structure of formula II-3:
  • the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof wherein
  • the compound is an acetate, hydrochloride and trifluoroacetate salt containing the structure of formula II-3.
  • Step 1 the resin is coupled with a terminal carboxyl compound under basic conditions;
  • the base includes, but is not limited to, an organic base and an inorganic base, preferably DIEA, TEA, NMM;
  • Step 2 De-Fmoc protection in piperazine in DMF solution
  • Step 3 using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent;
  • the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;
  • Step 4 Deprotection of Fmoc in piperazine in DMF solution
  • Step 5 using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent;
  • the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;
  • Step 6 Deprotection of Fmoc in piperazine in DMF solution
  • Step 7 using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent;
  • the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;
  • Step 8 Deprotection of Fmoc in piperazine in DMF solution
  • Step 9 using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent;
  • the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;
  • Step 10 De-Fmoc protection in piperazine in DMF solution
  • Step 11 Under acidic conditions, the peptide resin is cleaved to obtain a compound which is a salt containing the structure of Formula I; the compound is subjected to HPLC purification and salt-transfer to give a salt of the compound.
  • the -A-COOH group is a R e group, and the R e (if any of them has a free amino group, which is blocked by a suitable protecting group) is selected from the following structures:
  • Step 1 the compound i-1 and the amino acid ester are obtained by condensation reaction to obtain the compound i-2 of the formula;
  • Step 2 the compound i-2 is hydrolyzed and condensed to obtain the compound i-3;
  • Step 3 the compound i-3 is hydrolyzed and condensed to obtain the compound i-4;
  • Step 4 the compound i-4 is hydrolyzed and condensed to obtain the compound i-5;
  • Step 5 The compound i-5 of the formula is deprotected to obtain a compound, and the compound is a salt containing the structure of the formula (I);
  • R e (if any of them has a free amino group, which is blocked by a suitable protecting group) is selected from the group consisting of:
  • PG is an amino-protecting group, including but not limited to an alkoxycarbonyl group, an acyl group, an alkyl-based amino protecting group; for example, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, a fluorenylmethoxycarbonyl group, Wait;
  • the condensation reaction is to dissolve the substrate in a solvent (including but not limited to dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl
  • a condensing agent including but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT
  • excipients including but not limited to Copper chloride, copper chloride dihydrate, copper chloride other hydrate
  • base including but not limited to organic bases and inorganic bases, preferably N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine
  • the hydrolysis reaction is a solution in which the substrate is dissolved in a solvent (including but not limited to tetrahydrofuran, methanol, ethanol, water, acetone, diethyl ether, methyl tert-butyl ether).
  • a solvent including but not limited to tetrahydrofuran, methanol, ethanol, water, acetone, diethyl ether, methyl tert-butyl ether.
  • the corresponding hydrolyzate can be obtained by reacting with a base (including but not limited to an organic base and an inorganic base, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide) at a suitable temperature (-30 ° C to 30 ° C).
  • the deprotection reaction is carried out in the presence of a deprotecting reagent at room temperature or under heating.
  • Preferred deprotecting agents include hydrogen, acidic reagents such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, or alkaline agents such as sodium hydroxide, potassium hydroxide, lithium hydroxide, piperidine, and the like.
  • acidic reagents such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • alkaline agents such as sodium hydroxide, potassium hydroxide, lithium hydroxide, piperidine, and the like.
  • compositions and methods of treatment are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically thereof thereof An acceptable salt or ester, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents for preventing or treating a kappa opioid receptor-associated disease.
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents including, but not limited to, other opioid receptor agonists (eg, morphine, fentanyl, Oxymorphone or oxycodone), antidepressants, anticonvulsants, tranquilizers, antihistamines, ion channel blockers, non-steroidal anti-inflammatory drugs and diuretics.
  • opioid receptor agonists eg, morphine, fentanyl, Oxymorphone or oxycodone
  • antidepressants eg, anticonvulsants, tranquilizers, antihistamines, ion channel blockers, non-steroidal anti-inflammatory drugs and diuretics.
  • the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or Use of the pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a disease associated with a kappa opioid receptor.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising the same for use in preventing or treating a disease associated with a kappa opioid receptor.
  • the invention provides a method of preventing or treating a disease associated with a kappa opioid receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition comprising the same.
  • the diseases associated with the kappa opioid receptor described in the present invention are selected from the group consisting of pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma.
  • the pain includes neuropathic pain, somatic pain, visceral pain, skin pain, arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, pain after medical treatment, eye pain Pain associated with otitis pain, cancer pain, and gastrointestinal disorders.
  • the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or The use of a pharmaceutical composition according to the invention for the preparation of a medicament for increasing the level or activity of a kappa opioid receptor in a cell.
  • the cell is a cell line or a cell from a subject.
  • the compound, or a stereoisomer, polymorph, solvate thereof, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or in the present invention are for use in an in vivo method.
  • the compound, or a stereoisomer, polymorph, solvate thereof, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or in the present invention are for use in an in vitro method.
  • the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or
  • the pharmaceutical composition of the invention for use in increasing the level or activity of a kappa opioid receptor in a cell.
  • the cell is a cell line or a cell from a subject.
  • the compound, or a stereoisomer, polymorph, solvate thereof, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or in the present invention are for use in an in vivo method.
  • the compound, or a stereoisomer, polymorph, solvate thereof, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or in the present invention are for use in an in vitro method.
  • the invention provides a method of increasing the level or activity of a kappa opioid receptor in a cell comprising administering to the cell an effective amount of a compound of the invention, or a stereoisomer thereof, A crystalline form, a solvate, or a metabolite thereof, a prodrug or a pharmaceutically acceptable salt or ester, or a pharmaceutical composition as described herein.
  • the cell is a cell line or a cell from a subject.
  • the method is performed in vivo.
  • the method is performed in vitro.
  • the compounds of the invention have a smaller ability to penetrate the blood-brain barrier and lower entry into the brain.
  • the compounds of the invention have reduced toxic side effects on the central nervous system at effective concentrations that achieve peripheral analgesic effects.
  • a compound of the invention When a compound of the invention is administered to a subject in need thereof at a prophylactically or therapeutically effective concentration, it exhibits a low or minimal ability to penetrate the blood-brain barrier.
  • the kappa opioid receptor (hereinafter also referred to interchangeably as the kappa receptor) is distributed in peripheral tissues (including skin and body tissues) and viscera of human or other mammals. It has also been found that kappa receptors are also present in the brain. Activation of kappa receptors in peripheral tissues can cause inhibition of pain and inflammatory responses, while activation of kappa receptors in the brain causes sedative effects and can also cause severe irritability and hallucinations.
  • the compounds of the invention when administered in an effective amount, exhibit substantially no penetration of the blood-brain barrier, thereby minimizing or even completely eliminating many penetrating abilities to the blood-brain barrier.
  • the sedative and hallucinogenic effects of other ⁇ agonists when administered in an effective amount, exhibit substantially no penetration of the blood-brain barrier, thereby minimizing or even completely eliminating many penetrating abilities to the blood-brain barrier.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • SM-5 (reference Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 290, #1, p. 101-108) (0.90 g, 2.20 mmol) was dissolved in DMF (30 ml) at 0 °C HOBT (0.37 g, 2.2 mmol) and HBTU (0.86 g, 2.20 mmol) were added, and reacted for 5 min, then DIEA (0.28 g, 2.20 mmol) was added and reacted at 0 ° C for 5 min.
  • the reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used. The resin did not change color, the reaction was completed, the liquid was taken out, washed with DMF, and used directly for the next reaction.
  • SM-8(Fmoc-D-Leu-OH) (0.78 g, 2.20 mmol) was dissolved in DMF (10 mL).
  • EtOAc (0.37 g, 2.2 mmol) and EtOAc (0.86 g, 2.20 mmol)
  • DIEA 0.28 g, 2.20 mmol
  • the reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used. The resin did not change color, the reaction was completed, the liquid was taken out, washed with DMF, and used directly for the next reaction.
  • SM-11 (Fmoc-D-Phe-OH) (0.86 g, 2.20 mmol) was dissolved in DMF (10 mL). HOBT (0.37 g, 2.2 mmol) and HBTU (0.86 g, 2.20 mmol) After reacting for 5 min, DIEA (0.28 g, 2.20 mmol) was further added, and the reaction was carried out at 0 ° C for 5 min. The reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used. The resin did not change color, the reaction was completed, the liquid was taken out, washed with DMF, and used directly for the next reaction.
  • SM-14 (Fmoc-D-Phe-OH) (0.86 g, 2.20 mmol) was dissolved in DMF (10 mL). HOBT (0.37 g, 2.2 mmol) and HBTU (0.86 g, 2.20 mmol) After reacting for 5 min, DIEA (0.28 g, 2.20 mmol) was further added, and the reaction was carried out at 0 ° C for 5 min. The reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used, the resin was not changed in color, the reaction was completed, the liquid was taken out, and washed with DMF. The resin was taken out and dried under vacuum, and used directly for the next reaction.
  • the trifluoroacetate salt of the structure of the formula II-1 obtained in Example 1 was salted by HPLC into an acetate salt containing the structure of the formula II-1.
  • the potency of the compounds of the invention as kappa opioid receptor agonists was determined by measuring the ability of the compounds of the examples to inhibit adenylate cyclase activity.
  • CHO stably expressing the human kappa opioid receptor (KOR) gene were cultured in MESAM plus nucleosides medium (Invitrogen) containing 5% FBS.
  • NKH477 Tocris stimulating solution (5uL), digest, resuspend, count and take 5uL Add to it, mix gently, and incubate at 37 ° C for 30 minutes.
  • cAMP D 2 and anti-cAMP compound conjugates were separately added using a cAMP detection kit (Cisbio), and incubated for 1 hour at room temperature. Using envision (Perkin Elmer) plate reader, using a four parameter curve fitting equation EC 50.
  • Example compounds of the invention have excellent agonistic potency at the ⁇ opioid receptor.
  • Other compounds of the invention have similar superior agonistic potency to the kappa opioid receptor.
  • Example 1 Male SD rats were administered intravenously (IV) to a compound of Example 1 at 1 mg/kg and 20 mg/kg, and the vehicle was a sodium chlorate-containing 10 mM sodium acetate buffer (pH 4.5 ⁇ 0.2).
  • IV intravenously
  • Whole blood and brain tissue were collected at different time points after IV administration.
  • Whole blood was centrifuged to separate plasma, and brain tissue was added with physiological saline to prepare brain tissue homogenate. Plasma and brain tissue homogenate were treated with precipitated protein and analyzed by LC-MS/MS.
  • the mass spectrometer model is API 5500 and the liquid chromatograph model is the Waters ACQUITY I CLASS system.
  • the column was Thermo Hypersil Gold C18 column (50*2.1 mm, 1.9 ⁇ m); mobile phase A was 0.2% formic acid in water, mobile phase B was acetonitrile; flow rate was 0.4 mL/min, and column temperature was 40 °C.
  • the ion source used is the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).

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Abstract

L'invention concerne un composé de sel d'ammonium quaternaire de peptide court et son utilisation. En particulier, l'invention concerne un type de composé de sel d'ammonium quaternaire de peptide court ou un stéréoisomère, un polymorphe, un solvate de celui-ci, ou un métabolite, un promédicament ou un sel ou un ester pharmaceutiquement acceptable, ou une composition pharmaceutique de celui-ci, ainsi qu'un procédé de préparation du composé et une utilisation dans la prévention ou le traitement de maladies associées à des récepteurs opioïdes de type kappa. Le composé polyamide selon la présente invention a une excellente puissance agoniste du récepteur opioïde de type kappa, une capacité hydrophile et ainsi une pénétration réduite de la barrière hémato-encéphalique et une capacité réduite à pénétrer dans le cerveau. Le composé selon l'invention présente d'excellentes propriétés médicamenteuses, telles qu'une sélectivité plus élevée vis-à-vis des récepteurs opioïdes de type kappa, une dépendance réduite, des propriétés pharmacocinétiques améliorées, une sécurité améliorée, une bonne adaptation au patient, et/ou est moins sujet à induire une tolérance aux médicaments.
PCT/CN2018/121939 2018-01-03 2018-12-19 Composé de sel d'ammonium quaternaire de peptide court et son utilisation Ceased WO2019134510A1 (fr)

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Cited By (2)

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US11492374B2 (en) 2020-06-25 2022-11-08 Humanwell Pharmaceutical US Peptides for treatment of medical disorders
US12215173B2 (en) 2019-08-07 2025-02-04 HUMANWELL PHARMACEUTICAL US, Inc. Kappa opioid receptor peptide amide ligands

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CN101535336A (zh) * 2006-11-10 2009-09-16 卡拉治疗学股份有限公司 合成酞酰胺及其二聚体
CN101627049A (zh) * 2006-11-10 2010-01-13 卡拉治疗学股份有限公司 合成酞酰胺
US20100075910A1 (en) * 2006-11-10 2010-03-25 Cara Therapeutics, Inc. Synthetic peptide amides and dimeric forms thereof

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US5760023A (en) * 1997-07-14 1998-06-02 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith
CN107098871B (zh) * 2016-02-23 2021-07-02 江苏恒瑞医药股份有限公司 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用

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CN101535336A (zh) * 2006-11-10 2009-09-16 卡拉治疗学股份有限公司 合成酞酰胺及其二聚体
CN101627049A (zh) * 2006-11-10 2010-01-13 卡拉治疗学股份有限公司 合成酞酰胺
US20100075910A1 (en) * 2006-11-10 2010-03-25 Cara Therapeutics, Inc. Synthetic peptide amides and dimeric forms thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12215173B2 (en) 2019-08-07 2025-02-04 HUMANWELL PHARMACEUTICAL US, Inc. Kappa opioid receptor peptide amide ligands
US11492374B2 (en) 2020-06-25 2022-11-08 Humanwell Pharmaceutical US Peptides for treatment of medical disorders

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