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CN111315758B - Short peptide quaternary ammonium salt compound and application thereof - Google Patents

Short peptide quaternary ammonium salt compound and application thereof Download PDF

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CN111315758B
CN111315758B CN201880071083.XA CN201880071083A CN111315758B CN 111315758 B CN111315758 B CN 111315758B CN 201880071083 A CN201880071083 A CN 201880071083A CN 111315758 B CN111315758 B CN 111315758B
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pain
compound
group
pharmaceutically acceptable
kappa opioid
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CN111315758A (en
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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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    • A—HUMAN NECESSITIES
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Abstract

The invention discloses a short peptide quaternary ammonium salt compound and application thereof, in particular to a short peptide quaternary ammonium salt compound, or a stereoisomer, a polymorph, a solvate, or a metabolite, a prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition thereof, a preparation method of the compound and application of the compound in preventing or treating diseases related to kappa opioid receptors. The polyamide compounds of the present invention have excellent kappa opioid receptor agonistic potency, hydrophilic ability and thus less ability to penetrate the blood brain barrier and lower access to the brain. The compounds of the invention have superior pharmaceutical properties for kappa opioid receptors, higher selectivity, lower addiction, improved pharmacokinetic properties, improved safety, good patient compliance, and/or less susceptibility to tolerance.

Description

Short peptide quaternary ammonium salt compound and application thereof
Technical Field
The invention relates to the field of medicines, in particular to a short peptide quaternary ammonium salt compound, a pharmaceutical composition containing the same and application of the short peptide quaternary ammonium salt compound in preventing or treating kappa opioid receptor related diseases.
Background
Opioid receptors (μ, δ and κ) are widely present in the central and peripheral nervous systems. Traditional opioid receptor agonists (e.g., 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. However, systemic administration of conventional opioid analgesics can produce side effects such as respiratory depression, drug addiction, constipation, nausea, confusion, tolerance, etc. Kappa opioid receptor agonists are distinguished from mu opioid receptor agonists, which do not lead to 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, 31-836). By directly administering a low dose of kappa opioid receptor agonist to the peripheral afflicted area, systemic reactions are not produced, thereby avoiding undesirable symptoms such as sedation and anxiety. Peripheral opioid receptor agonists are administered peripherally without any analgesic effect in the normal state of the body, and peripheral opioid receptor function is enhanced in the presence of inflammation or tissue injury, and analgesic effects are exerted after administration of the opioid receptor agonist (Persson T, calafat J, janssen H et al biochem. In addition, the body is also not susceptible to tolerance to kappa opioid receptor agonists (Stein a, helmke K, szopko C et al, dtsch.med.wochenschr.,1996,121,255).
Auh and Ro et al injected Complete Freund's Adjuvant (CFA) into the right hind plantar surface of SD rats caused hyperalgesia, 3 days later three concentrations of U50488 (a specific kappa opioid receptor agonist) were injected into the right hind plantar surface of the rats. The results of the study showed that: peripheral administration of kappa opioid receptor agonists significantly reduced pain and hyperalgesia, and at high doses the sex differences in the anti-hyperalgesic effect were more pronounced, this result was also further demonstrated in the clinical pain model (Auh QS, ro JY. Neurosci. Lett.,2012,524,111-115). It has been reported that activation of kappa opioid receptors can inhibit inflammatory hyperalgesia by stimulating PI3kγ/AKT signaling through the nNOS/NO signaling pathway (Cunha TM, souza GR, domingues AC et al, mol. Pain,2012,8,10).
First generation kappa opioid receptor agonists include spirolin (Spiradoline) and etadolin (Enadoline), which can be administered orally into the brain. Although the side effects of the above drugs are smaller than morphine at the effective dose, their further development has been stopped due to the agitation and illusion of the side effects. Second generation kappa opioid receptor agonists (e.g., acimadolin (Asimadoline)) are similar in chemical structure to the first generation kappa opioid receptor agonists, but are more selective in their outer periphery (Barber a, bartoszyk G, bender H et al, br.j. Pharmacol.1994,113, 1317-1327). However, due to the poor anesthetic effect at licensed doses, their development as opioid anesthetics has been abandoned and is used to treat digestive system diseases such as irritable bowel syndrome (CAMILLERI m.
CN101627049B discloses a class of synthetic peptides with a polyamide structure, which can be used as ligands for kappa opioid receptors.
Although some kappa opioid receptor agonists already exist in the art, there remains a need for novel kappa opioid receptor agonists with high peripheral selectivity.
Disclosure of Invention
The present inventors have surprisingly obtained, through intensive research and creative efforts, a new class of short peptide quaternary ammonium salt compounds having not only excellent kappa opioid receptor agonistic potency (high affinity for kappa opioid receptors) but also very large hydrophilic capacity and thus smaller ability to penetrate the blood brain barrier and lower access to the brain.
Accordingly, in one aspect, the present invention provides a short peptide quaternary ammonium salt compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt comprising the structure of formula (I):
Wherein:
R a and R b are each independently substituted with a group selected from H, deuterium, halogen, hydroxy, C 1-6 alkoxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -CONH 2、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; preferably H, deuterium;
n is 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 substituted with a group selected from H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, C 1-6 alkoxy, mercapto, C 1-6 alkylmercapto, amino, -CONH 2、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; preferably H, deuterium, C 1-6 alkyl, more preferably H, deuterium, C 1-4 alkyl;
R x、Ry、Rz is each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 1-6 alkoxyalkyl, PEG, oxyanion; the above-mentioned C 1-6 alkyl, C 3-10 cycloalkyl, 3-to 10-membered heterocyclyl, C 1-6 alkoxyalkyl, PEG may also be optionally substituted with one or more hydroxy, C 1-6 alkoxy, amino, alkylamino, amidino, guanidino, azido, halogen, carboxylic acid, ester, amide, sulfonic acid, sulfonamide, phosphoric acid, phosphate, phosphoramide, phosphoramidate, C 6-10 aryl, 5-to 10-membered heteroaryl; preferably, each R x、Ry、Rz is independently selected from C 1-6 alkyl; more preferably, each R x、Ry、Rz is independently selected from C 1-4 alkyl;
Or any two of R x、Ry and R z form a ring with the nitrogen atom, and the ring is a 4-8 membered heterocycle;
r e may be selected from:
Preferably R e is
Wherein the bond extending to the left in the structure described above for R e indicates that the structure is bonded to the remainder of the molecule of formula (I), namely:
r e may be selected from:
Preferably R e is
The salt is selected from pharmaceutically acceptable salts thereof including, but not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate. Preferably, the pharmaceutically acceptable salt thereof is selected from acetate, hydrochloride and trifluoroacetate.
In another aspect, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, in combination with one or more pharmaceutically acceptable carriers.
In the present invention, the pharmaceutical composition is administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.
In another aspect, the invention provides the use of a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a 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.
Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a disease associated with a kappa opioid receptor.
In another aspect, the invention provides a method of preventing or treating a disease associated with kappa opioid receptors comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present invention.
In the present invention, the kappa opioid receptor-associated disorder is selected from pain, inflammation, itch, edema, hyponatremia, hypokalemia, ileus, cough, and glaucoma; preferably, the pain is selected from 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, post-medical treatment pain, ocular pain, otitis pain, cancer pain and pain associated with gastrointestinal disorders.
In another aspect, the invention provides the use of a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention, for the preparation of a reagent, wherein the reagent is for increasing kappa opioid receptor levels or activity in a cell; preferably, 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 an in vitro method.
In another aspect, the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention, for use in increasing kappa opioid receptor levels or activity in a cell; preferably, 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 an in vitro method.
Another aspect of the invention is to provide 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 present invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present invention; preferably, the cell is a cell line or a cell from a subject; preferably, the method is performed in vivo; preferably, the method is performed in vitro.
Detailed Description
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive (inclusive) or open-ended and do not exclude additional unrecited elements or method steps.
As used herein, the term "short peptide quaternary ammonium salt compound" refers to a compound, stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, according to any of the formulae of the present application. The short peptide quaternary ammonium salt compound preferably contains one or more amide bonds formed by the condensation of the same or different L-amino acids or D-amino acids.
As used herein, the term "alkyl" is defined as a saturated aliphatic hydrocarbon group, including straight and branched chain saturated aliphatic hydrocarbon groups. In some embodiments, the alkyl group has 1 to 6, for example 1 to 4 carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 6 carbon atoms (e.g., 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 substituted with 1 or more (such as 1 to 3) suitable substituents, such as halogen (in which case the group is referred to as "halo C 1-6 alkyl" or "C 1-6 haloalkyl", e.g., CF 3、C2F5、CHF2、CH2F、CH2CF3、CH2 Cl or-CH 2CH2CF3, etc.). The term "C 1-4 alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon cyclic group (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] nonyl, decalinyl, etc.), in some embodiments, the cycloalkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, e.g., the cycloalkyl group herein has 3 to 15 carbon atoms, e.g., the term "C 3-10 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon cyclic group of 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo [1.1.1] pentyl), in some embodiments, the C 3-10 cycloalkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, e.g., methyl groups.
As used herein, the term "heterocyclyl" refers to a saturated or unsaturated mono-or bicyclic group having 2,3, 4,5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from O, S, S (=o), S (=o) 2, and NR, wherein R represents a hydrogen atom, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group; the heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. In some preferred embodiments, at least one carbon atom (e.g., one or two) of the heterocyclic groups is substituted with an oxy (=o). In particular, 3-10 membered heterocyclyl is a group having 3-10 ring-forming carbon atoms and heteroatoms including, for example, but not limited to, oxiranyl, aziridinyl, azetidinyl (azetidinyl), oxetanyl (oxetanyl), tetrahydrofuranyl, dioxolyl (dioxolinyl), pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, or trithianyl (trithianyl).
As used herein, the term "alkoxy" refers to an alkyl-O-group. The "C 1-6 alkoxy group" means a straight-chain or branched aliphatic saturated hydrocarbyloxy group having an alkyl moiety of the above-mentioned "C 1-6 alkyl group", and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferred is a C 1-4 alkoxy group.
As used herein, the term "alkylmercapto" refers to a group in which a sulfur atom is attached to an alkyl group, and refers to an alkyl-S-group. "C 1-6 Alkylmercapto" means a group in which the above-mentioned C 1-6 alkyl group is bonded to a sulfur atom, and may be, for example, a methylthio group, an ethylthio group, a propylthio group, or an isopropylthio group. C 1-4 alkylmercapto is preferred.
As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl group; "C 1-6 alkoxyalkyl" refers to a straight-chain or branched aliphatic saturated hydrocarbyloxy group in which the alkyl moiety is the above-described "C 1-6 alkyl" and the alkyl groups attached to the O atoms may be the same or different. Examples of C 1-6 alkoxyalkyl groups are CH3OCH2-、CH3(CH2)3OCH2CH2-、CH3OCH(CH3)- and the like.
As used herein, the term "PEG" is a polyethylene glycol having a group of HO- (CH 2CH2O)m -, or CH 3(CH2)mO-(CH2CH2O)m -structure.
As used herein, the term "alkylamino" refers to a chemical group having an alkyl-NH-structure.
As used herein, the term "ester group" refers to a chemical group having the structure-COORE, wherein RE is selected from the group consisting of alkyl, heteroalkyl, heterocycloalkyl, cycloalkyl, aryl, and heteroaryl as described herein.
As used herein, the term "amido" refers to an amino group as described below attached to the parent molecular moiety through a carbonyl or sulfonyl group. Includes "C-amide" or "N-amide", wherein "C-amide" is a chemical group having a-C (=o) -NR structure; "N-amide" is a chemical group having an RC (=o) NH-structure, wherein R is an alkyl group as defined herein.
As used herein, the term "sulfonamide" refers to "N-sulfonamide" or "S-sulfonamide"; "N-sulfonamide" refers to a compound having an alkyl-S (=o) 2 NH-group; "S-sulfonamide" refers to a compound having a-S (=o) 2 N-R group, wherein R is alkyl as defined herein.
As used herein, the term "aryl" refers to an all-carbon monocyclic or polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. In some embodiments, the aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, such as oxygen, nitrogen, or sulfur; further, the heteroaryl group refers to a monocyclic, bicyclic or tricyclic aromatic group having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be the same or different, such as oxygen, nitrogen or sulfur; and, the heteroaryl group may be a benzo-fused group. In particular, the heteroaryl group is selected from 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 their benzo derivatives. A 5-10 membered heteroaryl is one having 5-10 ring atoms and containing at least one heteroatom, which may be the same or different, such as oxygen, nitrogen or sulfur; and, the heteroaryl group may be a benzo-fused group.
As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.
As used herein, the "Ph" group represents phenyl.
The term "substitution" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the designated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a substantially stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in substantially stable compounds.
The term "optionally" means that a group or substituent described herein may be unsubstituted or substituted with a particular group, radical.
The term "one or more" as used herein means 1 or more than 1, such as 2,3, 4, 5 or 10, under reasonable conditions.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
If a compound, group or substituent described herein is described as: by "optionally" substituted with a specified group or radical, it is meant that the compound, group or substituent may be (1) unsubstituted or (2) substituted with the specified group or radical.
The compounds of the invention may also contain one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including 1H, 2 H (D or deuterium) and 3 H (T or tritium); c may be in any isotopic form, including 12C、13 C and 14 C; o may be in any isotopic form, including 16 O and 18 O; etc.
The term "stereoisomer" refers to an isomer formed as a result of the presence of at least one asymmetric center in a compound. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, it may result in racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the application may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the present invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetates, adipates, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate.
Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.
For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts:properties, selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art. In some preferred embodiments, the pharmaceutically acceptable salt is selected from formate, acetate, hydrochloride, and trifluoroacetate salts.
As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in the present application, including physiologically hydrolyzable esters that hydrolyze under physiological conditions to release the free acid or alcohol forms of the compounds of the present application. The compounds of the application may themselves be esters. The compounds of the application may exist in the form of solvates and hydrates, and the amount of solvent or water may be present in stoichiometric or non-stoichiometric proportions.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention.
The present invention further includes within its scope prodrugs of the compounds of the present invention. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Thus, in these instances, the term "administering" as used in the methods of treatment of the present invention shall include treating various diseases or conditions with a prodrug form of one or more of the claimed compounds, but which converts to the above-described compounds in vivo upon administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrug", ed.H. Bundgaard, elsevier, 1985.
During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, at Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting groups may be removed at a suitable subsequent stage using methods known in the art.
Compounds of formula (I)
In one embodiment, the present invention provides a compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt comprising the structure of formula (I):
Wherein:
R a and R b are each independently substituted with a group selected from H, deuterium, halogen, hydroxy, C 1-6 alkoxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -CONH 2、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
n is 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 substituted with a group selected from H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, C 1-6 alkoxy, mercapto, C 1-6 alkylmercapto, amino, -CONH 2、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r x、Ry、Rz is each independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 1-6 alkoxyalkyl, PEG, oxyanion; the above-mentioned C 1-6 alkyl, C 3-10 cycloalkyl, 3-to 10-membered heterocyclyl, C 1-6 alkoxyalkyl, PEG may also be optionally substituted with one or more hydroxy, C 1-6 alkoxy, amino, alkylamino, amidino, guanidino, azido, halogen, carboxylic acid, ester, amide, sulfonic acid, sulfonamide, phosphoric acid, phosphate, phosphoramide, phosphoramidate, C 6-10 aryl, 5-to 10-membered heteroaryl;
Or any two of R x、Ry and R z form a ring with the nitrogen atom, and the ring is a 4-8 membered heterocycle;
r e may be selected from:
wherein the bond extending to the left in the above group for R e represents that the group is bonded to the remainder of the molecule of formula (I), namely:
r e may be selected from:
The salt is selected from pharmaceutically acceptable salts thereof including, but not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate.
In a preferred embodiment of the invention, R a and R b are each independently selected from H, deuterium, 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, deuterium.
In a preferred embodiment of the invention, p is any integer from 2 to 4, i.e. p=2, 3 or 4.
In a preferred embodiment of the invention, R c and R d are each independently substituted with a group selected from H, deuterium, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; more preferably, R c and R d are each independently selected from H, deuterium, C 1-6 alkyl; h, deuterium, C 1-4 alkyl are further preferred. Still more preferably, R c and R d are each independently selected from H, deuterium, 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.
In a preferred embodiment of the invention, each R x、Ry、Rz is independently selected from the following substituents: c 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 1-6 alkoxyalkyl, PEG, oxyanion; more preferably, each R x、Ry、Rz is independently selected from C 1-6 alkyl; more preferably, each R x、Ry、Rz is independently selected from C 1-4 alkyl. More preferably, R x、Ry、Rz is methyl. In a preferred embodiment of the invention, R e is selected from:
More preferably, R e is
Wherein the bond extending to the left in the structure described above for R e indicates that the structure is bonded to the remainder of the molecule of formula (I), namely:
R e is selected from:
More preferably, R e is
In a preferred embodiment of the present invention, the salt is selected from pharmaceutically acceptable salts thereof including, but not limited to, acetate, hydrochloride, trifluoroacetate.
In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt comprising the structure of formula II:
Wherein: r x、Ry、Rz、Re, p are as defined above.
In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt comprising the structure of formula II-1:
In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, is an acetate, hydrochloride or trifluoroacetate salt comprising the structure of formula II-1.
In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt comprising the structure of formula II-2:
In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, is an acetate, hydrochloride or trifluoroacetate salt comprising the structure of formula II-2.
In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt comprising the structure of formula II-3:
In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, is an acetate, hydrochloride or trifluoroacetate salt comprising the structure of formula II-3.
Preparation method
In another aspect, there is provided a process for the preparation of a compound of the invention, which is a salt comprising the structure of formula (I), selected from the following processes:
The method comprises the following steps:
Step one: coupling the resin with a terminal carboxyl compound under alkaline conditions; the base includes, but is not limited to, organic bases and inorganic bases, preferably DIEA, TEA, NMM;
step two: removing Fmoc protection in a DMF solution of piperidine;
Step three: using Fmoc-protected D-amino acid as a substrate, and coupling with peptide resin successively under the action of a coupling agent; such coupling agents include, but are not limited to: HATU, HBTU, EDCI, pyBOP, CDI, HOBT;
step four: removing Fmoc protection in a DMF solution of piperidine;
Step five: using Fmoc-protected D-amino acid as a substrate, and coupling with peptide resin successively under the action of a coupling agent; such coupling agents include, but are not limited to: HATU, HBTU, EDCI, pyBOP, CDI, HOBT;
step six: removing Fmoc protection in a DMF solution of piperidine;
Step seven: using Fmoc-protected D-amino acid as a substrate, and coupling with peptide resin successively under the action of a coupling agent; such coupling agents include, but are not limited to: HATU, HBTU, EDCI, pyBOP, CDI, HOBT;
Step eight: removing Fmoc protection in a DMF solution of piperidine;
Step nine: using Fmoc-protected D-amino acid as a substrate, and coupling with peptide resin successively under the action of a coupling agent; such coupling agents include, but are not limited to: HATU, HBTU, EDCI, pyBOP, CDI, HOBT;
Step ten: removing Fmoc protection in a DMF solution of piperidine;
Step eleven: under acidic conditions, peptide resin is completely cracked to obtain a compound, wherein the compound is a salt containing a structure shown in a formula I; the compound is subjected to HPLC purification and salt conversion to obtain the salt of the compound.
Wherein the-A-COOH group is a R e group, said R e (which is blocked by a suitable protecting group if there is a free amino group) being selected from the following structures:
Wherein the bond extending to the left in the structure described above for R e indicates that the structure is bonded to the remainder of the molecule of formula (I), namely: r e (which is blocked by a suitable protecting group if any) is selected from the following structures:
the remaining groups are as defined above.
The second method is as follows:
step one: the general formula compound i-1 and amino acid ester are subjected to condensation reaction to obtain a general formula compound i-2;
step two: the compound i-2 of the general formula is subjected to hydrolysis reaction and condensation reaction to obtain a compound i-3 of the general formula;
step three: the compound i-3 with the general formula is subjected to hydrolysis reaction and condensation reaction to obtain a compound i-4 with the general formula;
step four: the compound i-4 with the general formula is subjected to hydrolysis reaction and condensation reaction to obtain a compound i-5 with the general formula;
step five: deprotecting a compound I-5 shown in the general formula to obtain a compound, wherein the compound is a salt containing a structure shown in the formula (I);
Wherein R e (which is blocked by a suitable protecting group if there is a free amino group) is selected from:
Wherein the bond extending to the left in the structure described above for R e indicates that the structure is bonded to the remainder of the molecule of formula (I), namely: r e (which is blocked by a suitable protecting group if any) is selected from:
Wherein PG is an amino protecting group including, but not limited to, alkoxycarbonyl, acyl, alkyl amino protecting groups; for example: t-butoxycarbonyl, benzyloxycarbonyl, benzyl, fluorenylmethoxycarbonyl, Etc.;
the remaining groups are as defined above.
In some preferred embodiments, the condensation reaction is to dissolve the substrate in a solvent (including but not limited to dichloromethane, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or a single or mixed solvent), add a condensing agent (including but not limited to HATU, HBTU, EDCI, pyBOP, CDI, HOBT) at a suitable temperature (-30 ℃ C. To 30 ℃ C.), an auxiliary material (including but not limited to copper chloride, copper chloride dihydrate, copper chloride other hydrates), and a base (including but not limited to organic and inorganic bases, preferably N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine), and react with the corresponding amino acid ester for a suitable time to obtain the target product with high optical purity.
In some preferred embodiments, the hydrolysis reaction is a reaction of the substrate in a solvent (including but not limited to tetrahydrofuran, methanol, ethanol, water, acetone, diethyl ether, methyl t-butyl ether, single or mixed solvents) at a suitable temperature (-30 ℃ C. To 30 ℃ C.) with a base (including but not limited to organic and inorganic bases, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide) to yield the corresponding hydrolysis product.
In some preferred embodiments, the deprotection reaction is carried out in the presence of a deprotection reagent at room temperature or with heating. Preferred deprotecting reagents include hydrogen, acidic reagents such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., or basic reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide, piperidine, etc. One skilled in the art can make appropriate selections and manipulations with reference to textbooks Greene's Protective Groups in Organic Synthesis (4 th Edition) and the like commonly used in the art to remove one or more protecting groups.
Pharmaceutical compositions and methods of treatment
In another aspect, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers. In another embodiment, the pharmaceutical composition may further comprise one or more other therapeutic agents, for example, other therapeutic agents for preventing or treating kappa opioid receptor-associated diseases.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may 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, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation or by inhalation.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.
Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.
The term "effective amount" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the disorder being treated.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is 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 or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, this amounts to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.
The compounds of the invention may be present in the pharmaceutical composition in an amount or in an amount of from about 0.01mg to about 1000mg, suitably from 0.1 to 500mg, preferably from 0.5 to 300mg, more preferably from 1 to 150mg, particularly preferably from 1 to 50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg etc.
As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such disorder or condition, or one or more symptoms of such disorder or condition to which such term applies.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
In another embodiment, the pharmaceutical 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 (e.g., morphine, fentanyl, oxymorphone, or oxycodone), antidepressants, anticonvulsants, tranquilizers, antihistamines, ion channel blockers, non-steroidal anti-inflammatory drugs, diuretics, and the like.
In another aspect, the invention provides the use of a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a 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.
In another aspect, the invention provides a compound of the invention, or a pharmaceutical composition comprising the same, for use in the prevention or treatment of a disease associated with kappa opioid receptors.
In another aspect, the invention provides a method of preventing or treating a disease associated with kappa opioid receptors, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition comprising the same.
The kappa opioid receptor-associated diseases described herein are selected from pain, inflammation, itching, edema, hyponatremia, hypokalemia, ileus, 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, post-medical treatment pain, ocular pain, otitis pain, cancer pain and pain associated with gastrointestinal disorders.
In another aspect, the invention provides the use of a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention, for the preparation of a reagent, wherein the reagent is used to increase kappa opioid receptor levels or activity in a cell.
In some preferred embodiments, the cell is a cell line or a cell from a subject.
In some preferred embodiments, the compounds, or stereoisomers, polymorphs, solvates, or metabolites, prodrugs or pharmaceutically acceptable salts or esters thereof, or the pharmaceutical compositions described herein are used in vivo methods.
In some preferred embodiments, the compounds, or stereoisomers, polymorphs, solvates, or metabolites, prodrugs or pharmaceutically acceptable salts or esters thereof, or the pharmaceutical compositions described herein are used in an in vitro method.
In another aspect, the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate, or metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention, for use in increasing kappa opioid receptor levels or activity in a cell.
In some preferred embodiments, the cell is a cell line or a cell from a subject.
In some preferred embodiments, the compounds, or stereoisomers, polymorphs, solvates, or metabolites, prodrugs or pharmaceutically acceptable salts or esters thereof, or the pharmaceutical compositions described herein are used in vivo methods.
In some preferred embodiments, the compounds, or stereoisomers, polymorphs, solvates, or metabolites, prodrugs or pharmaceutically acceptable salts or esters thereof, or the pharmaceutical compositions described herein are used in an in vitro method.
In another aspect, 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 as described herein, or a stereoisomer, polymorph, solvate, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition as described herein.
In some preferred embodiments, the cell is a cell line or a cell from a subject.
In some preferred embodiments, the method is performed in vivo.
In some preferred embodiments, the method is performed in vitro.
Advantageous technical effects
The compounds of the invention have less penetration of the blood brain barrier and less ability to enter the brain. In some preferred embodiments, the compounds of the invention have reduced toxic side effects on the central nervous system at concentrations effective to achieve peripheral analgesic effects.
When the compounds of the present invention are administered to an individual in need thereof at prophylactically or therapeutically effective concentrations, they exhibit little or no ability to penetrate the blood brain barrier. Kappa opioid receptors (hereinafter also interchangeably referred to as kappa receptors) are distributed in peripheral tissues (including skin and somatic tissues) and viscera of humans or other mammals. Kappa receptors have also been found to be present in the brain. Activation of kappa receptors in peripheral tissues can cause pain and inhibition of inflammatory responses, while activation of kappa receptors in the brain causes sedative effects and can also lead to severe dysphoria and hallucinations. In certain embodiments, the compounds of the present invention exhibit substantially no penetration of the blood brain barrier when administered in an effective amount, thereby minimizing or even completely eliminating the sedative and phantom effects of many other kappa agonists that have some penetration of the blood brain barrier.
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Embodiment one:
(R) -5- ((R) -2- ((R) -2- ((R) -2-amino-3-phenylpropionamido) -4-methylpentanoylamino) -6- (4-amino-4-carboxypiperidin-1-yl) -N, N, N-trimethyl-6-oxohexanoyl-1-ammonium salt (formula II-1), compound 1 is the trifluoroacetate salt of formula II-1
The reaction scheme for example one is as follows:
step one:
1.00g of 2-CTC Resin was weighed into a polypeptide reactor, 8ml of methylene chloride was added to swell for 1 hour, and the excess solvent was then removed. SM-2 (1.02 g,2.20 mmol) was dissolved in 30ml of dichloromethane, DIEA (0.42 g) was added under ice-bath, stirred for 10 min, and finally added to the polypeptide reactor and reacted for 1.5 h under nitrogen. After the reaction was completed, 5ml of methanol was added to react for 0.5 hours. The solvent was drained, washed with dichloromethane (20 ml) and then DMF (20 ml) and drained and used directly in the next reaction.
Step two:
10ml of piperidine/DMF (V: V=1:3) was added to the polypeptide reactor, the liquid was withdrawn after 5 minutes of reaction, 10ml of piperidine/DMF (V: V=1:3) was added again, and the liquid was withdrawn after 15 minutes of reaction. The resin was washed with DMF and the last wash was checked with pH paper and shown to be neutral and used directly in the next reaction.
Step three:
SM-5 (ref 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), HOBT (0.37 g,2.2 mmol) and HBTU (0.86 g,2.20 mmol) were added at 0deg.C, reacted for 5min, DIEA (0.28 g,2.20 mmol) was added, and reacted for 5min at 0deg.C. The reaction solution was added to the solid phase reactor and reacted for 1 hour, the resin was developed with ninhydrin (heated to 110 ℃ C.), the resin was not colored, the reaction was completed, the liquid was withdrawn, washed with DMF and directly used for the next reaction.
Step four:
20ml of piperidine/DMF (V: V=1:3) was added to the solid phase reactor, the reaction was withdrawn for 5 minutes, and 20ml of piperidine/DMF (V: V=1:3) was added thereto, and the reaction was withdrawn for 15 minutes. The resin was washed with DMF and the final wash effluent was checked with pH paper and shown to be neutral and used directly in the next reaction.
Step five:
SM-8 (Fmoc-D-Leu-OH) (0.78 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) were added at 0deg.C, reacted for 5min, and DIEA (0.28 g,2.20 mmol) was added and reacted for 5min at 0deg.C. The reaction solution was added to the solid phase reactor and reacted for 1 hour, the resin was developed with ninhydrin (heated to 110 ℃ C.), the resin was not colored, the reaction was completed, the liquid was withdrawn, washed with DMF and directly used for the next reaction.
Step six:
20ml of piperidine/DMF (V: V=1:3) was added to the solid phase reactor, the reaction was withdrawn for 5 minutes, and 20ml of piperidine/DMF (V: V=1:3) was added thereto, and the reaction was withdrawn for 15 minutes. The resin was washed with DMF and the final wash effluent was checked with pH paper and shown to be neutral and used directly in the next reaction.
Step seven:
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) were added at 0deg.C, reacted for 5min, and DIEA (0.28 g,2.20 mmol) was added and reacted for 5min at 0deg.C. The reaction solution was added to the solid phase reactor and reacted for 1 hour, the resin was developed with ninhydrin (heated to 110 ℃ C.), the resin was not colored, the reaction was completed, the liquid was withdrawn, washed with DMF and directly used for the next reaction.
Step eight:
20ml of piperidine/DMF (V: V=1:3) was added to the solid phase reactor, the reaction was withdrawn for 5 minutes, and 20ml of piperidine/DMF (V: V=1:3) was added thereto, and the reaction was withdrawn for 15 minutes. The resin was washed with DMF and the final wash effluent was checked with pH paper and shown to be neutral and used directly in the next reaction.
Step nine:
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) were added at 0deg.C, reacted for 5min, and DIEA (0.28 g,2.20 mmol) was added and reacted for 5min at 0deg.C. The reaction mixture was added to a solid phase reactor and reacted for 1 hour, the resin was developed with ninhydrin (heated to 110 ℃ C.), the resin did not change color, the reaction was completed, the liquid was withdrawn, and washed with DMF. The resin was taken out and dried in vacuo and used directly in the next reaction.
Step ten:
20ml of piperidine/DMF (V: V=1:3) was added to the solid phase reactor, the reaction was withdrawn for 5 minutes, and 20ml of piperidine/DMF (V: V=1:3) was added thereto, and the reaction was withdrawn for 15 minutes. The resin was washed with DMF and the final wash effluent was checked with pH paper and shown to be neutral. The resin was used directly in the next reaction.
Step eleven:
the dried resin was placed in a solid phase reactor and TFA (50 ml, 5% water) was added, the reaction was carried out for 1 hour, the liquid was withdrawn, TFA (50 ml, 5% water) was added, the reaction was carried out for 0.5 hour, and the liquid was withdrawn. The TFA solutions were combined and spin-dried to give 1.2g of crude product. Preparative HPLC gave 88mg (purity: 97.6%) of the product as trifluoroacetate salt having the structure of formula II-1 (Compound 1).
ESI-MS(m/z):723.4
1H NMR(400MHz,DMSO-d6)δ7.34-7.22(m,10H),4.81-4.61(m,2H),4.36-4.29(m,1H),4.05-3.95,(m,1H),3.80-3.62(m,4H),3.30-3.29(m,2H),3.28-3.05(m,3H),3.05-2.95(s,9H),2.96-2.81(m,1H),2.15-1.80(m,2H),1.80-1.55(m,6H),1.55-1.40(m,3H),1.39-1.25(m,2H),0.86-0.81(m,6H).
Example two
The trifluoroacetate salt having the structure of formula II-1 obtained in example I was converted to an acetate salt having the structure of formula II-1 by HPLC.
Biological experiments
1. Experiment on kappa opioid receptor agonism potency
The potency of the compounds of the invention as kappa opioid receptor agonists was determined by measuring the inhibition of adenylate cyclase activity by the compounds of the examples.
Cell culture: hamster ovary cells CHO stably expressing the human Kappa Opioid Receptor (KOR) gene were cultured in MEMa plus nucleosides% FBS-containing medium (Invitrogen).
Stimulation: the test compound was diluted to 11 concentration gradients at 4-fold gradient, transferred to 100nl to 384 well plates, then a stimulus solution (5 uL) containing NKH477 (Tocris) was added, cells were digested, resuspended, counted, 5uL added thereto, gently mixed, and incubated at 37 ℃ for 30 minutes.
And (3) detection: cAMP D 2 and anti-cAMP compound conjugate were added separately using cAMP detection kit (Cisbio) according to instructions and incubated for 1 hour at room temperature. EC 50 was obtained using envision (Perkin Elmer) read plates and fitting using a four parameter equation.
Test results
Examples numbering EC50(pM)
Example 1 25
The results can be seen by the above EC 50: the compounds of the examples of the present invention have excellent agonistic potency at the kappa opioid receptor. Other compounds of the invention have similarly excellent agonistic potency at the kappa opioid receptor.
2. Rat PK experiment
Male SD rats were given 1mg/kg and 20mg/kg of Compound one by intravenous Injection (IV), with vehicle medium being 10mM sodium acetate buffer (pH 4.5.+ -. 0.2) containing sodium chloride. Whole blood and brain tissue were collected at various time points after IV administration. And (3) centrifuging whole blood to obtain plasma, adding physiological saline into brain tissue to prepare brain tissue homogenate, and carrying out LC-MS/MS analysis after the plasma and the brain tissue homogenate are treated by precipitated proteins.
The mass spectrometer model was API 5500 and the liquid chromatograph model was Waters ACQUITY I CLASS systems. The column was Thermo Hypersil Gold C column (50 x 2.1mm,1.9 μm); mobile phase A is 0.2% formic acid water solution, mobile phase B is acetonitrile; the flow rate was 0.4mL/min and the column temperature was 40 ℃. The adopted ion source is ESI source positive ion mode, and the scanning mode is Multiple Reaction Monitoring (MRM).
Test results
As can be seen from the table, the compound of the example I has obvious difference in exposure amount in rat blood and brain under the condition of intravenous injection administration of 20mg/kg, has obvious peripheral selectivity and has brain input amount of <0.03%.
Abbreviations in the present invention have the following meanings:
Various modifications of the application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims (7)

1. A short peptide quaternary ammonium salt compound, wherein the compound is trifluoroacetate salt containing a structure shown in a formula II-1:
2. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of claim 1 and one or more pharmaceutically acceptable carriers.
3. The pharmaceutical composition according to claim 2, which is administered by the oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or transdermal route.
4. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 2 or 3 for the manufacture of a medicament for the prevention or treatment of a kappa opioid receptor-associated disorder selected from pain, inflammation and itch.
5. The use of claim 4, wherein the pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain, and skin pain.
6. The use of claim 4, wherein the pain is selected from the group consisting of arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-medical treatment pain, ocular pain, otitis pain, cancer pain, and pain associated with gastrointestinal disorders.
7. The use of claim 4, wherein the pain is selected from post-surgical pain.
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