EP0843550A1 - Inhibiteurs de la monoxyde d'azote synthetase (nos) - Google Patents

Inhibiteurs de la monoxyde d'azote synthetase (nos)

Info

Publication number
EP0843550A1
EP0843550A1 EP96928121A EP96928121A EP0843550A1 EP 0843550 A1 EP0843550 A1 EP 0843550A1 EP 96928121 A EP96928121 A EP 96928121A EP 96928121 A EP96928121 A EP 96928121A EP 0843550 A1 EP0843550 A1 EP 0843550A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
alkyl
aryl
substituted aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96928121A
Other languages
German (de)
English (en)
Other versions
EP0843550A4 (fr
Inventor
Adnan M. M. Mjalli
Sepehr Sarshar
Chengzhi Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ontogen Corp
Original Assignee
Ontogen Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ontogen Corp filed Critical Ontogen Corp
Publication of EP0843550A1 publication Critical patent/EP0843550A1/fr
Publication of EP0843550A4 publication Critical patent/EP0843550A4/xx
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of compounds which are inhibitors of nitric oxide synthase (NOS) .
  • NOS nitric oxide synthase
  • the present invention also includes within its scope methods of treatment where nitric oxide is involved in the biological functions of the human body, e.g. hypotension, inflammation, the damage due to inflammation, acute and/or chronic pain, neuronal disorders such as stroke, memory disorders, and depression, autoimmune diseases, including allograft rejection, diabetes, septic and endotoxic shock and the like.
  • Nitric oxide is an important component of endothelium-derived relaxing factors (EDRFs). EDRFs have been shown to be involve in the regulation of blood flow and vascular resistance. In addition to the vascular endothelium, macrophages have also been reported to produce nitric oxide in the body which is a component of their cell killing and/or cytostatic function. Nitric oxide is produced in mammalian cells by nitric oxide synthase (NOS) by conversion of L-arginine to citrulline. Moncada, S., Palmer.R. M. J., and Higgs, E. A.
  • NOS nitric oxide synthase
  • eNOS In general eNOS is constitutively expressed and produces reletively low levels of NO. Activity of eNOS is dependent on Ca 2+ influx. eNOS is found in vascular smooth muscle cells which is not identical to the form of enzyme found in neurons. Formation of NO by the eNOS in vascular endothelial cells is believed to play a role in regulating blood pressure by relaxing muscles and allowing the vessel to dialate, which lower the blood pressure Pollock, J. S., Forstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H. H. W., Nakane, M. and Murad, F. (1991) Proc. Natl. Acad.
  • iNOS is not dependent on elevated Ca 2+ concentration and generally expressed only after induction by certain cytokines or by bacterial lipopolysaccharide (LPS)
  • LPS bacterial lipopolysaccharide
  • the present invention relates to the use of compounds of general formula 1 which are inhibitors of NOS:
  • R is selected from the group consisting of: 1) -NH-C 0 -C 10 alkyl -aryl, N-(C 0 -C 10 alkyl substituted aryl) 2 , -C 0 -C 10 alkyl substituted aryl, -N(C 0 -C 10 alkyl substituted aryl) 2 (C o -C 10 alkyl), in which "aryl” is optionally attached to compound 1 through C or N and is selected from the group consisting of isoindanolyl, isoindolinyl, tetrahydroquinolyl, phenyl, naphthyl, pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, pyrazinyl.pyrimidyl, quinolyl, isoquinolyl,
  • -O-C C 6 alkyl -S-C C 6 alkyl, -NH- C, -C 6 alkyl, -N (C, -C 6 alkyl) 2 , -C(O) -C, -C 6 alkyl, C(O)NHC 0 -C 10 alkyl, -NHC(O) C C 6 alkyl,
  • W i) NH 2 ii) NHC 0 - C 10 alkylaryl where aryl is as defined in 1 or iii) ZC(O)MR 3 wherein Z, M and R 3 is as defined above; R 2 is hydrogen; or R, and R ⁇ , taken together forming another aryl group; and X is hydrogen, halo, alkyl, alkoxy, hydroxy, nitro, amino, trifluoromethyl and aryl.
  • the compounds described herein are indicated in the prophylaxis or treatment for a patient suffering from hypotension caused by an excess production of nitric oxide from arginine in vascular cells in the patient induced by therapy with a cytokine, or exposure to a bacterial endotoxin, i.e. septic shock or from immunosuppressant therapy.
  • the present invention also includes within its scope methods of adininstrating to said patient a therapeutically effective amount, i.e. an effective NOS inhibitory amount of a compound or the corresponding pharmaceutically acceptable salt, ester or solvate selected from the compounds depicted in Formula 1 in an inert pharmaceutical carrier.
  • a therapeutically effective amount i.e. an effective NOS inhibitory amount of a compound or the corresponding pharmaceutically acceptable salt, ester or solvate selected from the compounds depicted in Formula 1 in an inert pharmaceutical carrier.
  • R ! is aniline or substituted aniline, and the following:
  • R 4 is alkyl as defined above or:
  • R 5 Rg R 7 and Rg are alkyl, aryl or substituted aryl as defined above.
  • the compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • Pharmaceutically acceptable salts of the compounds of Formula 1, where a basic or acidic group is present in the structure are also included within the scope of this invention.
  • an acidic substituent such as -COOH
  • a basic group such as amino or a basic heteroaryl radical, such as pyridyl
  • an acidic salt such as hydrochloride, hydrobromide, acetate, maleate, pamoate, methanesulfonate, p-toluenesulfonate, and the like
  • suitable dosage form for oral or parenteral adminstration form.
  • pharmaceutically acceptable esters can be employed, e.g., methyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • solvates are useful in the methods of treatment of this invention.
  • the term "therapeutically effective amount” or “effective NOS inhibitory amount” shall mean that amount of compound, as depicted in Formula 1 or its pharmaceutical salt, ester etc. that will elicit the biological or NOS inhibitory response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the commercially available 1 ,2 -naphthoquinone s 1 or 2 is reacted with the appropriate amine at equal molar ratio in a proper reaction solvent such as DMSO or a lower molecular weight alcohol, such as ethanol (Scheme A, at about 60°C) or in a pH 8-9 aqueous buffer solution (Scheme B, at room temperature) as described above.
  • a proper reaction solvent such as DMSO or a lower molecular weight alcohol, such as ethanol (Scheme A, at about 60°C) or in a pH 8-9 aqueous buffer solution (Scheme B, at room temperature) as described above.
  • the reaction products are recovered from the reaction mixtures by the partition between an organic solvent such as ethyl acetate, methylene chloride, and chloroform and water.
  • the organic layer is then dried with sodium sulfate and evaporated in vacuo, yielding the desired products as the residue.
  • a lysate fraction was prepared by lysing the harvested cells in liquid nitrogen and thawing by incubation in a 37° C water bath and run over an ADP sepharose column for partial purification. The assay was validated and optimized.
  • bNOS was isolated according to the proceedure disclosed in Proc. Nat. Acad. Sci. USA Vol. 88 pp. 365-369, January 1991. To a 96-well microtiter plate the following were added:
  • the resulting solution was incubated at 37'C for 20 minutes.
  • the reaction was stopped by the addition of 75 ml of a Stop buffer.
  • Nitric Oxide Synthase activity was assayed by adding 10 mL of crude lysate 10 mL of substrate and 10 mL of a selected Compound as depicted in Formula 1 in DMSO to 70 mL of assay buffer in a 96-well microtiter plate. The wells were mixed gently and incubated for 90 minutes at 37°C. The reaction was stopped by adding 2 units of L-lactic dehydrogenase (5 mL of stock solution) and 5 mmole of sodium pyruvate (10 mL of stock solution). The solution was incubated for an additional 15 minutes at 37°C. 100 mL of Griess reagent was added and read absorbance at 560 nm. The inhibitory concentraction 50 or IC 50 for the Compounds depicted in examples
  • Footnote: a. ' — ' means the data is not available.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • a compound of Formula 1 may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non ⁇ irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non ⁇ irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • phospholipids such as cholesterol, stearylamine, or phosphatidylcholines.
  • creams, ointments, jellies, solutions or suspensions, etc. containing the compounds of Formula 1 are employed.
  • the selected compound is adminstered at a dosage level of from about 0.1 mg to about 200mg/kg of the body weight of the subject being treated.
  • This dosage has to be individualized by the clinician based on the specific clinical condition of the subject being treated.
  • the selected NOS inhibitors may be combined with or replace other therapeutic agents such as alpha, -adrenergic modulators which are currently being used to treat hypotension in septic or cytokine treated patients.
  • These modulators include, for example, epinephrine, norepinephrine dopamine and the like. Again, the dosage needs to be individualized by the clinician.

Abstract

La présente invention décrit des procédés utiles pour l'inhibition de la monoxyde d'azote synthétase inductible, par l'administration d'un composé de la formule (I).
EP96928121A 1995-08-09 1996-08-07 Inhibiteurs de la monoxyde d'azote synthetase (nos) Withdrawn EP0843550A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US207895P 1995-08-09 1995-08-09
US2078P 1995-08-09
PCT/US1996/013001 WO1997005871A1 (fr) 1995-08-09 1996-08-07 Inhibiteurs de la monoxyde d'azote synthetase (nos)

Publications (2)

Publication Number Publication Date
EP0843550A1 true EP0843550A1 (fr) 1998-05-27
EP0843550A4 EP0843550A4 (fr) 1998-06-03

Family

ID=21699164

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96928121A Withdrawn EP0843550A1 (fr) 1995-08-09 1996-08-07 Inhibiteurs de la monoxyde d'azote synthetase (nos)

Country Status (4)

Country Link
EP (1) EP0843550A1 (fr)
AU (1) AU6770996A (fr)
CA (1) CA2229074A1 (fr)
WO (1) WO1997005871A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2764292B1 (fr) * 1997-06-10 2000-12-29 Innothera Lab Sa Utilisation de derives de tetracycles dicetoniques, nouveaux composes obtenus et leur application en therapeutique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0631776A1 (fr) * 1993-07-02 1995-01-04 Roussel Uclaf Utilisation de dérivés de la bêta-naphtoquinone pour l'accélération de la prolifération des cellules endothéliales et de l'inhibition des no synthases

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4882339A (en) * 1987-07-10 1989-11-21 Ciba-Geigy Corporation 4-Amino-substituted 1,2-dihydroxynaphthalene derivatives useful in inhibiting 5-lipoxygenase activity in mammals

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0631776A1 (fr) * 1993-07-02 1995-01-04 Roussel Uclaf Utilisation de dérivés de la bêta-naphtoquinone pour l'accélération de la prolifération des cellules endothéliales et de l'inhibition des no synthases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9705871A1 *

Also Published As

Publication number Publication date
EP0843550A4 (fr) 1998-06-03
WO1997005871A1 (fr) 1997-02-20
AU6770996A (en) 1997-03-05
CA2229074A1 (fr) 1997-02-20

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