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USOO93394.96B2

(12) United States Patent (10) Patent No.: US 9,339,496 B2 Kirihara et al. (45) Date of Patent: May 17, 2016

(54) COMPOSITION FORTREATING OR (58) Field of Classification Search PREVENTING COMPRISINGA None COMPOUND, AND A See application file for complete search history. BETA-RECEPTOR ANTAGONST (56) References Cited (71) Applicant: SANTEN PHARMACEUTICAL CO., LTD., Osaka-shi, Osaka (JP) U.S. PATENT DOCUMENTS (72) Inventors: Tomoko Kirihara, Ikoma (JP); Atsushi 2008.OO45545 A1* 2/2008 Prasanna et al...... 514/256 Shimazaki, Ikoma (JP); Masatsugu 2012/O190852 A1* 7/2012 Hagihara et al...... 544,333 Nakamura, Ikoma (JP) FOREIGN PATENT DOCUMENTS (73) Assignee: SANTEN PHARMACEUTICAL CO., WO WO 2004/O19951 A1 3, 2004 LTD., Osaka (JP) WO WO 2004/045644 A1 6, 2004 WO WO 2010/113957 A1 10/2010 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 7 days. Ophthalmic (Medline Plus, http://www.nlm.nih.gov/ medlineplus/druginfo/meds/a882043.html.* (21) Appl. No.: 13/939,381 Higginbotham ("Considerations in glaucoma therapy: fixed combi nations versus their component .” Clinical Ophthalmol (22) Filed: Jul. 11, 2013 ogy. 2010; 4:1-9).* Glaucol Patient information Leaflet (Steripak Ltd, Dec. 2011).* (65) Prior Publication Data Berenbaum (Pharmacological Reviews, 1989).* US 2014/OO18396 A1 Jan. 16, 2014 U.S. Appl. No. 13/982,437, filed Jul 11, 2013; confirmation No. 3O25. Related U.S. Application Data (60) Provisional application No. 61/671,219, filed on Jul. * cited by examiner 13, 2012. Primary Examiner — Marcos SZnaidman (51) Int. Cl. Assistant Examiner — Rayna B Rodriguez A6 IK3I/444 (2006.01) (74) Attorney, Agent, or Firm — Holtz, Holtz & Volek PC A6 IK 45/06 (2006.01) CO7D 40/4 (2006.01) (57) ABSTRACT A6 IK3I/498 (2006.01) A composition for treating or preventing glaucoma or ocular A 6LX3/5377 (2006.01) hypertension including aisopropyl (6-4-(pyrazol-1-yl)ben A6 IK3I/542 (2006.01) Zyl(pyridin-3-ylsulfonyl)aminomethylpyridin-2-ylamino) A 6LX3/55.75 (2006.01) acetate and a beta-receptor antagonist, in a combined phar (52) U.S. Cl. maceutically acceptable amount. As for the administration CPC ...... A6 IK3I/444 (2013.01); A61 K3I/498 form, these drugs may be administered concomitantly or may (2013.01); A61K3I/5377 (2013.01); A61 K be administered as a combination drug. 3.1/542 (2013.01); A61 K3I/55.75 (2013.01); A61K 45/06 (2013.01); C07D401/14 (2013.01) 17 Claims, No Drawings US 9,339,496 B2 1. 2 COMPOSITION FORTREATING OR been known at all as to what effect of such a combination is PREVENTING GLAUCOMA COMPRISINGA exerted on the . SULFONAMIDE COMPOUND, AND A BETA-RECEPTOR ANTAGONST SUMMARY OF THE INVENTION

CROSS-REFERENCE TO RELATED Problems that the Invention is to Solve APPLICATIONS It is a very interesting Subject to discover a combination of This application claims the benefit of U.S. Provisional preventive ortherapeutic drugs for glaucoma or ocular hyper Application No. 61/671,219 filed Jul. 13, 2012, the entire 10 tension, which is useful as a preventive or therapeutic agent contents of which are incorporated by reference herein. for glaucoma or ocular hypertension. TECHNICAL FIELD Means for Solving the Problems 15 The present inventors made intensive studies on the effect The present invention relates to a preventive ortherapeutic of a combination of preventive or therapeutic agents for glau agent for glaucoma or ocular hypertension, or an intraocular coma or ocular hypertension, and as a result, they found that pressure lowering agent comprising a combination of by combining isopropyl (6-4-(pyrazol-1-yl)benzyl (pyri isopropyl (6-4-(pyrazol-1-yl)benzyl (pyridin-3-ylsulfo din-3-ylsulfonyl) aminomethylpyridin-2-ylamino)acetate nyl)aminomethylpyridin-2-ylamino) acetate with other pre with other preventive or therapeutic agent for glaucoma or ventive or therapeutic drug for glaucoma or ocular hyperten ocular hypertension, the intraocular pressure lowering effect S1O. is enhanced as compared with the case where each agent is used singly, and thus completed the invention. That is, the BACKGROUND ART invention relates to the following aspects. 25 (1) A preventive or therapeutic agent for glaucoma or Glaucoma is an intractable ocular disease with a risk of ocular hypertension, comprising a combination of isopropyl blindness, involving an increase in intraocular pressure due to (6-4-(pyrazol-1-yl)benzyl (pyridin-3-ylsulfonyl) various predisposing factors and the disorder of internal tis aminomethylpyridin-2-ylamino)acetate with one or more Sues of eyeballs (retina, an optic nerve, and the like). Agen other preventive or therapeutic drugs for glaucoma or ocular eral method of treating glaucoma is intraocular pressure low 30 hypertension (with the proviso that is excluded). ering therapy, which is exemplified by pharmacotherapy, (2) An intraocular pressure lowering agent, comprising a laser therapy, surgical therapy, and the like. combination of isopropyl (6-4-(pyrazol-1-yl)benzyl (pyri In the pharmacotherapy, a drug Such as a sympathomimetic din-3-ylsulfonyl)aminomethylpyridin-2-ylamino)acetate drug (a nonselective stimulant such as diplivefrin oran O-re with one or more other preventive or therapeutic drugs for ceptoragonist Such as ), a sympatholytic drug (a 35 glaucoma or ocular hypertension (with the proviso that taflu B-receptor antagonist Such as timolol, , . prost is excluded). nipradillol, , or , or an (3) The preventive or therapeutic agent or the intraocular C-receptor antagonist Such as hydrochloride), a pressure lowering agent according to the above (1) or (2), (such as ), a carbonic wherein the other preventive ortherapeutic drug for glaucoma anhydrase inhibitor (such as ), a 40 or ocular hypertension (with the proviso that tafluprost is (such as isopropyl , , or excluded) is one or more preventive or therapeutic agents ) is used. Further, Rho-kinase inhibitors (such as selected from the group consisting of a nonselective sym SNJ-1656), adenosine agonists (such as INO-8875), seroto pathomimetic drug, an O2-receptor agonist, an O-receptor nin antagonists (BVT-28949), and the like have been under antagonist, a B-receptor antagonist, a parasympathomimetic development as novel drugs. Other than these, a prostaglan 45 drug, a carbonic anhydrase inhibitor, a prostaglandin and a din E2 receptor Subtype 2 agonist (EP2 agonist) is known to Rho-kinase inhibitor. have an intraocular pressure lowering effect, and it is reported (4) The preventive or therapeutic agent or the intraocular in WO 2010/113957 that a sulfonamide compound having pressure lowering agent according to the above (3), wherein high EP2 receptor selectivity and a potent EP2 agonistic the nonselective is diplivefrin. activity is promising as a therapeutic drug for glaucoma. 50 (5) The preventive or therapeutic agent or the intraocular There are several reports of the combined use of drugs pressure lowering agent according to the above (3) or (4), having an intraocular pressure lowering effect to treat glau wherein the C-receptor agonist is brimonidine or apracloni coma. For example, Japanese Patent No. 2726672 reports the dine. combined administration of a sympatholytic drug with a pros (6) The preventive or therapeutic agent or the intraocular taglandin. WO 2002/38158 discloses a method of treating 55 pressure lowering agent according to any one of the above (3) glaucoma by the combined administration of several drugs to (5), wherein the O.-receptor antagonist is bunaZosin. having an intraocular pressure lowering effect to eyes. WO (7) The preventive or therapeutic agent or the intraocular 2004/019951 reports the combined administration of a Rho pressure lowering agent according to any one of the above (3) kinase inhibitor with a prostaglandin, and WO 2004/045644 to (6), wherein the B-receptorantagonist is timolol, befunolol. reports the combined administration of a Rho-kinase inhibi 60 carteolol, nipradillol, betaxolol, levobunolol or metipranolol. tor with a B-receptor antagonist. (8) The preventive or therapeutic agent or the intraocular However, there have been no reports specifically disclosing pressure lowering agent according to any one of the above (3) a combination of isopropyl (6-4-(pyrazol-1-yl)benzyl (py to (7), wherein the parasympathomimetic drug is pilocarpine. ridin-3-ylsulfonyl)aminomethylpyridin-2-ylamino)acetate, (9) The preventive or therapeutic agent or the intraocular which has a high EP2 receptor selectivity and a potent EP2 65 pressure lowering agent according to any one of the above (3) agonistic activity, with other preventive or therapeutic drug to (8), wherein the carbonic anhydrase inhibitor is dorzola for glaucoma or ocular hypertension, and naturally, it has not mide, or acetazolamide. US 9,339,496 B2 3 4 (10) The preventive or therapeutic agent or the intraocular bination of the present compound with other preventive or pressure lowering agent according to any one of the above (3) therapeutic drug for glaucoma or ocular hypertension. Glau to (9), wherein the prostaglandin is isopropyl unoprostone, coma in the invention includes primary open angle glaucoma, latanoprost, travoprost or bimatoprost. normal tension glaucoma, hypersecretion glaucoma, ocular (11) The preventive or therapeutic agent or the intraocular 5 hypertension, acute angle-closure glaucoma, chronic angle pressure lowering agent according to any one of the above (3) closure glaucoma, combined-mechanism glaucoma, steroid to (10), wherein the Rho-kinase inhibitor is (R)-trans-N-(py induced glaucoma, amyloid glaucoma, neovascular glau ridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)- coma, malignant glaucoma, capsular glaucoma, plateau iris (+)-N-(1H-pyrrolo2,3-bipyridin-4-yl)-4-(1-aminoethyl)- syndrome and the like. benzamide, 1-(5-isoquinolinesulfonyl)homopiperazine or 10 In the invention, the combination of the present compound 1-(5-isoquinolinesulfonyl)-2-methylpiperazine. with one or more other preventive or therapeutic drugs for Incidentally, from the above-described respective configu glaucoma or ocular hypertension is preferably a combination rations (1) to (11), one or more configurations can be arbi of the present compound with one to three other preventive or trarily selected and combined. therapeutic drugs for glaucoma or ocular hypertension, and Herein after in the specification, “the other preventive or 15 more preferably a combination of the present compound with therapeutic drugs for glaucoma or ocular hypertension' one or two other preventive ortherapeutic drugs for glaucoma means “the other preventive or therapeutic drugs for glau or ocular hypertension. coma or ocular hypertension except for tafluprost' The other preventive or therapeutic drug for glaucoma or ocular hypertension in the invention may be any as long as the Advantage of the Invention drug has an intraocular pressure lowering effect and is useful for treating glaucoma, and examples thereof include a non By the combined administration ofisopropyl (6-4-(pyra selective sympathomimetic drug, an O-receptor agonist, an Zol-1-yl)benzyl (pyridin-3-ylsulfonyl) C-receptor antagonist, a f-receptor antagonist, a parasym aminomethylpyridin-2-ylamino) acetate with one or more pathomimetic drug, a carbonic anhydrase inhibitor, a pros other preventive or therapeutic drug for glaucoma or ocular 25 taglandin, a Rho-kinase inhibitor and the like. In the case hypertension to eyes, the intraocular pressure lowering effect where the present compound is combined with two other is enhanced. Therefore, the invention is useful as a preventive preventive ortherapeutic drugs for glaucoma or ocular hyper or therapeutic agent for glaucoma or ocular hypertension or tension, the two other preventive or therapeutic drugs for an intraocular pressure lowering agent. glaucoma or ocular hypertension are preferably two preven 30 tive or therapeutic agents selected from the group consisting MODE FOR CARRYING OUT THE INVENTION of a B-receptor antagonist, a carbonic anhydrase inhibitor and a prostaglandin, and more preferably a B-receptor antagonist The invention is directed to a preventive or therapeutic and a carbonic anhydrase inhibitor, or a B-receptor antagonist agent for glaucoma or ocular hypertension or an intraocular and a prostaglandin. pressure lowering agent, comprising a combination ofisopro 35 Specific examples of the nonselective sympathomimetic pyl (6-4-(pyrazol-1-yl)benzyl (pyridin-3-ylsulfonyl) drug include diplivefrin. Specific examples of the C-receptor aminomethylpyridin-2-ylamino) acetate (hereinafter also agonist include brimonidine and . Specific referred to as “present compound') represented by the fol examples of the C-receptor antagonist include bunaZosin. lowing formula (1) with one or more other preventive or Specific examples of the B-receptor antagonist include therapeutic drugs for glaucoma or ocular hypertension, where 40 timolol, befunolol, carteolol, nipradillol, betaxolol, these drugs complement and/or enhance their intraocular levobunolol and metipranolol. Specific examples of the para pressure lowering effects each other. sympathomimetic drug include pilocarpine. Specific examples of the carbonic anhydrase inhibitor include dor Zolamide, brinzolamide and acetazolamide. III 45 Specific examples of the prostaglandin include prostaglan dins disclosed in JP-A-59-1418 (particularly, a natural pros taglandin Such as prostaglandin F2C), such as latanoprost disclosed in JP-T-3-501025, prostaglandins such as isopropyl unoprostone disclosed in JP-A-2-108, prostag 50 landins such as bimatoprost disclosed in JP-T-8-501310, prostaglandins such as travoprost disclosed in JP-A-10 182465, prostaglandins such as AL-6598 disclosed in Surv Opthalmol 47 (Suppl 1): S13-S33, 2002, and prostaglandins such as PF-04475270 disclosed in Exp Eye Res. 89: 608-17, 55 2009. Among these, the prostaglandin is preferably PGF2C. or a PGF2C. derivative, more preferably isopropyl unoprostone, latanoprost, travoprost or bimatoprost. The Rho-kinase inhibitor in the invention refers to a com pound which inhibits serine/threonine kinase activated with 60 the activation of Rho. Examples of Such a compound include compounds which inhibit ROKO. (ROCK-II), p160ROCK (ROKB, ROCK-I) or other proteins having a serine/threonine The present compound in the invention can be synthesized kinase activity. Specific examples of the Rho-kinase inhibitor by the method described in WO 2009/113600 or WO 2010/ include Rho-kinase inhibitors such as (R)-trans-N-(pyridin 113957. 65 4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide and (R)- The invention is characterized in that glaucoma or ocular (+)-N-(1H-pyrrolo2,3-bipyridin-4-yl)-4-(1-aminoethyl) hypertension is prevented or treated by administering a com benzamide disclosed in WO 98/06433 and WO 00/09162, US 9,339,496 B2 5 6 Rho-kinase inhibitors such as 1-(5-isoquinolinesulfonyl)ho acid, and esters obtained by condensation of a carboxyl group mopiperazine and 1-(5-isoquinolinesulfonyl)-2-methylpip in the other preventive or therapeutic drug for glaucoma or erazine disclosed in WO97/23222 and Nature, 389, 990-994 ocular hypertension with an alcohol Such as methanol, etha (1997), Rho-kinase inhibitors such as (1-benzylpyrrolidin-3- nol, propanol or isopropyl alcohol. Specific examples of the yl)-(1H-indazol-5-yl)amine disclosed in WO 01/56988, Rho amide include amides obtained by condensation of an amino kinase inhibitors such as (1-benzylpiperidin-4-yl)-(1H-inda group in the present compound and/or the other preventive or zol-5-yl)amine disclosed in WO 02/100833, Rho-kinase therapeutic drug for glaucoma or ocular hypertension with a inhibitors such as N-2-(4-fluorophenyl)-6,7-dimethoxy-4- carboxylic acid such as acetic acid, propionic acid, isopropi quinazolinyl-N-(1H-indazol-5-yl)amine disclosed in WO onic acid, butyric acid, isobutyric acid or pivalic acid, and 02/076976, Rho-kinase inhibitors such as N-4-(1H-indazol 10 amides obtained by condensation of a carboxyl group in the 5-yl)-6,7-dimethoxy-N-2-pyridin-4-yl-quinazolin-2,4-di other preventive or therapeutic drug for glaucoma or ocular amine disclosed in WO 02/076977, and Rho-kinase inhibitors hypertension with an amine Such as methylamine, ethy Such as 4-methyl-5-(2-methyl-1,4-diazepan-1-sulfonyl)iso lamine, propylamine or isopropylamine. quinoline disclosed in WO99/64011. Among these, particu Further, the present compound and the other preventive or larly, (R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl)cyclohex 15 therapeutic drug for glaucoma or ocular hypertension in the anecarboxamide, (R)-(+)-N-(1H-pyrrolo2,3-bipyridin-4- invention may be in the form of a hydrate or a solvate. yl)-4-(1-aminoethyl)benzamide, 1-(5-isoquinolinesulfonyl) As the administration form, the present compound and the homopiperazine O 1-(5-isoquinolinesulfonyl)-2- other preventive or therapeutic drug for glaucoma or ocular methylpiperazine is preferred. hypertension may be administered in the form of a plurality of In the case where the present compound is combined with preparations obtained by separately formulating the respec two other preventive or therapeutic drugs for glaucoma or tive components (concomitant administration), and also, the ocular hypertension, specific examples of the two other pre respective components may be administered in the form of ventive or therapeutic drugs for glaucoma or ocular hyperten one preparation obtained by mixing the respective compo sion include timolol and , timolol and latano nents (combination drug). The case of the combination drug prost, and timolol and travoprost. 25 is preferred. Further, in the case where the present compound The present compound and the other preventive or thera is combined with a plurality of the other preventive or thera peutic drug for glaucoma or ocular hypertension in the inven peutic drugs for glaucoma or ocular hypertension, the respec tion include salts thereof. Such a salt is not particularly lim tive components may be concomitantly administered, or a ited as long as it is a pharmaceutically acceptable salt, and combination drug obtained by mixing arbitrary components examples of the salt include a salt with an inorganic acid, a salt 30 among the present compound and the other preventive or with an organic acid, a quaternary ammonium salt, a salt with therapeutic drugs for glaucoma or ocular hypertension and a halogen ion, a salt with an alkali metal, a salt with an the remaining component(s) may be concomitantly adminis alkaline earth metal, a metal salt, a salt with ammonia, and a tered, or a combination drug obtained by mixing all of the salt with an organic amine. Examples of the salt with an components may be formed. inorganic acid include salts with hydrochloric acid, hydro 35 The preparation of the invention can be administered orally bromic acid, hydroiodic acid, nitric acid, Sulfuric acid, phos or parenterally. The formulation of the preparation does not phoric acid or the like. Examples of the salt with an organic require a special technique, and can be achieved using a acid include Salts with acetic acid, oxalic acid, fumaric acid, widely used technique. Examples of the dosage form include maleic acid. Succinic acid, citric acid, tartaric acid, adipic an , an ophthalmic ointment, an injection, a tablet, a acid, gluconic acid, glucoheptonic acid, glucuronic acid, 40 capsule, a granule and a powder, and an eye drop or an terephthalic acid, methanesulfonic acid, lactic acid, hippuric ophthalmic ointment is preferred. acid, 1.2-ethanedisulfonic acid, isethionic acid, lactobionic In the case where the present compound and the other acid, oleic acid, pamoic acid, polygalacturonic acid, Stearic preventive or therapeutic drug for glaucoma or ocular hyper acid, tannic acid, tri fluoromethanesulfonic acid, benzene tension are separately formulated, the respective preparations Sulfonic acid, p-toluenesulfonic acid, lauryl Sulfate, methyl 45 can be prepared according to a known method. For example, Sulfate, napthalenesulfonic acid, Sulfosalicylic acid or the the preparation of the present compound can be prepared with like. Examples of the quaternary ammonium salt include Salts reference to the Preparation Example described in WO 2009/ with methyl bromide, methyl iodide or the like. Examples of 113600 or WO 2010/113957. As the preparation of the other the salt with a halogen ion include salts with a chloride ion, a preventive or therapeutic drug for glaucoma or ocular hyper bromide ion, an iodide ion or the like. Examples of the salt 50 tension, a preparation which has already been commercially with an alkali metal include Salts with , Sodium, potas available Such as dipivefrin, brimonidine, apraclonidine, sium or the like. Examples of the salt with an alkaline earth bunaZosin, timolol, befunolol, carteolol. nipradillol, betax metal include Salts with calcium, magnesium or the like. olol, levobunolol, metipranolol, pilocarpine, dorzolamide, Examples of the metal salt include salts with iron, zinc or the brinzolamide, acetazolamide, isopropyl unoprostone, latano like. Examples of the salt with an organic amine include Salts 55 prost, travoprost, bimatoprost, COSOPT (registered trade with triethylenediamine, 2-aminoethanol. 2.2-iminobis(etha mark) combination ophthalmic solution, Xalacom (registered nol), 1-deoxy-1-(methylamino)-2-D-Sorbitol, 2-amino-2- trademark) combination ophthalmic solution, or DuoTrav (hydroxymethyl)-1,3-propanediol, procaine, N,N-bis(phe (registered trademark) combination ophthalmic Solution, or a nylmethyl)-1,2-ethanediamine or the like. preparation similar thereto can also be used. The preparation In addition, the present compound and the other preventive 60 of a Rho-kinase inhibitor can be prepared with reference to ortherapeutic drug for glaucoma or ocular hypertension in the the Preparation Example described in the above-described invention also include derivatives thereof such as an ester and WO 00/09162, WO 97/23222 or the like. an amide. Specific examples of the ester include esters In the case where a single preparation comprising an arbi obtained by condensation of a hydroxyl group in the other trary combination among the present compound and a pre preventive or therapeutic drug for glaucoma or ocular hyper 65 ventive or therapeutic drug for glaucoma or ocular hyperten tension with a carboxylic acid Such as acetic acid, propionic sion is prepared, the preparation can be carried out in acid, isopropionic acid, butyric acid, isobutyric acid or pivalic accordance with a known method. US 9,339,496 B2 7 8 In the case where an eye drop is prepared, by adding the The dose of the nonselective sympathomimetic drug varies present compound or the other preventive ortherapeutic drug depending on the type of the drug, but it can be administered for glaucoma or ocular hypertension to purified water, a once or several times per day at a daily dose of generally from buffer or the like, followed by stirring, and then, adjusting the 1 to 5000 lug. More specifically, in the case of dipivefrin, a pH of the resulting mixture with a pH adjusting agent, daily dose of from 2 to 3000 ug is generally used, and such a whereby a desired eye drop can be prepared. Further, if nec dose can be appropriately increased or decreased depending essary, a widely used additive can be used in the eye drop, and on the age or symptoms of the patient or the like. Also for examples of the additive include a tonicity agent, a buffer, a other nonselective sympathomimetic drugs, the dose thereof Surfactant, a stabilizer and a preservative. Examples of the can be determined on the basis of the same criteria. The tonicity agent include sodium chloride and concentrated 10 concentration of the nonselective sympathomimetic drug in glycerin. Examples of the buffer include Sodium phosphate, an eye drop is not particularly limited, but in the case of Sodium acetate, boric acid, borax and citric acid. Examples of dipivefrin, an eye drop containing diplivefrin at a concentra the Surfactant include polyoxyethylene Sorbitan monooleate, tion of from 0.001 to 3 w/v %, preferably from 0.04 to 0.1 w/v. polyoxyl Stearate and polyoxyethylene hydrogenated castor %, more preferably 0.04 w/v % or 0.1 w/v % can be instilled oil. Examples of the stabilizer include sodium citrate and 15 once or several times per day. disodium edetate. Examples of the preservative include ben The dose of the C-receptor agonist varies depending on Zalkonium chloride and paraben. the type of the drug, but it can be administered once or several Any pH of the eye drop is permitted as long as it falls within times per day at a daily dose of generally from 2 to 3000 ug. the range that is acceptable for an ophthalmic preparation, but More specifically, in the case of brimonidine, a daily dose of is preferably in the range of from 4 to 8, more preferably in the from 2 to 1000 g is generally used and in the case of apra range of from 5 to 7. , a daily dose of from 20 to 3000 ug is generally In the case where an ophthalmic ointment is prepared, the used. Such a dose can be appropriately increased or decreased preparation can be carried out using a widely used base. depending on the age or symptoms of the patient or the like. Examples of the base include white petrolatum and liquid Also for other C-receptor agonists, the dose thereof can be paraffin. 25 determined on the basis of the same criteria. The concentra In the case where an oral preparation Such as a tablet, a tion of the C-receptor agonist in an eye drop is not particu capsule, a granule or a powder is prepared, the preparation larly limited, but, in the case of brimonidine, an eye drop can be carried out by adding an extender, a lubricant, a binder, containing brimonidine at a concentration of from 0.01 to 5 a disintegrant, a coating agent or a film forming agent as w/v %, preferably from 0.1 to 0.5 w/v %, more preferably 0.1 needed. Examples of the extender include lactose, crystalline 30 w/v '%, 0.15 w/v '%, 0.2 w/v '% or 0.5 w/v '% can be instilled cellulose, starch and a vegetable oil. Examples of the lubri once or several times per day. Further, in the case of apra cant include magnesium stearate and talc. Examples of the clonidine, an eye drop containing apraclonidine at a concen binder include hydroxypropyl cellulose and polyvinylpyr tration of from 0.01 to 5 w/v %, preferably from 0.5 to 1 w/v. rolidone. Examples of the disintegrant include carboxym %, more preferably 0.5 w/v% or 1 w/v% can be instilled once ethyl cellulose calcium and low-substituted hydroxypropyl 35 or several times per day. methyl cellulose. Examples of the coating agent include The dose of the C-receptorantagonist varies depending on hydroxypropylmethyl cellulose, macrogol and a silicone the type of the drug, but it can be administered once or several resin. Examples of the film forming agent include a gelatin times per day at a daily dose of generally from 1 to 5000 ug. film. More specifically, in the case ofbunaZosin, a daily dose of The dose of the present compound and the other preventive 40 from 2 to 3000 g is generally used, and Such a dose can be or therapeutic drug for glaucoma or ocular hypertension can appropriately increased or decreased depending on the age or be appropriately changed depending on the dosage form, symptoms of the patient or the like. Also for other C.-receptor severity of symptoms, age or body weight of the patient to antagonists, the dose thereof can be determined on the basis which the present compound or the drug is to be administered, of the same criteria. The concentration of the C-receptor administration route, medical opinion or the like. Hereinafter, 45 antagonist in an eye drop is not particularly limited, but, in the the case of instillation administration will be mainly case of bunaZosin, an eye drop containing bunaZosin at a described as an example. concentration of from 0.001 to 0.3 w/v '%, preferably from As for the dose of the present compound, in the case of an 0.003 to 0.03 w/v %, more preferably 0.01 w/v % can be eye drop, the present compound can be generally adminis instilled once or several times per day. tered once or several times per day at a daily dose of from 0.05 50 The dose of the B-receptor antagonist varies depending on to 500 ug, which can be appropriately increased or decreased the type of the drug, but it can be administered once or several depending on the age or symptoms of the patient or the like. times per day at a daily dose of generally from 5 to 5000 ug. The concentration of the present compound in the eye drop is More specifically, in the case of timolol, a daily dose of from not particularly limited, but an eye drop containing the 5 to 1500 ug is generally used, in the case of befunolol, a daily present compound at a concentration of from 0.00001 to 3 55 dose of from 10 to 2000 ug is generally used, in the case of w/v %, preferably from 0.0001 to 1 w/v %, more preferably carteolol, a daily dose of from 10 to 5000 ug is generally used, from 0.001 to 0.1 w/v %, further more preferably from 0.003 in the case of nipradillol, a daily dose of from 10 to 1250 ug is to 0.03 w/v '% can be instilled once or several times per day. generally used, in the case of betaxolol, a daily dose of from Incidentally, the concentration of the present compound in an 50 to 1000 ug is generally used, in the case of levobunolol, a eye drop may be calculated on the basis of the weight of the 60 daily dose of from 5 to 5000 ug is generally used, and in the present compound either in a free form or in the form of a salt case of metipranolol, a daily dose of from 5 to 5000 ug is (hereinafter, the same shall apply). Further, in the case of an generally used. Such a dose can be appropriately increased or ophthalmic ointment, the present compound can be generally decreased depending on the age or symptoms of the patient or administered once or several times at a daily dose of generally the like. Also for other B-receptor antagonists, the dose from 0.0001 to 30 mg, preferably from 0.0003 to 10 mg, more 65 thereof can be determined on the basis of the same criteria. preferably from 0.001 to 3 mg, further more preferably from The concentration of the B-receptor antagonist in an eye drop 0.003 to 1 mg. is not particularly limited, but, in the case of timolol, an eye US 9,339,496 B2 9 10 drop containing timolol at a concentration of from 0.01 to 5 The dose of the prostaglandin varies depending on the type w/v%, preferably from 0.1 to 0.5 w/v %, more preferably 0.1 of the drug, but it can be administered once or several times w/v 96, 0.25 w/v '% or 0.5 w/v '% can be instilled once or per day at a daily dose of generally from 0.1 to 1000 ug. More several times per day. Further, in the case of befunolol, an eye specifically, in the case of latanoprost, a daily dose of from 1 drop containing befunolol at a concentration of from 0.01 to to 5ug is generally used, in the case ofisopropyl unoprostone, 5 w/v %, preferably from 0.25 to 1 w/v %, more preferably 0.25 w/v '%, 0.5 w/v '% or 1 w/v '% can be instilled once or a daily dose of from 30 to 300 ug is generally used, in the case several times per day. In the case of carteolol, an eye drop of bimatoprost, a daily dose of from 2 to 30 Jug is generally containing carteolol at a concentration of from 0.01 to 5 w/v. used, and in the case of travoprost, a daily dose of from 0.5 to %, preferably from 1 to 2 w/v '%, more preferably 1 w/v '% or 10 5 Jug is generally used. Such a dose can be appropriately 2 w/v '% can be instilled once or several times per day. In the increased or decreased depending on the age or symptoms of case of nipradillol, an eye drop containing nipradillol at a the patient or the like. Also for other prostaglandins, the dose concentration of from 0.01 to 5 w/v %, preferably 0.25 w/v% thereof can be determined on the basis of the same criteria. can be instilled once or several times per day. In the case of 15 The concentration of the prostaglandin in an eye drop is not betaxolol, an eye drop containing betaxolol at a concentration particularly limited, but, in the case of latanoprost, an eye of from 0.01 to 5 w/v %, preferably from 0.25 to 0.5 w/v %, drop containing latanoprostata concentration of from 0.0001 more preferably 0.25 w/v% or 0.5 w/v% can be instilled once or several times per day. In the case of levobunolol, an eye to 5 w/v %, preferably from 0.0005 to 1 w/v %, more prefer drop containing levobunolol at a concentration of from 0.01 ably 0.001 to 0.1 w/v %, further more preferably 0.005 w/v% to 5 w/v %, preferably from 0.25 to 0.5 w/v %, more prefer can be instilled once or several times per day. In the case of ably 0.25 w/v % or 0.5 w/v % can be instilled once or several isopropyl unoprostone, an eye drop containing isopropyluno times per day. In the case of metipranolol, an eye drop con prostone at a concentration of from 0.001 to 5 w/v '%, pref taining metipranolol at a concentration of from 0.01 to 5 w/v. erably from 0.01 to 1 w/v %, more preferably 0.12 to 0.15 w/v %, preferably 0.3 w/v '% can be instilled once or several times per day. 25 %, further more preferably 0.12 w/v % or 0.15 w/v % can be The dose of the parasympathomimetic drug varies depend instilled once or several times per day. In the case of bimato ing on the type of the drug, but it can be administered once or prost, an eye drop containing bimatoprost at a concentration several times per day at a daily dose of generally from 5 to of from 0.0001 to 5 w/v %, preferably from 0.001 to 1 w/v %, 300000 ug. More specifically, in the case of pilocarpine, a 30 more preferably 0.01 to 0.03 w/v %, further more preferably daily dose of from 5 to 200000 ug is generally used, and such 0.01 w/v '% or 0.03 w/v '% can be instilled once or several a dose can be appropriately increased or decreased depending times per day. In the case of travoprost, an eye drop containing on the age or symptoms of the patient or the like. Also for travoprost at a concentration of from 0.0001 to 5 w/v '%, other parasympathomimetic drugs, the dose thereof can be determined on the basis of the same criteria. The concentra preferably 0.001 to 1 w/v% more preferably 0.004 w/v % can tion of the parasympathomimetic drug in an eye drop is not 35 be instilled once or several times per day. particularly limited, but, in the case of pilocarpine, an eye The dose of the Rho-kinase inhibitor varies depending on drop containing pilocarpine at a concentration of from 0.01 to the type of the drug, but it can be administered once or several 20 w/v%, preferably from 0.1 to 5 w/v%, more preferably 0.5 times per day at a daily dose of generally from 0.025 to 10000 w/v '%, 1 w/v '%, 2 w/v '%, 3 w/v 96 or 4 w/v '% can be instilled 40 ug, and Such a dose can be appropriately increased or once or several times per day. decreased depending on the age or symptoms of the patient or The dose of the carbonic anhydrase inhibitor varies the like. The concentration of the Rho-kinase inhibitor in an depending on the type of the drug, but it can be administered eye drop is not particularly limited, but an eye drop containing once or several times per day at a daily dose of generally from the Rho-kinase inhibitor at a concentration of from 0.0001 to 10 to 10000 ug. More specifically, in the case of dorzolamide, 45 5 w/v %, preferably from 0.001 to 1 w/v % can be instilled a daily dose of from 10 to 10000 ug is generally used and in once or several times per day. the case of brinzolamide, a daily dose of from 20 to 5000 ug Such a dose is applied when the present compound and the is generally used. Such a dose can be appropriately increased other preventive or therapeutic drug for glaucoma or ocular or decreased depending on the age or symptoms of the patient hypertension are concomitantly administered. In the case 50 where a combination drug comprising an arbitrary combina or the like. Also for other carbonic anhydrase inhibitors, the tion of the present compound and the other preventive or dose thereof can be determined on the basis of the same therapeutic drugs for glaucoma or ocular hypertension is criteria. The concentration of the carbonic anhydrase inhibi administered, a preparation in which the mixing ratios are tor in an eye drop is not particularly limited, but, in the case of appropriately selected so that the daily dose of each compo dorzolamide, an eye drop containing dorzolamide at a con 55 nent falls within the above-described dose range is prepared, centration of from 0.01 to 5 w/v %, preferably from 0.5 to 2 and the thus prepared combination preparation can be admin w/v%, more preferably 0.5 w/v %, 1 w/v% or 2 w/v % can be istered once or several times per day. instilled once or several times per day. Further, in the case of Hereinafter, preparation examples and pharmacological brinzolamide, an eye drop containing brinzolamide at a con tests will be shown, but these are for understanding the inven centration of from 0.01 to 5 w/v %, preferably from 0.1 to 2 60 tion better, and are not meant to limit the scope of the inven w/v '%, more preferably 1 w/v '% can be instilled once or tion. several times per day. Further, in the case of acetazolamide, an eye drop containing acetazolamide at a concentration of from PREPARATION EXAMPLES 0.01 to 5 w/v %, preferably from 1 to 5 w/v % can be used. 65 Incidentally, in the case where acetazolamide is orally admin Hereinafter, specific preparation examples of an eye drop istered, a daily dose of from 250 to 1000 mg can be used. and an ophthalmic ointment containing the present com US 9,339,496 B2 11 12 pound and the other preventive or therapeutic drug for glau Preparation Example 5 coma or ocular hypertension according to the invention will be shown. Preparation Example 1 5 Eye Drop (in 100 mL) Present compound 0.01 g Brinzolamide 1 g Sodium dihydrogen phosphate O.15 Eye Drop (in 100 mL) Glycerin ydrogen phosp Present compound 0.01 g 10 Polyoxyl 35 castor oil 1.7g Dipivefrin hydrochloride 0.04g Disodium edietate 0.05 g Sodium dihydrogen phosphate 0.15g Benzalkonium chloride 0.005g Glycerin C.S. Diluted hydrochloric acid C.S. Polyoxyl 35 castor oil 1.7g Sodium hydroxide C.S. Disodium edetate 0.05 g Purified water C.S. Benzalkonium chloride 0.005g 15 Diluted hydrochloric acid C.S. Sodium hydroxide C.S. Purified water C.S. Preparation Example 6 2O Preparation Example 2 Eye Drop (in 100 mL) Present compound 0.01 g Eye Drop (in 100 mL) 25 Dorzolamide hydrochloride 1 g Timolol maleate 0.5g Present compound 0.01 g Sodium dihydrogen phosphate 0.15g Timolol maleate 0.25g Glycerin C.S. Sodium dihydrogen phosphate 0.15g Polyoxyl 35 castor oil 1.7g Glycerin C.S. Disodium edietate 0.05 g Polyoxyl 35 castor oil 1.7g Benzalkonium chloride 0.005g Disodium edetate 0.05 g 30 Diluted hydrochloricydrochloric ac1acid C.S. Benzalkonium chloride 0.005g Sodium hydroxide C.S. Diluted hydrochloric acid C.S. Purified water C.S. Sodium hydroxide C.S. Purified water C.S.

35 Preparation Example 7 Preparation Example 3

40 Eye Drop (in 100 mL) Eye Drop (in 100 mL) Present compound 0.01 g Present compound 0.01 g Isopropyl unoprostone 0.12g Timolol maleate 0.5g Sodium dihydrogen phosphate 0.15g Sodium dihydrogen phosphate 0.15g Glycerin C.S. Glycerin C.S. Polyoxyl 35 castor oil 1.7g Polyoxyl 35 castor oil 1.7g 45 Disodium edietate 0.05 g Disodium edetate 0.05 g Benzalkonium chloride 0.005g Benzalkonium chloride 0.005g Diluted hydrochloric acid C.S. Diluted hydrochloric acid C.S. Sodium hydroxide C.S. Sodium hydroxide C.S. Purified water C.S. Purified water C.S. 50

Preparation Example 4 Preparation Example 8

55 Eye Drop (in 100 mL) Eye Drop (in 100 mL) Present compound 0.01 g Present compound 0.01 g Dorzolamide hydrochloride 0.5g Latanoprost 0.005g Sodium dihydrogen phosphate 0.15g 60 Sodium dihydrogen phosphate 0.15g Glycerin C.S. Glycerin C.S. Polyoxyl 35 castor oil 1.7g Polyoxyl 35 castor oil 1.7g Disodium edetate 0.05 g Disodium edietate 0.05 g Benzalkonium chloride 0.005g Benzalkonium chloride 0.005g Diluted hydrochloric acid C.S. Diluted hydrochloric acid C.S. Sodium hydroxide C.S. Sodium hydroxide C.S. Purified water C.S. 65 Purified water C.S. US 9,339,496 B2 13 14 Preparation Example 9 Preparation Example 13

Eye Drop (in 100 mL) 5 Eye Drop (in 100 mL) Present compound 0.01 g Present compound 0.01 g Bimatoprost 0.01 g Brimonidine tartrate 0.2g Sodium dihydrogen phosphate 0.15g Sodium dihydrogen phosphate 0.15g Glycerin C.S. Glycerin C.S. Polyoxyl 35 castor oil 1.7g Polyoxyl 35 castor oil 1.7g 10 Disodium edietate 0.05 g Disodium edetate 0.05 g Benzalkonium chloride 0.005g Benzalkonium chloride 0.005g Diluted hydrochloric acid C.S. Diluted hydrochloric acid C.S. Sodium hydroxide C.S. Sodium hydroxide C.S. Purified water C.S. Purified water C.S. 15 Preparation Example 14 Preparation Example 10 2O Eye Drop (in 100 mL) Eye Drop (in 100 mL) Present compound 0.01 g BunaZosin hydrochloride 0.01 g Present compound 0.01 g Sodium dihydrogen phosphate 0.15g Travoprost 0.004g 25 Glycerin C.S. Sodium dihydrogen phosphate 0.15g Polyoxyl 35 castor oil 1.7g Glycerin C.S. Disodium edietate 0.05 g Polyoxyl 35 castor oil 1.7g Benzalkonium chloride 0.005g Disodium edetate 0.05 g Diluted hydrochloric acid C.S. Benzalkonium chloride 0.005g Sodium hydroxide C.S. Diluted hydrochloric acid C.S. 30 Purified water C.S. Sodium hydroxide C.S. Purified water C.S. Preparation Example 15

Preparation Example 11 35 Eye Drop (in 100 mL) Present compound 0.01 g Eye Drop (in 100 mL) Pilocarpine hydrochloride 0.5g 40 Sodium dihydrogen phosphate 0.15g Present compound 0.01 g Glycerin C.S. Latanoprost 0.005g Polyoxyl 35 castor oil 1.7g Timolol maleate 0.5g Disodium edietate 0.05 g Sodium dihydrogen phosphate 0.15g Benzalkonium chloride 0.005g Glycerin C.S. Diluted hydrochloric acid C.S. Polyoxyl 35 castor oil 1.7g 45 Sodium hydroxide C.S. Disodium edetate 0.05 g Purified water C.S. Benzalkonium chloride 0.005g Diluted hydrochloric acid C.S. Sodium hydroxide C.S. Purified water C.S. Preparation Example 16 50

Preparation Example 12 Ophthalmic Ointment (in 100 g) Present compound 0.01 g 55 Timolol maleate 0.5g Liquid paraffin 10.0 g Eye Drop (in 100 mL) White petrolatum C.S. Present compound 0.01 g Brimonidine tartrate 0.1 g Sodium dihydrogen phosphate 0.15g 60 Preparation Example 17 Glycerin C.S. Polyoxyl 35 castor oil 1.7g Disodium edetate 0.05 g Benzalkonium chloride 0.005g Diluted hydrochloric acid C.S. Ophthalmic Ointment (in 100 g) Sodium hydroxide C.S. Purified water C.S. 65 Present compound 0.01 g Isopropyl unoprostone 0.12g US 9,339,496 B2 15 16 -continued (Test Method) An intraocular pressure lowering effect when the present Ophthalmic Ointment (in 100 g) compound and timolol were concomitantly administered was Liquid paraffin 10.0 g examined. As comparison Subjects, intraocular pressure low White petrolatum C.S. ering effects when the present compound or timolol was administered singly were also examined. As a control, the base and physiological saline were administered. Preparation Example 18 (Drugs and Animals Used in Test) 10 Present compound solution: a 0.001 w/v '% present com pound Solution (instillation amount: 50 LL) Ophthalmic Ointment (in 100 g) Timolol solution: a timolol eye drop (trade name: Timoptol Present compound 0.01 g (registered trademark) eye drop (0.5%), in which the active Latanoprost 0.005g 15 ingredient is timolol maleate having an equivalent timolol Liquid paraffin 10.0 g content of 0.5 w/v '%; instillation amount: 50 L). White petrolatum C.S. Experimental animal: Japanese white rabbit (strain: JW, Sex: male, six rabbits per group) In the above formulations, by changing the amount of the present compound to 0.001 g, 0.003 g, 0.03 g, 0.1 g, etc., and (Administration Method and Measurement Method) by changing the type and amount of the other preventive or 1 Concomitant Administration of Present Compound and therapeutic drug for glaucoma or ocular hypertension and/or Timolol the additive, an eye drop or an ophthalmic ointment having a (1) One drop of a 0.4% oxybuprocaine hydrochloride eye desired combination and a desired concentration can be pre drop (trade name: Benoxil (registered trademark) eye drop pared. 25 (0.4%)) was instilled into both eyes of each experimental Pharmacological Tests animal to effect local anesthesia. Example 1 (2) Intraocular pressure was measured immediately before administering the test compound Solution, and the measured In order to study the usefulness of the combination of the 30 intraocular pressure was defined as initial intraocular pres present compound with a B-receptor antagonist, an intraocu SUC. lar pressure lowering effect when the present compound and (3) The present compound solution was instilled into one timolol were concomitantly administered to experimental eye of each experimental animal (the other eye was not treated). A few minutes later, the timolol solution was animals (rabbits with normal intraocular pressure) was exam 35 ined. instilled into the same eye. (Preparation of Test Compound Solution) (4) At 2, 4 and 6 hours after instilling the present compound (1) Preparation of Base solution, one drop of the 0.4% oxybuprocaine hydrochloride To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% eye drop was instilled into the eyes for which intraocular disodium edetate/10% glycerin solution, 1 mL of a 1% ben 40 pressure was to be measured to effect local anesthesia, and Zalkonium chloride solution, 30 mL of purified water, and 50 then, intraocular pressure was measured. The intraocular mL of a 2% boric acid/0.2% sorbic acid solution were added pressure was measured in triplicate for each eye to obtain an and dissolved. After confirming that a solution was obtained, average of three measurements, which is shown as the result. an appropriate amount of a sodium hydroxide Solution or 2. Single Administration of Present Compound diluted hydrochloric acid was added thereto to adjust the pH 45 A test was carried out in the same manner as in the above of the preparation to around 6.5. Then, an appropriate amount described concomitant administration test except that physi of purified water was added thereto to make the total volume ological Saline was used in place of the timolol solution. 100 mL. (2) Preparation of Present Compound Solution 3 Single Administration of Timolol To 0.8 g of polyoxyl 35 castor oil, 0.001 g of the present 50 A test was carried out in the same manner as in the above compound was added, and then, 10 mL of a 0.5% disodium described concomitant administration test except that the edetate/10% glycerin solution, 1 mL of a 1% benzalkonium base was used in place of the present compound solution. chloride solution, 30 mL of purified water, and 50 mL of a 2% 4Control boric acid/0.2% sorbic acid solution were added thereto and A test was carried out in the same manner as in the above dissolved. After confirming that a solution was obtained, an 55 appropriate amount of a sodium hydroxide solution ordiluted described concomitant administration test except that the hydrochloric acid was added thereto to adjust the pH of the base was used in place of the present compound solution and preparation to around 6.5. Then, an appropriate amount of physiological saline was used in place of the timolol solution. purified water was added thereto to make the total volume 100 (Results and Discussion) mL. 60 An intraocular pressure lowering degree (change relative (3) Preparation of Physiological Saline to the average of the control group) at 4 hours after instillation Commercially available physiological saline (trade name: for each administration group is shown in Table 1. The Otsuka Normal Saline, obtained from Otsuka Pharmaceutical intraocular pressure lowering degree (change relative to the Factory, Inc.) was used as such. average of the control group) is expressed as an average of (4) Preparation of Timolol Solution 65 differences for 6 rabbits in each group between an average of A commercially available timolol eye drop was used as intraocular pressure change (AIOP) from the initial intraocu Such. lar pressure of the control group and AIOP of each individual. US 9,339,496 B2 17 18 TABLE 1. (4) Preparation of Latanoprost Solution A commercially available latanoprost eye drop was used as Intraocular pressure lowering Such. degree (change relative to average of control group) (Test Method) Administration group at 4 hours after instillation (mmHg) 5 An intraocular pressure lowering effect when the present Control group O.O compound and latanoprost were concomitantly administered Present compound single 1.6 was examined. As comparison Subjects, intraocular pressure administration group lowering effects when the present compound or latanoprost Timolol single administration group 2.3 Present compound and timolol 6.4 10 was administered singly were also examined. As a control, the concomitant administration base and physiological saline were administered. group (Drugs and Animals Used in Test) Present compound solution: a 0.0006 w/v '% present com As apparent from Table 1, the intraocular pressure lower pound Solution (instillation amount: 20 LL) ing degree (change relative to the average of the control 15 Latanoprost solution: a latanoprost eye drop (trade name: group) at 4 hours after instillation of the present compound Xalatan (registered trademark) eye drop (0.005%), (instilla and timolol concomitant administration group was larger tion amount: 20 LL)) than that of each drug single administration group, i.e., the Experimental animal: Cynomolgus monkey (sex: male, six present compound administration group or the timolol monkeys per group) administration group, and moreover, the intraocular pressure (Administration Method and Measurement Method) lowering degree was larger than the Sum of the intraocular 1 Concomitant Administration of Present Compound and pressure lowering degrees (changes relative to the average of Latanoprost the control group) at 4 hours after instillation caused by the (1) One drop of a 0.4% oxybuprocaine hydrochloride eye single administration of each drug. Accordingly, the effect of drop (trade name: Benoxil (registered trademark) eye drop the combination of the present compound with timolol was (0.4%)) was instilled into both eyes of each experimental Synergistic. animal to effect local anesthesia. From the above results, it was found that by combining the (2) Intraocular pressure was measured immediately before present compound with a B-receptor antagonist, a synergistic administering the test compound Solution, and the measured intraocular pressure was defined as initial intraocular pres intraocular pressure lowering effect is obtained. 30 SUC. Example 2 (3) The present compound solution was instilled into one eye of each experimental animal (the other eye was not In order to study the usefulness of a combination of the treated). A few minutes later, the latanoprost Solution was present compound with a prostaglandin, an intraocular pres 35 instilled into the same eye. Sure lowering effect when the present compound and latano (4) At 2, 4, 6 and 8 hours after instilling the present com prost were concomitantly administered to experimental ani pound solution, one drop of the 0.4% oxybuprocaine hydro mals (monkeys with normal intraocular pressure) was chloride eye drop was instilled into the eyes for which examined. intraocular pressure was to be measured to effect local anes (Preparation of Test Compound Solution) 40 thesia, and then, intraocular pressure was measured. The (1) Preparation of Base intraocular pressure was measured in triplicate for each eye to To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% obtain an average of three measurements, which is shown as disodium edetate/10% glycerin solution, 1 mL of a 1% ben the result. Zalkonium chloride solution, 30 mL of purified water, and 50 2. Single Administration of Present Compound mL of a 2% boric acid/0.2% sorbic acid solution were added 45 A test was carried out in the same manner as in the above and dissolved. After confirming that a solution was obtained, described concomitant administration test except that physi an appropriate amount of a sodium hydroxide Solution or ological Saline was used in place of the latanoprost solution. diluted hydrochloric acid was added thereto to adjust the pH 3 Single Administration of Latanoprost of the preparation to around 6.5. Then, an appropriate amount A test was carried out in the same manner as in the above of purified water was added thereto to make the total volume 50 described concomitant administration test except that the 100 mL. base was used in place of the present compound solution. (2) Preparation of Present Compound Solution 4Control To 0.8g of polyoxyl 35 castor oil, 0.0006 g of the present A test was carried out in the same manner as in the above compound was added, and then, 10 mL of a 0.5% disodium described concomitant administration test except that the edetate/10% glycerin solution, 1 mL of a 1% benzalkonium 55 base was used in place of the present compound solution and chloride solution, 30 mL of purified water, and 50 mL of a 2% physiological Saline was used in place of the latanoprost boric acid/0.2% sorbic acid solution were added thereto and Solution. dissolved. After confirming that a solution was obtained, an (Results and Discussion) appropriate amount of a sodium hydroxide solution ordiluted An intraocular pressure lowering degree (change relative hydrochloric acid was added thereto to adjust the pH of the 60 to the average of the control group) at 8 hours after instillation preparation to around 6.5. Then, an appropriate amount of for each administration group is shown in Table 2. The purified water was added thereto to make the total volume 100 intraocular pressure lowering degree (change relative to the mL. average of the control group) is expressed as an average of (3) Preparation of Physiological Saline differences for 6 monkeys in each group between an average Commercially available physiological saline (trade name: 65 of intraocular pressure change (AIOP) from the initial Otsuka Normal Saline, obtained from Otsuka Pharmaceutical intraocular pressure of the control group and AIOP of each Factory, Inc.) was used as such. individual. US 9,339,496 B2 19 20 TABLE 2 (Test Method) Intraocular pressure lowering An intraocular pressure lowering effect when the present degree (change relative to compound and brimonidine were concomitantly adminis average of control group) tered was examined. As comparison Subjects, intraocular Administration group at 8 hours after instillation (mmHg) 5 pressure lowering effects when the present compound or bri Control group O.O monidine was administered singly were also examined. As a Present compound single 1.6 control, the base and physiological Saline were administered. administration group Latanoprost single administration 1.5 (Drugs and Animals Used in Test) group 10 Present compound solution: a 0.0006 w/v '% present com Present compound and latanoprost 3.3 pound Solution (instillation amount: 20 LL) concomitant administration group Brimonidine Solution: a brimonidine eye drop (trade name: ALPHAGAN (registered trademark) P (0.15%), (instillation As apparent from Table 2, the intraocular pressure lower amount: 20 LL)) ing degrees at 8 hours after instillation of the present com 15 Experimental animal: Cynomolgus monkey (sex: male, six pound and latanoprost concomitant administration group was monkeys per group) larger than that of each drug single administration group, i.e., the present compound administration group or the latanoprost (Administration Method and Measurement Method) administration group, and moreover, was larger than the Sum 1 Concomitant Administration of Present Compound and of the intraocular pressure lowering degrees (changes relative Brimonidine to the average of the control group) at 8 hours after instillation (1) One drop of a 0.4% oxybuprocaine hydrochloride eye caused by the single administration of each drug. Accord drop (trade name: Benoxil (registered trademark) eye drop ingly, the effect of the combination of the present compound (0.4%)) was instilled into both eyes of each experimental with latanoprost was synergistic. animal to effect local anesthesia. From the above results, it was found that by combining the 25 (2) Intraocular pressure was measured immediately before present compound with a prostaglandin, a synergistic administering the test compound Solution, and the measured intraocular pressure lowering effect is obtained. intraocular pressure was defined as initial intraocular pres Example 3 SUC. 30 (3) The present compound solution was instilled into one In order to study the usefulness of a combination of the eye of each experimental animal (the other eye was not present compound with an O-receptoragonist, an intraocular treated). A few minutes later, the brimonidine solution was pressure lowering effect when the present compound and instilled into the same eye. brimonidine were concomitantly administered to experimen (4) At 2, 4, 6 and 8 hours after instilling the present com tal animals (monkeys with normal intraocular pressure) was 35 pound solution, one drop of the 0.4% oxybuprocaine hydro examined. chloride eye drop was instilled into the eyes for which (Preparation of Test Compound Solution) intraocular pressure was to be measured to effect local anes (1) Preparation of Base thesia, and then, intraocular pressure was measured. The To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% intraocular pressure was measured in triplicate for each eye to disodium edetate/10% glycerin solution, 1 mL of a 1% ben 40 obtain an average of three measurements, which is shown as Zalkonium chloride solution, 30 mL of purified water, and 50 the result. mL of a 2% boric acid/0.2% sorbic acid solution were added 2. Single Administration of Present Compound and dissolved. After confirming that a solution was obtained, A test was carried out in the same manner as in the above an appropriate amount of a sodium hydroxide Solution or described concomitant administration test except that physi diluted hydrochloric acid was added thereto to adjust the pH 45 ological Saline was used in place of the brimonidine solution. of the preparation to around 6.5. Then, an appropriate amount of purified water was added thereto to make the total volume 3 Single Administration of Brimonidine 100 mL. A test was carried out in the same manner as in the above (2) Preparation of Present Compound Solution described concomitant administration test except that the To 0.8g of polyoxyl 35 castor oil, 0.0006 g of the present 50 base was used in place of the present compound solution. compound was added, and then, 10 mL of a 0.5% disodium 4Control edetate/10% glycerin solution, 1 mL of a 1% benzalkonium A test was carried out in the same manner as in the above chloride solution, 30 mL of purified water, and 50 mL of a 2% described concomitant administration test except that the boric acid/0.2% sorbic acid solution were added thereto and base was used in place of the present compound solution and dissolved. After confirming that a solution was obtained, an 55 physiological saline was used in place of the brimonidine appropriate amount of a sodium hydroxide solution ordiluted Solution. hydrochloric acid was added thereto to adjust the pH of the preparation to around 6.5. Then, an appropriate amount of (Results and Discussion) purified water was added thereto to make the total volume 100 An intraocular pressure lowering degree (change relative mL. 60 to the average of the control group) at 2 hours after instillation (3) Preparation of Physiological Saline for each administration group is shown in Table 3. The Commercially available physiological saline (trade name: intraocular pressure lowering degree (change relative to the Otsuka Normal Saline, obtained from Otsuka Pharmaceutical average of the control group) is expressed as an average of Factory, Inc.) was used as such. differences for 6 monkeys in each group between an average (4) Preparation of Brimonidine Solution 65 of intraocular pressure change (AIOP) from the initial A commercially available brimonidine eye drop was used intraocular pressure of the control group and AIOP of each as such. individual. US 9,339,496 B2 21 22 TABLE 3 (Test Method) An intraocular pressure lowering effect when the present Intraocular pressure lowering degree (change relative to compound and brinzolamide were concomitantly adminis average of control group) tered was examined. As comparison Subjects, intraocular Administration group at 2 hours after instillation (mmHg) 5 pressure lowering effects when the present compound or brin Control group O.O Zolamide was administered singly were also examined. As a Present compound single 2.6 control, the base and physiological Saline were administered. administration group (Drugs and Animals Used in Test) Brimonidine single administration 1.8 group 10 Present compound solution: a 0.0006 w/v '% present com Present compound and brimonidine 5.3 pound Solution (instillation amount: 20 LL) concomitant administration group Brinzolamide Suspension: a brinZolamide ophthalmic Sus pension (trade name: AZopt (registered trademark) Oph As apparent from Table 3, the intraocular pressure lower thalmic Suspension (1%), (instillation amount: 20 uL)) ing degrees at 2 hours after instillation of the present com 15 Experimental animal: Cynomolgus monkey (sex: male, pound and brimonidine concomitant administration group five or six monkeys per group) was larger than that of each drug single administration group, (Administration Method and Measurement Method) i.e., the present compound administration group or the bri 1 Concomitant Administration of Present Compound and monidine administration group, and moreover, was larger Brinzolamide than the Sum of the intraocular pressure lowering degrees (changes relative to the average of the control group) at 2 (1) One drop of a 0.4% oxybuprocaine hydrochloride eye hours after instillation caused by the single administration of drop (trade name: Benoxil (registered trademark) eye drop each drug. Accordingly, the effect of the combination of the (0.4%)) was instilled into both eyes of each experimental present compound with brimonidine was synergistic. animal to effect local anesthesia. From the above results, it was found that by combining the 25 (2) Intraocular pressure was measured immediately before present compound with an O-receptor agonist, a synergistic administering the test compound Solution, and the measured intraocular pressure lowering effect is obtained. intraocular pressure was defined as initial intraocular pres SUC. Example 4 (3) The present compound solution was instilled into one 30 eye of each experimental animal (the other eye was not In order to study the usefulness of a combination of the treated). A few minutes later, the brinzolamide Suspension present compound with a carbonic anhydrase inhibitor, an was instilled into the same eye. intraocular pressure lowering effect when the present com (4) At 2, 4, 6 and 8 hours after instilling the present com pound and brinzolamide were concomitantly administered to pound solution, one drop of the 0.4% oxybuprocaine hydro experimental animals (monkeys with normal intraocular 35 chloride eye drop was instilled into the eyes for which pressure) was examined. intraocular pressure was to be measured to effect local anes (Preparation of Test Compound Solution) thesia, and then, intraocular pressure was measured. The (1) Preparation of Base intraocular pressure was measured in triplicate for each eye to To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% obtain an average of three measurements, which is shown as disodium edetate/10% glycerin solution, 1 mL of a 1% ben 40 the result. Zalkonium chloride solution, 30 mL of purified water, and 50 mL of a 2% boric acid/0.2% sorbic acid solution were added 2. Single Administration of Present Compound and dissolved. After confirming that a solution was obtained, A test was carried out in the same manner as in the above an appropriate amount of a sodium hydroxide Solution or described concomitant administration test except that physi diluted hydrochloric acid was added thereto to adjust the pH 45 ological saline was used in place of the brinzolamide Suspen of the preparation to around 6.5. Then, an appropriate amount Sion. of purified water was added thereto to make the total volume 3 Single Administration of Brinzolamide 100 mL. A test was carried out in the same manner as in the above (2) Preparation of Present Compound Solution described concomitant administration test except that the To 0.8g of polyoxyl 35 castor oil, 0.0006 g of the present 50 base was used in place of the present compound solution. compound was added, and then, 10 mL of a 0.5% disodium 4Control edetate/10% glycerin solution, 1 mL of a 1% benzalkonium A test was carried out in the same manner as in the above chloride solution, 30 mL of purified water, and 50 mL of a 2% described concomitant administration test except that the boric acid/0.2% sorbic acid solution were added thereto and base was used in place of the present compound solution and dissolved. After confirming that a solution was obtained, an 55 physiological saline was used in place of the brinzolamide appropriate amount of a sodium hydroxide solution ordiluted Suspension. hydrochloric acid was added thereto to adjust the pH of the preparation to around 6.5. Then, an appropriate amount of (Results and Discussion) purified water was added thereto to make the total volume 100 An intraocular pressure lowering degree (change relative mL. 60 to the average of the control group) at 4 hours after instillation (3) Preparation of Physiological Saline for each administration group is shown in Table 4. The Commercially available physiological saline (trade name: intraocular pressure lowering degree (change relative to the Otsuka Normal Saline, obtained from Otsuka Pharmaceutical average of the control group) is expressed as an average of Factory, Inc.) was used as such. differences for 5 or 6 monkeys in each group between an (4) Preparation of brinzolamide suspension 65 average of intraocular pressure change (AIOP) from the initial A commercially available brinzolamide eye drop was used intraocular pressure of the control group and AIOP of each as such. individual. US 9,339,496 B2 23 24 TABLE 4 nyl)aminomethyl pyridin-2-ylamino)acetate may be in the form of a salt thereof, and the timolol may be in the form of a Intraocular pressure lowering salt thereof. degree (change relative to average 7. The composition according to claim 6, wherein the com of control group) position is obtained by mixing isopropyl (6-4-(pyrazol-1- Administration group at 4 hours after instillation (mmHg) 5 yl)benzyl (pyridin-3-ylsulfonyl) aminomethylpyridin-2- Control group O.O ylamino)acetate or a salt thereof and timolol or a salt thereof. Present compound single 2.5 8. The composition according to claim 6, wherein the com administration group position is obtained by providing a separate preparation for Brinzolamide single administration 1.6 group 10 each of isopropyl (6-4-(pyrazol-1-yl)benzyl (pyridin-3-yl Present compound and brinzolamide 3.2 sulfonyl)aminomethylpyridin-2-ylamino)acetate or a salt concomitant administration group thereof and timololora Salt thereof, for a concomitant admin istration. 9. The composition according to claim 6, wherein the As apparent from Table 4, the intraocular pressure lower timolol is in the form of timolol maleate. ing degree at 4 hours after instillation of the present com 15 10. The composition according to claim 9, wherein the pound and brinzolamide concomitant administration group timolol moiety of the timolol maleate is in a concentration of was larger than that of each drug single administration group, 0.5 W/V 9%. i.e., the present compound administration group or the brin 11. A method for treating glaucoma or ocular hypertension Zolamide administration group. or for lowering interocular pressure comprising (i) adminis From the above results, it was found that by combining the tering to a patient in need thereofa pharmaceutically effective present compound with a carbonic anhydrase inhibitor, a amount of a composition comprising 0.001 to 0.1 w/v '% of potent intraocular pressure lowering effect is obtained. isopropyl (6-4-(pyrazol-1-yl)benzyl (pyridin-3-ylsulfo What is claimed is: nyl)aminomethylpyridin-2-ylamino)acetate and 0.1 to 0.5 1. A composition for treating glaucoma or ocular hyper w/v '% of timolol or (ii) concomitantly individually adminis tension comprising 0.001 to 0.1 w/v 9% of isopropyl (6-4- 25 tering to a patient in need thereof 0.001 to 0.1 w/v '% of (pyrazol-1-yl)benzyl (pyridin-3-ylsulfonyl) isopropyl (6-4-(pyrazol-1-yl)benzyl (pyridin-3-ylsulfo aminomethylpyridin-2-ylamino)acetate and 0.1 to 0.5 w/v. nyl)aminomethyl pyridin-2-ylamino)acetate and 0.1 to 0.5 % of timolol, in a combined pharmaceutically effective w/v '% of timolol, in a combined pharmaceutically effective amount, wherein the isopropyl (6-4-(pyrazol-1-yl)benzyl amount, wherein the isopropyl (6-4-(pyrazol-1-yl)benzyll (pyridin-3-ylsulfonyl)aminomethylpyridin-2-ylamino)ac 30 (pyridin-3-ylsulfonyl)aminomethyl pyridin-2-ylamino)ac etate may be in the form of a salt thereof, and the timolol may etate may be in the form of a salt thereof, and the timolol may be in the form of a salt thereof. be in the form of a salt thereof. 2. The composition according to claim 1, wherein the com 12. The method according to claim 11, wherein the method position is obtained by mixing isopropyl (6-4-(pyrazol-1- is for treating glaucoma or ocular hypertension. yl)benzyl (pyridin-3-ylsulfonyl) aminomethylpyridin-2- 35 13. The method according to claim 12, wherein the glau ylamino)acetate or a salt thereof and timolol or a salt thereof. coma is a condition selected from the group consisting of 3. The composition according to claim 1, wherein the com primary open angle glaucoma, normal tension glaucoma, position is obtained by providing a separate preparation for hypersecretion glaucoma, acute angle-closure glaucoma, each of isopropyl (6-4-(pyrazol-1-yl)benzyl (pyridin-3-yl chronic angle-closure glaucoma, combined-mechanism sulfonyl)aminomethylpyridin-2-ylamino)acetate or a salt 40 glaucoma, steroid-induced glaucoma, amyloid glaucoma, thereofand timololora Salt thereof, for a concomitant admin neovascular glaucoma, malignant glaucoma, capsular glau istration. coma and plateau iris Syndrome. 4. The composition according to claim 1, wherein the 14. The method according to claim 11, wherein the timolol timolol is in the form of timolol maleate. is in the form of timolol malteate. 5. The composition according to claim 4, wherein the 45 15. The method according to claim 12, wherein the timolol timolol moiety of the timolol maleate is in a concentration of is in the form of timolol maleate. 0.5 W/V 9%. 16. The method according to claim 14, wherein the timolol 6. A composition for lowering intraocular pressure com moiety of the timolol maleate is in a concentration of 0.5 w/v. prising 0.001 to 0.1 w/v% ofisopropyl (6-4-(pyrazol-1-yl) %. benzyl (pyridin-3-ylsulfonyl)aminomethyl pyridin-2- 50 17. The method according to claim 15, wherein the timolol ylamino)acetate and 0.1 to 0.5 w/v '% of timolol, in a moiety of the timolol maleate is in a concentration of 0.5 w/v. combined pharmaceutically effective amount, wherein the %. isopropyl (6-4-(pyrazol-1-yl)benzyl (pyridin-3-ylsulfo