WO2010041449A1 - Agent antiallergique comprenant un agoniste du rxr en tant que principe actif - Google Patents

Agent antiallergique comprenant un agoniste du rxr en tant que principe actif Download PDF

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WO2010041449A1
WO2010041449A1 PCT/JP2009/005235 JP2009005235W WO2010041449A1 WO 2010041449 A1 WO2010041449 A1 WO 2010041449A1 JP 2009005235 W JP2009005235 W JP 2009005235W WO 2010041449 A1 WO2010041449 A1 WO 2010041449A1
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group
saturated
unsaturated
alkenyl
alkyl
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PCT/JP2009/005235
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Japanese (ja)
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杉本幸雄
加来田博貴
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国立大学法人 岡山大学
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

Definitions

  • the present invention relates to a novel use of a retinoid X receptor (RXR) agonist that is a nuclear receptor. More specifically, the present invention relates to an antiallergic agent containing an RXR agonist as an active ingredient.
  • RXR retinoid X receptor
  • Allergic disease refers to a disease caused by an excessive immune response to a specific antigen. Allergic diseases are classified from type I allergies to type V allergies according to the mechanism of their occurrence. Moreover, it is classified into immediate allergy or delayed allergy according to the time when the allergic reaction reaches the maximum. The time to reach the maximum allergic reaction is 30 minutes to several hours for the antibody-related reaction, and in this case it is classified as an immediate allergy, and it takes 24 to 48 hours for the reaction with T lymphocytes. Classified as delayed allergy. Typical allergic diseases are frequently seen in type I, and examples include hay fever, allergic rhinitis, bronchial asthma, atopic dermatitis, plant allergy, urticaria, PIE syndrome, anaphylactic shock and the like.
  • antiallergic agents As antiallergic agents, antiallergic agents other than steroids are not effective enough to treat chronic and severe allergic symptoms at present.
  • steroids which are the most powerful antiallergic agents, are used in the induction / hate of infection, peptic ulcer, central obesity (moon face), induction / hate of diabetes, depression, osteoporosis and fractures.
  • Adrenal insufficiency, abnormal fat deposition, hirsutism, subcutaneous bleeding, skin atrophy, cataracts, glaucoma, edema, hypertension, congestive heart failure and arrhythmias have many unavoidable side effects that limit their use .
  • drugs that have the same efficacy as steroids and have reduced side effects.
  • Non-Patent Documents 1-3 a compound targeting a peroxisome proliferator-responsive receptor (PPAR) whose transcription is regulated by a fatty acid has an antiallergic action.
  • PPAR peroxisome proliferator-responsive receptor
  • RXR retinoid X receptor
  • RXR is one of the nuclear receptors that are ligand-dependent transcription factors that are thought to have 9-cis retinoic acid and docosahexaneenoic acid (DHA) as endogenous ligands. The function is exhibited as a homodimer or by forming heterodimers with various nuclear receptors (Non-patent Document 4).
  • RXR heterodimer partners include retinoic acid receptor (RAR), which is involved in cell differentiation and proliferation, vitamin D receptor (VDR), which is also involved in cell differentiation, proliferation or bone metabolism, and lipid metabolism.
  • RAR retinoic acid receptor
  • VDR vitamin D receptor
  • TR thyroid hormone receptor thyroid hormone receptor
  • PXR involved in CYP3A4 expression known as drug metabolizing enzymes. Therefore, the function of RXR and the activity expression of these nuclear receptors are closely related, and an agonist or antagonist that controls RXR function can control the function of these heterodimers.
  • the RAR agonist Am80 (generic name: tamibarotene: treatment for relapsed or refractory acute promyelocytic leukemia: 4-[(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthyl) carbamoyl] benzoic acid: Non-patent document 6) shows almost no cell differentiation-inducing action when present alone at a concentration of 3.3 ⁇ 10 -10 M, whereas it acts on Am80 and RXR. When a substance is used in combination, the RXR agonist acts as a synergist of Am80, and a significant differentiation inducing action is observed (Non-patent Document 7).
  • RXR agonists are not limited to actions via RXR-containing nuclear receptor heterodimers.
  • tamoxifen used for breast cancer treatment is an estrogen receptor (ER) that does not form a heterodimer with RXR, but its RXR agonist improves resistance to estrogen-resistant breast cancer. Then, it is reported (nonpatent literature 8).
  • ER estrogen receptor
  • Non-patent Document 9 a carcinogenesis preventing effect by RXR agonist alone or in combination with tamoxifen has been reported.
  • Non-patent Document 10 The effectiveness of RXR agonists in taxol-resistant cancer has also been reported (Non-patent Document 10).
  • the anti-angiogenic action of RXR agonists has been reported (Non-patent Document 11).
  • the RXR agonist has an interesting physiological activity even when administered alone. For example, it has been reported that when an RXR agonist is administered to a type II diabetes model mouse, insulin resistance is improved and blood glucose level is reduced (Non-patent Document 12).
  • RXR agonists and antagonists are generally referred to as rexinoid compounds, and new rexinoid compounds have been disclosed recently (Patent Document 1), but there is no report of antiallergic action.
  • An object of the present invention is to provide a novel antiallergic agent that acts effectively on allergic diseases and has reduced side effects.
  • this invention consists of the following. 1. New antiallergic agent containing RXR agonist as active ingredient. 2. 2. The novel antiallergic agent according to item 1 above, wherein the RXR agonist is a compound represented by the following general formula I: Wherein R 1 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups. R 2 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkoxy, alkyl, alkenyl, alkynyl and aryl groups.
  • W is NR 3 or CR 3 and R 3 is selected from hydrogen, linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • X 1 is selected from CH or N.
  • Y 1 is selected from CH or N.
  • X 2 is selected from CH, CR 4 , or N.
  • Y 2 is selected from CH, CR 4 , or N.
  • R 4 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro and amino groups.
  • RXR agonist is a compound represented by the following general formula II: Wherein R 5 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups. R 6 is selected from the group consisting of branched, unsubstituted or substituted, saturated or unsaturated, alkyl groups, alkenyl groups.
  • R 3 is selected from hydrogen, straight or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • X 1 is selected from CH or N.
  • Y 1 is selected from CH or N.
  • Y 2 is selected from CH, CR 7 , or N.
  • R 7 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and alkoxy groups.
  • Z is selected from a carboxylic acid, a carboxylic acid ester, or a hydroxamic acid, directly or through a saturated or unsaturated alkyl group, alkenyl group, alkynyl group.
  • RXR agonist is a compound represented by the following general formula III: Wherein R 5 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups. R 6 is selected from the group consisting of branched, unsubstituted or substituted, saturated or unsaturated, alkyl groups, alkenyl groups. R 3 is selected from hydrogen, straight or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • X 2 is selected from CH, CR 4 , or N.
  • R 4 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro and amino groups.
  • Y 1 is selected from CH or N.
  • Y 2 is selected from CH, CR 7 , or N.
  • R 7 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and alkoxy groups.
  • Z is selected from a carboxylic acid, a carboxylic acid ester, or a hydroxamic acid, directly or through a saturated or unsaturated alkyl group, alkenyl group, alkynyl group. ) 5).
  • the RXR agonist is a compound represented by the general formula II or III, wherein R 5 and R 6 are both isopropyl groups, X 1 is CH or N, and X 2 is CH, CR 4 , or N. Y 1 and Y 2 are both N, Z is a carboxylic acid ester, carboxylic acid or a salt thereof, and is located at the meta position with respect to Y 1 and Y 2 , and R 3 is selected from ethyl and isopropyl. 5.
  • the novel antiallergic agent according to 3 or 4 above which is selected. 6).
  • the RXR agonist is a compound represented by the general formula II or III, wherein R 5 is an isopropyl group or isobutyl group, X 1 is CH or N, and X 2 is CH, CR 4 , or N.
  • R 6 is an isopropyl group, X 1 is CH or N, Y 1 is CH or N, Y 2 is CH or N, Z is a carboxylic acid ester, carboxylic acid or a salt thereof, and 5.
  • the novel antiallergic agent according to 3 or 4 above, which is located in a meta position with respect to Y 1 and Y 2 and R 3 is an ethyl group. 7).
  • the RXR agonist is a compound represented by the general formula II or III, wherein R 5 is an isopropyl group or an isobutyl group, R 6 is an isopropyl group, X 1 is CH, X 2 is CH, CR 4 or N, Y 1 is N, Y 2 is CH, Z is a carboxylic acid, is located at the meta position with respect to Y 1 and Y 2 , and R 3 is an ethyl group 5.
  • R 5 is an isopropyl group or an isobutyl group
  • R 6 is an isopropyl group
  • X 1 is CH
  • X 2 is CH
  • CR 4 or N CR 4 or N
  • Y 1 is N
  • Y 2 is CH
  • Z is a carboxylic acid
  • the RXR agonist is R 5 is an isopropyl group
  • R 6 is an isopropyl group
  • X 1 is CH
  • X 2 is CH
  • CR 4 or N
  • Y 1 is N
  • Y 2 is CH
  • Z is hydroxamic acid or acrylic hydroxamic acid, and is located at the meta position relative to Y 1 and Y 2
  • R 3 is an ethyl group 5.
  • the novel antiallergic agent according to item 1 above, wherein the RXR agonist is a compound represented by the following formula IV.
  • the anti-allergic agent comprising the RXR agonist of the present invention as an active ingredient is expected to have the same efficacy as a steroid preparation that is effective in treating allergic diseases, and side effects are significantly reduced compared to steroids. It is an excellent drug.
  • the RXR agonist as an active ingredient used in the antiallergic agent of the present invention suppresses symptoms of allergic diseases with a mechanism of action different from the glucocorticoid receptor activating action of steroids. Steroids exhibit various side effects through the glucocorticoid receptor (GR), one of the nuclear receptors, whereas RXR agonists do not act on GR, reducing these side effects. Be expected.
  • steroid drugs inhibit not only Th2-type lymphocytes that are involved in the development of allergic diseases but also Th1-type lymphocytes that are important for protection against infection by bacteria and viruses. There is induction / hate of infectious diseases.
  • RXR receptor-related compounds rexinoid compounds
  • Th2-type lymphocytes Th2-type lymphocytes
  • Th1-type lymphocytes J Immunol., 176 (9), pp.5161-5166. Therefore, side effects such as induction and ashamed of infectious diseases are not expected.
  • an ⁇ 2 receptor agonist and adrenaline or a salt thereof provides a more effective local anesthetic effect than when adrenaline or a salt thereof, or an ⁇ 2 receptor agonist is added to a local anesthetic as a single agent. Therefore, the amount of adrenaline or a salt thereof used can be reduced, and as a result, side effects due to adrenaline or a salt thereof can be reduced.
  • Example 2 It is a figure which shows the effect of the RXR agonist (NEt-3IP) with respect to the antigen-induced sneezing reaction in a mouse allergic rhinitis model.
  • Example 1 It is a figure which shows the effect of the RXR agonist (NEt-3IP) with respect to the antigen-induced nasal scratching behavior in a mouse allergic rhinitis model.
  • Example 2 It is a figure which shows the effect by continuous administration of the RXR agonist (NEt-3IP) with respect to an antigen-induced sneezing reaction and nasal scratching behavior in a mouse allergic rhinitis model.
  • Example 3 It is a figure which shows the effect of the RXR agonist (NEt-3IP) with respect to histamine induction
  • Example 4 It is a figure which shows the effect of the RXR agonist (NEt-3IP) with respect to the substance P induction
  • Example 5 It is a figure which shows the RXR agonist (NEt-3IP) repeated administration protocol to a mouse allergic rhinitis model.
  • Example 6 It is a figure which shows the effect with respect to an antigen induction sneezing reaction (A) and antigen induction nasal scratching behavior (B) by the RXR agonist (NEt-3IP) repeated administration to a mouse allergic rhinitis model.
  • Example 6 It is a figure which shows the effect of the RXR agonist (NEt-3IB) with respect to the antigen-induced sneezing reaction in a mouse allergic rhinitis model.
  • Example 7) It is a figure which shows the effect of the RXR agonist (NEt-3IB) with respect to the antigen-induced nasal scratching behavior in a mouse allergic rhinitis model.
  • Example 8 It is a figure which shows the repeated administration protocol of the RXR agonist (NEt-3IP) to a mouse allergic rhinitis model.
  • Example 9 It is a figure which shows the effect of the 5th day and the 10th day by the repeated administration of the RXR agonist (NEt-3IP) to a mouse allergic rhinitis model.
  • Example 9 It is a figure which shows the influence of the non-selective PPAR antagonist (BADGE) with respect to the nasal symptom suppression effect of NEt-3IP.
  • BADGE non-selective PPAR antagonist
  • Example 10 It is a figure which shows the influence of the PPAR (alpha) selective antagonist (GW6471) or the PPAR (gamma) selective antagonist (GW9662) with respect to the nasal symptom suppression effect of NEt-3IP. (Example 10) It is a figure which shows the influence of the LXR antagonist (AA-23) with respect to the nasal symptom suppression effect of NEt-3IP. (Example 11)
  • the RXR agonistic substance may be a compound having such properties and is not particularly limited.
  • the RXR agonist may be a compound known per se, for example, a compound represented by the following general formula I, preferably a compound represented by the following general formula II or III .
  • R 1 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • R 2 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkoxy, alkyl, alkenyl, alkynyl and aryl groups.
  • W is NR 3 or CR 3 and R 3 is selected from hydrogen, linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • X 1 is selected from CH or N.
  • Y 1 is selected from CH or N.
  • X 2 is selected from CH, CR 4 , or N.
  • Y 2 is selected from CH, CR 4 , or N.
  • R 4 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro and amino groups.
  • Z is selected from a carboxylic acid, a carboxylic acid ester, or a hydroxamic acid, directly or through a saturated or unsaturated alkyl group, alkenyl group, alkynyl group.
  • R 5 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • R 6 is selected from the group consisting of branched, unsubstituted or substituted, saturated or unsaturated, alkyl and alkenyl groups.
  • R 3 is selected from hydrogen, linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • X 1 is selected from CH or N.
  • Y 1 is selected from CH or N.
  • Y 2 is selected from CH, CR 7 , or N.
  • R 7 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and alkoxy groups.
  • Z is selected from a carboxylic acid, a carboxylic acid ester, or a hydroxamic acid, directly or through a saturated or unsaturated alkyl group, alkenyl group, alkynyl group.
  • R 5 is selected from the group consisting of linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • R 6 is selected from the group consisting of branched, unsubstituted or substituted, saturated or unsaturated, alkyl and alkenyl groups.
  • R 3 is selected from hydrogen, linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and aryl groups.
  • X 2 is selected from CH, CR 4 , or N.
  • R 4 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro and amino groups.
  • Y 1 is selected from CH or N.
  • Y 2 is selected from CH, CR 7 , or N.
  • R 7 is selected from linear or branched, unsubstituted or substituted, saturated or unsaturated, alkyl, alkenyl, alkynyl and alkoxy groups.
  • Z is selected from a carboxylic acid, a carboxylic acid ester, or a hydroxamic acid, directly or through a saturated or unsaturated alkyl group, alkenyl group, alkynyl group. )
  • the alkyl group, alkenyl group and alkynyl group may be a cycloalkyl group, a cycloalkenyl group and a cycloalkynyl group, respectively.
  • cycloalkyl means a saturated cyclic carbon chain
  • cycloalkenyl and cycloalkynyl each mean a cyclic carbon chain containing at least one double or triple bond.
  • the cycloalkyl group, cycloalkenyl group, cycloalkynyl group and aryl group may be monocyclic, polycyclic or condensed cyclic.
  • Examples of the preferred compound of the present invention include the following compounds.
  • R 5 and R 6 are both isopropyl groups
  • X 1 is CH or N
  • Y is both N
  • Z is a carboxylic acid ester, carboxylic acid or a salt thereof
  • the carboxylic acid ester include methyl ester, ethyl ester, and t-butyl ester.
  • R 5 is an isopropyl group or an isobutyl group
  • R 6 is an isopropyl group
  • X 1 is CH or N
  • Y 1 is CH or N
  • Y 2 is N
  • Z Is a carboxylic acid ester, carboxylic acid or a salt thereof, and is located at the meta position with respect to Y 1 and Y 2
  • R 3 is an ethyl group.
  • the carboxylic acid ester include methyl ester, ethyl ester, and t-butyl ester.
  • Examples of other preferable compounds of the present invention include the following compounds.
  • R 5 and R 6 are both isopropyl groups, X 2 is CH, Y 1 is N, Y 2 is CH, and Z is a carboxylic acid ester, carboxylic acid or a salt thereof.
  • R 3 is selected from ethyl and isopropyl.
  • the carboxylic acid ester include methyl ester, ethyl ester, and t-butyl ester.
  • the compound represented by any one of the general formulas I to III may be a pharmaceutically acceptable salt.
  • the present invention when there are isomers (for example, optical isomers, geometric isomers, and compatible isomers), the present invention is directed to those isomers. And also solvates, hydrates and crystals of various shapes.
  • the pharmaceutically acceptable salt includes general pharmacologically and pharmaceutically acceptable salts.
  • specific examples of such salts are as follows.
  • Examples of basic addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts and triethylamine salts; dicyclohexylamine salts and ethanolamines.
  • Aliphatic amine salts such as salts, diethanolamine salts, triethanolamine salts and brocaine salts; aralkylamine salts such as N, N-dibenzylethylenediamine; and heterocyclic aromatics such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts
  • tetramethylammonium salt tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, Quaternary ammonium salts such as tiger butyl ammonium salt; arginine; basic amino acid salts such as lysine salts.
  • the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate Salts; for example, acidic amino acids such as aspartate and glutamate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate
  • Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate
  • sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate
  • Patent Document 1 International Publication WO2008 / 105386 pamphlet
  • Any of the compounds included in the scope of the present invention can be produced by appropriately modifying or altering the starting materials and reagents used in these production methods and reaction conditions. Moreover, it is not limited to the method specifically described above.
  • the antiallergic agent refers to a drug such as a drug having an effect on a so-called allergic disease, and can be used prophylactically or therapeutically for allergic diseases, preferably therapeutically.
  • the allergic disease is not particularly limited as long as it is a so-called allergic disease, and examples thereof include type I allergy, type II allergy, and type IV allergy. Specific examples include hay fever, allergic rhinitis, bronchial asthma, atopic dermatitis, plant allergy, urticaria, PIE syndrome, anaphylactic shock and the like.
  • an antiallergic agent comprising the RXR agonist of the present invention as an active ingredient
  • an effective amount can be administered orally or parenterally.
  • the dosage can be appropriately determined depending on the administration route and administration method.
  • the active ingredient can be used in the range of 0.01 to 1000 mg per adult day.
  • dosage forms suitable for oral administration include tablets, capsules, powders, fine granules, granules, solutions, and syrups.
  • dosage forms suitable for parenteral administration include injection. Agents, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches, and the like.
  • the preparation can be a solid formulation or a liquid formulation.
  • examples of the preparation include tablets, pills, powders, granules, solutions, suspensions or capsules.
  • excipients such as lactose, starch, calcium carbonate, crystalline cellulose, or silicic acid according to conventional methods; binders such as carboxymethylcellulose, methylcellulose, calcium phosphate, or polyvinylpyrrolidone; sodium alginate, Additives such as disintegrants such as sodium bicarbonate, sodium lauryl sulfate and monoglyceride stearate; lubricants such as glycerin; absorbents such as kaolin and colloidal silica; lubricants such as talc and granular boric acid can be used.
  • Pills, powders or granules are formulated according to conventional methods using additives in the same manner as described above.
  • Liquid preparations such as solutions and suspensions are also formulated according to conventional methods.
  • carriers include glycerol esters such as tricaprylin, triacetin, iodized poppy oil fatty acid ester; water; alcohols such as ethanol; oily bases such as liquid paraffin, coconut oil, soybean oil, sesame oil, and corn oil. .
  • the above-mentioned powders, granules, liquid preparations and the like can also be wrapped in capsules such as gelatin.
  • the pharmaceutically acceptable carrier in the present specification includes other commonly used adjuvants, fragrances, tonicity agents, pH regulators, stabilizers, propellants, adhesives, preservatives and the like as appropriate. Can be selected and included.
  • Ointment bases include, for example, fatty oils such as castor oil, olive oil, sesame oil, safflower oil; lanolin; white, yellow or hydrophilic petrolatum; wax; higher alcohols such as oleyl alcohol, isostearyl alcohol, octyldodecanol, hexyl decanol And glycols such as glycerin, diglycerin, ethylene glycol, propylene glycol, sorbitol, and 1,3-butanediol.
  • fatty oils such as castor oil, olive oil, sesame oil, safflower oil
  • lanolin white, yellow or hydrophilic petrolatum
  • wax higher alcohols
  • oleyl alcohol isostearyl alcohol
  • octyldodecanol hexyl decanol
  • glycols such as glycerin, diglycerin, ethylene glycol, propylene glycol, sorbitol,
  • ethanol dimethyl sulfoxide, polyethylene glycol or the like may be used as a solubilizer.
  • a preservative such as paraoxybenzoic acid ester, sodium benzoate, salicylic acid, sorbic acid or boric acid; an antioxidant such as butylhydroxyanisole or dibutylhydroxytoluene may be used.
  • absorption promoters such as diisopropyl adipate, diethyl sebacate, ethyl caproate, ethyl laurate may be added.
  • the compound of the present invention can also be used after forming an inclusion compound with ⁇ , ⁇ , ⁇ -cyclodextrin, methylated cyclodextrin or the like.
  • Ointment can be manufactured by a normal method.
  • the cream an oil-in-water cream is preferable in terms of stabilizing the compound of the present invention.
  • the base fatty oils, higher alcohols, glycols and the like are used as described above, and emulsifiers such as diethylene glycol, propylene glycol, sorbitan monofatty acid ester, polysorbate 80, and sodium lauryl sulfate are used. Further, a preservative and an antioxidant as described above may be added as necessary. Further, as in the case of an ointment, it can also be used as an inclusion compound for cyclodextrin and methylated cystodextrin.
  • the cream can be produced by a usual method.
  • Lotion agents include suspension type, emulsion type, and solution type lotion agents.
  • the suspension lotion is obtained by using a suspending agent such as sodium alginate, tragacanth or sodium carboxymethylcellulose, and adding an antioxidant or a preservative as necessary.
  • the emulsification type lotion is obtained by an ordinary method using an emulsifier such as sorbitan monofatty acid ester, polysorbate 80, sodium lauryl sulfate.
  • the solution-type lotion is preferably an alcohol-type lotion and can be obtained by an ordinary method using an alcohol such as ethanol. As a liquid agent, what melt
  • dosage forms such as pasta agents, cataplasms, and aerosols can be mentioned.
  • Such a preparation can be produced by a usual method.
  • the preparation for nasal administration is given as a liquid or powder composition.
  • the base of the liquid agent water, saline, phosphate buffer, acetate buffer and the like are used, and a surfactant, an antioxidant, a stabilizer, a preservative, and a viscosity imparting agent may be further included.
  • the base of the powdery agent is preferably a water-absorbing one.
  • polyacrylic acid salts such as water-soluble sodium polyacrylate, calcium polyacrylate, and ammonium polyacrylate, methylcellulose, hydroxyethylcellulose, hydroxy Cellulose lower alkyl ethers such as propyl cellulose and sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, amylose, pullulan and the like, and poorly water-soluble crystalline cellulose, ⁇ -cellulose, cellulose such as sodium carboxymethyl cellulose, hydroxypropyne starch , Starches such as carboxymethyl starch, cross-linked starch, amylose, amylopectin, pectin, proteins such as gelatin, casein, sodium caseinate, Examples include gums such as rabia gum, tragacanth gum and glucomannan, polyvinylpolypyrrolidone, crosslinked polyacrylic acid and its salts, crosslinked vinyl polymers such as crosslinked polyvinyl alcohol and polyhydroxyethyl methacrylate, etc. May
  • Formulations for administration by injection are given as sterile aqueous or non-aqueous solutions, suspensions, or emulsifiers.
  • Non-aqueous solutions or suspensions are pharmaceutically acceptable carriers such as vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable organic esters such as ethyl oleate, iodized poppy oil fatty acid esters
  • Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents and may be sustained release.
  • solutions, suspensions, and emulsifiers can be sterilized by appropriately performing, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation.
  • a sterile solid preparation can be produced and used by dissolving in sterile water or a sterile solvent for injection immediately before use.
  • the compound of the present invention can also be used after forming an inclusion compound with ⁇ , ⁇ , ⁇ -cyclodextrin, methylated cyclodextrin or the like. Moreover, the injection in the form of lipolysis may be used.
  • Example 1 Effect of NEt-3IP in an allergic rhinitis mouse model
  • the allergic rhinitis mouse model is a BALB / c male mouse.
  • 1 ⁇ g of the antigen ovalbumin and 100 ⁇ g of the aluminum hydroxide gel adjuvant are suspended in 0.2 ml of physiological saline and sensitized. , 5, 14, and 21 days.
  • ovalbumin physiological saline solution 100 mg / ml
  • mice Prior to the start of the experiment, mice were placed in an observation cage (width 31 cm, depth 18 cm, height 25 cm) and acclimated to the environment for 10 minutes. 2 ⁇ l of ovalbumin physiological saline solution (100 mg / ml) was intranasally administered into both nasal cavities with a micropipette and then returned to the observation cage to measure allergic rhinitis symptoms. Allergic rhinitis symptoms were evaluated by measuring the number of sneezing reactions and nasal scratching behaviors elicited immediately after the instillation of the antigen for 30 minutes.
  • the RXR agonist was orally administered to the mouse model 3 hours before antigen induction.
  • a NEt-3IP solution prepared by dissolving 20 mg of the compound represented by the following formula IV (NEt-3IP) in 10 ml of physiological saline was prepared. 0.1 g ml was administered per g.
  • a solvent was administered instead of the NEt-3IP solution.
  • Example 2 Effect of NEt-3IP in an allergic rhinitis mouse model (2)
  • the allergic rhinitis mouse model produced by the same method as in Example 1 was observed for antigen-induced nasal scratching behavioral response by nasal administration of ovalbumin physiological saline as in Example 1.
  • the NEt-3IP solution was orally administered to the mouse model 3 hours before antigen induction by the same method as in Example 1.
  • a solvent was administered instead of the NEt-3IP solution.
  • Example 3 Effect of NEt-3IP in an allergic rhinitis mouse model (3)
  • the allergic rhinitis mouse model produced by the same method as in Example 1 was observed for the antigen-induced sneezing reaction and nasal scratching behavior in which ovalbumin physiological saline was administered nasally as in Example 1.
  • a NEt-3IP solution was prepared in the same manner as in Example 1, and a low dose (3 mg / kg) was orally administered once a day for 5 consecutive days, 3 hours before antigen induction.
  • a solvent was administered instead of the NEt-3IP solution.
  • Example 4 Effect of NEt-3IP on histamine-induced dorsal skin scratching behavior in mice ICR male mice were used as experimental animals. First, an operation was performed in which a small powerful magnet (1 mm wide, 3 mm long) was embedded in the hind limb of the mouse, and the experiment was started after a minimum of one day had passed since this operation. Pruritus behavior was induced by intradermal administration of histamine (100 nmol) physiological saline solution at a volume of 0.05 ml / site to the rostral dorsal region of a shaved mouse using a 30G injection needle.
  • the mouse After initiating the reaction, the mouse is placed in an observation cage (width 31 cm, depth 18 cm, height 25 cm), and the number of scratching behaviors by the hind limbs for 60 minutes is automatically measured using an automatic scratching behavior measuring device (MicroAct: Neuroscience) Measured.
  • an automatic scratching behavior measuring device MicroAct: Neuroscience
  • the NEt-3IP solution was orally administered to the mice 3 hours before histamine induction.
  • a solvent was administered instead of the NEt-3IP solution.
  • Example 5 Effect of NEt-3IP on substance P-induced dorsal skin scratching behavior in mice ICR male mice were used as experimental animals. First, an operation was performed in which a small powerful magnet (1 mm wide, 3 mm long) was embedded in the hind limb of the mouse, and the experiment was started after a minimum of one day had passed since this operation. Pruritus behavior was induced by intradermal administration of substance P (100 nmol) physiological saline solution at a volume of 0.05 ml / site into the rostral dorsal region of a shaved mouse using a 30G injection needle.
  • substance P 100 nmol
  • physiological saline solution at a volume of 0.05 ml / site into the rostral dorsal region of a shaved mouse using a 30G injection needle.
  • the mouse After initiating the reaction, the mouse is placed in an observation cage (width 31 cm, depth 18 cm, height 25 cm), and the number of scratching behaviors by the hind limbs for 60 minutes is automatically measured using an automatic scratching behavior measuring device (MicroAct: Neuroscience) Measured.
  • an automatic scratching behavior measuring device MicroAct: Neuroscience
  • NEt-3IP solution was orally administered to the mice 3 hours before substance P induction.
  • a solvent was administered instead of the NEt-3IP solution.
  • the allergic rhinitis mouse model is a BALB / c male mouse.
  • 1 ⁇ g of the antigen ovalbumin and 100 ⁇ g of the aluminum hydroxide gel adjuvant are suspended in 0.2 ml of physiological saline and sensitized. , 5, 14, and 21 days.
  • ovalbumin physiological saline solution 100 mg / ml was intranasally administered into each nasal cavity by 2 ⁇ l nasally three times a week as a local sensitization.
  • mice Prior to the start of the experiment, mice were placed in an observation cage (width 31 cm, depth 18 cm, height 25 cm) and acclimated to the environment for 10 minutes.
  • the ovalbumin physiological saline solution was intranasally administered into both nasal nasal cavities and then returned to the observation cage to measure allergic rhinitis symptoms.
  • Allergic rhinitis symptoms were evaluated by measuring the number of sneezing reactions and nasal scratching behaviors elicited immediately after the instillation of the antigen for 30 minutes.
  • RXR agonist was orally administered 3 times a week from 28 to 63 days after the first sensitization, 3 hours before antigen induction.
  • prepare NEt-3IP solutions in which 20 mg of the compound represented by formula IV (NEt-3IP) is dissolved in 10 ml of physiological saline, 0.1 mg / kg, 1 mg / kg and 10 mg / kg. It administered so that it might become. In the case of 10 mg / kg administration, 0.1 mg / ml was administered per 20 kg of body weight.
  • a solvent was administered instead of the NEt-3IP solution. The protocol for repeated administration is shown in FIG.
  • FIG. 7A a reduction in the number of sneezing was observed depending on the dose of NEt-3IP, and RXR agonists may be effective against sneezing, which is one of allergic symptoms. Indicated.
  • FIG. 7B a reduction in the number of nasal scratching behaviors was observed depending on the dose of NEt-3IP, and RXR agonists were effective against nasal itching, which is one of allergic symptoms. It was shown that there is.
  • the allergic rhinitis mouse model is a BALB / c male mouse.
  • 1 ⁇ g of the antigen ovalbumin and 100 ⁇ g of the aluminum hydroxide gel adjuvant are suspended in 0.2 ml of physiological saline and sensitized. , 5, 14, and 21 days.
  • ovalbumin physiological saline solution 100 mg / ml was intranasally administered into each nasal cavity by 2 ⁇ l nasally three times a week as a local sensitization. After the first sensitization day 56, it was used for drug efficacy evaluation.
  • mice Prior to the start of the experiment, mice were placed in an observation cage (width 31 cm, depth 18 cm, height 25 cm) and acclimated to the environment for 10 minutes. 2 ⁇ l of ovalbumin physiological saline solution (100 mg / ml) was intranasally administered into both nasal cavities with a micropipette and then returned to the observation cage to measure allergic rhinitis symptoms. Allergic rhinitis symptoms were evaluated by measuring the number of sneezing reactions and nasal scratching behaviors elicited immediately after the instillation of the antigen for 30 minutes.
  • the RXR agonist was orally administered to the mouse model 3 hours before antigen induction.
  • RXR agonist 20 mg of the compound (NEt-3IB) shown in Table 1 was dissolved in 10 ml of physiological saline and administered at 30 mg / kg.
  • a solvent was administered instead of the NEt-3IB solution.
  • Example 8 Effect of NEt-3IB in an allergic rhinitis mouse model (2)
  • the allergic rhinitis mouse model produced by the same method as in Example 7 was observed for the antigen-induced nasal scratching behavioral response by nasal administration of ovalbumin physiological saline as in Example 1.
  • the NEt-3IB solution was orally administered to the mouse model 3 hours before antigen induction by the same method as in Example 7.
  • a solvent was administered instead of the NEt-3IB solution.
  • Example 9 Effect of repeated administration of NEt-3IP and duration of action
  • ovalbumin physiological saline is administered nasally to a mouse model of allergic rhinitis prepared by the same method as in Example 1.
  • Antigen-induced sneezing reaction and nasal scratching behavior were observed.
  • a NEt-3IP solution was prepared in the same manner as in Example 1, and a low dose (3 mg / kg) was orally administered once a day for 5 consecutive days, 3 hours before antigen induction.
  • a solvent was administered instead of the NEt-3IP solution.
  • the administration protocol is shown in FIG.
  • Example 10 Effect of PPAR antagonist on nasal symptom suppression effect of NEt-3IP
  • ovalbumin physiological saline was administered nasally to a mouse model of allergic rhinitis prepared by the same method as in Example 1. Antigen-induced nasal scratching behavioral responses were observed.
  • NEt-3IP solution was orally administered to the above mouse model by the same method as in Example 1 3 hours before antigen induction, and each non-selective PPAR antagonist (antagonist) (BADGE) was administered with NEt-3IP.
  • BADGE non-selective PPAR antagonist
  • An intraperitoneal administration (ip) was performed one minute before, or a PPAR ⁇ selective antagonist (GW6471) or a PPAR ⁇ selective antagonist (GW9662) was administered intranasally (in) 10 minutes before antigen induction.
  • Example 11 Effect of LXR antagonist on nasal symptom suppression effect of NEt-3IP
  • ovalbumin physiological saline was administered nasally to a mouse model of allergic rhinitis prepared by the same method as in Example 1.
  • Antigen-induced nasal scratching behavioral responses were observed.
  • NEt-3IP solution was orally administered to the mouse model by the same method as in Example 1 3 hours before antigen induction, and each type of subtype selective LXR antagonist (AA-23) was administered 10 minutes before antigen induction. Intranasal administration (in).
  • antagonism was observed for the effect of NEt-3IP on improving nasal symptoms in a dose-dependent manner with AA-23.
  • the antiallergic agent of the present invention containing an RXR agonist as an active ingredient has a significant dose-dependent effect in a mouse allergic rhinitis model. Since RXR agonists do not exhibit cyclooxygenase inhibitory activity, they do not affect prostaglandin production and do not induce peptic ulcer, a common side effect of steroids. In addition, unlike steroids, RXR agonists do not affect the production of endogenous corticosteroids by feedback, and therefore do not induce adrenal insufficiency or withdrawal syndrome.
  • the novel antiallergic agent of the present invention can be said to be an excellent antiallergic agent with few side effects and can be used for the prevention or treatment of allergic diseases.
  • many antiallergic agents cannot be used to treat chronic and severe allergic symptoms, whereas the antiallergic agent of the present invention is also used for chronic and severe allergic diseases. Is expected to do.

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Abstract

La présente invention concerne un nouvel agent antiallergique qui peut agir efficacement sur Les maladies allergiques et qui présente des effets secondaires indésirables réduits. L’agent antiallergique comprend un agoniste du RXR en tant que principe actif. L’agoniste du RXR à utiliser en tant que principe actif pour l’agent antiallergique peut prévenir des maladies allergiques à l’aide d’un mécanisme d’action différent de celui de l’activité d’activation des récepteurs des glucocorticoïdes d’un stéroïde. Alors qu’un stéroïde produit divers effets secondaires indésirables par l’intermédiaire d’un récepteur de glucocorticoïde (GR) qui est l’un des récepteurs nucléaires, l’agoniste du RXR n’agit pas sur un GR et peut donc être utilisé comme un nouvel agent antiallergique qui peut agir efficacement sur les maladies allergiques et qui présente des effets secondaires indésirables réduits.
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US11576881B2 (en) 2011-12-13 2023-02-14 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11690832B2 (en) 2016-03-10 2023-07-04 Io Therapeutics Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones
US11896558B2 (en) 2021-12-07 2024-02-13 Io Therapeutics, Inc. Use of an RXR agonist and taxanes in treating Her2+ cancers
US11998521B2 (en) 2021-12-07 2024-06-04 Io Therapeutics, Inc. Use of an RXR agonist in treating drug resistant HER2+ cancers

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US11793781B2 (en) 2011-12-13 2023-10-24 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11576881B2 (en) 2011-12-13 2023-02-14 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11103489B2 (en) 2015-06-30 2021-08-31 National University Corporation Okayama University Drug for preventing or treating inflammatory bowel disease
CN107708696A (zh) * 2015-06-30 2018-02-16 国立大学法人冈山大学 炎症性肠病的预防或治疗用药剂
JPWO2017043616A1 (ja) * 2015-09-10 2018-06-28 国立大学法人 岡山大学 炎症性呼吸器疾患の予防又は治療用医薬組成物
US11026932B2 (en) 2015-09-10 2021-06-08 National University Corporation Okayama University Medicinal composition for preventing or treating inflammatory respiratory disease
TWI645851B (zh) * 2015-09-10 2019-01-01 國立大學法人岡山大學 視黃醇類ｘ受體促效劑之用途
WO2017043616A1 (fr) * 2015-09-10 2017-03-16 国立大学法人 岡山大学 Composition médicamenteuse pour la prévention ou le traitement d'une maladie respiratoire inflammatoire
CN108025075A (zh) * 2015-09-10 2018-05-11 国立大学法人冈山大学 炎症性呼吸器官疾病的预防或治疗用医药组合物
US11690832B2 (en) 2016-03-10 2023-07-04 Io Therapeutics Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones
US11690831B2 (en) 2016-03-10 2023-07-04 Io Therapeutics, Inc. Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones
US11517549B2 (en) 2017-09-20 2022-12-06 Io Therapeutics, Inc. Treatment of disease with esters of selective RXR agonists
US11896558B2 (en) 2021-12-07 2024-02-13 Io Therapeutics, Inc. Use of an RXR agonist and taxanes in treating Her2+ cancers
US11998521B2 (en) 2021-12-07 2024-06-04 Io Therapeutics, Inc. Use of an RXR agonist in treating drug resistant HER2+ cancers

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