WO2002036572A1 - Remedies for extraocular inflammatory diseases - Google Patents

Abstract

Remedies and/or preventives for extaocular inflammatory diseases or eye itch. More particularly, remedies and/or preventives for extaocular inflammatory diseases or eye itch which comprise as the active ingredient compounds represented by the following general formula (I), nontoxic salts thereof or hydrates of the same: (I) wherein R1- represents a carbon ring which binds to the piperidine ring together with the carbon atom at the binding site or spiro-binds at the 4-position; R2 represents alkyl; R3 represents alkyl, alkenyl, alkynyl or halogeno; R4 represents hydrogen, aminoalkyl or carbon ring alkyl optionally substituted by aminoalkyl; i is from 0 to 3; and n is from 0 to 3. These compounds have effects of treating inflammatory diseases and eye itch in a small dose.

Description

 Agent for the treatment of extraocular inflammatory diseases

 The present invention relates to a therapeutic agent for extraocular inflammatory disease or ocular pruritus,

 More specifically, the general formula (I)

yarn

(The definition of each symbol will be described later.)

A therapeutic and / or prophylactic agent for extraocular inflammatory diseases or ocular pruritus comprising, as an active ingredient, a condensed piperidine compound represented by the formula: or an acid addition salt thereof or a hydrate thereof.

Background art

 The discovery that macrophages, one of the immunocompetent cells, produce large amounts of nitrate, has shown that nitric oxide (NO) is produced in vivo [P'r oc. Natl. Acad. Sci. USA, 82, 7738-7742 (1985); J. Immunol., 131, 550-565 (1987)]. In the circulatory system field, a substance having a relaxing action released from vascular endothelial cells was discovered and named vascular endothelium-derived relaxing factor (EDRF). Furthermore, the body of this EDRF was found to be NO [Nature, 327, 524-526 (1987)].

5 NO Sには少なくとも非誘導型 （血管内皮型および神経型） および誘導型のァ イソザィムが存在する。 血管内皮型 NO Sは、 主に血管内皮細胞に存在し、 細胞 内カルシウム濃度により活性が制御されている。 神経型 NO Sは、 中枢神経細胞 、 末梢神経細胞、 滕島 /3細胞、 消化管神経、 副腎髄質、 腎臓緻密斑等に存在し、 血管内皮型 N0Sと同様に細胞内カルシウム濃度により活性が制御されている。0 血管内皮型 K[OSおよび神経型 NOS (constitutive NOS, c一 NOSと略記 する） は細胞内に恒常的に存在し、 生理的変化による酵素量の変化はほとんど見 られない。 誘導型 NO S (inducible N0S、 i— NOSと略記する） は、 肝実質 細胞、 好中球、 マクロファージ、 平滑筋、 線維芽細胞、 腎メサンギゥム細胞、 消 化管上皮、 塍島 ]3細胞、 血管平滑筋細胞、 グリア細胞等に存在する。 これは通常5 細胞内で認められず、 エンドトキシンや各種サイ ト力イン等による刺激により綉 導される。 NO, which has been shown to be produced in vivo as described above, is generated by nitrogen monoxide synthase (abbreviated as NOS) based on L-arginine by the following pathway.

There are at least non-inducible (vascular endothelial and neuronal) and inducible isozymes in 5NOS. Vascular endothelial NOS is mainly present in vascular endothelial cells, and its activity is controlled by intracellular calcium concentration. Nerve-type NOS is present in central nerve cells, peripheral nerve cells, Tengshima / 3 cells, gastrointestinal nerves, adrenal medulla, kidney compact plaques, etc. Have been. 0 Vascular endothelial K [OS and neural NOS (abbreviated as constitutive NOS, c-NOS) are constantly present in cells, and there is almost no change in the amount of enzymes due to physiological changes. Inducible NOS (inducible NOS, abbreviated as i-NOS) refers to hepatic parenchymal cells, neutrophils, macrophages, smooth muscle, fibroblasts, renal mesangial cells, gastrointestinal epithelium, 塍 shima] 3 cells, blood vessels Present in smooth muscle cells, glial cells, etc. This is not usually observed in 5 cells, and is suggested by stimulation by endotoxin or various cytokins.

The effects of NO produced by NOS are diverse, including, for example, vasorelaxation, platelet aggregation inhibition, adhesion inhibition, leukocyte adhesion / migration inhibition, sympathetic nervous activity inhibition, endotoxin shock, endotoxin / sitekine. Hypotension, due to. Between nerve cells , Ischemic brain cell damage, antitumor, bactericidal action, autoimmune disease, insulin-dependent diabetes, arthritis, post-transplant tissue damage, rejection and the like. .

 NOS inhibitors are useful in analyzing the physiological activity of NO in vivo, and have a potential to be used as therapeutics for shock and ischemic diseases. Agent development is currently underway.

 For example, there are arginine analogs as substrate competitors, N-ω-monomethyl-L-arginine (L-ΝΜΜΑ), Ν ”ω-two-stroke L-arginine (L-ΝΝΑ), Ν—ω-nitro-L— Arginine methyl ester (L-NAME), Ν-ω-amino-L-arginine (L-ΝΑΑ), Ν-ω-iminoethyl-ornithine (L-Ν) and the like. In addition, difactory dendrimes (DP I), G2-chelon donium (DT I.), calcineurin and the like are examples of cofactor competitive inhibitors.

 As a specific example of the suppression of inflammation in the eyes by OS inhibitors, for example, in allergic conjunctivitis, excessive production of NOS increases NO production and vascular permeability. These have been reported to be suppressed by L-NAMEI [Cornea, ϋ, 84-91 (2000)]. In the acute phase of allergic conjunctivitis, NO production is enhanced and edema is formed by the production of prostaglandin E2. It is known that L—N AM E inhibits prostaglandin E 2 production by inhibiting NO production [Prostaglandins, 52, 431-446 (1996)].

 Ocular pruritus often accompanies extraocular inflammatory diseases such as allergic conjunctivitis and spring catarrh. It has been reported that pruritus media may have NO in addition to histamine and substance P [Medical History, 197, 595-598 (2001)]. Although there is no specific report on itchy pruritus, in animal models of atopic dermatitis, L-NAME has been shown to suppress the pruritic response [Nihon Pharmacological Journal, 1Η, ΠΡ-21Ρ (1999)] .

On the other hand, the compound represented by the general formula (I) has been filed as a NOS inhibitor (EP 870763). NOS inhibitors inhibit the synthesis of NO in vivo, and are therefore known to be useful in the treatment of various diseases that are thought to be involved in NO. Among them, it is suggested that this may be effective for inflammatory itching. However, the efficacy of NOS inhibitors in each disease could only be determined for certain compounds. Disclosure of the invention

 As mentioned in the previous topic, it is known that L-NAME, one of the NS inhibitors, is useful for pruritus in allergic conjunctivitis and atopic dermatitis. However, there are many unknowns as to which compound having a NOS inhibitory effect is effective for extraocular inflammation and ocular pruritus. Accordingly, the present inventors have focused on the present compound represented by the general formula (I), and as a result of diligent research, have found that the present compound significantly suppresses the formation of edema at a low dose in a conjunctivitis model. After confirming, it was found for the first time that it was actually effective in inflammation in the external eye. In addition, the present compound was found to remarkably suppress ocular pruritus observed in allergic conjunctivitis model, and was found to be actually useful for the treatment of ocular pruritus. ·

 That is, the present invention provides a compound represented by the general formula (I):

H (wherein, one R ¹ — is united with the carbon atom at the bonding position and is fused to the bond d or bond e of the piperidine ring, or is spiro-bonded to the 4-position. Represents a 4-membered carbon ring,

R ² represents C 6 alkyl,

6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or halo Represents a gen atom

R ⁴ represents a hydrogen atom, amino-C 1-4 alkyl, or carbocyclic mono-C 1-4 alkyl optionally substituted with amino-C 1-4 alkyl;

 i represents 0 or an integer of 1 to 3,

n represents 0 or an integer of 1 to 3.

However, a plurality of R ² or R ³ may be the same or different. The present invention relates to a therapeutic and / or prophylactic agent for extraocular inflammatory diseases or ocular pruritus comprising, as an active ingredient, a condensed piperidine compound represented by the formula: or an acid addition salt thereof or a hydrate thereof. — Among the compounds H represented by the general formula (I), preferred compounds are those represented by the general formula (IA)

(The symbols in the formula represent the same meaning as defined above.)

 Or a non-toxic salt thereof or a hydrate thereof. Of the compounds represented by the general formulas (I) and (IA), more preferred compounds are those represented by the formula (Ia).

A fused piperidine compound represented by the formula ((+)-trans- ₃ -imino- _5- methyl-7-chloro-2-2-azabicyclo [4. · 1.0] heptane) and its non-toxic salts TJP01 / 09495 or its hydrate. '

 The compounds represented by the general formulas (I), (IA) and (Ia) used in the present invention may be administered in the form of the following acid addition salts. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitric acid, or acetate, or lactic acid. Salt, 'tartrate, oxalate, fumarate, maleate, quaternary salt, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, Organic salts such as glucuronate and dalconate are preferred, and hydrochloride is preferred.

 The present compound represented by the general formulas (I), (IA) and (Ia) or a salt thereof may be converted into a hydrate by a known method. '

(Production method of the present compound).

 The compounds represented by the general formulas (I), (IA) and (Ia) can be produced by the method described in EP 87 0763.

[Pharmacological activity of the compound]

 The present compounds represented by the general formulas (I), (IA) and (Ia) have potent NOS inhibitory activity and, as described later, were effective in an inflammation model of the extraocular region. In addition, since NOS has been implicated in inflammatory diseases, this compound is effective for all inflammatory diseases of the extraocular region including conjunctivitis, regardless of whether it is non-allergic or allergic.

 Further, the present compounds represented by the general formulas (I), (IA) and (Ia) have an inhibitory effect on pruritus in an inflammation model of the extraocular region and are effective against ocular pruritus, as described later. .

[Toxic]

The toxicity of this compound was sufficiently low, confirming that it is safe enough for use as a pharmaceutical. For example, for intravenous administration in mice, the formula (I a The maximum tolerated dose of the compound represented by) was 30 mg kg.

[Application to pharmaceutical products]

 The present food, the acid addition salt or the hydrate thereof represented by the general formulas (I), (IA) and (la) are allergic conjunctivitis, non-allergic conjunctivitis, blepharitis, eye surgery Treatment of inflammation associated with (cataract surgery, glaucoma filtration surgery, myopia correction surgery, etc.), inflammatory diseases of the outer eye such as spring catarrh, scleritis (especially allergic conjunctivitis, non-allergic conjunctivitis) or eye pruritus And Z or useful for prevention.

 In order to use the present compound, an acid addition salt or a hydrate thereof represented by the general formulas (I), (IA) and (la) for the above-mentioned purpose, it is usually necessary to administer the compound systemically or locally through the oral route. Or it is administered in parenteral form. '

 The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, in the range of lmg to 100 mg per day, once or several times a day Or parenteral (preferably eye drops) once to several times a day in the range of 10 ηg to 1 Omg per adult per dose.

 Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range. .

 When the present compound is administered, it is used as eye drops, injections, external preparations, suppositories and the like for parenteral administration, and solid preparations and liquid preparations for oral administration for oral administration. Dosage forms of eye drops for parenteral administration include eye drops, suspension-type eye drops, emulsion-type eye drops, dissolution-in-use eye drops, and eye drops.

These eye drops are prepared according to a known method. For example, ophthalmic solutions include isotonic agents (sodium chloride, concentrated glycerin, etc.), buffering agents (sodium phosphate, sodium acetate, etc.), surfactants (Polysorbate 80 (trade name), polystearate). Oxil 40, polyoxyethylene hydrogenated castor oil, etc.), stabilizers (sodium citrate, sodium edetate, etc.), preservatives (benzalkonium chloride, paraben, etc.) ) Are added as necessary. These are sterilized in the final step or prepared by aseptic procedures.

 Injections for parenteral administration include solutions, suspensions, emulsions and solid injections which are dissolved or suspended in a solvent before use. Injectables are prepared by dissolving, suspending or emulsifying one or more active substances 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 the like, and combinations thereof are used. Furthermore, this injection contains a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (trade name), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. Is also good. These are prepared by sterilization or aseptic processing in the final step. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used before dissolving it in sterile or sterile distilled water for injection or other solvents before use.

 Other preparations for parenteral administration include one or more active substances and are formulated as topical solutions, ointments, salves, inhalants, sprays, suppositories, and intravaginal preparations formulated in a conventional manner Pessaries etc. are included.

 Sprays may be used in addition to commonly used diluents, as well as buffers that provide isotonicity with stabilizers such as sodium bisulfite, for example, isotonic agents such as sodium chloride, sodium citrate or citric acid. The preparation of ρ-sprays which may contain an agent is described in detail, for example, in US Pat. Nos. 2,868,691 ′ and 3,095,355.

Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules, and those made of a material such as gelatin that can be absorbed are preferably used. In such solid dosage forms for oral use, the one or more active substances may be as such or excipients (such as lactose, mannitol, glucose, microcrystals. Cellose, starch, etc.), binders ( Hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant. (Calcium cellulose glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, solubilizer (Glutamic acid, aspartic acid, etc.), etc., and used in pharmaceutical preparations according to the usual methods. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers.

 Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (such as purified water, ethanol or a mixture thereof). Further, this liquid preparation 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. BRIEF DESCRIPTION OF THE FIGURES

 Figure 1 shows the three groups treated with the compound (5-6 animals per group, 10-12 eyes), control group (6 animals per group, 12 eyes), diclofenac-administered group It is a graph showing the average value of the difference in edema weight in a total of 5 groups (6 animals per group, 12 eyes). '

 Figure 2 shows the Zymosan-induced model with 3 groups (1 group, 6 mice, 12 eyes), control group (6 groups, 12 eyes), diclofenac group (6 animals, 1 group) 2 is a graph showing the difference in edema weight in the five groups (2 eyes) in total, as an average value. Fig. 3 shows a total of 4 groups of the guinea pig passive sensitization allergic unilateral conjunctivitis model: 3 groups treated with the compound (6 mice per group, 12 eyes) and control group (6 mice per group, 12 eyes). 5 is a graph showing the absorbance at 620 nm as an average value.

 Figure 4 shows a total of 4 groups of the guinea pig active sensitization allergic conjunctivitis model: 3 groups treated with the compound (9 mice per group, 1 S eye) and control group (9 mice per group, 18 eyes). 4 is a graph showing the edema score 30 minutes after the onset of conjunctivitis in an average value.

Fig. 5 shows three groups of the guinea pig active sensitizing allergic conjunctivitis model: the group administered with the compound (8 mice / group, 16 eyes) and the control group (8 groups / group, 16 eyes). 5 is a graph showing the average number of eye pulls for 60 minutes after conjunctivitis is induced. JP01 / 09495 Best mode for carrying out the invention

 Hereinafter, the present invention will be described in detail with reference to experimental examples, but the present invention is not limited thereto.

 [Formulation example]

 Examples of general formulations of the ophthalmic solution and ointment of the present invention are shown below.

 1) Eye drops (1 Om in 1)

 1 mg of this compound

 Concentrated glycerin 250 mg

 Polysorbate 80 200 ms

 Sodium dihydrogen phosphate hydrate

 1 N sodium hydroxide

 1 N hydrochloric acid

 Sterile purified water By appropriately changing the amount of this compound and additives, the concentration of this compound becomes 0.0001%, 0.001%, 0.005%, 0.05%, 0.1%, 0.1%. Eye drops of 5%, 1.0%, 3.0%, 5.0% (w / v) can also be prepared.

 2) Eye ointment (in 100 g)

 This compound 10 Omg White petrolatum 90 g

 In the same manner as in liquid paraffin, eye ointments containing lmg, 5mg, 10mg, and 50mg of the present compound can be prepared.

 [Pharmacological test].

 1. Effect of this compound on experimental model of conjunctivitis induced by force lagenin in rats

 [experimental method]

Four-week-old male Wister rats were subjected to the experiment. Was dissolved in physiological saline to a concentration of 1% (W / V) at room temperature, and the resulting solution was treated with urethane anesthesia. Edema was induced by injecting 5 O jtiL / eye into both eyes of the rats under the eyelid conjunctiva.

 The test compound was administered by eye drops at 5 jtiL / eye. The administration was performed 1 hour before edema induction, 0, 1, 2, 3, 4, 5, 6, and 7 hours.

 As the test compound, the present compound (monohydrochloride) represented by the formula (式 a) at various concentrations was used. In addition, diclofenac (0.1% W / V), which is widely used as a non-steroid anti-inflammatory agent, was used as a comparative compound, and physiological saline was used as a control.

 Eight hours after challenge, the rat was decapitated and the scalp was directed toward the eyelid and peeled. The skin and the edema site were separated along the eyelid margin, and the edema weight was measured.

 [Experimental result] '

 Figure 1 shows the average edema weight.

 The compound at a concentration of 0.001%, 0.011% and 0.1% significantly suppressed edema compared to the control and comparison compound diclofenac, and the degree was concentration-dependent.

 2. Effect of the Compound on Zymozan-induced Rat Experimental Conjunctivitis Model ''

 [experimental method]

 Four-week-old male Wister rats were subjected to the experiment. Zymosan is suspended in physiological saline at a concentration of 3% (W / V) at room temperature, and the resulting suspension is injected into the eyes of rats under urethane anesthesia under the eyelid conjunctiva at 50 iL / eye. Caused edema.

 Administration of the test compound was performed by eye drops at 5 L / eye. Administration was 1 hour before, 0, 1 and 2 hours after edema induction.

 As the test compound, the present compound (monohydrochloride) represented by the formula (Ia) at various concentrations was used. Diclofenac (0, 1% W / V), which is widely used as a nonsteroidal anti-inflammatory drug, was used as a comparative compound, and physiological saline was used as a control. '

 Three hours after the challenge, the rats were decapitated and the scalp was directed toward the eyelids and peeled. Skin rot and 'edema site' were separated along eyelid 緣 and edema weight was measured.

 [Experimental result]

Figure 2 shows the average edema weight. The 0.1% concentration of the compound significantly suppressed edema as compared to the control. on the other hand

The comparison compound diclofenac was ineffective.

 3. Effect on guinea pig passive sensitization allergic conjunctivitis model

 [experimental method]

 Five week old male Hartley guinea pigs were subjected to the experiment. The anti-ovalbumin serum was diluted with physiological saline to an antibody titer of 1:64, and the obtained solution was injected into the eyes of guinea pigs under ether anesthesia at a rate of 100 L / eye, under the conjunctiva of the eyelid. Forty-eight hours later, 2.5% (W / V) ovalbumin solution was instilled into each eye at 10 L / eye to induce allergic conjunctivitis, and at the same time, 1% (W / V) Evansbull monostain was applied. 1.5 ml / kg was administered intravenously.

 The administration of the test compound was performed by eye drops for each 1 O ^ LZ eye. The administration was performed 1 hour and 15 minutes before the onset of conjunctivitis.

 As the test compound, the present compound (monohydrochloride) represented by the formula (Ia) at various concentrations was used. '

 Thirty minutes after the induction, the guinea pig was decapitated, the scalp was cut along the midline, and the conjunctival tissue was removed. The dye leaked into the conjunctival tissue is extracted with 0.5% (W / V) sodium sulfate-acetone (3.:7) mixture (5 mL) for at least 48 hours, and the absorbance at 620 nm is measured. It was quantified by: .

 [Experimental charcoal fruit]

 Figure 3 shows the average absorbance at 620 nm.

 This compound suppresses dye leakage to conjunctival tissue in a concentration of 0.001% (W / V) to 0.1% (W / V) more clearly than control, and the degree of inhibition is concentration-dependent. It was a target. -

4. Effects on guinea pig active sensitization allergic ^ conjunctivitis model

[Experimental method] 'Five week old male Hartley guinea pigs were subjected to the experiment. 0.1% (W / V) aluminum hydroxide gel-adsorbed ovalbumin dissolved in physiological saline was injected subconjunctivally into the eyes of guinea pigs under ether anesthesia in 100 LZ eyes each. Seventeen days later, apply 2.5 L (W / V) ovalbumin solution to both eyes at 10 L / eye. When administered to 495 eyes, allergic conjunctivitis was induced.

 The administration of the test compound was performed by eye drops at a dose of 10 / xL / eye. The administration was performed 1 hour and 15 minutes before the onset of conjunctival inflammation.

 As the test compound, the present compound (hydrochloride) represented by the formula (la) at various concentrations was used.

 At 30 minutes after the induction, the condition of the conjunctiva of each eye was visually observed, and the condition of the edema was scored according to the following criteria, and the conjunctival inflammation was evaluated. '

 <Edema score criteria>

 0: No edema is observed in the conjunctiva with the eyes open.

 0.5: Slight edema in upper and lower conjunctiva when eyelids open.

 1: When the upper and lower eyes are slightly lifted from the eyeball and the eyes are opened, clear edema is observed.

 2: The upper and lower eyelids are well above the eyeballs, and edema is observed without opening the eyelids.

 3: Upper and lower eyelids It is observed that the edema covers a part of the cornea even if the eyelids are not opened with the f's floating above the eyeballs.

 4: The upper and lower eyelids are well above the eyeball, and edema is observed to cover about 2/3 of the cornea without opening the eyelids.

 The criteria for this score were created according to inilamm. Res., 48, 325-336 (1999).

 [Experimental result]

 Figure 4 shows the average edema score.

 The compound significantly inhibited edema at concentrations of 0.001% (W / V) to 0.1% (W / V) compared to the control, and the degree of inhibition was concentration-dependent.

 From the experimental results of 1. to 4., it is confirmed that this compound is effective for all inflammatory diseases of the external eye including conjunctivitis, regardless of whether it is non-allergic or allergic.

 5. Effect of the compound on itching

Five week old male Hartley guinea pigs were subjected to the experiment. 0.1% (W / V) aluminum hydroxide gel-adsorbed ovalbumin dissolved in physiological saline was added to ether Injected 100 ^ LZ eyes were injected subconjunctivally into both eyes of a drunk guinea pig. 17 Then, allergic conjunctivitis was induced by instilling a 2.5% (W / V) ovalbumin solution into both eyes at 10 L / eye.

 The administration of the test compound was performed by eye drops for each of the OjLZ eyes. The administration was performed 1 hour, 15 minutes and 5 minutes before the induction of conjunctivitis.

 As the test compound, the present compound (monohydrochloride) represented by the formula (Ia) at various concentrations was used.

 The behavior of the guinea pig was recorded on a video for 60 minutes after the provocation, and the number of eye pulling was measured by counting the series of actions of pulling eyes with the hind limb for each eye as one time.

 [Experimental result]

 Figure 5 shows the number of eye drops for 60 minutes after conjunctivitis was induced.

 This compound significantly reduced the number of eye contact at concentrations of 0.01% (W / V) to 0.03% (W / V) as compared to the control. '. From this experimental result, it is confirmed that the present compound is effective for ocular pruritus. Industrial applicability

 The present invention relates to a therapeutic agent for extraocular inflammatory disease or ocular pruritus. That is, the present compound represented by the general formula (I), (IA) or the formula (la), its acid addition salt or its hydrate is allergic ^ conjunctivitis: non-allergic conjunctivitis, blepharitis, eye Treatment of inflammation associated with surgery (cataract surgery, glaucoma filtration surgery, myopia correction surgery, etc.), inflammatory diseases of the outer eye such as spring catarrh, scleritis (especially allergic conjunctivitis, non-allergic conjunctivitis) or eye pruritus / Or useful for prevention.

Claims

Claims The active ingredient is represented by the general formula (I

 H (Wherein, —R ′ ¹ — is a 3- or 4-membered carbon fused to the bond d or bond e of the piperidine ring together with the carbon atom at the bond position, or a spiro bond at the 4-position. Represents a prime ring, R ² represents C.1-6 alkyl, R ³ represents C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or octagen, R ⁴ represents a hydrogen atom, an amino-C 1-4 alkyl, or a carbocyclic mono-C 1-4 alkyl optionally substituted with amino-C 1-4 alkyl;  i represents 0 or an integer of 1 to 3, n represents 0 or an integer of 1 to 3. However, a plurality of R ² or R ³ may be the same or different. ) A condensed piperidine compound represented by the formula: or an acid addition salt thereof or a hydrate thereof. A therapeutic and / or prophylactic agent for extraocular inflammatory disease or ocular pruritus. 2. The active ingredient has the general formula (ΓΑ) (R ² ) n  (I A)  H (The symbols in the formula have the same meanings as in claim 1.)  3. The therapeutic and / or prophylactic agent for external ocular inflammatory disease or pruritus in the eye according to claim 1, which is a condensed piperidine compound represented by the formula: or a non-toxic salt thereof or a hydrate thereof.  3. The active ingredient has the formula (la)

3. The therapeutic and / or prophylactic agent for inflammatory diseases of the extraocular region or pruritus of the eye according to claim 1 or 2, which is a condensed piperidine compound represented by the formula: or a non-toxic salt thereof or a hydrate thereof.  4. Claim 1, 2 or claim 3, wherein the extraocular inflammatory disease is allergic conjunctivitis 3 treatments and prophylactic or prophylactic agents.  5. The therapeutic and / or preventive agent according to claim 1, 2 or 3, wherein the extraocular inflammatory disease is non-allergic conjunctivitis.  6. The method according to claim 1, 2 or 3, wherein the extraocular inflammatory disease is blepharitis. 7. Claim 1, 2 or 3 wherein the extraocular inflammatory disease is inflammation associated with eye surgery A therapeutic and / or prophylactic agent according to one of the preceding claims. +  8. The therapeutic and / or prophylactic agent according to claim 1, 2 or 3, wherein the extraocular inflammatory disease is spring catarrhal or scleritis.  9. General formula (I)

(Wherein, R ^{1 and} R ¹ are taken together with the carbon atom at the bonding position and are condensed to bond d or bond e of the piperidine ring, or a 3- or 4-membered carbon that is spiro-bonded to the 4-position. Represents a ring, R ² represents C 1-6 alkyl,  R represents C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or hagen atom, R ⁴ represents a hydrogen atom, amino-C 1-4 alkyl, or carbocyclic mono-C 1-4 alkyl which may be substituted by amino-C 1-4 alkyl, and 'i is 0 or an integer of 1-3. Represent,  n represents 0 or an integer of 1 to 3. However, a plurality of R or R ³ may be the same or different from each other. ) A method for treating and / or preventing extraocular inflammatory disease or pruritus of the eye, comprising administering to a patient an effective amount of the condensed piperidine compound represented by the formula, an acid addition salt thereof, or a hydrate thereof. 10. The condensed piperidine compound has the general formula (1A)

 H (The symbols in the formula have the same meanings as in claim 9.)  10. The method for treating and / or preventing external inflammatory disease or ocular pruritus according to claim 9, which is represented by:  10 1 1. The fused piperidine compound is represented by the formula (Ia)

11. The method for treating or preventing extraocular inflammatory disease or ocular pruritus according to claim 9 or 10, which is represented by the following formula.  12. The treatment method and / or prevention method according to claim 9, 10 or 20, wherein the extraocular inflammatory disease is allergic conjunctivitis.  1 3. The treatment method and / or prevention method according to claim 9, 10 or 11, wherein the extraocular inflammatory disease is non-allergic conjunctivitis. \  1 4. The method of claim 9, 10 or 11, wherein the extraocular inflammatory disease is blepharitis. '25 1 5. The treatment method and the Z or prevention method according to claim 9, 10 or 11, wherein the extraocular inflammatory disease is inflammation associated with eye surgery. 16. The treatment method according to claim 9, 10 or 11, wherein the extraocular inflammatory disease is spring catarrhal or scleritis.  17. General formula (I) for the manufacture of a therapeutic and / or prophylactic agent for extraocular inflammatory diseases or pruritus

(Wherein, R ¹ — is a force condensed to the bond d or bond e of the piperidine ring together with the carbon atom at the bond position, or a 3- or 4-membered carbon that is subiro bonded to the 4-position. Represents a prime ring, R ² represents C 1-6 alkyl; 1¾ ³ represents 〇 1-6 Arukiru, C 2 to 6 alkenyl, C. 2 to 6 alkynyl or halo gen atom, R ⁴ represents a hydrogen atom, an amino-C 1-4 alkyl, or a carbocyclic mono-C 1-4 alkyl optionally substituted with amino-C 1-4 alkyl;  i represents 0 or an integer from]. to 3, n represents 0 or an integer of 1 to 3. However, a plurality of R ² or R ³ may be the same or different. ') Use of a condensed piperidine compound represented by the formula (1), an acid addition salt thereof, or a hydrate thereof 8. A fused piperidine compound represented by the general formula (IA)

 H (The symbols in the formula have the same meaning as described in claim 17.) Use of the condensed piperidine compound, the acid addition salt thereof, or the hydrate thereof according to claim 17, which is represented by ''.  19. A fused piperidine compound represented by the formula (Ia)

Use of the condensed piperidine compound, its acid addition salt or its hydrate according to claim 17 or 18, which is represented by:  20. Use of the condensed piperidine compound according to claim 17, 18 or 19, wherein the extraocular inflammatory disease is allergic conjunctivitis, an acid addition salt thereof, or a hydrate thereof. .  1. The use of the condensed piperidine compound, the acid addition salt thereof or the hydrate thereof according to claim 17, 18 or 19, wherein the extraocular inflammatory disease is non-allergic conjunctivitis. 22. Use of the condensed piperidine compound, the acid addition salt thereof or the hydrate thereof according to claim 17, 18 or 19, wherein the extraocular inflammatory disease is blepharitis. 23. Use of the condensed piperidine compound, the acid addition salt thereof or the hydrate thereof according to claim 17, 18 or 19, wherein the extraocular inflammatory disease is inflammation associated with eye surgery. 24. Use of the condensed piperidine compound according to claim 17, 18 or 19, wherein the extraocular inflammatory disease is spring catarrhal or scleritis.