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WO2007125720A1 - Inducteur d'expression de chaperon moleculaire - Google Patents

Inducteur d'expression de chaperon moleculaire Download PDF

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Publication number
WO2007125720A1
WO2007125720A1 PCT/JP2007/057046 JP2007057046W WO2007125720A1 WO 2007125720 A1 WO2007125720 A1 WO 2007125720A1 JP 2007057046 W JP2007057046 W JP 2007057046W WO 2007125720 A1 WO2007125720 A1 WO 2007125720A1
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WIPO (PCT)
Prior art keywords
atom
pharmaceutical composition
disease
endoplasmic reticulum
group
Prior art date
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PCT/JP2007/057046
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English (en)
Japanese (ja)
Inventor
Takashi Kudo
Kazunori Imaizumi
Masatoshi Takeda
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University of Miyazaki NUC
Shionogi and Co Ltd
University of Osaka NUC
Original Assignee
Osaka University NUC
University of Miyazaki NUC
Shionogi and Co Ltd
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Application filed by Osaka University NUC, University of Miyazaki NUC, Shionogi and Co Ltd filed Critical Osaka University NUC
Priority to JP2008513114A priority Critical patent/JP5131700B2/ja
Publication of WO2007125720A1 publication Critical patent/WO2007125720A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/26—Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
    • 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
    • A61P25/14—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
    • A61P25/28—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
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition having an action of inducing expression of an endoplasmic reticulum molecular chaperone.
  • the present invention also relates to a pharmaceutical composition effective for suppressing cell death due to endoplasmic reticulum stress, or a pharmaceutical composition effective as a preventive or therapeutic agent for neurodegenerative diseases based on the molecular chaperone expression inducing action.
  • Alzheimer's disease and Parkinson's disease are representative of progressive neurodegenerative diseases accompanied by marked loss of neurons.
  • a part of Alzheimer's disease (AD) is familial AD (FAD) with a genetic mutation. The majority are sporadic AD (SAD) without a family history.
  • Both ADs are characterized by senile plaques composed of amyloid protein (A / 3) deposited in the brain and neurofibrillary tangles caused by abnormal phosphorylation of tau protein. For this reason, it is thought that an increase in amyloid protein (A / 3) is deeply related to the pathology of Alzheimer's disease (Amyloid cascade hypothesis) (Non-patent document 1).
  • amyloid precursor A / 3 / ⁇ -secretor inhibitor that lowers A ⁇ by suppressing the excision of amyloid protein (A) from protein (APP) and amyloid vaccine have been proposed and developed (non-patent literature) 2 and 3).
  • Non-Patent Documents 4 to 9 In addition, in many of the neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, there is a common pathological condition that unfolded proteins are aggregated and accumulated in nerve cells. In recent years, this abnormal protein accumulation (this state is called “ER stress”) has been implicated in the development of various neurodegenerative diseases. (Non-Patent Documents 4 to 9).
  • endoplasmic reticulum when a protein synthesized in the ribosome matures, a sugar chain is added. A folded three-dimensional structure is formed by a modification such as a sulfide bond. The protein correctly folded in the endoplasmic reticulum is transported to the gonores. The protein that fails to fold is retained in the endoplasmic reticulum until the correct conformation is achieved (endoplasmic reticulum stress). If the endoplasmic reticulum stress is excessive or persists for a long time, the cells die and die. However, the endoplasmic reticulum stress response (which is a defense mechanism to avoid such cell death)
  • Unfolding Protein Response exists and contributes to the maintenance of cell survival.
  • Such defense mechanisms can be roughly divided into the following three categories.
  • This mechanism induces chaperone molecules present in the endoplasmic reticulum at the transcriptional level to unwind abnormal proteins.
  • a signal is transmitted downstream to induce a molecular chaperone (also called “ER chaperone” or “ER molecular chaperone”).
  • Molecular chaperone is an endoplasmic reticulum-specific molecule (folding enzyme) whose expression is induced by endoplasmic reticulum stress (Non-patent Documents 10 and 11), and is extremely important for folding of newly secreted proteins and membrane proteins in the endoplasmic reticulum. Playing a role.
  • the sensor or transducer protein that induces the molecular chaperone is IRE1 a or A.
  • GRP glucose regulatory proteins
  • GRP78 / Bip is a molecular chaperone that has been analyzed, and for the rat GRP78 gene, the CORE region located in the upstream region and the C1 region containing the CCAAT sequence have been shown to be important for transcriptional control ( Non-patent literature 12-: 14).
  • yeast the transcriptional control sequence (UPRE sequence: CAGNGTG) of the GRP78 gene of budding yeast has been clarified (Non-patent Document 15), and there is a sequence similar to the UPRE sequence in the upstream region of the human GRP78 gene. It is clear that there is.
  • the molecular chaperone induction mechanism endoplasmic reticulum stress response (UPR)
  • the endoplasmic reticulum-related degradation mechanism (ERAD) function effectively against endoplasmic reticulum stress. Therefore, if these biological defense functions are enhanced, it is possible to protect against excessive endoplasmic reticulum stress, and to avoid pathological conditions and diseases caused by endoplasmic reticulum stress, and neuronal cell death. Conceivable. From this point of view, various techniques for inducing molecular chaperone expression have been proposed, focusing on UPR.
  • a representative compound among the compounds (I) according to the present invention is a known compound (for example, Non-Patent Document 16).
  • Non-Patent Document 1 Hardy, J.A. & Selkoe, D.J., Science, 19, 353-356
  • Non-Patent Document 2 Beher, D. & Graham, S. L., Expert. Opin. Investig. Drugs, 14, 1385-
  • Non-Patent Document 3 Gilman, S. et al "Neurology, 10, 1553-1562 (2005)
  • Non-Patent Document 4 Kitada, T. Et al., Nature 392, 605-608 (1998).
  • Non-Patent Document 5 Imai, Y. et al "Cell 105, 891-902 (2001).
  • Non-Patent Document 6 Nishitoh, H. et al., Genes Dev. 16, 1345-1355 (2002).
  • Non-Patent Document 7 Katayama, T et al "Nat Cell Biolog, 8, 479-485 (1999).
  • Non-patent literature 8 Katayama, T. et al "J. Biol. Chem. 276, 43446-43454 (2001)
  • Non-patent literature 9 Yasuda, Y. et al" Biochem. Biophys. Res. Commun. 296, 313- 318 (2
  • Non-Patent Document 10 Kozutsumi, Y. et al., Nature, 332, 462-464 (1988)
  • Non-Patent Document 11 Lee, A.S., Trends Biochem. ScL, 12, 20-23 (1987)
  • Non-Patent Document 12 Resendez, E. et al., Mol. Cell. Biol., 8, 4579-4584 (1988)
  • Non-Patent Document 13 Wooden, S.K.et al., Mol. Cell. Biol., 11,5612-5623 (1991)
  • Non-Patent Document 14 Li.W.W. et al., Mol. Cell. Biol., 14, 5533-5546 (1994)
  • Non-Patent Document 15 Mori. K. et al., Genes Cells, 1, 803-817 (1996)
  • Non-Patent Document 16 Journal of the Chemical Society, Perkin Transactions 2 (2002), (2), 3
  • An object of the present invention is to focus on UPR as a biological defense mechanism against endoplasmic reticulum stress, and to provide a method for increasing the level of molecular chaperone particularly in nerve cells. More specifically, an object of the present invention is to provide a compound having an action of inducing molecular chaperone expression, and a pharmaceutical composition containing the compound as an active ingredient. In addition, the present invention provides a novel molecular chaperone expression inducer, a cell death inhibitor against endoplasmic reticulum stress, and a neurodegenerative disease therapeutic agent for the pharmaceutical composition based on the molecular chaperone expression inducing action of the pharmaceutical composition. The purpose is to provide usage. Means for solving the problem
  • the inventors of the present invention have made extensive studies to achieve the above object.
  • the 1-phenyl-thiocyanatoalkane-1-one derivative (I) represented by the following formula was converted into a nerve cell. Is found to increase the expression level of molecular chaperone (GRP78 / Bip) and to develop resistance to endoplasmic reticulum stress. Further, the compound is administered to nerve cells to give molecular chaperone (GRP78 / Bip). It was confirmed that when the expression level of Bip) was increased, the production of amyloid protein (A) from amyloid precursor protein (APP) was inhibited and A production was suppressed.
  • GRP78 / Bip molecular chaperone
  • the present invention has the following aspects:
  • R 1 and IT each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; Alk represents a lower alkylene chain; X represents an oxygen atom or a sulfur atom)
  • a pharmaceutical composition comprising: a compound represented by formula (1-phenyl-thiocyanatoalkane_1_one derivative):
  • R 1 'and IT are both hydroxyl groups or fluorine atoms, or R 1 chlorine atoms, and R 2 ' is a hydrogen atom
  • Item 2 A pharmaceutical composition according to Item 1, comprising a compound represented by the above or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • Item 3 The pharmaceutical composition according to Item 1 or 2, which is a molecular chaperone expression inducer.
  • Item 4 The pharmaceutical composition according to Item 1 or 2, which is a cell death inhibitor against endoplasmic reticulum stress.
  • Item 5 The pharmaceutical composition according to Item 1 or 2, which is a preventive or therapeutic agent for a neurodegenerative disease.
  • Item 6 The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, or mild cognitive impairment Item 6.
  • Item 7 A method for preventing or treating a neurodegenerative disease, comprising a step of administering the pharmaceutical composition according to Item 1 or 2 to a subject.
  • Item 8 The prevention or treatment method according to Item 7, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, or mild cognitive impairment.
  • Item 9 A method for producing a preventive or therapeutic agent for a neurodegenerative disease:
  • R 1 and IT each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; Alk represents a lower alkylene chain; X represents an oxygen atom or a sulfur atom)
  • R 1 'and IT are both a hydroxyl group or a fluorine atom, or R 1 force S is a chlorine atom, and R 2 ' is a hydrogen atom
  • Item 12 The use according to Item 9, which is a compound represented by:
  • the 1-phenyl-thiocyanatoalkane-1-one derivative (I) and the pharmaceutical composition comprising this as an active ingredient provided by the present invention are molecular shunts involved in endoplasmic reticulum stress response (UPR).
  • URR endoplasmic reticulum stress response
  • composition provided by the present invention has the following formula (I):
  • R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; Alk represents a lower alkylene chain; X represents an oxygen atom or a sulfur atom.
  • examples of the halogen atom defined by R 1 and R 2 include a chlorine atom, a fluorine atom, an iodine atom, and a bromine atom. Preferred are a chlorine atom and a fluorine atom.
  • examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms.
  • examples of the lower alkoxy group include those having 1 to 6 carbon atoms, specifically, methoxyl group, ethoxyl group, propoxyl group, isopropoxyl group, butoxyl group, secondary butoxynole group and A tertiary butoxyl group can be exemplified.
  • R 1 and R 2 may be the same or different from each other.
  • examples of the lower alkylene chain defined by Alk include straight-chain or branched alkylene chains having 1 to 6 carbon atoms. Specific examples include a methylene chain, an ethylene chain, a propylene chain, a butylene chain, and an ethylmethylene chain. A methylene chain is preferred.
  • X may be either an oxygen atom or a sulfur atom, but is preferably an oxygen atom.
  • the position of the group represented by is not particularly limited, but is preferably a para position relative to the R 1 group or the R 2 group. More preferably, it is para to the R 1 group.
  • Alk is preferably a methylene chain.
  • X is preferably an oxygen atom
  • R 1 and R 2 are the same or different, and a halogen atom (preferably Chlorine atom or fluorine atom), hydroxyl group, and hydrogen atom.
  • a halogen atom preferably Chlorine atom or fluorine atom
  • hydroxyl group preferably hydroxyl group
  • hydrogen atom preferably hydrogen atom.
  • Specific examples of such a compound include an ⁇ -thiocyanatotophenone compound having a substituent at the 3-position and / or 4-position represented by the following formula ( ⁇ ).
  • the compound includes, specifically, to (3,4-dihydroxy-phenyl) -2-thiocyanatoethanone (molecular weight: 209.22) in which both R 1 ′ and R 2 ′ are hydroxyl groups; R 1 And R "are both fluorine atoms 1- (3,4-difluoro-phenyl) -2-thiocyanatoethanone (molecular weight: 213.20); and R 1 is a chlorine atom and IT is a hydrogen atom 1 -(4-Chloro-phenyl) -2-thiocyanato-ethanone (molecular weight: 211.67), preferably 1- (3,4-dihydroxy-phenyl) where R 1 'and R 2 ' are both hydroxyl groups ) -2-Thiocyanato-ethanone
  • thiothionatacetophenone compounds represented by the following formula ( ⁇ ) are commercially available (for example, Maybrige (UK), Chemst mark (France), etc.).
  • Y represents a leaving group such as halogen, methanesulfonyloxy, p-toluenesulfonyloxy, etc.
  • ZSCN represents a metal or ammonium salt of thiocyanate.
  • R 1 R 2 , Alk, And X is as described above.
  • compound a and thiocyanate (ZSCN) prepared by a known method are -20 ° C to 200 ° C, preferably 0 ° C to 100 ° C, in a solvent such as toluene, tetrahydrofuran and dimethylformamide.
  • Compound (I) can be obtained by reacting at 0 ° C. for 0.5 to 24 hours, preferably 1 to 10 hours.
  • a substituent such as a hydroxyl group hinders the reaction, it may be protected in advance at a necessary stage, and the protecting group may be removed after the reaction with thiocyanate.
  • the salt is usually a pharmaceutically acceptable salt such as a salt with an inorganic base or an organic base.
  • the inorganic base include alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; aluminum and ammonium.
  • organic bases include primary amines such as ethanolamine; secondary amines such as jetylamine, diethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, trimethylamine, and triethylamine. And tertiary amines such as pyridine, picoline and triethanolamine.
  • the above compound may be a solvate of a free substance or a salt thereof.
  • solvates include hydrates.
  • the compound (I) has an effect of inducing expression of a molecular chaperone gene (Experimental Example)
  • the molecular chaperone gene refers to the gene of a molecular chaperone that is localized in the lumen of the endoplasmic reticulum and plays an important role in folding secreted proteins and membrane proteins in the endoplasmic reticulum.
  • ORP150 gene Ikeda, J. et al, Biochem. Biophys. Res. Common., 230, 94-99 (1997)
  • GRP94 gene Maki. RGet al., Proc. Natl. Acad. Sci. USA, 87, 5658-5662 (1990)
  • GRP78 gene Ting J. and Lee, AS DNA, 7, 275-286 (19 88)
  • calreticulin gene Rosokeach, LA.
  • GRP78 gene ERp72 gene
  • GRP58 gene PDI gene
  • FKBP13 gene FKBP13 gene and the like.
  • GRP78 gene GRP78 gene
  • ORP150 gene GRP94 gene that are highly expressed in nerve cells.
  • the molecular chaperone expression-inducing action of compound (I) can be evaluated based on the amount of transcript (mRNA) or gene product (protein) of the molecular chaperone gene.
  • the amount of (protein) increases from that of untreated cells, the action of inducing molecular chaperone expression of the compound can be evaluated.
  • the pharmaceutical composition of the present invention containing compound (I) as an active ingredient can be effectively used as a molecular chaperone expression inducer.
  • the ratio of the compound (I) contained in the pharmaceutical composition may be any amount as long as the pharmaceutical composition has a molecular chaperone expression-inducing action, for example, 0.1 to 100 weights. % As appropriate You can. Preferably:! To 60% by weight, more preferably 3 to 40% by weight.
  • compound (I) can relieve endoplasmic reticulum stress by folding proteins based on the molecular chaperone expression-inducing action and suppressing accumulation of abnormal proteins in the endoplasmic reticulum. It can suppress cell death caused by endoplasmic reticulum stress or enhance resistance to endoplasmic reticulum stress (see Experimental Example 2).
  • the cell death inhibitory effect of compound (I) on endoplasmic reticulum stress is the ratio of viable cells when an endoplasmic reticulum stress inducer is allowed to act on cells in the presence of compound (I). It can be evaluated by comparing with the ratio of viable cells when an endoplasmic reticulum stress inducer is allowed to act on cells in the presence.
  • tuna mycin (tunicamycin: Tm), which inhibits N-glycosinolation of proteins, calcium ionophore A23187, which depletes calcium storage, and thapsigargin, which inhibits calcium ATPase ( thapsigargin (Tg) is known.
  • Tm tuna mycin
  • thapsigargin which inhibits calcium ATPase
  • the pharmaceutical composition of the present invention comprising compound (I) as an active ingredient can be effectively used as a cell death inhibitor against endoplasmic reticulum stress or a resistance enhancer against endoplasmic reticulum stress.
  • the ratio of the compound (I) contained in the pharmaceutical composition may be any amount as long as the pharmaceutical composition has a cell death inhibitory action or a resistance enhancing action against endoplasmic reticulum stress.
  • it can be appropriately selected from the range of 0.1 to 100% by weight.
  • compound (I) relieves endoplasmic reticulum stress and suppresses the production of amyloid protein A involved in the onset and progression of neurodegenerative diseases such as Alzheimer's disease based on the expression-inducing action of molecular chaperones. (See Experimental Example 3).
  • the A ⁇ production inhibitory action of the compound (I) is such that the compound (I) is allowed to act on cells capable of expressing the amyloid precursor protein ( ⁇ ), and the ratio of amyloid protein ⁇ / 3 in the cells. Can be evaluated by comparing with the case where compound (I) is not allowed to act. In this case, based on the decrease in the amount of A ⁇ produced by the action of the compound (I), the action of inhibiting the formation of ⁇ can be evaluated for the compound (I).
  • ⁇ ⁇ of compound (I) The production inhibitory action is based on the movement of cocoons from the site where the enzyme that cleaves A j3 from APP ( ⁇ -secretase) acts.
  • the pharmaceutical composition of the present invention containing Compound (I) as an active ingredient can be effectively used as a preventive or therapeutic agent for neurodegenerative diseases.
  • the harm IJ of compound (I) contained in the pharmaceutical composition is that the pharmaceutical composition is affected by endoplasmic reticulum stress based on the molecular chaperone expression inducing action, preferably the molecular chaperone expression inducing action.
  • it may be an appropriate amount, for example, from 0.1 to 100% by weight.
  • it is 1-60 weight%, More preferably, it is 3-40 weight%.
  • the neurodegenerative diseases targeted by the present invention include diseases in which the onset involves ER stress or cell death due to ER stress. Examples include Alzheimer's disease, mild cognitive impairment (MCI), Parkinson's disease, stroke (cerebral infarction), polyglutamine disease, prion disease, diabetes, glaucoma and the like. Alzheimer's disease, mild cognitive impairment (MC1), and Parkinson's disease are preferable.
  • the pharmaceutical composition of the present invention is usually an effective amount of a compound (I) effective in inducing molecular chaperone expression, and thus in suppressing cell death and / or suppressing A production due to endoplasmic reticulum stress. ) And a pharmaceutically acceptable carrier or additive.
  • the administration method of the pharmaceutical composition of the present invention includes oral administration and parenteral administration such as intravenous administration, intramuscular administration, subcutaneous administration, transmucosal administration, transdermal administration, and rectal administration.
  • parenteral administration such as intravenous administration, intramuscular administration, subcutaneous administration, transmucosal administration, transdermal administration, and rectal administration.
  • oral administration and intravenous administration are preferred, and more preferred is oral administration.
  • the pharmaceutical composition of the present invention can be prepared into various forms of preparations (dosage forms) depending on the strength and the administration method. Each formulation (dosage form) will be described below, but the dosage form used in the present invention is not limited to these, and various dosage forms usually used in the field of pharmaceutical preparations can be used.
  • the dosage forms for oral administration include powders, granules, capsules, pills, tablets, and elixirs. Examples include sills, suspensions, emulsions and syrups, and can be appropriately selected from these. In addition, these formulations can be modified such as sustained release, stabilization, easy disintegration, hard disintegration, entericity, easy absorption, and the like.
  • dosage forms for intravenous administration, intramuscular administration, or subcutaneous administration include injections and infusions (including dry products for preparation at the time of use), which can be selected as appropriate. .
  • dosage forms for transmucosal administration, transdermal administration, or rectal administration include mastication agents, sublingual agents, buccal agents, troches, ointments, patches, liquids, etc. You can choose here depending on the location.
  • these formulations can be modified such as sustained release, stabilization, easy disintegration, difficulty disintegration, and easy absorption.
  • the pharmaceutical composition of the present invention may contain pharmaceutically acceptable carriers and additives depending on the dosage form (oral administration or various parenteral administration dosage forms).
  • Pharmaceutically acceptable carriers and additives include solvents, excipients, coating agents, bases, binders, lubricants, disintegrants, solubilizers, suspending agents, thickeners, emulsifiers. , Stabilizers, buffers, tonicity agents, soothing agents, preservatives, flavoring agents, fragrances, and coloring agents.
  • Stabilizers buffers, tonicity agents, soothing agents, preservatives, flavoring agents, fragrances, and coloring agents.
  • the ability to list specific examples of pharmaceutically acceptable carriers and additives below The present invention is not limited to these.
  • Examples of the solvent include purified water, sterilized purified water, water for injection, physiological saline, laccase oil, ethanol, glycerin and the like.
  • Excipients include starches (for example, potato starch, wheat starch, corn starch), lactose, glucose, sucrose, crystalline cellulose, calcium sulfate, calcium carbonate, sodium bicarbonate, sodium chloride, talc, titanium oxide, Examples include trehalose and xylitol.
  • binder examples include starch and derivatives thereof, cellulose and derivatives thereof (for example, methinoresenorelose, ethinoresenorelose, hydroxypropenoresenorelose, strong noroxymethylcellulose), gelatin, sodium alginate, tragacanth, Examples thereof include natural polymer compounds such as gum arabic, synthetic polymer compounds such as polyvinylinolepyrrolidone and polybutal alcohol, dextrin, hydroxypropyl starch and the like.
  • Lubricants include light anhydrous carboxylic acid, stearic acid and its salts (eg, magnesium stearate), talc, waxes, wheat starch, macrogol, hydrogenated plants. Oil, sucrose fatty acid ester, polyethylene glycol, silicone oil and the like.
  • disintegrant examples include starch and derivatives thereof, agar, gelatin powder, sodium hydrogen carbonate, calcium carbonate, cellulose and derivatives thereof, hydroxypropyl starch, strength lupoxymethylcellulose and salts thereof, and cross-linked products thereof, low substitution type And hydroxypropylcellulose.
  • solubilizers include cyclodextrin, ethanol, propylene glycol, and polyethylene glycol.
  • suspending agent include sodium carboxymethyl cellulose, polypinyl pyrrolidone, gum arabic, tragacanth, sodium alginate, aluminum monostearate, citrate, and various surfactants.
  • thickening agent examples include sodium carboxymethylcellulose, polypinylpyrrolidone, methinoresenololose, hydroxypropino methenoresenorelose, polyvinylino oleconole, tragacanth, gum arabic, sodium alginate and the like.
  • emulsifier examples include gum arabic, cholesterol, tragacanth, methylcellulose, lecithin, various surfactants (for example, polyoxyl 40 stearate, sorbitan sesquioleate, polysorbate 80, sodium lauryl sulfate).
  • surfactants for example, polyoxyl 40 stearate, sorbitan sesquioleate, polysorbate 80, sodium lauryl sulfate.
  • Stabilizers include tocopherols, chelating agents (eg EDTA, thioglycolic acid), inert gases (eg nitrogen, carbon dioxide), reducing substances (eg sodium hydrogen sulfite, sodium thiosulfate, ascorbic acid, longgarit And the like.
  • chelating agents eg EDTA, thioglycolic acid
  • inert gases eg nitrogen, carbon dioxide
  • reducing substances eg sodium hydrogen sulfite, sodium thiosulfate, ascorbic acid, longgarit And the like.
  • Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium citrate, boric acid and the like.
  • Examples of isotonic agents include sodium chloride, glucose and the like.
  • Examples of soothing agents include local anesthetics (pro-in hydrochloride, lidocaine), pendyl alcohol, glucose, sorbitol, amino acids and the like.
  • Examples of the corrigent include sucrose, saccharin, licorice extract, sorbitol, xylitol, dariserine and the like.
  • Examples of the fragrances include spruce tincture and rose oil.
  • Examples of the colorant include water-soluble food dyes and lake dyes.
  • Preservatives include benzoic acid and its salts, paraoxybenzoic acid esters, Examples include robutanol, reverse soap, benzyl alcohol, phenol, tiromesal, dehydroacetic acid, boric acid, and the like.
  • Coating agents include sucrose, hydroxypropylcellulose (HPC), shellac, gelatin, glycerin, sonolebithonole, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polybutylpyrrolidone (PVP), hydroxypropylmethylcellulose phthalate ( HPMCP), cellulose acetate phthalate (CAP), methyl methacrylate, monomethacrylic acid copolymer, and the polymers described above.
  • HPMC hydroxypropylcellulose
  • HPMCP polybutylpyrrolidone
  • HPMCP hydroxypropylmethylcellulose phthalate
  • CAP cellulose acetate phthalate
  • Examples of the base include petrolatum, liquid paraffin, carnauba wax, beef tallow, hardened oil, paraffin, beeswax, vegetable oil, macrogol, macrogol fatty acid ester, stearic acid, sodium carboxymethylcellulose, bentonite, cacao butter, wittebuzole, Gelatin, stearyl alcohol, caroline lanolin, cetanol, light liquid paraffin, hydrophilic salmon, single ointment, white ointment, hydrophilic ointment, macrogol ointment, hard fat, oil-in-water emulsion base, water-in-oil emulsion Mention may be made of sexing agents.
  • DDS drug delivery system
  • DDS preparations include sustained-release preparations, topical preparations (troches, buccal tablets, sublingual tablets, etc.), drug release control preparations, enteric preparations and gastric preparations, etc. It is a preparation with the optimal dosage form, taking into account the best availability and side effects.
  • the pharmaceutical composition of the present invention is used as a molecular chaperone expression inducer, a cell death inhibitor against endoplasmic reticulum stress, or a neurodegenerative disease preventive / therapeutic agent
  • its oral dose is compound (I).
  • the range of 0.03 to 300 mg / kg in terms of the amount is more preferable, and more preferably 0.:! To 50 mgZkg.
  • increase the dose so that the effective blood concentration of compound (I) is in the range of 0.2-50 8/111, preferably 0.3 S SO zg / mL. That power S.
  • These dosages may vary depending on age, sex, body type, and the like.
  • the present invention also relates to a method for preventing and treating a neurodegenerative disease in a subject by administering the pharmaceutical composition of the present invention to the subject.
  • the neurodegenerative disease targeted here is, as described above, endoplasmic reticulum stress or Includes diseases involving cell death due to endoplasmic reticulum stress.
  • diseases involving cell death due to endoplasmic reticulum stress include Alzheimer's disease, mild cognitive impairment (MCI), Parkinson's disease, stroke (cerebral infarction), polyglutamine disease, prion disease, diabetes, glaucoma and the like.
  • Alzheimer's disease, mild cognitive impairment (MC1), and Parkinson's disease are preferable.
  • the subjects targeted by the present invention include patients who may suffer from neurodegenerative diseases.
  • Neurodegenerative diseases are caused by environmental factors, drugs, inheritance and aging. For this reason, people exposed to contaminated water, contaminated air or pesticides (patients), patients addicted to narcotics, patients who develop side-effect disorders due to drugs, and hereditary patients also have the above-mentioned neurodegeneration. Included in patients who may have the disease.
  • the administration method of the pharmaceutical composition to the subject is not particularly limited, and is oral administration, intravenous administration, intramuscular administration, subcutaneous administration, transmucosal administration, transdermal administration, and intrarectal administration.
  • Parenteral administration such as administration can be mentioned.
  • Oral administration and intravenous administration are preferred.
  • the dose is 0.03 to 300 mg / kg, preferably 0.1 to 50 mg / kg, converted into the amount of compound (I) in the case of oral administration, and compound in the case of intravenous administration.
  • the ratio (I) include an effective blood concentration in the range of 0.2 to 50/1 ⁇ / 111, preferably 0.5 to 20 ⁇ g / mL.
  • neuroblastoma SK-N-SH cells were exposed to l-50 / i M of (3,4-dihydroxy-phenyl) -2-thiocyanato-ethanone (BIX) for 6 hours.
  • BIX (3,4-dihydroxy-phenyl) -2-thiocyanato-ethanone
  • SK-N-SH cells are grown to 80% confluence in 24-well plates, then using Lipofectamine 2000 reagent (Invitrogen), a reporter plasmid with the firefly luciferase gene under the control of the GRP78 / Bip promoter (0.2 ⁇ g) was transfected. Also. As a control, SK-N-SH cells were transfected using the control plasmid pRL-SV40 (0.02 ⁇ g) (Promega) having the Renill luciferase gene under the control of the SV40 enhancer and the promoter (control). cell). After 12 hours, each SK-N-SH cell was treated with 1-50 ⁇ ⁇ or 300 ⁇ thapsigargin (Tg) (endoplasmic reticulum stress inducer) (control) for 6 hours.
  • Tg endoplasmic reticulum stress inducer
  • 32 P_ labeled cDNA probe prepared from GRP78 / Bip cDNA was hybridized, washed with 2xSSC, 0.1% SDS and 0.1xSSC, 0.1% SDS, then IP plate It was exposed on (Fuji Film) and analyzed with the BAS1800 system (Fuji Film).
  • FIG. Figure 1 shows that BIX has the effect of inducing molecular chaperone gene expression in a concentration-dependent manner.
  • Neuroblastoma SK-N-SH cells were cultured for 12 hours in the presence of 5 ⁇ of BIX, and this was then added to the endoplasmic reticulum stress inducer Tsuyu forcemycin (Tm) at a rate of 0.5 ⁇ g / ml
  • Tm endoplasmic reticulum stress inducer
  • the SK-N-SH cells were transferred to fresh culture medium and further cultured for 12 to 48 hours, and the number of viable SK-N-SH cells was measured. The number of viable cells was measured by staining cells that had undergone apoptosis with Hoechst33258 staining and distinguishing them from viable cells. Specifically, the cultured cells were treated with 4% paraformaldehyde at 4 ° C for 30 minutes, and then with PBS for 5 minutes.
  • BIX ⁇ Tm is the result of the BIX treatment group (cultured in the presence of BIX and then in the presence of Tm), and Normal ⁇ Tm is the BIX non-treatment group (after culture in the absence of BIX, the presence of Tm
  • the results of (cultured under) (control group) are shown.
  • the results (Fig. 2) are shown as the ratio of the number of viable cells (cell viability) when the number of viable cells during the 12-hour Tm treatment in the control group is 1.
  • the cell viability of the BIX-treated group was higher than that of the non-treated group (control group) (inhibition of cell death) over time, 28, 36 and 48 hours. From this, it can be seen that BIX has an action of imparting resistance to endoplasmic reticulum stress to cells and suppressing cell death due to endoplasmic reticulum stress.
  • SY5Y / APPsw (a SY5Y cell with APP having a Swedish mutation was transformed into a parent cell line) was cultured in the presence of 0 to 10 ⁇ g / ml BIX for 8 hours. Next, this was washed with PBS, Nonidet P-40 lysis buffer (1% Nonidet P-40, 20 mM HEPES pH 7.6, lOOmM NaCl, 3 mM MgCl, 5 mM dithiothreitol, 0.1% protease inhibitor cock tail (Sigma It was added to) and lysed. Cell lysates were sonicated 3 times for 5 seconds on ice and centrifuged at 15000 ⁇ m for 5 minutes.
  • the supernatant was transferred to a new tube and boiled for 5 minutes in SDS sample buffer. Apply to each lane of 10-15% SDS-PAGE so that the amount of protein is equivalent, and after electrophoresis, transfer to PVDF membrane, and the first antibody [anti-APP antibody (Chemicon, Temecula, CA, USA;, i ⁇ A ⁇ antibodies, 4G8 and 6E10 (bignet Pathology systems Inc., Dedham, MA, USA)].
  • APP the precursor of amyloid protein
  • BIX concentration increased. Therefore, BIX immatures APP by inducing a molecular chaperone (Bip), which makes APP resistant to ⁇ secretase cleavage and suppresses A j3 production and secretion by ⁇ cleavage. It is thought that.
  • BIX (5 or 20 xg / 2 z 1) dissolved in 10% DMSO was administered into the ventricle of mice (20-27 g, male, DDY mice) (obtained from SLC), and then one side middle cerebral artery ( MCA) was closed with an obturator and hypoxic conditions were caused artificially to cause endoplasmic reticulum stress.
  • BIX was administered into the ventricles by inserting a needle through the skull based on the brain chart.
  • the degree of neurological damage can be scored and evaluated according to the following criteria from the behavior of the mouse.
  • the brain was decapitated and the brain was taken out, and the forebrain was divided into 5 mm intervals from the olfactory brain (see A in Fig. 4).
  • Each section was stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC) to identify the infarct site, recorded as an image using a digital camera, and infarcted using Image J.
  • TTC 2,3,5-triphenyltetrazolium chloride
  • the ratio of brain edema can also be calculated according to the following equation.
  • FIG. 4B The results of TTC staining are shown in Fig. 4B.
  • the right side is the result of the BIX administration group
  • the left side is the result of the BIX non-administration group (control group).
  • the white area of the brain is where the infarction is occurring.
  • the area of the infarct area for each section is shown in FIG. 5A
  • the volume of the infarct area in the section 6 mm from the mouse olfactory brain is shown in FIG. 5B.
  • the compound (I) represented by BIX has an action of inducing molecular chaperone expression, and accordingly, suppresses cell death due to endoplasmic reticulum stress, and amyloid protein (A / It turns out that it has the effect
  • FIG. 4 In Experimental Example 4, A is a diagram showing the cutting pattern of the forebrain, and B is a diagram showing the result of TTC staining of the cut brain section.
  • FIG. 5 A is the area of the infarct area of each brain section, B is the volume of the infarct area in the 6 mm section from the olfactory brain, with and without BIX (5, 20 zg) administration (control) The comparison results are shown in the case of.

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Abstract

La présente invention concerne une composition pharmaceutique ayant une activité d'induction de l'expression d'un chaperon de réticulum endoplasmique, qui peut être utilisé de manière efficace pour empêcher la mort des cellules provoquée par un stress de réticulum endoplasmique ou pour empêcher l'occurrence ou la progression d'une maladie neurodégénérative ou guérir d'une maladie neurodégénérative. La composition pharmaceutique comprend un composé représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci ou un solvate du composé ou du sel, en tant que substance active. (I) dans laquelle R1 et R2 représentent indépendamment un atome d'hydrogène, un atome d'halogène, un groupe hydroxyle, un groupe alkyle inférieur ou un groupe alcoxy inférieur ; Alk représente une chaîne alkylène inférieure ; et X représente un atome d'oxygène ou un atome de soufre.
PCT/JP2007/057046 2006-04-27 2007-03-30 Inducteur d'expression de chaperon moleculaire Ceased WO2007125720A1 (fr)

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Cited By (1)

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EP3934754A4 (fr) * 2019-03-08 2022-11-23 The Regents Of The University Of California Compositions et méthodes pour traiter une insuffisance respiratoire

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WO2004110418A2 (fr) * 2003-06-10 2004-12-23 Kalypsys, Inc. Composes carbonyle utilises comme inhibiteurs de l'histone desacetylase a des fins therapeutiques

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3934754A4 (fr) * 2019-03-08 2022-11-23 The Regents Of The University Of California Compositions et méthodes pour traiter une insuffisance respiratoire

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