WO2003055890A1 - Composes derives de thienopyrimidine utilises comme inhibiteurs de la prolylpeptidase, inducteurs d'apoptose et agents de traitement anticancereux - Google Patents
Composes derives de thienopyrimidine utilises comme inhibiteurs de la prolylpeptidase, inducteurs d'apoptose et agents de traitement anticancereux Download PDFInfo
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- WO2003055890A1 WO2003055890A1 PCT/US2002/041168 US0241168W WO03055890A1 WO 2003055890 A1 WO2003055890 A1 WO 2003055890A1 US 0241168 W US0241168 W US 0241168W WO 03055890 A1 WO03055890 A1 WO 03055890A1
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- HQAPZXZYMBTCBL-UHFFFAOYSA-N CC(C)CNc1nc(NCc(cc2)ccc2C(O)=O)c2[s]ccc2n1 Chemical compound CC(C)CNc1nc(NCc(cc2)ccc2C(O)=O)c2[s]ccc2n1 HQAPZXZYMBTCBL-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to:
- compositions comprising one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient;
- X is OR 3 or NR 3 IU; Ri is selected from the group consisting of hydrogen and -( -C5) alkyl;
- R is selected from the group consisting of
- R 3 is selected from the group consisting of hydrogen and -(C ⁇ -C 5 ) alkyl
- R 4 is selected from the group consisting of: (a) -(CH 2 ) m -A, where A is:
- (a2) a saturated or fully unsaturated four to eight membered heterocyclic ring, containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring system contains at least one carbon atom and wherein said ring is optionally substituted with up to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, -(C 1 -C 5 ) alkoxy, -(CVC 5 ) alkylamino, and -(C Cs) linear or branched alkyl optionally substituted by halogen, (a3) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or fully unsaturated five to eight membered
- (b4) a saturated or fully unsaturated four to eight membered heterocyclic ring, containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, (b5) -(C 6 -C 10 )-aryl, wherein (b4) and (b5) are optionally substituted with up to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, -(CrC 5 ) alkoxy-, -(C 1 -C5) alkylamino and -(C 1 -C 5 ) linear or branched alkyl optionally substituted by halogen;
- R 3 and ⁇ form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight-membered heterocyclic ring, containing zero to four additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said ring structure contains at least one carbon atom and wherein said ring is optionally substituted by one to two substituents selected from the group consisting of amino, cyano, hydroxy, - (CrC 5 ) alkoxy-, -(C ⁇ -C 5 ) alkylamino and -(C ⁇ -C 5 ) linear or branched alkyl optionally substituted by halogen;
- R 5 is:
- R 6 and R 7 are independently selected from the group consisting of
- the preferred compounds of the invention have general formula (I) and are further defined below.
- the definitions for the various groups and variables represent the preferred definitions when they differ from those as broadly defined above, and are to be understood as independent of each other.
- the preferred compounds of the invention have the formula (I) ) q -R 2
- X is NR 3 R t ;
- Ri is selected from the group consisting of hydrogen and -(C ⁇ -C 5 ) alkyl
- R 2 is selected from the group consisting of (a) -(C 6 -C 8 ) cycloalkyl; (b) phenyl; and
- R 3 is selected from the group consisting of hydrogen and -(C 1 -C 5 ) alkyl
- i is selected from the group consisting of:
- A is: (al) -(C 5 -C 8 ) cycloalkyl, optionally substituted with -(C ⁇ -C 5 ) alkoxy, or -(C ⁇ -C 5 ) alkylamino, (a2) a saturated or fully unsaturated five to six membered heterocyclic ring, containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring system contains at least one carbon atom and wherein said ring is optionally substituted with up to two substituents selected from the group consisting of cyano, halogen, oxo, -(CrC 5 ) alkoxy, -(C ⁇ -C 5 ) alkylamino, and -(C ⁇ -C 5 ) linear or branched alkyl optionally substituted by halogen,
- (a3) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or fully unsaturated five to eight membered carbocycle, (a4) phenyl substituted with a saturated or fully unsaturated five to six membered heterocyclic ring, containing one to two heteroatoms selected from the group consisting of nitrogen and oxygen,
- R 3 and j form, together with the nitrogen to which they are attached, a saturated five to eight-membered heterocyclic ring, containing zero to one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said ring structure contains at least one carbon atom and wherein said ring is optionally substituted by one to two substituents selected from the group consisting of -(CrC 5 ) alkoxy-, -(C ⁇ -C 5 ) alkylamino and -(C ⁇ -C 5 ) linear or branched alkyl optionally substituted by halogen;
- R 6 and R 7 are independently selected from the group consisting of
- a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated six membered carbocycle, and
- n and p are independently an integer from 0 - 5; n is an integer from 0 - 3; q is an integer from 0 - 1 ; and q + (m or p) equals an integer from 1 - 6;
- the more preferred compounds of the invention have general formula (I) and are further defined below.
- the definitions for the various groups and variables represent the more preferred definitions when they differ from those as broadly defined above, and are to be understood as independent of each other.
- R 2 is selected from the group consisting of
- R 3 is hydrogen
- (a3) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a fully unsaturated six membered carbocycle,
- R 3 and R 4 form, together with the nitrogen to which they are attached, a saturated five to six-membered heterocyclic ring, containing zero to one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said ring structure contains at least one carbon atom and wherein said ring is optionally substituted by one to two substituents selected from the group consisting of -(C 1 -C 5 ) alkoxy, and -(CrCs) linear or branched alkyl optionally substituted by halogen;
- R 5 is:
- R 6 and R 7 are independently selected from the group consisting of
- n and p are independently an integer from 0 - 3; n is an integer from 0 - 1 ; q is an integer from 0 - 1 ; and q + (m or p) equals an integer from 1 - 4;
- Salts are especially the pharmaceutically acceptable salts of compounds of formulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae
- Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid.
- Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, ⁇ -aminobutyric acid (GAB A), gluconic acid, glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, fumaric acid, oxalic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tart
- pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, NN-diethylamine, NN- dicyclohexylamine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
- alkaline cations
- Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of formula (I) or (II) in vivo. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).
- prodrugs of the disclosed compounds of formula (I) and (II) are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
- Major drug biotransformation reactions include N- dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al, publ. by McGraw-Hill, pages 12-18, (2001), which is hereby incorporated by reference).
- halogen refers to fluorine, chlorine, bromine, and iodine substituents for the purposes of this invention.
- the alkyl may be fully substituted, up to perhalo.
- fused bicyclo ring refers to a substituent which is a two ring structure which share two carbon atoms.
- the bonding between the fused bicyclo ring and the compound and/or atom to which it is attached can be through either of the two rings.
- compositions comprising a therapeutically effective amount of one or more of the compounds of formula (I) or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient.
- Compounds for the purpose of forming pharmaceutical compositions for the inhibiting apoptosis, inducing apoptosis or treating cancer also includes the compounds of formula (I) wherein A is optionally hydrogen and the remaining variables are as defined above.
- Brown et al. U.S. Patent 5,280,026 disclosed compounds where A is hydrogen. However, these compounds were utilized as inhibitors of the ⁇ ⁇ + ATPase enzyme useful in the treatment of gastric acid secretion.
- compositions are prepared so that they may be administered orally, dermaily, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
- Dermal administration includes topical application or transdermal administration.
- Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques.
- One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition.
- These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition), Managing Editor, John E. Hoover, Mack Publishing Co., (1970) or Pharmaceutical Dosage Form and Drug Delivery Systems (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, (1995), each of which is hereby incorporated by reference.
- Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CC1 2 F 2 , F 2 C1C- CC1F 2 and CC1F 3 ) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylpara
- clarifying agents include but are not limited to bentonite
- emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate
- encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
- flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
- humectants include but are not limited to glycerin, propylene glycol and sorbitol
- levigating agents include but are not limited
- compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures.
- the compositions of the invention can also have an additional apoptosis inducers as an active ingredient. Examples of known apoptosis inducers (see e.g.
- Calbiochem's 2001 Signal Transduction Catalog, pages 702-704, the contents of which are incorporated by reference) which can be added to the described invention include but are not limited to A23187, N-Acetyl-L-cysteine, actinomycin D, tyrphostin A9, tyrphostin A25, AG 490, AG 1714, anandamide, anisomycin, aphidicolin, bafilomycin Al, berberine hemisulfate, betulinic acid, bleomycin sulfate, CAFdA, calphostin C, camptothecin, CAPE, chelerythrine chloride, 2-chloro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine 5'-triphosphate, colcemid, cochicine, corticosterone, cycloheximide, cyclophosphamide monohydrate, cyclosporine A, daunorubicin hydroclor
- Optional cancer treatment agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fiuorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazin
- cancer treatment agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ.
- cancer treatment agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone.
- the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
- the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
- the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
- the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
- the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
- the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
- the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
- the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
- the term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.
- Thin-layer chromatography was performed on Whatman ® pre-coated glass-backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science ® silica gel
- Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected.
- Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me Si ( ⁇ 0.00) or residual protonated solvent (CHC1 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
- Carbon ( 13 C) ⁇ MR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; d 3 -MeOD; ⁇ 49.0; d 6 -DMSO ⁇ 39.5) as standard.
- HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120 A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonirile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total ran time was 6.5 minutes.
- Step 1 2,4-dichlorothiophenol[3,2-d]pyrimidine.
- a solution of dry DMF (8 mL) in POCl 3 (400 mL) was stirred at rt for 20 min. under Ar before it was added to thieno[3,2-d]pyrimidine-2,4-diol (100.0 g, 595 mmol).
- the suspension was heated to a gentle reflux. After 5 h, the resultant dark yellow solution was cooled to 70 °C and slowly poured into vigorously stirred cold (0 °C) water (4000 mL) at a rate that kept the internal temperature below 20 °C. A solid precipitated immediately, after 10 min, the solution was filtered.
- Step 3 Methyl 4-[( ⁇ 2-[(2-thienylmethyl)ammo]thieno[3,2-d]pyrimidin-4-yl ⁇ amino) methyljbenzoate.
- Apoptosis (programmed cell death) is an essential process in the development and maintenance of homeostasis in an organism (1).
- the growth fraction of a tumor is governed by the rate of cellular division as well as the rate of cell death: if the rate of division exceeds that of cell death, then net tumor expansion occurs.
- net growth rates of tumors do not generally correlate directly with the rate, of cell division within the tumor, as assessed by the abundance of mitotic figures.
- aberrant apoptotic rate plays an important role in tumor growth and expansion (2, 3).
- Proteases are attractive cancer drug targets since they are known to regulate apoptotic signal transduction (8, 9).
- work on apoptosis initiated by specific inhibitors of the proteasome complex has been reported in the literature, where lactacystin and other proteasome inhibitors are shown to cause apoptosis in a number of cell lines (10, 11).
- prolylpeptidase As an intracellular protease involved in the repression of apoptosis and, as such, prolylpeptidase is thought to be an anti- apoptotic factor (12, 13).
- Prolylpeptidase is a serine protease that is irreversibly inactivated by diispropyl-fluorophosphate (DFP) through covalent modification of Serl54 (12) and unpublished data. It is the only known human serine protease that is fully active without additional post-translational removal of inhibitory peptide. In addition, the enzyme is localized to novel non-lysosomal cytosolic vesicles (14).
- prolylpeptidase as well as prolylpeptidase purified from natural sources are active as dimeric proteins (106 kDa), based on size exclusion chromatography, although the gene encodes a putative enzyme with a predicted mass of 58 kDa (15).
- prolylpeptidase has been identified in a number of solid tumor cell lines of different histological types including those from colon (HCT116 and DLD1), prostate (PC3), and breast (MDA-MB-435).
- expression data for prolylpeptidase mRNA shows a very limited distribution across adult human tissues, with highest levels observed in the testis, and moderate levels in prostate, skeletal muscle and brain.
- Increased expression of prolylpeptidase mRNA in human tumor specimens and the published biological data on the enzyme suggest that prolylpeptidase plays an important role in tumor cell growth or survival. In summary, these data suggest that selective inhibition of prolylpeptidase activity in tumor cells could lead to increased apoptotic rates and growth inhibition.
- Test compounds were diluted serially 1:5 in 5% DMSO/95% water and 5 ⁇ L was added to give 100 ⁇ L as a final volume to a well containing prolylpeptidase enzyme in buffer. Drug had a final concentration ranging from 10 ⁇ M to 0.12 ⁇ M.
- the Ala-Pro- AFC dipeptide substrate (AFC is 7-amino-4-trifluoro-methylcoumarin) in MTEN buffer was used at a final concentration of 200 ⁇ L and the reaction was initiated with 10 nM final concentration of recombinant prolylpeptidase. The reaction was allowed to proceed for 20 min at room temperature and quenched with 20 ⁇ L of 1 M Glycine-HCl pH 2.5.
- Ala-Pro-AFC is a dipeptide substrate with a conjugated AFC fluorophore at the C-terminus. Hydrolysis of the dipeptide substrate releases free AFC which is excited at 400 nm and emission of 505 nm in a spectrofluorometer.
- Assay buffer is 50 mM MTEN Buffer pH 4.5 (50 n M MES, 25 mM Tris, 25 mM ethanolamine, 100 mM NaCl).
- Enzyme storage buffer was 50 mM Tris pH 7.0, 50% glycerol and was stored at -80 °C. It was diluted in assay buffer just prior to initiation of the assay.
- the induction of apoptosis by prolylpeptidase inhibitors was measured in whole cells using the multiparameter apoptosis assay (MPA).
- MPA multiparameter apoptosis assay
- the assay uses the ArrayScan II (Cellomics Inc.
- test compounds were dissolved in 100% DMSO and diluted serially 1:2 in
- DMEM fetal calf serum
- DMSO concentration 0.25% 10% fetal calf serum
- the final drag concentrations ranged from 25 ⁇ M to 0.39 ⁇ M.
- Cells were exposed to compound for either one or 24 hours depending on the experiment.
- the MPA assay was run according to the manufactures' protocol.
- Example 15 was tested in the above apoptosis assay and found to induce apoptosis below a concentration of 25 ⁇ M.
Abstract
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