JP6628252B2 - Pharmaceutical composition for treatment of ischemic eye disease - Google Patents

Description

  This patent application claims the priority of Japanese Patent Application No. 2014-38457 filed on February 28, 2014, which is hereby incorporated by reference in its entirety. Shall be

  The present invention relates to a compound for treating ischemic eye disease, a pharmaceutical composition containing the compound, a method for producing a medicament for treating ischemic eye disease comprising using the compound, and a medicament for treating ischemic eye disease. And a method for treating an ischemic ocular disease, which comprises administering the compound in the production of the compound and administering the compound or a pharmaceutical composition. Ischemic ocular diseases treated according to the present invention include, for example, central retinal artery occlusion, branch retinal artery occlusion, ischemic optic neuropathy, central retinal vein occlusion, branch retinal vein occlusion or diabetic retinopathy. Including.

  Ischemic eye disease is a general term for diseases caused by ocular ischemia. Regarding the incidence and incidence of ischemic eye disease in Japan, for example, the incidence of central retinal artery occlusion is 500 / year, branch retinal artery occlusion is 5000 / year, and ischemic optic neuropathy is 1000 / year. The estimated prevalence of central retinal vein occlusion is -140,000, branch retinal vein occlusion is 1.4 million, and diabetic retinopathy is -3 million-5000 / year.

  Central retinal artery occlusion is a disease that results in severe visual loss due to occlusion of the central retinal artery, the only blood vessel that feeds the retina. Branched retinal artery occlusion is a disease in which a visual field defect corresponding to an ischemic site occurs due to occlusion of a branch of a retinal artery.

  Ischemic optic neuropathy is a disease that results in impaired vision and visual field due to obstruction of the short posterior ciliary artery that nourishes the optic nerve.

  Central retinal vein occlusion results from occlusion of the central retinal vein, resulting in hemorrhage of the entire retina. Branch retinal vein occlusion results from obstruction of the branches of the retinal veins, resulting in bleeding in localized areas of the retina. Occlusion of capillaries at the site of bleeding causes ischemic changes. Central retinal vein occlusion and branch retinal vein occlusion reduce vision by themselves, but can also result in further vision loss due to retinal ischemia and its complications such as vitreous hemorrhage and neovascular glaucoma. is there.

Diabetic retinopathy is one of the complications of diabetes and accounts for many of the causes of blindness in adults in Japan. When hyperglycemia damages microvessels of the retina and causes retinal ischemia, new blood vessels are formed in the retina. When retinal ischemia itself or bleeding or edema of new blood vessels occurs, visual acuity decreases. It often causes severe diseases that lead to blindness such as vitreous hemorrhage and retinal detachment.
In addition, optic nerve disease or optic nerve disorder may occur due to ocular ischemia caused by compression of an artery due to high intraocular pressure.

  At present, no effective treatment method for ischemic eye disease has been established, and patients have a high probability of permanent visual impairment such as blindness. Therefore, new treatment methods are needed.

Retinal ischemia: mechanisms of damage and potential therapeutic strategies.Neville N. Osborne, Robert J. Casson, John P.M.Wood, Glyn Chidlow, Mark Graham, Jose Melena. Progress in Retinal and Eye Research 23 (2004) 91-147 Ischemic optic neuropathies-where are we now? Sohan Singh Hayreh. Graefes Arch Clin Exp Ophthalmol (2013) 251: 1873-1884

  An object of the present invention is to provide a medicament capable of treating ischemic eye disease.

The present invention provides a compound of formula (I) for the treatment of ischemic eye disease:
(In the formula,
Ra is each independently halo, hydroxy, alkyl, halo substituted alkyl, aryl, halo or alkyl substituted aryl, alkoxy, hydroxy or carboxy substituted alkoxy, aryloxy, halo or alkyl substituted aryloxy, CHO, C (O)-. Selected from the group consisting of alkyl, C (O) -aryl, C (O) -alkyl-carboxyl, C (O) -alkylene-carboxyester and cyano;
m is an integer selected from 0 to 4]
Or an oxide, ester, prodrug, pharmaceutically acceptable salt or solvate thereof (hereinafter, referred to as the compound of the present invention).

  In a further aspect, the present invention provides a pharmaceutical composition for the treatment of ischemic eye disease, comprising a compound of formula (I) or an oxide, ester, prodrug, pharmaceutically acceptable salt or solvate thereof. provide.

  In a further aspect, the present invention provides a compound of formula (I) or an oxide, ester, prodrug, pharmaceutically acceptable salt or solvent thereof for the manufacture of a pharmaceutical composition for the treatment of ischemic eye disease. Provides use of Japanese food.

  In a further aspect, the present invention relates to a method for the treatment of ischemic ocular diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined above or an oxide, ester, prodrug, pharmaceutically Administering a salt or solvate acceptable to the patient.

  In a further aspect, the ischemic ocular disease is central retinal artery occlusion, branch retinal artery occlusion, ischemic optic neuropathy, central retinal vein occlusion, branch retinal vein occlusion, diabetic retinopathy or ocular hypertension. Optic nerve disease or optic nerve disorder.

  The compounds of the present invention can be used for retinal artery occlusion, branch retinal artery occlusion, ischemic optic neuropathy, central retinal vein occlusion, branch retinal vein occlusion, diabetic retinopathy or optic nerve disease based on ocular hypertension. It can treat ischemic eye diseases such as optic nerve disorders.

FIG. 1 shows an electroretinogram (ERG) of a retinal ischemic rat to which Compound 32 was orally administered. FIG. 2 shows an electroretinogram (ERG) of a retinal ischemic rat to which compound 32 was administered intraperitoneally. FIG. 3 is a graph showing b-wave amplitude of a retinal ischemic rat to which Compound 32 was intraperitoneally administered.

Definitions Unless defined otherwise, the terms used herein have the meaning as commonly understood by one of ordinary skill in the fields of organic chemistry, medicine, pharmacy, molecular biology, microbiology, and the like. The following provides definitions for some of the terms used herein, but these definitions supersede general understanding herein.

"Alkyl" means a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. “C _xy alkyl” refers to an alkyl group having _{x to y} carbons. Alkyl is, for example, linear and branched hydrocarbyl groups such as methyl _(CH 3 -), ethyl _{(CH 3 CH 2 -),} n- propyl _{(CH 3 CH 2 CH 2 -} ), isopropyl _{((CH 3) 2} CH -), n-butyl _{(CH 3 CH 2 CH 2 CH} 2 -), isobutyl _{((CH 3) 2 CHCH 2} -), sec- butyl _{((CH 3) (CH 3} CH 2) CH -), t - butyl _{((CH 3) 3 C -} ), n- pentyl _{(CH 3 CH 2 CH 2 CH} 2 CH 2 -) and neopentyl _{((CH 3) 3 CCH 2} -) means, but not limited thereto.

  The prefix "substituted" on a group means that one or more hydrogen atoms of the group is replaced with the same or different designated substituent.

"Alkylene" means a divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. "C _xy alkylene" means alkylene having xy carbons. Alkylidene and alkylene groups include branched and straight-chain hydrocarbyl groups.

  "Alkoxy" refers to the group -O-alkyl, where alkyl is as defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy and n-pentoxy.

“Aryl” or “Ar” means a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having one ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl). Aryl groups typically include phenyl and naphthyl.
“Aryloxy” refers to the group —O-aryl, where aryl is defined herein, that includes, for example, phenoxy and naphthoxy.

“Cyano” or “carbonitrile” refers to the group —CN.
“Carboxyl” or “carboxy” means —COOH or a salt thereof.
"Carboxyl ester" or "carboxy ester" refers to the group -C (O) O-alkyl, where alkyl is as defined herein.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
"Hydroxy" or "hydroxyl" refers to the group -OH.

  Unless otherwise specified, the nomenclature of substituents not explicitly defined herein is by naming the terminal portion of the functional group and then naming the functional group adjacent toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to (aryl)-(alkyl) -OC (O)-.

  It is understood that the above definitions are not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

  "Compound", as used herein, refers to compounds included in Formula (I) as described herein, and specific compounds of Formula (I), and their oxides, esters, prodrugs, pharmaceuticals Means a chemically acceptable salt or solvate. The term further includes stereoisomers and tautomers of the compound or compounds.

  "Solvate" of a compound means a compound as defined above in association with a stoichiometric or non-stoichiometric amount of solvent. Solvates include solvates of oxides, esters, prodrugs or pharmaceutically acceptable salts of the compounds of formula (I). Solvents are volatile, non-toxic and / or acceptable for human administration in trace amounts. Suitable solvates include water.

  "Stereoisomer" means a compound that differs in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds of formula (I) and any pharmaceutically acceptable salts, esters, oxides and prodrugs thereof, may contain asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can result in compounds that exist in enantiomeric, diastereomeric, and other stereoisomeric forms that can be defined as absolute stereochemistry, such as the (R)-or (S) -form. As a result, all such possible isomers of the compounds, the individual stereoisomers in their optically pure form, their mixtures, racemic mixtures (or racemates), mixtures of diastereomers and one diastereomer Stereomers are intended. The terms "S" and "R" configuration, as used herein, are as defined by IUPAC 1974 RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Appl. Chem. 45: 1330 (1976).

  "Tautomers" include other forms of compounds or ring atoms bound to both a ring-NH-group and a ring = N-group in which the positions of the protons are different, such as enol keto and imine enamine tautomers A tautomeric form of a heteroaryl group is meant, for example, pyrazole, imidazole, benzimidazole, triazole and tetrazole.

  "Pharmaceutically acceptable salt" means pharmaceutically acceptable salts derived from a variety of organic and inorganic counterions well known in the art, such as sodium, potassium, calcium, magnesium, ammonium and tetraalkyl Includes salts with ammonium, as well as salts with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, tartaric acid, mesylic acid, acetic acid, maleic acid and oxalic acid. A pharmaceutically acceptable salt of a compound means a pharmaceutically acceptable salt, including salts of oxides, esters or prodrugs of the compound of formula (I).

  As used herein, the term "pharmaceutically acceptable salt" includes non-toxic acid or alkaline earth metal salts of the compounds of formula (I). These salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or by separately reacting a base or acid function with a suitable organic or inorganic acid or base, respectively. Representative salts are: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, Digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, fumarate, hydrochloride, hydrogen bromide Acid salt, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectic acid Salt, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p- Containing toluene sulfonate and undecanoate but not limited thereto. Also, basic nitrogen-containing groups include alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfate, decyl, lauryl, myristyl. And quaternized with reactants such as long chain halides such as stearyl chloride, bromide and iodide, aralkyl halides such as benzyl and phenethyl chloride and others. This gives a product that dissolves or disperses in water or oil.

  Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, sulfuric and phosphoric acids and oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid. Contains organic acids such as acids. The base addition salt can be used in situ during the final isolation and purification of the compound of formula (I) or with a carboxylic acid group and a suitable base, such as a hydroxide, carbonate or bicarbonate or ammonia of a pharmaceutically acceptable metal cation, Alternatively, it can be produced by separately reacting an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include alkali and alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, and non-toxic ammonium, quaternary ammonium and amine cations, such as limited But not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

  As used herein, the term "ester" means an ester that is hydrolyzed in vivo, including those that are readily degraded in the human body to release the parent compound or a salt thereof. Suitable ester groups are, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic, alkenoic, cycloalkanoic and alkandioic acids, wherein each alkyl or alkenyl group is advantageously Having up to 6 carbon atoms). Examples of specific esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

  The term "prodrug", as used herein, is intended for use in contact with human or animal tissues without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment. Means a prodrug of the compound, balanced by a reasonable benefit / risk ratio, and effective for the intended use, as well as possibly the zwitterionic form of the compound of the invention. Prodrugs are compounds that are rapidly transformed in vivo, for example by hydrolysis, in the blood to yield the parent compound of the above formula. For a general description, see T. Higuchi and V. Stella, Pro drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press. , 1987, both of which are incorporated herein by reference.

  One of skill in the art will appreciate that compounds of Formula (I) or any pharmaceutically acceptable salts, esters, oxides and prodrugs thereof can be processed in vivo by metabolism in the human or animal body or cells to yield metabolites. It will be clear to you. The term "metabolite" as used herein means a derivative of any formula produced in a subject after administration of the parent compound. Derivatives may be produced from the parent compound by biochemical transformations in a variety of subjects, such as oxidation, reduction, hydrolysis or conjugation, including, for example, oxide and demethylated derivatives. Metabolites of the compounds of the present invention can be identified using routine techniques known in the art. For example, Bertolini, G. et al., J. Med. Chem. 40: 2011 2016 (1997); Shan, D. et al., J. Pharm. Sci. 86 (7): 765 767; Bagshawe K., Drug Res. 34: 220 230 (1995); Bodor, N., Advances in Drug Res. 13: 224 331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, IK, Design. and Application of Prodrugs, Drug Design and Development (Krogsgaard Larsen et al., eds., Harwood Academic Publishers, 1991). It is to be understood that individual compounds that are metabolites of a compound of Formula (I) or any of their pharmaceutically acceptable salts, esters, oxides and prodrugs are included in embodiments of the present invention. .

  In certain embodiments, the compound of the present invention is a compound of formula (I) or an oxide, ester thereof, wherein Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, and alkoxy. Prodrug, pharmaceutically acceptable salt or solvate.

  In certain embodiments, the compound of the present invention is a compound of formula (I) or an oxide, ester, prodrug, pharmaceutically acceptable compound thereof, wherein Ra is independently selected from the group consisting of halo and alkyl. Salt or solvate.

  In certain embodiments, the compounds of the present invention are compounds of formula (I) or an oxide, ester, prodrug, pharmaceutically acceptable compound thereof, wherein Ra is two and one is halo and the other is alkyl. Salt or solvate.

  In certain embodiments, the compound of the present invention is a compound selected from compounds 1-53 described in Table 1 below, or an oxide, ester, prodrug, pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the compound of the present invention has a formula
(Compound 32 in Table 1 above) or an oxide, ester, prodrug, pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.

  Methods for synthesizing compounds of formula (I), in particular compounds of compound numbers 1 to 53, are described in detail in WO 2012/014994 and WO 2012/043891. The entirety of these documents is incorporated herein by reference.

Administration and Pharmaceutical Compositions In one embodiment of the invention, a pharmaceutically acceptable carrier comprising at least one compound of formula (I), alone or with additional agents, suitable for administration to a human or animal subject. There is provided a pharmaceutical composition for the treatment of ischemic eye disease, comprising:

  In one embodiment of the present invention, there is provided a compound of formula (I) for the treatment of ischemic eye disease. In a further embodiment of the present invention there is provided the use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of ischemic eye disease.

  "Subject" means an animal, including humans and non-human mammals.

  As used herein, "treat" or "treatment" refers to reducing or eliminating the cause of a disease, slowing or stopping the progression of a disease, in a subject suffering from the disease, and / or Alternatively, it means suppressing, reducing, alleviating, improving, or eliminating symptoms of a disease, for example, abnormalities in visual function.

  Ischemic eye diseases treated by the compounds of formula (I) include all eye diseases caused or associated with ocular ischemia, such as central retinal artery occlusion, branch retinal artery occlusion, Includes optic neuropathy, central retinal vein occlusion, branch retinal vein occlusion, diabetic retinopathy and optic nerve disorders or disorders based on ocular hypertension. In some embodiments, the ischemic eye disease is an acute ischemic eye disease. In certain embodiments, the ischemic ocular disease is associated with ischemia-reperfusion injury.

  Generally, the compounds of the present invention will be administered in therapeutically effective amounts and in pharmaceutically acceptable dosage forms. The actual amount of the compound, ie, the active ingredient, will depend on many factors, such as the severity of the disease being treated, the age and relative health of the subject, the ability of the compound to be used, the route and form of administration, and other factors. The compounds of the present invention can be administered one or more times a day, preferably three or four times a day. All these factors are within the skill of the attending clinician.

  The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. However, specific dosage levels for any particular subject will depend on the activity, age, weight, general health, sex, diet, time of administration, route of administration, rate of elimination, of the particular compound used. It is understood that the combination of the drugs and the specific disease to be treated are based on a variety of factors, including the severity of the disease. Therapeutically effective amounts in certain circumstances can be readily determined by routine experimentation, and are within the skill and judgment of ordinary clinicians.

  Generally, a therapeutically effective amount will be in a total daily dose administered to a host in a single or divided dose, for example, from about 0.001 to about 1000 mg / kg body weight / day, or from about 1.0 to about 30 mg / kg body weight. / Day amount. Dosage unit compositions may contain such submultiples thereof to make up the daily dose.

  Suitable pharmaceutically acceptable carriers or diluents include, for example, processing agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, carboxy. Includes sodium methylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of one or more thereof. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils such as those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. it can. In certain embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991).

  The choice of formulation is based on a variety of factors, such as the drug dosage form and the bioavailability of the drug substance. The agent can be administered as a pharmaceutical composition by any one or a combination of two or more of the following routes: oral, systemic (eg, transdermal, intranasal or by suppository), topical (eg, Ophthalmic, intravitreal, subconjunctival, intrathecal or percutaneous administration or parenteral (eg, by subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection or infusion techniques), preferably oral, ophthalmic Intravitreal, subconjunctival, intra-Tenon or intraperitoneal administration. In one embodiment, the topical administration is eye drops, subconjunctival injection, Tenon's capsule injection, vitreous injection, etc., especially vitreous injection. An exemplary method of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. The composition may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable composition. Another method of administration is inhalation, which delivers the therapeutic agent directly to the respiratory tract (see US Pat. No. 5,607,915). Topical administration also includes the use of transdermal administration such as transdermal patches or iontophoretic devices.

  Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents or suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-propanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or dispersion medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

  Suppositories for rectal administration of the drug include the drug and suitable nonirritating excipients that are solid at room temperature but liquid at the rectal temperature, and thus melt and release the drug in the rectum, such as cocoa butter and polyethylene. It can be produced by mixing glycol.

  Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example, sucrose, lactose or starch. Such dosage forms may also contain, as is normal practice, additives other than inert diluents, eg, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

  Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. . Such compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, cyclodextrins and sweetening, flavoring and flavoring agents.

  The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may contain stabilizers, preservatives, excipients and the like. Examples of lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithin). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq. (1976).

  The compounds of the present invention can be dispersed in aerosol form using a compressed gas. Inert gases suitable for this purpose are nitrogen, carbon dioxide and the like. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

  For delivery by inhalation, the compounds of the invention may be formulated as a solution, suspension, aerosol propellant or dry powder and filled into a suitable dispenser for administration. There are various types of pharmaceutical inhalation devices, nebulizers, inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). The nebulizer device creates a high velocity air stream that sprays the therapeutic agent, which is formulated in a liquid form, as a mist that is delivered to the subject's respiratory tract. An MDI is typically a formulation packaged in a compressed gas. When activated, the device releases a predetermined amount of therapeutic agent by compressed gas, and is thus a reliable method of administering a fixed amount of compound. The DPI releases a therapeutic agent in the form of a free-flowing powder that can be dispersed by the device into the subject's respiratory airflow. To obtain a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A fixed amount of therapeutic agent is stored in capsule form and is released with each actuation.

  The compounds of the present invention can also be administered in the form of eye drops. Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl stearate 40, and polyoxyethylene hydrogenated castor oil. Agents: stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride and paraben can be used as needed. The pH may be in the range acceptable for ophthalmic preparations, but is usually in the range of 4 to 8. The eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.

  Injections for intravitreal administration include isotonic agents such as sodium chloride; buffering agents such as sodium phosphate; surfactants such as polyoxyethylene sorbitan monooleate; thickeners such as methyl cellulose as required. It can be used and prepared.

  The following examples illustrate the invention but do not limit its scope.

Example 1
Compound 32: Synthesis of 4-amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo] naphthalene-1-sulfonic acid sodium salt
(I) 2- (4-fluoro-2-methylphenyl) -5-nitropyridine 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol), tetrakis (triphenylphosphine) palladium (0.35 g, 0.3 mmol) was added to 1,2-dimethoxyethane (50 ml), and degassing and nitrogen replacement were performed three times under reduced pressure. After stirring at room temperature for 20 minutes under a nitrogen atmosphere, 4-fluoro-2-methylphenylboronic acid (31.5 mmol) and a 2M aqueous solution of sodium carbonate (31.5 ml) were added, and the mixture was heated to 80 ° C. After reacting at 80 ° C. for 3 hours, the mixture was cooled to room temperature, and extracted by adding ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave the title compound.

(Ii) 6- (4-Fluoro-2-methylphenyl) pyridin-3-ylamine Ethanol (20 ml) and water (5 ml) were mixed, iron powder was added, and the mixture was heated to 70-80 ° C. Ammonium chloride (0.1 g, 2.1 mmol) was added, then 2- (4-fluoro-2-methylphenyl) -5-nitropyridine (10.0 mmol) obtained in (i) was added, and 70-80 was added. The reaction was performed at a temperature of 1 hour. After completion of the reaction, the iron powder was filtered while hot with Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, and water was added for crystallization and filtration to obtain the title compound.

(Iii) 4-Amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo] naphthalene-1-sulfonic acid sodium salt (6- (4-fluoro-) obtained in (ii) 2-Methylphenyl) pyridin-3-ylamine (58.9 mmol) was dissolved in 99% acetic acid (50 ml), and 35% hydrochloric acid (25 g) was added to form a hydrochloride. Under ice-cooling, a 36% aqueous solution of sodium nitrite (12 g, 62.5 mmol) was added dropwise at 0-5 ° C, and the reaction was carried out for about 15 minutes. Amidosulfuric acid was added and the reaction was further performed for 5 minutes to obtain a diazo liquid. 4-Amino-1-naphthalenesulfonic acid (13.0 g, 58.4 mmol) was suspended in water (130 ml) and adjusted to pH 8-9 with a 10% aqueous sodium hydroxide solution. The mixture was cooled to 5-10 ° C, and the obtained diazo liquid was added dropwise at 5-10 ° C. At that time, the pH was adjusted with a 10% aqueous sodium hydroxide solution so as to maintain the pH at 7-9. After completion of the dropwise addition, the reaction was carried out at 5-10 ° C. for 1 hour, and then the temperature was raised to room temperature. Salting out was performed with a saturated saline solution, and the precipitated crystals were filtered by suction. Purification by column chromatography gave the title compound.
¹ H-NMR δ [ppm] = 9.22 (1H, d, J = 2.4 Hz), 8.76 (1H, d, J = 8.1), 8.49-8.44 (2H, m), 8.34 (1H, s), 7.82 ( 2H, bs), 7.67-7.47 (4H, m), 7.21-7.11 (2H, m), 2.41 (3H, s)
¹³ C-NMR (DMSO-d6) δ [ppm] = 163.5, 160.3, 158.2, 147.1, 146.7, 145.4, 138.8, 138.7, 136.1, 136.1, 132.4, 132.1, 131.8, 131.7, 129.2, 128.6, 128.3, 127.2, 125.1, 124.6, 124.2, 124.0, 117.3, 117.1, 116.6, 112.9, 112.6, 20.4, 20.4

Example 2
Creation of retinal ischemia rat model
A retinal ischemia (I / R) rat model was created using Thy1-GFP rats (Magill CK et al. Arch Facial Plast Surg 2010) donated by Washington University. Male rats, 8-10 weeks of age, were anesthetized by intramuscular injection of ketamine (80 mg / kg of body weight) and xylazine (5 mg / kg of body weight), and a 33G needle was inserted into the anterior chamber of the eye. The saline was perfused and the intraocular pressure was raised to 150 mmHg. After confirming collapse of the retinal artery by fundus observation, high intraocular pressure was maintained for 60 minutes to create a retinal ischemia rat model.

Example 3
Measurement of Retinal Potential in Retinal Ischemia Rats The electroretinogram (ERG) was measured in retinal ischemia rats to which Compound 32 was orally administered.
From day 3 before the I / R, Compound 32 (50 mg / kg) dissolved in physiological saline was orally administered to rats once a day by gastric tube. Control rats received saline alone in the same manner. The electroretinogram (ERG) was measured before and 7 days after the start of I / R. The rats were dark-adapted 24 hours before the ERG measurement, and examined under general anesthesia (80 mg / kg ketamine + 5 mg / kg xylazine intramuscular injection) and mydriasis (0.5% phenylephrine, 5% neosinedin). Under dark adaptation, Ganzfeld was stimulated at 3 cds / m ² in full-field ERG and waveforms were recorded with a contact lens-type electrode worn on the cornea. The results are shown in FIG.

  As shown in FIG. 1, in the rats to which the compound 32 was administered, the decrease in the amplitude of the b-wave and the a-wave was mild compared to the control rats to which the physiological saline was administered. In addition, the extension of the b-wave latency was slight. This result indicates that the administration of Compound 32 suppressed the decrease in visual function due to ischemia and / or ischemia reperfusion.

Example 4
Measurement of Retinal Potential in Retinal Ischemia Rats An electroretinogram (ERG) was measured in retinal ischemia rats to which Compound 32 was intraperitoneally administered.
From day 3 before the I / R, Compound 32 (50 mg / kg) dissolved in physiological saline was administered to rats once a day by intraperitoneal injection. Control rats received saline alone in the same manner. The electroretinogram (ERG) was measured before and 7 days after the start of I / R. The rats were dark-adapted 24 hours before the ERG measurement, and examined under general anesthesia (80 mg / kg ketamine + 5 mg / kg xylazine intramuscularly) and under mydriasis (0.5% phenylephrine, 5% neosinedin). Under dark adaptation, Ganzfeld was stimulated at 3 cds / m ² in full-field ERG and waveforms were recorded with a contact lens-type electrode worn on the cornea. FIG. 2 shows the results.

  As shown in FIG. 2, in the rats to which the compound 32 was administered, the decrease in the amplitude of the b-wave and the a-wave was mild compared to the control rats to which the physiological saline was administered. In addition, the extension of the b-wave latency was slight. This result indicates that the administration of Compound 32 suppressed the decrease in visual function due to ischemia and / or ischemia reperfusion.

Example 5
Measurement of Retina Potential in Retinal Ischemia Rats In the same manner as in Example 4, the electroretinogram (ERG) was measured in retinal ischemia rats (N = 11) and control rats (N = 11) to which compound 32 was intraperitoneally administered. . The results are shown in Table 2 and FIG.

  As shown in FIG. 3, before the I / R, the b-wave amplitude was 0.562 ± 0.155 mV (mean ± standard deviation) in the rats to which Compound 32 was administered, and the b-wave amplitude in the control rats to which physiological saline was administered. There was no significant difference at 0.617 ± 0.110 mV (mean ± standard deviation) (P = 0.37). The b-wave amplitude 7 days after I / R was 0.214 ± 0.144 mV (mean ± standard deviation) in the rats administered with Compound 32, and 0.104 ± 0.034 mV in the control rats administered saline. (Mean ± standard deviation) was significantly greater in compound 32 treated rats (P = 0.03). This result indicates that the administration of Compound 32 suppressed the decrease in visual function due to ischemia and / or ischemia reperfusion.

  From the above test results, it is understood that the compounds of the present invention, especially Compound 32, can be used for treating ischemic eye disease.

Claims (14)

Formula (I) for the treatment of ischemic eye disease:

(In the formula,
Ra is halo, hydroxy, C _1-6 alkyl, halo substituted C _1-6 alkyl, C _1-6 alkoxy, hydroxy or carboxy substituted C _1-6 alkoxy, CHO, C (O) —C _1-6 alkyl, C _{(O) -C 1-6} alkyl - is selected from the group consisting of carboxy ester and cyano, - carboxyl, C _{(O) -C 1-6} alkylene
m is an integer selected from 0 to 4]
Or a pharmaceutically acceptable salt or solvate thereof , provided that the ischemic eye disease is not normal tension glaucoma . The pharmaceutical composition according to claim 1, wherein Ra is each independently selected from the group consisting of halo, hydroxy, _C1-6alkyl , halo-substituted _C1-6alkyl and _C1-6alkoxy . The pharmaceutical composition according to claim 1 or 2, wherein Ra is each independently selected from the group consisting of halo and _C1-6alkyl . Ra exists two, one is halo and the other is C _1-6 alkyl A pharmaceutical composition according to any one of claims 1 to 3.   The compound is 4-amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo] naphthalene-1-sulfonic acid or a pharmaceutically acceptable salt or solvate thereof; The pharmaceutical composition according to any one of claims 1 to 4.   The pharmaceutical composition according to any one of claims 1 to 5, wherein the ischemic eye disease is an acute ischemic eye disease.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the ischemic eye disease is associated with ischemia-reperfusion injury.   Ischemic eye disease, central retinal artery occlusion, branch retinal artery occlusion, ischemic optic neuropathy, central retinal vein occlusion, branch retinal vein occlusion, diabetic retinopathy or optic nerve disease based on ocular hypertension or The pharmaceutical composition according to any one of claims 1 to 7, which is an optic nerve disorder.   The pharmaceutical composition according to any one of claims 1 to 8, wherein the ischemic eye disease is central retinal artery occlusion, branch retinal artery occlusion, or ischemic optic neuropathy.   The pharmaceutical composition according to any one of claims 1 to 9, wherein the ischemic eye disease is central retinal artery occlusion or branch retinal artery occlusion.   The pharmaceutical composition according to any one of claims 1 to 10 for topical administration.   The pharmaceutical composition according to any one of claims 1 to 11, which is used for vitreous administration.   The pharmaceutical composition according to any one of claims 1 to 10 for oral administration.   Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a pharmaceutical composition for the treatment of ischemic eye disease.