KR100594377B1 - Novel 2-oxo-piperidine derivative? compound having anti-inflammatory activity, preparation method thereof and a composition containing the same for treating inflammatory disease - Google Patents

Abstract

The present invention provides novel 2-oxo-piperidine derivative (I) 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 exhibits a strong inhibitory activity against the production of cytokines such as tumor necrosis factor-α (TNF-α), nitric oxide (NO), and the composition containing the same, Available as a medicament.

Anti-inflammatory substances, inflammatory diseases, arthritis

Description

Novel 2-oxo-piperidine derivative (I) compound having anti-inflammatory activity, preparation method thereof, and composition for the treatment of inflammatory disease comprising the same , preparation method approximately and a composition containing the same for treating inflammatory disease}

The present invention relates to a novel 2-oxo piperidine derivative (I) compound having anti-inflammatory activity, a preparation method thereof, and a composition for the treatment of inflammatory diseases including 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 decreases.

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 activity correlates with the depth of lesions (Mankin et al. Arthritis Rhenum . 21 , pp761-766, (1978), Woessner et al. Arthritis Rhenum . 26 , pp 63-68, (1983) and Ibid . 27 , pp305-312, (1984)). 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 cells and is processed from 26 kD precursor forms to 17 kD active forms. 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, using specific antibodies to block the effects of TNF can lead to the effects of 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)), and have been shown to be beneficial in many 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 (hereinafter known as tumor necrosis factor-α convertase (TNF-C)) as well as other MPs from their inactive to active form It has been found to be convertible (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 discloses compounds that are hydroxamic acid derivatives and inhibitors of cytokines, and British Patent Publication Nos. 2 268 934 and International Publication No. 94124140 describe the hydroxylation of MMP as an inhibitor of TNF production. Mate inhibitors are 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 orotai-potassium acid, chloroquinones and D-phenicamine. Therapies such as antirheumatic agents, gout inhibitors such as colchicine, and immunosuppressants such as cyclophosphamide, azathioprine, methotrexate, and levamisol have been treated with chemotherapy using various agents.

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, especially for the treatment of rheumatoid arthritis.

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 It was found that the 2-oxo piperidine derivative compound of showed excellent inhibitory activity of NO and TNF-α production, thereby completing the present invention.

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel 2-oxo piperidine derivative compound anti-inflammatory material, a method for preparing the same, and a composition for the treatment of an inflammatory disease including the same.

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

(Ⅰ)

(Ⅰ)

Where

,

이고,X is -OH, -NHOH, -NHOCH ₂ Ph,

,

ego,

n is an integer from 1 to 5,

R is an optionally substituted substituent, optionally, a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms substituted with R`, an alkenyl group, an alkynyl group and an aryl group,

R` is a substituent selected from a hydrogen atom, a thiophenyl group, a naphthyl group, a pyrrole group, and a furyl group.

General formula Particularly preferred groups of compounds of (I) include the following compounds and pharmaceutically acceptable salts thereof:

3- (2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid,

N-benzyloxy-3- (2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide,

3- (1-allyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -N-hydroxypropionamide,

N-hydroxy-3- (1-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide,

N-hydroxy-3- [1- (naphthalen-2-yl-methyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,

N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide.

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

The compounds of the present invention represented by the general formula (I) may be prepared with pharmaceutically acceptable salts and solvates according to conventional methods 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, gluconic 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 above general formula (I) include salts of acidic or basic groups which may be present in compounds of general formula (I), 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 the compound of Formula (I), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.

The following 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 3. have. Some compounds of the present invention were synthesized according to procedures not included in the scope of Schemes 1 to 3, 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. At this time, 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 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 obtained from 3- (2-oxo-1,2,5,6, -tetrahydropyridin-3-yl) propionic acid (g) and N-benzyloxy- from compound (d) in scheme (1). The production process for obtaining 3- (2-oxo-1,2,5,6-tetrahydropyridin-3-yl) propionamide (h) is shown.

Compound (d) in Scheme (1) is reacted with triethylsilane in trifluoroacetic acid to obtain compound (f), where R 'is an alkyl group, followed by metal hydroxide salts such as lithium hydroxide in THF-water mixed solvent Compound (g) can be obtained by addition. Additionally compound (g) is reacted with benzyloxyamine (BnONH ₂ ) in dichloromethane solvent in the presence of EDC to give compound (h).

In this case, triethylsilane is preferably used in an amount of 1 to 1.5 equivalents based on compound (d), preferably lithium hydroxide as the metal hydroxide, and its amount is preferably used in an amount of 2-3 equivalents based on compound (g). Do.

Reaction formula (3) shows the manufacturing process of the 2nd step for obtaining compound (j) and (k) from compound (f) in said reaction formula (2).

Compound (i) in Scheme (2) is added to hexamethyldisilylazide sodium (NaHMDS) in THF solvent, and then allyl bromide is added to obtain compound (j). In a second step, compound (i) is added to an amine salt in methanol solution to obtain compound (j), or hydroxide salt is added to a compound of THF-water to obtain compound (k). The amount of NaHMDS used in the reaction is preferably 1 to 1.5 equivalents based on compound (f), and 1 to 1.5 equivalents on allyl bromide.

Derivatives of the present invention have excellent anti-inflammatory effects by showing 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, resulting in inflammation-related It is useful for treating diseases.

Accordingly, the present invention provides a pharmaceutical composition for treating inflammatory diseases, comprising the compound of the general formula (I) as an active ingredient and a pharmaceutically acceptable carrier.

The compounds of formula (I) 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 rose, 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, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. 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.

Reference Example 1. 3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -N-hydroxypropionamide (e1) synthesis

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).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.122 (d, J = 9.0 Hz, 1H), 6.415-6.331 (m, 3H), 4.505 (s, 2H), 3.750 (s, 3H), 3.744 (s, 3H), 3.271 (t, J = 6.9 Hz, 2H), 2.552 (m, 2H), 2.381 (m, 2H), 2.220 (m, 2H)

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 170.1, 165.4, 160.2, 158.5, 135.8, 133.5, 130.4, 117.5, 104.2, 98.3, 55.3, 44.9, 44.6, 32.8, 27.1, 23.8

Compounds of Reference Examples 2 and 3 having the physical properties shown in Table 1 were prepared by performing a manufacturing process similar to the preparation method described in Reference Example 1.

Reference Example 2. Synthesis of 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid (e2)

Reference Example 3. Synthesis of (2-oxo-1-phenethyl-piperidin-3-yl) -N-hydroxyacetamide (e3)

Reference Example Chemical structure NMR spectral data 2

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 ) 3

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)

Example 1.Synthesis of 3- (2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid (g)

3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid (e2) obtained in Reference Example 2 (50 mg, 0.157 mmol) of trifluoroacetic acid (1 mL) solution and triethylsilane (0.074 mL, 0.465 mmol) were added and then heated at 80 ° C. for 20 minutes. The solution was distilled under reduced pressure to remove the solvent, and then the precipitated solid was recrystallized from a mixture of methanol and ethyl acetate to obtain the compound (g) in a yield of 50% (13 mg).

¹ H-NMR (300 MHz, CD ₃ OD) δ 6.51 (m, 1H), 3.31 (m, 2H), 2.50 (m, 4H), 2.32 (m, 2H)

¹³ C-NMR (75 MHz, CD ₃ OD) δ 176.7, 168.6, 138.4, 134.5, 40.3, 34.1, 27.1, 25.0

Example 2. Synthesis of N-benzyloxy-3- (2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide (h)

To a solution of compound (g) obtained in Example 1 (29 mg, 0.171 mmol) in DMF (0.5 mL), BnONH ₂ .HCl (30 mg, 0.188 mmol), diisopropylmethylamine (0.033 mL, 0.189 mmol), EDC (43 mg, 0.224 mmol) and DMAP (5 mg, 0.041 mmol) were added and then stirred at room temperature overnight. The mixture was diluted with ethyl acetate solution (7 mL) and then washed with 5% HCl solution (1 mL) and saturated sodium carbonate solution (1 mL). 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: methanol / chloroform = 1/20) to give the title compound (h) in a yield of 55% (126 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.28 (s, br, 1H), 7.35 (m, 5H), 6.45 (s, br, 1H), 5.70 (s, br, 1H), 4.87 (s, 2H), 3.47 (s, br, 2H), 2.53 (m, 2H), 2.27 (m, 4H)

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 170.1, 166.9, 137.8, 135.6, 133.0, 129.1, 128.5, 78.0, 39.7, 32.8, 26.9, 24.1

Example 3. Synthesis of 3- (1-allyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -N-hydroxypropionamide (j1)

Step 1. Synthesis of 3- (2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid methyl ester (f)

3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionic acid methyl ester (d) obtained in Reference Example 1 (310) mg, 0.930 mmol) was added triethylsilane (0.222 mL, 1.395 mmol) to a trifluoroacetic acid (3 mL) solution, followed by heating at 80 ° C. for 20 minutes. The solution was distilled under reduced pressure to remove the solvent, and then dissolved in chloroform (20 mL), and then the organic layer was washed with saturated sodium carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was then dried over magnesium sulfate and then 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 (f) in 55% yield (126 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.64 (s, br, 1H), 6.35 (t, J = 3.0 Hz, 1H), 3.59 (s, 3H), 3.31 (m, 2H), 2.48 (m , 4H), 2.26 (m, 2H)

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 173.4, 166.8, 136.1, 133.5, 51.4, 39.5, 33.1, 26.0, 24.0

Step 2. Synthesis of 3- (1-allyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid methyl ester (i1)

NaHMDS (1.0 M in THF, 0.220 mL, 0.220 mmol) was slowly added to THF (0.5 mL) solution of Compound (f) (40 mg, 0.218 mmol) obtained in the first step at -79 ° C, followed by stirring for 30 minutes. It was. Allyl bromide (0.028 mL, 0.327 mmol) was added to the reaction mixture, which was then stirred at 0 ° C. for 3 hours. Then, a saturated ammonia chloride solution (2 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (7 mL). The organic layer was washed with ammonia chloride solution (2 mL) and saturated brine (2 mL), 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 / hexane = 1/2) to give the title compound (i1) in 74% yield (36 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.28 (m, 1H), 5.74 (m, 1H), 5.14 (m, 2H), 3.99 (d, J = 5.7 Hz 2H), 3.61 (s, 3H) , 3.27 (t, J = 6.9 Hz, 2H), 2.51 (m, 4H), 2.27 (m, 2H)

¹³ C-NMR (75 MHz, CDCl ₃ ) δ 173.6, 164.6, 134.3, 134.1, 133.3, 117.1, 51.4, 49.0, 44.6, 33.3, 26.6, 23.8

Step 3. Synthesis of 3- (1-allyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -N-hydroxypropionamide (j1)

NH ₂ OK (1.7 M suspension in methanol, 0.122 mL, 0.207 mmol) was added to a methanol solution of the compound (i1) (24 mg, 0.11 mmol) obtained in the second 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 (j1) in 48% yield (11 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.39 (br t, 1 H), 5.78-5.67 (m, 1 H), 5.17 (d, J = 5.4 Hz, 1 H), 5.12 (s, 1H), 3.98 ( d, J = 5.4 Hz, 2H), 3.30 (t, J = 7.0 Hz, 2H), 2.54-2.28 (m, 6H)

Example 4 Synthesis of N-hydroxy-3- (1-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide (j2)

Step 1. Synthesis of 3- (1-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid methyl ester (i2)

NaHMDS (1.0 M in THF, 0.220 mL, 0.220 mmol) was slowly added to THF (0.5 mL) solution of Compound (f) (80 mg, 0.44 mmol) obtained in the first step of Example 3 at -79 ° C. After stirring for 30 minutes. Methyl bromide (0.48 mL, 0.48 mmol) was added to the reaction mixture, which was then stirred at 0 ° C. for 3 hours. Then, saturated ammonia chloride solution (2 mL) was injected into the reaction mixture, and the mixture was diluted with ethyl acetate (7 mL). The organic layer was washed with ammonia chloride solution (2 mL) and saturated brine (2 mL), 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 (i2) in 72% yield (62 mg).

Step 2. Synthesis of N-hydroxy-3- (1-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide (j2)

NH ₂ OK (1.7 M suspension in methanol, 0.122 mL, 0.207 mmol) was added to a methanol solution of the compound (50 mg, 0.25 mmol) obtained in the first 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 = 1/20) to give the title compound (j2) in 35% yield (19 mg).

¹ H-NMR (300 MHz, CD ₃ OD) δ 6.15 (t, J = 4.3 Hz, 1H), 3.41 (t, J = 7.2 Hz, 2H), 2.97 (s, 3H), 2.51 (t, J = 7.5 Hz, 2H), 2.35 (m, 2H), 2.22 (t, J = 7.5 Hz, 2H)

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

To a methanol solution of the compound (5d, 70 mg, 0.22 mmol) obtained from the third step of Scheme 1 (R substituent: naphthalen-2-yl-methyl group), NH ₂ OK (1.7 M suspension in methanol, 0.64 mL, 1.08) mmol) was injected at 0 ° C. and stirred at room temperature for 5 hours. The mixture was neutralized with acetic acid (0.020 mL), distilled under reduced pressure, and then filtered through solid with 10% methanol / chloroform and distilled under reduced pressure. The obtained primary compound was purified by column chromatography method (silica gel column, eluent: methanol / chloroform = 1/9) to give the title compound in 95% yield (61 mg) (see Table 2).

Example 6. N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -1,2,5,6-tetrahydro-pyridin-3-yl]- Synthesis of Propionamide

To a methanol solution of the compound (6d, 60 mg, 0.20 mmol) obtained from the third step of Scheme 1 (R substituent: 2-thiophen-2-yl-ethyl group), NH ₂ OK (1.7 M suspension in methanol, 0.60 mL) , 1.02 mmol) was injected at 0 ° C. and stirred at room temperature for 5 hours. The mixture was neutralized with acetic acid (0.020 mL), distilled under reduced pressure, and then filtered through solid with 10% methanol / chloroform and distilled under reduced pressure. The obtained primary compound was purified by column chromatography method (silica gel column, eluent: methanol / chloroform = 1/9) to give the title compound in 73% yield (44 mg) (see Table 2).

Example Chemical structure NMR spectral data 5

8.07-7.99 (m, 1H), 7.83-7.74 (m, 2H), 7.50-7.29 (m, 4H), 6.32 (br t, 1H), 5.01 (s, 2H), 3.44 (s, 2H), 3.15 (q, J = 6.9 Hz, 2H), 2.71-2.54 (m, 2H), 2.42 (s, 2H), 2.09 (s, 2H) 6

7.11 (d, J = 4.8 Hz, 1H), 6.89 (t, J = 3.9 Hz, 1H), 6.82 (s, 1H), 6.35 (br t, 1H), 3.64-3.59 (m, 2H), 3.22 ( t, J = 3.22 Hz, 2H), 3.09-3.04 (m, 2H), 2.54-2.50 (m, 2H), 2.35 (s, 2H), 2.20 (s, 2H)

Experimental Example 1. Pharmacological Activity Experiment

In order to search for the efficacy of the compounds of Examples 1 to 6, the following experiment was performed.

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

The ability of compounds of the invention to inhibit 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 to 5 × 10 ⁶ cells / ml) under culture conditions of 5% CO ₂ and 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 3 below (AA means IC ₅₀ 's <1 μM, A means IC ₅₀ 's <5 μM, B means IC ₅₀ 's <10 μM and C means IC ₅₀ 's> 10 μM). ).

As shown in Table 3 below, the effects of the compounds of the present invention on the production of NO from macrophages were measured. As a result, the compounds of the present invention had 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 macrophage 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 (1 × 10 ⁶ cells / ml to 5 × 10 ⁶ cells / ml) under culture conditions of 5% CO ₂ and 37 ° C., followed by appropriate concentration. Was treated to cells ((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 fluid was quantified using an ELISA assay kit (Quantikine colorimetric sandwich ELISA assay kit, manufactured by R & D systems, USA).

The experimental results are shown in Table 3 below (AA means IC ₅₀ 's <1 μM, A means IC ₅₀ 's <5 μM, B means IC ₅₀ 's <10 μM and C means IC ₅₀ 's> 10 μM). ).

As shown in Table 3 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 C C 2 C C 3 C C 4 C C 5 A A 6 A AA

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 Available as a medicament for treatment.

Claims (3)

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

(Ⅰ) Where X is -NHOH, -NHOCH ₂ Ph,

,

ego, n is an integer from 1 to 5, R is a hydrogen atom or lower alkyl group having 1 to 4 carbon atoms, alkenyl group, alkynyl group or aryl group having 5 to 6 carbon atoms substituted with R`, R` is a substituent selected from a thiophenyl group, a naphthyl group, a pyrrole group, and a furyl group, (

) Means a single bond or a double bond. The method of claim 1, N-benzyloxy-3- (2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide, 3- (1-allyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -N-hydroxypropionamide, N-hydroxy-3- (1-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide, N-hydroxy-3- [1- (naphthalen-2-yl-methyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide and Compound selected from N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide . A pharmaceutical composition for treating an inflammatory disease comprising the compound according to any one of claims 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient.