WO2017082393A1 - Prophylactic and therapeutic agent for glaucoma - Google Patents

Abstract

Provided is a compound that is useful for preventing and treating glaucoma, in particular, normal-tension glaucoma. A prophylactic and/or therapeutic agent for glaucoma that comprises, as an active ingredient, a PPARα agonist selected from among (R)-2-[[3-[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propy]aminomethyl]phenoxy]butyric acid, a salt thereof, a solvate of the same and fenofibrate.

Description

Glaucoma preventive and therapeutic agent

The present invention relates to a drug for preventing or treating glaucoma, particularly normal-tension glaucoma.

Glaucoma is characterized by visual field loss due to degeneration of retinal ganglion cells following optic nerve axon disorder, and is currently the leading cause of blindness in Japan. High intraocular pressure can be cited as a cause of glaucoma, but the number of glaucoma without high intraocular pressure, that is, normal-tension glaucoma is about 70% of all glaucoma patients in Japan. It is becoming a social problem.

<Current main treatment of glaucoma relies on anti-glaucoma eye drops having a lowering of intraocular pressure or lowering of intraocular pressure by open surgery. For high-tension glaucoma or normal-tension glaucoma with high baseline intraocular pressure, it is considered possible to obtain a therapeutic effect by reducing intraocular pressure, but for normal-tension glaucoma with low baseline intraocular pressure, It is frequently seen that visual field impairment progresses even if a decrease is obtained. In normal-tension glaucoma, fragility of the phloem, oxidative stress, mitochondrial damage, involvement of TNF associated with glial cell activity, involvement of immune cells, etc. have been pointed out, and there are many causes other than these intraocular pressures It is considered. The only treatment currently performed in the clinic is a drop in intraocular pressure. Considering the treatment of normal-tension glaucoma that is frequently observed in clinical practice, the therapeutic effect is presumed to be limited.

Several anti-glaucoma eye drops have reported a slight neuroprotective effect at the level of basic research, but their main pharmacological actions all reduce intraocular pressure and it is unclear whether they are truly neuroprotective It is. Therefore, the development of truly effective neuroprotective drugs is urgently needed in clinical practice in glaucoma, and it is thought that neuroprotective treatment can save many blind people in the future.

PPARα agonists have an excellent lipid metabolism improving action and are widely used as therapeutic agents for hyperlipidemia (Non-patent Document 1). As an effect on eye diseases, there are reports (Non-patent Documents 2 and 3) that are useful for the treatment of diabetic retinopathy or macular degeneration.

On the other hand, as for the effects of PPARα agonists on glaucoma, only 1967 was reported that clofibrate, which is one of the fibrate agents, reduced the high intraocular pressure in a few glaucoma patients (Non-patent Document 4). In addition, it is said that no particular effect on normal intraocular pressure was found in the literature. Although this document suggests the involvement of blood free fatty acids and blood viscosity increase in angle-closure glaucoma, no improvement in glaucoma visual field impairment associated with hyperlipidemia treatment has been reported so far.

Patent Document 1 discloses the use of the serum amyloid A gene in the diagnosis and treatment of glaucoma, and mentions a PPARα agonist as one of the factors that inhibit the interaction between the serum amyloid A protein and its receptor. . However, no specific therapeutic effect on glaucoma has been shown.

On the other hand, in Patent Document 2, the following formula (1):

Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom, a methyl group or an ethyl group; R ^3a , R ^3b , R ^4a and R ^4b are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, Hydroxyl group, C _1-4 alkyl group, trifluoromethyl group, C _1-4 alkoxy group, C _1-4 alkylcarbonyloxy group, di-C _1-4 alkylamino group, C _1-4 alkylsulfonyloxy group, C _{1-4 represents} an alkylsulfonyl group, C _1-4 alkylsulfinyl group, or C _1-4 alkylthio group, or R ^3a and R ^3b or R ^4a and R ^4b are bonded to each other to represent an alkylenedioxy group; An oxygen atom, a sulfur atom or N—R ⁵ (R ⁵ represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkylsulfonyl group, a C _1-4 alkyloxycarbonyl group); Y represents an oxygen atom , S (O) _l group (l represents a number from 0 to 2), Cal N represents a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group, or an NH group; Z represents CH or N; n represents a number from 1 to 6; m represents a number from 2 to 6 ), A salt thereof, or a solvate thereof has a selective PPARα activation action, and is not accompanied by weight gain or obesity in mammals including humans. It is disclosed that it is useful as a preventive and / or therapeutic agent for arteriosclerosis, diabetes, diabetic complications (diabetic nephropathy, etc.), inflammation, heart disease and the like. However, there is no description or suggestion of how these compounds act on glaucoma.

Thus, a PPARα agonist that can be used practically as a prophylactic or therapeutic agent for glaucoma has not been known so far.

International Patent Publication No. 2005/060542 International Patent Publication No. 2005/023777

There is a need for a drug that can treat glaucoma, particularly glaucoma that is refractory to normal-tension glaucoma or intraocular pressure reduction therapy. The present invention relates to providing a new drug for the prevention or treatment of glaucoma, particularly normal-tension glaucoma.

The present inventors have eagerly used NMDA (N-methyl-D-aspartate) -induced retinal disorder model rats as normal-tension glaucoma models in order to find compounds useful for the prevention and treatment of glaucoma, particularly normal-tension glaucoma. As a result of repeated research, the following formula (A), which is quite surprisingly known as a PPARα agonist:

(R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid represented by the formula (2) The compound disclosed as Example 85) and fenofibrate have been found to inhibit retinal ganglion cell death and have completed the present invention.

That is, the present invention relates to the following inventions.
[1] (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid or a salt thereof or a solvent thereof A prophylactic and / or therapeutic agent for glaucoma comprising a PPARα agonist selected from Japanese and fenofibrate as an active ingredient.
[2] The prophylactic and / or therapeutic agent according to the above [1], wherein the glaucoma is normal-tension glaucoma.
[3] In patients in need of prophylaxis and / or treatment, (R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] amino A method for preventing and / or treating glaucoma, comprising administering an effective dose of a PPARα agonist selected from [methyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and fenofibrate.
[4] The prevention and / or treatment method according to the above [3], wherein the glaucoma is normal-tension glaucoma.
[5] (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] for use as a prophylactic and / or therapeutic agent for glaucoma ] Aminomethyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and a PPARα agonist selected from fenofibrate.
[6] The (R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy] described in [5] above, wherein the glaucoma is normal-tension glaucoma. PPARα agonist selected from:) propyl] aminomethyl] phenoxy] butyric acid or salts thereof or solvates thereof, and fenofibrate.
[7] (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy)] for producing a preparation for the prevention and / or treatment of glaucoma Use of a PPARα agonist selected from propyl] aminomethyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and fenofibrate.
[8] The use according to [7] above, wherein the glaucoma is normal-tension glaucoma.
[9] (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid or a salt thereof or a solvent thereof A retinal ganglion cell death inhibitor comprising as an active ingredient a PPARα agonist selected from Japanese and fenofibrate.
[10] In patients in need of prophylaxis and / or treatment, (R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] amino A method of inhibiting retinal ganglion cell death, comprising administering an effective dose of a PPARα agonist selected from methyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and fenofibrate.
[11] (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] for use as a retinal ganglion cell death inhibitor Aminomethyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and a PPARα agonist selected from fenofibrate.
[12] (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] for producing a preparation for suppressing retinal ganglion cell death ] Aminomethyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and use of a PPARα agonist selected from fenofibrate.

According to the present invention, a drug for prevention or treatment of glaucoma, particularly normal-tension glaucoma can be provided.

Retinal ganglion cells and amacrine cells were quantified by cresyl violet staining when compound A of the present invention (50 mg / kg) was orally administered to a model of NMDA-induced retinal damage (administered daily until 7 days after NMDA vitreous administration). This is the result. The vertical axis represents the ratio of the number of nerve cells in the drug administration group to the physiological saline intravitreal administration group (control group). The numerical value is expressed as an average value ± standard error, and * indicates that the p value is less than 0.05. It is the result of retinal ganglion cells and amacrine cells obtained by oral administration of fenofibrate (100 mg / kg) orally to an NMDA-induced retinal disorder model by cresyl violet staining and quantification. The vertical axis represents the ratio of the number of nerve cells in the drug administration group to the physiological saline intravitreal administration group (control group). The numerical value is expressed as an average value ± standard error, and * indicates that the p value is less than 0.05. It is the result of retinal ganglion cells and amacrine cells quantified by cresyl violet staining when the compound A of the present invention (1 or 10 μM) was intravitreally administered to an NMDA-induced retinal disorder model. The vertical axis represents the ratio of the number of nerve cells in the drug administration group to the physiological saline intravitreal administration group (control group). The numerical value is expressed as an average value ± standard error, and * indicates that the p value is less than 0.05. It is the result of retinal ganglion cells and amacrine cells quantified by cresyl violet staining when fenofibric acid (1 or 10 μM) was intravitreally administered to an NMDA-induced retinal disorder model. The vertical axis represents the ratio of the number of nerve cells in the drug administration group to the physiological saline intravitreal administration group (control group). The numerical value is expressed as an average value ± standard error, and * indicates that the p value is less than 0.05. It is the result of retinal ganglion cell and amacrine cell when clonylated violet staining was performed when clofibrate (10 μM) of the present invention was intravitreally administered to an NMDA-induced retinal disorder model. The vertical axis represents the ratio of the number of nerve cells in the drug administration group to the physiological saline intravitreal administration group (control group). The numerical value is expressed as an average value ± standard error, and * indicates that the p value is less than 0.05.

In the present invention, the PPARα agonist is (R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid or its Selected from salts or solvates thereof, and fenofibrate.

(R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid (hereinafter referred to as Compound A) Can be produced, for example, according to the method described in Patent Document 2 and the like. It can also be produced according to methods described in documents such as Tetrahedron, 64 (35), 8155-8158 (2008). Furthermore, it can also be formulated according to a conventional method.

The salt of compound A is not particularly limited as long as it is pharmaceutically acceptable; for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt Organic base salts such as trialkylamine salts; mineral acid salts such as hydrochlorides and sulfates; organic acid salts such as acetates.

Compound A or a salt thereof may be in the form of a pharmaceutically acceptable solvate, and examples of the solvate include hydrates, alcohol solvates (for example, ethanol solvates) and the like.
The salt or solvate of Compound A can be produced by a conventional method.

Fenofibrate is a chemical name: 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropionic acid (1-methylethyl), and is a drug widely used as a therapeutic agent for hyperlipidemia. Fenofibrate can be synthesized by a known method, or a commercially available product can be used.

As shown in the examples described later, the PPARα agonist of the present invention suppresses retinal neuronal cell death induced by intravitreal administration of NMDA by oral administration or intravitreal administration. Therefore, glaucoma, particularly normal-tension glaucoma, is suppressed. It is useful as a preventive or therapeutic agent or a retinal ganglion cell death inhibitor.

The PPARα agonist of the present invention can treat glaucoma independent of intraocular pressure, but this is not intended to exclude the combined use of the present invention and intraocular pressure lowering therapy. Intraocular pressure lowering therapy that can be used in conjunction with the present invention includes, but is not limited to, administration of drugs for the treatment of glaucoma or ocular hypertension, laser or surgery.

When the PPARα agonist of the present invention is used for the prevention or treatment of glaucoma, particularly normal-tension glaucoma, the dosage varies depending on the patient's weight, age, sex, symptom, dosage form, number of administrations, etc. Is a compound A or a salt thereof or a solvate thereof, or fenofibrate for an adult in a range of 0.01 to 10000 mg, preferably 0.05 to 3000 mg, more preferably 0.1 to 1000 mg per day. Can be mentioned.

Hereinafter, the present invention will be described more specifically by way of examples. However, the present invention is not limited to these examples.

<Test compound>
1) (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid (Compound A): 2 according to the method described in Example 85.
2) Fenofibrate: “Fenofibrate” (Sigma-Aldrich) was used.

Example 1 Effect of Oral Drug Administration on NMDA-Induced Retinopathy Model Rat <Test Method>
The inhibitory effect on ganglion cell damage was examined using a rat NMDA-administered glaucoma model. Using Wistar rats, vehicle or NMDA (20 nmol) was injected into the vitreous body from the ciliary flat part using a 30 gauge needle under pentobarbital anesthesia. On the day before injection of physiological saline or NMDA vitreous and for one week after the injection, Compound A 50 mg / kg (n = 6) or physiological saline (n = 4) as a control was orally administered once a day using a gastric sonde. Seven days after the injection of the vitreous body, after euthanasia by excessive anesthesia with pentobarbital, both eyes were removed and a retinal extension specimen was prepared. Retinal ganglion cells and amacrine cells were stained with cresyl violet, photographed under a microscope, and the nerve cell area for the entire retina was calculated with NIH imageJ software. The obtained numerical value converted the ratio with respect to the physiological saline administration group (control). Statistical analysis was performed by Mann-Whitney U test. In addition, fenofibrate 100 mg / kg was administered in the same manner in place of compound A, and the effect of fenofibrate on a rat model of NMDA-induced injury was examined.

<Result>
The results of the neuroprotective effect of Compound A against NMDA-induced damage are shown in FIG. 1, and the results of fenofibrate (denoted as “Feno” in the figure) are shown in FIG. Intravitreal administration of NMDA significantly decreased the retinal ganglion cell and amacrine cell regions, and this decrease was significantly suppressed by oral administration of Compound A or fenofibrate. In addition, the number of nerve cells by oral administration of Compound A or fenofibrate did not change under the conditions of intravitreal administration of Vehicle. For this reason, Compound A and fenofibrate showed a neuroprotective action against retinal neuronal cell death induced by NMDA, suggesting effectiveness in glaucoma exhibiting retinal neuronal loss and degeneration.

Example 2 Effect of Intravitreal Drug on NMDA-Induced Retinopathy Model Rat <Test Method>
The inhibitory effect on ganglion cell damage was examined using a rat NMDA vitreous administration glaucoma model. Using Wistar rats, under Pentobarbital anesthesia, Compound A 1 or 10 μM (n = 4 or 6) containing Vehicle or NMDA (20 nmol) or 5 μL of physiological saline (n = 4) as a control, 30 gauge It injected into the vitreous from the ciliary flat part using the needle. Seven days after the vitreous injection, after euthanasia due to pentobarbital overanesthesia, both eyes were removed and flat mount specimens were prepared. The retinal ganglion cells and amacrine cells were stained with Cresyl Violet, photographed under a microscope, and the nerve cell area for the entire retina was calculated with NIH imageJ software. The obtained numerical value converted the ratio with respect to the physiological saline administration group (control). Statistical analysis was performed by Mann-Whitney U test. In addition, instead of Compound A, fenofibric acid active metabolite fenofibric acid 1 or 10 μM (n = 4 or 6) was similarly administered intravitreally, and the effect of fenofibric acid on NMDA-induced injury rat model was examined. . Furthermore, clofibrate 1 or 10 μM (n = 4 or 6) was similarly administered intravitreally instead of compound A, and the effect of clofibrate on a rat model of NMDA-induced injury was examined.

<Result>
The results of Compound A by flat mount are shown in FIG. 3, the results of fenofibric acid are shown in FIG. 4, and the results of clofibrate are shown in FIG. Similar to oral administration, Compound A significantly suppressed neuronal loss even in intravitreal administration. Fenofibrate is rapidly metabolized in the blood to produce the active metabolite fenofibric acid. For this reason, although the effect at the time of intravitreal administration was examined using fenofibric acid, fenofibric acid significantly suppressed the decrease of nerve cells. On the other hand, clofibrate, which has been reported to have an intraocular pressure lowering effect, did not show a neuroprotective effect even when administered intravitreally. Therefore, unlike clofibrate, Compound A and fenofibrate showed a protective action against retinal neuronal cell death induced by NMDA, suggesting effectiveness in glaucoma showing detachment and degeneration of retinal neurons.

As described above, the results of FIGS. 1 to 5 show that neuronal cell death in the NMDA-induced retinal injury model is significantly suppressed by oral administration of Compound A and a PPARα agonist of fenofibrate. In addition, it was suggested that the active metabolite fenofibric acid of compound A and fenofibrate suppresses retinal cell death even when administered intravitreally, and PPARα activation is involved. On the other hand, clofibrate did not suppress retinal cell death even when administered intravitreally, and it was newly found that the PPARα agonist has an effect that cannot be predicted from clinical reports of clofibrate.

(R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid or a salt thereof of the present invention or a solvent thereof Japanese and fenofibrate are PPARα agonists that can be administered as oral agents, and are useful as medicaments for the prevention or treatment of glaucoma, particularly normal-tension glaucoma.

Claims (12)

1. (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, And a prophylactic and / or therapeutic agent for glaucoma comprising a PPARα agonist selected from fenofibrate as an active ingredient.
2. The prophylactic and / or therapeutic agent according to claim 1, wherein the glaucoma is normal-tension glaucoma.
3. (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, And a retinal ganglion cell death inhibitor comprising a PPARα agonist selected from fenofibrate as an active ingredient.
4. (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl for use as a prophylactic and / or therapeutic agent for glaucoma ] Phenol] PPARα agonist selected from butyric acid or a salt thereof, or a solvate thereof, and fenofibrate.
5. The (R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] amino according to claim 4, wherein the glaucoma is normal-tension glaucoma. Methyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and a PPARα agonist selected from fenofibrate.
6. (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] for use as a retinal ganglion cell death inhibitor PPARα agonist selected from phenoxy] butyric acid or a salt thereof or a solvate thereof, and fenofibrate.
7. (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] amino for producing a preparation for the prevention and / or treatment of glaucoma Use of a PPARα agonist selected from [methyl] phenoxy] butyric acid or a salt thereof or a solvate thereof, and fenofibrate.
8. The use according to claim 7, wherein the glaucoma is normal-pressure glaucoma.
9. (R) -2-[[3- [N- (Benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl for producing a preparation for suppressing retinal ganglion cell death ] Phenoxy] Use of a PPARα agonist selected from butyric acid or a salt thereof or a solvate thereof, and fenofibrate.
10. In patients in need of prevention and / or treatment, (R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy A method for preventing and / or treating glaucoma, comprising administering an effective dose of a PPARα agonist selected from butyric acid or a salt thereof, or a solvate thereof, and fenofibrate.
11. The method for prevention and / or treatment according to claim 10, wherein the glaucoma is normal-pressure glaucoma.
12. In patients in need of prevention and / or treatment, (R) -2-[[3- [N- (benzoxazol-2-yl) -N-3- (4-methoxyphenoxy) propyl] aminomethyl] phenoxy A method for inhibiting retinal ganglion cell death, comprising administering an effective dose of a PPARα agonist selected from butyric acid or a salt thereof or a solvate thereof, and fenofibrate.

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