JP2005047909A - Remedy for pruritus containing piperidine derivative as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a remedy for pruritus containing a piperidine derivative as an active ingredient. <P>SOLUTION: This remedy for the pruritus contains a compound (I) (the piperidine derivative) shown in the figure. This remedy for the pruritus has an excellent pruritus preventive effect, so as to be useful as the remedy for all of the pruritus, including ocular pruritus, dermatic pruritus, and systemic pruritus. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a therapeutic agent for pruritus containing a piperidine derivative as an active ingredient.

  Itching is perceived as itching when the itching receptor present at the skin-mucosal epidermis-dermis junction is stimulated by a transmitter (pruritus-inducing substance), and the stimulation is transmitted to the central nervous system. As a transmitter that induces itch, for example, histamine, kinin, bile salt, substance P, prostaglandin and the like are widely known. Itching from allergic factors is presumed to involve a transmitter such as histamine released from mast cells, and it is known that antihistamines have a stronger effect than antiallergic agents.

  As pruritus, for example, eye pruritus, skin pruritus, ear / nose pruritus, general pruritus, etc. occurring in humans and animals are known. Itching is a disease that causes itching of the eyes, eyelids, eyelid edges, etc. due to pollen, dust, mites, molds, pet hair, contact lenses, cosmetics, etc. May become congested or the conjunctival nipple may become red and proliferate. When severe, lesions appear in the cornea and sclera and may progress to spring catarrh.

By the way, Patent Document 1 relates to piperidine derivatives having PDE4 inhibitory activity, and in the specification, these piperidine derivatives are used for inflammatory diseases such as nephritis, allergic diseases such as allergic rhinitis, autoimmune diseases. It is described that it is effective as a therapeutic agent. However, it is not described at all that the piperidine derivative described in Patent Document 1 shows effectiveness against itching, which is the most important symptom associated with allergic diseases.
International Publication No. 02/14280 Pamphlet

  The piperidine derivatives described in Patent Document 1 are known to have various pharmacological effects as pharmaceuticals, but finding an effect on itching as a new pharmacological effect is an interesting subject.

  As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that the piperidine derivative represented by the general formula (I) exhibits an excellent pruritus-suppressing action, leading to the present invention. In addition, the present inventors, among piperidine derivatives represented by the general formula (I), {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid Or it discovered that the solvate had the inhibitory effect which was especially excellent with respect to an itchy eyelid, and completed this invention.

That is, the present invention
(1) The following general formula (I)

(Wherein R ¹ represents 1) a hydrogen atom or 2) a cyano group, and R ² and R ³ each independently represent 1) a C1-8 alkyl group, 2) a C3-7 cycloalkyl group, 3) C1-8 alkyl group substituted with C3-7 cycloalkyl group, 4) C1-8 alkyl group substituted with 1-3 halogen atoms, 5) hydrogen atom, 6) substituted with phenyl group A C1-8 alkyl group, 7) a C1-8 alkyl group substituted with a C1-8 alkoxy group, or 8)

(Wherein n represents 1 to 5), R ⁴ and R ⁵ each independently represents 1) a hydrogen atom, or 2) a C1-8 alkyl group, or R ⁴ and R ^5. , together with the bond to which carbon atoms represent a saturated carbon ring of C3-7, ^{R 6} is 1) hydroxyl group, 2) C1-8 alkoxy group, 3) -NHOH group, or 4) a phenyl group, Represents a C1-8 alkoxy group substituted with, and m represents 0 or an integer of 1-4. A therapeutic agent for pruritus comprising a compound represented by the above formula, a salt thereof, or a solvate thereof as an active ingredient:
(2) The agent for treating pruritus according to (1) above, wherein the compound is {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid,
(3) The pruritus treatment according to (2) above, wherein the active ingredient is {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid monohydrate Agent,
(4) The pruritus therapeutic agent according to (1), wherein the pruritus is eye itching,
(5) The pruritus treatment agent according to the above item (1), which is a liquid agent,
(6) The therapeutic agent for pruritus according to (1), which is an external preparation,
(7) The pruritus treatment agent according to the above (5), wherein the solution is an eye drop,
(8) The pruritus treatment agent according to the above item (6), wherein the external preparation is an ointment,
(9) The agent for treating pruritus according to (8) above, wherein the ointment is an eye ointment,
(10) The therapeutic agent for pruritus according to (7) above, which is an eye drop containing 0.01 to 1% (w / v) of an active ingredient,
(11) The pruritus treatment agent according to (1) above, a steroidal anti-inflammatory drug, a nonsteroidal anti-inflammatory drug, an antiallergic drug, an antihistamine drug, a glaucoma drug, an antibiotic, an antibacterial drug, an antiviral drug, and A pharmaceutical comprising a combination of one or more selected from antifungal agents,
(12) A method for treating pruritus, comprising administering to a mammal an effective amount of a compound represented by the general formula (I) described in (1) above, a salt thereof, or a solvate thereof,
(13) Use of the compound represented by the general formula (I) described in the preceding item (1), a salt thereof, or a solvate thereof for producing an agent for treating pruritus.

In general formula (I), C1-8 alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof. The C1-8 alkoxy group includes methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy groups and isomers thereof. A halogen atom means a chlorine, bromine, fluorine, or iodine atom. A C3-7 cycloalkyl group is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl group. The saturated carbon ring of C3-7 representing together with the carbon atom to which R ⁴ and R ⁵ are attached, C3-7 cycloalkyl group, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups It is.

  The piperidine derivatives of the present invention include all isomers unless otherwise specified. For example, the alkyl group, alkoxy group and alkylene group include straight-chain and branched-chain ones. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbons (R, S isomers, α, β isomers, enantiomers, diastereomers) , Optically active substances having optical activity (D, L, d, l form), polar forms (high polar form, low polar form) by chromatographic separation, equilibrium compounds, mixtures of these in any proportion, racemic mixture, All are included in the present invention.

  Salts of the compounds represented by the general formula (I) include all pharmacologically acceptable salts. The pharmacologically acceptable salt is preferably water-soluble with low toxicity. Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salt, tetrabutylammonium salt, etc.), organic amines (Triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine, arginine, N-methyl-D-glucamine, etc.) salt, acid adduct salt (inorganic acid salt ( Hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salt (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumaric acid Salt, maleate, benzoate, citrate, methanesulfonate, ethane Sulfonic acid salts, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.), etc.).

  Examples of the solvate of the compound represented by the general formula (I) include solvates such as water and alcohol solvents (ethanol and the like). The solvate is preferably non-toxic and water-soluble. The solvates of the compounds of the present invention include alkali (earth) metal salts, ammonium salts, organic amine salts, acid adduct salts, etc. of the compounds of the present invention, such as water, alcohol solvents (ethanol etc.), etc. The solvate is also included.

  The compound of the present invention can be converted into the above salt, the above N-oxide, and the above solvate by a known method.

In general formula (I), R ¹ is preferably a cyano group, and R ² is preferably a C1-8 alkyl group, a C3-7 cycloalkyl group, or a C3-7 cycloalkyl group. A C1-8 alkyl group, particularly preferably a methyl group, an ethyl group, an isopropyl group, a 2-methylpropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclopropylmethyl group, and R ³ is preferably a C1-8 group. An alkyl group, or a C1-8 alkyl group substituted with 1 to 3 halogen atoms, particularly preferably a methyl group, an ethyl group, an isopropyl group, a 2-methylpropyl group, or a difluoromethyl group, and R ⁴ and the ^{R 5,} is preferably a hydrogen atom, the ^{R 6,} preferably hydroxyl or -NHOH group, particularly good Properly is a hydroxyl group. The piperidine derivative represented by the general formula (I) is preferably 4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid or a hydrate thereof (hydration Preferred is a monohydrate (4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid monohydrate).

  The compound represented by formula (I), a salt thereof, or a solvate thereof can be produced according to the method described in WO 02/14280.

  Further, the therapeutic agent for pruritus of the present invention is 1) complementation and / or enhancement of the therapeutic effect of the agent of the present invention, 2) improvement of kinetics / absorption of the agent of the present invention, reduction of dosage, and / or 3). In order to reduce the side effects of the agent of the present invention, it may be administered in combination with other drugs as a concomitant drug.

  The combination agent of the agent of the present invention and other agents may be administered in the form of a combination preparation in which both components are mixed in one preparation, or may be administered in separate preparations. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration by the time difference may be such that the agent of the present invention is administered first and the other agent may be administered later, or the other agent may be administered first and the agent of the present invention may be administered later. Each administration method may be the same or different.

  The other drug may be a low molecular weight compound, and may be a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. Also good. The dosage of other drugs can be appropriately selected based on the clinically used dose. The mixing ratio of the agent of the present invention and other agents can be appropriately selected depending on the age and weight of the administration subject, the administration method, the administration time, and the like. For example, 0.01 to 100 parts by weight of another drug may be used with respect to 1 part by weight of the agent of the present invention. Two or more other drugs may be administered in combination at an appropriate ratio. In addition, other drugs that complement and / or enhance the therapeutic effect of the agent of the present invention include not only those that have been found so far, but also those that will be found in the future based on the mechanism described above.

  Examples of the other drugs include steroidal anti-inflammatory drugs (for example, dexamethasone, prednisolone, etc.), non-steroidal anti-inflammatory drugs (for example, diclofenac sodium, pranoprofen, etc.), antiallergic drugs (for example, tranilast, fumarate). Ketotifen acid, sodium cromoglycate, etc.), antihistamines (eg, diphenhydramine hydrochloride), glaucoma drugs (eg, pilocarpine hydrochloride, physostigmine salicylate, timolol, isopropyl unoprostone), antibiotics (eg, gentamicin sulfate, sulfate) Fradiomycin, tobramycin, sulbenicillin, cefmenoxime, erythromycin, colistin, oxytetracycline, polymyxin B, chloramphenicol, micronomycin, dibekacin, Somycin, etc.), antibacterial drugs (for example, sulfamethizole, sulfamethoxazole, ofloxacin, norfloxacin, lomefloxacin hydrochloride, enoxacin, ciprofloxacin hydrochloride, sinoxacin, sparfloxacin, tosufloxacin tosylate, nalidixic acid, pipemide Acid trihydrate, pipemidic acid, fleroxacin, levofloxacin, etc.), antiviral drugs (eg, idoxuridine, acyclovir, etc.), antifungal agents (eg, pimaricin, fluconazole, miconazole, amphotericin B, flucytosine, itraconazole, etc.), etc. Is mentioned.

  The piperidine derivative of the present invention has a therapeutic / suppressive effect against pruritus such as eye itching, skin itching, otolaryngitis, and generalized pruritus occurring in humans and animals. More preferably, it is used as a therapeutic agent for eye itch.

  Eye itching in the present invention is a disease that causes itching of the eyes, eyelids, eyelid edges, etc. due to pollen, dust, mites, molds, pet hair, contact lenses, cosmetics, eye trauma, etc. Some pruritus associated with allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, blepharitis, dry eye, conjunctivitis, corneal herpes, corneal ulcers, etc. included.

  The pruritus treatment agent of the present invention exhibits an excellent pruritus-suppressing effect against itching, as is apparent from the results of the eye itching inhibition test described below.

  The agent for treating pruritus according to the present invention can be formulated using a technique widely used as a single preparation or a combination preparation by adding a pharmaceutically acceptable additive as necessary.

  Moreover, the agent for treating pruritus and the concomitant drug of the present invention can be administered parenterally or orally. Examples of oral preparations include liquids for internal use (for example, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions, etc.), solid preparations for internal use (for example, tablets (sublingual tablets, oral cavity) And pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules), powders, granules, lozenges, etc.). Examples of parenteral agents include liquids (eg, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops, etc.), eye drops (eg, aqueous eye drops (aqueous eye drops) Liquid, aqueous suspension ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), non-aqueous ophthalmic solution (non-aqueous ophthalmic solution, non-aqueous suspension ophthalmic solution, etc.))), and external preparations (eg, ointment (eye ointment) Etc.), gels, creams, poultices, poultices, liniments, etc.), sprays, inhalants, sprays, nasal drops, suppositories (eg rectal suppositories, vaginal suppositories, etc.) It is done. These preparations may be release control agents such as immediate-release preparations and sustained-release preparations. These preparations can be produced by a known method, for example, a method described in the Japanese Pharmacopoeia.

  The liquid for internal use as an oral preparation is produced, for example, by dissolving, suspending or emulsifying the active ingredient in a diluent (for example, purified water, ethanol or a mixture thereof) generally used. Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  The solid preparation for internal use as an oral preparation includes, for example, an active ingredient as an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (for example, hydroxypropylcellulose, polyvinylpyrrolidone, aluminum metasilicate). Magnesium oxide, etc.), disintegrating agents (eg, calcium calcium glycolate), lubricants (eg, magnesium stearate), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc. According to the formulation. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers.

  An external preparation as a parenteral preparation is produced and prepared by a known method or a commonly used formulation. For example, an ointment is manufactured and prepared by kneading or melting an active ingredient in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recall, macrogol, etc.), vegetable oil (eg, castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, anti-rash agent Can be used alone or in admixture of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced and prepared, for example, by melting an active ingredient in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), gelling agent (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agent (eg, triethanolamine, diisopropanolamine, etc.), One selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption enhancers, and anti-rash agents, or a mixture of two or more types may be used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced and prepared, for example, by melting or emulsifying an active ingredient in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ethers) , Fatty acid esters, etc.), water, absorption accelerators, rash prevention agents, or a mixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced, for example, by melting an active ingredient in a base, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (eg, polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, a solubilizing agent, a tackifier, and a rash prevention agent may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced, for example, by melting an active ingredient in a base and spreading and applying it on a support. The base for patch is selected from known or commonly used ones. For example, those selected from a polymer base, fats and oils, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is, for example, an active ingredient dissolved, suspended in or alone or selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc. Produced and prepared by emulsification. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The spray and the spray are produced by a known or commonly used formulation. For example, in addition to commonly used diluents, it contains a buffer that provides isotonicity with a stabilizer such as sodium bisulfite, for example, an isotonic agent such as sodium chloride, sodium citrate or citric acid. May be.

  Inhalants include aerosols, inhalable powders or inhalable liquids, and the inhalable liquids may be used by dissolving or suspending in water or other suitable medium at the time of use. These inhalants are, for example, in the case of inhalation solutions, antiseptics (for example, benzalkonium chloride, parabens, etc.), coloring agents, buffering agents (for example, sodium phosphate, sodium acetate, etc.), isotonicity An agent (for example, sodium chloride, concentrated glycerin, etc.), a thickener (for example, cariboxyvinyl polymer, etc.), an absorption accelerator, etc. are appropriately selected as necessary. In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.), colorants, antiseptics An agent (for example, benzalkonium chloride, paraben, etc.), an absorption accelerator and the like are appropriately selected as necessary. A nebulizer (for example, an atomizer, a nebulizer, etc.) is usually used when administering an inhalation solution, and an inhalation administration device for powdered drugs is usually used when administering an inhalable powder.

  The parenteral injection includes solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent when used. An injection is used, for example, by dissolving, suspending or emulsifying an active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good. These are sterilized in the final process or manufactured and prepared by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.

  Preferred dosage forms for use as an eye itch treatment agent include eye drops, eye ointments, tablets and the like, and more preferably eye drops or eye ointments. These can be formulated using widely used techniques. For example, in the case of eye drops, isotonic agents, buffers, pH adjusters, solubilizers, thickeners, stabilizers, preservatives and the like can be appropriately added as additives. In addition, a stable eye drop can be obtained by adding a pH adjuster, a thickener, a dispersant and the like to suspend the drug.

  Examples of isotonic agents include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.

  Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, and ε-aminocaproic acid.

  Examples of the pH adjuster include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.

  Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, and the like.

  Examples of thickeners and dispersants include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like. Examples of stabilizers include edetic acid and sodium edetate. be able to.

  Examples of preservatives (preservatives) include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, and chlorobutanol. Can also be used.

  The eye drop containing the agent for treating pruritus according to the present invention desirably has a pH set to 4.0 to 8.5, and preferably has an osmotic pressure ratio set to around 1.0.

  The dose of the active ingredient when used as an agent for treating pruritus can be appropriately selected depending on the symptom, age, dosage form, etc., but if it is an oral preparation, it is preferably 1 mg to 100 mg, more preferably 5 mg to 30 mg per day. What is necessary is just to administer several times (for example, 1-3 times). If it is an eye drop, it preferably has a concentration of 0.001 to 10% (w / v), more preferably 0.01 to 1% (w / v). What is necessary is just to instill several times (for example, 1 to 8 times). In the case of an eye ointment, an ointment preferably has a concentration of 0.001 to 10% (w / w), more preferably 0.01 to 1% (w / w) once to several times a day (for example, 1 (4 times) may be applied.

  Of course, as described above, the dose varies depending on various conditions, and therefore, a dose smaller than the above dose may be sufficient or may be necessary beyond the range.

  As is apparent from the results of pharmacological tests described later, the piperidine derivative represented by the general formula (I) exhibits an excellent pruritus-suppressing effect on eye itching. Therefore, the piperidine derivative of the present invention is useful as a therapeutic agent for all kinds of pruritus such as eye itching, skin itching and systemic itching.

  Pharmacological tests and formulation examples are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[Pharmacological test]
Using an albumin-induced eye itching model, the eye itching inhibitory action of the piperidine derivative of the present invention was examined.

1. Eye itching suppression test using albumin-induced eye itching model (experimental method)
Aluminum hydroxide gel adsorbed ovalbumin (20 μg / mL) was dissolved in physiological saline, and 100 μL each was injected under the binocular conjunctiva of a 5-week-old male Hartley guinea pig for active sensitization. On day 14 after sensitization, 10 μL / eye of ovalbumin 1.0% (W / V) physiological saline was administered to both eyes.

  As test compounds, 0.01% (W / V) and 0.1% (W / V) of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidine-1 -Il} acetic acid monohydrate (hereinafter referred to as “Compound A”) was prepared by suspending it in 0.1% hydroxypropylmethylcellulose, and 30 minutes prior to ovalbumin ophthalmic administration, Each eye was instilled at 10 μL / eye. As a control, 0.1% hydroxypropylmethylcellulose was used.

  The action of the guinea pig for 60 minutes after the ovalbumin instillation was video-recorded, and the eye scratching inhibitory action was evaluated by counting the number of eye scratches when each test compound solution and the control were instilled. Table 1 shows the eye scratching behavior inhibition rate (average value) relative to the control calculated according to the following formula. The number of examples is 8 eyes each.

Eye scratching behavior inhibition rate = 100 − ([number of eye scratches of test compound] ÷
[Control eye scratches]) x 100

(Experimental result)
As is apparent from Table 1, Compound A: {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid monohydrate administered by eye drops The number of eye scratches is markedly reduced compared to the control, and the degree of this depends largely on the concentration of the test compound. From the above results, it has been clarified that the piperidine derivative represented by the general formula (I) has an excellent eye itching inhibitory action.

[Formulation example]
The typical formulation example used for this invention is shown below.

1. Eye Drops An eye drop of the following formulation is prepared using a widely used method.

Formulation Example 1
Compound A 100mg in 100ml
Concentrated glycerin 500mg
Polysorbate 80 200mg
Sodium dihydrogen phosphate dihydrate appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount

  In the same manner as in Formulation Example 1, eye drops containing 10 mg, 50 mg, and 1000 mg of Compound A in 100 ml can be prepared. Further, in place of compound A, other piperidine derivatives of the present invention can be used.

2. Eye ointment An eye ointment of the following formulation is prepared using a commonly used method.

Formulation Example 2
Compound A 60mg in 100g
Liquid paraffin 10g
White petrolatum

  In the same manner as in Formulation Example 2, various concentrations of eye ointment can be prepared by appropriately changing the amount of Compound A added. Further, in place of compound A, other piperidine derivatives of the present invention can be used.

Claims (13)

The following general formula (I)

(Wherein R ¹ represents 1) a hydrogen atom or 2) a cyano group, and R ² and R ³ each independently represent 1) a C1-8 alkyl group, 2) a C3-7 cycloalkyl group, 3) C1-8 alkyl group substituted with C3-7 cycloalkyl group, 4) C1-8 alkyl group substituted with 1-3 halogen atoms, 5) hydrogen atom, 6) substituted with phenyl group A C1-8 alkyl group, 7) a C1-8 alkyl group substituted with a C1-8 alkoxy group, or 8)

(Wherein n represents 1 to 5), R ⁴ and R ⁵ each independently represents 1) a hydrogen atom, or 2) a C1-8 alkyl group, or R ⁴ and R ^5. , together with the bond to which carbon atoms represent a saturated carbon ring of C3-7, ^{R 6} is 1) hydroxyl group, 2) C1-8 alkoxy group, 3) -NHOH group, or 4) a phenyl group, Represents a C1-8 alkoxy group substituted with, and m represents 0 or an integer of 1-4. ), Or a salt thereof, or a solvate thereof as an active ingredient. The agent for treating pruritus according to claim 1, wherein the compound is {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. The therapeutic agent for pruritus according to claim 2, wherein the active ingredient is {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid monohydrate. The agent for treating pruritus according to claim 1, wherein the pruritus is eye pruritus. The agent for treating pruritus according to claim 1, which is a liquid. The agent for treating pruritus according to claim 1, which is an external preparation. The agent for treating pruritus according to claim 5, wherein the liquid preparation is an eye drop. The agent for treating pruritus according to claim 6, wherein the external preparation is an ointment. The agent for treating pruritus according to claim 8, wherein the ointment is an eye ointment. The pruritus treatment agent according to claim 7, which is an eye drop containing 0.01 to 1% (w / v) of an active ingredient. The pruritus treatment agent according to claim 1 and a steroidal anti-inflammatory drug, a nonsteroidal anti-inflammatory drug, an antiallergic drug, an antihistamine, a glaucoma drug, an antibiotic, an antibacterial drug, an antiviral drug, and an antifungal drug A pharmaceutical comprising a combination of one or more selected. A method for treating pruritus, comprising administering an effective amount of a compound represented by the general formula (I) according to claim 1, a salt thereof, or a solvate thereof to a mammal. Use of the compound represented by the general formula (I) according to claim 1, a salt thereof, or a solvate thereof for producing an agent for treating pruritus.