JP2012250948A - Combination of adenosine derivative and carbonic anhydrase 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 a carbonic anhydrase inhibitor 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 a carbonic anhydrase 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, 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 with other intraocular pressure lowering agents, and naturally there is no description regarding the combined effect of the present compound and the carbonic anhydrase 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 carbonic anhydrase inhibitor.

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 intensive studies 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 a carbonic anhydrase inhibitor as 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. The detailed test method and the results will be described in the pharmacological test section described later. By combining this compound with a carbonic anhydrase inhibitor, a remarkable enhancement of the intraocular pressure lowering action and / or the persistence of the action can be achieved. A significant improvement was seen.

  That is, the present invention is a prophylactic or therapeutic agent for glaucoma or ocular hypertension in which the present compound and a carbonic anhydrase inhibitor 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 a carbonic anhydrase inhibitor. .

  Moreover, the other aspect of this invention is the intraocular pressure lowering agent which combined this compound and the carbonic anhydrase inhibitor.

  Another aspect of the present invention is a preventive or therapeutic agent for glaucoma or ocular hypertension in which the present compound and a carbonic anhydrase inhibitor are combined, wherein the carbonic anhydrase inhibitor is dorzolamide, brinzolamide or acetazolamide. 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 action of each other by combining the present compound and a carbonic anhydrase inhibitor. In addition, it is a prophylactic or therapeutic agent for glaucoma or ocular hypertension, wherein the carbonic anhydrase inhibitor is dorzolamide, brinzolamide or acetazolamide.

  Another aspect of the present invention is an intraocular pressure lowering agent comprising a combination of the present compound and a carbonic anhydrase inhibitor, wherein the carbonic anhydrase inhibitor is dorzolamide, brinzolamide or acetazolamide. is there.

  When this compound and a carbonic anhydrase inhibitor 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.

  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 a carbonic anhydrase inhibitor, for preventing or treating glaucoma or ocular hypertension, It is an intraocular 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.

  Any carbonic anhydrase inhibitor may be used in the present invention as long as it has an intraocular pressure lowering action and is useful for the treatment of glaucoma. Specific examples of the carbonic anhydrase inhibitor having an intraocular pressure lowering action include dorzolamide, brinzolamide, and acetazolamide, which are already sold as therapeutic agents for glaucoma.

  In the present invention, the present compound and carbonic anhydrase inhibitor also include salt forms. They are not particularly limited as long as they are pharmaceutically acceptable salts. Specific examples of the salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc. when the present compound and / or carbonic anhydrase inhibitor contains a basic group such as an amino group. Salts with inorganic acids, 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, sulfuric acid lauryl ester, sulfuric acid Examples thereof include salts with organic acids such as methyl, naphthalene sulfonic acid and sulfosalicylic acid. In addition, when the present compound and / or carbonic anhydrase inhibitor contains an acidic group such as a carboxyl group, a salt with an alkali metal such as lithium, sodium or potassium, or an alkaline earth metal such as calcium or magnesium. Salt, salt with ammonia, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) ) -1,3-propanediol, procaine, and salts with organic amines such as N, N-bis (phenylmethyl) -1,2-ethanediamine.

  In addition, the present compound and carbonic anhydrase inhibitor referred to in the present invention also 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 carbonic anhydrase inhibitor and a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid, and carbonic anhydrase. Examples include esters obtained by condensing a carboxyl group in an inhibitor and an alcohol such as methanol, ethanol, propanol, or isopropyl alcohol. Specific examples of amides include amides and carbonic anhydrases that are condensed with an amino group in the present compound and / or carbonic anhydrase inhibitor and a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid. Examples thereof include amides obtained by condensing a carboxyl group in an inhibitor and an amine such as methylamine, ethylamine, propylamine, and isopropylamine. In addition, this compound, ester and amide possessed by carbonic anhydrase inhibitor are each substituted with other ester and amide exemplified above (for example, methyl ester in this compound is substituted with ester other than methyl ester) Etc.) are also encompassed by the present compounds and carbonic anhydrase inhibitors in the present invention.

  Furthermore, the present compounds and carbonic anhydrase 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 carbonic anhydrase 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 carbonic anhydrase inhibitor are separately prescribed (combined administration), or in the form of one preparation containing the respective components. (Mixture) may be administered.

  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 this compound and a carbonic anhydrase inhibitor are formulated separately, 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 1). As a preparation of a carbonic anhydrase inhibitor, a preparation such as dorzolamide, brinzolamide, acetazolamide or the like already marketed as a therapeutic agent for glaucoma can be used. Moreover, also when preparing one formulation which mix | blended this compound and a carbonic anhydrase 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 carbonic anhydrase 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. For example, in the case of an eye drop, the concentration of the present compound in the eye drop is not particularly limited, but is usually within a range of 0.00001 to 5 w / v%, and within a range of 0.0001 to 1 w / v%. It is preferable that it is in the range of 0.003 to 0.3 w / v%. The concentration of the present compound in the eye drop may be calculated based on the weight of the free form of the present compound and its salt (hereinafter the same).

  The dose of the carbonic anhydrase inhibitor varies depending on the type of drug, but the daily dose is usually in the range of 10 to 10,000 μg, and can be administered once or divided into several times a day. More specifically, in the case of dorzolamide, the daily dose is 10 to 10,000 μg, in the case of brinzolamide, the daily dose is 20 to 5000 μg, and when acetazolamide is orally administered, the daily dose is 250 ˜1000 mg is usually used, and the dose can be appropriately increased or decreased depending on the age, symptoms, etc. of the patient. In addition, doses of other carbonic anhydrase inhibitors can be determined based on similar criteria. The concentration of the carbonic anhydrase inhibitor in the eye drop is not particularly limited, but in the case of dorzolamide, it is usually in the range of 0.01 to 5 w / v% and in the range of 0.5 to 2 w / v%. Preferably, it is 0.5 w / v%, 1 w / v%, or 2 w / v%. In the case of brinzolamide, it is usually in the range of 0.01 to 5 w / v%, preferably 1 w / v%. In the case of acetazolamide, it is usually in the range of 0.01 to 5 w / v%, and preferably in the range of 1 to 5 w / v%.

  These dosages are applied when the compound and a carbonic anhydrase inhibitor are administered in combination. When administering a preparation containing the compound and a carbonic anhydrase inhibitor, the daily dosage is used. Can be administered once or several times a day by preparing a preparation with an appropriately selected blending ratio so that the amount is less than or equal to the amount of each component described above.

  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 a carbonic anhydrase inhibitor in the present invention are shown below.

[Formulation Example 1]
Eye drops (in 100 mL)
0.01 g of this compound
Dorzolamide 0.5g
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
Dorzolamide 2g
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
Dorzolamide 0.5g
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
Dorzolamide 2g
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 In the above formulation, by changing the type and amount of this compound and carbonic anhydrase inhibitor, and by changing the amount of the additive appropriately, the desired combination and the desired concentration Eye drops can be adjusted.

[Pharmacological test]
In order to examine the usefulness of the combination of this compound and a carbonic anhydrase inhibitor, the effect of lowering intraocular pressure when this compound and a carbonic anhydrase inhibitor were administered in combination to experimental animals was examined. Dorzolamide (Test 1) and Brinzolamide (Test 2) were used as carbonic anhydrase inhibitors.

(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 carbonic anhydrase inhibitor solution A commercially available carbonic anhydrase inhibitor ophthalmic solution was used as it was.

(Test method)
The effect of lowering intraocular pressure when this compound and a carbonic anhydrase inhibitor were administered in combination was examined. As a comparative control, the effect of lowering intraocular pressure when this compound was administered alone or a carbonic anhydrase inhibitor 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: 0.001 w / v% The present compound solution (eye drop amount: 50 μL)
Carbonic anhydrase inhibitor solution: Dorzolamide ophthalmic solution (trade name: Torsopt ophthalmic solution 1%, ophthalmic volume: 50 μL)
Experimental animal: Japanese white rabbit (strain: JW, sex: male, 5 per group)
(Test 2)
The present compound solution: 0.001 w / v% The present compound solution (eye drop amount: 50 μL)
Carbonic anhydrase inhibitor solution: Brinzolamide ophthalmic solution (Brand name: Ezopt Suspension Ophthalmic Solution 1%, ophthalmic volume: 50 μL)
Experimental animal: Japanese white rabbit (strain: JW, sex: male, 3-4 animals per group)
(Administration method and measurement method)
[1] Concomitant administration of this compound and a carbonic anhydrase inhibitor (1) One drop of 0.4% oxybuprocaine hydrochloride ophthalmic solution (trade name: Benokiseal 0.4% solution) is instilled into both eyes of a laboratory animal and applied locally. Anesthetized.
(2) The intraocular pressure was measured immediately before administration of the test compound solution to obtain the initial intraocular pressure.
(3) A carbonic anhydrase 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 carbonic anhydrase inhibitor solution was replaced with physiological saline, and the others were tested in the same manner as in the combined administration test.

[3] Single administration of carbonic anhydrase inhibitor 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, the carbonic anhydrase inhibitor solution was replaced with physiological saline, and the others were tested in the same manner as the above combined administration test.

(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 each group. Table 2 shows 4 animals in the control group and this compound alone administration group, and 3 animals in the brinzolamide alone administration group and this compound and brinzolamide combination administration group. The average value is shown.

  As is clear from Table 1, the combined administration group of the present compound and dorzolamide exhibited an intraocular pressure lowering action superior to that of the drug alone administration group, that is, the present compound administration group and the dorzolamide administration group.

  As is clear from Table 2, the maximum intraocular pressure drop of the combination group of this compound and brinzolamide (average value for the control group) is larger than that of the drug alone administration group, that is, the present compound administration group and the brinzolamide administration group, and The maximum intraocular pressure drop caused by administration of each drug alone (vs. the average value for the control group) was greater than the sum, and the combined effect of this compound and brinzolamide was synergistic.

  From the above, it was found that a stronger effect of lowering intraocular pressure can be obtained by combining this compound with a carbonic anhydrase 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 carbonic anhydrase inhibitor 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 carbonic anhydrase inhibitor, which complement and / or enhance each other's action, prevent or treat glaucoma or ocular hypertension Agent.   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 a carbonic anhydrase inhibitor are combined.   The preventive or therapeutic agent for glaucoma or ocular hypertension according to claim 1 or 2, wherein the carbonic anhydrase inhibitor is dorzolamide, brinzolamide or acetazolamide.   The intraocular pressure-lowering agent according to claim 3, wherein the carbonic anhydrase inhibitor is dorzolamide, brinzolamide, or acetazolamide.