WO2004011516A1 - Nouveau compose ayant une activite hypocholesterolemiante - Google Patents

Nouveau compose ayant une activite hypocholesterolemiante Download PDF

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Publication number
WO2004011516A1
WO2004011516A1 PCT/JP2003/009643 JP0309643W WO2004011516A1 WO 2004011516 A1 WO2004011516 A1 WO 2004011516A1 JP 0309643 W JP0309643 W JP 0309643W WO 2004011516 A1 WO2004011516 A1 WO 2004011516A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
formula
integer
acid
Prior art date
Application number
PCT/JP2003/009643
Other languages
English (en)
Japanese (ja)
Inventor
Yukio Nagasaki
Kazunori Kataoka
Takehiko Ishii
Tohru Nakamura
Yoshiko Hamamichi
Original Assignee
Taisho Pharmaceutical 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 Taisho Pharmaceutical Co.,Ltd. filed Critical Taisho Pharmaceutical Co.,Ltd.
Priority to AU2003252724A priority Critical patent/AU2003252724A1/en
Publication of WO2004011516A1 publication Critical patent/WO2004011516A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent

Definitions

  • the present invention relates to a novel compound having a cholesterol lowering / suppressing action.
  • An object of the present invention is to provide a blood cholesterol lowering agent which is easy to take. Disclosure of the invention
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a polymer having a cationic functional group and a polyoxyethylene chain introduced into a polymer having a main chain of polyacrylic acid or polyacrylic acid.
  • the inventors have found that the compound exhibits a cholesterol lowering effect and is water-soluble, and has completed the present invention.
  • one embodiment of the present invention is a compound represented by the following formula (I):
  • R 1 and R 2 are the same or different and represent an alkyl group or an aryl group, R 3 represents a hydrogen atom or a methyl group, R 4 represents an alkoxy group, and k represents an integer of 1 to 6. And m represents an integer of 5 to 500, and n represents an integer of 3 to 100. ] Or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention is a cholesterol-lowering agent comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • FIG. 1 is a 1 H-NMR chart of compound (A).
  • FIG. 2 is a 1 H-NMR chart of compound (B).
  • FIG. 3 is a 1 H-NMR chart of compound (C).
  • FIG. 4 is a graph showing total cholesterol in plasma in a test example. BEST MODE FOR CARRYING OUT THE INVENTION
  • alkyl group in the definition of R 1 and R 2 represents a linear or branched alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, t-butyl group, pentyl group, isopentyl group, 1-ethylpropyl group and the like.
  • R 1 and R 2 is an alkyl group having 1 to 5 carbon atoms, a more preferred example is an alkyl group having 1 to 3 carbon atoms, and a particularly preferred example is a methyl group or an alkyl group. It is a tyl group.
  • R 3 represents a hydrogen atom or a methyl group, preferably methyl group.
  • R 4 is an alkoxy group having 1 to 5 carbon atoms, a more preferred example is an alkoxy group having 1 to 3 carbon atoms, and a particularly preferred example is a methoxy group.
  • k is an integer of 1 to 6, preferably 2 or 3, and more preferably 2.
  • m and n are integers of 1 or more, preferably, m is 5 to 5000, and n is 3 to 1000. More preferably, m is from 10 to: L 000 and n is from 10 to 500.
  • the polymerization degree (m and n) of the compound of the formula (I) of the present invention can be controlled by the molar ratio of the initiator, the molar ratio of the monomer, and the reaction temperature. Revision of Nikkan Kogyo Shimbun (1986)).
  • the “pharmaceutically acceptable salt” in the present invention includes, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, butyric acid, lactic acid, malic acid, cunic acid, Salts with organic acids such as tartaric acid, fumaric acid, maleic acid, p-toluenesulfonic acid and methanesulfonic acid, and salts with acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, butyric acid, lactic acid, malic acid, cunic acid
  • Salts with organic acids such as tartaric acid, fumaric acid, maleic acid, p-toluenesulfonic acid and methanesulfonic acid
  • salts with acidic amino acids such as aspartic acid
  • the compound of the formula (I) of the present invention can be produced by the following reaction formula.
  • a compound represented by the formula (V) (wherein RR 2 , R 3 and k have the same meanings as described above), for example, 2-dimethylaminoethyl methacrylate is added and polymerized. Terminate the polymerization reaction with a reaction terminator (eg, acid or alcohol).
  • a reaction terminator eg, acid or alcohol
  • reaction solution is dropped into a cooled poor solvent (for example, isopropyl alcohol) to precipitate the target compound, and the precipitate is dissolved in an appropriate good solvent (for example, tetrahydrofuran) and frozen. by drying to recover, compounds of formula (I) of interest (R ⁇ R 2, R 3 , R 4, k, m and n are defined as above.) is obtained.
  • a cooled poor solvent for example, isopropyl alcohol
  • an appropriate good solvent for example, tetrahydrofuran
  • the cholesterol-lowering agent of the present invention can be formulated into a liquid, a jelly or the like by utilizing the property of dissolving the compound of the formula (I) in water. Further, the compound of the formula (I) can be formulated as a solid by mixing it with a solid preparation which is dissolved at the time of use and a common solid preparation such as a tablet or powder. No special method is required for formulation, and each formulation can be prepared by an ordinary method.
  • the cholesterol-lowering agent of the present invention can be orally administered to an adult in an amount of 0.1 to 20 g once or several times a day.
  • the dose can be appropriately increased or decreased depending on age, body weight, symptoms and the like.
  • Carriers used for the preparation of preparations for internal liquids include surfactants such as sucrose fatty acid esters, polyoxyl stearate, polyoxyethylene polyoxypropylene glycols, polyoxyethylene monofatty acid esters, and synthetic aluminum gayate.
  • Thickeners such as magnesium, magnesium gayate, magnesium carbonate, magnesium oxide, magnesium metasilicate and organic acid and inorganic acid pH adjusters such as citrate buffer and phosphate buffer Yes, as well as solubilizers, buffers, preservatives, fragrances, Dyes, sweeteners and the like can be used.
  • Carriers used in the preparation of solid preparations include carriers such as lactose, starch, sugar, mannitol, crystalline cellulose, etc., binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, PVP, and carboxymethyl.
  • binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, PVP, and carboxymethyl.
  • disintegrants such as cellulose calcium and low-substituted hydroxypropylcellulose, lubricating agents such as magnesium stearate, hydrogenated castor oil, and talc.
  • dissolution aids, buffers, preservatives, flavors Dyes, flavoring agents and the like can be used.
  • the cholesterol-lowering agent of the present invention may optionally contain other active ingredients in addition to the above components within a range that does not impair the effects of the present invention.
  • the protonated solution was freeze-dried, and the recovered product was subjected to Soxhlet extraction for one day using the solvent THF to remove unreacted prepolymer.
  • Soxhlet extraction the polymer remaining on the filter was dissolved in methanol, the methanol was evaporated, then dissolved in water, lyophilized, and collected.
  • reaction solvent ⁇ (THF) 10 mL of a reaction solvent ⁇ (THF) and 0.016 mL of 2-methoxyethanol as a reaction starting material were added to an eggplant flask.
  • the reaction initiator was metallized by adding an equimolar amount of potassium naphthylene to obtain an initiator.
  • 1.2 mL of ethylene oxide was added, and the mixture was stirred at room temperature for 2 days to polymerize ethylene oxide.
  • Plasma samples were fasted from the morning of the blood collection day, and after 7 hours, the abdomen was incised under ether anesthesia, and EDTA blood was collected from the inferior vena cava. The collected blood was centrifuged at 3000 rpm / 4 ° C for 5 minutes to obtain plasma. Total cholesterol in the obtained plasma was measured using a clinical test kit (Cholesterol C-II-Test II Co .: Wako Pure Chemical Industries).
  • the compound of formula (I) of the present invention exhibited an excellent blood cholesterol lowering effect by adsorbing bile acids and cholesterol and promoting excretion in feces.
  • 5 quality against water Since it has a solubility of at least%, it can be formulated into a dosage form that is easy to take, such as a liquid preparation or a gel preparation. Furthermore, there is no roughness in the mouth even when blended in a solid preparation. Therefore, it has become possible to provide a cholesterol-lowering agent that has not been conventionally taken and is easy to take.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Obesity (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Graft Or Block Polymers (AREA)

Abstract

L'invention concerne un composé de la formule (I) dans laquelle R1 et R2 peuvent être identiques ou différents l'un de l'autre et ils représentent des groupes alkyle ou allyle, R3 représente un atome d'hydrogène ou un groupe méthyle, R4 représente un groupe alkoxy C1-5; n est un nombre entier de 3 à 1000, et un sel pharmaceutiquement actif dudit composé.
PCT/JP2003/009643 2002-07-30 2003-07-30 Nouveau compose ayant une activite hypocholesterolemiante WO2004011516A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003252724A AU2003252724A1 (en) 2002-07-30 2003-07-30 Novel compound having cholesterol lowering activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-221492 2002-07-30
JP2002221492A JP2006052236A (ja) 2002-07-30 2002-07-30 コレステロール低下作用を有する新規化合物

Publications (1)

Publication Number Publication Date
WO2004011516A1 true WO2004011516A1 (fr) 2004-02-05

Family

ID=31184863

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2003/009643 WO2004011516A1 (fr) 2002-07-30 2003-07-30 Nouveau compose ayant une activite hypocholesterolemiante

Country Status (3)

Country Link
JP (1) JP2006052236A (fr)
AU (1) AU2003252724A1 (fr)
WO (1) WO2004011516A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013781A1 (fr) * 1992-01-14 1993-07-22 Hisamitsu Pharmaceutical Co., Inc. Reducteur du taux de cholesterol
JPH05506880A (ja) * 1990-05-21 1993-10-07 スミス・クライン・アンド・フレンチ・ラボラトリース・リミテッド 化合物
JPH06192111A (ja) * 1992-12-25 1994-07-12 Sekisui Chem Co Ltd 経口コレステロール低下剤
JP2001288233A (ja) * 2000-04-06 2001-10-16 Shiseido Co Ltd 新規高分子およびこれを用いた化粧料

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05506880A (ja) * 1990-05-21 1993-10-07 スミス・クライン・アンド・フレンチ・ラボラトリース・リミテッド 化合物
WO1993013781A1 (fr) * 1992-01-14 1993-07-22 Hisamitsu Pharmaceutical Co., Inc. Reducteur du taux de cholesterol
JPH06192111A (ja) * 1992-12-25 1994-07-12 Sekisui Chem Co Ltd 経口コレステロール低下剤
JP2001288233A (ja) * 2000-04-06 2001-10-16 Shiseido Co Ltd 新規高分子およびこれを用いた化粧料

Also Published As

Publication number Publication date
JP2006052236A (ja) 2006-02-23
AU2003252724A1 (en) 2004-02-16

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