KR20080016249A - Thiazole derivatives, preparation thereof and pharmaceutical compositions comprising the same - Google Patents

Abstract

A novel thiazole derivative is provided to inhibit effectively the enzymatic activity of 5-lipoxygenase(5-LO) acting when an arachidonic acid is converted into a leukotriene metabolite, thereby being used as a prophylactic and therapeutic agent of various inflammatory diseases and cancers. A thiazole derivative is represented by the formula(1), wherein each R1 and R2 is independently H, OR7, NO2, halogen or C1-4 linear, branched, or cyclic alkyl; each R3, R4, R5 and R6 is independently H, CF3, OR7, CO2R7, NR7R8, NO2, NHCOR7, C(=O)R7, SR7, halogen, C1-4 linear, branched or cyclic alkyl(in which each R7 and R8 is independently H, unsubstituted or F-substituted C1-6 linear, branched, or cyclic alkyl, or aryl); X is NH, O, S or SO2; Y is C or N. A method for preparing a thiazole derivative represented by the formula(1a) comprises a step of reacting an acetophenone derivative represented by the formula(2) with an aniline derivative represented by the formula(2) and a thiocyanate salt, wherein the R1 to R6, and Y are same as defined above. A pharmaceutical composition for preventing or treating asthma, chronic obstructive lung disease, arthritis, psoriasis, atopic dermatitis, allergy, enteritis, and cancer comprises the thiazole derivative, or a pharmaceutically acceptable salt thereof, a hydrate, solvate or isomer thereof as an effective ingredient.

Description

THIAZOLE DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME}

The present invention provides a novel thiazole derivative that inhibits the activity of 5-lipoxygenase (5-LO), which is an enzyme acting when arachidonic acid is converted into a leukotriene metabolite, and a method for preparing the same. It relates to a pharmaceutical composition containing this as an active ingredient.

Aspirin, a nonsteroidal drug, is the most widely used antipyretic and analgesic drug, but is limited in its use due to side effects that cause damage to the gastrointestinal tract and kidneys for use in treating all inflammatory diseases (Biochem. , 1433 (2001). Therefore, various studies have been attempted to inhibit 5-LO and cyclooxygenase (COX) and minimize side effects of COX inhibitors.

Arachidonic acid (AA) is a polyunsaturated fatty acid that is the most abundant in the cell membrane, and phospholipase A2 is activated and separated from the membrane for various external stimuli. AA is metabolized by two enzymes, COX and 5-LO, to synthesize proinflammatoryoids, prostanoids (PGs) and leukotrienes (LTs).

LO (lipoxygenase) is divided into 5-LO, 12-LO, and 15-LO according to the position of oxygen incorporation into the carbon of arachidonic acid, which is a substrate, and 5-, 12-, 15-HPETE ( hydroperoxy-eicosatetraenoic acid) (see Prostaglandins Other Lipid Mediat., 62, 255 (2000)). Although the biological effects of 12-LO and 15-LO are not well known, 5-LO is known to be involved in the synthesis of leukotriene (LT), an important mediator of potent inflammatory responses.

5-LO is normally located in the cytoplasm under normal conditions, but when the cell is activated, the amount of Ca increases, and 5-LO moves from the cytoplasm to the nuclear membrane and binds to the 5-LO activating protein (FLAP) to bind the substrate, arachidonic acid, to leukotriene. To. It is known that leukotriene synthesized inside the nucleus expresses other genes, that is, LTB4 binds to PPAR alpha and activates expression of genes related to fat metabolism.

Leukotriene is a paracrine hormone that displays a variety of biological activities by specific G protein-coupled receptors (GPCRs) (Cell. Mol. Life Sci., 59, 742 (2002)). LTB4 primarily promotes migration to the site of inflammation as a potent chemoactic agent for inflammatory cells, neutrophils, macrophages and eosinophils. It also promotes penetration into tissues by facilitating adhesion to the endothelium and plays an important role in immune responses by promoting the secretion of inflammation-related cytokines of macrophages and lymphocytes. Cysteinyl-LTs (LTC4, D4, E4) are known as slow-reacting substance of anaphylaxis (SRSA) and are associated with acute hypersensitivity (Science, 220, 568 (1983)). ). It causes airway contraction by constrictor of smooth muscle (100-1000 times of histamine). In addition, it promotes mucous secretion, induces proliferation of bronchial smooth muscle, and constricts vascular endothelial cells to increase permeability of blood vessels, resulting in plasma ejection. Thus, leukotriene is an important mediator of various inflammation-related diseases, namely arthritis, asthma, enteritis, psoriasis and allergic rhinitis.

Therefore, by controlling LT synthesis process based on the induction of LTB4 and various biological activities of cysteinyl LT, it can be applied to the treatment of asthma, allergy and various inflammatory diseases, and several strategic approaches have been taken so far.

(1) 5-LO enzyme inhibition (direct inhibitors)

Oxidation / Reduction Inhibitors: Interfere with the redox cycle of 5-LO

<5-LO Oxidation / Reduction Inhibitor>

Representative antioxidants include pyrazoline derivatives, such as phenidone and BW-755C (see Trends Pharmacol. Sci., 13, 323 (1992)). This strongly inhibits 5-LO but has side effects and is not selective for 5-LO. In particular, it causes methemoglobin and genotoxicity. Currently docebenone and lonapalene have clinical effects on psoriasis and arthritis.

Iron-chelator

Hydroxamic acid and N-hydroxyurea derivatives were developed as representative compounds as iron-chelators, among which the first 5-LO inhibitor commercially available as zileuton was used as a treatment for asthma. (See J. Pharmacol. Exp. Ther., 256, 929 (1991)). However, this compound has hepatotoxicity, side effects of drug interactions have been reported and improved, and ABT-761 is currently in phase 3 clinical trials (see Eur. Respir. J., 11, 617 (1998)).

<5-LO Iron-chelator>

 Non-oxidative / reducing competitive inhibitors: compete with arachidonic acid, a substrate in the active site

Due to the side effects of 5-LO inhibitors based on iron-chelators and redox, 5-LO inhibitors have been developed that target active sites. ZD-2138 and L-697,198 with improved bioavailability, but are no longer in development due to pharmacokinetic problems (J. Med. Chem., 37, 512 (1994) and J. Med. Chem) , 39, 3951 (1996).

Non-oxidative / reduction competitive inhibitor of 5-LO

(2) FLAP inhibition (indirect inhibitors)

A strategy that targets FLAP, which is important for 5-LO activity rather than a direct inhibitor for 5-LO, has been introduced, MK-, a 5-LO inhibitor that inhibits cells but does not show inhibition in purely isolated 5-LO or in lysed cell eluates. 866 was first developed. Furthermore, MK-0591 and Bay-X-1005 are in clinical trials for asthma disease (see Farmaco, 57, 235 (2002)).

<FLAP inhibitor>

(3) LT receptor antagonists

LTB4 and cysteinyl LT synthesized in inflammatory cells react through receptors of various cells. To date, three drugs for receptor antagonists have been developed and marketed (see Neth. J. Med., 53, 176 (1998)), but these are effective for asthma but insufficient therapeutic effects for other inflammatory diseases. .

<Cysteinyl-LT Receptor Antagonist>

(4) Dual COX / 5-LO Inhibitors

Considering the proinflammatory effects of leukotriene and prostanoids, two synthetic mechanisms can be inhibited, minimizing the superior anti-inflammatory effects and the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors. The development of dual inhibitors is required. Indeed, COX inhibition by NSAIDs not only inhibits vasodilation and gastric protective prostaglandin synthesis, but also promotes arachidonic acid metabolism by 5-LO, increasing the synthesis of leukotriene, an proinflammatory agent. In addition, COX-2 and 5-LO play an important role in the progression of pancreas, lung, colon and prostate cancer, and dual inhibitors can be applied to the prevention and treatment of such diseases.

Lipofelone is a pyrrolizine strain that is in phase 3 clinical trials for the treatment of osteoarthritis and is known to have pain relief and asthma treatment in other inflammation models (Eur. J. Pharmacol. 453, 131 (2002)]. It has been reported to inhibit 5-LO and COX-1 but not cause damage to the gastrointestinal tract. While Compound (7) below selectively inhibits COX-2.

Dual COX / 5-LO Inhibitor

Based on this mechanism of action, new drug development was carried out using 5-LO, and the only commercially available JILUTON, which directly inhibits 5-LO, is a side effect of hepatotoxicity, interaction with other drugs, and rapid metabolism in vivo. Use has been restricted. Therefore, it is necessary to develop a drug that can selectively regulate 5-LO activity and minimize side effects.

Therefore, the present inventors continue to research to improve the side effects of the existing compounds and improve the pharmacokinetic properties in vivo as a result, the thiazole derivative effectively inhibits the activity of 5-LO asthma, The present invention was completed by confirming that it can be usefully used for the prevention or treatment of various inflammatory diseases such as chronic obstructive pulmonary disease, arthritis, psoriasis, atopic dermatitis, allergy, enteritis and cancer.

Accordingly, an object of the present invention by effectively inhibiting the activity of 5-lipoxygenase (5-lipoxygenase, 5-LO), various inflammatory diseases such as asthma, chronic obstructive pulmonary disease, arthritis, psoriasis, atopic dermatitis, allergy, enteritis And thiazole derivatives having a prophylactic or therapeutic effect on cancer, and methods for preparing the same.

Another object of the present invention to provide a pharmaceutical composition containing the compound as an active ingredient.

In order to achieve the above object, the present invention provides a thiazole derivative of Formula 1 and a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof:

Where

R ₁ and Each R ₂ is independently H, OR ₇ , NO ₂ , halogen, or C ₁ -C ₄ linear, branched or cyclic alkyl;

R ₃ , R ₄ , R ₅ and R ₆ are each independently H, CF ₃ , OR ₇ , CO ₂ R ₇ , NR ₇ R ₈ , NO ₂ , NHCOR ₇ , C (= O) R ₇ , SR ₇ , Halogen, C _{1 to} C ₄ linear, branched or cyclic alkyl,

Wherein R ₇ and R ₈ are each independently H, unsubstituted or F-substituted C _{1 to} C ₆ linear, branched or cyclic alkyl, aryl;

X is NH, O, S or SO ₂ ,

Y is C or N.

The present invention also provides a method for preparing the thiazole derivative of Chemical Formula 1.

The present invention also provides a pharmaceutical composition comprising the thiazole derivative of Formula 1 or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient.

In addition, the present invention provides an enzyme activity inhibitor of 5-lipoxygenase having the thiazole derivative of Formula 1 or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient.

Hereinafter, the present invention will be described in more detail.

Preferred compounds as thiazole derivatives of formula 1 according to the invention

1) 2-[(4-hydroxyphenyl) amino] -4- (4-bromophenyl) thiazole;

2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

3) 2-[(4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

4) 2-[(4-hydroxyphenyl) amino] -4- (4-nitrophenyl) thiazole;

5) 2-[(4-hydroxyphenyl) amino] -4- (3-chlorophenyl) thiazole;

6) 2-[(4-hydroxyphenyl) amino] -4- (3-methylphenyl) thiazole;

7) 2-[(4-hydroxyphenyl) amino] -4- (2-methylphenyl) thiazole;

8) 2-[(4-hydroxyphenyl) amino] -4- (2-fluorophenyl) thiazole;

9) 2-[(4-hydroxyphenyl) amino] -4- (3-fluorophenyl) thiazole;

10) 2-[(4-hydroxyphenyl) amino] -4- (2-methoxyphenyl) thiazole;

11) 2-[(4-hydroxyphenyl) amino] -4- (2,4-dichlorophenyl) thiazole;

12) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dichlorophenyl) thiazole;

13) 2-[(4-hydroxyphenyl) amino] -4- (3,4-dichlorophenyl) thiazole;

14) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dimethylphenyl) thiazole;

15) 2-[(4-hydroxyphenyl) amino] -4- (2,4-difluorophenyl) thiazole;

16) 2-[(4-hydroxyphenyl) amino] -4- (5-chloro-2-methoxyphenyl) thiazole;

17) 2-[(4-hydroxyphenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole;

18) 2-[(3-chloro-4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

19) 2-[(4-hydroxy-3-nitrophenyl) amino] -4- (4-chlorophenyl) thiazole;

20) 2-[(4-hydroxy-2-methylphenyl) amino] -4- (4-chlorophenyl) thiazole;

21) 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

22) 2-[(4-hydroxy-3,5-dimethylphenyl) amino] -4- (4-chlorophenyl) thiazole;

23) 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole;

24) 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4- (fluorophenyl) thiazole;

25) 2-[(2,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

27) 2-[(2,3,5-trimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

28) 2-[(2-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

29) 2-[(3-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

30) 2-[(2-hydroxy-4-methylphenyl) amino] -4- (4-chlorophenyl) thiazole;

31) 2-[[(4-acetamino) phenyl] amino] -4- (4-bromophenyl) thiazole;

32) 2-[[(4-acetamino) phenyl] amino] -4- (4-fluorophenyl) thiazole;

33) 2-[[(3-acetamino) phenyl] amino] -4- (4-chlorophenyl) thiazole;

34) 2-[[(3-acetamino) phenyl] amino] -4- (4-fluorophenyl) thiazole;

35) 2-[(4-aminophenyl) amino] -4- (4-bromophenyl) thiazole;

36) 2-[(4-aminophenyl) amino] -4- (4-chlorophenyl) thiazole;

37) 2-[(4-aminophenyl) amino] -4- (3-methylphenyl) thiazole;

38) 2-[(4-aminophenyl) amino] -4- (2-methylphenyl) thiazole;

39) 2-[(4-aminophenyl) amino] -4- (4-fluorophenyl) thiazole;

40) 2-[(4-aminophenyl) amino] -4- (4-nitrophenyl) thiazole;

41) 2-[(4-aminophenyl) amino] -4- (4-methoxyphenyl) thiazole;

42) 2-[(4-aminophenyl) amino] -4- (2-methoxyphenyl) thiazole;

43) 2-[(4-aminophenyl) amino] -4- (3,4-dichlorophenyl) thiazole;

44) 2-[(4-aminophenyl) amino] -4- (2,5-dichlorophenyl) thiazole;

45) 2-[(4-aminophenyl) amino] -4- (2,4-dichlorophenyl) thiazole;

46) 2-[(4-aminophenyl) amino] -4- (2,5-dimethylphenyl) thiazole;

47) 2-[(4-aminophenyl) amino] -4- (2,4-difluorophenyl) thiazole;

48) 2-[(4-aminophenyl) amino] -4-phenylthiazole;

49) 2-[(4-aminophenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole;

50) 2-[(2-aminophenyl) amino] -4- (4-chlorophenyl) thiazole;

51) 2-[(3-aminophenyl) amino] -4- (4-chlorophenyl) thiazole;

52) 2-[(3-aminophenyl) amino] -4- (4-fluorophenyl) thiazole;

53) 2-[(4-methoxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

54) 2-[(4-fluorophenyl) amino] -4- (4-chlorophenyl) thiazole;

55) 2-[[4-trifluoromethylphenyl] amino] -4- (4-chlorophenyl) thiazole;

56) 2-[[4-ethoxycarbonylphenyl] amino] -4- (4-chlorophenyl) thiazole;

57) 2-[[4-carboxyphenyl] amino] -4- (4-chlorophenyl) thiazole;

58) 2-[[4- (methylamino) phenyl] amino] -4- (4-chlorophenyl) thiazole;

59) 2-[[4- (methylamino) phenyl] amino] -4- (4-fluorophenyl) thiazole;

60) 2-[[4- (benzylamino) phenyl] amino] -4- (4-chlorophenyl) thiazole;

61) 2-[(2,3,5-trimethyl-4-methoxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

62) 2- [4-phenoxy] -4-phenylthiazole;

63) 2- [4-nitrophenoxy] -4-phenylthiazole;

64) 2- [4-pyridyloxy] -4-phenylthiazole;

65) 2-[(4-aminophenyl) thio] -4-phenylthiazole; or

66) 2-[(4-aminophenyl) sulfonyl] -4-phenylthiazole,

More preferably

1) 2-[(4-hydroxyphenyl) amino] -4- (4-bromophenyl) thiazole;

2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

3) 2-[(4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

4) 2-[(4-hydroxyphenyl) amino] -4- (4-nitrophenyl) thiazole;

5) 2-[(4-hydroxyphenyl) amino] -4- (3-chlorophenyl) thiazole;

6) 2-[(4-hydroxyphenyl) amino] -4- (3-methylphenyl) thiazole;

7) 2-[(4-hydroxyphenyl) amino] -4- (2-methylphenyl) thiazole;

8) 2-[(4-hydroxyphenyl) amino] -4- (2-fluorophenyl) thiazole;

9) 2-[(4-hydroxyphenyl) amino] -4- (3-fluorophenyl) thiazole;

10) 2-[(4-hydroxyphenyl) amino] -4- (2-methoxyphenyl) thiazole;

12) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dichlorophenyl) thiazole;

13) 2-[(4-hydroxyphenyl) amino] -4- (3,4-dichlorophenyl) thiazole;

14) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dimethylphenyl) thiazole;

15) 2-[(4-hydroxyphenyl) amino] -4- (2,4-difluorophenyl) thiazole;

16) 2-[(4-hydroxyphenyl) amino] -4- (5-chloro-2-methoxyphenyl) thiazole;

17) 2-[(4-hydroxyphenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole;

23) 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole;

24) 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4- (fluorophenyl) thiazole;

25) 2-[(2,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole;

30) 2-[(2-hydroxy-4-methylphenyl) amino] -4- (4-chlorophenyl) thiazole;

39) 2-[(4-aminophenyl) amino] -4- (4-fluorophenyl) thiazole;

40) 2-[(4-aminophenyl) amino] -4- (4-nitrophenyl) thiazole;

41) 2-[(4-aminophenyl) amino] -4- (4-methoxyphenyl) thiazole;

43) 2-[(4-aminophenyl) amino] -4- (3,4-dichlorophenyl) thiazole;

45) 2-[(4-aminophenyl) amino] -4- (2,4-dichlorophenyl) thiazole;

46) 2-[(4-aminophenyl) amino] -4- (2,5-dimethylphenyl) thiazole; And

47) 2-[(4-aminophenyl) amino] -4- (2,4-difluorophenyl) thiazole; or

50) 2-[(2-aminophenyl) amino] -4- (4-chlorophenyl) thiazole,

Even more preferably

2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole;

8) 2-[(4-hydroxyphenyl) amino] -4- (2-fluorophenyl) thiazole;

15) 2-[(4-hydroxyphenyl) amino] -4- (2,4-difluorophenyl) thiazole;

22) 2-[(4-hydroxy-3,5-dimethylphenyl) amino] -4- (4-chlorophenyl) thiazole;

23) 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole;

26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; or

27) 2-[(2,3,5-trimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole,

Even more preferably

2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; or

26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole.

The structural formulas of the compounds of the present invention are as shown in Table 1 below.

Pharmaceutically acceptable salts of the compounds of formula 1 according to the present invention may include acid addition salts formed with pharmaceutically acceptable free acids. Organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, metalsulfonic acid may be used as the organic acid. , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid and the like can be used, with methanesulfonic acid and hydrochloric acid being preferred.

Addition salt according to the present invention is a conventional method, that is, after dissolving the compound of formula 1 in a water miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an aqueous acid solution of an inorganic acid It can be prepared by precipitation or crystallization. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration. The thiazole derivative represented by Chemical Formula 1 of the present invention includes not only pharmaceutically acceptable salts thereof, but also all possible solvates and hydrates that can be prepared therefrom, and also includes all possible stereoisomers.

The present invention also provides a method for preparing the thiazole derivative of Chemical Formula 1.

1) Preparation of Compound of Formula 1a (X = NH)

In the present invention, a method for preparing a thiazole derivative when X in Formula 1 is NH includes a step of obtaining the following Formula 1a by reacting an acetophenone derivative of Formula 2 with an aniline derivative and a thiocyanate salt of Formula 3 below: do.

In the above formula, R _{One To} R _{6 It} is as defined in the formula (1).

When the manufacturing process of the compound of Formula 1a is illustrated as a reaction scheme, it may be represented as follows.

Wherein R ₁ to R ₆ and Y are the same as defined in Chemical Formula 1.

Specifically, in the reaction scheme, the compound of Formula 1a is dissolved in the solvent of the compound of Formula 2 and then reacted with an equivalent or excess of an aniline derivative and the thiocyanate salt of Formula 3 at room temperature to the boiling point of the solvent used for 1 hour to 24 hours. After diluting, the mixture may be diluted with an organic solvent such as ethyl acetate, dichloromethane, chloroform, or tetrahydrofuran, washed with water, dried, concentrated under reduced pressure, and separated and purified.

The acetophenone derivatives of formula (2) and the aniline derivatives of formula (3) used as starting materials in the process of the present invention may be prepared using commercially available compounds or by known methods (see Tetrahedron Lett, 42, 8947 (2001)). It can manufacture and use.

In addition, the thiocyanate salt used at this time is sodium thiocyanate, potassium thiocyanate, etc., and is used equivalent or excess.

In the reaction, the reaction solvent may be used alone or mixed with an alcohol solvent such as methanol or ethanol or an ether solvent such as tetrahydrofuran or dioxane.

2) Method of Preparation of Compound of Formula 1 (X = O, S or SO ₂ )

In the present invention, the preparation method of the thiazole derivative in the case of X = O, S or SO ₂ of the formula (1)

i) preparing a compound of formula 4 by heating and refluxing the acetophenone derivative of formula 2 with a thiocyanate salt in an organic solvent and then saturating with HCl gas; And

ii) reacting the compound of formula 4 with the compound of formula 5 in an organic solvent in the presence of a base to obtain formula 1.

Formula 1

Formula 2

In the above formulas, R ₁ to R ₆ and Y are as defined in Formula 1, and X is O, S or SO ₂ .

When the process for preparing the compound of Formula 1 (X = O, S or SO ₂ ) is shown as a reaction scheme, it may be represented as follows.

Wherein R ₁ to R ₆ and Y are as defined in Formula 1, and X is O, S or SO ₂ .

Specifically, the compound of Formula 2 is dissolved in an organic solvent and heated to reflux with a thiocyanate salt, and then saturated with HCl gas at 0 ° C. for 30 minutes to 1 hour, and then left at 0 ° C. for 10 hours to 24 hours. To obtain the compound of formula 4 as an intermediate.

The compound of Formula 4 was dissolved using an ether solvent such as tetrahydrofuran, dioxane, ditlo methane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, etc. alone or in combination. After the compound of Formula 5 and an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, DBU, or the like, such as NaOH, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ Reaction in the presence of, to obtain a compound of formula 1 (X = O, S or SO ₂ ) by separation and purification.

The thiocyanate salt used in the reaction includes sodium thiocyanate, potassium thiocyanate, and the like or an excess thereof.

The reaction solvent may be used alone or in combination with an alcohol solvent such as methanol or ethanol or an ether solvent such as tetrahydrofuran or dioxane.

For wherein X is SO ₂ in formula (I) compounds are prepared by adding the compound dissolved in thiophenyl thiazole derivatives wherein X is S of formula (I) in a solvent comprising the reaction with m -CPBA (m-chloroperbenzoic acid) can do. At this time, the solvent may include dichloromethane, chloroform, the reaction may be carried out for 1 hour to 24 hours at 0 ℃ to room temperature.

Thus prepared thiazole derivatives of Formula 1 and pharmaceutically acceptable salts, hydrates, solvates or isomers thereof of the present invention are 5-lye, an enzyme that acts when the arachidonic acid is converted to a leukotriene metabolite. It can be usefully used as an inhibitor of enzymatic activity of foxy genease.

In addition, the present invention is an asthma, chronic obstructive pulmonary disease, arthritis, psoriasis, atopic dermatitis, allergic to the thiazole derivative represented by the formula (1) and a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient It provides a pharmaceutical composition for the prevention and treatment of various inflammatory diseases and cancer, such as enteritis.

The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. It is manufactured by. Solid form preparations for oral administration may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose or gelatin with the compound of the present invention. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, 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, Utopepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to the judgment of a doctor or a pharmacist.

Hereinafter, the present invention will be described in more detail with reference to 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>

In the present invention, the molecular structure of the prepared compounds was confirmed by comparison between calculated values and measured values by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement, and elemental analysis.

Example 1: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (4-bromophenyl) thiazole

Dissolve 0.50 g (1.80 mmol) of 2-bromo-4'-bromoacetophenone as a compound of formula 2 in 10 ml of ethanol, and 0.19 g (2.34 mmol) of sodium thiocyanate and 0.22 g of p -aminophenol as a compound of formula 3 (2.39 mmol) was added at room temperature and then heated to reflux for 3 hours. After the reaction was completed, the reaction solution was diluted with 10 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and recrystallized with a methylene chloride solvent to obtain the target compound (0.3 g, 48% yield).

¹ H NMR (DMSO, 300Mhz): δ 6.54 (d, 2H), 7.39 (d, 2H), 7.55 (s, 1H), 8.06 (d, 2H), 8.20 (d, 2H), 9.09 (s, 1H ), 9.97 (s, 1 H)

MS (m / e) M ⁺ 348 (Br ⁸¹ ), 346 (Br ⁷⁹ )

Example 2: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole

Dissolve 0.50 g (2.14 mmol) of 2-bromo-4'-chloroacetophenone as a compound of formula 2 in 10 ml of ethanol, and 0.23 g (2.84 mmol) of sodium thiocyanate and 0.26 g of p -aminophenol as a compound of formula 3 ( 2.39 mmol) was added at room temperature and then heated to reflux for 12 hours. After the reaction was completed, the reaction solution was diluted with 10 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and separated and purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1). Compound (0.45 g, 69% yield) was obtained.

¹ H NMR (300 MHz, DMSO): δ 6.74 (d, 2H), 7.28 (s, 1H), 7.45 (dd, 4H), 7.89 (d, 2H), 9.12 (s, 1H), 9.92 (s, 1H)

MS (m / e) M ⁺ 303

Example 3: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole

2-Bromo-4'-fluoroacetophenone was used as the compound of formula 2 to obtain the target compound (0.49 g, 62% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.76 (d, 2H), 7.19-7.27 (m, 3H), 7.48 (d, 2H), 7.90-7.95 (m, 2H), 9.13 (s, 1H) , 9.90 (s, 1H)

MS (m / e) M ⁺ 286, 166, 152, 134, 120

Example 4: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (4-nitrophenyl) thiazole

2-Bromo-4'-nitroacetophenone was used as the compound of formula 2 to obtain the target compound (0.32 g, 83% yield) under the same methods and conditions as in Example 1.

¹ H NMR (DMSO, 300 Mhz): δ 6.68 (d, 2H), 7.39 (d, 2H), 7.55 (s, 1H), 8.06 (d, 2H), 8.20 (d, 2H), 9.09 (s, 1H), 9.97 (s, 1H)

MS (m / e) M ⁺ : 313 (M +), 267

Example 5: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (3-chlorophenyl) thiazole

2-Bromo-3'-chloroacetophenone was used as the compound of formula 2 to obtain the target compound (0.21 g, 61% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.75 (d, 2H), 7.35-7.37 (m, 2H), 7.42-7.45 (m, 3H), 7.84 (d, 1H), 7.90 (d, 1H) , 9.17 (s, 1H), 9.94 (s, 1H)

MS (m / e) M ⁺ 302, 168, 133, 89, 65

Example 6: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (3-methylphenyl) thiazole

2-Bromo-3'-methylacetophenone was used as the compound of formula 2 to obtain the target compound (0.21 g, 68% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.08 (s, 3H), 6.75 (d, 2H), 7.11 (d, 1H), 7.30 (t, 1H), 7.45 (d, 2H), 7.68 (d , 2H), 9.11 (s, 1H), 9.88 (s, 1H)

MS (m / e) M ⁺ 282, 150, 108, 84, 57

Example 7: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (2-methylphenyl) thiazole

2-Bromo-2'-methylacetophenone was used as the compound of formula 2 to obtain the target compound (0.19 g, 65% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.44 (s, 3H), 6.72 (d, 2H), 6.81 (s, 1H), 7.21-7.24 (m, 3H), 7.43 (d, 2H), 7.59 (t, 1H), 9.19 (s, 1H), 9.83 (s, 1H)

MS (m / e) M ⁺ 282, 147, 131, 63

Example 8: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (2-fluorophenyl) thiazole

2-Bromo-2'-fluoroacetophenone was used as the compound of formula 2 to obtain the target compound (0.12 g, 17% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.74 (d, 2H), 7.13 (d, 1H), 7.23-7.36 (m, 3H), 7.45 (d, 2H), 8.09 (t, 1H), 9.16 (s, 1 H), 9.93 (s, 1 H)

MS (m / e) M ⁺ 286, 166, 152, 120, 109

Example 9: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (3-fluorophenyl) thiazole

2-Bromo-3'-fluoroacetophenone was used as the compound of formula 2 to obtain the target compound (0.20 g, 46% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 6.74 (d, 2H), 7.11 (t, 1H), 7.34 (s, 1H), 7.45 (m, 3H), 7.64 (d, 1H), 7.72 (d , 1H), 9.14 (s, 1H), 9.93 (s, 1H)

MS (m / e) M ⁺ 286, 166, 152, 134, 120

Example 10 Preparation of 2-[(4-hydroxyphenyl) amino] -4- (2-methoxyphenyl) thiazole

2-Bromo-2'-methoxyacetophenone was used as the compound of formula 2 to obtain the target compound (0.23 g, 79% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.83 (s, 3H), 6.58 (d, 2H), 6.85-6.94 (m, 2H), 7.09-7.14 (m, 2H), 7.29 (d, 2H) , 7.95 (d, 1H), 8.95 (s, 1H), 9.65 (s, 1H),

MS (m / e) M ⁺ 298, 164, 131, 121, 109, 77

Example 11: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (2,4-dichlorophenyl) thiazole

2-Bromo-2 ', 4'-dichloroacetophenone was used as the compound of formula 2 to obtain the target compound (0.36 g, 55% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.76 (d, 2H), 7.19-7.27 (m, 3H), 7.48 (d, 2H), 7.90-7.95 (m, 2H), 9.13 (s, 1H) , 9.90 (s, 1H)

MS (m / e) M ⁺ 336, 301, 202, 166, 134, 123, 65

Example 12 Preparation of 2-[(4-hydroxyphenyl) amino] -4- (2,5-dichlorophenyl) thiazole

2-Bromo-2 ', 5'-dichloroacetophenone was used as the compound of formula 2 to obtain the target compound (0.05 g, 47% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 6.73 (d, 2H), 7.36-7.42 (m, 3H), 7.56 (d, 1H), 7.93 (d, 1H), 9.19 (s, 1H), 9.95 (s, 1H)

MS (m / e) M ⁺ 336, 301, 202, 166, 134, 123

Example 13: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (3,4-dichlorophenyl) thiazole

2-Bromo-3 ', 4'-dichloroacetophenone was used as the compound of formula 2 to obtain the target compound (0.08 g, 68% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 6.75 (d, 2H), 7.42 (d, 3H), 7.66 (d, 1H), 7.86 (d, 1H), 8.08 (d, 1H), 9.16 (s , 1H), 9.96 (s, 1H)

MS (m / e) M ⁺ 336, 202, 166, 134, 120

Example 14 Preparation of 2-[(4-hydroxyphenyl) amino] -4- (2,5-dimethylphenyl) thiazole

2-Bromo-2 ', 5'-dichloroacetophenone was used as the compound of formula 2 to obtain the target compound (0.12 g, 72% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.30 (s, 3H), 2.40 (s, 3H), 6.71-6.80 (m, 3H), 7.03-7.15 (m, 2H), 7.40-7.43 (m, 3H), 9.08 (s, 1H), 9.84 (s, 1H)

MS (m / e) M ⁺ 296, 153, 77, 65

Example 15 Preparation of 2-[(4-hydroxyphenyl) amino] -4- (2,4-difluorophenyl) thiazole

2-Bromo-2 ', 4'-difluoroacetophenone was used as the compound of formula 2 to obtain the target compound (0.20 g, 62% yield) under the same methods and conditions as in Example 2.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 6.72 (d, 2H), 7.11 (s, 1H), 7.20 (t, 1H), 7.37 (t, 1H), 7.47 (d, 2H), 8.11 (q , 1H), 9.15 (s, 1H), 9.94 (s, 1H)

MS (m / e) M ⁺ 304, 170, 140, 127

Example 16: Preparation of 2-[(4-hydroxyphenyl) amino] -4- (3-chloro-6-methoxyphenyl) thiazole

2-Bromo-3'-chloro-6'-methoxyacetophenone was used as the compound of formula 2 to obtain the target compound (0.18 g, 47% yield) under the same methods and conditions as in Example 2.

¹ HNMR (300MHz, DMSO-d ₆ ): δ 3.92 (s, 3H), 6.75 (d, 2H), 7.12 (d, 1H), 7.31 (m, 4H), 8.06 (s, 1H), 9.15 (s , 1H), 9.86 (s, 1H)

MS (m / e) M ⁺ 332

Example 17 Preparation of 2-[(4-hydroxyphenyl) amino] -4- (3-fluoro-6-methoxyphenyl) thiazole

2-bromo-3'-fluoro-6'-methoxyacetophenone was used as the compound of formula 2 to obtain the target compound (0.25 g, 64% yield) under the same method and conditions as in Example 2.

¹ H NMR (300 MHz, DMSO): 3.91 (s, 3H), 6.75 (d, 2H), 7.10 (d, 1H), 7.40 (s, 1H), 7.42 (d, 2H), 7.81 (d, 1H) , 9.12 (s, 1H), 9.86 (s, 1H)

MS (m / e) M ⁺ 316

Example 18 Preparation of 2-[(3-chloro-4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole

Using 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 4-amino-2-chlorophenol as the compound of formula 3, the target compound (0.15 g, 52% yield).

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 6.96 (d, J = 8.7 Hz, 1H), 7.36-7.43 (m, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.79 (d , J = 2.7 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 9.79 (s, 1H), 10.13 (s, 1H).

MS (m / e) M ⁺ 337

Example 19 Preparation of 2-[(4-hydroxy-3-nitrophenyl) amino] -4- (4-chlorophenyl) thiazole

2-Bromo-4'-chloroacetophenone as the compound of Formula 2 and 4-amino-2-nitrophenol as the compound of Formula 3 were used in the same manner and in the same manner as in Example 2 to obtain the target compound (0.39 g, 52% yield).

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 6.93 (d, J = 9.0 Hz, 1H), 7.22-7.29 (m, 2H), 7.4 (dd, J = 8.7, 2.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 8.45 (d, J = 2.7 Hz, 1H), 10.22 (s, 1H), 10.36 (s, 1H).

MS (m / e) M ⁺ 348

Example 20 Preparation of 2-[(4-hydroxy-2-methylphenyl) amino] -4- (4-chlorophenyl) thiazole

Using 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 4-amino-3-methylphenol as the compound of formula 3, the target compound (0.49 g, 72% yield).

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.25 (s, 3H), 6.67 (s, 1H), 6.67-6.77 (m, 2H), 7.28-7.35 (m, 4H), 7.72 (d, J = 8.4 Hz, 2H).

MS (m / e) M ⁺ 317

Example 21 Preparation of 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole

2-Bromo-4'-chloroacetophenone as the compound of Formula 2 and 4-amino-2,6-dichlorophenol as the compound of Formula 3 were used to obtain the target compound (0.21). g, 40% yield).

¹ H NMR (300 MHz, DMSO): δ 7.44 (s, 1 H), 7.50 (d, 2 H), 7.68 (s, 2 H), 9.71 (br, 1 H), 10.33 (s, 1 H)

MS (m / e) M ⁺ 371

Example 22 Preparation of 2-[(4-hydroxy-3,5-dimethylphenyl) amino] -4- (4-chlorophenyl) thiazole

By using 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 4-amino-2,6-dimethylphenol as the compound of formula 3, the target compound (0.31) was prepared. g, 72% yield).

¹ H NMR (300 MHz, CDCl ₃ ); δ = 2.26 (s, 6H), 7.29 (s, 1H), 7.36 (S, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.00 (s, 1H), 9.91 (s, 1H)

MS (m / e) M ⁺ 331

Example 23 Preparation of 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole

By using 2-bromo-4'-fluoroacetophenone as the compound of formula 2 and 4-amino-2-chloro-6-methylphenol as the compound of formula 3, Compound (0.27 g, 39% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.25 (s, 3H), 4.68 (s, 1H), 6.67 (s, 1H), 6.95-6.96 (m, 1H), 7.02-7.29 (m, 4H) , 7.74-7.79 (m, 2H), 7.97 (d, J = 3.6 Hz, 1H)

MS (m / e) M ⁺ 334, 214, 182, 123

Example 24 Preparation of 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4- (fluorophenyl) thiazole

By using 2-bromo-4'-fluoroacetophenone as the compound of Formula 2 and 4-amino-2,6-dichlorophenol as the compound of Formula 3, the target compound ( 0.11 g, 31% yield).

¹ H NMR (300 MHz.DMSO): δ 7.15 (s, 1 H), 7.20 (t, 1 H), 7.69 (s, 2 H), 7.83 (m, 2 H), 12.1 (br, NH)

MS (m / e) M ⁺ 354

Example 25 Preparation of 2-[(2,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole

By using 2-bromo-4'-fluoroacetophenone as the compound of Formula 2 and 4-amino-2,5-dimethylphenol as the compound of Formula 3, the target compound ( 0.11 g, 52% yield).

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.18 (s, 3H), 2.21 (s, 3H), 6.62 (s, 1H), 6.72 (s, 1H), 7.04 (t, J = 8.7 Hz, 2H ), 7.15 (s, 1H), 7.67 (brs, 1H), 7.75-7.80 (m, 2H), 8.55 (brs, 1H)

MS (m / e) M ⁺ 314, 299, 281, 152

Example 26 Preparation of 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole

By using 2-bromo-4'-fluoroacetophenone as the compound of formula 2 and 4-amino-2,6-dimethylphenol as the compound of formula 3, the target compound ( 0.47 g, 65% yield).

¹ H NMR (300 MHz. CDCl ₃ ): δ 2.26 (s, 6H), 6.63 (s, 1H), 6.99 (s, 2H), 7.04 (t, 2H), 7.76 (m, 2H)

MS (m / e) M ⁺ 314

Example 27 Preparation of 2-[(2,3,5-trimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole

By using 2-bromo-4'-fluoroacetophenone as the compound of formula 2 and 4-amino-2,3,5-trimethylphenol as the compound of formula 3, Compound (0.33 g, 73% yield) was obtained.

¹ H NMR (300Mhz, CDCl ₃ ): δ2.22 (s, 6H), 2.24 (s, 3H), 6.59 (s, 1H), 7.02 (m, 3H), 7.73 (m, 2H)

MS (m / e) M ⁺ 328

Example 28 Preparation of 2-[(2-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole

Using the 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 2-aminophenol as the compound of formula 3, the target compound (0.27 g, 42% yield) was prepared in the same manner and in the same manner as in Example 1. Got.

¹ H NMR (300 MHz, DMSO); δ = 6.63 (t, 3H), 7.33 (t, 1H), 7.46 (d, 1H), 7.49 (s, 1H), 7.89 (d, 1H), 7.92 (s, 1H), 8.26 (t, 1H) , 9.50 (s, 1H), 9.89 (d, 1H)

MS (m / e) M ⁺ 304, 302, 285

Example 29 Preparation of 2-[(3-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole

Using the 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 3-aminophenol as the compound of formula 3, the target compound (0.52 g, 80% yield) was prepared in the same manner and in the same manner as in Example 2. Got.

¹ H NMR (300 MHz, DMSO); delta = 6.37 (dd, 1H), 7.01 (m, 2H), 7.32 (s, 1H), 7.39 (s, 1H), 7.48 (d, 2H), 7.95 (d, 2H), 9.43 (s, 1H) , 10.17 (s, 1H)

MS (m / e) M ⁺ 304, 302, 285

Example 30 Preparation of 2-[(2-hydroxy-4-methylphenyl) amino] -4- (4-chlorophenyl) thiazole

Using 2-bromo-4'-chloroacetophenone as the compound of Formula 2 and 2-amino-5-methylphenol as the compound of Formula 3, the target compound (0.32 g, 80% yield).

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 2.16 (s, 3H), 6.58 (d, 1H), 6.65 (s, 1H) 7.24 (s, 1H), 7.40 (d, 2H), 7.82 (d, 2H), 8.09 (d, 1H) 9.34 (s, 1H), 9.74 (s, 1H)

MS (m / e) M ⁺ 316, 299, 283, 179

Example 31 Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (4-bromophenyl) thiazole

By using 2-bromo-4'-bromoacetophenone as the compound of Formula 2 and p -aminoacetanilide as the compound of Formula 3, the target compound (0.33 g, 76 % Yield).

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 2.03 (s, 3H), 7.38 (s, 1H), 7.52-7.63 (m, 6H), 7.87 (d, 2H), 9.84 (s, 1H) , 10.19 (s, 1H)

MS (m / e) M ⁺ 388, 347

Example 32 Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (4-fluorophenyl) thiazole

Using the 2-bromo-4'-fluoroacetophenone as the compound of Formula 2 and p -aminoacetanilide as the compound of Formula 3, the target compound (0.38 g, 58 % Yield).

¹ H NMR (DMSO, 300 Mhz); δ 2.08 (s, 3H), 7.28 (m, 3H), 7.58 (d, 2H), 7.66 (d, 2H), 7.99 (dd, 1H), 9.89 (s, 1H), 10.22 (s, 1H)

MS (m / e) M ⁺ 327, 285

Example 33 Preparation of 2-[[(3-acetamino) phenyl] amino] -4- (4-chlorophenyl) thiazole

2-Bromo-4'-chloroacetophenone as the compound of Formula 2 and m -aminoacetanilide as the compound of Formula 3 were used to obtain the target compound (0.47 g, 63%). Yield).

¹ H NMR (300MHz, DMSO): δ 2.07 (s, 3H), 7.06 (d, 1H), 7.21 (t, 1H), 7.40 (s, 1H), 7.43 (m, 3H), 7.99 (d, 2H ), 8.02 (s, 1H), 9.93 (s, 1H), 10.30 (s, 1H)

MS (m / e) M ⁺ 343, 328

Example 34 Preparation of 2-[[(3-acetamino) phenyl] amino] -4- (4-fluorophenyl) thiazole

2-Bromo-4'-fluoroacetophenone as a compound of Formula 2 and m-aminoacetanilide as a compound of Formula 3 were used to obtain the target compound (1.53 g, 57). % Yield).

¹ H NMR (300MHz, DMSO): δ 2.06 (s, 3H), 7.06 (d, 1H), 7.21 (m, 4H), 7.44 (d, 1H), 8.00 (m, 2H), 8.13 (s, 1H ), 9.92 (s, 1H), 10.26 (s, 1H)

MS (m / e) M ⁺ 327, 312

Example 35 Preparation of 2-[(4-aminophenyl) amino] -4- (4-bromophenyl) thiazole

0.20 g (0.52 mmol) compound obtained in Example 31 was added to 1-2 ml of 8N hydrochloric acid at room temperature, and the mixture was heated to reflux for 5 hours. After the reaction was completed, the reaction solution was basified with 6N sodium hydroxide, washed with 10 ml of ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated using silica gel column chromatography (hexane: ethyl acetate = 2: 1). Purification gave the target compound (0.16 g, 92% yield).

¹ H NMR (300 MHz, DMSO): δ 4.86 (br, 2H), 6.57 (d, 2H, J = 8.6 Hz), 7.26 (dd, 3H, J = 8.6 Hz), 7.59 (d, 2H, J = 8.4 Hz), 7.82 (d, 2H, J = 8.4 Hz), 9.70 (s, 1H)

MS (m / e) M ⁺ 346, 164

Example 36 Preparation of 2-[(4-aminophenyl) amino] -4- (4-chlorophenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (4-chlorophenyl) thiazole

2-Bromo-4'-chloroacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3 were used to obtain the target compound (0.24 g, 55%). Yield).

¹ H NMR (300 MHz, DMSO): δ 1.85 (s, 3H), 7.19 (s, 1H), 7.29 (t, 1H), 7.75 (d, 2H), 9.66 (s, 1H), 10.02 (s, 1H )

MS (m / e) M ⁺ 344

Step 2) Preparation of 2-[(4-aminophenyl] amino] -4- (4-chlorophenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.03 g, 85% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO): δ 4.89 (br, 2H), 6.56 (d, 2H), 7.22 (s, 1H), 7.29 (d, 2H), 7.45 (d, 2H), 7.87 (d, 2H ), 9.70 (s, 1 H)

MS (m / e) M ⁺ 303, 301

Example 37 Preparation of 2-[(4-aminophenyl) amino] -4- (3-methylphenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (3-methylphenyl) thiazole

2-Bromo-3'-methylacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3 were used to obtain the target compound (0.15 g, 46%). Yield).

¹ H NMR (300 MHz, DMSO): δ 2.03 (s, 3H), 2.37 (s, 3H), 7.12 (d, 1H), 7.26-7.34 (m, 6H), 9.84 (s, 1H), 10.16 (s , 1H)

MS (m / e) M ⁺ 323, 281

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (3-methylphenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.08 g, 88% yield) was obtained under the same methods and conditions as in Example 35.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.25 (s, 3H), 4.76 (brs, 2H), 6.47 (d, 2H), 6.99-7.01 (m, 2H), 7.16-7.21 (m, 3H) , 7.55-7.58 (m, 2H), 9.55 (s, 1H)

MS (m / e) M ⁺ 281, 147, 133, 118

Example 38 Preparation of 2-[(4-aminophenyl) amino] -4- (2-methylphenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (2-methylphenyl) thiazole

2-Bromo-2'-methylacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3 were used to obtain the target compound (0.16 g, 55%). Yield).

¹ H NMR (300 MHz, DMSO): δ 2.01 (s, 3H), 2.47 (s, 3H), 6.92 (s, 1H),

6.81 (s, 1H), 7.24 ~ 7.27 (m, 3H), 7.49 ~ 7.64 (m, 5H) 9.82 (s, 1H), 10.13 (s, 1H)

MS (m / e) M ⁺ 323, 280

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (2-methylphenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.07 g, 70% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 2.45 (s, 3H), 4.80 (brs, 2H), 6.54 (d, 2H), 6.76 (s, 1H), 7.21-7.27 (m, 5H), 7.59 (t, 1H), 9.62 (s, 1H )

MS (m / e) M ⁺ 281, 150, 131, 115

Example 39 Preparation of 2-[(4-aminophenyl) amino] -4- (4-fluorophenyl) thiazole

Using the compound obtained in Example 32, the target compound (0.19 g, 96% yield) was obtained in the same manner as the Example 35.

¹ H NMR (DMSO, 300 Mhz); δ 4.90 (br, 2H), 6.56 (d, 2H), 7.13 (s, 1H), 7.20 (dd, 4H), 7.88 (dd, 2H), 9.68 (s, 1H)

MS (m / e) M ⁺ 285

Example 40 Preparation of 2-[(4-aminophenyl) amino] -4- (4-nitrophenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (4-nitrophenyl) thiazole

2-Bromo-4'-nitroacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3 were used to obtain the target compound (0.22 g, 76%). Yield).

¹ H NMR (300 MHz, DMSO): δ 2.04 (s, 3H), 7.55 to 7.71 (m, 5H), 8.17 to 8.32 (m, 4H), 9.75 (s, 3H), 10.31 (s, 1H),

MS (m / e) M ⁺ 354

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (4-nitrophenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.09 g, 98% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 4.67 (brs, 2H), 6.36 (d, 2H), 7.05 (d, 2H), 7.31 (s, 1H), 7.89 (d, 2H), 8.04 (d, 2H), 9.59 (s, 1H)

MS (m / e) M ⁺ 312, 266, 133, 107, 89

Example 41 Preparation of 2-[(4-aminophenyl) amino] -4- (4-methoxyphenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (4-methoxyphenyl) thiazole

By using 2-bromo-4'-methoxyacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3, the target compound (0.31 g, 30) was prepared in the same manner and in the same manner as in Example 2. % Yield).

¹ H NMR (300 MHz, DMSO): δ 1.90 (s, 3H), 3.67 (s, 3H), 6.80 to 6.66 (d, 2H), 7.00 (s, 1H), 7.40 (d, 2H), 7.50 (d , 2H), 7.72 (d, 2H), 9.72 (s, 1H), 10.01 (s, 1H)

MS (m / e) M ⁺ 339, 297

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (4-methoxyphenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.05 g, 50% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 3.79 (s, 3H), 4.83 (brs, 2H), 6.57 (d, 2H), 6.96-6.98 (m, 3H), 7.27 (d, 2H), 7.80 (d, 2H), 9.62 (s, 1H )

MS (m / e) M ⁺ 297, 150, 133

Example 42 Preparation of 2-[(4-aminophenyl) amino] -4- (2-methoxyphenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (2-methoxyphenyl) thiazole

By using 2-bromo-2'-methoxyacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3, the target compound (0.13 g, 40 % Yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.05s, 3H), 3.95 (s, 3H), 7.07-7.15 (m, 2H), 7.30-7.39 (m, 2H), 7.55-7.73 (m, 4H ), 8.17 (d, 1H), 9.86 (s, 1H), 10.12 (s, 1H)

Mass (m / e) M ⁺ 339 , 296, 164, 131, 121

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (2-methoxyphenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.06 g, 70% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 3.91 (s, 3H), 4.84 (brs, 2H), 6.57 (d, 2H), 7.01-7.11 (m, 2H), 7.21-7.31 (m, 4H), 8.10 (d, 2H), 9.59 (s , 1H)

MS (m / e) M ⁺ 297, 150, 133, 107, 65

Example 43 Preparation of 2-[(4-aminophenyl) amino] -4- (3 ', 4'-dichlorophenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (3 ', 4'-dichlorophenyl) thiazole

Using the 2-bromo-3 ', 4'-dichloroacetophenone as the compound of formula 2 and p-aminoacetanilide as the compound of formula 3, the target compound (0.16 g) , 55% yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 1.92 (s, 3H), 7.41 (m, 6H), 7.79 (d, 1H), 8.01 (s, 1H), 9.75 (s, 1H), 10.13 (s , 1H)

Mass (m / e) M ⁺ 377 , 335, 133, 118

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (3,4-dichlorophenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.43 g, 97% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 4.86 (brs, 2H), 6.57 (d, 2H), 7.26 (d, 2H), 7.37 (s, 1H), 7.66 (d, 1H), 7.85 (d, 1H), 8.07 (s, 1H) , 9.74 (s, 1H)

MS (m / e) M ⁺ 335, 165, 133, 118, 107, 65

Example 44 Preparation of 2-[(4-aminophenyl) amino] -4- (2 ', 5'-dichlorophenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (2 ', 5'-dichlorophenyl) thiazole

Using the 2-bromo-2 ', 5'-dichloroacetophenone as the compound of formula 2 and p-aminoacetanilide as the compound of formula 3, the target compound (0.16 g) was prepared. , 55% yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.02 (s, 3H), 7.39-7.46 (m, 2H), 7.50-7.70 (m, 5H), 8.46 (s, 1H), 9.85 (s, 1H) , 10.23 (s, 1H)

Mass (m / e) M ⁺ 377 , 335, 133, 118

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (2 ', 5'-dichlorophenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.04 g, 95% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 4.87 (brs, 2H), 6.56 (d, 2H), 7.22 (d, 2H), 7.33 (s, 1H), 7.56 (d, 1H), 7.95 (d, 1H), 9.73 (s, 1H)

MS (m / e) M ⁺ 335, 165, 133, 118, 107, 65

Example 45 Preparation of 2-[(4-aminophenyl) amino] -4- (2 ', 4'-dichlorophenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (2 ', 4'-dichlorophenyl) thiazole

2-bromo-2 ', 4'-dichloroacetophenone as the compound of formula (2) and p-aminoacetanilide as the compound of formula (3) using the same methods and conditions as in Example 2 (0.32 g) , 32% yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 1.99 (s, 3H), 7.38 (s, 1H), 7.50-7.60 (m, 5H), 7.69 (d, 1H), 7.98 (d, 1H), 9.84 (s, 1H), 10.12 (s, 1H)

Mass (m / e) M ⁺ 377, 335, 133, 107

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (2,4-dichlorophenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.05 g, 25% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ4.85 (s, 2H), 6.55 (d, 2H), 7.24 (d, 3H), 7.50 (d, 1H), 7.67 (s, 1H), 7.93 (d, 1H), 9.71 (s, 1H)

MS (m / e) M ⁺ 335, 165, 133, 118, 107, 65

Example 46 Preparation of 2-[(4-aminophenyl) amino] -4- (2 ', 5'-dimethylphenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (2 ', 5'-dimethylphenyl) thiazole

2-Bromo-2 ', 5'-dimethylacetophenone as the compound of formula (2) and p-aminoacetanilide as the compound of formula (3) using the same methods and conditions as in Example 2 , 32% yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.31 (s, 3H), 2.41 (s, 3H), 6.88 (s, 1H), 7.05 (d, 1H), 7.15 (d, 1H), 7.41 (s , 1H), 7.49 (d, 2H), 7.56 (d, 2H), 9.80 (s, 1H), 10.10 (s, 1H)

Mass (m / e) M ⁺ 337 , 294, 130, 108, 77, 43

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (2,5-dimethylphenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.03 g, 85% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 2.30 (s, 3H), 2.40 (s, 3H), 4.82 (brs, 2H), 6.54 (d, 2H), 6.74 (s, 1H), 7.03-7.26 (m, 4H), 7.41 (s, 1H ), 9.60 (s, 1 H)

MS (m / e) M ⁺ 295, 150, 128, 108, 77

Example 47 Preparation of 2-[(4-aminophenyl) amino] -4- (2 ', 4'-difluorophenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (2 ', 4'-difluorophenyl) thiazole

By using 2-bromo-2 ', 4'-difluoroacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3, the target compound ( 0.25 g, 55% yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.03 (s, 3H), 7.22 (t, 2H), 7.34 (t, 1H), 7.57 (q, 4H), 8.15 (q, 1H), 9.85 (s , 1H), 10.22 (s, 1H)

Mass (m / e) M ⁺ 345 , 303, 170, 133

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (2 ', 4'-difluorophenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.12 g, 97% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 4.86 (s, 2H), 6.57 (d, 2H), 7.16-7.36 (m, 4H), 8.08 (q, 1H), 9.72 (s, 1H)

MS (m / e) M ⁺ 303, 170, 133, 118, 65

Example 48 Preparation of 2-[(4-aminophenyl) amino] -4-phenylthiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4-phenylthiazole

2-Bromoacetophenone was used as the compound of Formula 2 and p-aminoacetanilide was used as the compound of Formula 3 to obtain the target compound (0.19 g, 60% yield) under the same method and conditions as in Example 2.

NMR (300MHz, DMSO): δ2.02 (s, 3H), 7.28 (t, 2H), 7.39 (t, 2H), 7.51 (d, 2H), 7.61 (d, 2H), 7.89 (d, 2H) , 9.83 (s, 1H), 10.16 (s, 1H)

Mass (m / e) M ⁺ 309

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4-phenylthiazole

Using the compound obtained in Step 1, the target compound (0.08 g, 79% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO): δ 4.94 (br, 2H), 6.59 (d, 2H), 7.17 (s, 1H), 7.30 (d, 3H), 7.40 (t, 2H), 7.88 (d, 2H ), 9.69 (s, 1 H)

MS (m / e) M ⁺ 267

Example 49 Preparation of 2-[(4-aminophenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole

Step 1) Preparation of 2-[[(4-acetamino) phenyl] amino] -4- (5-fluoro-2-methoxyphenyl) thiazole

By using 2-bromo-5-fluoro-2-methoxyacetophenone as the compound of Formula 2 and p-aminoacetanilide as the compound of Formula 3, the target compound ( 0.46 g, 64% yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.03 (s, 3H), 3.92 (s, 3H), 7.12 (d, 2H), 7.47 (s, 1H), 7.56 (q, 4H), 7.85 (d , 1H), 9.84 (s, 1H), 10.14 (s, 1H)

Mass (m / e) M ⁺ 357 , 314, 149, 107, 43

Step 2) Preparation of 2-[(4-aminophenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.14 g, 77% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 3.91 (s, 3H), 4.87 (brs, 2H), 6.58 (d, 2H, J = 8.5 μs), 7.10 (d, 2H, J = 6.2 μs), 7.25 (d, 2H, J = 8.5 μs) , 7.34 (s, 1H), 7.81 (d, 1H, J = 10.3 μs), 9.63 (s, 1H)

MS (m / e) M ⁺ 315, 133, 107, 55, 40

Example 50 Preparation of 2-[(2-amino) phenylamino] -4- (4-chlorophenyl) thiazole

Step 1) Preparation of 2-[[(2-acetamino) phenyl] amino] -4- (4-chlorophenyl) thiazole

Using the 2-bromo-4-chloroacetophenone as the compound of formula 2 and O-aminoacetanilide as the compound of formula 3, the target compound (0.46 g, 64% yield) was prepared in the same manner and in the same manner as in Example 2. )

¹ H NMR (300 MHz, DMSO): δ 2.07 (s, 3H), 7.03 (t, 1H), 7.19 (T, 1H), 7.39 (S, 1H), 7.44 (t, 3H), 7.89 (d, 2H ), 8.12 (d, 1H), 9.38 (s, 1H)

MS (m / e) M ⁺ 343, 325

Step 2) Preparation of 2-[(2-amino) phenylamino] -4- (4-chlorophenyl) thiazole

Using the compound obtained in Step 1, the target compound (0.03 g, 55% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300MHz, DMSO): δ 5.00 (s, NH2), 6.61 (t, 1H), 6.75 (d, 1H), 6.91 (t, 1H), 7.25 (s, 1H), 7.44 (d, 2H ), 7.50 (d, 1H), 7.85 (d, 1H), 9.11 (s, 1H)

MS (m / e) M ⁺ 301, 268

Example 51 Preparation of 2-[(3-amino) phenylamino] -4- (4-chlorophenyl) thiazole

Using the compound obtained in Example 33, the target compound (0.20 g, 90% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300MHz, DMSO): δ 5.13 (s, NH2), 6.22 (d, 1H), 6.79 (d, 1H), 6.93 (m, 2H), 7.35 (s, 1H), 7.45 (d, 2H ), 7.94 (d, 2H), 9.98 (s, 1H)

MS (m / e) M ⁺ 301

Example 52 Preparation of 2-[(3-aminophenyl) amino] -4- (4-fluorophenyl) thiazole

Using the compound obtained in Example 34, the target compound (0.39 g, 90% yield) was obtained in the same manner as the Example 35.

¹ H NMR (300 MHz, DMSO): δ 6.22 (d, 1H), 6.75 (d, 1H), 6.94 (m, 2H), 7.16 (m, 3H), 7.92 (m, 2H), 9.91 (s, 1H )

MS (m / e) M ⁺ 285

Example 53 Preparation of 2-[(4-methoxyphenyl) amino] -4- (4-chlorophenyl) thiazole

Using the 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 4-methoxy aniline as the compound of formula 3, the target compound (0.21 g, 53% yield) was prepared under the same method and conditions as in Example 2. )

¹ H NMR (300 MHz, DMSO-d ₆ ); δ3.72 (s, 3H), 6.91 (d, 2H), 7.32 (s, 1H) 7.45 (d, 2H), 7.62 (d, 2H), 8.00 (d, 2H), 10.07 (s, 1H, NH ),

MS (m / e) M ⁺ 316, 301.

Example 54 Preparation of 2-[(4-fluorophenyl) amino] -4- (4-chlorophenyl) thiazole

The target compound (0.28 g, 43% yield) using the same method and conditions as in Example 2 using 2-bromo-4'-chloroacetophenone as the compound of Formula 2 and 4-fluoro aniline as the compound of Formula 3 Got.

¹ H NMR (300 MHz, CDCl ₃ ); δ 6.78 (s, 1H), 7.02 (m, 2H), 7.34 (m, 5H), 7.77 (d, 2H), MS (m / e) M ⁺ 304, 168 .

Example 55 Preparation of 2-[[4-trifluoromethylphenyl] amino] -4- (4-chlorophenyl) thiazole

Using the 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 4-trifluoromethyl aniline as the compound of formula 3, the target compound (0.34 g, 45 % Yield).

¹ H NMR (300 MHz, CDCl ₃ ); δ 6.89 (s, 1H), 7.34 (d, 2H), 7.49 (d, 2H), 7.57 (d, 2H), 7.70 (d, 2H)

MS (m / e) M ⁺ 354, 218, 168

Example 56 Preparation of 2-[[4-ethoxycarbonylphenyl] amino] -4- (4-chlorophenyl) thiazole

By using 2-bromo-4'-chloroacetophenone as the compound of formula 2 and 4-ethoxycarbonyl aniline as the compound of formula 3, the target compound (0.23 g, 30) was prepared in the same manner and in the same manner as in Example 2. % Yield).

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 1.30 (t, 3H), 4.28 (q, 2H), 7.47 (m, 3H), 7.81 (d, 2H), 7.95 (m, 4H), 11.81 (s, 1H, NH)

MS (m / e) M ⁺ 358, 330, 313, 285

Example 57 Preparation of 2-[[4-carboxyphenyl] amino] -4- (4-chlorophenyl) thiazole

0.10 g (0.27 mmol) of the compound obtained in Example 56 was dissolved in 5 ml of tetrahydrofuran, 0.7 ml (1.35 mmol) of 2N-NaOH was added, and the mixture was reacted for 2 hours while heating to 50 ° C. Subsequently, the reaction solution was diluted with 20 ml of water, acidified with 1 N -HCl solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the residue obtained by concentration under reduced pressure was recrystallized with ethyl acetate and n-hexane to obtain the desired compound. (0.074 g, 83% yield) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 7.47 (m, 3H), 7.79 (d, 2H), 7.91 (m, 4H), 10.69 (s, 1H, NH), 12.55 (br-s, 1H,)

MS (m / e) M ⁺ 330, 286, 194

Example 58 Preparation of 2-[[4- (methylamino) phenyl] amino] -4- (4-chlorophenyl) thiazole

0.30 g (1.0 mmol) of the compound obtained in Example 36 was dissolved in 10 ml of methanol, 0.43 ml (5.0 mmol) of aqueous formaldehyde solution (35%) and 0.15 ml (2.5 mmol) of acetic acid were added, followed by stirring for about 10 minutes. 0.12 g (2.0 mmol) of hydride was added thereto and reacted at room temperature for 2 hours. Subsequently, the reaction solution was diluted with 40 ml of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the residue obtained by concentration under reduced pressure was separated and purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain a target compound. (0.12 g, 41% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ); δ 3.53 (s, 3H), 3.76 (br-s, 2H, 2NH-), 6.61 (s, 1H), 6.71 (d, 2H), 7.14 (d, 2H), 7.32 (d, 2H), 7.77 (d, 2H)

Example 59 Preparation of 2-[[4- (methylamino) phenyl] amino] -4- (4-fluorophenyl) thiazole

Step 1) Preparation of 2-[[(4-methyl-acetamino) phenyl] amino] -4- (4-fluorophenyl) thiazole

100 mg (0.31 mmol) of the compound obtained in Example 32 was dissolved in 2 mL of N, N-dimethylformamide and 37 mg (0.93 mmol) of sodium hydride were stirred at 0 ° C. for 10 minutes. To this reaction mixture was added 32 ml of dimethyl sulfate (0.34 mmol) dropwise and stirred for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 2: 1), to obtain 44 mg (42%) of 2-[[(4-methyl-acetamino) phenyl] amino] -4- (4 -Fluorophenyl) thiazole compound was obtained.

¹ H NMR (300 MHz, DMSO); δ 2.07 (s, 3H), 3.49 (s, 3H), 7.15 (s, 1H), 7.20 (t, 2H), 7.41 (d, 1H), 7.65 (d, 1H), 7.88 (m, 2H), 10.06 (s, 1 H)

MS (m / e) M ⁺ 341

Step 2) Preparation of 2-[[4- (methylamino) phenyl] amino] -4- (4-fluorophenyl) thiazole

32 mg (0.09 mmole) of the compound obtained in step 1) was added to 3 ml of 6N hydrochloric acid at room temperature, and the mixture was heated to reflux for 2 hours. After the reaction was completed, the reaction solution was basified with 2N sodium hydroxide, washed with 10 ml of ethyl acetate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give silica gel column chromatography (hexane: ethyl acetate = 1: 1). Separation and purification gave the target compound (27 mg, 96% yield).

¹ H NMR (300 MHz, DMSO); δ 3.41 (s, 3H), 5.28 (s, 2H), 6.61 (d, 2H), 7.04 (t, 3H), 7.19 (t, 2H), 7.87 (dd, 2H)

MS (m / e) M ⁺ 299

Example 60 Preparation of 2-[[4- (benzylamino) phenyl] amino] -4- (4-chlorophenyl) thiazole

0.30 g (1.0 mmol) of the compound obtained in Example 36 was dissolved in 10 ml of methanol, and 0.13 ml (1.2 mmol) of benzaldehyde was added thereto, stirred at 50 ° C. for 20 minutes, and then cooled to room temperature. 0.08 g (2.0 mmol) of sodium borohydride was added to the reaction mixture, followed by reaction at room temperature for 2 hours. Subsequently, the reaction solution was diluted with 40 ml of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the residue obtained by concentrating under reduced pressure was separated and purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1). The desired compound (0.30 g, 77% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ); δ 4.70 (s, 2H), 6.63 (d, 2H), 6.67 (s, 1H), 7.17 (d, 2H), 7.25-7.37 (m, 8H)

Example 61 Preparation of 2-[(2,3,5-trimethyl-4-methoxyphenyl) amino] -4- (4-fluorophenyl) thiazole

2-Bromo-4'-fluoroacetophenone as the compound of Formula 2, and 2,3,5-trimethyl-4-methoxyaniline as the compound of Formula 3, were used in the same manner and in the same manner as in Example 2. The desired compound (0.20 g, 43% yield) was obtained.

¹ H NMR (300Mhz, CDCl ₃ ): δ 2.20 (s, 3H), 2.25 (s, 3H), 2.29 (s, 3H), 3.72 (s, 3H), 6.64 (s, 1H), 6.82 (br , NH), 7.03 (t, 2H), 7.18 (s, 1H), 7.75 (m, 2H)

MS (m / e) M ⁺ 342

Example 62 Preparation of 2- [4-aminophenoxy] -4-phenylthiazole

Step 1) Preparation of 2-chloro-4-phenylthiazole

10 g (50.2 mmol) of 2-bromoacetophenone was dissolved in 150 ml of ethanol, 5.3 g (65.3 mmol) of sodium thiocyanate were added, followed by heating under reflux for 1 hour. The reaction solution was then concentrated under reduced pressure, diluted with 150 ml of water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the solid obtained was again dissolved in 300 ml of ethyl ether, and HCl gas was saturated at 0 ° C. for 1 hour, and then left at 0 ° C. for 16 hours. The reaction solution was washed three times or more with water, and then the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). 2-chloro-4-phenylthiazole (7.5 g, 83% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ); δ 7.25-7.45 (m, 4H), 7.83 (dd, 2H)

MS (m / e) M ⁺ 195, 134

Step 2) Preparation of 2- [4-aminophenoxy] -4-phenylthiazole

0.3 g (1.53 mmol) of 2-chloro-4-phenylthiazole obtained in step 1) was dissolved in 10 ml of dimethylformamide, 0.18 g (1.99 mmol) of phenol and 0.63 g (4.6 mmol) of K ₂ CO ₃ were added, followed by 100 ° C. Stir at 15 h. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was separated and purified using silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain a target compound ( 0.35 g, 91% yield).

¹ H NMR (300 MHz, CDCl ₃ ); δ 6.98 (s, 1 H), 7.24-7.43 (m, 8 H), 7.80 (d, 1 H)

MS (m / e) M ⁺ 253, 225, 180, 134

Example 63 Preparation of 2- [4-nitrophenoxy] -4-phenylthiazole

0.30 g (1.53 mmol) of 2-chloro-4-phenylthiazole obtained in step 1) of Example 62 was mixed with 0.28 g (1.99 mmol) of 4-nitrophenol and heated at 140 ° C. for 8 hours. The reaction solution was dissolved in chloroform and separated and purified using silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the target compound (0.12 g, 25% yield).

¹ H NMR (300 MHz, CDCl ₃ ); δ 7.12 (s, 1 H), 7.32-7.42 (m, 3 H), 7.54 (dd, 2H), 7.77 (d, 2H), 8.29 (d, 2H)

Example 64 Preparation of 2-[(4-pyridyloxy] -4-phenylthiazole

0.3 g (1.53 mmol) of 2-chloro-4-phenylthiazole obtained in step 1) of Example 62 was dissolved in 10 ml of dimethylformamide, and 0.19 g (1.99 mmol) of 4-hydroxypyridine and 0.63 g of K ₂ CO ₃ ( 4.6 mmol) was added and stirred at 100 ° C. for 15 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified using silica gel column chromatography (5% methanol / dichloromethane) to obtain a target compound ( 0.32 g, 84% yield).

¹ H NMR (300 MHz, CDCl ₃ ); δ 6.49 (d, 2H), 7.30 (s, 1H), 7.39-7.48 (m, 3H), 7.87 (d, 2H), 8.17 (d, 2H)

MS (m / e) M ⁺ 254, 226, 134

Example 65 Preparation of 2-[(4-aminophenyl) thio] -4-phenylthiazole

Step 1) Preparation of 2-[(4-acetaminophenyl) thio] -4-phenylthiazole

0.5 g (2.5 mmol) of 2-chloro-4-phenylthiazole obtained in step 1) of Example 62 was dissolved in 10 ml of dimethylformamide, and 0.60 g (3.32 mmol) of 4-acetamino thiophenol and 1.06 K ₂ CO _{3 were added.} g (7.67 mmol) was added followed by stirring at 100 ° C. for 5 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was separated and purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a white solid state. 2-[(4-acetaminophenyl) thio] -4-phenylthiazole (0.52 g, 64% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ); δ 2.20 (s, 3H), 7.26-7.42 (m, 4H), 7.42-7.62 (m, 4H), 7.82 (d, 2H)

MS (m / e) M ⁺ 326, 284, 252

Step 2) Preparation of 2-[(4-aminophenyl) thio] -4-phenylthiazole

0.20 g (0.61 mmol) of 2-[(4-acetaminophenyl) thio] -4-phenylthiazole compound obtained in step 1) was dissolved in 3 ml of ethanol, 5 ml of 6N aqueous hydrochloric acid solution was added thereto, and then, the mixture was heated to 100 ° C. for 30 minutes. Heated. The reaction mixture was cooled, neutralized to pH 8 with 2 N- NaOH aqueous solution, extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue obtained by silica gel column chromatography (hexane: ethyl acetate = 2: Purification was carried out using 1) to obtain the target compound (0.17g, 98% yield).

¹ H NMR (300 MHz, CDCl ₃ ); δ 3.95 (br-s, 2H, NH 2), 6.71 (d, 2H), 7.24-7.50 (m, 6H), 7.83 (d, 2H)

MS (m / e) M ⁺ 284, 252, 142, 134

Example 66 Preparation of 2-[(4-aminophenyl) sulfonyl] -4-phenylthiazole

Step 1) Preparation of 2-[(4-acetaminophenyl) sulfonyl] -4-phenylthiazole

0.20 g (0.61 mmol) of 2-[(4-acetaminophenyl) thio] -4-phenylthiazole obtained in step 1) of Example 65 was dissolved in 15 ml of dichloromethane and 0.23 g of m- CPBA (70%) ( 0.92 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and separated and purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2-[(4-acetaminophenyl) sulfonyl] -4-phenyl as a white solid. Thiazole (0.18 g, 86% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ); δ 2.19 (s, 3H), 7.36-7.41 (m, 3H), 7.71-7.83 (m, 5H), 8.03 (d, 2H)

MS (m / e) M ⁺ 358, 316, 293, 252

Step 2) Preparation of 2-[(4-aminophenyl) sulfonyl] -4-phenylthiazole

0.10 g (0.29 mmol) of the compound obtained in step 1) was dissolved in 2 ml of ethanol, 5 ml of an aqueous 6 N -hydrochloric acid solution was added, and then heated to about 100 ° C. for 30 minutes. The reaction solution was cooled, neutralized to a pH of about 8 with 2N-NaOH aqueous solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue obtained by silica gel column chromatography (hexane: ethyl acetate = 2: 1). Purified and purified using to obtain the target compound (85 mg, 93% yield).

¹ H NMR (300 MHz, CDCl ₃ ); δ 4.27 (br-s, 2H, NH ₂ ), 6.68 (d, 2H), 7.34-7.43 (m, 6H), 7.68 (s, 1H), 7.83-7.91 (m, 4H)

MS (m / e) M ⁺ 316, 252, 156

Test Example

Various pharmacological actions were investigated by performing the following experiments on the compounds of Formula 1 according to the present invention. However, the following test examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Test Example 1: Determination of titer of 5-LO inhibitor

In order to effectively amplify 5-LO activity, rat complementary DNA was prepared from RNA using reverse transcriptase, and then transduced into a baculoviral vector to be expressed in insect cells. The virus-infected insect cells (Sf21, American Type Culture Collection, Manassas, VA) were incubated for 60 hours, centrifuged, and the supernatant was discarded and only concentrated cultured cells were taken. Cultured cells were suspended in buffer to disrupt the cells by ultrasound.

Ultrasonic rupture of 5-LO-overexpressed cells in the reaction buffer solution with the ATP concentration lowered to 20 μM was performed by reacting the cell eluate obtained with the compound of 1 μM concentration for 4 minutes in advance, and the substrate of arachidonic acid to 80 μM. The reaction was initiated with addition, after 4 minutes the same amount of FOX solution (methanol: xylenol orange, iron sulfate, sulfuric acid in water (9: 1)) was added and developed. Degree was measured at 575 nm. Inhibitory effect of 5-LO ex vivo enzyme reaction of the compound of the present invention was compared with that of the control drug, giluton, and the results are shown in Table 2 below.

From the above results, it was confirmed that the compounds of the present invention were superior to the inhibitory effect of 5-LO in vitro enzyme reaction than the control drug, ziruton.

Test Example 2: Determination of Cell-Based 5-Lipoxygenase Enzyme Product LTB4 Inhibition

RBL-2H3 (American Type Culture Collection, Manassas, VA), a basophilic leukemia cell derived from a mouse, was dispensed into 4 wells of ⁴ × 10 ⁵ cells in a 24-well plate to maintain the cells for 4-5 hours. The compound prepared in the example was pretreated for 10 minutes and A23187 (Sigma, St. Louis, MO) The inhibition rate of the cell-based 5-LO enzyme product LTB4 of the example compound was determined by enzyme immunoassay (ELISA) at 1 μM by addition of 10 μM. The results are shown in Table 3 below.

From the above results, the compounds of the present invention was able to confirm that the inhibition rate of the cell-based 5-LO enzyme product LTB4 was superior to the reference drug, zyrutone.

Test Example 3 Measurement of Inhibition Concentration of Intracellular 5-LO Enzyme Product LTB4

Inhibition of LTB4 production in RBL-2H3 cells (American Type Culture Collection, Manassas, VA) was measured at various concentrations and the 50% activity inhibitory concentration (IC ₅₀ ) was calculated for the representative compounds prepared in the above examples. . Example 4 The inhibitory concentration of production of the cell-based 5-LO enzyme product LTB4 is shown in Table 4.

From the above results, the compound of the present invention was found to be more effective in inhibiting the production of the cell-based 5-LO enzyme product LTB4 than the control drug, giluton, and particularly, Examples 21, 22, and 26 were remarkably superior.

Test Example 4: Ear inflammation experiment induced by arachidonic acid (AA)

Six-week-old BALB / c mice (20-25 g, male) were acclimated to the general environment for 3-4 days, followed by 30 minutes of oral administration of the example compounds in an amount of 100 mg / kg. mg of arachidonic acid was applied. After 1 hour, the thickness of the ears was expressed as the difference between the right ear and the untreated left ear, and a portion of the treated ear was obtained to evaluate the activity of myeloperoxidase (MPO). Peel the ear tissue with a 2 mm punch, crush the homogenizer in potassium phosphate buffer (pH 6.0) containing 300 μl 0.5% hexadecyltrimethylammonium bromide (HTAB), and then centrifuge The supernatant was separated by. MPO activity was measured at 460 nm after 20 μl of supernatant was reacted with 150 μl of 0.167 mg / ml o -dianisidine and phosphate buffer solution containing 0.0005% H ₂ O ₂ (pH 6.0) for 10 minutes. To determine the anti-inflammatory effect of the example compounds in the acute inflammation model induced by arachidonic acid, the results are shown in Table 5 below.

From the above results, it was confirmed that the compound of the present invention has an anti-inflammatory effect similar to that of the control drug, giluton.

Test Example 5: Determination of Inflammatory Inhibitory Effect on Atopic Dermatitis

To determine the degree of 5-LO inhibition against atopic dermatitis, 100 μg of example compounds were applied to the right ear of 8-week old BALB / c rats (males) 30 minutes prior to treatment and treated with 2 mg of arachidonic acid for inflammation. , After 1 hour by measuring the thickness of the ear and the activity of the MPO from the tissue of the ear to confirm the efficacy of each compound against inflammation-induced results are shown in Table 6 below.

From the above results, it was confirmed that the compound of the present invention is superior to the 5-lipogenase inhibitory effect against atopic dermatitis than the control drug giluton.

Test Example 6: Determination of Inhibitory Effect on Lymph Node Activity

0.5% dinitrochlorobenzene (DNCB) and Example compounds were applied to the ears of 8-week-old BALB / c rats for 3 days and the thickness and local lymph nodes of the ear were extracted on the 6th day. Activity of local lymph nodes).

From the above results, the compound of Example 26 inhibits ear edema caused by DNCB to a level similar to that of the control drug, giluton, but it can be seen that the rate of inhibition of the activity of local lymph nodes of DNCB which causes contact atopy is significantly higher.

Experimental Example 7: Determination of Contact Atopic Induction Inhibitory Effects in an Atopic Induction Model

The hairless 8-week-old NC / Nga rats (males) were treated with 1% dinitrochlorobenzene (DNCB) and subjected to sensitization, followed by application of 0.4% DNCB up to 5 weeks at 1 week intervals. . In Example 26, the compound was treated once daily from 4 weeks, and the treatment of DNCB was stopped at 5 weeks, and after 2 weeks, scoring, blood IgE analysis, and histological examination were performed to confirm drug efficacy. The results are shown in Table 8 below.

*% Inhibition of IgE after drug treatment (4 weeks) before drug treatment (8 weeks)

From the above results, it was confirmed that the compound according to the present invention is excellent in atopic induction inhibitory effect.

Test Example 8: Enzyme Specificity Experiment

There are three types of LOs, which can be broadly divided into 5-LO, 12-LO, and 15-LO. Of these, 12-LO and 15-LO are closely related to prostate, breast cancer and atherosclerosis, respectively. However, 12-LO and 15-LO enzymes play an important role in the resolution of inflammation, and their inhibition can slow natural healing of acute inflammation. In addition, non-specific reactions to 12-LO and 15-LO can cause side effects because it can also react with other physiologically essential proteins.

Therefore, in this experiment, in order to examine the inhibitory effect of the compound of the present invention on 12-LO and 15-LO, 12-LO is an eluate prepared from human platelets, 15-LO using an enzyme obtained from rabbit erythrocytes The enzyme specificity of each lipoxygenase was carried out by the FOX screening method for the example compounds of the present invention. The results are shown in Table 9 below.

The inhibitory effect on heterologous lipoxygenase activity by several representative compounds was shown to have a slight inhibitory effect on 12-lipoxygenase compared to the control group, but the inhibitory effect on 15-lipoxygenase was There was no.

Test Example 9: Side Effects of Redox 5-LO Inhibitor: Methemoglobin Induction

Redox-based 5-LO inhibitors oxidize coordinating Fe ²⁺ ions in the heme structure of hemoglobin to induce methemoglobin to form a Heinz body, an irregular structure in red blood cells, that affects its function Crazy The whole blood of rats was mixed with the compound of the present invention and maintained at 37 ° C. for 1 hour, measured at 630 nm, and completely oxidized with potassium ferricyanide to induce total methemoglobin, which was induced by the compound. Relative amounts were measured. The results are shown in Table 10 below.

From the above results, it was confirmed that the mehemoglobin-induced effect of the redox-based inhibitor, which is an inhibitory effect on 5-LO, was much lower than that of the control group, phenidone. .

On the other hand, the compound according to the present invention can be formulated in various forms according to the purpose.

The following are some examples of formulation methods containing the compound as an active ingredient according to the present invention, but the present invention is not limited thereto.

Formulation Example 1 Tablet (Direct Pressure)

After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.

Formulation Example 2: Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.

Formulation Example 3: Powders and Capsules

After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.

Formulation Example 4: Injection

Injectables were prepared by containing 100 mg of the active ingredient, mannitol 180 mg, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

As described above, the thiazole derivative of Formula 1 of the present invention effectively inhibits the enzymatic activity of 5-lipoxygenase (5-LO), which acts when the arachidonic acid is converted to a leukotriene metabolite, resulting in asthma, It can be used as a preventive and therapeutic agent for various inflammatory diseases such as chronic obstructive pulmonary disease, arthritis, psoriasis, atopic dermatitis, allergy, enteritis and cancer.

Claims (11)

Thiazole derivatives of Formula 1, or pharmaceutically acceptable salts, hydrates, solvates or isomers thereof: Formula 1

Where R ₁ and Each R ₂ is independently H, OR ₇ , NO ₂ , halogen, or C ₁ -C ₄ linear, branched or cyclic alkyl; R ₃ , R ₄ , R ₅ and R ₆ are each independently H, CF ₃ , OR ₇ , CO ₂ R ₇ , NR ₇ R ₈ , NO ₂ , NHCOR ₇ , C (= O) R ₇ , SR ₇ , Halogen, C _{1 to} C ₄ linear, branched or cyclic alkyl, Wherein R ₇ and R ₈ are each independently H, unsubstituted or F-substituted C _{1 to} C ₆ linear, branched or cyclic alkyl, aryl; X is NH, O, S or SO ₂ , Y is C or N. The method of claim 1, A compound selected from the group consisting of: 1) 2-[(4-hydroxyphenyl) amino] -4- (4-bromophenyl) thiazole; 2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 3) 2-[(4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 4) 2-[(4-hydroxyphenyl) amino] -4- (4-nitrophenyl) thiazole; 5) 2-[(4-hydroxyphenyl) amino] -4- (3-chlorophenyl) thiazole; 6) 2-[(4-hydroxyphenyl) amino] -4- (3-methylphenyl) thiazole; 7) 2-[(4-hydroxyphenyl) amino] -4- (2-methylphenyl) thiazole; 8) 2-[(4-hydroxyphenyl) amino] -4- (2-fluorophenyl) thiazole; 9) 2-[(4-hydroxyphenyl) amino] -4- (3-fluorophenyl) thiazole; 10) 2-[(4-hydroxyphenyl) amino] -4- (2-methoxyphenyl) thiazole; 11) 2-[(4-hydroxyphenyl) amino] -4- (2,4-dichlorophenyl) thiazole; 12) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dichlorophenyl) thiazole; 13) 2-[(4-hydroxyphenyl) amino] -4- (3,4-dichlorophenyl) thiazole; 14) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dimethylphenyl) thiazole; 15) 2-[(4-hydroxyphenyl) amino] -4- (2,4-difluorophenyl) thiazole; 16) 2-[(4-hydroxyphenyl) amino] -4- (5-chloro-2-methoxyphenyl) thiazole; 17) 2-[(4-hydroxyphenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole; 18) 2-[(3-chloro-4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 19) 2-[(4-hydroxy-3-nitrophenyl) amino] -4- (4-chlorophenyl) thiazole; 20) 2-[(4-hydroxy-2-methylphenyl) amino] -4- (4-chlorophenyl) thiazole; 21) 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 22) 2-[(4-hydroxy-3,5-dimethylphenyl) amino] -4- (4-chlorophenyl) thiazole; 23) 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole; 24) 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4- (fluorophenyl) thiazole; 25) 2-[(2,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 27) 2-[(2,3,5-trimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 28) 2-[(2-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 29) 2-[(3-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 30) 2-[(2-hydroxy-4-methylphenyl) amino] -4- (4-chlorophenyl) thiazole; 31) 2-[[(4-acetamino) phenyl] amino] -4- (4-bromophenyl) thiazole; 32) 2-[[(4-acetamino) phenyl] amino] -4- (4-fluorophenyl) thiazole; 33) 2-[[(3-acetamino) phenyl] amino] -4- (4-chlorophenyl) thiazole; 34) 2-[[(3-acetamino) phenyl] amino] -4- (4-fluorophenyl) thiazole; 35) 2-[(4-aminophenyl) amino] -4- (4-bromophenyl) thiazole; 36) 2-[(4-aminophenyl) amino] -4- (4-chlorophenyl) thiazole; 37) 2-[(4-aminophenyl) amino] -4- (3-methylphenyl) thiazole; 38) 2-[(4-aminophenyl) amino] -4- (2-methylphenyl) thiazole; 39) 2-[(4-aminophenyl) amino] -4- (4-fluorophenyl) thiazole; 40) 2-[(4-aminophenyl) amino] -4- (4-nitrophenyl) thiazole; 41) 2-[(4-aminophenyl) amino] -4- (4-methoxyphenyl) thiazole; 42) 2-[(4-aminophenyl) amino] -4- (2-methoxyphenyl) thiazole; 43) 2-[(4-aminophenyl) amino] -4- (3,4-dichlorophenyl) thiazole; 44) 2-[(4-aminophenyl) amino] -4- (2,5-dichlorophenyl) thiazole; 45) 2-[(4-aminophenyl) amino] -4- (2,4-dichlorophenyl) thiazole; 46) 2-[(4-aminophenyl) amino] -4- (2,5-dimethylphenyl) thiazole; 47) 2-[(4-aminophenyl) amino] -4- (2,4-difluorophenyl) thiazole; 48) 2-[(4-aminophenyl) amino] -4-phenylthiazole; 49) 2-[(4-aminophenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole; 50) 2-[(2-aminophenyl) amino] -4- (4-chlorophenyl) thiazole; 51) 2-[(3-aminophenyl) amino] -4- (4-chlorophenyl) thiazole; 52) 2-[(3-aminophenyl) amino] -4- (4-fluorophenyl) thiazole; 53) 2-[(4-methoxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 54) 2-[(4-fluorophenyl) amino] -4- (4-chlorophenyl) thiazole; 55) 2-[[4-trifluoromethylphenyl] amino] -4- (4-chlorophenyl) thiazole; 56) 2-[[4-ethoxycarbonylphenyl] amino] -4- (4-chlorophenyl) thiazole; 57) 2-[[4-carboxyphenyl] amino] -4- (4-chlorophenyl) thiazole; 58) 2-[[4- (methylamino) phenyl] amino] -4- (4-chlorophenyl) thiazole; 59) 2-[[4- (methylamino) phenyl] amino] -4- (4-fluorophenyl) thiazole; 60) 2-[[4- (benzylamino) phenyl] amino] -4- (4-chlorophenyl) thiazole; 61) 2-[(2,3,5-trimethyl-4-methoxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 62) 2- [4-phenoxy] -4-phenylthiazole; 63) 2- [4-nitrophenoxy] -4-phenylthiazole 64) 2- [4-pyridyloxy] -4-phenylthiazole; 65) 2-[(4-aminophenyl) thio] -4-phenylthiazole; And 66) 2-[(4-aminophenyl) sulfonyl] -4-phenylthiazole. The method of claim 2, A compound selected from the group consisting of: 1) 2-[(4-hydroxyphenyl) amino] -4- (4-bromophenyl) thiazole; 2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 3) 2-[(4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 4) 2-[(4-hydroxyphenyl) amino] -4- (4-nitrophenyl) thiazole; 5) 2-[(4-hydroxyphenyl) amino] -4- (3-chlorophenyl) thiazole; 6) 2-[(4-hydroxyphenyl) amino] -4- (3-methylphenyl) thiazole; 7) 2-[(4-hydroxyphenyl) amino] -4- (2-methylphenyl) thiazole; 8) 2-[(4-hydroxyphenyl) amino] -4- (2-fluorophenyl) thiazole; 9) 2-[(4-hydroxyphenyl) amino] -4- (3-fluorophenyl) thiazole; 10) 2-[(4-hydroxyphenyl) amino] -4- (2-methoxyphenyl) thiazole; 11) 2-[(4-hydroxyphenyl) amino] -4- (2,4-dichlorophenyl) thiazole; 12) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dichlorophenyl) thiazole; 13) 2-[(4-hydroxyphenyl) amino] -4- (3,4-dichlorophenyl) thiazole; 14) 2-[(4-hydroxyphenyl) amino] -4- (2,5-dimethylphenyl) thiazole; 15) 2-[(4-hydroxyphenyl) amino] -4- (2,4-difluorophenyl) thiazole; 16) 2-[(4-hydroxyphenyl) amino] -4- (5-chloro-2-methoxyphenyl) thiazole; 17) 2-[(4-hydroxyphenyl) amino] -4- (5-fluoro-2-methoxyphenyl) thiazole; 23) 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole; 24) 2-[(3,5-dichloro-4-hydroxyphenyl) amino] -4- (4- (fluorophenyl) thiazole; 25) 2-[(2,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; 30) 2-[(2-hydroxy-4-methylphenyl) amino] -4- (4-chlorophenyl) thiazole; 39) 2-[(4-aminophenyl) amino] -4- (4-fluorophenyl) thiazole; 40) 2-[(4-aminophenyl) amino] -4- (4-nitrophenyl) thiazole; 41) 2-[(4-aminophenyl) amino] -4- (4-methoxyphenyl) thiazole; 43) 2-[(4-aminophenyl) amino] -4- (3,4-dichlorophenyl) thiazole; 45) 2-[(4-aminophenyl) amino] -4- (2,4-dichlorophenyl) thiazole; 46) 2-[(4-aminophenyl) amino] -4- (2,5-dimethylphenyl) thiazole; 47) 2-[(4-aminophenyl) amino] -4- (2,4-difluorophenyl) thiazole; And 50) 2-[(2-aminophenyl) amino] -4- (4-chlorophenyl) thiazole. The method of claim 3, A compound selected from the group consisting of: 2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; 8) 2-[(4-hydroxyphenyl) amino] -4- (2-fluorophenyl) thiazole; 15) 2-[(4-hydroxyphenyl) amino] -4- (2,4-difluorophenyl) thiazole; 22) 2-[(4-hydroxy-3,5-dimethylphenyl) amino] -4- (4-chlorophenyl) thiazole; 23) 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole; 26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; And 27) 2-[(2,3,5-trimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole. The method of claim 4, wherein A compound selected from the group consisting of: 2) 2-[(4-hydroxyphenyl) amino] -4- (4-chlorophenyl) thiazole; And 26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole. A method for preparing a thiazole derivative of Formula 1a comprising reacting an acetophenone derivative of Formula 2 with an aniline derivative and a thiocyanate salt of Formula 3 below: Formula 1a

Formula 2

Formula 3

Wherein R ₁ to R ₆ and Y are as defined in claim 1. The method of claim 6, The thiocyanate salt is sodium thiocyanate or potassium thiocyanate. The method of claim 6, The solvent is an alcohol solvent, an ether solvent or a mixture thereof. A 5-lipoxygenase (5-LO) inhibitor comprising the thiazole derivative of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient. Thiazole derivatives of claim 1, or asthma, chronic obstructive pulmonary disease, arthritis, psoriasis, atopic dermatitis, allergic, enteritis, and the like, including as an active ingredient a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof A pharmaceutical composition for preventing or treating a disease selected from the group consisting of cancer. The method of claim 10, A pharmaceutical composition, wherein the thiazole derivative of Formula 1 is selected from the group consisting of the following compounds, and these are for the treatment of atopic dermatitis: 22) 2-[(4-hydroxy-3,5-dimethylphenyl) amino] -4- (4-chlorophenyl) thiazole; 23) 2-[(3-chloro-4-hydroxy-5-methylphenyl) amino] -4- (4-fluorophenyl) thiazole; 26) 2-[(3,5-dimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole; And 27) 2-[(2,3,5-trimethyl-4-hydroxyphenyl) amino] -4- (4-fluorophenyl) thiazole.