TWI253345B - 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

1253345 发明, INSTRUCTION DESCRIPTION C TECHNICAL FIELD OF THE INVENTION The present invention relates generally to the field of ophthalmology. In particular, the present invention relates to the use of heterophilic compounds to treat eye diseases including visual field impairment and glaucoma, which can reduce intraocular pressure (Figure 〇p) and produce ocular dilatation. [Previous Background of the Invention Although the basic cause of glaucoma is not fully understood at present, glaucoma is characterized by damage to the ocular nerve head, accompanied by a decrease in the normal field of view. One risk factor for glaucomatous loss of sight is increased IOP, which in the past was treated with drugs and/or surgical treatment to reduce elevated IOP. Although the elevated I0P line is positively correlated with the rate of decline in visual field impairment in glaucoma, loss of field of view may also occur at levels of IOP that are considered to be within the normal range. Therefore, the factor of 15 S, alone or accompanied by increased cake, may affect the incidence and progress rate of loss of sight. In order to maintain normal health and function, the retina and ocular nerve fibers, * (God, and Foot) must receive appropriate nutrients and oxygen supply, and must remove the carbon dioxide and other metabolic wastes they produce. . This item has been completed by the second and the woven Wei Dehuan. As used herein, "microcirculation," refers to the flow of blood through the #vines, allowing nutrients, gases, and waste to pass through their walls. Blood flow to the eye depends on perfusion pressure (systemic blood pressure reduction) Off! 0P). Some tissues have the ability to maintain blood (ie, auto-adjust) within a range of perfusion pressures, resulting in an increase in system blood pressure 6 1253345 玖, description of the invention

Or ocular cells apotosis. In the case of an ocular nerve head or a visual palsy, a state of visual dysfunction may occur before the death of the neuron. Therefore, if it involves ischemia in glaucoma or some other ischemic retinopathy or ocular nerve fiber dysfunction caused by eyelid necrosis, its prevention may protect neurons from death or function. Impairment. Can contribute to the reduction of the diameter of the lumen of the blood vessel. Conversely, a decrease in force may result in vasodilation; however, the vessel expands to the point of maximum level. Perfusion layer The vasodilatation and antispasmodic activity of certain isoquinoline sulfonium compounds has been demonstrated relative to non-ocular tissues. See, for example, EP 187 187 371 B1, which is assigned to U.S. Patent No. 4,678,783. These vascular microscopic associations may be associated with inhibition of 15 myosin·light chain kinase activity. Myosin-light chain kinase is an enzyme required for stimulation-systolic coupling of vascular smooth muscle contractile activity. Inhibition of this enzyme causes vascular smooth muscle relaxation (i.e., vasodilation) and may result in increased blood flow. SUMMARY OF THE INVENTION The present inventors believe that limiting the circulation of nutrient blood to the choroid, microcirculatory disturbances of the retina and ocular nerve head may be involved in the progression of visual field impairment. Although not theoretically bound, the inventors of the present invention concluded that compounds that enhance oxygen and nutrient delivery via enhanced ocular blood flow may be beneficial in preventing ocular nerve heads. 12 533 7 玖 玖 玖 玖 玖 发明 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且Progression of visual impairment associated with bloody eye neuropathy. The present invention proposes a composition and method for treating glaucoma (with or without ocular hypertension) and ocular ischemia which may cause retinopathy and ocular neuropathy. The composition contains an isoquinoline sulfonium compound which can reduce or prevent damage to the ocular nerve head or retina and reduce IOP to a normal level, thereby reducing or preventing loss of sight. In another embodiment of the compositions and methods of the present invention, the composition © may further comprise a pseudomud polymer, a gelling polysaccharide, a finely divided drug carrier matrix 10 (as defined below), or a combination of these components. These added ingredients provide enhanced comfort and deliver sustained drug release and delivery to the eye. DETAILED DESCRIPTION OF THE INVENTION The elevation of the IOP is associated with the clinical display characteristics of glaucoma eyelid neuropathy. Ocular nerve dysfunction may be the result of pressure-induced changes in the structure of the ocular nerve head and/or reduced circulation to the head and retina of the eye. In addition to affecting vascular resistance and blood flow, the inventors of the present invention also found that certain heterologous quinoidine compounds also reduce intraocular pressure. The isoquinoline sulfonium compound of the present invention is a compound 20 of the formula (I) shown below, and a pharmaceutically acceptable salt thereof. 8 Ϊ253345 玖, invention description 〇 R2 R3

Wherein R1 represents a hydrogen atom, a gas atom or a hydroxyl group; and when R1 represents a hydrogen atom, A represents an ethyl group, and the ethyl group is unsubstituted or an alkyl group having from 丄 to 5 carbon atoms, benzene Substituted by a benzyl group or a benzyl group, R and R are directly bonded to each other to form a trimethylene group which is unsubstituted or a phenyl group having a working to 6 carbon atoms, a phenyl group or a benzyl group. a substituent, and R represents a hydrogen atom and a filament having 1 to 6 carbon atoms; and 10 when R1 represents a gas atom or a via group, A represents an alkylene group having 2 to 6 carbon atoms, and the alkyl group may be Han 2 and Han 3 are not bonded to each other and are each represented by a hydrogen atom or a burnt group having up to 6 carbon atoms, or R 2 and R 3 , which are unsubstituted or substituted by a group having 1 to 6 carbon atoms. Directly bonding and bonding to each other, thereby forming an extended ethyl group which is unsubstituted or substituted with an alkyl group having from 丄 to 6 carbon atoms, or 幵7 胄 dimethylene, the Sanya a methyl group which is unsubstituted or substituted with an alkyl group having 1 to 6 carbon atoms; and R an epiatomic atom having 1 to 6 groups of a burnt group or a neck group; Acceptable salt thereof. Regarding the above-mentioned yard bases, they may be a direct bond base or a branched base. Each of the compounds and methods for their synthesis are disclosed in U.S. Patent No. 9 12 533 045, the disclosure of which is incorporated herein by reference. Other isoquinoline sulfonium derivatives and their synthetic methods are disclosed in U.S. Patent No. 4,525,589, the disclosure of which is incorporated herein by reference. Preferably, the isoindoline sulfonium compound of the present invention is hexahydro-1-(5-isoquinolinesulfonyl 5 fluorenyl)-1Η-1,4-diazepane, also known as 1-(5- Isoporphyrinsulfonyl)-hexahydropyrazine, and is shown below as the compound (Π), and a pharmaceutically acceptable salt thereof.

The best one is the hydrochloride salt of the compound (Π). The compound (Π) hydrochloride known as fasudU, AT-877, and HA-1077 is manufactured by Asahi Chemical Industry, Co., Ltd. (曰本). In addition, the compound (Π) and its preferred metabolite can be expressed by the following formula:

ν^/ΝΗ (ra) where R=H or OH. 10 1253345 发明Inventive Description In general, for topical administration, an amount of isoporphyrinsulfonyl compound between about 0_001 and about 1% by weight is used in the composition of the present invention. It is preferably used in an amount of from about 1 to about 3% by weight, and particularly preferably in an amount of from about 1 to about 2.0% by weight. 5 The compositions of the present invention may additionally comprise ingredients that provide sustained release and/or comfort. These components include pseudomud polymers, gelatinous polysaccharides and finely divided drug carrier matrices. These components 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 of these patents are incorporated herein by reference. For the purposes of the present invention, the term "mimetic polymer" includes carbomers (discussed below), mucopolysaccharides (such as hyaluronate, chondroitin sulfate) and cellulosic polymers (such as methylcellulose, Hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl cellulose). 15 Preferred pseudomucin polymers useful in the present invention are anionic and have a molecular weight between about 50,000 and 6 million ampoules. These preferred polymers are characterized by having a carboxylic acid functional group and preferably having from 2 to 7 carbon atoms per functional group. The gel formed in the preparation of the ophthalmic polymer dispersion has a viscosity of between about 1,000 and about 300,000 depsis (cps). A suitable polymer is a 20-based vinyl polymer', preferably referred to as a carbomer, such as CARBOPOL® (Goodrich Co., Cleveland, Ohio). Particularly preferred are [eight 118 〇?〇1^© 934 and 940. Typical amounts of such polymers are between about 0.05 and about 8.0% by weight, depending on the viscosity of the desired composition. Pourable 1253345 玖, DESCRIPTION OF THE INVENTION The poured liquid composition typically comprises between about 0.05 and about 2.0% by weight of the polymer. As used herein, "segmented drug carrier matrix" (''DCS") means subdivided solids, colloidal particles, or soluble polymers and/or multiple electrolytes that can selectively adsorb or bind to drug molecules. Examples of DCS include 5, but are not limited to: subdivided oxidized oxide, such as fuming oxidized oxidized stone, sulphate and bentonite; ion exchange resins, which may be anionic, cationic or nonionic in nature; and soluble polymers such as Alginic acid, pectin, soluble carrageenan, CARBOPOL®, and polystyrene sulfonic acid. Typically, the DCS component is used at a level of from about 0.05 to about 10.0% by weight. For granular DCS, the average particle size ranges from about 1 to about 20 microns. The amount of DCS and its characteristics (e.g., cross-linking, particle size) can be varied to produce a time-release profile that is desirable for the drug of choice. A preferred DCS is an ion exchange resin. Certain trees used in chromatography are the ideal DCS to be used in conjunction with a drug in the compositions of the present invention. These resins are conveniently obtained, for example, from Rohm & Haas (Philadelphia, Philadelphia) under the name AMBERLITE® and from Dow Chemical Co. (Michigan, MI) under the name DOWEX17. Commercially available resins have an average particle size of from about 40 to about 150 microns. These commercially available particles can be most conveniently reduced to a particle size range of from about 1.0 to about 25 microns by ball milling according to the known 20 technique. At least 95% of the resulting spherical particles preferably have a diameter of less than 20 microns. Typical levels of ion exchange resin are from about 〇5 to about 10.0% by weight and have an average particle size of between about 1 and about 20 microns. 12 1253345 发明Invention Description In addition to the above main components, the composition of the present invention may further comprise various compounding ingredients such as antimicrobial preservatives and t-nicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, cyclobutanol, methyl paraben, propyl paraben, edetate sodium, sorbic acid, p〇iyqUaterniumi and other agents generally known to those skilled in the art. Examples of suitable agents which can be used to adjust the concentration of the formulation or the osmolality of the formulation, if the typical amount of the preservative used is between 〇·〇01 and about L0% by weight, include • gasification Na, gasification, mannitol, dextrose, glycerol and propylene glycol. 10 The typical amount of such agents when used is between about 1 and about 10.0% by weight. As will be appreciated by those skilled in the art, the compositions can be formulated into a variety of forms suitable for topical ophthalmic delivery including solutions, suspensions, emulsions, gels, and erodible solid ocular inserts. Preferably, the composition is aqueous, having a pH between about 3 5 15 and about 8.0 and an osmolality of about 280 to about 320 milliosmoles per kilogram (mOsm/kg). The compositions of the present invention may also include non-aqueous formulations such as: substantially non-aqueous liquids, substantially non-aqueous semi-solid compositions, and solid compositions or materials. In the first category, substantially non-aqueous liquids include isos-quinoline-xanthine compounds dissolved or suspended in one or more of the following: plant and mineral oils, such as liquid stone loam, corn oil, castor oil, sesame oil, and Peanut oil; triglycerides, such as triglyceride/octanoate commonly used in foods and cosmetics; liquid lanolin and lanolin derivatives and perfluorocarbons. The second category, semi-solid composition 13 1253345 玖, the invention description 'including the different materials of one or more of the following: the various stone fats, such as white 'yellow, red, etc.; wool Fat and lanolin derivatives 'gelling mineral oils having a hydrocarbon matrix, such as plastibase 13; stone bad fat / ethylene carbonate blend; stone butterfly fat with surfactants and polyglycols 5, for example, 0 〇 〇 〇 丨A combination of 40 stearate and polyethylene glycol. In the third category, a solid composition or thing, including an isoindolinic scutellaria compound, is associated with a u) non-erodible device that is inserted into the conjugated capsular sac of the eye and subsequently removed, such as Alza-type diffusion or osmotic control polymer 胄· and (H) bio-surnamed polymers, which no longer need to be removed from the binding membrane vesicles 10 'eg substantially anhydrous but water-soluble polymers and resins (eg fiber More than 'polyacids, etc.'. Particularly preferred are biorecognizable inserts as described and detailed in U.S. Patent No. 4,540, issued to Lloyd, and U.S. Patent No. 4,73,13 (B〇ndi et al). The non-aqueous f-base shell consisting essentially of polyethylene glycol is a mixture of the invention. The entire contents of both of these patents are incorporated herein by reference. As will be appreciated by those skilled in the art, the present invention may also be administered intraocularly, around the eye, or systemically (e.g., parenterally or orally). Intraocular or periocular administration can be accomplished by incorporating an isoindoline sulfonate compound into a surgical priming solution for use in 20 ophthalmic surgeries, or preferably, via intravitreal or periocular injection. These injection treatments typically require from about 0.1 nM to about 1 mM (about 0.02 ng to 500 micrograms) of the isoindoline sulfonium compound for each treated eye. Preferably, 14 1253345 每一 for each eye in the treatment, and about 200 11] to about 160 13 (about 40 ng to 80 μg). Preferred routes of administration are oral and intravenous. The oral dose of the isoquinoline sulfonium compound of the present invention is typically from about 1.0 to about 1000 mg, from 1 to 4 times per day. Preferred oral doses range from about 10 to about 250 mg, 2 to 3 times every 5 days. The intravenous administration of the isoquinoline sulfonium compound of the present invention is typically from about 0.01 to about 100 mg, from 1 to 4 times per day. A preferred dosage range for intravenous administration is from about 1.0 to about 30 mg, 2 to 3 times per day.

The invention is also directed to methods of treating glaucoma and other ocular disorders and abnormalities associated with loss of visual field. The treatment can be accomplished by administering a therapeutically effective amount of a sulphate compound in a topical, intraocular, intraocular or 10 systemic manner. A preferred method comprises topically administering to the affected eye a therapeutically effective amount of a composition of the invention. The frequency and dosage are determined by the physician based on various clinical factors. The preferred method typically involves the topical application of one or two drops (or an equivalent amount of a solid or semi-solid dosage form) to the affected eye, preferably one to three times per day. L Embodiment 3 The following examples are presented to further illustrate the various aspects of the invention, but are not intended to limit the scope of the invention in any way. 20 Example 1 For the high intraocular pressure monkeys, the eyes of the Zew Zealand Albino (ΝΑΖ) and Dutch Belted (DB) rabbits were administered topically, the compound guanidine hydrochloride, also known as fasudil hydrochloride or only fasudil. The results are shown in Table 1. For example, 15 1253345 发明, invention description, listed in Table 1, compound π can effectively reduce IOP of normal intraocular pressure and low intraocular pressure (laser induced) primates. In NZA rabbits, IOP can be significantly reduced below baseline during four hours of dosing. Compound 11 also reduced the IOP of DB rabbits; however, the reduction in IOP did not continue as in the NZA Rabbit Study 5. Table 1 Fasudil for high intraocular pressure and normal intraocular pressure monkeys, New Zealand

Effect of IOP reduction in Albino rabbits and Dutch Belted rabbits Animal wedge type 1 line IOP fmmHq) Relative change 1 NR 2 HR 3 HR 4 HR f 6 HR Fluted H10P (n=9j f 32.1±3.2 21 9± 6.7 i - 14.6±6.5 II 23.4±4.4 i Laser treatment ΜΙΟΡ (η=9) 38.2±3.3 t5.9±6.8 X 16.t±4.8 i - 7.1^:4.9 I 芷啬MfOP (π-9) 20.4士1.4 18.9±5.5 i-21.7±5,2 i 11.1±5.3 i Dutch Belted Rabbit (n-7) ft 37.4.1:0,6 33.7±2.1 i 18.CH:3.7 i 10.815.2 i 6.6t3 .9 i Dutch Belted Rabbit (n=7) ff 32.1 ±0.4 33.ϊ±2.7 i 25.2 soil 3_5丄16,7±3.9 i 11.7±4.0 i — NZA Rabbit (n=7) ft 27.2±0.3 36.2±3.7 i 35.513.6 > 26,1 ±3.9 i 22.5±3.8 i [ο · All drugs are given locally to the eye with a dose of 500 μg (2 x 25 μl). The Fasudil system is formulated with 〇·〇1% The salt of the benzalkonium phosphate was buffered in saline. + No significant relative to baseline values of IOP was observed in the untreated normal intraocular pressure eye or in the vehicle-treated high intraocular pressure eye. ++ No machine observed for baseline values in the untreated front side Significant IOP change. MIOP = intraocular pressure in monkeys. Number of animals in the study. Example 2 Compound Π (hydrochloride) was administered at a dose of 75 and 150 μg 'partially 16 1253345 玖, invention instructions to DutchBelted (DB) Rabbit's eyes. The results are shown in Table 2. Table 2 Fasudil dose-response study of Dutch Belted rabbit IOP Compound-Chan-fOP | Test if for micro-change gas h; _二_____ 蘩1 group Fasudil 150 uq OD 33.Ot.OQ Q£t3.S i 11.5±3.2 i 14.6r3.5 1 3 4 2.7 i 0.5r3.2 t 橥1 group 1 foot 33.θ±0.6 3 3+1.9 l 3.7 dead 2.4丄5.7±2.6i 0±2.4 i 2.1 Soil 3.2 Γ 112 Turtle Fasudil 75 ug OD 34.3±0.8 3.2±2.8 i 3.3±1.9i 1.7±2,7i 52±22 X 2.9 ± 2.1 丄i2 group 33.8±0.6 1.1±0.6 t 5.9 ± 2.6 T 6.0 ± 3.9 t 4.5 ± 1.9 T 1, 9 ± 3.4 t All drugs were administered to the eye in a localized manner (l x 30 μl). All compounds were formulated into phosphate buffered saline containing 〇·〇1% benzalkonium chloride. N=6 animals/group; 〇D = drug-treated eyes; 〇S = contralateral eyes treated with vehicle. Ίο Example 3 A dose study similar to that described in Example 2 was performed with NZA rabbits. The compound guanidine (hydrochloride) was administered by topical ophthalmology at doses of 50, 125 and 250 micrograms. The results of this study are presented in Table 3. Table 3 Fasudil dose-response study of NDA rabbit IOP 17 15 1253345 玖, invention description Compound s nickel ΟΡ (mmHq) 0.5 hr % at baseline: - 4 hr Shooting group i Fasudi { 20.6:03 5.5±6.7i 21 .U5.4 i 24.9±6J l 25.1±4.1 l 16.3±4.0i l.il os 21.2±.5 1ί±3.7ά 4.4 soil 3.4 T 2.7±3.2 T 2.7±3.9 t 5.4±3.6 T group ^asudii 03⁄4- 20.41.7 2.8±3.8 T 11.6±2.9 i 11.0±4.7 i 7.014.8 丄5.1 ±2.7 i 21.31-.6 5.3±2.6 t 8.3±6.0 T 7.3±4.6 T 7.2±5.3 T 17 on 6.5卞Fasudi! 50 Ηη — 21.3±.5 16j:3.0 i 3.2±3.1 T 2.114.7 T 1.7±4.3 i 10.8±5.7 " 21 41.8 6 7±4.1 T 9.1-1.7 t 3.6±3.3 T 9.8±7.6 T * 7 4± 4.5 Γ All drugs are administered to the eye in a localized manner (lx 30 μl). All compounds were formulated into phosphate buffered saline containing 001% benzalkonium chloride 5 N == 6 animals per group; 〇 D = drug treated eyes; 〇 s = contralateral treated with vehicle eye. Example 4 The effect of repeated administration of a compound ΐ on the magnitude and duration of ΐορ reduction was evaluated in normal intraocular pressure monkeys. As shown in Table 4, a total of 900 micrograms of the compound π (hydrochloride) administered in three divided doses of 1 〇 10 minutes resulted in a significant decrease in IOP. Table 4 Effect of repeated dosing of Fasudil on IOP of normal intraocular pressure Cynomolgus wolf 18 1253345 玖, invention description Baseline ΙΟΡ (mmHg) % change relative to baseline ～ 1 hr 3 hr 5 hr Fasudil 900 Mg OS 20,6 Soil 0.8 23.1 ±2.8 i 23" soil 3.3丄19.3 soil 3,2 i mm — 3 χ 30 μΙ OS 20.2±0.8 41±1.8 丄0.3±4.4 T ........—~~ 1.1±3.7丄

Fasudil is administered locally at 3 x 30 microliters (lx 30 microliters, 1 minute apart). N = 10 drug treatment groups and n = 5 vehicle treatment groups. Fasudil was formulated in discate buffered saline containing 0.01% benzylamine. Example B Topical Ophthalmic Formulary Ingredients % (w/v) Compound I (hydrochloride) 1.5 Ampicillin 0.01 Phosphate Buffer Salt & Appropriate amount to 100

Example 6 Topical Ophthalmic Formula with Sustained Release 19 1253345 玖, Description of the Invention Component % (w/v) Compound I (Citrate) 1·0 Carbomer 934P 〇r Carboaer 974P 0.5 NaCI 0.4 Mannitol 2.4 B Disodium sulphate 0.01 BAC 0.01 Water for injection to 100 NaOH or HC1 for pH adjustment

Example 7 Systemic Formulation (oral) Ingredient Weight ratio Compound 1 (hydrochloride) 50 Sodium citrate 20 Alginic acid 5 Polyvinylpyrrole 15 Magnesium stearate 5

Preparation· The dry composition was sufficiently blended, and the resulting mixture was used to make an ingot each having a size of 10 mg of the compound hydrazine (hydrochloride). 20 1253345 Rose, invention description Example 8 Intraocular or periocular preparation (for use in the injection of vitreous or periocular) Ingredient% (w/v) Compound I (hydrochloride) 0.002 No-balanced salt solution ..........- % Appropriate amount to 100!

Example Q Treatment (partial) A patient suffering from a high 10 卩 and 1 〇 / or loss of sight was treated by topical administration with the formulation of Example 5. The victim eye is administered 1 to 4 times a day with a 30 micron dose to reduce the progression of 101> and/or loss of sight. Example 10 Method of Treatment (System) A patient suffering from a high 101 > and / / 15 or loss of sight was treated by oral administration with the formulation of Example 7. One or more of the red agents administered orally one to four times a day thereby reducing the progression of IOP and/or loss of field of view. Example 1 1 Treatment (intraocular or periocular) The patient was treated with the Example 8 agent via vitreous or periocular. 21 1253345 Cleavage, Invention Description A patient with a South IOP and/or loss of sight. The administration of 10 to 25 microliters of the agent per month to the affected eye is a reduction in I〇p and/or loss of field of sight. Example 12 A topical administration of other isoquinoline sulfonamide to the eyes of NZA rabbits. The results are shown in Table 5 below. Table 5 Effect of other isoquinoline sulfonate amines on IOA rabbit IOP

Baseline ΙΟΡ (mmHa) of compound relative to base change % 1 hr 3 hr 5hr 20.4+0.8 14.612.6 ί 7.214.1 1 〇.9±3.5 T 19.510.5 7.7 soil 4.3 i 14,5 soil 0.5 丄0.8± 2.3 i 〇\〇0 15.6 Soil 0.5 16.8±5J T 16.0±5.7 T 37.014.1 T OD 16.2±0,3 9.9±3.5 i 9.4±1.9 1 3·3±3,8 T

10 All drugs were administered topically to the eye at a dose of 500 μg (2 x 25 μL). All compounds were formulated in an acid buffered saline solution containing 0.01% benzylammonium chloride, and n = 7 in all cases. 22 1253345 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明Therefore, the embodiments described above are to be considered as illustrative and not restrictive, and the scope of the invention is shown in the appended claims. [Simple description of the map] (none) 23

Claims (1)

1253345 Pick up, apply for patent scope No. 92104976, please apply for a patent scope revision. This 95-year revision of the flood season is used to treat a person with a blue sputum, a wide eye, two eye pressure, ocular ischemia and related diseases. One or more ophthalmic ophthalmic compositions comprising a therapeutically effective amount of a right-handed rigging day/, a compound having the following formula as a therapeutically active component: 0 R2 R3 1253345 picking, patent application scope R2 and R3 are not bonded to each other and each represents a hydrogen atom or an alkyl group having 丄 to 6 carbon atoms, or R2 and R3 are directly bonded to each other, thereby forming an extended ethyl group, The ethylidene group is unsubstituted or substituted with an alkyl group having 1 to 6 carbon atoms, or forms a trimethylene group which is unsubstituted or substituted with an alkyl group having one carbon atom. And R4 represents a hydrogen atom, a filament having 1 to 6 carbon atoms or a lung base; and a pharmaceutically acceptable salt thereof and ophthalmically acceptable for use therewith Carrier; but the following compounds are excluded... (m) where R is Η or 0ii. An ophthalmic composition for treating a patient with a lupus eye, a high intraocular pressure, an ocular ischemic-related disease, a patient having a condition of 53⁄4 guest, including a therapeutically effective amount Compound: (I) 1253345 pick, patent application range where R1 represents a hydrogen atom, a gas atom or a radical; and when R1 represents a hydrogen atom, A represents an ethyl group, and the ethyl group is unsubstituted or has a hydrazine to 6 Substituted by a pyridyl group, a phenyl group or a benzyl group, 5 R and R are directly bonded to each other to form a triindenylene group which is unsubstituted or has a enthalpy to 6 carbon atoms. Substituted by an alkyl group, a phenyl group or a benzyl group, and R4 represents a hydrogen atom and an alkyl group having 1 to 6 carbon atoms; however, the following compounds are excluded: 10 And when R1 represents a chlorine atom or a via group, A has an alkylene group having 2 to 6 carbon atoms, and the alkylene group may be unsubstituted or substituted with an alkyl group having 1 to 6 carbon atoms; , 15 R and R are not bonded to each other and each represents a hydrogen atom or an alkyl group having from 丨 to 6 carbon atoms, or R2 and R3 are directly bonded to each other, thereby forming an exoethyl group which is unsubstituted Or substituted with an alkyl group having 1 to 6 carbon atoms, or formed a trimethylene group which is unsubstituted or substituted with an alkyl group having from 5 to 6 carbon atoms; and 20 1253345 ^ /, 1 to 6 carbon atoms of the alkyl or sulfhydryl group; and its musically acceptable carrier; and 1 颂 and the ophthalmologically acceptable 2 for use: =::: _ amount... Equation 10 (m) wherein R is OH. 3. The composition of the patent of the patent, wherein the final composition of the compound has a 7-degree of about 0.001 to about 1 〇. 4. The patent of claim 2, the composition of the second item, wherein the final composition of the compound is from about OOi to about 1% by weight. 5. The composition of claim i, wherein the compound has a final composition of from 7 to about 3.0% by weight. 6. The composition of the second aspect of the patent scope, wherein the final composition of the compound is from about 〇 1 to about 3. 〇 by weight. 7. The composition of claim 5 or 6, wherein the pharmaceutically acceptable salt is a hydrochloride salt. 8. The composition of claim 2 or 2, wherein the compound has a 2" final composition concentration of about 〇·〇] to about 3.0% by weight, and the pharmaceutically acceptable amount is 1,253,345, and the patent application scope is affected by salt. For the hydrochloride. The composition has a composition concentration of from about 0.1 to about 2.0% by weight as in the eighth aspect of the patent application. Where the compound is ultimately