WO1998024453A1 - Medicaments pour la myelopathie - Google Patents

Medicaments pour la myelopathie Download PDF

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Publication number
WO1998024453A1
WO1998024453A1 PCT/JP1997/004477 JP9704477W WO9824453A1 WO 1998024453 A1 WO1998024453 A1 WO 1998024453A1 JP 9704477 W JP9704477 W JP 9704477W WO 9824453 A1 WO9824453 A1 WO 9824453A1
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WO
WIPO (PCT)
Prior art keywords
force
imino
sodium salt
lanosyl
bis
Prior art date
Application number
PCT/JP1997/004477
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English (en)
Japanese (ja)
Inventor
Kenji Okajima
Yuji Taoka
Yoji Ezure
Original Assignee
Nippon Shinyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Publication of WO1998024453A1 publication Critical patent/WO1998024453A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical

Definitions

  • the present invention relates to a preventive or therapeutic agent for spinal cord disorders and pathological conditions derived therefrom, comprising a Lewis-type sugar chain derivative as an active ingredient.
  • Sialyl Lewis X represented by the above structural formula is composed of tetrasaccharides of sialic acid, galactose, fucose, and N-acetyltilcosamine.
  • sialyl Lewis A in which fucose is bonded to the 4-position of N-acetylacetylcosamine and sialylgalactose is bonded to the 3-position, is also widely present in human tissues. These sugar chains exist as minor components on the cell surface and are involved in various cell activities.
  • inflammation and blood clot formation associated with inflammation, rheumatism, asthma, infectious diseases, immune diseases, AIDS, cancer, and other diseases are caused by the adhesion of white blood cells and cancer cells to vascular endothelial cells (cell adhesion) as one step. I do.
  • cell adhesion is mainly due to the ganglioside replacement paper present on the cell surface (Rule 26).
  • the compound according to the present invention inhibits cell adhesion of leukocytes by binding to selectin.
  • a patent application was filed as a prophylactic / therapeutic agent for rheumatism, asthma, and immune diseases (WO 93/15098).
  • applications such as International Publication WO94 / 05152 and International Publication WO95 / 04751 have been filed, and there are descriptions on anti-inflammatory agents, therapeutic agents for immunological diseases, and anti-cancer agents.
  • Lewis-type glycan derivatives are effective for the prevention and treatment of spinal cord disorders.Furthermore, there are no known preventive or therapeutic methods using Lewis-type glycan derivatives for spinal cord disorders. Not been.
  • the present invention provides a Lewis-type sugar chain derivative as a new or previously unknown novel preventive or therapeutic agent for spinal cord disorder (hereinafter referred to as a preventive or therapeutic agent).
  • Spinal cord injury is caused by spinal cord injury, spinal cord surgery, and spinal cord ischemia-reperfusion injury, resulting in severe sequelae and complications such as paralysis of motor function and impairment of spinal cord tissue.
  • paraplegia associated with surgery such as thoracic aortic aneurysm, thoracoabdominal aortic aneurysm, or dissecting aortic aneurysm requiring descending aortic blockade.
  • paraplegia develops, its prognosis and recovery are extremely poor, and the patient will be forced to undergo a new fighting illness with mental and physical distress.Prevention of postoperative paraplegia during the above surgery Greatest effort and great care is taken.
  • due to the diversity of blood circulation to the spinal cord its effects have not been sufficient.
  • composition comprising a compound represented by the following general formula or a pharmaceutically acceptable salt thereof as an active ingredient is effective in preventing and treating spinal cord disorders. It was found to be effective, and the invention was completed.
  • the present invention relates to a prophylactic / therapeutic agent for spinal cord disorders comprising a Lewis-type sugar chain derivative represented by the following general formula [I] as an active ingredient.
  • G is a hydroxyl group or acetamide
  • B is an oxygen atom or a nitrogen atom substituted with -A-R
  • one of L and E is fucoh.
  • the other is lanosyl, and the other is sialic acid (2 ⁇ 3).
  • Lanosil or Lactohi. Is lanosyl, and M represents hydrogen, a hydroxyl group, or tyrka'lactopyranoside (the bonding position is the 3-position).
  • A— is one (CH2) m—,-(CH2) n— NR e —CO— O—, — CO—O—, one (CH 2 ) n—CO—O—, -C 2 H 4 ( OC 2 H 4 ) p— OCH 2— C 0— 0—,
  • R a and R b are the same or different and each represents a linear or branched, saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated acyl group. ).
  • w and Y are different from each other, one represents galactopyranosyl and the other represents fucopyranosyl.
  • this galactobilanosyl the hydrogen atom of the 3-position hydroxyl group is
  • R e and R a are the same or different and each represents a lower alkyl, a lower alkenyl, or a hydroxyl group.
  • -A-R is the same as the above, or represents a combination of A and R, and each of which may be substituted, represents alkyl, alkenyl, alkynyl, alkoxycarbonyl, or aralkyl.
  • the Lewis-type sugar chain derivative according to the present invention includes a sialyl Lewis-type sugar chain derivative represented by either of the following general formulas [III] or [IV].
  • —A—R are taken together to form a straight-chain or branched-chain alkyl having 1 to 30 carbons, alkenyl having 3 to 30 carbons or 3 to 3 carbons.
  • Ring with alkynyl having 0, alkoxycarbonyl having 2 to 30 carbon atoms, alkoxyalkoxyalkyl having 3 to 30 carbon atoms, alkoxyalkoxyalkoxyamide alkyl having 5 to 30 carbon atoms, or alkoxy having 1 to 20 carbon atoms Represents benzyl which may be substituted.
  • V and Q are different from each other, one represents sialic acid (2 ⁇ 3) galactobilasyl and the other represents fucopyranosyl.
  • M represents a hydroxyl group or I tilka 'lactobilant' (bonding position is 3-position).
  • V and Q are the same as above.
  • examples of the “lower alkyl” include linear or branched ones having 1 to 6 carbon atoms. Representative examples include methyl, ethyl, propyl, isopropyl, butyl, Isobutyl and hexyl.
  • saturated or unsaturated aliphatic hydrocarbon includes linear or branched C1-C30, preferably linear C12-C20 alkyl or Alkenes can be mentioned, for example, pentyl, hexyl, octyl, decyl, dodecyl,
  • Replacement form Tetradecyl, palmityl, stearyl, icosanyl, docosanil, tetracosanil, hexacosanyl, octacosanil, isohexyl, 9-dodecenyl, 9-tetradecenyl, 9-hexadecenyl, 6-octadecenyl, oleyl, 9-docoenyl, 13-docoenyl , Y-linolenyl and ⁇ -linolenyl.
  • examples of the "saturated or unsaturated acyl” include straight-chain or branched-chain acyl having 1 to 30 carbon atoms, preferably straight-chain having 12 to 20 carbon atoms.
  • examples include: valeryl, isovaleryl, hexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoil, 6-octadecenoyl, 13-docosenoyl, arakidoyl, elaidyl, 9,12-noctadeyl.
  • examples of the “lower alkenyl” include straight-chain or branched-chain ones having 2 to 6 carbon atoms. Representative examples thereof include butyl, aryl, propyl, and isopropyl. , 2-butul, 2-pentyl and 2-hexenyl.
  • examples of the “alkyl” represented by ⁇ and R together include a linear or branched alkyl having 1 to 30 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and the like.
  • the alkyl represented by these A and R as ⁇ represents a C 2-6 acyl, a C 2-6 alkoxycarbonyl, a cyano, a lower alkyl group rubamoyl, a nitro, a C 2-6 carbon acylamino, a lower Alkylthio, hydroxyl, aryloxy with 6 to 8 carbon atoms, and replacement paper (Rule 26) Is a substituted or unsubstituted benzene ring, or one or more substituents such as a hydroxyl group, lower alkoxy having 1 to 6 carbon atoms, lower alkyl, halogen, cyano, lower alkyl group, rubamoyl, nitro, acylamino having 2 to 6 carbon atoms, lower alkylthio.
  • carboxy or phenyl lower alkyl examples thereof include propionylmethyl, norrelylethyl, vivapropylpropyl, methoxycarbonylbutyl, ethoxycarbonylpentyl, propoxycarbylhexyl, and 3- Cyanopropyl, methylcarbamoylethyl, propyl-lubamoylpentyl, 6-nitrohexyl, acetamidomethyl, butyrylaminoethyl, methylthiopropyl, ethylthiobutyl, propylthiopentyl, butylthiohexyl, 2- Droxityl, 2,3-dihydroxypropyl, 5-hydroxypentyl, 2,4,6-trihydroxyhexyl, 2-phenoloxybutyl, 4-phenoxybutyl, 6-phenoxyhexyl, P-trifluoromethylphenethyl 4- (m-dimethylaminophenyl)
  • alkyl represented by A and R together includes an alkyl substituted with a 5-membered unsaturated heterocyclic ring which is unsubstituted or substituted with lower alkyl.
  • a 5-membered unsaturated heterocyclic ring thiophene, furan, pyrrol and imidazole are preferred, and for example, furfuryl, 5-methyl-furfuryl, 2-tur and 5-methyl-2-tur are preferred.
  • examples of “alkenyl” represented by A and R as — include alkenyl having 3 to 30 carbon atoms, and are preferably aryl, oleyl, vaccenyl, linoleyl, and arachidonyl.
  • examples of the “alkyl” represented by A and R together include alkynyl having 3 to 30 carbon atoms.
  • examples thereof include 2-probyl, 3-butul, and 2-o replacement paper (Rule 26). ) Cutinyl, 9-decinyl, 9-octadecynyl, 9-pentacoshell and the like.
  • examples of “aralkyl” represented by A and R together include benzyl which may be substituted with alkoxy having 1 to 20 carbon atoms, such as methoxybenzyl, propoxybenzyl, and pentyl.
  • Preferred are hydroxybenzyl, heptoxybenzyl, nonyloxybenzyl, pendecyloxybenzyl, tridecyloxybenzyl, pentadecyloxybenzyl, heptadecyoxybenzyl, eicosiloxybenzyl and the like, with hexyloxybenzyl being particularly preferred.
  • a benzene ring is unsubstituted, or as at least one substituent, a hydroxyl group, a lower alkoxy having 1 to 6 carbon atoms, a lower alkyl, a halogen, a cyano, a lower alkyl.
  • substituents include carbamoyl, nitro, C2 to C6 acylamino, lower alkylthio or carboxy-substituted C7 to C20 phenyl lower alkyl.
  • m-methoxyphenyl, P-trifluoromethylphenethyl, 4- (m-dimethylaminophenyl) butyl, 5- (m-cyanophenyl) pentyl, 6- (p-pothamoylphenyl) ) Hexyl and 3- (2,4-dinitrophenyl) propyl are preferred, and (3,4-dihydroxyphenyl) propyl, (4-hydroxy-3-methoxyphenyl) propyl, P-methylbenzyl, m -Bromobenzyl, P-hexyloxybenzyl, m- (propionylaminomethyl) benzyl, P- (valerylaminoethyl) phenethyl, 4- (3-methylthio-4-hydroxyphenyl) butyl, P-carboxy Benzyl is preferred.
  • the compound according to the present invention can be used for treatment as it is, but can be used in the form of a pharmaceutically acceptable salt by a known method.
  • a pharmaceutically acceptable replacement sheet Salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, P-toluenesulfonic acid, benzenesulfonic acid And salts of organic acids such as ⁇ tansulfonic acid.
  • alkali metal salts such as lithium salt, sodium salt and potassium salt, magnesium salt, calcium salt, and barium salt Alkali earth metal salts can be mentioned.
  • the hydrochloride can be obtained by dissolving the compound of the present invention in an alcohol solution of hydrochloric acid.
  • ⁇ - (3- ⁇ -sulfo--D- is lactopyranosyl)-(1 ⁇ 4) - ⁇ - [( ⁇ -lefcohylanosyl)-(1 ⁇ 3)] -1,5-di'-doxy-, 5 -Imino- ⁇ -triacontyl -D- ⁇ '/ Resirenadium salt
  • Preferred compounds of the present invention include, for example,
  • the compound according to the present invention is, for example, a method described in Japanese Patent Application No. 8-155801, Japanese Patent Publication No. 59-43459, International Publication WO95 / 13068, Japanese Patent Application Laid-Open No. 61-205455, or the like. It can be manufactured according to.
  • the compounds according to the present invention have extremely low toxicity.
  • the compound of the present invention When the compound of the present invention is administered as a prophylactic / therapeutic agent for spinal cord disorders, it can be applied alone or in combination with or mixed with a drug that can be administered simultaneously.
  • the compound of the present invention is used as a pharmaceutical composition containing, for example, 0.01% to 99.5%, preferably 0.1% to 90%, as it is or in a pharmaceutically acceptable nontoxic and inert carrier. Can be administered.
  • the pharmaceutical compositions are desirably administered in unit dosage form.
  • the pharmaceutical composition of the present invention can be administered orally, intraosseously, topically (such as transdermally), or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods.
  • oral administration or intravenous administration is preferred.
  • Replacement form (Rule 26) It is desirable to adjust the dose as a therapeutic agent for spinal cord disorder in consideration of the patient's condition such as age, weight, etc., the administration route, the nature and extent of the disease, and the like.
  • the amount of the active ingredient per day is from 10 mg to:! Og Z day Z human, preferably from 100 mg to 5 gZ day human. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It is also desirable to administer the drug divided into two or three times a day.
  • solid or liquid dosage units such as powders, powders, fine granules, tablets, dragees, films, capsules, granules, suspensions, liquids, syrups, drops, sublingual tablets It can be done with other dosage forms.
  • Powders are prepared by comminuting the compound of the present invention to an appropriate degree. Powders are prepared by comminuting the compound of the present invention with a suitable finely divided material and then admixing it with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch and mannitol. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
  • Capsules are manufactured by first filling powdered powders, powders, or granules as described in the section on tablets as described above into a capsule shell such as a gelatin capsule.
  • Lubricants and superplasticizers such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene dalicol are mixed with the powder and then filled. You can also. Add disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose monocalcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, sodium carbonate. The effectiveness of the medicament when the capsule is taken can be improved.
  • the fine powder of the compound according to the present invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapped with a gelatin sheet to form a soft capsule.
  • Tablets are made by adding excipients to make a powder mixture, granulating or slugging, and then adding disintegrants or lubricants or by tableting the powder mixture directly.
  • Replacement Paper (Rule 26) You.
  • the powder mixture is prepared by mixing the appropriately powdered substance with the above-mentioned diluents and bases and, if necessary, binding agents (eg, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, poly).
  • Burpyrrolidone, polyvinyl alcohol, etc.), dissolution retarders (eg, paraffin, wax, hydrogenated castor oil, etc.), resorbents (eg, quaternary salts) and adsorbents (eg, bentonite, kaolin, dicalcium phosphate, etc.) ) May be used together.
  • the powder mixture can be first moistened with a binder such as syrup, starch paste, acacia, cellulose solution or polymer solution, stirred and mixed, dried and ground to form granules.
  • a binder such as syrup, starch paste, acacia, cellulose solution or polymer solution
  • the granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salts, talc, mineral oil and the like as a lubricant.
  • the lubricated mixture is then tableted.
  • the uncoated tablets thus produced can be coated with a film coating.
  • the compound according to the present invention may be directly tabletted after mixing with a fluid inert carrier without going through the steps of granulating and slugging as in J ⁇ .
  • a transparent or translucent protective coating consisting of a shellac sealing coating, or alternatively or on top of it, a coating of sugar or a polymeric material, and a polish coating of wax can also be used.
  • compositions such as solutions, syrups, elixirs and the like can also be presented in dosage unit form so that a given quantity contains a certain amount of the compound according to the invention.
  • Syrups are prepared by dissolving the compound of the present invention in an aqueous solution containing a suitable sweetening agent
  • elixirs are prepared by using a non-toxic alcoholic carrier.
  • Suspensions are formulated by dispersing the compound of the invention in a non-toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives eg, palmit oil, saccharin
  • flavoring agents eg, palmit oil, saccharin
  • replacement form (Rule 26)
  • dosage unit formulations for oral administration can be microencapsulated. The formulation can also provide an extended period of action or sustained release by coating or embedding in polymers, waxes and the like
  • Administration into tissues can be performed by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension.
  • a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection for example, a solution or suspension.
  • a fixed amount of the compound of the present invention is suspended or dissolved in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and the suspension or solution is sterilized. It is manufactured by Non-toxic salts or salt solutions may be added to make the injection solution isotonic.
  • Rectal administration can be carried out by preparing the compound of the present invention as a solid soluble or insoluble in water having a low melting point and using a suppository.
  • the tablets After weighing and mixing at a ratio of, the tablets are manufactured using a tableting machine.
  • mice Male Wistar rats (weight: 270-350 g) were used in the experiments. What. Under surgical anesthesia, a laminectomy of the 12th thoracic vertebra was performed using an anesthesia under anesthesia. A spinal cord compression ischemic injury model was prepared by compressing with a weight for 20 minutes. The compound of the present invention (15 mg / kg) dissolved in 5% cholesterol was injected into the vein 30 minutes before or 30 minutes after the compression injury. In the control group and leukocyte deprivation group, only 5% glucose was injected intravenously 30 minutes before the compression injury, and in the sham operation group, only laminectomy was performed.
  • the number of neutrophil infiltrates was calculated from the measurement of MFO activity.
  • the spinal cord tissue was removed from the thoracic vertebral region 3 cm after the injury up to 1 cm above the thoracic vertebra and immersed in ice-cooled 0.9% NaCl solution within 1 hour to measure MFO activity.
  • the tissue section was sonicated for 30 seconds in 20 mM phosphate buffer (pH 6.0) containing 9 volumes of 0.5% hexadecyltrimethylammonium (Pharmaphlomid (Sigma), and the tissue section was treated with 10% homogenate. did.
  • the homogenate was centrifuged (10,000 rpm, 20 min), and the obtained supernatant fraction was used as an enzyme solution.
  • the MPO enzyme reaction was started by adding 0.1 ml enzyme solution to a 0.6 ml mixture containing 0.1 M phosphate buffer (pH 6.0), 1.25 mg / ml o-dianisidine and 0.05% H 2 O 2 . .
  • the activity value was determined from the change in absorbance at 460 nm for 5 minutes after the start of the reaction.
  • Fig. 1 shows the results.
  • Damage from compression ischemia increased MFO activity by about 10-fold (vs. sham group) and caused neutrophil infiltration.
  • the compound of the present invention reduced the MPO activity to 1/3 of the injured group and suppressed neutrophil infiltration 30 minutes before the injury.
  • the number of neutrophils infiltrated in the leukocyte depleted group due to knight ⁇ -gen mustard was lower than that in the damaged group.
  • a rat is used as a replacement sheet (Rule 26) by using a plate on which a smooth surface of Raha'- is attached. We recorded and compared the maximum angle that we could rest on the board for 5 seconds without slipping down. Figure 3 shows the results.
  • the maximum angle at which the sham surgery group could rest on the ramp without slipping was about 53 degrees.
  • the temperature was reduced to 42 degrees, but in the group to which the compound of the present invention was administered, the angle was recovered to a maximum angle of 45 degrees or more in both the groups before and after the injury (P ⁇ 0.01). Also, the maximum angle was about 45 degrees in the leukocyte dead group.
  • the compound of the present invention inhibits leukocyte infiltration and has an excellent protective and ameliorating effect (preventive or therapeutic effect) on lower limb motor function paralysis due to spinal cord injury.
  • FIG. 1 is a graph showing the results of Test Example 1.
  • the vertical axis represents MPO activity (U / g).
  • FIG. 2 is a graph showing the results of Test Example 2.
  • the vertical axis is tall! ] Represents the score.
  • the score of ⁇ was evaluated according to the following criteria.
  • the number of animals in each group was 20 in the damaged group, 10 in the pre-administration group of the compound of the present invention, 10 in the group after administration of the compound of the present invention, and 10 in the leukocyte killed group.
  • FIG. 3 is a graph showing the results of Test Example 3.
  • the vertical axis represents the angle (°) of the inclined plate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Substances prophylactiques ou thérapeutiques contre la myélophatie, qui contiennent comme principe actif des dérivés de la chaîne glucidique de Lewis représentés par la formule générale (I), dans laquelle G représente hydroxy ou acétamide; B représente oxygène ou azote A-R-substitué; L ou E représente l'un fucosyle, l'autre galactopyranosyl-sialate (2→3) ou galactopyranosyl; et M représente hydrogène, hydroxy ou éthylgalactosyle en position 3.
PCT/JP1997/004477 1996-12-05 1997-12-05 Medicaments pour la myelopathie WO1998024453A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP32501596 1996-12-05
JP8/325015 1996-12-05

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WO1998024453A1 true WO1998024453A1 (fr) 1998-06-11

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis
JPH08502721A (ja) * 1992-04-03 1996-03-26 ジ・アップジョン・カンパニー 医薬的に活性な二環式‐複素環アミン
JPH08109134A (ja) * 1994-10-11 1996-04-30 Sanwa Kagaku Kenkyusho Co Ltd 細胞変成抑制並びに臓器毒性軽減剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis
JPH08502721A (ja) * 1992-04-03 1996-03-26 ジ・アップジョン・カンパニー 医薬的に活性な二環式‐複素環アミン
JPH08109134A (ja) * 1994-10-11 1996-04-30 Sanwa Kagaku Kenkyusho Co Ltd 細胞変成抑制並びに臓器毒性軽減剤

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