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(12) United States Patent (10) Patent No.: US 9,339,496 B2 Kirihara Et Al

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(12) United States Patent (10) Patent No.: US 9,339,496 B2 Kirihara Et Al 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 GLAUCOMA COMPRISINGA None SULFONAMIDE 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. Timolol 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 medications.” 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 intraocular pressure. 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 tafluprost 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 brimonidine), a sympatholytic drug (a 35 glaucoma or ocular hypertension (with the proviso that taflu B-receptor antagonist Such as timolol, befunolol, carteolol. prost is excluded). nipradillol, betaxolol, levobunolol or metipranolol, or an (3) The preventive or therapeutic agent or the intraocular C-receptor antagonist Such as bunaZosin hydrochloride), a pressure lowering agent according to the above (1) or (2), parasympathomimetic drug (such as pilocarpine), a carbonic wherein the other preventive ortherapeutic drug for glaucoma anhydrase inhibitor (such as acetazolamide), a prostaglandin 40 or ocular hypertension (with the proviso that tafluprost is (such as isopropyl unoprostone, latanoprost, travoprost or excluded) is one or more preventive or therapeutic agents bimatoprost) 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 sympathomimetic drug 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, brinzolamide 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.
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