JP2012250952A - COMBINATION OF ADENOSINE DERIVATIVE AND Rho KINASE INHIBITOR - Google Patents

Abstract

PROBLEM TO BE SOLVED: To find out a combination of 4-{3-[6-amino-9-((2R,3R,4S,5S)-5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]-2-propynyl}-piperidine-1-carboxylic acid methyl ester and other ocular hypotensive agents, which is useful as a prophylactic or curative drug of glaucoma or ocular hypertension.SOLUTION: Combination use of 4-{3-[6-amino-9-((2R,3R,4S,5S)-5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]-2-propynyl}-piperidine-1-carboxylic acid methyl ester and Rho kinase mutually supplements and/or enhances ocular hypotensive actions. The administration form may be made adjunctly or made as combination of drugs.

Description

  The present invention relates to 4- {3- [6-amino-9-((2R, 3R, 4S, 5S) -5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl) -9H-purine-2- [Il] -2-propynyl} -piperidine-1-carboxylic acid methyl ester (hereinafter also referred to as “the present compound”) and a Rho kinase inhibitor are related to a preventive or therapeutic agent for glaucoma or ocular hypertension.

  Glaucoma is a refractory eye disease that has a risk of leading to blindness due to increased intraocular pressure due to various etiologies and damage to internal tissues of the eyeball (retina, optic nerve, etc.). As a method for treating glaucoma, intraocular pressure lowering therapy is generally used, and representative examples include drug therapy, laser therapy, and surgical therapy.

Drug therapy, sympathomimetics (nonselective stimulants such as epinephrine, alpha ₂ receptor agonists such as apraclonidine), sympathetic nerve blockers (timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, methylcarbamoyl β receptor blockers such Plano roll (Metipranolol), α ₁ receptor blockers such bunazosin hydrochloride), parasympathetic agonists (such as pilocarpine) and carbonic anhydrase inhibitors (acetazolamide), prostaglandins (isopropyl Drugs such as unoprostone, latanoprost, travoprost, bimatoprost) are used. In addition, Rho kinase inhibitors (such as SNJ-1656), adenosine agonists (such as INO-8875), serotonin blockers (BVT-28949) and the like are under development as new drugs.

  On the other hand, recently, a Rho kinase inhibitor has been found as a therapeutic agent for glaucoma based on a new mechanism of action (see International Publication No. 00/09162 (Patent Document 1)). It is disclosed in IOVS, 42 (1), 137-144 (2001) (Non-patent Document 1) that Rho kinase inhibitors decrease intraocular pressure by promoting aqueous humor outflow from the trabecular meshwork outflow pathway. Furthermore, the non-patent document 1, IOVS, 42 (5), 1029-1037 (2001) (non-patent document 2) that the mechanism of action is the reconstruction of the cytoskeleton in trabecular meshwork cells. Has been suggested.

  In addition, it is reported in US Patent Application Publication No. 2010/0093770 (Patent Document 2) that this compound exhibits an excellent intraocular pressure lowering effect and is useful as a preventive or therapeutic agent for glaucoma or ocular hypertension. Has been.

  By the way, there are some reports regarding the combined use of drugs having a lowering effect on intraocular pressure for the purpose of treating glaucoma. For example, Japanese Patent No. 2726672 (Patent Document 3) reports the administration of a combination of a sympatholytic agent and a prostaglandin. In addition, International Publication No. 2002/38158 (Patent Document 4) discloses a method for treating glaucoma by administering a combination of several drugs having an intraocular pressure lowering action to the eye. Further, International Publication No. 2004/019951 (Patent Document 5) discloses a combination of a Rho kinase inhibitor and prostaglandins, and International Publication No. 2004/045644 (Patent Document 6) discloses a Rho kinase inhibitor. And the combination of β receptor blockers have been reported.

  However, in any report, there is no description regarding the combination of the present compound with other intraocular pressure lowering agents, and of course, there is no description regarding the combined effect of the present compound and a Rho kinase inhibitor.

  As described above, there have been no reports on the prevention or treatment effect of glaucoma or ocular hypertension when the present compound is combined with a Rho kinase inhibitor.

International Publication No. 00/09162 US Patent Application Publication No. 2010/0093770 Japanese Patent No. 2726672 International Publication No. 2002/38158 International Publication No. 2004/019951 International Publication No. 2004/045644

IOVS, 42 (1), 137-144 (2001) IOVS, 42 (5), 1029-1037 (2001)

  Finding a combination of the present compound useful as a prophylactic or therapeutic agent for glaucoma or ocular hypertension and other intraocular pressure lowering agents is a very interesting subject.

  As a result of intensive studies on the effects of the combination of the present compound and other intraocular pressure-lowering agents, the present inventors have compared intraocular pressure as compared to when each drug is used alone by combining the present compound and a Rho kinase inhibitor. It has been found that the lowering action is enhanced and / or the durability of the action is improved, and the present invention has been completed. Detailed test methods and results will be described in the following pharmacological test section. By combining this compound with a Rho kinase inhibitor, a remarkable enhancement of the intraocular pressure-lowering effect and / or a long-lasting effect of the action can be achieved. Improvement was seen.

  That is, the present invention is a preventive or therapeutic agent for glaucoma or ocular hypertension, which is a combination of the present compound and a Rho kinase inhibitor.

  Another aspect of the present invention is a prophylactic or therapeutic agent for glaucoma or ocular hypertension characterized by combining and / or enhancing the action of each other by combining the present compound and a Rho kinase inhibitor, It is.

  Another embodiment of the present invention is an intraocular pressure-lowering agent that combines the present compound and a Rho kinase inhibitor.

  Another aspect of the present invention is a prophylactic or therapeutic agent for glaucoma or ocular hypertension in which the present compound is combined with a Rho kinase inhibitor, wherein the Rho kinase inhibitor is (R) -trans-N- ( Pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1 -Aminoethyl) benzamide, 1- (5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine is a preventive or therapeutic agent for glaucoma or ocular hypertension.

  Another aspect of the present invention is a prophylactic or therapeutic agent for glaucoma or ocular hypertension characterized by combining and / or enhancing the effects of each other by combining the present compound and a Rho kinase inhibitor. Wherein the Rho kinase inhibitor is (R) -trans-N- (pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide, 1- (5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine. A preventive or therapeutic agent for glaucoma or ocular hypertension.

  Another aspect of the present invention is an intraocular pressure lowering agent comprising a combination of the present compound and a Rho kinase inhibitor, wherein the Rho kinase inhibitor is (R) -trans-N- (pyridin-4-yl)- 4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide, 1 It is a prophylactic or therapeutic agent for glaucoma or ocular hypertension which is-(5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine.

  When this compound and a Rho kinase inhibitor are combined and administered to the eye, the enhancement of the intraocular pressure lowering action and / or the persistence of the action is improved. Therefore, the present invention is useful as a preventive or therapeutic agent for glaucoma or ocular hypertension, and an intraocular pressure lowering agent.

  The present invention relates to 4- {3- [6-amino-9-((2R, 3R, 4S, 5S) -5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-] represented by the following formula (1). Yl) -9H-purin-2-yl] -2-propynyl} -piperidine-1-carboxylic acid methyl ester (this compound) in combination with a Rho kinase inhibitor, a prophylactic or therapeutic agent for glaucoma or ocular hypertension, eye A pressure-lowering agent that complements and / or enhances the action of each other.

  The present compound in the present invention can be synthesized by a method described in International Publication No. 2003/029264, International Publication No. 2006/015357, International Publication No. 2007/136817, or the like.

  The Rho kinase inhibitor in the present invention means a compound that inhibits serine / threonine kinase activated with the activation of Rho. Examples include compounds that inhibit ROKα (ROCK-II), p160ROCK (ROKβ, ROCK-I) and other proteins with serine / threonine kinase activity. Specific examples of the Rho kinase inhibitor include (R) -trans-N- (pyridin-4-yl) -4- (1) disclosed in WO 98/06433 and WO 00/09162. Rho kinase inhibitors such as -aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide 1- (5-isoquinolinesulfonyl) homopiperazine, 1- (5-isoquinolinesulfonyl) -2-methylpiperazine and the like disclosed in WO 97/22322, Nature, 389, 990-994 (1997) Rho kinase inhibitors are disclosed in WO 01/56888 (1-benzylpyrrolidin-3-yl)-(1H- Rho kinase inhibitors such as danazol-5-yl) amine are disclosed in WO 02/100833 such as (1-benzylpiperidin-4-yl)-(1H-indazol-5-yl) amine The Rho kinase inhibitor is N- [2- (4-fluorophenyl) -6,7-dimethoxy-4-quinazolinyl] -N- (1H-indazole-5- 5 disclosed in WO 02/076976. Yl) Rho kinase inhibitors such as amines, N-4- (1H-indazol-5-yl) -6,7-dimethoxy-N-2-pyridin-4-disclosed in WO 02/076977 Rho kinase inhibitors, such as yl-quinazoline-2,4-diamine, are disclosed in 4-methyl-5- (2-meso, disclosed in WO 99/64011. Le - [1,4] diazepane-1-sulfonyl) Rho kinase inhibitors such as isoquinoline and the like. Among others, (R) -trans-N- (pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3-b Pyridin-4-yl) -4- (1-aminoethyl) benzamide, 1- (5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine is preferred.

  The present compounds and Rho kinase inhibitors in the present invention also include salt forms. They are not particularly limited as long as they are pharmaceutically acceptable salts. As specific examples of the salt, when the present compound and / or Rho kinase inhibitor contains a basic group such as an amino group, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salt with inorganic acid, oxalic acid, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1 , 2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate And salts with organic acids such as naphthalenesulfonic acid and sulfosalicylic acid. When the present compound and / or Rho kinase inhibitor contains an acidic group such as a carboxyl group, a salt with an alkali metal such as lithium, sodium or potassium, a salt with an alkaline earth metal such as calcium or magnesium, Salt with ammonia, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl)- Examples thereof include salts with organic amines such as 1,3-propanediol, procaine, and N, N-bis (phenylmethyl) -1,2-ethanediamine.

  In addition, the present compound and Rho kinase inhibitor in the present invention include derivatives such as esters and amides. Specific examples of the ester include an ester obtained by condensing a hydroxyl group in the present compound and / or Rho kinase inhibitor and a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid, Rho kinase inhibitor Examples thereof include esters obtained by condensing a carboxyl group therein and alcohols such as methanol, ethanol, propanol, and isopropyl alcohol. Specific examples of the amide include an amide obtained by condensing an amino group in the present compound and / or a Rho kinase inhibitor and a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid, a Rho kinase inhibitor Examples thereof include amides in which a carboxyl group therein is condensed with an amine such as methylamine, ethylamine, propylamine, and isopropylamine.

  Furthermore, the present compounds and Rho kinase inhibitors in the present invention may take the form of hydrates or solvates.

  The present invention is characterized in that glaucoma or ocular hypertension is prevented or treated by combining the present compound and a Rho kinase inhibitor. As glaucoma in the present invention, primary open-angle glaucoma, normal-tension glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed-angle glaucoma, chronic closed-angle glaucoma, mixed glaucoma, steroid glaucoma, amyloid glaucoma Angiogenic glaucoma, malignant glaucoma, capsular glaucoma of the lens, plateau iris syndrome, etc. are exemplified.

  As the dosage form, it may be administered in the form of two preparations in which the present compound and the Rho kinase inhibitor are separately formulated (combination administration), or in the form of a single preparation in which the respective components are combined ( It may be administered as a mixture).

  The preparation of the present invention can be administered either orally or parenterally, and no special technique is required for the preparation, and the preparation can be prepared using a widely used technique. Examples of the dosage form include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, and eye drops or eye ointments are preferable.

  When the present compound and Rho kinase inhibitor are formulated separately, the formulations can be prepared according to known methods, respectively. For example, a preparation of the present compound can be prepared with reference to the preparation examples described in US Patent Application Publication No. 2010/0093770 (Patent Document 2). A Rho kinase inhibitor preparation can be prepared with reference to the preparation examples described in International Publication No. 00/09162, International Publication No. 97/22322 and the like. Moreover, also when preparing one formulation which mix | blended this compound and Rho kinase inhibitor, it can prepare according to a well-known method.

  In the case of eye drops, for example, isotonic agents such as sodium chloride and concentrated glycerin, buffers such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil, etc. Surfactants, stabilizers such as sodium citrate and sodium edetate, and known additives such as preservatives such as benzalkonium chloride and paraben can be added as necessary.

  In the case of an eye drop, the pH may be in a range acceptable for ophthalmic preparations, and a pH range of 4 to 8 is preferable. The osmotic pressure ratio with respect to physiological saline may be within the range acceptable for ophthalmic preparations, preferably in the range of greater than 0 to 4 or less, more preferably in the range of greater than 0 to 2 or less, and further in the range of greater than 0 to 1 or less. A range of more than 0 and 0.5 or less is most preferable.

  In the case of an eye ointment, it can be prepared using a widely used base such as white petrolatum or liquid paraffin. Oral preparations such as tablets, capsules, granules, powders, etc. are binding agents such as lactose, crystalline cellulose, starch, vegetable oils, lubricants such as magnesium stearate and talc, hydroxypropylcellulose, polyvinylpyrrolidone, etc. An agent, a disintegrating agent such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol and silicone resin, and a filming agent such as a gelatin film can be added as necessary.

  For reference, some of the formulation examples are described in the Examples section below, but the formulation examples do not limit the scope of the present invention.

  The dosage of the present compound and Rho kinase inhibitor can be determined according to the patient's symptoms, age, dosage form, route of administration and the like. An example of administration by eye drops will be briefly described below.

  The daily dose of this compound is usually 0.005 to 7500 μg, preferably 0.05 to 1500 μg, more preferably 1.5 to 450 μg, and is divided into once or several times a day. These doses can be appropriately increased or decreased depending on the age and symptoms of the patient. Although there is no restriction | limiting in particular in the density | concentration of this compound in eyedrops, It exists in the range of 0.00001-5 w / v%, Preferably it is in the range of 0.0001-1 w / v%, More preferably, it is 0.003-0. Eye drops with a concentration in the range of 3 w / v% can be instilled once or several times a day. The concentration of the compound in the eye drop may be calculated based on the weight of either the free form of the compound or its salt (hereinafter the same).

  The dosage of the Rho kinase inhibitor varies depending on the type of drug, but the daily dosage is usually in the range of 0.025 to 10,000 μg, and can be administered once or divided into several times a day. The dose can be appropriately increased or decreased depending on the age and symptoms of the patient. The concentration of the Rho kinase inhibitor in the ophthalmic solution is not particularly limited, but an eye drop having a concentration within the range of 0.01 to 1 w / v% can be instilled once or several times a day.

  These doses are applied when the present compound and a Rho kinase inhibitor are administered in combination. When administering a preparation comprising the present compound and a Rho kinase inhibitor, the daily dose is as described above. A preparation having an appropriately selected blending ratio can be prepared so that the amount of each of the components is less than or equal to the amount, and the blended preparation can be administered once or several times a day.

  Formulation examples and pharmacological tests are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

[Formulation example]
Specific formulation examples of eye drops containing the present compound and Rho kinase inhibitor in the present invention are shown below.

[Formulation Example 1]
Eye drops (in 100 mL)
0.01 g of this compound
(R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide
0.01g
Sodium dihydrogen phosphate 0.15g
Glycerin 0.54g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount [Formulation Example 2]
Eye drops (in 100 mL)
0.01 g of this compound
(R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide
0.3g
Sodium dihydrogen phosphate 0.15g
Glycerin 0.54g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount [Formulation Example 3]
Eye drops (in 100 mL)
This compound 0.1g
(R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide
0.01g
Sodium dihydrogen phosphate 0.15g
Glycerin 0.54g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount [Formulation Example 4]
Eye drops (in 100 mL)
This compound 0.1g
(R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide
0.3g
Sodium dihydrogen phosphate 0.15g
Glycerin 0.54g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount [Formulation Example 5]
Eye ointment (in 100g)
0.03 g of this compound
(R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide
0.1g
Liquid paraffin 10.0g
Appropriate amount of white petrolatum In the above formulation, it is possible to adjust the ophthalmic solution of the desired combination and desired concentration by changing the type and amount of the present compound and Rho kinase inhibitor, and appropriately changing the amount of additive. it can.

[Pharmacological test]
In order to examine the usefulness of the combination of this compound and a Rho kinase inhibitor, the effect of lowering intraocular pressure when this compound and a Rho kinase inhibitor were administered in combination to experimental animals was examined. (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide dihydrochloride was used as a Rho kinase inhibitor.

(Preparation of test compound solution)
(1) Preparation of base 900 mL of purified water was added to 4.7 g of concentrated glycerin and dissolved. After dissolution, 1.5 g of sodium dihydrogen phosphate was added and dissolved. Further, 50 mL of 0.1 w / v% benzalkonium chloride solution was added and stirred, and an appropriate amount of sodium hydroxide solution was added to adjust the pH of the preparation to around 6.0, and then an appropriate amount of purified water was added to make the total amount 1000 mL. .

(2) Preparation of this compound solution (osmotic pressure ratio: 0.25)
To 0.94 g of concentrated glycerin, 180 mL of purified water was added and dissolved. After dissolution, 0.3 g of sodium dihydrogen phosphate and 0.2 g of the present compound were added and dissolved. Further, 10 mL of a 0.1 w / v% benzalkonium chloride solution was added and stirred, an appropriate amount of sodium hydroxide solution was added, and the pH of the preparation was adjusted to around 6.0, and then an appropriate amount of purified water was added to make the total amount 200 mL. . Of this, 1 mL was diluted to 100 mL with a base to prepare a 0.001 w / v% compound solution.

(3) Preparation of physiological saline Commercially available physiological saline (trade name: Otsuka raw food injection, obtained from Otsuka Pharmaceutical Factory Co., Ltd.) was used as it was.

(4) Preparation of Rho kinase inhibitor solution (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide 0.00322 g Was dissolved in physiological saline, and sodium hydroxide was added to neutralize the solution (pH 6.0 to 7.0). Then, physiological saline was added to make the total volume 3.22 mL, 0.1 w / v% A Rho kinase inhibitor solution was prepared.

(Test method)
The intraocular pressure lowering effect when this compound and a Rho kinase inhibitor were administered in combination was examined. As a comparative control, the intraocular pressure lowering effect when this compound was administered alone or a Rho kinase inhibitor alone was also examined. For the control, a base and physiological saline were administered.

(Drugs and animals used in the study)
The present compound solution: 0.001 w / v% The present compound solution (eye drop amount: 50 μL)
Rho kinase inhibitor solution: 0.1 w / v% (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide Hydrochloride solution (eye drops: 50 μL)
Experimental animal: Japanese white rabbit (strain: JW, sex: male, 5 per group)
(Administration method and measurement method)
[1] Concomitant administration of this compound and Rho kinase inhibitor (1) Local anesthesia with 0.4% oxybuprocaine hydrochloride ophthalmic solution (trade name: Benoxeal 0.4% solution) instilled into both eyes of experimental animals Did.
(2) The intraocular pressure was measured immediately before administration of the test compound solution to obtain the initial intraocular pressure.
(3) The Rho kinase inhibitor solution was instilled into one eye of an experimental animal (the contralateral eye was untreated). Since it is impossible to instill the compound solution at the same time, the compound solution was instilled into the same eye after a while.
(4) At 2 hours, 4 hours and 6 hours after the instillation of this compound solution, 0.4% oxybuprocaine hydrochloride ophthalmic solution was dropped into the intraocular pressure eye drop, and the intraocular pressure was measured after local anesthesia. The intraocular pressure was measured three times, and the average value is shown in the result.

[2] Single administration of this compound The Rho kinase inhibitor solution was replaced with physiological saline, and the others were tested in the same manner as the above combined administration test.

[3] Single administration of Rho kinase inhibitor The present compound solution was replaced with a base, and the others were tested in the same manner as the above combined administration test.

[4] Control The present compound solution was used as a base, the Rho kinase inhibitor solution was replaced with physiological saline, and the others were tested in the same manner as the above combination administration test.

(Results and Discussion)
Table 1 shows the maximum intraocular pressure drop of each administration group (vs. the control group average value). The maximum intraocular pressure decrease width (vs. the control group average value) is indicated by the maximum difference between the average intraocular pressure value fluctuation range (ΔIOP) from the initial intraocular pressure value of the control group and ΔIOP of each individual. Each group shows the average value of 5 animals.

  From Table 1, the combined administration group of this compound and (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide is Administration group of drug alone, that is, administration group of this compound and administration of (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide The intraocular pressure lowering effect was superior to that of the group.

  From the above, it was found that a stronger effect of lowering intraocular pressure can be obtained by combining this compound with a Rho kinase inhibitor.

Claims (5)

  4- {3- [6-Amino-9-((2R, 3R, 4S, 5S) -5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl) -9H-purin-2-yl]- A prophylactic or therapeutic agent for glaucoma or ocular hypertension in which 2-propynyl} -piperidine-1-carboxylic acid methyl ester and a Rho kinase inhibitor are combined.   4- {3- [6-Amino-9-((2R, 3R, 4S, 5S) -5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl) -9H-purin-2-yl]- A prophylactic or therapeutic agent for glaucoma or ocular hypertension, characterized by combining and / or enhancing the action of 2-propynyl} -piperidine-1-carboxylic acid methyl ester and a Rho kinase inhibitor. .   4- {3- [6-Amino-9-((2R, 3R, 4S, 5S) -5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl) -9H-purin-2-yl]- An intraocular pressure-lowering agent in which 2-propynyl} -piperidine-1-carboxylic acid methyl ester is combined with a Rho kinase inhibitor.   The Rho kinase inhibitor is (R) -trans-N- (pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3 -B] pyridin-4-yl) -4- (1-aminoethyl) benzamide, 1- (5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine 2. A preventive or therapeutic agent for glaucoma or ocular hypertension according to 2.   The Rho kinase inhibitor is (R) -trans-N- (pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3 -B] pyridin-4-yl) -4- (1-aminoethyl) benzamide, 1- (5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine. The intraocular pressure-lowering agent described.