WO1994007491A1

WO1994007491A1 - Analgesic, anticonjunctivitic or chronic rheumatism remedy containing quinolizinone compound or salt thereof, and preparation for topical application thereof

Info

Publication number: WO1994007491A1
Application number: PCT/JP1993/001396
Authority: WO
Inventors: Jun Hiroi; Kyoichi Shimomura; Takehisa Hata; Akira Kagayama; Sumihisa Kimura; Seiji Sawai; Satoshi Ueda
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1992-10-05
Filing date: 1993-09-29
Publication date: 1994-04-14
Also published as: CN1091287A; AU4834493A

Abstract

An analgesic, anticonjunctivitic or chronic rheumatism remedy containing a quinolizinone compound represented by formula (I) or a salt thereof, and a stable anticonjunctivitic preparation for topical application containing the above compound or salt and a cellulose derivative. In formula (I), R1 represents aminocarbonyl, etc.; R4 represents hydrogen, etc.; R2 represents hydrogen, etc.; R3 represents aryloxy, etc.; and R?2 and R3¿ may be at any position of the quinolizinone ring and combined together to form -CH¿2?CH2CH2-, etc.

Description

04 1 1396

Specification

Analgesic, anti-conjunctivitis or anti- rheumatoid arthritis agent containing quinolizinone compound or its salt, and preparation for local administration

Technical field

The invention has the formula:

(Wherein R ¹ is a carboxy group, an amidated carboxy group, a cyano group, a thiocarbamoyl group or a tetrazolyl group;

R ⁴ is hydrogen or aryl group;

R ² is hydrogen, a hydroxy group, a lower alkyl group or a lower alkoxy group;

R ³ is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy,

A aryl group which may have a suitable substituent,

An arylthio group, an arylo group, an ar (lower) alkyl group, an arenesulfonyl group, a arylamino group or an aryloxy group which may have an appropriate substituent,

R ² and R ³ can be located at any position on the quinolidinone ring and are linked together to form one CH ₂ CH ₂ CH ₂ —, one CH-CH— or one CH = CH—CH = CH— Can be formed. ) Or a salt thereof, in particular, N- [5- (1H-tetrazolyl)] 111-phenoxy-14H-quinolidine-14-one-14-carboxamide or a salt thereof. Painkillers, anti-conjunctivitis agents or anti- (4) The present invention relates to a gusset, more particularly to a preparation for topical administration containing the quinolidinone compound represented by the above formula (I) or a salt thereof and a cellulose derivative, particularly to an eye drop when used for the above anticonjunctivitis use. Background art

The quinolidinone compound (I) used in the present invention is known, and is described, for example, in JP-A-60-222482.

Since this quinolidinone compound (I) is poorly soluble in water, its absorption from the gastrointestinal tract by oral administration is poor. Therefore, the inventors of the present invention have proposed an oral preparation containing a water-soluble polymer compound in a quinolidinone compound (I) in order to improve the absorption of the quinolidinone compound (I) (Japanese Patent Laid-Open No. — 4 7 1 2 4 gazette).

Since this quinolidinone compound (I) is poorly soluble in water, it is necessary to add a solubilizing agent when preparing a preparation for topical administration, especially an eye drop.

However, the conventional solubilizers used in eye drops have the following problems: even if the quinolidinone compound (I) is solubilized to prepare an eye drop, the quinolidinone compound (I) precipitates as crystals during long-term storage. there were. Disclosure of the invention

As a result of intensive studies, the inventors of the present invention have found that the quinolidinone compound (I) or a salt thereof has an analgesic action, an anti-conjunctivitis action, or an anti-chronic rheumatism action.

Accordingly, an object of the present invention is to provide an analgesic containing a quinolidinone compound (I) or a salt thereof, which is effective for pain, conjunctivitis or rheumatoid arthritis. An object of the present invention is to provide a meningitis agent or an anti-chronic rheumatoid agent.

The invention is useful for pain, conjunctivitis or rheumatoid arthritis. It is also expected to be useful for rhinitis, spring catarrh, contact dermatitis, urticaria and other eczema-like dermatitis, food allergies, and nephritis.

° On the other hand, this quinolidinone compound (I) is useful to be used as a topical preparation such as eye drops or nasal drops for the treatment of allergic conjunctivitis, spring catarrhal, allergic rhinitis and the like.

Therefore, the inventors of the present invention have conducted intensive studies in order to solve the above-mentioned problems in preparing a preparation for topical administration, and as a result, by using a cellulose derivative as a ^Q solubilizing agent for the quinolidinone compound (I), long-term storage was achieved. Even when the quinolidinone compound (I) does not precipitate, it has been found that a preparation for topical administration, particularly an eye drop, having excellent stability can be prepared.

Analgesics of the present invention, with respect Kinorijinon compound used in topical administration preparation for anti-conjunctivitis or anti-rheumatoid Riumachi agents and especially anti-conjunctivitis application ^{^{5 (I), R 1,}} R 2, R 3 and the definition and A preferred example will be described in detail as follows.

“Lower” shall mean from 1 to 6 carbon atoms unless otherwise indicated.

Preferred "lower alkyl moieties" of preferred "lower alkyl" and "ar (lower) alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. Such a straight-chain alkyl group having 1 to 6 carbon atoms or a branched-chain alkyl group is exemplified.

Preferable “lower alkoxy groups” include methoxy, ethoxy, 5-portoxy, isopropoxy, butoxy, tertiary butoxy, pen Preferred are those having 1 to 4 carbon atoms, such as a tiloxy group and a hexyloxy group.

Suitable "lower Arukeniruokishi group", Biniruokishi group, § Li Ruokishi group, 1 one propenyl Niruokishi group, 1 (or 2) - Buteyuruoki ⁵ group, 2-Penchiniruokishi group, preferably 2 carbon atoms There are four types.

Suitable “amidated carboxy groups” include amides (1-CONH ₂ ) which may have a suitable substituent on the nitrogen atom. Suitable substituents are described below. A heterocyclic ^Q group optionally having an appropriate substituent; and a aryl group optionally having an appropriate substituent.

More specifically, the term "heterocyclic group" refers to a saturated or unsaturated, monocyclic or polycyclic heterocyclic ring containing at least one heteroatom such as oxygen, zeolite, nitrogen atom and the like. Means a group.

The particularly preferred heterocyclic group may be, for example, the following heterocyclic group ⁵ . That is:

Unsaturated 3- to 8-membered, more preferably 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, virazolyl, pyridyl and their N-oxides, dihydropyridyls , Pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl; 1H-1,2,3-triazolinole; 2H-1,2,3-triazolyl, etc. ), Tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.), triazinyl (eg, 1,2,3-triazinyl; 1,2,4-triazinyl; 1,3,51-triazinyl) ; Other), etc.:

Saturated 3 to 8 members containing 1 to 4 nitrogen atoms, more preferably 5 or 6 members Heterocyclic groups such as pyrrolidinyl, imidazolidinyl, piberidino, piperazinyl, and the like;

Unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atoms, such as indril, isoindryl, indlidinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopi Rizil, etc .:

Unsaturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxaziazolyl (eg 1,2, 1,4-, 4-, 4-, 4-, 5-, 4-,-,-,-,-,-,-,-,-,-and-)

Saturated 3- to 8-membered and more preferably 5- or 6-membered heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as morpholinyl, sydnonyl, etc .:

Unsaturated condensed heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as benzoxazolyl, benzoxazodiazolyl, etc.

Saturated 3- to 8-membered, more preferably 5- or 6-membered, heteromonocyclic group containing 1-2 zeo atoms and 1-3 nitrogen atoms, such as thiazolidinyl, and the like:

Unsaturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic group containing 1-2 io atoms, such as phenyl, dihydrodithiinyl, dihydrodithionyl, and the like:

Unsaturated fused heterocyclic groups containing from 1 to 2 io atoms and from 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl and the like; An unsaturated 3- to 8-membered, more preferably 5- to 6-membered heteromonocyclic group containing one oxygen atom, such as furyl;

Unsaturated 3- to 8-membered, more preferably 5- to 6-membered heteromonocyclic group containing one oxygen atom and one to two zeo atoms, such as dihydrooxathiinyl; including one to two y-atoms Unsaturated condensed heterocyclic groups, for example, benzothenyl, benzodithiynyl and the like;

An unsaturated condensed heterocyclic group containing one oxygen atom and one or two zeo atoms, for example, a heterocyclic group such as benzoxathiinyl and the like can be mentioned.

In the above, the heterocyclic group may have one or more suitable substituents as described below. That is:

Lower alkyls (eg, methyl, ethyl, propyl, isopropylinole, butynole, isobynole, t-butynole, pentinole, neopentyl, hexinole, other);

Halogen (eg chlorine, bromine, fluorine or iodine), etc.

Suitable "aryl groups" include phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl and the like, and these are amino, nitro, for example, halogen such as chlorine, bromine, fluorine or iodine, the lower alkoxy, It may have one or more suitable substituents such as groups such as carboxy and hydroxy.

Suitable "aryl group" of "arylthio group", "ar (lower) alkyl group" and "aryl amino group" include those exemplified above.

Suitable "aroyl groups" include benzoyl, toluoyl, naphthoyl and the like.

Preferred “arene sulfonyl groups” include benzenesulfonyl, p Monotoluenesulfonyl and the like.

The “arylamino group” may have an appropriate substituent such as a lower alkyl group such as methyl and ethyl on the nitrogen atom.

Preferable "aryloxy groups" include fuunoxy, trioxy and the like.

Preferred “amidated carboxy groups” include carbamoyl, pyridylamide, pyrimidinylamide optionally having a lower alkyl group, virazinylamide, phenylamide optionally having a hydroxy group, and thiazolylamide. And triazinyl amide, triazolyl amide, pyridazinyl amide which may have a halogen, or tetrazolyl amide.

Suitable salts of the quinolidinone compound (I) include pharmaceutically acceptable salts, particularly commonly used non-toxic salts, and salts with bases and acid addition salts, that is, salts with inorganic bases, for example, Alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, salts with organic bases, for example, triethylamine salt, pyridine salt, picolin Organic amine salts such as salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N, dibenzylethylenediamin salt, hydrochloride, hydrobromide, sulfate, phosphate Organic acid addition salts, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluene Organic carboxylic or sulfonic acid addition salt of the scan sulfonic acid salts such as arginine, Asuparagin acid, salts with basic or acidic amino acids glutamic acid and the like.

The pharmaceutical composition of the invention may be in the form of a pharmaceutical preparation, for example, a quino lysino of the invention. Solid or semi-solid containing the compound (I) mixed with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral administration, parenteral administration or external use. It can be used in the form of a liquid or a liquid preparation. The active ingredient may be in the form of, for example, capsules, tablets, dragees, ointments or suppositories, but also as usual non-toxic medicaments for solutions, suspensions or emulsions and other forms suitable for use. It may be mixed with an acceptable carrier. Carriers that may be employed are water, glucose, lactose, gum arabic, gelatin, Man'ni' preparative Ichiru, starch paste, polyvinyl Nirupiro Li pyrrolidone, magnesium stearate-phosphate, talc, corn star ⁰ Ji, keratin, colloid Doshirika, potato starch , Urea and other carriers suitable for use in the manufacture of solid, semi-solid or liquid preparations, as well as by using auxiliaries, stabilizers, thickeners, buffers and coloring agents and flavoring agents. Is also good. The pharmaceutical composition may also contain a preservative or a bacteriostat ⁵ to stably maintain the activity of the active ingredient in the desired formulation. The active quinolidinone compound (I) is incorporated into the pharmaceutical composition in an amount sufficient to exert the desired therapeutic effect according to the disease process and conditions.

When this composition is applied to humans, it is preferably applied by intravenous administration, intramuscular administration, ocular administration or oral administration. The dose or therapeutically effective amount of the quinolidinone compound (I) 0 will vary depending on the type of disease to be treated, the age and condition of each individual patient, but the daily dose for treatment of the disease in humans or animals. The amount is usually about 0.01 to 5 mg, kg of the active ingredient, and is generally administered 1 to 3 times a day.

'Among the above-mentioned pharmaceutical compositions, the formulation 5 for topical administration, particularly for use in anti-conjunctivitis applications, will be described below. P9301396

9

The preparation for topical administration of the present invention is characterized by containing a quinolidinone compound (I) and a cellulose derivative. The quinolidinone compound (I) as the main drug may be a hydrate, and the salts thereof are preferably the salts of alkali metal such as sodium salt and potassium salt among the above-mentioned salts.

Among the quinolizinone compounds (I), N- [5- (1H-tetrazolyl)] 111-phenoxy-14H-quinolidine-14-one-13-carboxamide is preferred.

The cellulose derivative used as a solubilizing agent for the quinolidinone compound (I) in the preparation for topical administration of the present invention includes, for example, hydroxypropinolemethinoresenorelose, hydroxypropinoresenorelose, methinoresenorelose, and lysozolone. Reboximethynoresenorelose, canolepoximethynoresenorelose sodium, hydroxyxethyl cellulose, nitrocellulose, crystalline cellulose, etc., of which hydroxypropyl methylcellulose and methylcellulose are particularly preferred. preferable.

The compounding ratio of the quinolidinone compound (I) and the cellulose derivative in the preparation for topical administration of the present invention is usually from 1: 0.01 to 1: 100, preferably 1: 0.5 by weight. To 1:20.

The concentration of the quinolidinone compound (I) as the main drug in the preparation for topical administration of the present invention is from 0.005 to 0.5% by weight, preferably from 0.02 to 0.2% by weight.

The preparation for topical administration of the present invention has a pH of 7 with the addition of a buffer in view of the solubility and stability (degradability) of the quinolidinone compound (I) as the main drug and irritation to eyes and mucous membranes. 5-9.5 Preferably, the pH is adjusted to 8.0 to 9.0. Examples of the buffer used include boric acid, borax, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, and dihydrogen phosphate phosphate.

The preparation for topical administration of the present invention may further comprise, if desired, a tonicity agent (eg, sodium chloride), a preservative (eg, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, ethyl ethyl paraoxybenzoate) and the like. Additives commonly used in such eye drops may be added.

Formulations for topical administration of the present invention, Ru ^Q can be prepared as follows. That is, the above buffer and the cellulose derivative are added to the purified water to dissolve, then the quinolidinone compound (I) is added and dissolved, and if necessary, an isotonic agent, a preservative, and the like are added as appropriate. I do.

The preparation for topical administration of the present invention thus obtained is used as eye drops, nasal drops and the like.

5 In order to show the usefulness of the quinolidinone compound (I) or a salt thereof used in the analgesic agent, anticonjunctivitis agent or antirheumatic rheumatoid agent of the present invention, the results of pharmacological tests of this compound are shown.

[1] Test compound

N— [5— (1H—tetrazolyl)] 1-11 phenoxy 1 4H—quino 0 lysine 1—4 1one 1—3-carboxamide sodium salt

[2] Exam

(A) Analgesic effect (effect of Stretch acetate method in mice) ① Test method

Ten dd Y male mice 6 weeks old 5 (body weight 29.0-34.4 g) purchased from Shizuoka Prefectural Laboratory Animal Agriculture Cooperative were used per group. Animal weight After measurement, the test compound was orally administered, and 15 minutes later, 0.6% (V / V) drunk acid 20 m 1 / kg was intraperitoneally administered. The number of writhing symptoms from 10 minutes to 3 minutes after the administration of acetic acid was measured. As a test compound, a control group to which 0.5% methylcellulose was administered was provided at the time of use. For each group, the average value of the number of writhing times and the standard error of the soil were calculated. The significance test was performed by the t test (unpaired). Also ED ₅ . Values were calculated by the probit method. The maximum dose of the test compound was 10 Omg / kg, and four doses were studied up to 0.1 mgZkg in 10-fold dose.

② Test results

The test results are shown in Table 1 below. Table 1 Dose writhing symptoms EDs o

P.O.Number of cases Number of occurrences Change value Suppression rate

(mg / kg) (mg / kg) Solvent * 10 15.9 ± 0.6

0.1 10 15.9 ± 0.6 0.0 0.0

1 10 15.8 ± 0.8 -0.1 0.6 60.4

10 10 12.8 ± 0,6 «» -3.1. 19.5

100 10 6.5 ± 0, 7 * »-9.4 59.1

**: 1% significant compared to vehicle control group

'#: 0.5% methylcellulose

tt tt rl-l OO mg / kg Each value is the mean soil standard error

(B) Anti-conjunctivitis effect (effect on rat ocular conjunctivitis)

① Test method ―

A serum containing allogeneic IgE with a PCA titer of 1:64 was diluted 16-fold into the rat, and administered into the conjunctiva of the upper and lower right eye with a microsyringe in an amount of 5 μl. 48 hours later, Evans Blue and Ε Α (both containing 5 mg / ml) physiological saline were intravenously administered with 1 ml of Zrat to elicit a reaction. One hour after the induction of the reaction, the animals were killed and the conjunctiva above and below the left and right eyes were removed. The upper and lower conjunctiva was taken as one set, and the weight was measured, taken into a microtube, added with 100 μl of IN-II, and left at 37 overnight to dissolve the conjunctiva. The dye was extracted by adding 400/1 of acetone-2.5N phosphoric acid (17: 3) to the tissue lysate, stirring and centrifuging. Aliquot the supernatant 2001 into a 96-well microplate, measure the absorbance using a Titer-multiskan, and assuming a tissue volume of 50 y1, a calibration curve (0, 2, 4, 4). 8, 12, 16, and 2.0 tubes) were prepared, and the amount of dye in the tissue was calculated. Furthermore, the amount of pigment per g was calculated by dividing the amount of pigment in the tissue by the weight of the tissue.

The test compound was dissolved in 2% TC5-R, PH7.5 phosphate buffer (0.05%), and 10 μl of the solution was applied to the left and right eyes 10 minutes before the induction of the reaction.

② Test results

The results are shown in Table 2 below. Table 2

*: P <0.05; T t de n t T-te st

(C) Anti-rheumatic rheumatoid arthritis (Effect on rat carrageenan foot edema)

① Test method

Six-week-old SD rats (male, weight: 158 to 220 g) were used in each group. Paw edema was induced by subcutaneous injection of 1.0% 7 "-carazi-nanan saline 1 ml into the sole surface of the right hind foot. R Before subcutaneous injection of carazi-nan and 3 hours after subcutaneous injection The difference in paw volume was measured using a plethysmometer (p 1 ethysmometer) and used as a control group for edema.The test compound was dissolved or suspended in 0.5% methylcellulose, and subcutaneously injected with r-carazi mononan. One minute prior to oral administration, a dose of 5 m 1 / kg was evaluated by Student's t-test.

② Test results

The test results are shown in Table 3 below. Table 3 Test compound dose Increase in paw volume (ml) ^a Inhibition rate Control group 0 0.82 ± 0.07

Test compound 1 0.58 Sat 0.10 29.3

(a) Each value is the average value of each group Soil standard error

: P <0 .. 05 Comparison with control group

Next, the effects of the preparation for topical administration of the present invention will be described with reference to test examples.

Test example

beta test method

Each of the eye drops obtained in Examples 2 and 3 and Reference Examples 1 and 2 described below was filled in a 5 m1 eye drop container, and stored in a refrigerator (4 ° C) and room temperature for 6 months. The changes in the residual ratio of H and the main drug were examined.

In each sample, the initial pH was 8.50, and no crystal was precipitated.

The results are shown in Tables 4 and 5.

Table 4 Stability after storage in refrigerator for 6 months

Table 5 Stability after 6 months storage at room temperature

As is clear from Tables 4 and 5, crystal precipitation was observed when / 9-cyclodextrin was added as a solubilizer, and no crystal precipitation was observed when polyvinyl alcohol was added. However, a decrease in pH was observed, and when stored for a long period of time, H may further decrease and crystals may precipitate. On the other hand, in the eye drops of Examples 2 and 3 using the cellulose derivative of the present invention as a solubilizing agent, no crystal precipitation was observed, and the pH and the residual ratio of the main drug were stable with almost no change.

Example 1

One tablet produced a tablet having the following composition.

N-[5-(1 H-tetrazolyl)]-1-phenoxy

1 4 H—Quinolidine 1—4 1—1 3—Carboxamide

Sodium salt (active ingredient) 25 mg Lactose 150 mg Corn starch 60 mg Polyvinylpyrrolidone 10 mg Magnesium stearate 5 mg Active ingredient, lactose and corn starch are thoroughly mixed, and 20% of polyvinylpyrrolidone is added to this. An ethanol solution was added to wet, then dried at 45 ° C. and passed through a 20 mesh sieve. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

Example 2

Borax (1.5 g) and hydroxypropyl methylcellulose 2910 (0.5 g) were added to purified water (90 ml) and dissolved. Then, the sodium salt of N- [5- (1H-tetrazolyl)]-111-phenoxy- 14H-quinolinidine-141-one-3-carboxamide (0.1 g) was added and dissolved. Further, boric acid (0.7 to 0.9 g) was added and dissolved to adjust the pH to 8.50. The total amount was adjusted to 100 ml with purified water, and filtered through a 0.22 // m millipore filter to obtain eye drops.

Example 3 An eye drop was obtained in the same manner as in Example 2, except that methylcellulose (0.5 g) was used instead of hydroxypropyl methylcellulose 2910 (0.5 g).

Hereinafter, the eye drops of the reference example used in the test examples will be described.

Reference example 1

An ophthalmic solution was obtained in the same manner as in Example 2 except that 9-cyclodextrin (1 g) was used instead of hydroxypropyl methylcellulose 2910 (0.5 g).

Reference example 2

An ophthalmic solution was obtained in the same manner as in Example 2, except that polyvinyl alcohol (1 g) was used instead of hydroxypropyl methylcellulose 2910 (0.5 g).

Claims

The scope of the claims

Formula:

R ⁴ is hydrogen or aryl group;

R ² is hydrogen, hydroxy, lower alkyl or lower alkoxy; R ³ is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy,

An aryl group optionally having a substituent,

An arylthio group, an aryloyl group, an ar (lower) alkyl group, an arenesulfonyl group, an arylamino group or an aryloxy group which may have an appropriate substituent,

R ² and R ³ can be located at any position on the quinolidinone ring and are linked together to form one CH ₂ CH ₂ CH ₂ —, one CH = CH— or one CH = CH— CH = CH— An analgesic, an anti-conjunctivitis or a rheumatoid arthritis agent comprising a quinolizinone compound or a salt thereof represented by the formula:

2. The analgesic according to claim 1, which comprises N— [5- (1H-tetrazolyl)]-111-phenoxy-14H-quinolidine-14-one-3-carboxamide or a salt thereof. , Anti-conjunctivitis agents or anti-rheumatic rheumatoid agents.

3. Expression

(Wherein, R ¹ is a carboxy group, an amidated carboxy group, a cyano group, a thiocarbamoyl group or a tedazolyl group;

R ⁴ is hydrogen or aryl group;

R ² is hydrogen, a hydroxy group, a lower alkyl group or a lower alkoxy group;

R ³ is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy,

An aryl group optionally having a substituent,

R ² and R ³ can be located at any position on the quinolidinone ring and are linked together to form one CH ₂ CH ₂ CH ₂ —, one CH = CH— or one CH = CH—CH = CH — An anti-conjunctivitis agent comprising a quinolidinone compound represented by the formula: or a salt thereof.

4. The anti-conjunctivitis agent according to claim 3, which contains N- [5- (1H-tetrazolyl)] 1-1-phenoxy-14H-quinolidine-14-one-3-carboxamide or a salt thereof. .

5. Formula:

R is hydrogen or aryl group;

A aryl group which may have a suitable substituent,

An arylthio group, an arylo group, an ar (lower) alkyl group, an arenesulfonyl group, a arylamino group or an aryloxy group which may have a suitable substituent,

R ² and R ³ can be located at any position on the quinolidinone ring and are linked together to form one CH ₂ CH ₂ CH ₂ —, one CH = CH— or one CH = CH— CH = CH— A formulation for topical administration, which comprises a quinolidinone compound represented by the formula (I) or a salt thereof and a cellulose derivative.

6. The claim that the quinolizinone compound or a salt thereof is N- [5- (1H-tetrazolyl)]-111-phenoxy- 14H-quinolinidine-141-one-3-carboxamide or a salt thereof. 6. The formulation for topical administration according to item 5.

7. The preparation for topical administration according to claim 5 or 6, which is an eye drop.