KR100594376B1 - Novel 2-oxo-piperidine derivative compound II having anti-inflammatory activity, the preparation method thereof and the composition containing the same for treating inflammatory disease - Google Patents

Abstract

The present invention provides novel 2-oxo-piperidine derivative (II) compounds having excellent anti-inflammatory activity, methods for their preparation and compositions for the treatment of inflammatory diseases comprising the same.

Since the compound according to the present invention shows a strong inhibitory activity on the production of cytokines such as tumor necrosis factor-α (TNF-α), nitric oxide (NO), the composition containing the same for the treatment of inflammatory diseases, in particular arthritis Available as a medicament.

Anti-inflammatory, inflammatory disease, arthritis

Description

Novel 2-oxo-piperidine derivative compound II having anti-inflammatory activity, the preparation method approximately and the composition containing the same for treating inflammatory disease}

The present invention relates to novel 2-oxo piperidine derivative (II) compounds having anti-inflammatory activity, methods for their preparation and compositions for the treatment of inflammatory diseases comprising the same.

Inflammation is a normal condition in the body that responds to wounds or diseases. Injured or diseased joints are accompanied by swelling, pain, and stiff joints. Inflammation usually occurs in the case of arthritis, but sometimes results in a long and permanent disability.

In general, arthritis, or inflammatory disease of joints, occurs in various forms, such as rheumatoid arthritis (hereinafter referred to as RA) and joint inflammation related diseases.

Arthritis is a chronic polyarthritis that is characterized in particular by inflammatory changes in the synovial membrane of the lining of the articular capsule. It is a chronic progressive disease that causes swelling and pain in the joints of the whole body and, in severe cases, can become a physically handicapped person. In addition, arthritis diseases such as rheumatoid arthritis are progressive and develop joint disorders such as deformation and joint instability, often causing severe physical disorders due to lack of effective treatment and continued exacerbation.

Osteoarthritis (hereinafter referred to as OA) has a complex multifactorial causality and considerable diversity in its clinical manifestations, but an important factor causing OA is known as synovial inflammation. In addition, synovial injury can promote the dissociation of proteoglycans (PGs) as a result of the interaction between synovial cells and chondrocytes (chondrocytes), and activated synovial cells can induce a number of joint cartilage loss. Soluble factors (eg, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and prostaglandins). Direct injury of chondrocytes also promotes the production of matrix metalloproteinase (MMP) activity (eg collagenase, stromelysin and gelatinase) and various inflammatory mediators. In any case, the reduced functionality of articular cartilage results in OA disease development. Depletion of PG from OA joint tissue imparts abnormal mechanical stress to chondrocytes, subchondral bone cells and synovial cells as the elasticity that PG imparts to cartilage is reduced.

Osteoarthritis and rheumatoid arthritis are destructive diseases of articular cartilage characterized by local erosion of the cartilage surface. For example, studies have shown that articular cartilage from the femoral head of an OA patient has decreased the introduction of radioisotope-labeled sulfate compared to the control group, suggesting an increased rate of cartilage degradation in OA. (Mankin et al . J. Bone Joint Surg . 52A , pp424-434, 1970). Mammalian cells have four types of proteolytic enzymes: serine, cysteine, aspartic acid and metalloproteinases. Evidence has shown that metalloproteinases are responsible for the extracellular matrix degradation of articular cartilage in OA and PA patients. Increased activity of collagenase and stromelysin has been found in cartilage of OA patients, which is correlated with depth of lesion (Mankin et al. Arthritis Rhenum . 21 , pp761-766, 1978, Woessner et al. Arthritis Rhenum 26 , pp 63-68, 1983). In addition, agrecanase (which has recently been identified as a metalloproteinase enzyme active) has been found in OA and PA patients and has been demonstrated to provide specific cleavage products of proteoglycans (Lohmander LS et al . Arthritis) . Rheum . 36 , pp 1214-1222, 1993).

Tumor necrosis factor (TNF) is a cytokine bound to the cell and is processed from 26 kD precursor form to 17 kD active form. TNF has been shown to be the primary regulator of acute phase responses similar to those observed during inflammation, fever, and acute infections and shock in humans and animals. Excess TNF has been found to lead to death. Currently, the use of specific antibodies to block the effects of TNF can lead to rheumatoid arthritis, insulin-independent diabetes (Lohmander LS et al. Arthritis Rheum . 36 , pp1214-1222, 1993), Crohn's disease (Macdonald T. et al. Clin). Exp. Immunol. 81 , p301, 1990), have been shown to be beneficial in a number of situations, including autoimmune diseases.

Thus, compounds that inhibit the production of TNF are of therapeutic importance in the treatment of inflammatory diseases. Recently, substrate metalloproteinases or metalloproteinases (later known as tumor necrosis factor-α convertase (TNF-C)) as well as other metalloproteinases in their inactive form It has been found that it can be converted to the active form (Gearing et al., Nature , 370 , p555, 1994). Therefore, inhibiting this conversion and thus inhibiting the release of active TNF-α from the cells will be an important mechanism in the treatment of inflammatory diseases.

Since overproduction of TNF is prominent in many diseases characterized by MMP-mediated tissue degradation, compounds that inhibit both MMP and TNF production have particular advantages even in diseases involving both mechanisms.

Hydroxamate and carboxylate based MMP inhibitors disclose N-carboxyalkylpeptidyl compounds in WO 92/213260 and WO 90/05716 and WO 92/13831. A base collagenase inhibitor is disclosed, and International Publication No. 94/02446 discloses a metalloproteinase inhibitor which is a natural amino acid derivative of the formula: International Publication No. 95/09841 also describes compounds that are hydroxamic acid derivatives and inhibitors of cytokines, and British Patent Publication Nos. 2268934 and International Publication No. 94124140 disclose MMP's hydroxamate inhibitors as inhibitors of TNF production. Is disclosed.

Traditionally, arthritis has been associated with steroids such as cortisone and other corticosteroids, nonsteroidal anti-inflammatory agents such as aspirin, pyroxicam and indomethacin, gold agonists such as orothioactive acid, chloroquinones and D-phenicamine. It has been treated with chemotherapy using a variety of agents, including anti-rheumatic agents, gout inhibitors such as colchicine, and immunosuppressants such as cyclophosphoamide, azathioprine, methotrexate, and levamisol.

However, the above-mentioned treatments are not fundamental treatments, and steroid hormones have been widely used as known as arthritis treatments, but as their side effects become clear, their use has become difficult.

In addition, arthritis, especially chronic rheumatoid arthritis, causes severe pain in patients, so be sure to take anti-inflammatory drugs, etc. Until now, aspirin and betazoline drugs have been widely used as drugs to alleviate these pains or remove joint swelling. Has been used. However, aspirin and the like have a fatal effect on the stomach, so it is difficult to continue taking the amount needed to treat arthritis.

Existing chemotherapeutic agents have drawbacks such as side effects that hinder the long-term use of the drugs, lack of anti-inflammatory effects, and lack of efficacy against arthritis that has already occurred. Shin, furpenic acid and non-steroidal anti-inflammatory agent is used to prepare a degree.

Therefore, there is a need for a solution to these problems and the development of arthritis therapies that have symptomatic effects on acute inflammatory symptoms and pain, and most of the arthritis drugs currently in use have some differences or personal differences. It is very important to develop medicines with fewer side effects, because they have side effects, and especially for the treatment of rheumatoid arthritis, it is necessary to take the drug for a long time.

The inventors of the present invention continue the study to develop a substance showing a strong inhibitory activity against the production of NO and TNF-α by using a tumor necrosis factor-α convertase as a point of action, the present invention The 2-oxo-piperidine derivative compound of has been found to exhibit excellent NO and TNF-α production inhibitory activity, thus completing the present invention.

It is an object of the present invention to provide a 2-oxo-piperidine derivative compound that exhibits an excellent anti-inflammatory effect, a method for preparing the same, and a composition for treating an inflammatory disease comprising the same.

In order to achieve the above object, the present invention provides a 2-oxo-piperidine derivative compound having the chemical structure of formula (II), or a pharmacologically acceptable salt thereof, which is useful for the treatment of inflammation-related diseases:

(Ⅱ)

(Ⅱ)

Where

또는

이고, X is -OH, -NHOH, -NHOCH ₂ Ph,

or

ego,

n and m are each independently an integer from 1 to 5,

Y is optionally substituted with optionally substituted lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, nitro, halogen, amine, acetamide, carboamide, sulfonamide,

M is an optionally substituted substituent, optionally a lower alkyl having 1 to 3 carbon atoms, a substituent selected from phenyl substituted with R`,

R` is a substituent selected from a hydrogen atom, lower alkyl having 1 to 3 carbon atoms or lower alkoxy,

)은 단일 결합 또는 이중 결합을 의미한다.dotted line(

) Means a single bond or a double bond.

General formula Particularly preferred groups of compounds of (II) include the following compounds and pharmaceutically acceptable salts thereof:
3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxypropionamide,
N-hydroxy-3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionamide,
3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid,
3- (1-benzyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid,
3- [1- (4-Nitro-benzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid,
3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid,
3- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionic acid,
3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionic acid,
3- [1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-pyridin-2-ylpropionamide,
N-benzyloxy-3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
N- (2-amino-phenyl) -3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,
N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N- (2-amino-phenyl) -3- [1- (2-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-propionamide,
N- {4- [5- (2-hydroxycarbamoyl-ethyl) -6-oxo-3,6-dihydro-2H-pyridin-1-ylmethyl] -phenyl} -benzamide,
N-hydroxy-3- [1- (4-dimethylsulfonylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -1,2,5,6-tetrahydro-pyridin-3-yl} -propionamide ,
3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid,
3- [1- (4-Benzoylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid,
3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -1,2,5,6-tetrahydro-pyridin-3-yl} -propionic acid,
N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide,
N-hydroxy-2- [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide,
2- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide,
N-hydroxy-2- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide,
N-hydroxy-2- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide,
N-hydroxy-2- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide,
[1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid,
(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid,
(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid,
[2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid,
[2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid,
2- [1- (2,4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -N-hydroxy-acetamide,
(2-oxo-1-phenethyl-piperidin-3-yl) -acetic acid,
[2-oxo-1- (3-phenyl-propyl) -piperidin-3-yl] -acetic acid,
N-hydroxy-4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid,
N-hydroxy-4- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -butyramid,
N-hydroxy-4- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid and

N-hydroxy-4- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid.

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The present invention also provides a method for preparing the compound of Formula (II) and a pharmaceutical composition comprising the same as an active ingredient.

The compounds of the present invention represented by the general formula (II) may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.

As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.

Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of the general formula (II) above include salts of acidic or basic groups which may be present in compounds of general formula (II) unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and methods or processes for preparing salts known in the art It can be prepared through.

Another object of the present invention is to provide a method for preparing general formula (II), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.

The following reaction schemes represent the preparation steps of the representative compounds of the present invention. The various compounds of the present invention may be prepared by small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 8. have. Some compounds of the present invention have been synthesized according to procedures not included in the scope of Schemes 1-8, and detailed synthesis procedures for these compounds are described in their respective examples.

R 'is hydrogen or lower alkyl.

Scheme (1) shows a four-step preparation process for preparing compound (e) from the commercially available amine compound (a) as a starting material.

In the first step, compound (b) is prepared by reacting compound (a) with 1-bromo-3-butene in an organic solvent in the presence of a Hunig base.

In this case, acetonitrile (MeCN), dichloromethane, and the like may be used as the organic solvent, and diethylisopropylamine may be used as the Hunig base. Hunig base may be used in 2 to 3 equivalents relative to the starting compound (a), and their reaction may be carried out at temperatures ranging from room temperature to 0 ° C.

In the second step, compound (c) is reacted with monoacid in an organic solvent in the presence of compound (b) obtained in step 1 in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC). Manufacture. In this case, methylene chloride, dihydrofuran, or the like may be used as the organic solvent. In this case, the mono acid is preferably 2-methylene-pentanedioic acid-5-methyl ester, and the amount thereof may be used in an amount of 1 to 1.2 equivalents based on compound (b), and their reaction may range from room temperature to 0 ° C. It can be carried out at a temperature of.

In the third step, compound (c) is then converted to compound (d) in an organic solvent in the presence of a groove (I) catalyst (Grubb's (I) catalysis) such as a ruthenium catalyst. In this case, the amount of the catalyst is preferably used in 0.02 to 0.1 equivalents based on the compound (c), these reactions can be carried out at a temperature in the range of room temperature to 0 ℃.

Subsequently, in the fourth step, the compound (d) may be reacted with an amine salt in an alcohol solvent to obtain a compound (e) in which the substituent X in the compound of formula according to the present invention is -NHOH. The amine salt is preferably potassium hydroxyamide, the amount of which is preferably used in an amount of 2 to 3 equivalents based on compound (d), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C.

Scheme (2) is a compound (f) in which X is -OH in the compound of formula (I) according to the present invention by reacting compound (d) obtained in Scheme (1) with a metal hydroxide in an organic solvent such as tetrahydrofuran. It shows the manufacturing process to obtain. At this time, lithium hydroxide is preferably used as the metal hydroxide usable for the reaction, and the amount thereof is preferably used in the range of 2 to 3 equivalents based on the compound (d), and their reaction is performed at a temperature ranging from room temperature to 0 ° C. It is preferable to carry out.

Scheme (3) is a compound (f) obtained from Scheme (2) above in which the benzyloxyamine (BnONH ₂ ) in an organic solvent in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC) , A process for preparing compound (g) according to the present invention by reacting with pyridylamine or diaminobenzene.

In the above reaction, benzyloxyamine, pyridylamine or diaminobenzene is preferably used in a ratio of 1 to 1.5 equivalents based on compound (f), and their reaction is preferably performed at a temperature ranging from room temperature to 0 ° C. .

Scheme (4) shows a third step of preparation for preparing compounds (j and k) from compound (d) obtained in Scheme (2).

In the first step, compound (d) obtained in Scheme (2) is reacted with zinc in an organic solvent to obtain compound (h). At this time, zinc is preferably used in 2 to 5 equivalents based on compound (d).

In a second step, compound (h) is reacted with (AcO) 2 O, PhCOCl, MsCl or TsCl to obtain compound (i). In a third step, compound (i) is then reacted with an amine salt in an organic solvent such as methanol to obtain compound (j) in which the substituent X in the compound of formula is -NHOH or lithium hydroxide in an organic solvent such as tetrahydrofuran. And (k) in which substituent X is -OH. At this time, (AcO) 2 O, PhCOCl, MsCl or TsCl is preferably used in 1 to 3 equivalents relative to compound (h). In addition, as the amine salt usable in the reaction, triethylamine is preferable, and the amount of the amine salt is preferably used in an amount of 2 to 3 equivalents based on compound (i). In addition, lithium hydroxide is preferable as the hydroxide which can be used in the reaction, and its amount is preferably 2 to 3 equivalents relative to compound (i).

Scheme (5) shows a second step for preparing compound (l) from compound (d) obtained in Scheme (1).

In a first step, compound (d) is treated with Pd-C in an alcohol solvent to obtain compound (m), and then, in a second step, amine salt is treated to obtain compound (l). In this case, Pd-C is preferably used in 0.1 to 0.2 equivalents based on compound (d), and the amine salt is preferably used in 2 to 3 equivalents based on compound (m). In addition, the reaction is preferably carried out at room temperature to 0 ℃ temperature range.

 Scheme (6) shows a third stage of preparation to obtain compounds (p and q) by carrying out the same preparation as in schemes (1) and (2) from compound (b) in scheme (1).

In a first step, compound (b) in Scheme (1) is reacted with mono acid in an organic solvent in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC) to give compound (n). Manufacture. In this case, methylene chloride or the like may be used as the organic solvent. In this case, the mono acid may be used in 2-methylene-butanediic acid-4-methyl ester in an amount of 1 to 1.2 equivalents based on the amine compound (b), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C. .

In the second step, the compound (n) is then converted into the compound (o) by reacting in an organic solvent such as methylene chloride in the presence of a groove (I) catalyst (Grubb's (I) catalysis) such as a ruthenium catalyst. In this case, the amount of the catalyst is preferably used in 0.02 to 0.1 equivalents relative to compound (n), these reactions can be carried out at a temperature in the range of room temperature to 0 ℃.

Subsequently, in a third step, the compound (o) is reacted with an amine salt in an alcohol solvent to obtain a compound (p) in which the substituent X is -NHOH in the compound of the formula according to the present invention, or with a hydroxide salt in tetrahydrofuran. The reaction can yield compound (q) in which X is -OH. The amine salt may be used in 2 to 3 equivalents relative to compound (o), and their reaction may be carried out at a temperature ranging from room temperature to 0 ° C. In addition, lithium hydroxide is preferable as the hydroxide salt usable for the reaction, and the amount thereof is preferably used in an amount of 2 to 3 equivalents based on compound (o), and the reaction thereof is performed at a temperature ranging from room temperature to 0 ° C. It is desirable to.

Scheme (7) shows the preparation of the second stage where compound (s) is obtained by carrying out the same preparation as in Scheme 5 from compound (o) obtained from scheme (6).

Scheme (8) shows the third step of preparing a compound (v) by carrying out the same preparation process as in the reaction formula (1) from compound (b) in scheme (1).

In a first step, compound (b) in Scheme (1) is reacted with mono acid in an organic solvent in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC) to give compound (u) Manufacture. In this case, methylene chloride or the like may be used as the organic solvent. At this time, the mono acid may be used in 2-methylene-hexanediionic acid-6-methyl ester in an amount of 1 to 1.2 equivalents based on the amine compound (b), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C. . In the second step, the compound (t) is then converted into the compound (u) by reaction in an organic solvent such as methylene chloride in the presence of a groove (I) catalyst (Grubb's (I) catalysis) such as a ruthenium catalyst. In this case, the amount of the catalyst is preferably used in 0.02 to 0.1 equivalents relative to compound (u), these reactions can be carried out at a temperature in the range of room temperature to 0 ℃.

Subsequently, in a third step, the compound (u) is reacted with an amine salt in an alcohol solvent to obtain a compound (v) in which the substituent X in the compound of the formula according to the present invention is -NHOH. The amine salt can be used in 2 to 3 equivalents relative to compound (v), and their reaction is preferably carried out at a temperature in the range of room temperature to 0 ℃.

Derivatives of the present invention prepared from the above production method, showing a strong inhibitory activity against the production of NO and TNF-α using the tumor necrosis factor-α converting enzyme and sialic acid glycotransferase as a function point shows an excellent anti-inflammatory effect As a result, it is useful for treating inflammation-related diseases.

The present invention also provides a pharmaceutical composition for the treatment of inflammatory diseases, comprising the compound of formula (II) as an active ingredient and a pharmaceutically acceptable carrier.

The compounds of formula (II) of the present invention can be usefully used for the treatment of pain and inflammation caused by inflammatory diseases, in particular arthritis. The arthritis includes, for example, rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. It includes. In addition, the compounds of the present invention can be used to treat inflammatory symptoms, such as, for example, myositis, gingivitis, synovitis, ankylosing spondylitis, bursitis ( burstitis, burns, wounds, and the like. In addition, the compounds of the present invention are useful for treating inflammatory symptoms associated with diseases such as inflammatory bowel disease, Crohn's disease, Type I diabetes and the like.

Compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.

Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. Liquid preparations for oral use include suspensions, solution solutions, emulsions, and syrups.In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. May be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily. The compound of the present invention in the composition should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight relative to the total weight of the total composition.

In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1. Synthesis of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -N-hydroxypropionamide (e1)

Step 1. Synthesis of Butenyl-3-enyl- (2,4-dimethoxybenzyl) amine (b)

To a solution of 2,4-dimethoxybenzylamine (a) (0.740 mL, 4.926 mmol) in methylenechloride, 1-bromo-3-butene (0.500 mL, 4.926 mmol) and diisopropylethylamine (0.940 mL, 5.396 mmol ) Was injected under stirring and stirred at room temperature overnight. The resulting mixture was washed with saturated brine solution, and then the organic layer was dried over magnesium sulfate and distilled under reduced pressure. The obtained primary compound was purified by column chromatography method (silica gel column, eluent ethyl acetate) to give the title compound (b) in 40% yield (436 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.10 (d, J = 8.1 Hz, 1H), 6.41 (m, 2H), 5.75 (m, 1H), 5.01 (m, 2H), 3.78 (s, 3H), 3.77 ( s, 3H), 3.70 (s, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.24 (m, 2H)

Step 2. Synthesis of 4- [but-3-enyl- (2,4-dimethoxybenzyl) -carbamoyl] -pent-4-enoic acid methyl ester (c)

In a 0.5 M solution of methylene chloride of compound (b) obtained in step 1, monoacid (2-methylene-pentanedioic acid-5-methyl ester) (714 mg, 4.519 mmol), EDC (953 mg, 4.971 mmol) and DMAP (110 mg, 0.900 mmol) was injected and stirred at room temperature for 5 hours. The resulting mixture was diluted with ethyl acetate solution and washed with 5% HCl solution (10 mL) and saturated sodium carbonate solution (10 mL). The organic layer was dried over magnesium sulfate, distilled under reduced pressure, and then the obtained primary compound was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane = 1/2) to give the title compound (c) in a yield of 40% (1.39). g).

Step 3. Synthesis of 3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid methyl ester (d)

The methylene chloride solution (36 mL) of the compound (c) (130 mg, 0.360 mmol) and the ruthenium catalyst (20 mg, 0.024 mmol) obtained in the second step was stirred at room temperature for 24 hours. The primary compound obtained by distillation of the solvent under reduced pressure was purified by column chromatography method (silica gel column, eluent: methanol / chloroform = 1/10) to obtain the title compound (d) in a yield of 90% (108 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.17 (d, J = 8.9 Hz, 1H), 6.41 (m, 2H), 6.26 (t, J = 4.3 Hz, 1H), 4.53 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.62 (s, 3H), 3.28 (t, J = 7.1 Hz, 2H), 2.61-2.47 (m, 4H), 2.22 (m, 2H)

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 173.6, 164.8, 160.2, 158.5, 134.2, 133.9, 130.4, 118.0, 104.1, 98.3, 55.2, 51.3, 45.0, 44.3, 33.3, 26.6, 23.9

Step 4. Synthesis of 3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -N-hydroxypropionamide (e1)

NH ₂ OK (1.7 M suspension in methanol, 0.122 mL, 0.207 mmol) was added to a methanol solution of the compound (d) (46 mg, 0.138 mmol) obtained in the third step at 0 ° C., and the mixture was stirred at room temperature for 3 hours. . The mixture was neutralized with acetic acid (0.020 mL), diluted with ethyl acetate solution (10 mL), and the solid was filtered and distilled under reduced pressure. The obtained primary compound was purified by column chromatography method (silica gel column, eluent: methanol / chloroform = 1/10) to give the title compound (e1) in 73% yield (32 mg).

Compounds of Examples 2 to 6 having the physical properties shown in Table 1 were prepared by performing a preparation process similar to the preparation method described in Example 1 above.

Example 2: Synthesis of N-hydroxy-3- [1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (e2)

Example 3: Synthesis of N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (e3)

Example 4 Synthesis of N-hydroxy-3-(-2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (e4)

Example 5: Synthesis of N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionamide (e5)

Example 6: Synthesis of N-hydroxy-3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (e6)

Example Chemical structure NMR spectral data 2

7.28 (m, 5H), 6.44 (t, J = 4.3 Hz, 1H), 4.61 (s, 2H), 3.33 (m, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.28 (m, 4H ) 3

8.14 (d J = 8.4 Hz 2H), 7.40 (t J = 7.2 Hz 2H), 6.42 (br t 1H), 4.67 (s 2H), 3.32 (t J = 6.3 Hz 2H), 2.67-2.32 (m 6H) 4

7.29-7.18 (m 5H) 6.40 (br t 1H), 3.62 (t J = 7.2 Hz 2H), 3.19 (t J = 7.1 Hz 2H), 2.85 (t J = 7.1 Hz 2H), 2.54-2.44 (m 2H ), 2.18-2.15 (m 4H) 5

7.24-7.11 (m, 5H), 6.31 (br t, 1H), 3.35 (br t, 2H), 3.23 (br t, 2H), 2.55 (d, J = 6.6 Hz, 4H), 2.33 (s, 2H ), 2.18 (s, 2H), 1.80 (br t, 2H) 6

7,28-7.13 (m, 5H), 6.36 (t, J = 3.9, 1H), 3.39 (t, J = 6.75, 2H), 3.29 (t, J = 7.05, 2H), 2.62 (t, J = 7.05, 2H), 2.54 (t, J = 6.75, 2H) 2.40 (t, J = 6.75, 2H), 2.27 (ab, J = 6.0, 5.4, 2H), 1.58 (t, J = 2.7, 4H)

Example 7 Synthesis of 3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid (f1)

3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid methyl ester obtained in the third step of Example 1 d) (58 mg, 0.174 mmol) in THF solution (0.75 mL) was injected with an aqueous solution of LiOHH ₂ O (11 mg, 0.262 mmol) (0.25 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours, at room temperature for 1 hour, and then acidified to pH 2 with 5% HCl solution. The mixture was extracted with ethyl acetate solution (3 × 10 mL), and the organic layer was washed with saturated brine solution (10 mL), dried over magnesium sulfate and distilled under reduced pressure. The obtained primary compound was purified by column chromatography method (silica gel column, eluent: methanol / chloroform = 1/10) to give the title compound (f1) in a yield of 80% (44 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.16 (d, J = 8.9 Hz, 1H), 6.42 (m, 2H), 6.29 (t, J = 4.3 Hz, 1H), 4.54 (s, 2H), 3.76 (s, 3H), 3.76 (s, 3H), 3.29 (t, J = 7.2 Hz, 2H), 2.56 (m, 4H), 2.22 (m, 2H)

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 177.7, 165.1, 160.1, 158.5, 134.6, 133.9, 130.5, 117.7, 104.1, 98.3, 55.2, 44.9, 44.5, 33.5, 26.3, 23.8

Compounds of Examples 8 to 12 having the physical properties shown in Table 2 were prepared by performing a similar procedure to the preparation method described in Example 7.

Example 8: 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid (f2) synthesis

Example 9: 3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid (f3) synthesis

Example 10 Synthesis of 3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid (f4)

Example 11: 3- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionic acid (f5) synthesis

Example 12 Synthesis of 3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionic acid (f6)

Example  Chemical structure NMR spectral data 8

7.25 (m, 5H), 6.34 (t, J = 4.2 Hz, 1H), 4.60 (s, 2H), 3.26 (t, J = 7.1 Hz, 2H), 2.59 (m, 4H), 2.25 (m, 2H ) 9

8.16 (d J = 8.7 Hz 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.39 (t J = 4.3 Hz, 1H) 4.69 (s, 2H) 3.32 (t, J = 7.2 Hz, 2H) 2.64 -2.53 (m, 4H), 2.33 (dd J = 6.9 Hz, 5.7 Hz, 2H) 10

9.92 (br s 1H), 7.28-7.15 (m, 5H), 6.28 (t, J = 4.4, 1H), 3.60 (t J = 7.4, 2H) 3.16 (t, J = 7.2, 2H), 2.84 (t , J = 7.4, 2H) 2.58-2.48 (m, 4H) 2.15 (AB, J = 11.4, 6.8, 2H) 11

7.28-7.10 (m, 5H), 6.28 (br, t, 1H), 5.75-5.60 (m, 1H), 5.01 (d, J = 16.5 Hz, 2H), 3.41-3.26 (m, 3H) 2.63-2.26 (m, 7H) 1.84 (t, J = 6.8 Hz, 2H) 12

7.256-7.138 (m, 5H), 6.33 (br, t, 1H), 3.42 (t, J = 6.9, 2H), 3.32 (t, J = 7.35, 2H), 2.63 (t, J = 7.05, 2H) , 2.547 (d, J = 2.4, 4H), 2.30 (d, J = 4.5, 2H), 1.61 (q, J = 1.5, 4H)

Example 13. Synthesis of 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-pyridin-2-ylpropionamide (g1)

Compound (f2) (30 mg; 0.12 mmol) obtained in Example 8 was reacted with pyridylamine in an organic solvent in the presence of ethylenedichloride (EDC), and the column chromatography method (silica gel, methanol / chloroform = 1/20) to give the title compound (g1) in 39% yield (16mg).

Example 14. Synthesis of N- (2-amino-phenyl) -3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g2)

Compound (f2) (80 mg, 0.31 mmol) and 1,2-phenylenediamine (40 mg, 0.37 mol) obtained in Example 8 were diluted with EDC (77 mg, 0.40 mmol) and DMAP (1 mg, 3 mol%). Reaction with methylene chloride solvent (1 mL) under argon gas. After stirring for 13 hours at room temperature, 10 ml of 10% sodium hydroxide solution was added, and then the solvent was removed under reduced pressure. The residue was extracted with chloroform (50 mL) and then dried over magnesium sulfate, and then the solvent was removed. The residue was purified by column chromatography (silica gel, methanol / chloroform = 1/20) to give the title compound (g2) in 91% yield (96 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.29-7.19 (m, 5H), 7.13 (d, 1H, J = 7.8 Hz), 6.99-6.94 (m, 1H), 6.68 (t, 2H, J = 7.9 Hz), 6.37 (t, 1H, J = 8.4 Hz), 4.57 (t, 2H, J = 7.4 Hz), 3.88 (s, 2H), 3.29-3.21 (m, 2H) , 2.68 (t, 2H, J = 6.5 Hz), 2.59 (t, 2H, 6.5 Hz), 2.26-2.217 (m, 2H)

Compounds of Examples 15 and 16 having the physical properties shown in Table 3 were prepared by performing a similar procedure to the preparation methods described in Examples 13 to 14.

Example 15 N- (2-Amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propion Amide (g3) Synthesis

Example 16: N- (2-amino-phenyl) -3- [1- (2-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]- Propionamide (g4) Synthesis

Example Chemical structure Spectral data 15

8.23 (s, 1H), 7.12 (dd, 5H, J = 6.6 Hz), 6.979 (t, 1H, J = 7.5 Hz), 6.697 (t, 2H, J = 8.9 Hz), 6.408 (t, 1H, J = 7.4 Hz), 4.602 (s, 2H), 3.874 (s, 2H), 3.239 (t, 2H, J = 7.1 Hz), 2.702 (t, 2H, J = 6.8 Hz), 2.604 (t, 2H, J = 6.3 Hz), 2.260 (t, 5H, J = 6.3 Hz) 16

8.305 (s, 1H), 7.189-7.091 (m, 2H), 6.969-6.914 (m, 2H), 6.794-6.741 (m, 3H), 6.691-6.631 (m, 2H), 6.355 (t, 1H, J = 4.1 Hz), 4.539 (s, 2H) 3.965 (s, 2H), 3.707 (s, 3H), 3.253 (t, 2H, J = 7.0 Hz), 2.661-2.539 (m, 4H), 2.22 (dd, 2H, J = 7.1 Hz)

Example 17 Synthesis of N-benzyloxy-3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g5)

Compound (f6) (30 mg; 0.15 mmol) obtained in Example 12 was reacted with benzyloxyamine in an organic solvent in the presence of EDC to obtain a column chromatography method (silica gel column, eluent: ethyl acetate / chloroform). 1/1) gave the title compound (g5) in 75% yield (41 mg).

¹ H-NMR (300 MHz, CDCl 3) δ 7.41-7.15 (m, 1H), 6.34 (br t, 1H), 4.88 (s, 2H), 3.58 (t, J = 7.4 Hz, 2H), 3.16 (t , J = 7.2 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.53 (t, J = 6.8 Hz, 2H), 2.26 (br s, 1H), 2.19 (dd, J = 11.4, 7.1 Hz, 2H)

Example 18. 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-propionamide (j1) synthesis

Step 1. Synthesis of 3- [1- (4-Amino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (h)

Compound (d) obtained in the third step of Example 1 (50 mg, 0.16 mmol) was dissolved in methanol at room temperature, and then zinc (154 mg, 2.36 mmol) and acetic acid (0.16 mmol, 0.01 mL) were added thereto and then 80 ° C. It stirred for 2 hours, and obtained compound (h). Zinc was filtered through a thin layer of silica gel and purified by column chromatography (silica gel column, eluent: ethyl acetate / hexane = 1/1) to obtain the title compound (h) in 92% yield (43 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, 1H, J = 8.5 Hz), 8.11 (d, 1H, J = 8.4 Hz), 7.37 (t, 2H, J = 8.3 Hz), 6.33 ( t, 1H, J = 4.3Hz), 4.66 (d, 2H, J = 7.5Hz), 3.63 (s, 3H), 3.29 (t, 2H, J = 6.6Hz), 2.63 (t, 2H, J = 6.9 Hz), 2.54 (t, 2H, J = 6.6 Hz), 2.28 (t, 2H, J = 4.2 Hz)

Step 2. Synthesis of 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (i)

Compound (h) obtained in step 1 was dissolved in methylene chloride solution at (17.5 mg, 0.06 mmol) at room temperature, and then (AcO) 2 O (0.07 mmol, 6.0 μL) and triethylamine (0.08 mmol, 0.01 mL) at 0 ° C. Add DMAP (0.008 mmol, 1.0 mg) and stir for 3 hours. Stop the reaction with methanol. The mixture was extracted with ethyl acetate solution (3 × 10 mL each), washed with saturated brine solution, dried over magnesium sulfate and distilled under reduced pressure. The obtained compound was purified by column chromatography (silica gel column, eluent: ethyl acetate). The title compound (i) was obtained in 44% yield (46 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.40 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, J = 8.4 Hz), 6.29 (t, 1H, J = 4.2 Hz), 4.50 (s, 2H), 3.61 (s, 3H), 3.22 (t, 2H, J = 7.1 Hz), 2.59 (t, 2H, J = 7.1 Hz), 2.51 (d, 2H, J = 6.6 Hz), 2.22 (dd, 2H, J = 6.9 Hz), 2.09 (s, 3H)

Step 3. Synthesis of 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-propionamide (j1)

Compound (i) obtained in step 2 was reacted with an amine salt in an organic solvent such as methanol to obtain compound (j1).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.50 (d J = 8.0 Hz 2H), 7.23 (d J = 8.0 Hz 2H), 6.44 (br t 1H), 4.57 (S 2H), 3.33 (t, J = 6.5 Hz, 6H) 2.57 (br t, 2H) 2.30-2.26 (m, 4H) 2.10 (s, 2H)

Compounds of Examples 19 to 21 having the physical properties shown in Table 4 were prepared by performing a similar procedure to the preparation method described in Example 18.

Example 19: N- {4- [5- (2-hydroxycarbamoyl-ethyl) -6-oxo-3,6-dihydro-2H-pyridin-1-ylmethyl] -phenyl} -benzamide ( j2) synthesis

Example 20 N-hydroxy-3- [1- (4-dimethylsulfonylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide ( j3) synthesis

Example 21 N-hydroxy-3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -1,2,5,6-tetrahydro-pyridin-3-yl } -Propionamide (j4) synthesis

Example Chemical structure NMR spectral data 19

7.90 (t J = 7.05 Hz 2H), 7.67 (d, J = 8.10 Hz, 2H) 7.59-7.47 (m, 3H) 7.30 (d J = 8.10 Hz 2H), 6.45 (br t, 1H) 4.61 (s, 2H) 3.36 (t, J = 7.2, 2H) 3.30 (q, J = 1.5 Hz, 4H) 2.58 (br t, 2H) 20

7.24 (q, J = 8.6 Hz, 4H) 6.45 (br t, 1H) 4.58 (s, 2 H) 3.38-3.29 (m, 7H) 2.93 (s, 3H) 2.57 (t, 2H, J = 7.1) 2.34 -2.24 (m, 4H) 21

7.78 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.5 Hz, 2H) 7.27-7.21 (m, 4H) 6.97 (t, J = 7.2 Hz, 1H) 4.61 (d, J = 3.5 Hz , 1H) 3.47 (s, 4H) 3.3 6-3.30 (m, 1H) 2.71-.264 (m, 1H) 2.51-2.44 (m, 3H), 2.32 (d, J = 4.5 Hz, 1H)

Example 22. 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (k) synthesis

Compound (i) obtained in step 2 of Example 18 was reacted with lithium hydroxide in an organic solvent such as tetrahydrofuran to obtain compound (k) wherein substituent X was -OH.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.50 (d J = 8.0 Hz 2H), 7.23 (d J = 8.6 Hz 2H), 6.45 (t J = 4.5 Hz 1H), 4.58 (S 2H), 3.32 ( t, J = 7.5 Hz, 3H) 2.57 (t, J = 7.5 Hz, 2H) 2.46 (t, J = 7.5 Hz, 2H)

Compounds of Examples 23 and 24 having the physical properties shown in Table 5 were prepared by performing a similar procedure to the preparation method described in Example 22.

Example 23 Synthesis of 3- [1- (4-benzoylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (k2)

Example 24 3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -1,2,5,6-tetrahydro-pyridin-3-yl} -propionic acid (k3 ) synthesis

Example Chemical structure NMR spectral data 23

7.83 (d, J = 6.9 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.49-7.37 (m, 4H), 7.19 (d, J = 8.4 Hz, 2H), 6.33 (q, J = 4.5Hz, 1H) 3.26 (t, J = 7.2Hz, 3H) 2.54-2.40 (m, 4H) 2.24 (ab, J = 11.6Hz, 3.5Hz. 2H) 24

7.74 (d, J = 8.1 Hz, 4H), 7.18 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 8.1, 2H), 4.53 (s, 2H), 3.20 (br t, 2H), 2.40 (s, 9 H)

Example 25 Synthesis of N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide (m)

Step 1. Synthesis of [1- (2,4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -acetic acid methyl ester (l)

In the first step, the flask containing compound (d) was nitrogen-substituted and dissolved in an alcohol solvent. Palladium catalyst was added, nitrogen was removed, hydrogen gas was added, and then reacted at room temperature for 1 hour and a half. Palladium catalyst was filtered and column chromatography was performed (silica gel column, eluent: ethyl acetate / hexane = 1/1). Purification was carried out to give the title compound (1) in 95% yield.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.13 (d, 1H, J = 8.4 Hz), 6.42 (d, 2H, J = 7.2 Hz), 4.51 (ab, 2H, J = 32.9, 7.4 Hz), 3.76 (s, 6H), 3.66 (s, 3H), 3.24-3.18 (m, 2H), 2.93-2.72 (m, 2H), 2.56-2.43 (m, 1H), 1.98-1.55 (m, 4H)

Step 2. Synthesis of N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide (m)

Compound (m) was obtained by reacting compound (l) obtained from the first step with an amine salt.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.26-7.17 (m 5H), 3.61-3.44 (m 2H) 3.08-2.83 (m 4H), 2.56-2.16 (m 4H),

Example 26. 2- [1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide ( p1) synthesis.

Step 1. Synthesis of 3- (benzyl-but-3-enyl-carbamoyl) -but-3-enoic acid methyl ester (n)

Compound (b) obtained in the first step of Example 1 was injected into a methylene chloride solution with mono-acid (2-methylene-butanediionic acid 4-methyl ester), EDC and DMAP, followed by 5 at room temperature. The reaction was carried out for a time to obtain 3- (benzyl-but-3-enyl-carbamoyl) -but-3-enoic acid methyl ester (n).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.30-7.19 (m, 5H), 5.69 (br t, 1H), 5.23 (s, 2H), 5.00 (t, 2H, J = 12.6 Hz), 4.74 ( s, 2H), 3.61 (s, 3H), 3.42 (s, 4H), 2.30 (q, 2H, J = 7.2 Hz)

Step 2. Synthesis of [1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid methyl ester (o)

Compound (n) obtained in the first step is reacted in an organic solvent such as methylene chloride in the presence of a groove (I) catalyst (Grubb's (I) catalysis), such as a ruthenium catalyst, to [1- (2,4-dimethoxy- Benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid methyl ester (o).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.17 (d, 1H, J = 6.2 Hz), 6.42-6.36 (m, 3H), 4.54 (s, 2H), 3.76 (d, 6H, J = 3.0 Hz ), 3.66 (s, 3H), 3.35 (t, 2H, J = 6.9), 3.28 (s, 2H), 2.29 (ab, 2H, J = 11.3, 3.4 Hz)

Step 3. 2- [1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (p1 ) synthesis

Compound (o) obtained in the second step is reacted with an amine salt in an alcohol solvent to give 2- [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridine 3-yl] -N-hydroxy-acetamide compound (p1) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.14 (d, J = 8.7 Hz, 1H), 6.54 (br t, 1H) 6.44 (d, J = 6.0 Hz, 2H), 4.55 (s, 2H), 3.78 (s, 6H), 3.41-3.32 (m, 2H), 3.20 (s, 2H), 2.0 (d, J = 4.5Hz, 2H)

Compounds of Examples 27 to 30 having the physical properties shown in Table 6 were prepared by performing a preparation process similar to the preparation method described in Example 26.

Example 27 Synthesis of 2- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide (p2)

Example 28 N-hydroxy-2- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acet Amide (p3) Synthesis

Example 29 Synthesis of N-hydroxy-2- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide (p4)

Example 30 Synthesis of N-hydroxy-2- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide (p5)

Example Chemical structure Spectral data 27

7.34-7.22 (m, 5H), 6.58 (t, J = 4.5 Hz, 1H) 4.60 (s, 2H) 3.39-3.30 (m, 3H) 3.20 (s, 2H) 2.39-2.30 (m, 2H) 28

8.21 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H) 6.63 (t, J = 4.3 Hz, 1H), 4.75 (s, 2H), 3.41 (ab, J = 6.5 Hz , 4H), 2.43 (ab, J = 6.2 Hz, 2H) 29

7.22 (d, J = 6.5 Hz, 2H) 7.14 (s, 3H) 6.51 (br t, 1H) 3.43-3.32 (m, 5H) 3.11 (s, 1H) 2.59 (s, 2H) 2.29 (s, 2H) 1.84 (s, 2H) 30

7.28-7.13 (m, 5H), 6.54 (br t, 1H), 3.44-3.31 (m, 5H), 3.14 (s, 1H) 2.62 (t, J = 7.1 Hz, 2H), 2.34 (s, 2H) , 1.58 (t, J = 3.4 Hz, 4H)

Example 31. [1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid (q1) synthesis

Compound (o) obtained in the second step of Example 26 was reacted with a lithium hydroxide salt in trifluoroacetic acid (TFA) to give [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2 , 5,6-tetrahydro-pyridin-3-yl] -acetic acid (q1) was prepared.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.18 (d, J = 8.7 Hz, 1H), 6.54 (t, J = 4.3 Hz, 1H), 6.45 (d, J = 6.6 Hz, 2H), 4.60 ( s, 2H), 3.79 (s, 6H) 3.39 (t, J = 7.3 Hz, 2H), 3.34 (s, 2H), 2.32 (ab, J = 11.7 Hz, 3.6 Hz, 2H)

Compounds of Examples 32 to 35 having the physical properties shown in Table 7 were prepared by performing a similar procedure to the preparation method described in Example 31.

Example 32 Synthesis of (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q2)

Example 33: (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q3) synthesis

Example 34 Synthesis of [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid (q4)

Example 35 Synthesis of [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid (q5)

Example Chemical structure Spectral data 32

7.29-7.18 (m 5H) 6.50 (t, J = 4.5 Hz, 1H), 4.58 (s, 2H), 3.31 (d J = 7.2 Hz 4H), 2.29 (ab, J = 11.0 Hz, 3.5 Hz, 2H) 33

7.31-7.18 (m, 5H), 6.53 (t, J = 4.5 Hz, 1H), 3.67 (t, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.23 (t, J = 7.2 Hz, 2H ) 2.90 (t, J = 7.2 Hz) 2.23 (ab, J = 11.7 Hz, 3.6 Hz, 2H) 34

7.32-7.12 (m, 5H) 6.47 (br t, 1H) 3.56 (t, J = 10.8 Hz, 2H), 3.11 (s, 4H) 2.78 (d, J = 6.0 Hz, 2H) 2.14 (d, J = 10.8 Hz, 2H) 35

7.29-7.14 (m, 5H), 6.55 (t, J = 4.2 Hz, 1H), 3.46 (t, J = 6.7 Hz, 2H), 3.38 (t, J = 7.3 Hz, 2H), 3.31 (s, 2H ) 2.64 (t, J = 7.1 Hz, 2H) 2.37 (ab, J = 6.3 Hz, 2H) 1.67-1.58 (m, 4H)

Example 36. Synthesis of 2- [1- (2,4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -N-hydroxy-acetamide (s1)

Step 1. Synthesis of [1- (2,4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -acetic acid methyl ester (r)

Of [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid methyl ester (o) (26 mg, 0.08 mmol) 10% Pd-C (1.7 mg) was added to the methanol solution under argon pressure, and then the gas in the vessel was replaced with hydrogen using a pressure reducing apparatus. After stirring for 5 hours at room temperature, Pd-C was filtered off using silica gel, and then the primary compound obtained by distillation under reduced pressure was purified by column chromatography to obtain 99% (25 mg) of the compound (r). Got it.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.13 (d, J = 8.4 Hz, 2H), 6.41 (dd, J = 8.4 Hz, 2H), 6.41 (s, 1H), 4.51 (dd, J = 32.7 , 14.9 Hz, 2H), 3.76 (s, 6H), 3.66 (s, 3H), 3.22 (dd, J = 7.5, 4.6 Hz, 2H), 2.90 (dd, J = 15.9, 5.1 Hz, 1H), 2.76 (m, 1H), 2.52 (dd, J = 16.2, 7.5 Hz, 2H), 1.98-1.55 (m, 4H)

Step 2. Synthesis of 2- [1- (2,4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -N-hydroxy-acetamide (s1)

Compound (s) was obtained by reacting compound (r) obtained in the first step with an amine salt.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.15 (d, J = 9.0 Hz, 1 H), 6.46 (t, J = 4.65,2H), 4.56 (q, J = 7.2 Hz, 23.7 Hz, 2H), 3.79 (s, 6H), 3.31-3.19 (m, 2H), 2.86-2.69 (m, 2H), 2.41 (d, J = 14.1 Hz, 1H), 1.89-1.79 (m, 2H)

Compounds of Examples 37 to 38 having the physical properties shown in Table 8 were prepared by performing a preparation process similar to the preparation method described in Example 36.

Example 37 Synthesis of (2-oxo-1-phenethyl-piperidin-3-yl) -acetic acid (s2)

Example 38 Synthesis of [2-oxo-1- (3-phenyl-propyl) -piperidin-3-yl] -acetic acid (s3)

Example Chemical structure Spectral data 37

7.315-7.169 (m, 5H), 3.60 (t, J = 7.35, 1H), 3.15 (dd, J = 4.8, 11.1, 1H), 2.917-2.856 (m, 1H), 2.728-2.659 (m, 1H) , 1.698-1.426 (m, 4H), 1.23 (d, J = 7.05, 5H) 38

7.29-7.12 (m, 5H) 3.47-3.35 (m.2H) 3.29-3.23 (m, 2H) 2.63-2.45 (m.4H) 2.03-1.80 (m.4H) 1.59-.147 (m, 2H), 1.33-1.19 (m, 3H)

Example 39 N-hydroxy-4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid (v ) synthesis

Step 1. Synthesis of 5-[(4-methoxybenzyl) -but-3-enyl-carbamoyl] -hex-5-enoic acid methyl ester (t)

 Compound (b) obtained in step 1 of Example 1 was injected into a methylene chloride solution with mono-acid (2-methylene-butanediionic acid 4-methyl ester), EDC and DMAP, followed by 5 at room temperature. The reaction was carried out for a period of time to obtain 3-[(4-methoxybenzyl) -but-3-enyl-carbamoyl] -but-3-enoic acid methyl ester (t).

Step 2. Synthesis of 4- [1- (4-methoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyric acid methyl ester (u)

Compound (t) obtained in the first step is reacted in an organic solvent such as methylene chloride in the presence of a groove (I) catalyst (Grubb's (I) catalysis), such as a ruthenium catalyst, to give 4- (1-benzyl-2-oxo- Obtained by conversion to 1,2,5,6-tetrahydro-pyridin-3-yl) -butyric acid methyl ester (u).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.19 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.25 (t, J = 4.2 Hz, 1H), 4.54 ( s, 2H), 3.77 (s, 3H), 3.65 (s, 3H), 3.25 (t, J = 6.9 Hz, 2H) 2.33 (t, J = 7.3 Hz, 4H), 2.24 (q, J = 4.5 Hz , 2H), 1.80 (t, J = 7.2 Hz, 2H) 1.56 (s, 2H)

Step 3. N-hydroxy-4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid (v1) synthesis

Compound (u) obtained in the second step is reacted with an amine salt in an alcohol solvent to give N-hydroxy-4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetra Hydro-pyridin-3-yl] -butyramid compound (v1) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.19-7.15 (m, 2H), 6.83 (d, J = 7.8 Hz, 2H), 6.28 (br t, 1H), 4.53 (s, 2H), 3.76 ( s, 3H), 3.25 (dt, J A = 7.5 Hz, J B = 1.8 Hz, 2H), 2.38-2.23 (m, 6H), 1.85-1.76 (m, 2H)

Compounds of Examples 40 to 42 having the physical properties shown in Table 9 were prepared by performing a similar procedure to the preparation method described in Example 39.

Example 40 Synthesis of N-hydroxy-4- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -butyramid (v2)

Example 41 N-hydroxy-4- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid (v3) synthesis

Example 42 N-hydroxy-4- [2-oxo-1- (3-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid (v4) synthesis

Example Chemical structure Spectral data 40

7.29-7.13 (m, 5H), 6.24 (br t, 1H), 3.56 (t, J = 7.56 Hz 2H), 3.31-3.29 (m, 1H), 3.16 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.14-2.03 (m, 5H), 1.66-1.61 (m, 2H) 41

7.29-7.17 (m, 5H), 6.32 (br t, 1H), 3.46 (t, J = 7.3 Hz 2H), 3.35 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H ), 2.37-2.28 (m, 5H), 1.99-1.73 (m, 5H) 42

7.29-7.15 (m, 5H), 6.31 (br t, 1H), 3.45 (t, J = 6.5 Hz 2H), 3.32 (t, J = 7.1 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H ), 2.27 (d, J = 7.2 Hz, 6H), 1.60 (s, 6H)

Experimental Example 1. Pharmacological Activity Experiment

In order to search for the efficacy of the compounds of Examples 1 to 42 was carried out the following experiment.

1-1. Nitric oxide (NO) production inhibition experiment

The inhibitory ability of the compounds of the invention on nitric oxide (NO) production by macrophage activated by lipopolysaccharide (LPS) was tested. As an indicator of NO production, the amount of nitrite accumulated in the cell culture was measured. In the experiment, Raw 264.7 cells (ATCC, USA), one of the mouse macrophage cell lines, were used.

RAW 264.7 cells, which are macrophage cell lines of mice, were cultured in DMEM (Dulbeco's modified eagles medium) medium containing 5% fetal bovine serum (FBS). RAW 264.7 cells were incubated in a 96 well plate at a suitable concentration (1 × 10 ⁶ cells / ml ~ 5x 10 ⁶ cells / ml) under a culture condition of 5% CO ₂ at 37 ° C., followed by appropriate concentration. Was treated to cells (0.1-10 μM). Cells were activated by treatment with compounds at the same time as LPS (final concentration 0.3 μg / ml) (Sigma, USA). Cell cultures were collected 24 hours after treatment with LPS and compounds. The same volume of Griess reagent (1% sulfanylamide, 0.1% naphthylethylenediamine dihydrochloride and 2% phosphoric acid) (sulfanylamide, naphthylethylenediamine-Sigma; dihydrochloride- Fisher Scientific, USA) was added and reacted at room temperature for 10 minutes.

The degree of nitrous acid production was determined from a standard curve obtained by measuring absorbance at 540 nm and using nitrous acid as a standard. The IC ₅₀ value was defined as the concentration of the test compound at which the maximum of 540 nm absorbance was reduced by half.

The experimental results are shown in Table 10 below (AA means IC ₅₀ 's <1μΜ, A means IC ₅₀ 's <5μΜ, B means IC ₅₀ 's <10μΜ and C means IC ₅₀ 's> 10μΜ ).

As shown in Table 10 below, the effect of the compounds of the present invention on the production of NO from macrophages was measured. As a result, the compounds of the present invention were found to have excellent NO inhibitory activity.

1-2. Cell activity measurement (TNF-α)

By measuring the amount of TNF-α accumulated in the cell culture, the ability of the compounds of the present invention to inhibit TNF-α production was examined. In the experiment, Raw 264.7 cells (ATCC, USA), one of the mouse microphage cell lines, were used.

RAW 264.7 cells, the macrophage cell line of mice, were cultured in DMEM medium containing 5% fetal bovine serum (FBS). RAW 264.7 cells were incubated in a 96 well plate at a suitable concentration (1x10 ⁶ cells / ml ~ 5x10 ⁶ cells / ml) under a culture condition of 5% CO2 and 37 ° C. Cells were treated (0.1-10 μM). Cells were activated by treatment with LPS (final concentration 0.3 μg / ml) (Sigma, USA) while the cells were treated with the compound. Cell cultures were collected 24 hours after treatment with LPS and compounds. The amount of TNF-α present in the collected cell culture was quantified using an ELISA assay kit (Quantikine colorimetric sandwich ELISA assay kit, R & D systems, USA).

The experimental results are shown in Table 10 below (AA means IC ₅₀ 's <1μΜ, A means IC ₅₀ 's <5μΜ, B means IC ₅₀ 's <10μΜ and C means IC ₅₀ 's> 10μΜ ).

As shown in Table 10 below, the effect of compounds on the production capacity of TNF-α from macrophages was measured. As a result, it was confirmed that the compounds of the present invention had excellent TNF-α production inhibitory activity.

Example NO inhibitory activity TNF-α Inhibitory Activity One A B 2 A A 3 A A 4 AA A 5 AA A 6 AAA AA 7 C C 8 C C 9 C C 10 C C 11 C C 18 C C 19 C C 20 C C 21 A A 22 C C 23 C C 24 C C 25 B B 26 C C 27 C C 28 C C 29 C C 30 C C 31 C C 32 C C 33 C C 34 C C 35 C A 36 C C 37 C C 38 C C 39 C C 40 C C 41 A C 42 A C

The compound according to the present invention exhibits a strong inhibitory activity against the production of NO and TNF-α with tumor necrosis factor-α converting enzyme and sialic acid glycotransferase as a functioning point, so that the composition comprising the same It can be used as a medicament for treatment.

Claims (6)

A compound of formula (II): or a pharmacologically acceptable salt thereof:

(Ⅱ) Where X is -OH, -NHOH, -NHOCH ₂ Ph,

or

ego, n is an integer from 1 to 5, m is an integer of 1 or 2, Y is a substituted or unsubstituted substituent, selected from lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, nitro, halogen, amine, acetamide, carboamide, sulfonamide, M is a substituted or unsubstituted substituent, and is selected from lower alkyl or hydrogen atom having 1 to 3 carbon atoms, lower alkyl having 1 to 3 carbon atoms or phenyl substituted with lower alkoxy, dotted line(

) Means a single bond or a double bond. delete The method of claim 1, 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxypropionamide, N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide, 3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid, 3- [1- (4-Nitro-benzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid, N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide, N- (2-amino-phenyl) -3- [1- (2-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide, 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-propionamide, N- {4- [5- (2-hydroxycarbamoyl-ethyl) -6-oxo-3,6-dihydro-2H-pyridin-1-ylmethyl] -phenyl} -benzamide, N-hydroxy-3- [1- (4-dimethylsulfonylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide, N-hydroxy-3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -1,2,5,6-tetrahydro-pyridin-3-yl} -propionamide , 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid, 3- [1- (4-Benzoylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid, 3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -1,2,5,6-tetrahydro-pyridin-3-yl} -propionic acid, N-hydroxy-2- [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide, N-hydroxy-2- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide, [1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid, 2- [1- (2,4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -N-hydroxy-acetamide, N-hydroxy-4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid. delete N-hydroxy-3- [1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide, N-hydroxy-3- [2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide, N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionamide, N-hydroxy-3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionamide, 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid, 3- [2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid, 3- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionic acid, 3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydropyridin-3-yl] -propionic acid, 3- [1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-pyridin-2-ylpropionamide, N-benzyloxy-3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide, N- (2-amino-phenyl) -3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide, N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide, 2- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide, N-hydroxy-2- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide, N-hydroxy-2- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetamide, (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid, [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid, [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid, (2-oxo-1-phenethyl-piperidin-3-yl) -acetic acid, [2-oxo-1- (3-phenyl-propyl) -piperidin-3-yl] -acetic acid, N-hydroxy-4- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -butyramid, N-hydroxy-4- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid and N-hydroxy-4- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramid or a pharmacological thereof Acceptable salts. A pharmaceutical composition for treating an inflammatory disease comprising the compound of claim 1 or 5 or a pharmacologically acceptable salt thereof as an active ingredient.