Compound having lysine demethylase 3a inhibitory activity and use thereof

Abstract

The present invention achieves: a compound having lysine demethylase 3A inhibitory activity; a lysine demethylase 3A inhibitor containing the compound; and a therapeutic or prophylactic agent for abnormal angiogenesis containing the lysine demethylase 3A inhibitor. An azide-alkyne conjugate having a specific structure is used as an active ingredient of the lysine demethylase 3A inhibitor, or the therapeutic or prophylactic agent for abnormal angiogenesis.

Description

Compounds having lysine demethylase 3A inhibitory activity, and their applications

[0001] This invention relates to a compound having lysine demethylase 3A inhibitory activity and its use.

[0002] Neoangiogenesis can occur in the body under both physiological and pathological conditions. Under physiological conditions, normal neoangiogenesis occurs, for example, in fetal tissue (e.g., the retina), leading to the formation of normal tissue. On the other hand, under pathological conditions, abnormal neoangiogenesis occurs, for example, in the affected area of ​​disease (e.g., retinal ischemic disease, cancer, retinopathy of prematurity, age-related macular degeneration, diabetic macular edema, pathological myopia, macular edema associated with retinal vein occlusion, and neovascular glaucoma), leading to the onset or worsening of the disease.

[0003] Examples of abnormal angiogenesis include the formation of avascular areas (in other words, areas where blood vessels do not form) and the formation of abnormal blood vessels (in other words, the formation of blood vessels that run in a disordered manner).

[0004] The formation of avascular areas and abnormal blood vessels can occur independently or in combination. For example, in age-related macular degeneration and pathological myopia, the formation of abnormal blood vessels occurs independently. On the other hand, in retinal ischemic disease, cancer, retinopathy of prematurity, diabetic macular edema, macular edema associated with retinal vein occlusion, and neovascular glaucoma, avascular areas are formed first, followed by the formation of abnormal blood vessels.

[0005] Currently, anti-VEGF drugs are used as treatments for abnormal angiogenesis (see, for example, Non-Patent Documents 1 and 2). Non-Patent Documents 1 and 2 describe the use of aflibercept, bevacizumab, ranibizumab, and falisimab in the treatment of diabetic macular edema.

[0006] N Eng J Med., 2015 March 26; 372(13): 1193-1203, "Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema"Charles C Wykoff et al., Lancet., 2022 Feb 19; 399(10326): 741-755, "Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema(YOSEMITE and RHINE): two randomized, double-masked, phase 3 trials"

[0007] However, the conventional technologies described above have the problem that they are not sufficiently effective in treating abnormal angiogenesis.

[0008] For example, the conventional technologies described above have room for improvement in the following respects: (i) they only have the effect of temporarily reducing abnormal angiogenesis, raising concerns about the need for frequent administration; (ii) they affect both normal and abnormal angiogenesis, raising concerns about side effects; and (iii) anti-VEGF drugs suppress angiogenesis, raising concerns that they may not provide sufficient therapeutic effect on the formation of avascular areas.

[0009] One aspect of the present invention aims to realize a compound having lysine demethylase 3A inhibitory activity, a lysine demethylase 3A inhibitor containing the compound, and a therapeutic or prophylactic agent for abnormal angiogenesis containing the lysine demethylase 3A inhibitor.

[0010] The inventors synthesized various compounds and discovered that these compounds have an inhibitory effect on the activity of lysine demethylase 3A, as well as therapeutic and preventive effects on abnormal angiogenesis, thus completing the present invention. One embodiment of the present invention encompasses the following invention.

[0011] [1] (i) A compound represented by the following chemical formula 1, a salt thereof, a hydrate thereof, a solvate thereof, or a derivative thereof, and / or (ii) a compound represented by the following chemical formula 2, a salt thereof, a hydrate thereof, a solvate thereof, or a derivative thereof, as an active ingredient, a lysine demethylase 3A inhibitor:

[0012] In Chemical Formula 1, (1) X １ is -COOR １ (where R １ is hydrogen or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted fused ring, (2) Y 1 is a heterocyclic ring containing a nitrogen atom, (3) n is an integer from 0 to 20.

[0013] In Chemical Formula 2, (4) X ２ is -COOR ２ (where R ２ is hydrogen or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted fused ring (however, excluding the following functional group A from X ２ ),

[0014] (5) Y ２ is a heterocyclic ring containing a nitrogen atom, (6) Z ２ is hydrogen or any organic group, (7) n is an integer from 0 to 20.

[0015] [2] A therapeutic or preventive agent for abnormal angiogenesis, containing the lysine demethylase 3A inhibitor described in [1] as an active ingredient.

[0016] [3] The therapeutic or preventive agent for abnormal angiogenesis described in [2], wherein the abnormal angiogenesis is the formation of an avascular region and / or the formation of abnormal blood vessels.

[0017] [4] The above abnormal neovascularization is abnormal neovascularization associated with retinal ischemic disease, cancer, retinopathy of prematurity, age-related macular degeneration, diabetic macular edema, pathological myopia, macular edema associated with retinal vein occlusion, or neovascular glaucoma, and is a therapeutic or prophylactic agent for abnormal neovascularization as described in [2] or [3].

[0018] [5] (i) Compounds represented by the following chemical formula 1, salts thereof, hydrates thereof, solvates thereof, or derivatives thereof, and / or (ii) Compounds represented by the following chemical formula 2, salts thereof, hydrates thereof, solvates thereof, or derivatives thereof:

[0019] In chemical formula 1, (1)X １ is -COOR １ (Here, R １ (2) Y 1 (3) n is an integer from 0 to 20,

[0020] In chemical formula 2, (4)X ２ is -COOR ２ (Here, R ２ X is a hydrogen atom or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted fused ring (where X is a hydrogen atom or any organic group). ２ Therefore, excluding the following functional group A),

[0021] (5) Y ２ (6) Z is a heterocycle containing a nitrogen atom. ２ (7) n is an integer from 0 to 20.

[0022] According to one aspect of the present invention, a compound having lysine demethylase 3A inhibitory activity, a lysine demethylase 3A inhibitor containing the compound, and a therapeutic or prophylactic agent for abnormal angiogenesis containing the lysine demethylase 3A inhibitor can be realized.

[0023] This graph shows the results of the evaluation of the inhibitory activity of the azido-alkyne conjugate corresponding to chemical formula 1 in the embodiment of the present invention against lysine demethylase 3A. This graph shows the results of the evaluation of the inhibitory activity of the azido-alkyne conjugate corresponding to chemical formula 2 in the embodiment of the present invention against lysine demethylase 3A. This image and graph show the therapeutic and preventive effects of the azido-alkyne conjugate in the embodiment of the present invention against abnormal angiogenesis. This image and graph show the therapeutic and preventive effects of the azido-alkyne conjugate in the embodiment of the present invention against abnormal angiogenesis. This image and graph show the therapeutic and preventive effects of the azido-alkyne conjugate in the embodiment of the present invention against abnormal angiogenesis. This image and graph show the therapeutic and preventive effects of the azido-alkyne conjugate in the embodiment of the present invention against abnormal angiogenesis. This graph shows the results of the metabolic stability test of the azido-alkyne conjugate in the embodiment of the present invention. This image and graph show the therapeutic and preventive effects of the azido-alkyne conjugate in the embodiment of the present invention against abnormal angiogenesis. This image and graph show the therapeutic and preventive effects of the azido-alkyne conjugate in the embodiment of the present invention against abnormal angiogenesis. These images and graphs illustrate the therapeutic and preventive effects of the azide-alkyne conjugate according to an embodiment of the present invention on abnormal angiogenesis.

[0024] One embodiment of the present invention is described below, but the present invention is not limited thereto. The present invention is not limited to the configurations described below, and various modifications are possible within the scope of the claims, and embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present invention. Furthermore, all academic and patent documents mentioned herein are incorporated herein by reference. Also, unless otherwise specified herein, "A to B" representing a numerical range is intended to mean "A or more, B or less".

[0025] [1. Technical Concept of the Invention] In living organisms, normal angiogenesis occurs under physiological conditions, while abnormal angiogenesis occurs under pathological conditions. In order to form a normal living organism, it is necessary to promote normal angiogenesis while suppressing abnormal angiogenesis.

[0026] The inventors of this invention conducted research based on their own hypothesis that a substance capable of restoring a pathological condition that causes abnormal angiogenesis to a physiological condition that causes normal angiogenesis would be useful as a new therapeutic or preventive agent for abnormal angiogenesis.

[0027] Specifically, the inventors screened for new candidate substances for the treatment and prevention of abnormal angiogenesis, based on their unique hypothesis that substances targeting proteins that control the expression of genes subject to epigenetic regulation can reverse pathological conditions that cause abnormal angiogenesis back to physiological conditions that cause normal angiogenesis.

[0028] Numerous proteins are known to regulate the expression of genes subject to epigenetic regulation. The inventors of this invention have discovered that, among these proteins, substances that inhibit the activity of lysine demethylase 3A (KDM3A) are particularly useful as novel therapeutic and preventive agents for abnormal angiogenesis, and have completed the present invention.

[0029] [2. Compounds, their salts, their hydrates, their solvates, or their derivatives] A compound, its salt, its hydrate, its solvate, or its derivative according to one embodiment of the present invention is (i) a compound represented by the following chemical formula 1, its salt, its hydrate, its solvate, or its derivative, and / or (ii) a compound represented by the following chemical formula 2, its salt, its hydrate, its solvate, or its derivative:

[0030] In chemical formula 1, (1)X １ is -COOR １ (Here, R １(2) Y 1 (3) n is an integer from 0 to 20,

[0031] In chemical formula 2, (4)X ２ is -COOR ２ (Here, R ２ X is a hydrogen atom or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted fused ring (where X is a hydrogen atom or any organic group). ２ Therefore, excluding the following functional group A),

[0032] (5) Y ２ (6) Z is a heterocycle containing a nitrogen atom. ２ (7) n is an integer from 0 to 20.

[0033] [2-1. Compounds represented by chemical formula 1] In chemical formula 1, (1) X １ is -COOR １ (Here, R １ (2) Y 1 (3)n is an integer between 0 and 20, and is a heterocycle containing a nitrogen atom.

[0034] Regarding (1) above, X １ is -COOR １ It is possible. (See above R) １This can be hydrogen or any organic group. The above organic group is not limited and may be, for example, an alkyl group, an aryl group, an arylsulfonyl group, a fluoroalkyl group, an alkenyl group, a fluoroalkenyl group, an alkynyl group, a fluoroalkynyl group, an alkoxyl group, a fluoroalkoxyl group, an acetyl group, a carboxyalkyl group, an alkylamide group, an aromatic ring, a benzenesulfonyl group, a heterocycle (e.g., a heterocycle described later), or a fused ring (e.g., a fused ring described later).

[0035] Regarding (1) above, X １ This can be a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted fused ring.

[0036] The structure of the heterocycle described above is not limited and may be, for example, a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, a seven-membered ring, an eight-membered ring, or a nine-membered ring. Furthermore, the atoms constituting the heterocycle are not limited and may be, for example, a heterocycle containing a carbon atom (C), a nitrogen atom (N), and / or a sulfur atom (S).

[0037] The structure of the fused ring described above is not limited and may be, for example, a fused ring composed of (i) a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered ring and (ii) a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered ring. More specifically, the fused ring may be, for example, a fused ring composed of (iii) a 6-membered ring and (iv) a 5-membered or 6-membered ring. In this case, the (iii) 6-membered ring is an aromatic ring, and the (iv) 5-membered or 6-membered ring may be a heterocycle (for example, a heterocycle having the same structure as the heterocycle described above).

[0038] The above aromatic rings, heterocycles, and fused rings may be substituted with any substituent. Such substituents are not limited to, for example, alkyl groups, aryl groups, arylsulfonyl groups, fluoroalkyl groups, alkenyl groups, fluoroalkenyl groups, alkynyl groups, fluoroalkynyl groups, alkoxyl groups, fluoroalkoxyl groups, acetyl groups, carboxyalkyl groups, alkylamide groups, aromatic rings, benzenesulfonyl groups, heterocycles (e.g., the heterocycles mentioned above), fused rings (e.g., the fused rings mentioned above), or NO２ It is possible.

[0039] Regarding (2) above, Y 1 This is a heteroring containing nitrogen atoms. The structure of the heteroring is not limited and may be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, or a 9-membered ring. The number of nitrogen atoms (N) contained in the heteroring is not limited and may be, for example, 3 or more or 3.

[0040] Regarding (3) above, n is an integer between 0 and 20. For example, n could be an integer between 0 and 17, an integer between 0 and 15, an integer between 0 and 12, an integer between 0 and 10, an integer between 0 and 7, an integer between 0 and 5, or an integer between 0 and 3.

[0041] "X" in chemical formula 1 １ - (CH ２ ) ｎ The structure of "-" can more specifically be one of the following "structure A-1" to "structure A-16".

[0042] In the above structure A-1, n is an integer between 0 and 19. For example, n could be an integer between 0 and 16, an integer between 0 and 14, an integer between 0 and 11, an integer between 0 and 9, an integer between 0 and 6, an integer between 0 and 4, or an integer between 0 and 2.

[0043] In structures A-2, A-3, A-4, A-5, and A-6 described above, R may be hydrogen or any organic group. The organic group is not limited to, for example, alkyl groups, aryl groups, arylsulfonyl groups, fluoroalkyl groups, alkenyl groups, fluoroalkenyl groups, alkynyl groups, fluoroalkynyl groups, alkoxyl groups, fluoroalkoxyl groups, acetyl groups, carboxyalkyl groups, alkylamide groups, aromatic rings, benzenesulfonyl groups, heterocycles (e.g., the heterocycles described above), fused rings (e.g., the fused rings described above), or NO ２ It is possible.

[0044] "-Y" in chemical formula 1 １ The structure of "-" can more specifically be the following "structure B-1".

[0045] In the above structure B-1, the part indicated by the asterisk (one) is the "X" in chemical formula 1. １ - (CH ２ ) ｎ This is the point where it bonds with the "-" symbol. On the other hand, in the structure B-1 above, the points indicated by the two asterisks are the points where it bonds with the heterocycle (a six-membered ring containing one nitrogen atom (N)) in chemical formula 1.

[0046] [2-2. Compounds represented by chemical formula 2] In chemical formula 2, (4)X ２ is -COOR ２ (Here, R ２ X is a hydrogen atom or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted fused ring (where X is a hydrogen atom or any organic group). ２ (5) Y (excluding functional group A) ２ (6) Z is a heterocycle containing a nitrogen atom. ２ (7)n is an integer from 0 to 20.

[0047] Regarding (4) above, X ２ is -COOR ２ It is possible. (See above R) ２ The above R １ Since it could have the same configuration, we will omit the explanation here.

[0048] Regarding (4) above, X ２ X can be a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted fused ring (however, X ２ Therefore, excluding functional group A).

[0049] The above X ２ The constituent elements of X are: substituted or unsubstituted aromatic rings, substituted or unsubstituted heterocycles, and substituted or unsubstituted fused rings. ２ Except for the removal of functional group A, the above X １ Since the constituent elements may be the same as substituted or unsubstituted aromatic rings, substituted or unsubstituted heterocycles, and substituted or unsubstituted fused rings, we will omit their explanation here.

[0050] Regarding (5) above, Y ２ The above Y is a heterocycle containing a nitrogen atom. ２ This is the above Y １ Since it could have the same configuration, we will omit the explanation here.

[0051] Regarding (6) above, Z ２ is hydrogen or any organic group. The above organic group is not limited and may be, for example, an alkyl group, an aryl group, an arylsulfonyl group, a fluoroalkyl group, an alkenyl group, a fluoroalkenyl group, an alkynyl group, a fluoroalkynyl group, an alkoxyl group, a fluoroalkoxyl group, an acetyl group, a carboxyalkyl group, an alkylamide group, an aromatic ring, a benzenesulfonyl group, a heterocycle (e.g., the heterocycles mentioned above), or a fused ring (e.g., the fused rings mentioned above).

[0052] Regarding (7) above, n is an integer between 0 and 20. For example, n could be an integer between 0 and 17, an integer between 0 and 15, an integer between 0 and 12, an integer between 0 and 10, an integer between 0 and 7, an integer between 0 and 5, or an integer between 0 and 3.

[0053] "X" in chemical formula 2 ２ - (CH ２ ) ｎ The structure of "-" can more specifically be one of the following "structure A-1" to "structure A-14" and "structure A-16".

[0054] The structures A-1 to A-14 and A-16 in chemical formula 2 may be the same as those A-1 to A-14 and A-16 in chemical formula 1, so their explanation is omitted here.

[0055] "-Y" in chemical formula 2 ２ The structure of "-" is the same as "-Y" in chemical formula 1. １ Since it may be the same as the structure of "-" (structure B-1), a detailed explanation is omitted here. Note that in structure B-1 of chemical formula 2, the part indicated by the asterisk (one) is the same as "X" in chemical formula 2. ２ - (CH ２ ) ｎThis is the point where it bonds with the "-" symbol. On the other hand, in the structure B-1 above, the points indicated by the two asterisks are the points where it bonds with the heterocycle (a six-membered ring containing one nitrogen atom (N)) in chemical formula 2.

[0056] [2-3. Salts, hydrates, solvates, and derivatives of compounds represented by chemical formula 1 or chemical formula 2] The salts mentioned above are not limited to salts that are physiologically acceptable to administer to a subject as a pharmaceutical. Examples of the salts mentioned above include alkali metal salts (potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), organic acid salts (acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), and inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.).

[0057] The above-mentioned hydrates and solvates are not limited and may be, for example, hydrates and solvates that are physiologically acceptable for administration to a subject as pharmaceuticals. The number of water molecules and solvent molecules bound to one molecule of the compound is not limited.

[0058] The above derivatives refer to a group of compounds that are produced when a part of the molecule of a particular compound is substituted with another functional group or another atom. Examples of the above other functional groups include alkyl groups, alkoxy groups, alkylthio groups, aryl groups, aryloxy groups, arylthio groups, arylalkyl groups, arylalkoxy groups, arylalkylthio groups, arylalkenyl groups, arylalkynyl groups, allyl groups, amino groups, substituted amino groups, silyl groups, substituted silyl groups, silyloxy groups, substituted silyloxy groups, arylsulfonyloxy groups, alkylsulfonyloxy groups, and nitro groups. Examples of the above other atoms include carbon atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, sulfur atoms, phosphorus atoms, and halogen atoms.

[0059] [2-4. Methods for the Synthesis of Compounds Represented by Chemical Formula 1 or Chemical Formula 2, Their Salts, Their Hydrates, Their Solvates, or Their Derivatives] Compounds represented by Chemical Formula 1 or Chemical Formula 2, their salts, their hydrates, their solvates, or their derivatives can be synthesized from alkyne compounds and azide compounds according to known synthesis methods (e.g., click chemistry) (see also, for example, WO2011 / 089995). An example of a synthesis method is shown below. See also the examples described later for details on the synthesis method.

[0060] [3. Lysine demethylase 3A Inhibitors] A lysine demethylase 3A inhibitor according to one embodiment of the present invention is a lysine demethylase 3A inhibitor that contains a compound according to one embodiment of the present invention, a salt thereof, a hydrate thereof, a solvate thereof, or a derivative thereof as an active ingredient.

[0061] Compounds, salts, hydrates, solvates, or derivatives relating to one embodiment of the present invention have already been described in [2. Compounds, salts, hydrates, solvates, or derivatives thereof] above. These descriptions will be omitted below.

[0062] Lysine demethylase 3A is an enzyme that demethylates the methyl groups of specific lysine residues in histones. This demethylation partially loosens the chromatin structure formed by DNA and histones, making it easier for genes near the demethylated histone sites to be expressed. Lysine demethylase 3A inhibitors can suppress the expression of specific genes by inhibiting the process described above.

[0063] The amount of the active ingredient contained in the lysine demethylase 3A inhibitor according to one embodiment of the present invention is not limited. For example, when the lysine demethylase 3A inhibitor is considered as 100% by mass, the amount may be 0.00001% to 100% by mass, 0.0001% to 100% by mass, 0.001% to 100% by mass, 0.01% to 100% by mass, 0.1% to 100% by mass, and 0.1% by mass. It may be from mass% to 95 mass%, from 0.1 mass% to 90 mass%, from 0.1 mass% to 80 mass%, from 0.1 mass% to 70 mass%, from 0.1 mass% to 60 mass%, from 0.1 mass% to 50 mass%, from 0.1 mass% to 40 mass%, from 0.1 mass% to 30 mass%, from 0.1 mass% to 20 mass%, or from 0.1 mass% to 10 mass%.

[0064] A lysine demethylase 3A inhibitor according to one embodiment of the present invention may contain components other than the active ingredient described above.

[0065] Other components besides the active ingredients listed above are not limited to, but may include, for example, buffering agents, pH adjusters, isotonic agents, preservatives, antioxidants, high molecular weight polymers, excipients, solvents, and antibacterial agents.

[0066] Examples of the buffering agents mentioned above include phosphoric acid or phosphate, boric acid or borate, citric acid or citrate, acetic acid or acetate, carbonate or carbonate, tartaric acid or tartrate, ε-aminocaproic acid, and trometamol. Examples of the phosphates mentioned above include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. Examples of the borates mentioned above include borax, sodium borate, and potassium borate. Examples of the citrates mentioned above include sodium citrate, disodium citrate, and trisodium citrate. Examples of the acetates mentioned above include sodium acetate and potassium acetate. Examples of the carbonates mentioned above include sodium carbonate and sodium bicarbonate. Examples of the tartrates mentioned above include sodium tartrate and potassium tartrate.

[0067] Examples of the pH adjusting agents mentioned above include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, and potassium hydroxide.

[0068] Examples of the above-mentioned isotonic agents include ionic isotonic agents (e.g., sodium chloride, potassium chloride, calcium chloride, magnesium chloride) and nonionic isotonic agents (e.g., glycerin, propylene glycol, sorbitol, mannitol).

[0069] Examples of the above-mentioned preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol.

[0070] Examples of the above antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite.

[0071] Examples of the high molecular weight polymers mentioned above include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose phthalate acetate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, and atelocollagen.

[0072] Examples of the above excipients include lactose, sucrose, D-mannitol, xylitol, sorbitol, erythritol, starch, and crystalline cellulose.

[0073] Examples of the solvents mentioned above include water, physiological saline solution, and alcohol.

[0074] Examples of the above antibacterial agents include β-lactam, aminoglycoside, tetracycline, lincomycin, chloramphenicol, macrolide, ketolide, polypeptide, and glycopeptide antibiotics; and synthetic antibacterial agents such as pyridonecarboxylic acid (quinolone), fluoroquinolone, oxazolidinone, and sulfonamide.

[0075] The amount of components other than the active ingredient contained in the lysine demethylase 3A inhibitor according to one embodiment of the present invention is not limited, and for example, when the therapeutic agent and prophylactic agent are set to 100% by mass, it may be 0% to 99.9999% by mass, 0% to 99.999% by mass, 0% to 99.999% by mass, 0% to 99.99% by mass, 0% to 99.99% by mass, and 5% to 99.9% by mass. It may be a percentage by mass, 10% to 99.9% by mass, 20% to 99.9% by mass, 30% to 99.9% by mass, 40% to 99.9% by mass, 50% to 99.9% by mass, 60% to 99.9% by mass, 70% to 99.9% by mass, 80% to 99.9% by mass, or 90% to 99.9% by mass.

[0076] The target population for administration of the lysine demethylase 3A inhibitor according to one embodiment of the present invention is not limited, and may include, for example, cultured cells, cultured tissues, humans, and non-human animals (e.g., livestock, pets, and laboratory animals). Examples of non-human animals include monkeys, chimpanzees, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, and rats.

[0077] [4. Therapeutic or prophylactic agent for abnormal angiogenesis] The therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention is a therapeutic or prophylactic agent for abnormal angiogenesis that contains a lysine demethylase 3A inhibitor according to one embodiment of the present invention as an active ingredient. The therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention may also be a therapeutic or prophylactic agent for abnormal angiogenesis that consists of a lysine demethylase 3A inhibitor according to one embodiment of the present invention as an active ingredient.

[0078] A lysine demethylase 3A inhibitor according to one embodiment of the present invention has already been described in [3. Lysine Demethylase 3A Inhibitors] above. These descriptions will be omitted below.

[0079] The therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention has the following advantages: (i) it has the effect of fundamentally treating or preventing abnormal angiogenesis, so there is no concern about frequent administration; (ii) it does not affect normal angiogenesis, so there is no concern about side effects; and (iii) it does not suppress angiogenesis like anti-VEGF drugs, so it has a sufficient therapeutic effect on the formation of avascular areas.

[0080] In this specification, "therapeutic agent" means a drug that produces a therapeutic effect. The therapeutic effect refers to, but is not limited to, the effects exemplified below.

[0081] (1) Compared to cases where no therapeutic agent is administered, the severity of abnormal angiogenesis is reduced.

[0082] (2) Compared to cases where no therapeutic agent is administered, the treatment prevents an increase in the severity or progression of abnormal angiogenesis.

[0083] (3) Compared to cases where no therapeutic agent is administered, the rate of increase in the severity of abnormal angiogenesis or the rate of progression is reduced.

[0084] In this specification, "preventive agent" refers to a drug that provides a preventive effect. The preventive effect referred to above is intended to include, but is not limited to, the effects exemplified below.

[0085] (1) Compared to cases where no prophylactic agent is administered, the development of abnormal angiogenesis is prevented or the risk is reduced.

[0086] (2) Compared to cases where no prophylactic agent is administered, the recurrence of abnormal angiogenesis is prevented or the risk is reduced.

[0087] (3) To prevent or reduce the risk of signs of abnormal angiogenesis compared to cases where no prophylactic agent is administered.

[0088] Furthermore, the abnormal angiogenesis described above may be systemic or localized.

[0089] The types of abnormal angiogenesis described above are not limited. Abnormal angiogenesis may include the formation of avascular areas (in other words, areas where blood vessels do not form) and / or the formation of abnormal blood vessels (in other words, the formation of blood vessels that run in a disordered manner). Abnormal angiogenesis may include the formation of avascular areas, or it may include the formation of abnormal blood vessels, or it may include both the formation of avascular areas and the formation of abnormal blood vessels.

[0090] The therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention is a drug that uses a completely different mechanism of action from conventional anti-VEGF drugs and does not suppress angiogenesis. Therefore, as shown in the examples described later, the therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention can treat and prevent not only the formation of abnormal blood vessels but also the formation of avascular areas.

[0091] The diseases in which the above-mentioned abnormal neovascularization occurs are not limited. The above-mentioned abnormal neovascularization may be associated with retinal ischemic disease, cancer, retinopathy of prematurity, age-related macular degeneration, diabetic macular edema, pathological myopia, macular edema associated with retinal vein occlusion, or neovascular glaucoma. The above-mentioned abnormal neovascularization may be associated with retinal ischemic disease, cancer, retinopathy of prematurity, diabetic macular edema, macular edema associated with retinal vein occlusion, or neovascular glaucoma, accompanied by the formation of avascular areas. The above-mentioned abnormal neovascularization may be associated with age-related macular degeneration or pathological myopia, accompanied by the formation of abnormal blood vessels but without the formation of avascular areas.

[0092] A therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention can treat or prevent abnormal angiogenesis associated with the aforementioned diseases. Furthermore, a therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention can treat or prevent increased vascular permeability and ischemia caused by the aforementioned diseases.

[0093] An agent for the treatment or prevention of abnormal angiogenesis according to one embodiment of the present invention may be administered to a subject by any route of administration. Examples of the above-mentioned routes of administration include parenteral administration (e.g., ophthalmic administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, sub-Tenon's capsule administration, intraperitoneal administration), oral administration, transdermal administration, transmucosal administration, and intravenous administration. Therefore, the dosage form of the agent for the treatment or prevention of abnormal angiogenesis according to one embodiment of the present invention may be eye drops, oral medication, topical medication, injection, inhalation, etc.

[0094] The amount of active ingredient contained in the therapeutic or preventive agent for abnormal angiogenesis according to one embodiment of the present invention is not limited. For example, when the therapeutic and preventive agents are considered to be 100% by mass, the amount may be 0.00001% to 100% by mass, 0.0001% to 100% by mass, 0.001% to 100% by mass, 0.01% to 100% by mass, 0.1% to 100% by mass, or 0.1% by mass. It may be % to 95 mass%, 0.1 mass% to 90 mass%, 0.1 mass% to 80 mass%, 0.1 mass% to 70 mass%, 0.1 mass% to 60 mass%, 0.1 mass% to 50 mass%, 0.1 mass% to 40 mass%, 0.1 mass% to 30 mass%, 0.1 mass% to 20 mass%, or 0.1 mass% to 10 mass%.

[0095] When the therapeutic or preventive agent for abnormal angiogenesis according to one embodiment of the present invention is in liquid form, the amount of the active ingredient contained in the therapeutic or preventive agent for abnormal angiogenesis according to one embodiment of the present invention is not limited and may be, for example, (i) 100 nM to 100 mM, 1 μM to 100 mM, 10 μM to 100 mM, or 100 μM to 100 mM; (ii) 100 nM to 10 mM, 1 μM to 10 mM, 10 μM to 10 mM, or 100 μM to 10 mM; or (iii) 100 nM to 1 mM, 1 μM to 1 mM, 10 μM to 1 mM, or 100 μM to 1 mM.

[0096] A therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention may contain components other than the active ingredient described above. These components other than the active ingredient may be the same as the components other than the active ingredient described above in [3. Lysine demethylase 3A inhibitors].

[0097] The amount of components other than the active ingredient contained in the therapeutic or preventive agent for abnormal angiogenesis according to one embodiment of the present invention is not limited. For example, when the therapeutic and preventive agents are considered as 100% by mass, the amount of components other than the active ingredient may be 0% to 99.99999% by mass, 0% to 99.999% by mass, 0% to 99.999% by mass, 0% to 99.99% by mass, 0% to 99.99% by mass, or 5% to 99.9 It may be mass%, 10% to 99.9% by mass, 20% to 99.9% by mass, 30% to 99.9% by mass, 40% to 99.9% by mass, 50% to 99.9% by mass, 60% to 99.9% by mass, 70% to 99.9% by mass, 80% to 99.9% by mass, or 90% to 99.9% by mass.

[0098] The administration interval of the therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention is not limited and may be administered, for example, once every 12 hours, once a day, once every two days, once every three days, once every four days, or once every five days. The administration period of the therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention is not limited and may be, for example, three days, five days, seven days, ten days, fifteen days, or thirty days. Since the therapeutic or prophylactic agent according to one embodiment of the present invention can fundamentally treat or prevent abnormal angiogenesis, it does not require excessively frequent administration.

[0099] The target population for administration of the therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention is not limited to humans and non-human animals (e.g., livestock, pets, and laboratory animals). Examples of non-human animals include monkeys, chimpanzees, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, and rats.

[0100] [5. Others] <1> A method for inhibiting lysine demethylase 3A, comprising the step of administering a lysine demethylase 3A inhibitor according to one embodiment of the present invention to a subject (for example, cultured cells, cultured tissue, human, or non-human animal).

[0101] <2> A method for treating or preventing abnormal angiogenesis, comprising the step of administering a therapeutic or preventive agent for abnormal angiogenesis according to one embodiment of the present invention to a subject (for example, a human or a non-human animal).

[0102] <3> The abnormal angiogenesis described above is the formation of an avascular area and / or the formation of abnormal blood vessels, a method for treating or preventing abnormal angiogenesis as described in <2>.

[0103] <4> The abnormal neovascularization described above is abnormal neovascularization associated with retinal ischemic disease, cancer, retinopathy of prematurity, age-related macular degeneration, diabetic macular edema, pathological myopia, macular edema associated with retinal vein occlusion, or neovascular glaucoma, and is a method for treating or preventing the abnormal neovascularization described in <2> or <3>.

[0104] <5> Use of (i) a compound represented by chemical formula 1, a salt thereof, a hydrate thereof, a solvate thereof, or a derivative thereof, and / or (ii) a compound represented by chemical formula 2, a salt thereof, a hydrate thereof, a solvate thereof, or a derivative thereof, for the manufacture of a lysine demethylase 3A inhibitor according to one embodiment of the present invention, or a therapeutic or prophylactic agent for abnormal angiogenesis according to one embodiment of the present invention.

[0105] This invention may also contribute to achieving Goal 3 of the United Nations' Sustainable Development Goals (SDGs), "Ensure healthy lives and promote well-being for all."

[0106] The present invention will be described in more detail below based on examples, but the present invention is not limited to the following examples.

[0107] <1. Synthesis of Azide-Alkyne Conjugates> Various azide-alkyne conjugates were synthesized by reacting various azide compounds with various alkyne compounds in the presence of a copper catalyst, following click chemistry. For the synthesis procedure, please also refer to the synthesis procedure described in [2-4. Synthesis Method of Compounds Represented by Chemical Formula 1 or Chemical Formula 2, Their Salts, Their Hydrates, Their Solvates, or Their Derivatives] above.

[0108] Tables 1 to 3 below list the alkyne and azide compounds used in the click chemistry to synthesize the "azide-alkyne conjugate" corresponding to "Chemical Formula 1".

[0109] Table 4 below lists the alkyne compounds used in the click chemistry to synthesize the "azide-alkyne conjugate" corresponding to "Chemical Formula 2". The azide compounds used in the click chemistry to synthesize the "azide-alkyne conjugate" corresponding to "Chemical Formula 2" were Az1 to Az33 and Az35, as listed in Tables 2 and 3.

[0110] In the following, the abbreviations for azido-alkyne conjugates will be described according to the abbreviations of the azido compound and the alkyne compound used in the synthesis of the azido-alkyne conjugate. For example, the abbreviation for an azido-alkyne conjugate synthesized using an azido compound (AX) and an alkyne compound (AKY) will be "X-Y". More specifically, the abbreviation for an azido-alkyne conjugate synthesized using an azido compound (Az1) and an alkyne compound (Ak4) will be "Z1-4", the abbreviation for an azido-alkyne conjugate synthesized using an azido compound (Az1) and an alkyne compound (Ak5) will be "Z1-5", and the abbreviation for an azido-alkyne conjugate synthesized using an azido compound (Az1) and an alkyne compound (Ak6) will be "Z1-6".

[0111] The synthesis method for the "azide-alkyne conjugate" corresponding to "Chemical Formula 1" is described below. On a 96-well plate, a DMSO solution of the alkyne compound listed in Table 1 (final concentration 5.0 mM), a DMSO solution of the azide compound listed in Table 2 or Table 3 (final concentration 6.5 mM), a DMSO solution of TBTA (final concentration 0.5 mM), and an aqueous solution of copper(II) sulfate pentahydrate (final concentration 0.5 mM) were mixed. Then, an aqueous solution of sodium ascorbate (final concentration 0.5 mM) was added to the mixture, and the mixture was stirred at room temperature for 72 hours. The endpoint of the reaction was determined by analyzing the reaction product by TLC. No isolation or purification was performed on any of the reaction products.

[0112] The synthesis method for the "azide-alkyne conjugate" corresponding to "Chemical Formula 2" is described below. On a 96-well plate, a DMSO solution of the alkyne compound listed in Table 4 (final concentration 5.0 mM), a DMSO solution of the azide compound listed in Table 2 or Table 3 (final concentration 6.5 mM), a DMSO solution of TBTA (final concentration 0.5 mM), and an aqueous solution of copper(II) sulfate pentahydrate (final concentration 0.5 mM) were mixed. Then, an aqueous solution of sodium ascorbate (final concentration 0.5 mM) was added to the mixture, and the mixture was stirred at room temperature for 72 hours. The endpoint of the reaction was determined by analyzing the reaction products by TLC. No isolation or purification was performed on the reaction products.

[0113] To further understand the synthesis methods of each "azide-alkyne conjugate," a more detailed synthesis scheme for each "azide-alkyne conjugate" is shown below.

[0114] <Ethyl 7-azidoheptanoate> NaN3 is added to a DMF (20 mL) solution containing Ethyl 7-bromoheptanoate (2.37 g, 10.0 mmol). ３ (1.30 g, 20.0 mmol) was added, and the mixture was heated at 80°C for 18 hours. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with a brine, and then Na ２ SO ４ The organic phase was dried. After removing the solvent from the organic phase, the resulting residue was purified by column chromatography (hexane / AcOEt = 95 / 5 to 90 / 10) to obtain 1.79 g of a colorless oily product. The yield was 90%. The analytical data of the colorless oily product is shown below.

[0115] 1 H NMR (400 MHz, CDCl3) δ: 4.12 (q, J = 7.6 Hz, 2H), 3.26 (t, J = 7.2 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H), 1.67-1.57 (m, 4H), 1.43-1.31 (m, 4H), 1.25 (t, J = 7.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ: 173.7, 60.2, 51.3, 34.2, 28.6, 28.6, 26.4, 24.8, 14.2.

[0116] <tert-Butyl 6-bromonicotinate> 6-bromonicotinic acid (2.02 g, 10.0 mmol) and DMAP (123 mg, 1.00 mmol) are mixed in a t-BuOH (10 mL) solution with Boc ２ ​After adding O (3.21 g, 14.7 mmol), the mixture was heated at 60 °C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and the solvent was distilled off. The obtained residue was purified by column chromatography (changing from hexane / AcOEt = 100 / 0 to 90 / 10), and 1.82 g of a white solid was obtained. The yield was 71%. The analytical data of the white solid are shown below.

[0117] 1 H NMR (400 MHz, CDCl3) δ: 8.89 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 8.4, 2.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 1.59 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ: 163.6, 151.4, 146.2, 139.1, 127.8, 127.0, 82.6, 28.1.; HR-MS (ESI): m / z: calcd for C 10 H 13 BrNO2: 258.0124, found 258.0123 [M + H] + .

[0118] <tert-Butyl 6-((trimethylsilyl)ethynyl)nicotinate> tert-Butyl 6-bromonicotinate (1.55 g, 6.00 mmol) and PdCl ２ (PPh ３ ) ２ (211 mg, 0.300 mmol) and CuI (60.3 mg, 0.317 mmol) and Et ３To a solution of N (1.70 mL, 12.3 mmol) in MeCN (20 mL), trimethylsilylacetylene (1.25 mL, 9.00 mmol) was added under an argon atmosphere. The mixture was heated at 60 °C for 24 hours under an argon atmosphere. After completion of the reaction, the mixture was cooled to room temperature and the solvent was distilled off. The resulting residue was purified by column chromatography (changing from hexane / AcOEt = 100 / 0 to 95 / 5), and 1.49 g of a pale yellow solid was obtained. The yield was 90%. The analytical data of the pale yellow solid are shown below.

[0119] 1 H NMR (400 MHz, CDCl3) δ: 9.08 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 1.60 (s, 9H), 0.28 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ: 163.9, 150.9, 146.0, 136.9, 126.6, 126.5, 103.2, 97.9, 82.3, 28.1, -0.4.; HR-MS (ESI): m / z: calcd for C 15 H 22 NO2Si: 276.1414, found 276.1413 [M + H] + 。

[0120] <tert-Butyl 6-ethynylnicotinate> To a solution of tert-Butyl 6-((trimethylsilyl)ethynyl)nicotinate (1.38 g, 5.00 mmol) in MeOH (10 mL), K ２ CO ３ (346 mg, 2.50 mmol) was added, and then the mixture was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (10 mL) and water (10 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with brine and then Na ２ SO ４The organic phase was dried. After removing the solvent from the organic phase, the resulting residue was purified by column chromatography (hexane / AcOEt = 100 / 0 to 92 / 8) to obtain 945 mg of a grayish-white solid. The yield was 93%. The analytical data for the grayish-white solid is shown below.

[0121] 1 H NMR (400 MHz, CDCl3) δ: 9.11 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.29 (s, 1H), 1.60 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ: 163.7, 151.0, 145.3, 137.1, 127.0, 126.8, 82.4, 82.3, 79.5, 28.1.; HR-MS (ESI): m / z: calcd for C 12 H 14 NO2: 204.1019, found 204.1018 [M + H] + .

[0122] <tert-Butyl 6-(1-(7-ethoxy-7-oxoheptyl)-1H-1,2,3-triazol-4-yl)nicotinate> THF / H containing azide (401 mg, 2.01 mmol) and alkyne (407 mg, 2.00 mmol) ２ CuSO4 (10 mL / 5 mL) solution ４ ・5H ２ After adding O (51.2 mg, 0.205 mmol) and sodium L-ascorbate (117.9 mg, 0.595 mmol), the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the resulting organic phase was washed with a brine, followed by Na ２ SO ４ ​The organic phase was dried. After removing the solvent from the organic phase, the resulting residue was purified by column chromatography (hexane / AcOEt = 66 / 34 to 50 / 50) to obtain 743 mg of a white solid. The yield was 92%. The analytical data of the white solid is shown below.

[0123] 1 H NMR (400 MHz, CDCl3) δ: 9.12 (d, J = 2.0 Hz, 1H), 8.30 (dd, J = 8.4, 2.0 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 4.43 (t, J = 6.8 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 2.28 (t, J = 7.2 Hz, 2H), 2.00-1.94 (m, 2H), 1.62 (s, 9H), 1.64-1.58 (m, 2H), 1.42-1.35 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ: 173.5, 164.3, 153.3, 150.8, 147.7, 137.8, 126.5, 122.8, 119.3, 81.9, 60.3, 50.4, 34.1, 30.0, 28.4, 28.2, 26.1, 24.6, 14.2.; HR-MS (ESI): m / z: calcd for C 21 H 30 N4NaO4: 425.2159, found 425.2153 [M + Na] + .

[0124] <Ethyl 7-(4-(5-((methylsulfonyl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)heptanoate (TAB02-174)> tert-Butyl CH containing 6-(1-(7-ethoxy-7-oxoheptyl)-1H-1,2,3-triazol-4-yl)nicotinate (201 mg, 0.498 mmol) ２ Cl ２ ​(5 mL) of TFA was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed from the mixture by distillation, and then the mixture was azeotropically stirred three times with toluene. The resulting pale yellow solid was used directly in the next reaction.

[0125] CH4 containing the crude product ２ Cl ２ (5 mL) MeSO ２ NH ２ (95.4 mg, 1.00 mmol) of 2-chloro-1-methylpyridinium iodide (56 mg, 0.610 mmol) and DMAP (4.18 mg, 0.0342 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. ３ After slowly adding N (208 μL, 1.50 mmol), the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed from the mixture by distillation, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with 1 M hydrochloric acid and brine, and then Na ２ SO ４ The organic phase was dried using [a specific method]. After removing the solvent from the organic phase, the resulting residue was subjected to column chromatography (CHCl3). ３ The crude product was purified using a solution of cyclohexane / HCl (changing from 100 / 0 to 90 / 10), yielding 124 mg of a white solid. The crude product was then purified using a solution of cyclohexane / HCl. ３ Recrystallization was performed to obtain 117 mg of a white solid. The yield was 55% after two steps. The analytical data for this white solid is shown below.

[0126] 1 ​H NMR (400 MHz, CDCl3) δ: 9.03 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.23 ​​(dd, J = 8.4, 2.4 Hz, 1H), 8.21 (s, 1H), 4.44 (t, J = 7.4 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.48 (s, 3H), 2.29 (t, J = 7.4 Hz, 2H), 2.01-1.94 (m, 2H), 1.66-1.59(m, 2H), 1.40-1.37 (m, 4H), 1.24 (t, J = 7.2 Hz); 13 C NMR (100 MHz, CDCl3) δ: 173.7, 164.1, 154.4, 149.2, 147.1, 136.6, 125.6, 123.4, 119.8, 60.3, 50.5, 41.9, 34.1, 30.0, 28.4, 26.1, 24.6, 14.2.; HR-MS (ESI): m / z: calcd for C 18 H 25 N5NaO5S: 446.1469, found 446.1464 [M + Na] + .

[0127] <Ethyl 7-(4-(5-((methylsulfonyl)carbamyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)heptanoate Hydrochloride (TAB04-019)> Hydrochloric acid (1,4-dioxane solution, 4M, 4.0 mL) was added to a 1,4-dioxane (2.0 mL) solution containing TAB02-174 (84.7 mg, 0.200 mmol), and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed from the mixture by distillation to precipitate a solid. The solid was then dissolved in CHCl3. ３ The sample was washed and dried under reduced pressure to obtain 91.7 mg of a white solid. The yield was 99%.

[0128] <Ethyl 7-(4-(5-((methylsulfonyl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)heptanoate Sulfate (TAB04-020)> A solution of CHCl3 (2.0 mL) containing TAB02-174 (84.8 mg, 0.200 mmol) is mixed with H ２ SO ４ (8.81 mg, 0.0898 mmol) of acetone solution (2.0 mL) was slowly added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the precipitated solid was collected in CHCl3. ３ The sample was washed and dried under reduced pressure to obtain 80.3 mg of a white solid. The yield was 85%.

[0129] <7-(4-(5-((methylsulfonyl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)heptanoic acid (TAB02-181)> THF / H containing TAB02-174 (42.5mg, 0.100mmol) ２ LiOH·H in a 2.0 mL / 2.0 mL solution ２ After adding O (7.38 mg, 0.176 mmol), the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed from the mixture by distillation, and then 2 M hydrochloric acid was added to the mixture to adjust the pH to 2 and precipitate a solid. The solid was then heated to H ２ The sample was washed with oxygen and dried under reduced pressure at 60°C to obtain 34.4 mg of a white solid. The yield was 87%. The analytical data for the white solid is shown below.

[0130] 1 ​H NMR (400 MHz, DMSO-d6) δ: 12.38 (brs, 1H), 11.96 (brs, 1H), 9.08 (d, J = 2.4 Hz, 1H), 8.79 (s, 1H), 8.38 (dd, J = 8.0, 2.4 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 4.43 (t, J = 6.8 Hz, 2H), 3.40 (s, 3H), 2.17 (t, J = 7.2 Hz, 2H), 1.91-1.83 (m, 2H), 1.51-1.43 (m, 2H), 1.34-1.21 (m, 4H).; 13 C NMR (100 MHz, DMSO-d6) δ: 174.4, 164.9, 153.5, 149.7, 146.2, 137.4, 126.3, 124.5, 118.8, 49.6, 41.4, 33.5, 29.4, 27.8, 25.5, 24.2.; HR-MS (ESI): m / z: calcd for C 16 H 21 N5NaO5S: 418.1156, found 418.1151 [M + Na] + .

[0131] <Ethyl 6-(1-(7-ethoxy-7-oxoheptyl)-1H-1,2,3-triazol-4-yl)nicotinate (TAB03-022)> tert-Butyl CH containing 6-(1-(7-ethoxy-7-oxoheptyl)-1H-1,2,3-triazol-4-yl)nicotinate (100mg, 0.248mmol) ２ Cl ２ (5.0 mL) of TFA was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed from the mixture by distillation, and then the mixture was azeotropically stirred three times with toluene. The resulting pale yellow solid was used directly in the next reaction.

[0132] CH4 containing the crude product ２ Cl ２ (5.0 mL) EtOH (60.0 μL, 1.03 mmol) and Et ３After adding N (104 μL, 0.750 mmol) and EDCI·HCl (72.2 mg, 0.377 mmol), the mixture was stirred at room temperature for 10 hours. After the reaction was complete, water (5 mL) was added to the mixture, and the solvent was removed by distillation. The mixture was then extracted with ethyl acetate. The resulting organic phase was washed with a brine, and then Na ２ SO ４ The organic phase was dried. After removing the solvent from the organic phase, the resulting residue was purified by column chromatography (hexane / AcOEt = 66 / 34 to 50 / 50) to obtain 58.9 mg of a white solid. The yield after the two steps was 63%. The analytical data of the white solid is shown below.

[0133] 1 H NMR (400 MHz, CDCl3) δ: 9.16 (d, J = 1.8 Hz, 1H), 8.36 (dd, J = 8.3, 1.8 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.19 (s, 1H), 4.42 (t, J = 7.6 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 4.10 (q, J = 6.8 Hz, 2H), 2.27 (t, J = 7.2Hz, 2H), 2.00-1.93 (m, 2H), 1.65-1.57 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.41-1.34 (m, 4H), 1.23 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ: 173.5, 165.1, 153.7, 150.8, 147.6, 137.6, 125.0, 122.9, 119.4, 61.3, 60.2, 50.4, 34.1, 30.0, 28.4, 26.1, 24.6, 14.3, 14.2; HR-MS (ESI): m / z: calcd for C 19 H 26 N4NaO4: 397.1846, found 397.1844 [M + Na] + .

[0134] ​<6-(1-(6-carboxyhexyl)-1H-1,2,3-triazol-4-yl)nicotinic acid (TAB03-026)> tert-Butyl CH containing 6-(1-(7-ethoxy-7-oxoheptyl)-1H-1,2,3-triazol-4-yl)nicotinate (101 mg, 0.249 mmol) ２ Cl ２ (5.0 mL) of TFA was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed from the mixture by distillation, and then the mixture was azeotropically stirred three times with toluene. The resulting pale yellow solid was used directly in the next reaction.

[0135] MeOH / H containing crude product ２ NaOH (23.2 mg, 0.580 mmol) was added to a 5.0 mL / 5.0 mL solution of O, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed from the mixture by distillation, and then 2 M hydrochloric acid was added to the mixture to adjust the pH to 2 and precipitate a solid. The solid was then heated to H ２ The material was washed with O and dried under reduced pressure at 60°C to obtain 57.6 mg of a white solid. The yield after the two steps was 73%. The analytical data for the white solid is shown below.

[0136] 1 H NMR (400 MHz, DMSO-d6) δ: 9.06 (d, J = 2.4 Hz, 1H), 8.75 (s, 1H), 8.34 (dd, J = 8.3, 2.4 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 4.42 (t, J = 7.2 Hz, 2H), 2.17 (t, J = 7.2 Hz, 2H), 1.90-1.83 (m, 2H), 1.51-1.44 (m, 2H), 1.34-1.21 (m, 4H); 13 ​C NMR (100 MHz, DMSO-d6) δ: 174.4, 166.0, 153.3, 150.5, 146.4, 138.1, 125.3, 124.3, 119.0, 49.6, 33.5, 29.4, 27.8, 25.5, 24.2; HR-MS (ESI): m / z: calcd for C 15 H 28 N4NaO4: 341.1220, found 341.1217 [M + Na] + .

[0137] <Methyl 3-(azidomethyl)benzote> A solution of DMF (20 mL) containing Methyl 3-(bromomethyl)benzote (1.17 g, 5.11 mmol) is mixed with NaN. ３ After adding (650 mg, 10.0 mmol), the mixture was heated at 80°C for 14 hours. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with a brine, and then Na ２ SO ４ The organic phase was dried. After removing the solvent from the organic phase, the resulting residue was purified by column chromatography (hexane / AcOEt = 100 / 0 to 95 / 5) to obtain 930 mg of a colorless oily product. The yield was 95%. The analytical data of the colorless oily product is shown below.

[0138] 1 H NMR (400 MHz, CDCl3) δ: 8.02 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.0, 7.2 Hz, 1H), 4.41 (s, 2H), 3.93 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 166.6, 135.9, 132.5, 130.8, 129.5, 129.2, 129.0, 54.3, 52.2.

[0139] ​<tert-Butyl 6-(1-(3-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)nicotinate> THF / H containing azide (408 mg, 2.14 mmol) and alkyne (407 mg, 2.00 mmol) ２ CuSO4 (10 mL / 5.0 mL) solution ４ ・5H ２ O (50.1 mg, 0.201 mmol), TBTA (106 mg, 0.201 mmol), and sodium L-ascorbate (118 mg, 0.595 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the resulting organic phase was washed with a brine, followed by Na ２ SO ４ The organic phase was dried. After removing the solvent from the organic phase, the resulting residue was purified by column chromatography (hexane / AcOEt = 85 / 15 to 67 / 33) to obtain 735 mg of a white solid. The yield was 93%. The analytical data of the white solid is shown below.

[0140] 1 H NMR (400 MHz, CDCl3) δ: 9.08 (d, J = 2.0 Hz, 1H), 8.30 (dd, J = 8.0, 2.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 8.06-8.04 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.0, 8.0 Hz, 1H), 5.64 (s, 3H), 3.92 (s, 3H), 1.61 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ: 166.3, 164.2, 153.0, 150.8, 148.3, 137.9, 134.6, 132.7, 131.2, 130.2, 129.4, 126.6, 122.9, 119.4, 82.0, 54.0, 52.3, 28.2; HR-MS (ESI): m / z: calcd for C 21 H 22 ​N4NaO4: 417.1533, found 417.1525 [M + Na] + .

[0141] <Methyl 3-((4-(5-((methylsulfonyl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)benzoate (TAB03-122)> CH containing tert-Butyl 6-(1-(3-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)nicotinate (198 mg, 0.501 mmol) ２ Cl ２ (10 mL) of solution was mixed with TFA (5.0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed from the mixture by distillation, and then the mixture was azeotropically stirred three times with toluene. The resulting pale yellow solid was used directly in the next reaction.

[0142] CH4 containing the crude product ２ Cl ２ (5.0 mL) contains MeSO ２ NH ２ Et (96.4 mg, 1.01 mmol) was added to 2-Chromo-1-methylpyridinium iodide (156 mg, 0.609 mmol) and DMAP (5.23 mg, 0.0428 mmol), and the mixture was stirred at room temperature for 10 minutes. ３ After slowly adding N (208 μL, 1.50 mmol), the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed from the mixture by distillation, and the mixture was extracted with chloroform. The resulting organic phase was washed with 1 M hydrochloric acid and brine, and then Na ２ SO ４ The organic phase was dried using [a specific method]. After removing the solvent from the organic phase, the resulting residue was subjected to column chromatography (CHCl3). ３ The crude product was purified using a solution of cyclohexane / HCl (changing from 100 / 0 to 90 / 10), yielding 130 mg of a white solid. The crude product was then purified using a solution of cyclohexane / HCl. ３Recrystallization was performed to obtain 102 mg of a white solid. The yield was 49% after two steps. The analytical data for this white solid is shown below.

[0143] 1 H NMR (400 MHz, DMSO-d6) δ: 9.06 (d, J = 2.2 Hz, 1H), 8.89 (s, 1H), 8.36 (dd, J = 8.4, 2.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 8.0 Hz, 1H), 5.78 (s, 1H), 3.84 (s, 3H), 3.31 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ: 165.9, 165.2, 153.0, 149.8, 146.7, 137.5, 136.6, 133.1, 130.2, 129.5, 129.1, 128.8, 127.1, 124.9, 118.9, 52.6, 52.3, 41.3; HR-MS (ESI): m / z: calcd for C 18 H 17 N5NaO5S: 438.0843, found 438.0834 [M + Na] + .

[0144] <Benzyl Azide> A solution of DMF (20 mL) containing Benzyl bromide (3.43 g, 20.1 mmol) is mixed with NaN. ３ (1.95 g, 30.0 mmol) was added, and the mixture was heated at 60°C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with a brine, and then Na ２ SO ４ ​The organic phase was dried. After removing the solvent from the organic phase, the resulting residue was purified by column chromatography (hexane / AcOEt = 100 / 0 to 95 / 5) to obtain 2.44 g of a colorless oily product. The yield was 91%. The analytical data of the colorless oily product is shown below.

[0145] 1 H NMR (400 MHz, CDCl3) δ: 7.41-7.32 (m, 5H), 4.35 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ: 135.3, 128.8, 128.3, 128.2, 54.8.

[0146] <Methyl 6-((trimethylsilyl)ethynyl)nicotinate> Methyl 6-bromonicotinate (3.24 g, 15.0 mmol) and PdCl ２ (PPh ３ ) ２ (526 mg, 0.749 mmol) and CuI (143 mg, 0.751 mmol) and Et ３ Trimethylsilylacetylene (3.20 mL, 23.1 mmol) was added to a 30 mL solution of MeCN containing N (4.20 mL, 30.3 mmol) under an argon atmosphere. The mixture was heated at 50°C under an argon atmosphere for 12 hours. After the reaction was complete, the solvent was removed by distillation, and the residue was purified by column chromatography (hexane / AcOEt = 96 / 4 to 90 / 10) to obtain 3.32 g of a pale yellow solid. Yield 95%.

[0147] 1 1H NMR (400 MHz, CDCl3, δ; ppm) 9.15 (1H, d, J = 1.6 Hz), 8.24 (1H, dd, J = 8.2, 2.4 Hz), 7.52 (1H, dd, J = 8.2, 1.6 Hz), 3.95 (3H, s), 0.28 (9H, s); 13 ​​C NMR (100 MHz, CDCl3) 165.3, 151.0, 146.6, 137.1, 126.7, 124.8, 103.0, 98.5, 52.5, -0.42.

[0148] <Methyl 6-ethynylnicotinate> Methyl 6-((trimethylsilyl)ethynyl)nicotinate (3.27 g, 14.0 mmol) in a 30 mL solution of MeOH and K ２ CO ３ (3.87 g, 28.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered to remove the solid, and the solvent was removed from the mixture by distillation. The resulting residue was purified by column chromatography (hexane / AcOEt = 90 / 10 to 80 / 20) to obtain 2.10 g of a white solid. The yield was 93%. The analytical data of the white solid is shown below.

[0149] 1 H NMR (400 MHz, CDCl3) δ: 9.17 (d, J = 1.6 Hz, 1H), 8.27 (dd, J = 7.6, 1.6 Hz, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 3.96 (s, 3H), 3.31 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ: 165.1, 151.0, 145.8, 137.3, 127.0, 125.3, 82.2, 80.0, 52.6.

[0150] <Methyl 6-(1-benzyl-1H-1,2,3-triazol-4-yl)nicotinate (TAB02-184)> THF / H containing azide (280 mg, 2.10 mmol) and alkyne (322 mg, 2.00 mmol) ２ CuSO4 (10 mL / 5.0 mL) solution ４ ・5H ２ ​O (50.3 mg, 0.201 mmol), TBTA (106 mg, 0.200 mmol), and sodium L-ascorbate (121 mg, 0.611 mmol) were added, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the resulting organic phase was washed with a brine, followed by Na ２ SO ４ The organic phase was dried using [a specific method]. After removing the solvent from the organic phase, the resulting residue was subjected to column chromatography (CHCl3). ３ The mixture was purified using a method that changed AcOEt from 85 / 15 to 75 / 25, yielding 406 mg of a white solid. The yield was 69%. The analytical data for the white solid is shown below.

[0151] 1 H NMR (400 MHz, CDCl3) δ: 9.12 (d, J = 2.0 Hz, 1H), 8.36 (dd, J = 8.0, 2.0 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.42-7.37 (m, 3H), 7.35-7.32 (m, 2H), 5.60 (s, 2H), 3.95 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 165.6, 153.7, 150.8, 148.0, 138.0, 134.1, 129.2, 129.0, 128.3, 124.8, 123.0, 119.5, 54.5, 52.4; (ESI): m / z: calcd for C 16 H 14 N4NaO2: 317.1009, found 317.1005 [M + Na] + .

[0152] <6-(1-benzyl-1H-1,2,3-triazol-4-yl)nicotinic acid (TAB02-185)> MeOH / H containing TAB02-184 (147 mg, 0.500 mmol) ２ ​NaOH (42.8 mg, 1.07 mmol) was added to a 5.0 mL / 5.0 mL solution of O, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was removed from the mixture by distillation, and then 2 M hydrochloric acid was added to the mixture to adjust the pH to 2 and precipitate a solid. The solid was then heated to H ２ The sample was washed with O and dried under reduced pressure at 60°C to obtain 133 mg of a white solid. The yield was 95%. The analytical data for the white solid is shown below.

[0153] 1 H NMR (400 MHz, DMSO-d6) δ: 9.06 (d, J = 2.4 Hz, 1H), 8.82 (s, 1H), 8.34 (dd, J = 8.2, 2.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.39-7.31 (m, 5H), 5.68 (s, 2H); 13 C NMR (100 MHz, DMSO-d6) δ: 166.0, 153.1, 150.6, 146.7, 138.2, 135.8, 128.8, 128.3, 128.1, 125.4, 124.6, 119.1, 53.1; (ESI): m / z: calcd for C 15 H 12 N4NaO2: 303.0852, found 303.0850 [M + Na] + .

[0154] <2. Inhibitory Activity of Azide-Alkyne Conjugates Against Lysine Demethylase 3A> The synthesized azide-alkyne conjugates were subjected to AlphaScreen Assay without purification, and their inhibitory activity against lysine demethylase 3A was evaluated. In AlphaScreen Assay, recombinant enzymes from BPS Biosciences, Inc., and acceptor beads and donor beads from PerkinElmer, Inc. were used to evaluate the inhibitory activity against lysine demethylase 3A. The outline of AlphaScreen Assay is described below.

[0155] ​First, 2.5 μL of assay buffer solution (3% DMSO) containing a 100 μM sample (azide-alkyne conjugate) was added to a white, opaque OptiPlate™-384 well to create a control or blank.

[0156] Next, 5.0 μL of enzyme solution (assay buffer containing lysine demethylase 3A protein) was added to each well of the test plate (for the blank, 5.0 μL of assay buffer was added instead of the enzyme solution), and then 2.5 μL of the mixture (substrate peptide / 2-OG (50 μM) / Fe (5 μM) / Asc (100 μM)) was added. The final enzyme concentration was 0.2 nM, and the final substrate peptide concentration was 60 nM. The test plate was incubated at room temperature for 2 hours with gentle shaking (250 rpm).

[0157] Next, 5.0 μL (100 μg / mL) of epigenetic buffer containing antibody-conjugated acceptor beads was added to each well. The test plate was incubated at room temperature for 1 hour while gently shaking (250 rpm).

[0158] Next, 10 μL (50 μg / mL) of epigenetic buffer containing donor beads was added to each well. The test plate was incubated at room temperature for 30 minutes under light-shielding conditions.

[0159] The Alpha signals generated in each well were measured using an Ensight™ multilabel reader (PerkinElmer Ltd.) under conditions of excitation wavelength 615 nm and emission wavelength 655 nm.

[0160] Enzyme activity value A was calculated from the Alpha signal readings of the well containing the sample (azide-alkyne conjugate). Enzyme activity value B was calculated from the Alpha signal readings of the control well. The percentage of enzyme activity value A relative to enzyme activity value B (set as 100%) was calculated.

[0161] Figure 1 shows the evaluation results of the inhibitory activity of the "azide-alkyne conjugate" corresponding to "chemical formula 1" against lysine demethylase 3A. As is clear from Figure 1, it was found that the "azide-alkyne conjugate" corresponding to "chemical formula 1" has inhibitory activity against lysine demethylase 3A.

[0162] Figure 2 shows the evaluation results of the inhibitory activity of the "azide-alkyne conjugate" corresponding to "chemical formula 2" against lysine demethylase 3A. As is clear from Figure 2, it was found that the "azide-alkyne conjugate" corresponding to "chemical formula 2" has inhibitory activity against lysine demethylase 3A.

[0163] <3. Intravitreal administration of azido-alkyne conjugates> OIR model mice that developed abnormal angiogenesis (see "Kip M Connor et al., "Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis" Nat Protoc., 2009, 4(11), 1565-1573" and "Andreas Stabl et al., "The Mouse Retina as an Angiogenesis Model" Investigative Ophthalmology and Visual Science, June 2010, Vol.51, No.6, 2813-2826") were intravitreal-administered azido-alkyne conjugates with lysine demethylase 3A inhibitory activity, and their effect on abnormal angiogenesis was confirmed.

[0164] As described in <2. Inhibitory Activity of Azide-Alkyne Conjugates Against Lysine Demethylase 3A Inhibition> above, the inventors have succeeded in identifying numerous azido-alkyne conjugates that possess lysine demethylase 3A inhibitory activity. Tests to confirm the effect on abnormal angiogenesis require a long time, a lot of effort, and a lot of expense. Since it is not practical to conduct this test on all of the numerous azido-alkyne conjugates that possess lysine demethylase 3A inhibitory activity, the following azido-alkyne conjugates were used in this test as representatives of the numerous azido-alkyne conjugates.

[0165] Mice at 7 days of age (P7) were raised under 75% volume oxygen conditions for 5 days until they reached 12 days of age (P12). Subsequently, the 12-day-old (P12) mice were raised under atmospheric conditions. By switching the rearing conditions from high oxygen concentration to low oxygen concentration, abnormal neovascularization (formation of avascular areas (in other words, formation of areas where blood vessels do not form) and abnormal vascular formation (in other words, formation of blood vessels that run in a disordered manner)) was induced in the retina.

[0166] The mice described above were administered PBS containing azide-alkyne conjugates at various concentrations (e.g., 1 mM, 100 μM, 10 μM, or 1 μM) intravitreously into the right (or left) eye at 12 days of age (P12). As a control study, the same mice were administered PBS intravitreously into the left (or right) eye at 12 days of age (P12). The azide-alkyne conjugates tested showed high solubility in PBS.

[0167] At 17 days of age, the retinas were collected from the mice described above, and abnormal neovascularization on the retinas was observed under a microscope. Based on the observed images, the total retinal area, the avascular area, and the area of ​​abnormal vascularization were calculated.

[0168] Figure 3 shows the test results for TAB02-174 (ester prodrug of Z3-5) at a concentration of 10 μM, Figure 4 shows the test results for TAB02-181 (Z3-5) at a concentration of 10 μM, Figure 5 shows the test results for TAB02-184 at a concentration of 10 μM, Figure 6 shows the test results for TAB02-185 at a concentration of 10 μM, Figure 8 shows the test results for TAB04-019 at a concentration of 100 nM, Figure 9 shows the test results for TAB04-020 at a concentration of 100 nM, Figure 10 shows the test results for TAB02-174 at a concentration of 100 nM, and Figure 11 shows the test results for TAB03-122 at a concentration of 10 μM.

[0169] As is clear from the test results shown in Figures 3-6 and 8-11, the control mice showed widespread avascularization and abnormal vascularization on the retina. On the other hand, in mice administered these azid-alkyne conjugates, avascularization and / or abnormal vascularization were observed only in narrow areas of the retina.

[0170] On the other hand, the graphs shown in Figures 3 to 6 and 8 to 11 show the ratio of the area of ​​abnormal blood vessels to the total area of ​​the retina, and the ratio of the area of ​​avascular regions to the total area of ​​the retina. As is clear from the test results in the graphs shown in Figures 3 to 6 and 8 to 11, in the control mice, the formation of avascular regions and abnormal blood vessels was observed over a wide area of ​​the retina. In contrast, in mice administered these azid-alkyne conjugates, the formation of avascular regions and / or abnormal blood vessels was observed only in a narrow area of ​​the retina.

[0171] <4. Metabolic Stability Test of Azide-Alkyne Conjugates> The metabolic stability of TAB02-181 (Z3-5) and TAB02-174 (ester prodrug of Z3-5) was tested according to the method described in the literature "ACS Med. Chem. Lett. 2022 Aug 22; 13(10) 1582-1590".

[0172] 500 μM TAB02-181 (Z3-5) and TAB02-174 (ester prodrug of Z3-5) were mixed with liver microsomes (Sekisui Xeno Tech, LLC, Kansas City, KS, USA, final concentration 0.2 mg protein / mL), coenzyme group (1.3 mM NADPH, 3.3 mM G-6-P: Sigma, Marlborough, MA, USA, 3.3 mM MgCl2: Wako, Osaka, Japan), and 0.45 U / mL G6PDH (Oriental Yeast, Tokyo, Japan) at 37°C for 0 to 60 minutes. Two types of liver microsomes were used: human liver microsomes and mouse liver microsomes.

[0173] The mixtures were sampled at 0 minutes, 10 minutes, and 60 minutes after mixing. Acetonitrile was added to each mixture, which was then stirred, and subsequently centrifuged at 3500 rpm for 20 minutes.

[0174] After collecting the supernatant following centrifugation, the supernatant was subjected to LC-MS / MS, and the amounts of TAB02-181 (Z3-5) and TAB02-174 (ester prodrug of Z3-5) present in the supernatant were measured.

[0175] The ratio of the respective amounts of TAB02-181 (Z3-5) and TAB02-174 (ester prodrug of Z3-5) present in the supernatant at 10 minutes and 60 minutes after mixing was calculated relative to the respective amounts (100%) of TAB02-181 (Z3-5) and TAB02-174 (ester prodrug of Z3-5) present in the supernatant at 0 minutes after mixing.

[0176] Figure 7 shows the test results. As is clear from Figure 7, the amount of TAB02-174 (ester prodrug of Z3-5) decreased due to metabolism over time, while the amount of TAB02-181 (Z3-5) increased over time. This indicates that TAB02-174 (ester prodrug of Z3-5) was metabolized and converted to TAB02-181 (Z3-5). Furthermore, this indicates that TAB02-181 (Z3-5) is more stable in vivo compared to TAB02-174 (ester prodrug of Z3-5).

[0177] The present invention can be used as a lysine demethylase 3A inhibitor and for the treatment or prevention of abnormal angiogenesis.

Claims

1. A lysine demethylase 3A inhibitor comprising, as an active ingredient, (i) a compound represented by the following chemical formula 1, a salt thereof, a hydrate thereof, a solvate thereof, or a derivative thereof, and / or (ii) a compound represented by the following chemical formula 2, a salt thereof, a hydrate thereof, a solvate thereof, or a derivative thereof: In Chemical Formula 1, １ X １ is -COOR １ (where R 1 is hydrogen or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted condensed ring, In Chemical Formula 2, ２ X ２ is -COOR ２ (where R ２ is hydrogen or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted condensed ring (however, excluding the following functional group A from X (5) Y ２ is a heterocyclic ring containing a nitrogen atom, ２ (6) Z is hydrogen or any organic group, (7) n is an integer from 0 to 20.

2. A therapeutic or prophylactic agent for abnormal angiogenesis, comprising the lysine demethylase 3A inhibitor described in claim 1 as an active ingredient.

3. The above-mentioned abnormal angiogenesis is the formation of an avascular region and / or the formation of abnormal blood vessels, as described in claim 2, a therapeutic or prophylactic agent for abnormal angiogenesis.

4. The therapeutic or prophylactic agent for abnormal angiogenesis according to claim 2 or 3, wherein the abnormal angiogenesis is associated with retinal ischemic disease, cancer, retinopathy of prematurity, age-related macular degeneration, diabetic macular edema, pathological myopia, macular edema associated with retinal vein occlusion, or neovascular glaucoma.

5. (i) Compounds represented by the following chemical formula 1, salts thereof, hydrates thereof, solvates thereof, or derivatives thereof, and / or (ii) Compounds represented by the following chemical formula 2, salts thereof, hydrates thereof, solvates thereof, or derivatives thereof: In chemical formula 1, (1)X １ is -COOR １ (Here, R １ (2) Y 1 (3) n is an integer from 0 to 20, In chemical formula 2, (4)X ２ is -COOR ２ (Here, R ２ X is a hydrogen atom or any organic group), a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted fused ring (where X is a hydrogen atom or any organic group). ２ Therefore, excluding the following functional group A), (5) Y ２ (6) Z is a heterocycle containing a nitrogen atom. ２ (7) n is an integer from 0 to 20.

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