WO2009087900A1

WO2009087900A1 - Pharmaceutical agent for prevention or treatment of diseases accompanied by intraocular vascular hyperpermeability

Info

Publication number: WO2009087900A1
Application number: PCT/JP2008/073504
Authority: WO
Inventors: Hiroaki Nakamura
Original assignee: Daiichi Sankyo Company, Limited
Priority date: 2008-01-11
Filing date: 2008-12-25
Publication date: 2009-07-16
Also published as: TW200934484A

Abstract

Disclosed is a pharmaceutical agent useful for the prevention or treatment of retinal ischemic diseases. Specifically disclosed is a pharmaceutical agent for the prevention or treatment of diseases having intraocular vascular hyperpermeability including diabetic retinopathy (simple background retinopathy, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related macular degeneration, central serous choroidopathy, diabetic macular edema, cystoids macular edema, uveitis and Behcet's disease. The pharmaceutical agent comprises, as an active ingredient, an angiotensin II receptor blocker such as 4-(1-hydroxy-1-methylethyl)-2-propyl-1- [2'-(1H-tetrasol-5-yl)biphenyl-4-ylmethyl]imidazole-5- carboxylic acid.

Description

Medicament for prevention or treatment of diseases associated with increased intraocular vascular permeability

The present invention relates to a medicament for preventing or treating a disease associated with increased intraocular vascular permeability comprising an angiotensin II receptor antagonist as an active ingredient.

Angiotensin II receptor antagonist is used as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease such as cardiac hypertrophy, heart failure, or myocardial infarction, or stroke or nephritis. It is thought to be due to the inhibition of binding of angiotensin II, which has a strong vasoconstrictive action, to the angiotensin II receptor.
As an action of olmesartan on intraocular vascular disease, improvement of electroretinogram changes in a diabetic animal model (see, for example, Non-Patent Document 1), and suppression of retinal neovascularization in an animal model of proliferative retinopathy ( For example, see Patent Document 1). However, it is not conventionally known that olmesartan has a preventive or therapeutic effect on diseases in which vascular permeability is enhanced in the retina, such as in the early stage of diabetic retinopathy.

International Publication No. 2004/091659 Pamphlet

An object of the present invention is to provide a medicament useful for the prevention or treatment of retinal ischemic disease.

As a result of intensive studies to solve the above problems, the present inventors have found that olmesartan is highly effective in preventing or treating diseases in which intraocular vascular permeability such as diabetic macular edema is enhanced. . The present invention has been completed based on the above findings.

That is, the present invention
(1) A medicament for preventing or treating retinal ischemic disease, comprising an angiotensin II receptor antagonist as an active ingredient,
(2) a medicament for the prevention or treatment of retinal ischemic disease associated with increased intraocular vascular permeability, comprising an angiotensin II receptor antagonist as an active ingredient,
(3) Retinal ischemic disease with increased intraocular vascular permeability is diabetic retinopathy (simple retinopathy, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related macular degeneration, (2) the pharmaceutical agent according to (2), which is central serous chorioretinopathy, diabetic macular edema, cystoid macular edema, uveitis, or Behcet's disease
(4) An angiotensin II receptor antagonist is 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] The medicament according to (1) to (3) selected from the group consisting of imidazole-5-carboxylic acid and pharmacologically acceptable esters thereof, and pharmacologically acceptable salts thereof,
(5) An angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [ (2)-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylate.

According to a further preferred embodiment of the present invention, the angiotensin II receptor antagonist is 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl). ) Biphenyl-4-ylmethyl] imidazole-5-carboxylic acid and a pharmacologically acceptable ester thereof, and a pharmacologically acceptable salt thereof, the above medicament is provided, According to a particularly preferred embodiment, the angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl There is provided a medicament as described above which is -1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylate.

From another point of view, according to the present invention, an angiotensin II receptor antagonist for the manufacture of the above medicament, preferably 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2′- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid and pharmacologically acceptable esters thereof, and pharmacologically acceptable salts thereof Angiotensin II receptor antagonist selected from the group consisting of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl- The use of 1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylate is provided.

From another viewpoint, diseases associated with increased intraocular vascular permeability, preferably diabetic retinopathy (simple retinopathy, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related A method for the prevention or treatment of macular degeneration, central serous chorioretinopathy, diabetic macular edema, cystoid macular edema, uveitis, or Behcet's disease, comprising an angiotensin II receptor antagonist, preferably 4- (1- Hydroxy-1-methylethyl) -2-propyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid and pharmacologically acceptable An angiotensin II receptor antagonist selected from the group consisting of pharmaceutically acceptable salts thereof, and more preferably (5-methyl-2-oxo-1,3-dioxolene). -4-yl) methyl-l- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole Provided by the present invention is a method comprising the step of administering a prophylactically or therapeutically effective amount of 5-carboxylate to a mammal, including a human.

The inventors of the present invention are (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ジ 4- (1-hydroxy-1-methylethyl) -2, which is a kind of angiotensin II receptor antagonist. -Propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylate (hereinafter referred to as “olmesartan medoxomil”) is intraocular vascular permeability. It has been shown that olmesartan medoxomil has improved the disease associated with increased intraocular vascular permeability, as far as it is known, and is novel in this regard. Has already been used clinically as an antihypertensive drug, and there are almost no safety issues in patients with diseases with increased intraocular vascular permeability. It is a big feature.

The medicament of the present invention containing an angiotensin II receptor antagonist as an active ingredient is diabetic retinopathy (simple retinopathy, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related macular degeneration. It is useful for the prevention or treatment of diseases with increased vascular permeability in the eye, such as central serous chorioretinopathy, diabetic macular edema, cystoid macular edema, uveitis, or Behcet's disease.

Effect of olmesartan medoxomil in a neonatal rat oxygen-induced retinal vascular permeability model. N is the air rearing / solvent administration group, V is the oxygen load / solvent administration group, CS0.3 is the oxygen load / olmesartan medoxomil 0.3 mg / kg administration group, CS1 is the olmesartan medoxomil 1 mg / kg administration group, and CS3 is the olmesartan The medoxomil 3 mg / kg administration group is shown. Data are expressed as mean ± standard error. ## is P <0.01 (Student's-t test) for the breeding / solvent administration group, * is P <0.05 (Dunnett's test) for the oxygen loading / solvent administration group, and ** is in the oxygen loading / solvent administration group P <0.01 (Dunnett's test) is shown.

In the present invention, an angiotensin II receptor antagonist means a substance that can competitively or non-competitively inhibit the binding of angiotensin II to an angiotensin II receptor. The angiotensin II receptor antagonist may be a low molecular weight organic compound, peptide compound, saccharide compound, or a high molecular compound such as a protein, glycoprotein, or polysaccharide compound. Whether or not a certain substance has an angiotensin II receptor antagonistic activity can be easily confirmed by those skilled in the art, for example, according to the method described in US Pat. No. 5,616,599. As used herein, the term “angiotensin II receptor antagonist” should not be construed as limiting in any way, but in the broadest sense.

As an example of an angiotensin II receptor antagonist that can be suitably used for the medicament of the present invention, for example, 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazo- Mention may be made of (l-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylic acid, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable salts thereof. 4- (1-Hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid is known For example, it can be easily obtained by the method described in JP-A-5-78328 (US Pat. No. 5,616,599).

4- (1-Hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid The kind of salt that is physically acceptable is not particularly limited and can be appropriately selected by those skilled in the art. For example, alkali metal salts such as sodium salt, potassium salt, and lithium salt, alkali salts such as calcium salt, and magnesium salt are available. Metal salt such as earth metal salt, aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt; or ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine Alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexyl Amines such as amine salts, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Examples thereof include salts, but are not limited thereto. An alkali metal salt can be preferably used, and a sodium salt can be particularly preferably used.

4- (1-Hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid A physically acceptable ester means a compound in which the carboxylic acid moiety in the molecule of the compound is esterified. The kind of ester accept | permitted pharmacologically is not specifically limited, Those skilled in the art can select suitably. The ester is preferably one that can be cleaved in vivo by a biological method such as hydrolysis. Examples of the group constituting the ester (the group represented by R when the ester is represented by —COOR) include methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (iso C1-C4 alkoxy C1 such as propoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl A C1-C4 alkoxy group such as 2-methoxyethoxymethyl; a C1-C4 alkoxy C1-C4 alkyl group; a C6-C10 aryloxy C1-C4 alkyl group such as phenoxymethyl; Halogenated C1-C4 alkoxy such as trichloroethoxymethyl or bis (2-chloroethoxy) methyl C1-C4 alkyl group; C1-C4 alkoxycarbonyl such as methoxycarbonylmethyl C1-C4 alkyl group; cyano C1-C4 alkyl group such as cyanomethyl or 2-cyanoethyl; C1-C4 such as methylthiomethyl or ethylthiomethyl Alkylthiomethyl group; C6-C10 arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; C1-C4 alkylsulfonyl C1 optionally substituted with halogen such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl -C4 lower alkyl group; C6-C10 arylsulfonyl C1-C4 alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl Pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivalo Yloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyl Ryloxypropyl, 1-pivaloyloxy Propyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, C1-C7 aliphatic acyloxy C1-C4 alkyl group such as 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl or 1-pivaloyloxyhexyl; cyclopentylcarbonyl Oxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclope C5-C6 cycloalkylcarbonyloxy C1-C4 alkyl groups such as tilcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; C6-C10 arylcarbonyloxy C1-C4 alkyl groups such as benzoyloxymethyl, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (methoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) pentyl, 1- (ethoxycarbonyl) Rubonyloxy) hexyl, propoxycarbonyloxymethyl, 1- (propoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) butyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ) Ethyl, 1- (isopropoxycarbonyloxy) butyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) butyl, isobutoxycarbonyloxymethyl 1- (isobutoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) butyl, t-butoxycarbonyloxy Cymethyl, 1- (t-butoxycarbonyloxy) ethyl, pentyloxycarbonyloxymethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) propyl, hexyloxycarbonyloxymethyl, 1- (hexyloxy) C1-C6 alkoxycarbonyloxy C1-C4 alkyl groups such as carbonyloxy) ethyl or 1- (hexyloxycarbonyloxy) propyl; cyclopentyloxycarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxy) Carbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) A C5-C6 cycloalkyloxycarbonyloxy C1-C4 alkyl group such as ethyl, 1- (cyclohexyloxycarbonyloxy) propyl or 1- (cyclohexyloxycarbonyloxy) butyl; (5-methyl-2-oxo-1,3 -Dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methyl , (5- (C 1) such as (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl or (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; -C4 alkyl) -2-oxo-1,3-dioxolen-4-yl] methyl group; (5-phenyl-2-oxo-1,3-dioxolen-4- Yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolene- 4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl or [5- (4-chlorophenyl) -2-oxo-1,3-dioxolene [5- (C1-C4 alkyl, C1-C4 alkoxy or phenyl optionally substituted with halogen) -2-oxo-1,3-dioxolen-4-yl] methyl group such as -4-yl] methyl, Or a phthalidyl group which may be substituted with C1-C4 alkyl or C1-C4 alkoxy such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl. Preferably, a pivaloyloxymethyl group, a phthalidyl group or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group can be used, and more preferably (5-methyl A -2-oxo-1,3-dioxolen-4-yl) methyl group can be used.

4- (1-Hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylic acid ester When forming a pharmacologically acceptable salt, the type of pharmacologically acceptable salt can be appropriately selected by those skilled in the art and is not particularly limited. For example, a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide; nitrate; perchlorate; sulfate; phosphate; methanesulfonate, trifluoro C1-C4 alkane sulfonate which may be substituted with halogen such as methane sulfonate or ethane sulfonate; C1-C4 alkyl which may be substituted with benzene sulfonate, p-toluene sulfonate, etc. Good C6-C10 aryl sulfonates; C1-C6 fatty acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate or maleate; or glycine salt , Lysine salts, arginine salts, ornithine salts, amino acid salts such as glutamate or aspartate, and the like. Preferably, hydrochloride, nitrate, sulfate, or phosphate can be used, and particularly preferably, hydrochloride can be used.

As an angiotensin II receptor antagonist, 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4- Ylmethyl] imidazol-5-carboxylic acid or a pharmaceutically acceptable ester thereof can be used, more preferably 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [ A pharmacologically acceptable ester of 2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid can be used, and even more preferably, 4- (1-Hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid Acryloyloxy methyl ester, can be used phthalidyl ester, or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester. Most preferably, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H- Tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylate can be used.

4- (1-Hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid and drugs Hydrates or solvates can also be used as the substance selected from the group consisting of the physically acceptable esters thereof and the pharmacologically acceptable salts thereof.

4- (1-Hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid When using a physically acceptable ester, the ester compound may have one or more asymmetric carbons, but the pure form of optical isomers or diastereoisomers based on the asymmetric carbons. Stereoisomers such as isomers, or any mixture or racemate of stereoisomers can also be used.

Examples of the angiotensin II receptor antagonist that can be used in the present invention include imidazole derivatives (Japanese Patent Laid-Open Nos. 56-71073, 56-71074, 57-98270, No. 58-157768, USP 4,355,040, USP 4,340,598, etc., EP-253310, EP-291969, EP-324377, EP-403158, WO-9001307, JP-A-63-23868, And pyrrole, pyrazole, and triazole derivatives (USP 5,183,899, EP-323841, EP-409332, and JP-A-1-287071), benzimidazole derivatives (USP4, etc.). 880, 804, EP-0392317, EP 0399732, EP-0400835, EP-425921, EP-459136, JP-A-2001-10975, and JP-A-3-63264, etc.), azaindene derivatives (EP-399731 etc.), pyrimidone derivatives (EP-407342 etc.) Quinazoline derivatives (EP-411766 etc.), xanthine derivatives (EP-430300 etc.), condensed imidazole derivatives (EP-434038 etc.), pyrimidinedione derivatives (EP-442473 etc.), thienopyridone derivatives (EP-443568 etc.), heterocyclic rings Compounds (EP-445811, EP-483683, EP-518033, EP-520423, EP-588299, EP-603712, etc.), and the like, preferably, losartan, eprosartan, Candesartan cilexetil, Valsartan, Telmisartan, Irbesartan, Tasosartan, Azilsartan, or their metabolically active substances. In addition, physiologically acceptable salts of these compounds, hydrates or solvates of compounds in a free form or a salt form, or derivatives such as prodrugs can also be used. In addition, azilsartan medoxomil, azilsartan medoxomil, 2-cyclopropyl-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl- 4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl or a salt thereof and 2-cyclopropyl-1-{[2 '-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl- 2-Oxo-1,3-dioxol-4-yl) methyl or a salt thereof is regarded as a promising therapeutic agent for hypertension and the like, and is disclosed in WO 2005/080384 pamphlet or WO 2006/107062 pamphlet. Can be produced by the method disclosed in the above or the like, or a method analogous thereto.

The medicament of the present invention can be used for the prevention or treatment of diseases associated with increased intraocular vascular permeability. In the present specification, the term “prevention or treatment” includes improvement or cure of a disease, suppression of progression of the disease, prevention of onset, prevention of recurrence, and the like. The term “prevention or treatment” should not be construed as limiting in any way, but the term should be interpreted in the broadest sense.

Examples of diseases with increased vascular permeability in the eye include diabetic retinopathy (simple retinopathy, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related macular degeneration, centrality Including serous retina choroidopathy, diabetic macular edema, cystoid macular edema, uveitis, or Behcet's disease.

Diabetic retinopathy (simple retinopathy, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related macular degeneration, central serous chorioretinopathy, diabetic macular edema, cystoid macular edema , Uveitis, or Behcet's disease can be used for prevention or treatment of diseases in which vascular permeability is increased in the eye.
Since the above-mentioned angiotensin II receptor antagonist is generally an orally administered drug, it is desirable to administer the medicament of the present invention orally. However, the administration form of the medicament of the present invention is not limited to oral administration, and can be administered parenterally, for example, intravenous administration, rectal administration, transdermal administration, transmucosal administration, ophthalmic administration, etc. . Examples of unit dosage forms suitable for oral administration include, but are not limited to, powders, granules, tablets, capsules and the like. In preparing the unit dosage form, one or more pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents and the like as appropriate. Pharmaceutical additives can be used.

Pharmaceutical additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, alpha starch or dextrin; crystalline cellulose and the like Organic derivatives such as gum arabic; gum arabic; dextran; or pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, or magnesium metasilicate aluminate; calcium hydrogen phosphate Such as phosphates; carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate), lubricants (eg, stearic acid, calcium stearate or magnesium stearate) Metal stearate Talc; waxes such as bees wax or gay wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl such as sodium lauryl sulfate or magnesium lauryl sulfate Or a silicic acid such as silicic anhydride or silicic acid hydrate; or the above-mentioned starch derivatives), a binder (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or the above Compounds similar to the excipients), disintegrants (eg low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked carboxymethylcellulose nato Cellulose derivatives such as lithium; chemically modified starches and celluloses such as carboxymethyl starch, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone; or the above starch derivatives can be mentioned), emulsifiers (for example, bentonite or beegum Colloidal clays such as; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; or Nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters or sucrose fatty acid esters), stabilizers (eg methyl parabens) Are paraoxybenzoates such as propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid Can be mentioned), flavoring agents (for example, commonly used sweeteners, acidulants or fragrances can be mentioned), or diluents can be mentioned, but are not limited thereto. There is no.

The dose of the medicament of the present invention can be appropriately selected according to various factors such as administration route, type of active ingredient, patient age, weight, or symptom, purpose of prevention or treatment, etc. Can be administered in the range of about 0.001 to 1,000 mg, preferably 0.1 to 500 mg, more preferably about 5 to 80 mg as the weight of an angiotensin II receptor antagonist per adult day.

EXAMPLES Hereinafter, although an Example and a formulation example demonstrate this invention further more concretely, the scope of the present invention is not limited by the following Example.

Test Example Seven-day-old Brown-Norway rats (Nippon Charles River) were reared with mother rats under 70-75% oxygen until the age of 12 days. Then, it returned to air | atmosphere and was raised to 16 days after birth. During rearing in the atmosphere, a suspension of olmesartan medoxomil (solvent: 0.5% carboxymethylcellulose) or a solvent (0.5% carboxymethylcellulose) was orally administered once a day. After completion of administration, retinal vascular permeability was measured by a modification of the FITC-dextran method (Ishida et al., Invest. Ophthalmol. Vis. Sci. 2003; 44: 2155-2162). That is, under anesthesia by intraperitoneal administration of pentobarbital (50 mg / kg), FITC-dextran (molecular weight 4.4 kDa) 100 mg / kg was administered to the femoral vein. The chest was opened 10 minutes later, and a blood sample was obtained from the heart. Subsequently, after securing the drainage path by right atrial appendage incision, PBS was perfused with a pressure of 80 mmHg for 2 minutes from the cannula inserted into the left ventricle, and the retina was removed. The wet weight of the retina was measured, homogenized in 0.3 ml of distilled water, and filtered through a centrifugal filter (Millipore Ultrafree-MC; molecular weight 30,000). Meanwhile, plasma was obtained by centrifugation of the blood sample. The amount of pigment in retinal filtrate and plasma was measured with a microplate reader (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm), and the fluorescence of the retinal filtrate of animals not administered with the pigment was subtracted as a blank. Retinal vascular permeability was determined by dividing the retinal pigment concentration by the plasma pigment concentration and then dividing by the retinal wet weight.

Formulation Example 1: Capsule

After the powder of the above formulation is mixed and passed through a 60 mesh sieve, this powder is put into a 250 mg No. 3 gelatin capsule to form a capsule.

Formulation Example 2: Tablet

The powder of the said prescription is mixed and tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

According to the present invention, it is possible to provide a medicament useful for the prevention or treatment of diseases associated with increased intraocular vascular permeability.

Claims

A medicament for preventing or treating retinal ischemic disease, comprising an angiotensin II receptor antagonist as an active ingredient.
A medicament for the prevention or treatment of retinal ischemic disease associated with increased intraocular vascular permeability, comprising an angiotensin II receptor antagonist as an active ingredient.
Retinal ischemic disease with increased intraocular vascular permeability is diabetic retinopathy (simple retinopathy, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related macular degeneration, central serous fluid The medicament according to claim 2, which is diabetic choroidopathy, diabetic macular edema, cystoid macular edema, uveitis, or Behcet's disease.
Angiotensin II receptor antagonist is 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole The medicament according to claim 1 or 3, selected from the group consisting of -5-carboxylic acid and pharmacologically acceptable esters thereof, and pharmacologically acceptable salts thereof.
Angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2′- 4. The medicament according to claim 1, which is (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylate.