WO2020138011A1 - Terephthalic acid derivative having ring-fused structure - Google Patents

Abstract

The present invention addresses the problem of providing a compound which has a retinoic acid receptor agonist activity and is useful as a medicine that is capable of treating and/or preventing a retinal degenerative disease. The compound of the present invention is a compound represented by general formula (1)(where R1 and W are the same as described in the specification), or a pharmaceutically acceptable salt thereof.

Description

Terephthalic acid derivative with condensed ring structure

The present invention relates to a low molecular weight compound having a retinoic acid receptor (hereinafter also referred to as RAR) agonistic action, or a pharmaceutically acceptable salt thereof, and further for retinal degenerative diseases accompanied by photoreceptor degeneration It relates to a pharmaceutical composition as a medicine.

Retinitis pigmentosa is a progressive retinal degenerative disease that begins with the degeneration and loss of rods in the photoreceptor cells. In this disease, degenerative degeneration of photoreceptors causes progressive night blindness, visual field stenosis, and photophobia, resulting in diminished visual acuity and, in some cases, blindness. This disease is known as a hereditary disease, but there are many gene mutations that cause this disease, and the proposed mechanism of rod dropout is diverse. From such a situation, it is very difficult to narrow down the target molecules for drug discovery, and at present, there is no established drug as a small molecule therapeutic drug for retinitis pigmentosa.

As a potential treatment for retinitis pigmentosa, it is possible to protect the cone directly related to visual function by protecting the rod as described below from numerous animal experiments and human clinical trials. It has been established that it is possible to prevent narrowing of visual field and reduction of visual acuity (Non-Patent Document 1). Ie;
a) Even small improvements in rod survival lead to cone protection
b) Can support cone survival even with dysfunctional rods
c) If only a few cones in the macula can be left, it is possible to maintain the minimum visual acuity, for example, to allow self-walking.

Based on this idea, clinical trials have been conducted for trophic factors such as CNTF, valproic acid, vitamin A, docosahexaenoic acid (DHA), etc. for the purpose of protecting rods or cones, but it is clear so far. No effective drug has been reported and no low molecular weight compound has been approved by the FDA.

On the other hand, in recent years, many studies have been conducted on the possibility of retinal regeneration by mobilization of endogenous stem cells, but a sufficient number of endogenous stem cells to induce functional rods has been established. This is a big issue.

In addition to retinitis pigmentosa, age-related macular degeneration and macular dystrophy are examples of retinal degenerative diseases accompanied by photoreceptor degeneration. With respect to these diseases, degeneration of photoreceptor cells including rods is the essential form of the disease, and therefore, treatment and/or prevention can be expected by protection against rod degeneration and induction of rod regeneration. Therefore, establishing a method for protecting the degeneration of rods or a method for inducing an increase in endogenous rods is extremely significant in terms of providing a therapeutic method for these diseases.

Aging-related macular degeneration is a disease that causes visual impairment and blindness by causing damage to the macular tissue located in the center of the retina due to aging. This disease is classified into two types, wet type and dry type. Regarding the exudative type, drug therapy using an angiogenesis inhibitor (Patent Documents 1 and 2) and surgical methods exist, but they do not lead to normal recovery of visual acuity, and development of an effective therapeutic method is desired. ing. Currently, there is no effective treatment for the dry form.

Macular dystrophy is a group of retinal degenerative diseases accompanied by photoreceptor cell degeneration. In this disease group, damage to the macula due to a genetic cause causes significant visual loss and abnormal visual field. It is classified into Stargardt's disease, cone-rod dystrophy, Best's disease, X-linked juvenile retinolysis, occult macular dystrophy, and central ring-shaped reticulochoroidal dystrophy. Currently, there is no effective treatment.

Tamibarotene is a synthetic retinoid that exhibits a retinoic acid receptor agonist action and is used as a therapeutic drug for acute promyelocytic leukemia. Acute promyelocytic leukemia develops when the PML/RARα protein resulting from chromosomal translocation interferes with the differentiation of hematopoietic cells. Tamibarotene strongly activates the retinoic acid receptor moiety present in the PML/RARα protein, resulting in the promotion of hematopoietic cell differentiation. As another pharmacological action of tamibarotene, an action of inhibiting choroidal neovascularization in mice has been reported (Non-patent Document 2), but there is no mention of a rod regeneration inducing action or a rod degeneration protecting action. Although a plurality of compounds obtained by chemically modifying tamibarotene have been reported (Patent Document 3 and Non-Patent Document 3), there is no mention that these compounds also have a rod regeneration inducing action or a rod denaturing protective action.

International publication WO1998/045331 Pamphlet International publication WO1998/018480 Pamphlet International publication WO2009/057199 Pamphlet

The present invention shows a retinoic acid receptor (RAR) agonistic action, rod regeneration inducing action and/or rod degeneration protection action, and a therapeutic and/or prophylactic effect against retinal degenerative diseases accompanied by photoreceptor degeneration, The present invention provides a novel low molecular weight compound.

The present inventor conducted research on a novel low molecular weight compound having a retinoic acid receptor agonistic action. And, the compound of the specific structure disclosed in the present invention or a pharmaceutically acceptable salt thereof has a retinoic acid receptor agonistic action, exhibits a rod regeneration inducing action and/or a rod degeneration protecting action, and The present invention has been completed by finding that it is useful as a drug for retinal degenerative diseases accompanied by photoreceptor degeneration. The compound disclosed in the present invention or a pharmaceutically acceptable salt thereof has not been known so far, nor is their pharmacological activity known.

The present invention relates to the following [1] to [20].

[1] General formula (1)

[In the formula,
R ¹ represents a C _1-6 alkyl group or a hydrogen atom,
W is the formula (2A) to (2C)

(In the formula,
* Indicates a bond,
R ² represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkoxy C _1-6 alkyl group, or a phenyl C _1-6 alkyl group,
R ³ represents a C _1-20 alkyl group or a carboxy C _1-6 alkyl group,
R ⁴ represents a C _1-6 alkyl group. ) Indicates either. ]
A compound represented by or a pharmaceutically acceptable salt thereof.

[2] The compound according to [1], wherein R ¹ is a methyl group or a hydrogen atom, or a pharmaceutically acceptable salt thereof.
[3] The compound according to [1], wherein R ¹ is a methyl group, or a pharmaceutically acceptable salt thereof.

[4] W is from formula (3A) to (3C)

[In the formula,
* Indicates a bond,
R ⁵ represents an ethyl group, an isopropyl group, a cyclohexyl group, a 2-methoxyethyl group, or a benzyl group,
R ⁶ represents a methyl group, an n-pentadecyl group, or a 2-carboxyethyl group. ]
The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein
[5] W is expressed by equations (4A) to (4D)

[In the formula, * represents a bond. ]
The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein
[6] W is the formula (5A) or (5B)

[In the formula, * represents a bond. ]
The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof.

[7] R ¹ is a methyl group or a hydrogen atom;
W is from formula (3A) to (3C)

[In the formula,
* Indicates a bond,
R ⁵ represents an ethyl group, an isopropyl group, a cyclohexyl group, a 2-methoxyethyl group, or a benzyl group,
R ⁶ represents a methyl group, an n-pentadecyl group, or a 2-carboxyethyl group. ]
Indicates any of the following:
The compound according to [1], or a pharmaceutically acceptable salt thereof.

[8] R ¹ is a methyl group;
W is the formula (4A) to (4D)

[In the formula, * represents a bond. ]
Indicates any of the following:
The compound according to [1], or a pharmaceutically acceptable salt thereof.

[9] R ¹ is a methyl group;
W is the formula (5A) or (5B)

[In the formula, * represents a bond. ]
Indicates;
The compound according to [1], or a pharmaceutically acceptable salt thereof.

[10] The compound of the general formula (1) is
(5-Methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- Ill) carbamoyl] benzoate,
1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(−)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(+)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
1-(acetoxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(+)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(−)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
4-oxo-4-[1-({4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoyl}oxy)ethoxy]buta Noic Acid,
1-({[(propan-2-yl)oxy]carbonyl}oxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl ] Benzoate,
1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
1-{[(benzyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate, and {[ Selected from the group consisting of (2-methoxyethoxy)carbonyl]oxy}methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate [1] which is any one of the following, or a pharmaceutically acceptable salt thereof.

[11] The compound of the general formula (1) is 1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- Il)carbamoyl]benzoate, the compound according to [1], or a pharmaceutically acceptable salt thereof.
[12] The compound of the general formula (1) is (-)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro The compound according to [1], which is naphthalen-2-yl)carbamoyl]benzoate, or a pharmaceutically acceptable salt thereof.
[13] The compound of the general formula (1) is (+)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro The compound according to [1], which is naphthalen-2-yl)carbamoyl]benzoate, or a pharmaceutically acceptable salt thereof.
[14] The compound of the general formula (1) is 1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl ) The compound according to [1], which is carbamoyl]benzoate, or a pharmaceutically acceptable salt thereof.
[15] The compound of the general formula (1) is (+)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene -2-yl)carbamoyl]benzoate, the compound according to [1] or a pharmaceutically acceptable salt thereof.
[16] The compound of the general formula (1) is (-)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene -2-yl)carbamoyl]benzoate, the compound according to [1] or a pharmaceutically acceptable salt thereof.

[17] A retinoic acid receptor agonist comprising the compound according to any one of [1] to [16] or a pharmaceutically acceptable salt thereof.
[18] A rod regeneration inducer containing the compound according to any one of [1] to [16] or a pharmaceutically acceptable salt thereof as an active ingredient.
[19] A rod modification protector containing the compound according to any one of [1] to [16] or a pharmaceutically acceptable salt thereof as an active ingredient.
[20] A pharmaceutical composition comprising the compound according to any one of [1] to [16] or a pharmaceutically acceptable salt thereof as an active ingredient.
[21] Retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone-rod dystrophy, Best's disease, X-linked juvenile retinolysis, occult macular dystrophy, and central ring-shaped choroid retina choroid dystrophy The pharmaceutical composition according to [20], which is used for treatment and/or prophylaxis of a more selected disease.
[22] The pharmaceutical composition according to [20], for treating and/or preventing retinitis pigmentosa or age-related macular degeneration.
[23] The pharmaceutical composition according to any one of [20] to [22], which is topically administered to the eye.

[24] Retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, which comprises administering the compound according to any one of [1] to [16] or a pharmaceutically acceptable salt thereof. A method for treating and/or preventing a disease selected from the group consisting of cone-rod dystrophy, Best's disease, X-linked juvenile retinopathy of separation, occult macular dystrophy, and central ring-shaped reticulochoroidal dystrophy.
[25] A group consisting of retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone-rod dystrophy, Best's disease, X-linked juvenile retinosis, occult macular dystrophy, and central ring-shaped reticulochoroidal dystrophy The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [16], for use in the treatment and/or prevention of a disease selected from the following.
[26] Retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone-rod dystrophy, Best's disease, X-linked juvenile retinopathy, occult macular dystrophy, and central ring-shaped reticulochoroidal dystrophy A compound of any one of [1] to [16] or a pharmaceutically acceptable salt thereof for producing a medicament for treating and/or preventing a disease selected from use.

The compound of the present invention or a pharmaceutically acceptable salt thereof has a RAR agonistic action, exhibits a rod regeneration inducing action and/or a rod degeneration protecting action, and is used as a drug for retinal degenerative diseases involving photoreceptor cell degeneration. It is useful. That is, a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is administered to mammals (human, bovine, horse, pig or the like) or birds (chicken or the like) By doing so, it can be used for treatment and/or prevention of retinal degenerative diseases accompanied by photoreceptor degeneration. Examples of retinal degenerative diseases involving photoreceptor cell degeneration include retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone rod dystrophy, Best's disease, X-linked juvenile retinopathy, occult macular dystrophy, or central Examples include sex ring-shaped reticulochoroidal dystrophy, preferably retinitis pigmentosa or age-related macular degeneration.

After injuring the rods of the recombinant zebrafish Tg (rho:NTR-NanoLuc, myl7:DsRed2) produced in Test Example 2, after removing toxic radicals by washing with breeding water, the rods gradually became loose in 48 hours. It is a figure which shows that reproduction|regeneration was confirmed. The vertical axis represents the light emission amount (cps), and the horizontal axis represents the time after radical removal. 5 shows the results of the rod regeneration-inducing action and/or rod degeneration protecting action of the compound of Example 2 (FIG. 2A) and the compound of Example 4 (FIG. 2B) in the retinitis pigmentosa model of Test Example 3. The vertical axis represents the increase rate of rod markers (average of n=8) relative to the control calculated from the amount of luminescence, which is an index of rod regeneration inducing action and/or rod degeneration protecting action. *** indicates p<0.001 in Dunnett's multiple comparison test. Error bars indicate standard error. 5 shows the results of the regeneration-inducing action and/or rod degeneration-protecting action of the compound of Example 2 (FIG. 3A) and the compound of Example 4 (FIG. 3B) in the age-related macular degeneration model of Test Example 4. The vertical axis represents the increase rate of rod markers (average of n=8) relative to the control calculated from the amount of luminescence, which is an index of rod regeneration inducing action and/or rod degeneration protecting action. *** indicates p<0.001 in Dunnett's multiple comparison test, ** indicates p<0.01, and * indicates p<0.05. Error bars indicate standard error.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In the present invention, compound naming was performed according to ACD/Name 2016.2.2.

In the present invention, the “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethyl group Propyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1, Examples thereof include 1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group and 2-ethylbutyl group.

In the present invention, the “C _1-6 alkoxy group” refers to a group in which the above “C _1-6 alkyl group” is bonded to an oxygen atom. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, isopentoxy group, 2-methylbutoxy group, n-hexyloxy group. A group etc. can be mentioned.

In the present invention, _{"C 1-6} alkoxy _{C 1-6} alkyl group", one of the hydrogen atoms of the aforementioned _{"C 1-6} alkyl group" is substituted with the above-mentioned _{"C 1-6} alkoxy group" group Indicates. Examples thereof include methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isopropoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 1-propoxyethyl group, 1-isopropoxyethyl group and the like. it can.

In the present invention, the “C _3-8 cycloalkyl group” refers to a 3- to 8-membered monocyclic saturated hydrocarbon group (ring). For example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group can be mentioned.

In the present invention, the “phenyl C _1-6 alkyl group” refers to a group in which one hydrogen atom of the above “C _1-6 alkyl group” is substituted with a phenyl group. For example, benzyl group, 2-phenylethyl group, 1-phenylethyl group, 3-phenylpropyl group, 1-methyl-1-phenyl-ethyl group and the like can be mentioned.

In the present invention, the “C _1-20 alkyl group” refers to a linear or branched alkyl group having 1 to 20 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, 4-methylpentyl group , N-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group , N-heptadecyl group, n-octadecyl group, n-nonadecyl group, n-eicosyl group and the like.

In the present invention, the “carboxy C _1-6 alkyl group” refers to a group in which one hydrogen atom of the above “C _1-6 alkyl group” is substituted with a carboxy group. For example, 2-carboxyethyl group, 3-carboxypropyl group, 2-carboxypropyl group, 2-carboxy-1-methylethyl group, 5-carboxypentyl group and the like can be mentioned.

In the present invention, "protection of degeneration of rods" and "protection of degeneration of rods" means suppressing a decrease in cell number due to progressive rod cell death in retinal degenerative diseases accompanied by photoreceptor degeneration, and as a result , Protect the rod.

In the present invention, the “rod modification protector” refers to a drug that exhibits the above-mentioned “protecting the modification of the rod”.

In the present invention, “regeneration of rods” and “regeneration of rods” means that the number of cells in the rods decreased due to the condition is restored by newly proliferating the rods or differentiating into the rods. Indicates.

In the present invention, the terms “inducing rod regeneration” and “induction of rod regeneration” refer to promoting the above-mentioned “regeneration of rods”.

In the present invention, the “regeneration inducer of rod” refers to a drug that exhibits the above-mentioned “induction of regeneration of rod”.

Suitable substituents for the compound of the present invention are described below.

R ¹ is preferably a hydrogen atom or a methyl group. R ¹ is more preferably a methyl group.

W preferably represents any one of formulas (3A) to (3C). W more preferably represents either formula (3A) or (3B).

[Wherein * represents a bond, R ⁵ represents an ethyl group, an isopropyl group, a cyclohexyl group, a 2-methoxyethyl group, or a benzyl group, and R ⁶ represents a methyl group, an n-pentadecyl group, or A 2-carboxyethyl group is shown. ]

Even more preferably, W represents any of formulas (4A) to (4D).

[In the formula, * represents a bond. ]

W even more preferably represents either formula (5A) or (5B).

[In the formula, * represents a bond. ]

As the compound of the present invention, preferably,
(5-Methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- Ill) carbamoyl] benzoate,
1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(−)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(+)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
1-(acetoxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(+)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
(−)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
4-oxo-4-[1-({4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoyl}oxy)ethoxy]buta Noic Acid,
1-({[(propan-2-yl)oxy]carbonyl}oxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl ] Benzoate,
1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
1-{[(benzyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate, and {[ Selected from the group consisting of (2-methoxyethoxy)carbonyl]oxy}methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate Or a pharmaceutically acceptable salt thereof.
Particularly preferable compounds include the following.
1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate or pharmaceutically acceptable thereof salt.
(-)-1-[(Ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate or its pharmaceuticals Top acceptable salt.
(+)-1-[(Ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate or its pharmaceuticals Top acceptable salt.
1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate or a pharmaceutically acceptable salt thereof ..
(+)-1-(Hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate or its pharmaceutically Acceptable salt.
(-)-1-(Hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate or its pharmaceutically Acceptable salt.

The compound of the present invention or a pharmaceutically acceptable salt thereof has RAR agonist activity, rod regeneration inducing action, rod degeneration protecting action, solubility, cell membrane permeability, oral absorbability, blood concentration, metabolic stability, tissue. It has excellent properties in terms of migration, bioavailability, in vitro activity, in vivo activity, rapid onset of drug effect, sustained drug effect, physical stability, drug interaction, toxicity, etc., It is useful as a medicine.

The compound of the present invention can be converted into a pharmaceutically acceptable salt if desired. The pharmaceutically acceptable salt refers to a salt which has no significant toxicity and can be used as a medicine. The compound having RAR agonistic activity used in the present invention may be a compound having an acidic moiety, particularly a carboxy group, and thus can be converted to a salt by treating with a base.

Examples of salts based on acidic substituents are alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts and iron salts; ammonium salts and the like. Inorganic 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, dicyclohexylamine salt, N , N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris(hydroxymethyl)aminomethane salt and other organic amine salts; glycine salt, There are amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.

The compound of the present invention or a salt thereof may be left in the air or may be recrystallized to absorb water and become adsorbed with water to form a hydrate. A solvate is also included in the compound of the present invention or a salt thereof.

The compound of the present invention or a salt thereof may absorb a certain solvent to form a solvate, and such a solvate is also included in the compound of the present invention or a salt thereof.

The solvent capable of forming a solvate is not particularly limited as long as it has no significant toxicity and can be used as a medicine, and examples thereof include ethanol, 1-propanol, 2-propanol, 1-butanol, 2- Examples thereof include butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl sulfoxide, ethyl formate, ethyl acetate, propyl acetate, diethyl ether, tetrahydrofuran, formic acid, acetic acid, pentane, heptane, cumene, anisole and the like.

When the compound of the present invention has an asymmetric carbon atom in its molecule, optical isomers exist. These isomers and mixtures of these isomers can be used for the purposes of the present invention. Therefore, the single optical isomer of the compound having RAR agonistic activity used in the present invention and the mixture of optical isomers at any ratio are all included in the scope of the present invention.

The above optical isomers can be obtained by using an optically active starting material compound or by synthesizing the compound according to the present invention using an asymmetric synthesis or asymmetric induction method. Besides, it can be obtained by isolating the synthesized compound according to the present invention by a usual optical resolution method or a separation method utilizing an optically active carrier.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of atomic isotopes include deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), and the like. Also, the compound may be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

In a low molecular weight compound, by containing a deuterium atom ( ² H;D) in at least one of the hydrogen atoms constituting the compound, a profile useful as a medicine (eg, drug efficacy, safety, etc.) can be exhibited. Is known (Sanderson, Nature, 2009, DOI: 10.1038/458269a, Maltais et al, J. Med. Chem., 2009, 52, 7993-8001.). Also in the compound of the present invention, by introducing a deuterium atom into at least one hydrogen atom constituting the compound, the same effect as described above is expected.

The disease to be treated is a retinal degenerative disease accompanied by photoreceptor degeneration. Examples of retinal degenerative diseases involving photoreceptor cell degeneration include retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone rod dystrophy, Best's disease, X-linked juvenile retinopathy, occult macular dystrophy, or central Examples include sex ring-shaped reticulochoroidal dystrophy. The disease to be treated is preferably retinitis pigmentosa or age-related macular degeneration.

The compound of the present invention has a rod regeneration-inducing action and/or a rod degeneration protecting action, and therefore diseases whose symptoms are improved by this action, for example, retinitis pigmentosa, age-related macular degeneration, macular dystrophy (Stargardt's disease) , Cone-rod dystrophy, Best disease, X-linked juvenile retinopathy, occult macular dystrophy, central ring-shaped reticulochoroidal dystrophy) and/or excellent therapeutic effect on symptoms associated with these diseases and/ Or a preventive effect can be expected. The essential form of these diseases is known to be degeneration of photoreceptor cells including rods (see, for example, the following documents: retinitis pigmentosa (A, E), age-related macular degeneration (B), Stargardt's disease (C, E), cone-rod dystrophy (E), Best's disease (D, E), X-linked juvenile retinolysis (E), occult macular dystrophy (F), central ring-shaped reticulochoroid Dystrophy (G)), on the other hand, pathological conditions caused by photoreceptor degeneration have been shown to be improved by rod supply by transplantation (X). Therefore, according to the present invention, administration of a compound having a retinoic acid receptor agonist activity induces regeneration of endogenous rods to increase rods, and/or protects rods from degeneration. Since the number of rod cells decreased by the disease can be maintained, the present invention is effective for the treatment and/or prevention of the diseases accompanied by photoreceptor degeneration (preferably the above diseases).

A, Exp Eye Res. 2016 Sep;150:149-165.
B, Am J Ophthalmol. 2016 Aug;168:260-268.
C, Biochim Biophys Acta-Mol Cell Biol Lipid. 2009 Jul;1791(7):573-583.
D, Prog Retin Eye Res. 2017 May;58:70-88.
E, Dev Ophthalmol. 2014;53:44-52.
F, Jpn J Ophthalmol. 2015 Mar;59(2):71-80.
G, J Optom. 2013 Apr; 6(2): 114-122.
X, Nature. 2006 Nov 9;444(7116):203-207.

The age-related macular degeneration in the present invention includes both dry type and wet type. It is preferably atrophic.

Since the compound of the present invention has a rod regeneration inducing action and/or a rod degeneration protecting action, it is a treatment and/or prevention of both atrophic and exudative (preferably atrophic) age-related macular degeneration. It is also effective.

The macular dystrophy in the present invention refers to a group of retinal degenerative diseases in which the macular disorder is accompanied by photoreceptor cell degeneration due to a genetic cause, and deterioration of visual acuity, visual field abnormality and the like progress. Specifically, it indicates Stargardt's disease, cone-rod dystrophy, Best's disease, X-linked juvenile retinolysis, occult macular dystrophy, and central ring-shaped reticulochoroidal dystrophy.

The treatment in the present invention is to restore the visual function to the retina that has lost its function due to degeneration or loss. For that purpose, for example, it is necessary to increase the number of rods, induce the differentiation into rods, protect the degeneration of rods, and protect the loss of cone function. The compound can be suitably applied for this purpose.

The prevention of the present invention, the degeneration of rods, the probability of progression of dropout is increased, the number of rods is increased in a situation where the risk of developing a retinal degenerative disease involving photoreceptor cell degeneration is increased, or to rods The purpose is to eliminate the risk by inducing the differentiation of erythrocytes, protecting the degeneration of rods, and preventing the loss of cone function. The compound of the present invention can also be suitably applied to this prevention.

In any of the above-mentioned treatments and preventions, the mechanism of inducing rod regeneration or protecting rod degeneration by administering the compound of the present invention to retinal degenerative diseases accompanied by photoreceptor degeneration is proposed. It is what

The compound of the present invention or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof can be administered in various forms. The administration form is preferably by topical administration to the eye. For topical administration to the eye, liquids (eg eye drops, injections), ointments and the like can be applied.

In the case of a liquid, it can be used as a liquid, emulsion, or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions, or suspensions is not particularly limited as long as it can be used as a medical diluent, and examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated. Examples thereof include isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, the formulation may contain a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution, and a usual solubilizing agent, buffer, soothing agent, etc. May be included. For example, eye drops include isotonic agents such as sodium chloride and concentrated glycerin; pH adjusting agents such as hydrochloric acid and sodium hydroxide; buffering agents such as sodium phosphate and sodium acetate; polyoxyethylene sorbitan monooleate and stearic acid. Surfactants such as polyoxyl 40, polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; additives selected as necessary from preservatives such as benzalkonium chloride and paraben Can be used and prepared. The pH of the ophthalmic solution may be within the range acceptable for ophthalmic preparations, but is preferably within the range of 4-8.

Also, as an ointment, an ointment base for eye ointment can be prepared by using an auxiliary agent such as liquid paraffin. The above-mentioned preparation may contain a coloring agent, a preservative and the like, if necessary, and may further contain other pharmaceuticals.

The amount of the active ingredient compound contained in the above-mentioned preparation is not particularly limited and may be appropriately selected within a wide range, but normally it is contained in the total composition in an amount of 0.5 to 70% by weight, preferably 1 to 30% by weight.

The amount used depends on the symptoms, age, etc. of the patient (warm-blooded animal, especially human), but in the case of instillation or intravitreal injection of the liquid, the upper limit is 10 mg per eye (preferably 1 mg) per day. It is desirable that the lower limit of 0.001 mg (preferably 0.01 mg) be administered to an adult 1 to 6 times per day depending on the symptoms. This dosage and usage can also be applied to eye ointments.

In addition, by adding the compound of the present invention to cultured stem cells such as embryonic stem cells, adult stem cells, and induced pluripotent stem cells, in vitro effectively retina tissue such as sheet, organoid, and suspension state. It can also be manufactured. By transplanting the retinal tissue produced in vitro in this manner into the eyeball, it can be used for regenerative medicine.

[Manufacturing method]

Next, a typical method for producing the compound represented by the general formula (1) will be described. The compound of the present invention can be produced by various production methods, and the production methods shown below are examples, and the present invention should not be construed as being limited thereto.

The compound represented by the general formula (1), a pharmaceutically acceptable salt thereof, and an intermediate for producing the same utilize various characteristics of the basic skeleton or the type of the substituent, and various known production methods are applied. Can be manufactured. As a known method, for example, "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd edition, ACADEM PRESS, INC. , 1989, "Comprehensive Organic Transformations", VCH Publishers Inc. , 1989 and the like.

At that time, depending on the kind of the functional group existing in the compound, the functional group is protected with an appropriate protecting group at the stage of the raw material or the intermediate, or is replaced with a group which can be easily converted into the functional group. This may be effective in terms of manufacturing technology.

Such functional groups include, for example, amino group, hydroxyl group, carboxy group, and the like, and protective groups thereof include, for example, P.I. G. There is a protecting group described in "Protective Groups in Organic Synthesis (5th edition, 2014)" by Wuts.

The protecting group or the group that can be easily converted into the functional group may be appropriately selected and used according to the respective reaction conditions of the production method for producing the compound.
According to such a method, the desired compound can be obtained by introducing the group and carrying out the reaction, and then removing the protecting group or converting the group to the desired group, if necessary.

The starting materials and reagents used in the preparation of the compounds of the present invention can be purchased from commercial suppliers or can be synthesized by methods described in the literature or methods similar thereto.

The compound represented by the general formula (1) can be produced, for example, by the following method A. Compound 3 or compound 3'used in Method A can be purchased from a commercial supplier, or can be synthesized by Method B, Method C, a method described in the literature, or a method similar thereto. .. Known literatures include Synthesis 1986; 8,627-632 (1986) and the like.

The compound serving as a reaction substrate in the reaction in each of the following methods A to C has a functional group or partial structure that inhibits the intended reaction, such as an amino group, a hydroxy group, a carboxy group or a hetero atom on a cyclic compound. In this case, if necessary, a protecting group may be introduced into them and the introduced protecting group may be removed. The protecting group is not particularly limited as long as it is a commonly used protecting group, and may be, for example, the protecting group described in the above-mentioned "Protective Groups in Organic Synthesis (5th edition, 2014)". The reaction for introducing and removing these protecting groups can be carried out according to the conventional method described in the above literature.

The functional group of each compound of methods A to C below can be replaced with a group that can be easily converted into a desired functional group at the stage of a raw material or an intermediate, depending on its type. The conversion to the desired functional group can be performed at an appropriate stage according to a known method. Known methods include, for example, the methods described in the above-mentioned "ORGANICAL FUNCTIONAL GROUP PREPARATIONS", "Comprehensive Organic Transformations" and the like.

Each compound of the following methods A to C is isolated and purified as various solvates such as a non-solvate, a salt or a hydrate thereof. The salt can be produced by a usual method. Examples of the salt include hydrochloride, sulfate, etc., sodium salt, potassium salt, etc.

The solvent used in the reaction in each step of the following methods A to C is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting materials, and is selected from the following solvent group, for example. Solvent groups include aliphatic hydrocarbons such as n-hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane (methylene chloride), chloroform, carbon tetrachloride, dichloroethane. Halogenated hydrocarbons such as chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone; Esters such as ethyl acetate, propyl acetate and butyl acetate; Nitriles such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; Carboxylic acids such as acetic acid and propionic acid; Methanol, ethanol, 1-propanol, Alcohols such as 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N -Methyl-2-pyrrolidone, amides such as hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide, tetrahydrothiophene 1,1-dioxide; water; and mixtures thereof.

The acid used in the reaction of each step of the following methods A to C is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group. The acid group includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid, organic acids such as acetic acid, propionic acid, trifluoroacetic acid and pentafluoropropionic acid, and methanesulfonic acid. , Organic sulfonic acids such as trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and boron tribromide, indium (III) bromide, boron trifluoride, aluminum (III) chloride, trifluoromethane sulfone It consists of a Lewis acid such as trimethylsilyl acid.

The base used in the reaction of each step of the following methods A to C is not particularly limited as long as it does not inhibit the reaction, and is selected from the following base group. Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide, sodium hydroxide. , Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; lithium such as lithium diisopropylamide Alkylamides; silylamides such as lithium bistrimethylsilylamide and sodium bistrimethylsilylamide; alkyllithiums such as n-butyllithium, sec-butyllithium, tert-butyllithium; methylmagnesium chloride (methylmagnesium chloride), methylmagnesium bromide ( Methyl magnesium bromide), methyl magnesium iodide (methyl magnesium iodide), ethyl magnesium chloride (ethyl magnesium chloride), ethyl magnesium bromide (ethyl magnesium bromide), isopropyl magnesium chloride (isopropyl magnesium chloride), isopropyl magnesium bromide (odor Alkyl magnesium halide such as isopropylmagnesium chloride) and isobutylmagnesium chloride (isobutylmagnesium chloride); and triethylamine, tributylamine, N,N-diisopropylethylamine, 1-methylpiperidine, 4-methylmorpholine, 4-ethylmorpholine, Pyridine, picoline, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 2,6-di-tert-butyl-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5 -Diazabicyclo[4,3,0]-5-nonene (DBN), 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), an organic amine such as imidazole.

In the reaction of each step of methods A to C below, the reaction temperature varies depending on the solvent, the starting material, the reagent, etc., and the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, etc.

In the reaction of each step of methods A to C below, after the reaction is completed, the target compound of each step is isolated from the reaction mixture according to a conventional method. For the target compound, for example, (i) insoluble matter such as a catalyst is filtered off if necessary, and (ii) water and a solvent immiscible with water (eg, dichloromethane, diethyl ether, ethyl acetate, etc.) are added to the reaction mixture. The target compound is extracted with, the organic layer (iii) is washed with water, dried with a desiccant such as anhydrous magnesium sulfate, and the solvent (iv) is distilled off. If necessary, the obtained target compound is further purified by a conventional method, for example, recrystallization, reprecipitation, distillation, or column chromatography (including normal phase and reverse phase) using silica gel or alumina. can do. The obtained target compound is identified by a standard analytical technique such as elemental analysis, NMR, mass spectrometry, IR analysis and the like, and its composition or purity can be analyzed. In addition, the target compound of each step can be directly used in the next reaction without purification.

In each step of Method A to C below, an optically active amine such as (R)-(+)- or (S)-(-)-1-phenethylamine, or (+)- or (-)-10-camphor The optical isomers can be separated and purified by fractional recrystallization using an optically active carboxylic acid such as sulfonic acid, or separation using an optically active column.

[In the formula, R ¹ and W have the same meanings as described above. R ^6a represents a methyl group, an n-pentadecyl group, or a 2-carboxyethyl group protected with a protecting group. PG represents a protective group for a functional group existing in W (for example, when W has a carboxy group, PG can be a benzyl group or the like). X represents halogen, and examples thereof include iodine, bromine, chlorine and the like. ]

The reaction of each step of methods A to C is explained below.

Method A The compound represented by the general formula (1) can be obtained by using the compound 2 and the compound 3 (the following A-1) or the method using the compound 2 and the compound 3′ via the compound 1′ (the following). , A-2).

(A-1) Method using Compound 2 and Compound 3 A solvent (for example, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, pyridine, etc.) in a solvent inert to the reaction of Compound 2 with a base (eg, triethylamine, N,N-diisopropyl) It can be carried out by reacting with Compound 3 in the presence of ethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydrogencarbonate and the like). Suitably the reaction temperature is from room temperature to 100° C. and the reaction time is from 5 minutes to 6 days.

(A-2) Method using compound 2 and compound 3′ via compound 1′ Conversion from compound 2 to compound 1′ is performed using compound 2 and compound 3′ by the same method as in A-1. Can be implemented. The conversion of compound 1′ to compound 1 can be carried out by the deprotection method described in the above-mentioned “Protective Groups in Organic Synthesis (5th edition, 2014)”.

When compound 3 or compound 3'is represented by compound 3a, compound 3a can be produced by, for example, method B or method C.

Method B Compound 4 in a solvent inert to the reaction (eg, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, pyridine, etc.), a carboxylic acid activating reagent (eg, thionyl chloride, acid halide, oxalyl chloride, etc.), It can be carried out by activating with a suitable catalyst (N,N-dimethylformamide etc.) and then reacting with compound 5 and a halide (eg sodium iodide, sodium bromide etc.). Suitably the reaction temperature is 0° C. to 100° C. and the reaction time is 5 minutes to 3 days.

Method C: reacting compound 6 with compound 7, halide (eg sodium iodide, sodium bromide etc.) in a solvent inert to the reaction (eg dichloromethane, tetrahydrofuran, N,N-dimethylformamide, pyridine etc.) Can be implemented in. Suitably the reaction temperature is 0° C. to 100° C. and the reaction time is 5 minutes to 3 days.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
Elution in the column chromatography of the examples was carried out under observation by thin layer chromatography (TLC). In TLC observation, silica gel 60F ₂₅₄ or 60NH ₂ F ₂₅₄ S manufactured by Merck Ltd. was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector or coloration was used as a detection method. The reagent was adopted. As the silica gel for the column, silica gel SK-85 also manufactured by Merck, 1093851000 SILICA GEL 60, Fuji Silysia Chemical Chromatorex DIOL, or Fuji Silysia Chemical Chromatorex NH was used. In addition to these, an automatic refining device manufactured by Yamazensha, Shoko Science, or Biotage was used. The abbreviations used in the examples have the following meanings.
DMF=N,N-dimethylformamide, THF=tetrahydrofuran In the following examples, the nuclear magnetic resonance (hereinafter, ¹ H-NMR: 400 MHz or 500 MHz) spectra were obtained by using tetramethylsilane as a standard substance and a chemical shift value of a δ value. It is described in (ppm). The division pattern is indicated by s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad. For the mass spectrometry, either the ESI method, the APCI method, or the ESI/APCI method was used as the ion source.

Example 1
(5-Methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- Il)carbamoyl]benzoate

4-[(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl] benzoic acid (225 mg, CAS number: 94497-51-5) DMF (2.5 mL) solution, potassium carbonate (174 mg) and 4-(chloromethyl)-5-methyl-1,3-dioxole-2-one (75 μL) were added at 0° C., and then at room temperature. The reaction was carried out for 5 days. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=5/1 to 3/2) to give the title compound (250 mg). Obtained.
¹ H-NMR (CDCl ₃ )δ: 1.20-1.32 (12H, m), 1.63-1.68 (4H, m), 2.23 (3H, s), 5.09 (2H, s), 7.30 (1H, d, J = 8.8 Hz), 7.39-7.44 (1H, m), 7.48-7.53 (1H, m), 7.68-7.73 (1H, m), 7.92 (2H, d, J = 8.3 Hz), 8.13 (2H, d, J = 8.3 Hz).
MS (m/z): 464 (M+H) ⁺ .

Example 2
1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate (Example 2)
(-)-1-[(Ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate (Example 2a)
(+)-1-[(Ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate (Example 2b)

4-[(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (20.0 g) in DMF (114 mL) was added with potassium carbonate. (18.8 g) and 1-chloroethyl ethyl carbonate (9.17 mL) were added, and then the mixture was stirred at 50° C. for 6 hr. After water was poured into the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=9/1 to 0/1) to give the compound of the title Example 2 ( 23.0 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.32 (15H, m), 1.65-1.69 (7H, m), 4.19-4.25 (2H, m), 6.99-7.05 (1H, m), 7.30 (1H, d, J = 8.3 Hz), 7.38-7.44 (1H, m), 7.48-7.53 (1H, m), 7.68-7.74 (1H, m), 7.91 (2H, d, J = 8.3 Hz), 8.14 (2H , d, J = 8.3 Hz).
MS (m/z): 468 (M+H) ⁺ .

The compound (2.1 g) of the title example 2 obtained above was optically resolved under the following conditions to obtain (2a, first peak, 720 mg) and (2b, second peak, 750 mg). It was
Separation conditions Column: YMC CHIRALART Cellulose-C (registered trademark) (5 um), size 250 X 30 mm ID
Elution solvent: n-hexane/2-propanol=70/30
Flow rate: 42.6 mL/min
Temperature: Room temperature Detection: UV at 240 nm

2a (1st peak, retention time 15.1 minutes)
Optical purity: 99.9% ee or higher
[α] _D ²⁰ -60.244° (c=1.007, MeOH)

2b (2nd peak, retention time 19.5 minutes)
Optical purity: 99.7% ee
[α] _D ²⁰ +60.610° (c=1.003, MeOH)

Example 3
1-(acetoxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate

4-[(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (70 mg) in DMF (1.5 mL) was added with potassium carbonate. (56 mg) and 1-bromoethyl acetate (30 μL) were added, and then the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=10/1 to 3/1) to give the title compound (68 mg). Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.30 (12H, m), 1.61 (3H, d, J = 5.9 Hz), 1.65-1.69 (4H, m), 2.09 (3H, s), 7.11 (1H , q, J = 5.4 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.37-7.44 (1H, m), 7.48-7.55 (1H, m), 7.67-7.74 (1H, m), 7.91 ( 2H, d, J = 8.3 Hz), 8.13 (2H, d, J = 8.3 Hz).
MS (m/z): 438 (M+H) ⁺ .

Example 4
1-(Hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate (Example 4)
(+)-1-(Hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate (Example 4a )
(−)-1-(Hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate (Example 4b) )

To a solution of acetaldehyde (1.40 mL) in acetonitrile (50 mL) was added sodium iodide (3.10 g) at 0°C, hexadecanoyl chloride (2.50 mL) was added over 5 minutes, and then at 0°C for 1 hour. Stir for hours. After standing at 0° C. overnight, ice and n-hexane were poured, sodium thiosulfate pentahydrate (4.2 g) was added, and the organic layer was washed. Then, after saturated aqueous sodium hydrogen carbonate was added to wash the organic layer, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude 1-iodoethyl hexadecanoate (2.46 g).
4-[(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (2.00 g) in DMF (30 mL) was added at 0°C. Then, a solution of potassium carbonate (2.36 g) and the crudely purified 1-iodoethyl hexadecanoate (2.46 g) obtained above in THF (6 mL) was added, and then the mixture was stirred at room temperature for 7 hours. Water, ethyl acetate, and sodium thiosulfate pentahydrate (200 mg) were added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=30/1 to 5/1) to give the compound of the title Example 4 ( 2.11 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 6.8 Hz), 1.18-1.33 (38H, m), 1.60-1.71 (7H, m), 2.30-2.38 (2H, m), 7.13 (1H, q, J = 5.5 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.39-7.45 (1H, m), 7.50-7.55 (1H, m), 7.69-7.73 (1H, m), 7.92 (2H, d, J = 8.2 Hz), 8.14 (2H, d, J = 8.2 Hz).
MS (m/z): 634 (M+H) ⁺ .

The compound of Reference Example 4 (100 mg) obtained above was optically resolved under the following conditions to obtain (4a, 1st peak, 43 mg) and (4b, 2nd peak, 46 mg), respectively. It was
Separation conditions Column: CHIRLPAK IF, size 250 X 20 mm
Elution solvent: n-hexane/ethanol=95/5
Flow rate: 20 mL/min
Temperature: Room temperature Detection: UV at 254 nm

4a (1st peak, retention time 12.5 minutes)
Optical purity: 99.9% ee or higher
[α] _D ²⁰ +32.971° (c=1.009, CHCl ₃ ).

4b (2nd peak, retention time 14.2 minutes)
Optical purity: 97.0% ee
[α] _D ²⁰ -29.420° (c=1.001, CHCl ₃ )

Example 5
4-oxo-4-[1-({4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoyl}oxy)ethoxy]buta Noic acid

(Step 1) To a solution of benzyl 1-iodoethyl butanedioate 4-(benzyloxy)-4-oxobutanoic acid (1.00 g) in methylene chloride (20 mL) at 0° C., thionyl chloride (1.10 mL), After adding and DMF (catalytic amount), the mixture was stirred at room temperature for 1 hour. Then, after stirring at 35° C. for 2 hours, the solvent was distilled off under reduced pressure to obtain a residue. To a solution of acetaldehyde (810 μL) in acetonitrile (25 mL) was added sodium iodide (1.80 g) at 0° C., and then the residue obtained above in acetonitrile (6 mL) was added dropwise at 0° C. I left it overnight. Water, n-hexane and sodium thiosulfate pentahydrate (2.8 g) were added for extraction, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound (570 mg).

(Step 2) Benzyl 1-({4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoyl}oxy)ethyl butanedioate 4 -[(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (300 mg) in DMF (3 mL) at 0°C , Potassium carbonate (354 mg), and a solution of the compound (570 mg) obtained in Step 1 above in THF (3 mL) were added, and then the mixture was stirred at room temperature for 6 hours. Water, ethyl acetate, and sodium thiosulfate pentahydrate (200 mg) were added, the mixture was extracted 3 times with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=10/1 to 3/1) to give the title compound (165 mg). Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.32 (12H, m), 1.59 (3H, d, J = 5.4 Hz), 1.65-1.68 (4H, m), 2.66-2.71 (4H, m), 5.08 -5.11 (2H, m), 7.11 (1H, q, J = 5.4 Hz), 7.27-7.38 (6H, m), 7.38-7.42 (1H, m), 7.49-7.54 (1H, m), 7.66-7.72 (1H, m), 7.89 (2H, d, J = 8.3 Hz), 8.12 (2H, d, J = 8.3 Hz).
MS (m/z): 586 (M+H) ⁺ .

(Step 3) 4-oxo-4-[1-({4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoyl}oxy )Ethoxy]butanoic acid

7.5% Palladium-carbon (14 mg) was added to a solution of the compound (88 mg) obtained in Step 2 above in ethyl acetate (5 mL), and then the mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction solution was filtered through Celite, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=2/1 to 0/1). The title compound (71 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.31 (12H, m), 1.60-1.68 (7H, m), 2.65-2.71 (4H, m), 7.12 (1H, q, J = 5.5 Hz), 7.29 (1H, d, J = 8.3 Hz), 7.39-7.44 (1H, m), 7.50-7.54 (1H, m), 7.74-7.78 (1H, m), 7.90 (2H, d, J = 8.3 Hz), 8.10 (2H, d, J = 8.3 Hz).
MS (m/z): 496 (M+H) ⁺ .

Example 6
1-({[(propan-2-yl)oxy]carbonyl}oxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl ] Benzoate

DMF (16 mL) was charged with 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (0.29 g), 1-chloroethyl. Isopropyl carbonate (0.15 mL) and potassium carbonate (0.26 g) were added, and the mixture was heated with stirring at 50° C. for 6 hours. After water was poured into the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=9/1 to 0/1) to obtain the title compound (0.12 g). It was
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.35 (18H, m), 1.61-1.79 (7H, m), 4.86-4.96 (1H, m), 7.04 (1H, q, J = 5.5 Hz), 7.28 -7.34 (1H, m), 7.40-7.47 (1H, m), 7.50-7.57 (1H, m), 7.85-7.96 (3H, m), 8.16 (2H, d, J = 8.6 Hz).
MS (m/z): 482 (M+H) ⁺ .

Example 7
1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate

DMF (16 mL) was charged with 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (0.27 g), 1-chloroethyl. Cyclohexyl carbonate (0.19 g) and potassium carbonate (0.26 g) were added, and the mixture was heated with stirring at 50° C. for 6 hours. After water was poured into the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=9/1 to 0/1) to obtain the title compound (0.36 g). It was
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.57 (18H, m), 1.63-1.79 (9H, m), 1.88-1.99 (2H, m), 4.60-4.70 (1H, m), 7.05 (1H, q, J = 5.5 Hz), 7.32 (1H, d, J = 8.6 Hz), 7.40-7.47 (1H, m), 7.50-7.57 (1H, m), 7.73-7.78 (1H, m), 7.93 (2H , d, J = 8.6 Hz), 8.16 (2H, d, J = 8.6 Hz).
MS (m/z): 522 (M+H) ⁺ .

Example 8
1-{[(benzyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate

DMF (15 mL) was charged with 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (0.26 g), benzyl 1-. Chloroethyl carbonate (0.23 g) and potassium carbonate (0.24 g) were added, and the mixture was heated with stirring at 50° C. for 6 hours. After water was poured into the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=9/1 to 0/1) to obtain the title compound (0.068 g). It was
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.33 (12H, m), 1.65-1.72 (7H, m), 5.13-5.25 (2H, m), 7.06 (1H, q, J = 5.3 Hz), 7.29 -7.39 (6H, m), 7.40-7.47 (1H, m), 7.51-7.57 (1H, m), 7.86-7.96 (3H, m), 8.12 (2H, d, J = 8.6 Hz).
MS (m/z): 530 (M+H) ⁺ .

Example 9
{[(2-Methoxyethoxy)carbonyl]oxy}methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate

DMF (15 mL) was charged with 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid (0.27 g), chloromethyl 2 -Methoxyethyl carbonate (0.19 g) and potassium carbonate (0.25 g) were added, and the mixture was heated with stirring at 50° C. for 6 hours. After water was poured into the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=9/1 to 0/1) to give the title compound (0.089 g). Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.23-1.34 (12H, m), 1.64-1.73 (4H, m), 3.33-3.42 (3H, m), 3.57-3.67 (2H, m), 3.85-3.96 ( 1H, m), 4.24-4.39 (1H, m), 5.58-5.63 (1H, m), 6.00-6.07 (1H, m), 7.28-7.34 (1H, m), 7.41-7.49 (1H, m), 7.50-7.58 (1H, m), 7.86-8.00 (3H, m), 8.10-8.19 (2H, m).
MS (m/z): 484 (M+H) ⁺ .
(Test example)

[Test Example 1] Measurement of RAR agonist activity [Procedure]
The RAR agonist activity was measured by the following procedure. As the evaluation compounds, the compounds of Examples 1 to 9 were used.
1) Using Lipofectamine (registered trademark) 2000 Transfection Reagent (Thermo Fisher Scientific), in accordance with the manual attached to the kit, in addition to RAR synthetic response element luciferase reporter construct (3xDR5:luc), human RARα, human RARβ, HEK293A cells (Invitrogen) functionally co-expressing human RARγ were prepared. The introduced genes are shown in Table 1.
2) The gene-introduced cells were collected and seeded on a 384 well plate at 2×10 ⁵ cells/mL, and at the same time, the cells were brought into contact with the compound (10 steps of 4-fold dilution series from the maximum concentration of 25000 nM).
3) 24 hours after the compound exposure, the luminescence of each cell was measured by EnVision (Perkin Elmer Japan Co., Ltd.) using a Piccagene (registered trademark) luminescence kit (Toyo Beanet Co., Ltd.) (N=4).

[analysis]
Microsoft Excel 2010 was used for the calculation of the average value of the luminescence amount (cps) and the EC.

[Data processing]
In the evaluation of RAR agonist activity, the measured value of luminescence in cells without addition of compound (Negative control) was set to 100%, and RAR agonist activity (%) of the test compound was calculated by the following formula, and the average value thereof was used as the test compound. Plotted against concentration.

RAR agonist activity (%) = (Sample well measured value ÷ Negative control average value) × 100

As an index of the strength of RAR agonist activity, for RARα and RARβ, the concentration indicating a luminescence amount of 1000% based on Negative control is EC ₁₀₀₀ , for RARγ, the concentration indicating a luminescence amount of 500% based on Negative control. Was defined as EC ₅₀₀ . EC ₁₀₀₀ or EC ₅₀₀ was calculated by the GROWTH function (exponential regression) using the RAR agonist activity (%) and the concentration at two points where the luminescence amount by the test compound was 1000% or 500%.

[result]
Table 2 shows the measurement results of each compound of Example 1 to Example 9 in Test Example 1. Each compound showed agonistic activity against any RAR in a concentration-dependent manner.

[Test Example 2] Preparation of recombinant zebrafish Tg (rho:NTR-NanoLuc, myl7:DsRed2) and evaluation of the rod regeneration inducing effect of the compound

1. Preparation of recombinant zebrafish Tg (rho:NTR-NanoLuc, myl7:DsRed2) In order to prepare recombinant zebrafish Tg (rho:NTR-NanoLuc, myl7:DsRed2), first, In-Fusion (registered trademark) HD The plasmid pcDNA3.1-rho-ntr-nanoluc-myl7-dsred2 was prepared using the Cloning Kit. The vector creation method was based on the manual attached to the kit. The introduced nucleotide sequences are shown in SEQ ID NOs: 4 to 7 in the sequence listing. Using the prepared plasmid pcDNA3.1-rho-ntr-nanoluc-myl7-dsred2, recombinant zebrafish Tg (rho:NTR-NanoLuc, myl7:DsRed2) was prepared by a gene transfer method using I-SceI meganuclease. (Soroldoni D, Hogan BM, Oates AC., "Simple and efficient transgenesis with meganuclease constructs in zebrafish.", Methods Mol. Biol., 2009; 546: 117-130.). The specific procedure is as follows.
1) 1 μL of pcDNA3.1-rho-ntr-nanoluc-myl7-dsred2 (712 ng/μL), 1.5 μL of Meganuclease buffer (10X), 0.6 μL of I-SceI (New England Biolabs Japan KK; 5,000 units/mL), 1.5 μL of 0.5% phenol red (Sigma Aldrich Japan GK), and 10.4 μL of dH2O were mixed to prepare an injection solution.
2) 1 nL of the injection solution was injected into the cytoplasm of the 1-cell stage fertilized egg obtained from wild-type zebrafish using FemtoJet (registered trademark) (Eppendorf Co., Ltd.).
3) Dead eggs were removed in the evening of the day of injection, and on the third day after fertilization, recombinants showing transient expression were selected under the fluorescence microscope using DsRed2 expression in the heart as an index.
4) Breeding was performed until a recombinant in which DsRed2 was transiently expressed in the heart was laid, and a fertilized egg was obtained by mating with a wild-type zebrafish. The fertilized egg obtained was observed under a fluorescence microscope, and when a fertilized egg expressing DsRed2 in the heart was confirmed, it was indicated that the parent could inherit the introduced gene to the offspring, and this recombinant was Isolated as a founder.
5) After that, the offspring obtained by mating the founder with wild-type zebrafish are transgenic plants with stable expression, and this was used as a parent, and the test was conducted using the recombinant fry obtained by mating. ..
In the prepared zebrafish Tg (rho:NTR-NanoLuc, myl7:DsRed2), myocardium cell-specific myl7 promoter expresses a fluorescent protein DsRed2 that is cardiac tissue-specific, and a fluorescent stereomicroscope using dsRed2 as a marker. It can be easily confirmed below that it is a recombinant zebrafish. In this recombinant zebrafish, in addition to cardiac tissue-specific expression of DsRed2, rod-cell-specific reductase nitroreductase (NTR) and photoluminescent protein NanoLuc were detected by a rod-specific rho promoter. The fusion protein (NTR-NanoLuc) of is expressed. NTR-NanoLuc, which is expressed only in rods, does not affect the general condition under normal breeding conditions, but when the prodrug metronidazole is added, non-toxic metronidazole is converted into toxic radicals by NTR. By this mechanism, it was confirmed that by exposing this recombinant zebrafish to metronidazole, the rods were specifically killed to 13.5% without affecting the general condition. After the rod injury due to metronidazole treatment, this recombinant zebrafish was washed with breeding water to remove toxic radicals, and then it was confirmed that the zebrafish gently regenerate the rod naturally (Fig. 1). In the subsequent evaluations, conditions under which mild spontaneous regeneration occurs were used as controls for evaluating the effects of the compounds. The damage and spontaneous regeneration of the rods were confirmed by measuring the luminescence derived from the rod-specific NanoLuc expression in this recombinant zebrafish and conducting a quantitative evaluation.

After the rod injury by metronidazole using this recombinant zebrafish, the effect of the test compound on rod regeneration by exposing the test compound is quantitatively evaluated by measuring rod-specific luminescence derived from NanoLuc. be able to.

2. Evaluation of rod regeneration inducing effect of compounds [Procedure]
Using the produced recombinant zebrafish Tg (rho:NTR-NanoLuc, myl7:DsRed2), the compound was evaluated by the following procedure. As test compounds, the compounds of Examples 1 to 9 were used.
The procedure for compound evaluation is as follows.
1) On the day before egg collection, a combination of recombinant Tg (rho:NTR-NanoLuc, myl7:DsRed2) and wild type was used to place male and female zebrafish in a mating tank and isolate with a divider.
2) The next morning (8:00-11:00), remove the divider to mate, collect fertilized eggs, and select only fertilized eggs that have developed normally in the evening (16:00-18:00) of the same day. Breeded on a growth plate.
3) Three days after fertilization, 1 L of distilled water (60 mg of Instant Ocean (Napco Limited (Japan))) containing 10 mM metronidazole (Sigma Aldrich Japan GK) and 1% DMSO (Wako Pure Chemical Industries, Ltd.) was distilled water. It was dissolved in the solution (1) and transferred to (preparation), and it was raised in the dark for 24 hours to cause rod-specific damage. In addition, the non-injured controls were reared by rearing to the rearing water containing 1% DMSO.
4) Dilution series so that the test compound (Tissue Culture Treated Black Isoplate-96 TC (PerkinElmer Japan Co., Ltd.)) contains 2 concentrations of test compound (Activation (% of control) 50%) DMSO as a control was dispensed at 2.5 μL/well, and Egg water was further added at 147.5 μL/well.
5) Four days after fertilization, the juveniles were thoroughly washed with Egg water, and 100 μL of Egg water was added to each well in an assay plate containing the compound, and two fish were dispensed into each well.
6) After breeding for 2 days, 200 μL of Egg water was removed, ethyl 3-aminobenzoate methanesulfonate (Sigma Aldrich Japan GK; 0.4 mg/mL, 10 μL) was added, and euthanized.
7) Nano-Glo (registered trademark) Luciferase assay Substrate (Promega Corporation) was added to Nano-Glo (registered trademark) Luciferase assay buffer (Promega Corporation) at a ratio of 1:50, and 100 μL was added to each well. ..
8) After shaking for 1 hour using BIO-Mixer (Biotech Japan Co., Ltd.), the luminescence of NanoLuc (registered trademark) was measured using EnVision (PerkinElmer Japan Co., Ltd.).

[analysis]
Microsoft Excel 2010 was used for calculation of Luciferase activity (Activity (%)), average value, and EC ₅₀ with respect to Control.

[Data processing]
In the evaluation of the rod regeneration effect, the measured value of the luminescence amount in the zebrafish treated with DMSO which is the negative target compound (Negative control) is 0%, the mechanism of action is already known as the RAR agonist as the positive target compound, The present inventors have confirmed that there is a rod regeneration effect 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-Propenyl]benzoic acid (TTNPB) was treated at a concentration of 1 μM and the measured value (Positive control) in zebrafish was set as 100%, and Activity (%) was calculated as an index of activity by the following formula, and the average value was calculated. Was plotted against the test compound concentration. EC ₅₀ was defined as the concentration at which Activity (%) shows 50%. The EC ₅₀ was calculated by linear regression between two points where the activity of the test compound was 50%.

Activity (%) = (Sample well measured value-Negative control average value) ÷ ÷ (Positive control average value-Negative control average value) × 100

[result]
Table 3 shows the measurement results of each Example compound in Test Example 2. Each of the compounds exhibited a rod regeneration inducing effect in a concentration-dependent manner.

[Test Example 3] Evaluation of rod regeneration-inducing action and/or rod degeneration protecting action of a compound in a retinitis pigmentosa model

Using a zebrafish known as a retinitis pigmentosa model and a zebrafish that was used in Test Example 2 to quantify the expression level of the rod marker rhodopsin by luminescence, rod regeneration due to pathological conditions And/or pathological condition model fish capable of quantitative evaluation of rod degeneration protection was prepared, and the effect of the compound was verified by the following procedure. The compounds of Example 2 and Example 4 were used as test compounds.

Zebrafish retinitis pigmentosa model Tg(rho:hRHO(Q344X), omp:EGFP) (Nakao T, Tsujikawa M, Notomi S, Ikeda Y, Nishida K., "The role of mislocalized phototransduction in photoreceptor                   of this model used retinitis pigmentosa.", PLoS One., 2012; 7(4): e32472.; Zebrafish RH1:hRhodopsin (Q344X), a model of retinitis pigmentosa, was renamed by another method.) It is a recombinant zebrafish that rod-specifically expresses hRhodopsin (Q344X), which has been reported to cause degeneration, and shows ectopic expression of rhodopsin and photoreceptor death including rods, similar to human pathology. It is a model that is constantly recognized.

[Preparation of pathological model zebrafish whose effects can be quantified]
Zebrafish Tg (rho:NTR-NanoLuc prepared in Test Example 2 was prepared in order to prepare a recombinant zebrafish capable of quantitatively evaluating rod degeneration due to pathological conditions, rod regeneration against loss, and/or rod degeneration protection. , myl7:DsRed2) and zebrafish retinitis pigmentosa model Tg (rho:hRHO(Q344X), omp:EGFP) were combined to prepare a zebrafish. Tg (rho:NTR-NanoLuc, myl7:DsRed2) is a cardiac tissue-specific fluorescent protein DsRed2 is expressed by myel7 promoter specific for cardiomyocytes, and easily assembled under a fluorescence stereomicroscope using DsRed2 as a marker. It can be confirmed that it is a zebrafish. Tg(rho:hRHO(Q344X), omp:EGFP) is an olfactory cell-specific omp promoter that expresses the fluorescent protein EGFP that is specific to the olfactory cell. It can be confirmed that it is a recombinant zebrafish. In Test Example 3, by using zebrafish in which DsRed2 and EGFP are positive, quantitative evaluation of rod degeneration and/or rod degeneration protection of a test compound against rod degeneration and dropout due to pathological conditions of retinitis pigmentosa is performed. It was

[procedure]
1) On the day before egg collection, male and female zebrafish were placed in a mating tank and isolated with a divider.
2) The next morning (8:00-11:00), remove the divider to mate, collect fertilized eggs, and select only fertilized eggs that have developed normally in the evening (16:00-18:00) of the same day. Breeded on a growth plate.
3) The test compound and DMSO serving as a control were dispensed at 2.5 μL/well (DMSO final concentration 1%) to the assay plate, and Egg water was further added at 147.5 μL/well. In the screening, N=8 tests were conducted at each concentration.
4) Two fry three days after fertilization were dispensed into each well together with 100 μL of Egg water on the assay plate containing the compound.
5) After breeding for 2 days, 200 μL of Egg water was removed, and 3-aminobenzoic acid ethyl methanesulfonate (Sigma Aldrich Japan GK; 0.4 mg/ml, 10 μL) was added for euthanasia.
6) Nano-Glo (registered trademark) Luciferase assay Substrate (Promega Corporation) was added to Nano-Glo (registered trademark) Luciferase assay buffer (Promega Corporation) at a ratio of 1:50, and 100 μL was added to each well. ..
7) After shaking for 1 hour using BIO-Mixer (Biotech Japan Co., Ltd.), the luminescence of NanoLuc (registered trademark) was measured using EnVision (PerkinElmer Japan Co., Ltd.).

[analysis]
Microsoft Excel 2010 was used for calculation of Luciferase activity (Activity (% of control)), average value, and standard error for the negative control group.

[Data processing]
The activity of Luciferase (expressed as Activity (% of control)) by compound stimulation with respect to the measured value (Negative control) of luminescence in zebrafish treated with DMSO, which is a negative target compound, was calculated by the following formula.

Activity (% of control) = = (Sample well measurement value / DMSO control average value) × 100

Dunnett's multiple comparison test used SAS9.3 for Microsoft Windows Workstation 32-bit and its interlocking system EXSUS Ver.8.0.

[result]
The measurement results of the compounds of Example 2 and Example 4 are shown in FIG. Each compound showed a rod marker recovery in a concentration-dependent manner in a retinitis pigmentosa model, and exhibited a rod regeneration-inducing action and/or a rod degeneration protecting action.

[Test Example 4] Evaluation of rod regeneration-inducing action and/or rod degeneration protecting action of a compound in an age-related macular degeneration model

Using a zebrafish known as an age-related macular degeneration model and a zebrafish capable of quantifying the expression level of the rod marker rhodopsin produced in Test Example 2 by luminescence, rods were denatured or dropped due to the pathological condition. A pathological condition model fish capable of quantitative evaluation of regeneration and/or rod degeneration protection was prepared, and the effect of the compound was verified by the following procedure. The compounds of Example 2 and Example 4 were used as test compounds.

Zebrafish age-related macular degeneration model used Tg(rho:hHTRA1, omp:EGFP) (Oura Y, Nakamura M, Takigawa T, Fukushima Y, Wakabayashi T, Tsujikawa M, Nishida K, "High-Temperature Cause1         Photoreceptor Cell Death in Zebrafish Disease Models.", AmJ Pathol.20182018 Dec;188(12):2729-2744.; Age-related macular degeneration model Zebrafish Tg (rho:hsa.HTRA1) is named by another method. Is a recombinant zebrafish with rod-specific expression of hHTRA1 that has been reported as a risk gene for age-related macular degeneration in humans. It is a model in which photoreceptor cell death including the body is constantly observed.

[Preparation of pathological model zebrafish whose effects can be quantified]
Zebrafish Tg (rho:NTR-NanoLuc prepared in Test Example 2 was prepared in order to prepare a recombinant zebrafish capable of quantitatively evaluating rod degeneration due to pathological conditions, rod regeneration against loss, and/or rod degeneration protection. , myl7:DsRed2) and zebrafish age-related macular degeneration model Tg (rho:hHTRA1, omp:EGFP) were combined to prepare a zebrafish. Tg (rho:NTR-NanoLuc, myl7:DsRed2) is a cardiac tissue-specific fluorescent protein DsRed2 is expressed by myel7 promoter specific for cardiomyocytes, and easily assembled under a fluorescence stereomicroscope using DsRed2 as a marker. It can be confirmed that it is a zebrafish. Tg(rho:hHTRA1, omp:EGFP) expresses a fluorescent protein, EGFP, in an olfactory cell-specific manner by the olfactory cell-specific omp promoter, and is easily recombinant under a fluorescent stereomicroscope using EGFP as a marker. It can be confirmed that it is a fish. In Test Example 4, by using zebrafish in which DsRed2 and EGFP are positive, quantitative evaluation of rod degeneration and/or rod degeneration protection of a test compound against rod degeneration and loss due to age-related macular degeneration is observed. went.

[procedure]
1) On the day before egg collection, male and female zebrafish were placed in a mating tank and isolated with a divider.
2) The next morning (8:00-11:00), remove the divider to mate, collect fertilized eggs, and select only fertilized eggs that have developed normally in the evening (16:00-18:00) of the same day. Breeded on a growth plate.
3) The test compound and DMSO serving as a control were dispensed at 2.5 μL/well (DMSO final concentration 1%) to the assay plate, and Egg water was further added at 147.5 μL/well. In the screening, N=8 tests were conducted at each concentration.
4) Two fry three days after fertilization were dispensed into each well together with 100 μL of Egg water on the assay plate containing the compound.
5) After breeding for 2 days, 200 μL of Egg water was removed, and 3-aminobenzoic acid ethyl methanesulfonate (Sigma Aldrich Japan GK; 0.4 mg/ml, 10 μL) was added for euthanasia.
6) Nano-Glo (registered trademark) Luciferase assay Substrate (Promega Corporation) was added to Nano-Glo (registered trademark) Luciferase assay buffer (Promega Corporation) at a ratio of 1:50, and 100 μL was added to each well. ..
7) After shaking for 1 hour using BIO-Mixer (Biotech Japan Co., Ltd.), the luminescence of NanoLuc (registered trademark) was measured using EnVision (PerkinElmer Japan Co., Ltd.).

[analysis]
Microsoft Excel 2010 was used for calculation of Luciferase activity (Activity (% of control)), average value, and standard error for the negative control group.

[Data processing]
The Luciferase activity rate (expressed as Activity (% of control)) due to compound stimulation with respect to the measured value (Negative control) of the luminescence amount in the zebrafish treated with the negative target compound DMSO was calculated by the following formula.

Activity (% of control) = = (Sample well measurement value / DMSO control average value) × 100

Dunnett's multiple comparison test used SAS9.3 for Microsoft Windows Workstation 32-bit and its interlocking system EXSUS Ver.8.0.

[result]
The measurement results of the compounds of Example 2 and Example 4 are shown in FIG. In each model of age-related macular degeneration, the recovery of the rod marker was observed in a concentration-dependent manner, and each compound exhibited a rod regeneration-inducing action and/or a rod degeneration protecting action.

The compound represented by the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof has a retinoic acid receptor agonistic action, exhibits a rod regeneration inducing action and/or a rod degeneration protecting action, and , And can be used for the treatment and/or prevention of retinal degenerative diseases accompanied by photoreceptor degeneration. Specifically, retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone rod dystrophy, Best's disease, X-linked juvenile retinopathy, occult macular dystrophy, or central ring-shaped reticulochoroidal dystrophy, More preferably, it is useful as a therapeutic and/or prophylactic agent for retinitis pigmentosa or age-related macular degeneration.

SEQ ID NO: 1 nucleotide sequence of human RARα SEQ ID NO: 2 nucleotide sequence of human RARβ SEQ ID NO: 3 nucleotide sequence of human RARγ SEQ ID NO: 4: nucleotide sequence of cebrafish rho promoter site SEQ ID NO: 5: nucleotide sequence of cebrafish myl7 promoter site Sequence SEQ ID NO: 6: NTR-NanoLuc protein nucleotide sequence SEQ ID NO: 7: DsRed2 protein nucleotide sequence

Claims (26)

1. General formula (1)
   

   

   [In the formula,
   R ¹ represents a C _1-6 alkyl group or a hydrogen atom,
   W is the formula (2A) to (2C)
   

   

   (In the formula,
   * Indicates a bond,
   R ² represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkoxy C _1-6 alkyl group, or a phenyl C _1-6 alkyl group,
   R ³ represents a C _1-20 alkyl group or a carboxy C _1-6 alkyl group,
   R ⁴ represents a C _1-6 alkyl group. ) Indicates either. ]
   A compound represented by or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R ¹ is a methyl group or a hydrogen atom, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein R ¹ is a methyl group, or a pharmaceutically acceptable salt thereof.
4. W is from formula (3A) to (3C)
   

   

   [In the formula,
   * Indicates a bond,
   R ⁵ represents an ethyl group, an isopropyl group, a cyclohexyl group, a 2-methoxyethyl group, or a benzyl group,
   R ⁶ represents a methyl group, an n-pentadecyl group, or a 2-carboxyethyl group. ]
   The compound according to any one of claims 1 to 3, which represents any of the following, or a pharmaceutically acceptable salt thereof.
5. W is the formula (4A) to (4D)
   

   

   [In the formula, * represents a bond. ]
   The compound according to any one of claims 1 to 3, which represents any of the following, or a pharmaceutically acceptable salt thereof.
6. W is the formula (5A) or (5B)
   

   

   [In the formula, * represents a bond. ]
   The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
7. R ¹ is a methyl group or a hydrogen atom;
   W is from formula (3A) to (3C)
   

   

   [In the formula,
   * Indicates a bond,
   R ⁵ represents an ethyl group, an isopropyl group, a cyclohexyl group, a 2-methoxyethyl group, or a benzyl group,
   R ⁶ represents a methyl group, an n-pentadecyl group, or a 2-carboxyethyl group. ]
   Indicates any of the following:
   The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
8. R ¹ is a methyl group;
   W is the formula (4A) to (4D)
   

   

   [In the formula, * represents a bond. ]
   Indicates any of the following:
   The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
9. R ¹ is a methyl group;
   W is the formula (5A) or (5B)
   

   

   [In the formula, * represents a bond. ]
   Indicates;
   The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
10. The compound of the general formula (1) is
    (5-Methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- Ill) carbamoyl] benzoate,
    1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    (−)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    (+)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    1-(acetoxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    (+)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    (−)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    4-oxo-4-[1-({4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoyl}oxy)ethoxy]buta Noic Acid,
    1-({[(propan-2-yl)oxy]carbonyl}oxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl ] Benzoate,
    1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate,
    1-{[(benzyloxy)carbonyl]oxy}ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate, and {[ Selected from the group consisting of (2-methoxyethoxy)carbonyl]oxy}methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoate The compound according to claim 1, which is any one of the following, or a pharmaceutically acceptable salt thereof.
11. The compound of the general formula (1) is 1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl ] The compound of Claim 1 which is benzoate, or its pharmaceutically acceptable salt.
12. The compound of the general formula (1) is (-)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2 -Yl)carbamoyl]benzoate, or a pharmaceutically acceptable salt thereof.
13. The compound of the general formula (1) is (+)-1-[(ethoxycarbonyl)oxy]ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2 -Yl)carbamoyl]benzoate, or a pharmaceutically acceptable salt thereof.
14. The compound of the general formula (1) is 1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl] The compound of claim 1, which is benzoate, or a pharmaceutically acceptable salt thereof.
15. The compound of the general formula (1) is (+)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- Yil) carbamoyl] benzoate or a pharmaceutically acceptable salt thereof.
16. The compound of the general formula (1) is (-)-1-(hexadecanoyloxy)ethyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- Yil) carbamoyl] benzoate or a pharmaceutically acceptable salt thereof.
17. A retinoic acid receptor agonist comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.
18. A rod regeneration inducer containing the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient.
19. A rod denaturing protectant containing the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient.
20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient.
21. Selected from the group consisting of retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone-rod dystrophy, Best's disease, juvenile X-linked retinoschisis, occult macular dystrophy, and central cricoreticular choroid dystrophy The pharmaceutical composition according to claim 20, which is used for the treatment and/or prevention of diseases associated with the above.
22. The pharmaceutical composition according to claim 20, which is used for treatment and/or prevention of retinitis pigmentosa or age-related macular degeneration.
23. 23. The pharmaceutical composition according to any one of claims 20 to 22, which is topically administered to the eye.
24. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof is administered, and retinitis pigmentosa, age-related macular degeneration, Stargardt disease, cone rod dystrophy. , A method selected from the group consisting of Best disease, X-linked juvenile retinosis, occult macular dystrophy, and central ring-shaped reticulochoroidal dystrophy.
25. Selected from the group consisting of retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone-rod dystrophy, Best's disease, juvenile X-linked retinopathy of separation, occult macular dystrophy, and central cricoreticular choroid dystrophy The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a disease.
26. Selected from the group consisting of retinitis pigmentosa, age-related macular degeneration, Stargardt's disease, cone-rod dystrophy, Best's disease, juvenile X-linked retinopathy of separation, occult macular dystrophy, and central cricoreticular choroid dystrophy Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease according to claim 1.

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