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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61P9/00—Drugs for disorders of the cardiovascular system
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/40—Acylated substituent nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

• the present invention relates to compounds, aldehyde dehydrogenase 2 activators, pharmaceutical compositions, and therapeutic and/or prophylactic agents.
• Aldehyde dehydrogenase 2 is an enzyme that decomposes aldehydes such as acetaldehyde, and is involved in various diseases such as Fanconi anemia, osteoporosis, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). , alcoholic liver injury, pancreatitis, ischemia-reperfusion injury, peripheral artery disease, Alzheimer's disease, Parkinson's disease, esophageal cancer, head and neck cancer, pain, and diabetic retinopathy).
• ALDH2 Aldehyde dehydrogenase 2
• Fanconi anemia is an inherited bone marrow failure disease that is accompanied by symptoms such as aplastic anemia, leukemia, cancer, and malformations. It is important for stem cells that create blood in the bone marrow to properly degrade aldehydes and repair damaged genomes, but it has been reported that in FA patients, the genomic damage caused by aldehydes cannot be repaired, leading to progression of anemia ( For example, Non-Patent Document 1).
• transgenic mice expressing Aldh2*2 exhibit symptoms of osteoporosis, bone density decreases, and the differentiation ability of osteoblasts in the model mouse significantly decreases. It has also been reported that the ability to form osteoblasts having an ALDH2 gene mutation is reduced in humans as well (for example, Non-Patent Document 2).
• NAFLD and NASH are caused by the accumulation of neutral fat in the liver due to metabolic diseases, and it has been reported that the incidence of NAFLD is high in humans with a low ALDH2 activity genotype.
• Non-Patent Document 3 alcoholic liver damage and pancreatitis are caused by excessive drinking, and it is believed that acetaldehyde, which is produced when ethanol is decomposed in the body, is the main cause.
• pathological models of NAFLD, NASH, alcoholic liver damage, and pancreatitis it has been reported that the pathological conditions are improved by ALDH2 activating compounds or ALDH2 gene introduction (e.g., Non-Patent Documents 4, 5, and 6). .
• Ischemia-reperfusion injury is tissue damage that occurs when blood supply is resumed after an organ is left in a state of ischemia due to artery occlusion. It has been reported that ALDH2 activating compounds are effective for protection against ischemia-reperfusion injury (eg, Patent Document 1). Furthermore, a relationship between peripheral artery disease and ALDH2 has also been suggested (for example, Non-Patent Document 7).
• Non-Patent Documents 8 and 9 Although Alzheimer's disease and Parkinson's disease are neurodegenerative diseases of unknown cause, it has been reported that alcohol consumption and ALDH2 gene mutations contribute to the onset and progression of the disease (for example, Non-Patent Documents 8 and 9).
• Non-Patent Document 12 a relationship between esophageal cancer, alcohol consumption, and ALDH2, such as that esophageal cancer is reported to be more susceptible to disorders.
• Non-Patent Document 12 a relationship between head and neck cancer and ALDH2 has been reported.
• Pain is known to include inflammatory (nociceptive), neuropathic, and unexplained pain, but in an inflammatory pain model using mice, ALDH2 mutant mice were found to be more sensitive to pain stimuli. It has been reported that this effect is easily relieved by ALDH2 activating compounds (for example, Non-Patent Document 13). Furthermore, it has been reported in a rat model that activation of ALDH2 can be expected to have a medicinal effect on diabetic retinopathy (for example, Non-Patent Document 14).
• activating ALDH2 is expected to be effective in treating and/or preventing various diseases.
• compounds having an activation effect on ALDH2 for example, those described in Patent Documents 1 to 5 are known.
• An object of the present invention is to provide a compound having an ALDH2 activating effect, or an ALDH2 activator, a pharmaceutical composition, or a therapeutic or preventive agent containing the compound.
• the present invention includes the following embodiments.
• A is a heterocycle; R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, or alkynyl; R 3 is alkyl, alkenyl, or alkynyl; L is absent or alkylene; X 1 is a halogen; X 2 is hydrogen or halogen]
• the compound represented by formula (1) is the following formula (2): [In the formula, R 1 , R 2 , R 3 , L, X 1 and X 2 are as described above]
• [7A] The compound according to any one of [1] to [6B], a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 2 is hydrogen or alkyl.
• [7B] The compound according to any one of [1] to [7A], a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 2 is hydrogen.
• [7C] The compound according to any one of [1] to [7A], a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 2 is alkyl.
• [8A] The compound according to any one of [1] to [7C], wherein R 3 is alkyl, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
• [8B] The compound according to any one of [1] to [8A], a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 3 is unsubstituted alkyl, haloalkyl, or cycloalkyl.
• [8C] The compound according to any one of [1] to [8B], a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 3 is unsubstituted alkyl.
• [8D] The compound according to any one of [1] to [8B], a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 3 is haloalkyl.
• [8E] The compound according to any one of [1] to [8B], wherein R 3 is cycloalkyl, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
• [8F] The compound according to any one of [1] to [8B], a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 3 is methyl, ethyl, isopropyl, cyclopropyl, or fluoromethyl.
• [9] The compound according to any one of [1] to [8], wherein X 1 is fluorine, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
• the compound represented by formula (1) is the following compound: The compound according to any one of [1] to [10], a pharmaceutically acceptable salt thereof, or a prodrug thereof, selected from the group consisting of: [12] The prodrug or a pharmaceutically acceptable salt thereof according to any one of [1] to [11], wherein R 1 is -CH 2 -O-PO 3 H 2 .
• a pharmaceutically acceptable salt thereof, or a prodrug thereof selected from the group consisting of hepatitis (NASH), alcoholic liver disease, pancreatitis, ischemia-reperfusion injury, peripheral artery disease, Alzheimer's disease, Parkinson's disease, esophageal cancer, head and neck cancer, pain, and diabetic retinopathy. Treatment and/or prophylaxis for diseases.
• [A1] A method for activating aldehyde dehydrogenase 2, comprising administering to a patient in need thereof an effective amount of the compound according to any one of [1] to [13], a pharmaceutically acceptable salt thereof, or a prodrug thereof. A method that includes doing.
• a method for treating and/or preventing a disease selected from the group consisting of head and neck cancer, pain, and diabetic retinopathy the method comprising administering an effective amount of [1] to [13] to a patient in need thereof.
• a method comprising administering a compound according to any of the above, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
• [B1] The compound according to any one of [1] to [13], a pharmaceutically acceptable salt thereof, or a prodrug thereof, for use in activating aldehyde dehydrogenase 2.
• [B2] Fanconi anemia, osteoporosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, pancreatitis, ischemia-reperfusion injury, peripheral artery disease, Alzheimer's disease, Parkinson's disease, esophagus
• [C1] Use of the compound according to any one of [1] to [13], a pharmaceutically acceptable salt thereof, or a prodrug thereof for activating aldehyde dehydrogenase 2.
• [D1] Use of the compound according to any one of [1] to [14], a pharmaceutically acceptable salt thereof, or a prodrug thereof in the production of an aldehyde dehydrogenase 2 activator.
• NAFLD non-alcoholic fatty liver disease
• NASH non-alcoholic steatohepatitis
• alcoholic liver disease pancreatitis
• ischemia-reperfusion injury peripheral artery disease
• Alzheimer's disease Parkinson's disease
• esophagus The compound according to any one of [1] to [14], and a medicament thereof, for the production of a therapeutic and/or preventive drug for a disease selected from the group consisting of
• the present invention it is possible to provide a compound having an ALDH2 activating effect, or an ALDH2 activator, a pharmaceutical composition, or a therapeutic or preventive agent containing the compound.
• A is a heterocycle; R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, or alkynyl; R 3 is alkyl, alkenyl, or alkynyl; L is absent or alkylene; X 1 is a halogen; X 2 is hydrogen or halogen]
• the present invention relates to a compound represented by, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
• A preferably contains at least one nitrogen atom as a ring member atom.
• A is a 5- or 6-membered ring.
• A is an aromatic heterocycle.
• A is preferably a pyridine ring.
• alkyl, alkenyl, and alkynyl of R 1 to R 3 may be linear, branched, or cyclic.
• the alkyl, alkenyl, and alkynyl of R 1 to R 3 may be substituted with a substituent or may be unsubstituted.
• substituent include halogen (fluorine, chlorine, bromine, or iodine).
• the number of substituents can be, for example, 1, 2, or 3.
• R 1 to R 3 alkyl are each independently preferably an alkyl having 1 to 6 carbon atoms, more preferably an alkyl having 1 to 3 carbon atoms, and methyl. More preferably.
• the alkenyls of R 1 to R 3 are each independently preferably an alkenyl having 2 to 6 carbon atoms, more preferably an alkenyl having 2 to 4 carbon atoms.
• Each of R 1 to R 3 alkynyl is preferably an alkynyl having 2 to 6 carbon atoms, more preferably an alkynyl having 2 to 4 carbon atoms.
• R 1 is preferably hydrogen or alkyl, more preferably hydrogen or methyl, and even more preferably hydrogen.
• R 2 is preferably hydrogen or alkyl, more preferably hydrogen or methyl, and even more preferably hydrogen.
• R 3 is preferably alkyl, more preferably unsubstituted alkyl, haloalkyl or cycloalkyl, methyl, ethyl, isopropyl, cyclopropyl, or fluoromethyl (preferably difluoromethyl). It is more preferable that
• L is preferably absent or alkylene having 1 to 3 carbon atoms, and more preferably absent or methylene (-CH 2 -).
• X 1 is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine or chlorine, and even more preferably fluorine.
• X 2 is preferably hydrogen, fluorine, chlorine, bromine, or iodine, more preferably hydrogen, fluorine, or chlorine, and even more preferably hydrogen or fluorine.
• the compound represented by formula (1) is not particularly limited, but may be the following formula (2): [In the formula, R 1 , R 2 , R 3 , L, X 1 and X 2 are as described above] It is preferable that it is a compound represented by
• the compound represented by formula (1) is not particularly limited, but the following compounds are preferred.
• Prodrugs of the above compounds include, for example, phosphorylated prodrugs, more specifically those in which R 1 is -CH 2 -O-PO 3 H 2, and those in which R 1 is -CH 2 -O-PO 3 H 2 and nitrogen atoms which are ring member atoms of A. Mention may be made of those in which at least one is substituted with -CH 2 -O-PO 3 H 2 .
• Pharmaceutically acceptable salts of the above compounds or prodrugs are not particularly limited as long as they can be used as pharmaceuticals, but examples include hydrochlorides, sulfates, nitrates, phosphates, hydrobromides, etc.
• Inorganic acid salts fumarate, maleate, malate, tartrate, succinate, citrate, methanesulfonate, p-toluenesulfonate, acetate, lactate, palmitate, etc. Mention may be made of organic acid salts; alkali metal salts; and alkaline earth metal salts.
• solvates such as hydrates.
• solvates are intended to include the above-mentioned compounds, their pharmaceutically acceptable salts, or their prodrugs.
• stereoisomers e.g. enantiomers, diastereomers
• the individual stereoisomers and mixtures thereof e.g. racemates
• the above-mentioned compounds their pharmaceutically acceptable salts or prodrugs thereof.
• One embodiment of the present invention relates to an ALDH2 activator comprising a compound as described above, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
• the ALDH2 activator of this embodiment not only has an excellent ALDH2 activating effect, but also has even more excellent properties (for example, excellent metabolic stability and suppression of production of reactive metabolites).
• diseases associated with ALDH2 can be treated and/or prevented.
• One embodiment of the invention relates to a pharmaceutical composition comprising a compound as described above, a pharmaceutically acceptable salt thereof or a prodrug thereof.
• One embodiment of the present invention also relates to therapeutic and/or prophylactic agents comprising the above-mentioned compounds, their pharmaceutically acceptable salts or their prodrugs.
• diseases targeted by the pharmaceutical composition and therapeutic and/or preventive drug of the present embodiment include Fanconi anemia, osteoporosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol
• diseases targeted by the pharmaceutical composition and therapeutic and/or preventive drug of the present embodiment include Fanconi anemia, osteoporosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol
• sexual hepatopathy pancreatitis, ischemia-reperfusion injury, peripheral artery disease, Alzheimer's disease, Parkinson's disease, esophageal cancer, head and neck cancer, pain, and diabetic retinopathy.
• compositions and therapeutic and/or preventive agent of this embodiment can be administered orally or parenterally.
• Dosage forms for oral administration include, for example, tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions.
• Dosage forms for parenteral administration include, for example, injections, infusions, drops, eye drops, and suppositories.
• the pharmaceutical composition and therapeutic and/or prophylactic agent of this embodiment may include excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, as necessary. It may contain agents, preservatives, fragrances, flavoring agents, stabilizers, thickeners, etc.
• the dosage (based on active ingredients) of the pharmaceutical composition and therapeutic and/or prophylactic drug of this embodiment varies depending on the condition and weight of the patient, the type of compound, the type of disease, the route of administration, etc. can be determined. Examples include Fanconi anemia, osteoporosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver injury, pancreatitis, ischemia-reperfusion injury, peripheral artery disease, Alzheimer's disease, and Parkinson's disease. , esophageal cancer, head and neck cancer, pain, diabetic retinopathy, etc., for adults (body weight approximately 60 kg): 1 to 2000 mg for oral administration, and 1 to 2000 mg for parenteral administration. In some cases, 0.01 to 2000 (mg) may be administered.
• NASH nonalcoholic fatty liver disease
• NASH nonalcoholic steatohepatitis
• alcoholic liver injury pancreatitis
• ischemia-reperfusion injury peripheral artery disease
• step A1 compound (A1) is reacted with a strong base (eg, sodium hydride) and then reacted with a halide that provides R 3 (eg, iodomethane) to obtain compound (A2).
• compound (A2) is cyanated using a cyanating agent (for example, zinc cyanide) to obtain compound (A3).
• step A3 the cyano group of compound (A3) is reduced using a reducing agent (eg, sodium borohydride) and protected with a Boc group to obtain compound (A4).
• step A4 compound (A4) is deprotected to obtain compound (A5).
• step A5 compound (A6) is reacted with bis(pinacolato)diboron to obtain compound (A7).
• step A6 compound (A7) is reacted with 2-bromonicotinaldehyde to obtain compound (A8).
• step A7 the ester group of compound (A8) is hydrolyzed to obtain compound (A9).
• step A8 compound (A5) and compound (A9) are reacted to obtain compound (A10).
• step A9 compound (A10) is reacted with a reducing agent (eg, sodium borohydride) or a Grignard reagent that provides R 2 to obtain compound (A11).
• a reducing agent eg, sodium borohydride
• a Grignard reagent that provides R 2 to obtain compound (A11).
• the method for synthesizing the above compound or its pharmaceutically acceptable salt is not limited to the above scheme A, and those skilled in the art can appropriately set appropriate synthetic routes and reaction conditions depending on the structure of the final compound. Can be done.
• a prodrug of the above compound or a pharmaceutically acceptable salt thereof may be synthesized, for example, by introducing a phosphate group by a known method.
• each isomer can be resolved by a known method.
• Known methods include, for example, chromatography, enzymatic methods, and crystallization methods.
• the reaction mixture was diluted with dichloromethane, washed with 1 mol/L hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated brine, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (0.60 g).
• ESI-MS m/z 339.25 [M+1]+.
• the adduct (0.048 g, 0.05 mmol) was added and stirred at 100° C. for 16 hours.
• the reaction mixture was brought to room temperature, filtered through Celite, and the filtrate was evaporated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (0.30 g).
• ESI-MS m/z 433.20 [M+1]+.
• the reaction mixture was diluted with dichloromethane, washed with 1 mol/L hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated brine, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (0.37 g).
• ESI-MS m/z 383.13 [M+1]+.
• Comparative example 1 The following compound, which is a commercially available product, was used as Comparative Example 1. In addition, the following compound is a compound described in International Publication No. 2008/112164.
• Test Example 1-1 ALDH2 activation effect
• the activation effect of the test compound on the oxidation rate of acetaldehyde by ALDH2 was determined by the following method. Using a commercially available PicoProbe TM Aldehyde dehydrogenase Activity Assay Kit (manufactured by BioVision Inc.), a test was conducted under the following conditions with reference to the product's instruction manual. The following (1) to (3) were sequentially added to each well of a 384-well plate using a pipette.
• Table 1 shows the oxidation rate of acetaldehyde when the test compound was added, with the oxidation rate of acetaldehyde when the test compound was not added being 100%. From the results in Table 1, it was confirmed that the compounds of Examples 1 to 3 had an ALDH2 activating effect.
• Test Example 1-2 ALDH2 activation effect
• the activation effect of the test compound on the rate of oxidation of acetaldehyde by ALDH2 was determined by the following method. Using a commercially available PicoProbe TM Aldehyde dehydrogenase Activity Assay Kit (manufactured by Abcam), a test was conducted under the following conditions with reference to the product's instruction manual. The following (1) to (3) were sequentially added to each well of a 384-well plate using a pipette.
• Table 2 shows the oxidation rate of acetaldehyde when the test compound was added, with the oxidation rate of acetaldehyde when the test compound was not added being 100%. From the results in Table 2, it was confirmed that the compounds of Examples 4 to 9 had an ALDH2 activating effect.
• the mixture was centrifuged at 3220 ⁇ g for 20 minutes, and the unchanged concentration of the test compound in 200 ⁇ L of supernatant was measured by LC-MS/MS. Based on the obtained peak area of the unchanged substance, the residual rate (%) of the unchanged substance was calculated with the incubation time of 0 minutes as 100%.
• Results Table 3 shows the residual rate (%) of the unchanged compound after 30 minutes. It was confirmed that the compounds of Examples 1 to 9 have superior metabolic stability in mouse liver microsomes compared to conventional ALDH2 activators.
• Test Example 4 Reactive metabolite
• the risk of producing reactive metabolites of the test compound was investigated by measuring the production of glutathione conjugates by LC-MS/MS in the presence of human liver microsomes.
• the specific method is as follows.
• Method (1) 55 uL of 20 mg/mL human liver microsomes, 395 uL of 66.7 mM potassium phosphate buffer (pH 7.4), and 550 uL of 10 mM glutathione aqueous solution were added to a polypropylene tube.
• 0.55 uL of 20 mM test compound or positive control was added.
• (4) Add 20 uL of 10 mM NADPH solution to the T60 tube and 20 uL of potassium phosphate buffer to the T0 tube.
• the mouse was stimulated vertically for 6 seconds until the filament bent, and the mouse's escape response was scored in three stages (0: no response or startle response (shift without lifting the paw), 1: raise the paw, 2: raise the paw). lick or shake). Stimulation was performed 10 times, and the total value (escape score) of the 10 times was calculated.
• Example 3 The compound (Example 3) was dissolved in DMSO/PEG400 (1:1 volume ratio), and 2, 6 or 20 mg/kg of the compound (Vehicle group did not contain the compound) was added to carrageenan at a dosage volume of 5 mL/kg. The same amount was subcutaneously administered to the back of the neck three times, 15 minutes before injection, 30 minutes and 150 minutes after carrageenin injection. A 1.5% solution of carrageenan was prepared using physiological saline, and the solution was subcutaneously administered to the sole of the left hind paw at 7 ⁇ L/body.

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