US10385018B2 - 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors - Google Patents

4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors Download PDF

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US10385018B2
US10385018B2 US14/438,410 US201314438410A US10385018B2 US 10385018 B2 US10385018 B2 US 10385018B2 US 201314438410 A US201314438410 A US 201314438410A US 10385018 B2 US10385018 B2 US 10385018B2
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dihydro
oxo
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carboxylic acid
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Gianluca Mariano Enrico Papeo
Mikhail Yurievitch Krasavin
Paolo Orsini
Alessandra Scolaro
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Nerviano Medical Sciences SRL
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Definitions

  • the present invention provides novel substituted 4-carboxamido-isoindolinone derivatives which proved to be potent and selective poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors with respect to poly (ADP-ribose) polymerase-2 (PARP-2) and are thus useful in the therapy of cancer, cardiovascular diseases, nervous system injury and inflammation.
  • PARP-1 ADP-ribose polymerase-1
  • PARP-2 poly (ADP-ribose) polymerase-2
  • the present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
  • Poly (ADP-ribose) polymerases belong to a family of 18 members that catalyze the addition of ADP-ribose units to DNA or different acceptor proteins, which affect cellular processes as diverse as replication, transcription, differentiation, gene regulation, protein degradation and spindle maintenance.
  • PARP-1 and PARP-2 are the only enzymes among the PARPs that are activated by DNA damage and are involved in DNA repair.
  • PARP-1 is a nuclear protein consisting of three domains: the N-terminal DNA-binding domain containing two zinc fingers, the auto modification domain, and the C-terminal catalytic domain. PARP-1 binds through the zinc-finger domain to DNA single strand breaks (SSB), cleaves NAD + , and attaches multiple ADP-ribose units to target proteins such as histones and various DNA repair enzymes. This results in a highly negatively charged target, which in turn leads to the unwinding and repair of the damaged DNA through the base excision repair pathway. In knock out mouse models, deletion of PARP-1 impairs DNA repair but it is not embryonic lethal.
  • SSB DNA single strand breaks
  • Enhanced PARP-1 expression and/or activity have been shown in different tumor cell lines, including malignant lymphomas, hepatocellular carcinoma, cervical carcinoma, colorectal carcinoma, leukemia. This may allow tumor cells to withstand genotoxic stress and increase their resistance to DNA-damaging agents.
  • inhibition of PARP-1 through small molecules has been shown to sensitize tumor cells to cytotoxic therapy (e.g. temozolomide, platinums, topoisomerase inhibitors and radiation).
  • cytotoxic therapy e.g. temozolomide, platinums, topoisomerase inhibitors and radiation.
  • PARP inhibitors may be more effective in patients with tumors with specific DNA repair defects without affecting normal heterozygous tissues.
  • Putative patient population includes, besides BRCA mutants that represent the majority of hereditary breast and ovarian cancer, also a substantial fraction of sporadic cancers with defects in homologous recombination repair, a phenomenon termed “BRCAness”. For example, methylation of the promoters of the BRCA-1 or FANCF genes and amplification of the EMSY gene, which encodes a BRCA-2 interacting protein.
  • PARP-1 has also been implicated in angiogenesis.
  • PARP-1 inhibition seems to result in decreased accumulation of the transcription hypoxia-inducible factor 1 ⁇ , an important regulator of tumor cell adaptation to hypoxia.
  • Pro-inflammatory stimuli trigger the release of pro-inflammatory mediators that induce the production of peroxynitrate and hydroxyl radicals, which in turn yield to DNA single strand breakage with consequent activation of PARP-1.
  • Over activation of PARP-1 results in depletion of NAD+ and energy stores, culminating in cell dysfunction and necrosis.
  • This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation.
  • PARP-1 nuclear factor kB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines and inflammatory mediators.
  • WO 2007/047646 in the name of Janssen Pharmaceutica describes substituted dihydro-isoindolones useful for treating kinase disorders; Wender et al. claim in U.S. Pat. No. 7,232,842 isoindolone analogs as kinase inhibitors.
  • the Patent Application US 2008/0108659 of Lucas et al. describes 3-oxo-2,3-dihydro-1H-isoindoles as poly (ADP-ribose) polymerase inhibitors, also reported in: Bioorg. Med. Chem. Lett., 2010, 20, 1023-1026.
  • the present invention provides novel substituted 4-carboxamido-isoindolinone derivatives which proved to be potent and selective PARP-1 inhibitors with respect to PARP-2 and are thus useful in the therapy of cancer, cardiovascular diseases, nervous system injury and inflammation.
  • the present invention also provides method for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
  • a first object of the present invention is to provide a compound of formula (I):
  • R is hydrogen or fluorine
  • n, m, R1 and R2 have the following meanings:
  • R1 is 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl
  • R2 is a 3-, 5- or 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, aryl or heteroaryl;
  • n 1 and m is 0;
  • R1 is 3- to 6-membered cycloalkyl or aryl, each of which optionally further substituted with one or more linear or branched (C 1 -C 6 )-alkyl;
  • R2 is null, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (C 1 -C 6 )-alkyl;
  • n 2 or 3, and m is 0;
  • R1 is a 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (C 1 -C 6 )-alkyl; and
  • R2 is null, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (C 1 -C 6 )-alkyl;
  • n and m are each independently 1, 2 or 3;
  • R1 and R2 are each independently 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, aryl or heteroaryl;
  • the compounds of formula (I) as defined above are potent and selective PARP-1 inhibitors with respect to PARP-2 and are thus useful in cancer, cardiovascular diseases, nervous system injury and inflammation therapy.
  • the present invention also provides methods of synthesizing substituted 4-carboxamido-isoindolinone derivatives of formula (I) as defined above, through a process consisting of standard synthetic transformations.
  • the present invention also provides a method for treating diseases mediated by PARP-1 protein which comprises administering to a mammal in need thereof, preferably a human, an effective amount of a compound of formula (I), as defined above.
  • a preferred method of the present invention is to treat a disease mediated by PARP-1 protein selected from the group consisting of cancer, cardiovascular diseases, nervous system injury and inflammation.
  • carcinomas such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma
  • hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma
  • hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia
  • tumors of mesenchymal origin including fibrosarcoma
  • the method of the present invention also provides tumor angiogenesis and metastasis inhibition.
  • Another preferred method of the present invention is to treat specific types of cardiovascular diseases including, but not limited to, myocardial reperfusion injury, cardiomyopathy, diabetic cardiovascular dysfunction.
  • Another preferred method of the present invention is to treat specific types of nervous system injury including but not limited to: stroke, brain injury and neurodegenerative disorders.
  • Another preferred method of the present invention is to treat specific types of inflammation diseases including, but not limited to, colitis, arthritis and uveitis.
  • the present invention also provides an in vitro method for selectively inhibiting PARP-1 protein activity which comprises contacting the said protein with an effective amount of a compound of formula (I), as defined above.
  • the present invention further provides a method for treating diseases comprising a compound of formula (I), as defined above, in combination with radiation therapy or chemotherapy regimen for simultaneous, separate or sequential use in anticancer therapy.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and at least one pharmaceutically acceptable excipient, carrier or diluent.
  • the pharmaceutical composition of the present invention may further comprise one or more chemotherapeutic—e.g. cytostatic or cytotoxic—agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrix metalloproteinases inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g.
  • chemotherapeutic e.g. cytostatic or cytotoxic—agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrix metalloproteinases inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-
  • the chemotherapeutic agent is an alkylating agent. Even more preferably, the alkylating agent is temozolomide.
  • the invention provides a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
  • the chemotherapeutic agent is an alkylating agent.
  • the alkylating agent is temozolomide.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use as a medicament, preferably as a medicament with anticancer activity.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in a method of treating cancer.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with anticancer activity.
  • the compounds of formula (I) may have one or more asymmetric centers, and may therefore exist as individual optical isomers or racemic mixtures or diastereoisomers. Accordingly, all the possible isomers, and their mixtures of the compounds of formula (I) are within the scope of the present invention. As stated above, salts of the compounds of formula (I) are also within the scope of the present invention.
  • the present invention includes all of the isomers, tautomers, hydrates, solvates, N-oxides and pharmaceutically acceptable salts of the compounds of this invention.
  • a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • halogen we intend a fluorine, chlorine, bromine or iodine atom.
  • linear or branched (C 1 -C 6 )-alkyl we intend any of the groups such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • 3- to 6-membered cycloalkyl we intend, unless otherwise provided, a 3- to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated 7-electron system.
  • cycloalkyl groups without limitation, are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl.
  • heterocyclyl we intend a 4- to 6-membered, saturated or partially unsaturated carbocyclic ring where one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur; the heterocyclyl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
  • heterocyclyl groups are, for instance, pyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl and the like.
  • aryl refers to a mono-, bi- or poly-carbocyclic hydrocarbon with from 1 to 4 ring systems, optionally further fused or linked to each other by single bonds, wherein at least one of the carbocyclic rings is “aromatic”, wherein the term “aromatic” refers to completely conjugated ⁇ -electron bond system.
  • aryl groups are phenyl, ⁇ - or ⁇ -naphthyl or biphenyl groups.
  • heteroaryl refers to aromatic heterocyclic rings, typically 5- to 8-membered heterocycles with from 1 to 3 heteroatoms selected among N, O or S; the heteroaryl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
  • heteroaryl groups are, for instance, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, indazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-
  • any of the above mentioned groups when any of the above mentioned groups is optionally substituted, it may be substituted in any of its free position by one or more linear or branched (C 1 -C 6 ) alkyl groups.
  • pharmaceutically acceptable salt of compounds of formula (I) refers to those salts that retain the biological effectiveness and properties of the parent compound, therefore pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts with inorganic or organic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, (D) or (L) lactic, oxalic, ascorbic, fumaric, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, ethanesulfonic, p-toluenesulfonic, isethionic, succinic and salicylic acid.
  • inorganic or organic acids e.g., nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroace
  • Pharmaceutically acceptable salts of the compounds of formula (I) also include the salts with inorganic or organic bases, e.g., alkali or alkaline-earth metals, especially sodium, potassium, calcium, ammonium or magnesium hydroxides, carbonates or bicarbonates, and acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like.
  • inorganic or organic bases e.g., alkali or alkaline-earth metals, especially sodium, potassium, calcium, ammonium or magnesium hydroxides, carbonates or bicarbonates, and acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like.
  • the present invention provides compounds of formula (I) as defined above characterized in that
  • R is hydrogen or fluorine
  • n, m, R1 and R2 have the following meanings:
  • R1 is a 6-membered heterocyclyl
  • R2 is a 3- or 6-membered cycloalkyl, 6-membered heterocyclyl, aryl or heteroaryl;
  • n 1 and m is 0;
  • R1 is aryl, optionally further substituted with one or more linear or branched (C 1 -C 6 )-alkyl;
  • R2 is null
  • n 2 or 3, and m is 0;
  • R1 is a 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (C 1 -C 6 )-alkyl;
  • R2 is null, a 6-membered heterocyclyl or aryl
  • n 2 or 3, and m is 1;
  • R1 is a 6-membered heterocyclyl
  • R2 is aryl
  • the present invention provides compounds of formula (I) as defined above characterized in that
  • R is hydrogen or fluorine
  • n, m, R1 and R2 have the following meanings:
  • R1 is a 6-membered heterocyclyl
  • R2 is a 3- or 6-membered cycloalkyl, 6-membered heterocyclyl, aryl or heteroaryl;
  • n 2 or 3, and m is 0;
  • R1 is a 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (C 1 -C 6 )-alkyl;
  • R2 is null, a 6-membered heterocyclyl or aryl
  • the present invention provides compounds of formula (I) as defined above characterized in that:
  • R is hydrogen or fluorine
  • n, m, R1 and R2 have the following meanings:
  • R1 is a 6-membered heterocyclyl
  • R2 is a 3- or 6-membered cycloalkyl, 6-membered heterocyclyl, aryl or heteroaryl;
  • the present invention provides compounds of formula (I) as defined above characterized in that:
  • R is hydrogen or fluorine
  • n, m, R1 and R2 have the following meanings:
  • R1 is a piperidine ring and R2 is a cyclohexyl ring;
  • R1 is a piperidine ring and R2 is a pyridine ring;
  • a process of the present invention comprises one of the following sequences of steps:
  • Hal is halogen such as Cl, Br, and I;
  • Step f) esterifying the compound of formula (VII) obtained in step d) or e)
  • T is a (C 1 -C 6 )-alkyl or an aryl-(C 1 -C 6 )-alkyl and Hal is as defined above;
  • R1 and n are as defined above, and X is either R2-[CH 2 ] m —, wherein R2 and m are as defined above, or a suitable nitrogen protective group, when R1 is a nitrogen containing heterocyclyl;
  • R1 is a nitrogen containing heterocyclyl and X is a suitable nitrogen protective group
  • Step i) deprotecting the compound of formula (III), as defined above, so as to obtain either
  • R1 and n are as defined above;
  • R1 and n are as defined above, and X is either R2-[CH 2 ] m —, wherein R2 and m are as defined above, or a suitable nitrogen protective group, when R1 is a nitrogen containing heterocyclyl;
  • R1, n and X are as defined above;
  • R1, n and X are as defined above;
  • R1 is a nitrogen containing heterocyclyl and X is a suitable nitrogen protective group
  • Step i′ deprotecting a compound of formula (XX) as defined above;
  • Step o the compound resulting from aromatization of a compound of formula (XVII) is a compound of formula (XIX), i.e. when X is a labile nitrogen protective group, the following Step q is performed:
  • the processes above described comprises converting a compound of formula (I) into a different compound of formula (I) by known chemical reactions; and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into a free compound of formula (I).
  • Such known chemical reactions for possible conversions of compounds into different compounds comprise for instance a reductive amination (Cv1).
  • a compound of formula (I) can be carried out in a stepwise manner, whereby each intermediate is isolated and purified by standard purification techniques, like, for example, column chromatography, before carrying out the subsequent reaction.
  • two or more steps of the synthetic sequence can be carried out in a so-called “one-pot” procedure, as known in the art, whereby only the compound resulting from the two or more steps is isolated and purified.
  • Schemes 1-2 below show the preparation of a compound of formula (I) as defined above.
  • a compound of formula (X) can be obtained by halogenating 4-fluoro-2-methyl-phenylamine (XI) in a variety of ways and experimental conditions known in the art.
  • this reaction is conducted in the presence of N-bromosuccinimide, N-iodosuccinimmide, N-chlorosuccinimide, bromine, iodine, hydrobromic acid/hydrogen peroxide, in a suitable solvent, such as acetonitrile, N,N-dimethylformamide, dioxane, dimethylsulfoxide, acetic acid or water, at a temperature ranging from about room temperature to reflux and for a period of time varying from about 1 h to about 96 h.
  • a suitable solvent such as acetonitrile, N,N-dimethylformamide, dioxane, dimethylsulfoxide, acetic acid or water
  • a compound of formula (IX) can be obtained by a two-steps reaction sequence from a compound of formula (X) in a variety of ways and experimental conditions known in the art.
  • First step is preferably conducted in the presence of sodium nitrite/hydrochloric acid or tert-butylnitrite in a suitable solvent, such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid or water, at a temperature ranging from about ⁇ 20° C. to room temperature and for a period of time varying from 10 min to about 24 h.
  • a suitable solvent such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid or water
  • Second step is preferably carried out in the presence of sodium, copper or potassium cyanide, often in the presence of an additive such as copper or potassium chloride, in a suitable solvent, such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid, toluene or water, at a temperature ranging from about ⁇ 20° C. to reflux and for a period of time ranging from about 10 min to about 96 h.
  • a suitable solvent such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid, toluene or water
  • step c) the hydrolysis of a compound of formula (IX) to a give a compound of formula (VIII) can be carried out in a variety of ways, according to conventional methods for transforming a cyano group to amide.
  • this reaction is carried out in a suitable solvent such as, for instance, methanol, ethanol, butanol, 1,4-dioxane, toluene, water, or a mixture thereof, in the presence of a suitable acid or base, such as, for instance, sulfuric acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, sodium hydroxide, sodium carbonate, or a suitable reagent such as hydrogen peroxide, sodium perborate or indium(III) salts in the presence of acetaldoxime.
  • the reaction is carried out at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
  • a compound of formula (VIII) can be transformed into a compound of formula (VII) according to conventional methods.
  • the reaction is carried out in the presence of water by treatment with a base such as potassium or sodium carbonate, potassium or sodium hydroxide, in a suitable solvent such as, for instance, methanol or ethanol, at a temperature ranging from room temperature to reflux, for a time ranging from about 30 min to about 96 h.
  • a base such as potassium or sodium carbonate, potassium or sodium hydroxide
  • a suitable solvent such as, for instance, methanol or ethanol
  • this reaction can be conducted in the presence of sodium nitrite/acetic acid, sulfuric acid, phosphoric acid, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
  • the halogenation of 4-fluoro-2-methyl-benzoic acid (XII) into a compound of formula (VII) can be carried out in a variety of ways, according to conventional methods for halogenation reactions.
  • this reaction is carried out with tetrabutylammonium bromide and/or iodine in the presence of phenyliodine(III) bis(trifluoracetate) or phenyliodo(III) diacetate as halogen source in a suitable solvent such as, for instance, N,N-dimethylformamide or dichloroethane, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 48 h.
  • the catalyst is usually a metal, most often a palladium derivative such as, for instance, palladium(II) chloride or palladium(II) acetate.
  • a compound of formula (VII) can be transformed into a compound of formula (VI) according to conventional methods.
  • the reaction is carried out in the presence of hydrochloric acid, sulfuric acid or acetic acid by using as a solvent methanol, ethanol, water, or a mixture thereof, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
  • this reaction can be conducted with alkyl iodide, bromide or toluensulfonate in the presence of a suitable base, such as sodium or potassium carbonate, and sodium, lithium or potassium hydroxide, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
  • a suitable base such as sodium or potassium carbonate, and sodium, lithium or potassium hydroxide
  • step g) the transformation of a compound of formula (VI) into a compound of formula (V) can be carried out in a variety of ways, according to conventional methods for cyanation reactions.
  • this reaction is carried out in the presence of copper(I) cyanide or potassium hexacyanoferrate(II) as cyano source in a suitable solvent such as, for instance, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, toluene, xylene, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or a mixture thereof, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
  • a suitable solvent such as, for instance, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, toluene, xylene, N-methyl-2-pyrroli
  • a catalyst is usually a metal, most often a palladium derivative such as, for instance, tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride or palladium(II) acetate in the presence of a suitable base such as, for instance, sodium, potassium or cesium carbonate or cesium fluoride.
  • a suitable base such as, for instance, sodium, potassium or cesium carbonate or cesium fluoride.
  • a compound of formula (IV) can be obtained by a two-steps reaction sequence from a compound of formula (V) in the presence of a compound of formula (XIII) in a variety of ways and experimental conditions known in the art.
  • First step is preferably conducted in the presence of N-bromosuccinimide with a radical initiator such as benzoyl peroxide or azobisisobutyronitrile in a suitable solvent, such as carbon tetrachloride, chloroform, dichloromethane or methyl pivalate, at a temperature ranging from about room temperature to reflux and for a period of time varying from 10 min to about 24 h.
  • a radical initiator such as benzoyl peroxide or azobisisobutyronitrile
  • a suitable solvent such as carbon tetrachloride, chloroform, dichloromethane or methyl pivalate
  • Second step can be conducted both under basic or acidic conditions, such as in the presence of sodium or potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, pyridine or acetic acid, hydrochloric acid, in a suitable solvent, such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane or toluene, at a temperature ranging from room temperature to reflux and for a period of time varying from 1 h to about 96 h.
  • a suitable solvent such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane or toluene
  • step c′ the hydrolysis of a compound of formula (IV) to give either a compound of formula (I) or a compound of formula (III), can be carried out in a variety of ways and experimental conditions. Preferably it is carried out in a way analogous to that reported for step c).
  • a compound of formula (I) or a compound of formula (II) can be obtained by removing these protective groups under acidic conditions, preferably in the presence of an inorganic or organic acid such as hydrochloric, trifluoroacetic or methanesulphonic acid, boron tribromide or aluminium trichloride, in a suitable solvent, such as dichloromethane, dichloroethane, dioxane or a lower alcohol, such as methanol or ethanol, at a temperature ranging from room temperature to reflux.
  • an inorganic or organic acid such as hydrochloric, trifluoroacetic or methanesulphonic acid, boron tribromide or aluminium trichloride
  • a suitable solvent such as dichloromethane, dichloroethane, dioxane or a lower alcohol, such as methanol or ethanol
  • X is a nitrogen protective group such as benzyloxycarbonyl and the like
  • a compound of formula (I) or a compound of formula (II) can be obtained by removing these protective groups under reducing conditions, such as, for instance, in the presence of hydrogen and a hydrogenation catalyst in a suitable solvent, such as ethanol, methanol, ethyl acetate, or a mixture thereof.
  • the catalyst is usually a metal, most often a palladium derivative such as, for instance, palladium on carbon, palladium hydroxide or palladium black.
  • X is a nitrogen protective group such as methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethoxycarbonyl and the like
  • a compound of formula (I) or a compound of formula (II) can be obtained by removing these protective groups under basic conditions such as, for instance, sodium, potassium or cesium carbonate, sodium, potassium or barium hydroxide, hydrazine, piperidine, morpholine or the like, in a suitable solvent, such as methanol, ethanol, water, N,N-dimethylformamide, N,N-dimethylacetamide or the like, at a temperature ranging from room temperature to reflux.
  • a suitable solvent such as methanol, ethanol, water, N,N-dimethylformamide, N,N-dimethylacetamide or the like
  • step l) the reductive alkylation of a compound of formula (II), in the presence of a compound of formula (XIV), to give a compound of formula (I), can be conducted in a variety of ways, according to conventional methods for carrying out reductive amination.
  • this reaction is carried out in a suitable solvent such as, for instance, methanol, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, benzene, toluene, or a mixture thereof, in the presence of a suitable reducing agent such as, for instance, sodium borohydride, tetraalkylammonium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride, tetramethylammonium triacetoxy borohydride and in the presence of an acid or basic catalyst, such as, for instance, acetic acid, trifluoroacetic acid, zinc chloride, zinc bromide, tin(IV) chloride, titanium(IV) chloride, boron trifluoride or triethylamine, diisopropylethylamine or pyridine, at a temperature ranging from about 0° C. to reflux and for a time varying from about 1 h to about 96 h
  • a compound of formula (XVI) can be obtained from furan-2-carbaldehyde (XV) through reductive amination in the presence of a compound of formula (XIII).
  • this reaction is carried out in a suitable solvent such as, for instance, methanol, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, benzene, toluene, or a mixture thereof, in the presence of a suitable reducing agent such as, for instance, sodium borohydride, tetraalkylammonium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride or tetramethylammonium triacetoxy borohydride, and in the presence of an acid or basic catalyst, such as, for instance, acetic acid, trifluoroacetic acid, zinc chloride, zinc bromide, tin(IV) chloride, titanium(IV) chloride, boron trifluoride or tri
  • a suitable solvent such
  • step n) the Diels-Alder reaction, performed on a compound of formula (XVI) to give a compound of formula (XVII), can be conducted in a variety of ways, according to conventional methods for carrying out these reactions.
  • this reaction is carried out in a suitable solvent such as, for instance, tetrahydrofuran, benzene, toluene or o-xylene, in the presence of maleic anhydride at a temperature ranging from about room temperature to reflux and for a time varying from about 1 h to about 96 h.
  • step o) the transformation of a compound of formula (XVII) into either a compound of formula (XVIII) or a compound of formula (XIX), can be carried out in a variety of ways, according to conventional methods.
  • this reaction is carried out in a suitable solvent such as, for instance, tetrahydrofuran, toluene or water, in the presence of hydrochloric acid, p-toluenesulfonic acid or phosphoric acid, at a temperature ranging from about room temperature to reflux and for a time varying from about 1 h to about 24 h.
  • a suitable solvent such as, for instance, tetrahydrofuran, toluene or water
  • hydrochloric acid, p-toluenesulfonic acid or phosphoric acid at a temperature ranging from about room temperature to reflux and for a time varying from about 1 h to about 24 h.
  • a compound of formula (XVIII) can be reacted either to deliver a compound of formula (I) or a compound of formula (XX) in a variety of ways and experimental conditions, which are widely known in the art of condensation reactions.
  • a compound of formula (XVIII) is reacted with ammonia or ammonia source such as ammonium salts, in the presence of an activating agent such as carbonyldiimidazole, benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, dicyclohexyl carbodiimide, diisopropyl carbodi
  • this reaction is carried out in a suitable solvent such as, for instance, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dichloromethane or 1,4-dioxane, and in the presence of a proton scavenger such as, for example, pyridine, triethylamine or diisopropylethylamine, at a temperature ranging from room temperature to reflux, for a time ranging from about 30 min to about 96 h.
  • a suitable solvent such as, for instance, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dichloromethane or 1,4-dioxane
  • a proton scavenger such as, for example, pyridine, triethylamine or diisopropylethylamine
  • step i′ the deprotection of a compound of formula (XX) to give a compound of formula (XXI), can be carried out in a variety of ways and experimental conditions. Preferably it is carried out in a way analogous to that reported for step i).
  • step l′ the reductive alkylation of a compound of formula (XXI), in the presence of a compound of formula (XIV), to give a compound of formula (I), can be carried out in a variety of ways and experimental conditions. Preferably it is carried out in a way analogous to that reported for step l).
  • step q) the protection of compound of formula (XIX) to give a compound of formula (XVIII), where X is a suitable nitrogen protective group, may be carried out in a variety of ways and experimental conditions.
  • the protective group is tert-butoxycarbonyl
  • the reaction may be carried out in the presence of di-tert-butyl dicarbonate in a variety of solvents such as methanol, ethanol, acetonitrile, tetrahydrofuran or dichloromethane, in the presence of a base, such as pyridine, N,N-dimethylaminopyridine, triethylamine, diisopropylethylamine, sodium or potassium carbonate, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
  • a base such as pyridine, N,N-dimethylaminopyridine, triethylamine, diisopropylethylamine, sodium or potassium
  • the reductive alkylation of a compound of formula (I) to give another compound of formula (I) may be carried out in a variety of ways and experimental conditions. Preferably, it is carried out in a way analogous to that reported for step l).
  • Substituted isoindolinone derivatives can be prepared using standard procedures in organic synthesis as reported, for instance, in Smith, Michael—March's Advanced Organic Chemistry: reactions mechanisms and structure—6 th Edition, Michael B. Smith and Jerry March, John Wiley & Sons Inc., New York (N.Y.), 2007. It is known to the skilled person that transformation of a chemical function into another may require that one or more reactive centers in the compound containing this function have to be protected in order to avoid undesired side reactions. Protection of such reactive centers, and subsequent deprotection at the end of the synthetic transformations, can be accomplished following standard procedures described, for instance, in: Green, Theodora W. and Wuts, Peter G. M.—Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., New York (N.Y.), 1999.
  • a compound of formula (I) contains one or more asymmetric centers
  • said compound can be separated into the single isomers by procedures known to those skilled in the art. Such procedures comprise standard chromatographic techniques, including chromatography using a chiral stationary phase, or crystallization. General methods for separation of compounds containing one or more asymmetric centers are reported, for instance, in Jacques, Jean; Collet, André; Wilen, Samuel H.—Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (N.Y.), 1981.
  • a compound of formula (I) can also be transformed into a pharmaceutically acceptable salt according to standard procedures that are known to those skilled in the art.
  • a compound of formula (I) that is obtained as a salt can be transformed into the free base or the free acid according to standard procedures that are known to the skilled person.
  • the starting materials of the process of the present invention i.e. 4-fluoro-2-methyl-phenylamine (XI), 4-fluoro-2-methyl-benzoic acid (XII), furan-2-carbaldehyde (XV) and compounds of formula (XIII) and (XIV) are either commercially available or can be prepared by using well-known methods.
  • PARP-1 is a DNA damage-induced polymerase that catalyzes the cleavage of NAD+ into nicotinamide and ADP-ribose and then uses the latter to synthesize branched nucleic-acid like poly(ADP-ribose) polymers.
  • ADP-ribosylated protein is PARP-1 itself, followed by histones.
  • PARP-1 is responsible for 90% of this DNA damage-induced activity while the remaining 10% is due to PARP-2.
  • the identification of compounds capable of binding several PARP proteins is carried out through a screening method including the steps of
  • R 11 is hydrogen or a methyl group
  • B is (CH 2 ) n —NH group wherein n is 2 to 6; m is 0 or 1 and X --- is a counterion, and
  • both the PARP protein and the 5H-phenanthridin-6-one-derived probe of formula (IP) are pre-mixed, or the PARP protein and the test compound are pre-mixed.
  • the PARP proteins are PARP-1, PARP-2 and PARP-3.
  • the term “PARP protein” encompasses full-length native proteins as well as fragments thereof. More preferably, R 11 is hydrogen or methyl, m is 0 or 1; when m is 1, n is 3 or 6, X --- is trifluoroacetate.
  • the 5H-phenanthridin-6-one-derived probe (IP) was selected for its capability of binding to the PARP proteins, both encompassing full-length native proteins and fragments thereof.
  • the polarization signal can be measured, e.g., by a plate reader such as the Saphire2 (Tecan). Data analysis was performed, e.g., by using the Dynafit software. Displacement data were also fitted, e.g., by using Excel spreadsheet (Microsoft Inc. Seattle, USA) to a four parameter logistic model (4PL), or Hill-Slope model.
  • the assay was used to test compounds of the present invention. The displacement ability of the test compounds of formula (I) is in correlation with the compounds affinity for the NAD pocket of the enzyme.
  • Specific probes of formula (IP) used in the assay are:
  • a compound of formula (IP) as defined above can be prepared as described in WO 2010/133647.
  • the assay is based on the use of a probe of formula (IP) that binds to the NAD binding pocket and takes advantage of the significant change in the polarization signal observed upon binding of the probe to PARP-1, -2 and -3.
  • the ability of the probe of formula (IP) to bind full-length PARP-1, -2 and -3 has been previously reported (WO 2010/133647).
  • the assay has been validated as described in WO 2010/133647.
  • Affinity binding constants (Kd) and DC 50 s (the compound concentration at which the polarization signal is diminished by 50% compared to untreated controls) of the test compounds can be determined as explained in WO 2010/133647.
  • X is the logarithm of concentration
  • IC 50 is the response; IC 50 starts at bottom and goes to top with a sigmoid shape.
  • MDA-MB-436 breast cancer BRCA-1 mutated cells were grown at the density of 600 cells/cm 2 in RPMI medium supplemented with 10% Fetal Bovine Serum. 24 h later different doses of compounds were added starting from 10 ⁇ M concentration in duplicates. Ten days later, cells were fixed and stained with crystal violet. Colonies were counted using Infrared Scanner (Odyssey Li-Cor). Anti proliferative IC 50 was calculated using Prism.
  • the pharmacokinetic profile and the oral bioavailability of the compounds have been investigated in the mouse (Balb, Nu/Nu, Harlan, Italy) in ad hoc pharmacokinetic studies.
  • the compounds were formulated in 10% tween 80/dextrose for intravenous bolus administration while oral administrations were performed using the compounds formulated in 0.5% methylcellulose.
  • a single administration at the dose of 10 mg/kg was given and three male animals for each route were used. All blood samples were taken from retro-orbital vein at 5 min, 30 min, 1 h, 3 h, 6 h, 24 h after intravenous administration and 15 min, 30 min, 1 h, 3 h, 6 h, 24 h after oral administration.
  • Plasma samples were prepared by plasma proteins precipitation adding 200 ⁇ L of acetonitrile to 20 ⁇ L of plasma in a 96 well plate. After capping and vortex mixing, the plate was centrifuged for 15 min at 4000 rpm. The supernatant was considered as final extract and injected onto the LC-MS-MS system (UPLC system: Waters Acquity using BEH C18 50*2.1 mm 1.7 ⁇ m analytical column; MS instrument: Waters TQD equipped with Electro-Spray source operating in positive ion mode). Lower limit of quantification is 5.0 ng/mL, upper limit of quantification is 5000 ng/mL.
  • Non-compartmental method linear trapezoidal rule and linear regression analysis of natural log-transformed plasma concentrations vs. time data was used. Absolute bioavailability (F) was calculated from the ratio of average oral to IV (intravenous) dose-normalized plasma AUC (area under curve) values.
  • AUC area under the plasma concentration vs. time curve up to the last detectable concentration
  • Vdss volume of distribution at steady state
  • mice athymic Nu/Nu male mice, from Harlan (Italy), were maintained in agreement with the European Communities Council Directive no. 86/609/EEC concerning the protection of animals used for experimental or other scientific purposes, in cages with paper filter cover, food and bedding sterilized and acidified water. Fragments of Capan-1 human pancreatic cancer tumors were implanted subcutaneously. Mice bearing a palpable tumor (100-200 mm 3 ) were selected and randomized into control and treated groups. Each group included seven animals. The treatment started one day after randomization. Compound of formula (I) was administered by oral route as a methocel suspension at the indicated doses and times.
  • Tumor dimension was measured regularly by calipers during the experiments and tumor mass was calculated as described in Simeoni M. et al., Cancer Res 64, 1094-1101 (2004).
  • Representative compounds of formula (I) were evaluated for their anti-tumor activity on Capan-1 BRCA-2 mutated mouse model in combination with temozolomide.
  • Compounds of formula (I) and temozolomide were both administered by oral route. Tumor growth was assessed by caliper. The two diameters were recorded and the tumor weight was calculated according to the following formula: length (mm) ⁇ width 2 /2.
  • the effect of the antitumor treatment was evaluated as the delay in the onset of an exponential growth of the tumor (see for references Anticancer drugs 7:437-60, 1996). This delay (T-C value) was defined as the difference of time (in days) required for the treatment group (T) and the control group (C) tumors to reach a predetermined size (1 g).
  • Toxicity was evaluated on the basis of body weight reduction and animal survival rate.
  • the T-C observed when Compounds of formula (I) were combined with temozolomide was superior to the one expected by the simple addition of T-C obtained by the single treatments, thus indicating strong synergism.
  • the present invention provides compounds of formula (I) useful in therapy.
  • Compounds of formula (I) of the present invention suitable for administration to a mammal, e.g., to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, conditions of the patient and administration route.
  • a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 1 to about 1000 mg per dose, from 1 to 5 times daily.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g., orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g., intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • the present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent.
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulation
  • the liquid dispersions for oral administration may be, e.g., syrups, emulsions and suspensions.
  • the syrups may contain, as carrier, saccharose or saccharose with glycerine and/or mannitol and sorbitol.
  • the suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier.
  • the suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • FCS Fretal Calf Serum
  • FBS Fetal Bovine Serum
  • PBS Phosphate Buffered Saline
  • Triethylamine (0.41 mL, 2.9 mmol) and 3-morpholin-4-yl-propylamine (XIII) (140 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90° C. for 3 h. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. The organic phase was dried over Na 2 SO 4 , filtered and evaporated.
  • the resultant dark mixture was cooled to room temperature, diluted with methyl-tert-butylether (200 mL) and treated with a solution of sodium metabisulfite (250 g) in water (500 mL) under efficient stirring. Then, this yellow colored mixture was acidified by slowly adding conc. hydrochloric acid (130 mL). The aqueous layer was separated and extracted twice with methyl-tert-butylether (mL100 ⁇ 2). The combined organic extracts were treated with a solution of sodium hydroxide pellets (80 g) in water (300 mL) under stirring.
  • the thick reaction mixture was diluted with methyl-tert-butylether (100 mL) and washed with water (600 mL); the aqueous layer was separated and extracted twice with methyl-tert-butylether (70 mL ⁇ 2). The combined organic extracts were washed with brine (50 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to a solid residue. This material was purified by chromatography (eluant n-hexane/ethyl acetate 9:1), affording 26.2 g (81%) of product as colorless oil.
  • Method B a solution of 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII) (5.5 g, 15.3 mmol) and carbonyldiimidazole (3.7 g, 22.8 mmol) in dry tetrahydrofuran (80 mL) was stirred at room temperature for 4 h. Then concentrated aqueous ammonia (25 mL) was added and the reaction mixture was left at room temperature until the disappearance of the starting material (3 h). The solvent was evaporated under reduced pressure and the resulting crude primary amide (1.1 g, 20%) was employed without any further purification.
  • XVIII 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylic acid
  • XVIII 2-(1-tert-butoxycarbonyl
  • Method B to a solution of 2-piperidin-4-yl-2,3-dihydro-1H-isoindole-4-carboxylic acid amide hydrochloride (4.4 g, 14.8 mmol) and cyclohexanone (2.2 g, 22.45 mmol) in N,N-dimethylformamide (100 mL), glacial acetic acid (4.5 mL) and tetramethylammonium triacetoxyborohydride (11.8 g, 44.85 mmol) were added. The resulting solution was allowed to stir overnight at room temperature.

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US11773064B2 (en) 2012-10-26 2023-10-03 Nerviano Medical Sciences S.R.L. 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors

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