KR20090010186A - Salicylic acid derivative compound and pharmaceutical composition containing them - Google Patents

Abstract

A salicylic acid derivative compound and a pharmaceutical composition containing the same are provided to treat and prevent a brain disorder, ophthalmopathyn pain and inflammation disease, to suppress excitotoxicity and to prevent the damage of stomach caused by the side effect of an anti-inflammatory agent. A salicylic acid derivative compound or a pharmaceutically allowable salt is indicated as the chemical formula 1. In the chemical formula, X is O or S; R1 is hydrogen or alkyl; R2 is hydrogen, alkyl or alkanoyl; R4 is the phenyl, biphenyl or naphthyl which are substituted or non substituted with at least one selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, haloalkoxy and nitro; and n is an integer of 2-4.

Description

Salicylic Acid Derivative Compound and Pharmaceutical Composition Comprising The Same {SALICYLIC ACID DERIVATIVE COMPOUND AND PHARMACEUTICAL COMPOSITION CONTAINING THEM}

The present invention relates to a novel salicylic acid derivative compound having a specific formula, a pharmaceutical composition comprising the same, and a method for treating or preventing the same.

Glutamate is a slow excitatory neurotransmitter and alpha-amino-3-hydroxy-5-methyl-4-isoxosol through the activity of N-methyl-D-aspartate (NMDA) glutamate receptors. Propionic acid (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA) is an excitatory neurotransmitter of the central nervous system that mediates rapid excitatory neurotransmission through the activation of glutamate receptors. Bioactive properties of NMDA glutamate receptors play an important role in learning, memory, and plasticity of the nervous system (Siegel, GJ et al ., Basic Neurochemistry , 6 ^th edition, Lippincott Williams & Wilkins: 315-333 (1999)). Another property of the NMDA glutamate receptor is that excessive excitability leads to neuronal cell death [Olney, JW and Sharpe, LG, Science , 166: 386-388 (1969); Olney, JW and Ho, OL, Nature , 227 (258): 609-611 (1970). Administering an antagonist of NMDA glutamate receptor, Wang R. and Zhang D. Eur J Neurosci. 2005; 22 (9): 2376-80, Alzheimer's dementia (Miguel-Hidalgo et al., Brain Res . 958 , 210-221 (2002)), stroke (Park CK et al., Ann . Neurol . 24 , 543-551 (1988)), Huntington's disease (Verhagen Metman L et al., Neurology. 2002; 59 (5): 694 -9.), Spinal cord injury (Faden et al., J Neurotrauma. 1988; 5 (1): 33-45), Parkinson's disease (Rabey et al., J. Neural Transm. Park Dis.Dement.Sect . 4 , 277-282 (1992)), such as brain diseases; Eye diseases such as glaucoma (Pang et al., Invest Ophthalmol. Vis. Sci. 40 , 1170-1176 (1999)) and diabetic retinopathy (Smith et al., Drug News Perspect . 15 , 226-232 (2002)) ; Neuropathic pain (Chaplan SR et al., J Pharmacol Exp Ther. 1997; 280 (2): 829-38) and the like.

However, results showing the toxicity of NMDA receptor antagonists have also been reported, raising questions about the safety of the drug. Phencyclidine and pseudo-NMDA receptor antagonist MK-801 (dizocilpine maleate), tiletamine or ketamine at low concentrations induce subcutaneous injection of brain cells in specific areas of the cerebral cortex Degeneration has been reported to be observed (Olney, JW et al., Science , 244: 1360-1362 (1989)). Toxicity by such NMDA receptor antagonists is a serious obstacle to development of the treatment of brain diseases such as stroke.

It has been found that free radicals act as the main mechanism in the cerebral nervous system diseases and eye diseases. Free radicals occur due to increased free radical production or impairment of free radical elimination mechanisms in the cell, and the resulting free radicals induce the oxidation of proteins, lipids and nucleic acids, which are essential for cell function and survival. Will lead to. Administration of antioxidants is known as Lou Gehrig's disease (Andreassen OA et al., Neuroreport 11 , 2491-2493 (2000)), Alzheimer's dementia (Sung S et al., FASEB J. 18. 323-325 (2004)), stroke (Kuroda S et al., J Cereb Blood Flow Metab. 1999; 19 (7): 778-87), Huntington's disease (Andreassen et al., Neuroreport. 2001; 12 (15): 3371-3), spinal cord injury ( Brain diseases such as Faden & salzman., Trends Pharmacol . Sci . 13 , 29-35 (1992)), Parkinson's disease (Prasad et al., J. Am. Coll. Nutr . 18 , 413-423 (1999)), and the like; Glaucoma (Neufeld et al., J. Glaucoma . 11 , 221-225 (2002)), diabetic retinopathy (Chung et al., Arzneimittelforschung . 55 , 573-580 (2005)) and macular degeneration (Richer et al., . optometry 75, ocular diseases, such as 216-230 (2004)); There are many reports demonstrating therapeutic effectiveness in neuropathic pain (Chaplan SR et al., J Pharmacol Exp Ther. 1997; 280 (2): 829-38).

However, antioxidants such as Vitimin E or acetyl-L-carnitine have not shown therapeutic effects in Alzheimer's dementia and Parkinson's disease (Hudson & Tabet, 2003; Thal et al., 2003; Luchsinger et al., 2003; Morens et. al., 1996). In clinical development as a treatment for brain diseases, known antioxidants are hampered by low potency and blood brain barrier (BBB) permeability (Gilgun-Sherki et al., 2002; Molina et al., 1997).

As mentioned above, these limitations must be overcome in developing therapeutics of antioxidants and glutamate receptor antagonists.

Inflammation is a vascular and cellular response to damage factors derived from damaged cells and foreign substances introduced into the body. Inflammatory mediators include: 1) prostaglandin, leukotriene, lipoxins, and 2) platelet activation factor, a metabolite of arachidonic acid. ), 3) cytokines such as tumor necrosis factor-alpha, interleukin-1 (IL-1), monocyte chemoattractant protein (MCP-1), and macrophage inflammatory protein-1alpha (MCP-1alpha) Chemokines, such as chemokines, 4) nitric oxide (NO), 5) free radicals, 6) histamine, and vasodilators such as serotonin are known. The main purpose of the inflammatory reaction is to remove foreign substances and damaged cells (or tissue), but the inflammatory response causes chronic diseases such as rheumatoid arthritis, pancreatitis, gastritis, colitis and arteriosclerosis.

Nonsteroidal anti-inflammatory drugs (NSAIDs), which are drugs that inhibit the action of cyclooxygenase, which are involved in the production of prostaglandins, have been developed and widely used to alleviate the symptoms of inflammatory diseases including pain. However, due to its side effects have become a major obstacle to use. In particular, gastrointestinal disorders such as dyspepsia, gastritis, ulcers, bleeding, and perforation are common side effects after taking NSAIDs. Coxib, a selective cyclooxygenase-2 (COX-2) enzyme inhibitor that has less side effects from gastrointestinal tract injuries, has been developed and used in the treatment of arthritis and pain with celecoxib and rofecoxib. However, in 2005, the U.S. FDA reported that long-term use of celecoxib, rofecoxib, and valdecoxib caused heart disease, and Coxib drugs as arthritis drugs were restricted. In addition, clinical studies of celecoxib and rofecoxib were discontinued for safety reasons.

In inflammatory diseases, free radicals produced by neutrophils, macrophages, and monosites are known to mediate inflammatory reactions and cause tissue damage. Indeed, the administration of drugs that remove free radicals has been shown to affect gastrointestinal damage (Matthews GM et al., Helicobacter. 2005; 10 (4): 298-306) and pancreatic injury (Shi C et al., Pancreatology. 2005). 5 (4-5): 492-500), atherosclerosis (Tardif JC. Curr Atheroscler Rep. 2005; 7 (1): 71-7), bowel injury (Oz HS et al., J Nutr Biochem. 2005; 16 (5): 297-304), joint injury (Henrotin YE et al., Osteoarthritis Cartilage. 2003; 11 (10): 747-55), kidney injury (Tian N et al., Hypertension. 2005; 45 (5): 934-9), liver injury (Loguercio C et al., Free Radic Biol Med. 2003; 34 (1): 1-10) and cardiovascular injury (Haidara MA et al., Curr Vasc Pharmacol. 2006; 4 (3): 215-27) have been shown to be effective. In addition, the administration of nonsteroidal anti-inflammatory drugs leads to gastric mucosal injury side effects by the generation of free radicals, which is reported to be reduced by the administration of antioxidants (Graziani G et al., Gut. 2005; 54 (2): 193-200).

Technical challenge

Therefore, the technical problem to be achieved by the present invention is to provide a novel compound useful for the treatment or prevention of brain diseases, eye diseases, pain and inflammatory diseases, pharmaceutical compositions comprising the same and methods of treatment or prevention using the same.

In other words, the present invention suppresses excitatory toxicity, has no side effects of gastric damage of known anti-inflammatory drugs, exhibits cytoprotective action at low concentrations, and discovers antioxidants to detect brain diseases, eye diseases, pain and inflammation. The aim is to develop therapeutics that have efficacy and safety against diseases.

Technical solution

In order to achieve the above technical problem, the present invention provides a salicylic acid derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

Formula 1

In Formula 1, X is O or S; R ₁ is hydrogen or alkyl; R ₂ is hydrogen, alkyl or alkanoyl; R ₃ is hydrogen or alkyl; R ₄ is phenyl, biphenyl or naphthyl substituted or unsubstituted with any one or more selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, haloalkoxy and nitro; n is an integer from 2 to 4.

The present inventors found that the salicylic acid derivative compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is useful for the treatment or prevention of cerebral nervous system diseases, eye diseases, pain and inflammatory diseases while preparing and evaluating various compounds. It was.

Hereinafter, the salicylic acid derivative compound of the present invention, a pharmaceutical composition comprising the same, and a treatment or prevention method using the same will be described in more detail.

The present invention provides a salicylic acid derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

<Formula 1>

In Formula 1, X is O or S; R ₁ is hydrogen or alkyl; R ₂ is hydrogen, alkyl or alkanoyl; R ₃ is hydrogen or alkyl; R ₄ is phenyl, biphenyl or naphthyl substituted or unsubstituted with any one or more selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, haloalkoxy and nitro; n is an integer from 2 to 4.

More specifically, in Formula 1, alkyl is preferably alkyl having 1 to 5 carbon atoms, and more preferably alkyl having 1 or 3 carbon atoms. Specifically, the alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl and tert-butyl, but is not limited thereto. It is preferable that alkoxy is C1-C5 alkoxy, and it is more preferable that it is C1-C3 alkoxy. Specifically, as the alkoxy, methoxy, ethoxy and protoxy groups are preferred, but are not limited thereto. Halogen is preferably, but not limited to, fluorine, chlorine, bromine and iodine.

Preferred examples of the salicylic acid derivative compound represented by Formula 1 include 2-hydroxy-5- (2- (phenoxy-ethylamino) -benzoic acid (compound 1) and 5- [2- (4-fluorophenoxy) Ethylamino] -2-hydroxybenzoic acid (compound 2), 5- [2- (4-chlorophenoxy) ethylamino] -2-hydroxybenzoic acid (compound 3), 5- [2- (4-bromo Phenoxy) ethylamino] -2-hydroxybenzoic acid (compound 4), 5- [2- (2,6-difluoro-phenoxy) ethylamino] -2-hydroxybenzoic acid (compound 5), 2- Hydroxy-5- [2- (2-pentafluoro-phenoxy) ethylamino] -benzoic acid (compound 6), 5- [2- (2,4-dichloro-phenoxy) ethylamino] -2-hydroxy Hydroxybenzoic acid (compound 7), 2-hydroxy-5- [2- (2,4,5-trichlorophenoxy) ethylamino] benzoic acid (compound 8), 5- [2- (2,6-dichloro- 4-fluorophenoxy) ethylamino] -2-hydroxybenzoic acid (compound 9), 2-hydroxy-5- (2-p-tolyloxyethylamino) benzoic acid (compound 10), 5- [2- ( 2,6-dime -Phenoxy) -ethylamino] -2-hydroxy-benzoic acid (compound 11), 5- [2- (4-chloro-2-methylphenoxy) ethylamino] -2-hydroxybenzoic acid (compound 12), 2-hydroxy-5- [2- (4-trifluoromethylphenoxy) ethylamino] benzoic acid (compound 13), 2-hydroxy-5- [2- (4-methoxy-phenoxy) ethylamino ] -Benzoic acid (compound 14), 2-hydroxy-5- [2- (4-trifluoromethyl-phenoxy) ethylamino] benzoic acid (compound 15), 2-hydroxy-5- [2- (2 Nitrophenoxy) ethylamino] benzoic acid (compound 16), 2-hydroxy-5- [2- (naphthalen-2-yloxy) ethylamino] -benzoic acid (compound 17), 2-hydroxy-5- [2- (6-Methyl-naphthalen-2-yloxy) ethylamino] -benzoic acid (compound 18), 5- [2- (biphenyl-4-yloxy) -ethylamino] -2-hydroxy-benzoic acid (Compound 19), 2-hydroxy-5- (3-phenoxypropylamino) benzoic acid (Compound 20), 5- [3- (4-fluorophenoxy) propylamino] -2-hydroxybenzoic acid (compound 21), 5-{[2- (4-Chlorophenoxy) ethyl] methylamino} -2-hydroxybenzoic acid (Compound 22), 2-hydroxy-5- {methyl- [2-naphthalen-2-yloxy)- Ethyl] -amino} -benzoic acid (compound 23) and 2-hydroxy-5- (2-phenylsulfonylethylamino) benzoic acid (compound 24).

"Pharmaceutically acceptable salts" of the present invention refer to salts that are made from non-toxic or less acid or base. If the compounds of the present invention are relatively acidic, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base and a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, salts consisting of sodium, potassium, calcium, ammonium, magnesium or organic amino. When the compounds of the present invention are relatively basic, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid and a suitable inert solvent. Pharmaceutically acceptable acid addition salts include propionic acid, isobutyl acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic, fumaric acid, manderic acid, phthalic acid, benzenesulfonic acid, p-torylsul Phonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide, phosphorous acid Salts formed of, and the like, but are not limited thereto. It also includes, but is not limited to, salts of amino acids such as arginate and analogs of organic acids such as glucuronic or galactunoric acids.

Some compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrate forms. Some compounds of the present invention may exist in crystalline or amorphous form, and all such physical forms are included within the scope of the present invention. In addition, some compounds of the present invention may have asymmetric carbon atoms or double bonds which are optical centers, such that racemates, enantiomers, diastereomers, geometric isomers, etc. may be present, and these are also included in the scope of the present invention. .

The present invention also provides a pharmaceutical composition comprising a salicylic acid derivative compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or additive. The salicylic acid derivative compounds of the present invention or pharmaceutically acceptable salts thereof may be administered alone or in admixture with any convenient carrier, excipient, etc., and such dosage forms may be single or repeated dose formulations.

The pharmaceutical composition of the present invention may be a solid preparation or a liquid preparation. Solid preparations include, but are not limited to, powders, granules, tablets, capsules, suppositories, and the like. Solid agents may include, but are not limited to, excipients, flavors, binders, preservatives, disintegrants, lubricants, fillers and the like. Liquid formulations include, but are not limited to, solutions such as water, propylene glycol solutions, suspensions, emulsions, and the like, and may be prepared by adding suitable colorants, flavors, stabilizers, viscosity agents, and the like.

For example, the powder may be prepared by simply mixing the salicylic acid derivative compound of the present invention with a suitable pharmaceutically acceptable excipient such as lactose, starch, microcrystalline cellulose. Granules are compounds of the present invention or pharmaceutically acceptable salts thereof; Pharmaceutically acceptable excipients; And a pharmaceutically acceptable binder such as polyvinylpyrrolidone and hydroxypropyl cellulose, and then prepared by using a wet granulation method using a solvent such as water, ethanol, isopropanol, or a dry granulation method using a compressive force. Can be. Tablets may also be prepared by mixing the granules with a suitable pharmaceutically acceptable glidant such as magnesium stearate and then tableting using a tableting machine.

The pharmaceutical composition of the present invention may be administered orally, by injection (eg, intramuscular injection, intraperitoneal injection, intravenous injection, infusion, subcutaneous injection, implant), inhalant, nasal administration, depending on the condition and condition of the individual to be treated. It may be administered as a vaginal agent, rectal agent, sublingual agent, transdermal agent, topical agent, and the like, but is not limited thereto. It may be formulated into a suitable dosage unit dosage form comprising a pharmaceutically acceptable carrier, excipient, vehicle, conventionally used and nontoxic, depending on the route of administration. Depot formulations capable of continually releasing the drug for a period of time are also within the scope of the present invention.

The present invention is also used for the treatment or prevention of brain diseases, eye diseases, pain and inflammatory diseases of the salicylic acid derivative compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, that is, the salicylic acid derivative compound represented by the formula (1) or a pharmaceutical thereof It provides a composition for the treatment or prevention of brain diseases, eye diseases, pain or inflammatory diseases, characterized in that it comprises an acceptable salt. More specifically, the salicylic acid derivative compounds of the present invention or salts thereof include degenerative brain diseases such as Alzheimer's dementia, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, cerebrovascular diseases such as stroke, acute brain and spinal cord injury, as well as glaucoma, macular degeneration and It is also applicable to the treatment of major eye diseases of diabetic retinopathy, and can be used for inflammatory diseases and pains such as arteriosclerosis, gastritis, colitis, arthritis, nephritis, hepatitis and degenerative diseases.

In the use for the treatment of the above-mentioned diseases, in particular cerebral nervous system diseases, the salicylic acid derivative compounds of the present invention may be administered from about 0.01 mg / kg to about 100 g / kg daily, from about 0.1 mg / kg to about 10 g A daily dose of / kg is preferred. However, the dosage may vary depending on the condition of the patient (age, sex, weight, etc.), the severity of the condition being treated, the compound used and the like. If desired, the total daily dose may be divided for convenience and divided several times throughout the day.

In addition, the present invention provides a method for preparing a salicylic acid derivative compound represented by the formula (1). For example, one embodiment of the salicylic acid derivative compound of the present invention may be prepared by reacting a compound of Formula 2 with a compound of Formula 3.

Formula 2

Formula 3

The compound of Formula 2 may be prepared according to Scheme 1, but is not limited thereto.

<Scheme 1>

For example, the reaction conditions of Scheme 1 (a) MeOH, H ₂ SO ₄ , reflux, 6 hours; (b) DIBOC, NaHCO ₃ , THF / H ₂ O, room temperature, 7 hours; (c) acetyl chloride, DMF, K ₂ CO ₃ , room temperature, 6 hours; (d) 1,4-dioxane (4N-HCl), room temperature, 8 hours, and the like may be used, but is not limited thereto.

More specifically, the salicylic acid derivative compound of Formula 1 may be prepared according to Scheme 2, but is not limited thereto.

<Scheme 2>

For example, the reaction conditions of Scheme 2 (a) DCC, MC, room temperature, 2 hours; (b) acetic acid, NaBH ₄ , 1,4-dioxane, reflux, 20 minutes; (c) CH ₃ I, DMF, K ₂ CO ₃ , 40, 6 hours; (d) acetic acid, HCl / H ₂ O, reflux, 12 hours, and the like may be used, but is not limited thereto.

1 is a result of evaluating the anti-inflammatory action of Compound 11 (100uM) of an embodiment of the present invention using a BV-2 cell line. The amounts of NO, TNF-α and IL-6 produced by LPS were measured and shown.

2 is a result of evaluating the effect of compound 11 using the arthritis animal model induced by collagen. After collagen administration, compound 11 (25 mg / kg / day) and the comparison group methotrexate (MTX, 1 mg / kg / week) were intraperitoneally injected. After that, the results observed by naked eye for 4 weeks were evaluated by arthritis index.

3 is a result of evaluating the effect of compound 11 using the arthritis animal model induced by collagen. After collagen administration, compound 11 (25 mg / kg / day) and the comparison group methotrexate (MTX, 1 mg / kg / week) were intraperitoneally injected. Thereafter, the amounts of the cytokines TNF-α and IL-1β were measured by ELISA.

Embodiment for Invention

Hereinafter, the following examples and the like will be described in order to describe the present invention in more detail. However, embodiments according to the present invention may be modified in many different forms and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided by way of example in order to facilitate a specific understanding of the present invention.

Synthesis Example 1 Preparation of 5- [2- (4-chlorophenoxy) ethylamino] -2-hydroxybenzoic acid (Compound 3)

A) 2-acetoxy-5-aminobenzoic acid methyl ether (1.06 g, 5.07 mmole), 4-chlorophenoxyacetic acid (0.09 g, 5.57 mmole) and DCC (1.14) in MC (30 ml) dried at room temperature under nitrogen atmosphere. g, 5.55 mmole) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered off and MC was removed under reduced pressure. The residue was recrystallized in methanol / ethyl acetate / hexane to give 1.33 g (76.1% yield) of methyl ether of 2-acetoxy-5- [2- (4-chlorophenoxy) acetylamino] benzoate as a white solid.

_{1H NMR (DMSO- d 6):} 8.27 (d, 1H), 7.89 (q, 1H), 7.35 (d, 2H), 7.18 (d, 1H), 7.02 (d, 2H), 4.71 (s, 2H) , 3.81 (s, 3H), 2.23 (s, 2H)

B) 2-acetoxy-5- [2- (4-chlorophenoxy) acetylamino] benzoic acid methyl ether (1.33 g, 3.54 mmole) and NaBH ₄ (0.69) in 1,4-dioxane (30.0 ml) at room temperature. g, 17.7 mmole) was added and cooled to 0 ° C. Acetic acid (1.06 g, 17.7 mmole) was diluted in 1,4-dioxane and then carefully added dropwise. The reaction mixture was stirred at room temperature for 15 minutes and then reacted by refluxing for 10 minutes. Ice cubes were added to the reaction mixture and then the solvent was removed under vacuum. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over MgSO ₄ anhydride. The residue was purified by column chromatography with ethyl acetate / hexanes and recrystallized under ethyl acetate / hexanes to give 2-acetoxy-5- [2- (4-chlorophenoxy) ethylamino] benzoate 0.54 on white solid. g (42.3% yield) was obtained.

Melting point: 108 ° C., 1 H NMR (CDCl ₃ ): 7.22 (q, 2H), 7.19 (d, 1H), 6.88 (d, 1H), 6.82-6.76 (m, 3H), 4.15 (t, 2H), 3.92 (s, 3 H), 3.51 (t, 2 H), 2.25 (s, 3 H); 13C NMR (CDCl ₃ ): 170.162, 164.937, 156.806, 145.453, 141.654, 129.193, 125.811, 124.188, 123.118, 117.870, 115.603, 114.670, 66.542, 52.162, 43.335, 21.007

C) Add 2-acetoxy-5- [2- (4-chlorophenoxy) ethylamino] benzoic acid methyl ether (544 mg, 1.49 mmole) and acetic acid (10.0 ml) to 6 N HCl (40.0 ml) at room temperature. It was. The reaction mixture was refluxed and stirred for 10 hours. After the solvent was removed in vacuo, the residue was washed with ether and water to obtain 0.40 g (85.9% yield) of 5- [2- (4-chlorophenoxy) ethylamino] -2-hydroxybenzoic acid as a gray solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.28 (q, 2H) 7.16 (d, 1H), 6.97 (t, 2H), 6.61 (q, 1H), 6.54 (d, 1H), 4.01 (t, 2 H), 3.24 (s, 2 H); 13C NMR (DMSO- d ₆ ): 172.538, 157.173, 153.570, 139.168, 129.082, 124.038, 119.966, 117.698, 116.098, 115.711, 113.292, 66.893, 43.527

C ₁₅ H ₁₄ ClNO ₄ Elemental Analysis of

Table 1

Synthesis Example 2 Preparation of 5- [2- (4-fluorophenoxy) ethylamino] -2-hydroxybenzoic acid (Compound 2)

A) Synthesis Example using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 4-fluorophenoxyacetic acid (0.94 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) 1.27 g (69.2% yield) of the white solid 2-acetoxy-5- [2- (4-fluorophenoxy) acetylamino] benzoic acid methyl ether was obtained by the same method as A>.

1 H NMR (DMSO- d ₆ ): 8.26 (d, 1H), 7.88 (q, 1H), 7.19-7.01 (m, 6H), 4.69 (s, 2H), 3.80 (s, 3H), 2.26 (s, 3H)

B) 2-acetoxy-5- [2- (4-fluorophenoxy) acetylamino] benzoic acid methyl ether (1.27 g, 3.51 mmole), NaBH ₄ (0.66 g, 17.5 mmole) and acetic acid (1.05 g, 17.5 0.53 g (43.3% yield) of 2-acetoxy-5- [2- (4-fluorophenoxy) ethylamino] benzoic acid methyl ether in the same manner as in <B> of <Synthesis Example 1> using mmole) )

Melting point: 90 ° C., 1 H NMR (CDCl ₃ ): 7.24 (d, 1H), 6.95 (t, 2H), 6.90 (d, 1H), 6.80 (m, 3H), 4.15 (t, 2H), 3.91 ( s, 3H), 3.45 (t, 2H), 2.24 (s, 3H); 13 C NMR (CDCl ₃ ): 170.147, 164.937, 158.316, 155.949, 154.311, 154.289. 145.514, 141.585, 124.150, 123.080, 117.832, 115.823, 115.595, 115.360, 115.284, 114.624, 66.822, 52.117, 43.373, 20.977

C) Experiment in the same manner as in <C> of Synthesis Example 1, using 2-acetoxy-5- [2- (4-fluorophenoxy) ethylamino] benzoic acid methyl ether (0.53 g, 1.52 mmole) 0.37 g (84.7% yield) of 5- [2- (4-fluorophenoxy) ethylamino] -2-hydroxybenzoic acid as a gray solid was obtained.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.06 (q, 3H), 6.94 (m, 3H), 6.75 (d, 1H), 4.13 (t, 2H), 3.31 (t, 2H) ; 13C NMR (DMSO- d ₆ ): 171.954, 157.506, 155.171, 154.594, 152.926, 140.814, 121.907, 117.463, 115.802, 115.635, 115.575, 112.587, 111.328, 111.350, 67.007, 43.300

C ₁₅ H ₁₄ FNO ₄ Elemental Analysis of

TABLE 2

Synthesis Example 3 Preparation of 5- [2- (4-bromophenoxy) ethylamino] -2-hydroxybenzoic acid (Compound 4)

A) Synthesis example using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 4-bromophenoxyacetic acid (1.28 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) The experiment was carried out in the same manner as in A> of 1>, to obtain 1.32 g (63.7% yield) of 2-acetoxy-5- [2- (4-bromophenoxy) acetylamino] benzoate methyl ether on a white solid.

_{1H NMR (DMSO- d 6):} 8.25 (d, 1H), 7.91 (q, 1H), 7.46 (d, 2H), 7.18 (d, 1H), 6.97 (d, 2H), 4.68 (s, 2H) , 3.81 (s, 3H), 2.34 (s, 3H)

B) 2-acetoxy-5- [2- (4-bromophenoxy) acetylamino] benzoic acid methyl ether (1.32 g, 3.23 mmole), NaBH ₄ (0.61 g, 16.1 mmole) and acetic acid (0.96 g, 16.1 Experiment using the same method as B) of <Synthesis Example 1> using mmole) to give 0.61 g (46.1% yield) of 2-acetoxy-5- [2- (4-bromophenoxy) ethylamino] benzoate. Was obtained as a white solid.

Melting point: 102-103 ° C., 1 H NMR (CDCl ₃ ): 7.35 (d, 2H), 7.21 (d, 1H), 6.94 (d, 1H), 6.82 (m, 3H), 4.12 (t, 2H), 3.90 (s, 3 H), 3.42 (t, 2 H), 2.21 (s, 3 H); 13C NMR (CDCl ₃ ): 170.519, 165.294, 157.672, 145.803, 142.026, 132.493, 124.560, 123.483, 118.243, 116.483, 115.035, 113.526, 66.846, 52.535, 43.685, 21.388

C) Experiment in the same manner as in <C> of Synthesis Example 1, using 2-acetoxy-5- [2- (4-bromophenoxy) ethylamino] benzoic acid methyl ether (0.61 g, 1.49 mmole) 0.46 g (87.4% yield) of 5- [2- (4-bromophenoxy) ethylamino] -2-hydroxybenzoic acid was obtained as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.41 (d, 2H), 7.04 (d, 1H), 6.87 (q, 1H), 6.74 (d, 2H), 6.79 (d, 1H) , 4.14 (t, 2 H), 3.41 (t, 2 H); 13C NMR (DMSO- d ₆ ): 171.204, 156.976, 152.539, 139.730, 131.418, 121.658, 116.925, 116.144, 111.965, 111.381, 111.222, 66.113, 42.860

C ₁₅ H ₁₄ BrNO ₄ Elemental Analysis of

TABLE 3

Synthesis Example 4 Preparation of 5- [2- (2,4-dichlorophenoxy) ethylamino] -2-hydroxybenzoic acid (Compound 7)

A) Synthesis using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 2,4-dichlorophenoxyacetic acid (1.23 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) By the same method as A) in Example 1>, 1.62 g (77.5% yield) of 2-acetoxy-5- [2- (2,4-dichlorophenoxy) acetylamino] benzoate methyl ether was obtained as a white solid.

_{1H NMR (DMSO- d 6):} 8.23 (d, 1H), 7.83 (q, 1H), 7.58 (d, 1H), 7.34 (q, 1H), 7.19 (d, 1H), 7.11 (d, 1H) , 4.87 (s, 3H), 3.80 (s, 3H), 2.26 (s, 3H)

B) 2-acetoxy-5- [2- (2,4-dichlorophenoxy) acetylamino] benzoic acid methyl ether (1.62 g, 3.93 mmole), NaBH ₄ (0.74 g, 1.96 mmole) and acetic acid (1.17 g, 19.6 mmole) was used in the same manner as in <B> of <Synthesis Example 1>, and 0.81 g (51.8%) of methyl ether of 2-acetoxy-5- [2- (2,4-dichlorophenoxy) ethylamino] benzoate Yield) was obtained as a white solid.

Melting point: 72-73 ° C., 1 H NMR (CDCl ₃ ): 7.33 (d, 1H), 7.22 (d, 1H), 7.12 (m, 1H), 6.89 (d, 1H), 6.79 (m, 2H), 4.12 (t, 2H), 3.82 (s, 3H), 3.51 (t, 3H), 2.29 (s, 3H); 13C NMR (CDCl ₃ ): 170.132, 164.891, 152.514, 145.339, 141.638, 129.739, 127.441, 126.038, 124.157, 123.604, 123.065, 118.022, 114.632, 114.291, 67.839, 52.132, 43.115, 20.977

C) Experiment in the same manner as in <C> of Synthesis Example 1, using 2-acetoxy-5- [2- (2,4-dichlorophenoxy) ethylamino] benzoate methyl ether (0.81 g, 2.03 mmole) To give 0.53 g (76.8% yield) of 5- [2- (2,4-dichlorophenoxy) ethylamino] -2-hydroxybenzoic acid as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.48 (s, 1H), 7.29 (d, 1H), 7.11 (m, 2H), 6.95 (d, 1H), 6.75 (d, 1H) , 4.16 (s, 1 H), 3.41 (s, 1 H); 13C NMR (DMSO- d ₆ ): 171.840, 152.850, 152.751, 140.776, 129.074, 127.830, 124.410, 122.355, 121.816, 117.395, 114.900, 112.465, 111.343, 68.183, 43.125

C ₁₅ H ₁₃ C ₁₂ NO ₄ Elemental Analysis of

Table 4

Synthesis Example 5 Preparation of 2-hydroxy-5- [2- (2,4,5-trichlorophenoxy) ethylamino] benzoic acid (Compound 8)

A) using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 2,4,5-trichlorophenoxyacetic acid (1.42 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) Experiment by the same method as A) of <Synthesis Example 1>, and 1.63 g (71.7% yield) of 2-acetoxy-5- [2- (2,4,5-trichlorophenoxy) acetylamino] benzoate Was obtained as a white solid.

_{1H NMR (DMSO- d 6):} 6.23 (d, 1H), 7.80 (t, 2H), 7.45 (s, 1H), 7.20 (d, 1H), 4.94 (s, 2H), 3.80 (s, 3H) , 2.26 (s, 3 H)

B) 2-acetoxy-5- [2- (2,4,5-trichlorophenoxy) acetylamino] methyl ether benzoate (1.63 g, 3.64 mmole), NaBH ₄ (0.48 g, 18.2 mmole) and Experimented with the same method as B) of <Synthesis Example 1> using acetic acid (1.09 g, 18.2 mmole), 2-acetoxy-5- [2- (2,4,5-trichlorophenoxy) ethylamino] 0.48 g (27.8% yield) of methyl benzoate was obtained as a white solid.

Melting point: 129-131 ° C., 1 H NMR (CDCl ₃ ): 7.42 (s, 1H), 7.27 (d, 1H), 6.98 (s, 1H), 6.91 (d, 1H), 6.82 (q, 1H), 4.19 (t, 2H), 3.91 (s, 3H), 3.61 (t, 2H), 2.24 (s, 3H); 13C NMR (CDCl ₃ ): 170.177, 164.926, 152.840, 145.180, 141.927, 131.119, 130.801, 124.612, 124.332, 123.247, 122.057, 118.196, 114.996, 114.859, 68.165, 52.246, 43.153, 21.060

C) same as <C) of <Synthesis Example 1> using 2-acetoxy-5- [2- (2,4,5-trichlorophenoxy) ethylamino] benzoate methyl ether (0.43 g, 1.01 mmole) Experimental method yielded 0.32 g (84.4% yield) of 2-hydroxy-5- [2- (2,4,5-trichlorophenoxy) ethylamino] benzoic acid as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.73 (s, 1H), 7.47 (d, 1H), 7.34 (q, 1H), 6.92 (d, 1H), 4.34 (t, 2H) , 3.57 (t, 2 H); 13C NMR (DMSO- d ₆ ): 171.150, 156.763, 152.751, 130.371, 130.333, 126,033, 122.931, 121.134, 117.949, 115.453, 112.966, 66.886, 46.121

C ₁₅ H ₁₂ C ₁₃ NO ₄ Elemental Analysis of

Table 5

Synthesis Example 6 Preparation of 5- [2- (2,6-dichloro-4-fluorophenoxy) ethylamino] -2-hydroxybenzoic acid (Compound 9)

A) 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole) and 2,6-dichloro-4-fluorophenoxyacetic acid (1.33 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) Using the same method as in <A> of <Synthesis Example 1>, 1.47 g of 2-acetoxy-5- [2- (2,6-dichloro-4-fluorophenoxy) acetylamino] benzoic acid methyl ether 67.2% yield) was obtained as a white solid.

1 H NMR (DMSO- d ₆ ): 8.30 (d, 1H), 7.92 (q, 1H), 7.59 (d, 2H), 7.20 (d, 1H), 4.61 (s, 2H), 3.84 (s, 3H) , 2.34 (s, 3 H)

B) 2-acetoxy-5- [2- (2,6-dichloro-4-fluorophenoxy) acetylamino] benzoic acid methyl ether (1.47 g, 3.41 mmole), NaBH ₄ (0.64 g, 17.1 mmole) and Using acetic acid (1.02 g, 17.1 mmole) in the same manner as in <B> of <Synthesis Example 1>, 2-acetoxy-5- [2- (2,6-dichloro-4-fluorophenoxy) ethyl 0.76 g (53.3% yield) of methyl aminobenzoate was obtained as a white solid.

Melting point: 103-105 ° C., 1 H NMR (CDCl ₃ ): 7.22 (s, 1H), 7.03 (d, 2H), 6.93 (d, 1H), 6.91 (q, 1H), 4.17 (t, 2H), 3.90 (s, 3 H), 3.58 (t, 2 H), 2.24 (s, 3 H); 13C NMR (CDCl ₃ ): 170.101, 164.982, 158.831, 156.351, 145.552, 141.775, 129.648, 129.527, 124.233, 118.029, 116.384, 116.133, 114.791, 52.147, 44.093, 21.030

C) <Synthesis Example 1> C) using 2-acetoxy-5- [2- (2,6-dichloro-4-fluorophenoxy) ethylamino] benzoate methyl ether (0.76 g, 1.82 mmole) In the same manner as in the above, 0.54 g (82.3% yield) of 5- [2- (2,6-dichloro-4-fluorophenoxy) ethylamino] -2-hydroxybenzoic acid was obtained as a gray solid.

Melting point: 300 ° C.>, 1 H NMR (DMSO- d ₆ ): 7.45 (d, 2H), 7.05 (d, 1H), 6.93 (q, 1H), 6.76 (d, 1H); 13C NMR (DMSO- d ₆ ): 171.871, 158.257, 155.815, 152.956, 147.564, 147.526, 140.511, 128.915, 128.794, 122.036, 117.448, 116.591, 116.333, 112.458, 111.358, 71.686, 43.595

C ₁₅ H ₁₂ C ₁₂ FNO ₄ Elemental Analysis of

Table 6

Synthesis Example 7 Preparation of 2-hydroxy-5- (2-p-tolyloxyethylamino) benzoic acid (Compound 10)

A) Synthesis Example 1 using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 4-methylphenoxyacetic acid (0.92 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) By the same method as> A), 1.42 g (79.5% yield) of 2-acetoxy-5- (2-p-tolyloxyacetylamino) benzoate methyl ether was obtained as a white solid.

_{1H NMR (DMSO- d 6):} 8.26 (d, 1H), 7.88 (t, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 6.89 (d, 1H), 4.65 (s, 2H) , 3.80 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H)

B) 2-acetoxy-5- (2-p-tolyloxyacetylamino) benzoate methyl ether (1.42 g, 3.92 mmole), NaBH ₄ (0.74 g, 19.6 mmole) and acetic acid (1.18 g, 19.6 mmole) In the same manner as in <B> of <Synthesis Example 1>, 0.37 g (27.2% yield) of white acetate of 2-acetoxy-5- (2-p-tolyloxyethylamino) benzoate was obtained.

Melting point: 96-98 ° C., 1H NMR (CDCl ₃ ): 7.22 (d, 1H), 7.066 (d, 2H), 6.88 (d, 1H), 6.79-6.73 (m, 4H), 4.07 (t, 2H ), 3.81 (t, 3H), 3.45 (t, 2H), 2.29 (t, 5H); 13C NMR (CDCl ₃ ): 170.139, 164.906, 156.010, 145.590, 141.479, 130.126, 129.724, 124.074, 122.951, 117.802, 114.556, 114.116, 66.155, 52.079, 43.373, 20.969, 20.492

C) 2-hydroxy using 2-acetoxy-5- (2-p-tolyloxyethylamino) benzoate methyl ether (367 mg, 1.02 mmole) in the same manner as in <C> of <Synthesis Example 1> 0.29 g (92.6% yield) of -5- (2-p-tolyloxyethylamino) benzoic acid was obtained as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.08 (d, 1H), 7.05 (d, 2H), 6.94 (q, 1H), 6.78 (q, 3H), 4.04 (t, 2H) , 3.35 (t, 2 H), 2.21 (s, 3 H); 13C NMR (DMSO- d ₆ ): 171.939, 156.126, 152.895, 140.829, 129.658, 129.089, 121.892, 117.418, 114.179, 112.556, 111.282, 66.332, 43.337, 20.176

C ₁₆ H ₁₇ NO ₄ Elemental Analysis of

TABLE 7

Synthesis Example 8 Preparation of 5- [2- (4-chloro-2-methylphenoxy) ethylamino] -2-hydroxybenzoic acid (Compound 12)

A) using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 4-chloro-2-methylphenoxyacetic acid (1.17 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) Experimental by the same method as A) in <Synthesis Example 1>, 1.20 g (57.3% yield) of 2-acetoxy-5- [2- (4-chloro-2-methylphenoxy) acetylamino] benzoic acid methyl ether was white. Obtained as a solid.

_{1H NMR (DMSO- d 6):} 8.21 (s, 1H), 7.83 (q, 1H), 7.23 (m, 3H), 6.92 (d, 1H), 4.78 (s, 2H), 3.91 (s, 3H) , 3.25 (s, 3H), 2.24 (d, 3H)

B) 2-acetoxy-5- [2- (4-chloro-2-methylphenoxy) acetylamino] benzoic acid methyl ether (1.20 g, 2.91 mmole), NaBH ₄ (0.55 g, 14.5 mmole) and acetic acid (0.87 g, 14.5 mmole) was used in the same manner as in <B> of <Synthesis Example 1> to obtain 2-acetoxy-5- [2- (4-chloro-2-methylphenoxy) ethylamino] benzoate methyl ether 0.42 g (38.1% yield) was obtained as a white solid.

Melting point: 61-62 ° C., 1 H NMR (CDCl ₃ ): 7.21 (d, 1H), 7.08 (t, 2H), 6.90 (d, 1H), 6.78 (q, 1H), 6.67 (d, 1H), 4.06 (t, 2H), 3.81 (s, 3H), 3.51 (t, 2H), 2.25 (s, 3h), 2.17 (s, 3H); 13C NMR (CDCl ₃ ): 170.154, 164.899, 154.880, 145.514, 141.525, 130.240, 128.389, 126.144, 125.181, 124.135, 123.050, 117.756, 114.548, 111.871, 66.709, 52.117, 43.365, 20.969, 16.229

C) The same method as <C> of <Synthesis Example 1> using 2-acetoxy-5- [2- (4-chloro-2-methylphenoxy) ethylamino] benzoate methyl ether (0.42 g, 1.11 mmole) Experiment was carried out to give 0.29 g (82.4% yield) of 5- [2- (4-chloro-2-methylphenoxy) ethylamino] -2-hydroxybenzoic acid as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.21-7.02 (m, 3H), 6.97 (d, 1H), 6.91 (d, 1H), 6.78 (d, 1H), 4.12 (t, 2H), 3.41 (t, 2H), 2.12 (s, 3H); 13C NMR (DMSO- d ₆ ): 171.628, 155.095, 153.085, 140.094, 129.620, 128.232, 126.116, 123.606, 122.241, 117.349, 112.609, 112.405, 111.965, 66.962, 43.497, 15.808

C ₁₆ H ₁₆ ClNO ₄ Elemental Analysis of

Table 8

Synthesis Example 9 Preparation of 2-hydroxy-5- [2- (4-trifluoromethylphenoxy) ethylamino] benzoic acid (Compound 13)

A) 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 4-trifluoromethylphenoxyacetic acid (1.22 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) were used. Experiment by the same method as A) of Synthesis Example 1>, and 1.48 g (70.8% yield) of 2-acetoxy-5- [2- (4-trifluoromethylphenoxy) acetylamino] benzoate as a white solid was obtained. Got it.

Melting point: 300 ° C., 1 H NMR (DMSO- d ₆ ): 8.25 (d, 1H), 7.83 (q, 1H), 7.68 (d, 2H), 7.18 (q, 3H), 4.84 (s, 2H), 3.80 (s, 3H), 2.68 (s, 3H)

B) 2-acetoxy-5- [2- (4-trifluoromethylphenoxy) acetylamino] benzoic acid methyl ether (1.48 g, 3.59 mmole), NaBH ₄ (0.68 g, 17.9 mmole) and acetic acid (1.07 g) , 17.9 mmole) and 0.52 g (2-acetoxy-5- [2- (4-trifluoromethylphenoxy) ethylamino] benzoic acid methyl ether in the same manner as in <B> of <Synthesis Example 1> 36.9% yield) was obtained as a white solid.

Melting point: 116 ° C., 1 H NMR (CDCl ₃ ): 7.53 (d, 2H), 7.26 (t, 1H), 6.97 (d, 2H), 6.91 (d, 1H), 6.82 (m, 1H), 4.19 ( t, 2H), 3.82 (s, 3H), 3.57 (t, 2H), 2.31 (s, 3H); 13C NMR (CDCl ₃ ): 170.169, 164.967, 160.682, 145.324, 141.889, 126.872, 126.834, 126.797, 124.324, 123.285, 118.014, 114.867, 114.366, 66.542, 52.223, 43.395, 21.045

C) In the same manner as in <C> of Synthesis Example 1, using 2-acetoxy-5- [2- (4-trifluoromethylphenoxy) ethylamino] benzoate methyl ether (0.52 g, 1.32 mmole) The experiment yielded 0.36 g (80.3% yield) of 2-hydroxy-5- [2- (4-trifluoromethylphenoxy) ethylamino] benzoic acid as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.85 (m, 1H), 7.62 (m, 3H), 7.12 (d, 1H), 7.06 (t, 2H), 4.36 (t, 2H) , 3.68 (t, 2 H); _{13C NMR (DMSO- d 6):} 170.536, 166.600, 160.995, 160.297, 159.372, 131.137, 128.960, 126.791, 126.754, 125.639, 123.379, 122.954, 121.672, 121.308, 118.267, 114.945, 114.225, 113.360, 63.670, 48.608

C ₁₆ H ₁₄ F ₃ NO ₄ Elemental Analysis of

Table 9

Synthesis Example 10 Preparation of 2-hydroxy-5- [2- (2-nitrophenoxy) ethylamino] benzoic acid (compound 16)

A) Synthesis example using 2-acetoxy-5-aminobenzoic acid methyl ether (1.02 g, 5.07 mmole), 2-nitrophenoxyacetic acid (1.11 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) Experiments were carried out in the same manner as in A> of 1>, to obtain 1.72 g (87.3% yield) of 2-acetoxy-5- [2- (2-nitrophenoxy) acetylamino] benzoate as a white solid.

_{1H NMR (DMSO- d 6):} 8.24 (d, 1H), 7.91 (q, 1H), 7.82 (q, 1H), 7.64 (m, 1H), 7.30 (d, 1H), 7.15 (t, 1H) , 4.96 (s, 2H), 3.81 (s, 3H), 2.27 (s, 3H)

B) 2-acetoxy-5- [2- (2-nitrophenoxy) acetylamino] benzoic acid methyl ether (1.72 g, 4.41 mmole), NaBH ₄ (0.84 g, 22.6 mmole) and acetic acid (1.35 g, 22.6 Using mmole), 0.94 g (57.1% yield) of methyl acetate of 2-acetoxy-5- [2- (4-nitrophenyl) ethylamino] benzoate was obtained in the same manner as in B) of <Synthesis Example 1>. Obtained as a white solid.

Melting point: 80 ° C., 1 H NMR (CDCl ₃ ): 7.84 (q, 1H), 7.51 (m, 1H), 7.23 (t, 1H), 7.03 (m, 2H), 6.88 (d, 1H), 6.84 ( q, 1H), 4.23 (t, 2H), 3.82 (s, 3H), 3.57 (t, 2H), 2.27 (s, 3H)

C) Experiment in the same manner as in <C> of <Synthesis Example 1> using 2-acetoxy-5- [2- (4-nitrophenyl) ethylamino] benzoic acid methyl ether (0.94 g, 2.52 mmole) 0.66 g (82.2% yield) of -hydroxy-5- (2-phenylsulfonylethylamino) benzoic acid was obtained as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.82 (q, 1H), 7.62 (m, 1H), 7.38 (d, 1H), 7.11 (d, 1H), 7.08 (t, 1H) , 6.94 (q, 1 H), 6.78 (d, 1 H), 4.32 (t, 2H), 3.43 (t, 2H); 13C NMR (DMSO- d ₆ ): 171.522, 153.199, 150.855, 139.760, 139.373, 134.163, 124.729, 122.173, 120.497, 117.402, 115.112, 112.443, 112.124, 67.947, 43.330

C ₁₅ H ₁₄ N ₂ O ₆ Elemental Analysis of

Table 10

Synthesis Example 11 Preparation of 2-hydroxy-5- [2- (naphthalen-2-yloxy) ethylamino] benzoic acid (Compound 17)

A) Synthesis using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), naphthalen-2-yloxyacetic acid (1.12 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) The experiment was carried out in the same manner as in A> of 1>, to obtain 1.69 g (84.6% yield) of 2-acetoxy-5- [2- (naphthalen-2-yloxy) -acetylamino] benzoate as a white solid.

_{1H NMR (DMSO- d 6):} 8.31 (d, 1H), 7.94 (q, 1H), 7.88-7.78 (m, 3H), 7.45 (t, 1H), 7.35 (m, 3H), 7.20 (d, 1H), 4.82 (s, 2H), 3.81 (s, 3H), 2.23 (s, 3H)

B) 2-acetoxy-5- [2- (naphthalen-2-yloxy) acetylamino] benzoic acid methyl ether (1.69 g, 4.29 mmole), NaBH ₄ (0.81 g, 21.4 mmole) and acetic acid (1.28 g, 21.4 0.76 g (46.9% yield) of 2-acetoxy-5- [2- (naphthalen-2-yloxy) ethylamino] benzoic acid methyl ether by experiment by the same method as B) of <synthesis example 1> using mmole) Was obtained as a white solid.

Melting point: 167-169 ° C., 1 H NMR (CDCl ₃ ): 7.81 (t, 3H), 7.43 (t, 1H), 7.32 (t, 2H), 7.18 (t, 1H), 6.92 (m, 2H), 6.21 (t, 1 H), 4.22 (t, 2 H), 3.89 (s, 3 H), 3.53 (t, 2H), 2.21 (t, 3H); 13C NMR (CDCl ₃ ): 169.489, 164.696, 156.066, 146.343, 139.639, 134.034, 129.074, 128.293, 127.292, 126.503, 126.177, 124.046, 123.401, 122.757, 118.555, 116.568, 113.125, 106.550, 66.438, 52.021, 42.3021, 42.3021

C) Experiment in the same manner as in <C Synthesis Example 1>, using 2-acetoxy-5- [2- (naphthalen-2-yloxy) ethylamino] benzoate methyl ether (0.76 g, 2.01 mmole) 0.53 g (81.8% yield) of 2-hydroxy-5- [2- (naphthalen-2-yloxy) -ethylamino] benzoic acid was obtained as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.83 (t, 3H), 7.52 (s, 1H), 7.44 (t, 1H), 7.34 (t, 3H), 7.18 (m, 1H) , 6.92 (d, 1 H), 4.29 (t, 2 H), 3.62 (t, 2 H); 13C NMR (DMSO- d ₆ ): 171.097, 156.649, 155.732, 133.989, 129.173, 128.460, 127.353, 126.579, 126.276, 126.033, 123.591, 118.495, 117.956, 113.095, 106.793, 64.679, 46.500

C ₁₉ H ₁₇ NO ₄ Elemental Analysis of

Table 11

Synthesis Example 12 Preparation of 2-hydroxy-5- (3-phenoxypropylamino) benzoic acid (Compound 20)

A) Synthesis Example 1 using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 3-phenylpropionic acid (0.92 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) By the same method as> A), 1.41 g (70.7% yield) of 2-acetoxy-5- (3-phenoxypropionylamino) benzoate was obtained as a white solid.

_{1H NMR (DMSO- d 6):} 8.26 (d, 1H), 7.84 (q, 1H), 7.26 (t, 2H), 7.16 (d, 1H), 6.91 (m, 3H), 4.28 (t, 2H) , 3.81 (s, 3H), 2.83 (t, 2H), 2.27 (s, 3H)

B) 2-acetoxy-5- (3-phenoxypropionylamino) benzoate methyl ether (1.41 g, 3.94 mmole), NaBH ₄ (0.74 g, 19.7 mmole) and acetic acid (1.18 g, 19.7 mmole) Experiment by the same method as B) of <synthesis example 1>, 0.54 g (40.1% yield) of 2-acetoxy-5- (3-phenoxypropylamino) benzoate was obtained as a white solid.

Melting point: 60-61 ° C., 1 H NMR (CDCl ₃ ): 7.25 (t, 2H), 7.15 (d, 1H), 6.91 (t, 1H), 6.88 (m, 3H), 6.69 (q, 1H), 4.02 (t, 2H), 3.80 (s, 3H), 3.28 (t, 2H), 2.27 (s, 3H), 2.03 (m, 2H); 13C NMR (CDCl ₃ ): 170.101, 164.990, 158.399, 145.893, 141.123, 129.254, 123.998, 123.020, 120.646, 117.324, 114.260, 114.215, 65.654, 52.003, 41.355, 28.834, 20.939

C) Using 2-acetoxy-5- (3-phenoxypropylamino) benzoic acid methyl ether (0.54 g, 1.58 mmole), the same procedure as in <C) of <Synthesis Example 1> was carried out. 0.39 g (85.9% yield) of-(3-phenoxypropylamino) benzoic acid was obtained as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.98 (d, 1H), 7.71 (d, 1H), 7.24 (q, 2H), 7.15 (d, 1H), 7.87 (t, 3H) , 4.05 (2H), 3.39 (t, 2H), 2.16 (m, 2H); 13C NMR (DMSO- d ₆ ): 170.323, 160.138, 157.939, 129.582, 129.203, 127.762, 124.213, 120.459, 118.426, 114.255, 113.550, 64.421, 48.070, 25.409

C ₁₆ H ₁₇ NO ₄ Elemental Analysis of

Table 12

Synthesis Example 13 Preparation of 5- [3- (4-fluorophenoxy) propylamino] -2-hydroxybenzoic acid (Compound 21)

A) using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 4-fluorophenoxypropionic acid (1.02 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) Experimental procedure in the same manner as in A) of Synthesis Example 1 gave 1.38 g (72.3% yield) of 2-acetoxy-5- [3- (4-fluorophenoxy) propionylamino] benzoate as a white solid. .

1 H NMR (DMSO- d ₆ ): 8.24 (d, 1H), 7.82 (q, 1H), 7.16 (d, 1H), 7.10 (m, 2H), 6.94 (m, 2H), 4.23 (t, 2H) , 3.80 (t, 3H), 2.82 (t, 2H), 2.24 (s, 3H)

B) 2-acetoxy-5- [3- (4-fluorophenoxy) propionylamino] benzoic acid methyl ether (1.38 g, 3.67 mmole), NaBH ₄ (0.69 g, 18.3 mmole) and acetic acid (1.09 g, 18.3 mmole) was used in the same manner as in <B> of <Synthesis Example 1> to obtain 0.53 g (39.5% yield) of methyl acetate of 2-acetoxy-5- [3- (4-fluorophenoxy) propylamino] benzoate. ) Was obtained as a white solid.

Melting point: 56 ° C., 1 H NMR (CDCl ₃ ): 7.16 (d, 1H), 6.93 (m, 2H), 6.94-6.79 (m, 3H), 6.70 (q, 1H), 4.00 (t, 2H), 3.81 (s, 3 H), 3.30 (t, 2 H), 2.28 (s, 3 H), 2.04 (m, 2 H); 13C NMR (CDCl ₃ ): 170.162, 165.035, 158.217, 155.858, 154.607, 145.878, 141.229, 124.089, 123.118, 117.377, 115.785, 115.557, 115.314, 115.239, 114.313, 66.428, 52.079, 41.348, 28.933, 20.985

C) Experiment in the same manner as in <C> of Synthesis Example 1, using methyl 2-acetoxy-5- [3- (4-fluorophenoxy) propylamino] benzoate (0.53 g, 1.45 mmole) 0.36 g (81.5% yield) of 5- [3- (4-fluorophenoxy) propylamino] -2-hydroxybenzoic acid was obtained as a gray solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.05 (m, 3H), 6.92 (q, 3H), 6.88 (q, 1H), 4.02 (t, 2H), 3.12 (t, 2H) , 1.96 (m, 2 H); 13C NMR (DMSO- d ₆ ): 171.779, 157.332, 154.989, 154.625, 152.971, 140.526, 121.900, 117.349, 115.689, 115.491, 115.469, 115.415, 112.678, 111.502, 65.809, 40.812, 28.261

C ₁₆ H ₁₆ FNO ₄ Elemental Analysis of

Table 13

Synthesis Example 14 Preparation of 5-{[2- (4-chlorophenoxy) ethyl] methylamino} -2-hydroxybenzoic acid (Compound 22)

A) Synthesis Example 1 using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 4-chlorophenoxyacetic acid (0.94 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) Experiment by the same method as> A) to give 1.20 g (62.5% yield) of 2-acetoxy-5- [2- (4-chlorophenoxy) acetylamino] benzoate as a white solid.

_{1H NMR (DMSO- d 6):} 8.27 (d, 1H), 7.89 (q, 1H), 7.35 (d, 2H), 7.18 (d, 1H), 7.02 (d, 2H), 4.71 (s, 2H) , 3.81 (s, 3H), 2.23 (s, 2H)

B) 2-acetoxy-5- [2- (4-chlorophenoxy) acetylamino] benzoic acid methyl ether (1.20 g, 3.17 mmole), NaBH ₄ (0.59 g, 15.8 mmole) and acetic acid (0.95 g, 15.8 mmole ) Was tested in the same manner as in <B> of <Synthesis Example 1>, and 0.61 g (53.0% yield) of 2-acetoxy-5- [2- (4-chlorophenoxy) ethylamino] benzoate was white. Obtained as a solid.

Melting point: 108 ° C., 1 H NMR (CDCl ₃ ): 7.22 (q, 2H), 7.19 (d, 1H), 6.88 (d, 1H), 6.82-6.76 (m, 3H), 4.15 (t, 2H), 3.92 (s, 3 H), 3.51 (t, 2 H), 2.25 (s, 3 H); 13C NMR (CDCl ₃ ): 170.162, 164.937, 156.806, 145.453, 141.654, 129.193, 125.811, 124.188, 123.118, 117.870, 115.603, 114.670, 66.542, 52.162, 43.335, 21.007

C) Methyl ether (0.50 g, 1.50 mmole) and K ₂ CO ₃ ( ₂ -acetoxy-5- [2- (4-chlorophenoxy) ethylamino] benzoate in DMF (10.0 mL) dried at room temperature under nitrogen atmosphere. 0.50 g) and CH ₃ I (0.30 ml, 1.80 mmole) were added. It was refluxed at 40 and stirred for 6 hours. The suspension was filtered off and the DMF was removed under reduced pressure. The residue was diluted with ethyl acetate and extracted with water and brine. 0.48 g (84.8% yield) of 2-acetoxy-5-{[2- (4-chlorophenoxy) ethyl] methylamino} methyl acid benzoate as a white solid by removing the organic layer under reduced pressure and recrystallization under ethyl acetate / hexane Got it.

Melting point: 109 ° C., 1 H NMR (CDCl ₃ ): 7.4 (s, 1H), 7.3 (m, 3H), 7.0 (s, 2H), 6.8 (d, 2H), 4.2 (t, 2H), 3.83 ( s, 3H), 3.80 (t, 2H), 3.0 (s, 3H), 2.3 (s, 3H)

D) In the same manner as in <C> of Synthesis Example 1, using 2-acetoxy-5-{[2- (4-chlorophenoxy) ethyl] methylamino} methyl acid benzoate (0.31 g, 0.93 mmole) The experiment yielded 0.21 g (80.8% yield) of 5-{[2- (4-chlorophenoxy) ethyl] methylamino} -2-hydroxybenzoic acid as a white solid.

Melting point: 300 ° C>, 1 H NMR (DMSO- d ₆ ): 7.3 (d, 2H), 7.1 (m, 2H), 6.9 (d, 2H), 6.8 (d, 1H), 4.2 (t, 2H) , 3.6 (t, 2H), 2.9 (s, 3H); 13 C NMR (DMSO- d ₆ ): 171.69, 156.91, 152.77, 141.95, 128.97, 124.08, 121.81, 117.38, 115.95, 112.44, 112.32, 65.57, 51.92

C ₁₆ H ₁₆ ClNO ₄ Elemental Analysis of

Table 14

Synthesis Example 15 Preparation of 2-hydroxy-5- (2-phenylsulfonylethylamino) benzoic acid (Compound 24)

A) Synthesis Example 1 using 2-acetoxy-5-aminobenzoic acid methyl ether (1.03 g, 5.07 mmole), 2-phenylselfenyl acetic acid (0.93 g, 5.57 mmole) and DCC (1.14 g, 5.55 mmole) By the same method as> A), 1.55 g (85.0% yield) of 2-acetoxy-5- (2-phenylsulfurylacetylamino) benzoate methyl ether was obtained as a white solid.

_{1H NMR (DMSO- d 6):} 8.17 (d, 1H), 7.78 (q, 1H), 7.37 (d, 2H), 7.30 (t, 2H), 7.16 (q, 2H), 3.85 (s, 2H) , 3.79 (s, 3H), 3.25 (s, 3H)

B) 2-acetoxy-5- (2-phenylsulfurylacetylamino) benzoate methyl ether (1.55 g, 4.31 mmole), NaBH ₄ (0.81 g, 21.5 mmole) and acetic acid (1.29 g, 21.5 mmole) Experiment by the same method as B) of <Synthesis Example 1>, 0.72 g (48.3% yield) of 2-acetoxy-5- (2-phenylsulfonylethylamino) benzoic acid methyl ether was obtained as a white solid.

Melting point: 87-88 ° C., 1 H NMR (CDCl ₃ ): 7.35 (t, 2H), 7.27 (m, 2H), 7.20 (m, 2H), 7.13 (d, 1H), 6.85 (d, 1H), 6.66 (q, 1H), 3.81 (s, 3H), 3.29 (t, 2H), 3.09 (t, 2H), 2.29 (s, 3H); 13C NMR (CDCl ₃ ): 170.185, 164.853, 145.135, 141.388, 134.449, 129.914, 128.867, 126.463, 124.074, 122.951, 117.612, 114.503, 52.124, 52.094, 42.455, 33.331, 20.985

C) Using 2-acetoxy-5- (2-phenylsulfurylethylamino) benzoate methyl ether (0.72 g, 2.08 mmole), the same procedure as in <C> of <Synthesis Example 1> was carried out. 0.51 g (84.7% yield) of 5- (2-phenylsulfonylethylamino) benzoic acid was obtained as a white solid.

Melting point: 300 ° C>, 1H NMR (DMSO- d ₆ ): 7.35-7.27 (m, 4H), 7.16 (t, 1H), 6.97 (d, 1H), 6.84 (m, 1H), 6.73 (d, 1H), 3.22 (t, 2H), 3.11 (t, 2H); 13 C NMR (DMSO- d ₆ ): 171.711, 152.759, 140.427, 135.612, 128.862, 128.066, 125.570, 121.733, 117.425, 112.503, 111.115. 43.193, 31.605

C ₁₅ H ₁₅ NO ₃ Elemental Analysis of S

Table 15

Synthesis Example 16 Preparation of 5- [2- (2,6-dimethyl-phenoxy) -ethylamino] -2-hydroxy-benzoic acid (Compound 11)

A) Preparation of a: Ethyl bromoacetate (54 mL, 0.49 mol) was added to a 500 mL DMF suspension of 2,6-dimethylphenol (50 g, 0.41 mol) and K ₂ CO ₃ (51 g, 0.25 mol). It was added dropwise for minutes, and the resulting mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction mixture to stop the reaction and stirred for 2 hours at room temperature.

After dilution with EtOAc (700 mL), the reaction was washed with water (500 mL, twice) and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and dried to give a (76 g, 89%) as a pale yellow oil. The product was used in the next step without further purification.

B) Preparation of b: 200 mL THF solution of the above compound 14 (76 g, 0.36 mol) was added to an 800 mL ether suspension of LiAlH ₄ (16 g, 0.42 mol) for 1.5 hours (softly refluxed), and overnight Stirred. The reaction in the cold water bath was stopped by successively adding water (21 mL, added dropwise for at least 30 minutes), 15% NaOH (21 mL) and water (63 mL). After stirring for 30 minutes at room temperature, the solid formed was separated by filtration. The filtered filter cake was washed with diethyl ether and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in dichloromethane, washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and dried to yield b (60 g, 98%) as a light pink solid. The product was used in the next step without further purification.

1 H NMR (400 MHz, CDCl 3) 7.0-6.9 (m, 3H), 3.98-3.89 (m, 4H), 2.30 (s, 6H).

C) Preparation of d: DMSO (42 mL, 0.59 mol) was added to a solution of oxalyl chloride (23 mL, 0.27 mol) in dichloromethane (500 mL) for 30 minutes at -78 ° C. After 30 minutes stirring, a solution of dichloromethane (200 mL) of compound 15 (30 g, 0.18 mol) was added at -40 to -60 ° C for 40 minutes. Some starting material left in the dropping funnel was added using dichloromethane (50 mL). The reaction mixture was slowly warmed to 0 ° C. for 30 minutes and the reaction was stopped by the slow addition of N, N-diisopropylethylamine (140 mL, 0.8 mol) (for 1 hour). The reaction mixture was concentrated at 25 ° C. under reduced pressure. The oily residue was dissolved in diethyl ether, washed with 1 N HCl (300 mL), 1 MK ₂ HPO ₄ (200 mL, twice) and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was dried to give c (35 g) as a pale yellow oil. The product was used in the next step without further purification.

AcOH (12 mL, 0.2 mol) in a solution of 1,2-dichloroethane (500 mL) in c (33 g, 0.2 mol) and 2-acetoxy-5-aminobenzoic acid methyl ether (33 g, 0.2 mol) Was added. After 30 minutes, sodium triacetoxyborohydride (42 g, 0.2 mol) was added to the reaction at ice bath temperature. The reaction mixture was stirred at rt overnight. After the reaction was stopped with water (10 mL), the reaction mixture was washed with water, saturated NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified using column chromatography (20% EtOAc / hexanes). The oily product was crystallized from 10% EtOAc / hexanes to give d (45 g, 72%) as a white solid.

1 H NMR (400 MHz, CDCl 3) 10.18 (s, OH, 1H), 7.09 (d, 1H, J = 2.8 Hz), 6.99-6.86 (m, 5H), 4.00 (br s, NH, 1H), 3.95 ( t, 2H, J = 5.2 Hz), 3.90 (s, 3H), 3.45 (t, 2H, J = 5.2 Hz), 2.24 (s, 6H)

D) Preparation of Compound 11: A suspension of d (35 g, 0.11 mol) of 6 N HCl (200 mL) and AcOH (100 mL) was refluxed overnight and then cooled. NaOH (48 g, 1.2 mol) was added to the reaction mixture with stirring to neutralize (pH-5). The suspension was poured into ice water (1 L) and filtered. The solid was washed with distilled water (1 L), EtOAc (500 mL) and diethyl ether (500 mL) and dried in vacuo to yield Compound 11 (27 g, 90 mmol, 82%) as a white solid.

1 H NMR (400 MHz, DMSO-d6) 7.00 (d, 1H, J = 2.8 Hz), 6.95-6.83 (m, 5H), 6.72 (d, 1H, J = 8.8 Hz), 3.80 (t, 2H, J = 5.6 Hz), 3.33 (t, 2H, J = 5.6 Hz), 2.14 (s, 6H) LCMS calc. for C 17 H 19 NO 4 (M + H +): 302, found 302.

<Example 1> Evaluation of inhibition of excitatory toxicity by NMDA due to cytoprotective effect

In order to induce neuronal death by excitatory toxicity in cultured cerebral cortical neurons (DIV 11-15) 100 uM NMDA alone or in combination with 10-1000 uM of compounds 2, 3, 7, 11 or 17 After 24 minutes, the activity of LDH liberated out of the cells was measured 24 hours later to quantify neuronal cell death and determine the IC ₅₀ value. The results are summarized in Table 16 (NMDA toxicity). As a result, the compounds 2, 3 and 11 showed a somewhat higher IC ₅₀ value, it was confirmed that these compounds almost completely inhibit the death of neurons due to excitatory toxicity induced by NMDA at 1 mM.

<Example 2> Antioxidant effect evaluation

(2-1) FeCl ₂ Inhibition of Antioxidant Toxicity by

In order to induce neuronal death by oxidative toxicity in cultured cerebral cortical neurons (DIV 11-15), 50 uM FeCl ₂ (promotes the production of OH. By Fenton reaction) alone or 0.01-30 Add with uM compound 1-24. The control group was treated with 50 uM of FeCl ₂ and vitamin E, a well-known antioxidant. In the same manner as in Example 1, 24 hours after drug treatment, the activity of LDH released out of cells was measured to quantify neuronal cell death and to obtain IC ₅₀ values. The results are shown in Table 16 (Fe ²⁺ toxicity). As a result, it was confirmed that the compounds 1 to 24 have a very low IC ₅₀ value for the death of neurons induced by FeCl ₂ . Compounds 1 to 24 inhibited the concentration of neurons induced by FeCl ₂ concentration-dependently. More specifically, compounds 4, 7, 9, 10 and 13 are oxidized by FeCl ₂ at 1 uM, compound 14 at 3 uM, compound 16 at 10 uM, and compound 17 at low concentrations of 0.3 uM Neuronal cell death caused by toxic toxicity was completely inhibited.

(2-2) Evaluation of DPPH Free Radical Scavenging Capacity

It was evaluated whether the oxidative toxicity inhibitory effects of the compounds 1 to 24 measured in Example 2 were related to the free radical scavenging effect. Specifically, by reducing the absorbance at 517 nm by directly reacting the stable free radical 1,1-diphenyl-2-picrylhydrazine (DPPH) with compounds 1 to 24 of the present invention, the IC ₅₀ value was determined. . The results are shown in Table 16 (DPPH clearing). As a result, all of compounds 1 to 24 had free radical scavenging ability and acted 2 to 5 times stronger than vitamin E.

<Example 3> Anti-inflammatory effect evaluation

The inhibitory effect of the salicylic acid derivative compounds of the present invention on NO, an inflammatory factor involved in the inflammatory response, was observed. LPS and the compound of the present invention were simultaneously treated with 10 uM, 30 uM or 100 uM, respectively, in a BV2 / RAW 297.6 cell line, followed by incubation for 24 hours, and 50 ul of the culture was taken in a 96-well plate. Thereafter, 50 ul of Griess reagent was added thereto, reacted at room temperature for 10 minutes, and the absorbance was measured at 540 nm using an ELISA reader. IC ₅₀ of each compound was calculated and shown in Table 16 (NO inhibition). As can be seen in Table 16 below, the IC ₅₀ of Compound 11 was 17.17 uM, the IC ₅₀ of Compound 21 was 11.4 uM, and the IC ₅₀ of Compound 22 was 16.3 uM. As described above, the salicylic acid derivative compound of the present invention effectively inhibits NO activity involved in the inflammatory reaction and thus may be used as an anti-inflammatory agent.

<Example 4> Amyloid beta production inhibitory effect

The inhibitory effects of the compounds of the present invention on amyloid beta production, a major factor in Alzheimer's dementia, were observed. No treatment was performed on the CHO cell line, and the compounds of the present invention were treated with 20 uM, 60 uM or 100 uM, respectively, for 24 hours, and then 50 ul of the culture was reacted using an ELISA kit provided by Biosource. The absorbance was then measured at 540 nm with an ELISA reader, and the IC ₅₀ of each compound was calculated and shown in Table 16 (Aβ inhibition). The IC ₅₀ of compound 8 was 22.9 uM and the IC ₅₀ of compound 11 was 50.67 uM.

Table 16

In Table 16, 'ND' means not determined.

<Example 5> Anti-inflammatory action evaluation of compound 11

The inhibitory effect of compound 11 of the present invention on NO, the inflammatory cytokines TNF-α and IL-6, which are involved in the inflammatory response, was observed. The BV2 microglia cell line was treated with lipopolysaccharide (lipopolysaccharide, LPS), which is a bacterial toxin inflammatory drug, and 100 μM of the compound 11 of the present invention at the same time for 24 hours. Thereafter, 50ul of the culture solution was taken into a 96-well plate, 50ul of Gries's reagent was added thereto, reacted at room temperature for 10 minutes, and the absorbance was measured at 540nm with an ELISA reader. The amounts of the cytokines TNF-α and IL-6 were measured by ELISA. As a control, a culture solution treated with LPS for 24 hours was used. The results are shown in FIG.

As can be seen from the results in FIG. 1, it was confirmed that 100 uM compound 11 reduced NO produced by LPS by about 65%, and TNF-α and IL-6 by about 30-40%. As such, Compound 11, which is an embodiment of the present invention, effectively inhibits the amount of NO activity and cytokines involved in the inflammatory response, and thus is very effective as an anti-inflammatory agent.

<Example 5> Protective effect of Compound 11 in animal models of arthritis

In order to evaluate the effectiveness of compound 11, which is an embodiment of the present invention, a collagen-induced arthritis model, which is an animal model of rheumatoid arthritis, was used. Bovine type II collagen was mixed with complete Freund's adjuvant to make an emulsion, followed by intradermal injection into the base of the tail of DBA / 1LacJ mice for 8-10 weeks. Two weeks later, intradermal boosting was performed in the same manner. One week after the second collagen intradermal injection, 25 mg / kg / day of Compound 11 was injected into the abdominal cavity, 1 mg / kg / week of methotrexate into the control group, and 10% vehicle was injected as a control. The incidence of arthritis was observed daily for two to three weeks, and the results were evaluated by the following arthritic index according to edema. As assessed by the arthritic index, Compound 11 showed a marked reduction. The results are shown in FIG.

-Arthritis Index-

Four paws are rated 0-4, 16 total

0 points-normal

1 point-mild edema and redness limited to the tarsal bone in the ankle joint

2 points-Mild swelling and redness from the ankle joint to the tarsal bone

3 points-moderate swelling and redness from the ankle joint to the metatarsal bone

4 points-edema and redness throughout the toes in the ankle joint

In addition, the amount of TNF-α and IL-1β as markers of inflammation in the same model was measured by ELISA method. The results are shown in FIG. As shown in FIG. 3, compound 11 showed a significant reducing effect.

Hereinafter, a specific disease to which the salicylic acid derivative compound of the present invention or a pharmaceutically acceptable salt thereof may be applied will be described. However, the following application examples are only for illustrating the present invention, and the spirit of the present invention is not limited to the following application examples.

<Application example 1> Ischemic stroke (Hypoxid ischemia)

Stroke is a disease caused by a disorder of blood circulation in the brain (thrombosis, embolism or stenosis). Circulatory gut causes nerve cell death. When stroke occurs, the excitatory neurotransmitter glutamate accumulates at the neuronal junction, and neuronal cell death rapidly progresses due to the transient activity of Ca ²⁺ -permeable glutamate receptors. Indeed, NMDA receptor antagonists are known to significantly reduce brain cell death by ischemic stroke, which accounts for 80% of strokes. After the stroke, the electron transport system in the mitochondria is damaged and the production of free radicals increases. Increased free radicals lead to destruction of cell membrane lipids, gene damage, and protein degeneration, leading to necrotic necrosis. Antioxidants have the effect of inhibiting necrosis of ischemic neurons. Therefore, administration of the compound having the antioxidant and excitatory toxicity inhibitory effects of the present invention can effectively prevent or treat stroke.

<Application example 2> Alzheimer's disease (AD)

Alzheimer's dementia is the most common cause of dementia. Histopathologically, neurofibrillary tangles, amyloid plaques and severe neuronal death are hallmarks of Alzheimer's dementia. Recently, many papers have reported that neuronal cell death observed in Alzheimer's dementia is associated with oxidative stress. First, it is known that the increase of metal groups (Fe, Al and Hg) that can stimulate free radical production, the second, the increase of lipid peroxidation, and the third, the oxidation of protein and DNA are increased in Alzheimer's disease. In addition, memantine, an NMDA receptor antagonist, has been shown to improve learning and memory in the dementia model and has been marketed as a treatment for dementia, which indirectly shows that excitatory toxicity is involved in dementia. Therefore, the compounds of the present invention that exhibit antioxidant and excitatory toxicity inhibitory effects can be used as a treatment for Alzheimer's dementia.

<Application example 3> Parkinson's disease

Parkinson's disease is a degenerative neurological disorder accompanied by dopamine neuronal cell death in the vaginal tract, showing various symptoms such as tremor, muscle stiffness, complete exercise, abnormal posture, and inability to exercise. Oxidative toxicity has been suggested as a major cause of neuronal necrosis. Increases in lipid peroxidation, DNA oxidation, protein carbonyl and nitrotyrosine are found in the black matter. There are reports of protective effects (Prasad KN et al., J Am Coll Nutr. 1999; 18 (5): 413-23). And some NMDA receptor antagonists inhibited dopamine neuronal cell death in animal models of Parkinson's disease (Nash JE et al., Exp Neurol. 2000 Sep; 165 (1): 136-42). Therefore, the compounds of the present invention which exhibit antioxidant and excitatory toxicity inhibitory effects can be used very effectively in the treatment of Parkinson's disease.

<Application example 4> Lou Gehrig Disease or Amyotrophic lateral sclerosis (ALS)

Lou Gehrig Disease is a disease called amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND). Degenerative changes in motor neurons are a hallmark of Lou Gehrig's disease. Several hypotheses have been established about the causes of selective neuronal death in Lou Gehrig's disease. First, excitatory neurotoxicity is known to be involved in the process of apoptosis in ALS. In patients with ALS, the glutamate transporter protein in glial cells is reduced, and it has been reported that the injection of ionic glutamate receptor agonists into the spine of rats shows similar pathological changes as in patients with ALS. Second, evidence is accumulating that oxidative toxicity, in addition to excitatory neurotoxicity, is involved in neuronal cell death in ALS. Recent findings of SOD-1 gene mutations suggest the importance of oxidative toxicity in hereditary Lou Gehrig's disease. In addition, an increase in the protein carbonyl group and nitrotyrosine, an indicator of oxidative toxicity, has been reported in the brains of patients with Lou Gehrig's disease. Therefore, the compounds of the present invention that exhibit antioxidant and excitatory toxicity inhibitory effects can be used as a therapeutic agent for amyotrophic lateral sclerosis.

<Application example 5> Huntington's disease

Huntington's disease (HD) mainly involves the death of interneurons of the brain striatum. Since such pathological properties of HD are similarly reproduced by treatment with NMDA receptor agonists, selective neuronal cell death in HD is known to be mediated by NMDA receptors. In addition, there is a lot of evidence that oxidative toxicity, including mitochondrial damage, the production of free radicals is the main cause of neuronal cell death in HD, and drugs that inhibit free radicals have been proposed as HD therapeutics. Therefore, it can be seen that administration of a compound having an effect of inhibiting antioxidant and excitatory toxicity according to the present invention can effectively treat or prevent Huntington's disease.

<Application Example 6> Traumatic brain injury and spinal cord injury

Excitatory neurotoxicity is also closely involved in the degeneration of brain cells that appear after traumatic brain injury (TBI) and spinal injury (TSCI). NMDA receptor antagonists are known to reduce neuronal cell death following TBI and TSCI. Oxidative toxicity and apoptosis are closely involved in the degeneration of brain cells following traumatic brain injury and spinal injury. Brain and spinal injuries cause paraplegia and limb paralysis, and neuronal cell death is observed from the injury site to a distant site, but no treatment or treatment has been developed. Brain and spinal injuries have been reported to involve Ca ²⁺ influx, disruption of cell membranes, and peroxidation of lipids due to oxidative toxicity. Recently, evidence suggests that cell death is involved in secondary damage. In addition, caspase inhibitors, enzymes involved in cell death, have been reported to reduce neuronal death. Thus, the compounds of the present invention or pharmaceutically acceptable salts thereof can be effectively used for the treatment of brain and spinal cord injury.

<Application Example 7> Glaucoma, macular degeneration and diabetic retinopathy

In the case of glaucoma, blood flow to the retina is blocked by an increase in intraocular pressure, which leads to an ischemic state of retinal nerve cells. At this time, glutamate, a neurotransmitter, is excessively secreted into the neurosynthesis, resulting in excitatory toxicity, and a lot of evidence of death due to ischemia has recently been published. It is also known that the death of retinal neurons caused by free radicals produced during blood reperfusion. In addition, recently, the results of inhibiting optic nerve cell death have been reported using a cell necrosis inhibitor (antioxidant and antagonist of NMDA receptor) in the animal test of glaucoma. In addition, there are many reports that neuronal degeneration of diabetic retinopathy and macular degeneration is observed to increase free radicals, excitatory toxicity and cell death. Therefore, administering the compounds of the present invention to inhibit the death of such optic nerve cells is very effective in treatment.

<Application Example 8> Rheumatoid Arthritis

The salicylic acid derivative compound of the present invention showed a similar or somewhat superior effect in the collagen-induced arthritis model compared to the control method, methotrexate (currently prescribed as a therapeutic agent for arthritis, but has side effects). In addition, the salicylic acid derivative compounds of the present invention inhibited the production of collagen-induced inflammatory cytokines. These results indicate that the salicylic acid derivative compound of the present invention can be used as a therapeutic agent for arthritis.

<Application example 9> Pancreatitis

Acute pancreatitis is an inflammation of the pancreatic tissue due to digestive enzymes or cholelithiasis in the pancreatic fluid, which causes the bile to reflux into the pancreas. Pancreatitis can cause a variety of symptoms, ranging from minor edema to severe bleeding. Chronic pancreatitis is a case of repeated acute pancreatitis, chronic pancreatitis, and chronic form from the beginning. Pancreatitis has been reported to be associated with inflammation, and COX inhibitors have been shown to be protective in pancreatitis models and to inhibit the production of inflammatory markers TNF-α and prostagladin (Song AM et al., Am J). Physiol Gastrointest Liver Physiol. 2002; 283 (5): G1166-74). Therefore, the salicylic acid derivative compound of the present invention can be used for the treatment of pancreatitis.

<Application example 10> Pain

In surgery, cancer patients, trauma, etc., damage to peripheral and nerve tissues increases the sensitivity of pain transmission, leading to neuropathic pain. Activation of NMDA receptors has been found to inevitably work in the course of neuropathic pain, and therefore results have been reported that antagonists of NMDA receptors will be used as therapeutics [Parson CG, Eur. J. Pharmacol ., 429: 71-8 (2001). Therefore, the compounds of the present invention, which exhibit an effect of preventing neuronal cell death by NMDA, can be used as a pain treatment.

The present invention provides a salicylic acid derivative compound represented by the formula (1) or a pharmaceutically acceptable salt thereof having an excitatory toxicity inhibitory effect, antioxidant effect, cytoprotective effect and anti-inflammatory effect, pharmaceutical compositions comprising them and methods of treating or preventing the same To provide. The pharmaceutical composition according to the present invention is caused by degenerative cranial nerve diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, convulsive diseases such as epilepsy, stroke, trauma, hydrocephalus It is effective in the treatment or prevention of retinal diseases such as brain injury, glaucoma, diabetic retinopathy, pain diseases caused by neuropathic pain, arteriosclerosis, gastritis, colitis, arthritis, nephritis, hepatitis, cancer, and degenerative diseases.

Claims (15)

The salicylic acid derivative compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: <Formula 1>

In Formula 1, X is O or S; R ₁ is hydrogen or alkyl; R ₂ is hydrogen, alkyl or alkanoyl; R ₃ is hydrogen or alkyl; R ₄ is phenyl, biphenyl or naphthyl substituted or unsubstituted with any one or more selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, haloalkoxy and nitro; n is an integer from 2 to 4. According to claim 1, wherein the salicylic acid derivative compound 2-hydroxy-5- (2- (phenoxy-ethylamino) -benzoic acid, 5- [2- (4-fluorophenoxy) ethylamino] -2-hydroxybenzoic acid, 5- [2- (4-chlorophenoxy) ethylamino] -2-hydroxybenzoic acid, 5- [2- (4-bromophenoxy) ethylamino] -2-hydroxybenzoic acid, 5- [2- (2,6-difluoro-phenoxy) ethylamino] -2-hydroxybenzoic acid, 2-hydroxy-5- [2- (2-pentafluoro-phenoxy) ethylamino] -benzoic acid, 5- [2- (2,4-dichloro-phenoxy) ethylamino] -2-hydroxybenzoic acid, 2-hydroxy-5- [2- (2,4,5-trichlorophenoxy) ethylamino] benzoic acid, 5- [2- (2,6-dichloro-4-fluorophenoxy) ethylamino] -2-hydroxybenzoic acid, 2-hydroxy-5- (2-p-tolyloxyethylamino) benzoic acid, 5- [2- (2,6-Dimethyl-phenoxy) -ethylamino] -2-hydroxy-benzoic acid, 5- [2- (4-chloro-2-methylphenoxy) ethylamino] -2-hydroxybenzoic acid, 2-hydroxy-5- [2- (4-trifluoromethylphenoxy) ethylamino] benzoic acid, 2-hydroxy-5- [2- (4-methoxy-phenoxy) ethylamino] -benzoic acid, 2-hydroxy-5- [2- (4-trifluoromethyl-phenoxy) ethylamino] benzoic acid, 2-hydroxy-5- [2- (2-nitrophenoxy) ethylamino] benzoic acid, 2-hydroxy-5- [2- (naphthalen-2-yloxy) ethylamino] -benzoic acid, 2-hydroxy-5- [2- (6-methyl-naphthalen-2-yloxy) ethylamino] -benzoic acid, 5- [2- (biphenyl-4-yloxy) -ethylamino] -2-hydroxy-benzoic acid, 2-hydroxy-5- (3-phenoxypropylamino) benzoic acid, 5- [3- (4-fluorophenoxy) propylamino] -2-hydroxybenzoic acid, 5-{[2- (4-chlorophenoxy) ethyl] methylamino} -2-hydroxybenzoic acid, 2-Hydroxy-5- {methyl- [2-naphthalen-2-yloxy) -ethyl] -amino} -benzoic acid and A salicylic acid derivative compound or a pharmaceutically acceptable salt thereof, which is any one selected from the group consisting of 2-hydroxy-5- (2-phenylsulfonylethylamino) benzoic acid. The salicylic acid derivative compound of claim 1 or claim 2 or a composition for treating or preventing degenerative brain nerve disease, characterized in that it comprises a pharmaceutically acceptable salt thereof. The method of claim 3, wherein the neurodegenerative disease is any one selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease and Alzheimer's disease. A composition for treating or preventing stroke, degenerative brain injury or degenerative spinal cord injury, comprising the salicylic acid derivative compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof. The salicylic acid derivative compound of claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, characterized in that the composition for the treatment or prevention of eye diseases. 7. The composition for treating or preventing ocular disease according to claim 6, wherein the ocular disease is any one selected from the group consisting of glaucoma, senile macular degeneration and diabetic retinopathy. The salicylic acid derivative compound of claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, characterized in that the composition for treating or preventing inflammatory diseases. The salicylic acid derivative compound of claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, characterized in that the composition for treating or preventing pain diseases caused by neuropathic pain. The composition for antioxidation, comprising the salicylic acid derivative compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof. A method of treating or preventing degenerative brain neuron disease, comprising administering a salicylic acid derivative compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof. A method of treating or preventing stroke, degenerative brain injury or degenerative spinal cord injury, comprising administering the salicylic acid derivative compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof. A method of treating or preventing ocular disease, comprising administering a salicylic acid derivative compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof. A method of treating or preventing an inflammatory disease comprising administering the salicylic acid derivative compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof. A method for treating or preventing pain diseases caused by neuropathic pain, comprising administering the salicylic acid derivative compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

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