JP2011148704A - Phenylimidazole derivative and therapeutic and/or prophylactic agent for retinal disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine useful for therapy and/or prophylaxis of retinal disorders. <P>SOLUTION: The compound is represented by formula (I). [In formula (I), (a) represents 1 or 2; R<SP>0</SP>represents amino or the like; R<SP>1</SP>to R<SP>4</SP>independently represent hydrogen or the like; R<SP>5</SP>represents amino or the like; R<SP>6</SP>represents substituted alkyl; b represents 1 to 4; d represents one integer of 0 to 3; and R<SP>7</SP>and R<SP>8</SP>independently represent halogen or the like]. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel phenylimidazole derivative and a therapeutic and / or prophylactic agent for retinal disorders containing at least one selected from these derivatives as an active ingredient.

When the retina receives external light, the energy is absorbed by the visual substance (rhodopsin) in the inner and outer segments of the photoreceptor cell and converted into an electrical signal. Intracellular visual conduction pathways are visual cells, bipolar cells, and ganglion cells in that order, and then transmitted to the visual cortex of the cerebral occipital lobe via the visual pathway and perceived as an image.
It is said that photoreceptor cells are easily denatured because a large amount of higher unsaturated fatty acids such as docosahexaenoic acid and arachidonic acid are present in the photoreceptor outer segment where this visual substance exists. Moreover, since the degeneration of photoreceptor cells is almost irreversible, it causes severe visual impairment.
It is known that the degeneration of photoreceptor cells occurs genetically, but is also caused by various oxidative stresses such as light (ultraviolet rays), iron, oxygen, and radiation. In particular, the light that the eye receives over its lifetime is representative of oxidative stress in the retina and is considered a major cause of retinal damage.
A typical retina choroidal disease associated with retinal damage, particularly retinal photopathy, is age-related macular degeneration (hereinafter referred to as “AMD”). AMD is a disease that causes degeneration of the macular region of the retina with aging, and continues to increase as the aging society progresses. Especially in Europe and the United States, it is the top cause of blindness. AMD is accompanied by neovascularization arising from the choroid, exudative AMD that produces subretinal hemorrhage, edema, serous retinal detachment (hereinafter referred to as “Wet AMD”), and no neovascularization arising from the choroid. In addition, there is an atrophic type (hereinafter referred to as “Dry AMD”) in which retinal pigment epithelial cells, choroidal capillaries, and other map-like atrophy lesions are recognized. Wet AMD has a fast progression, poor prognosis, and severe visual impairment. On the other hand, although Dry AMD progresses slowly, when a lesion spreads to the macula, it causes a high degree of visual impairment. In addition, both are progressive and often binocular.
For the treatment of Wet AMD, photodynamic therapy, laser treatment (laser photocoagulation), surgical treatment (neovascularization, foveal movement, etc.) are used, but there are various prognostic issues, Treatment satisfaction is extremely low, and VEGF-related therapeutic agents and the like have been developed as medical treatments, but satisfactory therapeutic effects are not mentioned due to administration routes, side effects and the like. In addition, almost no medical treatment has been performed for Dry AMD.

  On the other hand, Patent Document 1 describes a dihydrobenzofuran derivative having an excellent antioxidant action and tissue migration. However, some of these derivatives have a therapeutic and / or prophylactic effect and some do not, in an actual animal model of retinal photopathy due to their chemical structure.

WO2007 / 052794 Publication Pamphlet

  An object of the present invention is to provide a medicament useful for the treatment and / or prevention of retinal disorders.

  In order to solve the above-mentioned problems, the present inventors diligently searched for a new compound using an animal model of retinal photopathy. As a result, a compound group having a therapeutic and / or prophylactic effect against retinal photopathy was found while maintaining an excellent antioxidant action and tissue transferability by oral administration, and the present invention was completed.

（式（Ｉ）中、ａは、１又は２を表す。
Ｒ^０は、アミノ基、Ｃ_１−６アルキル基で置換されたアミノ基、Ｃ_１−６アルキルカルボニルアミノ基、Ｃ_１−６アルコキシカルボニルアミノ基、Ｃ_１−６アルキルスルホニルアミノ基、水酸基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルカルボニルオキシ基、Ｃ_１−６アルコキシカルボニルオキシ基又はＣ_１−６アルキルスルホニルオキシ基を表す。
Ｒ^１〜Ｒ^４は、それぞれ独立して、水素原子、Ｃ_１−６アルキル基又はＣ_１−６ハロアルキル基を表す。
Ｒ^５は、Ｇ又はＧで置換されたＣ_１−６アルキル基を表す。
Ｇはアミノ基、Ｃ_１−６アルキル基で置換されたアミノ基、Ｃ_１−６アルキルカルボニルアミノ基、Ｃ_１−６アルコキシカルボニルアミノ基、Ｃ_１−６アルキルスルホニルアミノ基、水酸基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルカルボニルオキシ基、Ｃ_１−６アルコキシカルボニルオキシ基又はシアノ基を表す。
Ｒ^６は、Ｇで置換されたＣ_１−６アルキル基を表す。
ｂは、１〜４のいずれかの整数を表し、ｂが２以上のときＲ^５は、同一又は相異なってもよい。
ｄは、０〜３のいずれかの整数を表し、ｄが２以上のときＲ^６は、同一又は相異なってもよい。
Ｒ^７及びＲ^８は、それぞれ独立して、ハロゲン原子又はＧ以外の有機基を表す。
ｅは、０〜３のいずれかの整数を表し、ｅが２以上のときＲ^７は、同一又は相異なってもよい。ただし、ｂ＋ｅ≦４である。
ｆは、０〜３のいずれかの整数を表し、ｆが２以上のときＲ^８は、同一又は相異なってもよい。ただし、ｄ＋ｆ≦３である。）
で表される化合物又はその塩に関する。 That is, the present invention
(1) Formula (I)

(In formula (I), a represents 1 or 2.
R ⁰ is an amino _{group, C 1-6} alkyl-substituted amino group with a _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkoxycarbonylamino _{group, C 1-6} alkylsulfonylamino group, a hydroxyl group, C _{A 1-6} alkoxy group, a C _1-6 alkylcarbonyloxy group, a C _1-6 alkoxycarbonyloxy group or a C _1-6 alkylsulfonyloxy group is represented.
R ^{1 to} R ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 haloalkyl group.
R ⁵ represents G or a C _1-6 alkyl group substituted with G.
G is an amino _{group, C 1-6} alkyl-substituted amino group with a _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkoxycarbonylamino _{group, C 1-6} alkylsulfonylamino group, a hydroxyl _{group, C 1- A 6} alkoxy group, a C _1-6 alkylcarbonyloxy group, a C _1-6 alkoxycarbonyloxy group or a cyano group;
R ⁶ represents a C _1-6 alkyl group substituted with G.
b represents any integer of 1 to 4, and when b is 2 or more, R ⁵ may be the same or different.
d represents any integer of 0 to 3, and when d is 2 or more, R ⁶ may be the same or different.
R ⁷ and R ⁸ each independently represents a halogen atom or an organic group other than G.
e represents an integer of 0 to 3, and when e is 2 or more, R ⁷ may be the same or different. However, b + e ≦ 4.
f represents any integer of 0 to 3, and when f is 2 or more, R ⁸ may be the same or different. However, d + f ≦ 3. )
Or a salt thereof.

Furthermore, the present invention provides
(2) The present invention relates to a retinal disorder therapeutic agent and / or preventive agent comprising as an active ingredient at least one selected from the group consisting of the compound represented by the formula (I) and a salt thereof.

  The compound represented by the formula (I) or a salt thereof according to the present invention effectively treats and / or prevents retinal disorders, particularly retinal light disorders.

Hereinafter, the present invention will be described in detail.
1) Compound represented by formula (I) or a salt thereof In the compound represented by formula (I) or a salt thereof, a represents 1 or 2. When a is 1, it is a 2,3-dihydrobenzofuran ring, and when it is 2, it is a chroman ring. Preferred is a 2,3-dihydrobenzofuran ring in which a is 1.

R ⁰ is an amino _{group, C 1-6} alkyl-substituted amino group with a _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkoxycarbonylamino _{group, C 1-6} alkylsulfonylamino group, a hydroxyl group, C _{Represents a 1-6} alkoxy group, a C _1-6 alkylcarbonyloxy group, a C _1-6 alkoxycarbonyloxy group or a C _1-6 alkylsulfonyloxy group, preferably an amino group or a hydroxyl group, particularly preferably an amino group; is there.

Specific examples of R ⁰ include an amino group; an amino group substituted with a C _1-6 alkyl group such as methylamino group, ethylamino group, n-propylamino group, dimethylamino group, diethylamino group, diisopropylamino group; C _1-6 alkylcarbonylamino groups such as methylcarbonylamino group, ethylcarbonylamino group, n-propylcarbonylamino group, isopropylcarbonylamino group; methoxycarbonylamino group, ethoxycarbonylamino group, n-propoxycarbonylamino group, iso C _1-6 alkoxycarbonylamino group such as propoxycarbonylamino group; C _1-6 alkylsulfonylamino group such as methanesulfonylamino group and ethanesulfonylamino group; hydroxyl group; methoxy group, ethoxy group, n-propoxy group, isopropoxy Base C _1-6 alkoxy group; a methyl carbonyloxy group, ethyl carbonyloxy group, n- propyl carbonyloxy group, C _1-6 alkylcarbonyloxy group such as an isopropyl carbonyloxy group; a methoxycarbonyl group, an ethoxycarbonyl group, Examples thereof include C _1-6 alkoxycarbonyloxy groups such as an n-propoxycarbonyloxy group and isopropoxycarbonyloxy group, preferably an amino group or a hydroxyl group, particularly preferably an amino group.

R ^{1 to} R ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group or a C _1-6 haloalkyl group, preferably a C _1-6 alkyl group.

Specific examples of the C _1-6 alkyl group of R ^{1 to} R ⁴ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an isobutyl group, a t-butyl group, An n-pentyl group, n-hexyl group, etc. are mentioned, Preferably a methyl group is mentioned.
Specific examples of the C _1-6 haloalkyl group include a chloromethyl group, a fluoromethyl group, a bromomethyl group, a dichloromethyl group, a difluoromethyl group, a dibromomethyl group, a trichloromethyl group, a trifluoromethyl group, a bromodifluoromethyl group, 1 1,1-trifluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 1-bromoethyl group, pentafluoroethyl group and the like.

The imidazole ring which is a substituent on the benzene ring in the formula (I) is substituted at any position of the o-position, m-position or p-position with respect to the piperazine ring in the formula (I). Preferably, substitution at the m-position is preferred.
The imidazole ring may be any bond of imidazol-1-yl, imidazol-2-yl, imidazol-4-yl or imidazol-5-yl when bonded to the benzene ring, preferably imidazole- 1-yl.

R ⁵ represents G or a C _1-6 alkyl group substituted with G. Here, G is an amino _{group, C 1-6} alkyl-substituted amino group with a _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkoxycarbonylamino _{group, C 1-6} alkylsulfonylamino group, a hydroxyl group Represents a C _1-6 alkoxy group, a C _1-6 alkylcarbonyloxy group, a C _1-6 alkoxycarboxy group or a cyano group, preferably an amino group.
Specific examples of G include an amino group; an amino group substituted with a C _1-6 alkyl group such as a methylamino group, an ethylamino group, an n-propylamino group, a dimethylamino group, a diethylamino group, or a diisopropylamino group; C _1-6 alkylcarbonylamino groups such as carbonylamino group, ethylcarbonylamino group, n-propylcarbonylamino group, isopropylcarbonylamino group; methoxycarbonylamino group, ethoxycarbonylamino group, n-propoxycarbonylamino group, isopropoxy C _1-6 alkoxycarbonylamino group such as carbonylamino group; C _1-6 alkylsulfonylamino group such as methanesulfonylamino group and ethanesulfonylamino group; hydroxyl group; methoxy group, ethoxy group, n-propoxy group, isopropoxy group Etc. C _1-6 alkoxy group; a methyl carbonyloxy group, ethyl carbonyloxy group, n- propyl carbonyloxy group, C _1-6 alkylcarbonyloxy group such as an isopropyl carbonyloxy group; a methoxycarbonyl group, an ethoxycarbonyl radical, n -C _1-6 alkoxycarbonyloxy group such as propoxycarbonyloxy group and isopropoxycarbonyloxy group; a cyano group, preferably an amino group.

Here, as the C _1-6 alkyl group substituted with G, specifically, an aminomethyl group, an aminoethyl group, a methylaminomethyl group, a dimethylaminomethyl group, a dimethylaminoethyl group, an acetylaminomethyl group, Examples include methoxycarbonylaminomethyl group, methanesulfonylaminomethyl group, hydroxymethyl group, methoxymethyl group, methoxycarboxymethyl group, cyanomethyl group and the like.

R ⁶ represents a C _1-6 alkyl group substituted with G. Examples of the C _1-6 alkyl group substituted with G include the same groups as those exemplified for R ⁵ .

b represents the number of substitutions of R ⁵ and is an integer of 1 to 4, and when b is 2 or more, R ⁵ may be the same or different.
d represents the number of substitutions of R ⁶ and is an integer of 0 to 3, and when d is 2 or more, R ⁶ may be the same or different.

R ⁷ or R ⁸ each independently represents a halogen atom or an organic group other than G. Here, as a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom is mentioned.

As organic groups other than G, arylamino groups such as benzylamino group, phenylamino group and phenylethylamino group, preferably C _6-10 arylamino group; nitro group; formyl group; methyl group, ethyl group, n- C _1-6 alkyl groups such as propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, n-pentyl group and n-hexyl group; C such as vinyl group and allyl group _2-6 alkenyl group; C _2-6 alkynyl group such as ethynyl group, 1-propynyl group and propargyl group; C _2-6 alkenyloxy group such as vinyloxy group and allyloxy group; C such as ethynyloxy group and propargyloxy group _2-6 alkynyloxy group; aryloxy group such as benzyloxy group and phenoxy group, preferably C _6-10 aryloxy group; Chloromethyl group, fluoromethyl group, bromomethyl group, dichloromethyl group, difluoromethyl group, dibromomethyl group, trichloromethyl group, trifluoromethyl group, bromodifluoromethyl group, 1,1,1-trifluoroethyl group, 1- C _1-6 haloalkyl groups such as chloroethyl group, 2-chloroethyl group, 1-bromoethyl group, pentafluoroethyl group; fluoromethoxy group, chloromethoxy group, bromomethoxy group, difluoromethoxy group, dichloromethoxy group, dibromomethoxy group, trifluoromethoxy group, trichloromethoxy group, tribromomethoxy group, trifluoroethoxy group, pentafluoroethoxy group, C _1-6 haloalkoxy groups such as heptafluoropropane n- propoxy, methylthio group, an ethyl thiocarbonyl radical, n Propyl thio group, isopropylthio group, n- butylthio group, isobutyl thiocarbonyl group, s- butyl thio group, t- butyl C _1-6 alkyl thio group such as a thiocarbonyl group; a methoxycarbonyl group, an ethoxycarbonyl C _1-6 alkoxycarbonyl groups such as carbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group and t-butoxycarbonyl group; aromatics such as phenyl group, 1-naphthyl group and 2-naphthyl group Group hydrocarbon group, preferably C _6-10 aromatic hydrocarbon group; furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, pyrrol-2-yl Group, pyrrol-3-yl group, oxazol-2-yl group, oxazole- 4-yl group, oxazol-5-yl group, thiazol-2-yl group, thiazol-4-yl group, thiazol-5-yl group, isoxazol-3-yl group, isoxazol-4-yl group, iso Oxazol-5-yl group, isothiazol-3-yl group, isothiazol-4-yl group, isothiazol-5-yl group, imidazol-1-yl group, imidazol-2-yl group, imidazol-4-yl Group, imidazol-5-yl group, pyrazol-1-yl group, pyrazol-3-yl group, pyrazol-4-yl group, pyrazol-5-yl group, 1,3,4-oxadiazol-2-yl Group, 1,3,4-thiadiazol-2-yl group, 1,2,3-triazol-4-yl group, 1,2,4-triazol-3-yl group, 1,2,4-triazole Unsaturated hetero 5-membered ring group such as 5-yl group; pyridin-2-yl group, pyridin-3-yl group, pyridin-4-yl group, pyridazin-3-yl group, pyridazin-4-yl group, pyrazine -2-yl group, pyrimidin-2-yl group, pyrimidin-4-yl group, pyrimidin-5-yl group, 1,3,5-triazin-2-yl group, 1,2,4-triazine-3- Unsaturated hetero 6-membered ring group such as yl group; tetrahydrofuran-2-yl group, tetrahydropyran-4-yl group, piperidin-3-yl group, pyrrolidin-2-yl group, morpholino group, piperidino group, piperazino group, etc. saturated heterocyclic group, preferably a 5-10 membered ring saturated heterocyclic group; methylthio group, ethylthio group, C _1-6 alkylthio group such as t-butylthio group; methylsulfonyl group, ethylsulfonyl group, t- Propargyl sulfonyl alkynylsulfonyl groups such as a group, preferably a C _2-6 alkynylsulfonyl group;; C _2-6 alkenyl-sulfonyl group such as an allyl sulfonyl group; Chirusuruhoniru C _1-6 alkylsulfonyl groups such as a group such as phenylsulfonyl group Arylsulfonyl group, preferably C _6-10 arylsulfonyl group; and the like.

e represents the number of substitutions of R ⁷ and is an integer of 0 to 3, and when e is 2 or more, R ⁷ may be the same or different. However, b + e ≦ 4.
f represents the number of substitutions of R ⁸ and is an integer of 0 to 3, and when f is 2 or more, R ⁸ may be the same or different. However, d + f ≦ 3.

  The salt of the compound represented by the formula (I) is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of such salts include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid. Salt; and the like. These can be easily produced by ordinary synthetic chemical techniques.

  When geometric isomers or optical isomers exist in the compound represented by the formula (I) or a salt thereof, these isomers are also included in the scope of the present invention. In addition, the compound represented by the formula (I) or a salt thereof may take the form of a hydrate or a solvate.

  When proton tautomerism exists in the compound represented by the formula (I) or a salt thereof, such tautomers are also included in the present invention.

  When the compound represented by the formula (I) or a salt thereof has crystal polymorphs and crystal polymorph groups (crystal polymorph system), those crystal polymorphs and crystal polymorph groups (crystal polymorphs) System) is also included in the present invention. Here, the crystal polymorph group (crystal polymorph system) means that the crystal form changes depending on the conditions and conditions (including the formulated state in this state) such as production, crystallization, and storage of these crystals. Means the individual crystal forms at each stage and the whole process.

2) Production method The compound represented by formula (I) and R ⁰ is an amino group can be produced, for example, by the method shown below.

^{(Wherein, R 1 ~R 4, a,} b and d~f are as defined above.
r ⁵ ~r ^{8 is} a substituent or conventional organic chemical conversion method corresponding to R 5 to R ^8, represent the inducible substituents R 5 to R ^8.
R ′ represents a hydrogen atom or an amino-protecting group. )

  That is, a compound represented by the formula (III) can be obtained by formylation by allowing an oxidant to act on the compound represented by the formula (II). The compound represented by the formula (II) used here can be synthesized, for example, by the method described in International Publication No. 2004/092153.

  More specifically, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (hereinafter referred to as “DBU”) is added to an alcohol solvent solution of compound (III) such as t-butanol. ) And other amines; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and sodium hydroxide; after adding a base such as at room temperature, saturated hydrocarbons such as n-hexane and water are added to the mixture. Furthermore, it can be carried out by adding an oxidizing agent such as potassium permanganate and boric acid and stirring the whole volume at -20 ° C to + 50 ° C, preferably -10 ° C to + 10 ° C.

  Further, the compound represented by the formula (III) and the compound represented by the formula (IV) are converted into a compound represented by the formula (I-1) by, for example, Michael addition reaction and subsequent general reduction reaction. It can be. Here, R ′ in the compound represented by formula (IV) is a hydrogen atom in advance, or when a protecting group is present, it may be deprotected by a general method in the reaction system.

  Further, the nitro group of the compound represented by the formula (I-1) is subjected to a hydrogenation reaction in the presence of a hydrogenation catalyst or is reduced using a general reducing agent, thereby reducing the formula (I-2). ) Can be obtained.

  There is no restriction | limiting in particular as a hydrogenation catalyst used for hydrogenation reaction, Well-known hydrogenation catalysts, such as palladium carbon, palladium hydroxide, platinum dioxide, Raney nickel, are mentioned.

  This hydrogenation reaction can be carried out in a suitable solvent. The solvent to be used is not particularly limited as long as it is an inert solvent for the reaction. For example, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran (hereinafter referred to as “THF”), ethers such as 1,4-dioxane; hydrocarbons such as benzene, toluene, xylene and cyclohexane; N, N -Amides such as dimethylformamide (hereinafter referred to as "DMF"); organic acids such as formic acid and acetic acid; esters such as ethyl acetate; and a mixed solvent composed of two or more of these;

  As a method using a reducing agent, for example, a method of reducing with hydrochloric acid and stannous chloride in an alcohol solvent such as methanol or ethanol; a mixed solvent of ketone solvent such as acetone or methyl ethyl ketone and water, and acetic acid and iron. And a method of reducing by using ammonium chloride, ammonium acetate, ammonium formate, or acetic acid and zinc in an alcohol or a mixed solvent of alcohol and water.

  In either case, the reaction temperature is in the temperature range from 0 ° C. to the boiling point of the solvent used.

The obtained compound represented by the formula (I-2) converts the substituents r ^{5 to} r ⁸ into substituents corresponding to R ^{5 to} R ⁸ , if necessary, by an existing organic chemical conversion method. By induction, the compound represented by the formula (I) of the present invention is obtained.

  The structure of the obtained compound can be identified and confirmed by measuring such a spectrum by infrared spectroscopy, nuclear magnetic resonance, mass spectrometry or the like.

3) Retinal disorder therapeutic agent and / or prophylactic agent The retinopathy therapeutic agent and / or prophylactic agent of the present invention is based on the compound represented by the formula (I) and the salt (hereinafter referred to as “the present compound”). It contains at least one selected from the group consisting of as an active ingredient.
The compound of the present invention can be used for the treatment and / or prevention of retinal disorders (preferably retinal photopathy), retina choroidal diseases associated with retinal disorders (preferably age-related macular degeneration, diabetic retinopathy, diabetic macular edema, particularly preferably It can be used for the treatment and / or prevention of age-related macular degeneration) and the treatment and / or prevention of eye diseases associated with retinal disorders.

  In the therapeutic agent and / or preventive agent for retinal disorders of the present invention, the therapeutically effective amount of the compound of the present invention can be appropriately selected according to age, weight, patient symptoms, patient constitution, dosage form and the like. Usually, the therapeutically effective daily dose can be 0.017 mg to 33.3 mg / day of the compound of the present invention per 1 kg of body weight, preferably 0.17 mg to 11.7 mg / day of 1 kg of body weight, more preferably , 1.7 mg to 33 mg / day of body weight per kg. For example, when administered to a human weighing 60 kg, the dose range of the compound of the present invention is 1 mg to 2.0 g per day, preferably 10 mg to 700 mg per day, more preferably 100 mg to 200 mg per day. Depending on the symptom of the patient, the constitution of the patient, the dosage form, etc., the dose may be outside this range.

  In addition to the compound of the present invention which is an active ingredient, the therapeutic agent and / or prophylactic agent of the present invention does not react with other ingredients, other drugs, adjuvants, etc. in addition to conventional pharmaceutical carriers or excipients. It can be set as the composition contained in a range. Such a composition may contain 1 to 99% by weight of an active ingredient and 99 to 1% by weight of a suitable pharmaceutical carrier or excipient, depending on the mode of administration. 5 to 75% by weight, with the balance being a suitable pharmaceutical carrier or excipient.

  As the excipient used in the retinal dysfunction therapeutic agent and / or prophylactic agent of the present invention, any commonly used excipient, for example, pharmaceutical mannitol, lactose, starch, gelatinized starch, magnesium stearate, saccharin sodium, Talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate and the like can be contained. In addition, for oral retinal disorder therapeutics and / or preventives, as a diluent, for example, lactose, sucrose, dicalcium phosphate and the like, and as a disintegrant, for example, croscarmellose sodium or a derivative thereof, As a binder, for example, magnesium stearate can be included, and as a lubricant, for example, starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose ether derivatives and the like can be contained.

The therapeutic agent and / or prophylactic agent for retinal disorders of the present invention can be administered in any manner as a medicament for the above diseases.
For example, it can be administered orally, nasally, parenterally, topically, transdermally or rectally, and also in solid, semi-solid, lyophilized powder or liquid dosage forms such as tablets, suppositories, pills, Appropriate agents that can be used for soft capsules, hard capsules, powders, liquids, injections, suspensions, aerosols, sustained-release preparations, etc. It can be shaped.

  Such formulations are prepared by conventional methods such as Remington's Pharmaceutical Sciences, 18th edition, Mac Publishing Company, Easton, Pennsylvania (Mack Publishing Company, Easton, Pennsyl 90). Can be produced according to the description taught in the above.

  As an injection, a sterile aqueous solution, non-aqueous solution, suspension, emulsion and the like can be contained. Specific examples of the aqueous solution and the diluent for the suspension include distilled water for injection and physiological saline. Specific examples of the non-aqueous solution and suspension diluent include vegetable oils such as propylene glycol, polyethylene glycol and olive oil; alcohols such as ethanol; polysorbate (trade name); and the like. These compositions can further contain additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (for example, lactose), solubilizers, solubilizers and the like. These can be used, for example, by filtration through a bacteria-retaining filter, producing a solid composition of a disinfectant and dissolving it in sterile water or a sterile solvent for injection before use.

  When the retinal disorder therapeutic agent and / or preventive agent of the present invention is used as a suppository, a carrier that gradually dissolves in the body as a carrier, such as polyoxyethylene glycol, polyethylene glycol (hereinafter referred to as “PEG”), Specifically, PEG1000 (96%) or PEG4000 (4%) is used, and 0.5 to 50% by weight of the compound of the present invention is dispersed in such a carrier.

When the retinal disorder therapeutic agent and / or prophylactic agent of the present invention is used as a liquid, water, saline, dextrose aqueous solution, glycerol, ethanol or the like is used as the carrier, and 0.5-50% by weight of the compound of the present invention is used as the carrier. At the same time, a solution or suspension obtained by dissolving or dispersing any pharmaceutical adjuvant is preferred.
The compound of the present invention may be appropriately added with one or more other retinal oxidative disorder inhibitors that do not react with the active ingredient, and may contain other components having other medicinal effects as appropriate. Good.

  When the compound of the present invention is used as an eye drop, one or more compounds of the present compound are added to a commonly used base solvent to form an aqueous solution or suspension, and the pH is 4 to 10, preferably 5 to 9. Can be adjusted. The eye drop is preferably sterilized to make it an aseptic product, and such sterilization can be performed at any stage of the production process.

  The concentration of the compound of the present invention in the eye drop is 0.0001 to 10% (W / V), preferably 0.001 to 3% (W / V), particularly preferably 0.01 to 1% (W / V). The dose can also be divided into several drops or the like once a day or several times depending on the patient's symptoms and the patient's constitution. The dosage is a guide and can be administered beyond this range.

  Various additives such as buffers, isotonic agents, preservatives, pH adjusters, thickeners, chelating agents, solubilizers, etc., are added as appropriate to the eye drops. May be.

  Specific examples of the buffer include citrate buffer, tartaric acid buffer, acetate buffer, amino acid and the like. Specific examples of the isotonic agent include saccharides such as sorbitol, glucose and mannitol; polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol; salts such as sodium chloride; Specific examples of the preservative include paraoxybenzoates such as methyl paraoxybenzoate and ethyl paraoxybenzoate; arylalkyl alcohols such as benzyl alcohol and phenethyl alcohol; sorbic acid or a salt thereof, and the like. Specific examples of the pH adjuster include phosphoric acid and sodium hydroxide. Specific examples of the thickener include hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and salts thereof. Specific examples of the chelating agent include sodium edetate, sodium citrate, condensed sodium phosphate and the like. Specific examples of the solubilizer include ethanol, polyoxyethylene hydrogenated castor oil, and the like.

When the compound of the present invention is used as an eye ointment, one or more of the compounds of the present invention are mixed with a commonly used eye ointment base such as purified lanolin, white petrolatum, macrogol, plastibase, liquid paraffin, etc. Those that have been sterilized to make an aseptic product are preferred.
The concentration of the compound of the present invention in the eye ointment is 0.0001 to 10% (W / W), preferably 0.001 to 3% (W / W), particularly preferably 0.01 to 1% (W / W). The dosage can be once or several times a day depending on the patient's symptoms and the patient's constitution. The dosage is a guide and can be administered beyond this range.

4) Embodiment

  EXAMPLES Hereinafter, although an Example demonstrates this invention further, the technical scope of this invention is not limited to a following example.

Example 1
Preparation of 4- (5-amino-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran-4-ylmethyl) -1- [4-amino-3-imidazol-1-ylphenyl] piperazine ( Compound No. 1-1)

Step 1: Production of 2-imidazol-1-yl-4-fluoronitrobenzene

  4.00 g of 2,4-difluoronitrobenzene, 1.71 g of imidazole and 3.82 g of potassium carbonate were suspended in 40 ml of dimethylformamide and stirred at room temperature for 1 day. Water was added to the reaction solution, extracted three times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1 (volume ratio)) to obtain 3.87 g of the desired product.

Step 2: Preparation of 2-imidazol-1-yl-4- (4-acetylpiperazin-1-yl) nitrobenzene

  2.87 g of 2-imidazol-1-yl-4-fluoronitrobenzene, 2.64 g of 1-acetylpiperazine and 3.36 g of potassium carbonate were suspended in 9 ml of dimethyl sulfoxide and stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, and the precipitated crystals were separated by filtration and washed successively with water and ether. Chloroform and methanol were added to the obtained solid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1 (volume ratio)) to obtain 5.78 g of the desired product.

Step 3: Production of 2-imidazol-1-yl-4-piperazin-1-ylnitrobenzene

  2.75 g of 2-imidazol-1-yl-4- (4-acetylpiperazin-1-yl) nitrobenzene was dissolved in 44 ml of concentrated hydrochloric acid and stirred for 8.5 hours while heating under reflux. After the reaction, the reaction mixture was cooled, neutralized with an aqueous sodium hydroxide solution, and extracted three times with a chloroform-methanol mixed solution. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.09 g of the desired product.

Step 4: 4- (5-Nitro-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran-4-ylmethyl) -1- [4-nitro-3-imidazol-1-ylphenyl] piperazine Manufacturing of

  1.05 g of 1- [4-nitro-3-imidazol-1-ylphenyl] piperazine and 1.05 g of 2,2,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-4-aldehyde Dissolved in 33 ml of methylene chloride. To this solution, 0.48 ml of acetic acid was added and stirred at room temperature for 2 hours. To this reaction solution, 1.63 g of sodium triacetoxyborohydride was added, and the whole volume was stirred overnight at room temperature. The reaction solution was neutralized with 1N aqueous sodium hydroxide solution and extracted with chloroform. After 2N hydrochloric acid was added to the organic layer and back extracted into the aqueous layer, the aqueous layer was neutralized with 1N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 (volume ratio)) to obtain 1.71 g of the desired product.

Step 5: 4- (5-Amino-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran-4-ylmethyl) -1- [4-amino-3-imidazol-1-ylphenyl] piperazine Manufacturing of

4- (5-Nitro-2,2,6,7-tetramethyl-2,3-dihydrobenzofuran-4-ylmethyl) -1- [4-nitro-3-imidazol-1-ylphenyl] piperazine 1.71 g Was dissolved in 57 ml of acetic acid, and 4.42 g of zinc powder was gradually added while cooling in an ice bath. After the addition, the whole volume was stirred at room temperature for 50 minutes. After completion of the reaction, the reaction solution was filtered, the solid was washed with chloroform, and then the solvent was distilled off from the filtrate under reduced pressure. Chloroform was added to the resulting residue, washed successively with 2N aqueous sodium hydroxide solution and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 (volume ratio)) to obtain 1.13 g of the desired product.
Melting point: 205-207 ° C

(Reference Example 1)
Production of 2,2,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-4-aldehyde 0.4 g of 60% sodium hydride was added to 50 ml of t-butanol and stirred at room temperature for 10 minutes. Thereto was added 0.80 g of 2,2,6,7-tetramethyl-4-nitromethyl-5-nitro-2,3-dihydrobenzofuran dissolved in 80 ml of t-butanol, and the mixture was stirred at room temperature for 20 minutes. To this solution, a solution prepared by dissolving 0.80 g of potassium permanganate and 0.63 g of boric acid in 1200 ml of n-hexane and 50 ml of water was added, and the whole volume was stirred at room temperature for 10 minutes. Sodium thiosulfate was added to the reaction solution and stirred until the color of the reaction solution became colorless. The resulting reaction solution was extracted with n-hexane, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.71 g of the desired product as a crude product.

Examples of the compounds of the present invention, including the compounds described in the above examples, are shown in the following table.
In the table, Me represents a methyl group, Et represents an ethyl group, n-Pr represents an n-propyl group, iPr represents an isopropyl group, n-Bu represents an n-butyl group, and Ac represents an acetyl group.

¹ H-NMR of Compound 1-25 (CDCl ₃ , δ ppm)
1.5 (s, 6H), 2.06 (s, 3H), 2.08 (s, 3H), 2.7 (br, 4H), 2.9 (s, 2H), 3.1 (br, 4H), 3.6 (s, 2H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9 (dd, 1H), 7.1 (s, 1H), 7.2 (s, 1H), 7.6 (s, 1H)

(Preparation of formulation)
A preparation containing the compound of the present invention was prepared by the following method.
Formulation Example 1 Preparation of oral preparation (active ingredient 10 mg tablet)

  In order to obtain the above composition, 50 g of the present compound, 407 g of lactose and 100 g of starch were mixed uniformly using a fluidized granulation coating apparatus (Okawara Seisakusho Co., Ltd.). This was sprayed and granulated with 200 g of a 10% hydroxypropylcellulose aqueous solution. After drying, a 20-mesh sieve is passed through, 20 g of carboxymethylcellulose calcium and 3 g of magnesium stearate are added, and a 7 mm × 8.4 R mortar is used with a rotary tableting machine (manufactured by Hata Iron Works Co., Ltd.). A tablet of 120 mg per tablet was obtained.

(Retinal light damage model test)
Use of a mouse retinal photopathy model (Journal of Biological Chemistry 2001; conforming to 276: 23000-23008) widely used as a retinal photopathy model, The improvement rate was evaluated. Here, the improvement rate for retinal light damage was calculated based on the behavior of the b wave in the electroretinogram.
The electroretinogram is a change in potential recorded when light is applied to the retina, and is used when the retinal function is evaluated electrophysiologically.
The basic form of this electroretinogram is a negative potential fluctuation (a wave) that occurs first by light irradiation, then a large positive potential fluctuation (b wave) that sharply drops after rising sharply, and a positive potential that increases more slowly. It is classified into fluctuation (c-wave), and is used for determination of retinal function, diagnosis of retinal disorders and accompanying reticulopathy. A decrease in the potential of each wave in this electroretinogram means a decrease in retinal function. That is, if some kind of disorder occurs in the retina due to various diseases, the amplitude of each wave on the electroretinogram changes such as a decrease.
In this test, the amplitude of the b wave in the light irradiation group to which only the base was administered was reduced to about 20% of that in the normal light group.

1. Preparation of test compound solution The test compound was suspended in a solvent (1% (w / v) methylcellulose aqueous solution) and 0.6% (w / v), 2% (w / v) and / or 6% (w / V) a test compound suspension was prepared.

2. Test and measurement method 1) Test compound group:
8-week-old BALB / c male mice (body weight: about 25 g) were raised in the dark for 24 hours, and then the test compound suspension was orally administered (3 to 30 mg / kg). One hour later, white light 5000 Looks were irradiated continuously for 2 hours. Then, after dark adaptation for 22 hours, retinal potential was measured using portable ERG & VEP LE-3000 (manufactured by Tome Corporation) or NEC SYNAX ER1100 (manufactured by NEC Sanei).
2) Light irradiation group:
Instead of the test compound suspension, only the solvent was orally administered, and the other procedures were the same as in the test compound group.
3) Normal light group:
Instead of the test compound suspension, only the solvent was orally administered, no light irradiation was performed, and from the dark adaptation for 22 hours, the same operation as in the test compound group was performed.

3. Calculation formula of b-wave improvement rate (%)

4). Test result As an example of the test result, the b-wave improvement rate when using the present compound 1-1, the present compound 1-13 and the reference compound A [compound described in (WO2007 / 052794)] as a test compound [ Table 5].

The compound of the present invention suppressed a decrease in the amplitude of the b wave in an animal model of retinal photopathy. That is, the compound of the present invention showed an effect of treating and / or preventing retinal photopathy in an animal model of retinal photopathy.
Further, in Reference Compound A having a similar chemical structure and action and effect, the effect of suppressing the decrease in the amplitude of the b wave was not observed even at a high dose.

  As described above, the compound of the present invention is expected to be useful as a therapeutic agent and / or preventive agent for retinal disorders, particularly as a therapeutic agent and / or preventive agent for retina choroidal diseases associated with retinal photopathy.

Claims (2)

Formula (I)

(In formula (I), a represents 1 or 2.
R ⁰ is an amino _{group, C 1-6} alkyl-substituted amino group with a _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkoxycarbonylamino _{group, C 1-6} alkylsulfonylamino group, a hydroxyl group, C _{A 1-6} alkoxy group, a C _1-6 alkylcarbonyloxy group, a C _1-6 alkoxycarbonyloxy group or a C _1-6 alkylsulfonyloxy group is represented.
R ^{1 to} R ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 haloalkyl group.
R ⁵ represents G or a C _1-6 alkyl group substituted with G.
G is an amino _{group, C 1-6} alkyl-substituted amino group with a _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkoxycarbonylamino _{group, C 1-6} alkylsulfonylamino group, a hydroxyl _{group, C 1- A 6} alkoxy group, a C _1-6 alkylcarbonyloxy group, a C _1-6 alkoxycarbonyloxy group or a cyano group;
R ⁶ represents a C _1-6 alkyl group substituted with G.
b represents any integer of 1 to 4, and when b is 2 or more, R ⁵ may be the same or different.
d represents any integer of 0 to 3, and when d is 2 or more, R ⁶ may be the same or different.
R ⁷ and R ⁸ each independently represents a halogen atom or an organic group other than G.
e represents an integer of 0 to 3, and when e is 2 or more, R ⁷ may be the same or different. However, b + e ≦ 4.
f represents any integer of 0 to 3, and when f is 2 or more, R ⁸ may be the same or different. However, d + f ≦ 3. )
Or a salt thereof. A therapeutic and / or prophylactic agent for retinal disorders comprising as an active ingredient at least one selected from the group consisting of the compound represented by the formula (I) and a salt thereof.