HK1224930A1 - Pharmaceutical composition containing glutarimide derivatives, and application thereof for treating eosinophilic diseases - Google Patents

Description

Pharmaceutical compositions comprising glutarimide derivatives and their use for the treatment of eosinophilic diseases

The invention relates to bioactive glutarimide (r у a men) derivative or its medicinal salt as being used for treating eosinophilic disease (a woman з a she yi piji yi ji xi ji shi ji.

Background

Eosinophils (ei з i phi ы) are innate immune cells. It is produced in the bone marrow and preferably circulates in the blood. The main effector function of eosinophils is the immediate release of cytoplasmic granules in response to activation by a variety of stimuli. Cytoplasmic granules contain pro-inflammatory mediators: cytokines, chemokines, lipids and neural mediators, growth factors and cationic proteins. The cationic proteins of eosinophils include 4 classes: major Basic Protein (MBP), Eosinophil Peroxidase (EPO), Eosinophil Cationic Protein (ECP), and eosinophil-derived neurotoxin (EDN). In combination, these proteins have a cytotoxic effect on both infectious microorganisms and host tissues, causing eosinophilic inflammation (e e.a yi з yi phi b), which leads to eosinophilic inflammation [ Hogan SP, Rosenberg HF, Moqbel R, etc.: biological properties and role in health and disease// clean Exp allergy.2008; 38(5): 709-50].

Eosinophil count in blood is usually 0.02-0.3 × 10⁹counts/L, or 0.5% to 5% of total leukocytes. An increased blood eosinophil count relative to normal levels is hypereosinophilia. Hypereosinophilia or hypereosinophilia in large numbers is a condition [ Hof ] when the eosinophil content in the blood is 15% or greater, usually when the total leukocyte count is increasedfman R, Benz jr.ej, Shattil SJ, etc., editors Hematology: basic Principles and practice, 4 th edition philiadelphia, Pa: churchilingston; 2005: 768]。

Elevated eosinophil levels in blood and tissues are associated with diseases of various etiologies and pathogenesis. It includes parasitic invasion; broad spectrum allergic diseases, for example, asthma, rhinitis, nasal polyp, eosinophilic colitis (e.g. e з a, e.g. pluck phi ы й a), eosinophilic syndrome (e.g. mei ji xi ji), xixi celli syndrome (e.g. з g. Rheumatic disease (rheumatoid arthritis, diffuse eosinophilic fasciitis (phi у з, ы й, and phia phi ы й phi), qiu-si syndrome (qiu yi ji zhi ji zhu ji), qiu-si syndrome (zhu ji zhi ji zhu ji ya ji), zhu-si syndrome (zhu ji zhao), nodulation arteritis (piji zhi ji), zhao zhang a), and nodulation arteritis (у з zhao zhu jia ji gao chi li ji shi ji shi ji shi ji shi ji); and pathological conditions of unknown etiology (eosinophilic esophagitis (e з a), e з a phi, i, ei), e, which are unique to the disease (e з a, g zhi ji, ei), e, enterogastritis (e ji (ji; 101: 81-121].

Of the allergic diseases, bronchial asthma is medically most important, which is a chronic inflammatory airway disease characterized by paroxysmal airflow obstruction, airway inflammation, and increased bronchial reactivity to non-specific allergens.

There is a lot of evidence that eosinophils are a key component of the allergic response in asthma. IL-3 and IL-5 secreted by mast cells provide for the accumulation of eosinophils in the lung, with subsequent activation of these cells, which is accompanied by the release of LTC4, eosinophil cationic protein, major basic protein, neurotoxin, Eosinophil Peroxidase (EPO), transforming growth factors and free radicals [ Blanchard C, Rothenberg me. biology of the eosinophil// adv immunol. 2009; 101: 81-121].

The activity of inflammatory processes in asthma has been found to be directly related to the Serum levels of eosinophil cationic protein [ Bjornsson E., Janson C., Hakansson L. et al. Vol.49: 400-407]. Lavage fluid from patients with bronchial asthma has an increased eosinophil count. Eosinophils have low affinity receptors for IgE on their surface and can be directly activated by causal and prominent allergens due to eosinophils. Eosinophils have also been found to have receptors for IL-2, IL-3, IL-5, GM-CSF, PAF and prostaglandins on their cell surface. Through these receptors, the above cytokines and lipid mediators are able to induce the activation of eosinophils, which release mediators (LTC4, PAF) and cytokines (IL-3, IL-4, IL-5, IL-8, GM-CSF, TGF β). Disruption of airway epithelium, which is caused by the action of eosinophil proteins, causes the development of bronchial hyperreactivity and a decrease in airway epithelial barrier function.

Now, since it has been found that there is a clear relationship between eosinophilia in tissues and several fibrotic diseases (endomyocardial fibrosis complicated with liver fibrosis in patients with eosinophilia syndrome, subepithelial fibrosis in nodular sclerosing Hodgkin's disease and bronchial asthma), much attention is being focused on the role of eosinophils in regeneration and remodulation of tissues [ Noguchi H. et al Tissue eosinophilia and eosinophilication in syndrome associated with fibrosis with// am. J. Pathol.1992, Vol.140. page 521-528 ].

Eosinophils are a source of many fibrogenic and growth factors, including transforming growth factor beta (TGF- β), Fibroblast Growth Factor (FGF) -2, Vascular Endothelial Growth Factor (VEGF), Matrix Metalloproteinase (MMP) -9, IL-1 β, IL-13, and IL-17. Clinical trials involving anti-IL-5 antibodies also supported the role of eosinophils in events associated with the deposition of specific matrix proteins in the reticular basement membrane [ Kay AB, Phipps S, Robinson DS.A role for eosinophils in air modification in asthma// Trends immunol 2004, Vol.25, pp.477-82 ].

Currently, the most common method for treating asthma is the use of corticosteroids (budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate) by inhalation. However, corticosteroids function by inducing general immunosuppression and there are adverse side effects caused by their long term administration, such as hypertension, osteoporosis and cataract development [ Barnes pj.new drugs for asthma// Semin Respir Crit Care med.2012; 33(6): 685-94]. Corticosteroids should be administered daily, and thus compliance with the required patient is another problem with successful use of the therapeutic. In addition, there are patients who are not corticosteroid sensitive who require alternative treatment. Selective targeting of eosinophils can overcome the side effects caused by the use of systemic immunosuppressive agents with pleiotropic effects.

Drugs that reduce eosinophilia by inhibiting the interaction between interleukin-5 and the receptor IL-5 Ra on the surface of eosinophils are currently in clinical trials. Such agents include humanized monoclonal anti-IL-5 antibodies (mAt) and concurrent IL-5R α inhibitors.

Among IL-5 neutralizing monoclonal antibodies, SB240563 (e.e pi з у cm a), GlaxoSmith Kline (GlaxoSmith Kline) is most effective. There are reports [ Nair P, Pizzichini MMM, Kjarsgaard M, etc.. Mepolizumab for prednisone-dependent asthma with sputemeosinophilia. NEJM.2009; 360: 985-93 mepiquat chloride treatment of prednisolone dependent asthma patients reduces eosinophilia in blood and sputum and, most importantly, improves patient quality by reducing exacerbation frequency and prednisolone dosage. Another clinical trial showed that administration of anti-IL-5 antibody (mepiquat chloride) to corticosteroid insensitive Asthma patients also resulted in a reduction in exacerbation frequency and improved patient Quality according to AQLQ (asset Quality of life, asthmatic Quality of life questionnaire). In addition to the effect on asthma, this experiment also showed the treatment effect [ Haldar P, Brightling CE, Hargadon B, etc.. Mepolizumab and exarbration of real ocular invasion of nejm.2009.2009 ] on polypoid sinus disease (pi з rf й f 3932 f у f xi h xi. 360: 973-84].

In an independent clinical trial of adults with polypoid sinus disease, meperizumab significantly reduced the levels of ECP and soluble forms of IL-5 ra in the blood, as well as the concentrations of IL-5 ra, IL-6 and IL-1b in the nose, according to the total polyp score, which were associated with disease remission [ Gevaert P, Van bruaere N, catreatt T, et al. 128(5): 989-995].

The use of anti-IL-5 antibodies is not limited to bronchial asthma and polypoid sinus disease. This treatment is also effective in other eosinophil-mediated diseases. For example, in patients with hypereosinophilic syndrome, meperizumab Treatment reduces eosinophilia in the blood and enables a reduction in the administered dose of prednisolone [ Rothenberg ME, Klion AD, Roufosse FE, et al. 358(12): 1215-28]. Treatment of eosinophilic esophagitis patients with Anti-IL-5 antibodies showed improved clinical performance associated with decreased dysphagia and 6-fold decrease in blood eosinophil count, and in some patients decreased esophageal epithelial hyperplasia [ Stein ML, Collins MH, villanuva JM, et al. 118(6): 1312-9]. Clinical trials of drugs in children have shown that patients with no more than 20 eosinophils in the blood in one field of view of the microscope have improved symptoms such as redness, fragility, and sulcus and vertical lines on the esophageal mucosa [ Assa' ad AH, Gupta SK, Collins MH, et al. 141(5): 1593-604].

Meprolimus was also successfully used as treatment of eosinophilic vasculitis (e o з a q xi pi bo pi xi pi у pi xi pi hi Kahn JE, Grandpeix-Guyodo C, Marroun I, etc. stable response time polarization ab in reactive Churg-Strauss syndrome j Allergy Clin im μ l.2010; 125: 267-70]. Monthly administration of meperizumab reduced blood eosinophil count to normal in 28-year-old women, prevented the development of corticosteroid asthma, and improved the condition of the lung parenchyma based on X-ray data [ Kim S, Marigowda G, Oren E, Israel E, Wechsler m.polizumab as a stereo-sparing therapy option in women with Churg-strausssyndrome.j Allergy clininirnunol.2010; 125: 1336-43]. In clinical trials with patients with eosinophilic vasculitis and marked eosinophilia, treatment with meprolimus allowed a reduction in the dose of corticosteroid. Also reduced eosinophilia, but after the end of the trial, exacerbations were repeated [ Oldhoff JM, darrow U, Werfel T, et al. 60(5): 693-6].

It is reported that meprolimus must be used as a treatment for childhood hypereosinophilic syndrome, eosinophilic esophagitis, childhood eosinophilic esophagitis, eosinophilic vasculitis and chronic obstructive bronchitis in the second phase of clinical trials for the treatment of adult asthma, eosinophilic esophagitis, childhood eosinophilic esophagitis and polypoid sinus disease as well as in the third phase of clinical trials [ Amini-Vaughan ZJ, Martinez-Moczygema M, HustonDP. Another drug, rayleigh mab (p e c pi з у cm a bi), Cephalon (which is also humanized monoclonal anti-IL-5 antibody SCH55700), was used in the second phase clinical trial as a treatment for eosinophilia syndrome and raynaud's disease, and in the third phase as a treatment for childhood asthma and eosinophilic esophagitis. All these allow to conclude that selective treatments aimed at reducing eosinophilia are promising approaches to the treatment of diseases mediated by this cell type (bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, polypoid sinus disease, eosinophilic esophagitis, eosinophilic vasculitis and hypereosinophilic syndrome).

However, mAt treatment has several disadvantages. Monoclonal antibodies are expensive therapeutic agents that should be administered for one or two months. One important factor is the problem that patients do not have to follow the physician's instructions, since they visit the physician's office many times to receive a drug injection. In addition, allotypic divergence between patients and therapeutic antibodies can cause monoclonal antibody-based therapies to become ineffective. High doses of mAt and the possibility of immune complex formation may also reduce the efficiency of passive immunization.

Further methods of providing therapeutic agents against pathological conditions characterized by hypereosinophilia are disclosed in WO 97/45448 and WO 03/040164. Application WO 97/45448 provides the use of "modified and variant forms of IL5 molecules capable of antagonizing or reducing IL-5 activity in another way" to ameliorate, reduce or reduce off-normal effects caused by the natural and mutated forms of IL 5. The antagonism is reported to be the result of a variant form of IL5 which binds to the low affinity chain of IL5R but not to the high affinity receptor. Acting in this way, the variants compete with IL5 for binding to its receptor without any effect on the physiological effects of IL 5.

Application WO 03/040164 provides a composition for vaccination targeting the endogenous formation of antibodies against IL-5, IL-13 and eotaxin (e @ t α c у), a key factor for eosinophil maturation, activation, localization and viability. The compositions comprise a virus-like particle and at least one protein or peptide of IL-5, IL-13, and/or eotaxin bound thereto. According to the invention, said composition can be used for the production of a vaccine for the treatment of allergic diseases with an eosinophilic component and as a medicament for the prevention or treatment of allergic diseases with an eosinophilic component.

Application No.8501176 provides for the use of antibodies that bind to IL-5R. These antibodies contain binding sites that recognize the IL-5 receptor (IL-5R) and the Fc fragment. The claimed method reduces eosinophil count in blood, medulla, gastrointestinal tract (e.g., esophagus, stomach, small intestine, and large intestine), or lung, thereby reducing the clinical manifestations of pulmonary asthma and chronic obstructive bronchitis in humans (http:// www.patentgenius.com/patent/8501176. html).

Yong Sup Lee et al, in students on the site-selective N-acetyliminium ionization: the preparation of histamine succinimides by fusing histamine dihydrochloride together with succinic anhydride by heating the starting reagent to 200 ℃ to 230 ℃ for 40 minutes is disclosed in synthesis of (+ -) -glycohidine and (+ -) -glycohidine, Heterocycles, Vol37, No 1.1994.

The disclosure of international application WO 2007/007054 discloses succinimide and glutarimide derivatives of general formula (I) which have an inhibitory effect on DNA methylation in cells, in particular tumour cells. The compounds disclosed in the publication were prepared as follows: an addition reaction between an amino derivative comprising a hydrocarbon chain and the corresponding anhydride or acid, or ester, followed by optional cyclization (if necessary in the presence of a base).

The method of synthesizing glutarimides includes heating a dicarboxylic acid or derivative thereof (e.g., anhydride, diester, etc.) with a primary amine or amide thereof (thermal cyclization) [ weiland-Hilgetag, ekperf Experimental method vorganichheskoi khimi [ Experimental Methods in Organic Chemistry ], n.n. suvorov, m., editors, 1968; page 446 ]; cyclization of monoamides of the corresponding dicarboxylic acids by using a dehydrating agent as a carboxyl activating agent, for example, acetic anhydride [ Shimotori et al, Asymmetric synthesis of lactic acid with lipase catalyst. Flavour and Fragrance Journal, 2007, V.22, No.6, p. 531-539 ]; acetyl chloride [ Ito et al, Chemical Hydrogenation of the amides Catalyzed by CpRu (PN) Complexes and Its Application to the asymmetry Synthesis of Paroxetine// Journal of the American Chemical Society, 2007, V.129, No.2, p.290- ]; carbonyldiimidazoles [ Polnisek, et al, Stereoselective nucleic acids additions to the carbon-nitrogen double bond.3.chiral acyliminium ions/Journal of organic chemistry, 1990, V.55, No.1, p. 215 + 223 ]; glutaric anhydride or succinic anhydride [ Ainhoa apparatus et al, systematic approach to the fused β -carboline system of amino synthesis [2, 3- α ] indolizinones a diene-amino reaction/Tetrahedron Letters, 2003, 44, 8445-.

The international publication of patent application WO 2007/000246 provides a method for the synthesis of glutarimides by alkylation of piperidine-2, 6-dione and pyrrolidine-2, 5-dione with the corresponding halogenated derivatives in DMF, followed by separation of the target substituted imide derivative by preparative chromatography, which is not suitable for large scale synthesis.

Accordingly, the object of the present invention is the use of non-toxic glutarimide derivatives for the effective treatment of eosinophilic diseases, preferably having allergic properties, such as bronchial asthma allergic colitis, eosinophilic colitis, allergic conjunctivitis, atopic dermatitis, churg-si syndrome, anaphylactic shock (alpha, phi, zhu, chi, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, and fibrosis.

Summary of The Invention

The present invention relates to the use of glutarimide derivatives of general formula (I) for the treatment of eosinophilic diseases:

wherein R is₁And R'₁Independently is hydrogen or C₁-C₆Alkyl groups, for example, methyl;

R₂is that

Optionally substituted by C₁-C₆Alkyl substitution, said eosinophilic disease preferably having allergic properties, for example bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg-strauss syndrome, anaphylactic shock, Kunck edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis as disclosed in application RU 2013116826, 4/12/2013.

The inventors found that glutarimide derivatives inhibit eosinophilia in various models of inflammation in all tested media (blood, bronchoalveolar lavage (BAL) and tissue). In particular in the rat model of sephadex-induced pneumonia, glutarimide derivatives reduce eosinophil count in BAL, and in the guinea pig model of ovalbumin-induced asthma, glutarimide derivatives reduce BAL and eosinophilia in blood.

The present invention therefore relates to a therapeutic method for the treatment of an eosinophilic disease, preferably with allergic properties, such as bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg strauss syndrome, anaphylactic shock, Kunck edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis, comprising administering to a patient an effective amount of a glutarimide derivative of general formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to a therapeutic agent for the treatment of an eosinophilic disease, preferably with allergic properties, such as bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg strauss syndrome, anaphylactic shock, Kunck edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis, wherein the therapeutic agent is a glutarimide derivative of general formula (I) or a pharmaceutically acceptable salt thereof.

Another subject of the present invention is a pharmaceutical composition for the treatment of an eosinophilic disease, preferably with allergic properties, such as bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg strauss syndrome, anaphylactic shock, kunck edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis, comprising an effective amount of a glutarimide derivative of general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The synthesis of glutarimide derivatives of the general formula (I) described above is disclosed in application RU 2013116826, 4/12/2013.

The compounds used in the present invention may be prepared by a process comprising: heating the initial dicarboxylic acid monoamide in the organic solvent or in the dehydrating agent itself with the dehydrating agent, optionally with addition of sodium acetate. The dehydrating agent used in the method may include dicarboxylic acid anhydride, organic acid chloroanhydride, and carbonyldiimidazole.

The starting dicarboxylic acid monoamides and the process for their preparation are disclosed in the publication of international application WO 1999/001103.

Detailed Description

Preferred compounds for use in the present invention are compounds of the general formula (I):

wherein R is₁And R'₁Independently hydrogen or methyl;

R₂is that

The most preferred compounds of the present invention are those shown in table 1.

TABLE 1

Pharmaceutically acceptable salts of the compounds according to the invention may include: organic acid addition salts (e.g., formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), inorganic acid addition salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), and salts with amino acids (e.g., aspartate, glutamate, etc.), with hydrochloride and acetate being preferred.

Glutarimide derivatives of general formula (I) have therapeutic activity against eosinophilic diseases.

In particular, the compounds of the invention are useful for the treatment of bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg-strauss syndrome, anaphylactic shock, Kunck edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis.

The compounds according to the invention are administered in an amount effective to provide the desired therapeutic effect.

The compounds of formula (I) may be administered orally, topically, parenterally, intranasally, by inhalation, and rectally in unit dosage forms containing a non-toxic pharmaceutically acceptable carrier.

The term "parenteral administration" as used herein refers to subcutaneous, intravenous, intramuscular injection or infusion.

The compounds according to the invention can be administered to the patient once daily at a dose of 0.1 to 30mg/kg body weight; preferably in a dose of 0.25 to 10mg/kg, once or more times daily.

Furthermore, it should be noted that the specific dose for a particular patient depends on a variety of factors including the activity of the compound used, the age, weight, sex, general health, diet of the patient, and also on the time and route of administration of the therapeutic agent and its rate of excretion from the body, the particular combination of uses of the therapeutic agent, and the severity of the disease in the individual to be treated.

The pharmaceutical compositions according to the invention comprise an amount of a compound of general formula (I) effective to achieve the desired technical result and can be administered in unit dosage forms (e.g. solid, semi-solid or liquid form) comprising as active ingredient a compound according to the invention in admixture with carriers or excipients suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal and intrarectal administration. In such compositions, the active ingredient may be combined with conventional non-toxic pharmaceutically acceptable carriers suitable for the preparation of solutions, tablets, pills, capsules, dragees, suppositories, emulsions, suspensions, ointments, gels and any other dosage forms.

Compounds which can be used as excipients are a variety of compounds, for example sugars (e.g. glucose, lactose or sucrose), mannitol or sorbitol, cellulose derivatives and/or calcium phosphates (e.g. tricalcium phosphate or calcium acid phosphate). As the binder, for example, such substances as: starch pastes (e.g., corn, wheat, rice, and potato starches), gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and/or polyvinylpyrrolidone. If desired, disintegrating agents may be used, such as the above-mentioned starches and carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate).

Additives which may optionally be used include flow control agents and lubricants, for example silica, talc, stearic acid and salts thereof (e.g. magnesium or calcium stearate) and/or propylene glycol.

The core of a coated pellet is usually coated with a layer that is resistant to the action of gastric acid. For this purpose, concentrated solutions of the saccharides may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, and suitable organic solvents or salts thereof.

Additives may also include stabilizers, thickeners, colorants, and fragrances.

As the ointment base, hydrocarbon ointment bases such as white petrolatum and yellow petrolatum (Vaselinum album and Vaselinum flavum), petrolatum (Oleum Vaselini), and white ointment and liquid ointment (Unguentum album and Unguentum flavum), and substances such as paraffin wax or wax may be used as additives for providing firmer texture; absorbent ointment bases such as hydrophilic petrolatum (Vaselinum hydrophyllicum), lanolin (Lanolin), and cold creams (Unguentum lenses); water-removable ointment bases, such as hydrophilic ointments (Unguentum hydrophyllum); water-soluble ointment bases, such as polyethylene glycol ointment (Unguentum GlycolisPolayaethylene); bentonite matrix, and the like.

Methylcellulose, sodium carboxymethylcellulose, propoxylcellulose, polyethylene glycol or polyethylene oxide or carbopol may be used as the gel matrix.

The base for suppositories may be a water-insoluble base such as cocoa butter; water-soluble or water-miscible bases, such as gelatin-glycerol or polyethylene oxide bases; or a combination base, such as a soap-glycerin base.

When prepared in unit dosage form, the amount of active agent used in combination with the carrier will vary depending upon the recipient being treated and the particular method of administration of the therapeutic agent.

For example, when the compound according to the invention is used in the form of a solution for injection, the amount of active agent in the solution is at most 5% by weight. The diluent may be 0.9% sodium chloride solution, distilled water, novocaine for injection solution, ringer's solution, glucose solution or a specific solubilizing aid. When the compounds according to the invention are administered in the form of tablets or suppositories, the amount is up to 200mg per unit dosage form.

The dosage forms according to the invention are prepared by conventional methods, such as mixing, granulating, forming coated pellets, dissolving and freeze-drying.

It should be noted that the compounds according to the invention do not have any side effects and contraindications for administration. Furthermore, in the toxicity test of the compounds according to the invention, no lethal cases were registered in experimental animals when administered orally at a dose of 1500 mg/kg.

Detailed descriptions of the compounds according to the present invention and their pharmacological activity studies are disclosed in the following examples, which are for illustrative purposes only and are not intended to limit the scope of the present invention.

Experimental part

The synthesis of glutarimide derivatives of the general formula (I) described above is disclosed in application RU 2013116826, 4/12/2013.

Synthesis examples of glutarimide derivatives of the general formula (I)

Materials and methods

In a solvent system: the identity of the compounds obtained was assessed by Thin Layer Chromatography (TLC) on a plate of "Kieselgel 60F 254" ("Merck", Germany) in chloroform-methanol (9: 1) (1) and chloroform-methanol (1: 1) (2).

The chromatograms and electropherograms were dyed with chlorotetratoluene reagent and pauli reagent (p e a t-b-bi cm pi a у pi, paul's reagent).

A Shimadzu analytical HPLC SCL10Avp LC/MS system for multi-component mixture analysis; mass spectrometer pesiex API 165(150) (canada). Conditions are as follows: column: water ACQUITY UPLC BEH C182.1X 50mm 1.7 μm, gradient elution System: water with 0.1% HCOOH-acetonitrile with 0.1% HCOOH.

Analytical grade reverse phase HPLC was performed on a Shimadzu HPLC chromatograph under the following conditions: column: luna C18(2)100A, 250X 4.6mm (SEQ ID NO: 599779-23), gradient elution System: phosphate buffer (pH 3.0): methanol (condition a); column: LiChrocart 250X 4mm 5 μm LiChrospher 100RP-8E 5 μm. C8 (SEQ ID NO: 1.50837.0001); gradient elution system: ammonium acetate buffer (pH 7.5): acetonitrile (condition B); gradient elution system: buffer containing 0.0025M sodium 1-hexylsulfonate (pH 3): acetonitrile (condition C); and a column: symmetry C18, 150 × 4.6 mm; gradient elution system: buffer containing 0.0025M sodium 1-hexylsulfonate (pH 3): acetonitrile (condition D).

Recording on a spectrometer (Bruker DPX-400, Germany)¹H NMR spectrum.

High-resolution mass spectra were obtained by matrix-assisted laser desorption ionization using an Ultraflex mass spectrometer ("Bruker", Germany) using 2, 5-dihydroxybenzoic acid as the matrix and using a time-of-flight mass spectrometer.

Example 1

1- (2- (1H-imidazol-4-yl) ethyl) piperidine-2, 6-dione (Compound 1)

To a 250mL flat bottom flask were added N, N' -dimethylformamide (60mL) and 2- (imidazol-4-yl) acetamide of 1, 5-glutaric acid (20 g). Carbonyldiimidazole (17.3 g; 1.2 eq.) is added with vigorous stirring. The reaction mixture was heated to 90 ℃ with stirring and maintained for 2 hours. By passing¹The reaction was controlled by H-NMR spectroscopy (sample diluted with thioether (0.5mL),and dissolving the precipitate in DMSO-d₆In (1). When the starting 2- (imidazol-4-yl) acetamide of 1, 5-glutaric acid was not present in the reaction mass, the mass was cooled and poured into three volumes of methyl tert-butyl ether (180 mL). The reaction mixture was allowed to stand for 1 hour, and the precipitate was filtered, washed with 60mL of methyl t-butyl ether and dried. The yield of crude 1- (2- (1H-imidazol-4-yl) ethyl) piperidine-2, 6-dione was 12.4g (67%).

The crude 1- (2- (1H-imidazol-4-yl) ethyl) piperidine-2, 6-dione (12g) and isopropanol (36mg) were added to a 100mL flat-bottomed flask. The mixture was heated to completely dissolve the residue, then 1.2g of activated carbon was added thereto, and the mixture was aged at boiling temperature for 1 hour. The hot solution was filtered through a preheated ceramic filter. The residue on the filter was washed with 6mL of hot isopropanol. The hot crude liquid was cooled to room temperature and allowed to stand overnight with stirring to crystallize. The precipitated crystals were filtered, washed with 6mL of cold isopropanol and dried. After recrystallization, the amount of 1- (2- (1H-imidazol-4-yl) ethyl) piperidine-2, 6-dione obtained was 10.1g (84%). Rf 0.43 (1). The product was analyzed by LC/MS method: a single peak with a retention time of 1.57 minutes; [ M + H ]]⁺208. HPLC under condition a: single peak with retention time of 15.5 minutes.¹H NMR(400.13MHz，DMSO-d₆M.d., J/Hz): 1.81 (quintuple, 2H, CH)₂CH₂CH₂，J＝6.5Hz)，2.58(m，6H，CH₂C，CH₂CH₂CH₂)；3.82(t，2H，CH₂N，J＝7.8Hz)，6.77(br.s，1H，CCH)，7.49(s，1H，NCHN)，11.81(br.s，1H，NH)。

If necessary, in the synthesis of the compounds according to the invention, the nitrogen atom in the heterocycle may be protected by using, for example, a carbamate protecting group such as tert-butyloxycarbonyl (Boc).

The compounds shown in table 2 were obtained according to the above method.

TABLE 2

Example 2

1- (2- (1, 3-benzothiazol-2-yl) ethyl) piperidine-2, 6-dione (Compound 4)

A mixture of 2- (1, 3-benzothiazol-2-yl) acetamide of 1, 5-glutaric acid (22 g; 0.075mol) and acetic anhydride (23 g; 0.225mol) was boiled in 150mL dioxane for 3 hours. Dioxane was removed under vacuum, 200mL water was added and the mixture was neutralized to neutral pH with 30% sodium hydroxide. The precipitated oil was triturated until crystals formed. By chromatography (SiCO)₂60-100 μm, eluent: ethyl acetate-hexane (1: 1)) was used to purify the precipitate. Yield 16.5g (79.9%). LC/MS, single peak with retention time of 2.26 min [ M + H ]]⁺275. HPLC under condition a, single peak with retention time of 9.3 min.¹H-NMR(400.13MHz，DMSO-d₆M.d., J/Hz): 1.85 (quintuple, 2H, CH)₂CH ₂ CH₂，J＝6.8Hz)；2.59(t，4H，CH ₂CH₂CH ₂，J＝6.8Hz)；3.24(t，2H，CH ₂C，J＝7.3Hz)；4.08(t，2H，CH ₂N，J＝7.3Hz)；7.43，7.49(t，1H，Ar，J＝7.6Hz)；7.96，8.04(d，1H，Ar，J＝7.6Hz)。

The compounds shown in table 3 were obtained according to the above method.

TABLE 3

Example 3

Coated tablets 2mg, 10mg and 100mg

Composition of coated tablets

Composition (I)	2mg	10mg	100mg
				Active agent(s):
a compound of the general formula I	2.00mg	10mg	100mg
				Additive:
microcrystalline cellulose	47.70mg	70.55mg	95.90mg
				Lactose monohydrate	49.00mg	67.50mg	99.00mg
Sodium starch glycolate	0.50mg	0.75mg	1.50mg
				Talc	0.40mg	0.60mg	1.20mg
Magnesium stearate	0.40mg	0.60mg	2.40mg
				Tablet core weight	100.00mg	150.00mg	300.00mg
Film coating	3.00mg	4.50mg	9.00mg
				Tablet weight	103.00mg	154.50mg	309.00mg

Biological activity assay

Materials and methods

Morphological studies of histological preparations were performed using light microscopy (Leica DM LS, Leica Microsystems, germany). The micro-morphometric analysis was performed using an eyepiece micrometer mounted on a microscope Leica DM LS. Micrographs were taken with a digital camera (Leica DC 320).

Mathematical analysis was performed on the obtained result with software Statistica 6.0 using a variation statistics (b a bright ad a ma zhi ji h ci й c t h t h t. Data were analyzed with descriptive statistics: the normal distribution of the data was confirmed according to the Shapiro-Wilk test. Since all data were fit to a normal distribution, variance between groups was analyzed by parametric methods such as t-test. If p < 0.05, the difference is considered significant.

The numerous examples provided below illustrate the biological activity of the claimed compounds of formula (I).

Example 4

Evaluation of the efficacy of the Compounds of formula (I) in an asthmatic Guinea pig model

Bronchial asthma was induced in guinea pigs by standard methods [ Ricciardolo FL, Nijkamp F, De RoseV, Folkerts G.the Guinea pig as an animal model for asthma// Current drug targets.2008 for 6 months; 9(6): 452-65]. Animals were immunized by once parenteral administration with 0.5mL of a solution containing 100. mu.g/mL ovalbumin (Sigma) and 100mg/mL aluminum hydroxide. The whole animal received an amount of 0.5mL of physiological saline solution.

Respiratory airway hyperactivity was induced on days 29, 30 and 31 by inhalation administration of increasing concentrations of ovalbumin of 0.1, 0.3 and 0.5mg/mL on induced days 1, 2 and 3 respectively. Inhalation continues for 5 minutes or until asphyxia symptoms become apparent (fall to one side). On day 32, animals received challenge doses of ovalbumin (1mg/mL) for 5 minutes while evaluating bronchospasm response.

Administering the compound of interest to the animal once daily for 6 or 10 days; the administration was terminated two days prior to administration of the challenge dose of antigen.

Bronchospasm response is assessed by changes in respiratory movement rate and depth, and by apneic symptoms (e.g., retrograde side). The lung volume map is recorded through real laboratory experimental equipment (ADInstructions, Australia) by using a basic recording station (E a з O b й E G T E G T E G E G E T E G E T E I) ((PowerLab 8sp.) and software LabCart.

Bronchoalveolar lavage (BAL) fluid and heart cavity blood were obtained from the animals 24 hours after administration of the challenge dose. BAL was collected as follows: under anesthesia, the device was administered using a syringe by irrigating the lungs through the trachea with 5mL of physiological saline solution heated to 37 ℃.

Using a Goryaev camera, the absolute number (cell count (b-fe-t з)) of the cell composition (k @ ч @ ы х ji) in 1 μ L of lavage fluid is counted in bronchoalveolar lavage. Then, BAL was centrifuged at 200g for 10 minutes. The residue was used to prepare swabs that were fixed in methanol and stained according to romanofski-giemsa (P kahwa) for gram-gram з to count the intrapulmonary cytograms.

Blood was analyzed by a hemocytometer to determine the white blood cell composition (pi e й k o phi pi cm у pi ы).

The study contained 3 experiments, where the first involved evaluation of the effect of the claimed compounds 1-6 on the cellular composition of BAL, the second and third experiments aimed at assessing the effect of compounds 1 and 2 on the cellular composition of BAL, the cellular composition of blood and the severity of bronchospasm.

Compounds 1-6 were administered to guinea pigs 10 times at a dose of 14mg/kg to establish cellular composition levels in BAL from 17.3 × 10⁹The cell/L is reduced to 2.5-6.3 × 10⁹Individual cells/L (see Table 4.) the compound studied preferably results in a reduced eosinophil count, in the control group, of 7.05 × 10 for eosinophils in BAL⁹Individual cells/L, and in the treated group, it was 0.60-1.61 × 10⁹Individual cells/L, i.e., a 91% -77% reduction.

Administration of the compound studied at lower doses (0.045, 0.14 and 1.4mg/kg) and in two regimens (10 and 6) showed that the compound reduced eosinophilia in BLAs over a broad dose range (0.045 to 14mg/kg) as well as in multiple treatment regimens (see table 5). Furthermore, the compounds reduced lymphocyte counts at all tested doses and also reduced monocyte counts in BAL at some doses, which indicates inhibition of local inflammatory responses in the lung.

The compounds studied reduced eosinophilia in the blood. In the control group, the eosinophil count in blood was 6 to 8 times higher than that of the intact animals. Administration of the compound under study was able to maintain counts at the level of intact animals (see table 6).

Evaluation of the severity of bronchospasm in guinea pigs in response to an inhaled challenge dose of ovalbumin showed that the compound studied not only reduced eosinophilia, but also reduced the clinical manifestations of the disease in a model of bronchial asthma. In particular, in the control group receiving placebo, 5 of 8 animals suffered from severe bronchospasm with acute and subacute phases; such compounds are absent or present in no more than two animals in the group of animals receiving the compound under study. Subsequently, the number of animals with normal respiration rate and depth (no bronchospasm) increased from 0-1 in the control group to 4-7 in the treated group (see Table 7).

The results obtained provide reliable evidence for: in experimental models of eosinophilia (particularly bronchial asthma, etc.), the claimed compounds inhibit eosinophilia and reduce the clinical manifestations of the disease.

Example 5

Evaluation of the efficacy of the Compounds of general formula (I) in the rat model of Sephadex-induced eosinophilic pneumonia

The sephadex-induced eosinophilic pneumonia rat model was achieved by standard methods [ Evaldsson C, Ryd e n I, uppugundri s. New flight into the sephadex model of lung inflammation// IntArch Allergy immunol.2011; 154(4): 286-94]. Sephadex G-200(Pharmacia, Sweden) was administered once to male Wistar rats by inhalation at a dose of 5 mg/kg. The compound of interest was administered to the animals by the intragastric route four times: 24 hours and 1 hour before and 24 hours and 45 hours after administration of the sephadex. According to the same protocol, reference formulation budesonide was administered by inhalation at a dose of 0.5 mg/kg. Bronchoalveolar lavage fluid is taken 48 hours after the dextran gel is inhaled, and the total lymphocyte count and the white blood cell composition (pi e й kq chi t xi t h у ю phi p cm y) in the lavage fluid are measured (pi e й k chi t h xi y). The number of rats in one group ranged from 7 to 10.

Analysis of BAL showed that administration of sephadex G-200 once by inhalation caused a significant flow of leukocytes into the lungs. The content of all cell types in the control group was increased relative to the intact animals; however, the greatest increase in eosinophils was noted (see tables 8-9).

Intragastric administration of the compound of formula (I) to rats reduced eosinophil count in BAL several fold. The claimed compounds exhibit activity over a wide range of tested doses.

Example 6

Evaluation of the efficacy of the Compounds of general formula (I) in the leukotriene-induced eosinophilic pneumonia Guinea pig model

The leukotriene-induced eosinophilic pneumonia guinea pig model was achieved by standard methods [ Underwood DC1, osborne RR, newholme SJ, Torphy TJ, n ay dw. persistent air way eosinophilia afterleukotrine (LT) D4administration in the Guinea pig: modulation by the LTD4 receiver antadonist, pranlukast, or an intercleukin-5 monoclonal antibody// AmJ Respir Crit Care Med.1996 Oct; 154(4Pt 1): 850-7]. Male guinea pigs (250- & 300g) were inhaled a 10mg/kg concentration (250 mL/hr flow rate) solution of leukotriene D4 (LTD4, Cayman Chemical, USA) for one minute under the conditions of a two-chamber plethysmograph (Emka technologies, France). The compound in question was administered to the animal by the intragastric route four times: 24 hours and 1 hour before inhalation of LTD4 and 24 hours and 45 hours after inhalation of LTD 4. The reference formulation montelukast (0.8mg/kg) was administered once by the intragastric route 1 hour before inhalation of LTD 4. Bronchoalveolar lavage fluid was taken 48 hours after LTD4 inhalation and the total lymphocyte count and leukocyte composition in the lavage fluid were determined. The number of guinea pigs in each group was 8.

BAL analysis showed that one dose of leukotriene D4 administered to guinea pigs by inhalation caused a significant flow of neutrophils, eosinophils and monocytes/macrophages into the lungs. The most significant increase in cell count (25) of eosinophils was observed (see table 10).

Intragastric administration of the compound of interest to guinea pigs reduced eosinophil count in BAL by 2.1-3.4 fold. The compounds have efficacy over a wide dosage range (0.14-14 mg/kg). Comparative efficacy analysis of the claimed compounds and montelukast showed that the effects of the claimed compounds and leukotriene receptor agonists are comparable in intensity.

Example 7

Evaluation of the efficacy of the Compounds of general formula (I) in a Guinea pig model of allergic rhinitis

The guinea pig model of allergic rhinitis was achieved by standard methods [ vishun n. thacarae, m.m. osama, suresh r. naik. therapeutic potential of curative in experimental induced allergenicities in guineea leads// Int immunopharmacol.2013 sep; 17(1): 18-25].

Guinea pigs (250-300g) were immunized with 4 (on days 0, 7, 14 and 21) intragastric administrations of ovalbumin (100 μ g/guinea pig) and aluminium hydroxide (5 mg/guinea pig), both diluted and suspended in physiological saline solution. On study day 28, an ovalbumin solution (60mg/mL) was administered intranasally to each nostril of the animal at a dose of 20 μ L. On day 35, animals received ovalbumin solution subcutaneously (200. mu.g/mL, 25. mu.L); the application site on the animal's back was pre-shaved. Swelling and redness at the injection site served as evidence of sensitization. On study day 42, ovalbumin solution (60mg/mL, 20. mu.L/nostril) was administered intranasally. A group of mock immunized animals was formed to control the development of precise allergic inflammation: on days 0, 7, 14 and 21, guinea pigs received an aluminum hydroxide solution (5 mg/guinea pig), and on days 28 and 35, they received a physiological saline solution, and on day 42, they received an ovalbumin solution (60mg/mL, 20 μ L/nostril).

The compound of interest (14mg/kg) was administered 3 times by the intragastric route 48, 24 and 1 hour before the last administration of ovalbumin. The reference formulation dexamethasone was administered once by the intragastric route 3 hours before the last intranasal administration of ovalbumin.

Clinical manifestations, such as sneezing and nasal itching, were recorded 2 hours after the last application of ovalbumin. Nasal lavage fluid was taken 24 hours after the last administration of ovalbumin and total lymphocyte counts and white blood cell composition were determined in the lavage fluid. The number of guinea pigs in one group was 8.

Analysis of nasal lavage fluid showed that allergic rhinitis was accompanied by a significant flow of leukocytes into the nasal cavity. The maximal increase in eosinophils was recorded (table 11).

Administration of the compound of formula (I) to guinea pigs three times reduced the eosinophil count in the nasal lavage to the level observed in sham-immunized animals. The effect of the claimed compounds and dexamethasone was comparable in intensity.

Clinical performance records of allergic rhinitis 2 hours after the last intranasal administration of ovalbumin showed a significant increase in the number of sneezes and nasal itching in the experimental animals, indicating the correctness of the achieved model of allergic rhinitis. Treatment with the compounds of formula (I) reduces the clinical manifestations of rhinitis to the levels observed in sham-immunized animals. The reference formulation had similar effects (see table 12).

TABLE 12

Clinical manifestations of allergic rhinitis in the Experimental model of guinea pig (M. + -. M, n ═ 8)

Group of	Sneezing several/2 hours	Itching in nose/2 hr
			Pseudo-immunity	5.3±1.2	9.7±1.3
Control	16.3±2.6＊	45.3±5.2＊
			Compound 1(14mg/kg)	5.9±1.1&	13.9±2.6&
Compound 5(14mg/kg)	7.1±1.3&	19,1±4,9&
			Dexamethasone (5mg/kg)	7.9±0.8&	16.7±1.8＊&

Note:

difference between the o-and the complete group, according to the t-test, p < 0.05

And the difference from the control group according to the t-test, p < 0.05

Example 8

Evaluation of the efficacy of the Compounds of formula (I) in the model of mice resistant to therapeutic dermatitis

Realize atopic dermatitis (a di zhi pi xi c ч e c chi q ri model [ mecanism of dinitrorbenzene-induced dermatism in micro ] of ore. role of specific agents in pathogenesis// PLoS one.2009; 4(11)].

On days 0 and 12 of the study, 100 μ L of a 2% solution of 1-chloro-2, 4-dinitrobenzene in 95% ethanol (DNCB, Sigma-Aldrich, USA) was applied to the shaved area of the back of male Balb/c mice. On study day 17, two 20 μ L of 2% DNCB in ethanol were administered to the right "study" ears 1 hour apart. On study days 8-17, the compound of interest and the reference formulation dexamethasone were administered once daily by the intragastric route.

On study day 18, animals were exposed to CO₂Euthanizing in the small chamber. The weight of the "study" and "control" ears was measured. Response Index (RI) was calculated as a percentage of the weight difference between the "study" and "control" ears.

This study shows that compounds of formula (I) reduce the response index in experimental models of atopic dermatitis. The effect of the claimed compounds was comparable to that of the steroid formulation dexamethasone (see table 13).

Watch 13

Response index in atopic dermatitis in mice (M ± M, n ═ 12)

Group of	Response index (%)
		Complete (complete)	-0.49±0.68
Control	93.8±5.4＊
		Compound 1(0.3mg/kg)	74.4±7.3＊&
Compound 1(3mg/kg)	69.5±8.2＊&
		Compound 1(30mg/kg)	69.1±8＊&
Dexamethasone (10mg/kg)	65.6±8＊&

Note:

difference between the o-and the complete group, according to the t-test, p < 0.05

And the difference from the control group according to the t-test, p < 0.05

The results obtained provide the basis for the following conclusions: in experimental models of eosinophilia (particularly, sephadex-induced eosinophilic lung inflammation in rats, leukotriene-induced eosinophilic lung inflammation in guinea pigs, allergic rhinitis and asthma in guinea pigs, atopic dermatitis in mice, etc.), the compounds of formula (I) significantly reduced eosinophilia.

Claims (16)

1. A therapeutic agent for the treatment of an eosinophilic disease, said therapeutic agent being a compound of general formula (I):

wherein R is₁And R'₁Independently is hydrogen or C₁-C₆An alkyl group;

R₂is that

Optionally substituted by C₁-C₆Alkyl substitution.

2. The therapeutic agent of claim 1, wherein R₁And R'₁Independently is hydrogen or methyl, and

R₂is that

3. The therapeutic agent according to claim 1, wherein the compound of the general formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

4. the therapeutic agent according to claim 1, wherein the eosinophilic disease is bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg-strauss syndrome, anaphylactic shock, Kunck edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis.

5. A pharmaceutical composition for the treatment of an eosinophilic disease, comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I):

wherein R is₁And R'₁Independently is hydrogen or C₁-C₆An alkyl group;

R₂is that

Optionally substituted by C₁-C₆Alkyl substitution.

6. The pharmaceutical composition of claim 5, wherein R₁And R'₁Independently is hydrogen or methyl, and

R₂is that

7. The pharmaceutical composition of claim 5, wherein the compound of formula (I) or the pharmaceutically acceptable salt is selected from the following compounds:

8. the pharmaceutical composition of claim 5, wherein the eosinophilic disease is bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg-strauss syndrome, anaphylactic shock, Kunck edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis.

9. A method of treating an eosinophilic disease, comprising administering to a patient an effective amount of a compound of formula (I):

wherein R is₁And R'₁Independently is hydrogen or C₁-C₆An alkyl group;

R₂is that

Optionally substituted by C₁-C₆Alkyl substitution.

10. The method of claim 9, wherein R₁And R'₁Independently is hydrogen or methyl, and

R₂is that

11. The method of claim 9, wherein the compound of formula (I) or the pharmaceutically acceptable salt is selected from the following compounds:

12. the method of claim 9, wherein the eosinophilic disease is bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg-strauss syndrome, anaphylactic shock, Kunck's edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis.

13. Use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic agent for the treatment of an eosinophilic disease,

wherein R is₁And R'₁Independently is hydrogen or C₁-C₆An alkyl group;

R₂is that

Optionally substituted by C₁-C₆Alkyl substitution.

14. The use of claim 13, wherein R₁And R'₁Independently is hydrogen or methyl, and

R₂is that

15. The use according to claim 13, wherein the compound of general formula (I) or the pharmaceutically acceptable salt is selected from the following compounds:

16. the use of claim 13, wherein the eosinophilic disease is bronchial asthma, allergic rhinitis, polypoid sinus disease, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, churg-strauss syndrome, anaphylactic shock, Kunck's edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis.