KR101127158B1 - Derivatives of N-2,2-disubstituted- 2H-cromene-6-yl-N,N'-disubstituted guanidine derivatives 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 , 2-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivatives.

Liver cirrhosis, collagen synthesis, guanidine benzopyran, solid phase synthesis, combinatorial chemistry

Description

N- (2,2-disubstituted-2H-chromen-6-yl) -N, N'-disubstituted guanidine derivatives showing hepatic fibrosis and cirrhosis inhibitory activity {Derivatives of N- (2,2-disubstituted-2H -cromene-6-yl) -N, N'-disubstituted guanidine derivatives for treating hepatic fibrosis and cirrhosis}             

1 is a graph showing the TGFβ receptor antagonist activity of N- (2,2-disubstituted-2H-chromen-6-yl) -N, N′ -disubstituted guanidine derivatives.

FIG. 2 is a graph showing the effects of N- (2,2-disubstituted-2H-chromen-6-yl) -N, N′ -disubstituted guanidine derivatives on cytotoxicity and collagen synthesis in LI90 cells.

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

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 in normal liver function, are transferred to myofibroblast form by rapid chronic liver damage and rapidly proliferate into collagen (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, in the present invention, a compound capable of inhibiting or preventing hepatic fibrosis using a hepatic stellate cell which plays a key role in the liver fibrosis process by synthesizing a substance having TGFβ receptor antagonistic activity, N- (2,2 -Double substituted -2H-chromen-6-yl) -N, N ' -It was confirmed that this heavy substituted guanidine derivative has an excellent preventive and therapeutic effect of 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. As a result of studies on antagonistic activity against hepatic fibroblasts, collagen synthesis and cell proliferation inhibition, guanidine-based benzopyran derivatives inhibited TGFβ receptor antagonism and collagen synthesis. The present invention was completed by confirming that.

Accordingly, an object of the present invention is to provide a N- (2,2-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivative useful for developing a liver fibrosis and cirrhosis therapeutic agent.

It is another object of the present invention to provide for use as an agent for the prevention and treatment of TGFβ activation and related diseases caused by overproduction and extracellular matrix such as excessively accumulated collagen.

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

In the above formula (1),

R ¹ and R ² each represent a C ₁ to C ₅ alkyl group, or a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a dioxobenzyl group, or an isovalin (methyl ester) group, respectively, or R Each of ¹ or R ² represents a 5 to 7 membered heteroaliphatic or aromatic cycle group forming a ring with the nitrogen to which it is attached;

R ³ represents hydrogen or an alkyl group of C ₁ to C ₅ ;

R ⁴ 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 denotes a phenyl or benzyl group substituted with 1 to 4 substituents selected from halogen, nitro group, C ₁ -C ₅ alkyl group and C ₁ -C ₅ alkoxy group.

In addition, 2 of benzopyrans in N- (2,2'-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivatives represented by the above general formula (1) If there is another substituent in the position to have 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 and R ² are each a phenyl group; A phenyl group substituted with 1 to 4 substituents selected from a halogen, a nitro group, a C ₁ to C ₅ alkyl group and a C ₁ to C ₅ alkoxy group; Benzyl groups; Benzyl groups substituted with halogen substituents; Dioxobenzyl group; A phenylpiperazinyl group forming a ring together with nitrogen to which R ¹ or R ² are each bonded, or 1 to 4 substituents selected from halogen, C ₁ -C ₅ alkyl group and C ₁ -C ₅ alkoxy group A substituted phenylpiperazinyl group or a morpholino group;

R ³ is hydrogen; Or a C ₁ to C ₅ alkyl group;

R ⁴ is hydrogen; C ₁ -C ₅ alkyl group; Phenyl group; Or a benzyl group.

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 , R ³ , and R ⁴ are each as defined above, ¬ represents a solid support in the form of a polymeric polymer selected from polystyrene, polystyrene-divinylbenzene, polymethacrylic acid-dimethylacrylamide and polyhydroxy methacrylic acid.

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.

The preparation method of the present invention according to Scheme 1 includes the following two steps manufacturing process. The 2,2-disubstituted-2H-6-amino-chromen represented by the formula (2) and the isothiocyanate derivative substituted with various R ¹ represented by the formula (3) are reacted A first step of synthesizing a thiourea derivative having R ¹ introduced therein; And reacting the thiourea derivative represented by Chemical Formula (4) with various amine derivatives substituted with R ² represented by Chemical Formula (5) to form N- (2,2) as the target compound represented by Chemical Formula (1). '-Disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivatives.

In addition, the present invention is characterized in that the unreacted amine derivative represented by the general formula (5) after the completion of the reaction is filtered out using a scavenger resin having an isocyanate group represented by the general formula (6). The guanidine derivative can be synthesized in a short time because many reactants can be purified at the same time by using the scavenger resin having an isocyanate 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 carrying out the preparation method according to the present invention, in consideration of using a solid phase scavenger resin in the final step, an organic solvent having excellent swelling effect of the solid phase resin is used. Specifically, as the reaction solvent, dichloromethane (CH ₂ Cl ₂ ), chloroform (CHCl ₃ ), and tetrahydrofuran (THF) are used as a solvent. In the first step, in order to introduce the R ¹ substituent, it is preferable to use 1.2 to 2.0 equivalents of isothiocyanate derivatives substituted with R ¹ represented by the above formula (3), preferably using 1.2 equivalents. This is excellent. In the second step, the amine derivative substituted with R ² represented by the formula (5) is returned to the thiourea derivative represented by the formula (4), and when the reaction is completed, the unreacted amine contains a solid isocyanate group. Since unreacted substances can be easily removed by adding scavenger resin and filtering, the desired guanidine-based benzopyran represented by the general formula (1) can be simultaneously reacted and treated after several reactions.

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 Formula (2) used as a raw material in the production method according to the present invention, to Formula (4) produced as a reaction intermediate N- (2,2-disubstituted-2H-chromen-6-yl) thiourea derivative represented, and N- (2,2-disubstituted- represented by the formula (1) to which the present invention is directed. 2H-chromen-6-yl) -N, N' -disubstituted guanidine derivatives having different substituents at position 2 of benzopyrans will have optical activity. May be performed to separate each pure optical isomeric compound.

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 a TGFβ receptor antagonistic activity, it can also be used as a prophylactic and therapeutic agent for various fibrotic diseases such as liver fibrosis, cirrhosis, pulmonary fibrosis, scleroderma, renal glomerular fibrosis 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 usually non-toxic to N- (2,2-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivatives or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable carriers, adjuvant and excipients may be added to formulate into conventional formulations in the pharmaceutical field, for example, oral or parenteral formulations such as tablets, capsules, troches, solutions, suspensions, and the like. Can be. 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. 0.01 to 1000 mg / day, and may be divided once to several times a day at regular time intervals, depending on the judgment of the doctor or pharmacist.

The present invention as described above is described in more detail based on the following representative examples and the compounds of the examples are shown in Table 1, but the present invention is not limited thereto.

Example 1: N- (2,2'- disubstituted -2H- chromen-6-yl) - N '- thiourea synthesis of (IV)

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

The benzopyrene compound represented by the formula (2a) (1.00 g, 5.7 mmol) was dissolved in dichloromethane (DCM, 15 mL), stirred at room temperature for 10 minutes, and then the phenylisothiocyanate salt represented by the formula (3a) ( C ₆ H ₄ NCS; 0.92 g, 6.8 mmol, 1.2 eq) was added and stirred at the same temperature for 15 hours. After completion of the reaction, 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 ) to obtain the title compound represented by the formula (4a) (1.15 g). , Yield 65%) was obtained.

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

The benzopyrene compound represented by the formula (2a) (1.00 g, 5.7 mmol) was dissolved in dichloromethane (DCM, 15 mL), stirred at room temperature for 10 minutes, and then 4-nitrophenylisothio represented by formula (3b). An acid salt (4-O ₂ NC ₆ H ₄ NCS; 1.22 g, 6.8 mmol, 1.2 eq) was added and stirred at the same temperature for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to obtain the desired intermediate compound represented by the formula (4b). Obtained as a yellow solid (1.50 g, 74% yield).

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), 6.94-6.6.83 (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 1-3) Synthesis of 1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -3- (4-nitro-phenyl) -thiourea (Formula 4c)

The desired intermediate compound represented by formula (4c) was obtained by the method of Example 1-1.

M / S 397.49

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

The desired intermediate compound represented by formula (4d) was obtained by the method of Example 1-1.

M / S 445.54

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

The desired intermediate compound represented by formula (4e) was obtained by the method of Example 1-1.

M / S 459.59

Example 2 Synthesis of Guanidine-Based Benzopyran Derivative (Formula 1)

Example 2-1) Synthesis of N- (2,2-dimethyl-2H-chromen-6-yl) -N ' -(4-nitro-phenyl) -N " -phenyl-guanidine (Compound No. 6)

The thiourea compound represented by the formula (4a) (50 mg, 0.16 mmol, 1 eq) was added to chloroform (CHCl ₃ , 5 mL), and the mixture was stirred at room temperature for 10 minutes. 1,3-diisopropylcarbodiimide (DIC; 0.029 mL, 0.19 mmol, 1.2 eq) and diisopropylethylamine (DIPEA; 0.033 mL, 0.19 mmol, 1.2 eq) were added and stirred at 50 ° C. for 10 minutes. 4-nitroaniline (44 mg, 0.32 mmol) represented by the formula (5a) was added to the reaction and stirred for 15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and polystyrene isocyanate (2.90 mmol / g, 0.35 g, 1 mmol) represented by Chemical Formula (6) was added thereto, followed by stirring for 30 minutes. The reaction mixture was filtered, the filtrate was repeatedly washed with chloroform (CHCl ₃ ), the filtrates were combined and concentrated under reduced pressure, and then separated and purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (3/1, v / v ). The title compound (Compound No. 6; 35 mg, yield 53%) was obtained.

Example 2-2) N- (2,2-dimethyl-2H-chromen-6-yl) -N ' -(4-nitro-phenyl) -N " -4-tolyl-guanidine (Compound No. 8) synthesis

The thiourea compound represented by the formula (4b) (69 mg, 0.16 mmol, 1 eq) was added to chloroform (CHCl ₃ , 5 mL) and stirred at room temperature for 10 minutes. 1,3-diisopropylcarbodiimide (DIC; 0.029 mL, 0.19 mmol, 1.2 eq) and diisopropylethylamine (DIPEA; 0.033 mL, 0.19 mmol, 1.2 eq) were added and stirred at 50 ° C. for 10 minutes. 4-methylaniline (0.035 mL, 0.32 mmol) represented by the formula (5b) was added to the reaction and stirred for 15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and polystyrene isocyanate (2.90 mmol / g, 0.35 g, 1 mmol) represented by Chemical Formula (6) was added thereto, followed by stirring for 30 minutes. The reaction mixture was filtered, the filtrate was repeatedly washed with chloroform (CHCl ₃ ), the filtrates were combined and concentrated under reduced pressure, and then separated and purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (3/1, v / v ). The title compound (Compound No. 8; 34 mg, yield 49%) was obtained.

Example 2-3) N- (2,2-dimethyl-2H-chromen-6-yl) -N ' -(4-fluoro-phenyl) -N " -(4-nitro-phenyl) -guanidine ( Synthesis of Compound No. 29)

The thiourea compound represented by the formula (4c) (64 mg, 0.16 mmol, 1 eq) was added to chloroform (CHCl ₃ , 5 mL) and stirred at room temperature for 10 minutes. 1,3-diisopropylcarbodiimide (DIC; 0.029 mL, 0.19 mmol, 1.2 eq) and diisopropylethylamine (DIPEA; 0.033 mL, 0.19 mmol, 1.2 eq) were added and stirred at 50 ° C. for 10 minutes. 4-Fluoroaniline (0.030 mL, 0.32 mmol) represented by the formula (5c) was added to the reaction and stirred for 15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and polystyrene isocyanate (2.90 mmol / g, 0.35 g, 1 mmol) represented by Chemical Formula (6) was added thereto, followed by stirring for 30 minutes. The reaction mixture was filtered, the filtrate was repeatedly washed with chloroform (CHCl ₃ ), the filtrates were combined and concentrated under reduced pressure, and then separated and purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (3/1, v / v ). The title compound (Compound No. 29; 44 mg, Yield 58%) was obtained.

Example 2-4) Synthesis of N- (2,2-dimethyl-2H-chromen-6-yl) -N ' -(4-methoxy-phenyl) -N " -(4-nitro-phenyl) -guanidine (Compound No. 36)

The thiourea compound represented by the formula (4d) (71 mg, 0.16 mmol, 1 eq) was added to chloroform (CHCl ₃ , 5 mL) and stirred at room temperature for 10 minutes. 1,3-diisopropylcarbodiimide (DIC; 0.029 mL, 0.19 mmol, 1.2 eq) and diisopropylethylamine (DIPEA; 0.033 mL, 0.19 mmol, 1.2 eq) were added and stirred at 50 ° C. for 10 minutes. 4-methoxyaniline (39 mg, 0.32 mmol) represented by the formula (5d) was added to the reaction and stirred for 15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and polystyrene isocyanate (2.90 mmol / g, 0.35 g, 1 mmol) represented by Chemical Formula (6) was added thereto, followed by stirring for 30 minutes. The reaction mixture was filtered, the filtrate was repeatedly washed with chloroform (CHCl ₃ ), the filtrates were combined and concentrated under reduced pressure, and then separated and purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (3/1, v / v ). The title compound (Compound No. 36; 37 mg, yield 43%) was obtained.

The results of synthesizing the compound represented by Chemical Formula 1 according to the present invention using the preparation methods of Examples 1 and 2 are shown in Table 1 below.                     

compound
number R ¹ R ² R ³ R ⁴ Structure confirmation data One Ph- Ph H H M / S 369.48 2 Ph- 4-Me-Ph- H H M / S 383.49 3 Ph- 4-F-Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ7.36-7.31 (m, 5H), 7.01 (m, 2H), 6.86 (t, 2H, J = 8.7 Hz), 6.65 (d, 1H), 6.64-6.61 (m, 2H), 6.32 (d, 1H), 5.72 (d, 1H), 1.43 (s, 6H); M / S 387.46 4 Ph- 4-Cl-Ph- H H M / S 403.92 5 Ph- 4-MeO-Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29-7.11 (m, 7H), 6.95 (d, 2H, J = 8.1 Hz), 6.86-6.81 (m, 2H), 6.67 (d, 2H, J = 7.2 Hz), 6.25 (d, 1H), 5.62 (d, 1H, J = 9.9 Hz), 3.75 (s, 3H), 1.38 (s, 6H); M / S 399.47 6 Ph- 4-NO ₂ -Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (d, 2H, J = 8.9 Hz), 7.34-7.16 (m, 7H), 6.90 (dd, 1H, J = 8.6 Hz, J = 2.5 Hz), 6.82 (d, 1H, J = 2.5 Hz), 6.71 (d, 1H, J = 8.6 Hz), 6.23 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 1.41 ( s, 6H); M / S 414.46 7 Ph- Bn- H H M / S 383.47 8 4-NO ₂ -Ph- 4-Me-Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.9 Hz), 7.21 (d, 2H, J = 8.9 Hz), 7.08 (s, 4H), 6.91 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz, 6.84 (d, 1H, J = 2.4 Hz), 6.66 (d, 1H, J = 8.4 Hz), 6.21 (d, 1H, J = 9.9 Hz), 5.63 (d, 1H, J = 9.9 Hz), 2.27 (s, 3H), 1.38 (s, 6H); M / S 428.50 9 4-NO ₂ -Ph- 3,5-Me-Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (d, 2H, J = 8.97 Hz), 7.20 (d, 2H, J = 8.97 Hz), 6.89 (dd, 1H, J = 8.46 Hz, J = 2.49 Hz), 6.82 (d, 1H, J = 2.49 Hz), 6.77 (s, 3H), 6.69 (d, 1H, J = 8.46 Hz), 6.22 (d, 1H, J = 9.83 Hz), 5.64 (d, 1H, J = 9.83 Hz), 2.24 (s, 6H), 1.39 (s, 6H); M / S 442.55

10 4-NO ₂ -Ph- 4-F-Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10 (d, 2H, J = 9.0 Hz), 7.26 (d, 2H, J = 9.0 Hz), 7.17 (m, 2H), 6.99 (m, 2H), 6.91 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz), 6.81 (d, 1H, J = 2.4 Hz), 6.73 (d, 1H, J = 8.4 Hz), 6.24 (d, 1H, J = 9.9 Hz), 5.66 (d, 1H, J = 9.9 Hz), 1.42 (s, 6H); M / S 432.47 11 4-NO ₂ -Ph- 4-Cl-Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ8.12 (d, 2H, J = 7.6 Hz), 7.29-7.14 (m, 4H), 7.10 (d, 2H, J = 8.7 Hz), 6.90 (d, 1H , J = 2.6 Hz, 6.79-6.71 (m, 2H), 6.23 (d, 1H, J = 9.8 Hz), 5.66 (d, 1H, J = 9.8 Hz), 1.40 (s, 6H); M / S 448.93 12 4-NO ₂ -Ph- 4-MeO-Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ8.11 (d, 2H, J = 8.9 Hz), 7.24 (d, 2H, J = 8.9 Hz), 7.14 (d, 2H, J = 8.8 Hz), 6.93 ( dd, 1H, J = 8.5 Hz, J = 2.3 Hz, 6.86 (m, 3H), 6.73 (d, 1H, J = 8.5 Hz), 6.25 (d, 1H, J = 9.8 Hz), 5.64 (d, 1H, J = 9.8 Hz), 3.78 (s, 3H), 1.42 (s, 6H); M / S 444.50 13 4-NO ₂ -Ph- 2-MeO-Ph- H H M / S 444.51 14 4-NO ₂ -Ph- iso-valine (methyl ester)- H H M / S 452.54 15 4-NO ₂ -Ph- Bn- H H M / S 428.48 16 4-NO ₂ -Ph- 4-F-Bn- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ8.14 (d, 2H, J = 8.99 Hz), 7.27 (m, 2H), 7.12 (d, 2H, J = 8.99 Hz), 7.03 (m, 2H), 6.85 (dd, 1H, J = 8.49 Hz, J = 2.60 Hz), 6.74 (d, 1H, J = 2.60 Hz), 6.70 (d, 1H, J = 8.49 Hz), 6.20 (d, 1H, J = 9.85 Hz), 5.65 (d, 1H, J = 9.85 Hz), 4.45 (s, 2H), 1.41 (s, 6H); M / S 446.49 17 4-NO ₂ -Ph- 4-Cl-Bn- H H M / S 462.95 18 4-NO ₂ -Ph- 4-NO ₂ -Ph- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ8.14 (d, 2H, J = 9.32 Hz), 8.12 (d, 2H, J = 8.49 Hz), 6.96 (d, 2H, J = 8.49 Hz), 6.82 ( d, 2H, J = 9.32 Hz, 6.70 (m, 2H), 6.62 (s, 1H), 6.22 (d, 1H, J = 9.81 Hz), 5.66 (d, 1H, J = 9.81 Hz), 3.55 ( t, 4H, J = 4.11 Hz), 3.45 (br-s, 4H), 1.41 (s, 6H); M / S 528.55 19 4-NO ₂ -Ph- Ph- piperazine- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10 (d, 2H, J = 8.7 Hz), 7.30 (d, 2H, J = 8.7 Hz), 6.92 (m, 5H), 6.75 (br-s, 1H ), 6.68 (d, 1H, J = 8.1 Hz), 6.63 (br-s, 1H), 6.22 (d, 1H, J = 9.9 Hz), 5.64 (d, 1H, J = 9.9 Hz), 3.54 (t , 4H, J = 5.0 Hz), 3.18 (br-s, 4H), 1.41 (s, 6H); M / S 483.57

20 4-NO ₂ -Ph- 2-MeO-Ph-piperazine- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10 (d, 2H, J = 8.7 Hz), 7.06-6.92 (m, 4H), 6.88 (d, 2H, J = 8.7 Hz), 6.74 (br-s , 1H), 6.68 (d, 1H, J = 8.1 Hz), 6.62 (br-s, 1H), 6.22 (d, 1H, J = 9.9 Hz), 5.64 (d, 1H, J = 9.9 Hz), 3.86 (s, 3H), 3.57 (t, 4H, J = 4.8 Hz), 3.06 (br-s, 4H), 1.41 (s, 6H); M / S 513.63 21 4-NO ₂ -Ph- 3-MeO-Ph-piperazine- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (d, 2H, J = 8.40 Hz), 7.18 (m, 1H), 6.93 (d, 2H, J = 8.4 Hz), 6.75 (br-s, 1H ), 6.67 (d, 1H, J = 8.40 Hz), 6.63 (br-s, 1H), 6.53 (d, 1H, J = 9.03 Hz), 6.45 (m, 2H), 6.21 (d, 1H, J = 9.78 Hz), 5.64 (d, 1H, J = 9.78 Hz), 3.79 (s, 3H), 3.52 (t, 4H, J = 4.91 Hz), 3.17 (br-s, 4H), 1.41 (s, 6H) ; M / S 513.64 22 4-NO ₂ -Ph- 4-F-Ph- piperazine- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ8.11 (d, 2H, J = 9.0 Hz), 7.03-6.95 (m, 3H), 6.91-6.85 (m, 2H), 6.74 (br-s, 1H) , 6.69 (d, 1H, J = 8.1 Hz), 6.62 (br-s, 1H), 6.22 (d, 1H, J = 9.9 Hz), 5.65 (d, 1H, J = 9.9 Hz), 3.53 (t, 4H, J = 5.0 Hz), 3.09 (br-s, 4H), 1.41 (s, 6H); M / S 501.58 23 4-NO ₂ -Ph- 4-Cl-Ph-piperazine- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ8.10 (d, 2H, J = 8.7 Hz), 7.22 (d, 2H, J = 7.5 Hz), 6.94 (d, 2H, J = 8.7 Hz), 6.83 ( d, 2H, J = 7.5 Hz), 6.75 (br-s, 1H), 6.68 (d, 1H, J = 8.4 Hz), 6.62 (br-s, 1H), 6.21 (d, 1H, J = 9.9 Hz ), 5.64 (d, 1H, J = 9.9 Hz), 3.52 (t, 4H, J = 5.3 Hz), 3.13 (br-s, 4H), 1.41 (s, 6H); M / S 518.03 24 4-NO ₂ -Ph- 4-Me-Ph- piperazine- H H M / S 497.61 25 4-NO ₂ -Ph- 3,4-dioxo- Bn- H H ¹ H NMR (300 MHz, CDCl ₃ ) δ8.14 (d, 2H, J = 8.9 Hz), 7.16 (d, 2H, J = 8.9 Hz), 6.87 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz), 6.81-6.76 (m, 4H), 6.70 (d, 1H, J = 8.5 Hz), 6.21 (d, 1H, J = 9.8 Hz), 5.96 (s, 2H), 5.64 (d, 1H, J = 9.8 Hz), 4.42 (s, 2 H), 1.40 (s, 6 H); M / S 472.51 26 4-NO ₂ -Ph- Ph- CH ₃ -CH ₂ CH ₃ ¹ H NMR (300 MHz, CDCl ₃ ) δ8.13 (d, 2H), 7.33-7.23 (m, 7H), 7.10 (t, 1H), 6.82 (s, 1H), 6.65 (s, 1H), 6.27 (d, 1H), 5.56 (d, 1H), 5.64 (d, 1H, J = 9.8 Hz), 2.20 (s, 3H), 1.62 (m, 2H), 1.46 (m, 2H), 1.37 (s, 3H), 0.92 (t, 3H); M / S 456.54

27 4-NO ₂ -Ph- 4-Me-Ph- CH ₃ -CH ₂ CH ₃ ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (d, 2H), 7.22 (d, 2H), 7.05 (m, 4H), 6.82 (s, 1H), 6.59 (s, 1H), 6.25 (d , 1H), 5.54 (d, 1H), 2.28 (s, 3H), 2.04 (s, 3H), 1.64 (m, 2H), 1.58 (m, 2H), 1.37 (s, 3H), 0.90 (t, 3H); M / S 470.58 28 4-NO ₂ -Ph- 4-MeO-Ph- CH ₃ -CH ₂ CH ₃ ¹ H NMR (300 MHz, CDCl ₃ ) δ8.10 (d, 2H), 7.28 (d, 2H), 7.15 (d, 2H), 6.86 (m, 3H), 6.62 (s, 1H), 6.26 (d , 1H), 5.55 (d, 1H), 3.78 (s, 3H), 2.20 (s, 3H), 1.66 (m, 2H), 1.60 (m, 2H), 1.40 (s, 3H), 0.91 (t, 3H); M / S 486.56 29 4-NO ₂ -Ph- 4-F-Ph- CH ₃ -CH ₂ CH ₃ ¹ H NMR (500 MHz, CDCl ₃ ) δ8.10 (d, 2H), 7.26 (d, 2H), 7.16 (m, 2H), 6.80 (s, 1H), 6.98 (t, 2H), 6.80 (s , 1H), 6.61 (s, 1H), 6.25 (d, 1H), 5.55 (d, 1H), 2.20 (s, 3H), 1.65 (m, 2H), 1.41 (m, 2H), 1.35 (s, 3H), 0.91 (t, 3H, J = 7.30 Hz); M / S 474.52 30 4-NO ₂ -Ph- 4-Cl-Ph- CH ₃ -CH ₂ CH ₃ ¹ H NMR (500 MHz, CDCl ₃ ) δ8.15 (d, 2H, J = 9.05 Hz), 7.28 (d, 2H, J = 9.05 Hz), 7.10 (d, 2H, J = 8.70 Hz), 6.80 ( s, 1H), 6.66 (s, 1H), 6.61 (d, 2H, J = 8.70 Hz), 6.27 (d, 1H, J = 9.95 Hz), 5.57 (d, 1H, J = 9.95 Hz), 2.20 ( s, 3H), 1.68 (m, 2H), 1.60 (m, 2H), 1.38 (s, 3H), 0.92 (t, 3H, J = 7.30 Hz); M / S 490.99 31 4-NO ₂ -Ph- 4-NO ₂ -Ph- CH ₃ -CH ₂ CH ₃ ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.18 (d, 4H, J = 9.2 Hz), 7.53 (d, 2H, J = 9.2 Hz), 7.40 (br-s, 2H), 6.83 (s, 1H ), 6.67 (s, 1H), 6.27 (d, 1H, J = 9.9 Hz), 5.59 (d, 1H, J = 9.9 Hz), 2.22 (s, 3H), 1.62-1.43 (m, 4H), 1.38 (s, 3H), 0.93 (m, 3H); M / S 501.55 32 4-NO ₂ -Ph- morpholine- CH ₃ -CH ₂ CH ₃ ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, 2H, J = 8.2 Hz), 6.94 (d, 2H, J = 8.2 Hz), 6.70 (s, 1H), 6.54 (s, 1H), 6.25 (d, 1H, J = 10.1 Hz), 5.55 (d, 1H, J = 10.1 Hz), 3.64 (m, 4H), 3.32 (m, 4H), 2.04 (s, 3H), 1.68-1.57 (m , 2H), 1.47-1.43 (m, 2H), 1.34 (s, 3H), 0.91 (t, 3H, J = 7.2 Hz); M / S 450.55 33 4-NO ₂ -Ph- (CH ₂ CH ₃ ) _2- CH ₃ -CH ₂ CH ₃ ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (d, 2H, J = 9.0 Hz), 7.05 (d, 2H, J = 9.0 Hz), 6.68 (s, 1H), 6.55 (s, 1H), 6.23 (d, 1H, J = 9.9 Hz), 5.54 (d, 1H, J = 9.9 Hz), 3.29 (q, 4H, J = 7.2 Hz), 2.16 (s, 3H), 1.64-1.57 (m, 4H ), 1.33 (s, 3H), 1.17 (t, 3H, J = 7.2 Hz), 0.90 (t, 6H, J = 7.2 Hz); M / S 436.54 34 4-NO ₂ -Ph- Ph- H -CH ₂ Ph M / S 504.59 35 4-NO ₂ -Ph- 4-Me-Ph- H -CH ₂ Ph M / S 518.63 36 4-NO ₂ -Ph- 4-MeO-Ph- H -CH ₂ Ph M / S 534.62 37 4-NO ₂ -Ph- 4-F-Ph- H -CH ₂ Ph M / S 522.59

38 4-NO ₂ -Ph- 4-Cl-Ph- H -CH ₂ Ph M / S 539.02 39 4-NO ₂ -Ph- 4-NO ₂ -Ph- H -CH ₂ Ph M / S 549.56 40 4-NO ₂ -Ph- Ph- CH ₃ -CH ₂ Ph M / S 518.63 41 4-NO ₂ -Ph- 4-Me-Ph- CH ₃ -CH ₂ Ph M / S 532.65 42 4-NO ₂ -Ph- 4-MeO-Ph- CH ₃ -CH ₂ Ph M / S 548.65 43 4-NO ₂ -Ph- 4-F-Ph- CH ₃ -CH ₂ Ph M / S 536.64 44 4-NO ₂ -Ph- 4-Cl-Ph- CH ₃ -CH ₂ Ph M / S 553.07 45 4-NO ₂ -Ph- 4-NO ₂ -Ph- CH ₃ -CH ₂ Ph M / S 563.63 46 4-NO ₂ -Ph- Ph-piperazine- CH ₃ -CH ₂ Ph M / S 587.74 47 4-NO ₂ -Ph- 2-MeO-Ph- piperazine- CH ₃ -CH ₂ Ph M / S 617.76 48 4-NO ₂ -Ph- 3-MeO-Ph- piperazine- CH ₃ -CH ₂ Ph M / S 617.76 49 4-NO ₂ -Ph- 4-F-Ph- piperazine- CH ₃ -CH ₂ Ph M / S 605.72 50 4-NO ₂ -Ph- 4-Cl-Ph-piperazine- CH ₃ -CH ₂ Ph M / S 622.17 51 4-NO ₂ -Ph- 4-Me-Ph- piperazine- CH ₃ -CH ₂ Ph M / S 601.76 52 4-NO ₂ -Ph- Ph- CH ₃ Ph M / S 490.5

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. 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. About 5 minutes after the reaction was stopped, the measured wavelength was measured at 450 nm and corrected wavelength 540 nm. Examples of the results for the part of the compound showing excellent activity among the results are shown in FIG. 1. As shown in Figure 1, these N- (2,2-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivatives showing antagonistic activity against the TGFβ receptor are The following experiments were performed in anticipation of being able to inhibit fibrosis in 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. As shown in FIG. 2, the compounds showing TGFβ receptor antagonistic activity also inhibited the proliferation and collagen production of hepatic stellate cells. These results suggest that N- (2,2-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivatives are hepatic stellate cells that aberrantly proliferate and activate to cause hepatic fibrosis. Inhibition of proliferation and inhibition of the synthesis and secretion of collagen from cells have a hepatic fibrosis inhibitory effect.

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 70% or more, thereby inhibiting the transcription of collagen genes.

As described above, the compound of the present invention, N- (2,2-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivative, has a TGFβ receptor antagonistic activity and a collagen inhibitory activity. It is very useful for the prevention and treatment of liver cirrhosis diseases, due to its inhibitory activity on liver and cirrhosis.

Claims (4)

N- (2,2-disubstituted-2H-chromen-6-yl) -N, N' -disubstituted guanidine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof Prevention and treatment of liver fibrosis, cirrhosis, pulmonary fibrosis, scleroderma, or renal glomerular fibrosis [Formula 1]

In the above formula (1), R ¹ and R ² each represent a C ₁ to C ₅ alkyl group, or a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a dioxobenzyl group, or an isovalin (methyl ester) group, respectively, or R Each of ¹ or R ² represents a 5 to 7 membered heteroaliphatic or aromatic cycle group forming a ring with the nitrogen to which it is attached; R ³ represents hydrogen or an alkyl group of C ₁ to C ₅ ; R ⁴ 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 denotes a phenyl or benzyl group substituted with 1 to 4 substituents selected from halogen, nitro group, C ₁ -C ₅ alkyl group and C ₁ -C ₅ alkoxy group. The method of claim 1, R ¹ and R ² are each a phenyl group; A phenyl group substituted with 1 to 4 substituents selected from a halogen, a nitro group, a C ₁ to C ₅ alkyl group and a C ₁ to C ₅ alkoxy group; Benzyl groups; Benzyl groups substituted with halogen substituents; Dioxobenzyl group; A phenylpiperazinyl group forming a ring together with nitrogen to which R ¹ or R ² are each bonded, or 1 to 4 substituents selected from halogen, C ₁ -C ₅ alkyl group and C ₁ -C ₅ alkoxy group A substituted phenylpiperazinyl group or a morpholino group; R ³ is hydrogen; Or a C ₁ to C ₅ alkyl group; R ⁴ is hydrogen; C ₁ -C ₅ alkyl group; Phenyl group; Or a benzyl group. delete delete

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