KR101135574B1 - Derivatives of N-2,2-disubstituted-2H-cromene-6-yl thiourea for treating hepatic fibrosis and cirrhosis - Google Patents

Abstract

The present invention is available N- (2 as an agent for preventing and treating liver diseases such as preventive and therapeutic agents as well as multiple fibers, for example proliferative diseases liver fibrosis, liver cirrhosis, pulmonary fibrosis, scleroderma, glomerular fibrosis is excellent in TGFβ receptor antagonistic activity It relates to a medicinal use of a, 2-disubstituted-2H-chromen-6-yl) thiourea derivative.

TGFβ receptor antagonist, liver cirrhosis, collagen, thiourea, solid phase synthesis, combinatorial chemistry

Description

Ν- (2,2-disubstituted-2Η-chromen-6-yl) thiourea derivatives exhibiting hepatic fibrosis and liver cirrhosis inhibitory activity {Derivatives of N- (2,2-disubstituted-2H-cromene-6-yl ) thiourea for treating hepatic fibrosis and cirrhosis}             

1 is a graph showing TGFβ receptor antagonistic activity of N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivatives.

2 is a graph showing the effect of N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivatives on LI90 cells on cytotoxicity and collagen synthesis.

Figure 3 is a graph showing the effect on collagen gene expression of N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivatives in LI90 cells.

The present invention is available N- (2 as an agent for preventing and treating liver diseases such as preventive and therapeutic agents as well as multiple fibers, for example proliferative diseases liver fibrosis, liver cirrhosis, pulmonary fibrosis, scleroderma, glomerular fibrosis is excellent in TGFβ receptor antagonistic activity It relates to a medicinal use of a, 2-disubstituted-2H-chromen-6-yl) thiourea derivative.

The liver is a biological tissue that plays a pivotal role in metabolism in and out of the body. Continued damage to the liver tissue, such as chronic drinking, binge drinking, viral hepatitis, and drug abuse, leads to chronic liver disease, liver fibrosis and cirrhosis. Liver fibrosis does not show any pain or subjective symptoms in the early stages. The death rate is high, causing social problems. In particular, liver disease is classified into several symptoms. Through early fatty liver, hepatitis, hepatic fibrosis and cirrhosis. Usually, the process of liver fibrosis is reversible, and if cirrhosis occurs, it is known to be irreversible, and treatment of liver disease can be cured by administering a therapeutic drug before the stage of liver fibrosis or in the state of early sclerosis. .

Liver cirrhosis is caused by fibrosis of liver tissue. Liver fibrosis is a condition in which the balance between the synthesis and degradation of connective tissue is lost. It is caused by excessive accumulation of connective tissue in liver tissue and is accompanied by necrosis or inflammation. In particular, hepatic stellate cells (HSCs), which play a role in the storage of vitamin A under normal liver function in the liver, metastasize to myofibroblast form by rapid chronic liver damage and rapidly proliferate to collagen. It is known to advance the process of fibrosis of the liver by increasing the production of extracellular matrix such as proteoglycan, hyaluronan, and the like, and generating excess connective tissues [Friedman et al., Proc. Natl. Acad. Sci. USA, 82: 8681 (1985) Gressner et al., Biochem. Biophys. Res. Commun., 151: 222 (1988) Gressner et al., J. Hepatol., 22: 28 (1995). In this process, TGFβ is produced, secreted and activated from various cells in liver tissues, especially Cooper cells or hepatic stellate cells activated by TGFβ, which induces proliferation and differentiation of hepatic stellate cells. It plays an important role in inducing overproduction and accumulation of extracellular matrix. In chronic liver disease such as hepatic fibrosis or cirrhosis, TGFβ is expressed only in liver tissues undergoing fibrosis and is known to play a role in promoting liver fibrosis by increasing extracellular matrix [Bauer and Schuppan, FEBS Lett. 502: 1-3 (2001); Bedossa and Paradis, J Hepatol., 22 (Suppl. 2): 37-4 (1995).

Until now, the development of therapeutic agents for the inhibition of liver fibrosis or the development of liver cirrhosis has been focused on the development of drugs that can suppress the excessive production of connective tissues represented by collagen of hepatic stellate cells or inhibit the proliferation of these cells. The development of effective therapeutics has been lacking, and recent studies on the inhibition of TGFβ action or the activation of TGFβ receptors, which are the most potent agents of fibrosis of hepatic stellate cells, are among the cytokines involved in fibrosis. Is being studied as a target.

Therefore, the present invention synthesizes a substance having a TGFβ receptor antagonist activity and searched for a compound capable of inhibiting or preventing liver fibrosis using hepatic stellate cells that play a key role in liver fibrosis, N- (2,2 It was confirmed that the bisubstituted-2H-chromen-6-yl) thiourea derivative has an excellent preventive and therapeutic effect on liver fibrosis.

The present inventors synthesized various benzopyran derivatives in view of the fact that natural products and compounds having a benzopyran skeleton exhibit a wide range of pharmacological effects of inhibiting active oxygen, and thus the TGFβ receptor, which is the substance that most strongly induces fibrosis of hepatic stellate cells. Studies on antagonistic activity against hepatic fibroblasts and collagen synthesis and inhibition of cell proliferation have shown that thiourea-based benzopyran derivatives have been shown to inhibit liver TGFβ receptor antagonism and collagen synthesis. The present invention was completed by confirming that the fibrosis inhibitory activity was exhibited.

Accordingly, an object of the present invention is to provide a novel N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivative useful for developing a cirrhosis therapeutic agent, and a method for preparing the same.

It is another object of the present invention to use the novel compounds described above for use as a prophylactic and therapeutic agent for TGFβ activation and overproduction and related diseases caused by extracellular matrix such as excessively accumulated collagen.

The present invention is characterized by the N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivative represented by the following formula (1).

In the above formula (1),

R ¹ is a C ₁ to C ₂₀ alkyl group, an amine group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a naphthyl group, or phenyl-X-, wherein X is a carbonyl group, or C ₁ to C Or an alkyl group of ₆ ) or a 5- to 7-membered heterocycle group forming a ring together with the nitrogen to which R ¹ is bonded;

R ² represents hydrogen or an alkyl group of C ₁ to C ₅ ;

R ³ represents hydrogen, a C ₁ to C ₅ alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; And

Substituted phenyl or substituted benzyl is halogen, nitro group, benzyloxy group, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ alkoxy group, C ₁ ~ C ₅ haloalkyl group, C ₁ ~ C ₅ Or a phenyl or benzyl group substituted with 1 to 4 substituents selected from alkyl sulfide groups and C ₁ to C ₅ alkylsulfanyl groups.

In addition, substituents different from each other at position 2 of benzopyran in the N- (2,2'-disubstituted-2H-chromen-6-yl) thiourea derivative represented by the general formula (1) When there is an optical activity, the present invention also includes isomer compounds of the compound represented by the formula (1).

In the compound represented by the formula (1) according to the present invention, preferably

R ¹ is a C ₁ to C ₂₀ linear, pulverized and cyclic alkyl group; Amine groups; Phenyl group; Halogen, nitro group, benzyloxy group, C ₁ -C ₅ alkyl group, C ₁ -C ₅ alkoxy group, C ₁ -C ₅ haloalkyl group, C ₁ -C ₅ alkylsulfide group, and C ₁ -C ₅ A phenyl group substituted with 1 to 4 substituents selected from an alkylsulfanyl group of C ₅ ; Benzyl groups; Benzyl groups substituted with halogen substituents; Naphthyl group; Or a piperidine group forming a ring together with a nitrogen to which R ¹ is bonded, a piperidine group substituted with a C ₁ to C ₅ alkoxycarbonyl, a piperazine group, or a phenyl substituted piperazine group;

R ² represents hydrogen or an alkyl group of C ₁ to C ₅ ;

Wherein R ³ will represent hydrogen, C ₁ ~ C ₅ alkyl group, or benzyl.

On the other hand, the present invention includes a method for preparing the compound represented by the formula (1) by a high-efficiency solution-phase synthesis technology, the preparation method is briefly shown in the following scheme 1.                     

In Scheme 1, R ¹ , R ² , and R ³ are each as defined above, ⓟ is a polymer form selected from polystyrene, polystyrene-divinylbenzene, polymethacrylic acid-dimethylacrylamide and polyhydroxy methacrylic acid The solid support of is shown.

The 2,2-disubstituted-2H-6-amino-chromen derivative represented by Formula (2) used as a raw material in the production method according to the present invention is a known compound, and is easily prepared by a known production method. Can be used.

According to the preparation method of the present invention according to Scheme 1, 2,2-disubstituted-2H-6-amino-chromen represented by Chemical Formula (2) and various R ¹ represented by Chemical Formula (3) The isothiocyanate derivative is reacted to synthesize a thiourea into which R ¹ is represented by formula (1).

In addition, the present invention also provides a method for removing the unreacted isothiocyanate derivative represented by the general formula (3) using a scavenger resin having an amine group represented by the chemical formula (4) after completion of the reaction. As a result, many thiourea-based benzopyran derivatives could be synthesized in a short time by using scavenger resin having an amine group in the post-reaction treatment.

Referring to the reaction process according to the invention, the composition of the solvent system and the selection range of the reaction conditions in detail.

In the present invention, an organic solvent having excellent swelling effect of a solid resin is used in consideration of using a solid scavenger resin in the final step. For example, dichloromethane (CH ₂ Cl ₂ ), chloroform (CHCl ₃ ) and tetrahydrofuran (THF) are used as the solvent. For isothiocyanate derivative represented by the general formula (3) for introducing the R ¹ substituent, it is preferable to use 1.2 to 2.0 equivalents with respect to the compound represented by the general formula (2), preferably using 1.2 equivalents. This is excellent. After completion of the reaction, the unreacted isothiocyanate can be easily removed by filtration of scavenger resin having an amine group, thereby allowing several reactions and post-reaction treatments at the same time.

In addition, in order to confirm the production of the target compound represented by Chemical Formula (1) according to the present invention, there is a multi-column chromatography equipment (Quad ³⁺ ; manufactured by Biotage, USA) and an automatic sample injection device in the final step after the reaction. After separation and purification by high performance liquid chromatography, the structure was analyzed by NMR and Mass spectra.

In addition, 2,2-disubstituted-2H-6-amino-chromen derivative represented by Chemical Formula (2) used as a raw material in the manufacturing process according to the present invention and the chemical formula (1) N- represented by (2,2-disubstituted -2H- chromen-6-yl) - N '- thiourea by an optical isomer is present bar, it performs a known separation and purification methods as necessary for each Pure optical isomeric compounds can also be separated.

Meanwhile, the compounds of the present invention can be usefully used as a prophylactic and therapeutic agent for various liver diseases caused by TGFβ activity, collagen synthesis activity, and cirrhosis activity. Accordingly, the present invention includes an agent for preventing and treating liver disease, in which the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is contained as an active ingredient. In addition, since the compound according to the present invention has TGFβ receptor antagonistic activity, it may be used as a prophylactic and therapeutic agent for various fibrotic diseases such as liver fibrosis, cirrhosis, pulmonary fibrosis, scleroderma, renal glomerulosis and the like.

Pharmaceutically acceptable salts in the present invention can be prepared by conventional methods in the art, for example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, and the like. Or pharmaceutically acceptable organic compounds, such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) It is also possible to form salts of acids, or to react with alkali metal ions such as sodium and potassium to form their metal salts, or to react with ammonium ions to form another form of a pharmaceutically acceptable salt.

In addition, the pharmaceutical compositions of the present invention are conventionally non-toxic pharmaceutically acceptable to N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivatives or pharmaceutically acceptable salts thereof. Carriers, adjuvant and excipients may be added to formulate into conventional formulations, such as tablets, capsules, troches, solutions, suspensions, or parenteral administration, in the pharmaceutical field. In addition, the dosage of the compound 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, and generally based on an adult patient having a weight of 70 kg. It is 0.01-1000 mg / day, and it can also divide and administer once a day to several times at fixed time intervals according to the judgment of a doctor or a pharmacist.

The present invention as described above has been described in more detail based on the following representative examples, but the present invention is not limited to these representative examples.

Example: N- (2,2- disubstituted -2H- chromen-6-yl) - N '- thiourea synthesis of (I)

Example 1) Synthesis of 1- (2,2-dimethyl-2H-chromen-6-yl) -3-phenyl-thiourea

The benzopyrene compound represented by the formula (2a) (100.0 mg, 0.57 mmol) was dissolved in dichloromethane (DCM, 2 mL), stirred at room temperature for 10 minutes, and then phenyl isothiocyanate represented by the formula (3a) ( C ₆ H ₄ NCS; 92.0 mg, 0.68 mmol, 1.2 eq) was added and stirred at the same temperature for 15 hours. After completion of the reaction, polystyrene diamine (3.0 mmol / g, 0.34 g, 1 mmol) represented by Formula (4) was added to the reaction, followed by stirring for 30 minutes. The reaction mixture was filtered, the filtrate was repeatedly washed with chloroform (CHCl ₃ ), the filtrates were combined, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ). Separation and purification afforded the title compound (115 mg, yield 65%) represented by Chemical Formula (1a).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23 (d, 1H, J = 7.9 Hz), 7.77 (s, 1H), 7.39 (s, 1H), 7.38-7.27 (m, 2H), 7.14-7.08 ( m, 3H), 7.00 (d, 2H), 6.82 (d, 1H, J = 8.5 Hz), 6.30 (d, 1H, J = 9.9 Hz), 5.69 (d, 1H, J = 9.9 Hz), 1.45 ( s, 6H); M / S 310.42

Example 2 Synthesis of 1- (2,2-dimethyl-2H-chromen-6-yl) -3- (4-nitro-phenyl) -thiourea

The benzopyrene compound represented by the formula (2a) (100 mg, 0.57 mmol) was dissolved in dichloromethane (DCM, 15 mL), stirred at room temperature for 10 minutes, and then 4-nitrophenyl isothiacia represented by the formula (3b). Nate (4-O ₂ NC ₆ H ₄ NCS; 122 mg, 0.68 mmol, 1.2 eq) was added and stirred at the same temperature for 15 hours. After completion of the reaction, polystyrene diamine (3.0 mmol / g, 0.34 g, 1 mmol) represented by Formula (4) was added to the reaction, followed by stirring for 30 minutes. The reaction mixture was filtered, the filtrate was repeatedly washed with chloroform (CHCl ₃ ), the filtrates were combined, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ). Separation and purification gave the title compound represented by the formula (1b) as a yellow solid (150 mg, yield 74%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.20 (d, 2H, J = 9.2 Hz), 7.75 (d, 2H, J = 9.2 Hz), 7.07 (m, 1H), 6.94-6.83 (m, 2H) , 6.30 (d, 1H, J = 9.8 Hz), 5.72 (d, 1H, J = 9.8 Hz), 1.47 (s, 6H); M / S 355.44

Example 3) Synthesis of 1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -3- (4-nitro-phenyl) -thiourea

The desired intermediate compound represented by formula (1c) was obtained by the method of Example 1-1.

M / S 397.49

Example 4) Synthesis of 1- (2-methyl-2-phenethyl-2H-chromen-6-yl) -3- (4-nitro-phenyl) -thiourea                     

The title compound represented by the formula (1d) was obtained by the method of Example 1.

M / S 445.54

Example 5) Synthesis of 1- (2,7-dimethyl-2-phenethyl-2H-chromen-6-yl) -3- (4-nitro-phenyl) -thiourea

The title compound represented by the formula (1e) was obtained by the method of Example 1.

M / S 459.59

In addition, the results of synthesizing the compound represented by Chemical Formula 1 according to the present invention based on the preparation method illustrated in the above Examples are shown in Table 1 below.                     

Compound number R ¹ R ² R ³ Structure confirmation data One Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.23 (d, 1H, J = 7.9 Hz), 7.77 (s, 1H), 7.39 (s, 1H), 7.38-7.27 (m, 2H), 7.14-7.08 (m, 3H), 7.00 (d, 2H), 6.82 (d, 1H, J = 8.5 Hz), 6.30 (d, 1H, J = 9.9 Hz), 5.69 (d, 1H, J = 9.9 Hz), 1.45 (s, 6H); M / S 310.42 2 4-NO ₂ -Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.20 (d, 2H, J = 9.2 Hz), 7.75 (d, 2H, J = 9.2 Hz), 7.07 (m, 1H), 6.94-6.83 (m, 2H ), 6.30 (d, 1H, J = 9.8 Hz), 5.72 (d, 1H, J = 9.8 Hz), 1.47 (s, 6H); M / S 355.44 3 3,4-di-Cl-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.73 (br, 1H), 7.59-7.58 (m, 1H), 7.43-7.40 (m, 1H), 7.36-7.32 (m, 1H), 7.06-7.02 ( m, 1H), 6.93-6.92 (m, 1H), 6.85-6.82 (m, 1H), 6.28 (d, 1H, J = 9.9 Hz), 5.69 (d, 1H, J = 9.9 H) 4 2,4-di-F-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.26 (br, 1H), 7.85-7.80 (m, 1H), 7.38 (br, 1H), 7.08-7.05 (m, 1H), 6.96-6.95 (m, 1H), 6.93-6.81 (m, 1H), 6.28 (d, 1H, J = 9.9 Hz), 5.68 (d, 1H, J = 9.9 Hz), 1.45 (s, 6H) 5 adamantyl H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.26-7.23 (m, 1H), 6.94-6.91 (m, 1H), 6.81-6.76 (m, 1H), 6.28 (d, 1H, J = 9.9 Hz) , 5.70 (d, 1H, J = 9.9 Hz), 2.18 (br, 6H), 2.09 (br, 2H), 1.67 (br, 6H), 1.60 (s, 1H), 1.44 (s, 6H) 6 2-ethyl-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (br, 1H), 7.41-7.38 (m, 1H), 7.30-7.23 (m, 4H), 7.08-7.04 (m, 1H), 6.99-6.98 (m , 1H), 6.78-6.76 (m, 1H), 6.26 (d, 1H, J = 9.8 Hz), 5.63 (d, 1H, J = 9.8 Hz), 2.64 (q, 2H), 1.42 (s, 6H) , 1.19 (t, 3H)

7 2,2,4-Trimethyl-pentyl H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.22 (br, 1H), 6.94-6.90 (m, 1H), 6.80-6.78 (m, 2H), 6.27 (d, 1H, J = 9.9 Hz), 5.84 (br, 1H), 5.68 (d, 1H, J = 9.9 Hz), 1.54 (s, 6H), 1.44 (s, 1H), 0.91 (s, 11H) 8

H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.59 (br, 2H), 7.43 7.29 (m, 7H), 7.07-6.97 (m, 4H), 6.78 (d, 1H, J = 8.4 Hz), 6.27 ( d, 1H, J = 9.9 Hz), 5.64 (d, 1H, J = 9.9 Hz), 5.08 (s, 2H), 1.43 (s, 6H) 9 Phenethyl H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.74 (br, 1H), 7.27-7.20 (m, 3H), 7.14-7.11 (m, 2H), 6.74-6.63 (m, 3H), 6.17 (d, 1H, J = 9.9 Hz), 5.81 (br, 1H), 5.66 (d, 1H, J = 9.9 Hz), 3.86 (t, 2H), 2.90 (t, 2H), 1.43 (s, 6H) 10 benzoyl H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 12.40 (br, 1H), 9.08 (br, 1H), 7.88 (d, 2H, J = 7.5 Hz), 7.87-7.51 (m, 3H), 7.38-7.35 (m, 2H), 6.80 (d, 1H, J = 9.0 Hz), 6.32 (d, 1H, J = 9.9 Hz), 5.65 (d, 1H, J = 9.9 Hz), 1.44 (s, 6H) 11 cyclohexyl H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.61 (br, 1H), 6.90 (m, 1H), 6.79-6.74 (m, 2H), 6.25 (d, 1H, J = 10.0 Hz), 5.67 (d , 1H, J = 10.0 Hz), 4.27-4.15 (m, 1H), 2.01 (br, 2H), 1.62 (br, 3H), 1.43 (s, 6H), 1.35 (br, 2H), 1.09 (br, 3H) 12 2,5-di-MeO-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.19 (br, 2H), 7.79 (br, 1H), 7.09-7.03 (m, 1H), 6.98-6.97 (m, 1H), 6.84-6.75 (m, 2H), 6.67-6.61 (m, 1H), 6.25 (d, 1H, J = 10.0 Hz), 5.67 (d, 1H, J = 10.0 Hz), 3.79 (s, 3H), 3.69 (s, 3H), 1.45 (s, 6 H) 13 1-naphthyl H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.98 (br, 1H), 7.93-7.86 (m, 3H), 7.60-7.50 (m, 4H), 7.07-6.97 (m, 2H), 6.75 (d, 1H, J = 8.4 Hz), 6.26 (d, 1H, J = 9.6 Hz), 5.63 (d, 1H, J = 9.6 Hz), 1.41 (s, 6H) 14 3-Cl-4-Me-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.89 (br, 1H), 7.59 (br, 1H), 7.39 (s, 1H), 7.22 (s, 2H), 7.07-7.02 (m, 1H), 6.95 -6.94 (m, 1H), 6.82-6.78 (m, 1H), 6.28 (d, 1H, J = 9.8 Hz), 5.67 (d, 1H, J = 9.8 Hz), 2.34 (s, 3H), 1.44 ( s, 6 H) 15

H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.85 (br, 1H), 7.67 (br, 1H), 7.30 (d, 2H, J = 8.61 Hz), 7.30 (d, 2H, J = 8.61 Hz), 7.25-7.23 (d, 2H, J = 8.61 Hz), 7.07 7.04 (m, 1H), 6.96-6.95 (m, 1H), 6.79 (d, 1H, J = 8.4 Hz), 6.27 (d, 1H, J = 9.9 Hz), 5.65 (d, 1H, J = 9.9 Hz), 2.47 (s, 3H), 1.44 (s, 6H)

16

H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.79 (br, 1H), 7.66 (br, 1H), 7.31 (s, 1H), 7.30-7.23 (m, 1H), 7.15 7.02 (m, 3H), 6.96-6.95 (m, 1H), 6.78 (d, 1H, J = 8.5 Hz), 6.27 (d, 1H, J = 10.0 Hz), 5.66 (d, 1H, J = 10.0 Hz), 2.47 (s, 3H ), 1.44 (s, 6H) 17 2-isopropyl-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (br, 1H), 7.38 7.22 (m, 4H), 7.07-6.98 (m, 1H), 6.76 (d, 1H, J = 8.5 Hz), 6.26 ( d, 1H, J = 9.8 Hz, 5.63 (d, 1H, J = 9.8 Hz), 3.17-3.13 (m, 1H), 1.42 (s, 6H), 1.24 (s, 6H) 18 5-Cl-2-MeO-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.09-6.95 (m, 3H), 6.85-6.73 (m, 3H), 6.31 (d, 1H, J = 9.8 Hz), 5.69 (m, 1H, J = 9.8 Hz), 3.73 (s, 3H), 1.46 (s, 6H) 19

H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.41 (br, 1H), 7.98 (s, 2H), 7.67 (s, 2H), 7.07-7.03 (m, 1H), 6.93-6.92 (m, 1H) , 6.84 (d, 1H, J = 8.5 Hz), 6.28 (d, 1H, J = 9.9 Hz), 5.71 (d, 1H, J = 9.9 Hz), 1.46 (s, 6H) 20

H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.02 (br, 1H), 7.28-7.24 (m, 3H), 6.89-6.67 (m, 3H), 6.23 (d, 1H, J = 9.8 Hz), 5.58 (d, 1H, J = 9.8 Hz), 3.36-3.22 (m, 2H), 1.44 1.09 (m, 18H) 21 3,5-di-Me-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.82 (br, 2H), 7.08 6.89 (m, 5H), 6.75 (d, 1H, J = 8.5 Hz), 6.27 (d, 1H, J = 9.6 Hz) , 5.64 (d, 1H, J = 9.6 Hz), 2.30 (s, 6H), 1.42 (s, 6H) 22

H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.30 (br, 1H), 7.89 (d, 1H, J = 8.5 Hz), 7.73-7.64 (m, 2H), 7.48 (br, 1H), 7.07-7.02 (m, 1H), 6.95-6.93 (m, 1H), 6.82 (d, 1H, J = 8.3 Hz), 6.29 (d, 1H, J = 9.8 Hz), 5.68 (d, 1H, J = 9.8 Hz) , 1.43 (s, 6H) 23 2-F-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.06-8.01 (m, 1H), 7.98 (br, 1H), 7.53 (br, 1H), 7.22-7.04 (m, 4H), 6.98-6.96 (m, 1H), 6.82 (d, 1H, J = 8.5 Hz), 6.29 (d, 1H, J = 9.8 Hz), 5.68 (d, 1H, J = 9.8 Hz), 1.45 (s, 6H) 24 3-Me-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.80 (br, 2H), 7.27-7.16 (m, 4H), 7.09-7.04 (m, 1H), 6.98-6.97 (m, 1H), 6.77 (d, 1H, J = 8.3 Hz), 6.28 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 2.35 (s, 3H), 1.43 (s, 6H) 25 3-MeO-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.58 (br, 2H), 7.30-7.24 (m, 2H), 7.09-6.89 (m, 4H), 6.78 (d, 1H, J = 8.5 Hz), 6.28 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 3.81 (s, 3H), 1.44 (s, 6H)

26 cyclopentyl H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.62 (br, 1H), 6.95 .81 (m, 1H), 6.80-6.76 (m, 2H), 6.27 (d, 1H, J = 10.0 Hz), 5.67 (d, 1H, J = 10.0 Hz), 4.70-4.59 (m, 1H), 2.12-1.99 (br, 2H), 1.67-1.55 (br, 4H), 1.44 (s, 1H), 1.40 1.25 (br, 2H) 27

H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.84 (br, 1H), 7.27 7.23 (m, 2H), 7.03-6.89 (m, 3H), 6.78-6.75 (m, 2H), 6.23 (d, 1H) , J = 9.6 Hz), 6.01 (br, 1H), 5.66 (d, 1H, J = 9.6 Hz), 1.44 (s, 12H) 28 undecyl H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.66 (br, 1H), 6.97-6.91 (m, 1H), 6.83-6.77 (m, 2H), 6.26 (d, 1H, J = 9.8 Hz), 5.68 (d, 1H, J = 9.8 Hz), 3.64-3.54 (m, 2H), 1.45 (s, 6H), 1.25 (s, 9H), 0.88 (t, 3H) 29

H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.03 (br, 1H), 8.03 (br, 1H), 7.73-7.68 (m, 1H), 7.52-7.45 (m, 2H), 7.09-7.03 (m, 1H), 6.94-6.93 (m, 1H), 6.85 (d, 1H, J = 8.5 Hz), 6.30 (d, 1H, J = 10.0 Hz), 5.71 (d, 1H, J = 10.0 Hz), 1.47 ( s, 6 H) 30 heptyl H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.69 (br, 1H), 6.97-6.91 (m, 1H), 6.83-6.77 (m, 2H), 6.26 (d, 1H, J = 10.0 Hz), 5.82 (br, 1H), 5.68 (d, 1H, J = 10.0 Hz), 3.64-3.54 (m, 2H), 1.45 (s, 6H), 1.26 (s, 9H), 0.87 (t, 3H) 31

H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.31 (br, 1H), 7.72-7.65 (m, 2H), 7.47-7.44 (m, 2H), 7.08-7.02 (m, 1H), 6.94-6.93 ( m, 1H), 6.81 (d, 1H, J = 8.5 Hz), 6.28 (d, 1H, J = 9.8 Hz), 1.45 (d, 1H, J = 9.8 Hz), 1.45 (s, 6H) 32 2-MeO-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.02 (br, 1H), 7.83 (br, 1H), 7.18-6.94 (m, 4H), 6.89-6.79 (m, 3H), 6.29 (d, 1H, J = 9.8 Hz), 5.67 (d, 1H, J = 9.8 Hz), 3.76 (s, 3H), 1.45 (s, 6H) 33

H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.93 (br, 1H), 7.46 (s, 1H), 7.17-7.13 (m, 2H), 7.9-7.03 (m, 1H), 6.97-6.95 (m. 1H), 6.79 (d, 1H, J = 8.5 Hz), 6.28 (d, 1H, J = 10.0 Hz), 5.67 (d, 1H, J = 10.0 Hz), 2.22 (s, 3H), 1.44 (s, 6H) 34 4-MeO-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.69 (br, 2H), 7.27 (d, 2H, J = 9.0 Hz), 7.08-7.04 (m, 1H), 6.98-6.97 (m, 1H), 6.91 (d, 2H, J = 9.0 Hz), 6.77 (d, 1H, J = 8.4 Hz), 6.27 (d, 1H, J = 9.9 Hz), 5.63 (d, 1H, J = 9.9 Hz), 3.80 (s , 3H), 1.43 (s, 6H)

35 octyl H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.70 (br, 1H), 6.97-6.91 (m, 1H), 6.83-6.77 (m, 2H), 6.26 (d, 1H, J = 9.8 Hz), 5.83 (br, 1H), 5.68 (d, 1H, J = 9.8 Hz), 3.64-3.54 (m, 2H), 1.71 1.51 (m, 2H), 1.45 (s, 6H), 1.25 (s, 10H), 0.87 (t, 3H) 36

H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.84 (br, 1H), 7.27-7.23 (m, 2H), 7.03-6.89 (m, 3H), 6.78-6.75 (m, 2H), 6.23 (d, 1H, J = 9.6 Hz), 6.01 (br, 1H), 5.66 (d, 1H, J = 9.6 Hz), 1.44 (s, 12H) 37 2-Cl-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.93 (br, 1H), 7.83 (br, 1H), 7.39-7.27 (m, 4H), 7.08-7.04 (m, 1H), 6.98-6.97 (m, 1H), 6.77 (d, 1H, J = 8.5 Hz), 6.27 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 1.44 (s, 6H) 38 2,6-di-Me-Ph H H ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.17-6.99 (m, 6H), 6.27 (d, 1H, J = 9.0 Hz), 5.61 (d, 1H, J = 9.0 Hz), 2.35 (s, 6H ), 1.43 (s, 6H) 39 3,5-di-methoxy-Ph H H ¹ H NMR (200 MHz, CDCl ₃ ): δ 6.78 (br, 1H), 6.70 (s, 1H), 6.58 (s, 1H), 6.23 (d, 1H, J = 10.0 Hz), 5.49 (d, 1H, J = 10.0 Hz), 3.75-3.73 (br, 4H), 2.15 (s, 3H), 1.69-1.56 (br, 6H), 1.52-1.36 (m, 2H), 1.34 (s, 6H), 0.89 (t , 3H, J = 7.1 Hz) 40 3,5-di-Me-Ph- Me H ¹ H NMR ( 200 MHz, CDCl ₃ ): δ 7.54 (br, 1H), 6.98-6.88 (m, 4H), 6.69 (s, 1H), 6.25 (d, 1H, J = 10.0 Hz), 5.59 (d , 1H, J = 10.0 Hz), 2.31 (s, 6H), 2.30 (s, 3H), 1.43 (s, 6H) 41 cyclopentyl Me H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.31 (br, 1H), 6.78 (s, 1H), 6.69 (s, 1H), 6.25 (d, 1H, J = 9.8 Hz), 5.63 (d, 1H , J = 9.8 Hz), 5.48-5.45 (m, 1H), 4.71-4.61 (m, 1H), 2.17 (s, 3H), 2.14-1.99 (br, 2H), 1.61-1.49 (br, 4H), 1.44 (s, 6H), 1.39-1.25 (br, 2H) 42 heptyl Me H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.40 (br, 1H), 6.79 (s, 1H), 6.70 (s, 1H), 6.25 (d, 1H, J = 10.0 Hz), 5.63 (d, 1H , J = 10.0 Hz), 3.63-3.53 (m, 2H), 2.18 (s, 3H), 1.71 1.48 (m, 2H), 1.44 (s, 6H), 1.24 (s, 8H), 0.87 (t, 3H ) 43

Me H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.93 (br, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 6.54 (br, 1H), 6.28 (d, 1H, J = 9.8 Hz ), 5.65 (d, 1H, J = 9.8 Hz), 2.30 (s, 3H), 1.45 (s, 6H) 44 benzoyl Me H ¹ H NMR (200 MHz, CDCl ₃ ): δ 9.20 (br, 1H), 7.93 7.88 (m, 2H), 7.66-7.50 (m, 3H), 7.32 (s, 1H), 6.70 (s, 1H), 6.30 (d, 1H, J = 9.8 Hz), 5.59 (d, 1H, J = 9.8 Hz), 2.28 (s, 3H), 1.44 (s, 6H)

45 undecyl Me H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.25 (br, 1H), 6.78 (s, 1H), 6.70 (s, 1H), 6.24 (d, 1H, J = 9.8 Hz), 5.62 (d, 1H , J = 9.8 Hz), 3.63-3.53 (m, 2H), 2.17 (s, 3H), 1.43 (s, 6H), 1.23 (s, 8H), 0.87 (t, 3H)
46 Me H ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.17 (br, 1H), 7.98-7.97 (m, 2H), 7.66 (s, 1H), 7.42 (br, 1H), 6.90 (s, 1H), 6.75 (s, 1H), 6.28 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 2.28 (s, 3H), 1.45 (s, 6H) 47 2-Cl-Ph Me H M / S 358.9 48 3-Cl-4-Me-Ph Me H M / S 372.9 49 2,6-di-Me-Ph Me H M / S 352.5 50 2-ethyl-Ph Me H M / S 352.5 51 3-methyl sulfanyl-Ph Me H M / S 370.5 52 2-MeO-Ph Me H M / S 354.5 53 3-Cl-2-Me-Ph Me H ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.65 (br, 1H), 7.20-7.11 (m, 2H), 6.91 (s, 1H), 6.71 (s, 1H), 6.25 (d, 1H, J = 9.8 Hz), 5.62 (d, 1H, J = 9.8 Hz), 2.27 (s, 3H), 2.18 (d, 3H), 1.42 (s, 6H) 54 4-NO ₂ -Ph Me H M / S 369.4 55 3-trifluoro methyl-Ph Me H M / S 392.4 56 phenethyl Me H M / S 352.5 57 4-MeO-Ph Me CH ₂ CH ₃ M / S 366.5 58 4-Me-Ph Me CH ₂ CH ₃ M / S 350.5 59 4-Cl-Ph Me CH ₂ CH ₃ M / S 370.9 60 4-NO ₂ -Ph Me CH ₂ CH ₃ M / S 381.4 61 4-F-Ph Me CH ₂ CH ₃ M / S 354.4 62 3,4-di-Me-Ph Me CH ₂ CH ₃ M / S 364.5 63

Me CH ₂ CH ₃ ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.31-7.21 (m, 2H), 6.92-6.85 (m, 4H), 6.73 (s, 1H), 6.61 (s, 1H), 6.24 (d, 1H, J = 10.0 Hz), 5.49 (d, 1H, J = 10.0 Hz), 3.98-3.93 (m, 4H), 3.27-3.21 (m, 4H), 2.17 (s, 3H), 1.71-1.57 (m, 2H) , 1.51-1.38 (m, 2H), 1.35 (s, 3H), 0.93-0.86 (m, 3H) 64 4-Cl-Bn Me CH ₂ CH ₃ M / S 400.9 65

Me CH ₂ CH ₃ ¹ H NMR (200 MHz, CDCl ₃ ): δ 6.87 (br, 1H), 6.68 (s, 1H), 6.58 (s, 1H), 6.23 (d, 1H, J = 10.2 Hz), 5.48 (d, 1H , J = 10.2 Hz), 4.35 (br, 2H), 3.67 (s, 3H), 3.22 (br, 2H), 2.59-2.49 (m, 1H), 2.14 (s, 3H), 2.02-1.50 (br, 6H), 1.46-1.34 (m, 5H), 0.88 (t, 3H, J = 7.3 Hz)

66

Me CH ₂ CH ₃ ¹ H NMR (200 MHz, CDCl ₃ ): δ 6.78 (br, 1H), 6.70 (s, 1H), 6.58 (s, 1H), 6.23 (d, 1H, J = 10.0 Hz), 5.49 (d, 1H , J = 10.0 Hz), 3.75-3.73 (br, 4H), 2.15 (s, 3H), 1.69-1.56 (br, 6H), 1.52-1.36 (m, 2H), 1.34 (s, 6H), 0.89 ( t, 3H, J = 7.1 Hz) 67

Me CH ₂ CH ₃ ¹ H NMR (200 MHz, CDCl ₃ ): δ 9.08 (br, 1H), 7.00 (s, 1H), 6.61 (s, 1H), 6.28 (d, 1H, J = 9.8 Hz), 5.47 (d, 1H , J = 9.8 Hz), 3.71 (s, 3H), 2.17 (s, 3H), 1.74-1.57 (m, 2H), 1.51-1.38 (m, 2H), 1.35 (s, 3H), 0.89 (t, 3H, J = 7.1 Hz) 68 4-MeO-Ph H CH ₂ Ph M / S 414.5 69 4-Me-Ph H CH ₂ Ph M / S 398.5 70 4-Cl-Ph H CH ₂ Ph M / S 418.9 71 4-NO ₂ -Ph H CH ₂ Ph M / S 429.5 72 4-F-Me-Ph H CH ₂ Ph M / S 402.5 73 3,4-di-Me-Ph H CH ₂ Ph M / S 412.5 74 4-MeO-Ph Me CH ₂ Ph M / S 428.5 75 4-Me-Ph Me CH ₂ Ph M / S 412.5 76 4-Cl-Ph Me CH ₂ Ph M / S 432.9 77 4-NO ₂ -Ph Me CH ₂ Ph M / S 443.5 78 4-F-Me-Ph Me CH ₂ Ph M / S 416.5 79 3,4-di-Me-Ph Me CH ₂ Ph M / S 426.6

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

Formulation 1: tablet (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: Tablet (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 the 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.

Experimental Example: Bioassay Experiment

Experimental Example 1) TGFβ Receptor Antagonistic Activity Test

TGFβ cytokine, produced and secreted by inflammatory cells and Kupffer cells during the damage of liver cells, the most important process of hepatic fibrosis / cirrhosis, induces the proliferation and differentiation of hepatic stellate cells, resulting in extracellular matrix such as collagen ( overproduction and accumulation of extracellular matrix). Therefore, a substance that inhibits the action of TGFβ to inhibit the proliferation and differentiation of hepatic stellate cells and the chemotactic mechanism of inflammatory cells may be developed as a therapeutic agent for liver fibrosis / liver cirrhosis.

In this experimental example, we searched for a substance that blocks intracellular signaling by TGFβ by competitively antagonizing the binding of TGFβ receptor and its endogenous ligand, TGFβ. TGFβ receptor dissolved in sodium carbonate solution was added to each well of the plate and attached overnight at 4 ° C. Purified biotin-TGFβ was dissolved in Tris-HCl buffer and then added to each well with the compound to be searched and reacted at room temperature for 1 hour to induce the binding reaction of TGFβ receptor and biotin-TGFβ. Each well was washed with PBS-0.05% Tween 20 solution (PBST buffer) and then streptavidin (Streptavidin) labeled with HRP was added and reacted at room temperature for 1 hour. After washing each well using PBST buffer, the reaction was stopped by adding TMB solution, a substrate of HRP, and reacting at room temperature for 20 minutes to develop color, and then adding the same amount of 1 M phosphoric acid solution. After stopping the reaction, absorbance was measured at a wavelength of 450 nm and a wavelength of 540 nm. As a result, these N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivatives exhibited antagonistic activity against TGFβ receptors, and a portion of the compound exhibited excellent receptor antagonistic activity of 50% or more in the results. An example of results for is shown in FIG. 1. In the above results, the compounds showing antagonistic activity against TGFβ receptor were expected to be able to inhibit fibrosis in hepatic stellate cells.

Experimental Example 2) Collagen Synthesis Inhibitory Activity Test

Hepatic fibrosis is a process by which hepatic stellate cells proliferate and become active, resulting in collagen accumulation by increasing collagen synthesis and decreasing degradation. Therefore, as hepatic fibrosis progresses, collagen synthesis is increased from activated hepatic stellate cells and collagen secretion is increased outside the cells. Therefore, the inhibitory effect of hepatic fibrosis can be confirmed by observing cytotoxicity and collagen synthesis effect of hepatic stellate cells.

LI90 cells, a human activated hepatic stellate cell line, were purchased from the Japanese Collection of Research Bioresources (JCRB) cell line bank in Japan. The LI90 cell line was incubated in 96-well plates for 24 hours with Dulbecco's modified Eagles Medium (DMEM) supplemented with 10% Fetal bovine serum (FBS). The fetal calf serum-free medium was changed and the drugs were treated at various concentrations. After 48 hours of drug treatment, cytotoxicity was measured by MTS assay using Promega's CellTiter 96 non radioactive cell proliferation assay kit. In addition, using the anti-rabbit human collagen antibody of ABcam of England, collagen in the culture was measured by ELISA method and the results are shown in FIG. 2. Most N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivatives that showed antagonistic activity on TGFβ receptors inhibited the proliferation of hepatic stellate cells and also inhibited collagen synthesis and secretion by more than 50%. It was. Therefore, it can be seen that these compounds have a hepatic fibrosis inhibitory effect by inhibiting the proliferation of hepatic stellate cells causing abnormal proliferation and activation to induce hepatic fibrosis, and inhibiting the synthesis and secretion of collagen from the cells.

Experimental Example 3) Collagen Gene Expression Inhibition

The main collagen involved in hepatic fibrosis is Type 1 collagen, which consists of α1 and α2 chains. Collagen expression involves a number of transcription factors at the collagen gene promoter site. In general, collagen expression increases as collagen transcription increases. Therefore, the degree of inhibition of hepatic fibrosis can be measured by observing a decrease in the activity of the collagen promoter. In this experimental example, the inhibitory effect of collagen promoter activity was measured by the following method.

Transfection with pCOL1A2-Luc plasmid in which the 3.3 kb promoter of type 1 collagen α2 chain (COL1A2) was inserted into the pGL3 base vector containing luciferase as a receptor gene in the same LI90 cell line used in Experimental Example 2 To correct for transfection, the Herpes simplex virus thymidine kinase (HSV-TK) vector containing the Renilla luciferase gene was simultaneously transfected with lipofectamine plus (Life Sciences, USA) for 24 hours. It was changed to DMEM without fetal calf serum. At this time, the chemicals were added together, cultured for 24 hours, and the cells were digested to measure luciferase activity using a Promega dual-luciferase assay kit. The ratio of the obtained fire fly luciferase activity to Renilla luciferase activity was determined, and the degree of activity inhibition was measured. The results are shown in FIG. 3. As in the result of Experimental Example 2, these compounds reduced Col1A2 promoter activity by 60% or more to inhibit the transcription of collagen gene, it was found that the amount of collagen expression is suppressed.

As mentioned above, the compound of the present invention, N- (2,2-bisubstituted-2H-chromen-6-yl) thiourea derivative, inhibits TGFβ receptor antagonistic activity, collagen synthesis inhibitory activity, and liver cirrhosis inhibitory activity. It is extremely useful for the prevention and treatment of liver cirrhosis.

Claims (6)

N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivative, characterized by the following formula (1): [Formula 1]

In the above formula (1), R ¹ is a C ₁ to C ₂₀ alkyl group, an amine group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a naphthyl group, or phenyl-X-, wherein X is a carbonyl group, or C ₁ to C Or an alkyl group of ₆ ) or a 5- to 7-membered heterocycle group forming a ring together with the nitrogen to which R ¹ is bonded; R ² represents hydrogen or an alkyl group of C ₁ to C ₅ ; R ³ represents hydrogen, a C ₁ to C ₅ alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; And Substituted phenyl or substituted benzyl is halogen, nitro group, benzyloxy group, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ alkoxy group, C ₁ ~ C ₅ haloalkyl group, C ₁ ~ C ₅ Or a phenyl or benzyl group substituted with 1 to 4 substituents selected from alkyl sulfide groups and C ₁ to C ₅ alkylsulfanyl groups. The method of claim 1, R ¹ is a C ₁ to C ₂₀ linear, pulverized and cyclic alkyl group; Amine groups; Phenyl group; Halogen, nitro group, benzyloxy group, C ₁ -C ₅ alkyl group, C ₁ -C ₅ alkoxy group, C ₁ -C ₅ haloalkyl group, C ₁ -C ₅ alkylsulfide group, and C ₁ -C ₅ A phenyl group substituted with 1 to 4 substituents selected from an alkylsulfanyl group of C ₅ ; Benzyl groups; Benzyl groups substituted with halogen substituents; Naphthyl group; Or a piperidine group forming a ring together with a nitrogen to which R ¹ is bonded, a piperidine group substituted with a C ₁ to C ₅ alkoxycarbonyl, a piperazine group, or a phenyl substituted piperazine group; R ² represents hydrogen or an alkyl group of C ₁ to C ₅ ; R ³ represents hydrogen, a C ₁ -C ₅ alkyl group, or a benzyl group. N- represented by the following formula (1) by reacting the 2,2-disubstituted-2H-6-amino-chromen represented by the following formula (2) with the isothiocyanate derivative represented by the following formula (3) Preparing a (2,2-disubstituted-2H-chromen-6-yl) thiourea derivative and Filtering and removing the unreacted isothiocyanate derivative represented by Formula (3) by adding a amine group-containing scavenger resin represented by Formula 4 below Manufacturing method characterized in that it comprises:

[Formula 1]

In the above formula, R ¹ , R ² , and R ³ are each as defined in claim 1, ⓟ is a polymer polymer selected from polystyrene, polystyrene-divinylbenzene, polymethacrylic acid-dimethylacrylamide and polyhydroxy methacrylic acid Solid support in the form of a. N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof Prevention and treatment: [Formula 1]

In formula (1), R ¹ , R ² , and R ³ are each as defined in claim 1 above. N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivative, or a pharmaceutically acceptable salt thereof, characterized in that represented by the following formula (1) Prevention and treatment of diseases selected from liver fibrosis, cirrhosis, pulmonary fibrosis, scleroderma, renal glomerulosis [Formula 1]

In formula (1), R ¹ , R ² , and R ³ are each as defined in claim 1 above. delete

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