US 20090082338A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0082338A1 Mizuno et al. (43) Pub. Date: Mar. 26, 2009 (54) PREVENTIVE OR REMEDY FOR (86). PCT No.: PCT/UP2006/312266 GLAUCOMA S371 (c)(1), 2), (4) Date: Dec. 19, 2007 (75) Inventors: Ken Mizuno, Tokyo (JP); Jiro (2), (4) . Matsumoto, Saitama (JP) (30) Foreign Application Priority Data Jun. 21, 2005 (JP) ................................. 2005-180535 Correspondence Address: Publication Classification OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, P.C. (51) Int. Cl. 194O DUKE STREET A6II 3/55 (2006.01) ALEXANDRIA, VA 22314 (US) A63/496 (2006.01) A6IP27/06 (2006.01) - 0 (52) U.S. Cl. .................................... 514/218: 514/253.05 (73) Assignee: so Co., Ltd., Nagoya-shi, Aichi (57) ABSTRACT There is provided a preventive for glaucoma or a preventive or a remedy for ocular hypertension, with a potent ocular (21) Appl. No.:y x- - - 11A993,1019 hypotensivey effect and prolongedyp duration thereof.p A preven tive or a remedy for glaucoma comprising a Rho kinase (22) PCT Filed: Jun. 20, 2006 inhibitor and an C. blocker in combination. Patent Application Publication Mar. 26, 2009 US 2009/0082338A1 Fig. 1 S S 5 Y D f CO 1. n n1 C - d O: H Z l O CD 2 Y S O - Fig. 2 TIME US 2009/0082338 A1 Mar. 26, 2009 PREVENTIVE OR REMEDY FOR nism of action (Patent Documents 1 and 2). Rho kinase GLAUCOMA inhibitors lower IOP by promoting aqueous outflow from the trabecular outflow pathway (Non-patent Document 2), and it TECHNICAL FIELD is further suggested that this action may be attributed to changes in the cytoskeleton of a trabecular meshwork cells 0001. The present invention relates to a preventive or a (Non-patent Documents 2 and 3). remedy for glaucoma or ocular hypertension. 0008. In the treatment of glaucoma and ocular hyperten Sion, drugs having an ocular hypotensive action are used in BACKGROUND ART combination to enhance the additive ocular hypotensive 0002 Glaucoma is a disease characterized by the elevation effects. For example, combination use of a prostaglandin and of intraocular pressure (IOP) due to various pathogenesis a sympathetic nerve blocker (Patent Document 3), or a com leads to damage and atrophy of the optic nerve resulting in the bination of some drugs having an ocular hypotensive action abnormal visual field, and thus visual acuity is gradually (Patent Document 4), and the like have been reported. Fur reduced. Since the optic nerve does not recover once atrophy thermore, combination use of a Rho kinase inhibitor and a B occurs, glaucoma is a refractory disease in that not only vision blocker (Patent Document 5) and a remedy for glaucoma is lost if glaucoma is untreated, but also the condition is only comprising a Rho kinase inhibitor and a prostaglandin in maintained even after Successful treatment, and recovery can combination (Patent Document 6) have also been reported. not be expected. Furthermore, ocular hypertension, which 0009. However, the above-mentioned known remedies may lead to development of glaucoma over a long time and therapies for glaucoma and ocular hypertension are far although in the absence of visual field defects, also has a from satisfactory in view of the potency of the ocular similar risk. hypotensive effect and the duration of action. In particular, it 0003 Glaucoma is classified into three types: congenital is more difficult to lower normal IOP in patients with normal (developmental) glaucoma, secondary glaucoma, and pri tension glaucoma rather than lower elevated IOP. The above mary glaucoma. Patients with congenital (developmental) mentioned existing drugs and combinations thereof have glaucoma are born with growth deficiency of the iridocorneal limitations in the treatment of normal tension glaucoma, and angle, and obstruction of the aqueous outflow causes this type enhancement of the ocular hypotensive action is needed in the of glaucoma. Secondary glaucoma arises as a result of inflam clinical setting. mation or injury and is caused by Such as uveitis or ocular 0010 Under such circumstances, there has been no report trauma as well as hemorrhage due to diabetes, long-term use on glaucoma treatment using a Rho kinase inhibitor and a of steroid hormones for the treatment of other diseases, and selective sympathetic nerve C. receptor blocking agent in the like. Primary glaucoma is a generic name of glaucomas of combination, and there has been no description about the types with unclear causes and occurs most commonly of cooperative effect of Such a combination. glaucomas, with a high incidence among middle aged and O011 Patent Document 1 WO00/09162 elderly persons. Primary glaucoma and secondary glaucoma 0012 Patent Document 2.JP-A-11-349482 are further Subdivided into two types, open-angle glaucoma (0013 Patent Document 3 Japanese Patent No. 2726672 and angle-closure glaucoma, depending on the blockage of 0014 Patent Document 4 WO02/38158 the aqueous outflow. While many patients develop normal 00.15 Patent Document 5 JP-A-2004-182723 tension glaucoma in the absence of elevated IOP, the primary 0016 Patent Document 6.JP-A-2004-107335 aim of glaucoma treatment is to lower the IOP 0017 Non-patent Document 1 Journal of Japanese Oph 0004 For the treatment of glaucoma, laser treatment (laser thalmological Society, 94(8), 762-768 (1990) trabeculoplasty), Surgical therapy (trabeculectomy or trabe (0018 Non-patent Document 2 IOVS, 42(1), 137-144 culotomy), or the like is performed when IOP cannot be (2001) controlled with a drug or a patient with angle-closure glau 0019 Non-patent Document 3) IOVS, 42(5), 1029-1037 coma has an acute glaucoma attack, but drug therapy is used (2001) as the first line therapy. 0005 Drugs used in the drug therapy of glaucoma include DISCLOSURE OF THE INVENTION sympathetic nerve stimulants (nonselective stimulants such 0020. An object of the present invention is to provide a as epinephrine and C stimulants such as apraclonidine), sym preventive or a remedy for glaucoma or ocular hypertension pathetic nerve blockers (B blockers such as timolol. with a potent ocular hypotensive effect and a prolonged dura befunolol, carteolol, nipradillol, betaxolol, levobunolol, and tion of action. metipranolol and C. blockers such as bunaZosin hydrochlo 0021. The inventors of the present invention conducted ride), parasympathetic nerve agonists (pilocarpine, etc.), car various researches in order to achieve the foregoing object. As bonic anhydrase inhibitors (acetazolamide, etc.), prostaglan a result, we have found that a potent ocular hypotensive effect dins (isopropyl unoprostone, latanoprost, travoprost, is exerted by administering a Rho kinase inhibitor and an O. bimatoprost, etc.), and so forth. blocker in combination, and the duration of action is pro 0006. Of these, bunaZosin hydrochloride is a drug first longed. developed as an agent for selectively blocking sympathetic 0022 Specifically, the present invention relates to the fol nerve C. receptors, unlike existing remedies for glaucoma. As lowings. its mechanism of action, bunaZosinhydrochloride locally acts 0023, 1) A preventive or a remedy for glaucoma compris on the eyes by instillation and lowers IOP by promoting ing a Rho kinase inhibitor and an O. blocker in combina aqueous outflow from the uveoscleral outflow pathway (Non tion. patent Document 1). 0024. 2) A preventive or a remedy for ocular hypertension 0007 Meanwhile, Rho kinase inhibitors have been found comprising a Rho kinase inhibitor and an C. blocker in as candidate remedies for glaucoma based on a novel mecha combination. US 2009/0082338 A1 Mar. 26, 2009 0025, 3) Use of a Rho kinase inhibitor and an C. blocker in a Rhokinase inhibiting action and can be produced by known combination for production of a preventive or a remedy for methods such as, for example, the method described in glaucoma. WO99f2O62O. 0026 4) Use of a Rhokinase inhibitor and an O blocker in 0036 Hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-di combination for production of a preventive or a remedy for azepine can be produced by known methods such as, for ocular hypertension. example, the method described in JP-A-61-227581 and, fur 0027 5) A method for preventing or treating glaucoma, ther, can be purchased and used as a drug (Eril.R S Injection wherein the method comprises administratinga Rhokinase nonproprietary name: fasudil hydrochloride hydrate, Asahi inhibitor and an O blocker in combination. Kasei Pharma). 0028 6) A method for preventing or treating ocular hyper 0037. Furthermore, Y-39983 is known to lower IOP in tension, wherein the method comprises administrating a rabbits with normal IOP from 1 hour after instillation, shows Rho kinase inhibitor and an C. blocker in combination. the maximum ocular hypotensive effect at 2 to 4 hours after 0029. According to the present invention, a preventive or a instillation, and has a potent action dependent on the concen remedy for glaucoma or ocular hypertension with a potent tration, with the maximum IOP reduction of 15 mmHg at a ocular hypotensive effect and a prolonged duration of action concentration of 0.1% (BIO Clinica, 1713), 1191-1194 can be provided. 2002: The 4th Int. Symp. Ocular Pharmacol. Pharm. Feb. 28, 2002, Seville 2002: 2: Annu. Meet. Assoc. Res. Vision BRIEF DESCRIPTION OF THE DRAWINGS Ophthalmol. May 1, 2005, Fort Lauderdale 2005: Abst. 3787/B145). 0030 FIG. 1 is a graph showing changes in IOP over time 0038 Examples of salts of (S)-(-)-1-(4-fluoro-5-iso in each treatment group. IOP is shown as a change from the quinolinesulfonyl)-2-methyl-1,4-homopiperazine and initial IOP (meantstandard error). O, bunaZosin alone group; hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine , (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1, include pharmaceutically acceptable salts such as salts of 4-homopiperazine alone group; A, bunaZosin plus (S)-(-)-1- inorganic acids Such as hydrochloric acid, Sulfuric acid, nitric (4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopip acid, hydrofluoric acid, and hydrobromic acid and salts of erazine group.