Novel peptide and pharmaceutical composition for treating eye diseases containing the novel peptide as an active ingredient

Abstract

To provide a novel peptide, and to provide a pharmaceutical composition for treating eye diseases containing the novel peptide as an active ingredient.SOLUTION: A compound of Formula 1 is provided, [R1 to R3 are each independently hydrogen, substituted or unsubstituted C1-6 alkyl, etc.; R4 and R5 are each independently hydrogen, substituted or unsubstituted C1-6 alkyl, etc.; R6 is hydrogen or substituted or unsubstituted C1-6 alkyl; the substituent is -C(=O)NH2; R7 is hydrogen or C1-6 alkyl; and R8 and R9 are hydrogen or unsubstituted C1-6 alkyl].SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a novel peptide and a pharmaceutical composition containing the same as an active pharmaceutical ingredient for treating ocular diseases. [Background technology]

[0002] Dry eye syndrome (DES) or keratoconjunctivitis sicca can be broadly defined as damage to the ocular surface due to impaired tear production (Joossen C et al., Exp. Eye Res., 146:172-178, 2016). Dry eye syndrome is known to be caused by a combination of various factors that result in impaired tear production and ocular damage and discomfort. The onset of dry eye syndrome is closely related to age, but its incidence is increasing among younger age groups due to long-term exposure to dry environments, such as the use of contact lenses, computers, and smart devices (Stern ME et al., Int. Rev. Immunol., 32:19-41, 2013).

[0003] Specifically, dry eye syndrome reduces mucus secretion from the corneal and conjunctival epithelium, as well as mucus secretion from mucus-secreting goblet cells, resulting in a dramatic decrease in ocular lubrication. Additionally, dry eye syndrome causes damage to the corneal surface, thereby increasing the penetration of fluorescein dye into the cornea. These symptoms of dry eye syndrome can be assessed as changes in tear secretion via the Schirmer test using cobalt chloride paper. Furthermore, corneal damage, which can accompany dry eye syndrome, can be easily assessed using common fluorescent dyes and a slit lamp fluorometer.

[0004] Meanwhile, most treatments for dry eye syndrome are limited to symptomatic treatments, which often have very low therapeutic efficacy. Currently, artificial tears are the first choice for treating dry eye syndrome. Because artificial tears, as a typical symptomatic treatment, only supplement insufficient tears, they also suffer from the disadvantage of needing frequent ocular administration (Kim CS et al., Nutrients 8. pii: E750, 2016). Autologous serum-derived sodium hyaluronate and eye drops have been developed and used in patients with dry eye syndrome. Additionally, synthetic compounds such as rebamipide (OPC-127959) and diquafosol sodium, which promote tear and mucus secretion, have been developed and used. However, long-term use of these drugs can cause various side effects, such as ocular hyperemia and corneal calcification (Bernauer W et al., Br. J. Ophthalmol., 90:285-288, 2006). Therefore, there is a need for the development of safe and effective therapeutic agents for treating dry eye syndrome. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, the present inventors have made efforts to develop a safe and effective therapeutic agent for treating eye diseases, and as a result, have completed the present invention by synthesizing new peptides, administering them to the eyes of rats with dry eye syndrome, and confirming the eye-protective effects through Schirmer's test and fluorescent dye deposition test. [Means for solving the problem]

[0006] To achieve the objectives of the present invention, one aspect of the present invention provides a compound represented by Formula 1:

[0007] Furthermore, another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys.

[0008] Additionally, another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys-

[0009] Furthermore, another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa.

[0010] Additionally, another aspect of the present invention provides a peptide having the amino acid sequence represented by PD-Glu-Gly-Gln-Leu-Glu-Leu-Ala-Gly-Pro-Lys.

[0011] Further, another aspect of the present invention is directed to amino acids selected from the group consisting of Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys, HyP-Gly-Gln-Leu-Gly-Leu-Ala, HyP-Gly-Gln-Glu-Gly-Leu-Gly, HyP-Gly-Gln-Leu-Gly-Leu, D- HyP(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu, HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln- D- Leu-Gly, and D- The present invention provides a peptide having any one amino acid sequence selected from the group consisting of HyP(2R,4S)-Gly-Gln-Leu-Gly.

[0012] Additionally, another aspect of the present invention provides a compound represented by formula 8:

[0013] Yet another aspect of the present invention provides a compound represented by formula 10:

[0014] Additionally, another aspect of the present invention provides a pharmaceutical composition for treating an ocular disease, comprising a compound or peptide as an active pharmaceutical ingredient.

[0015] Furthermore, another aspect of the present invention provides a method of treating an eye disease, comprising administering a compound or peptide to a subject. [Effects of the Invention]

[0016] When the novel peptides of the present invention are administered to the eye, they increase the amount of tear secretion and promote the recovery of damaged corneas, and therefore can be advantageously used as therapeutic agents for treating eye diseases. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows the sequences and characteristics of peptides prepared according to embodiments of the present invention. [Figure 2] FIG. 1 illustrates a process for synthesizing peptides prepared in accordance with embodiments of the present invention. [Figure 3] FIG. 1 shows a purification procedure for peptides prepared according to an embodiment of the present invention. [Figure 4] FIG. 1 confirms the purity of YDE-001 prepared according to an embodiment of the present invention via HPLC. [Figure 5] FIG. 1 confirms the purity of YDE-002 prepared according to an embodiment of the present invention via HPLC. [Figure 6] FIG. 1 confirms the purity of YDE-003 prepared according to an embodiment of the present invention via HPLC. [Figure 7] FIG. 1 confirms the purity of YDE-004 prepared according to an embodiment of the present invention via HPLC. [Figure 8] FIG. 1 confirms the purity of YDE-005 prepared according to an embodiment of the present invention via HPLC. [Figure 9] FIG. 1 confirms the purity of YDE-006 prepared according to an embodiment of the present invention via HPLC. [Figure 10] FIG. 1 confirms the purity of YDE-007 prepared according to an embodiment of the present invention via HPLC. [Figure 11] FIG. 1 confirms the purity of YDE-008 prepared according to an embodiment of the present invention via HPLC. [Figure 12] FIG. 1 confirms the purity of YDE-009 prepared according to an embodiment of the present invention via HPLC. [Figure 13] FIG. 1 confirms the purity of YDE-010 prepared according to an embodiment of the present invention via HPLC. [Figure 14] FIG. 1 confirms the purity of YDE-011 prepared according to an embodiment of the present invention via HPLC. [Figure 15] FIG. 1 confirms the purity of YDE-012 prepared according to an embodiment of the present invention via HPLC. [Figure 16] FIG. 1 confirms the purity of YDE-013 prepared according to an embodiment of the present invention via HPLC. [Figure 17] FIG. 1 confirms the purity of YDE-014 prepared according to an embodiment of the present invention via HPLC. [Figure 18] FIG. 1 confirms the purity of YDE-015 prepared according to an embodiment of the present invention via HPLC. [Figure 19] FIG. 1 confirms the purity of YDE-016 prepared according to an embodiment of the present invention via HPLC. [Figure 20] FIG. 1 confirms the purity of YDE-017 prepared according to an embodiment of the present invention via HPLC. [Figure 21] FIG. 1 confirms the purity of YDE-018 prepared according to an embodiment of the present invention via HPLC. [Figure 22] FIG. 1 confirms the purity of YDE-019 prepared according to an embodiment of the present invention via HPLC. [Figure 23]FIG. 1 confirms the purity of YDE-020 prepared according to an embodiment of the present invention via HPLC. [Figure 24] FIG. 1 confirms the purity of YDE-021 prepared according to an embodiment of the present invention via HPLC. [Figure 25] FIG. 1 confirms the purity of YDE-022 prepared according to an embodiment of the present invention via HPLC. [Figure 26] FIG. 1 confirms the purity of YDE-023 prepared according to an embodiment of the present invention via HPLC. [Figure 27] FIG. 1 confirms the purity of YDE-024 prepared according to an embodiment of the present invention via HPLC. [Figure 28] FIG. 1 confirms the purity of YDE-025 prepared according to an embodiment of the present invention via HPLC. [Figure 29] FIG. 1 confirms the purity of YDE-026 prepared according to an embodiment of the present invention via HPLC. [Figure 30] FIG. 1 confirms the purity of YDE-027 prepared according to an embodiment of the present invention via HPLC. [Figure 31] FIG. 1 confirms the purity of YDE-028 prepared according to an embodiment of the present invention via HPLC. [Figure 32] FIG. 1 confirms the purity of YDE-029 prepared according to an embodiment of the present invention via HPLC. [Figure 33] FIG. 1 confirms the purity of YDE-030 prepared according to an embodiment of the present invention via HPLC. [Figure 34] FIG. 1 confirms the purity of YDE-031 prepared according to an embodiment of the present invention via HPLC. [Figure 35] FIG. 1 confirms the purity of YDE-032 prepared according to an embodiment of the present invention via HPLC. [Figure 36] FIG. 1 confirms the purity of YDE-033 prepared according to an embodiment of the present invention via HPLC. [Figure 37] FIG. 1 confirms the purity of YDE-034 prepared according to an embodiment of the present invention via HPLC. [Figure 38] FIG. 1 confirms the purity of YDE-035 prepared according to an embodiment of the present invention via HPLC. [Figure 39] FIG. 1 confirms the purity of YDE-036 prepared according to an embodiment of the present invention via HPLC. [Figure 40] FIG. 1 confirms the purity of YDE-037 prepared according to an embodiment of the present invention via HPLC. [Figure 41] FIG. 1 confirms the purity of YDE-038 prepared according to an embodiment of the present invention via HPLC. [Figure 42] FIG. 1 confirms the purity of YDE-039 prepared according to an embodiment of the present invention via HPLC. [Figure 43] FIG. 1 confirms the purity of YDE-040 prepared according to an embodiment of the present invention via HPLC. [Figure 44] FIG. 1 confirms the purity of YDE-041 prepared according to an embodiment of the present invention via HPLC. [Figure 45] FIG. 1 confirms the purity of YDE-042 prepared according to an embodiment of the present invention via HPLC. [Figure 46] FIG. 1 confirms the purity of YDE-043 prepared according to an embodiment of the present invention via HPLC. [Figure 47] FIG. 1 confirms the purity of YDE-044 prepared according to an embodiment of the present invention via HPLC. [Figure 48] FIG. 1 confirms the purity of YDE-045 prepared according to an embodiment of the present invention via HPLC. [Figure 49] FIG. 1 confirms the purity of YDE-047 prepared according to an embodiment of the present invention via HPLC. [Figure 50] FIG. 1 confirms the purity of YDE-048 prepared according to an embodiment of the present invention via HPLC. [Figure 51] FIG. 1 confirms the purity of YDE-049 prepared according to an embodiment of the present invention via HPLC. [Figure 52] FIG. 1 confirms the purity of YDE-050 prepared according to an embodiment of the present invention via HPLC. [Figure 53] FIG. 1 confirms the purity of YDE-051 prepared according to an embodiment of the present invention via HPLC. [Figure 54] FIG. 1 confirms the purity of YDE-052 prepared according to an embodiment of the present invention via HPLC. [Figure 55] FIG. 1 confirms the purity of YDE-053 prepared according to an embodiment of the present invention via HPLC. [Figure 56] FIG. 1 confirms the purity of YDE-054 prepared according to an embodiment of the present invention via HPLC. [Figure 57] FIG. 1 confirms the purity of YDE-055 prepared according to an embodiment of the present invention via HPLC. [Figure 58] FIG. 1 confirms the purity of YDE-056 prepared according to an embodiment of the present invention via HPLC. [Figure 59] FIG. 1 confirms the purity of YDE-057 prepared according to an embodiment of the present invention via HPLC. [Figure 60] FIG. 1 confirms the purity of YDE-058 prepared according to an embodiment of the present invention via HPLC. [Figure 61] FIG. 1 confirms the purity of YDE-059 prepared according to an embodiment of the present invention via HPLC. [Figure 62] FIG. 1 confirms the purity of YDE-060 prepared according to an embodiment of the present invention via HPLC. [Figure 63] FIG. 1 confirms the purity of YDE-064 prepared according to an embodiment of the present invention via HPLC. [Figure 64]FIG. 1 confirms the purity of YDE-066 prepared according to an embodiment of the present invention via HPLC. [Figure 65] FIG. 1 confirms the purity of YDE-072 prepared according to an embodiment of the present invention via HPLC. [Figure 66] FIG. 1 confirms the purity of YDE-073 prepared according to an embodiment of the present invention via HPLC. [Figure 67] FIG. 1 confirms the purity of YDE-074 prepared according to an embodiment of the present invention via HPLC. [Figure 68] FIG. 1 confirms the purity of YDE-075 prepared according to an embodiment of the present invention via HPLC. [Figure 69] FIG. 1 confirms the molecular weight of YDE-001 prepared according to an embodiment of the present invention via ion-mass. [Figure 70] FIG. 1 confirms the molecular weight of YDE-002 prepared according to an embodiment of the present invention via ion-mass. [Figure 71] FIG. 1 confirms the molecular weight of YDE-003 prepared according to an embodiment of the present invention via ion-mass. [Figure 72] FIG. 1 confirms the molecular weight of YDE-004 prepared according to an embodiment of the present invention via ion-mass. [Figure 73] FIG. 1 confirms the molecular weight of YDE-005 prepared according to an embodiment of the present invention via ion-mass. [Figure 74] FIG. 1 confirms the molecular weight of YDE-006 prepared according to an embodiment of the present invention via ion-mass. [Figure 75] FIG. 1 confirms the molecular weight of YDE-007 prepared according to an embodiment of the present invention via ion-mass. [Figure 76] FIG. 1 confirms the molecular weight of YDE-008 prepared according to an embodiment of the present invention via ion-mass. [Figure 77]FIG. 1 confirms the molecular weight of YDE-009 prepared according to an embodiment of the present invention via ion-mass. [Figure 78] FIG. 1 confirms the molecular weight of YDE-010 prepared according to an embodiment of the present invention via ion-mass. [Figure 79] FIG. 1 confirms the molecular weight of YDE-011 prepared according to an embodiment of the present invention via ion-mass. [Figure 80] FIG. 1 confirms the molecular weight of YDE-012 prepared according to an embodiment of the present invention via ion-mass. [Figure 81] FIG. 1 confirms the molecular weight of YDE-013 prepared according to an embodiment of the present invention via ion-mass. [Figure 82] FIG. 1 confirms the molecular weight of YDE-014 prepared according to an embodiment of the present invention via ion-mass. [Figure 83] FIG. 1 confirms the molecular weight of YDE-015 prepared according to an embodiment of the present invention via ion-mass. [Figure 84] FIG. 1 confirms the molecular weight of YDE-016 prepared according to an embodiment of the present invention via ion-mass. [Figure 85] FIG. 1 confirms the molecular weight of YDE-017 prepared according to an embodiment of the present invention via ion-mass. [Figure 86] FIG. 1 confirms the molecular weight of YDE-018 prepared according to an embodiment of the present invention via ion-mass. [Figure 87] FIG. 1 confirms the molecular weight of YDE-019 prepared according to an embodiment of the present invention via ion-mass. [Figure 88] FIG. 1 confirms the molecular weight of YDE-020 prepared according to an embodiment of the present invention via ion-mass. [Figure 89] FIG. 1 confirms the molecular weight of YDE-021 prepared according to an embodiment of the present invention via ion-mass. [Figure 90]FIG. 1 confirms the molecular weight of YDE-022 prepared according to an embodiment of the present invention via ion-mass. [Figure 91] FIG. 1 confirms the molecular weight of YDE-023 prepared according to an embodiment of the present invention via ion-mass. [Figure 92] FIG. 1 confirms the molecular weight of YDE-024 prepared according to an embodiment of the present invention via ion-mass. [Figure 93] FIG. 1 confirms the molecular weight of YDE-025 prepared according to an embodiment of the present invention via ion-mass. [Figure 94] FIG. 1 confirms the molecular weight of YDE-026 prepared according to an embodiment of the present invention via ion-mass. [Figure 95] FIG. 1 confirms the molecular weight of YDE-027 prepared according to an embodiment of the present invention via ion-mass. [Figure 96] FIG. 1 confirms the molecular weight of YDE-028 prepared according to an embodiment of the present invention via ion-mass. [Figure 97] FIG. 1 confirms the molecular weight of YDE-029 prepared according to an embodiment of the present invention via ion-mass. [Figure 98] FIG. 1 confirms the molecular weight of YDE-030 prepared according to an embodiment of the present invention via ion-mass. [Figure 99] FIG. 1 confirms the molecular weight of YDE-031 prepared according to an embodiment of the present invention via ion-mass. [Figure 100] FIG. 1 confirms the molecular weight of YDE-032 prepared according to an embodiment of the present invention via ion-mass. [Figure 101] FIG. 1 confirms the molecular weight of YDE-033 prepared according to an embodiment of the present invention via ion-mass. [Figure 102] FIG. 1 confirms the molecular weight of YDE-034 prepared according to an embodiment of the present invention via ion-mass. [Figure 103]FIG. 1 confirms the molecular weight of YDE-035 prepared according to an embodiment of the present invention via ion-mass. [Figure 104] FIG. 1 confirms the molecular weight of YDE-036 prepared according to an embodiment of the present invention via ion-mass. [Figure 105] FIG. 1 confirms the molecular weight of YDE-037 prepared according to an embodiment of the present invention via ion-mass. [Figure 106] FIG. 1 confirms the molecular weight of YDE-038 prepared according to an embodiment of the present invention via ion-mass. [Figure 107] FIG. 1 confirms the molecular weight of YDE-039 prepared according to an embodiment of the present invention via ion-mass. [Figure 108] FIG. 1 confirms the molecular weight of YDE-040 prepared according to an embodiment of the present invention via ion-mass. [Figure 109] FIG. 1 confirms the molecular weight of YDE-041 prepared according to an embodiment of the present invention via ion-mass. [Figure 110] FIG. 1 confirms the molecular weight of YDE-042 prepared according to an embodiment of the present invention via ion-mass. [Figure 111] FIG. 1 confirms the molecular weight of YDE-043 prepared according to an embodiment of the present invention via ion-mass. [Figure 112] FIG. 1 confirms the molecular weight of YDE-044 prepared according to an embodiment of the present invention via ion-mass. [Figure 113] FIG. 1 confirms the molecular weight of YDE-045 prepared according to an embodiment of the present invention via ion-mass. [Figure 114] FIG. 1 confirms the molecular weight of YDE-047 prepared according to an embodiment of the present invention via ion-mass. [Figure 115] FIG. 1 confirms the molecular weight of YDE-048 prepared according to an embodiment of the present invention via ion-mass. [Figure 116]FIG. 1 confirms the molecular weight of YDE-049 prepared according to an embodiment of the present invention via ion-mass. [Figure 117] FIG. 1 confirms the molecular weight of YDE-050 prepared according to an embodiment of the present invention via ion-mass. [Figure 118] FIG. 1 confirms the molecular weight of YDE-051 prepared according to an embodiment of the present invention via ion-mass. [Figure 119] FIG. 1 confirms the molecular weight of YDE-052 prepared according to an embodiment of the present invention via ion-mass. [Figure 120] FIG. 1 confirms the molecular weight of YDE-053 prepared according to an embodiment of the present invention via ion-mass. [Figure 121] FIG. 1 confirms the molecular weight of YDE-054 prepared according to an embodiment of the present invention via ion-mass. [Figure 122] FIG. 1 confirms the molecular weight of YDE-055 prepared according to an embodiment of the present invention via ion-mass. [Figure 123] FIG. 1 confirms the molecular weight of YDE-056 prepared according to an embodiment of the present invention via ion-mass. [Figure 124] FIG. 1 confirms the molecular weight of YDE-057 prepared according to an embodiment of the present invention via ion-mass. [Figure 125] FIG. 1 confirms the molecular weight of YDE-058 prepared according to an embodiment of the present invention via ion-mass. [Figure 126] FIG. 1 confirms the molecular weight of YDE-059 prepared according to an embodiment of the present invention via ion-mass. [Figure 127] FIG. 1 confirms the molecular weight of YDE-060 prepared according to an embodiment of the present invention via ion-mass. [Figure 128] FIG. 1 confirms the molecular weight of YDE-064 prepared according to an embodiment of the present invention via ion-mass. [Figure 129]FIG. 1 confirms the molecular weight of YDE-066 prepared according to an embodiment of the present invention via ion-mass. [Figure 130] FIG. 1 confirms the molecular weight of YDE-072 prepared according to an embodiment of the present invention via ion-mass. [Figure 131] FIG. 1 confirms the molecular weight of YDE-073 prepared according to an embodiment of the present invention via ion-mass. [Figure 132] FIG. 1 confirms the molecular weight of YDE-074 prepared according to an embodiment of the present invention via ion-mass. [Figure 133] FIG. 1 confirms the molecular weight of YDE-075 prepared according to an embodiment of the present invention via ion-mass. [Figure 134] Photographs showing the procedure for extraorbital lacrimal gland resection. [Figure 135] FIG. 1 shows changes in body weight in rat models administered YDE-001 to YDE-028 into the eye. [Figure 136] FIG. 1 shows changes in body weight in rat models administered YDE-029 to YDE-043 into the eye. [Figure 137] 1 is a photograph showing the procedure for administering a drug to the eye of a rat model. [Figure 138] 1 shows photographs illustrating the procedure for measuring the amount of tear secretion in a rat model using cobalt chloride paper. [Figure 139] 1 shows photographs showing the results of measuring the amount of tear secretion using cobalt chloride paper in rat models administered YDE-001 to YDE-028 to the eyes. [Figure 140] FIG. 1 shows changes in tear secretion in rat models administered YDE-001 to YDE-028 to the eyes. [Figure 141] 1 shows photographs showing the results of measuring the amount of tear secretion using cobalt chloride paper in rat models administered YDE-029 to YDE-043 into the eyes. [Figure 142] FIG. 1 shows changes in tear secretion in rat models administered YDE-029 to YDE-043 into the eyes. [Figure 143] Photographs showing the procedure for administering a fluorescent substance to the eye of a rat model and confirming the resulting damage to the cornea. [Figure 144] 1 is a set of photographs showing the results of measuring, using a fluorescent substance, damage to the cornea of ​​rat models to which YDE-001 to YDE-028 were administered to the eyes. [Figure 145] FIG. 1 shows the penetration of fluorescent dyes to confirm recovery from corneal injury in rat models administered YDE-001 to YDE-028 into the eyes. [Figure 146] Photographs showing the results of measuring, using a fluorescent substance, damage to the cornea of ​​rat models administered YDE-029 to YDE-043 into the eyes. [Figure 147] FIG. 1 shows the penetration of fluorescent dyes to confirm recovery from corneal injury in rat models administered YDE-029 to YDE-043 into the eyes. [Figure 148] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells of plate No. 1. [Figure 149] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells in plate No. 2. [Figure 150] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells in plate No. 3. [Figure 151] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells in plate No. 4. [Figure 152] FIG. 1 shows the cell growth rate 72 hours after treatment with hEGF on human corneal epithelial cells in plate No. 1. [Figure 153] FIG. 1 shows the cell growth rate 72 hours after treatment with hEGF on human corneal epithelial cells in plate No. 2. [Fig. 154] FIG. 1 shows the cell growth rate 72 hours after treatment with hEGF on human corneal epithelial cells in plate No. 3. [Figure 155] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells in plate No. 4. [Figure 156] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YY-101 on human corneal epithelial cells. [Figure 157] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YY-102 on human corneal epithelial cells. [Figure 158] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-011 on human corneal epithelial cells. [Figure 159] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-038 on human corneal epithelial cells. [Figure 160] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-042 on human corneal epithelial cells. [Figure 161] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-043 on human corneal epithelial cells. [Figure 162] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-044 on human corneal epithelial cells. [Figure 163] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-045 on human corneal epithelial cells. [Fig. 164] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-049 on human corneal epithelial cells. [Figure 165] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-054 on human corneal epithelial cells. [Figure 166] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-057 on human corneal epithelial cells. [Figure 167] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-058 on human corneal epithelial cells. [Figure 168]FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-059 on human corneal epithelial cells. [Figure 169] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-060 on human corneal epithelial cells. [Figure 170] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-072 on human corneal epithelial cells. [Figure 171] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-073 on human corneal epithelial cells. [Fig. 172] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-074 on human corneal epithelial cells. [Figure 173] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-075 on human corneal epithelial cells. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention will be described in detail below.

[0019] One aspect of the present invention provides compounds represented by Formula 1:

[0020] [ka]

[0021] In the above formula, R 1 ~R 3 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~10 Alkoxy, substituted or unsubstituted C 1~10 Haloalkyl, substituted or unsubstituted C 2~10 Alkenyl, substituted or unsubstituted C 2~10 Alkynyl, substituted or unsubstituted C 1~10Alkylene, substituted or unsubstituted C 1~10 Alkenylene, substituted or unsubstituted C 1~10 Alkynylene, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 Arylalkyl, substituted or unsubstituted C 5~14 Arylalkynyl, substituted or unsubstituted C 8~16 Arylalkenyl, substituted or unsubstituted C 3~10 Heteroalkyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl or substituted or unsubstituted C 5~12 heteroaryl, wherein said heteroalkyl, heterocycloalkyl, or heteroaryl contains at least one of N, O, and S; Substitution refers to substitution with one or more non-hydrogen substituents, each non-hydrogen substituent being -X, -R a , -O - , =O, -OR a , -SR a , -S - , -N(R a )2, -N + (R a )3, =NR a , -C(X1)3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N-OH, =N2, -N3, -NHC(=O)R a , -C(=O)R a , -C(=O)NR a R a , -S(=O)2O - , -S(=O)2OH, -S(=O)2R a , -OS(=O)2OR a , -S(=O)2NR a , -S(=O)R a ,-OP(=O)(OR a )2, -C(=O)R a , alkylene-C(=O)R a , -C(=S)R a , -C(=O)OR a , alkylene-C(=O)OR a , -C(=O)O- , alkylene -C(=O)O-, -C(=S)OR a , -C(=O)SR a , -C(=S)SR a , -C(=O)NR a R a , alkylene-C(=O)NR a R a , -C(=S)NR a R a and -C(-NR a )NR a R a each X is independently selected from F, Cl, Br, or I; and each R a is hydrogen, C 1~6 Alkyl, C 5~12 Aryl, C 7~12 aryl, alkyl, or heterocycle; R 4 and R 5 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, -X2, -R b , -O - , =O, -CH2OR b -OR b X2 is F, Cl, Br or I, and R b is H, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 arylalkyl, or a substituted or unsubstituted heterocycle; R 6 is hydrogen or substituted or unsubstituted C 1~6 alkyl, the substituent is -C(=O)NH2, R 7 is hydrogen or C 1~6 is alkyl, R 8 and R 9 are each independently hydrogen or unsubstituted C 1~6 It is alkyl.

[0022] R b In the definition of substituted refers to substitution with a non-hydrogen substituent.

[0023] According to the convention used in the art, in the formulas herein

[0024] [ka] is used to indicate a bond where a moiety or substituent is attached to a core or backbone structure.

[0025] An "alkyl" is a hydrocarbon having primary, secondary, tertiary, and / or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1 to C6). 20 alkyl), 1 to 10 carbon atoms (i.e., C1 to C 10alkyl), or 1 to 6 carbon atoms (i.e., C1 to C6 alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3) CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH (CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl Examples include, but are not limited to, 2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3).

[0026] "Alkoxy" refers to a group having the formula -O-alkyl, where an alkyl group, as defined above, is attached to the parent compound through an oxygen atom. The alkyl portion of the alkoxy group contains 1 to 20 carbon atoms (i.e., C1 to C6). 20alkoxy), 1 to 12 carbon atoms (i.e., C1 to C 12 The alkoxy group may have 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -O-tBu).

[0027] A "haloalkyl" is an alkyl group, as defined above, in which at least one of the alkyl group's hydrogen atoms is replaced by a halogen atom. The alkyl portion of a haloalkyl group has 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 haloalkyl), or 1 to 6 carbon atoms (i.e., C1-C6 haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, and -CH2CF3.

[0028] "Alkenyl" refers to an alkyl group having primary, secondary, tertiary and / or cyclic carbon atoms and at least one area of ​​unsaturation, i.e., carbon-carbon sp 2 It is a hydrocarbon having a double bond. For example, an alkenyl group is a group having 2 to 20 carbon atoms (i.e., C2 to C6 20 alkenyl), 2 to 12 carbon atoms (i.e., C2 to C 12 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0029] An "alkynyl" is a hydrocarbon having primary, secondary, tertiary, and / or cyclic carbon atoms and at least two sites of unsaturation, i.e., one carbon-carbon sp triple bond. For example, an alkynyl group can be 2 to 20 carbon atoms (i.e., C2 to C6). 20 alkynyl), 2 to 12 carbon atoms (i.e., C2 to C 12 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkenyl groups include, but are not limited to, acetylene (-C≡CH) and propargyl (-CH2C≡CH).

[0030] "Alkylene" refers to a saturated hydrocarbon group, which may be branched, straight-chained, or cyclic, and has two valencies derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH-), 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCHCH-), and 1,4-butylene (-CHCHCHCHCH-).

[0031] "Alkenylene" refers to an unsaturated hydrocarbon group, which may be branched, straight-chain, and / or cyclic, and which has two valencies derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkene. For example, an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkenylene groups include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0032] "Alkynylene" refers to an unsaturated hydrocarbon group, branched, straight-chain, and / or cyclic, having two valencies derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkynylene groups include, but are not limited to, acetylenylene (-C≡C-), propargylene (-CHC≡C-), and 4-pentynylene (-CHCHCHC≡C-).

[0033] "Aryl" refers to an aromatic hydrocarbon group derived by the removal of one hydrogen atom from six carbon atoms of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, and substituted or unsubstituted biphenyl.

[0034] "Arylalkyl" refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, typically a terminal or other sp3 carbon atom, is replaced by an aryl group. Typical examples of arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl, each of which is substituted or unsubstituted. The arylalkyl group can have 7 to 20 carbon atoms. For example, the alkyl portion can have 1 to 6 carbon atoms, and the aryl portion can have 6 to 14 carbon atoms.

[0035] "Arylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom although sp2 carbon atoms are available, is replaced with an aryl group. The aryl portion of the arylalkenyl can be, for example, any aryl group described herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups described herein. An arylalkenyl group can have 8 to 20 carbon atoms. For example, the alkenyl portion can have 2 to 6 carbon atoms, and the aryl portion can have 6 to 14 carbon atoms.

[0036] "Cycloalkyl" refers to a saturated monocyclic or polycyclic ring containing only carbon atoms in the ring. Cycloalkyl groups can have 3 to 7 carbon atoms as monocyclic rings, 7 to 12 carbon atoms as bicycles, and up to about 20 carbon atoms as bicycles. Monocyclic cycloalkyls have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls can have 7 to 12 ring atoms arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 to 10 ring atoms arranged in a bicyclo[5,6] or [6,6] system or in a spiro-fused ring. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which can be substituted or unsubstituted.

[0037] "Arylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp3 carbon atom, is replaced with an aryl group, although sp3 carbon atoms can also be used. The aryl portion of the arylalkynyl can be, for example, any aryl group described herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups described herein. The arylalkynyl group can have 8 to 20 carbon atoms. For example, the alkynyl portion can have 2 to 6 carbon atoms, and the aryl portion can have 6 to 14 carbon atoms.

[0038] The term "substituted" with respect to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, etc., e.g., "substituted alkyl," "substituted alkylene," "substituted aryl," "substituted arylalkyl," "substituted heterocyclyl," and "substituted carbocyclyl (e.g., substituted cycloalkyl)" means that at least one hydrogen atom of the alkyl, alkylene, aryl, arylalkyl, heterocyclyl, or carbocyclyl (e.g., cycloalkyl) is each independently replaced with a non-hydrogen substituent. Exemplary substituents include -X, -R, -O, ... - , =O, -OR, -SR, -S - , -NR2, -N + R3, =NR, -C(X)3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N-OH, =N2, -N3, -NHC(=O)R, -C(=O)R, -C(=O)NRR, -S(=O)2O - , -S(=O)2OH, -S(=O)2R, -OS(=O)2OR, -S(=O)2NR, -S(=O)R, -OP(=O)(OR)2, -C(=O)R, alkylene-C(=O)R, -C(S)R, -C(=O)OR, alkylene-C(=O)OR, -C(=O)O -, alkylene-C(=O)O-, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, alkylene-C(=O)NRR, -C(=S)NRR, and -C(-NR)NRR, where each X is independently a halogen such as F, Cl, Br, or I, and R is independently H, alkyl, aryl, arylalkyl, or heterocycle, but is not limited to these. Alkylene, alkenylene, and alkynylene groups may be similarly substituted.

[0039] Those skilled in the art will understand that when moieties such as "alkyl," "aryl," and "heterocyclyl" are substituted with at least one substituent, they can be optionally referred to as "alkylene," "arylene," or "heterocyclylene," etc. (i.e., at least one hydrogen atom of the parent "alkyl," "aryl," or "heterocyclyl" moiety is replaced with a substituent as described herein). If an "alkyl," "aryl," or "heterocyclyl," etc. moiety is described herein or depicted in the drawings as being "substituted" (or is optionally substituted, e.g., the number of substituents is zero or a positive number), then the term "alkyl," "aryl," or "heterocyclyl," etc. should be understood to be interchangeable with "alkylene," "arylene," or "heterocyclylene," etc.

[0040] Those skilled in the art will recognize that the substituents and other moieties of compounds of Formula 1 should be selected to provide compounds that are sufficiently stable as pharmaceutically useful compounds that they can be formulated into acceptably stable pharmaceutical compositions. Compounds of Formula 1 that have such stability should be understood to fall within the scope of the present invention.

[0041] "Heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom such as O, N, or S. For example, if a carbon atom of an alkyl group that is attached to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group can be an alkoxy group (e.g., -OCH), an amine group (e.g., -NHCH or -N(CH)), or a thioalkyl group (e.g., -SCH), respectively. If a non-terminal carbon atom of an alkyl group that is not attached to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group can be an alkyl ether (e.g., -CHCH-O-CH), an alkylamine (e.g., -CHNHCH or -CHN(CH)), or a thioalkyl ether (e.g., -CH-S-CH), respectively. If the terminal carbon atom of an alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group can be a hydroxyalkyl group (e.g., -CHCH-OH), an aminoalkyl group (e.g., -CHNH), or an alkylthiol group (e.g., -CHCH-SH), respectively. For example, the heteroalkyl group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C1-C6 heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms.

[0042] The terms "heterocycle" or "heterocyclyl" as used herein include, but are not limited to, those described in such references as Paquette, Leo A., Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In certain embodiments of the present invention, "heterocycle" includes a "carbocycle," as defined herein, in which at least one (e.g., 1, 2, 3, or 4) carbon atom is replaced by a heteroatom (e.g., O, N, or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocycles include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, a carbonyl group.

[0043] Examples of heterocycles include pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-phenylpropanol ... -pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl , pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phtheridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, Examples include, but are not limited to, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isothiinoyl, and bis-tetrahydrofuranyl, each of which may be substituted or unsubstituted.

[0044] By way of example, the carbon-bonded heterocycle may be bonded at the 2, 3, 4, 5 or 6 position of pyrazine, at the 3, 4, 5 or 6 position of pyridazine, at the 2, 4, 5 or 6 position of pyrimidine, at the 2, 3, 5 or 6 position of pyrazine, at the 2, 3, 4 or 5 position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, at the 2, 4 or 5 position of oxazole, imidazole or thiazole, at the 3, 4 or 5 position of isoxazole, pyrazole or isothiazole, at the 2 or 3 position of aziridine, at the 2, 3 or 4 position of azetidine, at the 2, 3, 4, 5, 6, 7 or 8 position of quinoline, or at the 1, 3, 4, 5, 6, 7 or 8 position of isoquinoline, but this is not limited thereto. More typically, examples of carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, each of which may be substituted or unsubstituted.

[0045] By way of example, nitrogen-bonded heterocycles may be bonded at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or 1H-indazole, at the 2-position of isoindole or isoindoline, at the 4-position of morpholine, and at the 9-position of carbazole or β-carboline (each of which may be substituted or unsubstituted), but this is not limited thereto. More typically, examples of nitrogen-bonded heterocycles include 1-aziridinyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl (each of which may be substituted or unsubstituted).

[0046] "Heterocyclylalkyl" refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkylene moiety). Typical examples of heterocyclylalkyl groups include, but are not limited to, heterocyclyl-CH2- and 2-(heterocyclyl)ethan-1-yl. As used herein, the "heterocyclyl" moiety includes those described in references such as "Principles of Modern Heterocyclic Chemistry" and any of the heterocyclyl groups described above. Those skilled in the art will understand that a heterocyclyl group can be attached to the alkyl portion of a heterocyclylalkyl via a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. A heterocyclylalkyl group can have 2 to 20 carbon atoms. For example, the alkyl portion of a heterocyclylalkyl group can have 1 to 6 carbon atoms, and the heterocyclyl portion can have 1 to 14 carbon atoms. Examples of heterocyclylalkyl include, but are not limited to, 5-membered heterocycles containing sulfur, oxygen, and / or nitrogen, such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, and thiadiazolylmethyl; and 6-membered heterocycles containing sulfur, oxygen, and / or nitrogen, such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridazylmethyl, pyrimidylmethyl, and pyrazinylmethyl, each of which may be substituted or unsubstituted.

[0047] "Heterocyclylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom (although sp carbon atoms can also be used), is replaced with a heterocyclyl group (i.e., a heterocyclyl-alkenylene moiety). The heterocyclyl portion of the heterocyclylalkenyl group includes those described in references such as "Principles of Modern Heterocyclic Chemistry" and any of the heterocyclyl groups described herein. The alkenyl portion of the heterocyclylalkenyl group includes any of the alkenyl groups described herein. Those skilled in the art will recognize that a heterocyclyl group can be attached to the alkenyl portion of a heterocyclylalkenyl via a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. The heterocyclylalkenyl group can have from 3 to 20 carbon atoms. For example, the alkenyl portion of a heterocyclylalkenyl group can have from 2 to 6 carbon atoms, and the heterocyclyl portion can have from 1 to 14 carbon atoms.

[0048] "Heterocyclylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom (although sp carbon atoms can be used), is replaced with a heterocyclyl group (i.e., a heterocyclyl-alkynylene moiety). The heterocyclyl portion of the heterocyclylalkynyl group includes those described in sources such as "Principles of Modern Heterocyclic Chemistry" and any of the heterocyclyl groups described herein. The alkynyl portion of the heterocyclylalkynyl group includes any of the alkynyl groups described herein. Those skilled in the art will recognize that a heterocyclyl group can be attached to the alkynyl portion of a heterocyclylalkynyl via a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. The heterocyclylalkynyl group can have 3 to 20 carbon atoms. For example, the alkynyl portion of a heterocyclylalkynyl group can have from 2 to 6 carbon atoms, and the heterocyclyl portion can have from 1 to 14 carbon atoms.

[0049] "Heteroaryl" refers to an aromatic heterocyclyl containing at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be contained in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all of those listed in the definition of "heterocyclyl" herein, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, and pyrazyl, each of which can be substituted or unsubstituted.

[0050] "Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic carbocycles can have 7 to 12 ring atoms arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 to 10 ring atoms arranged in a bicyclo[5,6] or [6,6] system. Examples of monocyclic or bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, and naphthyl, each of which may be substituted or unsubstituted.

[0051] "Acyl" refers to -C(=O)-alkyl, -C(=O)-carbocycle (which is substituted or unsubstituted), and -C(=O)-heterocycle (which is substituted or unsubstituted), where the alkyl, carbocycle, or heterocycle moieties are as defined herein. Non-limiting examples of "acyl" include -C(=O)CH, -C(=O)CHCH, -C(=O)CH(CH), -C(=O)C(CH), -C(=O)-phenyl (which is substituted or unsubstituted), -C(=O)-cyclopropyl (which is substituted or unsubstituted), -C(=O)-cyclobutyl (which is substituted or unsubstituted), -C(=O)-cyclopentyl (which is substituted or unsubstituted), -C(=O)-cyclohexyl (which is substituted or unsubstituted), and -C(=O)-pyridyl (which is substituted or unsubstituted).

[0052] "Arylheteroalkyl" refers to a heteroalkyl, as defined herein, in which a hydrogen atom (which may be bonded to either a carbon atom or a heteroatom) is replaced with an aryl group, as defined herein. The aryl group can be bonded to a carbon atom of the heteroalkyl group or to a heteroatom of the heteroalkyl group, provided the resulting group is chemically stable. For example, an arylheteroalkyl group can have a formula such as -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, or -alkylene-S-alkylene-aryl. In addition, any alkylene moiety in the above formula may be further substituted with any of the substituents defined or exemplified herein.

[0053] "Heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen atom is replaced by a heteroaryl group, as defined herein. Non-limiting examples of heteroarylalkyl include -CH-pyridinyl, -CH-pyrrolyl, -CH-oxazolyl, -CH-indolyl, -CH-isoindolyl, -CH-purinyl, -CH-furanyl, -CH-thienyl, -CH-benzofuranyl, -CH-benzothiophenyl, -CH-carbazolyl, -CH-imidazolyl, -CH-thiazolyl, -CH-isoxazolyl, -CH-pyrazolyl, -CH-isothiazolyl, -CH-quinolyl, -CH-isoquinolyl, -CH-pyridazyl, -CH-pyrimidyl, -CH-pyrazyl, -CH(CH)-pyridinyl, -CH(CH)-pyrrolyl, -CH(CH)- -oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-purinyl, -CH(CH3)-furanyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazyl, -CH(CH3)-pyrimidyl and -CH(CH3)-pyrazyl.

[0054] "Silyloxy" refers to the group -O-SiR, where R includes alkyl, aryl (which may be substituted or unsubstituted), heteroaryl (which may be substituted or unsubstituted), or a combination thereof. Non-limiting examples of silyloxy include -O-Si(CH), -O-Si(CH)tBu, -O-Si(tBu)CH, -O-Si(tBu), -O-Si(CH)Ph, -O-Si(Ph)CH, and -O-Si(Ph).

[0055] The term "optionally substituted" refers to certain moieties of a compound of Formula 1 that have one, two, or more substituents (eg, an optionally substituted aryl group).

[0056] The term "ester thereof" refers to any ester of a compound in which any -COOH functional group of the molecule is replaced with a -COOR functional group or any -OH functional group of the molecule is replaced with a -C(=O)OR functional group, where the R portion of the ester can be any carbon-containing group that forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof. Examples of esters can also include esters of "tautomeric enols," as described below, such as those described above.

[0057] In the present invention, the compound represented by the above formula 1 can be an optical isomer L-form or D-form.

[0058] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0059] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0060] [ka] and R 7 but

[0061] [ka] and R 8 is H and R 9is H. Furthermore, the compound represented by the following formula 1-1 may be an optical isomer L-form or D-form. [ka]

[0062] R 1 is a substituted or unsubstituted C 1~6 Alkyl,

[0063] [ka] JPEG0007775250000008.jpg29141, where n may be an integer from 1 to 10, but is not limited thereto. a is hydrogen or C 1~6 It may be alkyl.

[0064] Specifically, R 1 teeth,

[0065] [ka] It may be one selected from the group consisting of:

[0066] More specifically, the compound may be a compound set forth in Table 1 below.

[0067] [Table 1] JPEG0007775250000011.jpg245130JPEG0007775250000012.jpg243132JPEG0007775250000013.jpg223134

[0068] The compound represented by the above formula 1 is R 1 but

[0069] [ka] and R 3 but

[0070] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0071] [ka] and R 7 but

[0072] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-2. Furthermore, the compound represented by formula 1-2 below can be an optical isomer L-form or D-form.

[0073] [ka]

[0074] In addition, R 2 is hydrogen, substituted or unsubstituted C 1~6 Alkyl,

[0075] [ka] where n may be an integer from 1 to 10, but is not limited thereto. a is hydrogen or C 1~6 It may be alkyl.

[0076] Specifically, R 2 teeth,

[0077] [ka] More specifically, the compound may be a compound set forth in Table 2 below. [Table 2] JPEG0007775250000022.jpg104130

[0078] The compound represented by the above formula 1 is R 3 but

[0079] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0080] [ka] and R 7 but

[0081] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-3. Furthermore, the compounds represented by formula 1-3 below can be optical isomers L or D.

[0082] [ka]

[0083] R 1 is C 1~6 Specifically, R 1 teeth,

[0084] [ka] It may be.

[0085] R 2 is C 1~6 Specifically, R 2 teeth,

[0086] [ka] It may be.

[0087] More specifically, the compound may be a compound set forth in Table 3 below.

[0088] [Table 3]

[0089] The compound represented by the above formula 1 is R 1 but

[0090] [ka] and R 2 is H and R 4 is -OH and R 5 is H and R 6 but

[0091] [ka] and R 7 but

[0092] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-4. Furthermore, the compounds represented by formula 1-4 below can be optical isomers L or D.

[0093] [ka]

[0094] R 3 is a substituted or unsubstituted C 1~6 Alkyl,

[0095] [ka] where n may be an integer from 1 to 10, but is not limited thereto. a is hydrogen or C 1~6 It may be alkyl.

[0096] Specifically, R 3 teeth,

[0097] [ka] It may be one selected from the group consisting of:

[0098] More specifically, the compound may be a compound set forth in Table 4 below.

[0099] [Table 4] JPEG0007775250000037.jpg65135

[0100] The compound represented by the above formula 1 is R 1 but

[0101] [ka] and R 2 is H and R 3 but

[0102] [ka] and R 6 but

[0103] [ka] and R 7 but

[0104] [ka] and R 8 is H and R 9 When is H, it can be represented by formula 1-5. Furthermore, the compounds represented by formula 1-5 below can be optical isomers L or D.

[0105] [ka]

[0106] R 4 and R 5 are each independently a substituted or unsubstituted C 1~6 Alkyl, -OR b , =O, -CH2OR b and -X2, where X2 may independently be a halogen such as F, Cl, Br, or I. R b is hydrogen or C 1~6 It may be alkyl.

[0107] Specifically, R 4 are H, -OH, =O, -CH2OR b and F, in such an event, R 5 can be H. Furthermore, R 4 may be CH3, and in such an event, R 5 can be CH3.

[0108] More specifically, the compound may be a compound set forth in Table 5 below.

[0109] [Table 5] JPEG0007775250000044.jpg72133

[0110] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0111] [ka] and R 4 is -OH and R 5 is H and R 7 but

[0112] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-6. Furthermore, the compounds represented by formula 1-6 below can be optical isomers L or D.

[0113] [ka]

[0114] R 1 is C 1~6 Specifically, R 1 teeth,

[0115] [ka] It may be.

[0116] R 6 is a substituted or unsubstituted C 1~6 alkyl, where the substituent may be -C(=O)NH2. Specifically, R 6 teeth,

[0117] [ka] It could be.

[0118] More specifically, the compound may be a compound set forth in Table 6 below.

[0119] [Table 6]

[0120] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0121] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0122] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-7. Furthermore, the compounds represented by formula 1-7 below can be optical isomers L or D.

[0123] [ka]

[0124] R 1 is C 1~6 Specifically, R 1 teeth,

[0125] [ka] It could be.

[0126] R 7 is the unsubstituted C 1~6 Specifically, R 7 teeth,

[0127] [ka] It could be JPEG0007775250000056.jpg1430.

[0128] More specifically, the compound can be a compound set forth in Table 7 below.

[0129] [Table 7]

[0130] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0131] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0132] [ka] and R 7 but

[0133] [ka] and R 9 When is H, it can be represented by formula 1-8. Furthermore, the compounds represented by formula 1-8 below can be optical isomers L or D.

[0134] [ka]

[0135] R 1 is C 1~6 Specifically, R 1 teeth,

[0136] [ka] It could be.

[0137] R 8 is hydrogen or C 1~6 Specifically, R 8 teeth,

[0138] [ka] It could be.

[0139] More specifically, the compound may be a compound set forth in Table 8 below.

[0140] [Table 8]

[0141] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0142] [ka] and R 4 is -OH and R 5 is H and R 6 but,

[0143] [ka] and R 7 but

[0144] [ka] and R 8 When is H, it can be represented by formula 1-9. Furthermore, the compounds represented by formula 1-9 below can be optical isomers L or D.

[0145] [ka]

[0146] R 1 is C 1~6 Specifically, R 1 teeth,

[0147] [ka] It could be.

[0148] R 9 is hydrogen or C 1~6 Specifically, R 9 teeth,

[0149] [ka] or

[0150] [ka] It could be.

[0151] More specifically, the compound may be a compound set forth in Table 9 below.

[0152] [Table 9]

[0153] The compound represented by the above formula 1 is R 2 is H and R4 is -OH and R 5 is H and R 6 but

[0154] [ka] and R 7 but

[0155] [ka] and R 8 When is H, it can be represented by formula 1-10. Furthermore, the compounds represented by formula 1-10 below can be optical isomers L or D.

[0156] [ka]

[0157] R 1 is C 1~6 Specifically, R 1 teeth,

[0158] [ka] It could be.

[0159] In such an event, R 3 is C 1~6 Specifically, R 3 teeth,

[0160] [ka] It could be.

[0161] In such an event, R 9 is C 1~6 Specifically, R 9 teeth,

[0162] [ka] It could be.

[0163] More specifically, the compound may be a compound set forth in Table 10 below.

[0164] [Table 10]

[0165] The compounds represented by the above formulas 1-1 to 1-10 include HyP-Gly-Gln-Glu-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asn-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Gln-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Gln-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-His-Gly-Leu-Ala-Gly-Pro -Lys, HyP-Gly-Gln-Lys-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ser-Gly-Leu-Ala-Gly-Pro-Lys, HyP- Gly-Gln-Thr-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ala-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Va l-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ile-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly-Leu -Ala-Gly-Pro-Lys, HyP-Gly-Gln-Phe-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Tyr-Gly-Leu-Ala-Gly-P ro-Lys, HyP-Gly-Gln-Trp-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ser (homo)-Gly-Leu-Ala-Gly-Pro-Ly s, HyP-Gly-Gln-Asp(Me)-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asn(Me)-Gly-Leu-Ala-Gly-Pro-Lys,D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、 D- Hyp(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu- D- Ala-Gly- D- Pro- D- Lys、 D- Hyp(2R,4R)-Gly- D- Gln- D- Leu-Gly- D- Leu- D- Ala-Gly- D- Pro- D- Lys、 HyP-Gly-Gln-Asp-Val-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ile-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Leu-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ala-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Phe-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Tyr-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Trp-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-His-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ser-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Thr-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Leu-Ala-Leu-Ala-Gly-Pro-Lys、 HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Tyr、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Leu、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Glu、HyP -Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Gln、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Nle(6-OH)、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 Hyp(2S,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、(4-オキソ)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、(5-オキソ)Pro- Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、(4-hydroxyMe)Pro-Gly-Gln-Leu-Gl γ-Leu-Ala-Gly-Pro-Lys、(4-フルオロ)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、(4-ジュュイ)Pro-Gly-Gln-Leu-Gly-Leu-Ala -Gly-Pro-Lys、(4-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、(5-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、 Hyp-Gly-Ala-Leu-Gly-Leu-Ala-Gly-Pro-Lys、Hyp-Gly-Gln-Leu-Gly-Ala-Ala-Gly-Pro-Lys、Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Ala-Pro-Lys、Hyp-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、 D- Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys D-It may be any one selected from the group consisting of Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala.

[0166] Another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys, wherein Xaa can be one selected from the group consisting of Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, Ile, Leu, Phe, Tyr, Trp, homoSer, Asp(Me) and Asn(Me).

[0167] The peptide may be a variant of collagen type II α1 derived peptide.Collagen type II α1 can be isolated from the extracellular matrix derived from animal chondrocytes.

[0168] The term "peptide" as used herein refers to a compound in which two or more amino acids are linked by peptide bonds. It is further classified into dipeptides, tripeptides, tetrapeptides, etc. according to the number of component amino acids. Oligopeptides have approximately 10 or fewer peptide bonds, while polypeptides have multiple peptide bonds. Additionally, peptides in the present invention include mutant peptides in which amino acid residues are substituted.

[0169] The term "HyP" as used herein refers to an amino acid called hydroxyproline, in which a hydroxyl group (-OH) is attached to the carbon atom at position 4 of the proline. HyP has the structure CHNO and can be represented by the following formula 2:

[0170] [ka]

[0171] HyP can include all isomers. In addition, HyP can be an isomer represented by the "2S,4R" stereochemistry unless otherwise specified.

[0172] The term "2S,4R" is represented by R and S, which indicate the stereochemical configuration of a chiral molecule. A typical chiral molecule has a chiral center, such as an asymmetric carbon atom. Because the chiral center has four different substituents (or substituted atoms), their priority is determined by a set procedure. Once the order of the four substituents is determined by (1), (2), (3), and (4), the lowest-order substituent (4) is placed farthest from the line of sight, and the remaining substituents are arranged from higher to lower order. R (or rectus in Latin, "right") indicates a configuration in which the sequence of (1), (2), and (3) rotates to the right. S (or sinister, "left") indicates a configuration in which this sequence rotates to the left.

[0173] The term "homoSer" as used herein refers to homoserine, an α-amino acid with a hydroxyl group in the side chain. HomoSer is not a proteinogenic amino acid, but is an intermediate in the biosynthesis of threonine and methionine in microorganisms and plants. HomoSer can have the following formula 3:

[0174] [ka]

[0175] The term "Asp(Me)" as used herein refers to an amino acid in which the hydrogen atom of the hydroxyl group (OH) attached to the carbon atom at position 4 of aspartic acid is replaced by a methyl group (CH). Asp(Me) can have the following formula 4:

[0176] [ka]

[0177] The term "Asn(Me)" as used herein refers to an amino acid in which the hydrogen atom of the amine group (NH) attached to the carbon atom at the 4-position of asparagine is replaced by a methyl group (CH). Asn(Me) can have the following formula 5:

[0178] [ka]

[0179] Additionally, another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys, wherein Xaa can be one selected from the group consisting of Val, Ile, Leu, Ala, Phe, Tyr, Trp, Ser, Thr and (N-Me)Gly.

[0180] The term "(N-Me)Gly" as used herein refers to an amino acid in which the hydrogen atom of the amine group (NH) attached to the carbon atom at the 2-position of glycine is replaced by a methyl group (CH). (N-Me)Gly can have the following formula 6:

[0181] [ka]

[0182] Another aspect of the present invention provides a peptide having the amino acid sequence HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa, wherein Xaa can be one selected from the group consisting of Tyr, Leu, Glu, Gln, Ala and Nle(6-OH).

[0183] The term "Nle(6-OH)" as used herein refers to an amino acid in which a hydroxyl group (-OH) is attached to the carbon atom at the 6-position of norleucine. Nle(6-OH) is a C5H 11NO3 and can be represented by the following formula 7:

[0184] [ka]

[0185] Another aspect of the present invention provides a peptide having an amino acid sequence represented by the formula: PD-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, wherein PD can be any one selected from the group consisting of the following formulae:

[0186] [ka]

[0187] Another aspect of the present invention is a method for the preparation of a nucleotide sequence comprising the amino acid sequence of Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys (SEQ ID NO: 54), Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys (SEQ ID NO: 55), HyP-Gly-Gln-Leu-Gly-Leu-Ala (SEQ ID NO: 56), HyP-Gly-Gln-Glu-Gly-Leu-Gly (SEQ ID NO: 57), HyP-Gly-Gln-Leu-Gly-Leu (SEQ ID NO: 58), D- HyP(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu (SEQ ID NO: 59), HyP-Gly-Gln-Leu-Gly (SEQ ID NO: 60), HyP-Gly-Gln- D- Leu-Gly (SEQ ID NO: 61), and D- The present invention provides a peptide having any one amino acid sequence selected from the group consisting of HyP(2R,4S)-Gly-Gln-Leu-Gly (SEQ ID NO: 62).

[0188] Another aspect of the present invention provides compounds represented by formula 8:

[0189] [ka]

[0190] The compound represented by the above formula 8 indicates a compound in which Asp is modified to aspartimide by a dehydration condensation reaction of the hydroxyl group (—OH) bound to the carbon atom at the 4-position of Asp in the amino acid sequence represented by HyP-Gly-Gln-Asp-Gly-Leu-Ala-Gly-Pro-Lys having an Asp-Gly peptide bond.

[0191] The modified compound may be a compound represented by formula 9 below:

[0192] [ka]

[0193] Another aspect of the present invention provides compounds represented by formula 10:

[0194] [ka]

[0195] The compound represented by formula 10 may be the compound represented by the amino acid sequence of SEQ ID NO:31.

[0196] Furthermore, the present invention provides pharmaceutical compositions for treating ocular diseases, comprising the compounds or peptides as active pharmaceutical ingredients.

[0197] Specifically, the eye disease may be one selected from the group consisting of retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, corneal and conjunctival epithelial disorder, proliferative vitreoretinopathy, pigmentary retinopathy, diabetic retinopathy, retinopathy of prematurity, retinopathy of immaturity, proliferative retinopathy, ischemic retinopathy, epidemic keratitis, atopic keratitis, superior limbal keratitis, pterygium keratitis sicca, phlyctenular keratoconjunctivitis, scleritis, corneal transplant rejection, choroidal neovascularization, neovascular glaucoma, ischemic optic neuropathy, retrolental fibroplasia, diabetic macula, neovascular iris disease, erythrochromia, myopia, von Hippel-Lindau syndrome, ocular histoplasmosis, central retinal vein occlusion, Sjogren's syndrome, and Stevens-Johnson syndrome. Preferably, the eye disease may be one selected from the group consisting of retinopathy, keratitis, macular degeneration, dry eye syndrome, and corneal and conjunctival epithelial disorder.

[0198] Corneal and conjunctival epithelial damage can be due to post-operative surgery, medications, trauma, or contact lens wear.

[0199] Specifically, a composition for treating an ocular disease, which comprises a compound or peptide as an active pharmaceutical ingredient, may further comprise at least one additive selected from the group consisting of a carrier, an excipient, a disintegrant, a sweetener, a coating agent, a swelling agent, a lubricant, a flavor, an antioxidant, a buffer, a bacteriostat, a diluent, a dispersant, a surfactant, and a binder. Specifically, a formulation for parenteral administration may be a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, or a suppository.

[0200] Another aspect of the invention provides a method of treating an ocular disease comprising administering to a subject a compound or peptide.

[0201] The dosage of the compound or peptide can be adjusted depending on various factors such as the type of disease, the severity of the disease, the type and amount of the active pharmaceutical ingredient and other ingredients contained in the pharmaceutical composition, the type of formulation, the patient's age, body weight, general health condition, sex and diet, the time and route of administration, the duration of treatment and concurrently used drugs.

[0202] However, for the desired effect, the effective amount of the compound or peptide contained in the pharmaceutical composition may be 0.0001 μg / day to 100 μg / day. In such an event, administration can be performed once a day or divided into several doses. Specifically, the concentration of the compound or peptide contained in the pharmaceutical composition may be 1000 μM to 0.001 μM. Furthermore, the concentration of the compound or peptide contained in the pharmaceutical composition may be 100 μM to 0.005 μM, or 50 μM to 0.02 μM.

[0203] In addition, if necessary, the concentration of the compound or peptide contained in the pharmaceutical composition may be 30 μM to 1 μM, and further, the concentration of the compound or peptide contained in the pharmaceutical composition may be 0.01 μM to 1 μM.

[0204] In addition, the subject may be a mammal, particularly a human. The route of administration can be appropriately selected by those skilled in the art, taking into consideration the administration method, the volume and viscosity of body fluids, etc. Specifically, administration can be carried out via any one route selected from the group consisting of topical application, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular, and intradermal. In particular, it can be applied to the eyes for use as an eye drop, preferably.

[0205] Another aspect of the present invention provides the use of a compound or peptide for the treatment of an ocular disease.

[0206] Another aspect of the present invention provides the use of a compound or peptide for the preparation of a pharmaceutical composition for treating an ocular disease. (Addendum) (Appendix 1) Formula 1: [ka] (In the formula, R 1 ~R 3 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~10 Alkoxy, substituted or unsubstituted C 1~10 Haloalkyl, substituted or unsubstituted C 2~10 Alkenyl, substituted or unsubstituted C 2~10 Alkynyl, substituted or unsubstituted C 1~10 Alkylene, substituted or unsubstituted C 1~10 Alkenylene, substituted or unsubstituted C 1~10 Alkynylene, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 Arylalkyl, substituted or unsubstituted C 5~14 Arylalkynyl, substituted or unsubstituted C 8~16 Arylalkenyl, substituted or unsubstituted C 3~10 Heteroalkyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl or substituted or unsubstituted C 5~12 heteroaryl, wherein said heteroalkyl, heterocycloalkyl, or heteroaryl contains at least one of N, O, and S; Substitution refers to substitution with non-hydrogen substituents, such as -X, -R a , -O - , =O, -OR a , -SR a , -S - , -N(R a )2, -N + (R a )3, =NR a , -C(X1)3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N-OH, =N2, -N3, -NHC(=O)R a , -C(=O)R a , -C(=O)NRa R a , -S(=O)2O - , -S(=O)2OH, -S(=O)2R a , -OS(=O)2OR a , -S(=O)2NR a , -S(=O)R a ,-OP(=O)(OR a )2, -C(=O)R a , alkylene-C(=O)R a , -C(=S)R a , -C(=O)OR a , alkylene-C(=O)OR a , -C(=O)O - , alkylene -C(=O)O-, -C(=S)OR a , -C(=O)SR a , -C(=S)SR a , -C(=O)NR a R a , alkylene-C(=O)NR a R a , -C(=S)NR a R a and -C(-NR a )NR a R a X1 may be at least one selected from the group consisting of F, Cl, Br or I, and R a is hydrogen, C 1~6 Alkyl, C 5~12 Aryl, C 7~12 arylalkyl or heterocycle; R 4 and R 5 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, -X2, -R b , -O - , =O, -CH2OR b , or -OR b X2 is F, Cl, Br or I, and R b is H, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 arylalkyl, or a substituted or unsubstituted heterocycle; R 6 is hydrogen or substituted or unsubstituted C 1~6 alkyl, the substituent is -C(=O)NH2, R 7 is hydrogen or C 1~6 is alkyl, R 8 and R 9 is hydrogen or unsubstituted C 1~6 alkyl) A compound represented by: (Appendix 2) R 1 is a substituted or unsubstituted C 1~6 Alkyl, [ka] and R a is hydrogen or C 1~6 2. The compound according to claim 1, wherein n is alkyl and n is an integer of 1 to 10. (Appendix 3) R 2 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, [ka] and R a is hydrogen or C 1~6 2. The compound according to claim 1, wherein n is alkyl and n is an integer of 1 to 10. (Appendix 4) R 3 is a substituted or unsubstituted C 1~6 Alkyl, [ka] and R a is hydrogen or C 1~6 2. The compound according to claim 1, wherein n is alkyl and n is an integer of 1 to 10. (Appendix 5) R 4 and R 5 each independently represents a substituted or unsubstituted C 1~6Alkyl, -OR b , =O, -CH2OR b and -X2, R b is hydrogen or C 1~6 2. The compound of claim 1, wherein the aryl group is alkyl. (Appendix 6) 6. The compound of claim 5, wherein X2 is F, Cl, Br or I. (Appendix 7) R 6 ~R 9 each independently represents hydrogen or a substituted or unsubstituted C 1~6 2. The compound of claim 1, wherein the substituent is -C(=O)NH2. (Appendix 8) R 1 but, [ka] 3. The compound of claim 2, selected from the group consisting of JPEG0007775250000095.jpg29164. (Appendix 9) R 2 but, [ka] 4. The compound of claim 3, selected from the group consisting of: (Appendix 10) R 3 but, [ka] 5. The compound of claim 4, which is one selected from the group consisting of: (Appendix 11) R 4 7. The compound of claim 6, wherein is selected from the group consisting of H, —OH, ═O, and —CH3. (Appendix 12) HyP-Gly-Gln-Glu-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asn-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Gln-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-His-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Lys-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Ser-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Thr-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Ala-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Val-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Ile-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Phe-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Tyr-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Trp-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Ser(ホモ)-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp(Me)-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asn(Me)-Gly-Leu-Ala-Gly-Pro-Lys、 D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、 D- Hyp(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu- D- Ala-Gly- D- Pro- D- Lys、 D- Hyp(2R,4R)-Gly- D- Gln- D- Leu-Gly- D- Leu- D- Ala-Gly-D- Pro- D- Lys、 HyP-Gly-Gln-Asp-Val-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ile-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Leu-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ala-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Phe-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Tyr-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Trp-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-His-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ser-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Thr-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Leu-Ala-Leu-Ala-Gly-Pro-Lys、 HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Tyr、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Leu、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Glu、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Gln、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Nle(6-OH)、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 Hyp(2S,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-oxo)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (5-oxo)Pro- Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-hydroxyMe)Pro-Gly-Gln-Leu-Gl y-Leu-Ala-Gly-Pro-Lys, (4-fluoro)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-dimethyl)Pro-Gly-Gln-Leu-Gly-Leu-Ala -Gly-Pro-Lys, (4-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (5-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Ala-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Ala-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Ala-Pro-Lys, Hyp-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, D- Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, and D- Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala The compound according to claim 1, which is any one selected from the group consisting of: (Appendix 13) A peptide having the amino acid sequence HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys, wherein Xaa is selected from the group consisting of Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, Ile, Leu, Phe, Tyr, Trp, homoSer, Asp(Me), and Asn(Me). (Appendix 14) A peptide having the amino acid sequence HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys, wherein Xaa is selected from the group consisting of Val, Ile, Leu, Ala, Phe, Tyr, Trp, Ser, Thr and (N-Me)Gly. (Appendix 15) A peptide having the amino acid sequence HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa, wherein Xaa is selected from the group consisting of Tyr, Leu, Glu, Gln, Ala and Nle(6-OH). (Appendix 16) A peptide having an amino acid sequence represented by the formula: PD-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, wherein PD is a peptide of the following formula: [ka] A peptide selected from the group consisting of: (Appendix 17) Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys, HyP-Gly-Gln-Leu-Gly-Leu-Ala, HyP-Gly-Gln-Glu-Gly-Leu-Gly, HyP-Gly-Gln-Leu-Gly-Leu, D- HyP(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu, HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln- D- Leu-Gly, and D- A peptide having any one amino acid sequence selected from the group consisting of HyP(2R,4S)-Gly-Gln-Leu-Gly. (Appendix 18) Formula 8: [ka] A compound represented by: (Appendix 19) Equation 10: [ka] A compound represented by: (Appendix 20) 20. A pharmaceutical composition for treating an eye disease, comprising as an active pharmaceutical ingredient a compound according to any one of claims 1 to 12, 18 and 19 or a peptide according to any one of claims 13 to 17. (Appendix 21) 21. The pharmaceutical composition according to claim 20, wherein the eye disease is one selected from the group consisting of retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca, and corneal and conjunctival epithelial disorder. (Appendix 22) A method for treating an eye disease, comprising administering to a subject a compound described in any one of claims 1 to 12, 18, and 19 or a peptide described in any one of claims 13 to 17.

[0207] Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are intended to further illustrate the present invention. The scope of the present invention is not limited thereby. [Example]

[0208] [Example 1] Preparation of YDE derivatives Protein analysis of the extracellular matrix derived from animal chondrocytes was performed at Baek's group of the Center of Biomedical Mass Spectrometry (Diatech Korea Co., Ltd., Seoul, Korea). Through the above protein analysis, proline-GQDGLAGPK (P-GQDGLAGPK), a portion of the amino acid sequence of collagen type II α1 protein, was obtained. By substituting a portion of the above peptide, YDE-001 to YDE-075 peptides were synthesized by ANYGEN (Gwangju, Korea) (Figure 1 and Table 11).

[0209] The process for synthesizing YDE-001 to YDE-075 peptides and their purification procedures performed by ANYGEN are illustrated in Figures 2 and 3.

[0210] [Table 11] JPEG0007775250000102.jpg220169JPEG0007775250000103.jpg222169JPEG0007775250000104.jpg222169JPEG0007775250000105.jpg148169

[0211] [Experimental Example 1] Analysis of YDE derivatives The YDE derivatives prepared in Example 1 were analyzed by HPLC. As a result, the synthesized YDE-001, YDE-002, YDE-003, YDE-004, YDE-005, YDE-006, YDE-007, YDE-008, YDE-009, YDE-010, YDE-011, YDE-012, YDE-013, YDE-014, YDE-015, YDE-016, YDE-017, YDE-018, YDE-019, YDE-020, YDE-021, YDE-022, YDE-023, YDE-024, YDE-025, YDE-026, YDE-027, YDE-028, YDE -029, YDE-030, YDE-031, YDE-032, YDE-033, YDE-034, YDE-035, YDE-036, YDE-037, YDE-038, YDE-039, YDE-040, YDE-041, YDE-042, YDE-043, Y DE-044, YDE-045, YDE-047, YDE-048, YDE-049, YDE-050, YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, The purities of YDE-060, YDE-064, YDE-066, YDE-072, YDE-073, YDE-074 and YDE-075 were 99.7%, 99.7%, 99.7%, 99.5%, 98.9%, 98.0%, 98.8%, 98.1%, 99.0%, 98.3%, 98.9%, 98.7%, 98.5%, 99.1%, 99.4%, 98.0%, 99.6%, 99.6%, 99.2%, 98.1%, 98.3%, 96.1%, 98.9%, 95.1%, 98.6%, 96.9%, 99.5%, and 98. The results were confirmed to be 0%, 98.1%, 98.8%, 98.2%, 97.2%, 98.6%, 98.8%, 98.7%, 99.2%, 98.7%, 98.1%, 97.5%, 96.5%, 97.4%, 98.7%, 97.8%, 95.5%, 97.5%, 97.2%, 96.9%, 99.3%, 98.0%, 99.4%, 96.4%, 95.1%, 98.6%, 97.4%, 98.8%, 97.4%, 95.8%, 98.9%, 96.9%, 98.8%, 97.7%, 95.0%, 97.9%, and 96.3% (Figures 4-68).

[0212] In addition, the YDE derivatives prepared in Example 1 were analyzed by ion-mass spectrometry. As a result, the synthesized YDE-001, YDE-002, YDE-003, YDE-004, YDE-005, YDE-006, YDE-007, YDE-008, YDE-009, YDE-010, YDE-011, YDE-012, YDE-013, YDE-014, YDE-015, YDE-016, YDE-017, YDE-018, YDE-019, YDE-020, YDE-021, YDE-022, YDE-023, YDE-024, YDE-025, YDE-026, YDE-027, YDE-028, YDE- 029, YDE-030, YDE-031, YDE-032, YDE-033, YDE-034, YDE-035, YDE-036, YDE-037, YDE-038, YDE-039, YDE-040, YDE-041, YDE-042, YDE-043, YDE -044, YDE-045, YDE-047, YDE-048, YDE-049, YDE-050, YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, YDE The molecular weights of YDE-060, YDE-064, YDE-066, YDE-072, YDE-073, YDE-074, and YDE-075 are 969.6, 954.8, 967.7, 977.1, 968.1, 926.9, 941.1, 910.7, 939.7, 953.0, 953.7, 987.8, 1003.8, 1025.9, 996.7, 1011.0, 1011.4, 968.7, 1044.4, 1061.4, 1084.5, 1035.0, 984.9, 999.1, 969.7, 942.0, 937.6, and 967. 3, 988.1, 960.6, 954.2, 991.1, 954.4, 990.7, 950.9, 937.6, 968.1, 955.4, 966.0, 709.3, 622.2, 486.8, 951.3, 951.3, 911.4, 967.5, 896.5, 911.0, 967.3, 911.2, 953.2, 967.2, 927.4, 896.4, 952.8, 953.4, 670.1, 953.3, 599.7, 486.5, 966.1, 895.8, 909.1 and 486.4 (Figures 69-133).

[0213] [Experimental Example 2] Evaluation of the ocular protective effect of YDE derivatives on dry eye syndrome [Experimental Example 2.1] Preparation of rats with dry eye syndrome To evaluate the ocular protective effects of YDE-001 to YDE-028 prepared in Example 1 against dry eye syndrome, a total of 320 male Sprague-Dawley rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Dry eye syndrome was then induced in 264 test rats via extraorbital lacrimal gland excision (ELGE). Eight test rats without ocular anomalies were subjected to a sham operation as a control group.

[0214] Using a rodent anesthesia machine (Surgivet, Waukesha, Wis., USA) and a ventilator (Model 687, Harvard Apparatus, Cambridge, UK), rats were anesthetized by inhaling a mixture of 2% to 3% isoflurane (Hana Pharm. Co., Hwasung, Korea), 70% N2O, and 28.6% O2. Then, a 10-mm transverse incision was made in the anterior part of the left tragus to excise the extraorbital lacrimal gland, located in the subcutaneous region above the masseter muscle and below the optic nerve. The skin was sutured using standard techniques. ELGE surgery lasted no longer than 5 minutes for each rat. Six days after ELGE surgery, the induction of dry eye syndrome was confirmed by Schirmer's test, which measured the amount of tear secretion. Meanwhile, each rat in the sham-operated control group was checked for the presence and location of the extraorbital lacrimal gland through a skin incision, and then the skin was sutured without removing the extraorbital lacrimal gland (Figure 134).

[0215] The mean body weight of the ELGE test group measured before ELGE surgery was 241.59 ± 13.56 g, and the mean body weight measured 6 days after ELGE surgery was 297.38 ± 34.02 g. The mean body weight of the control group measured before sham surgery was 240.13 ± 25.63 g, and the mean body weight measured 6 days after sham surgery was 297.38 ± 34.02 g (Figure 135).

[0216] The mean tear secretion volume in the control group was 8.34 ± 0.73 mm 3 The mean tear secretion volume in the ELGE study group was 3.55 ± 0.70 mm 3 Eight rats per group and a total of 32 groups were selected based on the average amount of tear secretion.

[0217] As a reference drug, 3% diquafosol sodium (Santen Pharmaceutical Co., Ltd., Tokyo, Japan, hereafter referred to as DS), which is currently on the market, was used.

[0218] This animal study was conducted with prior approval from the Animal Experiment Ethics Committee of Daegu Haany University (approval number DHU2017-003, January 12, 2017). All test animals were fasted for 18 hours, except for water, before ELGE surgery and terminal sacrifice.

[0219] The 32 groups are summarized in Table 12.

[0220] [Table 12]

[0221] In addition, to evaluate the ocular protective effects of YDE-029 to YDE-043 prepared in Example 1 against dry eye syndrome, a total of 200 Sprague-Dawley male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Dry eye syndrome was induced in 165 test rats via ELGE. Eight test rats without ocular malformations were subjected to sham surgery as a control group. ELGE was performed as described above.

[0222] The mean body weight of the ELGE test group measured before ELGE surgery was 264.09 ± 11.53 g, and the mean body weight measured 6 days after ELGE surgery was 316.13 ± 15.77 g. The mean body weight of the control group measured before sham surgery was 263.50 ± 9.24 g, and the mean body weight measured 6 days after sham surgery was 315.25 ± 10.85 g (Figure 136).

[0223] The mean tear secretion volume in the control group was 10.90 ± 1.69 mm 3 The mean tear secretion volume in the ELGE study group was 4.83 ± 0.99 mm 3 Eight rats per group and a total of 20 groups were selected based on the average amount of tear secretion.

[0224] As a reference drug, 3% DS, which is currently on the market, was used.

[0225] This animal study was conducted with prior approval from the Animal Experiment Ethics Committee of Daegu Haany University (approval number DHU2017-050, June 8, 2017). All test animals were fasted for 18 hours, except for water, before ELGE surgery and terminal sacrifice.

[0226] The 20 groups are summarized in Table 13.

[0227] [Table 13]

[0228] [Experimental Example 2.2] Administration of YDE derivatives For YDE-001 to YDE-028, the YDE series of YY-102 and 28 were each dissolved in saline at a concentration of 3 mg / ml and administered at a dose of 5 μl per eye at 9:30 am and 3:30 pm daily for 14 days starting 7 days after ELGE surgery for a total of 28 doses. DS solution was dissolved in saline at a concentration of 30 mg / ml and administered at a dose of 5 μl per eye twice daily for 14 days starting 7 days after ELGE surgery for a total of 28 doses. The sham control and ELGE control groups were administered the same stimuli as those administered. To prevent excessive eye dryness, the same volume of saline was applied in the same manner instead of the test substance.

[0229] Furthermore, for YDE-029 to YDE-043, YY-102 and 15 of the YDE series were each dissolved in saline at a concentration of 3 mg / ml and administered at a dose of 5 μl per eye at 9:30 am and 3:30 pm daily for 14 days, 7 days after ELGE surgery, for a total of 28 doses. DS solution was dissolved in saline at a concentration of 30 mg / ml and administered at a dose of 5 μl per eye twice daily for 14 days, 7 days after ELGE surgery, for a total of 28 doses. The sham control and ELGE control groups were administered the same stimuli as in the administration. To prevent excessive eye dryness, the same volume of saline was applied in place of the test substance in the same manner (Figure 137).

[0230] [Test Example 2.3] Confirmation of changes in tear secretion volume by YDE derivatives Six days after ELGE surgery, changes in tear secretion volume were measured on days 7 and 14 after administration of YDE-001 to YDE-043. The amount of tear secretion was measured by the decrease in the distance traveled by tears absorbed by 1 × 15 mm cobalt chloride paper (Toyo Roshi Kaisha, Japan).

[0231] Cobalt chloride paper was placed in the lateral canthus of the rat's eye for 60 seconds to absorb the tear fluid (Figure 139). The length of the absorbed area from the corner of the cobalt chloride paper was measured with an electronic digital caliper (Mitutoyo Corporation, Tokyo, Japan) (Figure 138).

[0232] Figure 139 shows the results of the study, where A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 treatment group, and E to A F are for the YDE-001 to YDE-028 treatment groups, respectively.

[0233] The results confirmed that the amount of tear secretion was reduced in the ELGE control group on days 7 and 14 after saline application 6 days after ELGE surgery compared with the sham control group. In the groups treated with YDE derivatives and the DS reference group, the amount of tear secretion increased compared with the ELGE control group, except for the groups treated with 0.3% solutions of YDE-9, YDE-10, YDE-17, YDE-19, YDE-20, YDE-21, YDE-22, YDE-25, YDE-27, and YDE-28, which did not show any significant changes in the amount of tear secretion after 14 days of administration. In particular, the amount of tear secretion increased by more than 20% in the groups treated with 0.3% solutions of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102 compared with the DS reference group.

[0234] The specific amount of tear secretion is shown in Figure 140 and Table 14.

[0235] [Table 14] JPEG0007775250000109.jpg16692

[0236] Figure 141 shows the results of the study, where A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 treatment group, and E to S are for the YDE-029 to YDE-043 treatment groups, respectively.

[0237] The results confirmed that the amount of tear secretion was reduced in the ELGE control group on days 7 and 14 after saline administration 6 days after ELGE surgery compared with the sham control group. In the groups treated with YDE derivatives and the DS reference group, the amount of tear secretion increased compared with the ELGE control group, except for the groups treated with 0.3% solutions of YDE-029, YDE-030, YDE-032, YDE-033, YDE-034, YDE-036, and YDE-41, which did not show any significant changes in the amount of tear secretion after 14 days of administration. In particular, the amount of tear secretion increased by more than 20% in the groups treated with 0.3% solutions of YDE-040, YDE-043, and YDE-042, respectively, compared with the DS reference group.

[0238] The specific amounts of tear secretion are shown in Figure 142 and Table 15.

[0239] [Table 15]

[0240] [Experimental Example 2.4] Confirmation of changes in corneal injury caused by YDE derivatives After administering YDE-001 to YDE-028 to each eye 14 times, changes in corneal permeability were checked.

[0241] To measure corneal permeability, the animal anesthetic Zolethyl 50™ (Virbac Lab., Carros, France) was injected intraperitoneally at a dose of 25 mg / kg. Then, saline containing 1% (v / v) fluorescent solution (fluorescein sodium salt, Tokyo Kasei Kogyo Co., Tokyo, Japan) was applied to the eyes at a dose of 5 μl per eye. The treated eyes were closed and fixed with tape. After 1 hour, the remaining fluorescent solution was removed using a cotton swab (Figure 142). After 12 to 24 hours, corneal permeability was measured using a tabletop model biomicroscope (Model SM-70N, Takagi Seiko Co., Nakano, Japan) equipped with a blue-light tungsten lamp and an eye dropper slit lamp (Figure 143).

[0242] Figure 144 shows the results of the study, where A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 treatment group, and E to A F are for the YDE-001 to YDE-028 treatment groups, respectively.

[0243] As a result, fluorescent dye penetration was increased in the ELGE control group compared with the sham control group. Fluorescent dye penetration was not reduced in the groups treated with 0.3% solutions of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27, and YDE-28 compared with the ELGE control group on day 14 after administration. Corneal penetration of fluorescent dye was reduced in the groups treated with YDE derivatives and the DS reference group compared with the ELGE control group, except for the groups treated with 0.3% solutions of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27, and YDE-28. Notably, the permeability of the fluorescent dye was reduced by more than 20% in groups treated with 0.3% solutions of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102 compared to the DS reference group.

[0244] Specific penetration properties of fluorescent dyes are shown in Figure 145 and Table 16.

[0245] [Table 16] JPEG0007775250000112.jpg24097JPEG0007775250000113.jpg7999

[0246] In addition, YDE-029 to YDE-043 were administered to each eye 14 times, and then changes in corneal permeability were checked. Corneal permeability measurements were performed in the same manner as described above (Figure 146).

[0247] As a result, fluorescent dye permeability increased in the ELGE control group compared with the sham control group. Fluorescent dye permeability did not decrease in the groups treated with 0.3% solutions of YDE-29, YDE-32, YDE-33, YDE-36, and YDE-41 compared with the ELGE control group on day 14 after administration. Corneal permeability of fluorescent dye decreased in the groups treated with YDE derivatives and the DS control group compared with the ELGE control group, except for the groups treated with 0.3% solutions of YDE-29, YDE-32, YDE-33, YDE-36, and YDE-41. Notably, fluorescent dye permeability decreased by more than 20% in the groups treated with 0.3% solutions of YDE-40, YDE-43, and YDE-42 compared with the DS control group.

[0248] Specific penetration properties of fluorescent dyes are shown in Figure 147 and Table 17.

[0249] [Table 17] JPEG0007775250000115.jpg14094

[0250] [Experimental Example 3] Evaluation of the stability of YDE derivatives To confirm the stability of each test substance in aqueous solution, 10 mg of each sample was dissolved in 1 ml of water to a concentration of 1 mg / ml, which was then placed in a glass vial, closed with a rubber cap, sealed with an aluminum cap, and stored under long-term storage conditions (25°C, 75% RH). The stability of the test substance was evaluated by measuring the amount of related substances at 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks under long-term storage conditions.

[0251] As a result, 66.5% of related substances were produced in YY-101 after 2 weeks. In contrast, 1.1% to 30.6% of related substances were produced in YDE-001 to YDE-028 after 12 weeks. The specific amounts are shown in Table 18.

[0252] [Table 18] JPEG0007775250000117.jpg25092JPEG0007775250000118.jpg2390

[0253] [Test Example 4] Evaluation of corneal injury recovery by YDE derivatives To confirm whether the YDE derivatives can reverse corneal injury, the cell growth rate of human primary corneal epithelial cells was checked.

[0254] Specifically, 5 × 10 cells were cultured per well on a 96-well culture plate (Perkin Elmer, 6005680) containing corneal epithelial cell basal medium (ATCC, ATCC PCS-700-030) in a corneal epithelial cell growth kit (ATCC, ATCC PCS-700-040). 3 Primary corneal epithelial cells (ATCC, ATCC PCS-700-010) were seeded onto the cells in the amount of 100 ml, and then cultured for 24 hours under conditions of 37°C and 5% CO2.

[0255] YDE-001 to YDE-075 were each dissolved in 100% DMSO (Sigma, D2660) to a concentration of 10 mM, which was then diluted with 100% DMSO to compound concentrations of 6, 1.9, 0.6, 0.2, 0.06, 0.02, 0.006, and 0.002 mM. 20 μl of the diluted YDE derivatives was added to a 96-well microplate (Greiner Bio-One, 651201) containing 380 μl of corneal epithelial cell basal medium, resulting in a 5% DMSO solution.

[0256] After 24 hours, 20 μl of each YDE derivative diluted in a 96-well microplate was added to the 96-well culture plate containing the cells. As a control, hEGF (Sigma, E9644) was added at the same concentration as the YDE derivatives. Cells treated with YDE derivatives or hEGF were cultured at 37°C and 5% CO for 48 and 72 hours (Figures 148-155).

[0257] Cultured cells were treated with CellTiter-Glo luminescence reagent (Promega, G7573) according to the manufacturer's instructions and incubated at room temperature for 30 minutes. Fluorescence (or luminescence) signals were then measured using an Envision 2014 multilabel plate reader. Measurements were normalized using a vehicle control (100% proliferating cells).

[0258] As a result, cell proliferation was observed at concentrations of 0.3 μM or less for YY-101, YY-102, YDE-011, YDE-038, YDE-042, YDE-043, YDE-044, YDE-045, YDE-049, YDE-054, YDE-057, YDE-058, YDE-059, and YDE-060. In particular, high cell proliferation rates were observed for YY-102, YDE-011, YDE-045, YDE-057, and YDE-060 (Figures 156 to 173). [Sequence table] SEQUENCE LISTING <110> YUYU PHARMA, INC. <120> NOVEL PEPTIDE AND PHARMACEUTICAL COMPOSITION FOR TREATMENT OF EYE DISEASES COMPRISING SAME NOVEL PEPTIDE AS ACTIVE INGREDIENT <130> PA23-176 <150> KR 10-2017-0061250 <151> 2017-05-17 <160> 63 <170> PatentIn version 3.5 <210> 1 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-001 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 1 Pro Gly Gln Glu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 2 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-002 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 2 Pro Gly Gln Asn Gly Leu Ala Gly Pro Lys 1 5 10 <210> 3 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-003 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 3 Pro Gly Gln Gln Gly Leu Ala Gly Pro Lys 1 5 10 <210> 4 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-004 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 4 Pro Gly Gln His Gly Leu Ala Gly Pro Lys 1 5 10 <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-005 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 5 Pro Gly Gln Lys Gly Leu Ala Gly Pro Lys 1 5 10 <210> 6 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-006 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 6 Pro Gly Gln Ser Gly Leu Ala Gly Pro Lys 1 5 10 <210> 7 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-007 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 7 Pro Gly Gln Thr Gly Leu Ala Gly Pro Lys 1 5 10 <210> 8 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-008 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 8 Pro Gly Gln Ala Gly Leu Ala Gly Pro Lys 1 5 10 <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-009 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 9 Pro Gly Gln Val Gly Leu Ala Gly Pro Lys 1 5 10 <210> 10 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-010 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 10 Pro Gly Gln Ile Gly Leu Ala Gly Pro Lys 1 5 10 <210> 11 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-011 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 11 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 12 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-012 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 12 Pro Gly Gln Phe Gly Leu Ala Gly Pro Lys 1 5 10 <210> 13 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-013 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 13 Pro Gly Gln Tyr Gly Leu Ala Gly Pro Lys 1 5 10 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-014 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 14 Pro Gly Gln Trp Gly Leu Ala Gly Pro Lys 1 5 10 <210> 15 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-026 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <220> <221> MOD_RES <222> (4)..(4) <223> Homo-Ser <400> 15 Pro Gly Gln Ser Gly Leu Ala Gly Pro Lys 1 5 10 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-027 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <220> <221> MOD_RES <222> (4)..(4) <223> Methylation, Asp(Me) <400> 16 Pro Gly Gln Asp Gly Leu Ala Gly Pro Lys 1 5 10 <210> 17 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-028 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <220> <221> MOD_RES <222> (4)..(4) <223> Methylation, Asn(Me) <400> 17 Pro Gly Gln Asn Gly Leu Ala Gly Pro Lys 1 5 10 <210> 18 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-057 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4S) <400> 18 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 19 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-058 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4S) <220> <221> MOD_RES <222> (3)..(3) <223> D-Gln <220> <221> MOD_RES <222> (4)..(4) <223> D-Leu <220> <221> MOD_RES <222> (6)..(6) <223> D-Leu <220> <221> MOD_RES <222> (7)..(7) <223> D-Ala <220> <221> MOD_RES <222> (9)..(9) <223> D-Pro <220> <221> MOD_RES <222> (10)..(10) <223> D-Lys <400> 19 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 20 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-060 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4R) <220> <221> MOD_RES <222> (3)..(3) <223> D-Gln <220> <221> MOD_RES <222> (4)..(4) <223> D-Leu <220> <221> MOD_RES <222> (6)..(6) <223> D-Leu <220> <221> MOD_RES <222> (7)..(7) <223> D-Ala <220> <221> MOD_RES <222> (9)..(9) <223> D-Pro <220> <221> MOD_RES <222> (10)..(10) <223> D-Lys <400> 20 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 21 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-015 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 21 Pro Gly Gln Asp Val Leu Ala Gly Pro Lys 1 5 10 <210> 22 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-016 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 22 Pro Gly Gln Asp Ile Leu Ala Gly Pro Lys 1 5 10 <210> 23 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-017 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 23 Pro Gly Gln Asp Leu Leu Ala Gly Pro Lys 1 5 10 <210> 24 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-018 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 24 Pro Gly Gln Asp Ala Leu Ala Gly Pro Lys 1 5 10 <210> 25 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-019 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 25 Pro Gly Gln Asp Phe Leu Ala Gly Pro Lys 1 5 10 <210> 26 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-020 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 26 Pro Gly Gln Asp Tyr Leu Ala Gly Pro Lys 1 5 10 <210> 27 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-021 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 27 Pro Gly Gln Asp Trp Leu Ala Gly Pro Lys 1 5 10 <210> 28 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-022 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 28 Pro Gly Gln Asp His Leu Ala Gly Pro Lys 1 5 10 <210> 29 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-023 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 29 Pro Gly Gln Asp Ser Leu Ala Gly Pro Lys 1 5 10 <210> 30 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-024 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 30 Pro Gly Gln Asp Thr Leu Ala Gly Pro Lys 1 5 10 <210> 31 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-025 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 31 Pro Gly Gln Asp Gly Leu Ala Gly Pro Lys 1 5 10 <210> 32 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-051 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 32 Pro Gly Gln Leu Ala Leu Ala Gly Pro Lys 1 5 10 <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-029 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 33 Pro Gly Gln Leu Gly Leu Ala Gly Pro Tyr 1 5 10 <210> 34 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-030 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 34 Pro Gly Gln Leu Gly Leu Ala Gly Pro Leu 1 5 10 <210> 35 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-031 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 35 Pro Gly Gln Leu Gly Leu Ala Gly Pro Glu 1 5 10 <210> 36 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-032 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 36 Pro Gly Gln Leu Gly Leu Ala Gly Pro Gln 1 5 10 <210> 37 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-033 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <220> <221> MOD_RES <222> (10)..(10) <223> Nle(6-OH) <400> 37 Pro Gly Gln Leu Gly Leu Ala Gly Pro Xaa 1 5 10 <210> 38 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-056 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 38 Pro Gly Gln Leu Gly Leu Ala Gly Pro Ala 1 5 10 <210> 39 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-073 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4S) <400> 39 Pro Gly Gln Leu Gly Leu Ala Gly Pro Ala 1 5 10 <210> 40 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-035 <220> <221> MOD_RES <222> (1)..(1) <223> (4-oxo)Pro <400> 40 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 41 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-036 <220> <221> MOD_RES <222> (1)..(1) <223> (5-oxo)Pro <400> 41 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 42 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-037 <400> 42 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 43 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-038 <220> <221> MOD_RES <222> (1)..(1) <223> (4-hydroxyMe)Pro <400> 43 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 44 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-039 <220> <221> MOD_RES <222> (1)..(1) <223> (4-Fluoro)Pro <400> 44 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 45 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-040 <220> <221> MOD_RES <222> (1)..(1) <223> (4-Dimethyl)Pro <400> 45 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-044 <220> <221> MOD_RES <222> (1)..(1) <223> (4-Me)Pro <400> 46 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 47 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-045 <220> <221> MOD_RES <222> (1)..(1) <223> (5-Me)Pro <400> 47 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 48 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-049 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 48 Pro Gly Ala Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 49 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-052 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 49 Pro Gly Gln Leu Gly Ala Ala Gly Pro Lys 1 5 10 <210> 50 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-054 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 50 Pro Gly Gln Leu Gly Leu Ala Ala Pro Lys 1 5 10 <210> 51 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-048 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 51 Pro Ala Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 52 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-074 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4S) <400> 52 Pro Ala Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 53 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-072 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4S) <400> 53 Pro Ala Gln Leu Gly Leu Ala Gly Pro Ala 1 5 10 <210> 54 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-047 <400> 54 Ala Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10 <210> 55 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-055 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 55 Pro Gly Gln Leu Gly Leu Ala Gly Ala Lys 1 5 10 <210> 56 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-041 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 56 Pro Gly Gln Leu Gly Leu Ala 1 5 <210> 57 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-059 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 57 Pro Gly Gln Glu Gly Leu Gly 1 5 <210> 58 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-042 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 58 Pro Gly Gln Leu Gly Leu 1 5 <210> 59 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-064 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4S) <220> <221> MOD_RES <222> (3)..(3) <223> D-Gln <220> <221> MOD_RES <222> (4)..(4) <223> D-Leu <220> <221> MOD_RES <222> (6)..(6) <223> D-Leu <400> 59 Pro Gly Gln Leu Gly Leu 1 5 <210> 60 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-043 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <400> 60 Pro Gly Gln Leu Gly 1 5 <210> 61 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-066 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp <220> <221> MOD_RES <222> (4)..(4) <223> D-Leu <400> 61 Pro Gly Gln Leu Gly 1 5 <210> 62 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-075 <220> <221> MOD_RES <222> (1)..(1) <223> D-4Hyp(2R, 4S) <400> 62 Pro Gly Gln Leu Gly 1 5 <210> 63 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <223> Amino acid sequence for YDE-034 <220> <221> MOD_RES <222> (1)..(1) <223> 4Hyp(2S, 4S) <400> 63 Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys 1 5 10

Claims

1. The structure shown in the table below, i.e. 【Chemistry 1】 【change】 A compound having a structure selected from:

2. The compound 【Chemistry 2】 (YDE-043).

2. The compound of claim 1, wherein:

3. A pharmaceutical composition for treating an eye disease, comprising a compound according to claim 1 or 2.

4. The pharmaceutical composition described in claim 3, wherein the eye disease is selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca, and keratoconjunctival epithelial disorder.

5. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for treating an eye disease.

6. The use described in claim 5, wherein the eye disease is selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca, and keratoconjunctival epithelial disorder.

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