WO2019205979A1 - Dérivé d'acide aminé non naturel, composition pharmaceutique le contenant, son procédé de préparation et son utilisation - Google Patents

Dérivé d'acide aminé non naturel, composition pharmaceutique le contenant, son procédé de préparation et son utilisation Download PDF

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WO2019205979A1
WO2019205979A1 PCT/CN2019/082787 CN2019082787W WO2019205979A1 WO 2019205979 A1 WO2019205979 A1 WO 2019205979A1 CN 2019082787 W CN2019082787 W CN 2019082787W WO 2019205979 A1 WO2019205979 A1 WO 2019205979A1
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alkyl
compound
group
hydrogen
pharmaceutically acceptable
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PCT/CN2019/082787
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English (en)
Chinese (zh)
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田强
宋帅
赵明亮
王太津
孙启正
蔡家强
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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Priority to CN201980015707.0A priority Critical patent/CN111770756B/zh
Publication of WO2019205979A1 publication Critical patent/WO2019205979A1/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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to non-natural amino acid derivatives, pharmaceutical compositions comprising the same, processes for their preparation and their use as arginase inhibitors. More specifically, the present invention relates to a non-natural amino acid derivative capable of inhibiting hydrolysis of arginine, thereby being useful for preventing or treating a disease or condition associated with arginase activity.
  • Arginase is a dinuclear manganese metalloenzyme with two subtypes: arginase I (ARG-1), which is expressed in the cytoplasm of cells, mainly in the liver; and arginase II ( ARG-2), expressed in mitochondria, is mainly found in the kidney, small intestine, brain, monocytes and macrophages.
  • ARG-2 arginase II
  • L-arginine is mainly metabolized by two pathways: one is hydrolysis to L-ornithine and urea by arginase; the other is oxidized by nitric oxide synthase (NOS). L-citrulline and nitric oxide are produced.
  • arginase not only participates in the ornithine cycle of the liver, but also affects the immune system of humans and mice, and also reduces the production of nitric oxide by hydrolyzing arginine, thereby triggering fibrosis and tissue regeneration, thereby promoting inflammation.
  • arginine deficiency also inhibits T cell immune responses, particularly inflammation-related immune responses, while pathogens can evade immune responses by synthesizing arginase (Nature, 1996, 383, 554-557; Pharm. Pat .Anal., 2014, 3(1), 65-85; Med. Res. Rev., 2017, 37(3), 475-513).
  • Arginase inhibitors are potential therapeutic agents for cancer, induced or spontaneous immune disorders, allergic asthma, inflammatory bowel disease, ulcerative colitis, atherosclerosis and hypertension, and others caused by pathogens Treatment of the disease.
  • Arginine hydrolysis is carried out by divalent manganese ions mediated nucleophilic attack of sulfhydryl carbon atoms via a tetrahedral transition state.
  • the organoboronic acid compound Under physiological pH conditions, the organoboronic acid compound is easily changed from sp 2 hybridization to sp 3 hybridized negative ion form. This structure is very similar to the tetrahedral transition state of the enzyme-catalyzed substrate, so the organoboric acid compound is used as the arginine.
  • Enzyme inhibitors have been extensively studied.
  • WO1999019295 discloses the inhibition of arginase by S-(2-dihydroxyborylethyl)-L-cysteine (BEC).
  • WO2010062366 reports the structure of another arginine analog, nor-NOHA:
  • the present invention provides non-natural amino acid derivatives which have good inhibitory effects on arginase (arginase I and/or arginase II) and have good physicochemical properties (eg solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, appropriate half-life and duration of action), improved safety (lower toxicity and / or fewer side effects, wider) The therapeutic window) and other excellent properties.
  • arginase I and/or arginase II have good physicochemical properties (eg solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, appropriate half-life and duration of action), improved safety (lower toxicity and / or fewer side effects, wider) The therapeutic window) and other excellent properties.
  • Some aspects of the invention provide a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Said compound has the structure of formula (I):
  • R 1 is selected from the group consisting of -OR a and -NR b R c ;
  • D is selected from C 2-6 alkylene, -CH 2 -C 3-10 cycloalkylene, -CH 2 -(3-10 membered heterocyclylene), -CH 2 -C 6-10 arylene, C 2-6 alkenylene, C 2-6 alkynylene, saturated or partially unsaturated C 3-10 cycloalkylene, saturated or partially unsaturated 3-10 membered heterocyclylene, C 6-10 An aryl group and a 5-14 membered heteroarylene group, and when D is a C 2-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, the hydrocarbon chain of the group is optional
  • k, m, n, and p are each independently 0, 1, or 2, provided that k, m, and n are not 0 at the same time;
  • heteroaryl and aralkyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH 2 , nitro, Sulfhydryl, -CO 2 H, -CO 2 C 1-6 alkyl, C 1-6 alkyl, halo C 1-6 alkyl, -OC 1-6 alkyl, -O-halogen C 1-6 Alkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-6 alkylene- OH, -C
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or Use of a medicament or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with arginase activity.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A medicament or a pharmaceutical composition of the invention for use in preventing or treating a disease or condition associated with arginase activity.
  • Another aspect of the invention provides a method of preventing or treating a disease or condition associated with arginase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof , esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • Another aspect of the invention provides a method of preparing a compound of the invention.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted by one or more (such as 1 to 3) suitable substituents Substituted by halogen (in this case the group is referred to as "haloalkyl”) (eg CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).
  • alkylene denotes the corresponding divalent group and includes, for example, “C 1-6 alkylene”, “C 2-6 alkylene”, “C 1-4 alkylene” and the like, and specific examples include However, it is not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.
  • alkenyl means a linear or branched monovalent hydrocarbon radical comprising at least one double bond, for example, having from 2 to 6 carbon atoms ("C 2-6 alkenyl").
  • the alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • alkenylene is a corresponding divalent group including, for example, "C 2-6 alkenylene", “C 2-4 alkenylene”, and the like, and specific examples thereof include, but are not limited to, vinylidene, arylene A propylene group, a butenylene group, a pentenylene group, a hexylene group, a cyclopentylene group, a cyclohexylene group, and the like.
  • alkynyl refers to a monovalent hydrocarbon radical containing one or more triple bonds, for example having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • alkynylene is a corresponding divalent group including, for example, “C 2-6 alkynylene", “C 2-4 alkynylene” and the like. Examples thereof include, but are not limited to, ethynylene, propynylene, butynylene, pentynylene, and hexynylene.
  • 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 has 3 to 15 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.
  • cycloalkylene refers to a saturation having, for example, 3 to 10, 3 to 8 or 3 to 6 ring carbon atoms (ie, “sub” Cycloalkyl” and “cycloalkyl”) or unsaturated (ie having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings including, but not limited to, (sub) rings Propyl (ring), (sub)cyclobutyl (ring), (sub)cyclopentyl (ring), (sub)cyclohexyl (ring), (sub)cycloheptyl (ring), (sub)cyclooctane A group (ring), a (sub)cyclononyl group (ring), a (sub)cyclohexenyl group (ring), and the like.
  • heterocyclyl means having, for example, 3-10, 3-8 or 3-6 ring atoms, at least one of which is a ring 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 and/or triple bonds in the ring). A cyclic group.
  • 3-10 membered (sub)heterocyclic (yl) has 2 to 9 (eg, 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N a saturated or partially unsaturated (sub)heterocyclic ring of one or more (e.g., 1, 2, 3 or 4) heteroatoms of O and S.
  • heterocyclylene group and the heterocyclic ring group include, but are not limited to, (meth)oxiranyl, (i)aziridine, (a) azetidinyl, (sub)oxy Oxetanyl, (i)tetrahydrofuranyl, (di)dioxolinyl, (i)pyrrolidinyl, (i)pyrrolidone, (im)imidazolidinyl, (Asia) Pyrazolyl, (i)pyrroline, (i)tetrahydropyranyl, (i)piperidinyl, (y)morpholinyl, (di)dithianyl, (sub) Thimorpholinyl, (i)piperazinyl or (tri)trithianyl.
  • the group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane, etc.).
  • the heterocyclylene group and the heterocyclic ring group may be optionally substituted by one or more (for example, 1, 2, 3 or 4) suitable substituents.
  • the terms "(sub)aryl” and “aryl” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6-10 (sub)aryl” and “C 6-10 aryl” mean an aromatic group containing from 6 to 10 carbon atoms, such as (phenylene)phenyl. (Benzene ring) or (methylene) naphthyl (naphthalene ring).
  • heteroaryl and “heteroaryl” refer to a monocyclic, bicyclic or tricyclic aromatic ring system, for example, having 5, 6, 8, 9, 10, 11, 12 , 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, Nitrogen or sulfur), and, in each case, may be benzofused.
  • “(sub)heteroaryl” or “heteroaryl” is selected from (i)thienyl, (i)furanyl, (i)pyrrolyl, (i)oxazolyl, (sub)thiazolyl, (i)imidazolyl, (i)pyrazolyl, (i)isoxazolyl, (i)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl And their benzo derivatives; or (i)pyridyl, (pyridazinyl), (i)pyrimidinyl, (i)pyrazinyl, (i)triazinyl, etc., and their benzo derivative.
  • aralkyl as used herein preferably denotes an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group for example, may have 6 to 10 carbon atoms
  • the heteroaryl group may have, for example, 5 to 10 ring atoms
  • the alkyl group may have, for example, 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • 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
  • Certain isotopically-labeled compounds of the invention e.g., those incorporating radioisotopes
  • are useful in drug and/or substrate tissue distribution studies e.g., assays).
  • the radioisotope ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes eg, 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • 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 acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.
  • 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 (e.g., hydrate) wherein the compound of the present invention contains a polar solvent such as water, methanol or ethanol as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent 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 m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
  • MCPBA m-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 the body or
  • the above compounds can be converted to the compounds 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, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has the structure of formula (I):
  • R 1 is selected from the group consisting of -OR a and -NR b R c ;
  • D is selected from C 2-6 alkylene, -CH 2 -C 3-10 cycloalkylene, -CH 2 -(3-10 membered heterocyclylene), -CH 2 -C 6-10 arylene, C 2-6 alkenylene, C 2-6 alkynylene, saturated or partially unsaturated C 3-10 cycloalkylene, saturated or partially unsaturated 3-10 membered heterocyclylene, C 6-10 An aryl group and a 5-14 membered heteroarylene group, and when D is a C 2-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, the hydrocarbon chain of the group is optional
  • k, m, n, and p are each independently 0, 1, or 2, provided that k, m, and n are not 0 at the same time;
  • heteroaryl and aralkyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH 2 , nitro, Sulfhydryl, -CO 2 H, -CO 2 C 1-6 alkyl, C 1-6 alkyl, halo C 1-6 alkyl, -OC 1-6 alkyl, -O-halogen C 1-6 Alkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-6 alkylene- OH, -C
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl (preferably methyl) and -CH(NH 2 )CH 3 .
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R 1 is -OH.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • R 2 is selected from the group consisting of hydrogen and C 1-6 alkyl, preferably R 2 is selected from the group consisting of hydrogen and methyl.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R 3 and R 4 are both hydrogen.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • -(X) k -(Y) m -(Z) n - group is selected from -CH 2 -CR"R"-CH 2 -, -CH 2 -CH 2 -CR'R"-CH 2 - -CH 2 -CR'R"-CH 2 -CH 2 -, -CH 2 -CH 2 -NR"'-CH 2 - and -CH 2 -NR"'-CH 2 -CH 2 -.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , wherein R' and R" are each independently selected from the group consisting of hydrogen, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 ,
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • R' and R" are each independently selected from the group consisting of hydrogen, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 ,
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , where R"' is selected from hydrogen,
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , where R"' is selected from hydrogen,
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof
  • D is a C 2-6 alkylene group, preferably a butylene group.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has the structure of formula (II):
  • the compound has any structure of the formula:
  • q is 2, 3, 4, 5 or 6, preferably q is 4.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound is selected from the group consisting of
  • the invention provides a method of preparing a compound of formula (II), comprising the steps of:
  • Hal is halogen, preferably chlorine, bromine or iodine
  • q' is an integer of q-2;
  • R a is hydrogen
  • R a is a carboxy protecting group, preferably a C 1-6 alkyl group, such as a methyl group
  • R a is the same as R a ;
  • R 2 is hydrogen
  • R 2 ' is an amino protecting group such as t-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz); and when R 2 is not hydrogen, R 2 ' is the same as R 2 ;
  • R 3 or R 4 When R 3 or R 4 is hydrogen, R 3 ' or R 4 ' are each independently C 1-6 alkyl, or R 3 ' and R 4' together with the group to which they are attached form a 5-8 membered ring. (E.g or And when both R 3 and R 4 are not hydrogen, R 3 ' and R 4 ' are the same as R 3 and R 4 , respectively;
  • reaction conditions of each step are as follows:
  • Step 1 Compound (II)-a and compound Reg-1 in a base (for example, diisopropylethylamine, triethylamine, pyridine, sodium carbonate, potassium acetate, potassium carbonate, potassium hydroxide, cesium carbonate, diiso) Reaction in the presence of lithium propylamide or lithium hexamethyldisilazide to prepare compound (II)-b;
  • a base for example, diisopropylethylamine, triethylamine, pyridine, sodium carbonate, potassium acetate, potassium carbonate, potassium hydroxide, cesium carbonate, diiso
  • Step 2 optionally adding a phosphine ligand to the compound (II)-b and the compound Reg-2 in the presence of a catalyst/accelerator (preferably a 1,5-cyclooctadiene phosphonium dimer) Preferably 1,2-bis(diphenylphosphino)ethane) is reacted to prepare compound (II)-c;
  • a catalyst/accelerator preferably a 1,5-cyclooctadiene phosphonium dimer
  • Step 3 reacting compound (II)-c in the presence of an acid (for example, hydrochloric acid) or a base (for example, lithium hydroxide or sodium hydroxide) to prepare a compound of formula (II), provided that R a ' and R a same, 'are the same and R 2 and R 3' R 2 and R 4 'are R 3 and R 4 are the same, the three steps do not exist.
  • an acid for example, hydrochloric acid
  • a base for example, lithium hydroxide or sodium hydroxide
  • compositions and methods of treatment are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, An N-oxide, an isotopically-labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous formulation.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or use of a prodrug or a pharmaceutical composition or pharmaceutical formulation of the invention in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with arginase activity.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug or a pharmaceutical composition or pharmaceutical preparation of the invention for preventing or treating a disease or condition associated with arginase activity.
  • the invention provides a method of preventing or treating a disease or condition associated with arginase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions or pharmaceutical formulations of the invention.
  • the disease or condition associated with arginase activity is selected from the group consisting of a cardiovascular condition, a sexual dysfunction, a wound healing disorder, a gastrointestinal disorder, an autoimmune disorder, an immune disorder, an infection, a lung disease, Liver disease, inflammation, hemolytic disease and cancer, preferably cancer, colon cancer, breast cancer and lung cancer (including non-small cell lung cancer), renal cell carcinoma, prostate cancer, multiple myeloma, acute myeloid leukemia, Neuroblastoma, glioblastoma or melanoma.
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
  • injection for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
  • transdermal administration or by oral, buccal, or oral administration.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • compositions of the invention may also comprise one or more additional therapeutic or prophylactic agents.
  • the structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).
  • the nuclear magnetic resonance spectroscopy ( 1 H NMR) measuring instrument was a Bruker 400 MHz nuclear magnetic resonance apparatus; the solvent was determined to be heavy water (D 2 O), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexamethylene diene.
  • the chemical shift ( ⁇ ) is given in parts per million (ppm).
  • MS mass spectrometer
  • ESI Agilent
  • Step 1 (2R,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (32 -b) synthesis
  • Step 4 Synthesis of 1-tert-butyl-2-methyl-2-(but-3-en-1-yl)-4-oxopyrrolidine-1,2-dicarboxylate (32-e)
  • Step 5 Synthesis of 1-tert-butyl-2-methyl-4-amino-2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (32-f)
  • Step 7 1-tert-Butyl-2-methyl-4-((S)-2-((tert-butoxycarbonyl)amino)propionamido)-2-(4-(4,4,5,5) Synthesis of tetrakis-methyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (32-h)
  • Step 8 Synthesis of 4-amino-2-(4-dihydroxyborylbutyl)pyrrolidine-2-carboxylic acid (32)
  • Step 1 1-tert-Butyl-2-methyl-2-(but-3-en-1-yl)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylate (34- Synthesis of a)
  • Step 2 1-tert-Butyl-2-methyl-4-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa) Synthesis of Boronocyclopentan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (34-b)
  • the inhibitory activity of the compound on arginase I was evaluated by the following experiment.

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Abstract

L'invention concerne un dérivé d'acide aminé non naturel représenté par la formule (I), une composition pharmaceutique le comprenant, son procédé de préparation, et son utilisation en tant qu'inhibiteur de l'arginase. Plus spécifiquement, la présente invention concerne un dérivé d'acide aminé non naturel qui est capable d'inhiber l'hydrolyse de l'arginine, et peut donc être utilisé pour prévenir ou traiter des maladies ou des troubles liés à l'activité de l'arginase.
PCT/CN2019/082787 2018-04-27 2019-04-16 Dérivé d'acide aminé non naturel, composition pharmaceutique le contenant, son procédé de préparation et son utilisation WO2019205979A1 (fr)

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WO2020161675A1 (fr) * 2019-02-08 2020-08-13 Astrazeneca Ab Inhibiteurs de l'arginase et leurs procédés d'utilisation
WO2022137156A1 (fr) 2020-12-22 2022-06-30 Oncoarendi Therapeutics S.A. Inhibiteurs d'arginase et leurs procédés d'utilisation
US11420984B2 (en) 2018-02-17 2022-08-23 Astrazeneca Ab Arginase inhibitors and methods of use thereof
CN115677776A (zh) * 2022-11-14 2023-02-03 清华大学 膦硼非天然氨基酸、多肽和蛋白质的制备方法及直接金属配位转化
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CN103068830A (zh) * 2010-04-22 2013-04-24 马尔斯公司 精氨酸酶抑制剂及其治疗应用
CN103249737A (zh) * 2010-10-26 2013-08-14 马尔斯公司 作为精氨酸酶抑制剂的硼酸盐
CN103402549A (zh) * 2010-12-31 2013-11-20 考瑞多制药公司 精氨酸酶抑制剂及其使用方法

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Publication number Priority date Publication date Assignee Title
US11420984B2 (en) 2018-02-17 2022-08-23 Astrazeneca Ab Arginase inhibitors and methods of use thereof
US11912727B2 (en) 2018-02-17 2024-02-27 Astrazeneca Ab Arginase inhibitors and methods of use thereof
US11952392B2 (en) 2018-08-22 2024-04-09 Astrazeneca Ab Arginase inhibitors and methods of use thereof
WO2020161675A1 (fr) * 2019-02-08 2020-08-13 Astrazeneca Ab Inhibiteurs de l'arginase et leurs procédés d'utilisation
WO2022137156A1 (fr) 2020-12-22 2022-06-30 Oncoarendi Therapeutics S.A. Inhibiteurs d'arginase et leurs procédés d'utilisation
CN115677776A (zh) * 2022-11-14 2023-02-03 清华大学 膦硼非天然氨基酸、多肽和蛋白质的制备方法及直接金属配位转化
CN115677776B (zh) * 2022-11-14 2024-02-06 清华大学 膦硼非天然氨基酸、多肽和蛋白质的制备方法及直接金属配位转化

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