JP2022152866A - Agent for treating or preventing presbyopia containing cholic acid or cholic acid derivative - Google Patents

Abstract

To provide a novel agent for treating or preventing presbyopia.SOLUTION: An agent for treating or preventing eye diseases such as presbyopia contains cholic acid or a cholic acid derivative having a predetermined structure as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to an agent for treating or preventing presbyopia.

Presbyopia is one of the eye aging phenomena that begins around the age of 40, and is commonly referred to as presbyopia. (accommodation). In order to see and focus on near and far objects, it is necessary for the light entering the eye to be refracted appropriately when passing through the lens. The eye has a function to adjust the thickness of the crystalline lens, such as contraction of body muscles. Ocular tissues involved in accommodative responses include the lens, zonules, lens capsule, and ciliary muscles. However, when the function of the ciliary muscle declines due to aging or the elasticity (or viscoelasticity) of the lens decreases, that is, when the lens hardens, it becomes difficult to adjust the thickness of the lens. When you look at , you can't focus well. This condition is presbyopia.

Reading glasses have been used to deal with presbyopia, and recently, there are reports of research and development of presbyopia therapeutic agents. For example, Patent Document 1 discloses that lipoic acid derivatives such as lipoic acid choline ester (also known as EV06, UNR844) are useful for treating presbyopia, and eye drops containing lipoic acid choline ester are available in the United States. Clinical development is underway. In addition, eye drops containing AGN-199201 and AGN-190584, eye drops containing PRX-100, and eye drops containing PresbiDrops (CSF-1) are also under clinical development as presbyopia treatment agents. there is Since ursodeoxycholic acid improves the elasticity of the lens, it is also expected as a therapeutic or preventive drug for presbyopia (Patent Document 2). However, the conditions of presbyopic patients are diverse, and there is still a strong demand for an increase in the types of eye disease therapeutic agents so that a therapeutic agent can be appropriately selected accordingly.

WO 2010/147957 pamphlet WO 2020/129964 pamphlet

Atarashii Ophthalmology, Vol. 28, No. 7, 985-988, 2011

All disclosures of prior art documents cited herein are hereby incorporated by reference to the extent not inconsistent with the present disclosure.

An object of the present application is to provide new means for treatment or prevention of presbyopia.

As a result of intensive research to solve the above problems, the present inventors found that the cholic acid or cholic acid derivative represented by the formula [I] surprisingly significantly improves the elasticity of the lens. I came up with the invention. Specifically, the present disclosure provides the following aspects of the invention.

［式中、
Ｒ^１、Ｒ^２およびＲ^３は、各々独立して、水素原子、ヒドロキシ基、オキソ基、ハロゲン原子、Ｃ_１－６アルキル基、またはＣ_１－６アルコキシ基であり、
Ｒ^４およびＲ^５は、各々独立して、水素原子、ヒドロキシ基、ハロゲン原子、Ｃ_１－６アルキル基、またはＣ_１－６アルコキシ基であり、
ただし、下式：

を除く］
の化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩を有効成分として含有する、老視の治療または予防のための剤／医薬組成物。
〔２〕 式［Ｉ］：

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５は、各々、〔１〕と同義である］
で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩を有効成分として含有する、水晶体の弾性の低下を伴う眼疾患の治療または予防のための剤／医薬組成物。
〔３〕 該眼疾患が眼の調節力の低下を伴う眼疾患である、〔２〕に記載の剤／医薬組成物。
〔４〕 式［Ｉ］：

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５は、各々、〔１〕と同義である］
で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩を有効成分として含有する、眼の調節力の低下を伴う眼疾患の治療または予防のための剤／医薬組成物。
〔５〕 式［Ｉ］で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩が、
式［ＩＩ］：

で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩である、〔２〕～〔４〕のいずれか一項に記載の剤／医薬組成物。
〔６〕 式［Ｉ］で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩が、下記式［ＩＩＩ］～［ＶＩＩＩ］から選択される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩である、〔２〕～〔５〕のいずれか一項に記載の剤／医薬組成物：

。
〔７〕 該眼疾患が老視である、〔２〕～〔６〕のいずれか一項に記載の剤／医薬組成物。
〔８〕 眼投与される、〔１〕～〔７〕のいずれか一項に記載の剤／医薬組成物。
〔９〕 点眼剤または眼軟膏である、〔１〕～〔８〕のいずれか一項に記載の剤／医薬組成物。
〔１０〕 式［Ｉ］で示される化合物もしくは式［Ｉ］で示される化合物のアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩の含有量が０．００００１～１０％（ｗ／ｖ）である、〔１〕～〔９〕のいずれか一項に記載の剤／医薬組成物。
〔１１〕 老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療または予防のための剤／医薬組成物の製造における、
式［Ｉ］：

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５は、各々、〔１〕と同義である］
で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩の使用。
〔１２〕 老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療または予防における使用のための、
式［Ｉ］：

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５は、各々、〔１〕と同義である］
で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩。
〔１３〕 老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患を治療または予防するための方法であって、その治療または予防を必要とする対象に有効量の
式［Ｉ］：

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５は、各々、〔１〕と同義である］
で示される化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩を投与することを含む方法。 [1] Formula [I]:

[In the formula,
R ¹ , R ² and R ³ are each independently a hydrogen atom, a hydroxy group, an oxo group, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group;
R ⁴ and R ⁵ are each independently a hydrogen atom, a hydroxy group, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group;
However, the following formula:

except for]
or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, an agent/pharmaceutical composition for treating or preventing presbyopia.
[2] Formula [I]:

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meaning as in [1]]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, for the treatment or prevention of ocular diseases accompanied by a decrease in the elasticity of the lens / pharmaceutical composition.
[3] The agent/pharmaceutical composition of [2], wherein the ocular disease is an ocular disease accompanied by a decrease in accommodation power of the eye.
[4] Formula [I]:

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meaning as in [1]]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. / pharmaceutical composition.
[5] a compound represented by formula [I] or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof,
Formula [II]:

The agent / pharmaceutical composition according to any one of [2] to [4], which is a compound represented by or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof.
[6] The compound represented by formula [I] or its amide conjugate, or an ester thereof, or a pharmaceutically acceptable salt thereof is a compound selected from the following formulas [III] to [VIII] or a compound thereof The agent/pharmaceutical composition according to any one of [2] to [5], which is an amide conjugate, an ester thereof, or a pharmaceutically acceptable salt thereof:

.
[7] The agent/pharmaceutical composition of any one of [2] to [6], wherein the eye disease is presbyopia.
[8] The agent/pharmaceutical composition of any one of [1] to [7], which is administered ocularly.
[9] The agent/pharmaceutical composition according to any one of [1] to [8], which is an eye drop or ophthalmic ointment.
[10] The content of the compound represented by formula [I] or the amide conjugate of the compound represented by formula [I], an ester thereof, or a pharmaceutically acceptable salt thereof is 0.00001 to 10% (w/v), the agent/pharmaceutical composition according to any one of [1] to [9].
[11] in the manufacture of an agent/pharmaceutical composition for the treatment or prevention of presbyopia, an ocular disease associated with decreased elasticity of the lens, or an ocular disease associated with decreased accommodative power of the eye,
Formula [I]:

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meaning as in [1]]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof.
[12] for use in the treatment or prevention of presbyopia, an ocular disease associated with decreased elasticity of the lens, or an ocular disease associated with decreased accommodation of the eye,
Formula [I]:

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meaning as in [1]]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof.
[13] A method for treating or preventing presbyopia, an eye disease associated with decreased elasticity of the lens, or an eye disease associated with decreased accommodation power of the eye, which is effective for a subject in need thereof Quantity Formula [I]:

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meaning as in [1]]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof.

Two or more of the configurations [1] to [13] can be arbitrarily selected and combined.

The agent/pharmaceutical composition of the present disclosure can improve the elasticity of the lens, which is important for adjusting the thickness of the lens, and is therefore useful for treating or preventing eye diseases such as presbyopia.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described in detail.

［式中、
Ｒ^１、Ｒ^２およびＲ^３は、各々独立して、水素原子、ヒドロキシ基、オキソ基、ハロゲン原子、Ｃ_１－６アルキル基、またはＣ_１－６アルコキシ基であり、
Ｒ^４およびＲ^５は、各々独立して、水素原子、ヒドロキシ基、ハロゲン原子、Ｃ_１－６アルキル基、またはＣ_１－６アルコキシ基であり、
ただし、下式：

を除く］
の化合物もしくはそのアミド結合体、もしくはそれらのエステル、またはそれらの医薬的に許容される塩（以下、「本開示の化合物」と称することがある）を有効成分として含有する剤／医薬組成物（以下、「本開示の剤／組成物」と称することがある）を提供する。
本開示の化合物／剤／組成物は老視を治療または予防するために使用されうる。本開示の化合物／剤／組成物は水晶体の弾性を向上するために使用されうる。さらに本開示の化合物／剤／組成物は眼の調節力を向上するために使用されうる。 The agents/compositions of the present disclosure are

[In the formula,
R ¹ , R ² and R ³ are each independently a hydrogen atom, a hydroxy group, an oxo group, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group;
R ⁴ and R ⁵ are each independently a hydrogen atom, a hydroxy group, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group;
However, the following formula:

except for]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as the "compound of the present disclosure") as an active ingredient / pharmaceutical composition containing hereinafter sometimes referred to as "agents/compositions of the present disclosure").
The compounds/agents/compositions of the disclosure can be used to treat or prevent presbyopia. The compounds/agents/compositions of the present disclosure can be used to improve the elasticity of the lens. Additionally, the compounds/agents/compositions of the present disclosure may be used to improve accommodation of the eye.

In one embodiment, R ¹ is a hydroxy or oxo group.

In one embodiment, ^R2 is a hydrogen atom, a hydroxy group, or an oxo group.

^In one embodiment, R3 is a hydrogen atom, a hydroxy group, or an oxo group.

In one embodiment, R ⁴ is a C _1-6 alkyl group (preferably a methyl group).

In one embodiment, R ⁵ is a C _1-6 alkyl group (preferably a methyl group).

In one embodiment,
R ¹ is a hydroxy group or an oxo group;
^R2 is a hydrogen atom, a hydroxy group, or an oxo group;
R ³ is a hydrogen atom, a hydroxy group, or an oxo group;
R ⁴ is a C _1-6 alkyl group (preferably a methyl group); and R ⁵ is a C _1-6 alkyl group (preferably a methyl group).

In one embodiment,
R ¹ is a hydroxy group, R ² is a hydroxy group, R ³ is a hydrogen atom, R ⁴ is a C _1-6 alkyl group, and R ⁵ is a C _1-6 alkyl group except.

In one embodiment, the compound represented by formula [I] is a compound selected from formulas [III] to [VIII] below. Here, the compound of formula [III] is cholic acid, the compound of formula [IV] is chenodeoxycholic acid, the compound of formula [V] is deoxycholic acid, the compound of formula [VI] is lithocholic acid, and the compound of formula [VII] is 7-ketolitocholic acid, and the compound of formula [VIII] is dehydrocholic acid.

In one embodiment, cholic acid, or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof is used as the active ingredient.

In one embodiment, chenodeoxycholic acid, or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof is used as the active ingredient.

In one embodiment, deoxycholic acid, or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof is used as the active ingredient.

In one embodiment, lithocholic acid, or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof is used as the active ingredient.

In one embodiment, 7-ketolitocholic acid, or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof is used as the active ingredient.

In one embodiment, dehydrocholic acid, or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof is used as the active ingredient.

In the present disclosure, halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

In the present disclosure, “C _1-6 alkyl” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of “C _1-6 alkyl” are methyl, ethyl, propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, t-butyl) and pentyl (eg n-pentyl, isopentyl, neopentyl).

In the present disclosure, “C _1-6 alkoxy group” means straight or branched chain alkoxy having 1 to 6 carbon atoms. Examples of “C _1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, t-butoxy.

In the present disclosure, "R ¹ is an oxo group" means that the hydrogens attached to the carbon atom to which R ¹ and R ¹ are attached are replaced together with "=O". The same applies when R ² /R ³ is an oxo group.

The amide conjugate of the compound represented by formula [I] means an amide conjugate having a —CO—NH— bond formed by dehydration condensation of the carboxyl group in formula [I] with the amino group of the amino compound. do.
Examples of such amino compounds include:
Amino acids: such as alanine, leucine, arginine, lysine, asparagine, methionine, aspartic acid, phenylalanine, cysteine, glutamine, serine, glutamic acid, threonine, glycine, tryptophan, histidine, tyrosine, isoleucine, and valine;
2-aminoadipic acid, 3-aminoadipic acid, 2-aminobutanoic acid, 4-aminobutanoic acid, 2,4-diaminobutanoic acid, 2-aminohexanoic acid, 6-aminohexanoic acid, β-alanine, 2-aminopentane acid, 2,3-diaminopropanoic acid, 2-aminopimelic acid, 2,6-diaminopimelic acid, cysteic acid, 2,4-diaminobutanoic acid, 2,6-diaminopimelic acid, 2,3-diaminopropanoic acid, 4- carboxyglutamic acid, homocysteine, homoserine, homoserine lactone, homoserine lactone, 5-hydroxylysine, allohydroxylysine, alloisoleucine, norleucine, norvaline, ornithine, allothreonine, thyroxine;
amino acid analogues: e.g. taurine;
is mentioned.

Specific examples of the amide conjugate of the compound of formula [I] include the compound of formula [Ia] and the compound of formula [Ib].

The ester of the compound represented by the formula [I] is, for example, a monohydric alcohol in which the carboxyl group in the formula [I] has 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms). and an ester formed by dehydration condensation.

For example, when the amino compound moiety has a carboxyl group and/or a sulfonic acid group, the carboxyl group and/or the sulfonic acid group have 1 to 1 carbon atoms. and an ester formed by dehydration condensation with a monohydric alcohol having 6 (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms).

Specific examples of the compound represented by formula [I] or the ester of the amide conjugate of the compound represented by formula [I] include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, Isobutyl esters, sec-butyl esters, tert-butyl esters, n-pentyl esters or n-hexyl esters may be mentioned. Examples of preferred esters include methyl esters, ethyl esters, n-propyl esters, isopropyl esters.

As another example, at least one hydroxyl group of the compound represented by the formula [I] or the amide conjugate of the compound represented by the formula [I] has 1 to 6 carbon atoms (preferably 1 to 1 4, more preferably a carboxylic acid ester formed by dehydration condensation with a carboxylic acid having 2 to 3 carbon atoms). Examples of specific carboxylic acid esters include formate, acetate, propionate, isopropionate, butyrate, isobutyrate, pivalate, valerate, or isovalerate. Examples of preferred carboxylic acid esters include acetates.

Salts of compounds of formula [I], salts of amide conjugates of compounds of formula [I], salts of esters of compounds of formula [I], and amides of compounds of formula [I] The ester salt of the conjugate is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate; acetate, trifluoroacetate, benzoate, oxalate, malonate , succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate , organic acid salts such as aspartate; metal salts such as sodium salts, potassium salts, calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as triethylamine salts and guanidine salts. includes sodium salts and potassium salts.

In the present disclosure, the compound represented by formula [I] or the amide conjugate of the compound represented by formula [I], or an ester thereof, or a pharmaceutically acceptable salt thereof is a hydrate or solvate may take the form of
Agents/compositions of the invention may contain a single or multiple compounds of the present disclosure.

The content of the compound represented by formula [I] or the amide conjugate of the compound represented by formula [I], or an ester thereof, or a pharmaceutically acceptable salt thereof is not particularly limited, and the dosage form, etc. can be selected from a wide range by

For example, the content of the compound represented by formula [I] or the amide conjugate of the compound represented by formula [I], an ester thereof, or a pharmaceutically acceptable salt thereof in the agent/composition of the present disclosure is 0.00001 to 10% (w/v), preferably 0.0001 to 5% (w/v), more preferably 0.001 to 3% (w/v), and even more It is preferably 0.01 to 2% (w/v), particularly preferably 0.15 to 1.5% (w/v). An example of the lower limit of the content is 0.00001% (w/v), a preferred example is 0.0001% (w/v), a more preferred example is 0.001% (w/v), and an even more preferred example. is 0.01% (w/v), a particularly preferred example is 0.1% (w/v), and a particularly preferred example is 0.15% (w/v). An example of the upper limit of the content is 10% (w/v), a preferred example is 5% (w/v), a more preferred example is 3% (w/v), and a particularly preferred example is 2% (w/v ), and a more particularly preferred example is 1.5% (w/v). A preferred range of the content can be indicated by a combination of the example of the lower limit and the example of the upper limit.

Furthermore, for example, the compound represented by formula [I] or the amide conjugate of the compound represented by formula [I] in the agent/composition of the present disclosure, or an ester thereof, or a pharmaceutically acceptable salt thereof The amount is 0.00001-10% (w/w), preferably 0.0001-5% (w/w), more preferably 0.001-3% (w/w), and further More preferably 0.01 to 2% (w/w), particularly preferably 0.15 to 1.5% (w/w). An example of the lower limit of the content is 0.00001% (w/w), a preferred example is 0.0001% (w/w), a more preferred example is 0.001% (w/w), and an even more preferred example. is 0.01% (w/w), a particularly preferred example is 0.1% (w/w), and a particularly preferred example is 0.15% (w/w). An example of the upper limit of the content is 10% (w/w), a preferred example is 5% (w/w), a more preferred example is 3% (w/w), and a particularly preferred example is 2% (w/w). ), and a more particularly preferred example is 1.5% (w/w). A preferred range of the content can be indicated by a combination of the example of the lower limit and the example of the upper limit.

In one embodiment, a compound of formula [I] or an amide conjugate of a compound of formula [I], or an ester thereof, or a pharmaceutically acceptable The content of salt is 0.3-10% (w/w) (eg 0.4-5% (w/w), 0.5-3% (w/w), 0.6-1.5% % (w/w), 0.8-1.3% (w/w)).

In the present disclosure, "% (w/v)" is the active ingredient contained in 100 mL of the drug (the compound represented by formula [I], the amide conjugate of the compound represented by formula [I], and their esters, and It means the mass (g) of the pharmaceutically acceptable salts thereof) and additives (surfactants, etc.). For example, 0.01% (w/v) of the compound of formula [I] means that 0.01 g of the compound of formula [I] is contained in 100 mL of the drug.

In the present disclosure, "% (w/w)" is the active ingredient contained in 100 g of the drug (the compound represented by formula [I], the amide conjugate of the compound represented by formula [I], and their esters, and It means the mass (g) of the pharmaceutically acceptable salts thereof) and additives (surfactants, etc.). For example, 0.01% (w/w) of the compound of formula [I] means that 0.01 g of the compound of formula [I] is contained in 100 g of the drug.

The compound represented by formula [I], the amide conjugate of the compound represented by formula [I], the ester of the compound represented by formula [I], or the ester of the amide conjugate of the compound represented by formula [I], When in the form of a salt or hydrate or solvate (including a hydrate or solvate of a salt), the compound represented by formula [I] in the drug or the amide bond of the compound represented by formula [I] or their esters, or their pharmaceutically acceptable salts, the content of said salts or hydrates or solvates (including hydrates or solvates of salts) formulated in the drug ), the mass of the compound represented by the formula [I], the amide conjugate of the compound represented by the formula [I], or the mass converted as a free form of an ester thereof, but the mass of the formula It is preferably the mass in terms of the free form of the compound represented by [I], the amide bond of the compound represented by formula [I], or the ester thereof.

When the agent/composition of the present disclosure contains multiple types of the compounds of the present disclosure, "the compound represented by formula [I] in the agent/composition of the present disclosure or the amide of the compound represented by formula [I] The content of a conjugate, or an ester thereof, or a pharmaceutically acceptable salt thereof" means the total content of a compound of the present disclosure in an agent/composition of the present disclosure.

By "presbyopia" in the present disclosure is meant a condition/disease that is judged as presbyopia based on common criteria used by physicians or professionals. For example, as a diagnostic criterion for presbyopia, ``has decreased near vision as a subjective symptom in a binocular test and binocular visual acuity (distance visual acuity measured under the same conditions as in daily life) at 40 cm is 0.4. (clinical presbyopia) and/or "accommodation of less than 2.5 diopters under unilateral full correction (corrected visual acuity (minority visual acuity) of 1.0 or greater in one eye) with or without subjective symptoms. There is (medical presbyopia). However, if you do not have an accommodometer or the like, you may use a 40 cm visual acuity of less than 0.4 as a simple method.

In the present disclosure, "ocular disease associated with decreased elasticity of the lens" means an eye disease that is considered to be associated with decreased elasticity of the lens in the field of ophthalmology, such as presbyopia (e.g. presbyopia due to aging), and drug-induced lens sclerosis.

In the present disclosure, "accommodative power of the eye" means the ability of the eye to automatically focus at distance and/or near vision. The term "ocular disease associated with a decrease in accommodation power of the eye" means an eye disease that is considered to be associated with a decrease in accommodation power of the eye in the field of ophthalmology, such as presbyopia (e.g. presbyopia due to aging), drugs, etc. induced lens hardening, and prolonged near vision-induced accommodation loss.

The effect of the agents/compositions of the present disclosure can be evaluated, for example, as an improvement in "eye accommodation."
Accommodative power of the eye is measured in diopters (D) and can be determined by the following equation (1).
Diopter (D) = 1/near point distance (m) (Equation 1)

In general, the accommodation power of the eye is 10 diopters or more at the age of 10 years, but it gradually declines thereafter to about 3 diopters at the age of about 45 years, and is almost lost at the age of about 60 years. When it drops to about 3 diopters, it becomes difficult to focus on a short distance (about 30 cm) in daily life, and subjective symptoms of presbyopia appear.

The effect of the agents/compositions of the present disclosure can be evaluated, for example, as an improvement in "visual acuity."
Visual acuity is measured as near visual acuity (naked eye, with distance vision corrected, corrected), and can be determined from fractional visual acuity, fractional visual acuity, and logMAR.

In general, the near vision is defined as about 40 cm, and when it drops below 0.4, it becomes difficult to see near objects and subjective symptoms of presbyopia appear. The agents/compositions of the present disclosure can be used to improve near vision (eg, distance-corrected bottom near vision).

Agents/compositions of the present disclosure may be effective within one year, preferably within six months, more preferably within one month, even more preferably within one week, and most preferably within one day after treatment. In addition, once the effect is exhibited, the effect continues for 1 day, preferably 1 week, more preferably 1 month, still more preferably 6 months, particularly preferably 1 year, and most preferably 3 years. can be demonstrated.

Agents/compositions of the present disclosure, for example, provide accommodation to the eye of at least about 0.5 diopters (preferably at least about 1 diopter, more preferably at least about 1.5 diopters, even more preferably at least about 2 diopters, even more preferably at least about 3 diopters, more preferably at least about 4 diopters, particularly preferably at least about 5 diopters, even more particularly preferably at least about 10 diopters).

Agents/compositions of the present disclosure may, for example, improve distance-corrected near visual acuities (DCNVA) by at least 0.5 logMAR (preferably at least 1.0 logMAR, more preferably at least 1 logMAR). About .5 logMAR, more preferably about 2.0 logMAR, more preferably about 3.0 logMAR, even more preferably about 4.0 logMAR, particularly preferably about 5.0 logMAR, most preferably about 6.0 logMAR ) can be administered to improve Distance-corrected lower near vision generally refers to near vision measured after correcting distance vision to ≤0.0 logMAR (minority visual acuity of 1.0 or more).

Agents/compositions of the present disclosure, for example, provide ocular accommodation of at least about 0.5 diopters (preferably at least about 1 diopters, more preferably at least about 1.5 diopters, even more preferably at least about 2 diopters, more preferably at least about 3 diopters, more preferably at least about 4 diopters, particularly preferably at least about 5 diopters, even more preferably at least about 10 diopters).

The agents/compositions of the present disclosure, for example, reduce distance-corrected near visual acuity (DCNVA) by at least 0.5 logMAR (preferably at least 1.0 logMAR, more preferably at least 1 logMAR). About .5 logMAR, more preferably about 2.0 logMAR, more preferably about 3.0 logMAR, even more preferably about 4.0 logMAR, particularly preferably about 5.0 logMAR, most preferably about 6.0 logMAR ) can be administered to restore up to

Treatment or prevention of presbyopia in the present disclosure includes improving elasticity of the lens, improving accommodation of lens thickness, and/or improving accommodation of the eye.

As described above, subjective symptoms of presbyopia generally appear at about 45 years of age, but age-related decline in eye accommodative power progresses from the teenage years. The agents/compositions of the present disclosure may be used after subjective symptoms of presbyopia appear, or may be used to prevent and/or slow the progression of presbyopia before subjective symptoms of presbyopia appear. .

Subjects to which the agents/compositions of the present disclosure are administered are domestic animals such as cows and pigs, rabbits, monkeys, dogs, cats, and mammals including humans, preferably humans.

In the present disclosure, "treatment" and "prevention" include treating disease and preventing disease, as well as alleviating disease symptoms, slowing disease progression, suppressing disease symptoms, and treating disease. It can include inducing improvement in symptoms.

The route of administration of the agents/compositions of the present disclosure may be oral or parenteral (eg, ophthalmic, nasal, dermal, mucosal, injection, etc.). Agents/compositions of the present disclosure are prepared by mixing an active ingredient with, for example, one or more pharmaceutically acceptable excipients, such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, suspensions. Oral preparations such as turbid preparations, or parenteral preparations such as eye drops, ophthalmic ointments, injections, suppositories, nasal preparations, etc. can be prepared by methods commonly used in the art. Preferred dosage forms of the agent/composition of the present disclosure include eye drops (eg, suspension eye drops) and ophthalmic ointments, from the viewpoint of better effects of the agent/composition of the present disclosure.

Pharmaceutically acceptable additives that can be contained in the agents/compositions of the present disclosure are not particularly limited, and can be appropriately selected according to administration routes, dosage forms, and the like. Examples of the pharmaceutically acceptable additives include surfactants, buffers, tonicity agents, stabilizers, preservatives, antioxidants, thickeners, solubilizers, suspending agents, agents, bases, solvents, pH adjusters, excipients, disintegrants, binders, fluidizing agents, lubricants, preservatives, antioxidants, coloring agents, sweeteners and the like.

When the agent/composition of the present disclosure is an eye drop, examples of additives that may be used include surfactants, buffers, tonicity agents, stabilizers, preservatives, antioxidants, thickening agents, agents, solvents, pH adjusters, and the like.

Examples of surfactants include cationic surfactants, anionic surfactants, nonionic surfactants, and the like.

The content of the surfactant when the agent/composition of the present disclosure is blended with the surfactant can be appropriately adjusted depending on the type of the surfactant, but for example, 0.01 to 1% (w/v) is preferred.

Examples of buffering agents include phosphoric acid and salts thereof, and hydrates and solvates thereof may be used.

Examples of phosphoric acid or salts thereof include phosphoric acid, trisodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate (disodium hydrogen phosphate) and the like, and hydrates thereof may also be used.

The content of the buffer when the agent/composition of the present disclosure is blended with the buffer can be appropriately adjusted depending on the type of the buffer. Preferably, 0.01 to 5% (w/v) is more preferred. Two or more buffering agents may be used together.

Examples of tonicity agents include ionic tonicity agents and nonionic tonicity agents. Ionic tonicity agents include sodium chloride and the like.

When the agent/composition of the present disclosure contains a tonicity agent, the content of the tonicity agent can be appropriately adjusted depending on the type of the tonicity agent. (w/v) is preferred, and 0.01% to 5% (w/v) is more preferred.

Examples of thickeners include hydroxypropylmethylcellulose and the like.

The content of the thickening agent when the agent/composition of the present disclosure is blended with the thickening agent can be appropriately adjusted depending on the type of the thickening agent, but for example, 0.001 to 5% (w/v) is preferred, and 0.01% to 3% (w/v) is more preferred.

When the agent/composition of the present disclosure is an aqueous formulation (eg, eye drops), its pH is preferably 4-8, more preferably 5-7.

Examples of solvents include, for example, water, physiological saline, and the like.

Examples of when the agent/composition of the present disclosure is an aqueous formulation (e.g., eye drops) include the compound represented by formula [I], an amide conjugate of the compound represented by formula [I], or an ester thereof, or pharmaceutically acceptable salts thereof, water, and ethyl pyruvate, sodium dihydrogen phosphate monohydrate _{( NaH2PO4.H2O} ), _disodium hydrogen phosphate _{( Na2HPO4} ), hydroxy Aqueous formulations containing additives selected from propylmethylcellulose, NaCl, and mixtures thereof are included. The "mixture thereof" means any combination of the specific additives listed.

As used herein, an "effective amount" is that amount of active ingredient necessary to provide patient benefit in disease symptoms.

The dosage and administration of the agents/compositions of the present disclosure are not particularly limited as long as the dosage and administration are sufficient to exhibit the desired efficacy. can be selected as appropriate.
For example, in the case of eye drops, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, particularly preferably 1 drop, 1 to 4 times a day, preferably 1 to 1 drop per day. Eye drops can be administered three times, more preferably once or twice a day, and particularly preferably once a day, every day to every week. Here, one drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, more preferably about 0.02 to about 0.05 mL. Yes, particularly preferably about 0.03 mL.

Although the duration of administration of the agents/compositions of the present disclosure can be determined by a physician or professional, in one embodiment, the agents/compositions of the present disclosure are administered to the eye, such as eye drops (e.g., suspensions) and ophthalmic ointments. The agent may be used continuously for at least 2 days, at least 3 days, at least 7 days, at least 10 days. In one embodiment, agents/compositions of the present disclosure may be administered at least once (eg, at least twice, at least three times) per day.

Although the results of pharmacological tests are shown below, they are for better understanding of the present invention and do not limit the scope of the present invention.

で表される化合物である。ＥＶ０６は、下記式（２）：

で表される化合物である。 [Pharmacological test 1]
Effects of ursodeoxycholic acid and lipoic acid choline ester (EV06) on the elasticity of the lens were confirmed. An evaluation test was performed with reference to the method described in InvestOphthalmol Vis Sci, 57, 2851-2863, 2016. Ursodeoxycholic acid has the following formula (1):

It is a compound represented by EV06 is represented by the following formula (2):

It is a compound represented by

(Preparation of test sample)
1) Preparation of base 0.1% (w/v) ethyl pyruvate, 0.269% (w/v) sodium dihydrogen phosphate monohydrate _{( NaH2PO4.H2O} ), 0.269% ₍ w/v) A base containing 433% (w/v) disodium hydrogen phosphate _{( Na2HPO4} ), 0.2% (w/v) hydroxypropyl methylcellulose, 0.5% (w/v) NaCl was prepared. .

2) Preparation of ursodeoxycholic acid sample A base was added to ursodeoxycholic acid and sonicated to prepare a 3.0% (w/v) suspension. The prepared 3.0% (w/v) suspension was diluted with base to prepare a 1.0% (w/v) suspension. Furthermore, the prepared 1.0% (w/v) suspension was diluted with a base to prepare a 0.3% (w/v) suspension. One day's worth of each was prepared just before use.

3) Preparation of EV06 sample A base was added to EV06 and sonicated to prepare a 1.5% (w/v) solution (one day's worth was prepared just before use).

(Test method)
1) Each test sample was administered to 8-month-old C57BL/6J mice once a day (QD), twice (BID), or three times (TID) (once at 9:00, twice at 9:00). , 17:00, and 3 times at 9:00, 13:00, and 17:00), 2.5 μL/eye was instilled into the right eye using a Pipetman for 14 days.
2) After the final instillation, the mice were euthanized by aspirating carbon dioxide, and the eyeballs were removed and rinsed with Hank's balanced salt solution (HBSS).
3) The sclera near the optic nerve was cut with a razor, the lens was extracted from the incision, and the extracted lens was immersed in HBSS.
4) The lens was placed on a slide glass, and an image of the lens was captured using an all-in-one fluorescence microscope BZ-9000 (Keyence) (image a).
5) Next, a sheet of cover glass (Corning ^{(registered trademark)} 22x22 mm Square) was placed on the lens, and an image in which the thickness of the lens varied due to the weight was captured in the same manner (image b).
6) The lens diameter of image a was subtracted from the lens diameter of image b, and the amount of change in the lens diameter was calculated using the following formula 1. Next, the lens elasticity improvement amount of each sample group compared with the base group was calculated by the following formula 2. The average value is the average of 5 eyes for the vehicle group and the average of 10 eyes for each ursodeoxycholic acid sample group and EV06 sample group.

(Calculation formula 1)
Amount of change in lens diameter = lens diameter of image b of each test sample - lens diameter of image a of each test sample

(Calculation formula 2)
Amount of lens elasticity improvement in each sample group = average value of change in lens diameter in each test sample group - average value of change in lens diameter in base group

(result)
Table 1 shows the results.

As is clear from Table 1, in the ursodeoxycholic acid sample group, both 1% and 3% once-daily instillation showed a strong effect of improving lens elasticity, and one-time instillation of 1.5% EV06 Since it did not show any effect, it showed a clearly stronger effect of improving lens elasticity than EV06.

[Pharmacological test 2]
Cholic acid and each cholic acid derivative were instilled into the eye once a day for 7 days to examine the effects on the elasticity of the lens.

(Preparation of test sample)
1) Preparation of base 0.1% (w/v) ethyl pyruvate, 0.269% (w/v) sodium dihydrogen phosphate monohydrate _{( NaH2PO4.H2O} ), 0.269% ₍ w/v) A base containing 433% (w/v) disodium hydrogen phosphate _{( Na2HPO4} ), 0.2% (w/v) hydroxypropyl methylcellulose, 0.5% (w/v) NaCl was prepared. .

2) Preparation of cholic acid sample and cholic acid derivative sample A base was added to each of cholic acid and cholic acid derivative and sonicated to prepare a 1.0% (w/v) suspension. One day's worth of each was prepared just before use.

(Test method)
1) 2.5 μL/eye of each test sample was instilled into both eyes of 8-month-old C57BL/6J mice once a day (around 1:30 p.m.) for 7 days using a Pipetman.
2) About 24 hours after the last instillation, the mice were euthanized by carbon dioxide aspiration, and the eyeballs were removed and rinsed with Hank's balanced salt solution (HBSS).
3) The sclera near the optic nerve was cut with a razor, the lens was extracted from the incision, and the extracted lens was immersed in HBSS.
4) The lens was placed on a slide glass, and an image of the lens was captured using an all-in-one fluorescence microscope BZ-9000 (Keyence) (image a).
5) Next, a sheet of cover glass (Corning ^{(registered trademark)} 22x22 mm Square) was placed on the lens, and an image in which the thickness of the lens varied due to the weight was captured in the same manner (image b).
6) The lens diameter of image a was subtracted from the lens diameter of image b, and the amount of change in the lens diameter was calculated using the following formula 1. Next, the lens elasticity improvement amount of each sample group compared with the base group was calculated by the following formula 2. The average value is the average of 10 eyes in each group.

(Calculation formula 1)
Amount of change in lens diameter = lens diameter of image b of each test sample - lens diameter of image a of each test sample

(Calculation formula 2)
Amount of lens elasticity improvement in each sample group = average value of change in lens diameter in each test sample group - average value of change in lens diameter in base group

(result)
Table 2 shows the results.

As is clear from Table 2, the cholic acid sample group and each cholic acid derivative sample group exhibited an effect of improving lens elasticity when instilled at 1.0% once a day for 7 days. Acid, 7-ketolitocholic acid, and dehydrocholic acid showed a strong effect of improving lens elasticity almost like ursodeoxycholic acid.

The agents/compositions of the present disclosure are useful for treating or preventing eye diseases such as presbyopia.

Claims (13)

Formula [I]:

[In the formula,
R ¹ , R ² and R ³ are each independently a hydrogen atom, a hydroxy group, an oxo group, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group;
R ⁴ and R ⁵ are each independently a hydrogen atom, a hydroxy group, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group;
However, the following formula:

except for]
or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, an agent/pharmaceutical composition for treating or preventing presbyopia. Formula [I]:

[wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined in claim 1]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, for the treatment or prevention of ocular diseases accompanied by a decrease in the elasticity of the lens / pharmaceutical composition. 3. The agent/pharmaceutical composition according to claim 2, wherein the ocular disease is an ocular disease associated with decreased accommodation of the eye. Formula [I]:

[wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined in claim 1]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. / pharmaceutical composition. A compound represented by formula [I] or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof,
Formula [II]:

The agent/pharmaceutical composition according to any one of claims 2 to 4, which is a compound represented by or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof. A compound or an amide conjugate thereof, wherein the compound represented by formula [I] or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof is selected from the following formulas [III] to [VIII] , or an ester thereof, or a pharmaceutically acceptable salt thereof, the agent/pharmaceutical composition according to any one of claims 2 to 5:

. The agent/pharmaceutical composition according to any one of claims 2 to 6, wherein said eye disease is presbyopia. The agent/pharmaceutical composition according to any one of claims 1 to 7, which is administered ocularly. The agent/pharmaceutical composition according to any one of claims 1 to 8, which is an eye drop or eye ointment. The content of the compound represented by formula [I] or the amide conjugate of the compound represented by formula [I], an ester thereof, or a pharmaceutically acceptable salt thereof is 0.00001 to 10% (w/ v), the agent/pharmaceutical composition according to any one of claims 1 to 9. In the manufacture of an agent/pharmaceutical composition for the treatment or prevention of presbyopia, an ocular disease associated with decreased elasticity of the lens, or an ocular disease associated with decreased accommodative power of the eye,
Formula [I]:

[wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined in claim 1]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof. for use in the treatment or prevention of presbyopia, an ocular disease associated with decreased elasticity of the lens, or an ocular disease associated with decreased accommodation of the eye,
Formula [I]:

[wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined in claim 1]
or an amide conjugate thereof, an ester thereof, or a pharmaceutically acceptable salt thereof. A method for treating or preventing presbyopia, an ocular disease associated with decreased elasticity of the lens, or an ocular disease associated with decreased accommodation of the eye, comprising an effective amount of formula [I]:

[wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined in claim 1]
or an amide conjugate thereof, or an ester thereof, or a pharmaceutically acceptable salt thereof.