WO2019144805A1 - Composé phényléthylamine substitué et son procédé de préparation et son utilisation - Google Patents

Composé phényléthylamine substitué et son procédé de préparation et son utilisation Download PDF

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WO2019144805A1
WO2019144805A1 PCT/CN2019/071063 CN2019071063W WO2019144805A1 WO 2019144805 A1 WO2019144805 A1 WO 2019144805A1 CN 2019071063 W CN2019071063 W CN 2019071063W WO 2019144805 A1 WO2019144805 A1 WO 2019144805A1
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alkyl
alkylene
group
compound
cycloalkyl
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PCT/CN2019/071063
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Chinese (zh)
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朱加望
宋智泉
郝小余
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Publication of WO2019144805A1 publication Critical patent/WO2019144805A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/45—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing nine carbon atoms
    • C07C13/465—Indenes; Completely or partially hydrogenated indenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/47—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing ten carbon atoms
    • C07C13/48—Completely or partially hydrogenated naphthalenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/02—Monocyclic hydrocarbons
    • C07C15/04—Benzene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

Definitions

  • the present invention relates to a substituted phenethylamine compound as a ⁇ opioid receptor agonist, a pharmaceutical composition comprising the same, a process for the preparation thereof, and a medicament for preventing and/or treating a mu opioid receptor (including but not limited to pain) The use of the disease).
  • drugs for the treatment of pain include non-steroidal anti-infectives, opioid agonists, calcium channel blockers, antidepressants, etc., which have a certain effect in controlling pain, but also bring a lot of A worrying side effect, so finding a safe and effective treatment for pain remains an unfinished and challenging R&D goal.
  • Opioids are a class of drugs that are effective in the treatment of pain, especially in the treatment of moderate and severe pain.
  • opioids have serious side effects such as tolerance, addiction, respiratory depression, nausea, and constipation (Williams, JT et al., Pharacol. Rev., 65, 223-254 (2013)), and are also abused. social problem.
  • Opioids activate transmembrane opioid G-protein coupled receptors (GPCRs), and subtypes of this receptor include ⁇ opioid receptor ( ⁇ OR), kappa opioid receptor ( ⁇ OR), and ⁇ opioid Receptor ( ⁇ opioid receptor, ⁇ OR), opioid receptors, etc. and their subtypes.
  • GPCRs G-protein coupled receptors
  • opioid receptor agonists Most of the opioid receptor agonists currently in clinical use are derivatives of morphine, small molecule compounds and peptide compounds, their selectivity for subtypes, selectivity for related GPCRs, and drug distribution and metabolism in vivo. They all have a certain relationship with the efficacy and side effects.
  • the present invention provides a novel substituted phenethylamine compound for use as a ⁇ opioid receptor agonist, which has excellent agonistic activity against ⁇ opioid receptors and weaker recruitment of ⁇ -repressor protein, and has better The drug-making properties of painkillers.
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug wherein the compound has the structure of formula (I):
  • R 3a , R 3b , R 4 , R 6a , R 6b , R 7a , R 7b , R 8 , R 9a , R 9b , R 10a and R 10b are each independently selected from H, halogen, - at each occurrence.
  • A is selected from the group consisting of a C 6-14 aromatic ring and a 5-14 membered heteroaryl ring;
  • alkyl, alkylene, cycloalkyl, alkenyl, nitrogen-containing heterocyclic, heterocyclic, aryl, aromatic, heteroaryl and heteroaryl rings are each optionally independently selected by one or more of them.
  • R h is each independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 , each occurrence.
  • An aryl group and a 5-10 membered heteroaryl group, and the plurality of Rh groups may be the same or different from each other;
  • g each independently represents an integer of 0, 1 or 2 at each occurrence;
  • n each independently represents any integer in 1-10, including the end value
  • n, p and q are each independently an integer of 0, 1, 2, 3 or 4.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, a solvate, an N-oxide, an isotope-labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous state preparation.
  • Another aspect of the invention provides a method of preparing a pharmaceutical composition of the invention, which comprises administering a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polycrystal thereof, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable salt for example, a pharmaceutically acceptable salt of a pharmaceutical composition of the invention.
  • the form, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or mixtures thereof, are combined with one or more pharmaceutically acceptable carriers.
  • kits comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxidation thereof, or a pharmaceutically acceptable salt thereof a compound, an isotope-labeled compound, a metabolite or a prodrug or a mixture thereof, or a pharmaceutical composition of the invention.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled
  • a compound, metabolite or prodrug or a pharmaceutical composition of the invention for the preparation of a medicament for the prevention or treatment of a mu opioid receptor-associated disease.
  • the medicament is for preventing or treating a painful disease.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled A compound, metabolite or prodrug or a pharmaceutical composition of the invention for use in the prevention or treatment of a mu opioid receptor-associated disease.
  • Another aspect of the invention provides a method of preventing or treating a mu opioid receptor-associated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, A construct, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug or a pharmaceutical composition of the invention.
  • the above-mentioned ⁇ opioid receptor-related diseases include, but are not limited to, pain-related diseases, and the diseases are further preferably moderate-to-severe pain-like diseases.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group.
  • C1-6 alkyl refers to a straight or branched chain hydrocarbon radical having from 1 to 6 carbon atoms.
  • alkylene refers to a saturated straight or branched divalent hydrocarbon group.
  • C1-6 alkylene refers to a straight or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms.
  • methylene, ethylene, propylene or butylene For example, methylene, ethylene, propylene or butylene.
  • haloalkyl refers to an alkyl group, optionally substituted with one or more (such as 1 to 3) halo.
  • halo C 1-6 alkyl refers to optionally substituted with one or more (such as one to three) halogen substituted C 1-6 alkyl group.
  • alkenyl refers to a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds.
  • C 2-6 alkenyl refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds, preferably containing one carbon carbon. Double bond C 2-6 alkenyl.
  • vinyl 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).
  • cyclooctyl cyclodecyl, 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] anthracenyl, decahydronaphthyl, etc.)), which is optionally substituted by one or more (such as 1 to 3) suitable substituents.
  • the cycloalkyl group may have 3 to 10 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl or ring). Hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • hydrocarbon ring refers to a saturated or unsaturated (ie, in the ring) having, for example, 5-10 (suitably 5-8, more suitably 5-6) ring carbon atoms.
  • One or more double bonds and/or triple bonds) monocyclic or polycyclic hydrocarbon rings including, but not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclohexyl rings, cycloheptyl rings, rings An octyl ring, a cyclononyl ring, a cyclohexenyl ring, and the like.
  • heterocyclyl or “heterocycle” as used herein, refers to having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, at least one of which An atom is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie “heterocycloalkyl") or partially unsaturated (ie having one or more double bonds and/or three in the ring) A cyclic group, which is optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • 3-10 membered heterocyclyl is taken to have 2-9 (eg, 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and independently selected A saturated or partially unsaturated heterocyclic group of one or more (e.g., 1, 2, 3 or 4) heteroatoms of N, O and S.
  • heterocyclic or heterocyclic rings include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxane Alkenyl (dioxolinyl), pyrrolidinyl, pyrrolidinone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, sulfur? A phenyl group, a piperazinyl group or a trithianyl group.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6-14 aryl or “C 6-14 aromatic ring” refers to an aromatic group containing from 6 to 14 carbon atoms, such as phenyl (cyclo) or naphthyl ( ring).
  • the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • heteroaryl or “heteroaryl ring” as used herein, refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one hetero atom selected from N, O and S, which preferably has 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular containing 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and additionally in each case It can be benzofused.
  • the heteroaryl or heteroaryl ring may be selected from the group consisting of thienyl (cyclo), furyl (cyclo), pyrrolyl (cyclo), oxazolyl (cyclo), thiazolyl (cyclo), imidazolyl (cyclo), pyridyl Azolyl (cyclo), isoxazolyl (cyclo), isothiazolyl (cyclo), oxadiazolyl (cyclo), triazolyl (cyclo), thiadiazolyl (ring), etc., and their benzo a derivative; or a pyridyl group (cyclo), a pyridazinyl group (cyclo), a pyrimidinyl group (cyclo), a pyrazinyl group (cyclo), a triazinyl group (ring), and the like, and a benzo derivative thereof.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • nitrogen-containing heterocycles include, but are not limited to, aziridine rings, azetidine rings, pyrrolidine rings, imidazolidine rings, oxazolidine rings, thiazolidine rings, pyrazolidine rings, pyrroline rings, and piperidines.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present.
  • the normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium (2 H), tritium (3 H)); isotopes of carbon (e.g.
  • Chlorine isotope eg 36 Cl
  • fluorine isotopes eg 18 F
  • iodine isotopes eg 123 I and 125 I
  • nitrogen isotopes eg 13 N and 15 N
  • oxygen isotopes eg 15 O
  • phosphorus isotope eg 32 P
  • sulfur isotope eg 35 S
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • a compound having one or more (eg, one, two, three or four) asymmetric centers it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and 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.
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • the chemical bonds of the compounds of the invention are depicted.
  • the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown.
  • solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • 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, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof
  • the compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug.
  • 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 hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.
  • 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).
  • the compounds of the invention may also be esters per se.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • N-oxides are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • the synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
  • MCPBA chloroperoxybenzoic acid
  • Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In 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 T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein the compound has the structure of formula (I):
  • R 3a , R 3b , R 4 , R 6a , R 6b , R 7a , R 7b , R 8 , R 9a , R 9b , R 10a and R 10b are each independently selected from H, halogen, - at each occurrence.
  • A is selected from the group consisting of a C 6-14 aromatic ring and a 5-14 membered heteroaryl ring;
  • alkyl, alkylene, cycloalkyl, alkenyl, nitrogen-containing heterocyclic, heterocyclic, aryl, aromatic, heteroaryl and heteroaryl rings are each optionally independently selected by one or more of them.
  • R h is each independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 , each occurrence.
  • An aryl group and a 5-10 membered heteroaryl group, and the plurality of Rh groups may be the same or different from each other;
  • g each independently represents an integer of 0, 1 or 2 at each occurrence;
  • n each independently represents any integer in 1-10, including the end value
  • n, p and q are each independently an integer of 0, 1, 2, 3 or 4.
  • each occurrence of R 2 is independently selected from the group consisting of H, halogen, —CF 3 , —CHF 2 , —OH, —OCF 3 , —OCHF 2 , —O(C 1-4 alkane).
  • each occurrence of R 2 is independently selected from the group consisting of H, F, Cl, -OH, -CF 3 , -OCF 3 , -OCH 3 , cyano, C 1-4 alkyl , C 3-6 cycloalkyl, -(C 1-4 alkylene)-O-(C 1-4 alkyl), -O-[(C 1-4 alkylene)-O] m - ( C 1-4 alkyl), -NH 2 , -NH(C 1-4 alkyl) and -N(C 1-4 alkyl) 2 ; wherein m is an integer of 1, 2, 3 or 4.
  • R 2 is each independently selected from the group consisting of H, F, Cl, -OH, -CF 3 , -OCF 3 , -OCH 3 , C 1-3 alkyl, -( C 1-3 alkylene)-O-(C 1-3 alkyl), -O-(C 1-3 alkylene)-O-(C 1-3 alkyl) and -N(C 1- 3 alkyl) 2 .
  • R 3a , R 3b , R 4 , R 6a , R 6b , R 7a , R 7b , R 8 , R 9a , R 9b , R 10a and R 10b are each independently present at each occurrence.
  • R 3a , R 3b , R 4 , R 6a , R 6b , R 7a , R 7b , R 8 , R 9a , R 9b , R 10a and R 10b are each independently present at each occurrence Selected from H, F, Cl, cyano, C 1-4 alkyl (preferably C 1-3 alkyl, more preferably methyl), C 3-6 cycloalkyl, -CF 3 , -CHF 2 , - OH, -OCF 3 , -OCHF 2 , -(C 1-3 alkylene)-O-(C 1-3 alkyl), -O-[(C 1-4 alkylene)-O] m - (C 1-4 alkyl) (preferably -O-(C 1-4 alkylene)-O-(C 1-4 alkyl)), -NH 2 , -NH(C 1-4 alkyl) ( Preferred is -NH(C 1-3 alkyl)),
  • R 5a and R 5b are each independently selected from H, F, Cl, -OH, -O- (C 1 - 4 alkyl) (preferably -O- (C 1-3 alkyl) ), C 1-6 alkyl (preferably C 1-4 alkyl, more preferably methyl or ethyl), C 3-6 cycloalkyl, -C 1-4 alkylene-OH (preferably -C 1- 3 alkylene-OH), C 2-5 alkenyl (preferably vinyl, propenyl or allyl), -O-[(C 1-4 alkylene)-O] m - (C 1-4 Alkyl) and a 3-6 membered heterocyclic group; or, R 5a and R 5b together with the nitrogen atom to which they are attached form a 5-7 membered nitrogen-containing heterocyclic ring (preferably a 5-6 membered nitrogen-containing heterocyclic ring); m is an integer of 1 or 2; and the alkyl, alkylene, cycloalkyl,
  • the base, cycloalkyl and heterocyclic groups are each optionally one or more independently selected from the group consisting of F, Cl, -CF 3 , -CHF 2 , -OH, -OCF 3 , -OCHF 2 , C 1-4 Alkyl, C 3-6 cycloal
  • R 11a and R 11b are each independently selected from H, F, Cl, cyano, C 1-4 alkyl (preferably C 1-3 alkyl, more preferably methyl or ethyl) , C 3-6 cycloalkyl, -CF 3 , -CHF 2 , -OH, -OCF 3 , -OCHF 2 , -(C 1-3 alkylene)-O-(C 1-3 alkyl), -O-[(C 1-4 alkylene)-O] m -(C 1-4 alkyl) (preferably -O-(C 1-3 alkylene)-O-(C 1-3 alkyl) )), -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -COOH and -CONH 2 ; m is an integer of 1 or 2.
  • A is selected from the group consisting of a benzene ring and a 5-6 membered heteroaryl ring. In a more preferred embodiment, A is a benzene ring, a thiophene ring, a pyrazine ring, a pyrimidine ring or a pyridine ring.
  • R 12 is each independently selected from the group consisting of H, halo, -CF 3 , -CHF 2 , -OH, -O-(C 1-4 alkyl), -OCF 3 , -OCHF 2 , cyano, C 1-4 alkyl, C 3-6 cycloalkyl, -COOH, -CONH 2 , -(C 1-4 alkylene)-O-(C 1-4 alkyl) , -O-[(C 1-4 alkylene)-O] m -(C 1-4 alkyl), -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 Alkyl) 2 and 3-6 membered heterocyclic groups; and m is an integer of 1, 2, 3 or 4.
  • R 12 is each independently selected from the group consisting of H, F, Cl, Br, -OH, -O-(C 1-3 alkyl), -CF 3 , -OCF 3 , cyano, C 1-3 alkyl, C 3-6 cycloalkyl, -(C 1-4 alkylene)-O-(C 1-4 alkyl), -O-[(C 1-3 Alkylene)-O] m -(C 1-3 alkyl), -NH 2 , -NH(C 1-3 alkyl) and -N(C 1-3 alkyl) 2 ; more preferably, R 12 is each independently selected from the group consisting of H, F, Cl, -OH, -O-(C 1-3 alkyl), -CF 3 , -OCF 3 , cyano, C 1-3 alkyl, C 3-6 cycloalkyl, -(C 1-4 alkylene)-O-(C 1-4 alkyl), -O-
  • R 12 is each independently selected from the group consisting of H, F, Cl, Br, -OH, -CF 3 , -OCF 3 , cyano, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -O-CH(CH 3 ) 2 , -(C 1-3 alkylene)-O-(C 1-3 alkyl), -O-( C 1-3 alkylene)-O-(C 1-3 alkyl) and -N(C 1-3 alkyl) 2 ; more preferably, R 12 is each independently selected from H, in each occurrence F, Cl, -OH, -CF 3 , -OCF 3 , cyano, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -O-CH(CH 3 ) 2 , -(C 1-3 alkylene)-O-(C 1-3 alkylene)-
  • n is an integer of 0, 1, 2 or 3. In a more preferred embodiment, n is an integer of 0, 1 or 2.
  • p is an integer of 0, 1, 2 or 3. In a more preferred embodiment, p is 0 or 1.
  • q is an integer of 0, 1, 2 or 3. In a more preferred embodiment, q is 0, 1 or 2.
  • the compounds of the invention have the structure of formula (II):
  • n is an integer of 0, 1, or 2;
  • the compound of the invention has the structure of formula (II'):
  • n is an integer of 0, 1, or 2;
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled a compound, metabolite or prodrug, wherein the compound is selected from the group consisting 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation Or a gaseous preparation.
  • the pharmaceutically acceptable carrier as used herein refers to an excipient and an additive used in the manufacture of a pharmaceutical preparation and formulation, and refers to a reasonable evaluation of safety in addition to the active ingredient, and is included in the pharmaceutical preparation.
  • the pharmaceutically acceptable carrier can be used for prototyping, acting as a carrier, improving stability, and having important functions such as solubilization, solubilization, slow release and release, and is important for affecting the quality, safety and effectiveness of the drug. ingredient. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants osmotic pressure regulator
  • flavoring agents preservatives
  • suspending agents coating materials
  • fragrances anti
  • Specific pharmaceutically acceptable carriers include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate, calcium phosphate , cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and the like.
  • the pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms of a human or animal patient.
  • various suitable dosage forms can be prepared depending on the route of administration.
  • the pharmaceutical composition can be formulated into any orally acceptable preparation including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions. Wait.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsules generally includes lactose and dried corn starch.
  • Oral suspensions are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents.
  • suitable emulsifying and suspending agents may also be added to the above oral formulation forms.
  • the pharmaceutical compositions When administered transdermally or topically, the pharmaceutical compositions may be in the form of a suitable ointment, lotion or lozenge, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which can be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and carriers which can be used for lotions or elixirs include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can also be administered in the form of an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the invention provides a pharmaceutical composition further comprising an additional therapeutic agent selected from the group consisting of, but not limited to, non-steroidal anti-infectives, other opioid agonists, calcium ion channels Blocker, antidepressant, or a combination thereof.
  • the invention also includes an article of manufacture.
  • Articles used herein are intended to include, but are not limited to, kits and packages.
  • the article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of the invention or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or mixtures thereof; and (c) packaging
  • the instructions illustrate that the pharmaceutical composition can be used to treat a pain condition (as defined above).
  • the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat a pain condition.
  • the article of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Being located within the first and second containers means that each container retains the item within its boundaries.
  • the first container is a container for containing a pharmaceutical composition. This container can be used for preparation, storage, transportation, and/or stand-alone/bulk sales.
  • the first container is intended to cover bottles, cans, vials, flasks, syringes, tubes (eg for use in cream products), or any other container used to prepare, contain, store or dispense a pharmaceutical product.
  • the second container is a container for containing the first container and optionally a package insert.
  • the second container include, but are not limited to, a box (e.g., a carton or plastic box), a box, a carton, a bag (e.g., a paper bag or a plastic bag), a pouch, and a rag bag.
  • the package insert may be physically adhered to the exterior of the first container via a cable tie, glue, staple or other attachment means, or it may be placed inside the second container without Any physical tool to which the first container adheres.
  • the package insert is located outside of the second container. When located outside of the second container, it is preferred that the package insert is physically adhered via a tie, glue, staple or other attachment means. Alternatively, it may abut or contact the exterior of the second container without physical adhesion.
  • the package insert is a trademark, label, label, etc., which lists information relating to the pharmaceutical composition located within the first container.
  • the information listed is typically determined by the regulatory agency (eg, the US Food and Drug Administration) that governs the area in which the article is to be sold.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved for use.
  • the package insert can be made of any material from which information contained therein or thereon can be read.
  • the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (e.g., printed or applied).
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopic label thereof
  • a compound, metabolite or prodrug, or a mixture thereof, or a pharmaceutical composition of the invention for the manufacture of a medicament for the prevention or treatment of a mu opioid receptor-associated disease.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof A labeled compound, metabolite or prodrug, or a mixture thereof or a pharmaceutical composition of the invention for use in the prevention or treatment of a mu opioid receptor-associated disease.
  • the invention provides a method of preventing or treating a mu opioid receptor-associated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester thereof, Stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the invention.
  • a mu opioid receptor-related disease which can be prevented or treated using the compound of the present invention includes, but is not limited to, a pain-like disease, and the disease is further preferably a moderate to severe pain-like disease.
  • "effective amount&quot refers to an amount of a compound that, after administration, will relieve to some extent one or more symptoms of the condition being treated.
  • 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. The amount of administration and the administration regimen of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical arts.
  • the composition or compound of the present invention is generally administered once a day to once every three days, preferably once a day, and the total amount of administration is from 0.01 to 1000 mg per time.
  • the dosage of the treatment varies, depending on the considerations, such as the age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the symptoms Duration; and other variables that can be adjusted by each physician.
  • the desired dose can be administered one or more times to achieve the desired result.
  • the pharmaceutical composition according to the invention may also be provided in unit dosage form.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing 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.).
  • improved pharmacokinetic properties eg improved bioavailability, appropriate half-life and duration of action
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • Thin layer chromatography was performed using a GF 254 (0.4-0.5 nm) silica gel plate from Yantai.
  • the reaction is monitored by thin layer chromatography (TLC) or LC-MS using a developing solvent system including, but not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, depending on
  • TLC thin layer chromatography
  • LC-MS LC-MS using a developing solvent system including, but not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, depending on
  • the polarity of the compound is adjusted to adjust the volume ratio of the solvent, or triethylamine or the like is added for adjustment.
  • the eluent system includes, but is not limited to, a dichloromethane and methanol system, and a n-hexane and ethyl acetate system.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine or the like.
  • the temperature of the reaction is room temperature (20 ° C to 30 ° C) unless otherwise specified in the examples.
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
  • the compounds of the invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials employed and suitable for effecting the conversion.
  • Those skilled in the art of organic synthesis should be aware that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require the following determination: modify the order of the synthetic steps or route another specific method route relative to one method to obtain the desired compound of the invention.
  • the present invention provides a process for the synthesis of a compound of formula (I) according to the procedure described in Scheme 1.
  • R 1P is the same as R 1 , or R 1P represents R 1 protected by a protecting group;
  • PG 1 and PG 2 each independently represent a carboxy protecting group, such as a C 1-6 alkyl group (preferably methyl or B) And a substituted silane group and a benzyl group;
  • R 5ap is the same as R 5a or R 5ap is an amino protecting group (preferably Boc);
  • R 5bp is the same as R 5b or R 5bp is an amino protecting group (preferably Boc).
  • Step 1 comprises reacting an alkylating agent with compound S-1 in the presence of a base to form compound IM-1.
  • the base is potassium carbonate.
  • the alkylating agent is an alkyl halide.
  • this step comprises reductive amination of the aldehyde and reducing agent with compound S-1 to form compound IM-1.
  • the aldehyde is formaldehyde.
  • the reducing agent is sodium borohydride.
  • this step comprises reacting an acylating reagent with compound S-1 in the presence of a base to form compound IM-1.
  • the base is triethylamine.
  • the acylating agent is (Boc) 2 O.
  • Step 2 comprises reducing the reagent treatment of compound IM-1 to yield compound IM-2.
  • the reducing agent is diisobutylaluminum hydride.
  • this step involves reacting a metal reagent with compound IM-1 to form compound IM-2.
  • the metal reagent is a Grignard reagent.
  • this step comprises the treatment of IM-1 by a reducing reagent treatment and an oxidizing reagent to form compound IM-2.
  • the reducing agent is lithium aluminum hydride.
  • the oxidizing agent is IBX.
  • this step involves the Wittig reaction of the phospho-ylide reagent with compound IM-2 to yield compound IM-3.
  • the phosphorus ylide reagent is ethoxycarbonylmethylenetriphenylphosphine.
  • this step comprises the Adol reaction of the ester with compound IM-2 in the presence of a base to form compound IM-3.
  • the base is sodium hydride.
  • the ester is ethyl acetate.
  • Step 4 comprises the compound IM-3 undergoing a metal catalyzed hydrogenation reaction to form compound IM-4.
  • the metal is Pd/C.
  • the hydrogenation reagent is hydrogen.
  • this step involves the addition reaction of an addition reagent with IM-3 to form compound IM-4.
  • the addition reagent is an alkylamine.
  • Step 5 comprises treating compound IM-4 with a base and an alkylating agent to form compound IM-5.
  • the base is potassium carbonate.
  • the alkylating agent is an alkyl halide.
  • Step 6 comprises reacting IM-5 with a alkylating agent in the presence of a base after deprotection to form compound IM-6.
  • the base is potassium carbonate.
  • the alkylating agent is an alkyl halide.
  • this step comprises reductive amination of IM-5 with a aldehyde and a reducing reagent after deprotection to form compound IM-6.
  • the aldehyde is formaldehyde.
  • the reducing agent is sodium borohydride.
  • this step comprises reacting IM-5 with a acylating reagent in the presence of a base after deprotection to form compound IM-6.
  • the base is triethylamine.
  • the acylating reagent is acetyl chloride.
  • Step 7 comprises treating compound IM-6 with a base for deprotection to yield compound IM-7.
  • the base is sodium hydroxide.
  • the reaction is carried out in a solvent, preferably methanol.
  • Step 8 comprises the compound IM-7 undergoing a condensation reaction in the presence of a condensation reagent followed by a deprotection reaction to form a compound of formula (I).
  • the condensation reagent is HATU.
  • Tyrosine methyl ester (SM-1-1) (10.00 g, 51.2 mmol) was dissolved in dichloromethane (250 mL) at room temperature, respectively, triethylamine (14.20 mL, 102.4 mmol) and (Boc) 2 O (12.93 mL, 56.3 mmol). The reaction was stirred for 4 hours at room temperature. The reactant was concentrated, and the crude product was purified by silica gel column chromatography to afford compound (SM-1-2) (13.20 g, yield 87%).
  • Step 6 Preparation of (R)-4-((tert-Butoxycarbonyl)amino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-7)
  • Step 8 Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-9)
  • Oxalyl chloride (0.64 mL, 7.53 mmol) was added to dichloromethane (5.0 mL) at -78 ° C. After 10 min, a solution of DMSO (1.43 mL, 20 mmol) in dichloromethane (5.0 mL) was added dropwise. After stirring at -78 ° C for 1 hour, a solution of the compound (10-3) (0.9 g, 5.0 mmol) in dichloromethane (5.0 mL) was added dropwise. After stirring at -78 ° C for 1 hour, triethylamine (1.40 mL, 10.0 mmol) was added dropwise to the reaction system. After stirring at -78 °C for 1 hour, it was transferred to EtOAc EtOAc (EtOAc). %), proceed directly to the next step.
  • EtOAc EtOAc EtOAc
  • Step 5 Preparation of (R)-4-(dimethylamino)-5-phenylpentanoic acid ethyl ester (10-6)
  • the title compound (TM14) was synthesized in a similar manner to that described in Example 5 except that in the first step, 2-methoxy-1-bromoethane was used instead of the methyl iodide in the first step of Example 5. .
  • the compound (15-1) is used instead of the compound (SM-1-6) of the sixth step in the embodiment A, and the steps described in the sixth step to the ninth step of the embodiment A are employed. A similar method was used to synthesize the compound (15-5).
  • 6-Bromo-2,3-dihydroquinolin-4(1H)-one (0.30 g, 1.26 mmol) was dissolved in DMF (6 mL), then potassium carbonate (0.36 g, 2.52 1.07 g, 7.56 mmol). The reaction was heated at 80 ° C for 16 hours, and the reaction was monitored by TLC. The reaction mixture was filtered, EtOAcjjjjjjj
  • the third step preparation of 6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-amine (105-4)
  • the compound (105-3) (0.10 g, 0.37 mmol) was dissolved in EtOAc (1M) (10 mL). The reaction was heated at 80 ° C for 16 hours, and the reaction was monitored by TLC. 2M HCl was added to the reaction mixture, and the mixture was heated to 80 ° C for 1 hour, and then EA was added to remove organic impurities. The aqueous layer was adjusted to basic with saturated sodium bicarbonate, and then extracted with EA three times. 0.08 g, yield 89%).
  • TM105 (30.0 mg, 0.07 mmol) was dissolved in dry methanol (15 mL) and then Pd/C (30.0 mg). The reaction was allowed to proceed for 16 hours at room temperature, and the reaction was monitored by TLC. The title compound (4 mg, yield 14%)
  • SM-1-7 (1.0 g, 2.96 mmol) was dissolved in methanol (10 mL) and then 15% NaOH (10 mL) aqueous solution was then allowed to react at room temperature for 2 hours. The reaction was monitored by TLC to the end point. After concentrating the reaction mixture, the mixture was diluted with DCM, and the mixture was separated, and then the mixture was evaporated to EtOAc. The title compound (900 mg, yield 98%).
  • 1,4-dibromobutane was used instead of the compound 1,4-dibromobutan-2-ol of the fifth step of Example 15, using the fifth step of Example 15 to The title compound TM74 was synthesized in a similar manner to that described in the sixth step.
  • This assay was to test the agonistic effects of compounds on the ⁇ opioid receptor ( ⁇ OR) G protein signaling pathway.
  • Activation of the ⁇ protein G signal pathway regulates intracellular cAMP levels, and changes in intracellular cAMP levels by homogeneous time-resolved fluorescence (HTRF) reflect the agonistic activity of the compound.
  • the maximal effect E max (100% of the maximum effect of 1 ⁇ M full agonist DAMGO (H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH)) based on the compound causing changes in cAMP levels and half of the maximum effect
  • the compound concentration EC 50 was used to evaluate the in vitro activity of the compounds.
  • Serial dilutions of the test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to the experimental plate (Corning-3824) using an Echo machine, transferring 30 nL per well, and transferring 30 nL positive control DAMGO (HPE) and negative control. DMSO (ZPE) to the corresponding wells. Then, 5 ⁇ L of stimulation buffer (STB) and 5 ⁇ L of h ⁇ OR/CHO cell suspension (10000 cells/well) were sequentially added to each well of the experimental plate, and the final concentrations of the compounds of IBMX and NKH477 in the 10 ⁇ L system were 100 ⁇ M and 1.5 ⁇ M, respectively. The plate was incubated for 40 min in a 37 ° C incubator. The cAMP levels were then tested according to the cAMP Dynamic 2 kit instructions.
  • STB stimulation buffer
  • h ⁇ OR/CHO cell suspension 10000 cells/well
  • the levels of the agonistic ⁇ OR G protein signaling pathway of the tested compounds were determined by the above assay, and the measured EC 50 and E max results are shown in Table 1 (100% with a maximum effect of 1 ⁇ M full agonist DAMGO).
  • the compounds of the present invention have strong agonistic activity on the ⁇ opioid receptor ( ⁇ OR) G protein signaling pathway.
  • This assay was to test the activity of the ⁇ opioid receptor ( ⁇ OR) to recruit ⁇ inhibitory protein 2 after activation by the compounds of the invention.
  • the mu opioid receptor ( ⁇ OR) was detected by enzyme fragment complementation (EFC) to recruit ⁇ inhibitory protein 2 after activation by the compound.
  • EFC enzyme fragment complementation
  • the agonist binds to the ⁇ opioid receptor ( ⁇ OR) overexpressing the ⁇ -gal fragment and recruits the ⁇ -inhibitor-coupled ⁇ -gal complementary fragment to form a fully catalytically active enzyme, which catalyzes the substrate to produce chemiluminescence.
  • the in vitro activity of the compounds was evaluated based on the maximum effect Emax (the maximum effect of 1 [mu]M full agonist DAMGO is 100%) at which the compound caused the level of ⁇ inhibitory protein 2 recruitment.
  • test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to a test plate (PerkinElmer) using an Echo machine, 60 nL per well, while transferring 60 nL positive control DAMGO (HPE) and negative control DMSO ( ZPE) to the corresponding hole.
  • 20 ⁇ L of U2OS/OPRM1 cell suspension (7500 cells/well) was added to each well of the assay plate, centrifuged at 300 rpm for 30 s, and incubated at room temperature for 2 hours.
  • 6 ⁇ L of PathHunter detection reagent was added to each well of the assay plate according to the PathHunter test kit instructions, and allowed to stand on Envision after standing at room temperature for 60 minutes.
  • Test compound activated ⁇ OR recruitment ⁇ 2 inhibitory protein level E max.
  • the compounds of the present invention have a weaker level of recruitment of ⁇ -inhibitor 2 after activation of the ⁇ opioid receptor ( ⁇ OR).

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Abstract

L'invention concerne un composé phényléthylamine substitué en tant qu'agoniste du récepteur μ-opioïde, une composition pharmaceutique le comprenant, son procédé de préparation et son utilisation pour prévenir et/ou traiter des maladies associées au récepteur μ-opioïde (y compris, mais sans s'y limiter, des maladies douloureuses).
PCT/CN2019/071063 2018-01-25 2019-01-10 Composé phényléthylamine substitué et son procédé de préparation et son utilisation WO2019144805A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810071755.9 2018-01-25
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CN114315755A (zh) * 2022-01-17 2022-04-12 上海皓元医药股份有限公司 一种Tubulysin及其类似物的关键中间体的合成方法

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CN112159401A (zh) * 2019-11-05 2021-01-01 中国人民解放军军事科学院军事医学研究院 偏向性激动剂及其医药用途
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CN114315755B (zh) * 2022-01-17 2023-10-10 上海皓元医药股份有限公司 一种Tubulysin及其类似物的关键中间体的合成方法

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