WO1994019347A1 - Remede contre l'arteriosclerose - Google Patents

Remede contre l'arteriosclerose Download PDF

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Publication number
WO1994019347A1
WO1994019347A1 PCT/JP1994/000274 JP9400274W WO9419347A1 WO 1994019347 A1 WO1994019347 A1 WO 1994019347A1 JP 9400274 W JP9400274 W JP 9400274W WO 9419347 A1 WO9419347 A1 WO 9419347A1
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Prior art keywords
group
thiazolidine
carbon atoms
hydrogen atom
dione
Prior art date
Application number
PCT/JP1994/000274
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English (en)
Japanese (ja)
Inventor
Teiki Iwaoka
Fumiko Tabata
Takao Yoshioka
Teiichiro Koga
Keijiro Saku
Original Assignee
Sankyo Company, Limited
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 Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU61147/94A priority Critical patent/AU6114794A/en
Publication of WO1994019347A1 publication Critical patent/WO1994019347A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an agent for preventing and / or treating arteriosclerosis containing a thiazolidine derivative as an active ingredient.
  • Arteriosclerosis is roughly classified into atherosclerosis (atherosclerosis), Monkeberg-type arteriosclerosis (media sclerosis), and atherosclerosis, and of these, atherosclerosis (atherosclerosis) in particular.
  • Sclerosis occupies an important place.
  • Atherosclerosis (porgy) arteriosclerosis mainly involves the accumulation of plaques called atheroma on the inner wall of the heart artery or the lining of the blood vessels, resulting in hardening and weakening of the aorta, and eventually bleeding due to destruction of blood vessels. To death. It is called atherosclerosis or atherosclerosis because the inner wall of blood vessels becomes plaque.
  • Glavind et al. Acta Pattiol. Microbiol. Scand., Vol. 20, p. 1 (1952) reported that there is a proportional relationship between the severity of arteriosclerosis and the mass of lipid peroxide in atheroma. The causal relationship between oxidation and arteriosclerosis has been actively discussed.
  • Yoshioka et al. For example, have shown that substituted phenols and thiazolidine derivatives have a blood glucose lowering effect and a serum lipid and serum lipid peroxide lowering effect, and describe the relationship between the effects of atherosclerosis (Yoshioka Et al., J. Med. Chem., 32, 421 (1989)). Recently, Goldstein et al. ( ⁇ Cell Biol., 82, 597 (1979); Sci. Am., 251, 52 (1984)) and Steinberg 6 (New Engl. J. ed., 320, Pp.
  • LDL oxidized low-density lipoprotein
  • the present inventors have studied for the purpose of preventing and / or treating arteriosclerosis, and as a result, have found a thiazolidine derivative as a compound that inhibits oxidative peroxidation of LDL, and furthermore, the derivative has an excellent effect in animal tests. And completed the present invention.
  • the present invention has the general formula
  • R 1 , R 2 , R 4 and R 5 are the same or different and each represent a hydrogen atom or a lower alkyl group.
  • R 3 has a hydrogen atom, a fatty acid group, a substituted group,
  • the present invention relates to a prophylactic and / or therapeutic agent for arteriosclerosis comprising as an active ingredient a thiazolidine derivative or a pharmacologically acceptable salt thereof having an aromatic acyl group or a lower alkoxycarbonyl group.
  • R 1 represents a lower alkyl group
  • the alkyl group may be, for example, a straight chain such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, and pentyl;
  • examples of the alkyl group include linear or branched carbon atoms having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pentyl. , Preferably 1 to 3, most preferably methyl.
  • examples of the acryl group include linear or branched carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, bentanoyl, hexanoyl, and heptanyl. To 7, preferably 1 to 4, most preferably acetyl.
  • examples of the acyl group include benzoyl, 4-122 benzoyl, 3-fluorobenzoyl, and 2-fluorobenzoyl.
  • Aromatic acyl having 7 to 11 carbon atoms optionally having 1 to 3 nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, hydroxy, etc.
  • R 3 represents a lower alkoxycarbonyl group
  • alkoxycarbonyl group examples include straight-chains such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl. Examples thereof include linear or branched carbon atoms having 2 to 7, preferably 2 to 4, and most preferably ethoxycarbonyl.
  • R 4 represents a lower alkyl group
  • alkyl group examples include linear or branched carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and pentyl. From 5 to 5, from i to 4, most preferably methyl, t-butyl, especially methyl.
  • the compound having the above general formula (I) of the present invention can be used in the form of a pharmaceutically acceptable non-toxic salt.
  • examples of such salts include salts with alkali metals such as sodium and potassium; alkaline earth metals such as calcium; basic amino acids such as lysine and arginine.
  • the compound having the general formula (I) has a basic group, it can be used in the form of a pharmacologically acceptable non-toxic acid-containing caro salt.
  • salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, succinic acid, maleic acid, fumaric acid, apple And organic acids such as acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, and methanesulfonic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid
  • acetic acid succinic acid
  • maleic acid fumaric acid
  • apple And organic acids such as acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, and methanesulfonic acid.
  • the carbon atoms at the 2-position of the chroman ring and the 5-position of the thiazolidine ring are asymmetric carbon atoms, and the stereoisomers based on these are also the present invention. Included in the compound of
  • R 1 represents a linear or branched lower alkyl group having 1 to 4 carbon atoms
  • R 2 represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms
  • R 3 is a hydrogen atom, a linear or branched aliphatic acyl group having 1 to 4 carbon atoms, an aromatic acyl group having 7 to 11 carbon atoms having no substitution, or linear Or a branched lower alkoxycarbonyl group having 2 to 4 carbon atoms;
  • R represents a linear or branched lower alkyl group having 1 to 4 carbon atoms
  • R 5 represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms.
  • R 1 represents a linear or branched lower alkyl group having 1 to 4 carbon atoms
  • R 2 represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms
  • R 3 represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group
  • R 4 represents a linear or branched lower alkyl group having 1 carbon atom
  • R 5 represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms.
  • R 1 represents a methyl group
  • R 2 represents a hydrogen atom or a methyl group
  • R 3 represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group
  • R 4 represents a methyl group or a t-butyl group
  • R 5 represents a hydrogen atom or a methyl group.
  • the compound having the general formula (I) of the present invention is a known compound and described in, for example, JP-A-60-51189, US Pat. No. 4,572,912, and European Patent 0139421.
  • the compound having the above general formula (I) of the present invention is used as it is or in the form of a pharmaceutically acceptable salt thereof.
  • human LDL is prepared by a conventional ultracentrifugation method ( ⁇ L. Goldstein et al., Methods in Enzraolog, 98, 241 (1983)). That is, the human blood is allowed to stand for a certain period of time, and then subjected to centrifugation at a low temperature and a low rotation speed for a certain period of time to obtain a serum. Add a specific gravity such as sodium chloride or sodium bromide to the obtained serum, and subject it to ultra-high-speed centrifugation at low temperature and high rpm for a certain period of time. Then, the lower layer of serum and high-density riboprotein (hereinafter referred to as “HDL”) are separated.
  • HDL high-density riboprotein
  • the specific gravity of the obtained LDL and HDL is adjusted again with a specific gravity adjusting agent such as potassium bromide or sodium bromide. Then, it is subjected to ultra-high-speed centrifugation for a certain period of time under low temperature and high rotation speed conditions, and the LDL of the upper layer of the obtained serum is collected.
  • the dialysate is dialyzed for a certain period of time against a saline solution containing a chelating agent such as ethylenediamine disodium salt (EDTA-2Na) and a physiological saline solution containing a ⁇ ⁇ ⁇ substance such as penicillin and streptomycin. Prepare an LDL sample for the experiment.
  • a specific gravity adjusting agent such as potassium bromide or sodium bromide.
  • a low-concentration solution of the test drug is prepared and then evaporated to dryness to form a film-like drug layer.
  • This is subjected to an oxidation reaction using an oxidizing agent such as Cu "or Fe 3+, and the T BARS (thiobarbituric acid reaction positive substance) value after the reaction is determined by a photometric method (Yagi et al., Vitamin, Volume 37, 105).
  • Page (1968) Furthermore, heme with a high-performance liquid chromatograph (High Performance Liquid Chroraatograph) is used. , Lipid peroxide research, 16 Vol. 1, No. 23, p.
  • the test drug is incorporated into the LDL, for example, by extracting the drug with an organic solvent such as black form and confirming it by high performance liquid chromatography.
  • an organic solvent such as black form
  • high performance liquid chromatography For example, the fact that LDL is not denatured by the drug solubilization operation is determined by electrophoresis (FT Hatch et al., Adv. Lip. Res., 6, 1 (196S)), gel filtration chromatography (FTHatch Adv. Lip. Res., Vol. 6, p. 1 (1968)).
  • Egret LDL The preparation of Egret LDL is performed in accordance with the preparation of the human LDL described above, and an experimental Egret LDL sample is prepared. Next, solutions of various concentrations of the test drug are prepared, and this is added to the WH ⁇ 1 cattle sample. This is subjected to an oxidation reaction using an oxidizing agent such as Cu 2+ , Fe 3t, etc., and the T BARS (thiobarbituric acid reaction positive substance) value after the reaction is measured by a fluorescence method (Yagi et al., Vitamin, 37, 105 pages) (1968))
  • the effect of suppressing macrophage foaming is measured by the following method. That is, intraperitoneal macrophages were detected from ddy mice (Edeison et al., In Vitro Methods in Cell-Mediated & Tumor Immunity, eds. Bloon, BR & David, ⁇ R. (Academic, New York), p. 333 (1976 ))) Add the oxidatively modified LDL and 14 C monoleic acid, and measure the amount of “C-cholesteryl ester produced in the cells.
  • WHHL rabbits are arbitrarily divided into a control group and a treatment group, and a standard feed is administered to the control group, and a mixed feed containing a drug is administered to the treatment group for a certain period.
  • the animals in the control group and the administration group are sacrificed, the aorta from the bow to the abdomen is taken, and the ratio of the total area of arteriosclerosis in the control group and the administration group is determined, and the anti-arterial effect can be observed.
  • the compound of the present invention having the above general formula (I) or the drug S ⁇ acceptable salt thereof has an excellent action of suppressing the oxidation of LDL and Z or peroxidation, and is actually effective in animal tests. Atherosclerosis was shown. Moreover, it is a compound having low toxicity.
  • the compound of the present invention having the general formula (I) or a pharmaceutically acceptable compound thereof Salts are useful as prophylactic and therapeutic agents for or against atherosclerosis, especially atherosclerosis.
  • the compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is administered in various forms.
  • the administration form include oral administration by t3 ⁇ 4, capsule, granule, powder, syrup, etc. or parenteral administration by injection (intravenous, intramuscular, subcutaneous), drip, suppository, etc. Can be.
  • These various preparations are commonly used in the pharmaceutical formulation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, turbidity agents, coating agents, etc. in the main drug according to the usual method. It can be formulated using known adjuvants. The amount used depends on the symptoms, age, body weight, administration method and dosage form, but usually 50 to 500 mg / day can be administered to an adult.
  • the preparation of human LDL is separated by ultracentrifugation using a conventional method, J.L. Goldstein et al. (J.L. Goldstein et al., Methods in Enz molog, 98, 241 (1983)). That is, 180 ml of human blood was allowed to stand for 2 hours, and then centrifuged at 4 and 3000 rpm for 15 minutes to obtain serum. The resulting serum was adjusted to a specific gravity of 1.019 by adding a bromide reamer, and then subjected to ultracentrifugation at 4, 39,000 rpm for 20 hours. After the completion of the ultracentrifugation operation, LDL and HDL in the lower layer of the obtained serum were collected.
  • the obtained LDL and HDL were added with potassium bromide again to adjust the specific gravity to 1.063, and then subjected to ultra-high-speed centrifugation at 4, 39, 000 rpm for 24 hours. Next, the LDL of the upper layer of the obtained serum was collected. Then, ethylenediamine 'disodium salt
  • Experimental human LDL samples were prepared by dialysis for 24 hours using a dialysate consisting of (EDTA-2Na) and a saline solution containing benicillin and streptomycin. Next, the test drug was dissolved in acetonitrile solution that was muted to a final drug concentration of 0.3 mM.
  • Created. Add 1.0 ml of the experimental human LDL sample to the film-like drug layer described above.
  • the test drug was solubilized in the above-mentioned LDL sample by ultrasonic dispersion at 20 ° C. for 10 minutes using a water tank type ultrasonic cleaner (Bransonic 220, manufactured by Daiwa Kagaku Co., Ltd.).
  • Lipid peroxide value was measured by Iwaoka et al. (Iwaoka et al., Lipid Peroxide Research, Vol. 16, No. 1, p. 23 (1992)). That is, reversed-phase high-performance liquid chromatography (separation column: octadecylsilylated silica gel (0DS), eluent: methanol / butanol (1: 1), flow rate: l ml / min) and normal-phase high-performance liquid chromatography (Separation column: silica gel, eluent: methanol / acetonitrile water (45: 50: 5), flow rate: 1 ml, min) and quantification was performed.
  • the incorporation of the test drug into the LDL is first determined by the gel-based chromatographic method of FTHatch et al. (FT Hatch et al., Adv. Lip. Res., Vol. 6, p. 1 (1968)). Isolated. That is, the gel was simply subjected to gel chromatography (gel-based column: Superrose 6, eluent: 0.15N aqueous sodium chloride solution containing 0.01% ethylenediamine-disodium salt and 0.02% sodium azide). Released. Next, the drug was extracted from the obtained LDL using a chromate form and confirmed by high performance liquid chromatography.
  • the drug was detected by reverse phase high performance liquid chromatography (separation column: octadecylsilylated silica gel (0DS), eluent: methanol, 1 ml / min).
  • electrophoresis method of FTHatch et al. FTHatch et al., Adv. Lip. Res., Vol. 6, p. 1 (1968)
  • LDL was not denatured by the drug solubilization operation. That is, a single band was confirmed by agarose gel electrophoresis using an agarose gel as a base material.
  • the gel permeation chromatography method of FTHatch et al was confirmed by the gel permeation chromatography method of FTHatch et al.
  • Table 2 shows the results of the inhibitory action on LDL oxidation / peroxidation.
  • the inhibition rate (%) by the T BARS value and the inhibition rate (%) by the lipid peroxide value were calculated from the following equations, respectively.
  • T BARS value (%) ⁇ (T BARS value in the absence of drug-T BARS value in the presence of drug) Z TBARS value in the absence of drug ⁇ x 100
  • Inhibition rate by lipid peroxide level (%) ⁇ (lipid peroxide value in the absence of drug-lipid peroxide value in the presence of drug) lipid peroxide value in the absence of drug ⁇ X 100
  • Human LDL was prepared by a conventional method, ultracentrifugation by J.L. Goldstein et al. (Pashi Goldstein et al., Methods in Enzymology, 98, 241 (1983)). That is, it was prepared and prepared in the same manner as in Example 1.
  • test drug is treated with an acetate solution or a solution prepared at a final drug concentration of 0.03, 0.1, 0.3, 1.0, 3.0, 10.0, 30.0, 100.0, 300.0 "M.
  • the evening solution was evaporated to dryness under a stream of nitrogen to form a film-like drug layer on the vessel wall.
  • 200 PI of 0.9% saline (Otsuka Pharmaceutical Co., Ltd.) was added and shaken to confirm that there was no drug layer on the vessel wall.
  • 0.5 mg protein / ml human LDL 400 "1 was added, and the mixture was subjected to ultrasonic treatment at about 20 ° C for 10 minutes to solubilize the drug in LDL.
  • the TBARS value is an index of oxidation of LDL
  • the lipid peroxide value is an index of oxidation of LDL lipid (Naito, Atherosclerosis, Vol. 18, No. 1, p. 33 (1990)).
  • Table 3 shows the results of the action of suppressing LDL oxidation / peroxidation.
  • ⁇ 1 ⁇ 1 Egret 0 was performed by the method of FTHatch et al. (FTHatch et al., Adv. Li P. Res., Vol. 6, p. 1 (1968)). That is, blood was collected from WH HL ⁇ herons using EDTA at a final concentration of 5 mM as an anticoagulant to obtain plasma. Obtained The plasma thus obtained was adjusted to a specific gravity of 1.019 by adding a sodium bromide solution, and then subjected to ultracentrifugation at 39,000 rpm for 1 hour at 39,000 rpm. After the completion of the ultracentrifugation operation, the lower LDL and HDL fractions were collected.
  • a sodium bromide solution was added thereto to adjust the specific gravity to 1.063. C, subjected to ultracentrifugation at 39,000 rpm for 24 hours. After the completion of the ultracentrifugation operation, the upper LDL fraction was collected. Next, dialysis was performed at 4 ° C. using 10 mM phosphate buffer (pH 7.5) containing 150 m of sodium chloride to prepare an experimental WHH L ⁇ egret LDL sample.
  • test drug was dissolved in ethanol to obtain various final drug concentrations.
  • the degree of inhibition of T BARS formation by 50% was determined by a conventional method.
  • the TB ARS value is an index of oxidation of LDL as described above (Naito, Atherosclerosis, Vol. 18, No. 1, p. 33 (1990)).
  • Table 4 shows the results of the inhibitory action on LDL oxidation.
  • Macrophages were collected by the method of Edelson et al. (In Vitro Methods in Cell-Mediated & Tumor Immunity, eds. Bloon, BR David, JR (Academic, New York), p. 333 (1976)). That is, about 10 ml of a physiological saline solution containing heparin dissolved to a final concentration of 1 M / ml was injected into the peritoneal cavity of female ddy mice, and collected together with intraperitoneal macrophages. After physiological saline containing macrophages obtained from 20 to 40 mice was pooled, it was centrifuged at 400 xg, 4 ° C for 10 minutes.
  • DMEM Dulbece's modified Eagle's medium
  • FCS Fetal Calf Serum
  • FCS Fetal Calf Serum
  • the ( 14C- CE) fraction was separated.
  • Table 4 shows the results of the action of suppressing foaming of macrophages.
  • the aorta was divided into 10 sections from the aortic arch to the abdominal aorta.
  • the intima area and the media area where atheroma mainly existed were measured, and the ratio between them, that is, the area ratio of atherosclerotic lesions was determined.
  • Acute toxicity was measured according to standard methods.
  • the acute toxicity of the exemplified compounds Nos. 2, 3, 4, and 10 was 300 mg / kg or more in all cases after oral administration.
  • the powder of the above formulation was mixed and passed through a 20-mesh sieve. Then, 340 mg of this powder was placed in a No. 2 gelatin capsule to prepare a capsule.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de prophylaxie ou de traitement de l'artériosclérose contenant un dérivé de thiazolidine représenté par la formule générale (I), ou un sel pharmaceutiquement acceptable ce dernier, en tant que principe actif; formule dans laquelle R?1, R2, R4 et R5¿ représentent chacun indépendamment hydrogène ou alkyle inférieur; et R3 représente hydrogène, acyle aliphatique, acyle aromatique ou alcoxycarbonyle inférieur éventuellement substitués. Ce composé est utile pour la prophylaxie et/ou le traitement de l'artériosclérose.
PCT/JP1994/000274 1993-02-24 1994-02-23 Remede contre l'arteriosclerose WO1994019347A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61147/94A AU6114794A (en) 1993-02-24 1994-02-23 Arteriosclerosis remedy

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP3496393 1993-02-24
JP5/34963 1993-02-24
JP12105593 1993-05-24
JP5/121055 1993-05-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046238A1 (fr) * 1996-06-07 1997-12-11 Glaxo Group Limited Medicaments pour ameliorer l'activation des cellules endotheliales
EP0930076A1 (fr) * 1996-07-15 1999-07-21 Sankyo Company Limited Compositions medicinales

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6051189A (ja) * 1983-08-30 1985-03-22 Sankyo Co Ltd チアゾリジン誘導体およびその製造法
JPS6136284A (ja) * 1984-07-27 1986-02-20 Sankyo Co Ltd チアゾリジン誘導体およびその製造方法
JPS62234085A (ja) * 1985-12-18 1987-10-14 Sankyo Co Ltd チアゾリジン誘導体を有効成分とする糖尿病性合併症治療剤
EP0277836A1 (fr) * 1987-02-04 1988-08-10 Sankyo Company Limited Dérivés de la thiazolidinone leur préparation et leur application
EP0207581B1 (fr) * 1985-02-26 1990-09-12 Sankyo Company Limited Dérivés de thiazolidine, leur préparation et utilisation
JPH04159282A (ja) * 1990-10-19 1992-06-02 Sankyo Co Ltd チアゾリジン化合物
JPH04225978A (ja) * 1990-04-27 1992-08-14 Sankyo Co Ltd ベンジリデンチアゾリジン化合物
JPH05202042A (ja) * 1992-01-24 1993-08-10 Sankyo Co Ltd 糖尿病性合併症治療剤

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6051189A (ja) * 1983-08-30 1985-03-22 Sankyo Co Ltd チアゾリジン誘導体およびその製造法
JPS6136284A (ja) * 1984-07-27 1986-02-20 Sankyo Co Ltd チアゾリジン誘導体およびその製造方法
EP0207581B1 (fr) * 1985-02-26 1990-09-12 Sankyo Company Limited Dérivés de thiazolidine, leur préparation et utilisation
JPS62234085A (ja) * 1985-12-18 1987-10-14 Sankyo Co Ltd チアゾリジン誘導体を有効成分とする糖尿病性合併症治療剤
EP0277836A1 (fr) * 1987-02-04 1988-08-10 Sankyo Company Limited Dérivés de la thiazolidinone leur préparation et leur application
JPH04225978A (ja) * 1990-04-27 1992-08-14 Sankyo Co Ltd ベンジリデンチアゾリジン化合物
JPH04159282A (ja) * 1990-10-19 1992-06-02 Sankyo Co Ltd チアゾリジン化合物
JPH05202042A (ja) * 1992-01-24 1993-08-10 Sankyo Co Ltd 糖尿病性合併症治療剤

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046238A1 (fr) * 1996-06-07 1997-12-11 Glaxo Group Limited Medicaments pour ameliorer l'activation des cellules endotheliales
US6040322A (en) * 1996-06-07 2000-03-21 Glaxo Wellcome Inc. Medicaments for ameliorating endothelial cell activation
EP0930076A1 (fr) * 1996-07-15 1999-07-21 Sankyo Company Limited Compositions medicinales
EP0930076A4 (fr) * 1996-07-15 2001-10-04 Sankyo Co Compositions medicinales
US6610682B2 (en) 1996-07-15 2003-08-26 Sankyo Company, Limited Pharmaceutical compositions and methods for the treatment of arteriosclerosis

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