JP2006219487A - Remedy for allergic conjunctival disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pharmacological effect (pharmaceutical use) of 9-cyclopentyl-7-ethyl-3-(thiophen-2-yl)-5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, and to provide the same of 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine. <P>SOLUTION: The substituted pyridine derivatives specified in the above are each useful as a remedy for allergic conjunctival disease, such as allergic conjunctivitis, spring catarrh, and atopic conjunctivitis, because the derivatives each exhibits an excellent allergic conjunctivitis symptom inhibitory effect on a model of the allergic conjunctivitis. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to 9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3 The present invention relates to a therapeutic agent for allergic conjunctival diseases containing pyridine, 2- (3-chlorophenoxy) -3- [3- (3-hydroxypyridin-4-yl) propoxy] pyridine or a salt thereof as an active ingredient. .

  Allergic conjunctival diseases are inflammatory diseases of the conjunctiva involving type I allergy, and allergens such as pollen, mites, house dust, fungi, pet hair are known as the cause. Allergic conjunctival diseases are roughly classified into allergic conjunctivitis, spring catarrh, and atopic keratoconjunctivitis. Allergic conjunctivitis is an allergic conjunctivitis in which no proliferative changes in the conjunctiva are observed. Seasonal manifestations are referred to as seasonal allergic conjunctivitis, and perennial perennial allergic conjunctivitis. It is called. Spring catarrh is an allergic conjunctival disease with proliferative changes such as proliferation and enlargement of the nipple of the eyelid conjunctiva, thickening of the conjunctiva, swelling and uplift of the limbal conjunctiva. Atopic keratoconjunctivitis is a chronic keratoconjunctival disease that occurs in association with atopic dermatitis. The main symptoms of these allergic conjunctival diseases include edema and hyperemia.

  On the other hand, 9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a ] Pyridine (Tofimilast) and 2- (3-chlorophenoxy) -3- [3- (3-hydroxypyridin-4-yl) propoxy] pyridine (OS-0217) are both substituted pyridine derivatives.

  Patent Document 1 describes that substituted pyridines such as Tofimilast have PDE-IV inhibitory activity and TNF inhibitory activity, and are effective for diseases such as asthma, arthritis, bronchitis, and psoriasis. 2 describes that substituted pyridine derivatives such as OS-0217 have PDE-IV inhibitory activity and exhibit a strong bronchodilator action.

However, in the above-mentioned patent documents, the effects of these compounds on eye diseases, particularly allergic conjunctival diseases are not studied at all.
Japanese Patent No. 3107827 International Publication No. 00/20391 Pamphlet

  As described above, Tofimilast and OS-0217 have various pharmacological effects as pharmaceuticals, but finding an efficacy against allergic conjunctival diseases as a new pharmacological effect is an interesting issue.

  We have prepared 9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo [4. , 3-a] Pyridine (Tofimilast) and 2- (3-Chlorophenoxy) -3- [3- (3-hydroxypyridin-4-yl) propoxy] pyridine (OS-0217) In the conjunctival inflammation suppression test using the allergic conjunctivitis model, it was found that these substituted pyridine derivatives exerted an excellent allergic conjunctival inflammation (edema / hyperemia) suppression effect in the present invention. It came.

That is, the present invention
(1) 9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3- a] a therapeutic agent for allergic conjunctival disease comprising pyridine, 2- (3-chlorophenoxy) -3- [3- (3-hydroxypyridin-4-yl) propoxy] pyridine or a salt thereof as an active ingredient,
(2) The therapeutic agent according to (1), wherein the allergic conjunctival disease is allergic conjunctivitis, spring catarrh or atopic keratoconjunctivitis,
(3) Before the allergic conjunctivitis is seasonal allergic conjunctivitis or perennial allergic conjunctivitis, and (4) Before the dosage form is eye drops or eye ointments (1) to (3) The therapeutic agent according to the above.

  9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine (Tofimilast) and 2- (3-chlorophenoxy) -3- [3- (3-hydroxypyridin-4-yl) propoxy] pyridine (OS-0217) inhibit conjunctival inflammation using the allergic conjunctivitis model described below As is clear from the results of the test, it has an excellent conjunctival inflammation (edema / hyperemia) inhibitory action against allergic conjunctival diseases.

  In the present invention, pharmaceutically acceptable salts are not particularly limited, such as salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, etc. Is mentioned. More preferred salts are hydrochloride, acetate and fumarate. Quaternary ammonium salts, hydrates and solvates are also encompassed by the pharmaceutically acceptable salts of the present invention. Furthermore, geometric isomers, optical isomers, tautomers, polymorphs and the like are also included in the active ingredients of the present invention.

  The therapeutic agent for allergic conjunctivitis, spring catarrh and atopic keratoconjunctivitis of the present invention (hereinafter referred to as "allergic conjunctival disease therapeutic agent"), if necessary, add a pharmaceutically acceptable additive, It can be formulated using a technique widely used as a single preparation or a combination preparation.

  The therapeutic agent for allergic conjunctival disease of the present invention can be administered either orally or parenterally. Preferred dosage forms 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, an eye drop can be prepared by appropriately blending an isotonic agent, buffer, pH adjuster, solubilizer, thickener, stabilizer, preservative and the like as an additive. 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. These preservatives are combined. Can also be used.

  The ophthalmic solution containing the therapeutic agent for allergic conjunctival disease of the present invention preferably has a pH of 4.0 to 8.5, and an osmotic pressure ratio of about 1.0.

  The dose of the active ingredient when used as a therapeutic agent for allergic conjunctival diseases can be appropriately selected depending on the symptoms, age, dosage form, etc. Preferably, it may be instilled in an amount of 0.01 to 3% (w / v) once to several drops (one to several times a day) (for example, 1 to 8 times). In the case of an eye ointment, a concentration of 0.001 to 10% (w / w), more preferably 0.01 to 3% (w / w) is preferably used once to several times a day (for example, 1 (4 times) may be applied. In the case of an oral preparation, 1 mg to 100 mg, more preferably 5 mg to 30 mg may be administered 1 to several times a day (for example, 1 to 3 times).

  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 described later, a conjunctival inflammation suppression test was conducted. As a result, 9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4-c] -1 , 2,4-Triazolo [4,3-a] pyridine (Tofimilast) and 2- (3-chlorophenoxy) -3- [3- (3-hydroxypyridin-4-yl) propoxy] pyridine (OS-0217) Because of its excellent inhibitory effect on edema and hyperemia, which are the main symptoms of allergic conjunctivitis in allergic conjunctivitis models, treatment of allergic conjunctival diseases such as allergic conjunctivitis, spring catarrh, and atopic keratoconjunctivitis Useful as an agent.

  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]
Conjunctival inflammation suppression test using an allergic conjunctivitis model Using an allergic conjunctivitis model, 9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4 -C] -1,2,4-triazolo [4,3-a] pyridine (hereinafter referred to as “Compound A”) and 2- (3-chlorophenoxy) -3- [3- (3-hydroxypyridine-4) -Il) propoxy] pyridine (hereinafter referred to as “compound B”) was examined for its inhibitory effect on conjunctival inflammation (edema / hyperemia).

(experimental method)
Active sensitization was carried out by suspending aluminum hydroxide gel-adsorbed ovalbumin in physiological saline (20 μg / mL) and injecting 100 μL each into the conjunctival eyeball of a 5-week-old male Hartley guinea pig. . On days 14 and 15 after sensitization, an ovalbumin 1.0% (W / V) physiological saline solution was instilled into both eyes at 10 μL / eye to induce allergic conjunctivitis.

  Compound A 1.0% suspended in 0.1% hydroxypropylmethylcellulose-containing physiological saline (W / V) 60 minutes and 30 minutes before ophthalmic ophthalmic administration on the 15th day after sensitization (total 2 times) Suspension (W / V) or 1.0% suspension of Compound B (W / V) was instilled into both eyes of the guinea pig at 10 μL / eye. As a control, 0.1% hydroxypropylmethylcellulose-containing physiological saline (W / V) was instilled into both eyes of the guinea pig at 10 μL / eye.

  On the 15th day after sensitization, 30 minutes after ovalbumin instillation, the conjunctivitis symptoms of guinea pigs instilled with compound A, compound B and control were evaluated by scoring according to the following evaluation criteria (Table 1).

Inhibition rate = 100 − ([mean value of conjunctival inflammation score of test compound] ÷ [mean value of conjunctival inflammation score of control]) × 100

Table 2 shows the conjunctival inflammation score (average value) and inhibition rate (%) for compound A (number of eyes: 16 eyes), and Table 3 shows the conjunctival inflammation score (average value) and inhibition rate (%) for compound B. Shown (18 eyes).

(Experimental result)
As is apparent from Tables 2 and 3, the conjunctival inflammation of guinea pigs administered with eye drops of Compound A or Compound B was markedly suppressed as compared with the control, and therefore, it was confirmed that it has an allergic conjunctival inflammation suppression effect.

[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 1000mg
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.

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

Formulation Example 2
Compound B 200mg in 100g
Liquid paraffin 10g
Appropriate amount of 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 B added.

Claims (4)

  9-cyclopentyl-7-ethyl-3- (thiophen-2-yl) -5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine , 2- (3-chlorophenoxy) -3- [3- (3-hydroxypyridin-4-yl) propoxy] pyridine or a salt thereof as an active ingredient, a therapeutic agent for allergic conjunctival diseases.   The therapeutic agent according to claim 1, wherein the allergic conjunctival disease is allergic conjunctivitis, spring catarrh or atopic keratoconjunctivitis.   The therapeutic agent according to claim 2, wherein the allergic conjunctivitis is seasonal allergic conjunctivitis or perennial allergic conjunctivitis. The therapeutic agent according to any one of claims 1 to 3, wherein the dosage form is an eye drop or an eye ointment.