WO2014129513A1 - Agent de prévention ou de traitement de la colite ulcéreuse et nouveau dérivé de fullerène - Google Patents

Agent de prévention ou de traitement de la colite ulcéreuse et nouveau dérivé de fullerène Download PDF

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WO2014129513A1
WO2014129513A1 PCT/JP2014/053950 JP2014053950W WO2014129513A1 WO 2014129513 A1 WO2014129513 A1 WO 2014129513A1 JP 2014053950 W JP2014053950 W JP 2014053950W WO 2014129513 A1 WO2014129513 A1 WO 2014129513A1
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fullerene
coor
hydrogen atom
carbon atoms
carbon
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PCT/JP2014/053950
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Japanese (ja)
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匡彦 増野
知之 大江
堤　康央
吉岡　靖雄
和馬 東阪
修一 山名
央江 青島
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国立大学法人大阪大学
ビタミンＣ６０バイオリサーチ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates to a preventive or therapeutic agent for ulcerative colitis and a novel fullerene derivative.
  • IBD Inflammatory Bowel Disease
  • UC Ulcerative colitis
  • CD Crohn's disease
  • Ulcerative colitis is an inflammatory disease of the large intestine that causes erosions and ulcers on the mucous membrane of the large intestine. Occasionally, diarrhea with melena and frequent abdominal pain appear as characteristic symptoms.
  • the lesion has the property of spreading continuously from the rectum and ascending (oral), and at most it extends from the rectum to the entire colon.
  • the peak age of onset is 20-24 years for males and 25-29 years for females.
  • Possible causes include the involvement of enteric bacteria, the abnormal immune system that normally prevents the immune system that protects against external enemies, or the involvement of changes in dietary habits. Not.
  • Patent Document 3 discloses various fullerene derivatives having a pyrrolidine skeleton and the like. For example, a fullerene derivative having a 2,2-dicarboxypyrrolidine skeleton without an optical isomer is specifically described. It is not disclosed with support.
  • the present invention has been made in view of the circumstances as described above, and it is an object to provide a preventive or therapeutic agent for ulcerative colitis and a novel fullerene derivative that can be supplied at a low price with high safety and effectiveness. It is said.
  • the prophylactic or therapeutic agent for ulcerative colitis of the present invention has the following formulas (I) to (III) at least one of the adjacent bonded carbon atom pairs constituting the carbon cluster skeleton of fullerene. :
  • R 1 is a hydrogen atom, — (CH 2 ) l COOR a , or —CH ((CH 2 ) m COOR a ) 2 (wherein l represents an integer of 1 to 6, m represents an integer of 0 to 6, R a represents a hydrogen atom or a hydrocarbon group having 1 to 3 carbon atoms), and R 2 to R 5 each independently represents a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, or — (CH 2 ) n COOR b (n represents an integer of 0 to 6; R b represents a hydrogen atom or 1 to 3 carbon atoms; a hydrocarbon group.) shows a .R 1 ⁇ R 5 are, -COOH is 1 or more, the sum of -COOR a or -COOR b is selected to be 2 to 4.)
  • R 6 and R 7 each independently represent a hydrocarbon group having 1 to 16 carbon atoms
  • R 8 to R 11 each independently represent a hydrogen atom or a carbon number.
  • .X indicating a hydrocarbon group of 1 to 16 - contains fullerene derivatives and pharmaceutically acceptable salts of these pharmacologically having an organic bond structure represented by any one of an anion) as an active ingredient.
  • the fullerene derivative of the present invention has one of the adjacent bond carbon atom pairs constituting the fullerene carbon cluster skeleton represented by the following formula (IV):
  • a and B represent carbon atoms constituting the fullerene carbon cluster skeleton and bonded adjacent to each other, and R 12 is a hydrogen atom, — (CH 2 ) 1 COOH, or —CH ((CH 2 ) m COOH) 2 (wherein l represents an integer of 1 to 6 and m represents an integer of 0 to 6.)
  • R 13 and R 14 are both — (CH 2 ) n COOH (where n is 0 to 6).
  • R 15 and R 16 are both hydrogen atoms or both hydrocarbon groups having 1 to 3 carbon atoms).
  • the prophylactic or therapeutic agent for ulcerative colitis of the present invention is highly safe and effective and can be supplied at a low price.
  • Example 3 It is a graph which shows the measurement result by ELISA of the amount of TNF- ⁇ in the supernatant in Example 3 (RAW264.7 cells).
  • 4 is a graph showing the measurement results by ELISA of the amount of IL-6 in the supernatant after LPS action in Example 3.
  • 4 is a graph showing the measurement results by ELISA of the amount of TNF- ⁇ in the supernatant after LPS action in Example 3.
  • 4 is a graph showing the measurement results by ELISA of the amount of IL-1 ⁇ in the supernatant after LPS action in Example 3.
  • 4 is a graph showing the measurement result by ELISA of the amount of IP-10 in the supernatant after LPS action in Example 3.
  • Example 4 is a graph showing the results of ELISA measurement of the amount of IFN- ⁇ in the supernatant after LPS action in Example 3. It is the figure which showed the result which put together the result of Example 3 with the result of Example 1,2.
  • 6 is a graph showing the measurement results by ELISA of the amount of TNF- ⁇ in the supernatant after the action of Poly (I: C) in Example 4.
  • 6 is a graph showing the measurement results by ELISA of the amount of IL-6 in the supernatant after the action of Poly (I: C) in Example 4.
  • 6 is a graph showing measurement results of MPO activity in the large intestine extracted from mice in the DSS administration group and the non-administration group in Example 5.
  • Example 2 is a graph showing the measurement results (Compounds 7 to 12, Compound 3) of IL-8 amount in the supernatant after IL-1 ⁇ action in Example 6 (Caco2 cells). It is a graph which shows the measurement result of ROS in Example 7 (Caco2 cell). It is a graph which shows the measurement result by ELISA of the amount of IL-8 in the supernatant after IL-1 ⁇ action in Example 7 (Caco2 cells). 10 is a graph showing measurement results of MLR (mixed lymphocyte reaction) in Example 8.
  • MLR mixed lymphocyte reaction
  • the preventive or therapeutic agent for inflammatory bowel disease of the present invention is effective for fullerene derivatives having an organic binding structure represented by any one of the above formulas (I) to (III) and pharmacologically acceptable salts thereof. Contains as a component.
  • fullerene having a carbon cluster skeleton in the fullerene derivative examples include C 60 , C 70 , and a mixture of C 60 and C 70 . Further, it may contain higher fullerenes and the like.
  • Examples of the pharmacologically acceptable salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and salts with organic bases such as amine.
  • fullerene derivatives having an organic bond structure represented by the formula (I) compounds having one carboxyl group at the 2-position or 5-position of the pyrrolidine skeleton are disclosed in, for example, Patent Document 3 (Japanese Patent Application Laid-Open No. 2004-292443). It can synthesize
  • fullerene derivatives having an organic bond structure represented by the formula (I) other compounds and compounds having an organic bond structure represented by the formula (IV) were synthesized according to the methods of Examples described later. can do.
  • This fullerene derivative preferably has 1 to 2 organic bond structures, and more preferably 1 to eliminate regioisomers.
  • R 1 is a hydrogen atom, — (CH 2 ) l COOR a , or —CH ((CH 2 ) m COOR a ) 2
  • l represents an integer of 1 to 6
  • m is 0 to 6
  • R a represents a hydrogen atom or a hydrocarbon group having 1 to 3 carbon atoms, l is preferably 1 to 3
  • m is preferably 0 to 3
  • R a is a hydrocarbon group.
  • R 2 to R 5 are each independently a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, or — (CH 2 ) n COOR b (wherein n represents an integer of 0 to 6 and R b represents a hydrogen atom or a hydrocarbon group having 1 to 3 carbon atoms) n is preferably 0 to 3 and R 1 to R 5 Is selected so that one or more of —COOH and the sum of —COOR a and —COOR b is 2 to 4.
  • the hydrocarbon group for R b is preferably a linear or branched alkyl group, In particular, it is a linear alkyl group.
  • R 12 represents a hydrogen atom, — (CH 2 ) 1 COOH, or —CH ((CH 2 ) m COOH) 2 (l represents an integer of 1 to 6, and m represents 0 to 6 Indicates an integer.) l is preferably 1 to 3, and m is preferably 0 to 3.
  • R 13 and R 14 are both — (CH 2 ) n COOH (n represents an integer of 0 to 6), and R 15 and R 16 are both hydrogen atoms, or both have 1 to 3 hydrocarbon groups.
  • n is preferably 0 to 3, and the hydrocarbon group is preferably a linear or branched alkyl group, particularly a linear alkyl group.
  • the fullerene derivative having an organic bond structure represented by the formula (II) can be synthesized by the method described in Patent Document 3, for example.
  • This fullerene derivative preferably has 1 to 2 organic bond structures, and more preferably 1 to eliminate regioisomers.
  • the fullerene derivative having an organic bond structure represented by the formula (III) can be synthesized, for example, by the method described in Patent Document 3.
  • This fullerene derivative preferably has 1 to 2 organic bond structures, and more preferably 1 to eliminate regioisomers.
  • the hydrocarbon group of R 6 and R 7 , R 8 to R 11 is preferably a linear or branched alkyl group having 1 to 16 carbon atoms, particularly a linear alkyl group, and a linear alkyl group having 1 to 5 carbon atoms. Examples of the alkyl group include a linear alkyl group having 1 to 3 carbon atoms.
  • the anion X ⁇ as the counter ion of the quaternary amine salt may be any pharmacologically acceptable one. For example, halogen ions such as iodide ions, inorganic acid ions such as sulfate ions, etc. , Organic acid ions, complex ions, and the like.
  • the prophylactic or therapeutic agent for ulcerative colitis of the present invention can be in various pharmaceutical dosage forms depending on the purpose of treatment. Specifically, tablets, coated tablets, pills, powders, granules, capsules Oral preparations such as liquids, suspensions and emulsions, and parenteral preparations such as injections and suppositories. These administration agents can be formulated by a conventional formulation method generally known in this field using a pharmaceutically acceptable carrier or the like.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, corn starch, Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dry starch, sodium alginate, agar powder, laminaran powder, Disintegrating agents such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, lactose; white sugar, stearic acid, potassium Disintegration inhibitors such as butter and hydrogenated oils; Absorption promoters such as quaternary ammonium salts and sodium lauryl
  • excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; Disintegrants such as laminaran powder and kanteng powder can be used.
  • the capsules are prepared by mixing with various carriers exemplified above according to conventional methods and filling them into hard gelatin capsules, soft capsules, and the like.
  • oral liquids, syrups, elixirs and the like can be produced by a conventional method using a corrigent, a buffer, a stabilizer, a corrigent and the like.
  • examples of the flavoring agent include sucrose, orange peel, citric acid, and tartaric acid
  • examples of the buffering agent include sodium citrate
  • examples of the stabilizer include tragacanth, gum arabic, and gelatin.
  • polyethylene glycol, cacao butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic glyceride and the like can be used as a carrier.
  • solutions, emulsions and suspensions are preferably sterilized and isotonic with blood.
  • diluents such as water, aqueous lactic acid, ethyl alcohol, Propylene glycol, macrogol, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.
  • a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizing agent, buffer, soothing agent, etc. It may be added.
  • each of the above preparations may be blended with a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other medicines as necessary.
  • the administration method of the prophylactic or therapeutic agent for ulcerative colitis of the present invention is not particularly limited, and is appropriately determined according to various preparation forms, patient age, sex and other conditions, patient symptom degree, and the like.
  • tablets, pills, powders, granules, capsules, solutions, suspensions and emulsions are orally administered.
  • the injection is administered intravenously alone or mixed with a normal fluid such as glucose or amino acid, and further administered alone, if necessary, intraarterially, intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally.
  • the dosage of the active ingredient of the preventive or therapeutic agent for ulcerative colitis of the present invention can be appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease, and the like.
  • the fullerene derivative and pharmacologically acceptable salt thereof, which are the active ingredients of the present invention, can be used safely because of their low toxicity, and the dose is usually about 10 to 4000 mg / day, preferably 100. A guideline of ⁇ 1000mg / day is recommended.
  • the prophylactic or therapeutic agent for ulcerative colitis of the present invention as a preparation can be administered once a day or divided into about 2 to 4 times a day.
  • tert-Butyl glyoxylate (7) Di-tert-butyl tartrate (2.0 g, 7.6 mmol) was dissolved in 10 mL of methanol and sodium metaperiodate (1.5 g, 7.0 mmol, 0.9 equivalent) was dissolved in 5 mL of purified water. They were mixed and stirred at 0 ° C. for 60 minutes. The reaction solution was extracted three times with dichloromethane and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. 2.1 g of tert-butyl glyoxylate (7) was obtained as a yellow oily substance.
  • the target product was washed with 1M sodium hydrogencarbonate, water, and 1M hydrochloric acid in that order, suction filtered, dried under reduced pressure at 70 ° C for 1 hour, and then brown solid 2-carboxy-N-ethoxycarbonylmethyl-5-ethoxy-carbonylpyrrolidino [60] fullerene (9) 116 mg (120 ⁇ mol, yield 82%) were obtained (Table 12).
  • Caco2 cells human intestinal epithelial cell line
  • inflammatory cytokine IL-1 ⁇ 125 ng / mL
  • FIG. 1 shows the results of proline type fullerene derivative compound 3
  • FIG. 2 shows the results of compounds 1-6.
  • RAW264.7 cells were seeded in a 96-well microtiter plate, and after adding each fullerene or NAC, 30 ⁇ m later, LPS (lipopolysaccharide) 1 ⁇ g / mL was allowed to act. Supernatants were collected 24 hours later, and cytotoxicity was evaluated as described above. The result is shown in FIG.
  • Fullerene derivative compounds 1-5 showed little cytotoxicity to RAW264.7 cells.
  • LPS was allowed to act on compounds 1 to 6, and the production tendency of various cytokines and chemokines was evaluated.
  • RAW264.7 cells (mouse macrophage cell line) were seeded in a 96-well microtiter plate, each fullerene or NAC was added and incubated for 24 hours, and then the supernatant was collected and TNF- ⁇ in the supernatant was collected. The amount was evaluated by ELISA. The result is shown in FIG.
  • FIG. 7 shows the amount of interleukin-1 ⁇ (IL-1 ⁇ ).
  • FIG. 8 shows the results
  • FIG. 9 shows the results of measuring the amount of interferon- ⁇ -induced protein-10 (IP-10)
  • FIG. 10 shows the results of measurement of the amount of interferon- ⁇ (IFN- ⁇ ).
  • Example 3 The results of Example 3 are summarized in FIG. 11 together with the results of Examples 1 and 2.
  • compounds 1-5 of the fullerene derivative suggested an anti-inflammatory effect even when compared with hydroxylated fullerene.
  • the overall anti-inflammatory effects of compounds 1 to 5 when RAW264.7 cells were stimulated with LPS were determined as compound 3 (proline-type C 60 derivative) and compound 5 (malonic acid C) among compounds 1 to 5. 60 derivative) was good.
  • Example 4 RAW264.7 cells were seeded in a 96-well microtiter plate, and after addition of each fullerene or NAC, 30 ⁇ m later, Poly (I: C) (polyinosinic-polycytidylic acid) 20 ⁇ g / mL was allowed to act. After incubating for 24 hours, the supernatant was recovered, and the result of measuring the amount of TNF- ⁇ in the supernatant is shown in FIG. 12, and the result of measuring the amount of IL-6 in the supernatant is shown in FIG.
  • Poly (I: C) polyinosinic-polycytidylic acid
  • Example 5 An in vivo drug efficacy evaluation test for ulcerative colitis was performed using a DSS-induced mouse colitis model.
  • a wide variety of models have been devised for the study of inflammatory bowel diseases, including spontaneous colitis models, colitis models based on chemical and immunological mechanisms, and genetically modified colitis models.
  • the mouse colitis model is frequently used in studies for evaluating the efficacy of ulcerative colitis, and is a method of inducing colitis by allowing a mouse to drink a dextran sulfate sodium (DSS) solution.
  • DSS dextran sulfate sodium
  • ⁇ C57BL / 6J male mice purchased at 7 weeks of age were preliminarily raised for 1 week and randomly divided into 2 groups, one of which was used as a control group and the other as a DSS administration group.
  • DSS molecular weight 36,000-40,000, MP Biomedicals
  • a 0.5% DMSO solution 2.5 mg / kg of Compound 3 or a 0.5% DMSO solution was intraperitoneally administered at 10 mL / kg for 7 days.
  • mice On the final day, the mice were euthanized, and after removing the large intestine tissue, the MPO activity in the large intestine mucosa was measured, and the mean value ⁇ standard error for each group of the values obtained from 5 to 7 animals per group was calculated.
  • MPO Myeloperoxidase
  • FIG. 3 In the group administered with Compound 3 ("Proline-3" in the figure), it showed a tendency to suppress the production of MPO, which is an indicator of ulcerative colitis, suggesting that it suppresses infiltration of neutrophils and the like It was.
  • Example 6 The proline-type fullerene derivative compounds 7 to 12 were evaluated for drug efficacy using cytokine production as an index in the same manner as in Example 1. A proline-type fullerene derivative dissolved in DMSO was used, and the proline-type fullerene derivative Compound 3 was also evaluated.
  • Example 2 As in Example 1, Caco2 cells (human intestinal epithelial cell line) were seeded in a 96-well microtiter plate, and after addition of each fullerene, inflammatory cytokine IL-1 ⁇ (125 ng / mL) was added 30 minutes later. ). After incubation for 24 hours, the supernatant was collected, and the amount of interleukin-8 (IL-8) in the supernatant was measured by ELISA. The result is shown in FIG. In the figure, Pro (7) to Pro (12) represent compounds 7 to 12, and Pro (3) represents compound 3.
  • DCFH-DA 2 ′, 7′-Dichlorodihydrofluorescin diacetate
  • DCFH-DA 2 ′, 7′-Dichlorodihydrofluorescin diacetate
  • FBS fetal bovine serum
  • Anti-Anti antibiotics
  • Invitrogen Carlsbad, CA
  • 50 ⁇ M 2-Mercaptoethanol 2- ME; GIBCO, Japan
  • 1 ⁇ MEM Non-Essential Amino Acids GIBCO
  • Roswell Park Memorial Institute 1640 culture medium containing 0.2 mM L-glutamine
  • the collected spleen cells are suspended in a solution of 155 mM NH 4 Cl (Nacalai Tesque, Kyoto, Japan) / 10 mM KHCO 3 (Nacalai Tesque) / 100 ⁇ M EDTA ⁇ 2Na ⁇ 2H 2 O (Nacalai Tesque). Removed. After further centrifugation, the suspension was suspended in the same culture solution as described above. MLR Untreated BALB / c mouse spleen cells (response cells) and untreated C57BL / 6 mouse spleen cells (stimulatory cells) were used. The cell recovery method was in accordance with the method for preparing spleen cells described above.
  • Mitomycin C (Wako Pure Chemicals, final concentration 250 ⁇ g / mL) was added to the stimulated cells, and cell growth was stopped by reacting at 37 ° C. for 30 minutes. Centrifugation was performed at 1500 rpm for 5 minutes at 4 ° C., and a washing operation was performed 3 times with the culture solution. Responding cells was adjusted to 1x10 7 cell / mL with RPMI1640 culture solution used in the spleen cells recovered in the previous section, stimulated cells were adjusted to 6x10 7 cells / mL.
  • proline type fullerene compound 3
  • hydroxylated fullerene compound 36
  • IFN- ⁇ production of IFN- ⁇ was suppressed in a concentration-dependent manner.
  • Similar reactions were observed with the immunosuppressants tacrolimus, cyclosporin A, dexamethasone, and rapamycin, and it was revealed that proline-type fullerene has an immunosuppressant-like action.

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Abstract

L'invention concerne un agent de prévention ou de traitement de la colite ulcéreuse, pouvant être obtenu à faible coût, dans des conditions de sécurité et d'efficacité élevées. L'invention concerne également un nouveau dérivé de fullerène. L'agent selon l'invention contient comme principe actif un dérivé de fullerène, ou un sel pharmaceutiquement acceptable de celui-ci, présentant une structure de liaisons organiques représentée par une formule de (I) à (III) (dans lesquelles A et B sont des atomes de carbone adjacents et liés, configurant le squelette de groupes carbonés du fullerène ; R1 est un atome d'hydrogène, -(CH2)lCOORa ou -CH((CH2)mCOORa)2 ; R2 à R5 représentent un atome d'hydrogène, un groupe hydrocarboné ou -(CH2)nCOORb ; R1 à R5 sont sélectionnés de sorte à comprendre au moins un -COOH, ainsi qu'un total de 2 à 4 -COORa et -COORb ; R6 et R7 sont des groupes hydrocarbonés ; R8 à R11 sont des atomes d'hydrogène ou des groupes hydrocarbonés ; et X- représente un anion) au niveau d'au moins une paire d'atomes de carbone voisins liés configurant le squelette de groupes carbonés du fullerène.
PCT/JP2014/053950 2013-02-19 2014-02-19 Agent de prévention ou de traitement de la colite ulcéreuse et nouveau dérivé de fullerène WO2014129513A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101802983B1 (ko) * 2016-05-03 2017-11-29 한국생명공학연구원 카르복실기를 포함하는 풀러렌 유도체의 제조방법, 이에 따라 제조된 풀러렌 유도체 및 이의 용도
WO2021175240A1 (fr) * 2020-03-06 2021-09-10 厦门福纳新材料科技有限公司 Application de fullerène et d'un dérivé associé lors de la régulation de la flore intestinale

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001302630A (ja) * 2000-03-06 2001-10-31 Long Y Chiang Ｅ異性体フラーレン誘導体
JP2006160664A (ja) * 2004-12-07 2006-06-22 Vitamin C60 Bioresearch Kk フリーラジカル疾患予防治療用組成物
JP2007513870A (ja) * 2003-10-10 2007-05-31 シー スィクスティ、インコーポレイテッド 置換フラーレン組成物及び酸化防止剤としてのその使用
JP2007145813A (ja) * 2005-10-21 2007-06-14 C Sixty Inc 置換フラーレン組成物及び酸化防止剤としてのその使用
US20100297070A1 (en) * 2007-10-19 2010-11-25 The Regents Of The University Of California COMPOSITIONS AND METHODS FOR AMELIORATING CNS INFLAMMATION, PSYCHOSIS, DELIRIUM, PTSD or PTSS
JP2011513400A (ja) * 2008-03-03 2011-04-28 ルナ イノベーションズ インコーポレイテッド 炎症のフラーレン治療
JP2013087108A (ja) * 2011-10-21 2013-05-13 Osaka Univ 炎症性腸疾患の予防または治療剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001302630A (ja) * 2000-03-06 2001-10-31 Long Y Chiang Ｅ異性体フラーレン誘導体
JP2007513870A (ja) * 2003-10-10 2007-05-31 シー スィクスティ、インコーポレイテッド 置換フラーレン組成物及び酸化防止剤としてのその使用
JP2006160664A (ja) * 2004-12-07 2006-06-22 Vitamin C60 Bioresearch Kk フリーラジカル疾患予防治療用組成物
JP2007145813A (ja) * 2005-10-21 2007-06-14 C Sixty Inc 置換フラーレン組成物及び酸化防止剤としてのその使用
US20100297070A1 (en) * 2007-10-19 2010-11-25 The Regents Of The University Of California COMPOSITIONS AND METHODS FOR AMELIORATING CNS INFLAMMATION, PSYCHOSIS, DELIRIUM, PTSD or PTSS
JP2011513400A (ja) * 2008-03-03 2011-04-28 ルナ イノベーションズ インコーポレイテッド 炎症のフラーレン治療
JP2013087108A (ja) * 2011-10-21 2013-05-13 Osaka Univ 炎症性腸疾患の予防または治療剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHOU, ZHIGUO ET AL.: "A novel class of compounds with cutaneous wound healing properties", JOURNAL OF BIOMEDICAL NANOTECHNOLOGY, vol. 6, 2010, pages 605 - 611 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101802983B1 (ko) * 2016-05-03 2017-11-29 한국생명공학연구원 카르복실기를 포함하는 풀러렌 유도체의 제조방법, 이에 따라 제조된 풀러렌 유도체 및 이의 용도
WO2021175240A1 (fr) * 2020-03-06 2021-09-10 厦门福纳新材料科技有限公司 Application de fullerène et d'un dérivé associé lors de la régulation de la flore intestinale

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