TW200301128A - Ophthalmic composition for the treatment of glaucoma, ocular hypertension, ocular ischemia and related disorders - Google Patents

Abstract

Isoquinolinesulfonyl compounds are used in ophthalmic compositions to treat glaucoma or other ischemia-borne disorders such as retinopathies or optic neuropathies. These compounds vasodilate ocular vessels, lower IOP and prevent or reduce the progress of visual field loss.

Description

200301128 发明. Description of the invention [Technical field to which the invention belongs] The present invention relates generally to the field of ophthalmology. In particular, the present invention relates to the use of isoquinoline sulfonyl compounds for the treatment of ocular diseases, including loss of vision and glaucoma. These compounds can reduce intraocular pressure (JOP) and produce ocular vasodilation.

Jt Background of the Invention Although the basic causes of glaucoma are not fully understood at present, glaucoma is characterized by damage to the optic nerve head, accompanied by a reduction of 10 in the normal field of vision. A risk factor for glaucomatous vision loss is increased IOP. In the past, glaucoma has been treated with drugs and / or surgical treatments in the past to reduce the increased IOP. Although the increased Iop is positively correlated with the rate of progression of visual field impairment in glaucoma, visual field loss may also occur at levels of IQP that are considered to be within the normal range. Therefore, 15 ’other factors, alone or accompanied by increased IOP, may affect the occurrence and rate of progression of visual field loss. • In order to maintain normal health and functioning, the retina and optic nerve head fibers (neurons) must receive proper nutrients and oxygen supply, and the carbon dioxide and other metabolic waste generated by them must be removed. This item 20 is performed by the microcirculation of these tissues. As used herein, "microcirculation" refers to the flow of blood through nutrient vessels, removing nutrients, gases, and wastes through their walls. Blood flow to the eye system depends on perfusion pressure (system blood pressure reduces IOP). Some tissues have the ability to maintain blood flow (ie, self-regulating) within a range of perfusion pressures, which increases the systemic blood pressure. 6 200301128 玖, description of the invention can contribute to the reduction of blood organ cavity diameter. Conversely, a decrease in systemic pressure in their tissues may cause vasodilation; however, there is still a point where perfusion pressure drops to the point where the vasodilation is maximized. Any further reduction in perfusion pressure results in a reduction in blood flow to the tissue (ischemia). Ischemia may also result from obstruction, vasospasm, increased vascular resistance, or other microcirculation disturbances. Long-term local hemorrhage may eventually lead to tissue necrosis or apotosis of the optic mesangial cells. In the case of the optic nerve head or retina, a state of visual dysfunction may occur before neurons die. Therefore, if ischemia is included in the ophthalmic nerve fiber death caused by glaucoma or some other ischemic retinopathy or ophthalmic nerve disease, its prevention may protect neurons from death or impaired function. . The vasodilating and antispasmodic activity of certain isoquinoline sulfonium compounds has been described relative to non-ocular tissues. See, for example, EP 0 187 371 B1 corresponding to U.S. Patent No. 4,678,783. These vascular microkines may be associated with inhibition of 15 myosin-light chain kinase activity. Myosin-light chain kinase is an enzyme required for the stimulation-contraction coupling of contractile activity in vascular smooth muscle. Inhibition of this enzyme causes relaxation of vascular smooth muscle (ie, vasodilation) and may result in increased blood flow. [Summary of the invention] 20 Summary of the invention The inventors believe that the microcirculation interference that restricts the flow of nutrient blood to the choroid, the retina and the optic nerve head may be included in the progress of visual field impairment. Although not bound by theory, the inventors of the present case have concluded that compounds that enhance oxygen and nutrient transport by enhancing ocular fluid flow may be beneficial for the prevention of ocular nerve heads 7 200301128 玖, description of the injury and possibly subsequent suppression or alteration of glaucoma and local Progression of visual field impairment associated with ischemic ophthalmic neuropathy. The present invention proposes compositions and methods that can be used to treat glaucoma (with or without ocular hypertension) and ocular ischemia that may cause retinopathy and ophthalmic neuropathy. The composition contains an isoquinoline sulfonium compound, which can reduce or prevent damage to the head or retina of the optic nerve and reduce IOP to a normal level, thereby reducing or preventing vision loss. In another embodiment of the composition and method of the present invention, the above composition may further include a pseudomucus polymer, a gelling polysaccharide, a finely divided drug carrier matrix 10 (defined below), or a combination of these components. These added ingredients can provide the composition with enhanced comfort and provide continuous drug release and delivery to the eye. Detailed description of the invention The increase in IOP is related to the clinical manifestations of glaucomatous neuropathy 15. Ophthalmic nerve dysfunction may be the result of pressure-induced changes in the structure of the optic nerve head and / or reduced circulation to the optic nerve head and retina. In addition to affecting vascular resistance and blood flow, the inventors have found that certain isoquinoline sulfonium compounds can also reduce intraocular pressure. The isoammonium sulfonium sulfonium compound of the present invention is a compound of formula (I) 20 shown below, and a pharmaceutically acceptable salt thereof. 8 200301128 发明, description of the invention

In the formula, R1 represents a hydrogen atom, a chlorine atom or a hydroxyl group; and when Ri represents a hydrogen atom, A represents an ethylidene group, which is an unsubstituted group or an alkyl group or benzene group having 丄 to ^ 5 carbon atoms. Substituted by benzyl or benzyl, R2 and R3 are directly bonded to each other to form a trimethylene group which is unsubstituted or is an alkyl group, phenyl group or benzyl group having i to 6 carbon atoms And R represents a hydrogen atom and an alkyl group having 1 to 6 carbon atoms; and 10 when R1 represents a gas atom or a hydroxyl group, A represents an alkylene group having 2 to 6 carbon atoms, the alkylene group May be unsubstituted, left substituted, or substituted with a sulphur group having 1 to 6 carbon atoms, r2 and r3 are not bonded to each other and each represents a hydrogen atom or a & * group having 1 to 6 carbon atoms, or R2 And R3 are directly bonded to each other, thereby forming an ethylene group, the ethylene 15 group is unsubstituted or substituted with a carbon atom having a carbon atom, or a trimethylene group is formed; the trimethylene group is unsubstituted Substituted or substituted by an alkyl group having 6 to 6 carbon atoms; and R represents a hydrogen atom, an linyl or fluorenyl group having 1 to 6 carbon atoms, and its pharmacological connection Salts. Regarding the above-mentioned alkyl groups, they may be straight-chain or branched-chain groups, and some compounds and their synthesis methods are disclosed in U.S. Patent No. 9,200301128 (ii), Invention Description No. 4,678,873, the entire contents of which are incorporated herein by reference. Other derivatives of risulin and its derivatives are disclosed in U.S. Patent No. 4,525,589, the entire contents of which are incorporated herein by reference. The preferred isoquinoline sulfonium compound of the present invention is hexahydro_fluorene β (5 • isofluorolinesulfonyl-5fluorenylfluorene-1,4-diaza heterocyclic line, also known as% isophilin yellow Hexahydroxanthine is shown below as a compound (1 [), and its pharmaceutically acceptable salts.

10 The best is the hydrochloride salt of the compound (Π). Compounds (Π) hydrochloride called fasudil, AT-877, and HA-1077 were produced by Asahi Chemical Industry, Co., Ltd: (Japan). In addition, the compound (Π) and a preferred metabolite thereof can be represented by the following formula: 15

Where R = H or OH. 10 200301128 (ii) Description of the invention Generally, for topical administration, an amount of isoquinolinesulfonyl compound is used in the composition of the present invention in an amount of about 0.001 to about 10.0% by weight. It is preferably used in an amount of about 0.01 to about 3.0% by weight, and particularly preferably used in an amount of about 0.1 to about 2.0% by weight. 5 The composition of the present invention may further contain ingredients which provide sustained release and / or comfort. Their ingredients include pseudomyxopolymers, gelling polysaccharides, and finely divided drug carrier matrices. These ingredients are discussed in more detail in U.S. Patent No. 4,911,920 issued on March 27, 1990 and U.S. Patent No. 5,212,162 issued on May 18, 1993. The entire contents of both patents are incorporated herein by reference. For the purposes of the present invention, the term "quasi-mucinous polymer" includes carbomers (discussed below), mucopolysaccharides (such as hyaluronic acid 'chondroitin sulfate), and cellulose polymers (such as methyl cellulose, Via propylmethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl cellulose). 15 Preferred mucoid polymers useful in the present invention are anionic and have a molecular weight between about 50,000 and six million channels. These preferred polymers are characterized by having a carboxylic acid functional group and preferably containing 2 to 7 stone counter atoms per functional group. The gel formed in the preparation of the ophthalmic polymer dispersion has a viscosity between about 1,000 and about 300,000 decibels (cps). Suitable polymers are 20-based vinyl polymers, preferably those known as carbomers, such as CARBOPOL® (Goodrich Co., Cleveland, Ohio). Particularly preferred are CARBOPOL® 934 and 940. Typical amounts of these polymers are between about 0.05 and about 8.0% by weight, depending on the viscosity of the desired composition. Pourable 11 200301128 玖, description of the invention The liquid composition to be poured usually contains a polymer amount of between about 0.05 and about 20% by weight. As used herein, "4 ,,,,, and segments of drug carrier matrix" ("DCS, f)" means finely divided solids, colloidal particles, hydrazones, or soluble polymers and / or multiple electrolytes, which can interact with drug molecules Selectively π and attached or combined. Examples of DCS include 5, but are not limited to · subdivided milk cuts, such as fuming oxygen cuts, osmates, and polydextrin; ion exchange resins, its basic ^ p ★ + ¾ 了 为Anionic, cationic or non-ionic; and soluble polymers such as alginic acid 'pectin, soluble carrageenin, CARBOPOL®' and polybenzyl sulfonic acid. Usually the DCS component is used at a level of about 0.05 to about 1.0. The weight% range is 0. For granules, the average particle size range is from about 1 to about 20 microns. The amount and properties (such as the amount of cross-linking, particle size) can be varied to produce a desired time for the selected drug. Release type. The preferred DCS is an ion exchange resin. Certain resins used in chromatography are ideal DCS for drug binding in the composition of the present invention. All resins can be easily obtained, such as From Rohm & Haas (Wisconsin, Philadelphia) The AMBERLITE® and the DowEX® from Dow ChemicalCo. (Milan, MI). Commercially available resins have an average particle size of about 40 to about 150 microns. Their commercially available particles can be milled according to known 20 techniques. And most conveniently reduced to a particle size range of about 1.0 to about 25 microns. At least 95% of the resulting spherical particles preferably have a diameter below 20 microns. A typical content of the ion exchange resin is from about 0.05 to about 10.0% by weight and It has an average particle diameter of about 1 to about 20 microns. 12 200301128 发明. Description of the invention In addition to the above-mentioned main ingredients, the composition of the present invention may further include various kinds of wounds such as anti-biological preservatives and tonicity agents. (Tonicity agents). Examples of suitable antimicrobial preservatives include: air benzylamine, thimerosal 'gas butanol', methyl parahydroxybenzoate, propyl parahydroxybenzoate, edetate sodium ), Sorbic acid, poiyq Uaterniumi and other agents commonly known to those skilled in the art. If their preservatives are used in a typical amount of 0.001 to about L0% by weight, they can be used to adjust Examples of suitable agents to adjust the tonicity or osmolality of the formulation include: sodium vaporization, potassium vaporization, mannitol, dextrose, glycerol, and propylene glycol. 10 Typical amounts are between about 0.1 and about 10.0% by weight. As understood by those skilled in the art, the composition can be formulated into a variety of forms suitable for topical ophthalmic delivery including solutions, suspensions, emulsions, gels, and erodible A solid solid eye insert. The composition is preferably an aqueous one having a pH between about 3.5 and 15 and about 8.0 and an osmolarity weight of about 280 to about 320 osmoles per kilogram (mOsm / kg). concentration. The composition of the present invention may also include non-aqueous formulations such as: substantially non-aqueous liquid, substantially non-aqueous semi-solid composition, and solid composition or stuff. In the first category, substantially non-aqueous liquids include isoquinine forest stone compounds that are dissolved or suspended in one or 20 of the following species: vegetable and mineral oils, such as liquid paraffin, corn oil, castor oil, sesame oil, And peanut oil; triglycerides, such as tridecanoic acid / caprylate commonly used in food and cosmetics; liquid lanolin and lanolin derivatives and perfluorocarbons. Second, semi-solid composition 13 200301128 128, invention description, including isoquinoline sulfonium compounds dissolved or suspended in one or more of the following: various paraffin lipids, such as white, yellow, red, etc .; lanolin and Lanolin derivatives; gelled mineral oils with a hydrocarbon matrix such as PLASTIBASE®; paraffin / ethylene glycol blends; paraffin with surfactants and polyethylene glycols5, for example, polyoxyl 40 stearate and polyethylene Diol combination. The third category is solid compositions or things, including isoquinoline sulfonium compounds associated with (i) non-erodible devices, which are inserted in the capsular capsular of the eye and subsequently removed, such as Alza-type diffusion or osmotic pressure-controlling polymer membranes, and (ii) bioerodible polymers, which do not need to be removed from the bound membrane sac 10, such as polymers and resins (such as fibers that are substantially anhydrous but water-soluble) Pigment, polycarboxylic acid, etc.). Particularly preferred are the bioerodible inserts described and detailed in U.S. Patent No. 4,540,408 (Lloyd) and U.S. Patent No. 4,730,013 (Bondi et al.), In which the The non-aqueous matrix entrains the isoammonium sulfonium sulfonium compound of the present invention. The entire contents of these 15 patents are incorporated herein by reference. As understood by those skilled in the art, the isoquinoline sulfonium compound of the present invention can also be administered intraocularly, around the eye, or systemically (such as parenterally or orally). Intraocular or periocular administration may be accomplished by incorporating an isoquinoline sulfonium compound in a surgical wash solution for 20 ophthalmic surgery, or, preferably, by intravitreal or periocular injection. Their injectable treatments typically require about 0.1 nM to about 1 mM (about 0.02 nanograms (ng) to 500 micrograms) of an isoporoline sulfonium compound for each treated eye. It is better to use 14 200301128 每一 per eye in their treatment, and the description of the invention uses about 2011 to about 1613 (about 40 nanograms to 80 micrograms). The preferred routes for systemic administration are oral and intravenous. The oral dose of the isoquinoline sulfonium compound of the present invention is typically about 10 to about 1000 mg, 1 to 4 times a day. The preferred oral dosage range is from about 10 to about 250,000 g, 2 to 3 times every 5 days. Intravenous administration of the heterophilin compound of the present invention is typically about 0.01 to about 100 milligrams, and it is about 4 to 4 times a day. A preferred dosage range for intravenous administration is about 1.0 to about 30 mg, 2 to 3 times a day. The invention also relates to methods for treating glaucoma and other eye diseases and abnormalities associated with vision loss. This treatment can be accomplished by administering a therapeutically effective amount of the isosulfoline sulfonium compound locally, intraocularly, around the eye, or systemically. A preferred method comprises topically administering to the affected eye of a patient a therapeutically effective amount of a composition of the invention. Its frequency and dosage are determined by the physician based on various clinical factors. The preferred method typically involves topically applying one or two drops (or an equivalent amount of a solid or semi-solid dosage form) to the injured eye as needed, preferably 15 to three times a day. I: Embodiment 3 The following examples are proposed to further explain the parts of the present invention, but are not intended to limit the scope of the present invention in any way. 20 Example 1 A compound II hydrochloride, also called fasudil hydrochloride or fasudil only, was administered topically to the eyes of a high intraocular pressure monkey, Zew Zealand Albino (NAZ) and Dutch Belted (DB) rabbits. The results are shown in Table 1. Such as 15 200301128 玖, Description of the invention Table 1. Compound π can effectively reduce normal and low intraocular pressure (laser-induced) primate IOP. In NZA rabbits, ιορ can be significantly reduced below baseline during a four hour dosing period. Compound n also reduced IOP in DB rabbits; however, the decrease in IOP was not as sustained in the NZA rabbit study 5. Table 1 Effect of Fasudil on IOP reduction in high intraocular pressure and normal intraocular pressure monkeys, New Zealand Albino rabbits and Dutch Belted rabbits Animal model I line # — fP pair:% change in plug line ......... ................. iOP fmmHg} Τηβιπ ,, Μ1 " '2 HR 3 HR 4 HR 6 HR Zhao Di shot treatment ΙΟΡ (n = 9) t 32.t ± 3.2 21 & ± 6.7 i-14.6 ± 6, 5 i · 23.4 ± 4A i Laser treatment MIT (η: 9) 38.2 ± 3.3 5.95.9 ± 6.8 i Ϊ6.1 ± 4.8 l — 7.1 ± 4.9 I ΊΕ / m Miop (η = 9) 20.4 ± 1.4 18.9 ± 5.5 i-21,7 ± 5,2 i -1t.1 ± 5.3 i Dutch Belted Rabbit (η · -7) ff 37.4 ^ 0.6 337 ± 2.1 i 18.0 ± 3.7 X 10.8 ± 5.2 i 6, 6 ± 3'9 i Dutch Betted Rabbit (n-7) ft 32.1 ± 0.4 33.1 ± 2.7 i 25.2 ± 3.5 丄 Ϊ67 ± 3 ^ 9T 11.7 ± 4.0 i-NZA Rabbit (n = 7m 27.2 ± 0.3 36.2 ± 3.7 i 35.5 ^ 3.6 i 26.1 ± 3.9 X 22.5 ± 3.8 i ** · 10 · All drugs were administered to the eye in a topical manner at a dose of 500 micrograms (2x 25 microliters). FasudiH was formulated in phosphate-buffered saline containing 0.01% chlorobenzylamine. + Normal on the opposite side untreated eye No significant IOP change from baseline was observed in the eyes or in the eyes with high intraocular pressure treated with excipients. ++ No significant changes in baseline IOP were observed in the anterior untreated eyes. MIOP = Intraocular pressure in monkeys. N == number of animals in the study. Example 2 Compound Π (hydrochloride) was administered topically at the doses of 75 and 150 micrograms 16 200301128 说明, the invention was introduced into the eyes of DutchBelted (DB) rabbits The results are listed in Table 2. Table 2 Dose-response study compounds of Fasudil to Dutch Belted rabbit IOP-1 line ... fOP factory, J for base ?, ru 3hr: r cord 1 Pasudil 150 uq OD 33.0 ± 0. θ 8.8 ± 3.8 1 11.5 ± 3.2 i 14 6 ± 3.5 i 3.4 ± 27 i 0.5 ± 3.2 T set 1 tincture 33.8 ± 0.6 3 3 ± 1.9 i 3.7i2.4 丄 5.7 ± 2.6i 0 ± 2A i 2.1 ± 3.2 Γ Group 2 Fasudil 75 ug OD 34.3 + 0.8 3.2 soil 2.8 i 3.3 ± 1.9i 1.7 ± 271 5.2 + 2.2 i 2,9 ± 2.1 i Wrap the test reagents in two groups 33.8 ± 0,6 t.1 ± 0.6 T 5.9 ± 2.6 t 6.0 ± 3.9 r 4.5 ± 1.9t 1.9 ± 3.4 t All drugs were administered to the eye topically (lx 30 μl). All compounds were formulated in phosphate-buffered saline containing 0.01% chlorocarbamine. N = 6 animals / group; OD = drug-treated eyes; s = vehicle-opposed contralateral eyes. 10 Example 3

A dose study similar to that described in Example 2 was performed with NZA rabbits. Compound II (hydrochloride) was administered topically ophthalmically in doses of 50, 125 and 250 micrograms. The results of this study are shown in Table 3. Table 3 Dose-response study of Fasudil on NPA rabbit IOP 15 17 200301128 玖, invention description compound top (miriHcf) 0.5 Nr ff 醪 Baseline%%: 4 hr Group 1 Fasudil 250 μα 00 20.6 t 0.3 5.5 6.7 ΐ 21.115.4 i 24,916,1 l 25.1 ± 4.1 i 16.3 ± 4.0 丄 Shaping_ OS 2t.2 ± .5 1.1 ± 3,7i 4.4 ± 3.4 T 2.7 ± 3.2T 27 ± 3.9 T 5.4 Pass Fasudll 125 uq OD 20'4 ± .7 2.8 ± 3.8 T 11-6 ± 2.9 i 1i.0 ± 4.7 l 7.0 ± 4.8 丄 5.1 ± 2.7i os 1,111111 21.3 + .6 5.3 ± 2,6 T 8.3 ± 6.0 T 7.3 ± 4.6 T 7.2 ± 5.3 T 17.116.5 t 5r ^ w J3cL Fasudil… | g welcome ... —, 21.3 ± .5 --------- 1.6 on 3.0 i 3.2 ± 3.1 T 2.1t4 .7 t 1.7 ± 4.3i 10,8 ± 5 JT Ο ΰΐΰΐExcipient OS 21 4 ± .8 6 7 ± 4.1 T 9.1.Ϊ1.7 T 3.6 ± 3.3 T 9.8 ± 7.6 T 7.414.5 t All medicines It was administered topically (1 x 30 microliters) to the eye. All the chemicals were formulated into phosphate-buffered saline 5 containing 0.1% oxybenzyl ammonium. N = 6 animals / group; OD = drug-treated eyes; s = vehicle-opposed contralateral eyes. Example 4 The effect of repeated doses of compound π on the magnitude and duration of Iop reduction in normal intraocular pressure monkeys was evaluated. As shown in Table 4, a total of 900 micrograms of compound JJ (hydrochloride) was administered in three separate intervals of 10 to 10 minutes, resulting in a significant decrease in IOP. Table 4 Effect of repeated administration of Fasudil on IOP of normal intraocular pressure Cynomolgus monkeys 18 200301128 玖, Description of Invention 1, ···· Compound 丨 OP (mmHg) "% change from baseline 1 hr 3 hr 5 hr Fasudil 900 pg OS 20.6 soil 0.8 23.1 ± 2,8 丄 23.1 ± 3,3 1 19.3 ± 3.2 i Shaped 殛 3 x 30 μΙ OS 20.2 soil 0,8 4.1 ± 1.8 丄 0.3 ± 4.4 T 丨 1.1 soil 3.7 丄

Fasudil was administered topically at 3 x 30 microliters (1 x 30 microliters, 10 minutes apart). N = 10 drug-treated group and N = 5 excipient-treated group. Fasudil was formulated 5 in phosphate-buffered saline containing 0.001% oxybenzyl ammonium. Example 5 Topical ophthalmic prescription Ingredient% (w / v) Compound I (hydrochloride) 1.5 Ammonium chlorobenzyl 0.01 Phosphate buffered saline Suitable to 100

Topical ophthalmic prescription with sustained release 19 200301128 玖, Description of composition% (w / v) Compound I (hydrochloride) 1.0 Carbomer 934P or Carbomer 974P 0.5 NaCl 0.4 Mannitol 2.4 Dinadium diacetate 0.01 BAC 0.01 Water for injection to 100% NaOH or HC for pH adjustment

Example 7 System formula (oral) Ingredients Weight ratio Compound I (hydrochloride) 50 Sodium citrate 20 Alginic acid 5 Polyvinyl pyrrole 15 Magnesium stearate 5

Preparation: The dry composition is fully blended, and the resulting mixture is used to form ingots each having a size such that it contains 10 mg of Compound II (hydrochloride). 20 200301128 发明, Description of Invention Example 8 Intraocular or Periocular Formulas (for intravitreal or intraocular injection) Composition% (w / v) Compound I (hydrochloride) 0.002 Sterile balanced salt solution amount Up to 100 i

Example 9 Therapeutic method (topical) Patients with high IOP and 10 / or loss of vision were treated by topical administration with the prescription of Example 5. A 30-micron prescription is administered to the victim's eyes 1 to 4 times a day to reduce the progression of ιορ and / or vision loss. Example 10 Therapeutic method (system) Patients with high IOP and / 15 or vision loss were treated with the prescription of Example 7 via oral administration. One or more of these lozenges are administered orally 1 to 4 times daily to thereby reduce the progression of IOP and / or vision loss. Example 11 Treatment Method (Intra- or Around-Eye) The patient of Example 8 was administered via intravitreal or around the eye to treat patients 21 200301128 发明, invention description Patients with high IOP and / or vision loss. Ten to 25 microliters of the prescription is administered to the affected eye once a month to reduce IOP and / or vision loss. Example 12 5 Other isoquinoline sulfonamide was administered topically to the eyes of NZA rabbits. The results are shown in Table 5 below. Table 5 Effects of other isoquinoline sulfonamides on IAP in NZA rabbits Baseline IOP (mrnHg) Variation of ffr Degaguang Hi ό20.4 ± 0.8 14,6 soil 2.6 i 7,2 soil 4.1 丄 0.9 ± 3.5 T ο 0 19.5 Soil 0.5 · 7 ± 4.3 i 14.510.5 ί 0.8 ± 2.3 ί ο 15.6 ± 0.5 16.8 ± 5.7 T 16.0 ± 5.7 ΐ 37.0 ± 4.1 T Η 00 16.2 ± 0 · 3 9 · 9 ± 3 · 5 i 9,4 ± 1.9 i 3.3 ± 3.8 t

All drugs were administered topically to the eyes at a dose of 500 micrograms (2 x 25 microliters). All compounds were formulated in phosphate-buffered saline containing 0.01% Benzyl Ammonium, and in all cases N = 7. 22 200301128 (ii) Description of the invention The invention has been described with reference to certain preferred embodiments; however, it must be understood that it can be implemented in other special forms or variations without departing from its intent as to its essential characteristics. Therefore, the embodiments described above are to be considered in all respects as illustrative and not restrictive, and the scope of the present invention is shown in the appended patent scope rather than the foregoing description. [Schematic description] (none)

twenty three

Claims (1)

20030112 ^ Patent application scope h An ophthalmic composition for treating patients with one or more conditions of glaucoma, high intraocular pressure, ocular ischemia and related diseases, comprising a therapeutically effective amount of The compound of formula is the only therapeutically active component: Wherein R represents a hydrogen atom, a chlorine atom or a radical; and when R1 represents a hydrogen atom, A represents an ethyl group, which is an unsubstituted group or an alkyl group or a phenyl group having 1 to 6 carbon atoms. Or substituted by benzyl, R2 and R3 are directly bonded to each other to form a trimethylene group, which is unsubstituted or substituted with an alkyl group, a phenyl group, or a benzyl group having 1 to 6 carbon atoms, and R4 represents a hydrogen atom And alkyl groups having 1 to 6 carbon atoms; and when R1 represents a gas atom or a hydroxyl group, A represents an alkylene group having 2 to 6 carbon atoms, and the alkylene group may be unsubstituted or having 1 to 6 carbon atoms; In the case of a 6 carbon atom substituted group, R2 and R3 are not bonded to each other and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R2 and R3 are directly bonded to each other, thereby forming an extension Ethyl, which is unsubstituted or substituted with an alkyl group having 24 to 200301128 patents, ranging from 1 to 6 carbon atoms, or forms a trimethylene, which is unsubstituted or Is substituted by an alkyl group having 1 to 6 carbon atoms; and R4 represents a hydrogen atom, an alkyl group or a fluorenyl group having 1 to 6 carbon atoms; 5 and its pharmaceutically acceptable salts and ophthalmology for its use Acceptable carrier. 2. An ophthalmic composition for treating a patient with one or more conditions of glaucoma, high intraocular pressure, ocular ischemia and related diseases, which comprises a therapeutically effective amount of a compound having the formula: Wherein R1 represents a hydrogen atom, a gas atom or a hydroxyl group; and when R1 represents a hydrogen atom, Lu A represents an ethyl group, which is an unsubstituted group or an alkyl group or a phenyl group having 1 to 6 carbon atoms. Or benzyl substituted, R2 and R3 are directly bonded to each other to form a trimethylene group, which is unsubstituted or substituted with an alkyl group, a phenyl group or a benzyl group having 1 to 6 carbon atoms And R4 represents a hydrogen atom and an alkyl group having 1 to 6 carbon atoms; however, the following compounds are excluded: 25 200301128, scope of patent application, R (m) When R1 is a gas atom or a hydroxyl group, Table A has an elongating group of 2 to 6 carbon atoms, and the elongating group may be unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms. , R and R are not bonded to each other and each represent a nitrogen atom or an alkyl group having 1 to 6 carbon atoms, or R2 and R3 are directly bonded to each other, thereby forming an ethylene group, which is not Substituted or substituted by an alkyl group having 1 to 6 carbon atoms, or forming a Sanya 10 A methyl group, the trimethylene group is unsubstituted or substituted with a sulphur group having 1 to 6 carbon atoms; and Table hydrogen atom, alkynyl or fluorenyl group having 1 to 6 carbon atoms; ^ its pharmaceutically acceptable salts and ophthalmologically acceptable for use 26 200301128 Lu, (a), the representative representative of the case is: No picture (2), the representative symbols of the representative diagrams are simply explained: No, if there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: