WO2001047516A1 - Immunosuppresseurs - Google Patents

Immunosuppresseurs Download PDF

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Publication number
WO2001047516A1
WO2001047516A1 PCT/JP2000/009407 JP0009407W WO0147516A1 WO 2001047516 A1 WO2001047516 A1 WO 2001047516A1 JP 0009407 W JP0009407 W JP 0009407W WO 0147516 A1 WO0147516 A1 WO 0147516A1
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WO
WIPO (PCT)
Prior art keywords
effect
present
immunosuppressant
immunosuppressants
administration
Prior art date
Application number
PCT/JP2000/009407
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English (en)
Japanese (ja)
Other versions
WO2001047516A9 (fr
Inventor
Satoshi Omura
Kanki Komiyama
Original Assignee
Gakkou Houjin Kitasato Gakuen
Japan Society For The Promotion Of Science
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 Gakkou Houjin Kitasato Gakuen, Japan Society For The Promotion Of Science filed Critical Gakkou Houjin Kitasato Gakuen
Priority to AU22302/01A priority Critical patent/AU2230201A/en
Publication of WO2001047516A1 publication Critical patent/WO2001047516A1/fr
Publication of WO2001047516A9 publication Critical patent/WO2001047516A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to an immunosuppressant.
  • autoimmune diseases are induced when an immune response to its components is caused by the breakdown of the immune system. These are generally called autoimmune diseases. Examples of autoimmune diseases include rheumatoid arthritis, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, and the like. Other diseases involving the immune system include hypersensitivity such as an allergic disease caused by an excessive reaction of the immune system to foreign foreign substances. In particular, after a period of time after the antigen sensitization, when the same antigen is again contacted, a strong cellular immunity is induced, and the pathological immune response that sometimes puts the host at risk is called delayed-type hypersensitivity. Calling.
  • rejection associated with organ transplants such as kidney transplants and bone marrow transplants is another issue that needs to be resolved in medical care.
  • rejection is essentially nothing other than the normal foreign body elimination mechanism of the living body, it is clearly a pathological condition in the sense that it interferes with the therapeutic effect.
  • therapeutic agents for suppressing the immune response so-called immunosuppressants.
  • Steroids, corticosteroids, antimetabolites, alkylating agents, alkyloids, etc. are known as the main immunosuppressants currently used, but their efficacy, durability and side effects However, they were not always satisfactory.
  • cyclosporin A which is widely used as a potent immunosuppressant
  • FK506 evening chlorimus
  • Macrosferlide B of the present invention was reported by the present inventor as a substance having an action of inhibiting cell adhesion (JP-A-8-325285). It was expected that a drug containing this substance as an active ingredient could be an effective anticancer drug. However, it has not been known that the use of this substance makes it possible to provide an immunosuppressant with fewer side effects. Disclosure of the invention
  • An object of the present invention is to provide an immunosuppressant having excellent immunosuppressive activity and having few side effects.
  • the present inventors have conducted intensive studies based on the above-mentioned problems, and as a result, have newly found that Macrospray B (JP-A-8-325285) having an effect of inhibiting cell adhesion has an immunosuppressive effect. Furthermore, the immunosuppressive effect of Macrospheride B was stronger than that of the clinically used immunosuppressant cyclosporine, and it was also found that there was no antibody-suppressing effect that was a problem as a side effect.
  • the present invention has been completed. Drugs containing macrospheride B as an active ingredient are highly effective immunosuppressants with a different mechanism of action than conventional drugs. That is, the present invention relates to an immunosuppressant comprising macrosphlide B represented by the following structural formula (1) as an active ingredient. Structural formula (1)
  • the present invention also relates to the immunosuppressant for suppressing an immune response due to cellular immunity.
  • the present invention also relates to a therapeutic agent comprising the immunosuppressive agent for suppressing delayed type hypersensitivity and / or rejection of a transplanted tissue.
  • the present invention relates to the use of the compound represented by the structural formula (1) in the production of an immunosuppressant.
  • the present invention relates to the use of the compound represented by the structural formula (1) in any of the following methods.
  • a method for treating an autoimmune disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, hemolytic anemia, multiple sclerosis, and ulcerative colitis relates to a method for treating an autoimmune disease, comprising a step of administering the compound described in 1). More specifically, the compound represented by the structural formula (1) A method for treating any autoimmune disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, hemolytic anemia, multiple sclerosis, and ulcerative colitis.
  • Macrosphula B which is an active ingredient of the immunosuppressant of the present invention, may be abbreviated as MSB in the present specification.
  • the obtained culture solution was divided into a liquid fraction and a bacterial cell fraction.
  • the liquid fraction was added with ethyl acetate, stirred sufficiently, and then subjected to liquid separation to obtain an ethyl acetate extracted fraction.
  • methanol was added thereto, and the mixture was sufficiently stirred.
  • the methanol fraction was concentrated under reduced pressure to remove methanol, and then extracted with ethyl acetate.
  • the ethyl acetate fractions obtained from both the liquid and bacterial cell fractions were combined and concentrated under reduced pressure to obtain 379.4 mg of an ethyl acetate extracted fraction.
  • the ethyl acetate-extracted fraction was adsorbed on two thin-layer silica gel layers (20 ⁇ 20 cm, thickness 0.5 mm, manufactured by Merck) and developed with a mixed solvent of form-methanol (9: 1).
  • a mixed solvent of form-methanol 9: 1.
  • a band showing orange-yellow fluorescence was fractionated under irradiation with an ultraviolet lamp (254, 366 nm), and eluted with a mixed solvent of form-methanol (1: 1).
  • the eluted fraction obtained was concentrated under reduced pressure to obtain 18.3 mg of crude substance I containing macrosphlides.
  • Macrospheride B of the present invention can also be chemically synthesized based on its structural information (Sunazuka T. et al. J. Am. Chem. So 119: 10247-10248, 1997). An example of the synthesis process will be described below.
  • Macross ferride has two molecules of trans- (4R, 5S) -dihydroxy-2-hexenoic acid and one molecule of (3S) -hydroxybutyric acid.
  • two asymmetric carbons of 1 are introduced at once by a regioselective asymmetric dihydroxylation reaction of (E, E) -hexa-2,4-dienoic acid ester, and the hydroxyl group at the 4-position is sterically added.
  • E, E regioselective asymmetric dihydroxylation reaction of (E, E) -hexa-2,4-dienoic acid ester, and the hydroxyl group at the 4-position is sterically added.
  • E, E regioselective asymmetric dihydroxylation reaction of (E, E) -hexa-2,4-dienoic acid ester
  • the hydroxyl group at the 4-position of this substance was converted to MEM and then hydrolyzed with 0.2N NaOH to obtain a carboxylic acid.
  • the MEM substance was deTBDMSed using TBAF to obtain alcohol.
  • the carboxylic acid form and the alcohol form were condensed by the Keck method using DCC, DMPA, and CSA, and then de-TBDMS-ized with AcOH acid to obtain an alcohol.
  • the t-Bu group and the TBDMS group were simultaneously deprotected under acidic conditions using TFA and thioan isole to give seco acid.
  • the macrosphlide B of the present invention can be mixed with a physiologically acceptable carrier, excipient, or diluent and administered orally or parenterally as a pharmaceutical composition.
  • Oral preparations can be in the form of granules, powders, tablets, capsules, solvents, emulsions, or suspensions.
  • parenteral preparations dosage forms such as injections, infusions, external preparations, or suppositories can be selected. Injections include subcutaneous injections, intramuscular injections, and intraperitoneal injections.
  • the topical drug may be a nasal agent or an ointment.
  • Pharmaceutical techniques for preparing macrosphlide B as a main component in such a dosage form are known.
  • tablets for oral administration can be produced by adding and mixing excipients, binders, disintegrants, lubricants, etc. to Macrospheride B, and compression-shaping.
  • Excipients include, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, etc.
  • binders for example, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, Gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol, polyoxyethylene, block polymer, MEG Lumin and the like.
  • Disintegrators include, for example, starch, agar, gelatin-free, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose calcium, and the like.
  • Lubricants include, for example, stearic acid. Magnesium, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like.
  • the tablet containing the immunosuppressant according to the present invention can be coated with a known coating for masking or enteric preparation.
  • a coating agent ethylcell polyoxyethylene glycol or the like can be used.
  • Macrosfride B is dissolved in ethanol, mixed with vegetable oil, and encapsulated with gelatin containing sorbitol to produce capsules (soft capsules).
  • the composition of the gelatin coating solution and the composition of the soft capsule are as follows.
  • Emulsion ointment composition After preparing the emulsion ointment base, add Macroslide B and mix to produce an ointment (emulsion ointment).
  • the composition of the emulsion ointment is as follows. • Emulsion ointment composition:
  • the ointment thus obtained can be expected to alleviate the symptoms of hypersensitivity by applying it to the affected area having hypersensitivity, particularly delayed type hypersensitivity, 2 to 4 times per day.
  • the number of times of application can be appropriately adjusted according to the symptoms.
  • Macroslide B is dissolved in ethanol at 50 vol "/. Ethanol is prepared by the method of injection. When used, it is mixed with physiological saline and other infusions. The composition of the injection is as follows.
  • the dose of the immunosuppressant containing Macrospheride B of the present invention is appropriately selected according to the method of administration (dosage form) and the state of the administration subject (physique, age, sex, symptoms). Generally, 0.01-1 mg, more preferably 0.05-0.5] parenterally, and 0.05-5 mg, more preferably 0.1-1.0 per kg of body weight. mg.
  • the immunosuppressant according to the present invention is particularly effective for suppressing an immune response caused by cell-mediated immunity.
  • Cell-mediated immunity is an immune response that is primarily provided by cytotoxic T cells, and is an immune response that is paired with humoral immunity provided by antibodies. Immune responses mediated by cellular immunity include immune responses such as delayed-type hypersensitivity and rejection of transplants.
  • the immunosuppressive agent of the present invention can be used as a therapeutic agent for delayed-type hypersensitivity and a therapeutic agent for rejection of transplanted tissues.
  • Providing an effective therapeutic agent is of great significance because these immune responses often result in serious life-threatening symptoms in the medical setting.
  • the immunosuppressant of the present invention strongly suppresses the function of cell-mediated immunity, which causes severe symptoms, but hardly affects the humoral immune function. This indicates that the immunosuppressant of the present invention can selectively suppress problematic symptoms while maintaining humoral immune function, which is one of the important defense mechanisms of the living body.
  • immunosuppressive drugs that are used continuously to increase the survival of transplanted tissues often suppress the host's overall immune function, which can lead to infection.
  • transplant medicine is about fighting rejection and infectious diseases.
  • humoral immune function can be maintained while suppressing only rejection, which is expected to greatly facilitate postoperative management of transplantation medicine.
  • the immunosuppressive agent according to the present invention is effective for immunosuppression during transplantation of heart, kidney, liver, etc., and also for the treatment of self-immune diseases such as rheumatism, systemic lupus erythematosus, scleroderma, and ulcerative colitis. It is valid.
  • Figure 1 is a photograph showing the effect of Macrosferlide B on suppressing allograft rejection.
  • a is a control
  • b is MSB administration
  • c is a photograph of the transplanted skin site after CPA administration.
  • FIG. 2 shows a casein and MSB administration schedule in an anti-inflammatory effect evaluation system.
  • FIG. 3 is a graph showing a decrease in MP0 activity due to administration of Macrospheride B.
  • FIG. 4 is a photograph showing the inhibitory effect of macrospheride B administration on swelling of feet.
  • FIG. 5 is a graph showing the inhibitory effect of macrospheride B administration on delayed-type hypersensitivity reaction.
  • Figure 6 is a graph showing the effect of macrospheride B administration on the antibody production system.
  • the back skin without thick blood vessels was incised at seven angles and peeled.
  • the tail skin of the donor was inserted into the incision, and a bandage was wrapped and fixed.
  • Drug administration to surgery Injected intraperitoneally under light ether anesthesia to avoid irritation. The dose was administered every day for the first 7 days and every other day after the 8th.
  • BDF1 female mice (6 weeks old) were sensitized with methylated bovine serum albumin (BSA) together with Freund immplete adjuvant.
  • BSA methylated bovine serum albumin
  • MSB10 and 20 mg / kg / day were intraperitoneally administered daily after sensitization.
  • FK506 (30 mg / kg / day) and cyclosporin A (100 mg / kg / day), which are clinically widely used, were orally administered daily after primary sensitization.
  • FIG. 4 The right foot ⁇ 24 hours after the secondary sensitization was shown in the photograph (Fig. 4). Sensitization with methylated BSA causes swelling of the feet when resensitized. In contrast, administration of MSB10 or 20 mg / kg / day significantly reduced swelling.
  • Figure 5 shows the difference in thickness between the right foot ⁇ (methylated BSA) and the left foot ⁇ (saline). Swelling was reduced in a dose-dependent manner with MSB, and MSB 20 mg / kg / day showed almost the same activity as FK506 30 mg / kg / day and cyclosporin A 100 mg / kg / day. This indicated that MSB completely suppressed the swelling of the foot induced by secondary sensitization.
  • mice Male ddY mice (5 weeks old) were suspended in PBS at a packed volume of 5% in PBS, and administered intravenously at 100 ⁇ l / mouse (3 mice / group). MSB was administered daily at 5 or 20 mg / kg / day, and blood was collected 7 days later. After separating the antiserum, the hemagglutinin titer of the hedged erythrocytes was measured.
  • Fig. 6 shows the results.
  • the antibody titers were comparable between the MSB-administered group and the untreated group, indicating no effect on the antibody production system.
  • the mechanism of action of cyclosporin A and FK506, which are currently used in the clinic, is to suppress the production of IL-2, and has activity to suppress antibody production.
  • MSB is thought to have a novel mechanism of action, mainly in that it suppresses cell-mediated immunity without affecting antibody production suppression.
  • the immunosuppressive effect of the macrospheride B of the present invention is stronger than cyclosporin already used clinically, effective treatment can be expected with a small amount of administration. Side effects can be minimized. In addition, there is no side effect of suppressing antibody production, which has been a problem with conventional drugs, so there is little risk of infections.
  • the present invention has great significance in providing an immunosuppressant having excellent immunosuppressive activity and having few side effects.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Abstract

L'invention concerne des immunosuppresseurs renfermant comme ingrédient actif un macrosphélide B représenté par la formule structurelle (1). Ces immunosuppresseurs exercent un effet immunosuppresseur plus fort que les immunosuppresseurs existants et cependant n'ont pas pour effet d'inhiber la production d'anticorps. Puisqu'ils ont un effet particulièrement élevé d'inhibition de l'immunité cellulaire, ces immunosuppresseurs sont utilisés en transplantation.
PCT/JP2000/009407 1999-12-28 2000-12-28 Immunosuppresseurs WO2001047516A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22302/01A AU2230201A (en) 1999-12-28 2000-12-28 Immunosuppressants

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11-375673 1999-12-28
JP37567399A JP2005231996A (ja) 1999-12-28 1999-12-28 免疫抑制剤

Publications (2)

Publication Number Publication Date
WO2001047516A1 true WO2001047516A1 (fr) 2001-07-05
WO2001047516A9 WO2001047516A9 (fr) 2002-07-25

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WO (1) WO2001047516A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08325285A (ja) * 1995-05-30 1996-12-10 Kitasato Inst:The 新規な細胞接着阻害剤マクロスフェライドａ及びｂ並びにそれらの製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08325285A (ja) * 1995-05-30 1996-12-10 Kitasato Inst:The 新規な細胞接着阻害剤マクロスフェライドａ及びｂ並びにそれらの製造法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUNAZUKA ET AL.: "Relative and absolute stereochemistries and total synthesis of (+)-macrosphelides A and B, potent, orally bioavailable inhibitors of cell-cell adhesion", J. AM. CHEM. SOC., vol. 119, no. 42, 1997, pages 10247 - 10248, XP002938040 *

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AU2230201A (en) 2001-07-09
WO2001047516A9 (fr) 2002-07-25
JP2005231996A (ja) 2005-09-02

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