KR0169357B1 - Novel 2-imidazolone derivatives and process for the preparation thereof - Google Patents

Abstract

The present invention provides a novel imidazolone derivative having anticancer action, that is, 4-phenyl-1-arylsulfonyl-4,5-dihydro-2-imidazolone derivative of the following general formula (I) and the following general formula ( The regioisomer represented by II), its manufacturing method, and its use as an anticancer agent.

Wherein Y is 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydrobenzofuran-5-yl or the following general formula (A) Represents indolin-5-yl,

Wherein R is hydrogen, C ₁ -C ₄ alkyl, true fluoromethyl, C ₁ -C ₄ acyl, chloroacetyl, trifluoroacetyl, bromoacetyl, hydroxyacetyl, mercaptoacetyl, C _1- C ₄ alkoxycarbonyl, substituted or unsubstituted phenyloxycarbonyl, hydroxycarbonylmethyl or esters thereof.

Description

Novel 2-imidazolone derivatives and preparation method thereof

The present invention provides novel imidazolone derivatives having anticancer activity, that is, 4-phenyl-1-arylsulfonyl-4 and 5-dihydro-2-imidazolone derivatives of the following general formula (I) and the following general formula ( The regioisomer represented by II), its manufacturing method, and its use as an anticancer agent.

Wherein Y is 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydrobenzofuran-5-yl or indole of formula (A) Lean-5-day,

Wherein R represents an alkoxy carbonyl group of C ₁ ~ C ₄ acyl, as cetyl, trifluoromethyl chloroacetyl, bromoacetyl, C ₁ ~ C _4.

Cancer disease, a modern incurable disease, consists of blood cancer and solid cancer, and solid cancer accounts for more than 90%. Currently, treatment of solid cancer is incurable except for a few. Accordingly, the possibility of treating a number of new synthetic and natural substances for solid cancer is being investigated.

Recently, sulfonylurea derivatives such as sulofenuri (LY186641: Drug of Future 1991, vol. 16, p517) and LY295501 (EP555036, USP920205) have been found to be novel substances with anticancer activity against solid cancers. Their mechanism of action is not different from conventional anticancer drugs, and it is found that there is no cross-resistant with existing anticancer drugs, and there are no side effects of conventional anticancer drugs. However, these derivatives are less effective in clinical trials, and toxic expressions such as hemolytic anemia, nephrotoxicity and methemoglobinemia have been found.

Accordingly, the present inventors have conducted extensive research to develop an anticancer agent having a strong anticancer effect by a similar mechanism of slofenyu while having no side effects unlike sloefenyu, and thus a novel N (N) -arylsulfonyl-2-imida. The invention of zolidinone derivatives and preparation methods thereof has already been filed with a patent application No. 93-937.

Accordingly, the present inventors prepared various new derivatives such as changing the structure of the aryl sulfonyl moiety in order to obtain a more effective compound of this series, and as a result, the novel N-arylsulfonyl-4,5-di The present invention has been completed by confirming that hydro-2-imidazolone derivatives exhibit a wide range of anticancer activity.

Structural design of novel N-arylsulfonyl-4,5-dihydro-2-imidazolone derivatives fixes the 4 position with phenyl and changes the arylsulfonyl moiety to a substituted aryl group with a substituted aryl group and a hetero atom I was. These specific N-arylsulfonyl-4,5-dihydro-2-imidazolone derivatives have effects on Zalope with human lung cancer cell A549, skin cancer melanoma cell SK-MEL-2 and brain cancer cell HCT15. Newer and the inventors of the present invention was found to have a stronger anti-cancer activity than the compound of the invention, of which selected specific compounds of human skin cancer melanoma cell Malme-3M, lung cancer cell A427, gastric cancer cell SNU-1, colon cancer cell SNUC4 , LFL cancer cells, HFL / B, lymphocytic cancer cells K562, colon cancer cell Colo205, gastric cancer cell KATOIII, and rat fibroblast L929 cancer cells. As shown in FIG. 3, it was confirmed that the anticancer effect was significantly superior to that of the compound of the present invention.

When Y represents the indolin-5-yl group of general formula (A) in general formula (I) and a compound, the compound of this invention can be represented by the following general formula (I-A).

In the general formula (Ⅰ-A) R represents an alkoxy carbonyl group of C ₁ ~ C ₄ acyl, chloroacetyl, trifluoroacetyl, bromoacetyl, C ₁ ~ C _4.

In the above formula (I-A), when R is alkoxycarbonyl, the compound may be represented by the following general formula (I-B).

Wherein R is a C ₁ ~ C ₄ alkyl group.

Among the compounds of the general formula (I-A) according to the invention, preferred are those compounds wherein R is acetyl, ethoxycarbonyl or chloroacetyl, and particularly preferred representative compounds are 4-phenyl-1- (N-acetylindolin-5 -Sulfonyl) -4,5-dihydro-2-imidazolone, 4-phenyl-1- (N-chloroacetylindolin-5-sulfonyl) -4,5-dihydro-2-imidazolone , 4-phenyl-1 (N-ethoxycarbonylindolin-5-sulfonyl) -4,5-dihydro-2-imidazolone. Particularly preferred compounds among the compounds of formula (II) include 3- (N-acetylindolin-5-sulfonyl) -4-phenyl-4,5-dihydro-2-imidazolone, 3- (N- Chloroacetylindolin-5-sulfonyl) -4-phenyl-4,5-dihydro-2-imidazolone, 3- (N-ethoxycarbonylindolin-5-sulfonyl) -4-phenyl- Such as 4,5-dihydro-2-imidazolone.

The invention also relates to a process for the preparation of compounds of general formula (I). Compounds of the general formula (I) according to the present invention are formulated with N-arylsulfonyl-2-alkoxy-4,5-dihydroimidazole of the general formula (III) in the presence of acid or base, (Or methanol) = 1: 9) or by performing a nucleophilic substitution reaction on an oxygen-bonded carbon site of 2-alkoxy under anhydrous conditions. The preparation method of the present invention is shown in Scheme 1 below.

R ₁ in the scheme is a methyl or ethyl group.

The acid or base used in this reaction should be at least 1 equivalent. For non-nucleophilic acids such as sulfuric acid, at least 1 equivalent of water is required. As the acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid may be used, and as the base, a water-soluble hydroxide base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, or the like may be used.

As the reaction solvent, water, C ₁ -C ₄ alcohol, ether, tetrahydrofuran, dimethyl sulfoxide and the like are preferable, and this reaction is usually performed well at 10 to 100 ° C.

In particular, the compound of general formula (I) is obtained quantitatively pure by adding the corresponding compound of general formula (III) with anhydrous HCl in anhydrous ether, stirring at room temperature for 1 hour or more, then filtration and washing with ether.

The general formula (III) compound, which is a starting material used in the preparation of the general formula (I) compound, is also a novel compound and 4-phenyl- of general formula (III) as an important intermediate for preparing the compound of the general formula (I). N-arylsulfonyl-2-alkoxy-4,5-polyhydroimidazoles constitute one of the objects of the present invention.

Wherein R ₁ and Y are as defined above.

Also provided is a process for the preparation of compounds of general formula (III) according to the invention.

According to the method for preparing the compound of formula (III), 4-phenyl-2-alkoxy-4,5-dihydroimidazole of formula (IV) is reacted with arylsulfonyl chloride (V) in the presence of a base to give 4 The positional isomer (III-a) of -phenyl-N-arylsulfonyl-2-alkoxy-4,5-dihydroimidazole (III) and (III) is obtained in a ratio of about 5: 1. This reaction is represented by Scheme 2 below.

R ₁ and Y in the above scheme are as defined above.

The main product (III) and its isomer (III-b) are separated and purified by chromatography to obtain pure main products (III) and (III-b).

In this reaction, one or more equivalents of pyridine, triethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide may be used. Most preferably this reaction is carried out using sodium bicarbonate as the base in a 1: 1 solvent of acetone and water. 10-50 degreeC is suitable for reaction temperature. Chromatography uses silica gel, and the mixed solvent of hexane and ethyl acetate provides the best separation effect. Usually, this reaction is carried out by first dissolving compound (IV) in acetone, adding sodium bicarbonate (1.5 to 3 equivalents) in the same amount of water, and then vigorously stirring with 1 equivalent of arylsulfonyl chloride (V). After stirring for 2-3 hours, dichloromethane is added, extraction is performed 3-4 times, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a crude product. Isomer separation is performed by column chromatography.

The compound of the general formula (IV) used in this reaction is a known compound described in Korean Patent Application No. 93-937 or the like.

Compounds of formula (II) are prepared in the same manner as in the preparation of compounds of formula (I) starting from the corresponding starting materials (III-b). The preparation method is represented by the following Scheme 3.

R ₁ and Y in the above scheme are as defined above.

The novel 4-phenyl-1-arylsulfonyl-4,5-polyhydro-2-imidazolone derivatives of general formula (I) according to the present invention are human lung cancer cells A549, skin cancer cells SK-MEL-2, Cytotoxicity of uterine cancer SK-OV-2, colorectal cancer XF498, and brain cancer cells HCT-15 cells was measured and compared with cytotoxicity of Zelofenaire, adriamycin, and cisplatin. Confirmed that it can. The invention is explained in more detail by the following examples and experimental examples.

Example 1

2-ethoxy-4-phenyl-1- (N-acetylindolin-5-sulfonyl) -4,5-dihydro-2-imidazole (Compound No. 1a) and isomers 2-ethoxy-4- Preparation of Phenyl-3- (N-acetylindolin-5-sulfonyl) -4,5-dihydro-2-imidazole (Compound No. 1b)]

0.95 g (0.005 mol) of 2-ethoxy-4-phenyl-4,5-dihydro-2-imidazole was dissolved in 20 ml of acetone, and sodium hydrogencarbonate (0.63 g, 1.5 equivalents) was dissolved in 20 ml of water. After the addition, N-acetylindolin-5-sulfonyl chloride (1.03 g, 1 equivalent) was added thereto, and the mixture was stirred vigorously at room temperature for 1 hour. After the reaction, the mixture was extracted four times with 20 ml of dichloromethane and the dichloromethane layer was dried over anhydrous forget-me-not, and the solvent was removed under reduced pressure to obtain a crude product. The crude product consists of a mixture of compound 1a and isomer 1b. Silica gel was used as an adsorbent and column chromatography was performed using ethyl acetate and hexane (3: 7) as a mobile phase to obtain 1.01 g (yield 49%) of compound 1a and 0.43 g (yield 21%) of regioisomer 1b thereof. It was. Obtained 2-ethoxy-4-phenyl-1- (N-acetylindolin-5-sulfonyl) -4,5-dihydro-2-imidazole (Compound No. 1a) and its isomer 2-ethoxy- Properties, yields and spectroscopic data of 4-phenyl-3- (N-acetylindolin-5-sulfonyl) -4,5-dihydro-2-imidazole (1b) are listed in Table 2.

EXAMPLES 2-7

Compounds 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, and 7b are synthesized according to the same method as the synthesis method of compounds 1a and 1b of Example 1 above. That is, 2-ethoxy-4-phenyl-4,5-dihydro-2-imidazole is reacted with N-ethoxycarbonylindolin-5-sulfonylchloride to give compounds 2a and 2b, and naphthalene- Reaction with 1-6sulfonylchloride affords compounds 6a and 6b. 2-methoxy-4-phenyl-4,5-dihydroimidazole is reacted with N-chloroacetylindolin-5-sulfonylchloride to give compounds 3a and 3b, 1,2,3,4-tetra Reaction with hydronaphthalene-2-sulfonylchloride to give compounds 4a and 4b, reaction with naphthalene-2-sulfonylchloride to give compounds 5a and 5b, 2,3-dihydrobenzofuran-5-sulfonyl Reaction with chloride affords compounds 7a and 7b. Physical properties, yields, and spectroscopic data of Compounds 2,3,4,5,6,7 are listed in Table 2.

Example 8

[Preparation of 1- (N-acetylindolin-5-sulfonyl) -4-phenyl-4,5-dihydro-2-imidazolone (Compound No. 8)]

5% HCl in 413 mg (0.0001 mol) of 2-ethoxy-1- (N-acetylindolin-5-sulfonyl) -4-phenyl-4,5-dihydro-2-imidazole (Compound No. 1a) 3 ml of ethanol was added, followed by stirring at room temperature for 3 hours. The precipitated product was filtered off, washed with a small amount of ethanol and dried to give 310 mg (yield 75%) of pure compound 8. Yield and constellation spectroscopic data are listed in Table 3.

[Examples 9-14]

Compounds 9, 10, 11, 12, 13 and 14 in Table 3 are prepared from the corresponding starting compounds 2a, 3a, 4a, 5a, 6a and 7a in Table 2 in the same manner as in the preparation of compound 8, respectively. That is, compound 9 is obtained from compound 2a, compound 10 from compound 3a, compound 11 from compound 4a, compound 12 from compound 5a, compound 13 from compound 6a, and compound 14 from compound 7a. The yield, physical properties and spectroscopic data of these compounds 9-14 are listed in Table 3.

[Examples 15-19]

[3- (N-acetylindolin-5-sulfonyl) -4-phenyl-4,5-dihydro-2-imidazolone (preparation of compound No. 15)]

Compound 15 was prepared by using 2-ethoxy-3- (N-acetylindolin-5-sulfonyl) -4-phenyl-4,5-dihydro-2-imidazole (Compound No. 1b) as a starting material. It is obtained by carrying out the same method as the method for preparing.

Compounds 16, 17, 18, 19 of Table 4 are prepared from the corresponding starting materials 2b, 4b, 5b, 6b of Table 1 in the same manner as Compound 15, respectively. That is, compound 16 is prepared from compound 2b, compound 17 from compound 4b, compound 18 from compound 5b, and compound 19 from compound 6b.

Yield, physical properties, and spectroscopic data of Compounds 15, 16, 17, 18, and 19 are shown in Table 3.

Experimental Example 1

[Measurement of anticancer activity on human lung cancer A549 cells and skin cancer SK-MEL-2 cells]

As a test compound, slow-open Newer (LY186641) was dissolved in dimethyl sulfoxide at a concentration of 20 mg / ml as a test compound, and RPMI1640 medium containing 5% fetal bovine serum was used as a log dose. Dilution adjusted the concentration of the compounds to 0.3, 1.0, 3.0, 10.0, 30.0, 100 μg / ml, respectively. Immediately before adding the medium solution of the compound to the cells, the filter is maintained with a 0.22 μm bacterial filter to maintain a sterile state. Cells in passage are dispersed in the medium and the cell number is 5 × 10 in 96 well flat-bottom microplates. The dogs are aliquoted and incubated for one day in a 5% carbon dioxide gas incubator for 24 hours and attached to the bottom. After removing the medium with an aspirator, 100 μl of each solution of the test compound prepared above was added to each well containing cells, and incubated in a 5% carbon dioxide gas incubator for 48 hours. After incubation, the medium was removed according to the method of SRB (Sulforhodamine B) analysis (Proc. Am. Assoc. Cancer Res., Vol. 30, 607, 1989), and 100 μl of 10% trichloroacetic acid was added thereto at 1 ° C. The cells were left to stand for time to fix the cells, and the plates were washed 5 to 6 times with distilled water. After washing, it was dried at room temperature, stained with 0.4% SRB staining solution, washed 5-6 times with 1% acetic acid solution, and then dried again at room temperature. 100 ml of 10 mM Trisma solution was added to the well of a small microplate, and SRB was eluted, and the absorbance was measured at 520 nm. From the absorbance, the number of surviving cells is calculated, and an IC value (concentration μg / ml that inhibits 50% growth) is calculated and compared with the number of cells when no drug is administered, and the anticancer activity is evaluated. IC value of each compound was calculated by the following method.

In the above formula, T is the average cell number after 48 hours of cultivation of the test group, C is the average cell number after 48 hours of cultivation of the control group (if no drug), and C ₀ is the average cell number at the start of the culture.

The calculated growth rate Y (%) and the logarithmic capacity are plotted to obtain the equation of the regression line Y = a + bx where b is the slope and a is the intercept. Substituting 50 for Y gives X equal to log ₁₀ IC ₅₀ and calculates the IC ₅₀ value from the schematic. The obtained IC ₅₀ values are listed in Table 5. As shown in Table 5, the compounds of the present invention can be seen to show better or similar anti-cancer activity than the control drug salopefen against three cancer cells.

Experimental Example 2

Extended anticancer activity measurement test

Human cancer cells included skin melanoma Malme-3M, lung cancer cells A427 and HFL / B, gastric cancer cells SNU-1 and KATOIII, colorectal cancer cells SNU-C4 and Colo-205, lymphoma sarcoma K562 and mouse cancer cells Subcellular L929 was targeted. As a comparative drug, salopenyue, cisplatin, doxorubicin were used, and the test method was a commonly used MTT search method (Cancer Res. Vol 48, 189-601, 1988).

The test compound and the control drug of the present invention were dissolved in the concentration of 20 mg / ㎖ in the dimethyl sulfoxide concentrations of zalopenuine, cisplatin, doxorubicin and dilute to log dose (Log Dose) with RPMI1640 medium containing 10% fetal calf serum. The concentration of the compound was adjusted to 0.0064, 0.032, 0.80, 4.0, 20, 100 µg / ml. The medium solution of the compound is filtered through a bacterial filter prior to addition to the cells to maintain a sterile state. 1 × 10 cells per 100 μL in a microplate with 96 wells 100 μl of individual medium and 100 μl of the medium prepared according to concentrations above were mixed in each well, and then cultured in a CO incubator for 3 days. Thereafter, 50 μl of a solution in which 2 mg of MTT was dissolved per 1 ml of medium was added to each well, and further incubated for 4 hours. Centrifuge the plate at 450 g for 5 minutes and remove the supernatant so that only 30 μl of supernatant is left, taking care not to disturb the formazan crystals formed at the bottom. 150 μl of dimethyl sulfoxide was added to the well to dissolve the dark blue formazan, and the absorbance was measured at 540 nm.

As shown in Table 6, not only the test compound of the present invention exhibited an excellent effect as compared to cisplatin or sagefenaur, and in particular, the compounds 8, 9, and 10 can be seen that the equivalent or superior effect with doxorubicin.

Note: a = not tested

Malme-3M: Human Melanoma Cells

A427 and HFL / B = human lung cancer cells

SNU-1 and KATOIII = human gastric cancer cells

SNU-C4 and Colo205 = human colon cancer cells

K562 = human lymphocyte cancer cell

L929 = rat fibroblast

Claims (9)

Imidazolone derivative of the following general formula (I). Wherein Y is 1-naphthyl, 2-naphthyl, 1, 2, 3, 4-tetrahydronaphthalen-6-yl, 2,3-dihydrobenzofuran-5-yl or of formula (A) Indolin-5-day, Wherein R represents an alkoxy carbonyl group to the C ₁ -C ₄ acyl, chloroacetyl, trifluoroacetyl, bromoacetyl, C ₁ -C _4. The imidazolone derivative of formula (I) according to claim 1, wherein Y represents indolin-5-yl of formula (A). The imidazolone derivative of formula (I) according to claim 1, wherein R is acetyl, ethoxycarbonyl or chloroacetyl. Imidazolone derivative of the following general formula (II). Wherein Y is as defined in claim 1. A process for preparing an imidazolone derivative of the following general formula (I) characterized by nucleophilic substitution reaction of a compound of the following general formula (III) in the presence of an acid or a base. Wherein Y is as defined in claim ₁ and R ₁ represents methyl or ethyl. A process according to claim 5, wherein the nucleophilic substitution is carried out under aqueous alcoholic or anhydrous conditions. Imidazolone derivative of the following general formula (III). Wherein R ₁ and Y are as defined in claim 5. Imidazolone derivative of the following general formula (III-B). Wherein R ₁ and Y are as defined in claim 5. To prepare an imidazolone derivative of the following formulas (III) and (III-b), characterized by reacting an imidazolone derivative of the following formula (IV) with an arylsulfonyl chloride of the following formula (V): Way. Wherein R ₁ and Y are as defined in claim 5.