JP2013035802A - Prophylactic or therapeutic agent for glaucoma or ocular hypertension - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide prophylactic or therapeutic agent for glaucoma or ocular hypertension with a strong ocular tension descending action and extended duration time.SOLUTION: The prophylactic or therapeutic agent for glaucoma or ocular hypertension is prepared by combining (A) a compound selected from (S)-6-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline, (S)-6-(7-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline, 6-{(2R, 7R)-2,7-dimethyl-1,4-diazepan-1-ylsulfonyl}isoquinoline, (R)-6-(2-methyl-1,4-diazokan-1-ylsulfonyl)isoquinoline, and (R)-6-(5-methyl-1,4,7-oxadiazonan-4-ylsulfonyl)isoquinoline, or its salt, and (B) one or two or more agents selected from prostaglandins, carbonic anhydrase inhibitors, αstimulants, β blockers, αblockers, and Rho-kinase inhibitors.

Description

  The present invention relates to a preventive or therapeutic agent for glaucoma or ocular hypertension.

  Glaucoma is defined as a disease characterized by functional structural abnormalities of the eye that has characteristic changes in the optic nerve and visual field and can usually improve or suppress optic nerve damage by sufficiently lowering intraocular pressure.

  The goal of glaucoma treatment is to maintain visual function, but lowering intraocular pressure, the most important risk factor, is the only reliable treatment based on evidence. As the treatment, drug therapy is first tried, and laser treatment and surgical treatment are applied when sufficient intraocular pressure reduction cannot be obtained.

Intraocular pressure-lowering drugs can be broadly divided into aqueous humor production inhibitors and aqueous humor drainers. Β-blockers (such as timolol, befunolol, carteolol, nipradilol, betaxol, levobanolol, metipranol), carbonic anhydrase inhibitors (dorzolamide, brinzolamide, acetazolamide, metazolamide, etc.) and sympathomimetic stimulants (Α ₂ stimulants such as brimonidine and apraclonidine, and non-selective stimulants such as epinephrine). Aqueous humor outflow promoters include prostaglandins (isopropyl unoprostone, latanoprost, travoprost, bimatoprost, tafluprost, etc.), α ₁ blockers (bunazosin, etc.), and parasympathomimetic drugs (pilocarpine, etc.) . In addition, Rho kinase inhibitors are being developed as a new class of drugs, and this class of drugs belongs to the aqueous humor outflow promoter.

  In pharmacotherapy for glaucoma, two or more drugs are often used in combination for the purpose of enhancing the intraocular pressure lowering effect. A mixture containing two active ingredients having an action of lowering intraocular pressure is also known. Furthermore, administration of a combination of two drugs having an intraocular pressure lowering action (Patent Documents 1-6) and a method of administering a combination of several drugs having an intraocular pressure lowering action (Patent Document 7) are also disclosed. On the other hand, Patent Document 8 discloses a low-molecular compound having a strong intraocular pressure lowering action.

Japanese Patent No. 2726672 WO2004 / 019951 pamphlet WO2004 / 045644 pamphlet JP 2006-348028 A WO2006 / 137368 pamphlet WO2007 / 007737 pamphlet WO2002 / 38158 pamphlet WO2010 / 146881 pamphlet

  An object of the present invention is to provide a preventive or therapeutic agent for glaucoma or ocular hypertension, which has a strong intraocular pressure lowering action and an extended duration.

As a result of studying the intraocular pressure lowering action of the combination of the isoquinoline-6-sulfonamide derivative described in Patent Document 8 and an existing intraocular pressure-lowering agent, the present inventors have found that a specific isoquinoline-6-sulfonamide derivative, When administered in combination with one or more selected from glandins, carbonic anhydrase inhibitors, α ₂ stimulants, β blockers, α ₁ blockers and Rho kinase inhibitors, a powerful intraocular pressure lowering effect is obtained. The present invention was completed by finding out that it was demonstrated and its duration was extended.

That is, the present invention relates to the following invention.
(1) (A) (S) -6- (2-Methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (compound 1), (S) -6- (7-methyl-1,4-diazepane) -1-ylsulfonyl) isoquinoline (compound 2), 6-{(2R, 7R) -2,7-dimethyl-1,4-diazepan-1-ylsulfonyl} inoquinoline (compound 3) (R) -6- ( 2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (compound 4) and (R) -6- (5-methyl-1,4,7-oxadiazonan-4-ylsulfonyl) isoquinoline ( Compound 5) to compound or salt thereof, and (B) one or two selected from prostaglandins, carbonic anhydrase inhibitors, α ₂ stimulants, β blockers, α ₁ blockers and Rho kinase inhibitors In combination with the above A preventive or therapeutic agent for glaucoma or ocular hypertension.

(2) (A) (S) -6- (2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (compound 1), (S) for preventing or treating glaucoma or ocular hypertension -6- (7-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (compound 2), 6-{(2R, 7R) -2,7-dimethyl-1,4-diazepan-1-ylsulfonyl } Inoquinoline (Compound 3) (R) -6- (2-Methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (Compound 4), and (R) -6- (5-Methyl-1,4,4) 7-oxadiazonan-4-ylsulfonyl) isoquinoline (compound 5) or a salt thereof, and (B) prostaglandins, carbonic anhydrase inhibitors, α ₂ stimulants, β blockers, α ₁ Blocker and Rho kinase A combination with one or more selected from inhibitors.

(3) (A) (S) -6- (2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (compound 1) for producing a preventive or therapeutic agent for glaucoma or ocular hypertension, (S) -6- (7-Methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (Compound 2), 6-{(2R, 7R) -2,7-dimethyl-1,4-diazepan-1 -Ylsulfonyl} inoquinoline (compound 3) (R) -6- (2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (compound 4), and (R) -6- (5-methyl-1) , 4,7-oxadiazonan-4-ylsulfonyl) isoquinoline (compound 5) or a salt thereof, and (B) prostaglandins, carbonic anhydrase inhibitors, α ₂ stimulants, β blockers , Α ₁ blockers and Rho Use of one or a combination of two or more selected from kinase inhibitors.

(4) (A) (S) -6- (2-Methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (compound 1), (S) -6- (7-methyl-1,4-diazepane) -1-ylsulfonyl) isoquinoline (compound 2), 6-{(2R, 7R) -2,7-dimethyl-1,4-diazepan-1-ylsulfonyl} inoquinoline (compound 3) (R) -6- ( 2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (compound 4) and (R) -6- (5-methyl-1,4,7-oxadiazonan-4-ylsulfonyl) isoquinoline ( A compound selected from compound 5) or a salt thereof, and (B) one or more selected from prostaglandins, carbonic anhydrase inhibitors, α ₂ stimulants, β blockers, α ₁ blockers and Rho kinase inhibitors Combine two or more types A method for preventing or treating glaucoma or ocular hypertension, characterized by comprising administering at the same time.

  According to the present invention, it is possible to provide a preventive or therapeutic agent for glaucoma or ocular hypertension having a strong intraocular pressure lowering action and an extended duration.

It is a graph which shows a time-dependent change of the intraocular pressure of each administration group. Intraocular pressure is shown as a change from the control eye (mean value ± standard error). ○: Isopropyl unoprostone single administration group, □: Compound 4 single administration group, Δ: Isopropyl unoprostone and compound 4 combination administration group It is a graph which shows a time-dependent change of the intraocular pressure of each administration group. Intraocular pressure is shown as a change from the control eye (mean value ± standard error). ○: Brinzolamide single administration group, □: Compound 4 single administration group, Δ: Brinzolamide and compound 4 combined administration group It is a graph which shows a time-dependent change of the intraocular pressure of each administration group. Intraocular pressure is shown as a change from the control eye (mean value ± standard error). ○: Brimonidine single administration group, □: Compound 4 single administration group, Δ: Brimonidine and compound 4 combination administration group It is a graph which shows a time-dependent change of the intraocular pressure of each administration group. Intraocular pressure is shown as a change from the control eye (mean value ± standard error). ○: Betaxolol single administration group, □: Compound 4 single administration group, Δ: Betaxolol and compound 4 combined administration group It is a graph which shows a time-dependent change of the intraocular pressure of each administration group. Intraocular pressure is shown as a change from the control eye (mean value ± standard error). ○: Bunazosin single administration group, Δ: Compound 4 single administration group, □: Bunazosin and compound 4 combination administration group It is a graph which shows a time-dependent change of the intraocular pressure of each administration group. Intraocular pressure is shown as a change from the control eye (mean value ± standard error). ○: (S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline alone administration group, □: compound 4 alone administration group, Δ: (S) -4 -Fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline and Compound 4 combination administration group

  The preventive or therapeutic agent for glaucoma or ocular hypertension of the present invention is a combination of the component (A) and the component (B). Hereinafter, in this specification, compounds 1 to 5 of component (A) are collectively referred to as isoquinoline-6-sulfonamide derivatives.

  The salt of the isoquinoline-6-sulfonamide derivative may be a pharmaceutically acceptable salt, and examples thereof include acid addition salts. Specifically, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid And salts of organic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid, camphor sulfonic acid and the like, and hydrochloride is particularly preferable.

  The isoquinoline-6-sulfonamide derivative or a salt thereof can exist not only as an unsolvated form but also as a hydrate or solvate. In the present invention, all crystal forms and hydrates or solvents are present. It includes Japanese products.

  The isoquinoline-6-sulfonamide derivative used in the present invention can be produced by a known method, for example, a method described in WO2010 / 146881.

  Among the components (B), the prostaglandins are not particularly limited as long as they have an intraocular pressure lowering effect and are useful for the treatment of glaucoma. Examples of prostaglandins having an intraocular pressure lowering action include prostaglandins (particularly natural prostaglandins such as prostaglandin F2α) disclosed in JP-A-59-1418, Prostaglandins such as latanoprost disclosed in JP-A-2-108, prostaglandins such as isopropyl unoprostone disclosed in JP-A-2-108, and prostaglandins such as bimatoprost disclosed in JP-A-8-501310. Gins, prostaglandins such as travoprost disclosed in JP-A-10-182465, prostaglandins such as tafluprost disclosed in JP-A-11-71344, and the like. Latanoprost and isopropyl unopros marketed as Emissions, bimatoprost, travoprost, or tafluprost are preferably used. These prostaglandins may be in the form of salts or esters.

  The carbonic anhydrase inhibitor is not particularly limited as long as it has an intraocular pressure lowering effect and is useful for the treatment of glaucoma. Examples of the carbonic anhydrase inhibitor having an intraocular pressure lowering action include dorzolamide, brinzolamide, acetazolamide, diclofenamide, and metazolamide. In particular, dorzolamide and brinzolamide are preferably used. These may take the form of salts or esters.

The α ₂ stimulating agent is not particularly limited as long as it has an intraocular pressure lowering effect and is useful for the treatment of glaucoma. Examples of the α ₂ stimulant having an intraocular pressure lowering action include brimonidine and apraclonidine, and brimonidine is particularly preferable. These may take the form of salts or esters.

  The β-blocker is not particularly limited as long as it has an intraocular pressure lowering effect and is useful for the treatment of glaucoma. As the β-blocker having an intraocular pressure lowering action, timolol, befnolol, carteolol, nipradilol, betaxol, levobunolol, and metipranol are preferably used, and betaxolol, timolol, or nipradilol is particularly preferable. These may take the form of salts or esters.

The α ₁ blocker is not particularly limited as long as it has an intraocular pressure lowering effect and is useful for the treatment of glaucoma. An example of an α ₁ stimulant having an intraocular pressure lowering effect is bunazosin. These may take the form of salts or esters.

  The Rho kinase inhibitor is not particularly limited as long as it has an intraocular pressure lowering effect and is useful for the treatment of glaucoma. Examples of Rho kinase inhibitors having an intraocular pressure lowering action are disclosed in commercially available fasudil [hexahydro-1- (5-isoquinolinesulfonyl) -1H-1,4-diazepine], WO099 / 20620 (S ) -4-Fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline, (R)-(+)-N- (1H-pyrrolo, disclosed in WO 98/06433. [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide, (S) -1- (4-chloro-5-isoquinolinesulfonyl) -3, disclosed in WO2007 / 02664 -(Methylamino) pyrrolidine and (S) -1- (4-chloro-5-isoquinolinesulfonyl) -3-aminopyrrolidine, and WO2009 / 09 Such as 6-amino isoquinoline derivatives as disclosed in 898 and the like. These may take the form of salts or esters.

  These components (B) may be used individually by 1 type, and may be used in combination of 2 or more type.

  When component (A) and component (B) are used in combination, as shown in the examples below, an intraocular pressure lowering action that is strong and / or prolonged in duration is observed even from normal intraocular pressure. Therefore, a medicine combining these is useful as a preventive or therapeutic agent for glaucoma and ocular hypertension. Here, as glaucoma, for example, primary open-angle glaucoma, normal-pressure glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateauris syndrome, mixed glaucoma, steroid glaucoma Capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma and the like. Ocular hypertension, also called ocular hypertension, refers to symptoms that show abnormally high intraocular pressure despite the absence of clear lesions in the optic nerve. High ocular pressure conditions are included.

  The prophylactic or therapeutic agent for glaucoma or ocular hypertension according to the present invention may be used as a compounding agent in a form containing an effective amount of each of the component (A) and the component (B) in one preparation at an appropriate compounding ratio. Even in a form in which component (A) and component (B) are contained in different preparations, a drug containing each effective amount of each of component (A) and component (B) is formulated separately. It may be a kit that can be used simultaneously or at intervals. When component (A) and component (B) are made into different preparations, the respective administration routes may be different. These preparations do not require any special technique, and can be prepared using a widely used technique. In particular, for a drug already sold as a glaucoma therapeutic drug, a commercially available formulation can be used.

  The above preparation is preferably used for ophthalmic preparations, particularly for eye drops. Such eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments, etc. Good. Such a preparation is prepared as a composition suitable for the dosage form, if necessary, as a pharmaceutically acceptable carrier, for example, an isotonic agent, a chelating agent, a stabilizer, a pH adjusting agent, a preservative, an antioxidant. , A solubilizing agent, a thickening agent, and the like, and can be produced by a method known to those skilled in the art.

  Isotonic agents include glucose, trehalose, lactose, fructose, mannitol, xylitol, sorbitol and other sugars, glycerin, polyethylene glycol, propylene glycol and other polyhydric alcohols, sodium chloride, potassium chloride, calcium chloride and other inorganic salts The blending amount is preferably 0 to 5% by mass with respect to the total amount of the composition.

  Examples of chelating agents include edetates such as disodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or its salts, sodium hexametaphosphate Citric acid and the like can be mentioned, and the blending amount is preferably 0 to 0.2% by mass with respect to the total amount of the composition.

  Examples of the stabilizer include sodium bisulfite and the like, and the blending amount is preferably 0 to 1% by mass with respect to the total amount of the composition.

  Examples of the pH regulator include acids such as hydrochloric acid, carbonic acid, acetic acid, citric acid, phosphoric acid, and boric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate. Examples include salts or hydrogen carbonates, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, bases such as trometamol, and the blending amount thereof is 0 to 20 mass based on the total amount of the composition. % Is preferred.

  As preservatives, sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid ester such as propyl paraoxybenzoate, butyl paraoxybenzoate, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, Examples include quaternary ammonium salts such as cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine, and the blending amount is 0 to 0.2% by mass with respect to the total amount of the composition. Is preferred.

  Examples of the antioxidant include sodium bisulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol and the like, and the blending amount is preferably 0 to 0.4% by mass with respect to the total amount of the composition.

  Examples of solubilizers include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polysorbate 80, macrogol, D-mannitol, etc. 0-3 mass% is preferable with respect to.

  Examples of the thickening agent include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and the like. 0-70 mass% is desirable with respect to the composition whole quantity.

When preparing eye drops, for example, the desired components described above are dissolved or suspended in an aqueous solvent such as sterilized purified water or physiological saline, or a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil. The osmotic pressure can be adjusted to a predetermined osmotic pressure and subjected to sterilization such as filtration sterilization. In addition, when preparing an eye ointment, an ointment base can be included in addition to the various components described above. The ointment base is not particularly limited, but is an oily base such as petrolatum, liquid paraffin, or polyethylene; an emulsion base obtained by emulsifying an oil phase and an aqueous phase with a surfactant; hydroxypropyl methylcellulose, carboxymethylcellulose A water-soluble base composed of polyethylene glycol or the like is preferred.

  When the preventive or therapeutic agent for glaucoma or ocular hypertension of the present invention is used as a kit, a drug containing the component (A) formulated as described above and a drug containing the component (B) are separately provided. And each pharmaceutical formulation can be designed to be removed from each package for use at the time of administration. Each pharmaceutical preparation can also be packaged in a form suitable for each combined administration.

When the prophylactic or therapeutic agent for glaucoma or ocular hypertension of the present invention is administered, the dosage varies depending on the patient's weight, age, sex, symptom, dosage form, number of administrations, etc. As an isoquinoline-6-sulfonamide derivative or a salt thereof, one having a concentration of usually 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v) once a day or Several times a concentration of 0.0001% to 10% (w / v) per day as a prostaglandin, carbonic anhydrase inhibitor, α ₂ stimulant, β blocker, α ₁ blocker or Rho kinase inhibitor The range of one time or several times is mentioned.
The number of administrations is not particularly limited, but it is preferable to administer once or several times. In the case of liquid eye drops, one to several drops may be instilled at a time. In the case of a kit, each single preparation may be administered simultaneously, or may be administered at intervals of 5 minutes to 24 hours.

  Hereinafter, the present invention will be described in more detail, but the present invention is not limited thereto.

[Formulation Example 1]
A typical formulation example of an eye drop of a combination agent of prostaglandins (latanoprost) and isoquinoline-6-sulfonamide derivative in the present invention is shown below.
Eye drops (in 100 mL)
Latanoprost 0.005g
Compound 1-5 0.3g
Polysorbate 80 0.15g
Sodium edetate 0.05g
Benzalkonium chloride 0.005g
Sodium dihydrogen phosphate hydrate 1.4g
Sodium hydrogen phosphate sodium hydrate 0.63g
Sodium chloride 0.3g
Purified water

[Formulation Example 2]
A typical formulation example of an eye drop of a combination agent of prostaglandins (isopropyl unoprostone) and isoquinoline-6-sulfonamide derivative in the present invention is shown below.
Eye drops (in 100 mL)
Isopropyl unoprostone 0.06g
Compound 1-5 0.3g
Polysorbate 80 0.15g
D-mannitol 0.2g
Concentrated glycerin 0.2g
Sodium edetate 0.05g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 3]
A typical formulation example of an eye drop of a combination agent of a carbonic anhydrase inhibitor (brinzolamide) and an isoquinoline-6-sulfonamide derivative in the present invention is shown below.
Eye drops (in 100 mL)
Brinzolamide 0.6g
Compound 1-5 0.3g
Carboxyvinyl polymer 1.0g
D-mannitol 0.2g
Edetate sodium hydrate 0.5g
Concentrated glycerin 2.0g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 4]
A typical formulation example of an eye drop of a combination agent of an α ₂ stimulant (brimonidine) and an isoquinoline-6-sulfonamide derivative in the present invention is shown below.
Eye drops (in 100 mL)
Brimonidine 0.01g
Compound 1-5 0.3g
Sodium dihydrogen phosphate hydrate 0.6g
Disodium hydrogen phosphate hydrate 1.4g
Benzalkonium chloride 0.01g
Sodium chloride 0.3g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 5]
A typical formulation example of an eye drop containing a β-blocker (timolol) and an isoquinoline-6-sulfonamide derivative in the present invention is shown below.
Eye drops (in 100 mL)
Timolol maleate 0.34g
Compound 1-5 0.3g
Boric acid 0.2g
Concentrated glycerin 0.25g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 6]
A typical formulation example of an eye drop of a combination agent of a β-blocker (betaxolol) and an isoquinoline-6-sulfonamide derivative in the present invention is shown below.
Eye drops (in 100 mL)
Betaxolol hydrochloride 0.5g
Compound 1-5 0.3g
Sodium edetate 0.05g
Concentrated glycerin 2.0g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 7]
A typical formulation example of an eye drop of a combination agent of an α ₁ blocker (bunazosin) and an isoquinoline-6-sulfonamide derivative in the present invention is shown below.
Eye drops (in 100 mL)
Bunazosin hydrochloride 0.01g
Compound 1-5 0.3g
Boric acid 0.5g
Concentrated glycerin 2.0g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 8]
A combination agent of Rho kinase inhibitor ((S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline) and isoquinoline-6-sulfonamide derivative in the present invention Examples of general preparations of these eye drops are shown below.
Eye drops (in 100 mL)
(S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline 0.4 g
Compound 1-5 0.3g
Sodium dihydrogen phosphate 0.8g
Sodium chloride 0.5g
Benzalkonium chloride 0.005g
Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Test Example 1]
In order to examine the usefulness of a combination of an isoquinoline-6-sulfonamide derivative and a prostaglandin (latanoprost), the effect of lowering intraocular pressure when both drugs were administered alone or in combination to experimental animals was compared.

(Preparation of test compound solution)
A. Preparation of Compound 4 ophthalmic solution: Compound 4 monohydrochloride was prepared by dissolving in the following base A at a concentration of 0.3% (w / v).
Base A (in 100 mL)
Sodium dihydrogen phosphate 0.8g
Sodium chloride 0.5g
Sodium hydroxide Appropriate amount Purified water Appropriate amount B. Preparation of latanoprost ophthalmic solution: Commercially available xalatan (registered trademark) ophthalmic solution 0.005% was used as it was.

(Animal and group composition)
Experimental animal: cynomolgus monkey (sex: male, 6 animals per group)
Group configuration: The following three groups were provided.
Compound 4 administration group: 0.3% ophthalmic solution of Compound 4 (instillation amount: 40 μL) was administered.
Latanoprost administration group: administered latanoprost ophthalmic solution 0.005% (instillation amount: 40 μL).
Compound 4 + latanoprost administration group: administered both a 0.3% solution of compound 4 (instillation amount: 40 μL) and latanoprost ophthalmic solution 0.005% (instillation amount: 40 μL).

(Administration method and measurement method)
1) Intraocular pressure was measured immediately before administration of the test compound solution.
2) Compound 4 was instilled into one eye of an experimental animal, and latanoprost was instilled into the same eye 5 minutes later. Base A was instilled into one eye.
3) The intraocular pressure was measured 1 hour, 3 hours, 5 hours and 7 hours after the drug instillation.

(Results and Discussion)
The experimental results are shown in Table 1.

As shown in Table 1, the intraocular pressure was further decreased in the combination group of compound 4 and latanoprost, compared with the compound 4 administration group and talataprost administration group, and improvement in the duration of action was observed.
From the above, it was found that by combining prostaglandins and isoquinoline-6-sulfonamide derivatives, a stronger effect of lowering intraocular pressure and an improvement in sustained effect can be obtained.

[Test Example 2]
In order to examine the usefulness of the combination of isoquinoline-6-sulfonamide derivative and prostaglandins (isopropyl unoprostone), we compared the effects of lowering intraocular pressure when both drugs were administered to experimental animals alone or in combination. did.

(Preparation of test compound solution)
A. Preparation of Compound 4 ophthalmic solution: Compound 4 monohydrochloride was prepared by dissolving it in Base A described in Test Example 1 at a concentration of 0.03% (w / v).
B. Preparation of isopropyl unoprostone ophthalmic solution: A commercially available Rescula (registered trademark) ophthalmic solution 0.12% was diluted with the same amount of Base A to prepare a 0.06% ophthalmic solution.
C. Preparation of combined ophthalmic solution: 0.12% of commercially available Rescula (registered trademark) ophthalmic solution and Compound 4 solution dissolved in Base A are mixed in the same amount, and 0.04% of Compound 4 is contained in isopropyl unoprostone. A 0.06% combination ophthalmic solution was prepared.

(Animal and group composition)
Experimental animal: New Zealand white rabbit (sex: male, 8 per group)
Group configuration: The following three groups were provided.
Compound 4 administration group: 0.03% ophthalmic solution of Compound 4 (instillation amount: 40 μL) was administered.
Isopropyl unoprostone administration group: isopropyl unoprostone 0.06% ophthalmic solution (instillation amount: 40 μL) was administered.
Combined administration group: Combined ophthalmic solution (instillation amount: 40 μL) was administered.

(Administration method and measurement method)
1) Intraocular pressure was measured immediately before administration of the test compound solution.
2) The test compound was instilled into one eye of an experimental animal, and the base B was instilled into one eye.
3) The intraocular pressure was measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours and 7 hours after the drug instillation.

(Results and discussion)
The test results are shown in FIG. The intraocular pressure indicates a change value from the control eye.
As is apparent from FIG. 1, the compound 4 and isopropyl unoprostone combination administration group showed a lowering of intraocular pressure than the drug alone administration group, that is, the compound 4 administration group or the isopropyl unoprostone administration group. And also showed an improvement in the duration of its action.
From the above, it was found that by combining prostaglandins and isoquinoline-6-sulfonamide derivatives, a stronger effect of lowering intraocular pressure and an improvement in sustained effect can be obtained.

[Test Example 3]
In order to examine the usefulness of the combination of an isoquinoline-6-sulfonamide derivative and a carbonic anhydrase inhibitor (brinzolamide), the effect of lowering intraocular pressure when both drugs were administered alone or in combination to experimental animals was compared.

(Preparation of test compound solution)
A. Preparation of Compound 4 ophthalmic solution: Compound 4 monohydrochloride was prepared by dissolving in the base A described in Test Example 1 at a concentration of 0.1% (w / v).
B. Preparation of brinzolamide ophthalmic solution: A commercially available Eizopt (registered trademark) suspension ophthalmic solution 1% was used as it was.

(Animal and group composition)
Experimental animal: New Zealand white rabbit (sex: male, 8 per group)
Group configuration: The following three groups were provided.
Compound 4 administration group: 0.1% ophthalmic solution of Compound 4 (instillation amount: 40 μL) was administered.
Brinzolamide administration group: administer 1% brinzolamide ophthalmic solution (instillation amount: 40 μL).
Compound 4 + brinzolamide administration group: Compound 4 solution 0.1% ophthalmic solution (instillation amount: 40 μL) and brinzolamide ophthalmic solution 1% (instillation amount: 40 μL) were administered.

(Administration method and measurement method)
1) Intraocular pressure was measured immediately before administration of the test compound solution.
2) Compound 4 was instilled into one eye of an experimental animal, followed by a 1% solution of brinzolamide ophthalmic solution in the same eye. Base A was instilled into one eye.
3) After measuring intraocular pressure 0.5 hours after instillation, tap water warmed to 37 ° C. was orally administered at 60 mg / kg.
4) The intraocular pressure was measured 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3.5 hours and 4.5 hours after the drug instillation.

(Results and discussion)
The test results are shown in FIG. The intraocular pressure indicates a change value from the control eye.
As is apparent from FIG. 2, the combination group of compound 4 and brinzolamide exhibits an intraocular pressure lowering action superior to that of the drug alone administration group, that is, the compound 4 administration group or the brinzolamide administration group, and the persistence of the action. Showed improvement.
From the above, it was found that by combining a carbonic anhydrase inhibitor and an isoquinoline-6-sulfonamide derivative, a stronger effect of lowering intraocular pressure and an improvement in sustained effect can be obtained.

[Test Example 4]
In order to examine the usefulness of a combination of an isoquinoline-6-sulfonamide derivative and an α ₂ stimulant (brimonidine), the effect of lowering intraocular pressure when experimentally administered both drugs alone or in combination was examined.

(Preparation of test compound solution)
A. Preparation of Compound 4 ophthalmic solution: Compound 4 monohydrochloride was dissolved in the following Base B to prepare Compound 4 ophthalmic solution having a concentration of 0.03% (w / v).
Base B (in 100 mL)
Boric acid 2g
Purified water appropriate amount Preparation of brimonidine ophthalmic solution: Brimonidine was dissolved in Base B to prepare a brimonidine ophthalmic solution having a concentration of 0.001% (w / v).
C. Preparation of combined ophthalmic solution: Both Compound 4 monohydrochloride and brimonidine were dissolved in Base B, and an ophthalmic solution containing 0.3% of Compound 4 and 0.001% of brimonidine was prepared.

(Animal and group composition)
Experimental animal: New Zealand white rabbit (sex: male, 8 per group)
Group configuration: The following three groups were provided.
Compound 4 administration group: 0.03% ophthalmic solution of Compound 4 (instillation amount: 40 μL) was administered.
Brimonidine administration group: administer 0.001% brimonidine ophthalmic solution (instillation amount: 40 μL).
Combined administration group: Combined ophthalmic solution (instillation amount: 40 μL) was administered.

(Administration method and measurement method)
1) Intraocular pressure was measured immediately before administration of the test compound solution.
2) The test compound was instilled into one eye of an experimental animal, and the base B was instilled into one eye.
3) The intraocular pressure was measured 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours and 5 hours after the drug instillation.

(Results and discussion)
The test results are shown in FIG. The intraocular pressure indicates a change value from the control eye.
As is clear from FIG. 3, the compound 4 and brimonidine combination administration group showed an intraocular pressure lowering action superior to the drug alone administration group, that is, the compound 4 administration group or the brimonidine administration group.
From the above, it was found that a stronger intraocular pressure lowering effect can be obtained by combining an α ₂ stimulant and an isoquinoline-6-sulfonamide derivative.

[Test Example 5]
In order to examine the usefulness of a combination of an isoquinoline-6-sulfonamide derivative and a β-blocker (betaxolol), the effect of lowering intraocular pressure when both drugs were administered alone or in combination to experimental animals was compared.

(Preparation of test compound solution)
A. Preparation of Compound 4 ophthalmic solution: Compound 4 monohydrochloride was prepared by dissolving it in Base A described in Test Example 1 at a concentration of 0.03% (w / v).
B. Preparation of Betaxolol ophthalmic solution: A commercially available Betoptic (registered trademark) 0.5% ophthalmic solution was used as it was.

(Animal and group composition)
Experimental animal: New Zealand white rabbit (sex: male, 8 per group)
Group configuration: The following three groups were provided.
Compound 4 administration group: 0.03% ophthalmic solution of Compound 4 (instillation amount: 40 μL) was administered.
Betaxolol administration group: 0.5% ophthalmic solution of betaxolol hydrochloride (instillation amount: 40 μL) was administered.
Compound 4 + betaxolol administration group: Both 0.03% ophthalmic solution (instillation amount: 40 μL) of compound 4 and 0.5% ophthalmic solution ophthalmic solution (instillation amount: 40 μL) were administered.

(Administration method and measurement method)
1) Intraocular pressure was measured immediately before administration of the test compound solution.
2) Compound 4 was instilled in one eye of an experimental animal, followed by betaxolol in the same eye. Base B was instilled into one eye.
3) The intraocular pressure was measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours and 7 hours after the drug instillation.

(Results and discussion)
The result of the test is shown in FIG. The intraocular pressure indicates a change value from the control eye.
As is clear from FIG. 4, the combined group of compound 4 and betaxolol showed an intraocular pressure lowering action superior to the group administered with the drug alone, ie, the compound 4 administered group or betaxolol administered group, and the persistence of the action. Showed improvement.
From the above, it has been found that a stronger intraocular pressure lowering effect and an improvement in sustained effect can be obtained by combining a β-blocker and an isoquinoline-6-sulfonamide derivative.

[Test Example 6]
In order to examine the usefulness of a combination of an isoquinoline-6-sulfonamide derivative and an α ₁ blocker (bunazosin), the effect of lowering intraocular pressure when both drugs were administered alone or in combination to an experimental animal was compared.

(Preparation of test compound solution)
A. Preparation of Compound 4 ophthalmic solution: Compound 4 monohydrochloride was dissolved in Base B described in Test Example 4 to prepare a Compound 4 solution having a concentration of 0.03%.
B. Preparation of bunazosin ophthalmic solution: A commercially available Detantol (registered trademark) 0.01% ophthalmic solution was diluted 2-fold with Base B to prepare 0.005% bunazosin hydrochloride ophthalmic solution.
C. Preparation of combined ophthalmic solution: The same amount of commercially available detantol (registered trademark) 0.01% ophthalmic solution as compound 4 solution dissolved in base B was mixed, and 0.04% of compound 4 was contained and bunazosin hydrochloride was added. A combined ophthalmic solution containing 0.005% was prepared.

(Animal and group composition)
Experimental animal: New Zealand white rabbit (sex: male, 7 birds per group)
Group configuration: The following three groups were provided.
Compound 4 administration group: 0.03% Compound 4 ophthalmic solution (instillation amount: 40 μL) was administered.
Bunazosin administration group: 0.005% bunazosin hydrochloride ophthalmic solution (instillation amount: 40 μL) was administered.
Combined administration group: Combined ophthalmic solution (instillation amount: 40 μL) was administered.

(Administration method and measurement method)
1) Intraocular pressure was measured immediately before administration of the test compound solution.
2) The test compound was instilled into one eye of an experimental animal, and the base B was instilled into one eye.
3) The intraocular pressure was measured 1 hour, 2 hours, 3 hours, 4 hours and 5 hours after the drug instillation.

(Results and discussion)
The test results are shown in FIG. The intraocular pressure indicates a change value from the control eye.
As is clear from FIG. 5, the compound 4 and bunazosin combination administration group showed an intraocular pressure lowering action superior to that of the drug alone administration group, that is, the compound 3 administration group or the bunazosin administration group. It showed improvement in sustainability.
From the above, it was found that by combining an α ₁ blocker and an isoquinoline-6-sulfonamide derivative, a stronger effect of lowering intraocular pressure and an improvement in sustained effect can be obtained.

[Test Example 7]
Usefulness of a combination of an isoquinoline-6-sulfonamide derivative and a Rho kinase inhibitor ((S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline) In order to investigate, the effect of lowering intraocular pressure when both drugs were administered alone or in combination to experimental animals was compared.

(Preparation of test compound solution)
A. Preparation of Compound 4 ophthalmic solution: Compound 4 monohydrochloride was dissolved in Base A to prepare Compound 4 ophthalmic solution having a concentration of 0.03% (w / v).
B. Preparation of (S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline ophthalmic solution: (S) -4-fluoro-5-[(2-methyl- 1,4-diazepan-1-yl) sulfonyl] isoquinoline was dissolved in Base A to prepare an ophthalmic solution having a concentration of 0.1% (w / v).
C. Preparation of combined ophthalmic solution: Compound 4 monohydrochloride and (S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline are dissolved in Base A and 0 Ophthalmic solution containing 0.03% of compound 4 and containing 0.1% of (S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline Prepared.

(Animal and group composition)
Experimental animal: New Zealand white rabbit (sex: male, 8 per group)
Group configuration: The following three groups were provided.
Compound 4 administration group: 0.03% ophthalmic solution of Compound 4 (instillation amount: 40 μL) was administered.
(S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline administration group: (S) -4-fluoro-5-[(2-methyl-1, 4-diazepan-1-yl) sulfonyl] isoquinoline 0.1% ophthalmic solution (ophthalmic dose: 40 μL) was administered.
Combined administration group: Combined ophthalmic solution (instillation amount: 40 μL) was administered.

(Administration method and measurement method)
1) Intraocular pressure was measured immediately before administration of the test compound solution.
2) The test compound was instilled into one eye of an experimental animal, and the base B was instilled into one eye.
3) The intraocular pressure was measured 1 hour, 2 hours, 3 hours, 4 hours and 5 hours after the drug instillation.

(Results and discussion)
The test results are shown in FIG. The intraocular pressure indicates a change value from the control eye.
As is clear from FIG. 6, the combination group of Compound 4 and (S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline is a drug single administration group, That is, the intraocular pressure lowering action was superior to the compound 4 administration group or the (S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline administration group.
From the above, it was found that a stronger intraocular pressure lowering effect can be obtained by combining a Rho kinase inhibitor and an isoquinoline-6-sulfonamide derivative.

Claims (9)

(A) (S) -6- (2-Methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline, (S) -6- (7-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline , 6-{(2R, 7R) -2,7-dimethyl-1,4-diazepan-1-ylsulfonyl} inoquinoline, (R) -6- (2-methyl-1,4-diazocan-1-ylsulfonyl) ) Isoquinoline, and a compound selected from (R) -6- (5-methyl-1,4,7-oxadiazonan-4-ylsulfonyl) isoquinoline or a salt thereof, and (B) prostaglandins, carbonic anhydride A prophylactic or therapeutic agent for glaucoma or ocular hypertension comprising a combination of one or more selected from elementary enzyme inhibitors, α ₂ stimulants, β blockers, α ₁ blockers and Rho kinase inhibitors.   The prostaglandins are latanoprost, travoprost, bimatoprost, tafluprost or isopropyl unoprostone, according to claim 1, wherein the glaucoma or ocular hypertension is prevented or treated.   The agent for preventing or treating glaucoma or ocular hypertension according to claim 1 or 2, wherein the carbonic anhydrase inhibitor is brinzolamide or dorzolamide. alpha ₂ stimulant, glaucoma prophylactic or therapeutic agent according to any one of claims 1 to 3 is brimonidine.   The agent for preventing or treating glaucoma or ocular hypertension according to any one of claims 1 to 4, wherein the β-blocker is betaxolol, timolol, or nipradilol. The agent for preventing or treating glaucoma or ocular hypertension according to any one of claims 1 to 5, wherein the α ₁ blocker is bunazosin.   The Rho kinase inhibitor is (S) -4-fluoro-5-[(2-methyl-1,4-diazepan-1-yl) sulfonyl] isoquinoline, or fasudil. The preventive or therapeutic agent for glaucoma or ocular hypertension as described.   The component (A) and the component (B) are separate preparations, respectively, or a preventive or therapeutic agent for glaucoma or ocular hypertension according to any one of claims 1 to 7.   The preventive or therapeutic agent for glaucoma or ocular hypertension according to any one of claims 1 to 7, wherein the component (A) and the component (B) are contained in one preparation.

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