KR20120035684A - NOVEL THIAZOLIDINONE COMPOUNDS AS IKK-β INHIBITORS AND PREPARATION THEREOF - Google Patents

Abstract

PURPOSE: A thiazolidinone compound with IKK-beta suppression and a pharmaceutical composition containing the same are provided to prevent and treat rheumatoid arthritis, degenerative arthritis, asthma, and cancer. CONSTITUTION: A thiazolidine-4-one derivative is denoted by chemical formula 1. A pharmaceutical composition for treating inflammatory diseases or cancer contains the compound of chemical formula 1 as an active ingredient. The inflammatory diseases include rheumatoid arthritis, degenerative arthritis, asthma, or chronic obstructive lung diseases. A method for preparing the thiazolidione compound comprises: a step of cyclizing aryl thiourea compound of chemical formula 2 with ethyl 2-chloroacetate or prepare 2-arylimino-thiazolidine-4-one compound of chemical formula 3 or 4; a step of condensing the compound of chemical formula 3 or 4 with aryl aldehyde compound of chemical formula 5.

Description

Novel thiazolidinone compounds as IKK-β inhibitors and preparation etc.

The present invention relates to a novel thiazolidinone compound or a pharmaceutically acceptable salt thereof, a method for preparing the compound, and a pharmaceutical composition comprising the compound as an active ingredient, which exhibits IKK-β inhibitory activity.

NF-κB was first known as a nuclear factor that induces the production of immunoglobulins in B lymphocytes in 1986. NF-κB is then a key transcription factor in immune and inflammatory reactions that increase the expression of many inflammatory cytokines, chemokines, immunoreceptors, and cell surface adhesion molecules (CAMs) in response to inflammatory reactions, infections, and other stressful situations. Known as the transcription factor. NF-κB is known to be present in almost all cells. NF-κB is a cytoplasmic protein complex that increases the gene expression rate by penetrating the nuclear membrane and binding to and stimulating specific sites (specific regions of the gene) in DNA-specific sequences, also called gene transcription proteins. do. Increasing the rate of expression of a particular gene by stimulation of NF-κB increases the production of several related enzymes and proteins, abnormally increasing the production of inflammatory prostaglandins and other egosanoids. In addition, increased activity of NF-κB causes the immune system to be overactive, exacerbating various autoimmune diseases and inflammatory responses.

The role of NF-κB can be summarized into three broad categories. It plays a key role in regulating general immune and inflammatory responses, cell proliferation, differentiation, killing and tumorigenization and internal signaling during normal vertebrate development.

Activation of NF-κB is involved in various inflammatory reactions, including rheumatoid arthritis. The classical and alternative pathways are known as NF-κB signaling pathways. The classical pathway is induced by the response to various inflammatory stimuli, including the proinflammatory cytokines TNF-α and IL-1, and by exposure to bacterial products such as lipopolysaccharide (LPS) or contact maintenance of T cell receptors. This pathway is defined by the rapid phosphorylation of IκB-α at the Ser32 and Ser36 positions and the degradation induced by a series of ubiquitins by the 26S proteasome. In the classical pathway, IκB phosphorylation is due to the activation of the IKK complex. Among the IKK complexes, IKK-β was the most IKB kinase. Classical pathways play an important role in intrinsic immunity, inflammation and inhibition of apoptosis. Alternative pathways are activated by NF-κB active derivatives such as B cell activator (BAFF) or lymphotoxin (LTb) of antitumor necrosis factor species. IKK-α is activated to phosphorylate p100 to p52. Phosphorylated IκB undergoes ubiquitin ligase and is then polyubiquitinated and destroyed, or p100 is processed by protease. Freed NF-κB migrates to the nucleus and binds to a promoter or enhancer region of the target gene. Activated NF-κB is released into the cytoplasm by binding to the newly synthesized IκB-α. Alternative pathways are known to play an important role in secondary immune system development, B cell maturation, and adaptive humoral immunity ( Nature Reviews , 2004 , 3 , 17-26).

IKK-β is a serine-threonine kinase consisting of 756 amino acids, shows 55% identity to IKK-α, and forms a heterodimer with homo dimers or IKK-α to phosphorylate IκB-α or IκB-β ( J Biol.Chem . 1998 , 273 , 30736-30741). IKK-β showed sustained kinase activity, and overexpression of this enzyme resulted in the expression of a large number of proinflammatory cytokines transcribed by NF-κB activity. In addition, the activation of IKK-β was observed in patients with rheumatoid arthritis or degenerative arthritis ( Cell , 1997 , 91 , 243-252; J. Immunol. 1999 , 162 , 3176-3187).

Recently reported data suggest that inflammatory diseases and cancer are closely related. The Anderson Cancer Center, University of Texas, USA, identified the process by which IKK-β inhibits TSC1 (tuberous sclerosis 1) and activates the mTOR (mammalian target of rapamycine) pathway to increase angiogenesis and cancer (Cell, Vol 130, 440-455, 10 August 2007). In other words, IKK-β activated by TNFα phosphorylates Ser487 and Ser511 of TSC1 to block the action of the TSC1 / TSC2 complex, which activates the mTOR pathway. The route of supply is revealed. In addition, mouse experiments confirmed that the IKK-β-activated mice had a relatively large tumor size compared to mice in which IKK-β was inactivated or mTOR was inhibited. In the clinical trials of breast cancer patients, the patients whose TSC1 / TSC2 complexes of tumor cells were blocked by phosphorylation were found to have a shorter lifespan compared to patients with activated TSC1 / TSC2 complexes.

As described above, IKK-β is required to develop selective IKK-β inhibitors as a factor for controlling various inflammatory diseases and carcinogenesis, but the IKK-β inhibitors developed to date are extremely rare. As the IKK-β inhibitor, Korean Patent Registration Nos. 822,681 and 796,965, etc., disclose compounds having thienopyridazine as a basic skeleton structure, and Korean Patent Registration No. 738,165 contains a heteroaromatic carboxamide as a basic skeleton structure. The compound which has the is disclosed.

Therefore, it is selective for IKK-β inhibition and has good pharmacokinetic profile, good ADME (absorption, distribution, metabolism, excretion), but effective for the treatment of inflammatory diseases and cancers such as rheumatoid arthritis, degenerative arthritis, asthma and chronic obstructive pulmonary disease. There is an urgent need for the development of IKK-β inhibitors.

The present inventors have completed the present invention by confirming that the newly designed and synthesized thiazolidinone derivatives exhibit IKK-β inhibitory activity.

It is an object of the present invention to provide a novel thiazolidinone compound or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method for preparing the novel compound.

In addition, the present invention, because the novel compound exhibits an IKK-β inhibitory activity, the prevention and treatment of inflammatory diseases and cancers such as rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive pulmonary disease, etc. comprising the new compound as an active ingredient Another purpose is to provide a medicament.

In order to achieve the above object, the present invention is characterized by a thiazolidinone compound represented by the following formula (1), a method for preparing the compound, and a pharmaceutical composition containing the compound, which are effective as IKK-β inhibitors.

[Formula 1]

In Chemical Formula 1,

를 나타내고;A is a single bond, or

Represents;

R ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a C ₁ -C ₆ alkoxy group, a phenoxy, a halosubstituted phenoxy, a piperazinylC ₁ -C ₆ alkoxy group, and ( N- (C ₁ -C ₆ alkyl) ) Piperazinyl) C ₁ -C ₆ alkoxy group selected from 1 to 3 substituted groups;

R ² represents a hydrogen atom, a halogen atom, a nitro group, an amine group, an acetoamino group, a carbamoyl group, a C ₁ -C ₆ alkylaminocarbonyl group, a di (C ₁ -C ₆ alkyl) aminocarbonyl group, C ₁ -C ₆ 1 to 3 substituted groups selected from alkylaminoC ₁ -C ₆ alkoxy groups, di (C ₁ -C ₆ alkyl) aminoC ₁ -C ₆ alkoxy groups, and pyrrolylC ₁ -C ₆ alkoxy groups.

The thiazolidinone compound represented by Chemical Formula 1 according to the present invention has excellent selectivity for IKK-β inhibition, and has a good pharmacokinetic profile, such as rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive pulmonary disease, and cancer. Has an effective effect on treatment and prevention.

The thiazolidinone compound represented by Chemical Formula 1 according to the present invention may have a chiral center, and in the case of such a compound, a racemic compound or all possible isomers thereof may be present. Accordingly, the present invention includes racemates, individual isomers or mixtures of these isomers.

In addition, the present invention includes a radioactive derivative of the thiazolidinone compound represented by Chemical Formula 1, and these radioactive compounds are useful in the field of biological research.

In addition, the thiazolidinone compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. For example, non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfate, phosphoric acid, nitric acid, or propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfonic acid Together with non-toxic organic acids, salts of these pharmaceutically acceptable acids can be formed.

The substituent in the thiazolidinone compound represented by Chemical Formula 1 according to the present invention will be described in more detail as follows. 'Alkyl group' includes all straight, pulverized and cyclic carbon chains having 1 to 8 carbon atoms, with preferred alkyl groups being methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t -Butyl group, cyclopentyl group, cyclohexyl group, and the like. "Alkoxy group" means an alkyl group of carbon connected to oxygen, wherein alkyl is as defined above.

를 나타내고; 상기 R¹은 수소, 2-클로로, 3-클로로, 2-메톡시, 3-메톡시, 3,5-디메톡시, 페녹시, 4-클로로페녹시, N-메틸피페라지닐에톡시, 및 N-메틸피페라지닐프로폭시로 이루어진 군으로부터 선택되고; 상기 R²는 수소, 4-클로로, 2-니트로, 3-니트로, 4-니트로, 2-니트로-4-클로로, 4-아미노, 4-아세토아미노, 3-카바모일, 4-카바모일, 디메틸아미노카보닐, 메틸아미노프로폭시, 디에틸아미노프로폭시, 및 피롤릴프로폭시로 이루어진 군으로부터 선택되는 화합물의 경우이다.In the thiazolidinone compound represented by Formula 1 according to the present invention, Preferably, A is a single bond, or

Represents; R ¹ is hydrogen, 2-chloro, 3-chloro, 2-methoxy, 3-methoxy, 3,5-dimethoxy, phenoxy, 4-chlorophenoxy, N -methylpiperazinylethoxy, and N -methylpiperazinylpropoxy; R ² is hydrogen, 4-chloro, 2-nitro, 3-nitro, 4-nitro, 2-nitro-4-chloro, 4-amino, 4-acetoamino, 3-carbamoyl, 4-carbamoyl, dimethyl In the case of compounds selected from the group consisting of aminocarbonyl, methylaminopropoxy, diethylaminopropoxy, and pyrrolylpropoxy.

In addition, the present invention is for the treatment and prevention of inflammatory diseases and cancer, such as rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive pulmonary disease, etc. containing the thiazolidinone compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient It is characterized by a pharmaceutical composition.

In addition, the present invention provides a therapeutic agent for inflammatory diseases and cancer-related diseases such as rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive pulmonary disease, etc. containing thiazolidinone compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It is characterized by.

Particularly preferred group of compounds among the compounds represented by Formula 1 include the following compounds and pharmaceutically acceptable salts thereof.

Specific examples of the compound represented by Formula 1 according to the present invention are as follows:

( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 1);

( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 2);

( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 3 );

( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 4 );

( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 5 );

( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 6 );

( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 7);

( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 8);

( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one ( Compound no. 9);

( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5-[(5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 10);

( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5-[(5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidine -4-one (Compound No. 11);

( 2E , 5Z )-{2- (3-hydroxyphenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 12);

( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 13);

( 2E , 5Z )-{2- (3-hydroxyphenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 14);

( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-acetaminophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 15);

( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-aminophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 16 );

( 2E , 5Z )-{2- (2-methoxyphenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 17);

( 2E , 5Z )-{2- (3-hydroxyphenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 18);

( 2E , 5Z )-{2- (3-methoxyphenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 19);

( 2E , 5Z )-{2- [4- (4-chlorophenoxy) phenyl] imino-5- [3- (3- ( N , N -diethylamino) propoxy) phenyl] methylene} Thiazolidin-4-one (Compound No. 20);

( 2E , 5Z )-{2- [3- (3- ( N -methylpiperazin-1-yl) propoxy) phenyl] imino-5- [5- (4-carbamoylphenyl) furan- 2-yl] methylene} thiazolidin-4-one (Compound No. 21);

( 2E , 5Z )-{2- [4- (4-chlorophenoxy) phenyl] imino-5- [4- (3- (pyrrolidin-1-yl) propoxybenzylidene} thiazoli Din-4-one (Compound No. 22);

( 2E , 5Z )-{2- [2- (2- ( N -methylpiperazin-1-yl) ethoxyphenyl] imino-5- [5- (4-chlorophenyl) furan-2- Il] methylene} thiazolidin-4-one (Compound No. 23); or

( 2E , 5Z )-{2- [3- (3- ( N -methylpiperazin-1-yl) propoxy) phenyl] imino-5- [5- (4-chlorophenyl) furan-2 -Yl] methylene} thiazolidin-4-one (Compound No. 24).

Meanwhile, the present invention includes a method for preparing a thiazolidinone compound represented by Chemical Formula 1, and the preparation method includes a manufacturing process as shown below.

Scheme 1

In Scheme 1, A, R ¹ , and R ² are each as defined in Chemical Formula 1.

Referring to the production method of the present invention according to the reaction scheme 1 in detail.

First, the arylthiourea compound represented by Formula 2 is cyclized with ethyl 2-chloroacetate to prepare 2-arylimino-thiazolidin-4-one compound represented by Formula 3 or Formula 4. do.

The cyclization reaction is carried out under the conditions in which the base is present, and the base used may be selected from hydroxides, carbonates, acetates and the like of alkali metals or alkaline earth metals. As the solvent, an inert organic solvent which does not affect the reaction may be used as an organic solvent commonly used in the art. Specific examples of organic solvents that can be used in the present invention include lower alcohols having 1 to 6 carbon atoms such as diethyl ether, methanol, ethanol, and propanol, tetrahydrofuran, or halogenated compounds such as chloroform, methylene chloride, acetonitrile, and the like. Nitrile compounds and the like can be used. The reaction temperature may be carried out in the range of -30 ℃ to the reflux temperature of the solvent used, more specifically in the temperature range of room temperature to 120 ℃, more specifically may be carried out within 30 ℃ to 80 ℃.

Then, by condensation reaction of the 2-arylimino-thiazolidin-4-one compound represented by Formula 3 or Formula 4 with the arylaldehyde compound represented by Formula 5, To prepare a thiazolidinone compound represented by.

The condensation reaction is carried out under the conditions in which the base is present, and piperidine is preferable as the base to be used. The temperature of the condensation reaction is in the range of 0 ° C to 100 ° C, preferably about 80 ° C.

In addition, the arylthiourea compound represented by Formula 2 used as a reactant in the preparation method according to Scheme 1 is prepared by a conventional organic synthesis method using commercially available arylamine or aryl isocyanate compounds as raw materials. Can be used.

In addition, the arylaldehyde compound represented by the formula (5) used as a reactant in the production method according to Scheme 1 by the Suzuki condensation reaction between the boronic acid compound and bromofuryl aldehyde compound as shown in Scheme 2 below It can manufacture and use.

Scheme 2

In Reaction Scheme 2, R ² is as defined in Formula 1, respectively.

Suzuki condensation reaction according to Scheme 2 may be carried out under a condition of heating at a temperature of 70 ℃ to 120 ℃ using a mixed solvent of ethanol and toluene in the presence of a palladium catalyst and a base. At this time, as a palladium catalyst, tetrakis (triphenylphosphine) palladium ((Ph ₃ P) ₄ Pd), Pd (OAc) ₂ , Pd (Cl) _2, etc. may be used, and preferably tetrakis ( Triphenylphosphine) palladium is used. The base may be selected from hydroxides, carbonates, acetates and the like of alkali or alkaline earth metals.

On the other hand, the compound represented by the formula (1) according to the present invention has IKK-β growth inhibitory action can be used as an active ingredient in the treatment of inflammatory diseases and cancer such as rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive pulmonary disease, etc. have. Therefore, the present invention includes the anticancer agent or the pharmaceutical composition for anticancer agent containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient as a scope. IKK-β growth inhibitory activity against the compounds according to the invention was measured.

Pharmaceutically acceptable salts of the compounds represented by Formula 1 used in the preparation of the pharmaceutical composition according to the present invention may be prepared by conventional methods in the art. For example, salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid Salts with organic acids such as lactic acid, gustyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid Salts with amino acids such as glutamine, lysine, arginine, tyrosine, proline, salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and alkali metals such as sodium and potassium Metal salts thereof, salts with ammonium ions and the like.

The pharmaceutical composition of the present invention may be prepared by adding a conventional nontoxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by Formula 1 or pharmaceutically acceptable salts thereof. In addition, the pharmaceutical composition of the present invention is prepared by oral or parenteral administration such as tablets, capsules, troches, solutions, suspensions, etc., which are common in the pharmaceutical field, to prevent various types of tumors. It can be used for treatment. Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

In addition, the dosage of the compound represented by Formula 1 according to 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. Based on an adult patient weighing 70 kg, the dosage is generally 0.01 mg to 5000 mg per day, and may be divided once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.

Hereinafter, the present invention will be described in detail with respect to the preparation method and efficacy of the compound according to the present invention through Examples and Experimental Examples. However, these Examples and Experimental Examples are only for helping the understanding of the present invention, the scope of the present invention is not limited to the Examples.

EXAMPLE

Example 1. 2- (2-methoxyphenylimino) thiazolidin-4-one

2-methoxyphenylthiourea (3.182 g, 17.46 mmol) and sodium acetate (4.29 g, 52.38 mmol) were added to ethanol and stirred at room temperature for 30 minutes. Ethyl 2-chloroacetate (3.737 mL, 34.92 mmol) was slowly added dropwise and then heated to 60 ° C. for 9 hours. After cooling to room temperature, ethanol was evaporated under reduced pressure, filtered under reduced pressure with ethyl acetate and washed with water to obtain the title compound in 80% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.80 (s, 0.5 × 1H), 7.16 (s, 1H), 7.07 (s, 1H), 6.93 (s, 1.5 × 1H), 3.93 (s, 2H ), 3.75 (s, 3 H)

Example 2. 2- (3-methoxyphenylimino) thiazolidin-4-one

In the same manner as in Example 1, 3-methoxyphenylthiourea and ethyl 2-chloroacetate were reacted to prepare the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.30 (d, J = 32.4 Hz, 2H), 6.73 (s, 1H), 6.54 (s, 1H), 3.97 (s, 2H), 3.74 (s, 3H)

Example 3. 2- (2-chlorophenylimino) thiazolidin-4-one

In the same manner as in Example 1, 2-chlorophenylthiourea and ethyl 2-chloroacetate were reacted to prepare the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.97 (bs, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 4.01 (s, 2H)

Example 4. 2- (3-chlorophenylimino) thiazolidin-4-one

In the same manner as in Example 1, 3-chlorophenylthiourea and ethyl 2-chloroacetate were reacted to prepare the title compound.

¹ H NMR (300 MHz, MeOD- d ₄ ) δ 7.93 (s, 0.5 × 1H), 7.54 (d, 1H), 7.85-7.33 (m, 1H), 7.19 (d, 1H), 7.05-6.96 (m , 1H), 4.07 (s, 0.5 × 2H), 3.97 (s, 0.5 × 2H)

Example 5. 2- (3,5-dimethoxyphenylimino) thiazolidin-4-one

In the same manner as in Example 1, 3,5-dimethoxyphenylthiourea and ethyl 2-chloroacetate were reacted to prepare the title compound.

^{1 H NMR (300 MHz, MeOD-} d 4) δ 6.93 (s, 1H), 6.36-6.30 (m, 2H), 4.05 (s, 0.5 × 2H), 3.96 (s, 0.5 × 2H), 3.79 (s , 6H)

 Example 6. 2- (3-hydroxyphenylimino) thiazolidin-4-one

In the same manner as in Example 1, 3-hydroxyphenylthiourea and ethyl 2-chloroacetate were reacted to prepare the title compound.

¹ H NMR (300 MHz, MeOD- d ₄ ) δ 7.34 (s, 0.5 × 1H), 7.22-7.14 (m, 1H), 7.03 (d, 0.5 × 1H), 6.69-6.29 (m, 2H), 4.04 (s, 0.5 × 2H), 3.95 (s, 0.5 × 2H)

Example 7. ( Z ) -2- [3- ( N -methylpiperazinylpropoxy) phenylimino] thiazolidin-4-one

In the same manner as in Example 1, 3- ( N -methylpiperazinylpropoxy) phenylthiourea was reacted with ethyl 2-chloroacetate to prepare the title compound.

¹ H NMR (300 MHz, MeOD- d ₄ ) δ 7.50-6.70 (4H), 4.06-3.52 (m, 4H), 2.71-2.63 (m, 10H), 2.43 (d, J = 7.8 Hz, 3H), 2.02 (quintet, J = 2.2 Hz, 2H)

Example 8. ( Z ) -2- [3- ( N, N -diethylaminopropoxy) phenylimino] thiazolidin-4-one

The title compound was prepared by reacting 3- ( N, N -diethylaminopropoxy) phenylthiourea with ethyl 2-chloroacetate in the same manner as in Example 1.

Example 9. 2-formyl-5-[(4-carbamoyl) phenyl] furan

4-aminocarbonylphenylboronic acid (200 mg, 1.212 mmol), 5-bromo-2-furalaldehyde (254.6 mg, 1.455 mmol) was added to a mixed solvent of ethanol (20 mL) and toluene (20 mL). Melted. To this was added an aqueous solution of potassium carbonate (10 mg) dissolved in water (2 mL) and tetrakis (triphenylphosphinepalladium ((Ph ₃ P) ₄ Pd; 8 mg)), followed by heating at 90 ° C. for one day. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL × 3) were added and extracted, and the organic layer was dried over anhydrous magnesium sulfate, and the filtrate was evaporated under reduced pressure to obtain the title compound in 100% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 8.35 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H) , 7.69 (d, J = 3.7 Hz, 1H), 7.64-7.56 (m, 2H), 7.36 (d, J = 3.7 Hz, 1H); ¹³ C NMR (75.5 MHz, DMSO- d ₆ ) δ 178.4, 167.7, 158.0, 152.3, 135.7, 129.7, 129.2, 129.0, 128.1, 125.8, 124.5, 109.8

Example 10. 2-formyl-5-[(4-methylcarbamoyl) phenyl] furan

In the same manner as in Example 8, 4-methylcarbamoylphenylboronic acid and 2-formyl-5-bromo-2-furan were reacted to prepare the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 9.57 (s, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H) , 7.62 (d, J = 3.7 Hz, 1H), 7.16 (d, J = 3.7 Hz, 1H), 2.07 (s, 3H)

Example 11. ( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidine -4-one (Compound No. 1)

2- (3,5-dimethoxyphenylimino) thiazolidin-4-one (30.0 mg, 0.1190 mmol), 2-formyl-5- (3-carbamoylphenyl) furan (25.6 mg, 0.1190 mmol), Piperidine (11.75 μL, 0.1190 mmol) was added to ethanol and heated to 80 ° C. overnight. After cooling to room temperature, the product was filtered under reduced pressure and washed with ethanol to obtain 40.0 mg (74.8%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.27 (d, J = 25.9 Hz 1H), 8.18 (d, J = 23.3 Hz, 1H), 7.94-7.69 (m, 2H), 7.62-7.42 (m , 3H), 7.32-7.12 (m, 1H), 7.36 (d, J = 6.4 Hz, 1H), 7.03 (s, 1H), 6.29 (s, 1H), 3.76 (s, 6H).

Example 12. ( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidine-4- On (Compound No. 2)

In the same manner as in Example 11, 2- (3-chlorophenylimino) thiazolidin-4-one (50.0 mg, 0.2206 mmol) and 2-formyl-5- (3-carbamoylphenyl) furan (47.5 mg , 0.2206 mmol) was dissolved in ethanol and piperidine (21.8 μL, 0.2206 mmol) was added dropwise and reacted at 80 ° C. for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to give 57.0 mg (61.0%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.27 (d, J = 26.7 Hz, 1H), 8.12-7.93 (m, 2H), 7.88-7.82 (m, 1H), 7.69-7.46 (m, 5H ), 7.31-7.34 (m, 4H)

Example 13. ( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 3)

In the same manner as in Example 11, 2- (3-chlorophenylimino) thiazolidin-4-one (60.0 mg, 0.2647 mmol) and 2-formyl-5- (4-nitrophenyl) furan (57.5 mg, 0.2647 mmol) was dissolved in ethanol and piperidine (26.1 μL, 0.2647 mmol) was added dropwise and reacted at 80 ° C. for 12 hours. The solid formed after the reaction was filtered, washed with hexane and ethanol and dried to give 108.1 mg (95.9%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.09 (bs, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.60-7.09 (m, 6H)

Example 14 ( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 4)

In the same manner as in Example 11, 2- (2-chlorophenylimino) thiazolidin-4-one (60.0 mg, 0.2647 mmol), 2-formyl-5- (4-nitrophenyl) furan (57.5 mg, 0.2647 mmol) and piperidine (26.1 μL, 0.2647 mmol) were reacted in ethanol and purified to give 90.7 mg (80.5%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.55 (bs, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.48-7.42 (m, 3H), 7.29 (t, J = 6.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.14 (s, 1H)

Example 15. ( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 5)

In the same manner as in Example 11, 2- (2-chlorophenylimino) thiazolidin-4-one (70.0 mg, 0.3088 mmol) and 2-formyl-5- (2-nitrophenyl) furan (67.1 mg, 0.3088 mmol) was reacted under piperidine (30.5 μL, 0.3088 mmol) and purified to give 105.4 mg (80.1%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.53 (bs, 1H), 7.87-7.79 (m, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.24-7.14 (m, 4H)

Example 16. ( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 6)

In the same manner as in Example 11, 2- (3-chlorophenylimino) thiazolidin-4-one (70.0 mg, 0.3088 mmol) and 2-formyl-5- (2-nitrophenyl) furan (67.1 mg, 0.3088 mmol) was dissolved in ethanol, piperidine (30.5 μL, 0.3088 mmol) was added dropwise, and reacted at 80 ° C. for 12 hours until a solid formed. The precipitate was filtered and washed with hexane and ethanol to give 127.2 mg (96.7%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.02 (s, 1H), 7.90-7.83 (m, 2H), 7.76-7.58 (m, 4H), 7.25 (d, J = 8.1 Hz, 1H), 7.17-7.02 (m, 3H)

Example 17. ( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidine -4-one (Compound No. 7)

2- (2-chlorophenylimino) thiazolidin-4-one (70.0 mg, 0.3088 mmol), 2-formyl-5- (4-chloro-2-nitrophenyl) furan in the same manner as in Example 11 (77.7 mg, 0.3088 mmol) and piperidine (30.5 μL, 0.3088 mmol) were reacted to give 132.8 mg (93.4%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.58 (bs, 1H), 8.06 (s, 1H), 7.86-7.79 (m, 2H), 7.53 (d, J = 7.9 Hz, 1H), 7.47 ( s, 1 H), 7.39 (t, J = 7.5 Hz, 1 H). 7.22-7.15 (m, 4H)

Example 18. ( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidine -4-one (Compound No. 8)

2- (3-chlorophenylimino) thiazolidin-4-one (70.0 mg, 0.3088 mmol) and 2-formyl-5- (4-chloro-2-nitrophenyl) furan in the same manner as in Example 11 (77.7 mg, 0.3088 mmol) and piperidine (30.5 μL, 0.3088 mmol) were reacted in ethanol and purified to give 138.0 mg (97.1%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.00 (d, J = 46.3 Hz, 1H), 7.93-7.83 (m, 2H), 7.57-7.42 (m, 3H), 7.27-7.03 (m, 4H )

Example 19. ( 2E , 5Z )-{2- (3,5-Dimethoxyphenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidine- 4-one (Compound No. 9)

In the same manner as in Example 11, 2- (3,5-dimethoxyphenylimino) thiazolidin-4-one (70.0 mg, 0.2774 mmol), 2-formyl-5- (2-nitrophenyl) furan ( 60.3 mg, 0.2774 mmol) and piperidine (27.4 μL, 0.2774 mmol) were added to ethanol and heated to 80 ° C. overnight. After cooling to room temperature, the product was filtered under reduced pressure and washed with ethanol to obtain 110.7 mg (88.4%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.04-7.63 (m, 4H), 7.48 (d, J = 31.4 Hz, 1H), 7.15 (d, J = 14.9 Hz, 2H), 7.02 (s, 1H), 6.34 (s, 1H), 6.22 (s, 1H), 3.75 (s, 6H)

Example 20. {2- (3,5-Dimethoxyphenylimino) -5-[(5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 10 )

In the same manner as in Example 11, 2- (3,5-dimethoxyphenylimino) thiazolidin-4-one (70.0 mg, 0.2774 mmol) and 2-formyl-5- (4-nitrophenyl) furan ( 60.3 mg, 0.2774 mmol) was dissolved in ethanol and piperidine (27.4 μL, 0.2774 mmol) was added dropwise and reacted at 80 ° C. for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 91% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.32 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.58-7.49 (m, 2H), 7.19 (d, J = 21.2 Hz, 1H), 7.02 (s, 1H), 6.43-6.33 (m, 2H), 3.77 ( s, 6 H)

Example 21. ( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5-[(5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene } Thiazolidin-4-one (compound number 11)

2- (3,5-dimethoxyphenylimino) thiazolidin-4-one (70.0 mg, 0.2774 mmol) and 2-formyl-5- (4-chloro-2-nitro in the same manner as in Example 11 above Phenyl) furan (69.8 mg, 0.2774 mmol) was dissolved in ethanol and piperidine (27.4 μL, 0.2774 mmol) was added dropwise and reacted at 80 ° C. for 12 hours. The solid produced after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 79.8% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.17 (d, J = 39.5 Hz, 1H), 7.94-7.79 (m, 2H), 7.49 (d, J = 32.9 Hz, 1H), 7.21-7.14 ( m, 2H), 7.02 (s, 1H), 6.35 (d, J = 6.9 Hz, 1H), 6.21 (s, 1H), 3.75 (s, 6H)

Example 22. ( 2E , 5Z )-{2- (3-hydroxyphenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidine-4 -On (Compound No. 12)

In the same manner as in Example 11, 2- (3-hydroxyphenylimino) thiazolidin-4-one (50.0 mg, 0.2400 mmol) and 2-formyl-5- (3-carbamoylphenyl) furan (51.7 mg, 0.2400 mmol) was dissolved in ethanol and piperidine (23.7 μL, 0.2400 mmol) was added dropwise to react. The solid produced after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to give the title compound in 61.0% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.5 (bs, 1H), 9.66 (d, J = 21.1 Hz, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.96-7.85 ( m, 2H), 7.61-7.11 (m, 7H), 6.58 (d, J = 7.5 Hz, 2H)

Example 23. ( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidine-4- On (Compound No. 13)

2- (2-chlorophenylimino) thiazolidin-4-one (50.0 mg, 0.240 mmol), 2-formyl-5- (4-carbamoylphenyl) furan (21.7 mg) in the same manner as in Example 11 above , 0.240 mmol) and piperidine (23.7 μL, 0.240 mmol) were reacted in ethanol and purified to afford the title compound in 98% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.56 (bs, 1H), 8.05 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H) , 7.58 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.45-7.42 (m, 2H), 7.35-7.23 (m, 3H), 7.14 (d, J = 3.6 Hz, 1H)

Example 24. (2 E, 5 Z) - {2- ( this 3-hydroxyphenyl) -5- [5- (4-carbamoyl-phenyl) furan-2-yl] methylene} -4-thiazolidine -On (Compound No. 14)

In the same manner as in Example 11, 2- (3-hydroxyphenylimino) thiazolidin-4-one (50.0 mg, 0.2400 mmol) and 2-formyl-5- (4-carbamoylphenyl) furan (51.7 mg, 0.2400 mmol) was dissolved in ethanol and piperidine (23.7 μL, 0.2400 mmol) was added dropwise and reacted at 80 ° C. for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 92% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.45 (bs, 1H), 9.66 (d, J = 13.5 Hz, 1H), 8.06-7.89 (m, 5H), 7.73 (d, J = 7.7 Hz, 6H), 7.57-7.39 (m, 3H), 7.23-6.55 (m, 4H)

Example 25. (2 E, 5 Z) - {2- (2- chloro-phenylimino) -5- [5- (4-acetamido-aminophenyl) furan-2-yl] methylene} thiazolidine-4 On (Compound No. 15)

In the same manner as in Example 11, 2- (2-chlorophenylimino) thiazolidin-4-one (50.0 mg, 0.2206 mmol), 2-formyl-5- (4-acetaminophenyl) furan (50.6 mg , 0.2206 mmol) and piperidine (21.7 μL, 0.2206 mmol) were reacted and purified to give the title compound in 87% yield.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.59 (bs, 1H), 10.17 (s, 1H), 8.13-7.47 (m, 6H), 7.40 (t, J = 4.8 Hz, 1H), 7.27- 7.21 (m, 2H), 7.09 (d, J = 3.4 Hz, 2H), 2.05 (s, 3H)

Example 26. (2 E, 5 Z) - {2- (2- chloro-phenylimino) -5- [5- (4-aminophenyl) furan-2-yl] methylene} thiazolidine-4-one (Compound No. 16)

tert -butyl 4- (5-((1 Z )-(( E ) -2- (2-chlorophenylimino) -4-oxothiazolidin-5-ylidene) methyl) furan-2-yl ) Phenylcarbamate (20.0 mg, 0.0403 mmol) was reacted in a mixed solution of dichloromethane and ethyl acetate (1: 1). Trifluoroacetic acid (TFA; 10.3 mL, 0.1330 mmol) was added dropwise at 0 ° C, and the mixed solution was stirred at room temperature for 10 hours. The mixture was extracted with ethyl acetate, concentrated under reduced pressure and purified by column chromatography to obtain the title compound in 80% yield.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (bs, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.41-7.39 (m, 2H), 7.27-7.20 (m, 4H), 7.04 (d, J = 3.3 Hz, 1H), 6.81 (s, 1H), 6.49 (d, J = 7.6 Hz, 2H), 5.61 (s, 2H)

Example 27. (2 E, 5 Z) - {2- (2- methoxy-phenyl) -5- [5- (4-carbamoyl-phenyl) furan-2-yl] methylene} -4-thiazolidine -On (Compound No. 17)

In the same manner as in Example 11, 2- (2-methoxyphenylimino) thiazolidin-4-one (100.0 mg, 0.4499 mmol) and 2-formyl-5- (4-carbamoylphenyl) furan (96.8 mg, 0.4499 mmol) was dissolved in ethanol and piperidine (44.4 μL, 0.4499 mmol) was added dropwise and reacted at 80 ° C. for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 98% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.15-7.84 (m, 3H) 7.65 (d, J = 8.2 Hz, 1H). 7.49-7.21 (m, 4H), 7.15-6.95 (m, 3H), 3.85 (d, J = 5.8 Hz, 3H)

Example 28. (2 E, 5 Z) - {2- ( this 3-hydroxyphenyl) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidine-4 On (Compound No. 18)

In the same manner as in Example 11, 2- (3-hydroxyphenylimino) thiazolidin-4-one (50.0 mg, 0.2400 mmol) and 2-formyl-5- (4-nitrophenyl) furan (52.2 mg , 0.2400 mmol) was dissolved in ethanol and piperidine (23.7 mL, 0.2400 mmol) was added dropwise to react. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 92% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.69 (s, 1H), 8.36-8.23 (m, 2H), 8.06-7.87 (m, 2H), 7.59-7.43 (m, 3H), 7.24-7.15 (m, 3H), 6.70-6.58 (m, 1H)

Example 29. (2 E, 5 Z) - {2- (3- methoxyphenyl) -5- [5- (4-carbamoyl-phenyl) furan-2-yl] methylene} -4-thiazolidine -On (Compound No. 19)

In the same manner as in Example 11, 2- (3-methoxyphenylimino) thiazolidin-4-one (60.0 mg, 0.2699 mmol) and 2-formyl-5- (4-carbamoylphenyl) furan (58.1 mg, 0.2699 mmol) was dissolved in ethanol and piperidine (26.7 μL, 0.4499 mmol) was added dropwise and reacted at 80 ° C. for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 92% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.14 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.58-7.33 (m, 5H), 7.56 (dd, J ₁ = 22.3 Hz, J ₂ = 3.4 Hz, 1H), 6.86-6.71 (m, 2H), 3.79 (d, J = 5.2 Hz, 3H )

Example 30. (2 E, 5 Z) - {2- [4- (4- chlorophenoxy) phenyl] imino -5- [3- (3- (N, N- diethylamino) propoxy) Phenyl] methylene} thiazolidin-4-one (Compound No. 20)

In the same manner as in Example 11, 2- [3- (3- ( N , N -diethylamino) propoxy) phenyl] imino-thiazolidin-4-one (114.0 mg, 0.3547 mmol) and 4- (4-Chlorophenoxy) phenylaldehyde (86.6 mg, 0.3724 mmol) was dissolved in ethanol and piperidine (35.0 mL, 0.3547 mmol) was added dropwise thereto and reacted at 80 ° C for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 85% yield.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.62 (d, J = 9.0 Hz, 2H), 7.53-7.43 (m, 4H), 7.16-7.06 (m, 4H), 6.96-6.91 (m, 3H ), 4.00-3.97 (m, 2H), 2.54 (t, J = 7.2 Hz, 2H), 1.83 (d, J = 6.3 Hz, 2H), 0.95 (t, J = 7.1 Hz, 6H)

Example 31. (2 E, 5 Z) - {2- [3- (3- (N- methylpiperazin-1-yl) propoxy) phenyl] imino-5- [5- (4-carbamoyl Phenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 21)

2- [3- (3- (4-methylpiperazin-1-yl) propoxy) phenyl] imino-thiazolidin-4-one (79.0 mg, 0.2267 mmol) in the same manner as in Example 11; 2-formyl-5- (4-carbamoylphenyl) furan (48.8 mg, 0.2267 mmol) was dissolved in ethanol and piperidine (22.4 mL, 0.2267 mmol) was added dropwise thereto and reacted at 80 ° C for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 90% yield.

C ₂₉ H ₃₁ N ₅ O ₄ S (M + H) LC-MS calcd 545.21, found 545.94

Example 32. (2 E, 5 Z) - {2- [4- (4- chlorophenoxy) phenyl] imino-5- [4- (3- (pyrrolidin-1-yl) propoxy-benzyl Riden} thiazolidin-4-one (compound number 22)

In the same manner as in Example 11, 2- [4- (3- (pyrrolidin-1-yl) propoxy) phenyl] imino-thiazolidin-4-one (114.0 mg, 0.3547 mmol) and 4- (4-Chlorophenoxy) phenylaldehyde (83.0 mg, 0.3724 mmol) was dissolved in ethanol, piperidine (35.0 mL, 0.3547 mmol) was added dropwise and reacted at 80 ° C for 12 hours. The solid produced after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to give 41.3 mg (21.7%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ -d ) δ 7.62 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 7.4 Hz, 2H), 7.46 (dd, J ₁ = 12.6 Hz, J ₂ = 8.9 Hz, 2H), 7.14 (t, J = 8.2 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.98-6.90 (m, 3H), 3.98 (t, J = 6.2 Hz, 2H) , 2.60 (t, J = 7.1 Hz, 2H), 1.89 (quintet, J = 6.3 Hz, 2H), 1.69 (s, 4H); ¹³ C NMR (75.5 MHz, CDCl ₃ - d ) δ 180.9, 169.8, 157.9, 157.7, 156.4, 155.1, 132.0, 130.6, 130.5, 130.0, 129.8, 128.5, 128.4, 127.8, 127.5, 125.4, 123.6, 122.9, 121.6 , 121.5, 119.2, 119.2, 115.5, 115.1, 66.4, 66.3, 54.0, 52.6, 28.3, 28.2, 23.5

Example 33. (2 E, 5 Z) - {2- [2- ( 2- ethoxyphenyl (N- methylpiperazin-1-yl) imino-5- [5- (4-chlorophenyl) Furan-2-yl] methylene} thiazolidin-4-one (Compound No. 23)

In the same manner as in Example 11, 2- [2- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl] imino-thiazolidin-4-one (95.3 mg, 0.2849 mmol) and 2-formyl-5- (4-chlorophenyl) furan (58.9 mg, 0.2849 mmol) was dissolved in ethanol and piperidine (28.3 mL, 0.2849 mmol) was added dropwise and reacted at 80 ° C for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to give 63.7 mg (43%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.84 (d, J = 8.4 Hz, 1H), 7.68-7.44 (m, 4H), 7.33-6.68 (m, 5H), 4.01 (d, J = 5.5 Hz, 2H), 2.45-2.35 (m, 8H), 2.16 (d, J = 3.5 Hz, 3H), 1.90-1.86 (m, 2H)

Example 34. (2 E, 5 Z) - {2- [3- (3- (N- methylpiperazin-1-yl) propoxy) phenyl] imino-5- [5- (4-chlorophenyl ) Furan-2-yl] methylene} thiazolidin-4-one (Compound No. 24)

In the same manner as in Example 10, 2- [3- (3- (4-methylpiperazin-1-yl) propoxy) phenyl] imino-thiazolidin-4-one (80.4 mg, 0.2307 mmol) and 2-formyl-5- (4-chlorophenyl) furan (47.7 mg, 0.2307 mmol) was dissolved in ethanol and piperidine (22.8 μL, 0.2307 mmol) was added dropwise, followed by reaction at 80 ° C for 12 hours. The solid formed after the reaction was filtered, washed with hexane and anhydrous ethanol and dried to obtain the title compound in 10% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.85 (d, J = 8.4 Hz, 1H), 7.68-7.44 (m, 3H), 7.33 (d, J = 3.9 Hz, 1H), 7.29-6.70 ( m, 5H), 4.07 (d, J = 4.5 Hz, 2H), 2.7 (t, J = 6.0 Hz, 2H), 2.18 (d, J = 2.5 Hz, 3H)

[Formulation example]

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1: tablets (direct pressure)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation 2: tablets (wet granulation)

After 5.0 mg of the active ingredient was sieved, 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 an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3: Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

Formulation 4: Injection

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

On the other hand, for the novel compound represented by the formula (1) according to the present invention was tested for the inhibitory effect on IKK-β by the method as shown in the following experimental example. As a result of the experiment, TR-FRET was used to determine the% inhibition of IKK-β, and IC ₅₀ was determined based on a few compounds showing excellent activity.

The% inhibition and IC ₅₀ of IKK-β of the novel compounds according to the invention were obtained using generally known TR-FRET methods, and the obtained% inhibition and IC ₅₀ are shown in Table 1 below.

Experimental Compound % Inhibition (10 μM) IC ₅₀ Compound number 2 53.8 9.40 Compound number 4 71.9 5.90 Compound number 5 71.9 5.90 Compound number 7 32.9 12.10 Compound number 12 59.3 6.60 Compound number 14 65.7 5.24 Compound number 19 80.8 1.72 Compound number 20 40.4 - Compound number 21 80.2 3.98 Compound number 22 80.3 6.91 Compound number 23 81.0 5.53 Compound number 24 76.8 5.64

As confirmed in Table 1, the thiazolidinone compound represented by Formula 1 according to the present invention exhibits inhibitory activity against IKK-β.

Since the thiazolidin-4-one derivative represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof shows excellent inhibitory activity as an IKK-β inhibitor, rheumatoid arthritis, degenerative arthritis, It is useful for the treatment and prevention of inflammatory diseases such as asthma and chronic obstructive pulmonary disease and cancer.

Claims (7)

A compound selected from a thiazolidin-4-one derivative represented by Formula 1 and a pharmaceutically acceptable salt thereof:
[Formula 1]

In Chemical Formula 1,
A is a single bond, or

Represents;
R ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a C ₁ -C ₆ alkoxy group, a phenoxy, a halosubstituted phenoxy, a piperazinylC ₁ -C ₆ alkoxy group, and ( N- (C ₁ -C ₆ alkyl) ) Piperazinyl) C ₁ -C ₆ alkoxy group selected from 1 to 3 substituted groups;
R ² represents a hydrogen atom, a halogen atom, a nitro group, an amine group, an acetoamino group, a carbamoyl group, a C ₁ -C ₆ alkylaminocarbonyl group, a di (C ₁ -C ₆ alkyl) aminocarbonyl group, C ₁ -C ₆ 1 to 3 substituted groups selected from alkylaminoC ₁ -C ₆ alkoxy groups, di (C ₁ -C ₆ alkyl) aminoC ₁ -C ₆ alkoxy groups, and pyrrolylC ₁ -C ₆ alkoxy groups.
The method according to claim 1,
A compound characterized by the presence of racemics, isomers or mixtures of these isomers.
The method according to claim 1,
A is a single bond, or

Represents;
R ¹ is hydrogen, 2-chloro, 3-chloro, 2-methoxy, 3-methoxy, 3,5-dimethoxy, phenoxy, 4-chlorophenoxy, N -methylpiperazinylethoxy, and N -methylpiperazinylpropoxy;
R ² is hydrogen, 4-chloro, 2-nitro, 3-nitro, 4-nitro, 2-nitro-4-chloro, 4-amino, 4-acetoamino, 3-carbamoyl, 4-carbamoyl, dimethyl A compound selected from the group consisting of aminocarbonyl, methylaminopropoxy, diethylaminopropoxy, and pyrrolylpropoxy.
Claim 1
( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 1);
( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 2);
( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 3 );
( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 4 );
( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 5 );
( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 6 );
( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 7);
( 2E , 5Z )-{2- (3-chlorophenylimino) -5- [5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 8);
( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5- [5- (2-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one ( Compound no. 9);
( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5-[(5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound number 10);
( 2E , 5Z )-{2- (3,5-dimethoxyphenylimino) -5-[(5- (4-chloro-2-nitrophenyl) furan-2-yl] methylene} thiazolidine -4-one (Compound No. 11);
( 2E , 5Z )-{2- (3-hydroxyphenylimino) -5- [5- (3-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 12);
( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 13);
( 2E , 5Z )-{2- (3-hydroxyphenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 14);
( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-acetaminophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 15);
( 2E , 5Z )-{2- (2-chlorophenylimino) -5- [5- (4-aminophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 16 );
( 2E , 5Z )-{2- (2-methoxyphenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 17);
( 2E , 5Z )-{2- (3-hydroxyphenylimino) -5- [5- (4-nitrophenyl) furan-2-yl] methylene} thiazolidin-4-one (Compound No. 18);
( 2E , 5Z )-{2- (3-methoxyphenylimino) -5- [5- (4-carbamoylphenyl) furan-2-yl] methylene} thiazolidin-4-one (compound Number 19);
( 2E , 5Z )-{2- [4- (4-chlorophenoxy) phenyl] imino-5- [3- (3- ( N , N -diethylamino) propoxy) phenyl] methylene} Thiazolidin-4-one (Compound No. 20);
( 2E , 5Z )-{2- [3- (3- ( N -methylpiperazin-1-yl) propoxy) phenyl] imino-5- [5- (4-carbamoylphenyl) furan- 2-yl] methylene} thiazolidin-4-one (Compound No. 21);
( 2E , 5Z )-{2- [4- (4-chlorophenoxy) phenyl] imino-5- [4- (3- (pyrrolidin-1-yl) propoxybenzylidene} thiazoli Din-4-one (Compound No. 22);
( 2E , 5Z )-{2- [2- (2- ( N -methylpiperazin-1-yl) ethoxyphenyl] imino-5- [5- (4-chlorophenyl) furan-2- Il] methylene} thiazolidin-4-one (Compound No. 23); and
( 2E , 5Z )-{2- [3- (3- ( N -methylpiperazin-1-yl) propoxy) phenyl] imino-5- [5- (4-chlorophenyl) furan-2 -Yl] methylene} thiazolidin-4-one (Compound No. 24);
Compound selected from the group consisting of.
A pharmaceutical composition for the treatment of inflammatory diseases or cancers, characterized in that the compound of any one of claims 1 to 4 as an active ingredient.
The method according to claim 5,
The inflammatory disease is a pharmaceutical composition, characterized in that selected from the group consisting of rheumatoid arthritis, degenerative arthritis, asthma, and chronic obstructive pulmonary disease.
Iii) arylthiourea compound represented by the following formula (2) is cyclized with ethyl 2-chloroacetate to prepare 2-arylimino-thiazolidin-4-one compound represented by the following formula (3) or (4). Process of doing; And

(Wherein R ¹ is as defined in claim 1 above)
Ii) a thiazolidinone compound represented by the following formula (1) by condensation reaction of a 2-arylimino-thiazolidin-4-one compound represented by the following formula (3) or (4) with an arylaldehyde compound represented by the following formula (5): Manufacturing process;

(Wherein R ¹ and R ² are each as defined in claim 1 above)
Method for producing a thiazolidinone compound, characterized in that it comprises a.