• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    It is an object of the present invention to provide a composition useful for inhibiting the secretion of substances in vivo such as VLDL into the blood. The present invention relates to an MTP deactivation composition comprising sulfur-containing amino acids such as cycloaliin and S-ethyl-L-cysteine or physiologically acceptable salts thereof.
    公开号:KR20010025074A
    申请号:KR1020007013055
    申请日:1999-04-16
    公开日:2001-03-26
    发明作者:야나기타데루요시；안노다카히코
    申请人:니뽄 신야쿠 가부시키가이샤；
    IPC主号:
    专利说明:

    MTP ACTIVITY-LOWERING COMPOSITIONS
    Natural sulfur-containing amino acids such as cycloaliin are mainly contained in plants of the genus Liliaceae and allium, such as onions, garlic and chives. It is also known that among the natural sulfur-containing amino acids, cycloaliin has a pharmacological action of fibrinolytic action, hypoglycemic action and blood lipid lowering action [eg, Atherosclerosis, 27, 347-351 (1977); See Japanese Patent Laid-Open No. 05-194237]. As for other natural sulfur-containing amino acids, pharmacological actions such as platelet aggregation inhibitory activity, cholesterol lowering action and anticancer action are known (Indian Journal of Experimental Biology, 34, 634-640 (1996), etc.).
    On the other hand, MTP (microsomal triglyceride transfer protein) is a protein of a heterodimer consisting of subunits of 58 KDa and 97 KDa in the endoplasmic reticulum lumen of the liver and small intestine, It is known to promote the transport of neutral lipids, in particular triglycerides (TG) (see, eg, Ishigami et al., 'Arteriosclerosis' 24 (10), 533-540 (1997)). The MTP aggregates the transmitted TG and apo B. As a result, ultra-low specific gravity lipoprotein (VLDL) particles are formed and VLDL is secreted into the blood.
    Excessive increase in blood VLDL is known to lead to various diseases related to lipid metabolism (Fujioka et al., 'Advanced Clinical Nutrition', Vol. 3, 81-91 (1993)). For example, excessive increases in blood VLDL are said to promote atherosclerosis through hypoHDL (high specific gravity lipoprotein) emia.
    Therefore, if it is possible to lower the activity of MTP in the endoplasmic reticulum lumen in the liver, which is involved in the biosynthesis of VLDL, the secretion of VLDL into the blood is suppressed, which is effective against various diseases caused by excessive increase in blood VLDL. .
    The present invention relates to sulfur-containing amino acids such as Cycloalliin ((1S, 3R, 5S) -5-methyl-1,4-thiazane-3-carboxylic acid 1-oxide) and extracts containing the same. .
    It is an object of the present invention to provide a composition useful for inhibiting the secretion of VLDL into the blood.
    As a result of intensive studies, the present inventors have found that sulfur-containing amino acids such as cycloaliin, which are contained in a bundle of onions (Alliumcepa L), have a function of lowering MTP activity and suppressing apo B secretion. The present invention was completed.
    Therefore, one of the present invention is characterized by containing a sulfur-containing amino acid represented by the following formula [I] or [Ia] (hereinafter referred to as 'amino acid of the present invention'), or a physiologically acceptable salt thereof. MTP activity lowering composition.
    In the formulas [I] and [Ia], R 1 represents H, alkyl or alkenyl. R 2 , R 3 represent the same or different H, alkyl or acyl, R 4 , R 5 represent the same or different H or alkyl, R 6 represents H, alkyl or acyl, p is 0 or 1 And q represents 0 or 1, r represents an integer of 1-3.
    Moreover, the apo B secretion inhibiting composition characterized by containing the amino acid of this invention or its physiologically acceptable salt, and the amino acid of this invention or its physiologically acceptable salt, It is characterized by the above-mentioned. The VLDL secretion inhibiting composition mentioned above is also mentioned as this invention.
    In the present invention, the alkyl may be, for example, linear or branched alkyl having 1 to 6 carbon atoms, and linear alkyl having 1 to 4 carbon atoms is suitable, but is not limited thereto. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, 1-methylpentyl, 2 -Methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl and 3-ethylbutyl.
    In the present invention, 'alkenyl' includes, for example, linear or branched alkenyl having 2 to 6 carbon atoms, and linear alkenyl having 2 to 4 carbon atoms is suitable, but is not limited thereto. Specific examples include vinyl, 1-propenyl, isopropenyl, allyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl , 3-hexenyl and 4-hexenyl.
    In the present invention, 'acyl' includes, for example, straight or branched acyl having 1 to 6 carbon atoms, and linear acyl having 2 to 4 carbon atoms is suitable, but is not limited thereto. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl.
    As a preferred embodiment of the present invention, R 1 is, for example, straight-chain alkyl having 1 to 4 carbon atoms or straight-chain alkenyl having 2 to 4 carbon atoms, and R 2 and R 3 are the same or different and are H or 2 to 4 carbon atoms. Chain acyl, R 4 is H, R 5 is straight alkyl having 1 to 4 carbon atoms, R 6 is H or straight acyl having 2 to 4 carbon atoms, p is 0 or 1, q is 0 or 1 And an amino acid of the present invention wherein r is 1 or 2 or a physiologically acceptable salt thereof, and the amino acid or a physiologically acceptable salt thereof of the present invention. APO B secretion inhibiting composition characterized by containing the above, and the amino acid of the present invention or its physiologically acceptable salt, VLDL secretion suppressing composition characterized by the above-mentioned.
    In a more preferred invention, for example, R 1 is methyl, ethyl, propyl, butyl, allyl or 1-propenyl, R 2 is H, R 3 is H or acetyl, R 4 is H and R 5 is methyl , Ethyl, propyl or butyl, R 6 is H or acetyl, p is 0 or 1, q is 0 or 1 and r is 1 or 2 or a physiologically acceptable salt thereof MTP activity lowering composition, comprising the amino acid of the present invention or a physiologically acceptable salt thereof, and the apo B secretion inhibiting composition, and the amino acid of the present invention or its physiological And VLDL secretion inhibiting composition characterized by containing an acceptable salt.
    Preferred embodiments of the present invention include cycloaliin, S-methyl-L-cysteine, S-ethyl-L-cysteine, S-propyl-L-cysteine, DL-methionine, DL-ethionine, and S-methyl-L- Characterized by containing an amino acid of the present invention, or a physiologically acceptable salt thereof, such as cysteine sulfoxide, S-ethyl-L-cysteine sulfoxide, LS-propyl-L-cysteine sulfoxide, or DL-methionine sulfoxide ATP B secretion inhibiting composition, comprising: an amino acid of the present invention or a physiologically acceptable salt thereof; and an amino acid of the present invention or a physiologically acceptable salt thereof A VLDL secretion suppressing composition characterized by including the above.
    Examples of the physiologically acceptable salts include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid; Salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, malic acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid; Alkali earth metal salts such as alkali metal salts such as sodium and potassium, calcium and magnesium; And aluminum salts.
    Most of the amino acids of the present invention are known compounds and are commercially available in addition to those which can be prepared by conventional methods. Cycloaliin, which is one of the amino acids of the present invention, is described in, for example, Acta Chem. Scand., 13, 623 (1959): J. Org. Chem., 31, 2862 (1966); Chem. Pharm. Bull., 29 (6) 1554-1560 (1981); It can manufacture by the method of Unexamined-Japanese-Patent No. 55-40658.
    The physiologically acceptable salt of the amino acid of this invention can also be easily synthesize | combined by those skilled in the art by the conventional method from the amino acid of this invention. For example, the hydrochloride of the amino acid of the present invention can be obtained by dissolving the amino acid of the present invention in an alcohol solution or ethyl acetate solution of hydrogen chloride, and the sodium salt of the amino acid of the present invention is obtained by stirring and mixing the amino acid of the present invention with sodium hydroxide. Can be.
    Moreover, since most of amino acids of this invention are contained in lily and green onions, such as onion, it can extract and isolate from green onions by a suitable extraction method, and can refine | purify as needed. For example, onion, garlic, chive can be mentioned.
    As a specific extraction method, for example, when an onion extract is obtained, a method of concentrating the juice obtained by compressing the raw diameter of the onion with a suitable pressing machine, or by using hot water or a solvent (e.g., Ether, n-butanol), and the method of distilling off water or a solvent is mentioned. The raw life of the onion can also be peeled, sterilized, or cut to a suitable size. In addition, the onion may be heated to inactivate the CS-lyase contained in the onion prior to the extraction treatment by pressing or hot water. In the case of hot water extraction, it may be treated with enzymes such as cellulase, pectinase and protease in order to increase the juice effect. The onion extract obtained in this way contains a total of about 0.1 to 0.3% by weight of the amino acids of the present invention. As for the individual amino acids of the present invention, cycloaliin is about 0.02% by weight in the onion extract, S-methyl-L About 0.02-0.05 weight% of cysteine sulfoxide and about 0.05-0.08 weight% of S-methyl-L-cysteine sulfoxide are contained.
    For example, in order to raise the content of cycloaliin in onion extract, the juice of a branched onion, the hot water extract, etc. can be heat-processed at 90-120 degreeC, or alkali-treated to pH 8-12. The two treatments can also be combined. In addition, prior to such heat treatment and / or alkali treatment, enzymes capable of cleaving γ-glutamyl peptide which is a precursor of cycloaliin contained in onions (eg, γ-glutamyl peptidase, γ-glutamyl transpeptidase) , Glutaminase). The cycloaliin can also be isolated and purified by treating the onion extract with ion exchange chromatography.
    The extract can be used as it is or as appropriate, for example, by adding an excipient such as dextrin or lactose to the extract to dry powder it.
    Therefore, the MTP activity lowering composition characterized by containing the extract which has the amino acid of this invention, the apo B secretion suppressing composition characterized by containing the said extract, and the VLDL secretion suppressing characterized by containing the said extract A composition is also mentioned as this invention. As an extract which has the amino acid of this invention, the extract (pax extract) extracted from green onion, for example is mentioned, As onion extract, onion extract, garlic extract, and chive extract are mentioned, for example.
    The composition according to the present invention (hereinafter referred to as 'the composition of the present invention') can be used as a food composition such as a pharmaceutical composition or a health food for animals including humans.
    The composition of the present invention varies depending on the condition of the taker such as age and weight, blood concentration of VLDL, and the like, but in general, 1 to 5000 mg per day for an adult in terms of the amino acid of the present invention or a physiologically acceptable salt thereof. It is suitable to take in the range of, preferably within the range of 100 to 2000 mg, more preferably within the range of 200 to 1500 mg. In some cases, even if it is below the range, it may be enough, and on the contrary, the capacity | capacitance beyond that range may be required. The number of daily doses of the composition of the present invention is preferably divided into 2 to 5 times. In addition, the composition of the present invention can be taken at any time before meals, between meals, and after meals, or can be taken with meals.
    The composition of the invention is in a form formulated in an amino acid of the invention or a physiologically acceptable salt thereof, or an extract having an amino acid of the invention as such or in a physiologically acceptable non-toxic or inert carrier, such as 0.01% It can be contained in the range of -99.5%, preferably in the range of 0.5% to 90%.
    As the carrier, one or more types of solid, semisolid, or liquid diluents, fillers, and other prescription preparations can be used. The composition of the present invention may take any form such as powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup and drop. In some cases, it may take the form of an injection.
    Hereinafter, the present invention will be described in more detail with reference to test examples.
    Test Example 1 Action of Lowering MTP Activity
    Six groups of SD rats weighing about 200 g were given 20 mg or 60 mg of the hydrochloride salt of the amino acid of the present invention dissolved in 10 ml of water three times a day for two weeks. The liver is then extracted and the liver is homogenized with buffer (50 mM Tris pH 7.4), 50 mM potassium chloride, 1.5 mM EDTA, leupesin (5 μg / mL) and 2 mM phenylmethylsulfonyl ), And centrifuged to make a liver homogenate. After adjusting with the said homogenization buffer so that the liver homogenate liquid might become the protein concentration of about 2 mg / mL, 1 part deoxycholate solution (0.56%, PH 7.5) was added to 10 parts homogenization liquid. MTP was released from the microsome fraction by reaction at 4 ° C for 30 minutes. Thereafter, the membrane fraction was removed by centrifugation to obtain a supernatant. The supernatant was diluted with Tris buffer (buffer containing 15 mM Tris, pH 7.4, 40 mM NaCl, 1 mM EDTA, 0.02% NaN 3 ), and the buffer was dialyzed overnight at 4 ° C. The dialysis solution was analyzed according to the method of JR Wetterau et al. (Science, 258, 999 (1992)) to measure the activity of MTP. The results are shown in Table 1.
    MTP ActivityMTP Activity (%) Control9.09 ± 1.0 Cycloaliin HCl, 20 mg6.12 ± 0.7 * Cycloaliin HCl, 60 mg4.92 ± 1.0 * S-methyl-L-cysteine HCl, 60 mg5.68 ± 0.6 * S-Methyl-L-cysteine sulfoxide HCl, 60 mg5.43 ± 0.6 * *: p <0.05 (Duncan multiple comparison test)
    From Table 1, it is clear that the amino acid salt of the present invention significantly lowers the activity of MTP.
    Test Example 2 Action to Suppress Secretion of Apo B (1)
    HepG2 cells (100 × 10 4 / dish) were seeded in 3.5 cm dishes and pre-cultured in 1 ml DME (containing 10% FCS) medium per dish. After preculture, cells were washed twice with DME medium and incubated for 24 hours under the conditions of 37 ° C., 95% air, 5% carbon dioxide by addition of test medium. The test medium was prepared by dissolving cycloaliin in dimethylsulfoxide and diluting with DME medium containing 1% BSA and 0.5 mM oleic acid so that the final concentration of cycloaliin was 10-6 M or 10-4 M.
    After incubation for 24 hours, the medium was recovered and the amount of Apo B secreted in the medium was measured by ELISA. Anti-human Apo B antibody (100-fold dilution) was put in 100 microliters of each well of the 96 well plate for ELISA, and incubated at 37 degreeC for 2 hours. Thereafter, 100 µL of Block Ace was added to each well, and the cells were incubated at 37 ° C for 2 hours. Each well was washed three times with PBS-Tween, and 100 μL of Apo B standard solution and HePG2 culture solution were added and incubated at 4 ° C. for 16 hours. Thereafter, each well was washed three times with PBS-Tween, and 100 μL of anti-human apo B-labeled antibody (200-fold dilution) was added thereto and incubated at 37 ° C. for 2 hours. Each well was washed three times with PBS-Tween, and then 100 μL of substrate solution was added thereto and incubated at 25 ° C. for 30 minutes. Thereafter, 50 µL of 4.5 MH 2 SO 4 was added to stop the reaction, and the secretion amount of Apo B was measured by measuring the absorbance at 482 nm. The results are shown in Table 2.
    Secretion of Apo BApo B secretion (μg / well) Control9.92 ± 0.80 Cycloaliin, 10 -6 M7.54 ± 1.13 * Cycloaliin, 10 -4 M7.67 ± 1.31 * *: p <0.01 (Duncan multiple comparison test)
    From Table 2, it is clear that cycloaliin significantly inhibits secretion of apo B.
    Test Example 3 Inhibition of Secretion of Apo B (2)
    HepG2 cells were incubated for 24 hours in DME medium containing 1% BSA, 0.5 mM oleic acid. Thereafter, it was exchanged with 1% BSA-DME medium containing 10 μM of the amino acid of the present invention and simultaneously 0.5 μci of [ 14 C] acetic acid was added. Cells and medium were recovered after 24 to 48 hours of culture. The recovered cells were homogenized by ultrasound and protein quantified, and then Apo B secretion was measured by ELISA. The results are shown in Table 3.
    Apo B secretion (ng / mg protein) After 24 hours of incubation (%)48 hours after incubation (%) Control2544 ± 425 (100)2080 ± 110 (100) S-methyl-L-cysteine2511 ± 173 (98.7)1906 ± 122 (91.6) S-ethyl-L-cysteine2390 ± 615 (93.9)994 ± 111 (47.8) S-n-propyl-L-cysteine2157 ± 86 (84.8)555 ± 23 (26.7)
    Test Example 4: Action to inhibit the secretion of TG
    HepG2 cells were incubated for 24 hours in DME medium containing 1% BSA, 0.5 mM oleic acid. Thereafter, it was exchanged with 1% BSA-DME medium containing 10 μM of the amino acid of the present invention and simultaneously 0.5 μci of [ 14 C] acetic acid was added. Cells and medium were recovered after 24 hours of culture. The recovered cells were homogenized by ultrasound, and the protein was quantified, and then the amount of triglyceride (TG) was measured from the amount of label lipid in the medium. The results are shown in Table 4.
    TG secretionTG secretion ([ 14 C] dpm × 10 -2 / mg protein) Control161.2 ± 2.2 S-methyl-L-cysteine128.2 ± 14.6 S-ethyl-L-cysteine102.2 ± 7.1 S-n-propyl-L-cysteine99.0 ± 9.3 S-n-propyl-L-cysteine sulfoxide105.8 ± 18.9 DL-methionine sulfoxide72.1 ± 8.5
    Since the composition of the present invention can lower the activity of MTP involved in VLDL biosynthesis and can suppress the secretion of apo B, the secretion of VLDL into the blood can be suppressed.
    权利要求:
    Claims (21)
    [1" claim-type="Currently amended] An MTP deactivation composition characterized by containing a sulfur-containing amino acid represented by the following formula [I] or [Ia] or a physiologically acceptable salt thereof:
    [Formula I]
    Formula Ia

    In formulas [I] and [Ia], R 1 represents H, alkyl or alkenyl, R 2 , R 3 represents the same or different, and H, alkyl or acyl, and R 4 , R 5 represents the same or different. Which represents H or alkyl, R 6 represents H, alkyl or acyl, p represents 0 or 1, q represents 0 or 1, and r represents an integer of 1-3.
    [2" claim-type="Currently amended] R 1 is straight alkyl of 1 to 4 carbon atoms or straight alkenyl of 2 to 4 carbon atoms, R 2 , R 3 are the same or different, H or straight acyl of 2 to 4 carbon atoms, R 4 is H , R 5 is straight alkyl having 1 to 4 carbon atoms, R 6 is H or straight acyl having 2 to 4 carbon atoms, p is 0 or 1, q is 0 or 1, and r is 1 or 2 A composition containing a sulfur-containing amino acid or a physiologically acceptable salt thereof represented by the formula [I] or [Ia] described in claim 1, wherein the composition contains a reduced activity of MTP.
    [3" claim-type="Currently amended] R 1 is methyl, ethyl, propyl, butyl, allyl or 1-propenyl, R 2 is H, R 3 is H or acetyl, R 4 is H, R 5 is methyl, ethyl, propyl or butyl Or a sulfur-containing amino acid represented by the formula [I] or [Ia] according to claim 1, wherein R 6 is H or acetyl, p is 0 or 1, q is 0 or 1, and r is 1 or 2. MTP activity lowering composition, characterized in that it contains a physiologically acceptable salt thereof.
    [4" claim-type="Currently amended] Sulfur-containing amino acids represented by the general formula [I] or [Ia] are cycloaliin, S-methyl-L-cysteine, S-ethyl-L-cysteine, S-propyl-L-cysteine, DL-methionine, and DL- Formula [I] according to claim 1, which is ethionine, S-methyl-L-cysteine sulfoxide, S-ethyl-L-cysteine sulfoxide, S-propyl-L-cysteine sulfoxide or DL-methionine sulfoxide Or a sulfur-containing amino acid represented by [Ia] or a physiologically acceptable salt thereof.
    [5" claim-type="Currently amended] An MTP deactivation composition comprising an extract having a sulfur-containing amino acid according to any one of claims 1 to 4.
    [6" claim-type="Currently amended] The composition for lowering MTP activity according to claim 4, wherein the extract having the sulfur-containing amino acid according to any one of claims 1 to 4 is a leek extract.
    [7" claim-type="Currently amended] 6. The composition of claim 5, wherein the leek extract is an onion extract, garlic extract or chive extract.
    [8" claim-type="Currently amended] An apo B secretion inhibiting composition comprising the sulfur-containing amino acid according to claim 1 or a physiologically acceptable salt thereof.
    [9" claim-type="Currently amended] An apo B secretion inhibiting composition comprising the sulfur-containing amino acid according to claim 2 or a physiologically acceptable salt thereof.
    [10" claim-type="Currently amended] An apo B secretion inhibiting composition comprising the sulfur-containing amino acid according to claim 3 or a physiologically acceptable salt thereof.
    [11" claim-type="Currently amended] An apo B secretion inhibiting composition comprising the sulfur-containing amino acid according to claim 4 or a physiologically acceptable salt thereof.
    [12" claim-type="Currently amended] An apo B secretion inhibiting composition comprising an extract having a sulfur-containing amino acid according to any one of claims 1 to 4.
    [13" claim-type="Currently amended] 13. The apo B secretion inhibiting composition according to claim 12, wherein the extract having the sulfur-containing amino acid according to any one of claims 1 to 4 is a leek extract.
    [14" claim-type="Currently amended] 14. Apo B secretion inhibitory composition according to claim 13, wherein the leek extract is an onion extract, garlic extract or chive extract.
    [15" claim-type="Currently amended] A VLDL secretion inhibiting composition comprising the sulfur-containing amino acid according to claim 1 or a physiologically acceptable salt thereof.
    [16" claim-type="Currently amended] A sulfur-containing amino acid or a physiologically acceptable salt thereof according to claim 2, wherein the VLDL secretion inhibiting composition is contained.
    [17" claim-type="Currently amended] A VLDL secretion inhibiting composition comprising the sulfur-containing amino acid according to claim 3 or a physiologically acceptable salt thereof.
    [18" claim-type="Currently amended] A VLDL secretion inhibiting composition comprising the sulfur-containing amino acid according to claim 4 or a physiologically acceptable salt thereof.
    [19" claim-type="Currently amended] A VLDL secretion inhibiting composition comprising an extract having a sulfur-containing amino acid according to any one of claims 1 to 4.
    [20" claim-type="Currently amended] 20. The VLDL secretion inhibiting composition according to claim 19, wherein the extract having the sulfur-containing amino acid according to any one of claims 1 to 4 is an allium extract.
    [21" claim-type="Currently amended] 21. The VLDL secretion inhibiting composition according to claim 20, wherein the leek extract is an onion extract, garlic extract or chive extract.
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    同族专利:
    公开号 | 公开日
    EP1080724A4|2004-06-23|
    WO1999061015A1|1999-12-02|
    CA2332511A1|1999-12-02|
    EP1080724A1|2001-03-07|
    AU3170699A|1999-12-13|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-05-22|Priority to JP98-141176
    1998-05-22|Priority to JP14117698
    1999-04-16|Application filed by 니뽄 신야쿠 가부시키가이샤
    1999-04-16|Priority to PCT/JP1999/002023
    2001-03-26|Publication of KR20010025074A
    优先权:
    申请号 | 申请日 | 专利标题
    JP98-141176|1998-05-22|
    JP14117698|1998-05-22|
    PCT/JP1999/002023|WO1999061015A1|1998-05-22|1999-04-16|Mtp activity-lowering compositions|
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