WO2003008396A1 - Optically active oxazine derivative - Google Patents

Abstract

(-)-6-[3-(2-Indanyloxy)-4-methoxyphenyl]-6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, its hydrate or its solvate; and drugs containing the above compound as the active ingredient which are useful in treating and/or preventing inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Description

 Technical Information-Optically active oxazine derivatives

 The present invention relates to a novel compound having a phosphodiesterase (PDE) IV inhibitory activity and a pharmaceutical composition containing the same. Background art

 (Earth) one 6- [3- (2-Indanyloxy) —4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-1 2H—1,3-oxazin-1-one (WO 98 Is known to have a strong phosphodiesterase (PDE) IV inhibitory effect, and to exert bronchodilator and anti-inflammatory effects, such as asthma and dermatitis. It is considered to be effective for autoimmune diseases such as inflammatory diseases, rheumatism and multiple sclerosis. Disclosure of the invention

(S) 1 6- [3- (2-Indanyloxy) 1-4-methoxyphenyl] — 6-methinole-3,4,5,6-tetrahydro-1 2H—1,3-oxazin — 2-one is racemic It has an asymmetric carbon at the 6-position in its isomer (specific rotation: 0 °), and it was expected that there were two types of isomers (+) — isomer and (1) one, but 3, 4, 5 The method for separating isomers of compounds having a 6,6-tetrahydro-2H-1,3, oxazin-12-one skeleton has not been generalized, and separation of isomers from racemic forms has not been achieved. In particular, the above-mentioned 16- [3- (2-indanolinoxy) -14-methoxypheninole] -16-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazine The 2-one does not have an acidic or basic functional group, and its separation cannot be achieved by a diastereomer optical resolution method using an optically active organic base or organic acid. Therefore, the difference in the phosphodiesterase (PDE) IV inhibitory action and the side effect was not known and could not be examined.

 The present inventor has conducted repeated studies to obtain each isomer purely, and as a result, (±) 16- [3- (2-indanyloxy) -14-methoxypheninole] -16-methinolay 3, 4 We have found a method for separating 5,5,6-tetrahydro-2H-1,3-oxazin_2-one into pure isomers by high performance liquid chromatography. The phosphodiesterase (PDE) IV inhibitory effect, anti-asthmatic effect, toxicity and water solubility of each isomer were examined, and the specific isomer had excellent properties as a drug. And completed the present invention.

 That is, the present invention relates to (1) 16- [3- (2-Indanyloxy) -14-methoxyphenyl] —6-methyl-1,3,4,5,6-tetrahydro-1 2H—1,3—o It relates to xazin-1-one or a hydrate or a solvate thereof.

 The present invention also relates to (1) 16- [3- (2-Indanyloxy) -14-methoxyphenyl] -16-methyl-1,3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one And a pharmaceutical comprising, as an active ingredient, a substance selected from the group consisting of hydrates and solvates thereof. '' The compounds of the present invention exhibit phosphodiesterase (PDE) IV inhibitory activity, and based on this, the medicaments of the present invention provide inflammatory diseases such as asthma, dermatitis, chronic obstructive pulmonary disease; multiple sclerosis; It is useful as a medicament for treating and / or preventing or preventing autoimmune diseases such as rheumatism.

 Further, the compound of the present invention has an ameliorating effect on allergic conjunctivitis, and based on this, the medicament of the present invention is used for the treatment and / or treatment of allergic eye diseases such as allergic conjunctivitis, spring catarrh, and spring keratoconjunctivitis. Useful as a medicament for prevention.

Furthermore, the compound of the present invention exhibits an inhibitory effect on TNF- _α production. Based on this, the medicament of the present invention is useful for treating allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis, osteoarthritis, etc.), diabetes, It is useful as a medicament for treating and / or preventing psoriasis, Crohn's disease and ulcerative colitis. In addition, the compound of the present invention exhibits NKi receptor antagonism. Based on this, the medicament of the present invention provides pain; vomiting; asthma, chronic obstructive pulmonary disease, dermatitis (atopic dermatitis, contact dermatitis) , Deprived measles, etc.), and is useful as a medicament for treating and preventing or preventing inflammatory diseases such as allergic eye disease and arthritis.

 In another aspect, the present invention provides (1) -6- [3- (2-indanyloxy) -14-methoxyphenyl] -16-methyl-3,4,5, Use of a substance selected from the group consisting of 6-tetrahydro-2H-1,3-oxazin-12-one and hydrates and solvates thereof; a phosphodiesterase (PDE) IV inhibitor containing the above substance; An ameliorating agent for allergic conjunctivitis containing the above substance; a TNF-a production inhibitor containing the above substance; and an NI ^ receptor antagonist containing the above substance are provided.

 And from yet another perspective,

 A method for inhibiting phosphodiesterase (PDE) IV in mammals, including humans, comprising: (1) 16- [3- (2-indanolinoxy) -14-methoxyphenyl] -16-methyl-3,4, Administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of 5,6-tetrahydro-12H-1,3-oxazine-12-one and hydrates and solvates thereof; Including methods;

 A method for treating and / or preventing an inflammatory disease such as asthma, dermatitis, or chronic obstructive pulmonary disease, multiple sclerosis, or an autoimmune disease such as rheumatism. Administering to a mammal, including a human, an amount;

 A method for ameliorating allergic conjunctivitis in a mammal, including a human, comprising the step of administering an effective amount of the above substance to a mammal, including a human;

 A method for treating and / or preventing allergic eye diseases such as allergic conjunctivitis, spring catarrhal, and spring keratoconjunctivitis, comprising the steps of treating the above substance and administering a Z or prophylactically effective amount to mammals including humans. ;

A method for suppressing the production of TNF-a in a mammal including a human, comprising a step of administering an effective amount of the above substance to a mammal including a human; A method for treating and preventing allergies, bronchial asthma, sepsis, arthritis (rheumatoid arthritis, osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, or ulcerative colitis; Administering to a mammal, including a human, a prophylactically effective amount;

 A method for antagonizing ΝΚ ^ receptor in a mammal L including mammals, comprising a step of administering an effective amount of the above substance to mammals including humans;

 Methods for treating and / or preventing inflammatory diseases such as pain, vomiting, or asthma, chronic obstructive pulmonary disease, dermatitis (atopic dermatitis, contact dermatitis, juniper, etc.), allergic eye disease, or arthritis And administering a therapeutic and / or prophylactically effective amount of said substance to a mammal, including a human.

 Is provided. BEST MODE FOR CARRYING OUT THE INVENTION

 The optically pure compound of the present invention can be prepared, for example, by using a high-performance liquid chromatography (HPLC) to prepare a racemic product produced by the method described in International Publication WO98 / 05344 in the following Examples. By treating under specific conditions as described, two types of optically active forms [ie, (1) 16- [3- (2-indanyloxy) -14-methoxyphenyl] -16-methyl-3,4 , 5,6-Tetrahydro-2H-1,3-oxazine-12-one and (+)-6- [3- (2-Indanyloxy) —4-methoxypheninole] -16-methyl-3,4,5 , 6-tetrahydro-2H-1,3-oxazine-1-2-one]. Further, by recrystallizing the obtained optically active substance with various solvents as needed, it is possible to obtain an optically active substance with higher purity.

Recrystallization of the optically active substance is performed using a single solvent such as methanol, ethanol, isopropanol, ptanol, acetone, ethynole acetate, chlorophonolem, n-hexane, cyclohexane, etc., or a mixed solvent combining two or more solvents. This can be done by: The optically active substance obtained by the above method is (1) one-piece [(one) one 6- [3- (2-indanyloxy) -14-methoxyethoxy-nore] 16-methyl-3,4,5,6-te Abbreviations for trahydro-2H—1, .3-oxazin-1-one] and (+) — body [(+)-16] [3- (2-indanoleoxy) -14-methoxyphenyl] 16— Methylo

PDE IV inhibitory activity of 3,4,5,6-tetrahydro 2H-1, 3-oxazin-12-one] in comparison with the racemic [(P)] It is shown in Table 1 below. Table 1 summarizes the results of Test Example 1 and Test Example 2 described below. table 1

上記表に示した様に、 （一） 一体はラセミ体の約 2倍の PDE IV阻害作用及ぴ抗喘 息作用を有すのに対し、 （+) —体はラセミ体の約 1/3の PDE IV阻害作用おょぴ 約 1 / 4以下の抗喘息作用しか有さず、 薬理活性は相当弱いがラセミ体と同程度の 毒性を示す。 さらに、 （一）一体はラセミ体に比べ水に対する溶解性が著しく高く、 各種液剤としての利用の可能性が高くなるとともに、消化管などにおける吸収性も 改善される可能性があり好ましい。以上の通り、 （一）一体はラセミ体に比べて PDE IV阻害薬および抗喘息薬などの医薬として極めて有用であることが確認された。 また、 （一） 一体がアレルギー性結膜炎に対する改善作用、 TNF— a産生抑制 作用、及び NK;^受容体拮抗作用を有することも新たに確認された。ラセミ体が PDE IV阻害薬おょぴ抗喘息薬として有用であることは国際公開 WO 9 8/0 4 5 3 4 号に開示されているが、 （一） 一体がアレルギー性眼疾患治療薬、 TNF— 産生 阻害薬、 及び N K i受容体拮抗薬として有用であることは示唆ないし教示されてい ない。 本発明の化合物を有効成分として含む医薬としては、上記の方法により得られる 光学活性な化合物並びにその水和物及ぴその溶媒和物からなる群から選ばれる物 質を単独で用いてもよいが、又は上記物質を薬学的に許容される担体と混合し、適 当な形態の医 袓成物として調製することもできる。

As shown in the above table, (1) one body has PDE IV inhibitory activity and anti-asthmatic effect about twice that of racemic body, whereas (+) — body has about 1/3 of racemic body Has an anti-asthmatic effect of about 1/4 or less, and has a pharmacological activity that is considerably weaker, but shows toxicity similar to that of the racemic form. Furthermore, (1) the monolith is preferable because it has a significantly higher solubility in water than the racemic form, which increases the possibility of being used as various liquid preparations, and may also improve the absorption in the digestive tract and the like. As described above, (1) it was confirmed that the whole was extremely useful as a drug such as a PDE IV inhibitor and an anti-asthmatic drug as compared with the racemic form. In addition, (1) it was newly confirmed that the monotherapy has an improving effect on allergic conjunctivitis, a TNF-a production inhibitory effect, and an NK; ^ receptor antagonistic effect. The usefulness of the racemate as a PDE IV inhibitor and an anti-asthmatic drug is disclosed in International Publication WO98 / 045354, but (1) a drug for treating allergic eye diseases, It is not suggested or taught to be useful as a TNF-production inhibitor or an NKI receptor antagonist. As a medicine containing the compound of the present invention as an active ingredient, a substance selected from the group consisting of optically active compounds obtained by the above method and hydrates and solvates thereof may be used alone. Alternatively, the above substance can be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition in an appropriate form.

 Pharmaceutical compositions suitable for systemic administration include, for example, pharmaceutical compositions suitable for oral administration such as granules, powders, tablets, pills, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids And pharmaceutical compositions suitable for parenteral administration such as injections (intravenous, intramuscular, subcutaneous), drops, ointments, suppositories, aerosols, inhalants and the like. Pharmaceutical compositions suitable for topical administration include eye drops, eye ointments, ointments, suppositories, aerosols, inhalants and the like.

 For the production of the above-mentioned pharmaceutical composition, one or more additives for pharmaceutical preparations as necessary, for example, a binder, a lubricant, a disintegrant, a preservative, a buffer, a thickener, and a dissolution agent Various commonly used additives for preparations such as auxiliaries, chelating agents, stabilizers, pH adjusters, and isotonic agents may be used.

 For example, pharmaceutical compositions for oral administration include: Excipients such as sucrose, microcrystalline cellulose, glucose, corn starch, sucrose, sorbitol, mannitol, erythritol, disintegrants such as calcium carboxymethylcellulose, hydroxypropylcellulose, calcium stearate, magnesium stearate, talc Lubricants such as polyethylene glycol, hydrogenated oil, hydroxypropyl cellulose, hydroxypropinolemethinoresenolellose, canoleboximetinolesenorelose, polyvinylinoleanolol, gelatin, gum arabic A desired dosage form can be prepared using a humectant such as, for example, a surfactant or a flavoring agent, if necessary.

For the preparation of a pharmaceutical composition for parenteral administration, a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, or tragacanth is used, and if necessary, a solubilizing agent (polybutylene) is used. Pyrrolidone, polyoxyethylene hydrogenated castor oil, polyethylene glycol, polysorbate 80, polyoxyethylene monostearate, etc.), preservatives (chlorobutanol, sodium dehydroacetate, Benzalkonium chloride, chlorinated cetylpyridinium, phenyl alcohol, paraoxybenzoic acid esters, bezetonium chloride, etc., buffers (borate buffer, phosphate buffer, carbonate buffer, acetate buffer) Agents, citrate buffer, etc.), stabilizers (sodium edetate, sodium bisulfite, etc.), pH adjusters (sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, acetic acid, citrate, phosphorus Acids, etc.), isotonic agents (sodium chloride, sodium chloride, glycerin, polyhydric alcohol, sorbitol, mannitol, glucose, etc.), soothing agents and the like.

 In the case of eye ointments, commonly used bases (white petrolatum for ophthalmology, plastic base, prototype, etc.) can be used, and examples of additives include liquid paraffin.

The dose of the medicament of the present invention, when orally administered as a preparation for systemic administration, is usually 0.01 to 1000 mg per day based on the weight of the compound of the present invention for an adult, and is preferably Is 0.01 to 100 mg. It is preferable that the dosage be appropriately increased or decreased depending on the age, medical condition, symptom, presence / absence of co-administered drug, and the like. The daily dose may be administered once a day or divided into two or three times a day at appropriate intervals, or may be administered intermittently every few days. When used as an injection for systemic administration, it is preferred that the compound of the present invention be administered continuously or intermittently to adults in a single dose of 0.001 to 100 mg. When the medicament of the present invention is administered topically, the daily dose for an inhalant is usually 0.001 to 300 mg, preferably 0.001 to 30 mg, for an adult. In the case of eye drops, it is usually used at a concentration of 0.01 to 3.0 ^ /%, and in the case of eye ointment, it is usually used at a concentration of 0.01 to 10.0 wZ v%. The dosage is preferably increased or decreased as appropriate depending on the age, medical condition, symptom, presence / absence of co-administered drug, and the like. In the case of an injection, it can be administered once or several times a day. In the case of eye drops, usually 1 to 6 times a day, 1 to 2 drops can be applied at a time, and in the case of eye ointment, an appropriate amount is usually applied to the conjunctival sac once or twice a day. be able to. Example

 Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples, but the scope of the present invention is not limited to the following Examples and Test Examples.

 <Example 1>

 (Earth) 6- [3- (2-Indanyloxy) -14-methoxyphenyl] -16-methyl-1,3,4,5,6-tetrahydro-2H-1,3-oxazin-12-one 70 g denatured ethanol After dissolving in 7.0 L, about 3.0 g of the sample solution was poured into the force ram at a time, and HPLC was performed under the following conditions.

Column: CHIRALPAK AS (10cm φ X50cm)

Solvent: denatured ethanol

Flow rate: lOOmL / min

The fractions of the first peak and the second peak were concentrated under reduced pressure, ethanol and _n- hexane were added to the obtained oily residue, and then concentrated under reduced pressure to obtain a powdery optically active substance. Was. By repeating the above operations, two types of optically active substances were obtained from (Sat) 70 g, (1) 31.5 g and (+)-body 29.6 g. The structure was confirmed by comparison with the racemic NMR before optical resolution. -

(1) Integral: retention time 50-62 minutes, column temperature 40. C

[c¾] ²⁰ _D one 68 ° (c two 1.00, MeOH)

One _{NMR (CDC 1 3) δ (} p pm)

1.68 (3H, s), 2.14 (1H, ddd, J = 14.0, 10.6, 5.6 Hz), 2.30 (1H, ddd, J = 14.0, 3.9, 3.9 Hz), 3.06 (1H, ddd, J = 10.6, 10.6) , 4.8 Hz), 3.20 (1H, dd, J = 16.7, 3.9 Hz), 3.22 (1H, dd, J = 16.7, 3.9 Hz), 3.25-3.30 (1H, m), 3.36 (1H, dd, J = 16.7, 6.6 Hz), 3.37 (1H, dd, 16.7, 6.6 Hz), 3.81 (3H, s), 5.21 (1H, dddd, J = 6.6, 6.6, 3.9, 3.9Hz), 6.13 (1H, broad), 6.86 (1H, d, J = 8.3Hz), 6.90 (1H, dd, J = 8.3, 2.2Hz), 6.95 (1H, d, J = 2.2Hz), 7.15-7.19 (2H, m), 7.21-7.23 (2H, m) (+) - Body: retention time ₆₉ to 88 min, column temperature 40 ° C

_{ί Υ ° Ό + 68 ° (} c = 1.00, MeOH)

(Sat) integral _{^{1 H- NMR (CDC 1 3)}} δ (p pm)

1.66 (3H, s), 2.11 (1H, ddd, J = 13.9, 10.3, 5.4Hz), 2.27 (1H, ddd, J = 13.9, 4.2, 4.2Hz), 3.00-3.07 (1H, m), 3.20 ( 1H, dd, J = 16.6, 3.7Hz), 3.22 (1H, dd, J = 16.6, 3.7Hz), 3.22-3.29 (1H, m), 3.36 (2H, dd, J = 16.6, 6.6Hz), 3.80 (3H, s), 5.21 (1H, dddd, 6.6, 6.6, 3.7, 3.7Hz), 6.13 (lH, broad), 6.86 (1H, .d, J = 8.3Hz), 6.90 (1H, dd, J = 8.3, 2.2Hz), 6.95 (1H, d, J = 2.2Hz), 7.14-7.18 (2H, m), 7.19-7.23 (2H, m)

<Example 2>

 Tablet manufacturing

 30 g of (1-) 1-6- [3- (2-Indanyloxy) -1-4-methoxyphenyl] -16-methinole-3,4,5,6-tetrahydro-1H-2, H--1,3-oxazine-2 On, lactose (253 g), corn starch (63 g), low-substituted hydroxypropyl cellulose (40 g) and calcium stearate (4 g) were mixed and compressed by a conventional method to produce a tablet containing the above-mentioned compound (1 Omg).

<Example 3>

 Manufacture of capsules

30 g of (1-)-6- [3- (2-indanyloxy) -1-4-methoxyphenyl] —6-methyl-1,3,4,5,6-tetrahydro 2H—1,3-oxazine-12-one, After mixing lactose (260 g), corn starch (66 g) and calcium stearate (4 g), the mixture was filled in a gelatin capsule by a usual method to prepare a capsule containing 1 mg of the compound. Example 4>

 Production of inhalants

 (-) One 6- [3- (2-Indanyloxy) 1-4-Methoxyphenyl '] One 6-Methyl-3,4,5,6-tetrahydro-12H- 1,3-oxazine-12-one Pulverize well and mix 0.15 g with a particle size of 1-5 / im and 6 Og of lactose (325 mesh, D.M.V.). Capsules are filled in the usual way, each capsule containing 50 g of the compound. Inhalation is performed by loading the capsule into a powder inhalation container.

<Example 5>

Manufacture of eye drops

 To sterilized purified water, 0.3 g of methylcellulose, a trace amount of sodium chloride solution, 2 g of sodium dihydrogen phosphate and an appropriate amount of sodium hydroxide were added, and after dissolution, dust removal and sterilization filtration were performed. This solution is dust-free and sterile (1-)-1-6- [3- (2-Indanyloxy) —4-methoxyphenyl] -16-methyl-3,4,5,6-tetrahydro-2H—1,3- 0.5 g of oxazin-2-one was suspended, and sterilized purified water was added to make a total volume of 100 mL. The obtained suspension was filled in a fixed volume into a washed, dried, and sterilized eye dropper, and a nozzle and a cap were provided to produce an eye drop. Example 6>

Manufacture of eye ointments

(1) 16- [3- (2-Indanyloxy) -14-methoxyphenyl] -16-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-12-one 0.5 g, purified Take lanolin 10.0 g, ophthalmic white petrolatum 80.Og, and liquid paraffin 0.5 g, prepare according to the ophthalmic ointment manufacturing method, and further add ophthalmic white petrolatum to prepare ophthalmic ointment 1 00 g was produced. Test Example 1>

 Isolation of phosphodiesterase (PDE) and measurement of PDE inhibitory activity

In order to examine the PDE inhibitory activity and selectivity of the compounds, four types of PDE isozymes, type I, type III, type IV and type V, were prepared [Trends Pharmaco co. Sci., 1 2, 1 9—2 7 (1 9 9 2)]. The type I PDE used was purchased from Sigma. PDE isozymes of types III, IV and V were partially purified from platelets (types III and V) or neutrophils (type IV) collected from rats. Each enzyme source was 2 OmM bistris, EDTA (ethylenediamine tetraacetic acid) 2 mM _N PMSF (Fermethylsulfonylfluoride) 0.1 mM, 2-mercaptoethanol 5 mM, Pepstatin 0.000 lmM, Roy Peptin is homogenized in a buffer (ρΗ6.5) containing 0.01 mM, centrifuged at 300000 XG for 30 minutes, and the centrifuged supernatant obtained is subjected to an exchange column (Q Sepharose Fast). Flow, manufactured by FANOLEMASIA), and eluted with 0-1% sodium acetate. Partially purified isozymes were identified by examining the effect of each known selective inhibitor.

The test substance was dissolved in DMS O (dimethyl sulfoxide) and added to 5 OmM Tris-HCl buffer containing 5 mM magnesium chloride. Additional PDE Aisozaimu and ³ H- c AMP in the reaction solution (III type, when the type IV PDE) or ³ H- c GMP (I-type, when the V-PDE) was added as a substrate, at 3 0 ° C The reaction was performed for 30 minutes. After the reaction, the reaction was stopped by immersing it in a boiling solution at 100 degrees for 5 minutes. Yo connexion generated nucleotide PDE 5 'over quinuclidine Reo in Chi peptidase ³ H- adenosine or ³ H - decompose Guanoshin, substrate and reaction products of unreacted Ion exchange force ram (QAE Se Fuadettasu, Pharmacia Co. ). The radioactivity of the eluted ³ H-nucleoside was measured with a liquid scintillation counter. Inhibitory activity of each test substance IC _5. The inhibitory activity against type IV is shown in Table 2. In addition, the inhibitory activity of each test substance on types I, III and V was less than 1/10 of the inhibitory activity on type IV. Table 2

<Test Example 2>

 Antigen-induced airway contraction inhibitory action (anti-asthmatic action)

Male Hartley guinea pigs were sensitized by intramuscular administration of 35 mg of ovalbumin (〇Α) and boosted 4 days later. Twenty-five to twenty-nine days after the first sensitization, guinea pigs anesthetized with pentobarbital were subjected to artificial respiration by introducing a tracheal force neura. Airway resistance was monitored by the Konzett-Roess 1 er method, and the increase in airway resistance induced by intravenous administration of 0.05 mg / kg OA was examined. The test substance was suspended in 0.5% carboxymethylcellulose and administered to the duodenum 45 minutes before the antigen administration. The effects of the compounds of the present invention are represented by _ED5Q values and are shown in Table 3. Table 3

<Test Example 3>

 Improving effect on Alargi conjunctivitis model

Wistar rats (Clear Japan) were used for the experiment. It albumen albumin which was suspended (OA, Sigma) 1 0 0 mu _§ and 1 0 mg Mizusani匕aluminum (Alum, manufactured by PIERCE Co.) in physiological saline of 1 m L, administered intraperitoneally to rats Sensitized by A Lergogenic conjunctivitis was induced by instillation of 10 μL of OA adjusted to a concentration of 3 OmgZniL with physiological saline in rats 3 weeks or more after the sensitization day. The drug was suspended in saline at a concentration of 1.0% (w / v) and instilled 10 minutes before OA induced conjunctivitis (diphenhydramine was added as a positive control at 0.3% (w / v). ) Was suspended in physiological saline and instilled 10 minutes before conjunctivitis was induced by OA). The effect of the drug was measured by counting the number of gestures (Itch-Scratch response: considered to be an index of itch) observed in the hind limb during 20 minutes after instillation of OA. The suppression rate was determined.

 Control group: physiological saline was instilled 10 minutes before inducing conjunctivitis with ΔA in rats sensitized beforehand. '

 Untreated group: Non-sensitized rats were instilled with saline.

 §Judgment · Α (：

(Test substance group-No treatment group)

Inhibition rate (%) = 100-X00

 (Control group

The results were as follows: (1) In one case, the suppression rate was 71.4% in 5 cases. Test Example 4>

 TNF- α production inhibitory action

Rats were bled into heparin-treated test tubes under pentobarbital anesthesia. Add an equal volume of RPMI-1640 medium to the collected blood, aliquot into 24 liters, add solvent (DMSO) or test drug dissolved in solvent, and add 30 minutes at 37 ° C, 5% .プ レ Pre-incubation was performed in ₂ . The reaction LP S a (Li Po polysaccharide) Start by添Ka卩, 4 hours, subjected to incubation at 37 ° C, 5% C_〇 _2, the reaction was stopped by ice bath. After stopping the reaction, the mixture was centrifuged at 3000 rpm at 4 ° C for 15 minutes, and TNF-α in the supernatant was measured by ELISA. Study drug The activity was evaluated by determining the production inhibition rate with respect to the solvent control group, and the test drug concentration that inhibited TNF- _α production by 50%.

As a result, (one) piece of IC _5. (M) was 0.11.

<Test Example 5>

 N K ^ receptor antagonism

Homogenizing CH0 cells expressing human NK ₁ receptors in pH 7. 4 in a buffer containing _{25mM Tris- HC1, 6mM MnCl 2,} ImM EDTA, 10 i M PMSF, and centrifuged 800 gs 10 minutes. The supernatant was centrifuged at lOOOOog X 1.0 hours, and the resulting sediment was resuspended in the above buffer. After measuring the amount of protein, it was diluted with a buffer containing 20 mM HEPES, 1.0 mM MnCl ₂ , and pH 7.4 containing 0.01% BSA to 0.02 mg protein / mL, and used as a NK receptor sample. .

 ! ^! ^ Affinity for the receptor was determined by measuring the inhibition of [¾] SR140333 binding. The test substance dissolved in DMS0 and [¾] SR140333 (final concentration 0.25 nM) were added to the NK receptor sample described above, and 25. After incubating for 90 minutes at C, the solution was suction-filtered with a glass filter, washed three times with 1 mL of 50 mM Tris-HC1 buffer pH 7.4, and the radioactivity on the filter was measured with a liquid scintillation counter. In addition, the test substance was added to the final concentration of 10 μM of caffeine, and the binding inhibitory activity of [¾] SR140333 was measured. '

 As a result, the (-) unit showed almost 100% suppression rate.

<Test Example 5>

Substance of isolated guinea pig bronchus: Inhibitory effect on Ρ (Ν Κ _Χ ) contraction A Hartley male guinea pig weighing 330 to 496 g was bled and killed, and the trachea was excised to prepare a chain specimen. This was suspended in load lg in organ bath bath filled with Krebs Henseleit solution containing 3 M indomethacin was bubbled through _{95% 0 2 + 5% C0} 2 gas mixture. The contraction response of the specimen was recorded with a pen recorder via an FD pickup and a strain pressure pump. After the specimen was stabilized, if a low concentration to a concentration of 10- ⁹ to 10-¾ the Sapusutansu P The shrinkage reaction was confirmed by cumulative addition. After the sample was washed several times with Krebs-Henseleit solution; / The compound of the present invention was added and allowed to act for 20 minutes. Thereafter, contraction was induced by cumulative addition of substance P.

 As a result, (1) In a dose-dependent manner, the graph of substance P-induced contraction in the isolated guinea pig bronchus was shifted to the right in a dose-dependent manner, indicating an antagonistic inhibitory effect. Industrial applicability

 The compound of the present invention has about twice the phosphodiesterase (PDE) IV inhibitory action and anti-asthmatic action as compared to the racemic form, and has a remarkably higher solubility in water as compared to the racemic form. It is extremely useful as an active ingredient of a medicament for treating and / or treating inflammatory diseases such as chronic obstructive pulmonary disease.

Claims

The scope of the claims 1. (1-)-6- [3- (2-Indanyloxy) -14-methoxyphenyl] -1-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazine-12-one or hydrates thereof Or a solvate thereof.  2. (I) I 6- [3- (2-Indanyloxy) 1-4-Methoxyphenyl] -6-Methyl-1,3,4,5,6-tetrahydro-2H-1, 3-oxazine-1-2-one and A medicament comprising, as an active ingredient, a substance selected from the group consisting of hydrates and solvates thereof.  3. The medicament according to claim 2, which is in the form of a pharmaceutical composition containing the above-mentioned substance as an active ingredient and a pharmaceutical additive.  4. The medicament according to claim 2 or 3 for treating and preventing or preventing inflammatory diseases.  5. The medical device according to claim 2 or 3 for treating and / or preventing asthma. 6. The medicament according to claim 2 or 3 for treating and preventing or preventing chronic obstructive pulmonary disease.  7. The medicament according to claim 2 or 3 for treating and preventing or preventing unilateral ocular disease.  8. (—) 1-6— [3- (2-Indanoleoxy) 1-4-Methoxyphenyl] 1-6—Methyl-3,4,5,6-tetrahydro 2H—1,3-oxazin-1-one And a phosphodiesterase IV inhibitor comprising a substance selected from the group consisting of hydrates and solvates thereof. 9. (I) 16- [3- (2-Indanyloxy) -14-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro 2H-1,3-oxazine-12-one and its hydration A TNF-production inhibitor comprising a substance selected from the group consisting of a substance and a solvate thereof. 10. (I) — 6— [3- (2-Ind-Roxy) 1-4-Methoxyphenyl] 6-Methinole 3,4,5,6-tetrahydro-1 2H— 1,3-oxazine-1 2— And a substance selected from the group consisting of hydrates and solvates thereof; ^ A receptor antagonist.