WO2008020625A1 - Composé de dibenzoylméthane et composition pharmaceutique contenant le composé en tant qu'ingrédient actif - Google Patents

Composé de dibenzoylméthane et composition pharmaceutique contenant le composé en tant qu'ingrédient actif Download PDF

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WO2008020625A1
WO2008020625A1 PCT/JP2007/066025 JP2007066025W WO2008020625A1 WO 2008020625 A1 WO2008020625 A1 WO 2008020625A1 JP 2007066025 W JP2007066025 W JP 2007066025W WO 2008020625 A1 WO2008020625 A1 WO 2008020625A1
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compound
cell death
endoplasmic reticulum
group
reticulum stress
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Japanese (ja)
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Osamu Hori
Satoshi Ogawa
Satoshi Hibino
Tominari Choshi
Munekazu Iinuma
Masashi Yamada
Hiroto Suzuki
Rika Murakami
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Kanazawa University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups

Definitions

  • the present invention relates to an endoplasmic reticulum stress controlling substance, and more particularly to a compound having an effect of suppressing cell death derived from endoplasmic reticulum stress and a pharmaceutical composition containing the compound as an active ingredient.
  • the endoplasmic reticulum is a place where secretory proteins and membrane proteins are regularly folded to adjust their three-dimensional structure, and has a variety of physiological functions as a reservoir of intracellular calcium and as a major organ of lipid metabolism. is doing.
  • physicochemical stresses such as ischemia, hypoxia, heat shock, and gene mutations increase the number of unfolded proteins in the endoplasmic reticulum, resulting in impaired function of the endoplasmic reticulum. Is known to cause ER stress (see Non-Patent Document 1).
  • Endoplasmic reticulum stress' Endoplasmic reticulum stress-derived cell death is caused by cerebral ischemia or neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine disease, and inflammatory neurological diseases such as multiple sclerosis.
  • Mental disorders such as manic depression, eye diseases such as glaucoma, arteriosclerosis and It is involved in the onset and progression of various diseases such as ischemic heart disease, gastric ulcer, viral hepatitis, fatty liver, diabetes, diabetic complications, renal diseases such as glomerulonephritis and renal failure, and cancer. It has been pointed out.
  • Dilinoleoylphosphatidylethanolamine having a specific structure containing two linoleic acids as fatty acids
  • cell death induction inhibitory activity particularly endoplasmic reticulum stress inhibition. It has been shown to have activity, and a pharmaceutical composition containing this as an active ingredient has been proposed.
  • Patent Document 2 shows that a polypeptide having a specific amino acid sequence has an endoplasmic reticulum stress-induced cell death inhibitory action.
  • Patent Document 3 shows that a fat-soluble extract component derived from Amaranthus has an endoplasmic reticulum stress-induced cell death inhibitory effect.
  • Herp is a gene with a ubiquitin-like domain in the endoplasmic reticulum that is thought to be related to the removal of unwanted proteins accumulated in the endoplasmic reticulum.
  • Patent Document 1 Japanese Unexamined Patent Publication No. 2005-247728
  • Patent Document 2 JP 2005-082557 A
  • Patent Document 3 Japanese Unexamined Patent Publication No. 2003-212790
  • Patent Document 4 Japanese Patent Laid-Open No. 2005-245247
  • Non-Patent Document 1 Mori, K., Cell., 2000, Vol. 101, p. 451—454
  • Non-Patent Document 2 Oyadomari, S, and M. Mori, Cell Death Differ , 2004, 11, 11, 381-389
  • an object of the present invention is to develop a compound having a high effect on endoplasmic reticulum stress control and to apply it.
  • DBM dibenzoylmethane compound having a specific structure
  • R to R are independently hydrogen atom, halogen atom, hydroxyl group, C A chain or branched alkyl group or alkoxy group, an aryl group or benzyloxy group, or at least one of adjacent substituents are connected to form a condensed aromatic ring together with the benzene ring in the formula.
  • the present invention relates to a composition for suppressing cell death caused by endoplasmic reticulum stress, which comprises at least one dibenzoylmethane compound represented by the formula:
  • R and R 1 are each independently a hydrogen atom, a halogen atom or
  • the present invention relates to the composition for suppressing cell death derived from endoplasmic reticulum stress, wherein the fused aromatic ring formed by linking a pair is a naphthyl ring formed together with a benzene ring in the formula.
  • At least one of a pair of R and R, R and R, R and R, R and R, R and R, R and R is
  • the present invention relates to the composition for suppressing cell death derived from endoplasmic reticulum stress, which is the same substituent.
  • the present invention further relates to the composition for suppressing cell death derived from endoplasmic reticulum stress, wherein the halogen atom is F, Cl, Br or I.
  • the present invention also relates to the aforementioned composition for suppressing cell death derived from endoplasmic reticulum stress, which is an alkyl group, a methyl group, an ethyl group or a propyl group.
  • the present invention relates to the composition for suppressing cell death derived from endoplasmic reticulum stress, which has an alkoxy group strength S and a methoxy group.
  • MIN6 cells which are insulin-producing cell lines
  • a certain type of DBM showed strong endoplasmic reticulum stress-derived cell death-suppressing activity, and when this mechanism of action was examined, the intracellular protein synthesis was slightly reduced to suppress endoplasmic reticulum stress. It was suggested that Furthermore, this DBM was suggested to have both an oxidative stress-derived cell death inhibitory effect and a mitochondrial protective effect, thereby completing the present invention.
  • this DBM also has neurite outgrowth and anti-inflammatory effects. Admitted.
  • the present invention also relates to the aforementioned composition for suppressing endoplasmic reticulum stress-derived cell death, which further has an action of suppressing oxidative stress-derived cell death, neurite outgrowth action or anti-inflammatory action.
  • the present invention also provides the following formula:
  • the present invention further provides the following formula: [Chemical 4]
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the dibenzoylmethane compound as an active ingredient.
  • the dibenzoylmethane-based compound having a specific structure of the present invention can exhibit a high effect that has not been obtained in the past in suppressing cell death caused by endoplasmic reticulum stress.
  • the compound since the compound has a basic skeleton widely used as an industrial product, the basic skeleton compound is easily available and the synthesis of the compound of the present invention is also easy. Therefore, a compound having an excellent effect can be obtained at a low cost, and the economic effect is great.
  • a compound having a specific preferable structure can also be obtained for neurite outgrowth action and / or anti-inflammatory action.
  • FIG. 1 is a table showing changes in substituents of dibenzoylmethane compounds and their cell death inhibitory effects in primary screening using F9 Herp-deficient cells in Example 1.
  • FIG. 2 is a graph showing the cell death inhibitory effect (mean ⁇ standard deviation) of Compound C, Compound F, Compound J, Compound and Compound N in the primary screening using F9 Herp-deficient cells in Example 1.
  • FIG. 2 is a graph showing the cell death inhibitory effect (mean ⁇ standard deviation) of Compound C, Compound F, Compound J, Compound and Compound N in the primary screening using F9 Herp-deficient cells in Example 1.
  • FIG. 3 is a graph showing the cell death inhibitory effect (mean soil standard deviation) of Compound 0, Compound P, and Compound R in the primary screening using F9 Herp-deficient cells in Example 1. is there.
  • FIG. 4 is a table showing the cell death inhibitory effects of Compound C, Compound E, Compound F, Compound J, Compound and Compound N in secondary screening using MIN6 cells and SH-SY5Y cells in Example 2. is there.
  • FIG. 5 is a table showing the cell death inhibitory effect of Compound 0, Compound P and Compound R in secondary screening using MIN6 cells and SH-SY5Y cells in Example 2.
  • FIG. 6 is a graph showing the endoplasmic reticulum stress of Compound E, Compound F, Compound J, and Compound N (induced by Tsuyu forcemycin) cell death inhibitory effect in secondary screening using MIN6 cells in Example 2. It is.
  • FIG. 7 is a graph showing the effect of compound E, compound J, and compound K on the endoplasmic reticulum stress (induced by tsuyu forcemycin) cell death inhibition in secondary screening using SH-SY5Y cells in Example 2. It is.
  • FIG. 8 is a graph showing the oxidative stress cell death inhibitory effect of Compound E, Compound F, Compound J, Compound and Compound N in secondary screening using MIN6 cells in Example 2.
  • FIG. 9 is a graph showing the oxidative stress cell death inhibitory effect of compound E, compound F, compound J, compound and compound N in secondary screening using SH-SY5Y cells in Example 2.
  • FIG. 10 is a graph showing the oxidative stress cell death inhibitory effect of compound 0, compound P, and compound R in secondary screening using SH-SY5Y cells in Example 2.
  • FIG. 11 is a graph showing the neuroprotective effect of Compound F, Compound J, and Compound K against 6-OHDA using SH-SY5Y cells in Example 2!
  • FIG. 12 is a graph showing the effect of Compound J on the suppression of endoplasmic reticulum stress-derived cell death in PC12 cells in Example 2.
  • FIG. 13 shows the effect of Compound J on the suppression of endoplasmic reticulum stress-derived cell death using SH-SY5Y cells in Example 3, A shows the result of metabolic labeling, and B shows the result by Northern blot method.
  • FIG. 15 shows the effect of Compound J on the suppression of oxidative stress-induced cell death using SH-SY5Y cells in Example 4,
  • A shows the measurement results using a fluorescent reagent, and B shows the northern plot method.
  • the result, C shows the result obtained with the mitochondrial membrane sensor kit.
  • FIG. 16 shows the effect of Compound R on endoplasmic reticulum stress-induced cell death suppression using SH-SY5Y cells in Example 4 (Northern plot method).
  • Example 6 A photomicrograph showing the neurite outgrowth effect of Compound J in Example 5.
  • the graph (A) of the nitric oxide metabolite (nitrite amount) showing the anti-inflammatory action of Compound J, and the NO producing enzyme (iNOS) and cycloxygenase 2 (COX2) (B) is a diagram showing evaluation of the expression of by Western blotting.
  • R to R each independently represent a hydrogen atom, a halogen atom, or a hydroxy acid.
  • alkyl group preferably a linear or branched alkyl group of c to c, aryl
  • R and R benzyloxy group or alkoxy group, preferably c-c linear or branched R and R, R and R, R and R may be bonded together to form a condensed aromatic ring together with the benzene ring in the formula.
  • R, R and R pairs may be the same or different.
  • R to R are the same or different.
  • R to R are the same or different.
  • a condensed aromatic ring is formed on the surface.
  • R and R 1 are each independently a hydrogen atom or a halogen atom.
  • R or R, R, R, R, R, R and R forces each independently
  • At least one pair of adjacent substituents may be linked to form a naphthyl ring together with the benzene ring in the formula.
  • halogen atom examples include F, Cl, Br, and I.
  • F, C, and Br are preferable, and C1 is particularly preferable.
  • At least one counter force is preferably the same halogen atom, particularly C 1.
  • the alkyl group is not particularly limited, but is a C to C linear or branched group.
  • alkyl group typically a methyl group, an ethyl group, a propyl group, or the like can be given.
  • the alkoxy group is not particularly limited, but c to branched
  • ком ⁇ онент typically include a methoxy group, an ethoxy group, a propoxy group, and the like, preferably a methoxy group.
  • the aryl group is not particularly limited, but is typically phenyl, 1-naphthyl. Nore, 2-naphthyl and the like.
  • R to R adjacent substituents are connected to form a condensed aromatic together with the benzene ring in the formula.
  • a naphthyl ring is typically formed with the benzene ring in the formula
  • the gibetane compound contained in the composition for suppressing cell death derived from endoplasmic reticulum stress of the present invention further has a neurite outgrowth action and / or an anti-inflammatory action in addition to the action of inhibiting oxidative stress-derived cell death.
  • the present invention also provides a novel dibenzoylmethane compound represented by the following structural formulas 3 to 5 About.
  • the method for producing the dibenzoylmethane-based compound of the present invention is not particularly limited, and can be obtained by general chemical synthesis.
  • the pharmaceutical composition of the present invention which can be used isolated from a natural product, comprises at least one dibenzoylmethane compound of the present invention as an active ingredient. Accordingly, the present invention also includes pharmaceutical compositions containing different types of dibenzoylmethane compounds of the present invention.
  • the subject of the pharmaceutical composition of the present invention is an endoplasmic reticulum stress-related disease, typically, cerebral ischemia or neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine disease, and multiple sclerosis.
  • Inflammatory neurological diseases such as manic depression, eye diseases such as glaucoma, arteriosclerosis and ischemic heart disease, gastric ulcer, viral hepatitis, fatty liver, diabetes, diabetic complications, glomerulonephritis and renal failure Kidney disease, cancer and the like.
  • the dosage of the pharmaceutical composition containing the dibenzoylmethane compound of the present invention as an active ingredient is appropriately set in consideration of various factors such as the administration route, the age, body weight, and symptoms of animals to be administered including humans. be able to.
  • the present invention is not limited to this, but preferably 0.001 to 1,000 mg / kg / day of the active ingredient is suitable.
  • the pharmaceutical composition comprising the dibenzoylmethane compound of the present invention as an active ingredient is not limited to the present invention, but oral administration or parenteral administration (intramuscular, subcutaneous, intravenous, suppository, (Transdermal, nasal, ophthalmic, etc.) can be administered.
  • Administration form of pharmaceutical composition comprising dibenzoylmethane compound according to the present invention as an active ingredient
  • examples of the present invention include, but are not limited to, administration forms such as tablets, coated tablets, capsules, granules, powders, solutions, syrups, and emulsions.
  • administration forms such as tablets, coated tablets, capsules, granules, powders, solutions, syrups, and emulsions.
  • These various preparations are prepared in accordance with conventional methods by adding an excipient, a binder, a disintegrant, a lubricant, a colorant, a flavoring agent to a pharmaceutical composition containing the dibenzoylmethane compound of the present invention as an active ingredient.
  • It can be formulated using known adjuvants that can be usually used in the pharmaceutical preparation technical field, such as agents, solubilizers, suspensions, and coating agents.
  • other compounds having an endoplasmic reticulum stress-derived cell death control action cannot be used.
  • binding agent examples include polybulol alcohol, polyvinylenoateolose, ethinoresenorelose, methinorescenellose, gum arabic, tragacanth, gelatin, shellac, hydroxypropinoresenorelose, hydroxypropinorestarch, and polyvinylpyrrolidone. Is mentioned.
  • Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextran, and pectin.
  • Examples of the lubricant include magnesium stearate, talc, polyethylene darcol, silica, hydrogenated vegetable oil, and the like.
  • As the colorant those permitted to be added to pharmaceuticals can be used.
  • As a flavoring agent cocoa powder, heart force brain, aromatic acid, heart force oil, dragon brain, cinnamon powder, menthol, peppermint oil, camphor, etc. can be used. These tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.
  • a pH adjuster, a buffer, a stabilizer, a preservative, etc. are added as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.
  • the injection may be a solid preparation or a preparation prepared at the time of use by lyophilization after storing the solution in a container. Further, one dose may be stored in a container, and multiple doses may be stored in the same container.
  • the amount of the pharmaceutical composition comprising the dibenzoylmethane compound of the present invention as an active ingredient can be arbitrarily determined according to its purpose and use (pharmaceutical composition such as food composition, preventive agent, therapeutic agent). can S, but the present invention is not limited thereto, as its content, usually on the total amount, 0. 001 to; 100 0/0 (w / w), in particular 0.1;! ⁇ 100 0/0 ( w / w)
  • dantrolene was 30 ⁇ M
  • ⁇ -tocopheronole was 120 ⁇ M
  • / 3-carotene was 100 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ as positive controls for the effect of suppressing cell death from endoplasmic reticulum stress in F9 Herp-deficient cells. Used at a concentration of.
  • FIG. 1 shows the effect of a plurality of dibenzoylmethane compounds in which the substituents in the above general formula were changed as shown in the table.
  • one is no cell death inhibitory effect
  • ++ is the same effect as dantrolene's cell death inhibitory effect
  • + is an intermediate inhibitory effect
  • +++ is dantrolene's cell death inhibitory effect It shows that it has the effect more than an effect.
  • DBM dimethoxydibenzoylmethanes
  • tsuyu forcemycin As a method of inducing endoplasmic reticulum stress, tsuyu forcemycin (Tm: l. ⁇ ⁇ g L ⁇ , 48 hours (MIN6 and SH-SY5Y cells), 0.75 j gZmL, 48 hours (PC12 cells))
  • the methods for inducing oxidative stress include HO (66 ⁇ M (MIN6 cells) and 44 ⁇ M (SH—SY5
  • 6-OHDA 6-hydroxydopamine
  • SH-SY5Y cells the neuroprotective effect on 6-hydroxydopamine (hereinafter referred to as 6-OHDA) (30 ⁇ , 24 hours), which is an experimental Parkinson's disease inducer, was examined using SH-SY5Y cells.
  • the test compound was administered under the conditions of pre-administration from 24 hours before 6-OHDA administration and simultaneous administration with 6-OHD A administration.
  • Cell viability was determined by MTT Atsey (see Hori O, et. Al, Genes Cells., 2004, 9 (5), p. 457-469). Also known as positive control of oxidative stress! /, N-acetyl cysteine (NAC) (1000 M) and probucol (80 M) were used together.
  • N-acetyl cysteine (NAC) 1000 M
  • probucol 80 M
  • Figure 6 and Figure 7 show the results of whether or not the test compound has an endoplasmic reticulum stress' endoplasmic reticulum stress-derived cell death inhibitory effect in MIN6 cells and SH-SY5Y cells as well as F9 Herp-deficient cells.
  • . 8 to 10 show the results of whether or not the test compound has an oxidative stress-derived cell death inhibitory effect.
  • FIG. 11 also shows the results of examining the presence or absence of a neuroprotective effect against 6-OHDA, an experimental Parkinson's disease inducer, using SH-SY5Y cells.
  • FIG. 12 shows the results regarding the presence or absence of the effect of Compound J on endoplasmic reticulum stress-derived cell death in PC 12 cells.
  • SH SY5Y cells are cultured for 24 hours in the presence of the test compound, and then 3 hours metabolic labeling with 35 S—Met (Amarsham Almacia Biotech). The extracted protein is separated by SDS-PAGE and Determine by geography.
  • N-acetylcystein (NAC) 1000 M
  • an oxidative stress inhibitor 1000 M
  • oxidative stress is reduced by simultaneous administration of Compound J or Compound R.
  • PC 12 cells were treated with Compound J (20-40 ⁇ M), N-Acetylcystine (NAC: lmM), ⁇ -Tocopherol (120 M), or Nerve Grouth Factor (NGF) (10 M).
  • the cells were cultured in the added serum-free medium or serum-free medium for 48 hours, and the progress of the neural protrusion was observed with a phase contrast microscope.
  • Macrophage cell line RAW264. 7 cells were stimulated with intracellular toxin (Lipopolysaccharide LPS) (0.1 g / ml), and Nitrite (NO monoacid in medium) was cultured 16 hours later.
  • toxin Lipopolysaccharide LPS
  • Nitrite NO monoacid in medium
  • Nitrogen (NO) metabolite) concentration was measured. At this time, the test substance was administered 6 hours before LPS administration, and simultaneously with LPS administration, and the effect on the amount of nitrite in the medium was examined. In addition, after intracellular protein extraction, the expression of NO producing enzyme (iNOS) and cycloxygenase 2 (CO X2) was evaluated by Western blotting.
  • iNOS NO producing enzyme
  • CO X2 cycloxygenase 2
  • NO nitric oxide
  • a in FIG. 18 Stimulation of macrophage cell line 264 7 cells with LPS increases production of nitric oxide (NO), a mediator of inflammation.
  • NO- Nitrite
  • Dibenzoylmethane compounds have an action to absorb ultraviolet rays (especially UVA), and in particular, one of its derivatives, Parsol 1789 (4-t-butyl-4'-methoxydibenzoyl). Noremethane) is widely used for sunscreen. However, there are reports that the direct action of DBM on cultured cells works to protect cells when irradiated with ultraviolet rays, and conversely it has an adverse effect on skin cells.
  • DBM, Compound J and Compound R have an endoplasmic reticulum stress control action and a strong antioxidant action. Furthermore, Compound J had a neurite outgrowth effect on PC 12 cells and an anti-inflammatory effect on RAW264. 7 cells. Based on these facts, it is considered possible to prevent and treat various diseases by using DBM as a new cytoprotective agent.
  • This compound showed ketoeenol tautomerism in the solution state, and the ratio of keto to enol was 1: 8.
  • protons in the enol form were assigned.
  • the dibenzoylmethane compound having the specific structure of the present invention can provide a high endoplasmic reticulum stress-derived cell death inhibitory effect.
  • a basic skeleton compound as a raw material is readily available and the synthesis of the compound of the present invention is easy. Therefore, the economic effect is also great.

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Abstract

L'invention concerne une composition permettant d'inhiber une apoptose induite par le stress du réticulum endoplasmique. Cette composition comprend au moins un composé de dibenzoylméthane représenté par la formule générale (I), dans laquelle R1 à R10 représentent indépendamment un atome d'hydrogène, un atome d'halogène, un groupe hydroxy, un groupe alkyle or alkoxy linéaire ou ramifié C1-C5, un groupe aryle ou un groupe benzyloxy, ou au moins une paire adjacente de R1 à R10 peut être liée et forme, avec un cycle de benzène de la formule, un cycle aromatique fusionné, à condition que des paires de R1 à R10, R2 et R9, R3 et R8, R4 et R7 et R5 et R6 puissent être identiques ou différentes l'une de l'autre.
PCT/JP2007/066025 2006-08-17 2007-08-17 Composé de dibenzoylméthane et composition pharmaceutique contenant le composé en tant qu'ingrédient actif WO2008020625A1 (fr)

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US10314832B2 (en) 2010-08-18 2019-06-11 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/β-catenin signaling pathway activators
US10434052B2 (en) 2014-08-20 2019-10-08 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles

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FRAZIER M.C. ET AL.: "Proteomic analysis of proteins altered by dibenzoylmethane in human prostatic cancer LNCaP cells", PROTEOMICS, vol. 4, 2004, pages 2814 - 2821, XP003021085 *
IMAIZUMI K.: "Alzheimer-byo to Shinkei Saibo Shi Mechanism -Presenilin 1 Hen'itai ni yoru Shohotai Stress Otosei no Shogai-", SHINKEI KAGAKU, vol. 38, no. 4, 1999, pages 89 - 96, XP003021086 *
SONG G.-Y. ET AL.: "Synthesis of Dibenzoylmethanes as Intermediates for Flavone Synthesis by a Modified Baker-Venkataraman Rearrangement", ARCHIVES OF PHARMACAL. RESEARCH, vol. 17, no. 6, 1994, pages 434 - 437, XP003021088 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10314832B2 (en) 2010-08-18 2019-06-11 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/β-catenin signaling pathway activators
KR20150119942A (ko) * 2013-02-22 2015-10-26 사뮤메드, 엘엘씨 Wnt/베타-카테닌 신호전달 경로 활성자로서 감마-디케톤
JP2016514100A (ja) * 2013-02-22 2016-05-19 サミュメッド リミテッド ライアビリティ カンパニー Ｗｎｔ／β−カテニンシグナル伝達経路活性化剤としてのγ−ジケトン
US9951053B2 (en) 2013-02-22 2018-04-24 Samumed, Llc γ-diketones as Wnt/β-catenin signaling pathway activators
US10457672B2 (en) 2013-02-22 2019-10-29 Samumed, Llc γ-diketones as Wnt/β-catenin signaling pathway activators
KR102252567B1 (ko) 2013-02-22 2021-05-17 사뮤메드, 엘엘씨 Wnt/베타-카테닌 신호전달 경로 활성자로서 감마-디케톤
US11034682B2 (en) 2013-02-22 2021-06-15 Samumed, Llc Gamma-diketones as wnt/β-catenin signaling pathway activators
US11673885B2 (en) 2013-02-22 2023-06-13 Biosplice Therapeutics, Inc. γ-diketones as Wnt/β-catenin signaling pathway activators
US10434052B2 (en) 2014-08-20 2019-10-08 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles
US11077046B2 (en) 2014-08-20 2021-08-03 Biosplice Therapeutics, Inc. Gamma-diketones for treatment and prevention of aging skin and wrinkles
US11839679B2 (en) 2014-08-20 2023-12-12 Biosplice Therapeutics, Inc. Gamma-diketones for treatment and prevention of aging skin and wrinkles

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