TW202330510A - Sulfur-containing compound useful for treating or preventing presbyopia or like - Google Patents

Abstract

The present disclosure provides: a sulfur-containing compound which has a predetermined structure and is useful for treating or preventing eye diseases such as presbyopia and cataracts; and an agent for treating or preventing eye diseases such as presbyopia and cataracts, the agent containing said sulfur-containing compound as an active ingredient.

Description

Sulfur-containing compounds useful for the treatment or prevention of presbyopia, etc.

The present invention relates to a sulfur-containing compound useful for treating or preventing eye diseases such as presbyopia and cataract, and an agent for treating or preventing eye diseases such as presbyopia and cataract containing the sulfur-containing compound as an active ingredient.

Presbyopia is one of the eye aging phenomena that begins around the age of 40. It is also commonly referred to as presbyopia. According to Non-Patent Document 1, it is defined as a condition characterized by a decline in accommodation with age (Age-Related Loss of Accommodation , age-related loss of regulatory capacity) diseases. Observing near objects or distant objects requires focusing. For this reason, the light entering the eye must be properly refracted when passing through the lens. Therefore, the eye has the function of adjusting the thickness of the lens, such as the contraction of the ciliary muscle located near the lens. The ocular tissues involved in the far-near accommodation response include the lens, the zonules of Qin's, the lens capsule, and the ciliary muscle. However, if the function of the ciliary muscle is reduced due to aging, or the elasticity (or viscoelasticity) of the lens is reduced, that is, the crystal is hardened, it is difficult to adjust the thickness of the lens, and it is difficult to focus smoothly when observing objects. This state is called presbyopia.

Patent Document 1 discloses the experimental results that lipoic acid can improve the elasticity of the lens of mice to treat presbyopia, and also discloses the synthesis examples of various lipoic acid derivatives (prodrugs). Lipoic acid choline ester (alias: EV06, UNR844), one of the disclosed prodrugs, is being clinically developed as eye drops in the United States. Also, Patent Document 2 discloses ester-type prodrugs obtained by various modifications of the carboxylic acid moiety of lipoic acid.

Cataract is a refractory disease that causes vision loss due to clouding of the lens. Cataracts can be classified into senile cataracts, diabetic cataracts, etc. according to their causes. [Prior Art Literature] [Patent Document]

[Patent Document 1] Specification of International Publication No. 2010/147957 [Patent Document 2] Specification of International Publication No. 2020/213693 [Non-patent literature]

[Non-Patent Document 1] New Ophthalmology, Vol.28, No.7, 985-988, 2011

All the disclosures of the prior art documents cited in this specification are incorporated in this specification by reference.

[Problem to be solved by the invention]

The object of the present invention is to provide a new treatment or prevention method for eye diseases such as presbyopia and cataract. [Technical means to solve the problem]

The inventors of the present invention conducted intensive research to solve the above-mentioned problems. As a result, they studied the effects of various sulfur-containing compounds on the therapeutic effect on presbyopia, and as a result unexpectedly found a Sulfur-containing compounds with a specific structure that more significantly improve the elasticity of crystals have completed the invention of the present invention. It is further found that these sulfur-containing compounds with specific structures have the effect of inhibiting crystal turbidity. Furthermore, the inventors of the present invention have also found that these sulfur-containing compounds having specific structures exhibit high migration properties to crystals. Specifically, the present invention provides the following aspects of the invention.

[1] An agent/composition for treating or preventing eye diseases, which contains a compound represented by formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 1] [In the formula, A is [chemical 2] , Here, A can be substituted by the same or different 1 to 3 R ¹ ; R ¹ are independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy ; W is a C _1-10 alkylene group; here, 1 to 3 methylene groups in the alkylene group can be independently substituted to be selected from O, NR ² (here, R ² is H or C _1-3 alkyl), and a divalent group in the group consisting of S(O) _0-2 ; and the alkylene group can be independently selected from -OH, halogen, C _1-3 alkyl, and At least one substituent in the group consisting of C _1-3 alkoxy is substituted; B is a saturated or unsaturated monocyclic heterocyclic group with four to seven members, where the monocyclic heterocyclic group is The ring contains carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , and can be substituted by the same or different 1 to 3 R ³ ; R ³ are respectively Independently selected from the group consisting of -OH, -SH, side oxygen (=O), side thiol (=S), halogen, C _1-3 alkyl, and C _1-3 alkoxy], the The eye disease is selected from the group consisting of presbyopia and cataract. [2] An agent/composition for the treatment or prevention of eye diseases accompanied by decreased elasticity of the lens, which contains the compound of formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 3] [In the formula, A, W and B are synonymous with [1]]. [3] The agent/composition as described in [2], wherein the eye disease is an eye disease accompanied by a decrease in eye accommodation. [4] An agent/composition for treating or preventing ocular diseases accompanied by decreased ocular accommodation, which contains the compound of formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 4] [In the formula, A, W and B are synonymous with [1]]. [5] The agent/composition as described in any one of [1] to [4], wherein the eye disease is presbyopia. [6] The agent/composition as described in [1], wherein the eye disease is cataract. [7] A crystalline highly migratory composition, which contains a compound of formula [I] or a pharmaceutically acceptable salt thereof: [Chem. 5] [In the formula, A, W and B are synonymous with [1]]. [8] The agent/composition as described in any one of [1] to [7], wherein A is [化6] [chemical 7] [chemical 8] [chemical 9] [chemical 10] [chemical 11] [chemical 12] or [Chem.13] , Here, A may be substituted by the same or different 1 to 3 R ¹ . [9] The agent/composition as described in any one of [1] to [8], wherein A is [Chem. 14] or [Chem.15] , Here, A may be substituted by the same or different 1 to 3 R ¹ . [10] The agent/composition as described in any one of [1] to [9], wherein A is [Chem. 16] or [Chem.17] , Here, A may be substituted by the same or different 1 to 3 R ¹ . [11] The agent/composition as described in any one of [1] to [10], wherein A is [Chem. 18] or [Chem.19] . [12] The agent/composition as described in any one of [1] to [11], wherein W is an alkylene group of -(CH ₂ ) _1-10 -, and the alkylene group can be independently selected from It is substituted with at least one substituent selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy. [13] The agent/composition as described in any one of [1] to [12], wherein W is an alkylene group of -(CH ₂ ) _1-10 -. [14] The agent/composition as described in any one of [1] to [11], wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-( CH ₂ ) _2-4 -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _1-9 -S -, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-, -(CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-( CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-( CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-( CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _1-2 -NH- (CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -, where the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B And the rightmost bond is bonded to A, and the W may be substituted by at least one substituent independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy . [15] The agent/composition as described in any one of [1] to [11] and [14], wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _{1 -9} -S-, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-, -(CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-(CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _{1- 2} -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -, where the leftmost bond is bonded to A and the rightmost bond is bonded to B, or the leftmost bond Bonded to B and the rightmost bond is bonded to A. [16] The agent/composition as described in any one of [1] to [15], wherein W is -(CH ₂ ) _4-6 -, or -(CH ₂ ) _4-6 -O- (here , the leftmost bond is bonded to A and the rightmost bond is bonded to B). [17] The agent/composition as described in any one of [1] to [16], wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic The heterocyclyl ring contains carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , and can be substituted by the same or different 1 to 3 R ³ . [18] The agent/composition as described in any one of [1] to [17], wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic The heterocyclic group is selected from imidazolyl, pyrazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, zozolidinyl, thiazolidinyl, isoxazolyl, 2, 3-dihydroisozozolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2 , a group consisting of 3-dihydro-1,3,4-oxadiazolyl, pyrimidinyl, and pyrimidinyl, which may be substituted by the same or different 1 to 3 R ³ . [19] The agent/composition as described in any one of [1] to [18], wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic The heterocyclyl ring contains carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 (wherein the heteroatom contains at least 1 N), and can Substituted by the same or different 1-3 R ³ , B is bonded to W via N in the ring. [20] The agent/composition as described in any one of [1] to [19], wherein B is [Chem. 20] . [21] The agent/composition according to any one of [1] to [20], which contains a compound or a pharmaceutically acceptable salt thereof selected from the following as an active ingredient: [Chem. 21] . [22] The agent/composition according to any one of [1] to [21], which contains a compound selected from the following or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 22] . [23] The agent/composition according to any one of [1] to [21], which contains a compound selected from the following or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 23] . [24] The agent/composition according to any one of [1] to [23], which contains a compound or a pharmaceutically acceptable salt thereof selected from the following as an active ingredient: [Chem. 24] . [25] The agent/composition according to any one of [1] to [24], which is administered to the eye. [26] The agent/composition as described in any one of [1] to [25], which is an eye drop or ophthalmic ointment. [27] The agent/composition as described in any one of [1] to [26], wherein the content of the active ingredient is 0.00001-10% (w/v). [28] The use of a compound of formula [I] or a pharmaceutically acceptable salt thereof, which is used for the treatment or prevention of presbyopia, cataract, eye diseases accompanied by decreased elasticity of the lens, or eye adjustment ability Agents/compositions for reduced eye diseases: [Chem. 25] [In the formula, A, W and B are synonymous with [1]]. [29] A compound of formula [I] or a pharmaceutically acceptable salt thereof, which is used for the treatment or prevention of presbyopia, cataracts, eye diseases accompanied by decreased elasticity of the lens, or eye diseases accompanied by decreased eye accommodation : [chem 26] [In the formula, A, W and B are synonymous with [1]]. [30] A method for treating or preventing presbyopia, cataracts, eye diseases accompanied by decreased lens elasticity, or eye diseases accompanied by decreased eye accommodation, comprising: administering effective Amount of the compound of formula [I] or its pharmaceutically acceptable salt: [Chemical 27] [In the formula, A, W and B are synonymous with [1]]. [31] A compound or a pharmaceutically acceptable salt thereof, which has the formula [I]: [Chem. 28] [In the formula, A is [chemical 29] , Here, A can be substituted by the same or different 1 to 3 R ¹ ; R ¹ are independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy ; W is a C _1-10 alkylene group; here, 1 to 3 methylene groups in the alkylene group can be independently substituted to be selected from O, NR ² (here, R ² is H or C _1-3 alkyl), and a divalent group in the group consisting of S(O) _0-2 ; and the alkylene group can be independently selected from -OH, halogen, C _1-3 alkyl, and At least one substituent in the group consisting of C _1-3 alkoxy is substituted; B is a saturated or unsaturated monocyclic heterocyclic group with four to seven members, where the monocyclic heterocyclic group is The ring contains carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , and can be substituted by the same or different 1 to 3 R ³ ; R ³ are respectively independently selected from the group consisting of -OH, -SH, side oxygen (=O), side thiol (=S), halogen, C _1-3 alkyl, and C _1-3 alkoxy, wherein, except]. [32] The compound as described in [31] or a pharmaceutically acceptable salt thereof, wherein A is [化30] [chem 31] [chem 32] [chem 33] [chem 34] [chem 35] [chem 36] or [Chem37] , Here, A may be substituted by the same or different 1 to 3 R ¹ . [33] The compound as described in [31] or [32] or the pharmaceutically acceptable salt thereof, wherein A is [化38] or [Chem39] , Here, A may be substituted by the same or different 1 to 3 R ¹ . [34] The compound as described in any one of [31] to [33] or a pharmaceutically acceptable salt thereof, wherein A is [化40] or [41] , Here, A may be substituted by the same or different 1 to 3 R ¹ . [35] The compound as described in any one of [31] to [34] or a pharmaceutically acceptable salt thereof, wherein A is [化42] or [43] . [36] The compound as described in any one of [31] to [35] or the pharmaceutically acceptable salt thereof, wherein W is an alkylene group of -(CH ₂ ) _1-10 -, and the alkylene group is It may be substituted with at least one substituent independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy. [37] The compound described in any one of [31] to [36] or a pharmaceutically acceptable salt thereof, wherein W is an alkylene group of -(CH ₂ ) _1-10 -. [38] The compound as described in any one of [31] to [35] or a pharmaceutically acceptable salt thereof, wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _{1- 4} -O-(CH ₂ ) _2-4 -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _1-9 -S-, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-, -(CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _{1- 2} -NH-(CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _{1- 2} -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _{1- 2} -S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _{1 -2} -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -, where the leftmost bond may be bonded to A and the rightmost bond to B, or the leftmost The bond is bonded to B and the rightmost bond is bonded to A, and the W can be independently selected from at least one of the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy 1 substituent substituted. [39] The compound as described in any one of [31] to [35] and [38], or a pharmaceutically acceptable salt thereof, wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, - (CH ₂ ) _1-9 -S-, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ - S-(CH ₂ ) _2-3 -S-, -(CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-(CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -( CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -, where the leftmost bond is bonded to A and the rightmost bond is bonded to B, Or the leftmost bond is bonded to B and the rightmost bond is bonded to A. [40] The compound described in any one of [31] to [39] or a pharmaceutically acceptable salt thereof, wherein W is -(CH ₂ ) _4-6 -, or -(CH ₂ ) _4-6 -O- (here, the leftmost bond is bonded to A and the rightmost bond is bonded to B). [41] The compound as described in any one of [31] to [40] or a pharmaceutically acceptable salt thereof, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where , the monocyclic heterocyclyl ring contains carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , and can be replaced by the same or different 1 to 4 heteroatoms 3 ^R3 substitutions. [42] The compound as described in any one of [31] to [41] or a pharmaceutically acceptable salt thereof, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where , the monocyclic heterocyclic group is selected from imidazolyl, pyrazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, zozolidinyl, thiazolidinyl, isozolidinyl, Azolyl, 2,3-dihydroisooxazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl, 1,3,4-oxazolyl A group consisting of diazolyl, 2,3-dihydro-1,3,4-oxadiazolyl, pyrimidinyl, and pyridyl, and may be substituted by the same or different 1 to 3 R ³ . [43] The compound as described in any one of [31] to [42] or a pharmaceutically acceptable salt thereof, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where , the monocyclic heterocyclyl ring contains carbon atoms and 1 to 4 identical or different heteroatoms selected from N, O and S(O) _0-2 (wherein, the heteroatom includes at least 1 N), and can be substituted by the same or different 1 to 3 R ³ , B is bonded to W through N in the ring. [44] The compound as described in any one of [31] to [43] or a pharmaceutically acceptable salt thereof, wherein B is [化44] . [45] The compound described in any one of [31] to [44] or a pharmaceutically acceptable salt thereof, which is selected from the following: [Chem. 45] . [46] The compound described in any one of [31] to [45] or a pharmaceutically acceptable salt thereof, which is selected from the following: [Chem. 46] . [47] The compound described in any one of [31] to [46] or a pharmaceutically acceptable salt thereof, which is selected from the following: [Chem. 47] . [48] The compound described in any one of [31] to [47] or a pharmaceutically acceptable salt thereof, which is selected from the following: [Chem. 48] . [49] A pharmaceutical composition comprising the compound according to any one of [31] to [48] or a pharmaceutically acceptable salt thereof.

Two or more of the above-mentioned configurations of [1] to [49] can be arbitrarily selected and combined. [Effect of Invention]

The compounds of the present invention increase the elasticity of the crystal which is important for the regulation of the thickness of the crystal. Therefore, it is useful for the treatment or prevention of eye diseases such as presbyopia. The compounds of the present invention inhibit clouding of crystals. Therefore, it is useful for the treatment or prevention of eye diseases such as cataract.

Embodiments of the present invention will be described in detail below.

The present invention provides a compound of formula [I] or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "the compound of the present invention"): [Chem. 49] [where, A is , Here, A can be substituted by the same or different 1 to 3 R ¹ ; R ¹ are independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy ; W is a C _1-10 alkylene group; here, 1 to 3 methylene groups in the alkylene group can be independently substituted to be selected from O, NR ² (here, R ² is H or C _1-3 alkyl), and a divalent group in the group consisting of S(O) _0-2 ; and the alkylene group can be independently selected from -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy groups are substituted by at least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent; B is a saturated or unsaturated group of four to seven members Saturated monocyclic heterocyclic group, here, the monocyclic heterocyclic group contains carbon atoms in the ring, and 1 to 4 identical or different heterocyclic groups selected from N, O and S(O) _0-2 atom, and can be substituted by the same or different 1 to 3 R ³ ; R ³ are independently selected from -OH, -SH, side oxygen (=O), side thiol (=S), halogen, C _{1 -3} alkyl groups, and C _1-3 alkoxyl groups].

As one embodiment of the compound of the present invention, A is [Chemical 50] [Chemical 51] [Chemical 52] [Chemical 53] [Chemical 54] [Chemical 55] [Chemical 56] or [Chemical 57] , Here, A may be substituted by the same or different 1 to 3 (preferably 1 to 2, more preferably 1) R ¹ .

In this specification, for example, "A is [Chemical 58] , Here, A can be substituted by the same or different 1 to 3 R ¹ "means that A is the following group [化59] , the group may be substituted by the same or different 1 to 3 R ¹ ".

As one embodiment of the compound of the present invention, A is [Chemical 60] or [Chemical 61] , Here, A may be substituted by the same or different 1 to 3 (preferably 1 to 2, more preferably 1) R ¹ .

As one embodiment of the compound of the present invention, A is [Chemical 62] or [chem63] .

As one embodiment of the compound of the present invention, A is [Chemical 64] [chem 65] [chem 66] [chem 67] [chem 68] [chem 69] [chem 70] or [chem 71] , Here, A may be substituted by the same or different 1 to 3 (preferably 1 to 2, more preferably 1) R ¹ .

As one embodiment of the compound of the present invention, A is [Chem. 72] or [chem 73] , Here, A may be substituted by the same or different 1 to 3 (preferably 1 to 2, more preferably 1) R ¹ .

As one embodiment of the compound of the present invention, A is [Chem. 74] or [chem 75] .

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-10 - (preferably -(CH ₂ ) _3-6 -, more preferably -(CH ₂ ) _4-6 -, Also, it is more preferably an alkylene group of -(CH ₂ ) _5-6 -), the alkylene group can be independently selected from -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy Substituents are substituted by at least one (for example, 1 to 5, 1 to 3, 1 to 2, or 1) substituent in the group consisting of radicals.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-10 - (preferably -(CH ₂ ) _3-6 -, more preferably -(CH ₂ ) _4-6 -, Furthermore, it is more preferably an alkylene group of -(CH ₂ ) _5-6 -).

As one embodiment of the compound of the present invention, W is -(CH ₂ ) ₅ -.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-9 -O- (preferably -(CH ₂ ) _3-6 -O-, more preferably -(CH ₂ ) _{4 -6} -O-, more preferably -(CH ₂ ) _5-6 -O-), -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 -O- (preferably -(CH ₂ ) _1-3 -O-(CH ₂ ) _2-3 -O-, more preferably -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-), - (CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-(preferably -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -O-), -(CH ₂ ) _1-9 -S- (preferably -(CH ₂ ) _3-6 -S-, more preferably -(CH ₂ ) _4-6 -S- , and more preferably -(CH ₂ ) _5-6 -S-), -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S- (preferably -(CH ₂ ) _1-3 -S-(CH ₂ ) _2-3 -S-, more preferably -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-), -(CH ₂ ) _{1 -2} -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-(preferably -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -S -), -(CH ₂ ) _1-9 -NH- (preferably -(CH ₂ ) _3-6 -NH-, more preferably -(CH ₂ ) _4-6 -NH-, and more preferably Preferably -(CH ₂ ) _5-6 -NH-), -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH- (preferably -(CH ₂ ) _1-3 -NH -(CH ₂ ) _2-3 -NH-, more preferably -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-), -(CH ₂ ) _1-2 -NH- (CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-(preferably -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -NH-), -( CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 - (preferably -(CH ₂ ) _1-3 -O-(CH ₂ ) _2-3 -, more preferably -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -), -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -(preferably- (CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -), -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -(preferably -(CH ₂ ) _1-3 -S-(CH ₂ ) _2-3 -, more preferably -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -), -(CH ₂ ) _1-2 - S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -(preferably -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -), -( CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 - (preferably -(CH ₂ ) _1-3 -NH-(CH ₂ ) _2-3 -, more preferably -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -), or -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -(preferably -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost The bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, At least one (for example, 1 to 5, 1 to 3, 1 to 2, or 1) substituent in the group consisting of C _1-3 alkyl and C _1-3 alkoxy is substituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-9 -O- (preferably -(CH ₂ ) _3-6 -O-, more preferably -(CH ₂ ) _{4 -6} -O-, and more preferably -(CH ₂ ) _5-6 -O-), where the leftmost bond is bonded to A and the rightmost bond is bonded to B, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, C Substitution by at least one (for example, 1 to 5, 1 to 3, 1 to 2, or 1) substituent in the group consisting of _1-3 alkyl and C _1-3 alkoxy.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-9 -O- (preferably -(CH ₂ ) _3-6 -O-, more preferably -(CH ₂ ) _{4 -6} -O-, more preferably -(CH ₂ ) _5-6 -O-), -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 -O- (preferably -(CH ₂ ) _1-3 -O-(CH ₂ ) _2-3 -O-, more preferably -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-), - (CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-(preferably -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -O-), -(CH ₂ ) _1-9 -S- (preferably -(CH ₂ ) _3-6 -S-, more preferably -(CH ₂ ) _4-6 -S- , and more preferably -(CH ₂ ) _5-6 -S-), -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S- (preferably -(CH ₂ ) _1-3 -S-(CH ₂ ) _2-3 -S-, more preferably -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-), -(CH ₂ ) _{1 -2} -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-(preferably -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -S -), -(CH ₂ ) _1-9 -NH- (preferably -(CH ₂ ) _3-6 -NH-, more preferably -(CH ₂ ) _4-6 -NH-, and more preferably Preferably -(CH ₂ ) _5-6 -NH-), -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH- (preferably -(CH ₂ ) _1-3 -NH -(CH ₂ ) _2-3 -NH-, more preferably -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-), -(CH ₂ ) _1-2 -NH- (CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-(preferably -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -NH-), -( CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 - (preferably -(CH ₂ ) _1-3 -O-(CH ₂ ) _2-3 -, more preferably -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -), -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -(preferably- (CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -), -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -(preferably -(CH ₂ ) _1-3 -S-(CH ₂ ) _2-3 -, more preferably -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -), -(CH ₂ ) _1-2 - S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -(preferably -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -), -( CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 - (preferably -(CH ₂ ) _1-3 -NH-(CH ₂ ) _2-3 -, more preferably -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -), or -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -(preferably -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost The key is bound to B and the rightmost key is bound to A (preferably the leftmost key is bound to A and the rightmost key is bound to B).

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-9 -O- (preferably -(CH ₂ ) _3-6 -O-, more preferably -(CH ₂ ) _{4 -6} -O-, and, more preferably, -(CH ₂ ) _5-6 -O-), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost The key on the right is bound to B and the rightmost key is bound to A (preferably the leftmost key is bound to A and the rightmost key is bound to B).

As one embodiment of the compound of the present invention, W is -(CH ₂ ) ₅ -O-, the leftmost bond is bonded to A and the rightmost bond is bonded to B.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _3-6 -O-, -(CH ₂ ) _1-3 -O-(CH ₂ ) _2-3 -O-, -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -O-, -(CH ₂ ) _3-6 -S-, -(CH ₂ ) _1-3 -S-(CH ₂ ) _{2 -3} -S-, -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -S-, -(CH ₂ ) _3-6 -NH-, -(CH ₂ ) _{1- 3} -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -NH-, -(CH ₂ ) _1-3 -O -(CH ₂ ) _2-3 -, -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -, -(CH ₂ ) _1-3 -S-(CH ₂ ) _{2- 3} -, -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -, -(CH ₂ ) _1-3 -NH-(CH ₂ ) _2-3 -, or -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -, Here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, C _1-3 At least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent in the group consisting of alkyl and C _1-3 alkoxy is substituted, preferably unsubstituted .

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _5-6 -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-, -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -O-, -(CH ₂ ) _5-6 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) _{2 -3} -S-), -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -S-, -(CH ₂ ) _5-6 -NH-, -(CH ₂ ) _{1 -2} -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -NH-, -(CH ₂ ) _1-2 - O-(CH ₂ ) _2-3 -, -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -, -(CH ₂ ) _1-2 -S-(CH ₂ ) _{2 -3} -, -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -, -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -, or -( CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -, where the leftmost bond is bonded to A and the rightmost bond is bonded to B, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, C _{1- 3} alkyl, and C _1-3 alkoxy at least 1 (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituents in the group consisting of C 1-3 alkoxy are substituted, preferably without replace.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 -O- (preferably -(CH ₂ ) _1-3 -O-( CH ₂ ) _2-3 -O-, and more preferably -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-), where the leftmost bond can be bonded to A and The rightmost bond is bonded to B, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), The W can be independently selected from at least one of the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy (such as 1 to 5, 1 to 3, 1 ~2, 1) substituents are substituted, preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O- (preferably -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -O-), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B is bonded and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, _{C -} At least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent in the group consisting of 3 alkyl and C _1-3 alkoxy is substituted, preferably not superseded.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-9 -S- (preferably -(CH ₂ ) _3-6 -S-, more preferably -(CH ₂ ) _{4 -6} -S-, and, more preferably, -(CH ₂ ) _5-6 -S-), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost The bond of W is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen , C _1-3 alkyl, and C _1-3 alkoxy at least one (such as 1 to 5, 1 to 3, 1 to 2, 1) substituents in the group consisting of Preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S- (preferably -(CH ₂ ) _1-3 -S-( CH ₂ ) _2-3 -S-, and more preferably -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-), where the leftmost bond can be bonded to A and The rightmost bond is bonded to B, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), The W can be independently selected from at least one of the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy (such as 1 to 5, 1 to 3, 1 ~2, 1) substituents are substituted, preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S- (preferably -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -S-), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B is bonded and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, _{C -} At least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent in the group consisting of 3 alkyl and C _1-3 alkoxy is substituted, preferably not superseded.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-9 -NH- (preferably -(CH ₂ ) _3-6 -NH-, more preferably -(CH ₂ ) _{4 -6} -NH-, and, more preferably, -(CH ₂ ) _5-6 -NH-), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost The bond of W is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen , C _1-3 alkyl, and C _1-3 alkoxy at least one (such as 1 to 5, 1 to 3, 1 to 2, 1) substituents in the group consisting of Preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH- (preferably -(CH ₂ ) _1-3 -NH-( CH ₂ ) _2-3 -NH-, and more preferably -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-), where the leftmost bond can be bonded to A and The rightmost bond is bonded to B, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), The W can be independently selected from at least one of the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy (such as 1 to 5, 1 to 3, 1 ~2, 1) substituents are substituted, preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-2 -NH-(CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH- (preferably -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -NH-), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B is bonded and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, _{C -} At least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent in the group consisting of 3 alkyl and C _1-3 alkoxy is substituted, preferably not superseded.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -(preferably -(CH ₂ ) _1-3 -O-(CH ₂ ) _2-3 -, and more preferably -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -), where the leftmost bond can be bonded to A and the rightmost bond can be bonded to B bond, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), which can be independently At least one selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy (for example, 1 to 5, 1 to 3, 1 to 2, 1 ) substituents are substituted, preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -(preferably -(CH ₂ )-O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, C _1-3 At least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent in the group consisting of alkyl and C _1-3 alkoxy is substituted, preferably unsubstituted .

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -(preferably -(CH ₂ ) _1-3 -S-(CH ₂ ) _2-3 -, and more preferably -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -), where the leftmost bond can be bonded to A and the rightmost bond can be bonded to B bond, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), which can be independently At least one selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy (for example, 1 to 5, 1 to 3, 1 to 2, 1 ) substituents are substituted, preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -(preferably -(CH ₂ )-S-(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -), here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, C _1-3 At least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent in the group consisting of alkyl and C _1-3 alkoxy is substituted, preferably unsubstituted .

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -(preferably -(CH ₂ ) _1-3 -NH-(CH ₂ ) _2-3 -, and more preferably -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -), where the leftmost bond can be bonded to A and the rightmost bond can be bonded to B bond, or the leftmost bond is bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), which can be independently At least one selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy (for example, 1 to 5, 1 to 3, 1 to 2, 1 ) substituents are substituted, preferably unsubstituted.

As one embodiment of the compound of the present invention, W is -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -(preferably -(CH ₂ )-NH-(CH ₂ ) ₂ -NH-(CH ₂ ) ₂ -), Here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B and the rightmost bond is bonded to A (preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B), the W can be independently selected from -OH, halogen, C _1-3 At least one (for example, 1 to 5, 1 to 3, 1 to 2, 1) substituent in the group consisting of alkyl and C _1-3 alkoxy is substituted, preferably unsubstituted .

As one embodiment of the compound of the present invention, B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic group contains carbon atoms in the ring, and is selected from N, O and S(O) _0-2 are the same or different 1 to 4 heteroatoms, and may be substituted by the same or different 1 to 3 R ³ .

As one embodiment of the compound of the present invention, B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic group is selected from pyrrolidinyl, imidazolidinyl, Ozolidinyl, thiazolidinyl, piperazolyl, piperidinyl, 𠰌linyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, dihydroisoazolyl , oxadiazolyl, dihydrodiazolyl, pyrimidinyl, pyridyl, pyridyl, furyl, thienyl, pyrrolyl, pyridyl, thiadiazolyl, thiadiazolyl, thiazolyl, and A group consisting of three R 3 groups, which may be substituted by the same or different 1 to 3 R ³ .

As one embodiment of the compound of the present invention, B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group. Here, the monocyclic heterocyclic group is selected from imidazolyl, pyrazolyl, 1 ,2,3-Triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, oxazolyl, thiazolidinyl, isoxazolyl, 2,3-dihydroisoazolyl, 1,2, 4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2,3-dihydro-1,3,4-oxazolyl A group consisting of diazolyl, pyrimidinyl, and pyrimidyl, and may be substituted by the same or different 1 to 3 R ³ .

As one embodiment of the compound of the present invention, B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic group contains carbon atoms in the ring, and is selected from N, O and S(O) _0-2 are the same or different 1 to 4 heteroatoms (wherein, the heteroatom contains at least 1 N), and may be substituted by the same or different 1 to 3 R ³ .

As one embodiment of the compound of the present invention, B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic group contains carbon atoms in the ring, and is selected from N, O and S(O) _0-2 are the same or different 1 to 4 heteroatoms (wherein, the heteroatom contains at least 1 N), and may be substituted by the same or different 1 to 3 ^R3 , B is bonded to W via N in the ring.

As one embodiment of the compound of the present invention, R ³ are each independently selected from -OH, -SH, side oxy (=O), side thio (=S), halogen, C _1-3 alkyl, and A group consisting of C _1-3 alkoxy groups.

As one embodiment of the compound of the present invention, R ³ are each independently selected from the group consisting of -OH, a side oxygen group (=O), and a side thio group (=S).

As one embodiment of the compound of the present invention, B is [Chem. 76] .

One embodiment of the compound of the present invention may, for example, be the following compound or a pharmaceutically acceptable salt thereof. [chem 77]

One embodiment of the compound of the present invention may, for example, be the following compound or a pharmaceutically acceptable salt thereof. [chem 78]

As one embodiment of the compound of the present invention, compounds of the formula [I] other than the following compounds or pharmaceutically acceptable salts thereof are exemplified. [chem 79]

As mentioned above, the compound of the present invention may be a dithiolane compound, a dithiane ring compound, or a pharmaceutically acceptable salt thereof. Regarding 1,2-dithiolane compound, 1,2-dithiane ring compound, Compounds, because they can be converted into ring-opened structures in vivo, so compounds with ring-opened 1,3-propanedithiol structures, 1,4-butanedithiol structures, or pharmaceutically acceptable compounds Salts can have the same effect as the 1,2-dithiolane compound and 1,2-dithiane ring compound.

Furthermore, the present invention provides an agent/composition containing the compound of the above formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient (hereinafter, sometimes referred to as "agent/composition of the present invention"). The agent/composition of the present invention may contain a compound selected from the above formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient, and may also contain a compound selected from the above formula [I] or a pharmaceutically acceptable salt thereof. Multiple types of acceptable salts are used as active ingredients. In particular, since a 1,2-dithiolane compound or a pharmaceutically acceptable salt thereof and a compound having a ring-opened 1,3-propanedithiol structure can be transformed into each other in a living body, it may contain One selected from these may be used as an active ingredient, and a plurality of selected from these may be contained as an active ingredient. Similarly, since the 1,2-dithiane ring compound or its pharmaceutically acceptable salt, and the compound having its ring-opened 1,4-butanedithiol structure can be transformed into each other in vivo, it may contain One selected from these may be used as an active ingredient, and a plurality of selected from these may be contained as an active ingredient.

The compound/agent/composition of the present invention can be used for treating or preventing presbyopia. The compounds/agents/compositions of the present invention can be used to increase the elasticity of crystalline lenses. Furthermore, the compounds/agents/compositions of the present invention can be used to improve eye accommodation. Furthermore, the compound of the present invention can be used as an active ingredient of a composition with high migration properties of crystals because it has higher migration property to crystals than lipoic acid. The compound/agent/composition of the present invention can be used for treating or preventing cataract. The compound/agent/composition of the present invention can be used to treat or prevent presbyopia and cataract simultaneously.

In one embodiment of the compound of the present invention, examples of A include a group represented by the following formula (this group may be substituted). A bond across a ring in the following formula means that "-WB" is bonded at a substitutable position in the ring. [chem 80] .

In one embodiment of the compound of the present invention, examples of A include a group represented by the following formula (this group may be substituted). A bond across a bond in the following formula means that "-WB" is bonded at a position where substitution can be made in the moiety. In one embodiment of the compound of the present invention, "-WB" is bonded to a carbon atom. [chem 81]

In the present invention, "halogen" means fluorine, chlorine, bromine or iodine.

In the present invention, "C _1-3 alkoxy" means a straight or branched alkoxy group having 1 to 3 carbon atoms. Examples of "C _1-3 alkoxy" include methoxy, ethoxy, propoxy, and isopropoxy.

In the present invention, "C _1-3 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 3 carbons. Examples of "C _1-3 alkyl" include methyl, ethyl, propyl, and isopropyl.

In the present invention, "C _1-10 alkylene" is a linear divalent saturated hydrocarbon group having 1 to 10 carbons, meaning 1 to 3 (preferably 1 to 2 1, and more preferably 1) methylene groups can be independently substituted to be selected from O, NR ² (here, R ² is H or C _1-3 alkyl), and S(O) _0-2 The base of the divalent base in the group formed. Examples of the alkylene group include methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, Nine methylene, ten methylene. Furthermore, as another example of the alkylene group, -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 -O-, - (CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _1-9 -S-, -(CH ₂ ) _1-4 - S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-, -(CH ₂ ) _{1- 9} -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-(CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-( CH ₂ ) _2-3 -, which is equal to the formula [I] where the leftmost bond is bonded to A and the rightmost bond is bonded to B, or the leftmost bond is bonded to B and the rightmost bond is bonded to A Bonding, preferably the leftmost bond is bonded to A and the rightmost bond is bonded to B.

In the present invention, "saturated monocyclic heterocyclic group" means that the ring contains carbon atoms and 1 to 4 same or different heteroatoms selected from N, O and S(O) _0-2 . A valence group of a 5-, 6- or 7-membered (preferably 5- or 6-membered) saturated monocyclic heterocyclic ring (the residue obtained by removing one hydrogen atom from the ring). Nitrogen can be properly oxidized (ie, N→O). The saturated monocyclic heterocyclic group may be bonded to W of the formula [I] via any carbon atom or nitrogen atom constituting the ring. Examples of the saturated monocyclic heterocyclic group include pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperidinyl, oxalinyl, and tetrahydrofuranyl. Preferable examples of the saturated monocyclic heterocyclic group include pyrrolidinyl, imidazolidinyl, oxazolidinyl and thiazolidinyl.

In the present invention, "unsaturated monocyclic heterocyclic group" means a tetracyclic group containing carbon atoms and 1 to 4 same or different heteroatoms selected from N, O and S(O) _0-2 in the ring. . A valence group of a 5-, 6- or 7-membered (preferably 5- or 6-membered) partially unsaturated or unsaturated monocyclic heterocyclic ring (the residue obtained by removing one hydrogen atom from the ring). Nitrogen can be properly oxidized (ie, N→O). The unsaturated monocyclic heterocyclic group may be bonded to W of formula [I] via any carbon atom or nitrogen atom constituting the ring. Preferred examples of the unsaturated monocyclic heterocyclic group include: imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, dihydroisozozolyl, and oxadiazole Dihydrodiazolyl, pyrimidinyl, pyridyl, pyridyl, furyl, thienyl, pyrrolyl, pyryl, thiadiazolyl, thiadiazolyl, thiazolyl, trisyl. Preferred examples of the unsaturated monocyclic heterocyclic group include: imidazolyl, pyrazolyl, 1,2,3-triazolyl, tetrazolyl, isoxazolyl, 2,3- Dihydroisodiazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2,3 -Dihydro-1,3,4-oxadiazolyl, pyrimidinyl, and pyridyl.

Preferred examples of saturated or unsaturated monocyclic heterocycles include imidazolyl, pyrazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, 㗁Azolidinyl, thiazolidinyl, isoxazolyl, 2,3-dihydroisoazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxazolyl Azolyl, 1,3,4-oxadiazolyl, 2,3-dihydro-1,3,4-oxadiazolyl, pyrimidinyl, and carbazolyl.

In the present invention, "substituted" means that at least one hydrogen atom is replaced by a group other than a hydrogen atom. However, the usual atomic valences can be maintained, and stable compounds can be obtained by substitution. When the substituents are pendant oxy (=O) and pendant thio (=S), two hydrogen atoms on the atom are substituted.

In one embodiment of the compound of the present invention, the "pharmaceutically acceptable salt" 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, etc.; acetate, trifluoroacetate, benzoate, oxalate, propane Di-acid salt, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, triflate, benzenesulfonate, p-toluenesulfonate Organic acid salts such as salt, glutamate, aspartate; metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt; inorganic salts such as ammonium salt; and organic amines such as triethylamine salt and guanidine salt Salt etc.; Preferable examples include: sodium salt, potassium salt.

In one embodiment of the compound of the present invention, the compound of the present invention may take the form of a hydrate or a solvate. The agent/composition of the present invention may contain a single species or a plurality of compounds of the present invention.

The compound of formula [I] or its pharmaceutically acceptable salt may exist isomers such as tautomers, geometric isomers or optical isomers, and the formula described in the case of unspecified stereochemistry , chemical structure or compound name, as long as no other notes are mentioned, all possible isomers and mixtures of the isomers in arbitrary ratios may also be included.

The deuterium-converted form obtained by converting any one or more of ¹ H in the compound of formula [I] into ² H(D) is also included in the compound represented by the compound of formula [I].

The content of the compound of the present invention in the agent/composition of the present invention (in the case of including a plurality of compounds of the present invention, the total content) is not particularly limited, and can be selected from a wide range according to the form of administration, etc. .

For example, the content of the compound of the present invention in the agent/composition of the present invention is 0.00001-10% (w/v), preferably 0.0001-5% (w/v), more preferably 0.001-3% (w/v) /v), more preferably 0.003 to 2% (w/v), more preferably 0.01 to 2% (w/v), especially preferably 0.03 to 1.5% (w/v), and more preferably 0.03 ~ 0.5% (w/v), and more preferably 0.03 ~ 0.3% (w/v). As an example of the lower limit of the content, 0.00001% (w/v) can be exemplified, 0.0001% (w/v) can be exemplified as a better example, and 0.001% (w/v) can be exemplified as a more preferable example. v), as a further better example, 0.003% (w/v) can be exemplified, as an even better example, 0.01% (w/v) can be exemplified, as a further better example, 0.02% (w/v) can be exemplified /v), and as a more preferable example, 0.03% (w/v) can be mentioned. As an example of the upper limit of the content, 10% (w/v) can be cited, 5% (w/v) can be cited as a better example, and 3% (w/v) can be cited as a more preferable example. v), as a particularly preferred example, 2% (w/v) can be cited, as a further preferred example, 1.5% (w/v) can be cited, and as a further preferred example, 1% (w/v) can be cited w/v). The preferred range of the content can be represented by a combination of the examples of the above-mentioned lower limit and the example of the upper limit.

Furthermore, for example, the content of the compound of the present invention in the agent/composition of the present invention is 0.00001-10% (w/w), preferably 0.0001-5% (w/w), more preferably 0.001-3% (w/w), more preferably 0.003 to 2% (w/w), more preferably 0.01 to 2% (w/w), especially preferably 0.03 to 1.5% (w/w), and more preferably It is 0.03-0.5% (w/w), and, more preferably, it is 0.03-0.3% (w/w). As an example of the lower limit of the content, 0.00001% (w/w) can be exemplified, 0.0001% (w/w) can be exemplified as a better example, and 0.001% (w/w) can be exemplified as a more preferable example. w), as a further better example, 0.0003% (w/w) can be exemplified, as an even better example, 0.01% (w/w) can be exemplified, as a further better example, 0.02% (w/w) can be exemplified /w), and as a more preferable example, 0.03% (w/w) can be mentioned. As an example of the upper limit of the content, 10% (w/w) can be cited, 5% (w/w) can be cited as a better example, and 3% (w/w) can be cited as a more preferable example. w), as a particularly preferred example, 2% (w/w) can be exemplified, as a further preferred example, 1.5% (w/w) can be exemplified, and as a further preferred example, 1% (w/w) can be exemplified w/w). In particular, the preferred range of the content can be represented by a combination of the examples of the above-mentioned lower limit and the example of the upper limit.

In the present invention, "% (w/v)" means the mass (g) of the active ingredient (compound of the present invention) or additive (surfactant, etc.) contained in 100 mL of the drug. For example, 0.01% (w/v) of the compound of the present invention means that the compound of the present invention contained in 100 mL of the drug is 0.01 g.

In the present invention, "% (w/w)" means the mass (g) of the active ingredient (compound of the present invention) or additive (surfactant, etc.) contained in 100 g of the drug. For example, 0.01% (w/w) of the compound of the present invention means that the compound of the present invention contained in 100 g of the drug is 0.01 g.

When the compound of the present invention is in the form of a salt or a hydrate or a solvate (including a hydrate or a solvate of a salt), the content of the compound of the present invention in the medicament may be the salt or solvate formulated in the medicament. The mass of hydrates or solvates (including hydrates or solvates of salts) may also be the mass converted into the free body, preferably the mass converted into the free body.

In the present invention, "presbyopia" means a symptom/disease judged as presbyopia based on the usual criteria used by doctors or experts. For example, as the criteria for the diagnosis of presbyopia, it can be cited: "In the binocular examination, the subjective symptoms manifested as decreased near-distance vision, and the binocular living vision (distance vision of both eyes measured under the same conditions as in daily life) ) in 40 cm visual acuity less than 0.4" (clinical presbyopia) and/or "regardless of subjective symptoms, the accommodative power does not reach 2.5 diopters in the case of complete correction of one eye (monocular corrected visual acuity (decimal visual acuity) is 1.0 or more)" ( medical presbyopia). However, in cases where there is no ocular accommodation meter, etc., the 40 cm visual acuity less than 0.4 can be simply used as the diagnostic criterion.

In the present invention, "eye diseases accompanied by decreased elasticity of the lens" refers to eye diseases accompanied by decreased elasticity of the lens in the field of ophthalmology, for example, presbyopia (such as presbyopia caused by aging), and diseases caused by drugs The hardening of crystals induced by etc.

In the present invention, "eye accommodation" means the function of the eye to automatically focus when viewing objects at a distance and/or when viewing objects at a short distance. "Eye diseases accompanied by decreased eye accommodation" means eye diseases accompanied by decreased eye accommodation in the field of ophthalmology, such as: presbyopia (such as presbyopia caused by aging), caused by drugs, etc. Induced hardening of the crystalline lens and decreased accommodation induced by prolonged close viewing of objects.

The effect of the agent/composition of the present invention can be evaluated based on, for example, the improvement of "eye adjustment power". The eye accommodation power can be measured in terms of diopters (D), and can be obtained by the following formula (1). Diopter (D) = 1/near point distance (m) (Formula 1)

Generally speaking, the eye accommodation power is above 10 diopters at the age of 10, and then gradually decreases to about 3 diopters at the age of 45, and almost disappears at the age of 60. If it is reduced to about 3 diopters, it will be difficult to focus at a close distance (about 30 cm) in daily life, so the subjective symptoms of presbyopia will appear.

The effect of the agent/composition of the present invention can be evaluated based on, for example, improvement of "vision". Visual acuity can be measured in the form of near vision (uncorrected, distance vision corrected, corrected), and calculated from decimal vision, fractional vision, and logMAR.

Generally speaking, the near-distance vision is set at about 40 cm. If it is reduced to less than 0.4, it will cause difficulty in observing nearby objects, and the subjective symptoms of presbyopia will appear. The agent/composition of the present invention can be used to improve near vision (eg near vision with distance vision correction).

The agent/composition of the present invention can exert its effect within 1 year after treatment, preferably within 6 months, more preferably within 1 month, further preferably within 1 week, and further preferably within 1 month Effective within 1 day. In addition, once the effect is exerted, the effect can be continued until one day later, preferably one week later, more preferably one month later, further preferably six months later, especially preferably one year later, and more preferably Preferably after 3 years.

The agent/composition of the present invention, for example, can increase eye accommodation by at least about 0.5 diopters (preferably at least about 1 diopter, more preferably at least about 1.5 diopters, more preferably at least about 2 diopters, and more preferably at least about 3 diopters, and more preferably at least about 4 diopters, more preferably at least about 5 diopters, and even more preferably at least about 10 diopters).

The agent/composition of the present invention, for example, can improve distance-corrected near visual acuities (DCNVA) by at least about 0.5 logMAR (preferably at least about 1.0 logMAR, more preferably at least about 1.5 logMAR, and further Preferably about 2.0 logMAR, more preferably about 3.0 logMAR, particularly preferably about 4.0 logMAR, especially preferably about 5.0 logMAR, and most preferably about 6.0 logMAR). Near vision under distance vision correction generally refers to near vision measured by correcting distance vision to ≦0.0 logMAR (decimal vision above 1.0).

The agent/composition of the present invention, for example, can restore eye accommodation to at least about 0.5 diopters (preferably at least about 1 diopter, more preferably at least about 1.5 diopters, more preferably at least about 2 diopters, and more preferably at least about 3 diopters, more preferably at least about 4 diopters, more preferably at least about 5 diopters, and even more preferably at least about 10 diopters).

The agent/composition of the present invention, for example, can restore distance-corrected near visual acuities (DCNVA) to at least about 0.5 logMAR (preferably at least about 1.0 logMAR, more preferably at least about 1.5 logMAR, Further preferably, about 2.0 logMAR, still more preferably about 3.0 logMAR, most preferably about 4.0 logMAR, especially preferably about 5.0 logMAR, still more preferably about 6.0 logMAR).

In the present invention, the treatment or prevention of presbyopia includes: improving the elasticity of the lens, improving the adjustment function of the thickness of the lens, and/or improving the adjustment ability of the eye.

As mentioned above, although the subjective symptoms of presbyopia generally appear at about 45 years old, the decline in eye accommodation caused by aging begins in the teens. The agent/composition of the present invention can be used after the subjective symptoms of presbyopia appear, and can also be used to prevent and/or delay the progress of presbyopia before the subjective symptoms of presbyopia appear.

In the present invention, "high crystallographic migration" means that when the compound is administered (preferably eye drop administration) into the body, the compound has higher migration property to the crystal than lipoic acid. There is no particular limitation on the method of testing whether it is "high migration of crystals". For example, it can be evaluated by the following method. - Tandem mass spectrometer (LC-MS/MS) to measure the concentration of compounds in crystals or aqueous humor.

In the present invention, "cataract" means a symptom/disease judged as cataract based on the usual criteria used by doctors or experts. "Cataract" includes, for example, senile cataract (senile cataract), juvenile cataract, traumatic cataract, diabetic cataract, atopic cataract, radiation-induced cataract, cataract caused by steroids, and uveitis, etc. Eye diseases complicated with concurrent cataract, congenital cataract, etc.

The agents/compositions of the present invention are administered to mammals including livestock such as cows and pigs, rabbits, monkeys, dogs, cats, and humans, preferably humans.

In the present invention, "treatment" and "prevention" may include alleviating the symptoms of the disease, delaying the progression of the disease, suppressing the symptoms of the disease, and improving the symptoms of the induced disease in addition to treating and preventing the disease.

The administration route of the agent/composition of the present invention can be oral or parenteral (such as eye, nose, skin, mucous membrane, injection, etc.). The agent/composition of the present invention is preferably ocularly administered from the standpoint that the agent/composition of the present invention is less irritating to the eyes and the effect of the agent of the present invention is more excellent. The agent/composition of the present invention can be prepared by mixing the active ingredient with, for example, one or more pharmaceutically acceptable additives, such as tablets, capsules, granules, powders, oral formulations, etc. Oral preparations such as elixirs, syrups, emulsions, and suspensions, or parenteral preparations such as eye drops, ophthalmic ointments, injections, suppositories, and nasal preparations. Preferred formulation forms of the agent/composition of the present invention include eye drops and ophthalmic ointments.

The pharmaceutically acceptable additives that can be contained in the agent/composition of the present invention are not particularly limited, and can be appropriately selected according to the route of administration, the form of the preparation, and the like. Examples of the pharmaceutically acceptable additives include surfactants, buffers, isotonic agents, stabilizers, preservatives, antioxidants, thickeners, solubilizers, and suspending agents. ), base, solvent, pH adjuster, excipient, disintegrant, binder, slip agent, lubricant, preservative, antioxidant, colorant, sweetener, etc.

When the agent/composition of the present invention is an eye drop, examples of usable additives include surfactants, buffers, isotonic agents, stabilizers, preservatives, antioxidants, Thickener, solvent, pH adjuster, etc.

As an example of a surfactant, a cationic surfactant, an anionic surfactant, a nonionic surfactant, etc. are mentioned.

When preparing the surfactant/composition of the present invention, the content of the surfactant can be appropriately adjusted according to the type of the surfactant, for example, it is preferably 0.01 to 1% (w/v).

As an example of a buffering agent, phosphoric acid or its salt etc. are mentioned, and the hydrate or solvate thereof may be mentioned.

Phosphoric acid or a salt thereof may, for example, be phosphoric acid, trisodium phosphate, sodium dihydrogen phosphate or sodium hydrogen phosphate (disodium hydrogen phosphate), or a hydrate thereof.

In the case of formulating a buffer in the agent/composition of the present invention, the content of the buffer can be appropriately adjusted according to the type of buffer, for example, preferably 0.001 to 10% (w/v), more preferably 0.01～5%(w/v). Two or more buffers can also be used together.

As an example of an isotonic agent, an ionic isotonic agent, a nonionic isotonic agent, etc. are mentioned. Sodium chloride etc. are mentioned as an ionic isotonic agent.

When the isotonic agent is formulated in the agent/composition of the present invention, the content of the isotonic agent can be appropriately adjusted according to the type of the isotonic agent, for example, preferably 0.001-10% (w/v), more preferably Preferably 0.01% to 5% (w/v).

As an example of a thickener, hydroxypropyl methylcellulose etc. are mentioned.

When the thickener is formulated in the agent/composition of the present invention, the content of the thickener can be appropriately adjusted according to the type of the thickener, for example, it is preferably 0.001-5% (w/v), and more Preferably 0.01% to 3% (w/v).

When the agent/composition of the present invention is an aqueous preparation (such as eye drops), its pH value is preferably 4-8, more preferably 5-7.

As an example of a solvent, water, physiological saline, etc. are mentioned, for example.

As an example of the case where the agent/composition of the present invention is an aqueous preparation (such as eye drops), it may include: a compound containing the compound of the present invention, water, and an agent selected from ethyl pyruvate, sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ ·H ₂ O), disodium hydrogen phosphate (Na ₂ HPO ₄ ), hydroxypropyl methylcellulose, NaCl, polyoxyl 35 castor oil, benzyl benzoate, and their mixed additives Aqueous preparations. The above "mixture thereof" means any combination of the specific additives listed above.

In this case, "effective amount" is the amount of active ingredient required to provide benefit to the patient in the symptoms of the disease.

The usage and dosage of the agent/composition of the present invention are not particularly limited as long as they are sufficient to exert the desired medicinal effect, and can be appropriately selected according to the symptoms of the disease, the age or weight of the patient, and the dosage form of the drug. . For example, in the case of eye drops, 1 to 5 drops per dose, preferably 1 to 3 drops, more preferably 1 to 2 drops, especially 1 drop, and 1 to 1 drops per day may be used. Eye drops are administered 4 times, preferably 1 to 3 times a day, more preferably 1 to 2 times a day, and most preferably 1 time 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, and most preferably about 0.03 mL.

In one embodiment, the medicament of the present invention can treat presbyopia, cataract, eye diseases accompanied by decreased lens elasticity, or eye diseases accompanied by decreased eye accommodation (for example, compared with EV06 or other lipoic acid prodrugs) For immediate effect. The administration period of the medicament of the present invention can be determined by a doctor or an expert. In one embodiment, the medicament of the present invention is eye drops (such as solutions, emulsions, suspensions) and ophthalmic ointment, etc., which can be administered continuously. Use for at least 2 days, at least 3 days, at least 7 days, at least 10 days. In one embodiment, the agent of the present invention can be administered at least once a day (for example, at least 2 times, at least 3 times).

In one embodiment, when the medicament of the present invention is administered to the eye, it has an effect on presbyopia, cataract, eye diseases accompanied by decreased elasticity of the lens, or eye diseases accompanied by decreased eye accommodation, and further May be low eye irritation.

synthesis The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using synthetic methods known in the field of organic synthetic chemistry, and the methods of the following examples, or variations thereon that can be sufficiently recognized by those skilled in the art. Preferred methods include those described in the following examples, but are not limited thereto. [Example]

The following shows the synthesis of compounds, and the results of pharmacological tests, dynamic tests and safety tests, but these are for better understanding of the present invention and do not limit the scope of the present invention.

[Synthesis of Compounds] Example 1 (R)-1-(1H-imidazol-1-yl)-5-(1,2-dithiolan-3-yl)pentane (compound 1)

(R)-5-(1,2-Dithiolan-3-yl)pentan-1-ol (Intermediate 1)

Under nitrogen atmosphere, 1 M borane-THF complex THF solution (72.8 ml, 72.8 mmol) was dropped into a solution of α-lipoic acid (10.0 g, 48.5 mmol) in THF (300 ml) at 0°C. After the reaction solution was stirred at 0° C. for 1 hour, methanol (12 ml) was added and extracted with ethyl acetate (300 ml, 3 times). After the organic layer was washed successively with saturated sodium bicarbonate solution (500 ml) and saturated brine (500 ml), it was concentrated under reduced pressure, and was purified by silica gel column chromatography (petroleum ether: ethyl acetate=7 : 3) The obtained residue was purified to obtain the labeled intermediate 1 (6.7 g, 71%) as a yellow oily substance. (R)-5-(1,2-Dithiolan-3-yl)pentan-1-ol (Intermediate 1) ¹ H-NMR(400 MHz, CDCl ₃ ) δ 1.32-1.80(m, 8H), 1.87-1.97 (m, 1H), 2.43-2.50(m, 1H), 3.09-3.22(m, 2H), 3.54- 3.62(m, 1H), 3.67(t, J = 6.9 Hz, 2H) MS = 193(M+H) ⁺

(R)-5-(1,2-Dithiolan-3-yl)pentan-1-yl 4-methylbenzenesulfonate (Intermediate 2)

Solution of (R)-5-(1,2-dithiolan-3-yl)pentan-1-ol (3.80 g, 19.8 mmol) in tetrahydrofuran (60 ml) at 0°C under nitrogen atmosphere 60% sodium hydride (3.95 g, 98.8 mmol) was added. After the reaction solution was stirred at 0° C. for 30 minutes, p-toluenesulfonyl chloride (3.77 g, 19.8 mmol) was added. The reaction solution was returned to room temperature and stirred for 16 hours. Aqueous ammonium chloride solution was added to the reaction liquid at 0°C, followed by washing with water (150 ml) and saturated brine (150 ml). The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=9:1), and the labeled intermediate 2 (2.2 g, 32 %). (R)-5-(1,2-Dithiolan-3-yl)pentan-1-yl 4-methylbenzenesulfonate (Intermediate 2) ¹ H-NMR(400 MHz, CDCl ₃ ) δ 1.35-1.43(m, 4H), 1.56-1.72(m, 4H), 1.85-1.96(m, 1H), 2.40-2.46(m, 1H), 2.45( s, 3H), 3.05-3.29(m, 2H), 3.48-3.58(m, 1H), 3.99-4.07(m, 2H), 7.37(d, J = 8.4 Hz, 2H), 7.80(d, J = 8.4 Hz, 2H) MS = 364(M+NH ₄ ) ⁺

(R)-1-(1H-imidazol-1-yl)-5-(1,2-dithiolan-3-yl)pentane (compound 1)

To a solution of imidazole (468 mg, 6.87 mmol) in THF (40 ml) was gradually added 60% sodium hydride (749 mg, 18.7 mmol) at 0°C under nitrogen atmosphere. Under a nitrogen atmosphere, the reaction solution was stirred at room temperature for 30 minutes, and (R)-5-(1,2-dithiolan-3-yl)pentan-1-yl 4 was added at room temperature - A solution of tosylate (2.16 g, 6.24 mmol) in tetrahydrofuran (5 ml), stirred for 16 hours. The reaction liquid was brought to 0° C., an ammonium chloride aqueous solution was added, and ethyl acetate (100 ml) was added, and the organic layer was washed with water (150 ml) and saturated brine (150 ml). The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1), and the marked compound 1 (300 mg, 20% ). (R)-1-(1H-imidazol-1-yl)-5-(1,2-dithiolan-3-yl)pentane (compound 1) ¹ H-NMR(400 MHz, CDCl ₃ ) δ 1.32-1.52(m, 4H), 1.65-1.94(m, 5H), 2.45-2.49(m, 1H), 3.12-3.29(m, 2H), 3.55- 3.58(m, 1H), 3.96(t, J = 7.2Hz, 2H), 6.92(s, 1H), 7.08(s, 1H), 7.50(s, 1H) MS = 243(M+H) ⁺

Example 2 (R)-1-(1H-pyrazol-1-yl)-5-(1,2-dithiolan-3-yl)pentane (compound 2)

In the same manner as the synthetic method of compound 1, from pyrazole (118 mg, 1.73 mmol) and (R)-5-(1,2-dithiolan-3-yl)pentan-1-yl 4- Tosylate (600 mg, 1.73 mmol) gave the title compound 2 (220 mg, 52%) as a yellow oil. (R)-1-(1H-pyrazol-1-yl)-5-(1,2-dithiolan-3-yl)pentane (Compound 2) ¹ H-NMR(400 MHz, CDCl ₃ ) δ 1.26-1.37(m, 2H), 1.41-1.55(m, 2H), 1.60-1.74(m, 2H), 1.81-2.00(m, 3H), 2.41- 2.51(m, 1H), 3.05-3.25(m, 2H), 3.51-3.59(m, 1H), 4.13(t, J = 7.2Hz, 2H), 6.24(t, J = 2.0 Hz, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.51(d, J = 2.0 Hz, 1H) MS = 243(M+H) ⁺

Example 3 (R)-3-[5-(1,2-Dithiolan-3-yl)pentane-1-yl]-1,3-oxazolidine-2-one (Compound 3)

(R)-2-[5-(1,2-dithiolan-3-yl)pentan-1-ylamino]ethan-1-ol (intermediate 3)

Under nitrogen atmosphere, in (R)-5-(1,2-dithiolan-3-yl)pentan-1-yl 4-methylbenzenesulfonate (800 mg, 2.31 mmol ) in acetonitrile (10 ml) was added ethanolamine (1.41 g, 23.1 mmol). After stirring the reaction solution at room temperature for 10 minutes, the temperature was raised to 60° C., and stirring was continued for 4 hours. The reaction solution was returned to room temperature, and water (30 ml) was added, followed by extraction with methylene chloride (10 ml, 8 times), and the organic layer was washed with saturated brine (10 ml, 2 times). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (750 mg) of the labeled intermediate 3. (R)-2-[5-(1,2-dithiolan-3-yl)pentan-1-ylamino)ethan-1-ol (intermediate 3) MS = 236(M+H)

(R)-3-[5-(1,2-Dithiolan-3-yl)pentane-1-yl]-1,3-oxazolidine-2-one (Compound 3)

Under nitrogen atmosphere, the crude product (R)-2-[5-(1,2-dithiolan-3-yl)pentan-1-ylamino)]ethane-1- Alcohol (750 mg, 2.31 mmol), carbonyldiimidazole (562 mg, 3.46 mmol) and 4-dimethylaminopyridine (28.2 mg, 0.23 mmol) in N,N-dimethylformamide (5 ml) The solution was stirred for 12 hours. After adding water to the reaction solution, extraction was performed with ethyl acetate (30 ml, 3 times). The organic layer was washed with saturated brine (15 ml, twice), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1), and then reversed-phase flash column chromatography (C18 silica gel, acetonitrile: water = 1: 9 to 7:3, 30 minutes) was purified, whereby the title compound 3 (217 mg, 36% (2 steps)) was obtained as a yellow oily substance. (R)-3-[5-(1,2-Dithiolan-3-yl)pentane-1-yl]-1,3-oxazolidine-2-one (Compound 3) ¹ H-NMR(400 MHz, CDCl ₃ ) δ 1.29-1.40(m, 2H), 1.42-1.51(m, 2H), 1.53-1.60(m, 2H), 1.63-1.75(m, 2H), 1.85- 1.96(m, 1H), 2.41-2.51(m, 1H), 3.06-3.22(m, 2H), 3.23-3.30(m, 2H), 3.48-3.67(m, 3H), 4.22-4.42(m, 2H ) MS = 262(M+H) ⁺

Example 4 (R)-1-[5-(1,2-dithiolan-3-yl)pentane-1-yl]-1H-1,2,3-triazole (Compound 4)

(R)-3-(5-Azidopentan-1-yl)-1,2-dithiolane (Intermediate 4)

Under nitrogen atmosphere, in (R)-5-(1,2-dithiolan-3-yl)pentan-1-yl 4-methylbenzenesulfonate (1.7 g, 4.91 mmol ) in N,N-dimethylformamide (20 ml) was gradually added sodium azide (319 mg, 4.91 mmol). After the reaction solution was stirred for 2 hours, water was added and extracted with ethyl acetate (100 ml, 3 times). The organic layer was washed with saturated brine (50 ml), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product (650 mg) of labeled Intermediate 4 as a yellow oily substance. (R)-3-(5-Azidopentan-1-yl)-1,2-dithiolane) (Intermediate 4) 1H-NMR(400 MHz, CDCl ₃ ) δ 1.33-1.54(m, 4H), 1.55-1.80(m, 4H), 1.93-1.98(m, 1H), 2.34-2.62(m, 1H), 3.04-3.39 (m, 4H), 3.58-3.62(m, 1H)

(R)-1-[5-(1,2-dithiolan-3-yl)pentan-1-yl]-4-trimethylsilyl-1H-1,2,3-triazole ( Intermediate 5)

Under nitrogen atmosphere, in (R)-3-(5-azidopentan-1-yl)-1,2-dithiolane) (600 mg, 2.77 mmol) in water (2 ml) and the third Add ethynyltrimethylsilane (325 mg, 3.32 mmol), copper sulfate pentahydrate (207 mg, 0.83 mmol) and sodium ascorbate (165 mg, 0.83 mmol) to a mixed solution of butanol (4 ml), and Stir at room temperature for 16 hours. After adding water to the reaction solution, extraction was performed with ethyl acetate (100 ml, 3 times). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude product (680 mg) of the labeled intermediate 5. (R)-1-[5-(1,2-dithiolan-3-yl)pentan-1-yl]-4-trimethylsilyl-1H-1,2,3-triazole ( Intermediate 5)

(R)-1-[5-(1,2-dithiolan-3-yl)pentane-1-yl]-1H-1,2,3-triazole (compound 4)

Under nitrogen atmosphere, in (R)-1-[5-(1,2-dithiolan-3-yl)pentan-1-yl]-4-trimethylsilyl-1H at room temperature - To a solution of 1,2,3-triazole (680 mg, 2.77 mmol) in tetrahydrofuran (20 ml) was gradually added 1 M tetrabutylammonium bromide tetrahydrofuran solution (28 ml, 28 mmol). The reaction solution was heated to 50° C. and stirred for 4 hours, returned to room temperature, and extracted with ethyl acetate (100 ml, 3 times) after adding water. After drying the organic layer over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain a yellow oily substance Labeled compound 4 (390 mg, 53% (2 steps)). (R)-1-[5-(1,2-dithiolan-3-yl)pentane-1-yl]-1H-1,2,3-triazole (compound 4) 1H-NMR(400 MHz, CDCl ₃ ) δ 1.15-1.42(m, 2H), 1.43-1.60(m, 2H), 1.59-1.78(m, 2H), 1.78-2.14(m, 3H), 2.46-2.49 (m, 1H), 3.04-3.35(m, 2H), 3.56-3.58(m, 1H), 4.40-4.43(m, 2H), 7.56(d, J = 1.0 Hz, 1H), 7.73(d, J = 1.0 Hz, 1H) MS = 244(M+H) ⁺

Example 5 (R)-1-[5-(1,2-dithiolan-3-yl)-pentan-1-yl]pyrrolidine-2,5-dione (Compound 5)

(R)-5-(1,2-Dithiolan-3-yl)pentane-1-amine (Intermediate 6)

Under nitrogen atmosphere, in (R)-3-(5-azidopentan-1-yl)-1,2-dithiolane) (600 mg, 2.76 mmol) in tetrahydrofuran (9 ml ) and water (1 ml) was gradually added 1 M trimethylphosphine tetrahydrofuran solution (16 ml, 216 mol). The reaction was stirred at room temperature for 4 hours. Methanol was added to the reaction solution, and the solvent was concentrated under reduced pressure to obtain the crude product of the labeled intermediate (550 mg). (R)-5-(1,2-Dithiolan-3-yl)pentane-1-amine (Intermediate 6) MS = 192(M+H) ⁺

(R)-1-[5-(1,2-Dithiolan-3-yl)-pentan-1-yl]pyrrolidine-2,5-dione (compound 5)

A solution of (R)-5-(1,2-dithiolan-3-yl)pentan-1-amine (550 mg, 2.76 mmol) in acetic acid (10 ml) at room temperature under nitrogen atmosphere Sodium acetate (453 mg, 5.52 mmol) and succinic anhydride (414 mg, 4.14 mmol) were gradually added to . The reaction solution was warmed to 110° C. and stirred for 16 hours. The reaction solution was returned to room temperature, and after adding water, it was extracted with ethyl acetate (50 ml, 3 times). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1), and the title compound 5 (218 mg, 29% (2 steps)) was obtained as a yellow oily substance. (R)-1-[5-(1,2-dithiolan-3-yl)-pentan-1-yl]pyrrolidine-2,5-dione (Compound 5) 1H-NMR(400 MHz, DMSO-d ₆ ) δ 1.26-1.39(m, 2H), 1.41-1.51(m, 2H), 1.55-1.87(m, 4H), 1.87-1.96(m, 1H), 2.42 -2.50(m, 1H), 2.71(s, 4H), 3.09-3.20(m, 2H), 3.49-3.58(m, 3H) MS = 274(M+H) ⁺

Compound 5 can also be synthesized in the following method

(R)-5-(1,2-dithiolan-3-yl)pentan-1-yl 4-methylbenzenesulfonate (500 mg, 1.44 mmol) and cesium carbonate ( To a solution of 705 mg, 2.17 mmol) of N,N-dimethylformamide (3 ml) was added pyrrolidine-2,5-dione (214 mg, 2.17 mmol), and stirred for 4 hours. Aqueous ammonium chloride solution (30 ml) was added to the reaction solution, followed by extraction with ethyl acetate (50 ml, 3 times). The organic layer was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1), and the title compound 5 (240 mg, 61%) was obtained as a yellow oily substance.

Example 6 (R)-2-[5-(1,2-dithiolan-3-yl)pentan-1-yloxy]pyrimidine (compound 6)

Solution of (R)-5-(1,2-dithiolan-3-yl)pentan-1-ol (600 mg, 3.12 mmol) in tetrahydrofuran (8 ml) at 0°C under nitrogen atmosphere Add 60% sodium hydride (374 mg, 9.36 mmol) to it, and stir at room temperature for 30 minutes. 2-Fluoropyrimidine (320 mg, 3.28 mmol) was added to the reaction solution, and stirred at room temperature for 16 hours. Aqueous ammonium chloride solution was added to the reaction liquid, followed by extraction with ethyl acetate (500 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1), and the title compound 6 (536 mg, 63%) was obtained as a yellow oily substance. (R)-2-[5-(1,2-dithiolan-3-yl)pentan-1-yloxy]pyrimidine (Compound 6) 1H-NMR(400 MHz, CDCl ₃ ) δ 1.49-1.75(m, 4H), 1.68-1.75(m, 2H), 1.75-1.88(m, 1H), 1.88-1.97(m, 1H), 2.43-2.51 (m, 1H), 3.09-3.22(m, 2H), 3.56-3.61(m, 1H), 4.37(t, J = 6.4 Hz, 2H), 6.94(t, J = 4.8 Hz, 1H), 8.52( d, J = 4.8 Hz, 2H) MS = 271(M+H) ⁺

Example 7 (R)-3-[5-(1,2-dithiolan-3-yl)pentan-1-yloxy]pyrrole (compound 7)

In the same manner as the synthetic method of compound 6, from (R)-5-(1,2-dithiolane-3-yl)pentan-1-ol (600 mg, 3.12 mmol) and 3-chloropyridine 𠯤 (357 mg, 3.12 mmol) was obtained as a yellow oily substance to obtain the marked compound 7 (290 mg, 34%). (R)-3-[5-(1,2-dithiolan-3-yl)pentan-1-yloxy]pyrrole (compound 7) ¹ H-NMR(400 MHz, CDCl ₃ ) δ 1.47-1.62(m, 4H), 1.67-1.78(m, 2H), 1.81-1.89(m, 2H), 1.91-1.98(m, 1H), 2.45- 2.54(m, 1H), 3.05-3.28(m, 2H), 3.55-3.66(m, 1H), 4.51-4.54(t, J = 6.4 Hz, 2H), 6.98(dd, J = 8.4, 1.2 Hz, 1H), 7.38(dd, J = 8.4, 4.0 Hz, 1H), 8.84(dd, J = 4.0, 1.2 Hz, 1H) MS = 271(M+H) ⁺

[Reference Pharmacological Test] The effect on the elasticity of the crystal of the crystal caused by the ester-type lipoic acid derivative (comparative compound 1) was confirmed. The method described in Invest Ophthalmol Vis Sci, 57, 2851-2863, 2016 was used as a reference, and the evaluation test was carried out. Comparative compound 1 is the following formula: [Chemical 82] The indicated compound. Synthesized by the method described in patent document 2.

(Preparation of test sample) 1) Preparation of base preparation containing 0.1% (w/v) ethyl pyruvate, 0.269% (w/v) sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ ·H ₂ O), 0.433% (w/v) disodium hydrogen phosphate (Na ₂ HPO ₄ ), 0.2% (w/v) hydroxypropyl methylcellulose, 0.5% (w/v) sodium chloride (NaCl), Base (aqueous solution) of 0.2% (w/v) polyoxyl 35 castor oil (hereinafter also referred to as CO35) and purified water (appropriate amount). Store refrigerated after preparation.

2) Preparation of diluent The preparation contains 0.1% (w/v) ethyl pyruvate, 0.269% (w/v) sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ ·H ₂ O), 0.433% (w/ v) Dilution of disodium hydrogen phosphate (Na ₂ HPO ₄ ), 0.2% (w/v) hydroxypropyl methylcellulose, 0.5% (w/v) sodium chloride (NaCl), and purified water (appropriate amount) liquid (aqueous solution). Store refrigerated after preparation.

3) Preparation of comparative compound 1 sample The base agent was added to Comparative Compound 1 and stirred to prepare a 0.3% (w/v) emulsion, which was diluted with a diluent to prepare a 0.1% (w/v) emulsion. Furthermore, the prepared 0.1% (w/v) emulsion was diluted with a diluent to prepare a 0.03% (w/v) emulsion. Furthermore, the prepared 0.03% (w/v) emulsion was diluted with a diluent to prepare a 0.01% (w/v) emulsion. Store refrigerated after preparation.

4) Preparation of EV06 sample EV06 is a compound represented by the following formula: [Chemical 83] . Add base agent to EV06 for sonication to prepare 1.5% (w/v) solution. Store frozen after preparation.

(experiment method) 1) 2.5 μL/eye of each test sample was dripped once a day (9:00 as standard) into the right eye of 8-month-old C57BL/6J mice using PIPETMAN for 14 days. 2) After the final eye drops, the mice were euthanized by inhalation of carbon dioxide, and the eyeballs were enucleated and rinsed with Hank's Balanced Salt Solution (HBSS). 3) Cut the sclera near the optic nerve with a razor, extract the crystal from the incision, and immerse the extracted crystal in HBSS. 4) Place the crystal on the glass slide, and use the integrated fluorescent microscope BZ-9000 (Keyence) to obtain the image of the crystal (image a). 5) Next, place a piece of cover glass (22x22 mm) on top of the crystal, and also obtain images of changes in the thickness of the crystal due to weight (image b). 6) Calculate the amount of change in crystal diameter by the following calculation formula 1 (that is, subtract the crystal diameter of image a from the crystal diameter of image b). Then, the amount of improvement in crystal elasticity of each sample group compared with the base group was calculated by the following calculation formula 2. Furthermore, regarding the average value, the average value of 5 eyes of the base group was compared with the average value of 10 eyes of the compound 1 sample group and the EV06 sample group.

(calculation formula 1) Variation of crystal diameter = crystal diameter of image b of each tested sample - crystal diameter of image a of each tested sample (calculation formula 2) The increase of crystal elasticity of each sample group = the average value of the change in crystal diameter of each test sample group - the average value of the change in crystal diameter of the base group

(Results) Table 1 shows the results. [Table 1] Table 1 Increased crystal elasticity (μm) 0.01% comparative compound 1 sample 12.2 0.03% comparative compound 1 sample 33.8 0.1% comparative compound 1 sample 34.1 0.3% comparative compound 1 sample 39.8 1.5%EV06 sample 5.8

It can be seen from Table 1 that when 0.03%, 0.1% and 0.3% of Comparative Compound 1 are instilled once a day, the result is stronger than that of 1.5% EV06, and the excellent crystal elasticity of Comparative Compound 1 can be confirmed. Improvement effect.

[Pharmacological Test 1] To study the effects of compound 2, compound 5, compound 6, and compound 7 on the elasticity of the lens caused by instilling compound 2, compound 5, compound 6, and compound 7 once a day for 2 weeks.

(Preparation of test sample) 1) Preparation of base preparation containing 0.1% (w/v) ethyl pyruvate, 0.269% (w/v) sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ ·H ₂ O), 0.433% (w/v) disodium hydrogen phosphate (Na ₂ HPO ₄ ), 0.2% (w/v) hydroxypropyl methylcellulose, 0.5% (w/v) sodium chloride (NaCl), Base (aqueous solution) of 1.0% (w/v) CO35 and purified water (appropriate amount). Store refrigerated after preparation. 2) Preparation of compound 2 sample Add base agent to compound 2 and stir to prepare 0.03% (w/v) suspension. Store refrigerated after preparation. 3) Preparation of compound 5 sample Add base agent to compound 5 and stir to prepare 0.03% (w/v) suspension. Add base to 0.03% (w/v) suspension and dilute to prepare 0.01% (w/v) suspension. Add base to 0.01% (w/v) suspension and dilute to prepare 0.003% (w/v) suspension. All were refrigerated after preparation. 4) Preparation of compound 6 sample Add base agent to compound 6 and stir to prepare 0.03% (w/v) suspension. Store refrigerated after preparation. 5) Preparation of compound 7 sample Add base agent to compound 7 and stir to prepare 0.03% (w/v) suspension. Store refrigerated after preparation. 6) Preparation of comparative compound 1 sample Add base agent to comparative compound 1 and stir to prepare a 0.03% (w/v) suspension, which is used for comparison of compounds 2 and 5-7. Store refrigerated after preparation.

(experiment method) 1) Add 2.5 μL/eye of each test sample to the eyes of 8-month-old C57BL/6J mice once a day (13:30 as standard) using PIPETMAN for 14 days. 2) About 0.5 hours after the final eye drops, the mice were euthanized by inhalation of carbon dioxide, and the eyeballs were enucleated and rinsed with Hank's Balanced Salt Solution (HBSS). 3) Cut the sclera near the optic nerve with a razor, extract the crystal from the incision, and immerse the extracted crystal in HBSS. 4) Place the crystal on the glass slide, and use the integrated fluorescent microscope BZ-9000 (Keyence) to obtain the image of the crystal (image a). 5) Next, place a piece of cover glass (22x22 mm) on top of the crystal, and also obtain images of changes in the thickness of the crystal due to weight (image b). 6) Calculate the amount of change in crystal diameter by the following calculation formula 1 (that is, subtract the crystal diameter of image a from the crystal diameter of image b). Then, the amount of improvement in crystal elasticity of each sample group compared with the base group was calculated by the following calculation formula 2. Furthermore, regarding the average value, it is the average value of 8 eyes for each group.

(calculation formula 1) Variation of crystal diameter = crystal diameter of image b of each tested sample - crystal diameter of image a of each tested sample (calculation formula 2) The increase of crystal elasticity of each sample group = the average value of the change in crystal diameter of each test sample group - the average value of the change in crystal diameter of the base group

(Results) Table 2 shows the results. [Table 2] Table 2 Increased crystal elasticity (μm) 0.03% compound 2 sample 59.4 0.003% compound 5 sample 52.0 0.01% compound 5 sample 54.8 0.03% compound 5 sample 65.5 0.03% compound 6 sample 57.3 0.03% compound 7 sample 52.4 0.03% comparative compound 1 sample 50.4

It can be seen from Table 2 that compound 5 exhibits a strong effect of improving the elasticity of crystals at concentrations of 0.003%, 0.01%, and 0.03% once a day, and it can be confirmed at any concentration compared with 0.03%. The compound 1 sample has a stronger crystal elasticity improvement effect. In addition, in the samples of compounds 2, 6 and 7, compared with the 0.03% comparative compound 1 sample at the same concentration, it also showed a stronger effect of improving the crystal elasticity of the crystal.

[Pharmacological Test 2] To study the effect of compound 5 on the elasticity of crystals caused by instilling compound 5 twice a day for 7 days.

(Preparation of Test Sample) 1) Preparation of Base A Preparation containing 5.0% (w/v) CO35, 0.1% (w/v) sodium hydrogen phosphate dodecahydrate (Na ₂ HPO ₄ ·12H ₂ O) , 0.8% (w/v) sodium chloride (NaCl), 0.01% (w/v) edetate sodium hydrate (C ₁₀ H ₁₄ N ₂ O ₈・2Na・2H ₂ O), and purified water (Appropriate amount) of the base (aqueous solution). Store refrigerated after preparation. 2) Preparation of Base B The preparation contained 0.1% (w/v) ethyl pyruvate, 0.269% (w/v) sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ ·H ₂ O), 0.433% (w /v) Disodium hydrogen phosphate (Na ₂ HPO ₄ ), 0.2% (w/v) hydroxypropyl methylcellulose, 0.36% (w/v) sodium chloride (NaCl), and purified water (appropriate amount) Base (aqueous solution). Store refrigerated after preparation. 3) Preparation of compound 5 sample Add base A to compound 5 and stir to prepare 0.25% (w/v) solution. Store refrigerated after preparation. 4) Preparation of EV06 sample Add base B to EV06 to prepare a 3% (w/v) solution. Store refrigerated after preparation.

(experiment method) 1) Add 2.5 μL/eye of each test sample to the eyes of 8-month-old C57BL/6J mice twice a day (9:00 and 17:00) using PIPETMAN for 7 days. 2) About 0.5 hours after the final eye drops, the mice were euthanized by inhalation of carbon dioxide, and the eyeballs were enucleated and rinsed with Hank's Balanced Salt Solution (HBSS). 3) Cut the sclera near the optic nerve with a razor, extract the crystal from the incision, and immerse the extracted crystal in HBSS. 4) Place the crystal on the glass slide, and use the integrated fluorescent microscope BZ-9000 (Keyence) to obtain the image of the crystal (image a). 5) Next, place a piece of cover glass (22x22 mm) on top of the crystal, and also obtain images of changes in the thickness of the crystal due to weight (image b). 6) Calculate the amount of change in crystal diameter by the following calculation formula 1 (that is, subtract the crystal diameter of image a from the crystal diameter of image b). Then, the amount of increase in crystallinity elasticity of each sample group compared with the base A group was calculated by the following calculation formula 2. In addition, regarding the average value, the average value of 9 eyes of the base A group, and the average value of 10 eyes of the compound 5 group and EV06 group.

(calculation formula 1) Variation of crystal diameter = crystal diameter of image b of each tested sample - crystal diameter of image a of each tested sample (calculation formula 2) The amount of increase in crystal elasticity of each sample group = the average value of the change in crystal diameter of each test sample group - the average value of the change in crystal diameter of base A group

(Results) Table 3 shows the results. [table 3] table 3 Increased crystal elasticity (μm) 0.25% compound 5 sample 53.5 3%EV06 sample 22.0

It can be seen from Table 3 that the 0.25% compound 5 sample instilled twice a day for 7 days showed a strong effect of improving the elasticity of crystals. In addition, compared with the EV06 sample with a higher concentration of 3%, it has a stronger effect on improving the crystal elasticity of the crystal.

[Pharmacological Test 3] The effect on the elasticity of the lens of the eye by instilling Compound 5 once a day for 4 weeks was studied using 23-month-old mice.

(Preparation of test sample) 1) Preparation of base preparation containing 5.0% (w/v) CO35, 0.1% (w/v) sodium hydrogen phosphate dodecahydrate (Na ₂ HPO ₄ ·12H ₂ O), 0.8% (w/v) sodium chloride (NaCl), 0.01% (w/v) edetate sodium hydrate (C ₁₀ H ₁₄ N ₂ O ₈・2Na・2H ₂ O), and purified water ( Appropriate amount) of the base (aqueous solution). Store refrigerated after preparation. 2) Preparation of compound 5 sample Add base agent to compound 5 and stir to prepare 0.5% (w/v) solution. Store refrigerated after preparation.

(experiment method) 1) Physiological saline solution or Compound 5 sample was added dropwise to the eyes of 23-month-old B6J aged mice once a day (13:00 as standard) using PIPETMAN at 2.5 μL/eye for 4 weeks. 2) About 0.5 hours after the final eye drops, the mice were euthanized by inhalation of carbon dioxide, and the eyeballs were enucleated and rinsed with Hank's Balanced Salt Solution (HBSS). 3) Cut the sclera near the optic nerve with a razor, extract the crystal from the incision, and immerse the extracted crystal in HBSS. 4) Place the crystal on the glass slide, and use the integrated fluorescent microscope BZ-9000 (Keyence) to obtain the image of the crystal (image a). 5) Next, place a piece of cover glass (22x22 mm) on top of the crystal, and also obtain images of changes in the thickness of the crystal due to weight (image b). 6) Calculate the amount of change in crystal diameter by the following calculation formula 1 (that is, subtract the crystal diameter of image a from the crystal diameter of image b). Then, the amount of improvement in crystal elasticity of each sample group compared with the base group was calculated by the following calculation formula 2. In addition, as for the average value, the average value of 8 eyes of the physiological saline group and the average value of 10 eyes of the compound 5 group were used.

(calculation formula 1) Variation of crystal diameter = crystal diameter of image b of each tested sample - crystal diameter of image a of each tested sample (calculation formula 2) The increase of crystal elasticity of each sample group = the average value of the change in crystal diameter of each test sample group - the average value of the change in crystal diameter of the physiological saline solution group

(Results) Table 4 shows the results. [Table 4] Table 4 Increased crystal elasticity (μm) 0.5% compound 5 sample 88.9

It can be seen from Table 4 that for 23-month-old mice, by instilling 0.5% compound 5 once a day for 4 weeks, it also showed a strong effect of improving the elasticity of the crystals, even if it was older, it also showed a significant effect Strong crystal elasticity improvement effect.

[Pharmacological Test 4] The effect on lens turbidity caused by instilling compound 5 three times a day for 4 weeks in SDT obese rats was studied.

(Preparation of test sample) 1) Preparation of base preparation containing 5.0% (w/v) CO35, 0.1% (w/v) sodium hydrogen phosphate dodecahydrate (Na ₂ HPO ₄ ·12H ₂ O), 0.8% (w/v) sodium chloride (NaCl), 0.01% (w/v) edetate sodium hydrate (C ₁₀ H ₁₄ N ₂ O ₈・2Na・2H ₂ O), and purified water ( Appropriate amount) of the base (aqueous solution). Store refrigerated after preparation. 2) Preparation of compound 5 sample Add base agent to compound 5 and stir to prepare 0.5% (w/v) solution. Store refrigerated after preparation.

(Test method) 1) Physiological saline solution or compound 5 sample was added dropwise to 5-week-old SDT three times a day (9:00, 13:00, 17:00 as standard) using PIPETMAN at 5 μL/eye Both eyes of obese rats for 4 weeks. 2) Every week, use Mydrin-P eye drops to dilate the pupils and perform crystal examination. Use a photographic slit lamp SL-8Z (Topcon Medical Japan) to observe the state of the crystal, score the turbidity of the crystal according to the criteria in Table 5, and take pictures. Furthermore, 0.5 is set as an intermediate value among the scores of 0, 1, 2, 3, and 4. Calculate the average value of the cataract scores of the physiological saline solution and the compound 5 sample group in each week. In addition, the average value is the average value of each 10 eyes of a physiological saline solution group and a compound 5 group. [table 5] Table 5 Judgment criteria cataract score Judgment criteria 0 normal clear lens 1 Slight cloudiness observed in the center of the crystal 2 Patch-like opacity observed in the center and periphery of the crystal 3 A uniform opalescent cloudiness is observed throughout the crystal 4 Mature cataract with nuclear opacities

(Results) Table 6 shows the results. [Table 6] Table 6 Cataract score before administration Cataract score in the first week of administration Cataract score in week 2 of administration Cataract score at week 3 Cataract score at week 4 saline solution 0.55 0.70 1.60 1.90 2.15 0.5% compound 5 sample 0.40 0.50 1.20 1.55 1.75

It can be seen from Table 6 that 0.5% compound 5 sample has a strong inhibitory effect on crystal turbidity when it is instilled 3 times a day for 4 weeks.

[Dynamic test 1] Using 1.5% (w/v) EV06 eye drops, 0.1% (w/v) comparative compound 1 eye drops and 0.1% (w/v) compound 2, 5 and 6 eye drops, each rabbit was given a single drop Eyes, lipoic acid and compounds 2, 5 and 6 were evaluated for crystal migration.

(Preparation method of eye drops) By the same method as the preparation of the test sample of Pharmacological Test 1, 1.5% (w/v) EV06 eye drops (solution), 0.1% (w/v) comparative compound 1 eye drops and 0.1% ( w/v) Compounds 2, 5 and 6 eye drops. Store refrigerated after preparation.

(experiment method) 50 μL of each eye drop was instilled once into both eyes of a rabbit (male Japanese white). After 0.5, 1, and 4 hours of instillation, the crystals after slaughtering were collected (4 eyes at each time point). The concentrations of lipoic acid and compounds 2, 5 and 6 in crystals were determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).

(Test results and discussion) The average concentration of lipoic acid or compounds 2, 5 and 6 in the crystals of the eye drops after 0.5, 1, and 4 hours of instillation, and the concentration in the crystals until 4 hours after instillation- The results of the area under the time curve (AUC) are shown in Table 7. Furthermore, the average value is the average value of 4 eyes. [Table 7] Table 7 eye drops 1.5% EV06 0.1% Comparative compound 1 0.1% Compound 2 0.1% Compound 5 0.1% Compound 6 Measurement object lipoic acid lipoic acid Compound 2 Compound 5 Compound 6 The mean value of the concentration in the eye lens after 0.5 hours of eye drops (ng/g) 5.96 7.24 9.62 74.3 6.06 The average concentration in the crystals of the eye after 1 hour of eye drops (ng/g) 7.11 5.81 20.5 40.2 8.51 The average concentration in the crystals of the eye after 4 hours (ng/g) 1.04 1.02 5.68 10.2 4.72 AUC (ng･hr/g) up to 4 hours after instillation 17.0 15.3 49.2 123 25.0

Using 0.1% (w/v) compound 2, 5 and 6 eye drops to rabbit eye drops once, the concentration and AUC of compound 2, 5 and 6 in the eye lens compared with 1.5% (w/v) EV06 eye drops Or 0.1% comparative compound 1 eye drops showed a higher value in the lipoic acid concentration and AUC in the crystals of the rabbit when it was instilled once. Therefore, these compounds are considered to have higher crystal migration properties than EV06 and Comparative Compound 1.

[Dynamic Test 2] Regarding the crystals taken from 0.03% (w/v) eye drops of comparative compound 1, and 0.03% (w/v) eye drops of compounds 2 and 5-7 in pharmacological test 1, lipoic acid and compound 2 were evaluated And 5 ~ 7 crystal migration.

(experiment method) Using the liquid crystals collected from mice slaughtered about 0.5 hours after the final eye drops in pharmacological test 1, lipoic acid and compound 2 in the liquid crystals were determined using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) And the concentration of 5-7.

(Test results and discussion) Table 8 shows the average concentrations of lipoic acid or compounds 2 and 5 to 7 in the crystals about 0.5 hours after the final instillation of each eye drop. Furthermore, the mean value is the mean value of 8 eyes. [Table 8] Table 8 eye drops 0.03% Comparative Compound 1 0.03% Compound 2 0.03% Compound 5 0.03% Compound 6 0.03% Compound 7 Measurement object lipoic acid Compound 2 Compound 5 Compound 6 Compound 7 The average concentration (ng/g) in the eye lens about 0.5 hours after the final eye drops 4.10 36.0 52.2 38.2 30.7

When 0.03% (w/v) eye drops of Compound 2 and 5-7 were administered once a day for 2 weeks, the concentration in the crystals of the eye drops was higher than that of 0.03% (w/v) Compound 1 eye drops. high value.

[Eye irritation test] (sample preparation) 1) Preparation of base The base was prepared by the same method as the preparation of the test sample of Pharmacological Test 1. 2) Preparation of samples of compounds 2, 5, 6, and 7 The base agent was added to compound 2 and stirred to prepare a 0.1% (w/v) suspension. The base agent was added to compound 5 and stirred to prepare a 0.1% (w/v) suspension. The base agent was added to compound 6 and stirred to prepare a 0.1% (w/v) suspension. The base agent was added to compound 7 and stirred to prepare a 0.1% (w/v) suspension. All were refrigerated after preparation.

(experiment method) With a pipette, add the base, 0.1% (w/v) compound 2 eye drops, 0.1% (w/v) compound 5 eye drops, 0.1% (w/v) compound 6 eye drops Solution, and 0.1% (w/v) Compound 7 eye drops were instilled 10 times (50 μL/eye/time) at 30-minute intervals in one eye of Japanese white rabbits, and 1 hour after the final eye drop, the gap was implemented. Eye irritation symptoms observed before the light (McDonald-Shadduck method). In addition, corneal epithelial injury observation was carried out 3 hours after the final eye drop. The observation of anterior ocular irritation symptoms was scored by the following criteria. +1: mild, +2: moderate, +3: severe

(Test results) Table 9 shows the test results. In 0.1% (w/v) compound 2 eye drops, 0.1% (w/v) compound 5 eye drops, 0.1% (w/v) compound 6 eye drops, and 0.1% (w/v) compound 7 No anterior eye irritation symptoms were observed in the eyes in which the eye drops were instilled. [Table 9] Table 9 eye drops Base 0.1% Compound 2 0.1% Compound 5 0.1% Compound 6 0.1% Compound 7 number of animals 3 3 3 3 3 Anterior eye irritation score conjunctival hyperemia - +1 +1 - - conjunctival edema - - - - - secretion - - - - - intracameral flare - - - - - light reflection - - - - - iris - - - - - corneal opacity - - - - - corneal angiogenesis - - - - - corneal epithelial injury - - - - - -: No observations that should be specially recorded; record the observations and scores of the instilled eye 1 hour after the final eye instillation. The conjunctival hyperemia observed in compounds 2 and 5 was a transient mild change that recovered 3 hours after the final eye drop, and tolerance was confirmed. In addition, corneal epithelial injury observation was carried out 3 hours after the final eye drop.

(Discussion) It shows that compound 2, compound 5, compound 6, and compound 7 eye drops have higher safety.

Claims (49)

An agent/composition for treating or preventing eye diseases, which contains a compound represented by formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 1] [In the formula, A is [chemical 2] , Here, A can be substituted by the same or different 1 to 3 R ¹ ; R ¹ are independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy ; W is a C _1-10 alkylene group; here, 1 to 3 methylene groups in the alkylene group can be independently substituted to be selected from O, NR ² (here, R ² is H or C _1-3 alkyl), and a divalent group in the group consisting of S(O) _0-2 ; and the alkylene group can be independently selected from -OH, halogen, C _1-3 alkyl, and At least one substituent in the group consisting of C _1-3 alkoxy is substituted; B is a saturated or unsaturated monocyclic heterocyclic group with four to seven members, where the monocyclic heterocyclic group is The ring contains carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , and can be substituted by the same or different 1 to 3 R ³ ; R ³ are respectively Independently selected from the group consisting of -OH, -SH, side oxygen (=O), side thiol (=S), halogen, C _1-3 alkyl, and C _1-3 alkoxy], the The eye disease is selected from the group consisting of presbyopia and cataract. An agent/composition for the treatment or prevention of eye diseases accompanied by decreased elasticity of the lens, which contains the compound of formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 3] [In the formula, A, W and B are synonymous with those in Claim 1]. The agent/composition according to claim 2, wherein the eye disease is an eye disease accompanied by a decrease in eye accommodation. An agent/composition for treating or preventing ocular diseases accompanied by decreased ocular accommodation, which contains the compound of formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 4] [In the formula, A, W and B are synonymous with those in Claim 1]. The agent/composition according to any one of claims 1 to 4, wherein the eye disease is presbyopia. The agent/composition according to claim 1, wherein the eye disease is cataract. A crystalline highly migratory composition, which contains a compound of formula [I] or a pharmaceutically acceptable salt thereof: [Chemical 5] [In the formula, A, W and B are synonymous with those in Claim 1]. The agent/composition according to any one of claims 1 to 7, wherein A is [Chem. 6] [chemical 7] [chemical 8] [chemical 9] [chemical 10] [chemical 11] [chemical 12] or [Chem.13] , Here, A may be substituted by the same or different 1 to 3 R ¹ . The agent/composition according to any one of claims 1 to 8, wherein A is [Chem. 14] or [Chem.15] , Here, A may be substituted by the same or different 1 to 3 R ¹ . The agent/composition according to any one of claims 1 to 9, wherein A is [Chem. 16] or [Chem.17] , Here, A may be substituted by the same or different 1 to 3 R ¹ . The agent/composition according to any one of claims 1 to 10, wherein A is [Chem. 18] or [Chem.19] . The agent/composition according to any one of claims 1 to 11, wherein W is an alkylene group of -(CH ₂ ) _1-10 -, and the alkylene group can be independently selected from -OH, halogen, C Substitution with at least one substituent in the group consisting of _1-3 alkyl and C _1-3 alkoxy. The agent/composition according to any one of claims 1 to 12, wherein W is an alkylene group of -(CH ₂ ) _1-10 -. The agent/composition according to any one of claims 1 to 11, wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 - O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _1-9 -S-, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-, -(CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-(CH ₂ ) ₂ -NH- (CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 - O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 - S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -, where the leftmost bond is bonded to A and the rightmost bond is bonded to B, or the leftmost bond is bonded to B and the rightmost bond is bonded to A Bonding, the W may be substituted by at least one substituent independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy. The agent/composition according to any one of claims 1 to 11 and 14, wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-(CH ₂ ) _{2- 4} -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _1-9 -S-, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-, - (CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-(CH ₂ ) ₂ - NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-(CH ₂ ) _{2- 3} -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-(CH ₂ ) _{2- 3} -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _1-2 -NH-(CH ₂ ) _{2 -3} -NH-(CH ₂ ) _2-3 -, here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B and the rightmost bond Bonded with A. The agent/composition according to any one of claims 1 to 15, wherein W is -(CH ₂ ) _4-6 -, or -(CH ₂ ) _4-6 -O- (here, the leftmost bond and A is bonded and the rightmost bond is bonded to B). The agent/composition according to any one of claims 1 to 16, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, and here, the monocyclic heterocyclic group includes in the ring A carbon atom and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 may be substituted by the same or different 1 to 3 R ³ . The agent/composition according to any one of claims 1 to 17, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic group is selected from imidazolyl , pyrazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, oxazolyl, thiazolidinyl, isoxazolyl, 2,3-dihydroisoxazole 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2,3-dihydro-1 , a group consisting of 3,4-oxadiazolyl, pyrimidinyl, and pyrimidyl, which may be substituted by the same or different 1 to 3 R ³ . The agent/composition according to any one of claims 1 to 18, wherein B is a saturated or unsaturated monocyclic heterocyclic group with five or six members, and here, the monocyclic heterocyclic group includes in the ring Carbon atom, and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 (wherein, the heteroatom contains at least 1 N), and can be replaced by the same or different 1 to 4 3 ^R3 substitutions, B is bonded to W via N in the ring. The agent/composition according to any one of claims 1 to 19, wherein B is [Chem. 20] . The agent/composition according to any one of claims 1 to 20, which contains a compound selected from the following or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical 21] . The agent/composition according to any one of claims 1 to 21, which contains a compound selected from the following or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical 22] . The agent/composition according to any one of claims 1 to 21, which contains a compound selected from the following or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical 23] . The agent/composition according to any one of Claims 1 to 23, which contains a compound selected from the following or a pharmaceutically acceptable salt thereof as an active ingredient: [Chem. 24] . The agent/composition according to any one of claims 1 to 24, which is administered to the eye. The agent/composition according to any one of Claims 1 to 25, which is eye drops or eye ointment. The agent/composition according to any one of claims 1 to 26, wherein the content of the active ingredient is 0.00001-10% (w/v). A use of a compound of formula [I] or a pharmaceutically acceptable salt thereof, which is used for the treatment or prevention of presbyopia, cataracts, eye diseases accompanied by decreased elasticity of the lens, or eye diseases accompanied by decreased eye regulation Agent/composition: [Chemical 25] [In the formula, A, W and B are synonymous with those in Claim 1]. A compound of formula [I] or a pharmaceutically acceptable salt thereof, which is used for the treatment or prevention of presbyopia, cataracts, eye diseases accompanied by decreased elasticity of the lens, or eye diseases accompanied by decreased eye accommodation: [Chem 26] [In the formula, A, W and B are synonymous with those in Claim 1]. A method for treating or preventing presbyopia, cataracts, eye diseases accompanied by decreased elasticity of the lens, or eye diseases accompanied by decreased eye accommodation, which comprises administering an effective amount of the formula to a subject in need of treatment or prevention The compound of [I] or its pharmaceutically acceptable salt: [Chemical 27] [In the formula, A, W and B are synonymous with those in Claim 1]. A compound or a pharmaceutically acceptable salt thereof, the compound having the formula [I]: [Chemical 28] [In the formula, A is [chemical 29] , Here, A can be substituted by the same or different 1 to 3 R ¹ ; R ¹ are independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy ; W is a C _1-10 alkylene group; here, 1 to 3 methylene groups in the alkylene group can be independently substituted to be selected from O, NR ² (here, R ² is H or C _1-3 alkyl), and a divalent group in the group consisting of S(O) _0-2 ; and the alkylene group can be independently selected from -OH, halogen, C _1-3 alkyl, and At least one substituent in the group consisting of C _1-3 alkoxy is substituted; B is a saturated or unsaturated monocyclic heterocyclic group with four to seven members, where the monocyclic heterocyclic group is The ring contains carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , and can be substituted by the same or different 1 to 3 R ³ ; R ³ are respectively independently selected from the group consisting of -OH, -SH, side oxygen (=O), side thiol (=S), halogen, C _1-3 alkyl, and C _1-3 alkoxy, wherein, except]. Such as the compound of claim 31 or its salt acceptable in medicine, wherein A is [Chemical 30] [chem 31] [chem 32] [chem 33] [chem 34] [chem 35] [chem 36] or [Chem37] , Here, A may be substituted by the same or different 1 to 3 R ¹ . The compound or pharmaceutically acceptable salt thereof as claimed in item 31 or 32, wherein A is [Chemical 38] or [Chem39] , Here, A may be substituted by the same or different 1 to 3 R ¹ . A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 33, wherein A is [化40] or [41] , Here, A may be substituted by the same or different 1 to 3 R ¹ . A compound or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 34, wherein A is [化42] or [43] . A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 35, wherein W is an alkylene group of -(CH ₂ ) _1-10- , and the alkylene group can be independently selected from- Substitution with at least one substituent selected from the group consisting of OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy. The compound or the pharmaceutically acceptable salt thereof according to any one of claims 31 to 36, wherein W is an alkylene group of -(CH ₂ ) _1-10 -. The compound according to any one of Claims 31 to 35 or the pharmaceutically acceptable salt thereof, wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-(CH ₂ ) _2-4 -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _1-9 -S-, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S -, -(CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-(CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-(CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-(CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _1-2 -NH-(CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -, Here, the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B and the most The bond on the right is bonded to A, and the W may be substituted by at least one substituent independently selected from the group consisting of -OH, halogen, C _1-3 alkyl, and C _1-3 alkoxy. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 35 and 38, wherein W is -(CH ₂ ) _1-9 -O-, -(CH ₂ ) _1-4 -O-( CH ₂ ) _2-4 -O-, -(CH ₂ ) _1-2 -O-(CH ₂ ) ₂ -O-(CH ₂ ) _2-3 -O-, -(CH ₂ ) _1-9 -S -, -(CH ₂ ) _1-4 -S-(CH ₂ ) _2-4 -S-, -(CH ₂ ) _1-2 -S-(CH ₂ ) ₂ -S-(CH ₂ ) _2-3 -S-, -(CH ₂ ) _1-9 -NH-, -(CH ₂ ) _1-4 -NH-(CH ₂ ) _2-4 -NH-, -(CH ₂ ) _1-2 -NH-( CH ₂ ) ₂ -NH-(CH ₂ ) _2-3 -NH-, -(CH ₂ ) _1-5 -O-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -O-( CH ₂ ) _2-3 -O-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -S-(CH ₂ ) _2-4 -, -(CH ₂ ) _1-2 -S-( CH ₂ ) _2-3 -S-(CH ₂ ) _2-3 -, -(CH ₂ ) _1-5 -NH-(CH ₂ ) _2-4 -, or -(CH ₂ ) _1-2 -NH- (CH ₂ ) _2-3 -NH-(CH ₂ ) _2-3 -, where the leftmost bond can be bonded to A and the rightmost bond can be bonded to B, or the leftmost bond can be bonded to B And the rightmost bond is bonded to A. The compound according to any one of Claims 31 to 39, or the pharmaceutically acceptable salt thereof, wherein W is -(CH ₂ ) _4-6 -, or -(CH ₂ ) _4-6 -O- (here, The leftmost bond is bonded to A and the rightmost bond is bonded to B). A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 40, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic The base ring includes carbon atoms and the same or different 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , and may be substituted by the same or different 1 to 3 R ³ . A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 41, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic The group is selected from imidazolyl, pyrazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, zozolidinyl, thiazolidinyl, isoxazolyl, 2,3- Dihydroisodiazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2,3 - a group consisting of dihydro-1,3,4-oxadiazolyl, pyrimidinyl, and pyridyl, which may be substituted by the same or different 1 to 3 R ³ . A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 42, wherein B is a five- or six-membered saturated or unsaturated monocyclic heterocyclic group, where the monocyclic heterocyclic The base ring contains carbon atoms, and 1 to 4 heteroatoms selected from N, O and S(O) _0-2 , the same or different (wherein, the heteroatoms contain at least 1 N), and can be replaced by the same Or different 1 to 3 R ³ substitutions, B is bonded to W via N in the ring. A compound or a pharmaceutically acceptable salt thereof as in any one of claims 31 to 43, wherein B is [化44] . A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 44, which is selected from the following: [Chem. 45] . The compound of any one of Claims 31 to 45 or its pharmaceutically acceptable salt is selected from the following: [Chem. 46] . The compound of any one of Claims 31 to 45 or its pharmaceutically acceptable salt, which is selected from the following: [Chemical 47] . A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 31 to 47, which is selected from the following: [Chemical 48] . A pharmaceutical composition comprising the compound according to any one of claims 31 to 48 or a pharmaceutically acceptable salt thereof.