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WO2024059263A1 - Procédés de préparation de dérivés maytansinoïdes dotés de lieurs peptidiques auto-immolables - Google Patents

Procédés de préparation de dérivés maytansinoïdes dotés de lieurs peptidiques auto-immolables Download PDF

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Publication number
WO2024059263A1
WO2024059263A1 PCT/US2023/032866 US2023032866W WO2024059263A1 WO 2024059263 A1 WO2024059263 A1 WO 2024059263A1 US 2023032866 W US2023032866 W US 2023032866W WO 2024059263 A1 WO2024059263 A1 WO 2024059263A1
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compound
formula
salt
carried out
acid
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Andrew Brian HAGUE
Lynette OH
Ijaz Ahmed
Lilian Radesca
Mark Cameron
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Immunogen Inc
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Immunogen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • the present invention relates to novel methods for preparing maytansinoid derivatives with self-immolative peptide linkers as well as their synthetic precursors.
  • Cell binding agent-drug conjugates including antibody-drug conjugates (ADC) are emerging as a powerful class of agents with efficacy across a range of abnormal cell growth or proliferative diseases (e.g., cancers).
  • Cell binding agent-drug conjugates (such as ADCs) are commonly composed of three distinct elements: a cell-binding agent (e.g., an antibody); a linker; and a cytotoxic moiety.
  • the linker component of ADC is an important element in developing targeted anti-cancer agents that possess an optimal therapeutic window, i.e., high activity at a low, non-toxic dose.
  • Maytansinoids are highly cytotoxic compounds, including maytansinol and C-3 esters of maytansinol, e.g., C-3 esters with N-methyl-L-alanine (MayNMA). It has been found that conjugates of maytansinoid derivatives with self-immolative peptide linkers and cell binding agents are highly potent as anti-proliferative agents, in particularly, as anticancer agents.
  • the present invention provides new methods for preparing maytansinoid derivatives with self-immolative peptide linkers as well as their synthetic precursors.
  • the methods disclosed herein can eliminate the cumbersome chromatography purifications, which are more efficient and suitable for large scale manufacturing process.
  • the present methods only introduce highly toxic maytansinoid moiety in the last reaction step, thereby reducing worker exposure to highly toxic material.
  • the present invention relates to a method of preparing a compound represented by Formula (I): or a salt thereof, comprising the steps of:
  • Formula (A) to form the compound of Formula (I) or a salt thereof.
  • the present invention relates to a method of preparing a compound of Formula (IV): or a salt thereof, comprising the step of reacting a compound of Formula (I): or a salt thereof (e.g., a TEA salt), with a compound of Formula (V): (V), to form the compound of Formula (IV) or a salt thereof, wherein DM is represented by the following formula:
  • the present invention provides a method of preparing a compound of Formula (II): or a salt thereof, comprising the step of reacting a compound of Formula (VI): with a compound of Formula (B) to form the compound of Formula (II) or a salt thereof, wherein the compound of Formula (II) is purified by precipitation.
  • compositions are described as having, including, or comprising (or variations thereof), specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components.
  • compound is intended to include compounds for which a structure or formula or any derivative thereof has been disclosed in the present invention or a structure or formula or any derivative thereof that has been incorporated by reference.
  • the term also includes, stereoisomers, geometric isomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) of a compound of all the formulae disclosed in the present invention.
  • the term also includes any solvates, hydrates, and polymorphs of any of the foregoing.
  • chiral refers to molecules that have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules that are superimposable on their mirror image partner.
  • stereoisomer refers to compounds that have identical chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds.
  • diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as crystallization, electrophoresis and chromatography.
  • enantiomers refer to two stereoisomers of a compound that are non- superimposable mirror images of one another.Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • salt refers to an organic or inorganic salts of a compound of the invention.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate,” ethanesulfonate, benzenesulfonate, p- toluenesulfonate, pamoate (/'. ⁇ ?., l,l’-methylene-bis-(2-hydroxy-3
  • a salt can involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion can be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a salt can have more than one charged atom in its structure. Instances where multiple charged atoms are part of the salt can have multiple counter ions. Hence, a salt can have one or more charged atoms and/or one or more counter ion.
  • the desired salt can be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the
  • the desired salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as triethylamine, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as glycine and arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as triethylamine, piperidine, morpholine and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • solvate means a compound that further includes a stoichiometric or non- stoichiometric amount of solvent such as water, isopropanol, acetone, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • Solvates or hydrates of the compounds are readily prepared by addition of at least one molar equivalent of a hydroxylic solvent such as methanol, ethanol, 1 -propanol, 2-propanol or water to the compound to result in solvation or hydration of the imine moiety.
  • precursor of a given group refers to any group which may lead to that group by any deprotection, a chemical modification, or a coupling reaction.
  • amino acid refers to naturally occurring amino acids or non-naturally occurring amino acid.
  • peptide refers to short chains of amino acid monomers linked by peptide (amide) bonds. In some embodiments, the peptides contain 2 to 20 amino acid residues. In other embodiments, the peptides contain 2 to 10 or 2 to 8 amino acid residues. In yet other embodiments, the peptides contain 2 to 5 amino acid residues. As used herein, when a peptide is a portion of a cytotoxic agent or a linker described herein represented by a specific sequence of amino acids, the peptide can be connected to the rest of the cytotoxic agent or the linker in both directions.
  • immunoconjugate refers to a compound or a derivative thereof that is linked to a cell binding agent (e.g., an antibody or antigen -binding fragment thereof).
  • cell-binding agent in the immunoconjugates of the present invention can be of any kind presently known, or that become known, including peptides and non-peptides that binds to a cell or cell component (e.g., receptor, protein, DNA, RNA, etc.).
  • these can be antibodies (such as polyclonal antibodies and monoclonal antibodies, especially monoclonal antibodies) or fragments thereof, lymphokines, hormones, growth factors, vitamins (such as folate etc., which can bind to a cell surface receptor thereof, e.g., a folate receptor), nutrient-transport molecules (such as transferrin), probodies, nanobodies, or any other cell-binding molecule or substance.
  • the term “cation” refers to an ion with positive charge.
  • the cation can be monovalent (e.g., Na + , K + , etc.), bi-valent (e.g., Ca 2+ , Mg 2+ , etc.) or multi-valent (e.g., Al 3+ etc.).
  • the cation is monovalent.
  • the term “acid” refers to any substance that in water solution tastes sour, changes the color of certain indicators (e.g., reddens blue litmus paper), reacts with some metals (e.g., iron) to liberate hydrogen, reacts with bases to form salts, and promotes certain chemical reactions (acid catalysis).
  • acids include the inorganic substances known as the mineral acids — sulfuric, nitric, hydrochloric, and phosphoric acids — and the organic compounds belonging to the carboxylic acid, sulfonic acid, and phenol groups. Such substances contain one or more hydrogen atoms that, in solution, are released as positively charged hydrogen ions.
  • acid examples include formic acid, acetic acid, trifluoroacetic acid (TFA), pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid (HC1), and trichloroacetic acid.
  • TFA trifluoroacetic acid
  • PPTS pyridinium p-toluenesulfonate
  • p-toluenesulfonic acid methanesulfonic acid
  • camphorsulfonic acid phosphoric acid
  • sulfuric acid hydrochloric acid (HC1)
  • trichloroacetic acid examples of acid includes formic acid, acetic acid, trifluoroacetic acid (TFA), pyridinium p-toluenesulfonate (PPTS), p-toluenesulf
  • base refers to a substance that can accept hydrogen ions (protons) or donate a pair of valence electrons.
  • suitable bases include imidazole, piperidine, 4-methylpiperidine, tetramethylpiperidine, morpholine, N-methylmorpholine, pyridine, 2,6-lutidine, dimethylformamide, piperazine, pyrrolidine, 1-methylpyrrolidine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine (DEA), a trialkylamine (e.g., N,N- diisopropylethylamine (DIPEA), triethylamine (TEA), and l,8-Diazabicycloundec-7-ene), a metal alkoxide (e.g., sodium tert-butoxide and potassium tert-butoxide), an alkyl metal (e.g., tert-butyllithium, methyl lithium,
  • Lewis acid refers to an acid substance which can employ an electron lone pair from another molecule in completing the stable group of one of its own atoms.
  • exemplary Lewis acids for use in the disclosed methods include boron trifluoride etherate (BF3*OEt2), zinc triflate, zinc chloride, magnesium bromide, magnesium triflate, copper triflate, copper (II) bromide, copper (II) chloride, magnesium chloride, and aluminum chloride (AICI3).
  • amorphous solid refers to any non-crystalline solid in which the atoms and molecules are not organized in a definite lattice pattern. Such solids include glass, plastic, and gel.
  • the “semi-amorphous solid” refers to semi-crystalline materials that display crystalline regions, called crystallites, within an amorphous matrix.
  • crystallization refers to the process by which a solid forms, where the atoms or molecules are highly organized into a structure known as a crystal. Some of the ways by which crystals form are precipitating from a solution, freezing, or more rarely deposition directly from a gas. Attributes of the resulting crystal depend largely on factors such as temperature, air pressure, and in the case of liquid crystals, time of fluid evaporation.
  • precipitation refers to the process of transforming a dissolved substance into an insoluble solid from a solution comprising the substance (e.g., saturated solution of the substance).
  • the solid formed is called the precipitate.
  • the clear liquid remaining above the precipitated or the centrifuged solid phase is also called the 'supernate' or 'supernatant'.
  • precipitation can occur by adding a co-solvent, in which the substance has low or no solubility, to a solution of the substance.
  • cooling a solution comprising the substance can result in precipitation.
  • organic solvent refers to carbon-based substances capable of dissolving or dispersing one or more other substances. Many classes of chemicals are used as organic solvents, including aliphatic hydrocarbons, aromatic hydrocarbons, amines, esters, ethers, ketones, and nitrated or chlorinated hydrocarbons.
  • organic solvents include dichloromethane (CH2CI2 or DCM), dichloroethane (DCE), acetonitrile (ACN or MeCN), ethyl acetate, methanol (MeOH), ethanol, tetrahydrofuran (THF), toluene, N- methylmorpholine (NMM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA or DM Ac), or any combination thereof.
  • CH2CI2 or DCM dichloromethane
  • DCE dichloroethane
  • ACN acetonitrile
  • MeCN ethyl acetate
  • MeOH methanol
  • THF tetrahydrofuran
  • NMM N- methylmorpholine
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • DMA or DM Ac dimethylacetamide
  • the present invention provides methods of preparing maytansinoid derivatives with self-immolative peptide linkers, which can be linked to cell binding agents (e.g., antibodies) to form immunoconjugates that are useful as medicaments, in particular as anti-proliferative agents (anticancer agents).
  • cell binding agents e.g., antibodies
  • the present invention also provides methods of preparing the related synthetic precursors.
  • the present invention provides a method of preparing a compound represented by Formula (I): or a salt thereof, comprising the steps of:
  • Formula (A) to form the compound of Formula (I) or a salt thereof.
  • the compound of Formula (I) is represented by a compound of Formula (la): or a salt thereof, and the method comprises the steps of:
  • the deprotecting agent in the reaction of step (a) is a base.
  • the base is piperidine, 4-methylpiperidien, piperazine, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), or morpholine.
  • the base is morpholine.
  • any suitable amount of deprotecting agent e.g., morpholine
  • the molar ratio of the deprotecting agent to the compound of Formula (II) or (Ila) is in the range of 1:1 to 20:1, 1:1 to 10:1, 1:1 to 5:1, or 1.5:1 to 2.5:1. In a specific embodiment, the molar ratio of the deprotecting agent to the compound of Formula (II) or (Ila) is 2:1.
  • any suitable solvents can be used for the reaction of step (a), which include but are not limited to DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, and toluene.
  • the solvent is DMF.
  • the reaction of step (a) can be carried out at a suitable temperature.
  • the reaction is carried out at a temperature between -50°C and 50°C, between 0°C and 40°C, between 5°C and 35°C, between 10°C and 30°C, or between 15°C and 25°C.
  • the reaction is carried out at a temperature between 15 °C and 25°C.
  • the compound of Formula (III) or (Illa) is purified by precipitation.
  • Any suitable solvents can used for the precipitation, which include DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, toluene, and tert-butyl methyl ether.
  • the precipitation is carried out in DMF and CH2CI2.
  • the compound of Formula (III) or (Illa) can be precipitated by mixing CH2CI2 with a DMF solution comprising the compound.
  • the volume ratio of DMF to CH2CI2 can be in the range of 1:100 to 100:1, 1:80 to 40:1, 1:60 to 1:1, 1:60 to 1:30, or 1:50 to 1:40. In a specific embodiment, the volume ratio of DMF to CH2CI2 is 1:48.
  • the compound of Formula (III) or (Illa) is obtained as an amorphous or semi-amorphous solid. In a specific embodiment, the compound of Formula (III) or (Illa) is obtained as an amorphous solid.
  • the compound of Formula (III) or (Illa) is further purified by crystallization.
  • Any suitable solvents can used for the crystallization.
  • the crystallization is carried out in one or more solvents including DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, toluene, or tertbutyl methyl ether.
  • the crystallization is carried out in acetonitrile.
  • the crystallization can be carried out at a suitable temperature. In some embodiments, the crystallization is carried out at a temperature between 0°C and 100°C, between 5°C and 80°C, between 10°C and 70°C, between 15 °C and 55 °C, between 17 °C and 23 °C, or between 47 °C and 53 °C. In a specific embodiment, the crystallization is carried out at a temperature between 17 °C and 53 °C.
  • the compound of Formula (III) or (Illa) is further purified by precipitation after crystallization. Any suitable solvents can used for the precipitation.
  • the precipitation is carried out in one or more solvents including DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, toluene, or tert-butyl methyl ether.
  • the precipitation is carried out in DMF and CH2CI2.
  • the compound of Formula (III) or (Illa) can be precipitated by mixing CH2CI2 with a DMF solution comprising the compound.
  • the precipitation can be carried out at a suitable temperature. In some embodiments, the precipitation is carried out at a temperature between 0°C and 100°C, between 5°C and 80°C, between 10°C and 70°C, between 15 °C and 55 °C, between 17 °C and 23 °C, or between 47 °C and 53 °C. In a specific embodiment, the precipitation is carried out at a temperature between 17 °C and 53 °C.
  • the compound of Formula (III) or (Illa) is obtained as an amorphous solid after the second precipitation.
  • the reaction in step (b) between the compound of Formula (III) or (Illa) or a salt thereof and the compound of Formula (A) is carried out in the presence of a base.
  • the base is N-methylmorpholine, triethylamine (TEA), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylpiperidine, 1 -methyip yrrolidine, or diisopropylethyalamine (DIPEA).
  • the base is triethylamine (TEA).
  • the molar ratio of the compound of Formula (A) to the compound of Formula (III) or (Illa) is in the range of 1:1 to 5:1, 1:1 to 3:1, 1:1 to 2:1, 1:1 to 1.5:1, 1:1 to 1.2:1 or 1:1 to 1.1 : 1. In a specific embodiment, the molar ratio of the compound of Formula (A) to the compound of Formula (III) or (Illa) is 1.05:1.
  • the molar ratio of base to the compound of Formula (III) or (Illa) is in the range of 1:1 to 20:1, 1:1 to 10:1, 1:1 to 5:1, 2:1 to 5:1 , 3:1 to 5:1 or 4.2:1 to 4.6:1. In a specific embodiment, the molar ratio of the base to the compound of Formula (III) or (Illa) is 4.4:1.
  • any suitable solvents can be used for the reaction of step (b).
  • the suitable solvents include DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, and toluene.
  • the reaction in step (b) is carried out in acetonitrile.
  • the reaction of step (b) can be carried out at a suitable temperature.
  • the reaction is carried out at a temperature between -50°C and 50°C, between 0°C and 40°C, between 5°C and 35°C, between 10°C and 30°C, or between 15°C and 25°C.
  • the reaction is carried out at a temperature between 15 °C and 25°C.
  • the compound of Formula (I) or (la) is purified by precipitation.
  • Any suitable solvents can used for the precipitation, which include DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, toluene, and tert-butyl methyl ether.
  • the precipitation is carried out in tert-butyl methyl ether.
  • the precipitation is carried out by adding tert-butyl methyl ether to an acetonitrile solution comprising the compound of Formula (I) or (la). The precipitation can be carried out at a suitable temperature.
  • the precipitation is carried out at a temperature between -100°C and 100°C, between -50°C and 80°C, between -40°C and 60°C, between -30 °C and 40 °C, between -30 °C to 25 °C, or between -20 °C to -16 °C. In a specific embodiment, the precipitation is carried out at a temperature of -30 °C.
  • the compound of Formula (I) or (la) is obtained as a salt.
  • the compound of Formula (I) or (la) is obtained as a triethylamine (TEA) salt.
  • the ratio of the compound of Formula (I) or (la) to TEA is in the range of 1:1.2 to 1:0.1, 1:1 to 1:0.8, or 1:0.8 to 1:0.5.
  • the compound of Formula (I) or (la) is obtained as triethylamine (TEA) salt, wherein the molar ratio of the compound and TEA is 1:1.
  • the present invention provides a method of preparing a compound of Formula (IV): or a salt thereof, comprising the step of reacting a compound of Formula (I): or a salt thereof (e.g., a TEA salt), with a compound of Formula (V): to form the compound of Formula (IV) or a salt thereof, wherein DM is represented by the following formula:
  • the compound of Formula (IV) is represented by a compound of Formula (IVa): or a salt thereof, and the method comprises the step of reacting a compound of Formula (la): or a salt thereof (e.g., a TEA salt), with a compound of Formula (Va):
  • reaction between the compound of Formula (I) or(Ia) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va) is carried out in the presence of an amide coupling reagent.
  • the “amide coupling reagent” is a reagent that activates a carboxylic group (e.g., the carboxylic group in the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt)) to facilitate the coupling reaction with an amine group (e.g., the amine group in the compound of Formula (V) or (Va)) to form an amide group (e.g., the amide group in the compound of Formula (IV) or (IVa) or a salt thereof).
  • a carboxylic group e.g., the carboxylic group in the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt)
  • an amine group e.g., the amine group in the compound of Formula (V) or (Va)
  • an amide group e.g., the amide group in the compound of Formula (IV) or (IVa) or a salt thereof.
  • the amide coupling reagent is a 2,4,6-trialkyl-l,3,5,2,4,6- trioxatriphosphorinane 2,4,6-trioxide, carbodiimide (e.g., A,A’-dicyclohexylcarbodiimide (DCC) or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)), 1,1 ’-carbonyldiimidazole (CDI), a uronium, an activated ester, a phosphonium, 2-alkyl-l-alkylcarbonyl-l,2- dihydroquinoline, 2-alkoxy-l-alkoxycarbonyl-l,2-dihydroquinoline, or alkylchloroformate.
  • carbodiimide e.g., A,A’-dicyclohexylcarbodiimide (DCC) or l-ethyl-3-(3-di
  • the amide coupling reagent is 2,4,6-trialkyl-l,3,5,2,4,6- trioxatriphosphorinane 2,4,6-trioxide.
  • the amide coupling reagent is 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (T3P).
  • the amide coupling reagent can be used in any forms including powder, crystals, liquid or solution.
  • the amide coupling reagent is a solution in a solvent. Any suitable solvents can be used to make a solution of an amide coupling reagent.
  • the amide coupling reagent is a solution of T3P in ethyl acetate (EtOAc).
  • the concentration of an amide coupling reagent in a solvent is in the range of 0-100 wt%, 20-100 wt%, 30-100 wt%, 50-100 wt%, or 60-100 wt%,.
  • the concentration of T3P in EtOAc is in the range of or 40-60 wt%.
  • any suitable amount of the amide coupling reagent can be used in the reaction between the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va).
  • a salt thereof e.g., a TEA salt
  • between 1.0 and 10.0 molar equivalents of the amide coupling reagent (e..g., T3P) relative to the amount of the compound of formula (V) or (Va) is used in the reaction.
  • 1.5-2.5, 1.0-3.0, 1.0-5.0, 1.0-6.0, 2.0-3.0, 2.0-4.0, 3.0-5.0, or 4.0-6.0 molar equivalent of T3P relative to the amount of the compound of formula (V) or (Va) is used.
  • 5.0 equivalent of T3P is used.
  • the reaction between the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va) is carried out in the presence of a base.
  • bases include, but are not limited to, triethylamine, imidazole, A(.V-diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and tetramethylpiperidine.
  • the base is pyridine.
  • reaction between the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va) is carried out in the presence of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (T3P) as the amide coupling reagent and pyridine as the base.
  • T3P 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
  • the reaction between the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va) can be carried out in any suitable organic solvent(s).
  • suitable solvents include DMF, DMSO, THF, CH2CI2, acetonitrile, ethyl acetate, dichloroethane, dimethylacetamide, methanol, ethanol, and toluene.
  • the solvent is acetonitrile.
  • the reaction between the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va) can be carried out at a suitable temperature.
  • the reaction is carried out at a temperature between -50°C and 50°C, between -30°C and 30°C, between -25°C and 25°C, or between -20°C and 20°C.
  • the reaction is carried out between -25°C and 25°C.
  • the reaction between the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va) is quenched with a mixture of an organic solvent and water.
  • said reaction is quenched with water.
  • the organic solvent can be DMF, DMSO, THF, CH2CI2, acetonitrile, ethyl acetate, dichloroethane, dimethylacetamide, methanol, ethanol, or toluene.
  • the reaction is quenched with a mixture of acetonitrile and water.
  • a volume ratio between 1:5 and 5:1, between 1:4 and 4:1, between 1:3 and 3:1, between 1:2 and 2:1, or a volume ratio of 1:1 of an organic solvent to water can be used for the quench.
  • the reaction is quenched with a mixture of acetonitrile and water at a volume ratio of 1:1.
  • Said reaction is quenched at a temperature between -78 °C and 0 °C, between - 78 °C and -15 °C, between -78 °C and -20 °C, between -20 °C and -15 °C, between -20 °C and -10 °C, or at a temperature of -15 °C .
  • the reaction between the compound of Formula (I), (la) or a salt thereof (e.g., a TEA salt) and the compound of Formula (V) or (Va) is carried out in the presence of N-hydroxy succinimide (NHS).
  • the present invention provides a method of preparing a compound of Formula (IV): or a salt thereof, with a deprotecting agent to form a compound of Formula (III): or a salt thereof; and
  • the present invention provides a method of preparing a compound of Formula (IVa): or a salt thereof, comprising the steps of:
  • the reactions of steps (a)-(c) are carried out as the corresponding reactions described in the first and second embodiments and any additional embodiments described therein.
  • the present invention provides a method of preparing a compound of Formula (II): or a salt thereof, comprising the step of reacting a compound of Formula (VI): with a compound of Formula (B) to form the compound of Formula (II) or a salt thereof, wherein the compound of Formula (II) is purified by precipitation.
  • the compound of Formula (II) is represented by a compound of Formula (Ila): or a salt thereof, and the method comprises the step of reacting a compound of Formula (Via): with the compound of Formula (B) to form the compound of Formula (Ila) or a salt thereof, wherein the compound of Formula (Ila) is purified by precipitation.
  • any suitable solvents can be used for said precipitation.
  • the suitable solvents include DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, toluene, and tert-butyl methyl ether.
  • the precipitation is carried out in CH2CI2 and tert-butyl methyl ether.
  • the precipitation is carried out by mixing tert-butyl methyl ether with a solution of the compound of Formula (II) or (Ila) or a salt thereof in CH2CI2.
  • the reaction between the compound of Formula (VI) or (IV a) and the compound of Formula (B) is carried out in the presence of an acid.
  • Any suitable acids can be used for said reaction, which include but are not limited to, trifluoroacetic acid (TFA), formic acid, acetic acid, hydrochloric acid, phosphoric acid, pyridinium p- toluenesulfonate (PPTS), p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and sulfuric acid.
  • TFA trifluoroacetic acid
  • PPTS pyridinium p- toluenesulfonate
  • p-toluenesulfonic acid methanesulfonic acid
  • camphorsulfonic acid and sulfuric acid.
  • the acid is trifluoroacetic acid (TFA).
  • the method of the present invention comprises the steps of: (a) reacting the compound of Formula (II) prepared by the method of the third embodiment with a compound of Formula (V): (V), to form a compound of Formula (VII): or a salt thereof;
  • the method of present invention comprises the steps of:
  • reaction between the compound of Formula (II) or (Ila) and the compound of Formula (V) or (Va) in step (a) is carried out in the presence of an amide coupling reagent.
  • the amide coupling reagent is a 2,4,6-trialkyl-l,3,5,2,4,6- trioxatriphosphorinane 2,4,6-trioxide, carbodiimide (e.g., VV-dicyclohcxylcarbodiimidc (DCC) or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)), 1,1 ’-carbonyldiimidazole (CDI), a uronium, an activated ester, a phosphonium, 2-alkyl-l-alkylcarbonyl-l,2- dihydroquinoline, 2-alkoxy-l-alkoxycarbonyl-l,2-dihydroquinoline, or alkylchloroformate.
  • carbodiimide e.g., VV-dicyclohcxylcarbodiimidc (DCC) or l-ethyl-3-(3-di
  • the amide coupling reagent is l-ethyl-3-(3- dimethylaminopropyl)c arbodiimide (EDC ) .
  • EDC l-ethyl-3-(3- dimethylaminopropyl)c arbodiimide
  • the reaction between the compound of Formula (II) or (Ila) and the compound of Formula (V) or (Va) in step (a) is carried out in the presence of a base.
  • the base is triethylamine, imidazole, N,N- diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine.
  • the base is V A-diisopropylcthylaminc.
  • the compound of Formula (VII), (Vila) or a salt thereof in step (b) is reacted with a deprotecting agent that is a base.
  • the base is piperidine, 4-methylpiperidien, piperazine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), or morpholine.
  • the base is morpholine.
  • the reaction between the compound of Formula (VII), (Vila) or a salt thereof and the deprotecing agent in step (b) is carried out in a suitable solvent including DMF, DMSO, THF, CH2C12, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, or toluene.
  • a suitable solvent including DMF, DMSO, THF, CH2C12, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, or toluene.
  • the solvent is DMF.
  • the reaction between the compound of Formula (VIII), (Villa) or a salt thereof and the compound of Formula (A) in step (c) is carried out in a solvent selected from DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, and toluene.
  • a solvent selected from DMF, DMSO, THF, CH2CI2, acetonitrile, dichloroethane, dimethylacetamide, methanol, ethanol, and toluene.
  • the solvent is DMF.
  • the present invention provides a method of preparing a compound of Formula (I): or a salt thereof, comprising the steps of:
  • the present invention provides a method of preparing a compound of Formula (la): or a salt thereof, comprising the steps of:
  • the present invention provides a method of preparing a compound of Formula (IV): or a salt thereof, comprising the steps of:
  • the present invention provides a method of preparing a compound of Formula (IVa): or a salt thereof, comprising the steps of: (a) reacting the compound of Formula (Ila) prepared by the method of the 3 rd specific embodiment with a deprotecting agent to form a compound of Formula (Illa): or a salt thereof; and
  • MCNE or EMCS 6-Maleimidocaproic acid N-succinimidyl ester
  • the product was transferred to an oven equipped with slow nitrogen bleed and dried at NMT than 28 °C until a constant weight is maintained to afford Compound Illa as amorphous or semi-amorphous material.
  • Amorphous Compound Illa is preferred for the next step of reaction because of higher solubility in MeCN.
  • the largest scale run using this process was 30 g with a second run using another 30 g Compound Ila.
  • Amorphous Compound Illa (1.0 eq, 1 wt) was dissolved in MeCN (30 vol) and heated to 50 ⁇ 3 °C under nitrogen. The suspension was cooled to 20 ⁇ 3 °C over 20 minutes and continued to stir for 1 h. The solid was filtered and washed with MeCN (2 x 5 vol) and dried to provide Compound Illa (yield, 80.7%) as a highly crystalline white solid. The largest scale run using this crystallization method is 30 g amorphous of Compound Illa.

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Abstract

L'invention concerne de nouveaux procédés améliorés de préparation de dérivés maytansinoïdes dotés de lieurs peptidiques auto-immolables ainsi que leurs précurseurs synthétiques.
PCT/US2023/032866 2022-09-15 2023-09-15 Procédés de préparation de dérivés maytansinoïdes dotés de lieurs peptidiques auto-immolables Ceased WO2024059263A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018160539A1 (fr) * 2017-02-28 2018-09-07 Immunogen, Inc. Dérivés de maytansinoïdes comprenant des lieurs peptidiques auto-immolables et conjugués correspondants
WO2020005945A1 (fr) * 2018-06-26 2020-01-02 Immunogen, Inc. Immunoconjugués ciblant l'adam9 et méthodes d'utilisation associés
WO2020014306A1 (fr) * 2018-07-10 2020-01-16 Immunogen, Inc. Anticorps anti-met, immunoconjugués et utilisations de ceux-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018160539A1 (fr) * 2017-02-28 2018-09-07 Immunogen, Inc. Dérivés de maytansinoïdes comprenant des lieurs peptidiques auto-immolables et conjugués correspondants
WO2020005945A1 (fr) * 2018-06-26 2020-01-02 Immunogen, Inc. Immunoconjugués ciblant l'adam9 et méthodes d'utilisation associés
WO2020014306A1 (fr) * 2018-07-10 2020-01-16 Immunogen, Inc. Anticorps anti-met, immunoconjugués et utilisations de ceux-ci

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"McGraw-Hill Dictionary of Chemical Terms", 1984, MCGRAW-HILL BOOK COMPANY
"The McGraw-Hill Dictionary of Chemical Terms", 1985, MCGRAW-HILL
ELIEL, E.WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC.

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