JP2012250950A - Combination of adenosine derivative and prostaglandin analog - 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 prostaglandin analogs 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- Yl] -2-propynyl} -piperidine-1-carboxylic acid methyl ester (hereinafter also referred to as “the present compound”) and prostaglandins 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, it is disclosed in US Patent Application Publication No. 2010/0093770 (Patent Document 1) that this compound exhibits an excellent intraocular pressure lowering action and is useful as a preventive or therapeutic agent for glaucoma or ocular hypertension. It has been reported.

  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 2) reports the administration of a combination of a sympathetic nerve blocker and a prostaglandin. In addition, International Publication No. 2002/38158 (Patent Document 3) discloses a method for treating glaucoma by administering a combination of several drugs having an action of lowering intraocular pressure to the eye. Furthermore, International Publication No. 2004/019951 (Patent Document 4) discloses administration of a combination of a Rho kinase inhibitor and prostaglandins, and International Publication No. 2004/045644 (Patent Document 5) 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 and other intraocular pressure-lowering agents, and naturally there is no description regarding the combined effect of the present compound and prostaglandins.

  As described above, there has been no report on the prevention or treatment effect of glaucoma or ocular hypertension when the present compound is combined with prostaglandins.

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

  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 diligent research on the effects of the combination of the present compound and other intraocular pressure-lowering agents, the present inventors have found that intraocular pressure can be increased by combining the present compound with prostaglandins compared to when each drug is used alone. 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 prostaglandins, the effect of lowering the intraocular pressure and / or the persistence of the action are remarkable. Improvement was seen.

  That is, the present invention is a preventive or therapeutic agent for glaucoma or ocular hypertension in which the present compound and prostaglandins are combined.

  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 prostaglandins. It is.

  Another aspect of the present invention is an intraocular pressure lowering agent in which the present compound and prostaglandins are combined.

  Another aspect of the present invention is a prophylactic or therapeutic agent for glaucoma or ocular hypertension in which the present compound and prostaglandins are combined, wherein the prostaglandins are PGF2α or a PGF2α derivative. It is a preventive or therapeutic agent for 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 action of each other by combining the present compound and prostaglandins. The prostaglandins are PGF2α or a PGF2α derivative, which 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 comprising a combination of the present compound and prostaglandins, wherein the prostaglandins are isopropyl unoprostone, latanoprost, travoprost. Or a preventive or therapeutic agent for glaucoma or ocular hypertension, which is bimatoprost.

  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 prostaglandins. Thus, the prostaglandins are isopropyl unoprostone, latanoprost, travoprost or bimatoprost, which is a prophylactic or therapeutic agent for glaucoma or ocular hypertension.

  Another aspect of the present invention is an intraocular pressure lowering agent obtained by combining the present compound and prostaglandins, wherein the prostaglandins are PGF2α or a PGF2α derivative.

  Another aspect of the present invention is an intraocular pressure lowering agent comprising a combination of the present compound and a prostaglandin, wherein the prostaglandin is isopropyl unoprostone, latanoprost, travoprost or bimatoprost. Agent.

  When this compound and prostaglandins are combined and administered to the eye, enhancement of the intraocular pressure lowering action and / or 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) and prostaglandins in combination for prevention or treatment of 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 prostaglandins in the present invention may be any prostaglandins that have an intraocular pressure lowering action and are useful for the treatment of glaucoma. Specific 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 Table 3-5010125, prostaglandins such as isopropyl unoprostone disclosed in Japanese Patent Application Laid-Open No. 2-108, and Japanese National Publication No. 8-501310 Prostaglandins such as bimatoprost disclosed in Japanese Laid-Open Patent Publication, prostaglandins such as travoprost disclosed in JP-A-10-182465, Surv Ophthalmol 47 (Suppl 1): disclosed in S13-S33, 2002 Prostagland such as AL-6598 Emissions such, Exp Eye Res. 89: 608-17, 2009, such as prostaglandins such as PF-0475270, and particularly latanoprost, isopropyl unoprostone, bimatoprost or travoprost already sold as a glaucoma therapeutic agent. . The prostaglandins in the present invention are preferably PGF2α or a PGF2α derivative, and more preferably isopropyl unoprostone, latanoprost, travoprost or bimatoprost.

  The present compounds and prostaglandins in the present invention also include salt forms. They are not particularly limited as long as they are pharmaceutically acceptable salts. Specific examples of the salt include, when the compound and / or prostaglandins include a basic group such as an amino group, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. 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 prostaglandins contain 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 compounds and prostaglandins in the present invention also include derivatives such as esters and amides. Specific examples of esters include esters obtained by condensing hydroxyl groups in the present compound and / or prostaglandins with carboxylic acids such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid, and prostaglandins. Examples thereof include esters obtained by condensing a carboxyl group therein and alcohols such as methanol, ethanol, propanol, and isopropyl alcohol. Specific examples of amides include amides and prostaglandins obtained by condensing an amino group in the present compound and / or prostaglandins with a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid. 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 prostaglandins 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 prostaglandins. 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 prostaglandins are separately prescribed (combined administration), or in the form of a single preparation containing the respective components ( 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 prostaglandins are formulated separately, formulations can be prepared according to known methods. 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 1). As preparations of prostaglandins, the above-mentioned JP-A-59-1418, JP-T-3-501005, JP-A-2-108, JP-A-8-501310, JP-A-10- It can be prepared with reference to formulation examples described in JP-A-182465, etc. Especially for latanoprost, isopropyl unoprostone, bimatoprost, travoprost and the like already sold as therapeutic agents for glaucoma Things can also be used. Moreover, also when preparing one formulation which mix | blended this compound and prostaglandins, 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 prostaglandins can be determined according to the patient's symptoms, age, dosage form, administration route 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 dose of prostaglandins varies depending on the type of drug, but the daily dose is usually in the range of 0.1 to 1000 μg and can be administered once or divided into several times a day. More specifically, in the case of latanoprost, the daily dose is 1 to 5 μg, in the case of isopropyl unoprostone, the daily dose is 30 to 300 μg, and in the case of bimatoprost, the daily dose is 2 to 30 μg. However, in the case of travoprost, a daily dose of 0.5 to 5 μg is usually used, and these doses can be appropriately increased or decreased depending on the age and symptoms of the patient. The doses of other prostaglandins can be determined based on the same criteria. The concentration of the prostaglandins in the eye drop is not particularly limited, but in the case of latanoprost, an eye drop having a concentration of 0.0001 to 5 w / v%, preferably 0.005 w / v% is 1 Can be instilled once or several times a day. In the case of isopropyl unoprostone, it is within the range of 0.001 to 5 w / v%, preferably within the range of 0.12 to 0.15 w / v%, more preferably 0.12 w / v% or 0.15 w. Eye drops with a concentration of / v% can be instilled once or several times a day. In the case of bimatoprost, it is within the range of 0.0001 to 5 w / v%, preferably within the range of 0.01 to 0.03 w / v%, more preferably 0.01 w / v% or 0.03 w / v%. Eye drops at a concentration of 1 to 5 times a day. In the case of travoprost, an eye drop having a concentration of 0.0001 to 5 w / v%, preferably 0.004 w / v%, can be instilled once or several times a day.

  These dosages are applied when the compound and prostaglandins are administered in combination. However, when administering a preparation containing the compound and prostaglandins, the daily dosage 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 prostaglandins in the present invention are shown below.

[Formulation Example 1]
Eye drops (in 100 mL)
0.01 g of this compound
Isopropyl unoprostone 0.12g
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
Isopropyl unoprostone 0.12g
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
Latanoprost 0.005g
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
Latanoprost 0.005g
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 drops (in 100 mL)
This compound 0.1g
Bimatoprost 0.03g
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 6]
Eye drops (in 100 mL)
This compound 0.1g
Bimatoprost 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 7]
Eye ointment (in 100g)
0.03 g of this compound
Isopropyl unoprostone 0.12g
Liquid paraffin 10.0g
Appropriate amount of white petrolatum [Formulation Example 8]
Eye ointment (in 100g)
0.03 g of this compound
Latanoprost 0.005g
Liquid paraffin 10.0g
White petrolatum appropriate amount [Formulation Example 9]
Eye ointment (in 100g)
0.03 g of this compound
Bimatoprost 0.03g
Liquid paraffin 10.0g
Appropriate amount of white petrolatum In the above formulation, it is possible to adjust the ophthalmic solution of a desired combination and a desired concentration by changing the type and amount of the present compound and prostaglandins and appropriately changing the amount of the additive. it can.

[Pharmacological test]
In order to investigate the usefulness of the combination of this compound and prostaglandins, the effect of lowering intraocular pressure when this compound and prostaglandins were administered in combination to experimental animals was examined. As prostaglandins, isopropyl unoprostone (Test 1) and bimatoprost (Test 2) were used.

(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)
(Test 1)
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 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 formulation to around 6.0, and then an appropriate amount of purified water was added to make the total volume 200 mL. A 1 w / v% solution of this compound was prepared. Of this, 3 mL was diluted to 100 mL with a base to prepare a 0.003 w / v% present compound solution.

(Test 2)
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 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 formulation to around 6.0, and then an appropriate amount of purified water was added to make the total volume 200 mL. A 1 w / v% solution of this compound was prepared. Of these, 10 mL was diluted to 100 mL with a base to prepare a 0.01 w / v% present 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 prostaglandin solution A commercially available prostaglandin ophthalmic solution was used as it was.

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

(Drugs and animals used in the study)
(Test 1)
The present compound solution: 0.003 w / v% The present compound solution (eye drop amount: 50 μL)
Prostaglandin solution: isopropyl unoprostone ophthalmic solution (trade name: Rescular ophthalmic solution 0.12%, ophthalmic dose: 50 μL)
Experimental animal: Japanese white rabbit (strain: JW, sex: male, 4-5 animals per group)
(Test 2)
The present compound solution: 0.01 w / v% The present compound solution (eye drop amount: 20 μL)
Prostaglandin solution: Bimatoprost ophthalmic solution (trade name: Lumigan ophthalmic solution 0.03%, ophthalmic volume: 20 μL)
Experimental animal: cynomolgus monkey (sex: male, group 6 animals)
(Administration method and measurement method)
[1] Concomitant administration of this compound and prostaglandins (1) One drop of 0.4% oxybuprocaine hydrochloride ophthalmic solution (trade name: Benoxeal 0.4% solution) is applied to both eyes of experimental animals for local anesthesia Did.
(2) The intraocular pressure was measured immediately before administration of the test compound solution to obtain the initial intraocular pressure.
(3) A prostaglandin 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, 6 hours and 8 hours after the instillation of this compound solution, 0.4% oxybuprocaine hydrochloride ophthalmic solution was dropped into the intraocular pressure measurement 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 prostaglandin 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 prostaglandins This compound solution was replaced with the 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, and the prostaglandin solution was replaced with physiological saline.

(Results and Discussion)
Tables 1 and 2 show the maximum intraocular pressure drop width (vs. control group average value) of each administration group in Test 1 and Test 2, respectively. 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. Table 1 shows the average value of 5 animals in the control group, the isopropyl unoprostone single administration group, and the combined administration group of this compound and isopropyl unoprostone, and the single compound administration group shows the average value of 4 animals. Each group shows the average value of 6 animals.

  As is clear from Tables 1 and 2, the combined administration group of the present compound and prostaglandins has a superior intraocular pressure lowering effect than the group administered with the drug alone, that is, the compound administered group and the prostaglandin administered group. showed that.

  From the above, it was found that a stronger intraocular pressure lowering effect can be obtained by combining this compound and prostaglandins.

Claims (7)

  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 prostaglandins are combined.   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 prostaglandins are combined to supplement and / or enhance the action of each other, thereby preventing or treating glaucoma or ocular hypertension .   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 and prostaglandins are combined.   The agent for preventing or treating glaucoma or ocular hypertension according to claim 1 or 2, wherein the prostaglandins are PGF2α or a PGF2α derivative.   The agent for preventing or treating glaucoma or ocular hypertension according to claim 4, wherein the prostaglandins are isopropyl unoprostone, latanoprost, travoprost or bimatoprost.   The intraocular pressure-lowering agent according to claim 3, wherein the prostaglandins are PGF2α or a PGF2α derivative.   The intraocular pressure-lowering agent according to claim 6, wherein the prostaglandins are isopropyl unoprostone, latanoprost, travoprost or bimatoprost.