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WO2008053764A1 - Composé actif anti-prion, agent actif anti-prion et procédé d'inhibition de la production d'une protéine prion anormale - Google Patents

Composé actif anti-prion, agent actif anti-prion et procédé d'inhibition de la production d'une protéine prion anormale Download PDF

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WO2008053764A1
WO2008053764A1 PCT/JP2007/070748 JP2007070748W WO2008053764A1 WO 2008053764 A1 WO2008053764 A1 WO 2008053764A1 JP 2007070748 W JP2007070748 W JP 2007070748W WO 2008053764 A1 WO2008053764 A1 WO 2008053764A1
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group
prion
substituent
phenyl
active compound
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PCT/JP2007/070748
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English (en)
Japanese (ja)
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Naoki Miyata
Takayoshi Suzuki
Hidehiko Nakagawa
Shigeru Ohta
Katsumi Doh-Ura
Tomoko Fukuuchi
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Nagoya City University
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Publication of WO2008053764A1 publication Critical patent/WO2008053764A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/52—Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to an anti-prion active compound having a pyrazolone skeleton that suppresses an increase in abnormal prion protein, an anti-prion activator and a method for inhibiting the production of abnormal prion protein using the same.
  • Prion disease represented by Creutzfeld's Jacob's disease is a general term for a group of neurodegenerative diseases in which prion protein is involved, and is characterized by the accumulation of degenerated abnormal prion protein in tissues such as the brain. To do.
  • the infectious agent of prion disease is considered to be this abnormal type prion protein, and abnormal type prion protein proliferates by converting prion protein expressed in normal tissues into abnormal type prion protein. For this reason, prion diseases also have an aspect like infectious diseases.
  • anti-prion active compound a compound that suppresses the growth of abnormal prion protein
  • Patent Document 1 lysosomal affinity drugs such as pentosan polysulfate, quinine, quinacrine and chloroquine, and reactive dyes such as reactive green and reactive red are effective as anti-prion active compounds. It is stated that there is! /
  • Patent Document 2 quinoline derivatives and naphthyl derivatives
  • Patent Document 3 chlorophyll derivatives
  • Patent Document 1 Japanese Patent Laid-Open No. 2003-40778
  • Patent Document 2 JP 2004-99553 A
  • Patent Document 3 Japanese Patent Publication No. 2003-155239 Disclosure of the invention
  • the present invention also provides an anti-prion activator and a method for inhibiting the production of an abnormal prion protein, which are effective in suppressing the proliferation of abnormal prion protein, using the anti-prion active compound of the present invention. It is a problem to be solved.
  • the anti-prion active compound of the present invention is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • An anti-prion active compound that inhibits the growth of abnormal prion protein It is a pyrazolone derivative represented by the following general formula (1).
  • R 1 may have a substituent! /, May have an aryl group or a substituent! /, Represents an alkyl group (including a cycloalkyl group), R 2 represents hydrogen, a substituent. It may have an aryl group, may have a substituent! /, A nitrogen-containing heterocyclic functional group, may have a substituent, an alkyl group (including a cycloalkyl group) or an acyl group.
  • R 3 represents an aryl group which may have a substituent, an alkyl group (including a cycloalkyl group) which may have a substituent, RCONH—, RNHCO—, ROCONH or RNHCONH (where R is an aryl) Groups or alkyl groups (including cycloalkyl groups) Note that the carbonyl group of the above formula (1) is actually interconverted with an enol-type tautomer, but for convenience, the above general formula (1) Expressed in
  • R 1 can be a phenyl group or a cycloalkyl group which may have a substituent.
  • R 2 may be hydrogen, a phenyl group, a pyridinole group, an alkyl group (including a cycloalkyl group) or a benzoyl group.
  • R 3 represents an alkyl group, an optionally substituted phenyl group, RCONH—, RNHCO—, ROCONH or R NHCONH— (where R represents an aryl group or an alkyl group (including a cycloalkyl group)).
  • R 1 is a phenyl group or a cycloalkyl group which may have a substituent
  • R 2 is hydrogen, a phenyl group, a pyridyl group, an alkyl group (a cycloalkyl group).
  • R 3 is an alkyl group, an optionally substituted phenenore group, RCONH—, RNHCO—, ROCONH or RNHCONH (where R is an aryl group or an alkyl group (including a cycloalkyl group) ) Indicates the power S.
  • R 2 and R 3 4-N
  • An anti-prion active agent can be produced by using the anti-prion active compound of the present invention. That is, the anti-prion active agent of the present invention contains the anti-prion active compound according to any one of claims 1 to 5 as an active ingredient.
  • the proliferation of abnormal prion protein is inhibited. That is, the method for inhibiting abnormal prion protein production according to the present invention is characterized in that the anti-prion active compound according to any one of claims 1 to 5 is administered to inhibit the proliferation of abnormal prion protein. .
  • Example 1 is edaravone
  • Examples 2 to 19 are a phenyl group present in edaborane. A methyl group at the 3-position of the pyrazolone ring is converted, or a substituent is introduced at the 4-position of the pyrazolone ring. (Specific structures are shown in Table 1 below).
  • Comparative Examples 1 to 4 are compounds described in Patent Document 1 or Patent Document 2 as anti-prion activation compounds.
  • Comparative Example 1 is quinine
  • Comparative Example 2 is quinidine
  • Comparative Example 3 Is MQAA (structure is shown in Table 1 below)
  • Comparative Example 4 is 4- (4-dimethylaminostyryl) quinoline.
  • Reagents used in the synthesis of anti-prion active compounds The physical property data measuring apparatus is as follows.
  • Elemental analysis was performed using a Yanaco CHN CORDER NT-5 analyzer, and all values agreed with the calculated values within 0.4%.
  • the high resolution mass spectrum was measured using a JEOL JMS-SX102A mass spectrometer.
  • GC-MS analysis was measured with Shimadzu GCMS-QP2010.
  • Example 10 As the anti-prion active compound of Example 10, a reagent from Tokyo Chemical Industry was used as it was. For all other reagents and solvents, commercially available reagents were purchased and used as they were. For flash column chromatography, silica gel 60 (particle size: 0.046-0.063 mm) manufactured by Merck & Co. was used.
  • the anti-prion active compound of Example 1 was edaravone, and a commercially available reagent (manufactured by Tokyo Chemical Industry Co., Ltd.) was used as it was.
  • the anti-prion active compound of Example 4 was 1-phenyl-3-trifluoromethyl-5-pyrazolone and was synthesized by the same method as in Example 2. That is, add phenylhydrazine (10.0 mmol) to a solution of 4, 4, 4-trifluoroacetoacetic acid ethyl ester (10.0 mmol) in 10 ml of ethanol. The mixture was refluxed for 15 hours, and the precipitate formed after cooling was collected by filtration. 85% of 1-phenyl-3-trifluoromethyl-5-pyrazolone, which is the anti-prion active compound of Example 3, was collected. Obtained in yield. Furthermore, the crude product is ethyl acetate / n -Purified by recrystallization from a mixed solvent of -hexane. The physical properties are shown below. mp 195-196. C;
  • Example 7 4-cyclohexyl hydrazine hydrochloride was used in place of cyclohexyl hydrazine hydrochloride in Example 2 (but ethanol was used in place of acetic acid as the solvent). Performing the same operation, it is an anti-prion active compound of Example 1 1 -(4-Chlorophenyl) -3-methyl-5-pyrazolone was synthesized. The crude product thus obtained was purified by recrystallization using ethanol as a solvent. The physical property data of this purified product is shown below.
  • the anti-prion active compound of Example 8 is 3-methyl-1,4-diphenyl-5-pyrazolone and was synthesized in the following two steps.
  • a suspension of sodium hydride (60%, 1.50 g, 37.5 mmol) in THF (30 mL) is cooled to 0 ° C, and a solution of phenylacetic acid ethyl ester (5.00 g, 30.5 mmol) in THF (10 mL) is added dropwise. . Then, stir at room temperature for 1 hour, add a solution of acetic anhydride (3.20 mL, 33.9 mmol) in THF (10 mL) at 0 ° C and stir for 1 hour. The reaction solution is poured into ice water and extracted with ethyl acetate.
  • the anti-prion active compound of Example 9 is 3-isopropenyl-1-phenyl-5-pyrazolone and was synthesized in the following two steps.
  • Monoethyl potassium malonate (9.80 g, 57.6 mmol), MgCl (6.00 g, 63.0 mmol) and triethylamine (17.50 mL, 126.0 mmol) were dissolved in acetonitrile (100 mL), and metacryloyl chloride was cooled with ice. Mouth ride (3.00 g, 28.7 mmol) is added dropwise. After stirring for 30 minutes, add 2 M hydrochloric acid and stir for another 30 minutes. The mixture is poured into ice water and extracted with ethyl acetate. The organic layer is separated, washed with water, saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate.
  • the anti-prion active compound of Example 9 was 4-isobutyl-3-methyl-1-phenyl-5-pyrazophane, which was synthesized in the following two steps.
  • Ethyl _3_oxobutanoate (3.00 g, 23.1 mmol) is added all at once to a solution of sodium ethoxide in ethanol (20%, 8.70 g, 25.6 mmol), and the mixture is warmed to 80 ° C. Then, a solution of isobutyl iodide (5.10 g 27.71 mmol) in THF (5.0 mL) was added dropwise over 2 hours, and the reaction solution was kept at 80 ° C. for another 2 hours. After cooling, pour in ice-cooled 2M hydrochloric acid and extract with ethyl acetate.
  • the anti-prion active compound of Example 13 was 3-methyl-1-phenyl-4- (pyridin-2-yl) -1H-5 (4H) -one and was synthesized in the following two steps.
  • the anti-prion active compound of Example 14 was 5-oxo-N, l-diphenyl-4,5-dihydro-1H-pyrazole-3-carboxamide and was synthesized in the following two steps.
  • the anti-prion active compound of Example 15 was 3-methyl-1- (pyridin-2-yl) -5-pyrazophane and was synthesized as follows. That is, 2-hydrazinoviridine (2.10 g, 20.0 mmoL) was added to acetic acid (20 mU) with 3-oxobutanoic acid ethyl ester (2 ⁇ 60 g, 20. OmmoL, 1 ⁇ 0 equivalent), and the mixture was added. The mixture was stirred at reflux temperature for 3 hours, the solvent was distilled off, the residue was extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate.
  • the anti-prion active compound of Example 16 is 1-methyl-4- (5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl) pyridinium iodide, and the following three steps was synthesized.
  • Stage 2> Using 3-oxo-3- (pyridin-4-yl) propionic acid ethyl ester obtained in the first step, 1-phenyl-3- (pyridin-4-yl) -5-pyrazolone was synthesized. In other words, 3-hydroxy-3- (pyridin-4-yl) propionic acid ethyl ester (1.63 g, 8. 45 mMol) was added to ethyl alcohol (20 mU in a solution of phenylhydrazine (912 mg, 1.
  • 1-methyl-4- (5-oxo-1-phenyl-iodide- 4,5-Dihydro-1H-pyrazol-3-yl) pyridinium was synthesized. That is, methyl iodide (3.0 mL, 38.0 equivalents) was added to a solution in which 1-phenyl-3- (pyridine-4-yl) -5-pyrazolone (300 mg, 1.26 mmoL) was added to black mouth form (10 mL). It was. The mixture was stirred at 60 ° C. for 18 hours. The solvent was distilled off and jetino ether was added.
  • the precipitated solid was collected by filtration and washed with jetyl ether and n-hexane to obtain 443 mg (yield 92%) of a brown solid.
  • the crude product (200 mg) was recrystallized with ethyl alcohol and n-hexane to give a brown solid of 1-methyl-4- (5_oxo-1-phenyl-4,5-dihydro- -pyrazole- 133 mg (yield 66%) of 3-yl) -pyridinium were obtained.
  • the melting point, 3 ⁇ 4-NMR data, and MS data are shown below.
  • the anti-prion active compound of Example 17 is 1- [4- (n-dodecyl) phenyl] -3_ (4-nitrophenyl) -5-pyrazolone, and was synthesized in the following four steps.
  • 4-dodecylphenylamine was synthesized as follows. That is, a mixture of l_ (n-dodec-1-ynyl) -4-nitrobenzene (7.81 g, 27.2 mmol) and palladium carbon (780 mg) in ethyl alcohol (80 mL) at room temperature for 7 days under a hydrogen atmosphere. Stir. The mixture was filtered through a celite layer, the organic layer was separated and dried over anhydrous sodium sulfate.
  • 4- (n-dodecyl) phenylhydrazine hydrochloride was synthesized as follows. That is, a solution of sodium nitrite (1.04 g, 15 mmoL, 3 equivalents) in water (10 mU) was added to 6N hydrochloric acid (15 mU, 4 (n dodecyl) phenylamine (1.30 g, 5. OmmoU was added under ice cooling). To the stirred suspension was added over 15 minutes.After another 30 minutes in the ice bath, stannous chloride (2.65 g, 14. OmmoL, 2.8 eq) was slowly added to 6N hydrochloric acid.
  • the anti-prion active compound of Example 18 is 1- [4- (n-dodecyl) phenyl] -3_ (4-methoxyphenyl) -5-pyrazolone, and 4- (n-dodecyl) phenyl of Example 17 Using hydrazine hydrochloride, it was synthesized as follows. That is, 4- (n-dodecyl) phenylhydrazine hydrochloride (31 2 mg, 1.0 mmoL) was added to acetic acid (10 mL) to a suspension of 4-methoxybenzoyl acetate ethyl ester (222 mg, 1.0 mmoL, 1.0 equivalent).
  • 3-methyl-1- (pyridin-2-yl) -4- (n-tridecyl) -5-pyrazolone was obtained as follows. Synthesized. That is, 2-hydrazinopyridine (35303 ⁇ 4, 3.201010 1.0 equivalent) was added to 2-acetyl-pentadecanoic acid ethyl ester (1.01 g, 3.2 mmoL) in acetic acid (10111) and refluxed for 7 hours.
  • reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and silica gel flash chromatography (n-hexane).
  • Elemental analysis calculated (C H N 0) C, 73.91; H, 9.87; N, 11.75; measured C, 73.69; H, 9.89; N, 11.
  • Comparative Example 1 was quinine, and a commercially available reagent was used as it was. This compound is patented 1.
  • Comparative Example 2 was quinidine, and a commercially available reagent was used as it was. This compound is an anti-prion active compound described in Patent Document 2.
  • Comparative Example 3 was MQAA (see the chemical formula below), and a commercially available reagent was used as it was. This compound is an anti-prion active compound described in Patent Document 2.
  • Comparative Example 4 was 4- (4-dimethylaminostyryl) quinoline (see the chemical formula below), and a commercially available reagent was used as it was. This compound is an anti-prion active compound described in Patent Document 2.
  • TSE Transmissible Spongiform Encephalopathy
  • ScN2a RML strain
  • N2a # 58 cells infected with Fukuoka-red
  • PrP normal prion protein
  • ScN2a cells and F3 cells were grown in an Opti-MEM (Invitrogen) culture medium supplemented with 10% ushi fetal serum using 6-well culture plates.
  • TSE-derived prion-infected mouse neuroblastoma cell line (N2a) to which an anti-prion active compound was added was grown until it became dense (3-4 days) in the culture vessel.
  • the anti-prion activity of the anti-prion active compound was measured by measuring the concentration of ScN2a! /, Which inhibits the formation of F3 abnormal prion by 50% (hereinafter referred to as “IC50”).
  • IC50 concentration of ScN2a! /, Which inhibits the formation of F3 abnormal prion by 50%
  • the cell lysate is digested with proteinase K (a protein-degrading enzyme) at a concentration of 10 mg / ml for 30 minutes (abnormal prion protein remains because it is not digested by proteinase K), and then GLASSFOG ( (Fine glass beads) and centrifuged at 15,000 X g for 5 minutes at 24 ° C.
  • the precipitate obtained by centrifugation was resuspended in a sample loading buffer (sample solution for electrophoresis) and boiled.
  • the sample thus obtained was separated by electrophoresis on a 15% Tris-glycine-SDS-polyacrylamide gel and transferred to a membrane for Western blotting.
  • Abnormal prion protein is SAF8 Detection was performed by binding 3 antibodies (stock solution applied at 1: 5000 dilution, available from France's SPI-Bio) and secondary antibody bound with alkaline phosphatase.
  • the signal detected by immunological reaction that is, the abnormal prion protein band detected on the membrane
  • CDP-Star detection reagent Amersham Biosciences, USA
  • the concentration was determined by a densitometer, which is a density measurement of the protein band. In the measurement, the concentration of the anti-prion active compound at 50% inhibition of the production of abnormal prion protein relative to the control group was determined from at least three independent experiments. ⁇ Result>
  • Table 1 shows the results of measuring the anti-prion activity as described above.
  • Example 10 Example 2
  • Example 19 and Example 5 showed relatively high anti-prion activity
  • Example 4 Example 13, Example 9, Example 15, Example 15 11, Example 12 and Example 14 also showed anti-prion activity.
  • Example 7, Example 19, Example 3, Example 17, Example 5, Example 11, and Example 8 have high anti-prion activity for at least one of F3 cells and ScN2a cells. It became clear to show.
  • R 2 may be hydrogen, An aryl group which may have a substituent, an alkyl group (including a cycloalkyl group) or an acyl group which may have a substituent, and R 3 may have a substituent! /, An aryl group , Substituents, alkyl groups (including cycloalkyl groups) ), RCONH—, RNHCO—, ROCONH— or RNHCONH— (wherein R is an aryl group or an alkyl group (including a cycloalkyl group), it is obvious that those skilled in the art have an anti-prion activity). This is a range that can be inferred.
  • the anti-prion active compound of the present invention can be used as a therapeutic drug for human prion diseases such as Creutzfeldt-Jakob disease, for which there is no effective treatment at present, and for veterinary drugs as a countermeasure for mad cow disease.
  • human prion diseases such as Creutzfeldt-Jakob disease
  • veterinary drugs as a countermeasure for mad cow disease.
  • systematic compound groups can be used, it is also useful as a research and development reagent for elucidating the infection / onset mechanism of prion diseases and developing therapeutic methods.

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Abstract

La présente invention concerne un composé actif anti-prion présentant un excellent effet de prévention de l'augmentation du taux d'une protéine prion anormale et elle concerne également un agent actif anti-prion et un procédé d'inhibition de la production d'une protéine prion anormale, utilisant tous deux le composé actif anti-prion. Le composé actif anti-prion est un dérivé de pyrazolone représenté par la formule générale (1). (1) dans laquelle R1 représente un groupe aryle qui peut porter un substituant ou un groupe alkyle (y compris un groupe cycloalkyle) qui peut porter un substituant ; R2 représente un atome d'hydrogène, un groupe aryle qui peut porter un substituant, un groupe fonctionnel hétérocyclique azoté qui peut porter un substituant, un groupe alkyle (y compris un groupe cycloalkyle) qui peut porter un substituant ou un groupe acyle ; et R3 représente un groupe aryle qui peut porter un substituant, un groupe alkyle (y compris un groupe cycloalkyle) qui peut porter un substituant, RCONH-, RNHCO-, ROCONH- ou RNHCONH- [dans lesquels R représente un groupe aryle ou un groupe alkyle (y compris un groupe cycloalkyle)].
PCT/JP2007/070748 2006-10-30 2007-10-24 Composé actif anti-prion, agent actif anti-prion et procédé d'inhibition de la production d'une protéine prion anormale WO2008053764A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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EP2151433A1 (fr) 2008-08-05 2010-02-10 Institut Pasteur Alkoxypyrazoles et leur procédé de préparation
EP2367798B1 (fr) * 2008-11-20 2018-02-28 Northwestern University Dérivés pyrazolone utiles dans le traitement de la sclérose latérale amyotrophique

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WO2004035522A1 (fr) * 2002-08-30 2004-04-29 Bf Research Institute, Inc. Sondes de diagnostic et remedes contre des maladies presentant une accumulation de la proteine du prion et methode de marquage
WO2006002421A2 (fr) * 2004-06-24 2006-01-05 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l'atp
US20060223812A1 (en) * 2004-07-17 2006-10-05 Max-Planck-Gesellschaft Zur Forderungder Wissenschaften, E.V. Treating neurodegenerative conditions

Patent Citations (3)

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WO2004035522A1 (fr) * 2002-08-30 2004-04-29 Bf Research Institute, Inc. Sondes de diagnostic et remedes contre des maladies presentant une accumulation de la proteine du prion et methode de marquage
WO2006002421A2 (fr) * 2004-06-24 2006-01-05 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l'atp
US20060223812A1 (en) * 2004-07-17 2006-10-05 Max-Planck-Gesellschaft Zur Forderungder Wissenschaften, E.V. Treating neurodegenerative conditions

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2151433A1 (fr) 2008-08-05 2010-02-10 Institut Pasteur Alkoxypyrazoles et leur procédé de préparation
EP2367798B1 (fr) * 2008-11-20 2018-02-28 Northwestern University Dérivés pyrazolone utiles dans le traitement de la sclérose latérale amyotrophique
US10167263B2 (en) 2008-11-20 2019-01-01 Northwestern University Treatment of amyotrophic lateral sclerosis

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