WO2010128663A1 - Inhibiteur de la production d'interleukine 2 - Google Patents

Inhibiteur de la production d'interleukine 2 Download PDF

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Publication number
WO2010128663A1
WO2010128663A1 PCT/JP2010/057763 JP2010057763W WO2010128663A1 WO 2010128663 A1 WO2010128663 A1 WO 2010128663A1 JP 2010057763 W JP2010057763 W JP 2010057763W WO 2010128663 A1 WO2010128663 A1 WO 2010128663A1
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Prior art keywords
dif
formula
carbon atoms
compound represented
alkyl group
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PCT/JP2010/057763
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English (en)
Japanese (ja)
Inventor
禅 久保原
正巳 村上
克典 高橋
吉輝 大島
晴久 菊地
Original Assignee
国立大学法人 群馬大学
国立大学法人 東北大学
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Application filed by 国立大学法人 群馬大学, 国立大学法人 東北大学 filed Critical 国立大学法人 群馬大学
Priority to JP2011512357A priority Critical patent/JP5630751B2/ja
Publication of WO2010128663A1 publication Critical patent/WO2010128663A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring

Definitions

  • the present invention relates to an interleukin-2 (IL-2) production inhibitor and an immunosuppressant containing the same.
  • IL-2 interleukin-2
  • Non-patent Document 1 During the past several decades, many immunosuppressive agents have been developed and used for the purpose of reducing anti-inflammatory agents and rejection during organ transplantation (Non-patent Document 1). Many immunosuppressive drugs target lymphocytes, but are classified into several types depending on the mechanism of action. For example, glucocorticoids exert an immunosuppressive effect mainly by suppressing gene expression of IL-2 and other mediators. Cyclophosphamide metabolites alkylate DNA bases and preferentially suppress immune responses from B lymphocytes. Cyclosporin A (CsA) and tacrolimus (FK506) suppress the production of IL-2 and other cytokines by suppressing the calcineurin activity of T cells.
  • CsA Cyclosporin A
  • FK506 tacrolimus
  • the cellular slime mold Dictyostelium discoideum (hereinafter referred to as slime mold) is a lower eukaryote that inhabits the fallen leaves of the forest and forms a fruiting body similar to mold.
  • slime molds and molds fungi
  • DIF-1 differentiation-inducing factor-1
  • DIF-1 is a low molecular weight compound containing chlorine that has been isolated and identified as a slime mold differentiation factor.
  • DIF-3 isolated at the same time has low differentiation-inducing activity and is known to be a degradation product of DIF-1.
  • the present inventors have investigated the pharmacological action of various DIF derivatives on mammalian cells and have reported that DIF-related compounds (DIFs) have an antitumor activity and an activity to promote cell glucose metabolism.
  • DIF-related compounds DIFs
  • analysis of “chemical structure-activity relationship” has shown that “antitumor activity” and “sugar metabolism promoting activity” possessed by DIFs can be separated by modification of DIF side chains (Non-patent Document 2). ⁇ 5).
  • An object of the present invention is to provide an IL-2 production inhibitor useful as an immunosuppressant or the like.
  • the present inventor has intensively studied to solve the above problems. As a result, it was found that the compound represented by any one of formulas (I) to (V) has an IL-2 production inhibitory action. From these facts, it was found that these compounds are useful as immunosuppressants and the like, and the present invention has been completed.
  • the present invention relates to an IL-2 production inhibitor comprising as an active ingredient a compound represented by any of the following formulas (I) to (V) or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to an immunosuppressive agent comprising the IL-2 production inhibitor.
  • the present invention also relates to a compound represented by any one of the following formulas (I) to (V) or a pharmaceutically acceptable salt thereof for suppressing IL-2 production or immunosuppression.
  • the present invention also relates to the use of a compound represented by any of the following formulas (I) to (V) or a pharmaceutically acceptable salt thereof in the production of IL-2 production suppression or immunosuppression.
  • the present invention also relates to an IL-2 production suppression method or immunosuppression method comprising a step of administering a compound represented by any of the following formulas (I) to (V) or a pharmaceutically acceptable salt thereof.
  • Compounds represented by formulas (I) to (V) are drugs that modulate the activity of mammalian immune system cells, anti-inflammatory agents, autoimmune diseases, allergy treatment agents, rejection inhibitors at the time of organ transplantation, etc. Can be suitably used. It can also be suitably used as a reagent for basic research such as IL-2IL expression and cytokine research.
  • the figure which shows the structure of various DIF related compounds The figure which shows the effect with respect to IL-2 (TM) mRNA amount (A), IL-2 (TM) protein amount (B), and cell proliferation (C) of various DIF related compounds (each 5 micromol) in Jurkat cell. 0.1% EtOH0.1 (vehicle) was used as a control, and 1 ⁇ M CsA and FK506 were used as positive controls. * Indicates that there is a significant difference at p ⁇ 0.05 vers 0.1% EtOH (by t-test).
  • TH-DIF-1, TM-DIF-1, Bu-DIF-3DIF and CP-DIF-3 Shows concentration-dependent effects of TH-DIF-1, TM-DIF-1, Bu-DIF-3DIF and CP-DIF-3 on IL-2 mRNA, IL-2 protein, and cell proliferation in Jurkat cells Figure.
  • the present invention is described in detail below.
  • the IL-2 production inhibitor of the present invention comprises a compound represented by any one of formulas (I) to (V) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 and R 3 represent the same group selected from hydrogen or an alkyl group having 1 to 5 carbon atoms.
  • X represents a halogen such as Cl, Br, or I, and Cl is more preferable.
  • the alkyl group includes a cycloalkyl group.
  • R 4 represents hydrogen or an alkyl group having 1 to 5 carbon atoms.
  • X represents a halogen such as Cl, Br, or I, and Cl is more preferable.
  • the compounds of formulas (I) to (V) or pharmaceutically acceptable salts thereof have an IL-2 production inhibitory effect. Therefore, it can be used as an active ingredient of an immunosuppressive agent.
  • the IL-2 production inhibitory effect means an effect of inhibiting IL-2 production at at least one of mRNA level and protein level, and preferably suppresses production at least at the protein level.
  • Examples of pharmaceutically acceptable salts of the compounds of formulas (I) to (V) include metal salts such as sodium, potassium, magnesium, calcium, ammonium salts, and the like.
  • the compounds of formulas (I) to (V) may be hydrates.
  • a medicament comprising a compound of formulas (I) to (V) or a pharmaceutically acceptable salt thereof is prepared according to a known means generally used in a method for producing a pharmaceutical preparation.
  • Pharmaceutically acceptable salt as it is or mixed with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules) It can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.) as a pharmaceutical preparation such as a liquid, injection, suppository, sustained-release agent and the like.
  • the content of the compound of formulas (I) to (V) or a salt thereof in the IL-2 production inhibitor or immunosuppressant is about 0.01 to about 100% by weight of the whole preparation.
  • the dose of the compound of formulas (I) to (V) or a salt thereof may be an amount effective for suppressing IL-2 production or immunosuppression, and varies depending on the administration subject, target organ, symptom, administration method, etc., and is particularly limited. Generally, however, it is about 0.1 to 100 mg, preferably about 1.0 to 50 mg, more preferably about 1.0 to 20 mg per day for a patient (assuming a body weight of 60 kg).
  • Examples of pharmacologically acceptable carriers include excipients, lubricants, binders and disintegrants in solid formulations, or solvents, solubilizers, suspending agents, isotonic agents, buffers in liquid formulations. And soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate and citrate.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the immunosuppressive agent of the present invention may be used in combination with other drugs.
  • DIFs DIF derivatives
  • DIFs Effect of DIFs on K562 human leukemia cells and mouse 3T3-L1 cells (Fig. 6)
  • DIF derivatives have antitumor activity (Kubohara, 1999; Shimizu et al. 2004; Gokan et al. 2005; etc.) and glucose metabolism promoting activity (Omata et al. 2007; Kubohara et al. 2008).
  • TH-DIF-1 has only been confirmed to have a high IL-2 expression inhibitory activity, and it can be particularly expected as a specific IL-2 expression inhibitor, a candidate substance for an immunosuppressant with few side effects, and a lead compound.
  • TM-DIF-1 group For the Control group, TM-DIF-1 group, and FK506 group, whole blood was collected 4 hours after ConA stimulation, and the serum IL-2 concentration was measured. As a result, TM-DIF-1 significantly suppressed IL-2 elevation caused by ConA stimulation. In addition, no acute toxicity or abnormal behavior of mice associated with TM-DIF-1 administration was observed.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Transplantation (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé représenté par l'une des formules (I) à (V) ou l'un de ses sels pharmaceutiquement acceptables en tant que principe actif pour un inhibiteur de la production d'interleukine 2. Dans la formule (I), R1, R2 et R3 représentent chacun un atome d'hydrogène ou le même groupe est choisi parmi des groupes alkyle ayant 1 à 5 atomes de carbone et X représente un atome d'halogène. Dans la formule (II), R4 représente un atome d'hydrogène ou un groupe alkyle ayant 1 à 5 atomes de carbone et X représente un atome d'halogène.
PCT/JP2010/057763 2009-05-07 2010-05-06 Inhibiteur de la production d'interleukine 2 WO2010128663A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2011512357A JP5630751B2 (ja) 2009-05-07 2010-05-06 インターロイキン−２産生抑制剤

Applications Claiming Priority (2)

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JP2009112974 2009-05-07
JP2009-112974 2009-05-07

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WO2010128663A1 true WO2010128663A1 (fr) 2010-11-11

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04108730A (ja) * 1990-08-24 1992-04-09 Kanehiro Tada アレルギー性疾患治療剤
US20080254130A1 (en) * 2003-08-29 2008-10-16 Bioderm Research Skin Antiaging & Brightening via Multi-function Treatment of Enzyme Dysfunction

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04108730A (ja) * 1990-08-24 1992-04-09 Kanehiro Tada アレルギー性疾患治療剤
US20080254130A1 (en) * 2003-08-29 2008-10-16 Bioderm Research Skin Antiaging & Brightening via Multi-function Treatment of Enzyme Dysfunction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAOMI G ET AL.: "Structural requirement of Dictyostelium differentiation- inducing factors for their stalk-cell-inducing activity in Dictyostelium cells and anti- proliferative activity in K562 human leukemic cells", BIOCHEMICAL PHARMACOLOGY, vol. 70, 2005, pages 676 - 685 *

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JPWO2010128663A1 (ja) 2012-11-01

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