KR20200137707A - Novel sulfadiazinyl derivative compound and use thereof - Google Patents

Abstract

The present invention provides a novel sulfadiazine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The novel sulfadiazine derivative compound, the optical isomer thereof or the pharmaceutically acceptable salt thereof according to the present invention exhibits excellent effects in the prevention and treatment of inflammatory diseases, especially inflammatory intestinal diseases through actions such as inhibiting calf intestinal alkaline phosphatase (CIAP) and inhibiting active oxygen.

Description

Novel sulfadiazine derivative compound and its use {NOVEL SULFADIAZINYL DERIVATIVE COMPOUND AND USE THEREOF}

The present invention relates to novel sulfadiazine derivative compounds and uses thereof.

Inflammatory Bowel Disease (IBD) is a collective term for chronic recurrent inflammatory diseases caused by abnormal immune system regulation in the small and large intestine. Inflammatory bowel disease, represented by Crohn's disease (CD) and ulcerative colitis (UC), is known to be an important etiology for immune response dysregulation (Braus et al., Clin Immunol, 2009, 132, 1). -9; McGuckin et al., Inflamm Bowel Dis, 2008, 15, 100-113).

Inflammatory bowel disease has been recognized as a rare disease in Asia, but the number of inflammatory bowel disease patients in the East is increasing rapidly since the 1980s due to the recent lifestyle habits that are gradually becoming westernized. Accordingly, research related to the improvement of inflammatory bowel disease is being actively conducted, and recently, as cytokines or cells related to inflammatory bowel disease have been identified, numerous biological agents that selectively attack specific molecules or pathways related to intestinal inflammation have been developed. Has become.

Current inflammatory bowel disease treatments include 5-aminosalicylic acid (5-ASA) drugs that block the production of prostaglandins[0004], for example, salparagine, or steroid-like immunosuppressants. I'm using it.

However, sulfaazine may have side effects such as abdominal weakness, headache, rash, liver disease, leukopenia, agranulocytosis, and male infertility. In addition, immunosuppressants of steroids cannot improve the long-term prognosis, and are limited to be used only in acute cases due to side effects such as induced infectious diseases, secondary adrenal insufficiency, peptic ulcer, diabetes, and mental disorders. have. Therefore, it is still necessary to develop a therapeutic agent for inflammatory bowel disease without side effects.

In order to solve the above-mentioned problems under this background, the present inventors have completed the present invention by developing novel sulfadiazine derivatives and confirming the effects of inhibiting alkaline phosphatase and inhibiting active oxygen in the intestine.

Korean Patent Application Publication No. 10-2015-0102515

The problem to be solved by the present invention is to provide a novel sulfadiazine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In addition, the present invention is to provide the use of the novel sulfadiazine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Compound of formula I

The present invention provides a novel sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in order to solve the above-described technical problem:

[Formula 1]

In Formula 1,

R is unsubstituted or aryl substituted with one or more C ₁ -C ₄ alkyl, -F, -Cl, -Br, -I, C ₁ -C ₃ alkoxy, or -NO ₂ , or unsubstituted or -F,- Straight or branched chain C ₁ -C ₁₀ alkyl substituted with Cl, -Br or -I.

In the above formula, C ₁ -C ₄ alkyl may be straight or branched chain alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

In the above formula, C ₁ -C ₃ alkoxy may be, for example, methoxy, ethoxy, propoxy or isopropoxy.

In the above formula, aryl is specifically phenyl.

In the above formula, linear or branched C ₁ -C ₁₀ alkyl is, for example, straight chain alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hectyl, heptyl, octyl, as well as branched chain alkyl having 3 to 10 carbon atoms. Includes.

Specifically, R is phenyl substituted with one or more -F, -Cl, C ₁ -C ₂ alkoxy or -NO ₂ . It is preferably phenyl substituted with one or two -F, -Cl, C ₁ -C ₂ alkoxy or -NO ₂ .

Specifically, R is unsubstituted straight-chain C ₁ -C ₈ alkyl. Preferably methyl, pentyl, hectyl or heptyl.

According to a specific embodiment, R may be any one selected from the following groups:

,

,

,

,

,

,

,

,

, 및

..

,

,

,

,

,

,

,

,

, And

..

In addition, according to an embodiment of the present invention, the compound of Formula 1 may be any one selected from the group consisting of the following compounds.

[Table 1]

The compounds represented by formula I of the present invention may contain one or more asymmetric carbons, and thus may exist as racemates, racemic mixtures, single enantiomers, diastereomer mixtures, and each diastereomer. have.

Such isomers can be separated by conventional techniques, for example, the compound represented by the formula (I) can be separated by column chromatography or HPLC. Alternatively, stereoisomers of each of the compounds represented by the formula (I) can be stereospecifically synthesized using optically pure starting materials and/or reagents of a known arrangement.

In the present invention, the pharmaceutically acceptable salt refers to a salt commonly used in the pharmaceutical industry, for example, an inorganic ion salt prepared from calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, Inorganic acid salts prepared from iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid Organic acid salts prepared from acids, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like; Sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; Amino acid salts prepared from glycine, arginine, lysine, etc.; And amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like, but the types of salts meant in the present invention are not limited by these listed salts.

Method for preparing the compound of formula 1

Preparation of the compound of Formula 1 of the present invention may be carried out in a sequential or convergent synthetic route through the reaction route of Scheme 1 below.

[Scheme 1]

In reaction 1, the acyl chloride compound containing the R group of (1) is reacted with KSCN to prepare the compound of (2), and sulfadiazine (3) is treated thereto to prepare the compound of formula 1 according to the present invention.

According to an embodiment of the present invention, the synthesis route of the sulfadiazine derivative compound of Formula 1 may be prepared according to the sequence described in the reaction scheme, but may be prepared by the method presented herein or a similar method, and the following scheme Is not limited to the order of. The starting material may be commercially available or prepared by a method similar to the method presented below.

Isolation and purification of the sulfadiazine derivative compound or intermediate prepared by the above method is a suitable separation or purification procedure used in the pharmaceutical industry, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick film chromatography, Preparative low pressure or high pressure liquid chromatography or a combination of these procedures can be achieved.

Use of compounds of formula 1

The present invention provides a use of a sulfadiazine derivative compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R is unsubstituted or aryl substituted with one or more C ₁ -C ₄ alkyl, -F, -Cl, -Br, -I, C ₁ -C ₃ alkoxy, or -NO ₂ , or unsubstituted or -F,- Straight or branched chain C ₁ -C ₁₀ alkyl substituted with Cl, -Br or -I.

The present invention provides a pharmaceutical composition comprising the sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising the sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, inflammatory diseases include pain (pain due to the production of harmful substances and nerve stimulation), fever (heat due to vasodilation), redness (redness due to vasodilation and increased blood flow), swelling (excessive inflow or limited outflow of fluid). Tumor), and loss of function (which may be partial or complete, temporary or permanent). Non-limiting examples of inflammatory diseases in which the compound of formula 1 according to the present invention can be used include dermatitis, allergy, psoriasis, eczema, prurtis, skin itching, urticaria, idiopathic chronic urticaria, scleroderma, nasal polyp, rhinitis, chronic Sinusitis, nasal congestion, nose itching, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, conjunctivitis, keratoconjunctivitis, blepharitis, dry eye, heart failure, arrhythmia, atherosclerosis, multiple sclerosis, inflammatory bowel disease, inflammatory pain, neurotic pain, Osteoarthritis pain and thyroid autoimmune disease.

In one embodiment of the present invention, the inflammatory disease may be an inflammatory bowel disease.

According to an embodiment of the present invention, the sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof inhibits CIAP (calf intestinal alkaline phosphatase), inhibits active oxygen, etc. Through the effect, it shows excellent effect in the prevention and treatment of inflammatory diseases, especially inflammatory bowel disease.

The pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for administration. Pharmaceutically acceptable carriers can be used by mixing saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and if necessary, antioxidants and buffers , Other conventional additives such as bacteriostatic agents may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets. Accordingly, the pharmaceutical composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository, or the like. These formulations can be prepared by a conventional method used for formulation in the art or by a method disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on each disease or ingredient. Can be.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenous, subcutaneous, intraperitoneal or topical application) according to a desired method, and the dosage may be the weight, age, sex, and health of the patient. The range varies depending on the condition, diet, administration time, administration method, excretion rate, and severity of disease. The daily dosage of the compound of Formula 1 of the present invention is about 0.01 to 1000 mg/kg, preferably 0.1 to 100 mg/kg, and may be administered once to several times a day.

In addition to the sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicinal effects.

The present invention is a method for treating or preventing an inflammatory disease, comprising administering a therapeutically effective amount of a sulfadiazine derivative compound of the above formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a mammal, including a human, Provides.

The term "therapeutically effective amount" used in the present invention refers to the amount of the sulfadiazine derivative compound of Formula 1 effective for the treatment of inflammatory diseases.

The treatment method of the present invention includes not only treating the disease itself before the onset of the symptom, but also inhibiting or avoiding the symptom thereof by administering the compound of Formula 1 above. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition, and the route to which the active ingredient is administered. The dose and frequency of dose will vary depending on the age, weight and response of the individual patient. A suitable dosage regimen can be readily selected by one of ordinary skill in the art taking these factors of course into account. In addition, the treatment method of the present invention may further include administration of a therapeutically effective amount of an additional active agent helpful in treating a disease together with the compound of Formula 1, and an additional active agent together with the compound of Formula 1 It can have synergistic or auxiliary effects.

The present invention provides a food composition for preventing or improving inflammatory diseases comprising the sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The food composition of the present invention can be used as a health functional food. The term "health functional food" refers to a food manufactured and processed using raw materials or ingredients having useful functions for the human body according to the Health Functional Food Act No.6727, and the term "functional" refers to the structure of the human body. And it means ingestion for the purpose of obtaining useful effects for health use such as controlling nutrients for function or physiological action.

The food composition of the present invention may contain ordinary food additives, and whether or not it is suitable as a "food additive" is determined according to the general rules and general test methods of food additives approved by the Food and Drug Administration, unless otherwise specified. It is judged according to the standards and standards for

For the purpose of preventing and/or improving inflammatory diseases, the food composition of the present invention may contain the compound of Formula 1 in an amount of 0.01 to 95%, preferably 1 to 80% by weight, based on the total weight of the composition. In addition, for the purpose of preventing and/or improving inflammatory diseases, it can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, beverages, and the like.

In addition, the present invention is to provide a use of the sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammatory diseases. The compound of Formula 1 for the manufacture of a drug may be mixed with acceptable adjuvants, diluents, carriers, etc., and may have a synergistic effect of active ingredients by being prepared as a complex formulation with other active agents.

The matters mentioned in the composition, use, and treatment method of the present invention apply equally unless contradictory to each other.

The novel sulfadiazine derivative compound of Formula 1 according to the present invention, its optical isomer or its pharmaceutically acceptable salt, inhibits CIAP (calf intestinal alkaline phosphatase) and inhibits active oxygen. , In particular, it shows excellent effects in the prevention and treatment of inflammatory bowel disease.

1 is a diagram showing the results of confirming the antioxidant activity of novel sulfadiazine derivative compounds according to the present invention.

Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in various different forms and is not limited to the embodiments described herein.

In the present invention, the reagents and solvents mentioned below were purchased from Sigma-Aldrich, TCI, unless otherwise specified, and the melting point was a digital Gallenkamp (Tokyo, Japan) model MPD.BM 3.5 instrument, and 1HNMR For data, a Bruker AM-300 spectrophotometer was used, and for 13CNMR, a Bruker 75 MHz NMR spectrometer was used. In addition, MS used a MAT312 instrument. In addition, an FTS 3000 MX spectrophotometer was used for FTIR spectra, and LECO-193 CHNS was used for elemental analysis.

Example 1-10. Preparation of sulfadiazine derivative compounds

Its specific reaction is shown by explanation in Scheme 1.

A solution of potassium thiocyanate (5 mmol) in acetone was stirred and then a solution of commercially available hydrochloric acid (5 mmol) in acetone (10 ml) was added dropwise to the reaction mixture (acyl chloride compound containing the R group). The reaction mixture was refluxed for 1 hour and a half, cooled, and a solution of sulfadiazine (5 mmol) in acetone (10 ml) was added, and the reaction mixture was stirred at 50° C. for 5-6 hours. The progress of the reaction was confirmed through TLC (n-hexane: ethyl acetate). After the reaction, the reaction mixture was placed on ice and the precipitate was collected by filter, drying and recrystallization from ethanol to obtain the desired compounds of Examples 1 to 10 in the best yield.

1.4-Fluoro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide [4-Fluoro-N-((4-(N-( pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl) benzamide]

Pale yellow, yield: 73%, mp: 235 °C, Rf=0.65 (n-hexane:ethyl acetate, 4:1), FTIR υ(cm ^-1 ) 3168.3 (NH, stretching), 2926.6 (Aromatic CH, stretching ), 1709.8 (C=O, stretching), 1609.5 (CC, stretching), 1447.3 (CH, bending), 1252.4 (C=S, stretching).

1 H NMR (DMSOd ₆ , 300 MHz); δ (ppm) 12.35 (s, 1H, NH), 11.74 (s, 1H, NH), 11.37 (s, 1H, NH), 8.61 (d, 2H, Ar-H, J) 8.2 Hz), 8.11 (d , 2H, Ar-H, J=7.6 Hz), 7.87 (d, 2H, Ar-H), 7.76 (d, 2H, Ar-H), 7.53 (d, 2H, Ar-H), 7.06 (t, 1H, Ar-H);

13C NMR (75 MHz DMSOd ₆ ) δ (ppm) 180.4 (C=S), 178.1 (C=O), 172.5, 158.8, 157.3, 151.4, 142.1, 140.3, 137.7, 134.2, 131.7, 130.7, 128.8, 124.1, 121.6, 120.4, 118.6, 116.3 (Ar-C),

2. 3,5-Dinitro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide [3,5-Dinitro-N-((4- (N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide]

Red solid, yield: 77%, mp: 225 °C, Rf=0.52 (n-hexane: ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3172.3 (NH, stretching), 2934.2 (Aromatic CH, stretching ), 1711.5 (C=O, stretching), 1633.6 (CC, stretching), 1430.3 (CH, bending), 1263.4 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.15 (s, 1H, NH), 11.63 (s, 1H, NH), 11.33 (s, 1H, NH), 8.31 (d, 2H, Ar-H, J=7.2 Hz), 8.12 (d , 2H, Ar-H, J=7.3 Hz), 7.97 (d, 2H, Ar-H), 7.66 (d, 2H, Ar-H), 7.43 (s, 1H, Ar-H), 7.03 (t, 1H, Ar-H);

13C NMR (75 MHz DMSO-d ₆ ) δ (ppm) 180.6 (C=S), 177.1 (C=O), 171.3, 168.3, 156.3, 150.4, 141.1, 139.3, 135.9, 132.1, 130.7, 129.9, 128.4, 125.3, 121.3, 120.2, 119.4, 116.6 (Ar-C),

3. 4-Chloro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide [4-Chloro-N-((4-(N-(pyrimidin -2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide]

Brown crystalline solid, yield: 90%, mp: 240 °C, Rf=0.61 (n-hexane:ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3176.3 (NH, stretching), 2956.3 (Aromatic CH, stretching), 1719.8 (C=O, stretching), 1613.6 (CC, stretching), 1427.2 (CH, bending), 1232.6 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.55 (s, 1H, NH), 11.63 (s, 1H, NH), 11.33 (s, 1H, NH), 8.31 (d, 2H, Ar-H, J=7.2 Hz), 8.21 (d , 2H, Ar-Ar-H, J=7.6 Hz), 7.67 (d, 2H, Ar-H), 7.56 (d, 2H, Ar-H), 7.33 (d, 2H, Ar-H), 7.13 ( t, 1H, Ar-H);

13C NMR (75 MHz DMSO-d ₆ ) δ(ppm) 179.4 (C=S), 177.1 (C=O), 171.4, 156.8, 155.3, 150.4, 143.1,140.8, 138.7, 134.7, 132.7, 130.6, 127.8, 123.1, 121.9, 120.1, 119.6,117.3 (Ar-C)

4.4-Methoxy-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide [4-Methoxy-N-((4-(N-( pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide]

Pale yellow solid, yield: 69%, mp: 254 °C, Rf=0.58 (n-hexane:ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3186.1 (NH, stretching), 2998.3 (Aromatic CH, stretching), 1689.8 (C=O, stretching), 1617.6 (CC, stretching), 1420.2 (CH, bending), 1289.6 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.11 (s, 1H, NH), 11.63 (s, 1H, NH), 11.23 (s, 1H, NH), 8.11 (d, 2H, Ar-H, J=7.5 Hz), 8.01 (d , 2H, Ar-H, J=7.1 Hz), 7.63 (d, 2H, Ar-H), 7.36 (d, 2H, Ar-H), 7.34 (d, 2H, Ar-H), 7.11 (t, 1H, Ar-H), 2.3 (s, 3H);

13C NMR (75 MHz DMSO-d ₆ ) δ(ppm) 182.4 (C=S), 179.1 (C=O), 173.2, 156.3, 153.3, 151.4, 145.1, 142.8, 139.5, 136.8, 133.6, 130.3, 128.7, 124.1, 122.6, 120.3, 119.2, 117.6 (Ar-C), 55 (CH ₃ )

5. 2-Chloro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide [2-Chloro-N-((4-(N-(pyrimidin -2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide]

White solid, yield: 76% mp: 243 °C, Rf=0.59 (n-hexane: ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3136.3 (NH, stretching), 2956.3 (Aromatic CH, stretching) , 1739.8 (C=O, stretching), 1623.6 (CC, stretching), 1417.2 (CH, bending), 1233.6 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.35 (s, 1H, NH), 11.33 (s, 1H, NH), 11.12 (s, 1H, NH), 8.32 (d, 2H, Ar-H, J=7.3 Hz), 8.12 (d , 2H, Ar-H, J=7.1 Hz), 7.63 (d, 2H, Ar-H), 7.46-7.23 (m, 4H, Ar-H), 7.12 (t, 1H, Ar-Ar-H);

13C NMR (75 MHz DMSO-d ₆ ) δ (ppm) 179.3 (C=S), 178.4 (C=O), 171.6, 154.6, 154.3, 151.4, 144.5, 141.7, 139.6, 133.4, 131.4, 130.2, 126.8, 122.1, 121.6, 120.4, 118.6, 116.3 (Ar-C)

6.2,4-Dichloro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide [2,4-Dichloro-N-((4-( N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide]

Pale yellow solid, yield: 71%, mp: 253 °C, Rf=0.62 (n-hexane:ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3138.6 (NH, stretching), 2957.4 (Aromatic CH, stretching), 1741.3 (C=O, stretching), 1624.3 (CC, stretching), 1418.2 (CH, bending), 1234.6 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.36 (s, 1H, NH), 11.34 (s, 1H, NH), 11.22 (s, 1H, NH), 8.43 (d, 2H, Ar-H, J=7.2 Hz), 8.23 (d , 2H, Ar-H, =6.5 Hz), 7.53 (d, 2H, Ar-H), 7.43-7.22 (m, 3H, Ar-H), 7.13 (t, 1H, Ar-H);

13C NMR (75 MHz DMSO-d ₆ ) δ (ppm) 179.7 (C=S), 177.9 (C=O), 171.5, 153.7, 154.1, 152.3, 145.2, 142.4, 138.6, 134.8, 132.7, 131.2, 127.3, 123.2, 121.9, 120.4, 118.5, 116.8 (Ar-C)

7.N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)butyramide [N-((4-(N-(Pyrimidin-2-yl)sulfamoyl) phenyl)carbamothioyl)butyramide]

Light brown solid, yield: 67%, mp: 176 °C, Rf=0.57 (n-hexane: ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3038.6 (NH, stretching), 2956.6 (Aromatic CH, stretching), 1696.4 (C=O, stretching), 1573.5 (CC, stretching), 1412.3 (CH, bending), 1163.2 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.75 (s, 1H, NH), 11.84 (s, 1H, NH), 11.57 (s, 1H, NH), 8.51 (d, 2H, Ar-H, J=6.5 Hz), 8.01 (d , 2H, Ar-H, J=3.9 Hz), 7.75 (d, 2H, Ar-H), 7.07 (t, 1H, Ar-H), 3.36 (t, 2H), 2.51 (quint, 2H), 2.43 (quint, 2H), 1.57 (quint, 2H), 1.55 (quint, 2H), 1.24 (sex, 2H), 0.85 (t, 3H);

13C NMR (75 MHz DMSO-d ₆ ) δ (ppm) 179.4 (C=S), 176.1 (C=O), 172.5, 158.8, 157.3, 142.1, 137.7, 130.7, 128.8, 124.1, 118.6, 116.3 (Ar- C), 40.51, 39.7, 36.2, 29.1, 25.4, 22.6, 14.4,

8. N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)octanamide [N-((4-(N-(Pyrimidin-2-yl)sulfamoyl)phenyl) )carbamothioyl)octanamide]

White solid, yield: 80%, mp: 215 °C, Rf=0.61 (n-hexane: ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3078.7 (NH, stretching), 2926.6 (Aromatic CH, stretching) ), 1699.8 (C=O, stretching), 1579.9 (CC, stretching), 1407.3 (CH, bending), 1152.4 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.75 (s, 1H, NH), 11.84 (s, 1H, NH), 11.57 (s, 1H, NH), 8.51 (d, 2H, Ar-H, J=6.5 Hz), 8.01 (d , 2H, Ar-H, J=3.9 Hz), 7.75 (d, 2H, Ar-H), 7.07 (t, 1H, Ar-H), 3.36 (t, 2H), 2.51 (quint, 2H), 2.43 (quint, 2H), 1.57 (quint, 2H), 1.55 (quint, 2H), 1.24 (sex, 2H), 0.85 (t, 3H);

13C NMR (75 MHz DMSO-d ₆ ) δ (ppm) 179.4 (C=S), 176.1 (C=O), 172.5, 158.8, 157.3, 142.1, 137.7, 130.7, 128.8, 124.1, 118.6, 116.3 (Ar- C), 40.51, 39.7, 36.2, 29.1, 25.4, 22.6, 14.4,

9.N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)heptanamide [N-((4-(N-(Pyrimidin-2-yl)sulfamoyl)phenyl) )carbamothioyl)heptanamide]

Yellow solid, yield: 75%, mp: 210 °C, Rf=0.58 (n-hexane: ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3108.3 (NH, stretching), 2928.6 (Aromatic CH, stretching ), 1676.8 (C=O, stretching), 1517.5 (CC, stretching), 1421.4 (CH, bending), 1276.9 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.64 (s, 1H, NH), 11.74 (s, 1H, NH), 11.43 (s, 1H, NH), 8.32 (d, 2H, Ar-H, J=6.3 Hz), 8.0 (d , 2H, Ar-H, J=3.2 Hz), 7.36 (d, 2H, Ar-H), 7.06 (t, 1H, Ar-H), 3.46 (t, 2H), 2.63 (quint, 2H), 2.33 (quint, 2H), 1.53 (quint, 2H), 1.31 (sex, 2H), 0.76 (t, 3H);

13C NMR (75 MHz DMSO-d ₆ ) δ (ppm) 178.5 (C=S), 175.3 (C=O), 171.8, 157.3, 156.4, 141.1, 136.4, 131.7, 127.2, 123.1, 119.6, 117.1 (Ar- C), 40.42, 39.4, 36.1, 28.1, 24.4, 15.4,

10. N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)acetamide [N-((4-(N-(Pyrimidin-2-yl)sulfamoyl)phenyl) )carbamothioyl)acetamide]

Yellow solid, yield: 70%, mp: 204 °C, Rf=0.54 (n-hexane: ethyl acetate, 4:1), FTIR υ (cm ^-1 ) 3095.4 (NH, stretching), 2934.6 (Aromatic CH, stretching ), 1685.6 (C=O, stretching), 1508.6 (CC, stretching), 1437.2 (CH, bending), 1262.3 (C=S, stretching).

1 H NMR (DMSO-d ₆ , 300 MHz); δ (ppm) 12.43 (s, 1H, NH), 11.64 (s, 1H, NH),11.36 (s, 1H, NH), 8.12 (d, 2H, Ar-H, J=6.3 Hz), 8.03 (d , 2H, Ar-H, J=3.2 Hz), 7.26 (d, 2H, Ar-H), 7.02 (t, 1H, Ar-H), 3.36 (s, 3H);

13CNMR (75 MHz DMSO-d ₆ ) δ (ppm) 178.3 (C=S), 176.2 (C=O), 172.6,151.3, 146.4, 131.1, 130.4, 129.7, 126.2, 123.7, 118.7, 116.1 (Ar-C ), 30.42,

Example 11. Measurement of Alkaline Phosphatase Inhibitory Activity

Inhibitors were screened by evaluating the compounds of Examples 1 to 10 for alkaline phosphatase. Specifically, Iqbal J. Analyt Bochem. The method described in 2011;2:231. was used. A 50 mM Tris-HCl buffer solution at pH 9.5 containing 5 mM MgCl ₂ and 0.1 mM ZnCl ₂ , a reaction mixture containing an Example compound and 5 μL enzyme (CIALP 0.025 U/mL) for 10 minutes, and then 10 μL of A substrate (0.5mM p-NPP (para nitrophenylphosphate disodium salt) was added, and the reaction was carried out for 30 minutes at 37° C. Then, the absorbance change of p-nitrophenolate released at 405 nm was measured.

The results are shown in Table 2.

[Table 2]

As can be seen in Table 2 above, all of the synthesized compounds exhibited CIAP inhibitory effects, and in particular, the compound of Example 3 exhibited the most excellent effect.

Example 12. Antioxidant activity confirmation

To measure the antioxidant activity, Larik FA, Saeed A, Channar PA, et al. Eur J Med Chem. Free radical scavenging activity was measured by partially modifying the method described in 2017;141:278. Specifically, DPPH assay was used. DPPH solution with a concentration of 150 μM was prepared, from which 100 μL was used for the assay. The increasing concentration and volume of 20 μL of the compound was adjusted to 200 μL by adding CH ₃ OH. Then, the reaction was allowed to stand at room temperature for 30 minutes, and then the experiment was performed. The assay was performed using a microplate reader (OPTI MAX, Tunable USA) at 517 nm. Ascorbic acid was used as a control. The number of reactions was compared to calculate the percent inhibition by the presence of the inhibitor being tested.

The results are shown in FIG. 1.

As can be seen in Figure 1, the compounds of Example 2 and Example 6 as the compounds according to the present invention showed particularly excellent antioxidant activity.

As described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it is obvious that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereby. something to do. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

A sulfadiazine derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R is unsubstituted or aryl substituted with one or more C ₁ -C ₄ alkyl, -F, -Cl, -Br, -I, C ₁ -C ₃ alkoxy, or -NO ₂ , or unsubstituted or -F,- Straight or branched chain C ₁ -C ₁₀ alkyl substituted with Cl, -Br or -I. The method of claim 1,
The aryl is phenyl, a sulfadiazine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
R is phenyl substituted with one or more -F, -Cl, C ₁ -C ₂ alkoxy or -NO _{2 A} sulfadiazine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
R is an unsubstituted linear C ₁ -C ₈ alkyl sulfadiazine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
R is a sulfadiazine derivative compound selected from the following groups, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

,

,

,

,

,

,

,

,

,

.
The method of claim 1,
A sulfadiazine derivative compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 is selected from the following compounds:
4-fluoro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide,
3,5-dinitro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide,
4-chloro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide,
4-methoxy-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide,
2-chloro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide,
2,4-dichloro-N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)benzamide,
N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)butyramide,
N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)octanamide,
N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)heptanamide, and
N-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)carbamothioyl)acetamide. A pharmaceutical composition for preventing or treating inflammatory diseases comprising the sulfadiazine derivative compound according to any one of claims 1 to 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 7, wherein the inflammatory disease is dermatitis, allergy, psoriasis, eczema, prurtis, skin itching, urticaria, idiopathic chronic urticaria, scleroderma, nasal polyp, rhinitis, chronic sinusitis, nasal congestion, nasal itching, asthma, Chronic obstructive pulmonary disease, rheumatoid arthritis, conjunctivitis, keratoconjunctivitis, blepharitis, dry eye, heart failure, arrhythmia, atherosclerosis, multiple sclerosis, inflammatory bowel disease, inflammatory pain, neurogenic pain, osteoarthritis pain, and thyroid autoimmune disease Any one selected from, a pharmaceutical composition for preventing or treating inflammatory diseases. The pharmaceutical composition of claim 8, wherein the inflammatory disease is an inflammatory bowel disease. A food composition for preventing or improving inflammatory diseases comprising the sulfadiazine derivative compound according to any one of claims 1 to 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

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