KR20120096847A - Novel stylbeneurea derivatives, pharmaceutically acceptable salts, method for preparation and composition containing thereof as an active ingredient for prevention and treatment of diseases induced by glycosidase - Google Patents

Abstract

PURPOSE: A stilbene and thiourea derivative is provided to have strong enzyme-inhibiting activity to glycosidase, and to be useful for preventing and treating disease caused by glycosidase. CONSTITUTION: A stilbene and thiourea derivative and pharmaceutically acceptable salts thereof are in chemical formula 1. In chemical formula 1, X is O or S, R1 is hydrogen, halogen, amino, or hydroxy group, R2 is C1-10 alkyl group, or aryl having one or more substituent, preferably phenyl, p-toluyl, p-aminophenyl, p-difluor, methoxyphenyl, etc. A composition for preventing and treating disease caused by glycosidase contains the stilbene and thiourea derivatives or pharmaceutically acceptable salts thereof as an effective ingredient.

Description

Novel stylbeneurea derivatives, pharmaceutically acceptable salts of novel stilbene urea and thiourea derivatives, pharmaceutically acceptable salts thereof, preparation methods thereof and compositions for preventing and treating diseases caused by glycosidase containing them , method for preparation and composition containing particular as an active ingredient for prevention and treatment of diseases induced by glycosidase}

The present invention relates to a novel stilbeneurea and stilbeneiourea derivatives, pharmaceutically acceptable salts thereof, a preparation method thereof, and a composition for the prevention and treatment of diseases caused by glycosidase containing them as an active ingredient. .

Stilbenes are abundantly present in edible plants and are known as precursors of flavonoids or isoflavonoids. These derivatives of stilbene are not only affecting the color of the plant as a component of the yellow pigment of the plant, but also protecting the plant from harmful ultraviolet rays (Natural Chemical Research, Woo Won-sik, Seoul National University Press). Stilbene derivatives are present in many grape varieties. Representative stilbenes include resveratrol, and the like, which are contained in plants such as peanuts, grapes, raspberries and cranberries. Such stilbene derivatives are described, for example, as antigenic (Liu, M. et. Al., J. Med. Chem. 2001, 44, 4443), anti-inflammatory (Babu, MA, et. Al., Bioorg. Med. Chem. 2003, 10, 4035), immunomodulation (Barfod, L., et. Al., Int. Immunopharmacol. 2002, 2, 545), nitric oxide inhibition (Rojas, J., et. Al., Bioorg.Med Chem. Lett. 2002, 12, 1951), anticancer (N. Asano, A. Kato, AA Watson, Mini Rev. Med. Chem. 2001, 1, 145), anti-HIV (Yagi, M., Kouno, T., Aoyagi. , Y., Murai, H., Nippon Nogeikagaku Kaishi. 1976,50,571) are known to exhibit a wide variety of pharmacological activity, including activity

On the other hand, glycosidase refers to an enzyme that hydrolyzes the binding portion of sugars in the metabolic process of carbohydrates and glycoproteins to monosaccharides or other absorbable polysaccharides. They are responsible for the processing and synthesis of complex carbohydrates and are known as essential enzymes in many biological molecular recognition processes (Bertozzi, CR et. Al, Science 2001, 291, 2357; Morenem, KW et. Al, Glycobiology 1994, 4, 113).

Recently, efforts to screen for such glycosidase inhibitors have been actively progressed. For example, since various types of glycosidase are involved in food digestive systems through the decomposition of starch, polysaccharides such as sucrose, and oligosaccharides, inhibitors against them have been reported to be useful as antidiabetics and anti-obesity agents. (Diabetes 1991 , 40, 825-830).

In addition, inhibitors of glycosidase competitively inhibit glycosidase involved in the production of mature glycoproteins from lipid-linked oligosaccharide intermediates. Thus, glycoproteins inhibit the production of normal glycoproteins in cells during the passage of Golgi in the endoplasmic reticulum (Nat. Rev. Drug. Discov. 2002, 1, 65-75) . As a result, immature glycoproteins accumulate by interfering with signaling between cells, between cells, and between tissues and tissues, thereby preventing the virus from binding to the host cell's receptors, Production is suppressed. Eventually, the growth of the virus is inhibited, and thus the development of glycosidase inhibitors can be usefully used as anticancer (Cancer Res. 1991, 51, 718-723) and antiviral (FEBS Lett. 1998, 430, 17-22) drugs. It is reported.

In addition, neuraminidase acts as an important enzyme involved in the growth of influenza viruses, and inhibiting their function can prevent the growth of influenza viruses. (Ryu.YB et. Al, Bioorg. Med. Chem. Lett. 2009, 17, 2744. Jeong. HJ, et, al. Bioorg. Med. Chem. 2009, 17, 6819.) Thus, neuraidase inhibitors are anti It can be used as a virus. Representative examples include Znamivir and Tamiflu.

Previously developed glycosidase inhibitors include, for example, aza sugar (Kato, A. et. Al., J. Med. Chem. 2005, 48, 2036), isoxazole (Schaller, C). et.al., Bioorg.Med.Chem.Lett. 1999, 9, 277), amino sugars (Chen, X. et. al., Chem. Rev. 2003, 103, 1955), and the like. have. However, most glycosidase inhibitors, including the glycosidase inhibitors, are in the form of sugar mimics, and their synthesis requires a complex and tedious multi-step process starting from carbohydrates or non-carbohydrates. there was.

Therefore, the present inventors, although the above-described stilbeneurea and stilbenchiourea derivatives have excellent pharmacological activity, the present inventors have not been studied as a glycosidase inhibitor, so that the inhibitory activity against glycosidase The present invention was completed by conducting research for synthesizing various stilbeneurea and stilbeneiourea derivatives.

It is an object of the present invention to provide novel stilbeneureas and stilbenchiourea derivatives.

Still another object of the present invention is to provide a composition for the prevention and treatment of diseases caused by glycosidase containing stilbeneurea and stilbenchurearea derivatives or pharmaceutically acceptable salts thereof as an active ingredient.

In order to achieve the above object, the present invention provides a novel stilbenurea and stilbenchiourea derivatives, pharmaceutically acceptable salts thereof, a method for preparing the same, and a disease caused by glycosidase containing them as an active ingredient. Prophylactic and therapeutic compositions are provided.

Hereinafter, the present invention will be described in detail.

The present invention provides novel stilbenurea and stilbenchureurea derivatives represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

Where

X is O or S;

R ₁ is hydrogen, halogen, amino, hydroxyl group;

R ₂ is an aryl having a C ₁ to C ₁₀ alkyl group or one or more substituents, and among these, phenyl, p-toluyl, p-aminophenyl o, p-difluoro, methoxyphenyl and the like are preferred. .

In the stilbeneurea and stilbenchiourea derivatives represented by Formula 1 according to the present invention, the R ₁ group is preferably substituted at positions 2, 3, and 4 of the benzene ring.

Preferred examples of the stilbeneurea and stilbenchiourea derivatives represented by Formula 1 according to the present invention are as follows:

1) (E) -1-phenyl-3- (4-styrylphenyl) urea;

2) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) urea;

3) (E) -1- (4-styrylphenyl) -3-p-tolylurea;

4) (E) -1- (4-fluorophenyl) -3- (4-styrylphenyl) urea;

5) (E) -1- (2,4-difluorophenyl) -3- (4-styrylphenyl) urea;

6) (E) -1- (4-chlorophenyl) -3- (4-styrylphenyl) urea;

7) (E) -1- (4-styrylphenyl) -3- (4-trifluoromethylphenyl) urea;

8) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) urea;

9) (E) -1- (4-aminophenyl) -3- (4-styrylphenyl) urea;

10) (E) -1- (4-cyanophenyl) -3- (4-styrylphenyl) urea;

11) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-ethylurea;

12) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-propylurea;

13) (E) -1- (4- (4-hydroxystyryl) phenyl) -3-phenylurea;

14) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-phenylurea;

15) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3-phenylurea;

16) (E) -1- (4- (4-hydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea;

17) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea;

18) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea;

19) (E) -1- (2,4-difluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;

20) (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea; 21) (E) -1- (2,4-difluorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) urea;

      22) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) urea;

      23) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea;

24) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-p-tolylurea;

25) (E) -1- (4-aminophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea;

26) (E) -1- (4-chlorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea;

27) (E) -1- (4-fluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;

28) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) urea;

29) (E) -1- (4- (4-hydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea;

30) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea;

31) (E) -1- (4- (4-hydroxystyryl) phenyl) -3-p-tolylurea;

32) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3-p-tolylurea;

33) (E) -1- (4-aminophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;

34) (E) -1- (4-aminophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) urea;

35) (E) -1- (4-chlorophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;

36) (E) -1- (4-chlorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) urea;

37) (E) -1-phenyl-3- (4-styrylphenyl) thiourea;

38) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) thiourea;

39) (E) -1- (4-styrylphenyl) -3-p-tolylthiourea;

40) (E) -1- (4-fluorophenyl) -3- (4-styrylphenyl) thiourea;

41) (E) -1- (2,4-difluorophenyl) -3- (4-styrylphenyl) thiourea;

42) (E) -1- (4-chlorophenyl) -3- (4-styrylphenyl) thiourea;

43) (E) -1- (4-styrylphenyl) -3- (4-trifluoromethylphenyl) thiourea;

44) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) thiourea;

45) (E) -1- (4-aminophenyl) -3- (4-styrylphenyl) thiourea;

46) (E) -1- (4-cyanophenyl) -3- (4-styrylphenyl) thiourea;

47) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-phenylthiourea;

48) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) thiourea;

49) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) thiourea;

50) (E) -1- (4-chlorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;

51) (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;

52) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-p-tolylthiourea;

53) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) thiourea;

54) (E) -1- (4-aminophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;

55) (E) -1- (4- (4-hydroxystyryl) phenyl) -3-phenylthiourea;

56) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3-phenylthiourea;

57) (E) -1- (4-fluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) thiourea;

58) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) thiourea;

59) (E) -1- (4- (4-hydroxystyryl) phenyl) -3- (4-methoxyphenyl) thiourea;

60) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) thiourea;

61) (E) -1- (4-chlorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) thiourea;

62) (E) -1- (2,4-difluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) thiourea;

63) (E) -1- (2,4-difluorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) thiourea;

64) (E) -1- (4-cyanophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;

65) (E) -1- (4-cyanophenyl) -3- (4- (4-hydroxystyryl) phenyl) thiourea;

66) (E) -1- (4-cyanophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) thiourea;

The stilbenurea and stilbenchiourea derivatives represented by Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by pharmaceutically acceptable free acid are useful. The stilbeneurea and stilbeneiourea derivatives represented by Formula 1 may be formed with pharmaceutically acceptable acid addition salts according to a conventional method in the art. Inorganic and organic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. can be used as the inorganic acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfuric acid. Phonic acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galluxuronic acid, embonic acid, glutamic acid or aspartic acid, and the like can be used. Preferably, hydrochloric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid. In addition, the stilbeneurea and stilbenchiourea derivatives represented by Formula 1 according to the present invention include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods. can do.

The present invention also provides a method for preparing stilbeneurea and stilbeneiourea derivatives represented by Chemical Formula 1.

Specifically, the preparation method according to the present invention is represented by the following Scheme 1, the compound of formula 2 is a step of obtaining a compound 4 by reacting the compound of formula 3 in the presence of a suitable base (step 1); Reducing compound 4 prepared in step 1 to Fe ^{+ 2} to obtain a compound of formula 5 (step 2); And the compound of formula 5 prepared in step 2 comprises the step of preparing an isocyanate or thi isocyanate compound (step 3).

<Reaction Scheme 1>

Wherein X, R ₁ and R ₂ are as defined in Formula 1 above

Hereinafter, the production method of the present invention is divided into stages.

In the preparation method according to the present invention, the base of step 1 is preferably sodium hydroxide, potassium butoxide, sodium hydride, butyllithium, and the like, more preferably potassium butoxide.

In the production method according to the present invention, the reaction solvent of step 1 is preferably chloroform, dichloromethane, tetrahydrofuran, dimethylformamide, and dimethylformamide is more preferable.

In the production method according to the invention, the reaction of Step 1 is preferably carried out for 1 to 2 hours at room temperature.

Compound (4) prepared as a result of the reaction of step 1 may be produced as a crystalline compound, and these compounds may be separated by conventional techniques such as recrystallization method using polarity difference of solvent.

In the production method according to the present invention, it is preferable to use iron as the catalyst of step 2, and the reaction solvent is preferably reacted under acidic conditions such as 5% acetic acid.

In the manufacturing method according to the invention, the step 2 is preferably performed for 1 to 2 hours at 80 ~ 95.

As a result of performing step 2, the stilbeneurea and stilbeneoleurea derivatives of the formula (5) of the present invention may be obtained in a mixture with a by-product. In this case, it is natural that these mixtures can be separated by conventional separation methods such as column chromatography.

Furthermore, the present invention provides the use of stilbeneurea and stilbeneiourea derivatives represented by Chemical Formula 1 or pharmaceutically acceptable salts thereof.

Specifically, it may be used as a composition for inhibiting the activity of glucosidase containing stilbeneurea and stilbenchiourea derivatives represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In this case, the glucosidase, neuramidase, etc. whose activity is inhibited by the said composition which concerns on this invention are mentioned.

Since various types of glycosidase are involved in food digestion through the decomposition of starch, polysaccharides such as sucrose and oligosaccharides, the glycosidase inhibitors can be used as antidiabetic and anti-obesity agents (Diabetes 1991, 40, 825-830). Therefore, the composition according to the present invention can be used as a composition for the prevention and treatment of diabetes, obesity, and the like by containing stilbeneurea and stilbenchiourea derivatives having glycosidase inhibitory activity as an active ingredient.

In addition, the composition according to the present invention contains a stilbeneurea and stilbenoeourea derivatives having glycosidase inhibitory activity as an active ingredient, thereby the mature glycoprotein (glycoprotein) from lipid-linked oligosaccharide intermediates Competitive inhibition of glycosidase involved in the production process can inhibit the production of normal glycoproteins in cells. The stilbeneurea and stilbeneiourea derivatives of the present invention interfere with signal transduction in cells, between cells and between cells, and between tissues and tissues, resulting in the accumulation of immature glycoproteins that bind viruses to host cell receptors. Is blocked. Therefore, production of the complexes necessary for the host cell and the virus to penetrate is suppressed, and as a result, the growth of the virus can be suppressed. Therefore, the composition containing the stilbeneurea and stilbenchiourea derivatives according to the present invention as an active ingredient prevents cancer or viral diseases, such as influenza virus (HN) or HIV (Human Immunodeficiency Virus) disease. It can be usefully used for treatment.

The composition containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention may be formulated and administered in the following various oral or parenteral dosage forms at the time of clinical administration, but is not limited thereto. is.

When formulated, it is prepared using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose or lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

The dosage of a compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Specifically, based on an adult patient weighing 70 kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day. In addition, depending on the judgment of the doctor or pharmacist may be divided doses once a day to several times at regular intervals.

According to the present invention, novel stilbeneurea and stilbenchurearea derivatives can be easily obtained. Furthermore, stilbeneurea and stilbenchiourea derivatives of the formula (1) according to the present invention exhibit strong enzyme inhibitory activity and competitive inhibition against glycosidase and neuramidase, including a-glucosidase and neuramidase. It can be usefully used to prevent and treat diseases caused by glycosidase.

¹ H-NMR, ¹³ C-NMR spectrum of (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea .
Figure 2 shows a through a Weber-Burk and Dyson equation of (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea. Aspects of a Competitive Inhibitory Mechanism of Glucosidase.
Figure 3 shows a-glucosidase of (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea according to pre-incubation. Inhibition pattern
Figure 4 shows the nucleus of the (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea through the web-Burk and Dison equation. Aspects of the competitive inhibition mechanism of Ramidases.
Fig. 5 is the ¹ H-NMR, ¹³ C-NMR spectrum of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-phenylthiourea.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example 1 Preparation of (E) -1-phenyl-3- (4-styrylphenyl) urea

Step 1: Preparation of (E) -1-nitro-4-styrylbenzene

Diethyl 4-nitrobenzylphosphonate (1.73 g) obtained by dropwise addition of 4-nitrobenzylbromide (2.0 g, 0.926 mmol) and triethylphosphite (2.3 g, 13.8 mmol) for 2 hours at 130-160. , 0.63 mmol) is dissolved in dimethylformamide and thi-potassium butoxide (0.71 g, 0.63 mmol) is added dropwise and stirred for about 20 minutes. Benzaldehyde (1 g, 9.42 mmol) is dissolved in dimethylformamide (5 ml), and slowly added dropwise, the reaction mixture is allowed to proceed for 2 hours at room temperature. After completion of the reaction, the mixture was extracted three times with water (50 ml) and ethyl acetate (30 ml). The organic layers were collected, dried over sodium sulfate, and concentrated under reduced pressure. The reaction mixture was separated by silica gel column chromatography to obtain the target compound (yellow powder, 0.76 g, 75.4%).

Step 2: Preparation of (E) -4-styrylbenzeneamine

(E) -1-nitro-4-styrylbenzene (0.76 g, 3.3 mmol) prepared in Step 1 using iron powder (0.3 g, 15.75 mmol) at 5% acetic acid for 1 to 2 hours. Reduced. After completion of the reaction, the iron powder was filtered off using celite, and extracted three times with saturated sodium bicarbonate and ethyl acetate (20 ml). The organic layer was collected and concentrated under high pressure, dried over sodium sulfate. The reaction mixture was separated by silica gel column chromatography to obtain the target compound (yellow powder, 0.51 g, 86.3%).

Step 3: Preparation of 1-phenyl-3- (4-styrylphenyl) urea

(E) -4-styrylbenzeneamine (0.51 g, 2.86 mmol) prepared in step 2 was dissolved in anhydrous dichloromethane and reacted with phenylisocyanate (0.4 g, 3.4 mmol). The reaction is allowed to proceed for 1 to 2 hours at room temperature. After completion of the reaction, the mixture was extracted three times with water (30 ml) and ethyl acetate (20 ml). The organic layers were collected, dried over sodium sulfate, and concentrated under reduced pressure. The reaction mixture was separated by silica gel column chromatography and recrystallized to give a target compound (ivory powder, 0.68 g, 82.8%) through a conventional separation method.

Melting Point: 186 ~ 188 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.74 (d, J = 8.1 Hz, 2H), 6.89-6.94 (m, 3H), 7.26 (m, 2H), 7.35-7.45 (m, 9H), 8.65 (s, 1 H), 8.70 (s, 1 H);

HERIMS m / z 314.3804 [M ⁺ ] (calcd for C ₂₁ H ₁₈ N ₂ O, 314.3802)

Example 2 Preparation of (E) -1- (4- (4-hydroxystyryl) phenyl) -3-phenylurea

In step 1 of Example 1, 4- (trit-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde, and in the second step, instead of (E) -1-nitro-4-styrylbenzene (E) -4-nitro-4- (trit-butyldimethylsilyloxy) styrylbenzene and in step 3 instead of (E) -4-styrylbenzeneamine (E) -4- (4-bis ( The same method as in Example 1 was conducted except that trit-butyldimethylsilyloxy) styryl) benzeneamine was used, and trit-butyldimethylsilyl group using tetrabutylammonium fluoride in a tetrahydrofuran solvent. The target compound (ivory powder, 0.41 g, 80.2%) was obtained.

Melting Point: 242 ~ 244 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.74 (d, J = 8.4 Hz, 2H), 6.89-6.94 (m, 3H), 7.26 (m, 2H), 7.35-7.45 (m, 8H), 8.65 (s, 1 H), 8.70 (s, 1 H), 9.50 (s, 1 H);

HERIMS m / z 330.1366 [M ⁺ ] (calcd for C ₂₁ H ₁₈ N ₂ O, 330.1368)

Example 3 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-phenylurea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine The target compound (pale yellow powder, 0.37 g, 82.8%) by the same method as in Examples 1 and 2, except that benzeneamine was used. Got.

Melting Point: 139 ~ 141 ℃

¹ H NMR (300MHz, DMSO-d ₆ ) d = 6.69 (d, J = 8.1Hz, 1H), 6.82 (d, J = 16.2Hz, 2H), 6.74 (m, 3H), 7.26 (t, 2H) , 7.43 (m, 6H), 8.65 (s, 1H), 8.70 (s, 1H), 9.0 (brs, 2H);

HERIMS m / z 346.1315. [M ⁺ ] (calcd for C ₂₁ H ₁₇ NO ₄ S, 346.1317)

Example 4 Preparation of (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3-phenylurea

3,5-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,5-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and (E) -4- instead of (E) -4-styrylbenzeneamine in step 3 (3,5-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine The target compound (ivory powder, 0.45 g, 84.5%) was obtained in the same manner as in Examples 1 and 2, except that benzeneamine was used. Got it.

Melting Point: 230 ~ 232 ℃

¹ H NMR (300MHz, DMSO-d ₆ ) d = 6.12 (s, 1H), 6.40 (s, 2H), 6.87-6.94 (m, 2H), 6.98 (d, J = 16.5 Hz, 1H), 7.24- 7.29 (m, 2H), 7.43-7.50 (m, 6H), 8.66 (s, 1H), 8.73 (s, 1H), 9.20 (s, 2H);

HERIMS m / z 346.1315 [M ⁺ ] (calcd for C ₂₁ H ₁₆ N ₂ O ₆ S, 346.1317).

Example 5 Preparation of (E) -1- (4- (4-hydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea

In step 1 of Example 1, 4- (trit-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde, and in the second step, instead of (E) -1-nitro-4-styrylbenzene, E) -4-nitro-4- (trit-butyldimethylsilyloxy) styrylbenzene and in step 3 instead of (E) -4-styrylbenzeneamine (E) -4- (4- (trit- Butyldimethylsilyloxy) styryl) benzeneamine, methoxyphenylisocyanate in place of phenyl isocyanate, except that methoxyphenylisocyanate was used in the same manner as in Examples 1 and 2 above (Ivory Powder, 0.31 g, 79.2%). )

Melting Point: 241 ~ 243 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 3.69 (s, 3H), 6.73 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 16.5 Hz, 2H), 7.35-7.44 (m, 8H), 8.65 (s, 1H), 8.46 (s, 1H), 8.62 (s, 1H), 9.50 (s, 1H);

HERIMS m / z 360.1479. [M ⁺ ] (calcd for C ₂₁ H ₁₆ FNO ₄ S, 360.1474)

Example 6 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, except that methoxyphenylisocyanate was used instead of phenylisocyanate, the target compound ( Ivory powder, 0.35 g, 81.1%).

Melting Point: 143 ~ 145 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 3.69 (s, 3H), 6.69 (d, J = 8.1 Hz, 1H), 6.86 (m, 5H), 6.94 (d, 1H), 7.33 (d , J = 8.7 Hz, 2H), 7.41 (m, 4H), 8.48 (s, 1H), 8.64 (s, 1H), 8.96 (brs, 2H)

HERIMS m / z 376.1423 [M ⁺ ] (calcd for C ₂₂ H ₂₀ N ₂ O ₄ , 376.1421).

Example 7 Preparation of (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea

3,5-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,5-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and (E) -4- instead of (E) -4-styrylbenzeneamine in step 3 (3,5-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, except that methoxyphenylisocyanate was used instead of phenylisocyanate, the target compound ( Ivory powder, 0.42 g, 83.2%).

Melting Point: 223 ~ 225 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 3.70 (s, 3H), 6.11 (s, 1H), 6.39 (d, J = 1.5 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H ), 6.92 (d, J = 16.2 Hz, 2H), 7.33 (d, J = 9.0 Hz, 2H), 7.40-7.48 (m, 4H), 8.46 (s, 1H), 8.65 (s, 1H), 9.20 (s, 2H)

HERIMS m / z 376.1423 [M ⁺ ] (calcd for C ₂₂ H ₂₀ N ₂ O ₄ 376.1418)

Example 8 Preparation of (E) -1- (2,4-difluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea

In step 1 of Example 1, 4- (trit-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde, and in the second step, instead of (E) -1-nitro-4-styrylbenzene, E) -4-nitro-4- (trit-butyldimethylsilyloxy) styrylbenzene and in step 3 instead of (E) -4-styrylbenzeneamine (E) -4- (4- (trit- Butyldimethylsilyloxy) styryl) benzeneamine and the target compound (ivory powder, 0.29) by the same method as in Examples 1 and 2, except that 2,4-difluorophenylisocyanate was used instead of phenyl isocyanate. g, 78.6.%).

Melting Point: 238 ~ 240 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.73 (d, J = 8.1 Hz, 2H), 6.89-7.06 (m, 3H), 7.26-7.46 (m, 7H), 8.08 (m, 1H) , 8.50 (s, 1 H), 9.06 (s, 1 H), 9.50 (s, 1 H);

HERIMS m / z 366.1180 [M ⁺ ] (calcd for C ₂₁ H ₁₆ F ₂ N ₂ O ₂ , 366.1183)

Example 9 Preparation of (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, the same method as in Examples 1 and 2, except that 2,4-difluorophenylisocyanate was used instead of phenyl isocyanate The target compound (gray brown powder, 0.33 g, 81.9%) was obtained.

Melting Point: 210 ~ 212 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.75 (d, J = 8.1 Hz, 1H), 6.88 (m, 2H), 7.00 (d, J = 16.2 Hz, 2H), 7.05 (m, 1H ), 7.35 (m, 1H), 7.45 (m, 4H), 8.13 (m, 1H), 8.55 (s, 1H), 8.96 (s, 1H), 9.11 (s, 2H)

HERIMS m / z 382.1129 [M ⁺ ] (calcd for C ₂₁ H ₁₇ NO ₅ S, 382.1127).

Example 10 Preparation of (E) -1- (2,4-difluorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) urea

3,5-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,5-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and (E) -4- instead of (E) -4-styrylbenzeneamine in step 3 (3,5-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, the same method as in Examples 1 and 2, except that 2,4-difluorophenylisocyanate was used instead of phenyl isocyanate This gave the target compound (ivory powder, 0.3 g, 83.6%).

Melting Point: 218 ~ 220 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.12 (t, 1H), 6.39 (d, J = 1.8 Hz, 2H), 6.93 (d, J = 16.5 Hz, 2H), 7.00-7.07 (m , 1H), 7.27-7.33 (m, 1H), 7.41-7.51 (m, 4H), 8.08 (m, 1H), 8.50 (s, 1H), 9.08 (s, 1H), 9.21 (s, 2H)

HERIMS m / z 382.1129 [M ⁺ ] (calcd for C ₂₁ H ₁₆ N ₂ O ₇ S, 382.1124).

Example 11 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) urea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, by the same method as in Examples 1 and 2, except that 4-fluorophenylisocyanate was used instead of phenyl isocyanate. Compound (gray brown powder, 0.48 g, 86.4%) was obtained.

Melting Point: 156 ~ 158 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.74 (d, J = 8.1 Hz, 1H), 6.86 (m, 2H), 6.98 (d, J = 16.8 Hz, 2H), 7.13 (m, 2H ), 7.48 (m, 6H), 8.73 (s, 2H), 9.00 (brs, 2H)

HERIMS m / z 364.1223 [M ⁺ ] (calcd for C ₂₁ H ₁₇ NO ₅ S, 364.1219).

Example 12 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, by the same method as in Examples 1 and 2, except that 4-trifluorophenylisocyanate was used instead of phenyl isocyanate. The desired compound (gray brown powder, 0.42 g, 84.2%) was obtained.

Melting Point: 168 ~ 170 ℃

¹ HNMR (300 MHz, DMSO-d ₆ ) d = 6.71 (d, J = 8.1 Hz, 1H), 6.84 (m, 2H), 6.92 (d, J = 16.8 Hz, 2H), 7.13 (m, 2H), 7.48 (m, 6H), 8.73 (s, 2H), 9.00 (brs, 2H)

HERIMS m / z 414.1189 [M ⁺ ] (calcd for C ₂₂ H ₁₇ F ₃ N ₂ O ₃ , 414.1189).

Example 13 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-p-tolylurea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, except that p-tolyl isocyanate was used instead of phenyl isocyanate, the target compound ( Ivory powder, 0.29 g, 80.4%).

Melting Point: 164 ~ 166 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 2.22 (s, 3H), 6.69 (d, J = 8.1 Hz, 1H), 6.82 (m, 2H), 6.92 (d, J = 14.7 Hz, 2H ), 7.06 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.41 (m, 4H), 8.55 (s, 1H), 8.66 (s, 1H), 8.90 (s , 1H), 9.02 (s, 1H)

HERIMS m / z 360.1474 [M ⁺ ] (calcd for C ₂₂ H ₂₀ N ₂ O ₃ , 360.1472).

Example 14 Preparation of (E) -1- (4-aminophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, a target compound by the same method as in Examples 1 and 2, except that 4-aminophenylisocyanate was used instead of phenylisocyanate. (Gray brown powder, 0.39 g, 81.9%) were obtained.

Melting Point: 220 ~ 221 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 4.79 (s, 2H), 6.49 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 17.1 Hz, 2H), 6.93 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 7.42 (m, 4H), 8.13 (s, 1H), 8.53 (s, 1H), 8. 89 (s, 1H), 9.02 (s, 1H)

HERIMS m / z 361.1426 [M ⁺ ] (calcd for C ₂₂ H ₁₉ N ₃ O ₃ , 395.0825).

Example 15 Preparation of (E) -1- (4-chlorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, a target compound by the same method as in Examples 1 and 2, except that 4-chlorophenylisocyanate was used instead of phenylisocyanate. (Ivory powder, 0.40 g, 82.2%) was obtained.

Melting Point: 216 ~ 218 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.74 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 16.5 Hz, 2H), 7.00 (m, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.50 (m, 6H), 8.78 (s, 1H), 8.84 (s, 1H), 9.01 (s, 2H)

HERIMS m / z 380.0928 [M ⁺ ] (calcd for C ₂₁ H ₁₇ ClN ₂ O ₃ , 395.0825).

Example 16 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-phenylthiourea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, except that phenylisothiocyanate was used in place of phenylisocyanate, the target compound ( Ivory powder, 0.51 g, 87.6%) was obtained.

Melting Point: 189 ~ 191 ℃

¹ H NMR (300 MHz; MeOD) d = 6.69 (1H, d, J = 8.1 Hz), 6.83 (2H, dd, J ₁ = 8.1, 2.1 Hz), 7.00 (2H, m), 7.10 (1H, m ), 7.30 (2H, m) 7.47 (6H, m), 8.92 (1H, s), 9.08 (1H, s), 9.78 (1H, s), 9.82 (1H, s)

HERIMS m / z 362.4448 [M ⁺ ] (calcd for C ₂₁ H ₁₈ N ₂ O ₂ S, 362.4445)

Example 17 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) thiourea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, except that 4-methoxyphenylisothiocyanate was used instead of phenylisocyanate, in the same manner as in Examples 1 and 2 above. The target compound (ivory powder, 0.48 g, 85.2%) was obtained.

Melting Point: 198 ~ 200 ℃

¹ H NMR (300 MHz; MeOD) d = 3.72 (3H, s), 6.69 (1H, d, J = 8.1 Hz), 6.83 (1H, dd, J = 8.1, 1.8 Hz), 6.88 (3H, m) , 6.95 (2H, d, J = 16.2 Hz), 7.29 (2H, d, J = 9.0 Hz), 7.44 (4H, m), 8.94 (1H, s), 9.06 (1H, s), 9.60 (1H, s), 9.63 (1 H, s)

HERIMS m / z 392.4708 [M ⁺ ] (calcd for C ₂₂ H ₂₀ N ₂ O ₃ S, 392.4706)

Example 18 Preparation of (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, except that 2,4-difluorophenylisothiocyanate was used instead of phenylisocyanate By the same method, the target compound (ivory powder, 0.46 g, 84.7%) was obtained.

Melting Point: 202 ~ 204 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) d = 6.76 (d, J = 8.1 Hz, 1H), 6.91 (m, 2H), 6.98 (d, J = 16.2 Hz, 2H), 7.05 (m, 1H ), 7.36 (m, 1H), 7.45 (m, 4H), 8.13 (m, 1H), 8.95 (s, 1H), 9.11 (s, 1H) 9.60 (1H, s), 9.63 (1H, s)

HERIMS m / z 398.0901 [M ⁺ ] (calcd for C ₂₁ H ₁₆ F ₂ N ₂ O ₂ S, 398.0899)

Example 19 Preparation of (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) thiourea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, except that 4-fluorophenylisothiocyanate was used instead of phenylisocyanate, in the same manner as in Examples 1 and 2 above. The target compound (pale yellow powder, 0.40 g, 79.2%) was obtained.

Melting Point: 200 ~ 202 ℃

¹ H NMR (300 MHz; MeOD) d = 6.70 (1H, d, J = 8.1 Hz), 6.82 (1H, d, J = 2.1 Hz), 6.89 (1H, d, J = 16.2 Hz), 6.96 (2H , m), 7.13 (2H, m), 7.45 (6H, m), 8.93 (1H, s), 9.08 (1H, s), 9.74 (1H, s), 9.82 (1H, s)

HERIMS m / z 380.4353 [M ⁺ ] (calcd for C ₂₁ H ₁₇ FN ₂ O ₂ S, 380.4351)

Example 20 Preparation of (E) -1- (4-chlorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea

3,4-bis (tri-butyldimethylsilyloxy) benzaldehyde (1 g, 0.42 mmol) was used instead of benzaldehyde in Step 1 of Example 1, and (E) -1-nitro-4-styryl in step 2 (E) -4-nitro-3,4-bis (tri-butyldimethylsilyloxy) styrylbenzene instead of benzene and in step 3 (E) -4- instead of (E) -4-styrylbenzeneamine (3,4-bis (tri-butyldimethylsilyloxy) styryl) benzeneamine, by the same method as in Examples 1 and 2, except that 4-chlorophenylisothiocyanate was used instead of phenylisocyanate. Obtained the target compound (ivory powder, 0.47 g, 82.1%).

Melting Point: 178 ~ 180 ℃

¹ H NMR (300 MHz; MeOD) d = 6.69 (1H, d, J = 8.4 Hz), 6.82 (1H, dd, J = 7.8, 1.5 Hz), 6.89 (1H, d), 6.95 (1H, d) , 7.00 (1H, d, J = 16.5 Hz), 7.35 (2H, d, J = 8.7 Hz), 7.44 (2H, d, J = 8.7 Hz), 7.49 (4H, m), 8.93 (1H, s) , 9.09 (1H, s), 9.85 (1H, s), 9.91 (1H, s)

HERIMS m / z 396.0699 [M ⁺ ] (calcd for C ₂₁ H ₁₇ ClN ₂ O ₂ S, 396.0697)

Table 1 below shows the structural formulas of the main stilbeneurea and stilbenchiourea derivatives according to the examples.

The following experiment was carried out to determine the glycosidase inhibitory activity by the stilbeneurea and stilbeneiourea derivatives of the formula (1) of the present invention.

Experimental Example 1 Measurement of a-glucosidase inhibitory activity of stilbeneurea and stilbenourea derivatives of the present invention by nitrophenol quantitative analysis

In order to investigate the glycosidase inhibitory activity by the stilbenurea and stilbenciourea derivatives of the present invention, a-glucosidase, a kind of glycosidase enzyme, was used. The substrate p-nitrophenyl-alpha-D-glucopyranoside is glycosylated using the amount of p-nitrophenyl produced by hydrolysis by a-glucosidase. Aze activity was investigated (J. Med. Chem. 2005, 48, 2036-2044).

Enzyme glucosidase was extracted from yeast (baker's yeast), and dissolved in a 96 well plate at 1 unit / ml with phosphate buffer (Potassium phosphate buffer, 0.07 M, pH 6.8)) and quantified at 100 ml. Next, 100 ml of the substrate, p-nitrophenyl-aD-glucosidase, dissolved in 5 mM concentration in phosphate buffer was quantified, and the steels prepared in Examples 2, 5, 6, 8, 10, and 12 of the present invention. Benurea and stilbeno-urea derivatives were dissolved in 50% DMSO as a solvent and quantified in 50 ml, and then reacted at 37 and 20 minutes to measure absorbance at 405 nm. The inhibition rate of glucosidase activity was determined by Equation 1 below. It was. Inhibitory effect was expressed as the concentration of inhibitor of inhibitors (IC ₅₀ ) that inhibits a-glucosidase by 50%. Kinetic constants for the inhibition pattern were determined using Lineweaver-buck plat and Dixon plat. Table 2 below shows the IC ₅₀ values for the a-glucosidase of the stilbenurea and stilbenchureaurea derivatives prepared in Examples 2, 5, 6, 8, 10 and 12.

A: absorbance value at 405 nm with added inhibitor

B: absorbance value at 405 nm without addition of inhibitor

derivative IC ₅₀ (mM) Ki (mM) Inhibition Example 1 143.3 ± 0.4 24.5 ± 1.2 Competitive inhibition Example 2 29.1 ± 0.3 17.0 ± 0.3 Competitive inhibition Example 3 42.1 ± 1.1 10.6 ± 0.5 Competitive inhibition Example 4 58.8 ± 0.8 - NT Example 5 19.5 ± 0.3 10.5 ± 0.2 Competitive inhibition Example 6 60.1 ± 1.5 - NT Example 7 104.7 ± 2.4 - NT Example 8 18.5 ± 1.2 9.4 ± 0.4 Competitive inhibition Example 9 8.4 ± 0.4 3.2 ± 0.3 Competitive inhibition Example 10 64.3 ± 1.3 - NT Example 11 19.8 ± 0.1 7.2 ± 0.4 Competitive inhibition Example 12 28.8 ± 0.4 12.1 ± 0.3 Competitive inhibition Example 13 63.6 ± 1.8 - NT Example 14 68.5 ± 2.2 - NT Example 15 14.3 ± 0.2 4.6 ± 0.3 Competitive inhibition Example 16 93.2 ± 0.7 - NT Example 17 50.0 ± 1.4 12.6 ± 0.2 Competitive inhibition Example 18 50.0 ± 0.6 17.2 ± 0.4 Competitive inhibition Example 19 58.6 ± 1.1 - NT Example 20 60.4 ± 2.2 - NT

  NT: not tested

As shown in Table 2, the stilbeneurea and stilbeneiourea derivatives of Examples 2, 5, 8, 9, 11, 12 and 15 according to the present invention were 29.1 ± 0.3, 19.5 ± 0.3, 18.5 ± 1.2, By showing IC ₅₀ values of 8.4 ± 0.4, 19.8 ± 0.1, 28.8 ± 0.4 and 14.3 ± 0.2 mM, it can be seen that the a-glucosidase inhibitory activity is excellent. In particular, inhibition of a-glucosidase of 2, 5, 8, 9, 11, 12, and 15 of stilbeneurea and stilbeneiourea derivatives, respectively, was shown to be a competitive inhibition. And inhibitors of stilbench urea-based inhibitors have competitive mechanisms such as competitive inhibition mechanisms.

Experimental Example 2 Measurement of Time-dependent Inhibitory Activity of the Stilbene Derivative of the Present Invention for a-glucosidase

Time-dependent inhibitory activity and progress curve were 0.05 units / ml a-glucosidase and p-nitrophenyl-alpha-D-glucopyranoside as substrates. It was performed at 37 with M potassium phosphate buffer. Enzyme activity was measured continuously at 405 nm ultraviolet spectrometer for 12 minutes. Time-dependent rate constants were obtained for 30 minutes with fixed substrate concentrations and different inhibitor concentrations. Data analysis was performed using a nonlinear regression program (Sigma plot. Spcc Inc.Chicago, Il, USA). Slow binding inhibition model analysis, which is an important parameter for inhibition activity, was obtained using Equations 2 and 3.

As shown in Figure 3 Example 9 showed a typical time-dependent inhibition of the activity increases with the pre-incubation time. In addition, the initial velocity (V _i ) and the steady-state rate (V _s ) decrease as the concentration of the inhibitor is shown in A of FIG. 3. Figure 3 B shows the time-dependent inhibition pattern even when the concentration of the inhibitor was measured and the degree of inhibition after pre-incubation.

Experimental Example 3 Determination of Neuramides Inhibitory Activity of the Stilbene Derivatives of the Present Invention by Fluorescence Spectrophotometry

Clostridium perfringens, one of the neuraminidase enzymes, was used to examine the neuraminidase inhibitory activity of the stilbeneurea and stilbeneiourea derivatives of the present invention. As a substrate, 4-methyl umbeliferyl sodium phosphate was produced by hydrolysis of the substrate by hydrolysis of the substrate by using 4-methyl umbeliferyl-aDN-acetyl-neuraminic acid sodium salt. The inhibitory activity was examined. (Bioorg. Med. Chem. Lett., 2008, 18, 6046-6049, Biochem., 1979, 94, 287-296)

The stilbeneurea and stilbeneiourea derivatives of the example were dissolved in methanol and added to each of 15 mL, mixed with 510 μL of 125 mM sodium acetate buffer (pH 5.0), and 4-methylumbellyryl-aDN-acetylneuraminin as a substrate. 60 μL of acid sodium salt (final concentration, 125 μM) was added and 15 μL of neuraminidase (0.1 unit / ml), an enzyme source, was reacted at 37 ° C. at room temperature, absorbed at 365 nm and luminescence at 450 nm. The inhibitory activity of neuraminidase was measured by measuring.

The IC ₅₀ values for the neuramides of the stilbenurea and stilbenchiourea derivatives of Examples 1, 3, 6, 9, 11, 15, 16, 17, 18, 19, and 20 were obtained and shown in Table 3 below. Indicated.

derivative IC ₅₀ (mM) Ki (mM) Inhibition Example 1 172 ± 0.8 26.5 ± 1.2 Competitive inhibition Example 2 37.1 ± 0.3 - NT Example 3 20.61 ± 0.4 1.72 ± 0.4 Competitive inhibition Example 4 34.1 ± 0.3 - NT Example 5 18.2 ± 0.6 4.3 ± 0.2 Competitive inhibition Example 6 4.45 ± 0.3 1.26 ± 0.2 Competitive inhibition Example 7 19.8 ± 1.1 1.56 ± 0.4 Competitive inhibition Example 8 16.5 ± 0.6 7.9 ± 0.3 Competitive inhibition Example 9 3.72 ± 0.5 1.32 ± 0.6 Competitive inhibition Example 10 17.8 ± 1.3 - NT Example 11 3.03 ± 0.6 1.37 ± 0.5 Competitive inhibition Example 12 14.2 ± 0.4 5.1 ± 0.4 Competitive inhibition Example 13 26.6 ± 1.5 - NT Example 14 21.5 ± 1.0 - NT Example 15 0.98 ± 1.3 0.9 ± 0.2 Competitive inhibition Example 16 24.17 ± 1.1 7.13 ± 0.5 Competitive inhibition Example 17 7.42 ± 0.4 12.6 ± 0.2 Competitive inhibition Example 18 20.04 ± 0.6 18.7 ± 0.4 Competitive inhibition Example 19 15.09 ± 1.0 13.9 ± 0.3 Competitive inhibition Example 20 8.64 ± 0.6 2.53 ± 0.6 Competitive inhibition

NT: not tested

From Table 3, the stilbenurea and stilbenchiourea derivatives of Examples 3, 6, 9, 11, 15, 17, 19 and 20 according to the present invention are 20.61 ± 0.4, 4.45 ± 0.3, 3.72 ± 0.5 and 3.03, respectively. By showing IC 50 values of ± 0.6, 0.98 ± 1.3, 7.42 ± 0.4, 15.09 ± 1.0 and 8.64 ± 0.6 mM, it can be seen that the neuraminidase inhibitory activity is excellent. In particular, the inhibition of neuramides of stilbeneurea and stilbeneiourea derivatives 3, 6, 9, 11, 15, and 17, respectively, was shown to be a competitive inhibition, and structurally chiral-free stilbeneurea and stilbenchs. Ourea-based inhibitors have superior inhibitory mechanisms, including competitive inhibitory mechanisms.

From the results of Experimental Examples 1 to 3, it can be seen that the stilbeneurea and stilbenchiourea derivatives of the present invention exhibit excellent glycosidase and neuramidase inhibitory activity. Accordingly, the compounds of the present invention can be usefully used for preventing and treating diabetes mellitus, obesity, viral diseases, inflammatory diseases, cancer, and the like caused by glycosidase.

Hereinafter, the formulation example for the composition of this invention is illustrated.

1. Preparation of powder

2 g of stilbeneurea and stilbeneiourea derivatives of formula 1

1 g lactose

The above components were mixed and packed in airtight bags to prepare powders.

2. Preparation of tablets

100 mg of stilbeneurea and stilbeneiourea derivatives of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. Preparation of Capsule

100 mg of stilbeneurea and stilbeneiourea derivatives of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

4. Preparation of Injection Solution

10 mg / ml of stilbeneurea and stilbeneiourea derivatives of formula 1

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

Dissolve the stilbenurea and stilbenciourea derivatives of formula 1 in a suitable volume of injectable sodium chloride BP, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and use the volume of injectable sodium chloride BP Was adjusted and mixed well. The solution was filled into a 5 ml Type I ampoule of clear glass, dissolved under glass and enclosed under an upper grid of air, and sterilized by autoclaving at 120 or more for 15 minutes to prepare an injection solution.

Claims (9)

The novel stilbenurea and stilbenchiourea derivatives represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
&Lt; Formula 1 >

Wherein X is O or S; R ₁ is hydrogen, halogen, amino, hydroxyl group; R ₂ is C ₁ -C ₁₀ alkyl group or aryl having one or more substituents, preferably these Phenyl, p-toluyl, p-aminophenyl o, p-difluoro, methoxyphenyl, etc.)
The novel stilbenurea and stilbenchiourea derivatives according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by the compound of formula (I).
According to claim 1, wherein the stilbeneurea and stilbeneiourea derivative represented by the formula (1)

1) (E) -1-phenyl-3- (4-styrylphenyl) urea;
2) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) urea;
3) (E) -1- (4-styrylphenyl) -3-p-tolylurea;
4) (E) -1- (4-fluorophenyl) -3- (4-styrylphenyl) urea;
5) (E) -1- (2,4-difluorophenyl) -3- (4-styrylphenyl) urea;
6) (E) -1- (4-chlorophenyl) -3- (4-styrylphenyl) urea;
7) (E) -1- (4-styrylphenyl) -3- (4-trifluoromethylphenyl) urea;
8) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) urea;
9) (E) -1- (4-aminophenyl) -3- (4-styrylphenyl) urea;
10) (E) -1- (4-cyanophenyl) -3- (4-styrylphenyl) urea;
11) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-ethylurea;
12) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-propylurea;
13) (E) -1- (4- (4-hydroxystyryl) phenyl) -3-phenylurea;
14) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-phenylurea;
15) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3-phenylurea;
16) (E) -1- (4- (4-hydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea;
17) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea;
18) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) urea;
19) (E) -1- (2,4-difluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;
20) (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea;
21) (E) -1- (2,4-difluorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) urea;
22) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) urea;
23) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea;
24) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-p-tolylurea;
25) (E) -1- (4-aminophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea;
26) (E) -1- (4-chlorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) urea;
27) (E) -1- (4-fluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;
28) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) urea;
29) (E) -1- (4- (4-hydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea;
30) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea;
31) (E) -1- (4- (4-hydroxystyryl) phenyl) -3-p-tolylurea;
32) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3-p-tolylurea;
33) (E) -1- (4-aminophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;
34) (E) -1- (4-aminophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) urea;
35) (E) -1- (4-chlorophenyl) -3- (4- (4-hydroxystyryl) phenyl) urea;
36) (E) -1- (4-chlorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) urea;
37) (E) -1-phenyl-3- (4-styrylphenyl) thiourea;
38) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) thiourea;
39) (E) -1- (4-styrylphenyl) -3-p-tolylthiourea;
40) (E) -1- (4-fluorophenyl) -3- (4-styrylphenyl) thiourea;
41) (E) -1- (2,4-difluorophenyl) -3- (4-styrylphenyl) thiourea;
42) (E) -1- (4-chlorophenyl) -3- (4-styrylphenyl) thiourea;
43) (E) -1- (4-styrylphenyl) -3- (4-trifluoromethylphenyl) thiourea;
44) (E) -1- (4-methoxyphenyl) -3- (4-styrylphenyl) thiourea;
45) (E) -1- (4-aminophenyl) -3- (4-styrylphenyl) thiourea;
46) (E) -1- (4-cyanophenyl) -3- (4-styrylphenyl) thiourea;
47) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-phenylthiourea;
48) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) thiourea;
49) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) thiourea;
50) (E) -1- (4-chlorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;
51) (E) -1- (2,4-difluorophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;
52) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3-p-tolylthiourea;
53) (E) -1- (4- (3,4-dihydroxystyryl) phenyl) -3- (4- (trifluoromethyl) phenyl) thiourea;
54) (E) -1- (4-aminophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;
55) (E) -1- (4- (4-hydroxystyryl) phenyl) -3-phenylthiourea;
56) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3-phenylthiourea;
57) (E) -1- (4-fluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) thiourea;
58) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-fluorophenyl) thiourea;
59) (E) -1- (4- (4-hydroxystyryl) phenyl) -3- (4-methoxyphenyl) thiourea;
60) (E) -1- (4- (3,5-dihydroxystyryl) phenyl) -3- (4-methoxyphenyl) thiourea;
61) (E) -1- (4-chlorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) thiourea;
62) (E) -1- (2,4-difluorophenyl) -3- (4- (4-hydroxystyryl) phenyl) thiourea;
63) (E) -1- (2,4-difluorophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) thiourea;
64) (E) -1- (4-cyanophenyl) -3- (4- (3,4-dihydroxystyryl) phenyl) thiourea;
65) (E) -1- (4-cyanophenyl) -3- (4- (4-hydroxystyryl) phenyl) thiourea;
66) (E) -1- (4-cyanophenyl) -3- (4- (3,5-dihydroxystyryl) phenyl) thiourea;
Novel stilbenurea and stilbenchureaure derivatives or pharmaceutically acceptable salts thereof, characterized in that any one selected from the group consisting of or pharmaceutically acceptable salts thereof.
A composition for inhibiting glycosidase activity, which comprises stilbeneurea and stilbeneiourea derivatives represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
A composition for preventing and treating diabetes caused by glycosidase containing as stilbenurea and stilbenchiourea derivatives represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
A composition for the prevention and treatment of obesity caused by glycosidase containing stilbenurea and stilbenchiourea derivatives represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
A composition for preventing and treating cancer caused by glycosidase containing as stilbenurea and stilbenchiourea derivatives represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
Composition for preventing and treating viral diseases controlled by glycosidase and neuramides containing stilbeneurea and stilbenchiourea derivatives represented by the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient .
According to claim 8, wherein the viral disease is influenza virus or HIV, characterized in that the composition for preventing and treating viral diseases caused by glycosidase and neuraidase.

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