JP2018135287A - Agent for preventing, treating, and/or inhibiting symptom development of cerebrovascular accidents and/or dementia - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel agent for preventing, treating, and/or inhibiting symptom development of cerebrovascular accidents and/or dementia, which may take the place of conventional and known cerebral protective agents.SOLUTION: The agent for preventing, treating, and/or inhibiting symptom development of cerebrovascular accidents and/or dementia contains as an active ingredient at least one compound represented by general formula (1) described in the specification or a substance enhancing activity or expression of GST.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a preventive, therapeutic and / or symptom progression inhibitor for cerebrovascular disorders and / or dementia.

  Cerebrovascular disorders are also called cerebrovascular diseases, and are roughly classified into two types: cerebral hemorrhage (hemorrhagic cerebrovascular disorder) and cerebral infarction (ischemic cerebrovascular disorder). Among these, cerebral infarction (ischemic cerebrovascular disorder) is further classified into cerebral thrombosis and cerebral embolism according to the cause of clogging blood vessels. A blood clot (thrombus) generated in the blood vessels of the brain clogs the blood vessels. On the other hand, cerebral embolism results from clogging of blood vessels in the brain after a thrombus generated in a blood vessel other than the brain such as the heart is carried on the bloodstream to the brain.

  Currently, edaravone (trade name: Radicut (registered trademark)) that captures free radicals (hydroxy radicals) is the only pharmacological treatment for acute cerebral infarction. Atherothrombotic cerebral infarction, lacunar infarction, cardiogenic cerebral embolism Although it has been clinically applied to the treatment of infectious diseases (Non-patent Document 1), no new therapeutic agent has appeared. Furthermore, edaravone has a short treatment time of less than 14 days, and serious side effects such as fulminant hepatitis and kidney damage (acute renal failure, nephrotic syndrome) are also problematic. For this reason, the development of therapeutic agents for cerebrovascular disorders such as cerebral infarction is an urgent issue.

  In Japan, where an aging society is arriving, especially in order to prevent the onset of cerebrovascular disorders such as cerebral infarction and dementia by taking a small amount over a long period of time from the viewpoint of “not ill”. The need for drugs and so-called supplements is also very strong. Therefore, the development of preventive drugs with few side effects on the premise of long-term use is a very high priority issue.

By the way, acrolein is known to be produced in the body in the metabolism process of amino acids and polyamines and in the process of peroxidation of membrane lipids, and is produced mainly from polyamines (especially spermine) at the time of tissue damage (non- Patent Documents 2 and 3). Spermine is present in cells at a concentration of the order of several mM to several tens of mM, and most of it exists in the form of a polyamine-RNA complex (Non-patent Document 4). When tissue is damaged, spermine is released from RNA and undergoes oxidative degradation by spermine oxidase, resulting in acrolein and hydrogen peroxide (H ₂ O ₂ ). Reported that the toxicity of this acrolein is involved (Non-Patent Document 3), and asymptomatic cerebral infarction (hidden cerebral infarction) holders are at risk of developing cerebrovascular disorder and dementia, respectively It has also been found to increase by 8.8 and 2 times. Acrolein is extremely cytotoxic even compared to reactive oxygen species (ROS) such as superoxide anion radical, hydrogen peroxide, and hydroxyl radical (Non-Patent Document 5), which are considered to cause cell damage. (Non-Patent Documents 6 and 7). In addition, acrolein having an aldehyde group is highly reactive and inactivates the protein by selectively reacting with residues such as cysteine, lysine and histidine of the protein to produce protein-conjugated acrolein (PC-Acro). Thus, it is considered that the occurrence of PC-Acro is also involved in the occurrence of cell damage due to cerebral infarction (Non-patent Document 3).

It has been reported that acrolein has a much faster interaction with a thiol group (SH group) than an interaction with an amino group (NH ₂ group) (Non-patent Document 7), and glutathione having an SH group (GSH). ) And the like, and its metabolism is known to be carried out by enzymes such as aldehyde dehydrogenase. GSH is known to be the most abundant thiol compound in cells, and is present in cells at a concentration on the order of several mM to several tens of mM (Non-Patent Documents 8 and 9). That is, acrolein binds to GSH to form an acrolein-GSH conjugate, is detoxified by enzymatic metabolism, and is excreted as a urinary metabolite. For this reason, when the GSH level is lowered, the metabolism of acrolein is lowered, and as a result, acrolein interacts with proteins and nucleic acids to inactivate these substances, thereby causing cell damage and the like, and thus cerebral infarction Such obstacles will become apparent.

  The reaction for converting acrolein to GSH by reacting with acrolein is catalyzed by an enzyme called glutathione-S-transferase (GST), and this GST acts as a site of action to exert a brain protective action. To date, no substance or substance capable of acting on GST to exert a brain protective action has been known.

The Edaravone Acute Brain Infarction Study Group.Effect of novel free radical scavenger, Edaravone (MCI-186), on acute brain infarction.Randomized, placebo-controlled, double-blind study at multicenter.Cerebrovasc Dis 2003; 15: 222-229 Uchida K, Kanematsu M, Morimitsu Y, Osawa T, Noguchi N, Niki E (1998) Acrolein is a product of lipid peroxidation reaction.Formation of free acrolein and its conjugate with lysine residues in oxidized low density lipoproteins.J Biol Chem 273, 16058-16066 Igarashi K, Kashiwagi K (2011) Protein-conjugated acrolein as a biochemical marker of brain infarction. Mol Nutr Food Res 55, 1332-1341 Igarashi K, Kashiwagi K (2010) Modulation of cellular function by polyamines.Int J Biochem Cell Biol 42, 39-51 Giorgio M, Trinei M, Migliaccio E, Pelicci PG (2007) Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol 8, 722-728 Yoshida M, Tomitori H, Machi Y, Hagihara M, Higashi K, Goda H, Ohya T, Niitsu M, Kashiwagi K, Igarashi K (2009) Acrolein toxicity: Comparison with reactive oxygen species.Biochem Biophys Res Commun 378, 313-318 Sharmin S, Sakata K, Kashiwagi K, Ueda S, Iwasaki S, Shirahata A, Igarashi K (2001) Polyamine cytotoxicity in the presence of bovine serum amine oxidase.Biochem Biophys Res Commun 282, 228-235 Perry TL, Berry K, Hansen S, Diamond S, Mok C (1971) Regional distribution of amino acids in human brain obtained at autopsy.J Neurochem 18, 513-519 Tomitori H, Nakamura M, Sakamoto A, Terui Y, Yoshida M, Igarashi K, Kashiwagi K (2012) Augmented glutathione synthesis decreases acrolein toxicity. Biochem Biophys Res Commun 418, 110-115

  An object of the present invention is to provide a novel cerebrovascular disorder and / or dementia prevention / treatment / symptom progression-suppressing drug that can replace a conventionally known cerebral protective drug.

  In view of the current state of the prior art as described above, the present inventors have intensively studied. In the process, a number of compounds were confirmed to have preventive and therapeutic effects on cerebrovascular disorders. As a result, it was surprisingly found that N-acetylcysteine (also referred to as “NAC” in the present specification) and ester derivatives thereof have a preventive / therapeutic effect on cerebral infarction in a cerebral infarction model mouse. .

  Based on the above findings, the present inventors set a hypothesis that NAC and its ester derivatives have a preventive effect on cerebral infarction, that the compound may be due to inhibition of acrolein production. . However, the hypothesis was rejected because there was no change in the amount of polyamine in the infarcted region of the brain of the cerebral infarction model mouse between the compound administration group and the control group.

  For this reason, as another mechanism hypothesis, the present inventors have contributed to the detoxification of acrolein by directly reacting the thiol group (—SH group) of NAC and its ester derivative with acrolein which is an aldehyde. I thought that. However, this hypothesis was also rejected. That is, the present inventors examined the amount of GSH and the amount of PC-Acro in the normal region and the infarcted region of the brain of the cerebral infarction model mouse. As a result, the amount of GSH tends to decrease in the infarcted region, and PC-Acro. The amount was decreasing. Based on these findings, the present inventors set a hypothesis that an increase in the expression level of GST may have a prophylactic / therapeutic effect on cerebral infarction in cerebral infarction model mice. Then, the hypothesis was verified by confirming that the expression level of GST actually increased, and the present invention was completed.

  That is, according to one aspect of the present invention, the following general formula (1):

In the formula, R is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 30 carbon atoms, or a substituted or unsubstituted alkynyl group having 2 to 30 carbon atoms. Substituted or unsubstituted aryl group having 6 to 30 carbon atoms, substituted or unsubstituted arylalkyl group having 7 to 30 carbon atoms, substituted or unsubstituted heteroaryl group having 3 to 30 carbon atoms, or substituted or unsubstituted A heteroarylalkyl group having 4 to 30 carbon atoms,
A prophylactic, therapeutic and / or symptom progression inhibitor of cerebrovascular disorder and / or dementia is provided, which comprises at least one of the compounds represented by the formula:

  Here, R in the general formula (1) is preferably a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, or a substituted or unsubstituted arylalkyl group having 7 to 30 carbon atoms. . R in the general formula (1) is more preferably a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an arylalkyl group having 7 to 14 carbon atoms. Further, R in the general formula (1) is more preferably a hydrogen atom, a methyl group, an ethyl group or a benzyl group.

  According to another aspect of the present invention, there is also provided a prophylactic, therapeutic and / or symptom progression inhibitor for cerebrovascular disorder and / or dementia, which contains a substance that enhances the expression or activity of GST as an active ingredient. Provided.

  Here, the GST is preferably GST-π, GST-θ and / or GST-μ. The substance that enhances the expression or activity of GST is preferably a compound represented by the above general formula (1). Furthermore, the above-described preventive, therapeutic and / or symptom progression inhibitor is preferably a cerebral infarction preventive, therapeutic and / or symptom progression inhibitor.

  In addition, about the cerebrovascular disorder and / or dementia prevention, treatment, and / or symptom progress inhibitor which concern on the form mentioned above, it is preferable that the continuous administration days are 15 days or more.

  Furthermore, according to still another aspect of the present invention, a food or drink for the prevention, treatment and / or suppression of symptom progression of cerebrovascular disorder and / or dementia, comprising as an active ingredient a substance that enhances the expression or activity of GST. Is also provided.

  Here, the substance that enhances the expression or activity of GST is preferably a compound represented by the general formula (1) described above. Moreover, it is preferable that the food / beverage products for prevention, treatment and / or symptom progression suppression described above are food / beverage products for prevention, treatment and / or symptom progression suppression of cerebral infarction. Furthermore, it is preferable that the food / beverage products which concern on the said form are a health food, a functional food, a food for specified health, a food supplement, a food with a disease risk reduction label, or a food for a sick person.

  According to still another aspect of the present invention, there is provided a method for preventing cerebrovascular disorder and / or dementia, comprising administering to a patient in need thereof an effective amount of a substance that enhances the expression or activity of GST. Also provided are methods of treating and / or inhibiting the development of symptoms thereof. Here, the substance that enhances the expression or activity of GST is preferably a compound represented by the general formula (1) described above.

  According to the present invention, a novel cerebrovascular disorder and / or dementia prevention / treatment / symptom progression inhibitory drug that can be substituted for a conventionally known cerebral protective drug is provided.

In the examples, photographs of brain sections showing the results of investigation on the therapeutic effect of NAC and its ester derivatives (3 types) on cerebral infarction using cerebral infarction model mice (upper row in FIG. 1), and infarct volume in each sample It is a graph (lower stage of Drawing 1) showing the computed result. In the examples, photographs of brain sections showing the results of investigation on the preventive effect of NAC and its ester derivatives (2 types) against cerebral infarction using cerebral infarction model mice (upper part of FIG. 2), and infarct volume in each sample It is a graph (lower stage of Drawing 2) showing the computed result. In an Example, it is a graph which shows the result of having measured the quantity of various polyamines in the infarction site | part of the cerebral infarction model mouse which administered either NAC and its ester derivative (2 types). In an Example, it is a graph which shows the result of having measured the quantity of the total glutathione (tGSH) in the infarction site | part of the cerebral infarction model mouse which administered either NAC and its ester derivative (2 types). In the examples, a photograph of a Western blotting band showing the results of measuring the amount of PC-Acro at the infarct site of a cerebral infarction model mouse administered with either NAC or its ester derivative (2 types) (A in FIG. 5), 6 is a graph (B in FIG. 5) showing the results of measuring the relative value of the PC-Acro amount in each sample. In the examples, a photograph of a Western blotting band showing the results of measuring the expression level of GST-π at the infarct site of a cerebral infarction model mouse administered with either NAC or its ester derivative (two types) (A in FIG. 6). ) And a graph (B in FIG. 6) showing the results of measuring the relative value of the expression level of GST-π in each sample. In the examples, a photograph of a band of Western blotting showing the results of measuring the expression level of GST-θ at the infarct site of a cerebral infarction model mouse administered with either NAC or its ester derivative (two types) (A in FIG. 7). ) And a graph (B in FIG. 7) showing the results of measuring the relative value of the expression level of GST-θ in each sample. In the examples, a photograph of a band of Western blotting showing the results of measuring the expression level of GST-μ at the infarct site of a cerebral infarction model mouse administered with either NAC or its ester derivative (two types) (A in FIG. 8). ), And a graph (B in FIG. 8) showing the result of measuring the relative value of the expression level of GST-μ in each sample. In an Example, it is a graph which shows the result of having measured the time-dependent change of the amount of free acrolein in presence or absence of GST-pi by the method of Alarcon et al.

  Hereinafter, specific embodiments for carrying out the present invention will be described in detail, but the technical scope of the present invention is not limited to the following specific embodiments.

  One embodiment of the present invention is the following general formula (1):

Is a preventive, therapeutic and / or symptom progression inhibitor of cerebrovascular disorder and / or dementia, which contains at least one of the compounds represented by (NAC or an ester derivative thereof) as an active ingredient.

  In General Formula (1), R is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 30 carbon atoms, a substituted or unsubstituted carbon number 2 to 2; 30 alkynyl groups, substituted or unsubstituted aryl groups having 6 to 30 carbon atoms, substituted or unsubstituted arylalkyl groups having 7 to 30 carbon atoms, substituted or unsubstituted heteroaryl groups having 3 to 30 carbon atoms, or A substituted or unsubstituted heteroarylalkyl group having 4 to 30 carbon atoms.

  The “alkyl group” is a linear or branched alkyl group having 1 to 30 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms, more preferably an alkyl group having 1 to 8 carbon atoms. And more preferably an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, 3- Methylbutyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, heptyl group, 1-methylhexyl group, 1- Examples include an ethylpentyl group, an octyl group, a 1-methylheptyl group, a 2-ethylhexyl group, a nonanyl group, and a decyl group.

  The “cycloalkyl group” is a cycloalkyl group having 3 to 30 carbon atoms, preferably a cycloalkyl group having 3 to 12 carbon atoms, and more preferably a monocyclic cycloalkyl group having 3 to 8 carbon atoms. And more preferably a monocyclic cycloalkyl group having 4 to 6 carbon atoms. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloheptyl group, and a cyclooctyl group.

  The “alkenyl group” is a linear or branched alkenyl group having 2 to 30 carbon atoms, preferably an alkenyl group having 2 to 10 carbon atoms, more preferably an alkenyl group having 2 to 6 carbon atoms. And more preferably an alkenyl group having 2 to 4 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, 1-methylethenyl, butenyl, 2-methylpropenyl, 1-methylpropenyl, pentenyl, 3-methylbutenyl, 2-methylbutenyl, 1-ethylpropenyl Group, hexenyl group, 4-methylpentenyl group, 3-methylpentenyl group, 2-methylpentenyl group, 1-methylpentenyl group, 3,3-dimethylbutenyl group, 1,2-dimethylbutenyl group, heptenyl group, Examples include 1-methylhexenyl group, 1-ethylpentenyl group, octenyl group, 1-methylheptenyl group, 2-ethylhexenyl group, nonenyl group, decenyl group, and the like.

  The “alkynyl group” is a linear or branched alkynyl group having 2 to 30 carbon atoms, preferably an alkynyl group having 2 to 10 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms. And more preferably an alkynyl group having 2 to 4 carbon atoms. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, 3-methylbutynyl, hexynyl, 4-methylpentynyl, 3-methylpentynyl, 3,3-dimethylbutynyl, Examples include heptynyl group, octynyl group, 3-methylheptynyl group, 3-ethylhexynyl group, noninyl group, decynyl group and the like.

  The “aryl group” is an aryl group having 6 to 30 carbon atoms, preferably an aryl group having 6 to 14 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms. Examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 1-anthracenyl group, and a 2-anthracenyl group, preferably a phenyl group.

  The “arylalkyl group” is a group having a structure in which at least one hydrogen atom of the “alkyl group” is substituted with the “aryl group”, and is an arylalkyl group having 7 to 30 carbon atoms, preferably It is an arylalkyl group having 7 to 14 carbon atoms. Examples of arylalkyl groups are benzyl, phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) Examples thereof include an ethyl group, a 3- (1-naphthyl) propyl group, and a 3- (2-naphthyl) propyl group, and among them, a benzyl group is preferable.

  The “heteroaryl group” is a heteroaryl group having 1 to 30 carbon atoms, preferably 1 selected from 0 to 2 nitrogen atoms, 0 to 1 oxygen atoms and 0 to 1 sulfur atoms. A 5- to 10-membered monocyclic or bicyclic heteroaryl group containing -4 heteroatoms. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, pyridyl, indolyl, isoindolyl, quinolyl, isoquinolyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, Or an oxazolyl group etc. are mentioned. The bonding position is not particularly limited, and may be bonded on any carbon atom or nitrogen atom as long as it is chemically stable. Of these, the heteroaryl group is preferably a monocyclic 5- or 6-membered heteroaryl group.

  The “heteroarylalkyl group” is a group having a structure in which at least one hydrogen atom of the “alkyl group” is substituted with the “heteroaryl group”. Examples of heteroarylalkyl groups include 2-pyrrolylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-thienylmethyl group, 2- (2-pyridyl) ethyl group, 2- (3-pyridyl) ethyl group, 2- (4-pyridyl) ethyl group, 3- (2-pyrrolyl) propyl group may be mentioned.

  The alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl group, heteroaryl group, or heteroarylalkyl group representing R in the general formula (1) may be substituted with a substituent. That is, a form in which at least one hydrogen atom of these groups is substituted with a substituent is also included in the technical scope of the present invention. In addition, as the “substituent” when the above group is substituted, for example, halogen such as fluorine, chlorine, bromine and iodine, alkyl group such as methyl group, ethyl group, tert-butyl group and dodecyl group; Aryl group such as phenyl group, p-tolyl group, xylyl group, cumenyl group, naphthyl group, anthryl group, phenanthryl group; alkoxy group such as methoxy group, ethoxy group, tert-butoxy group; phenoxy group, p-tolyloxy group, etc. An alkoxy group such as a methoxycarbonyl group, a butoxycarbonyl group, a 2-ethylhexyloxycarbonyl group, a phenoxycarbonyl group; an acyloxy group such as an acetoxy group, a propionyloxy group, a benzoyloxy group; an acetyl group, a benzoyl group, Isobutyryl group, acryloyl Acyl groups such as methacryloyl group and methoxalyl group; alkylsulfanyl groups such as methylsulfanyl group and tert-butylsulfanyl group; arylsulfanyl groups such as phenylsulfanyl group and p-tolylsulfanyl group; methylamino group and cyclohexylamino group Dialkylamino groups such as alkylamino group, dimethylamino group, diethylamino group, morpholino group, piperidino group; arylamino groups such as phenylamino group, p-tolylamino group, etc., hydroxy group, carboxy group, formyl group, mercapto group , Sulfo group, mesyl group, p-toluenesulfonyl group, amino group, nitro group, cyano group, trifluoromethyl group, trichloromethyl group, trimethylsilyl group, phosphinico group, phosphono group and the like. Among those listed above as substituents, substitutions included in the definition before substitution even after substitution (for example, a methyl group substituted with an ethyl group (= n-propyl group)) are excluded here. To do.

  In a preferred embodiment of the present embodiment, R in the general formula (1) is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, or a substituted or unsubstituted arylalkyl group having 7 to 30 carbon atoms. It is preferably a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an arylalkyl group having 7 to 14 carbon atoms, and preferably a hydrogen atom, a methyl group, an ethyl group, or a benzyl group. More preferred is a methyl group, an ethyl group or a benzyl group, and most preferred is an ethyl group or a benzyl group.

  In the general formula (1), the compound in which R is a hydrogen atom is N-acetylcysteine, which is an N-acetylated derivative of cysteine which is an amino acid. The compound in which R is a group other than a hydrogen atom in the general formula (1) is an ester derivative of N-acetylcysteine. Here, since cysteine is an amino acid having one asymmetric carbon, it exists in the form of L-enantiomer, D-enantiomer or racemic mixture thereof, but most of them are L-enantiomers in nature. It exists as an isomer. Similarly, N-acetylcysteine and its ester derivatives are also in the form of an L-enantiomer, D-enantiomer, racemic mixture thereof, or an enantiomerically enriched composition of one of the enantiomers. Any of these may be employed in the present invention. Of these, the L-enantiomer is preferably used. Here, the L-enantiomer of the compound represented by the general formula (1) is represented by the following general formula (2).

  In addition, the structure of the compound (all L-enantiomers) in which R in the general formula (2) is a hydrogen atom, a methyl group, an ethyl group, or a benzyl group is as follows. This is a particularly preferred group of compounds among the compounds.

  The compound represented by the general formula (1), which is an active ingredient of the agent for preventing, treating and / or symptom progression of cerebrovascular disorder and / or dementia according to this embodiment, is a preventive against cerebrovascular disorder and / or dementia. In order to express effects such as treatment and suppression of symptom progression, a compound that easily passes through the cerebral vascular endothelial cell membrane (so-called “blood-brain barrier”) is preferable. From such a viewpoint, the compound represented by the general formula (1) is preferably a compound having higher lipophilicity than the compound (N-acetylcysteine) in which R is a hydrogen atom. Here, in this specification, “log P value” can be used as an index of lipophilicity of a compound. Here, the “log P value” is also referred to as “octanol-water partition coefficient” or “log Pow”, and is a value of the ratio of the distribution concentration of a substance to each phase of a two-phase solvent system composed of n-octanol and water. The larger the value, the higher the lipophilicity (the lower the hydrophilicity). In the present specification, the value of the logP value can be measured by a flask shaking method described in JIS Z-7260-107: 2000. Further, the logP value can be estimated by a computational chemical method or an empirical method instead of the actual measurement.

  As a calculation method, Crippen's fragmentation method ("J. Chem. Inf. Comput. Sci.", 27, p21 (1987)), Viswanadhan's fragmentation method ("J. Chem. Inf. Comput. Sci."). ”, 29, p163 (1989)), Broto's fragmentation method (“ Eur. J. Med. Chem.-Chim. Theor. ”, 19, p71 (1984)), ClogP method (“ Leo , A., Jow, P.Y.C., Silipo, C., Hansch, C., J. Med. Chem., 18, 865 1975 "), etc., are preferably used, but the Crippen's fragmentation method ( "J. Chem. I nf.Comput.Sci. ", 27, p21 (1987)). However, when the measurement value by the flask shaking method mentioned above and the value estimated by the calculation chemical method or the empirical method are significantly different, the measurement value by the flask shaking method has priority.

  Also, from the viewpoint of easily passing through the blood-brain barrier, the molecular weight of the compound represented by the general formula (1) is preferably relatively small. Specifically, the molecular weight of the compound represented by the general formula (1) is preferably 1000 or less, more preferably 800 or less, still more preferably 500 or less, and particularly preferably 400 or less. Preferably it is 300 or less.

  The compound represented by the general formula (1), which is an active ingredient of the preventive, therapeutic and / or symptom progression inhibitor of cerebrovascular disorder and / or dementia according to this embodiment, A commercially available product may be used, or a product synthesized by itself may be used. Moreover, you may use what was extracted and refine | purified from the natural product depending on the case.

  The compound represented by the above general formula (1) may be the compound itself, and includes pharmaceutically acceptable salts, prodrugs and solvates of the compound as long as they are applicable. For example, a salt can be formed between a cation and a negatively charged group on the compound. Suitable cations include sodium cations, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. The compounds also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which can provide active compounds upon administration to a subject. Solvate means a complex formed between an active compound and a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid and ethanolamine.

  As described above, in the process of confirming the preventive / therapeutic effect on cerebrovascular disorder for a number of compounds, the present inventors have shown that NAC and its ester derivatives have a preventive / therapeutic effect on cerebral infarction in cerebral infarction model mice. It was found to show.

  Based on the above findings, the present inventors set a hypothesis that NAC and its ester derivatives have a preventive effect on cerebral infarction, that the compound may be due to inhibition of acrolein production. . However, the hypothesis was rejected because there was no change in the amount of polyamine in the infarcted portion of the brain of the cerebral infarction model mouse between the compound administration group and the control group (see Examples described later).

  For this reason, as another mechanism hypothesis, the present inventors have contributed to the detoxification of acrolein by directly reacting the thiol group (—SH group) of NAC and its ester derivative with acrolein which is an aldehyde. I thought that. However, this hypothesis was also rejected. That is, the present inventors examined the amount of GSH and the amount of PC-Acro in the normal region and the infarcted region of the brain of the cerebral infarction model mouse. As a result, the amount of GSH tends to decrease in the infarcted region, and PC-Acro. The amount was decreasing. Based on these findings, the present inventors set a hypothesis that an increase in the expression level of GST may have a prophylactic / therapeutic effect on cerebral infarction in cerebral infarction model mice. Then, by confirming that the expression level of GST actually increased, the hypothesis was verified and the present invention was completed (see Examples described later).

  Based on this finding, according to another aspect of the present invention, the prevention of cerebrovascular disorder and / or dementia, comprising as an active ingredient a substance that enhances the expression or activity of glutathione-S-transferase (GST). Also provided are therapeutic and / or symptom progression inhibitors.

  Here, in this embodiment, the GST whose expression or activity is enhanced is preferably GST-π, GST-θ and / or GST-μ. These GSTs are expressed in the mammalian brain, and it is known that acrolein serves as a substrate.

  As described above, according to the study by the present inventors, the compound represented by the general formula (1), which is an active ingredient of the agent according to one embodiment of the present invention, is a substance that enhances the expression of GST. It is one of. Therefore, the compound represented by the general formula (1) can be used as a “substance that enhances the expression or activity of GST”. However, a substance other than the compound represented by the general formula (1) may of course be used as the “substance that enhances the expression or activity of GST”. For the same reason as described above, the “substance that enhances the expression or activity of GST” is a compound that is more lipophilic than the compound (N-acetylcysteine) in which R is a hydrogen atom in the general formula (1). It is preferable. For the same reason, the molecular weight of the “substance that enhances the expression or activity of GST” is preferably 1000 or less, more preferably 800 or less, even more preferably 500 or less, and particularly preferably 400. Or less, most preferably 300 or less. Other examples of “substances that enhance GST expression or activity” include, but are not limited to, phenobarbital, aflatoxin B1, 3-methylcholanthrene, oltipraz, and the like.

  As described above, according to one embodiment of the present invention, a preventive, therapeutic and / or symptom progression inhibitor for cerebrovascular disorder and / or dementia is provided, but the term “cerebrovascular disorder” is broadly defined. Interpreted, a concept that encompasses both cerebral hemorrhage (hemorrhagic cerebrovascular disorder) and cerebral infarction (ischemic cerebrovascular disorder). Among them, the cerebrovascular disorder is preferably cerebral infarction (ischemic cerebrovascular disorder). Dementia refers to a state in which intellectual functions that have been developed or acquired have declined, and are considered to be one of intellectual disabilities (Kunitoshi Ueshima, Shinichi Niwa, NAKODO's ESSENTIAL WELL-ADVANCED SERIES). New Psychiatry, p69-70, 2008), in a broad sense, considered a disease presenting with intellectual and / or memory impairment. This dementia is mainly classified into cerebrovascular dementia and Alzheimer's dementia. In the present invention, the dementia is preferably cerebrovascular dementia.

  The effects of the agent according to the present embodiment on the prevention / treatment / symptom progression suppression of cerebrovascular diseases and / or dementia, for example, models that develop or may develop cerebrovascular diseases such as cerebral infarction or dementia in the future It can be evaluated by administering an agent according to this embodiment to an animal (for example, a model mouse) and comparing it with a control. Here, for example, the effect on a cerebral infarction model animal can be evaluated using the infarct volume as an index. The effect on the dementia model animal can be evaluated using learning ability as an index.

  In the present specification, “containing as an active ingredient” means that the agent according to this embodiment is sufficient for exhibiting effects such as desired prevention / treatment / symptom suppression for cerebrovascular disorder and / or dementia. Mean amount (ie, effective amount) means containing at least one compound represented by the general formula (1), or a substance that enhances the expression or activity of GST.

  Therefore, the compound represented by the general formula (1) or a substance that enhances the expression or activity of GST may be used as it is as a preventive, therapeutic and / or symptom progression inhibitor for cerebrovascular disorders and / or dementia. However, as long as it contains an active ingredient in such an effective amount and does not impair the above-described effects, the agent according to this embodiment enhances the expression or activity of the compound represented by the general formula (1) or GST. The substance may be in the form of a composition containing a pharmaceutically acceptable carrier according to a desired product form, other additives and the like. In addition, the agent according to this embodiment is mixed with additives such as excipients and is suitable for parenteral administration, oral administration or external administration, in addition to pharmaceutical compositions such as pharmaceuticals and quasi drugs, food and drinks, etc. Can be used in the form of

  When the compound represented by the general formula (1) according to the present invention or a substance that enhances the expression or activity of GST is used as a pharmaceutical (for example, a prophylactic / therapeutic / symptom progression inhibitor for various diseases described above). The dose varies depending on the target disease, administration subject, administration route, effective dose, and the like, but the dose can be easily selected depending on conditions such as the body weight of the subject person and can be appropriately selected by those skilled in the art. As used herein, “effective amount” means the amount of an agent or composition effective to produce any desired therapeutic effect at a reasonable benefit / risk ratio applicable to any medical treatment. . In general, in the case of oral administration, the dry weight of the compound represented by the general formula (1) according to the present invention or the substance that enhances the expression or activity of GST is preferably in the range of 1 to 2000 mg / day. Moreover, when mix | blending with food-drinks, it considers from the point of the effect, the fragrance at the time of addition, and a color tone, the compound represented by General formula (1) which concerns on this invention, or the substance which enhances the expression or activity of GST The concentration range is preferably about 0.01 to 50% by mass. There is no restriction | limiting in particular also about the administration days, It can set suitably in consideration of the various factors mentioned above. However, since the compound represented by the general formula (1) according to the present invention is an amino acid derivative, there is an advantage that the possibility of occurrence of side effects is extremely small. For this reason, compared with a conventionally known compound such as edaravone, which has a very short treatment time of 14 days or less, it is very safe when administered over a long period of time. From such a viewpoint, the preventive, therapeutic and / or symptom progression inhibitor for cerebrovascular disorder and / or dementia according to the present invention preferably has a continuous administration period of 15 days or more, and 30 days or more. More preferably, it is more preferably 45 days or more, particularly preferably 60 days or more, and most preferably 90 days or more.

  As mentioned in the Background section, in Japan, where an aging society is arriving, in particular, taking a small amount over a long period of time from the viewpoint of “not ill” can cause cerebrovascular disorders such as cerebral infarction and dementia. There is also a strong need for preventive drugs and so-called supplements to prevent onset. In this regard, the agent for preventing, treating and / or symptom progression of cerebrovascular disorder and / or dementia according to the present invention, which is very safe when administered over a long period of time (very unlikely to cause side effects) Is very promising as a medicine with few side effects on the premise of long-term use.

  When used in medicine, an effective amount of the above-mentioned active ingredient (a compound represented by the general formula (1) or a substance that enhances the expression or activity of GST) is added to one or more pharmaceutically acceptable carriers (additions) Agent) and / or diluent. As will be explained in detail below, the medicament according to the invention can be specifically formulated for administration in solid or liquid form. Examples of oral administration include liquid medicine (aqueous solution or non-aqueous solution or suspension), tablet, bolus, powder medicine, granule, paste for application to the tongue. For parenteral administration, for example, as a sterile solution or suspension, for example, a formulation for subcutaneous, intramuscular or intravenous injection, or a dosage form for topical use or administration into the vagina or rectum And can be formulated.

  “Pharmaceutically acceptable” means that within the scope of good medical judgment, commensurate with a reasonable benefit / risk ratio, and without problems and complications such as excessive toxicity, irritation, and allergic reactions, in humans and animals. Used to refer to compounds, materials, compositions, and / or dosage forms suitable for use in contact with tissue.

  “Pharmaceutically acceptable carrier” means a liquid or solid filling involved in transporting or transporting a cytostatic agent according to the present invention from one organ or part of the body to another organ or part of the body. It means a pharmaceutically acceptable material, composition or excipient, such as an agent, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the dosage form and not injurious to the patient. Some of the materials that can function as pharmaceutically acceptable carriers are exemplified below: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate. Cellulose and its derivatives; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; fats and oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; propylene Glycols such as glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; Buffering agents such as magnesium and aluminum hydroxide; including and compatible substances other non-toxic to be used in the drug formulation; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution. In some embodiments, the drug formulation is non-pyrogenic. That is, those that do not increase the patient's body temperature are preferred.

  In addition, wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, and colorants, release agents, coatings, sweeteners, flavors and fragrances, preservatives and antioxidants are also included in the composition. May be present.

  Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, etc .; ascorbyl palmitate, butylhydroxy Oil-soluble antioxidants such as anisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like Such a metal chelating agent can also be contained as needed.

  Suitable dosage forms of the invention for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with seasoned active ingredients, usually sucrose and gum arabic or tragacanth), powders, granules, or As a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or pastilles (gelatin and glycerin, or inert groups such as sucrose and gum arabic) And / or a gargle, etc., each containing a predetermined amount of a compound represented by the general formula (1) according to the present invention, or a substance that enhances the expression or activity of GST. The active ingredient of the present invention may be administered as a bolus, electuary or paste.

  In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is one or more pharmaceuticals such as sodium citrate or dicalcium phosphate. A top acceptable carrier and / or mixed with any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; eg carboxymethylcellulose, alginate, gelatin , Polyvinylpyrrolidone, binders such as sucrose and / or gum arabic; humectants such as glycerol; disintegration such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate Agents; dissolution retardants such as paraffin; 4 Absorption enhancers such as ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and Lubricants such as mixtures thereof; and colorants. In the case of capsules, tablets and pills, the drug composition may comprise a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules with excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be binders (eg, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium glycolate starch or crosslinked sodium carboxymethylcellulose), surfactants Alternatively, it can be prepared using a dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Solid dosage forms such as tablets of the pharmaceutical composition according to the invention, such as sugar-coated tablets, capsules, pills and granules, are optionally scored or coated with coatings such as enteric coatings well known in the pharmaceutical dispensing arts and It may be prepared using a shell. They use, for example, hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres in various ratios to provide the desired release profile, and slow or controlled release of the internal active ingredient. May be formulated to provide. They may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved in a sterile injectable medium such as sterile water immediately before use. . These compositions may optionally contain opacifiers, in compositions that release one or more active ingredients only in certain parts of the gastrointestinal tract or preferentially there, optionally in a delayed manner. There may be. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient may be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

  Liquid dosage forms for oral administration of the compound represented by the general formula (1) or the substance that enhances the expression or activity of GST according to the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions. There are suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active ingredient, inert diluents commonly used in the art, such as water and other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Like fatty acid esters of benzyl, propylene glycol, 1,3-butadiene glycol, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan Solubilizers and emulsifiers, and mixtures thereof.

  In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring and preserving agents.

  Suspensions may be suspended in addition to the active ingredient, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. A turbidity agent may be included.

  The pharmaceutical dosage form according to the invention for rectal or vaginal administration may be presented as a suppository. This suppository is a mixture of one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and one or more agents of the present invention. Which is solid at room temperature but liquid at body temperature, it will melt in the rectum or vaginal cavity and release the active compound.

  The dosage forms of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray dosage forms containing carriers as known to be suitable in the art.

  The dosage form for topical or transdermal administration of the preventive, therapeutic and / or symptom progression inhibitor of cerebrovascular disease according to the present invention is powder, spray, ointment, paste, cream, lotion, gel, solution, patch And including inhalation drugs. The active agent may be mixed under sterile conditions with a pharmaceutically acceptable base material and, if necessary, preservatives, buffers, or propellants.

  Ointments, pastes, creams and gels are in addition to the compounds of the invention, animal or vegetable fat, oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide Or an excipient such as a mixture thereof.

  Powders and sprays may contain, in addition to the active ingredient according to the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. The spray may further comprise customary high pressure gases such as chlorofluorinated hydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

  Transdermal patches have the added advantage of delivering the cytostatic agent of the present invention in a controlled manner to the body. Such dosage forms can be made by dissolving or dispersing the cytostatic agent of the present invention in an appropriate medium. It is also possible to increase the flux of the substance containing the cytostatic agent of the present invention across the skin using an absorption enhancer. The speed of such flux can be controlled by either providing a speed control membrane or by dispersing the compound in a polymer matrix or gel.

  A pharmaceutical composition comprising an agent according to the present invention suitable for parenteral administration comprises, together with the active ingredient of the present invention, one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions Or an emulsion, or a sterile powder that can be reconstituted in a sterile injectable solution or dispersion just prior to use, which makes the antioxidant, buffer, bacteriostat, preparations isotonic with the blood of the intended recipient. Solutes, or suspending or concentrating agents.

  Examples of suitable aqueous and non-aqueous carriers that can be used in pharmaceutical compositions containing the agents according to the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable There are mixtures, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. The inherent fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersants and by the use of surfactants.

  These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbate and the like. It is preferable to include isotonic agents such as sugar and sodium chloride in the composition. In addition, prolonged absorption of the injectable drug form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

  According to the present invention, a cerebrovascular disorder comprising administering to a patient in need thereof an effective amount of the compound represented by the above general formula (1) or a substance that enhances the expression or activity of GST. Also provided are methods for preventing and / or treating dementia and / or inhibiting the development of symptoms thereof.

  Moreover, according to this invention, the food / beverage products containing the compound represented by the general formula (1) mentioned above or the substance which enhances the expression or activity of GST are also provided. Here, the said food / beverage products are used for the use of the prevention, treatment, and / or symptom progress suppression of cerebrovascular disorder and / or dementia by containing the said active ingredient in an effective amount. That is, according to another aspect of the present invention, a cerebral vascular disorder and / or dementia containing the compound represented by the above general formula (1) or a substance that enhances the expression or activity of GST as an active ingredient Foods and beverages for preventing, treating and / or suppressing the progression of symptoms are also provided. According to still another aspect of the present invention, “a compound represented by the above general formula (1) used for the prevention, treatment and / or suppression of symptom progression of cerebrovascular disorder and / or dementia” Or a substance that enhances the expression or activity of GST ”, and further,“ in the manufacture of a medicament used for the prevention, treatment and / or suppression of symptom progression of cerebrovascular disorder and / or dementia ”described above. The invention “the use of the compound represented by the general formula (1) or a substance that enhances the expression or activity of GST” is also provided.

  In addition, "it contains an effective amount of an active ingredient" means containing an active ingredient in the quantity which can exhibit the effect as an active ingredient as a result of ingesting the amount which normally eats each food-drink.

  You may mix | blend with the food / beverage products which concern on this invention the active ingredient which concerns on this invention as it is, or with the form of the composition formed by mixing with another additive as needed. For example, the food and drink according to the present invention are prepared as food and drink by adding conventional additives such as stabilizers to the active ingredient according to the present invention, various proteins, sugars, fats, trace elements, vitamins, etc. It may be prepared by further blending them, liquid, semi-liquid or solid, paste, or a general food or drink with active ingredients added.

  In the present invention, the “food or drink” is not a drug and is not particularly limited as long as it is in a form that can be taken orally by mammals, and the form is also a liquid (solution, suspension, emulsion). Liquid, etc.), semi-liquid, powder, or solid molded product. Therefore, the food or drink may be in the form of a beverage, for example, or may be in the form of a dietary supplement tablet such as a so-called supplement.

  Specific examples of food and drink include instant noodles, retort foods, canned foods, microwave foods, instant soups and miso soups, freeze-dried foods, etc .; soft drinks, fruit juice drinks, vegetable drinks, soy milk drinks, coffee Beverages such as beverages, tea beverages, powdered beverages, concentrated beverages, nutritional beverages, alcoholic beverages; flour products such as bread, pasta, noodles, cake mixes, fried flour, bread crumbs; rice cakes, caramels, chewing gums, chocolates, cookies, Confectionery such as biscuits, cakes, pies, snacks, crackers, Japanese confectionery, dessert confectionery; sauces, processed tomato seasonings, flavor seasonings, cooking mixes, sauces, dressings, soups, curry and stew Seasonings; processed fats and oils, butter, margarine, mayonnaise, etc .; milk drinks, yogurts, lactic acid bacteria drinks Dairy products such as ice cream and cream; processed fishery products such as fish ham and sausages and fish paste products; processed livestock products such as livestock ham and sausages; canned agricultural products, jams and marmalades, pickles, boiled beans, cereals, etc. Processed agricultural products; frozen foods; nutritional foods.

  The food / beverage products according to the present invention can be suitably used for those who desire prevention / treatment / symptom suppression of cerebrovascular disorders such as cerebral infarction as described above and dementia.

  In the present invention, “food and beverage” includes foods classified as health foods, functional foods, foods for specified health use, dietary supplements, foods with a disease risk reduction label, or foods for the sick. Is done. Furthermore, the term “food or drink” can be used to include feed when used for mammals other than humans. The food for specified health mentioned here is subject to some legal restrictions in each country (for example, Japan) from the viewpoint of health when producing or selling food for the purpose of achieving desired effects. A certain food. Such a food may be a food that indicates that the food may reduce the disease risk, that is, a food with a disease risk reduction label. Here, the disease risk reduction label is a label for foods that may reduce the disease risk, and is based on or based on the standard established by the FAO / WHO Joint Food Standards Committee (Codex Committee). The display may be a prescribed display or an approved display with reference to FIG.

  In the food / beverage products of this invention, in addition to the active ingredient mentioned above, you may further add the component which has another function. Further, for example, the active ingredient of the present invention is added to foods, health foods, functional foods and supplements (for example, foods containing one or more vitamins such as minerals such as calcium and magnesium and vitamin K) consumed in daily life. By mix | blending, in addition to the effect by this invention, the food / beverage products which have the function based on another component can be provided.

  In the production of the food and drink according to the present invention, sugars, fragrances, fruit juices, food additives, stabilizers and the like that are used in normal food and drink formulation design can be added as appropriate. Manufacture of food-drinks can be implemented with reference to a manufacturing technique well-known in the said technical field. The food / beverage products according to the present invention can take various forms, and the food / beverage products according to the present invention may be manufactured according to known pharmaceutical manufacturing techniques. In that case, it can be produced using a carrier or an additive as described in the item of production of the agent or pharmaceutical according to the present invention. Moreover, in a manufacturing stage, it is good also as multifunctional food / beverage products by combining with the other component which exhibits functions other than the function in this invention, or another functional food.

  Hereinafter, preferred embodiments of the present invention will be described in more detail by way of examples. However, the technical scope of the present invention should not be construed as being limited to the following examples.

≪Statistical calculation≫
All data obtained by the experiments shown below were expressed as mean ± standard error values. In the evaluation of therapeutic effect, after analysis of variance, multiple comparison test was performed by Tukey's test. Moreover, in the evaluation of the preventive effect, after conducting analysis of variance, the multiple comparison test was performed by Dunnett's test. In addition, when the risk rate is 5% or less, an asterisk (*) is given as a statistically significant difference. Similarly, when the risk rate is 1% or less and 0.1% or less, ** mark and *** mark are given respectively. Further, Graph pad Prism 5 was used as statistical processing software. << Preparation of NAC and its ester derivative and preparation of a solution containing them >>
For NAC and NACMe, those purchased from Sigma were used. On the other hand, NACEt and NACBn were synthesized by the following method. All reagents and solvents used were commercially available.

(Synthesis example of NACEt)
Literature (Mechanistic proposal for the formation of specific immunogenic complexes via a radical pathway:. A key step in allergic contact dermatitis to olefinic hydroperoxides Johansson S., Redeby T., Altamore T.M., Nilsson U., Borje A., Chem Res. Toxicol., 22, 1774-1781 (2009)), N-acetylcysteine ethyl ester (NACEt) was synthesized.

  Specifically, thionyl chloride (1.1 equivalent) was added dropwise to a dry ethanol solution (4 mL / mmol) of N-acetylcysteine (1.0 equivalent) at 0 ° C., and the reaction system was allowed to warm to room temperature. It was. At this time, the disappearance of N-acetylcysteine was monitored by TLC using a silica gel plate (silica gel 60 F-254 (Merck)) and visualized using ultraviolet rays. Next, the solution was removed by evaporation, the residue was extracted with water and chloroform, the chloroform layer was evaporated, and then subjected to chromatography using a silica gel column (Wakogel C-200 (Wako Pure Chemical Industries)). . At this time, n-hexane: ethyl acetate (2: 1 by volume) was used as a solvent system for chromatography. The target compound is a white solid, the yield is 45%, and the melting point (uncorrected after measurement by Yanagimoto micro-hot stage) is 44 to 45 ° C. (document value: 44.1 to 44.5 ° C. (GC-MS analysis). of S. Nitrosothiols after conversion to S-nitroso-N-acetyl cystein easter ester and in-injector nitro e of et ecetate. Chromatgr. B Analyt. Technol.Biomed. Life Sci., 877, 3442-3 55, it was the (2009))).

The results of ¹ H-NMR measurement (measured at 400 MHz using NMR apparatus Varian 400-MR, internal standard is tetramethylsilane) and mass spectrometry (measured using mass spectrometer JEOL JMS-700) are as follows. The results were similar to those reported previously. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.32 (3H, t, J = 7.1 Hz, CH ₃ ), 1.34 (1H, t, J = 9.1 Hz, SH), 2.07 _{(3H, s, CH 3 CO} ), 3.03 (2H, dd, J = 9.1,4.0Hz, CH 2 -S), 4.20-4.33 (2H, m, OCH 2), 4.87 (1H, dt, J = 7.7, 4.0 Hz, 4 Hz; NCH), 6.38 (1H, brs, NH).
MS m / z: 191 (M) ^<+> .

(Synthesis example of NACBn)
Benzyl alcohol (2.0 mL, 19.3 mmol) and N, N′-diisopropylcarbodiimide (3.0 mL, 19.5 mmol) were added in CuCl (42.0 mg, 0.42 mmol) under argon atmosphere at room temperature for 15 hours. In the presence of. The crude product was purified by Al ₂ O ₃ open column chromatography (solvent system was 30% ethyl acetate / n-hexane) to give O-benzyl N, N′-diisopropylisourea (4.25 g).

The results of ¹ H-NMR measurement and ¹³ C-NMR measurement were as follows. ¹ H-NMR (CDCl ₃ , 400 MHz) a: 7.39-7.27 (5H, m), 5.12 (2H, s), 3.70 (1H, m), 3.45 (1H, br -S), 3.20 (1H, m), 1.12 (12H, d, J = 6.9 Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) a: 151.5, 138.0, 128.2, 127.6, 127.3, 66.6, 46.3, 43.4, 24.3, 24. 0.

  Meanwhile, O-benzyl N, N′-diisopropylisourea (1.92 g, 8.18 mmol) obtained above was added to a tetrahydrofuran (5 mL) solution of N-acetylcysteine (1.33 g, 8.15 mmol). And stirred at room temperature for 1.5 hours under an argon atmosphere. The reaction mixture was filtered through celite and the solvent was removed by evaporation. The crude product was purified by silica flash chromatography (solvent system 30% ethyl acetate / n-hexane) to give N-acetyl-O-benzylcysteine (1.21 g). The product was further purified by recrystallization from ethyl acetate / n-hexane.

The results of ¹ H-NMR measurement were as follows. ¹ H-NMR (CDCl ₃ , 400 MHz) a: 7.39-7.35 (5H, m), 6.37 (1H, br-s), 5.27 (1H, d, J = 12.2 Hz) 5.18 (1H, d, J = 12.2 Hz), 4.93 (1 H, ddd, J = 8.2, 4.1, 4.1 Hz), 3.08-2.95 (2H, m ), 2.06 (3H, s) 1.20 (1H, dd, J = 9.2, 9.2 Hz).

≪Preparation of cerebral infarction model mouse by photochemically induced thrombosis (PIT) method≫
In this example, all animal experiments were approved by the Chiba University Animal Experiment Committee and were conducted based on the Chiba University Animal Experiment Implementation Regulations.

  C57BL / 6 male mice were purchased from Japan SLC, and kept in the mouse room until 2 months of age. Then, they were used to prepare a thrombotic middle cerebral artery occlusion model developed by Watson et al. . This model applies a photosensitization reaction. Specifically, singlet oxygen is generated when a photosensitizer, Rose Bengal, is excited with green light having a wavelength of 540 nm. This singlet oxygen damages vascular endothelial cells, exposing the subendothelial tissue to activate platelets, forming a thrombus and blocking the blood vessel. This model is superior in reproducibility compared to a cerebral infarction model by vascular ligation and a cerebral infarction model by insertion of an embolus, and is excellent in that there is less individual death during the operation.

  In preparing a model mouse, first, the mouse was placed in a sealed container, and anesthesia was introduced using 3% isoflurane (Abbott Japan). Anesthesia was maintained with 1.5% isoflurane during the operation. After induction of anesthesia, the skin and temporal muscle were dissected along the left orbital margin of the mouse toward the temporal region, and then the dura mater was exposed until the middle cerebral artery passing under the dura was confirmed. Further, the skin and muscles of the mouse chest were incised to expose the vena cava, and Rose Bengal (Wako Pure Chemical Industries) was administered (20 mg / kg). Thereafter, the middle cerebral artery was irradiated with green light for 10 minutes using a xenon lamp (Hamamatsu Photonics), and the middle cerebral artery was occluded with a thrombus.

≪Therapeutic effect of NAC and its ester derivatives on cerebral infarction≫
The therapeutic effect on cerebral infarction of NAC and its three ester derivatives (NACMe, NACEt and NACBn) prepared above was examined by the following method using the cerebral infarction model mouse prepared above.

  Specifically, for the purpose of confirming the therapeutic effect on cerebral infarction, each compound was administered intraperitoneally at 150 mg / kg immediately after induction of cerebral infarction. Since dimethyl sulfoxide (DMSO) was used as a solvent for administering the compound, DMSO alone was administered in the control (negative control) group. In this experiment, NAC, NACMe, and NACEt were administered by diluting with 50% DMSO to a concentration of 15 mg / mL. In addition, NACBn was once diluted with 99.5% DMSO to a concentration of 30 mg / mL, and further diluted to a concentration of 15 mg / mL (50% DMSO) with purified water immediately before administration. did.

  Then, 24 hours after the induction of cerebral infarction, the skin of the chest was incised, and the diaphragm and ribs were cut from both sides of the serrated cartilage to open the thoracotomy. After blood sampling, the brain was removed and a brain slice 2 mm thick was prepared using a brain slicer. The brain sections thus prepared were incubated at 37 ° C. for 30 minutes in physiological saline containing 5% TTC (2,3,5-triphenyltetrazolium chloride) (Tokyo Chemical Industry). During incubation, colorless TTC is reduced by hydrogen generated in mitochondria to become deep red TPF (triphenylformazan), so that only living cells are stained red, and brain cells killed by infarction are stained. Instead, it falls out white. Taking advantage of this, a sample obtained by TTC staining of the brain section prepared above was photographed with a digital camera, and the white infarction portion was analyzed using the National Institute of Health Image program, which is an image processing program. The volume was quantified.

The results are shown in FIG. As shown in FIG. 1, the infarct volume was significantly reduced in the group to which each of the above four compounds was administered, compared to the control group. The average infarct volume was reduced by the administration of NAC is 46.7Mm ^3, the administration of NACMe is 46.8 mm ^3, the administration of NACEt a 46.7Mm ^3, in 51.4Mm ³ is administered NACBn there were.

≪Preventive effect of NAC and its ester derivatives on cerebral infarction≫
About the preventive effect with respect to the cerebral infarction of NAC prepared in the above and 2 types of its ester derivatives (NACEt and NACBn), it examined by the following methods using the cerebral infarction model mouse produced above.

  Specifically, for the purpose of confirming the preventive effect against cerebral infarction, each compound was administered once a day from 3 days before the induction of cerebral infarction to immediately before the induction of cerebral infarction (total 4 times), and 50 mg intraperitoneally. / Kg / dose (total 200 mg / kg). Again, since dimethyl sulfoxide (DMSO) was used as a solvent when administering the compound, only DMSO was administered in the control (negative control) group. In this experiment, NAC and NACEt were administered by diluting with 50% DMSO to a concentration of 5 mg / mL. For NACBn, diluted once with 99.5% DMSO to a concentration of 10 mg / mL, and further diluted with purified water to a concentration of 5 mg / mL (50% DMSO) immediately before administration. Administered.

  Thereafter, the brain was removed 24 hours after the induction of cerebral infarction, and the infarct volume was measured by the same method as described above.

The results are shown in FIG. As shown in FIG. 2, the infarct volume tended to decrease in the NAC prophylaxis administration group and the NACEt prophylaxis administration group, and the infarct volume significantly decreased in the NACBn administration group. The average infarct volume was reduced by prophylactic administration for NAC is about 29.5 mm ^3, the prophylactic administration of NACEt about 30.2 mm ^3, the prophylactic administration of NACBn was about 33.7 mm ^3.

≪Study of mechanism of reduction of infarct volume by prophylactic administration of NAC ester derivative≫
Subsequently, the mechanism by which the infarct volume was reduced by the prophylactic administration of the NAC ester derivative described above was examined.

(Changes in polyamine content in brain tissue)
First, changes in the amount of polyamine in brain tissue were examined. Here, for mice to which NAC and two of its ester derivatives (NACEt and NACBn) were each administered prophylactically, the brain was removed 24 hours after induction of cerebral infarction, and polyamines at normal and infarcted sites were extracted. Quantified by HPLC.

  More specifically, in extracting polyamine from brain tissue, a protein fraction of brain tissue was first prepared. In preparation of the protein fraction of brain tissue, the tissue was crushed using a bio smasher (nippi) in order to extract protein from the brain tissue of a cerebral infarction model mouse. At this time, the composition of the tissue disruption buffer was 10 mmol / L Tris / HCl (pH 7.5), 10% glycerol, 0.2 mM EDTA, 150 mM NaCl, 0.02 mmol / L FUT-175. The brain tissue homogenate prepared by tissue disruption was centrifuged at 10,000 rpm for 10 minutes at 4 ° C., and the supernatant was used as the protein fraction. The protein concentration was quantified using BCA Assay kit (Nacalai). At this time, bovine serum albumin (Nacalai) for protein quantification was used as a standard for the protein amount.

  Subsequently, 5 μL of 100% trichloroacetic acid is added to 100 μL of the protein fraction of brain tissue prepared by the above method to make a final concentration of about 5%, and the mixture is centrifuged at 10,000 rpm for 10 minutes at 40 ° C. Sorted. Thereafter, 190 μL of 5% trichloroacetic acid was added to the collected supernatant and centrifuged at 10,000 rpm for 10 minutes at 4 ° C., and 10 μL of the supernatant was measured by HPLC.

  Polyamine was quantified according to the method of Igarashi et al. The sample was separated using TSKgel polypinepak (4.6 mm × 50 mm) at a flow rate of 0.42 mL / min and a column temperature of 50 ° C. Buffer II (0.35M sodium citrate, 2M NaCl, 20% methanol, 1% Briji-35, 0.01% hexanoic acid) was used as an eluent. An orthophthalaldehyde solution (0.4M boric acid, 0.35M KOH, 0.06% orthophthalanolaldehyde, 37 mM 2-mercaptoethanol, 0.1% Briji-35) as a post-column reagent has a flow rate of 0.4 mL / Liquid was delivered in minutes. After the reaction, polyamine was detected under conditions of an excitation wavelength of 336 nm and a fluorescence wavelength of 470 nm.

  The results are shown in FIG. In FIG. 3, “PUT” indicates the amount of putrescine, “SPD” indicates the amount of spermidine, and “SPM” indicates the amount of spermine. As shown in FIG. 3, in any of the NAC, NACEt, and NACBn preventive administration groups, no change was observed in the amount of polyamine at the infarcted site as compared to the control group. From these results, it was suggested that the decrease in infarct volume by prophylactic administration of NAC or its ester derivative was not due to inhibition of acrolein production.

(Changes in glutathione levels in brain tissue)
Subsequently, the change in the amount of glutathione (GSH), which is an in vivo substance responsible for releasing the toxicity of acrolein, in the brain tissue was examined. Here, there are two types of glutathione, oxidized glutathione and reduced glutathione. Since the ratio of reduced glutathione exceeds 99% in the brain, both are collectively measured as total glutathione (tGSH). It was.

Specifically, when glutathione is extracted from brain tissue, 5 μL of 100% trichloroacetic acid is added per 100 μL of protein fraction of brain tissue prepared by the above method, and centrifuged at 40 ° C. and 10,000 rpm for 10 minutes. The supernatant was used as a sample. Glutathione was quantified using Northwest NWLSS ^™ G1 utatione Assay Product NWK-GSH01.

  The results are shown in FIG. As can be seen from the results shown in FIG. 4, at the infarct site, the amount of glutathione tended to decrease in the NAC preventive administration group, and the amount of glutathione significantly decreased in the NACEt or NACBn preventive administration group.

(Change in the amount of PC-Acro in brain tissue)
Subsequently, changes in the amount of PC-Acro in brain tissue were examined. As described above, PC-Acro means protein-conjugated acrolein, and an increase in this amount suggests that the degree of inactivation of the protein due to the binding of acrolein to a cysteine residue or the like is large.

The amount of PC-Acro was measured by SDS-polyacrylamide gel electrophoresis (PAGE) followed by Western blotting (ECL Western Blotting). SDS-PAGE was performed using e-PAGE (ATO), and was performed at a constant current of 20 mA per gel for 90 minutes. After separating 20 μg of protein (protein fraction of brain tissue prepared by the above method) by SDS-PAGE, it was stained with Coomassie Brilliant Blue R250 (CBB). As a sample to be analyzed by Western blot, proteins were transferred from a gel subjected to SDS-PAGE to a PVDF (Millipore) membrane at a constant voltage of 30 V over 16 to 18 hours. After blocking PVDF with Blocking One (Nacalai) at room temperature for 30 minutes, the primary antibody specifically recognizing PC-Acro (anti-acrolein monoclonal antibody (mouse IgG) (Nippon Oil)) was reacted for 1 hour, and then HRP The labeled secondary antibody was reacted for 1 hour. As an internal standard, β-actin was quantified using an anti-β-actin monoclonal antibody (mouse IgG) (Santa Cruz). For antibody dilution, Can get signal (Toyobo) was used. The membrane after the reaction was reacted with Chemi-Lumi One (Nacalai), and the target protein was detected with Amersham Imager 600 (GE healthcare). The density of the band was measured by Image Quant ^™ TL (GE healthcare).

  The results are shown in FIG. As can be seen from the results shown in FIG. 5, at the infarct site, the PC-Acro amount tends to decrease in the NAC prophylaxis group, and the PC-Acro amount significantly decreases in the NACEt or NACBn preventive administration group. It was.

  From the above results, the present inventors considered that the expression level of GST that catalyzes the glutathione conjugation reaction to acrolein is increased in the infarcted region of the prophylactic administration group of NAC and its ester derivatives.

(Changes in the expression level of various GSTs in brain tissue)
Therefore, the present inventors examined GST-π, GST-θ, and GST-μ, which are GST species expressed in a mammalian brain and using acrolein as a substrate, and examined their expression levels in brain tissue.

  The expression levels of these GST species were measured by SDS-PAGE and subsequent Western blotting in the same manner as described above. As primary antibodies, anti-GST-π antibody, anti-GST-θ antibody and anti-GST-μ antibody (all abcam) were used.

  The results are shown in FIGS. As can be seen from the results shown in FIGS. 6 to 8, in the infarcted region, the expression levels of the above three GST species tended to increase in the prophylaxis group of NAC and its ester derivatives. From this, the preventive effect of cerebral infarction by the above-mentioned NAC and its ester derivative is considered to be due to the promotion of detoxification by acrolein conjugation with glutathione by inducing the expression of GST.

(Influence of GST-π on glutathione conjugation of acrolein)
It has been reported that GST-π has a high substrate specificity of acrolein and that there is a relationship between blood GST-π farming rate and stroke start time in stroke patients. Therefore, the present inventors focused on GST-π and examined the influence of GST-π on glutathione conjugation of acrolein.

  Specifically, the change over time in the amount of free acrolein in the presence or absence of GST-π was measured by the method of Alarcon et al. The total volume of the reaction system was 300 μL, and 1 μg of GST-π (abcam) was added to 0.5 mM GSH, 10 μM acrolein, PBS (pH 7.5). Then, 50 μL of each reaction system was taken at 0, 20, 40, 60, 80, 100, and 120 seconds after adding GST-π, and the same amount of the reaction solution (92 mM m-aminophenol, 172 mM hydroxylamine hydrochloride). 3M HCl) and boiled for 10 minutes, followed by centrifugation at 40 ° C. and 10,000 rpm for 10 minutes. The fluorescent substance (7-hydroxyquinoline) in the supernatant was measured by HPLC. At this time, the supernatant was applied to a Mightysil RP-8GP (4.6 mm × 150 mm) column equilibrated with an eluent (0.5% phosphoric acid-acetonitrile [96: 4 (v / v)]), and the flow rate was 0. The sample was separated under a condition of 4 mL / min, and the fluorescence intensity was measured under the conditions of an excitation wavelength of 358 nm and a fluorescence wavelength of 510 nm.

  The results are shown in FIG. As shown in FIG. 9, the group to which GST-π was added promoted a decrease in the amount of free acrolein compared to the control group (GST-π non-added group). This suggests that GST-π contributes to attenuating the toxicity of acrolein by promoting glutathione conjugation to acrolein.

Claims (15)

The following general formula (1):
In the formula, R is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 30 carbon atoms. Group, substituted or unsubstituted alkynyl group having 2 to 30 carbon atoms, substituted or unsubstituted aryl group having 6 to 30 carbon atoms, substituted or unsubstituted arylalkyl group having 7 to 30 carbon atoms, substituted or unsubstituted A heteroaryl group having 1 to 30 carbon atoms, or a substituted or unsubstituted heteroarylalkyl group having 2 to 30 carbon atoms,
A prophylactic, therapeutic and / or symptom progression inhibitor of cerebrovascular disorder and / or dementia, comprising at least one compound represented by the formula:   The R in the general formula (1) is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, or a substituted or unsubstituted arylalkyl group having 7 to 30 carbon atoms. Prevention, treatment and / or symptom progression inhibitor.   The prevention, treatment and / or suppression of symptom progression according to claim 2, wherein R in the general formula (1) is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an arylalkyl group having 7 to 14 carbon atoms. Agent.   The preventive, therapeutic and / or symptom progression inhibitor according to claim 3, wherein R in the general formula (1) is a hydrogen atom, a methyl group, an ethyl group or a benzyl group.   A preventive, therapeutic and / or symptom progression inhibitor of cerebrovascular disorder and / or dementia, comprising a substance that enhances the expression or activity of GST as an active ingredient.   The preventive, therapeutic and / or symptom progression inhibitor according to claim 5, wherein the GST is GST-π, GST-θ and / or GST-μ.   The prevention, treatment, and treatment according to claim 5 or 6, wherein the substance that enhances the expression or activity of GST is a compound represented by the general formula (1) according to any one of claims 1 to 4. / Or symptom progression inhibitor.   The prevention, treatment and / or symptom progression inhibitor of any one of claims 1 to 7, which is a cerebral infarction prevention, treatment and / or symptom progression inhibitor.   The preventive, therapeutic and / or symptom progression inhibitor according to any one of claims 1 to 8, wherein the number of consecutive administration days is 15 days or more.   A food or drink for the prevention, treatment and / or suppression of symptom progression of cerebrovascular disorder and / or dementia, comprising a substance that enhances the expression or activity of GST as an active ingredient.   The food or drink according to claim 10, wherein the substance that enhances the expression or activity of GST is a compound represented by the general formula (1) according to any one of claims 1 to 4.   The food or drink according to claim 10 or 11, which is a food or drink for preventing or treating cerebral infarction and / or suppressing symptom progression.   The food or drink according to any one of claims 10 to 12, which is a health food, a functional food, a food for specified health use, a nutritional supplement, a food with a disease risk reduction label, or a food for a sick person.   A cerebrovascular disorder and / or dementia, comprising administering an effective amount of the compound represented by the general formula (1) according to any one of claims 1 to 4 to a patient in need thereof. A method of treating, and / or inhibiting the development of symptoms thereof.   Preventing, treating and / or inhibiting the progression of symptoms, including administering to a patient in need thereof an effective amount of a substance that enhances GST expression or activity Method.