JP5542059B2 - Antiallergic agent containing RXR agonist as active ingredient - Google Patents

Description

  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.

  This application claims the priority of Japanese Patent Application No. 2008-262580, which is incorporated herein by reference.

  An 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 the reaction with T lymphocytes takes 24 to 48 hours. 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.

  At present, antiallergic agents other than steroids cannot be used as therapeutic agents for allergic diseases because they are not sufficiently effective. On the other hand, 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 . Currently, what is required in the treatment of allergic diseases is the development of drugs that have the same efficacy as steroids and have reduced side effects.

  There are 48 known nuclear receptors in humans that control gene transcription in response to the binding of chemicals present in the nucleus. Among them, it is known that a compound targeting a peroxisome proliferator-responsive receptor (PPAR) whose transcription is regulated by a fatty acid has an antiallergic action (Non-patent Documents 1-3). PPAR does not function alone, but forms a PPAR-RXR dimer with retinoid X receptor (hereinafter abbreviated as “RXR”), which is one of the nuclear receptors, and exerts its action.

  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. In addition to PPAR and thyroid hormone receptor thyroid hormone receptor (TR), there are 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. (Non-patent document 5).

For example, 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 the nuclear receptor heterodimer containing RXR. For example, 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). Furthermore, a carcinogenesis preventing effect by RXR agonist alone or in combination with tamoxifen has been reported (Non-patent Document 9). The effectiveness of RXR agonists in taxol-resistant cancer has also been reported (Non-patent Document 10). In addition, the anti-angiogenic action of RXR agonists has been reported (Non-patent Document 11). In addition, 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.

International Publication WO2008 / 105386 Pamphlet

J Int Med Res., 36 (4), 830-6, 2008 Chest., 134 (1), 152-7, 2008 Otolaryngol Head Neck Surg., 139 (1), 124-30, 2008 Science, 290, pp.2140-2144, 2000 Cell, 83, pp.841-850, 1995 AmnoLake Tablets 2mg <Tamivalotene> Nippon Shinyaku sales package insert (prepared in June 2005) Journal of Medicinal Chemistry, 37, pp.1508-1517, 1994 Cancer Research, 58, pp.479-484, 1998 Cancer Letters, 201, pp.17-24, 2003 Clinical Cancer Research, 10, pp8656-8664, 2004 British Journal of Cancer, 94, pp.654-660, 2006 Nature, 386, pp.407-410, 1997

  An object of the present invention is to provide a novel antiallergic agent that acts effectively on allergic diseases and has reduced side effects.

  As a result of intensive studies to solve the above problems, the present inventors have found that RXR agonists have an antiallergic effect and completed the present invention.

（式中、R¹ 及びR ² は、それぞれ独立して直線若しくは分岐状のアルキル基である。R¹Oは、X¹に対しオルト位及びX²に対しパラ位に位置し、R ² は、X ¹ 及びX ² に対しメタ位に位置する。
Wは、NR³又はCR³であり、R³は水素又は直線、分岐状、若しくは環状のアルキル基から選択される。
X¹は、CHである。
X ² は、CH若しくはNから選択される。
Y¹ 及びY ² は、それぞれ独立してCH若しくはNから選択される。
Zは、-COOH、-CH＝CH-COOH、-CONHOH又は-CH＝CH-CONHOHでありY ¹ 及びY ² に対してメタ位に位置する。）
２．RXR作動性物質のWがNR ³ （R ³ は前記と同意義である）である、前項１に記載の新規抗アレルギー剤。
３．RXR作動性物質のX ² がCHである前項１又は２に記載の新規抗アレルギー剤。
４．RXR作動性物質のY ¹ 及びY ² がともにNである、前項１〜３のいずれか１に記載の新規抗アレルギー剤。
５．RXR作動性物質のY ¹ がNであり、Y ² がCHである、前項１〜３のいずれか１に記載の新規抗アレルギー剤。
６．RXR作動性物質が、以下の式IVで表される化合物である前項１に記載の新規抗アレルギー剤。

７．アレルギーが、アレルギー性鼻炎である、前項１〜６のいずれかに記載の新規アレルギー剤。 That is, this invention consists of the following.
1. A novel antiallergic agent comprising an RXR agonist consisting of a compound represented by the following general formula I as an active ingredient.

(Wherein, R ¹ and R ² are each independently linear or branched alkyl groups der and Ru. R ¹ O is located in the para position relative to the ortho position and X ² to X ^1, R ² Is in the meta position relative to X ¹ and X ² .
W is NR ³ or CR ³ and R ³ is selected from hydrogen or a linear, branched, or cyclic alkyl group.
X ¹ is, Ru CH der.
X ² is selected from CH or N.
Y ¹ and Y ² are each independently selected from CH or N.
Z is —COOH, —CH═CH—COOH, —CONHOH or —CH═CH—CONHOH, and is located at the meta position relative to Y ¹ and Y ² . )
2. 2. The novel antiallergic agent according to item 1 above, wherein W of the RXR agonist is NR ³ (R ³ is as defined above) .
3. Novel anti-allergic agent according to item 1 or 2 X ² of the RXR agonist is is CH.
4). 4. The novel antiallergic agent according to any one of 1 to 3 above, wherein Y ¹ and Y ² of the RXR agonist are both N.
5. A Y ¹ of RXR agonist is N, Y ² is CH, and novel antiallergic agent according to any one of the preceding 1 to 3.
6). 2. The novel antiallergic agent according to item 1 above, wherein the RXR agonist is a compound represented by the following formula IV.

7). 7. The novel allergic agent according to any one of 1 to 6 above, wherein the allergy is allergic rhinitis.

  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.

  In particular, 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. On the other hand, RXR receptor-related compounds (rexinoid compounds) are reported to act on Th2-type lymphocytes but not Th1-type lymphocytes (J Immunol., 176 (9), pp.5161-5166). Therefore, side effects such as induction and hatred of infectious diseases are not expected.

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 | guidance | derivation of the back skin in a mouse | mouth. Example 4 It is a figure which shows the effect of the RXR agonist (NEt-3IP) with respect to the substance P induction | guidance | derivation of the back skin in a mouse | mouth. (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. (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)

  Regarding the novel antiallergic agent comprising the RXR agonistic substance of the present invention as an active ingredient, 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 .

（式中、R¹は、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアリール基からなる群から選択される。
R²は、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルコキシ基、アルキル基、アルケニル基、アルキニル基及びアリール基からなる群から選択される。
Wは、NR³又はCR³であり、R³は水素、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアリール基から選択される。
X¹は、CH若しくはNから選択される。
Y¹は、CH若しくはNから選択される。
X²は、CH、CR⁴、若しくはNから選択される。
Y²は、CH、CR⁴、若しくはNから選択される。
R⁴は、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基、アルコキシ基、ハロゲン、ニトロ基及びアミノ基から選択される。
Zは、直接、若しくは飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基を介したカルボン酸、カルボン酸エステル、又はヒドロキサム酸から選択される。）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.
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. )

（式中、R⁵は直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアリール基からなる群から選択される。
R⁶は分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基からなる群から選択される。
R³は水素、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアリール基から選択される。
X¹は、CH若しくはNから選択される。
Y¹は、CH若しくはNから選択される。
Y²は、CH、CR⁷、若しくはNから選択される。
R⁷は、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアルコキシ基から選択される。
Zは、直接、若しくは飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基を介したカルボン酸、カルボン酸エステル、又はヒドロキサム酸から選択される。）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 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. )

（式中、R⁵は直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアリール基からなる群から選択される。
R⁶は分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基からなる群から選択される。
R³は水素、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアリール基から選択される。
X²は、CH、CR⁴、若しくはNから選択される。
R⁴は、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基、アルコキシ基、ハロゲン、ニトロ基及びアミノ基から選択される。
Y¹は、CH若しくはNから選択される。
Y²は、CH、CR⁷、若しくはNから選択される。
R⁷は、直線若しくは分岐状の、非置換若しくは置換の、飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基及びアルコキシ基から選択される。
Zは、直接、若しくは飽和若しくは不飽和の、アルキル基、アルケニル基、アルキニル基を介したカルボン酸、カルボン酸エステル、又はヒドロキサム酸から選択される。）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 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. )

  In the general formulas I to III, the alkyl group, alkenyl group, and alkynyl group may be a cycloalkyl group, a cycloalkenyl group, and a cycloalkynyl group, respectively. As used herein, cycloalkyl means a saturated cyclic carbon chain, and 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.
In the general formula II, 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, and Y ¹ And compounds located at the meta position relative to Y ² and R ³ selected from ethyl and isopropyl. Examples of the carboxylic acid ester include methyl ester, ethyl ester, and t-butyl ester.

Other preferable compounds of the present invention further include the following compounds.
In the general formula II, 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 , and R ³ is an ethyl group. Examples of 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.
In general formula III, 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. And compounds located at the meta position with respect to Y ¹ and Y ² , wherein R ³ is selected from ethyl and isopropyl. Examples of the carboxylic acid ester include methyl ester, ethyl ester, and t-butyl ester.

  More specifically, compounds shown in Table 1 are listed.

  In the present invention, the compound represented by any one of the general formulas I to III may be a pharmaceutically acceptable salt. In addition, in the compound represented by any one of the general formulas I to III or a salt thereof, when there are isomers (for example, optical isomers, geometric isomers, and compatible isomers), the present invention refers to those isomers. And also solvates, hydrates and crystals of various shapes.

In the present invention, 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 For example, 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.

  Examples of the acid addition salt 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, p-toluenesulfonate Salts; for example, acidic amino acids such as aspartate and glutamate.

  For the production method of the RXR agonist in the present invention, for example, the method described in Patent Document 1 (International Publication WO2008 / 105386 pamphlet) can be referred to. 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.

  In the present invention, 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. Can be used for In the present specification, 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.

  When the antiallergic agent comprising the RXR agonist of the present invention as an active ingredient is used prophylactically or therapeutically, it can be administered orally or parenterally in an effective amount. The dosage can be appropriately determined depending on the administration route and administration method. For example, in the case of oral administration, the active ingredient can be used in the range of 0.01 to 1000 mg per adult day.

  Examples of dosage forms suitable for oral administration include tablets, capsules, powders, fine granules, granules, solutions, and syrups. Examples of dosage forms suitable for parenteral administration include injection. Agents, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches, and the like.

  For oral administration, it can be a solid formulation or a liquid formulation. Examples of the preparation include tablets, pills, powders, granules, solutions, suspensions or capsules. When preparing tablets, 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 can be formulated according to conventional methods using additives as described above. Liquid preparations such as solutions and suspensions are also formulated according to conventional methods. Examples of 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.

  Examples of dosage forms for transdermal administration include ointments, creams, lotions, and liquids. 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 the like; glycols such as glycerin, diglycerin, ethylene glycol, propylene glycol, sorbitol, and 1,3-butanediol. Further, ethanol, dimethyl sulfoxide, polyethylene glycol or the like may be used as a solubilizer. If necessary, 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.

  In order to promote percutaneous absorption, absorption promoters such as diisopropyl adipate, diethyl sebacate, ethyl caproate, ethyl laurate may be added. For stabilization, the compound of the present invention can also be used after forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like.

  An ointment can be manufactured by a normal method. As the cream, an oil-in-water cream is preferable in terms of stabilizing the compound of the present invention. As 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.

  Examples of the lotion include suspension type, emulsion type, and solution type lotion. 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 | dissolved in alcohol solutions, such as ethanol, and added antioxidant and a preservative as needed is mentioned.

  In addition to these dosage forms, dosage forms such as pasta agents, cataplasms, and aerosols can be used. Such a preparation can be produced by a usual method.

  Formulations for nasal administration are given as liquid or powdered compositions. As 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. For example, 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, α-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 be. Furthermore, you may add antioxidant, a coloring agent, a preservative, an antiseptic | preservative, a corrigent etc. to a powdery agent. Such liquid agents and powder agents can be administered using, for example, a spray device.

  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 And Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents and may be sustained release. These solutions, suspensions, and emulsifiers can be sterilized by appropriately performing, for example, filtration through a bacteria retaining filter, blending of a bactericidal agent, or irradiation. In addition, 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 α, β, γ-cyclodextrin, methylated cyclodextrin, or the like. Moreover, the injection in the form of lipolysis may be used.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the scope of the following examples.

(Example 1) Effect of NEt-3IP in an allergic rhinitis mouse model (1)
The allergic rhinitis mouse model is a BALB / c male mouse. First, as a whole body sensitization, 1 μg of the antigen ovalbumin and 100 μg of the aluminum hydroxide gel adjuvant are suspended in 0.2 ml of physiological saline and sensitized. , 5, 14, and 21 days. Furthermore, from the 28th day of the first sensitization, ovalbumin physiological saline solution (100 mg / ml) was intranasally administered into each nasal cavity by 2 μl nasally three times a week as a local sensitization. After the first sensitization day 56, it was used for drug efficacy evaluation. 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 μl 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.

  RXR agonists were orally administered to the mouse model 3 hours prior to antigen challenge. As an RXR agonist, a NEt-3IP solution in which 20 mg of the compound represented by the following formula IV (NEt-3IP) was dissolved in 10 ml of physiological saline was prepared. 0.1 ml per g was administered. As a control, a solvent was administered instead of the NEt-3IP solution.

  As a result, as shown in FIG. 1, 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.

(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.

  NEt-3IP solution was orally administered to the mouse model 3 hours before antigen induction by the same method as in Example 1. As a control, a solvent was administered instead of the NEt-3IP solution.

  As a result, as shown in Fig. 2, 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.

(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 for the above mouse model by the same method 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. As a control, a solvent was administered instead of the NEt-3IP solution.

  As a result, as shown in FIG. 3, a reduction in the number of sneezing reactions and nasal scratching behavior was observed at a low dose of NEt-3IP (3 mg / kg). It was shown to have a stronger effect on the symptoms sneezing and nasal itching compared to the control group.

(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. 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.

  NEt-3IP solution was orally administered to the mice 3 hours before histamine induction by the same method as in Example 1. As a control, a solvent was administered instead of the NEt-3IP solution.

  As a result, as shown in FIG. 4, a reduction in histamine-induced dorsal skin scratching behavior was observed in a dose-dependent manner with NEt-3IP, and RXR agonists are one of the causes of itchiness in allergic symptoms. It was shown to be effective against skin itch caused by.

(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. 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.

  To the mice, NEt-3IP solution was orally administered 3 hours before substance P induction by the same method as in Example 1. As a control, a solvent was administered instead of the NEt-3IP solution.

  As a result, as shown in FIG. 5, a reduction in substance P-induced dorsal skin scratching behavior was observed in a dose-dependent manner with NEt-3IP, and RXR agonists are one of the causes of itching in allergic symptoms. It was shown that the substance P has an effect on the itchy skin feeling.

(Example 6) Effect of NEt-3IP in an allergic rhinitis mouse model (4)
The allergic rhinitis mouse model is a BALB / c male mouse. First, as a whole body sensitization, 1 μg of the antigen ovalbumin and 100 μg of the aluminum hydroxide gel adjuvant are suspended in 0.2 ml of physiological saline and sensitized. , 5, 14, and 21 days. Furthermore, from the 28th day of the first sensitization, ovalbumin physiological saline solution (100 mg / ml) was intranasally administered into each nasal cavity by 2 μl nasally three times a week as a local sensitization. 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.

  From the 28th day to the 63rd day after the first sensitization, RXR agonist was orally administered to the mouse model three times a week 3 hours before antigen induction. As an RXR agonist, prepare NEt-3IP solution 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 ml was administered per 20 g body weight. As a control, a solvent was administered instead of the NEt-3IP solution. The protocol for repeated administration is shown in FIG.

  As a result, as shown in 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. In addition, as shown in 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.

(Example 7) Effect of NEt-3IB in an allergic rhinitis mouse model (1)
The allergic rhinitis mouse model is a BALB / c male mouse. First, as a whole body sensitization, 1 μg of the antigen ovalbumin and 100 μg of the aluminum hydroxide gel adjuvant are suspended in 0.2 ml of physiological saline and sensitized. , 5, 14, and 21 days. Furthermore, from the 28th day of the first sensitization, ovalbumin physiological saline solution (100 mg / ml) was intranasally administered into each nasal cavity by 2 μl nasally three times a week as a local sensitization. After the first sensitization day 56, it was used for drug efficacy evaluation. 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 μl 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.

  RXR agonists were orally administered to the mouse model 3 hours prior to antigen challenge. As an RXR agonist, 20 mg of the compound shown in Table 1 (NEt-3IB) was dissolved in 10 ml of physiological saline and administered at 30 mg / kg. As a control, a solvent was administered instead of the NEt-3IB solution.

  As a result, as shown in FIG. 8, a reduction in the number of sneezing was observed by administration of NEt-3IB, and it was shown that the RXR agonist was effective against sneezing, which is one of allergic symptoms. .

(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.

  NEt-3IB solution was orally administered to the mouse model 3 hours before antigen induction by the same method as in Example 7. As a control, a solvent was administered instead of the NEt-3IB solution.

  As a result, as shown in FIG. 9, a reduction in the number of nasal scratching behaviors was observed by administration of NEt-3IB, and the RXR agonist was effective against nasal pruritus, which is one of allergic symptoms. It has been shown.

(Example 9) Effect of repeated administration of NEt-3IP and duration of action As in Example 1, 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 for the above mouse model by the same method 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. As a control, a solvent was administered instead of the NEt-3IP solution. The administration protocol is shown in FIG.

  As a result, as shown in FIGS. 11A and 11B, in the case of a low dose of NEt-3IP (3 mg / kg), a reduction in the number of sneezing reactions and nasal scratching behavior was observed on the fifth day, and RXR agonists It was shown that there is a stronger effect compared to the control group on sneezing and nasal itching that are allergic symptoms.

(Example 10) Effect of PPAR antagonist on nasal symptom suppression effect of NEt-3IP As in Example 1, 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. An intraperitoneal administration (ip) was performed one minute before, or a PPARα selective antagonist (GW6471) or a PPARγ selective antagonist (GW9662) was administered intranasally (in) 10 minutes before antigen induction.

  As a result, as shown in FIGS. 12 and 13, antagonism was observed in BADGE and GW9662 with respect to the nasal symptom improvement effect by NEt-3IP in a dose-dependent manner, but antagonism by GW6471 was not observed. .

(Example 11) Effect of LXR antagonist on nasal symptom suppression effect of NEt-3IP As in Example 1, 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).

  As a result, as shown in FIG. 13, antagonism was observed for the effect of NEt-3IP on improving nasal symptoms in a dose-dependent manner with AA-23.

  As described above in detail, 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. Central obesity (moon face), induction of diabetes (due to increased blood sugar level), hatred, short stature, femoral head necrosis, low potassium plasma, arteriosclerotic lesion, abnormal fat deposition, wild shoulder, hairy, subcutaneous bleeding, skin Many side effects observed in steroids such as atrophy, abnormal sweating, cataract, glaucoma, ocular protrusion, edema, hypertension, congestive heart failure, arrhythmia, steroid myopathy, leukocytosis, taste abnormalities, olfactory abnormalities, etc. Conceivable.

  As described above, 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. In addition, 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.

Claims (7)

A novel antiallergic agent comprising an RXR agonist consisting of a compound represented by the following general formula I as an active ingredient.

(Wherein, R ¹ and R ² are each independently linear or branched alkyl groups der and Ru. R ¹ O is located in the para position relative to the ortho position and X ² to X ^1, R ² Is in the meta position relative to X ¹ and X ² .
W is NR ³ or CR ³ and R ³ is selected from hydrogen or a linear, branched, or cyclic alkyl group.
X ¹ is, Ru CH der.
X ² is selected from CH or N.
Y ¹ and Y ² are each independently selected from CH or N.
Z is —COOH, —CH═CH—COOH, —CONHOH or —CH═CH—CONHOH, and is located at the meta position relative to Y ¹ and Y ² . ) The novel antiallergic agent according to claim 1, wherein W of the RXR agonist is NR ³ (R ³ is as defined above) . Novel anti-allergic agent according to claim 1 or 2 X ² is CH the RXR agonist. The novel antiallergic agent according to any one of claims 1 to 3, wherein Y ¹ and Y ² of the RXR agonist are both N. A Y ¹ of RXR agonist is N, Y ² is CH, and novel antiallergic agent according to any one of claims 1 to 3. The novel antiallergic agent according to claim 1 , wherein the RXR agonist is a compound represented by the following formula IV.

The novel allergic agent according to any one of claims 1 to 6 , wherein the allergy is allergic rhinitis.

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