KR100435085B1 - Novel sulfonyl-imidazolone derivative, manufacturing method thereof and anticancer composition containing the same - Google Patents

Abstract

PURPOSE: Provided are a novel sulfonyl-imidazolone derivative of the formula(1) and its pharmaceutically acceptable salt, a manufacturing method thereof and an anti-tumor composition containing the same as an active ingredient. CONSTITUTION: The 4-phenyl-1-(indolin-5-sulfonyl)-2-imidazolone derivative is represented by the formula(1), wherein R is chloroacetyl, C1-C5 alkylamino acetyl, C1-C4 alkoxy carbonyl. benzoyl, nitrobenzoyl, aminobenzoyl, ethoxybenzoyl, chlorobenzoyl, chloroacetyl aminobenzoyl, furanoyl, thiophenoyl and C1-C6 alkylcarbamoyl; and R1 is hydrogen or C1-C4 lower alcohol. The compound of the formula(1) is manufactured by reacting a compound of the formula(A) and a compound of the formula(B).

Description

New Sulfonylimidazolone Derivatives

The present invention relates to novel sulfonylimidazolone derivatives having anticancer activity. More specifically, the present invention provides 4-phenyl-1- (indoline-5-sulfonyl-2-imidazolone derivative represented by the following formula 1, pharmaceutically acceptable salt thereof, preparation method thereof, and the compound It relates to a novel anticancer composition containing as an active ingredient, a novel intermediate in the production method thereof and a production method thereof.

[Formula 1]

In the above formula

R is an aromatic compound such as chloroacetyl, C ₁ -C ₅ alkylaminoacetyl, C ₁ -C ₄ alkoxycarbonyl, substituted or unsubstituted benzoyl, furanoyl and chiphenoyl, alkyl of C ₁ -C ₆ Carbamoyl, substituted or unsubstituted phenylcarbamoyl and R 'represents hydrogen or lower alkyl of C ₁ -C ₄ .

The present invention also relates to compounds of formula (D) which are useful as intermediates for the preparation of 4-phenyl-1- (indolin-5-sulfonyl) -2-imidazolone derivatives.

[Formula D]

In the above formula,

R ′ represents hydrogen or lower alkyl of C ₁ -C ₄ .

Numerous drugs have been developed to conquer cancer, which has been treated as a modern incurable disease, but only about 60 drugs have been used. Among them, therapies for solid cancers, which actually account for more than 90% of cancers, are rare.

Under these circumstances, Sulofenur, which has a sulfonylurea structure, has recently been known to exhibit particularly excellent effects on solid cancers such as colorectal cancer and ovarian cancer. Zalapenuer does not block the synthesis of DNA, RNA, and protein, so there are no side effects such as nausea, vomiting, and hair loss. However, anemia and mild nephrotoxicity are adverse effects when used in excess. Therefore, various attempts have been made to develop an anticancer agent based on sulfonylurea structure such as salopenure.

Accordingly, the present inventors conducted an extensive and continuous study to develop a compound having superior anti-cancer effects, but without toxicity or side effects, because of the anticancer action by a mechanism similar to that of zelofenyu, and as a result, various novel Invented a diarylsulfonyl urea derivative and has already applied for four patents (see Korean Patent Application Nos. 93-937, 95-29425, 96-8823, 96-34920)

Thus, the present inventors prepared various new derivatives such as changing the structure of the 4,5-dihydro-2-imidazolone moiety in order to obtain a sulfonylurea compound having a stronger anticancer effect. Compounds of 4-phenyl-1- (indolyl-5-sulfonyl-2-imidazolone derivatives), that is, derivatives having unsaturated double bonds in the imidazolone ring, are also referred to as 4-phenyl-1- (indolin-5 Like the compounds of sulfonyl) -4,5-dihydro-2-imidazolone derivatives, it exhibits 10 to 100 times more potent anticancer effects than Zalopener and 10 times more potent than doxorubicin, anthracycline-based drug. In addition, the compound of 4-phenyl-1- (indolin-5-sulfonyl) -2-imidazolone derivative is 4-phenyl-1- (indolin-5-sulfonyl) -4, Unlike 5-dihydro-2-imidazolone derivatives, asymmetric carbon (chiral cent) at position 4 no er), thus eliminating the problem of isomer separation, making the synthesis much simpler and more economical.The present inventors have found that 4-phenyl-1- (indoline-5-sulfonyl-2-imidazolone) Various substituents were introduced into nitrogen to confirm their anticancer effects, and as a result, compounds introduced with substituents on indoline also showed significantly superior anticancer effects than that of slopagne or toxin rubicin. It was confirmed that the compound in which the carbamoyl group was introduced by using isocyanate in nitrogen showed a superior anticancer effect than doxorubicin, and thus the present invention was completed.

Accordingly, the present invention relates to 4-phenyl-1- (indolin-5-sulfonyl) -2-imidazolone derivative of the formula (1) and pharmaceutically acceptable salts thereof.

[Formula 1]

In the above formula,

R is an aromatic compound such as chloroacetyl, C ₁ -C ₅ alkylaminoacetyl, C ₁ -C ₄ alkoxy carbonyl, substituted or unsubstituted benzoyl, furanoyl and chiphenoyl, alkyl of C ₁ -C ₆ Carbamoyl, substituted or unsubstituted phenylcarbamoyl and R 'represents hydrogen or lower alkyl of C ₁ -C ₄ .

Among the compounds of formula 1 according to the invention, preferred are those wherein R is ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, 4-nitrobenzoyl, 4-aminobenzoyl, nicotinoyl, chiphenoyl, 4-chloroacetylaminobenzoyl , Allylaminoacetyl and t-butylaminoacetyl.

Particularly preferred compounds are those of the formula I, in which R is isopropylcarbamoyl, 4-aminobenzoyl, allylamino acetyl and R 'represents methyl.

As representative examples of the compound of formula 1 according to the present invention, the following compounds may be mentioned:

4-phenyl-1- [N- (ethoxycarbonyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N-ethylcarbamoylindoline-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N-ethylcarbamoyl-2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N-propylcarbamoyl-2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N-propylcarbamoylindoline-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N-isopropylcarbamoylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [t-butylcarbamoylindoline-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N-isopropylcarbamoyl-2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-nitrobenzoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-aminobenzoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-nitrobenzoyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-aminobenzoyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N-benzoylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-ethoxybenzoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (nicotinoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (furanoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (thiophenoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-chlorobenzoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-chloroacetylaminobenzoyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (4-chloroacetylaminobenzoyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (chloroacetyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (allylaminoacetyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (isobutylaminoacetyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (isopropylaminoacetyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (methylaminoacetyl) -2-methylindolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (isobutylaminoacetyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (isopropylaminoacetyl) indolin-5-sulfonyl] -2-imidazolone,

4-phenyl-1- [N- (t-butylaminoacetyl) indolin-5-sulfonyl] -2-imidazolone,

Compounds having an amino group in R in the compound of formula 1 according to the present invention may form pharmaceutically acceptable acid addition salts according to methods conventional in the art. Examples thereof include hydrochloric acid, sulfuric acid, acetic acid, bromo acid chloride, methanesulfonic acid, paratoluenesulfonic acid, and the like, and particularly preferably form hydrochloride.

The present invention also relates to a method for preparing the compound of Formula 1 above.

Representation of the production method of the present invention is shown in Schemes 1 and 2.

Scheme 1

Scheme 2

Wherein R and R 'are as defined above and X represents a halogen atom, alkylsulfonyl, substituted or unsubstituted benzenesulfonyl or acid anhydride.

The present invention also relates to a process for the preparation of formula (D), useful as an intermediate.

Representation of the production method of the present invention is shown in the following schemes 3, 4.

Scheme 3

Scheme 4

In the above formula

R and R 'are as defined above and M is an alkali metal such as sodium, potassium and the like.

Hereinafter, the manufacturing method of the present invention will be described in detail.

Compounds are obtained by combining the corresponding functional groups using Compound D in Scheme 1 or combining Compound A and Compound B in Scheme 2.

The preparation method for obtaining the compound of Formula 1 in Compound D may be a solvent such as benzene or toluene when R is carbamoyl indolin (compounds 2,3,4,5,6,7,8) and the reaction temperature is It takes 8-12 hours depending on the functional group being replaced by 50 ° C-80 ° C.

R is substituted or unsubstituted benzoyl, nicotinoyl, furanoyl, thiophenoyl indolin (compound 9,10,11,12,13,14,15,16,17,18, Dichloromethane, tetrahydrofuran, chloroform, etc. may be mentioned as an example of the solvent used for 19,20), Most preferably, dichloromethane is used. This reaction can also be carried out in the presence of a base, for example bases such as pyridine, dimethylaminopyridine, triethylamine, diethylamine, and particularly preferably pyridine. In general, the reaction is carried out at room temperature for 5 to 6 hours to afford the desired compound.

When R in the compound of Formula 1 is ethoxycarbonyl or chloroacetyl (1, 21), the reaction is carried out for 1 to 2 hours at room temperature using dichloromethane as a solvent to obtain the target compound.

In the case of the alkylamino indolin compound (compound 22, 23, 24, 25, 26, 27, 28) in the compound of formula 1, 4-phenyl-1- [N- (chloroacetyl) -indolin-5-sulfonyl )]-2-imidazolone (Compound 21) is obtained by reacting each of the corresponding amines with methanol, ethanol, tetrahydrofuran, dichloromethane and the like at room temperature for 4-8 hours using a solvent. Preferably tetrahydrofuran is used.

The target compound of the general formula (1) prepared by the method of the present invention can be separated and purified by conventional post-treatment processes such as chromatography, recrystallization and the like.

Compounds of formula D, which are intermediates according to the invention, can be prepared by the following process.

2-aminoacetophenone obtained by reacting 2-bromoacetophenone with hexamethylenetetraamine in a solvent such as chloroform, dichloromethane, carbon tetrachloride and the like is subjected to hydrochloric acid to crystallize to hydrochloride. The resulting 2-aminoacetophenone hydrochloride was dissolved in water or ethanol as a solvent to react with potassium citrate or sodium cyanate at 50 ° C-70 ° C for 4-6 hours while maintaining the pH of the reaction solution in an acidic manner. A is obtained.

Conventional manufacturing method (Journal of Heterocyclic Chemistry 32, 1197, 1995) yielded a very low yield of 30% by using water and ethanol as a mixed solvent, the production method of the present invention was very increased to 72% using a single solvent .

Indoline or 2-methylindolin is dissolved in a solvent such as methylene chloride, chloroform, or tetrahydrofuran and reacted with trifluoroacetic anhydride in the presence of a base such as pyridine or triethylamine to react with indolin or 2- The nitrogen of methylindolin is protected with trifluoroacetate and then reacted with chlorosulfonic acid to give compound B 'of Scheme 3.

As shown in Scheme 4, examples of the solvent used in the reaction of Compound A and Compound B 'obtained in Scheme 3 may include dimethylformamide, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, and the like. Dimethylformamide is preferably used. This reaction can also be carried out in the presence of a base, for example bases such as potassium carbonate, sodium carbonate, potassium t-butoxide, sodium hydride, and particularly preferably sodium hydride. In general, the reaction is carried out at 0 ℃ or room temperature for 5 to 6 hours to obtain the target compound C.

When the obtained compound C is suspended in a mixed solvent of water and methanol to react with potassium carbonate, the trifluoroacetate group is deprotected.

The novel 4-phenyl-1- (indolin-5-sulfonyl) -2-imidazolone and its derivatives according to the present invention have a strong anticancer effect against lung cancer, colorectal cancer, lymphoma, ovarian cancer, etc. It can be used as a clinically useful anticancer agent. Therefore, the present invention relates to an anti-cancer agent composition containing a diarylsulfonyl urea derivative of formula 1 and a salt thereof as an active ingredient.

An anticancer composition containing the compound of the present invention as an active ingredient may be combined with a conventional carrier in the pharmaceutical field when used clinically, such as tablets, capsules, troches, liquids, suspensions, etc. Injectable preparations, ointments, creams, liquids, etc., in the form of preparations for oral administration such as preparations, injectable solutions or suspensions, or ready-to-use injectable dry powders which can be prepared and used as injectable distilled water at the time of injection. It may be formulated into a variety of formulations, such as topical formulations.

Carriers that can be used in the compositions of the present invention are conventional in the pharmaceutical field, for example in the case of oral preparations, binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments And fragrances. In the case of injectables, there are preservatives, analgesics, solubilizers, stabilizers, and the like, and in the case of topical administration, there are bases, excipients, lubricants, and preservatives. Pharmaceutical preparations thus prepared can be administered orally or parenterally, eg, intravenously, subcutaneously, intraperitoneally or topically. In addition, in order to prevent the decomposition of the drug by gastric acid during oral administration, an antacid may be used in combination, or an oral administration solid preparation such as a tablet may be formulated into a formulation coated with enteric skin.

The dosage of the novel diarylsulfonylimidazolone derivative of formula 1 according to the present invention to the human body depends on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the severity of the disease to be treated, and the like. Although appropriately selected, generally an adult is allowed to receive an amount of 10 to 5000 mg, preferably 10 to 1000 mg per day. Therefore, when preparing the composition of the present invention in unit dosage form, each unit dosage form may be formulated to contain 10 to 5000 mg, preferably 10 to 1000 mg of the compound of formula 1 in consideration of the above-mentioned effective dose range. have. The unit dosage form thus formulated uses a specialized dosage method according to the judgment of the expert who monitors or observes the administration of the drug as needed and the needs of the individual, or several times, preferably 1 to 6 times at regular time intervals. May be administered.

The invention is illustrated in more detail by the following examples. The following examples illustrate the present invention and the present invention is not limited to the following examples.

Preparation Example 1 1,3-dihydro-4-phenyl-2-imidazolone (Compound A of Scheme 3)

18 g (90 mmol) of 2-bromoacetophenone is dissolved in 900 ml of chloroform, and 13.87 g (99 mmol) of hexamethylenetetraamine is added and stirred at 60 ° C for 4 hours. After cooling the reaction solution to room temperature, the resulting precipitate was filtered and dried, dissolved in 180 ml of ethanol and 90 ml of hydrochloric acid, and stirred at room temperature for 18 hours. The resulting white precipitate was filtered off and the filtrate was completely concentrated to recrystallize the yellow precipitate using methanol and ethyl acetate to give 13 g of 2-aminoacetophenone.

Yield: 84%

5.6 g (32.65 mmol) of 2-aminoacetophenone are dissolved in 200 ml of water in a three-necked flask equipped with a thermometer and heated to 70 ° C-80 ° C. While maintaining the pH of the reaction solution dropwise with concentrated hydrochloric acid, 2.9 g (35.92 mmol) of potassium cyanate was added in several portions. Potassium cyanate was added and the reaction solution was brought to pH 3-4 and stirred at 70 ° C.-80 ° C. for 4 hours. After stirring for 4 hours, the reaction solution was left at room temperature for 18 hours, and the resulting light brown precipitate was filtered to yield 3.7 g of the desired target compound.

Yield: 72%

Preparation Example 2 2-Methyl-5-sulfonylchloride-N-trifuluroacetate-indolin (Compound B ′ of Scheme 3)

10 ml (76.8 mmol) of 2-methylindolin are dissolved in 100 ml of dichloromethane, cooled to 0 ° C., and then 18.7 ml (220.23 mol) of pyridine and 24 ml (0.17 mol) of trifluoroacetic anhydride are added. The reaction solution was stirred at room temperature for 6 hours, diluted with 300 ml of dichloromethane and washed twice with 150 ml of 5% hydrochloric acid. The dichloromethane layer was dried over anhydrous forget-me-not and concentrated to give 15 g (yield: 85%) of 2-methyl-N-tripuloacetate-indolin.

25 ml (0.37 mol) of chlorosulfonyl acid were cooled to 0 ° C. in a three-necked flask equipped with a thermometer, and then 17 g (74.23 mmol) of 2-methyl-N-tripuloacetate-indolin was added slowly and stirred at 60 ° C. for 1 hour. The reaction solution is slowly added dropwise to 200 g of ice. At this time, the precipitate produced was filtered and dried to obtain 9.2 g of the target compound. Use of indolin as a starting material instead of 2-methylindolin yields 5-sulfonylchloride-N-tripuloacetate-indolin.

Yield: 80%

Preparation Example 3 Compound (C) of 4-Phenyl1- (N-trifluoacetyl-2-methyl-indolin-5-sulfonyl) -2-imidazolone Scheme 4

Compound A, 1,3-dihydro-4-phenyl-2-imidazolone (4 g, 24.84 mmol) obtained in Preparation Example 1 was suspended in 30 ml of dimethylformamide and cooled to 0 ° C. Add 60% sodium hydride (1.09 g, 27.3 mmol) and stir at 0 ° C. until the reaction solution in suspension is completely dissolved. It takes about 20-30 minutes. 2-Methyl-5-sulfonylchloride-N-trifluoroacetate indoline and Compound B obtained in Preparation Example 2 were added to the reaction solution, and the mixture was stirred at room temperature for 4-5 hours. The reaction solution was cooled back to 0 ° C. and 20-30 ml of water was added little by little to precipitate. The precipitate was filtered and dried to yield 7.6 g of the target compound 4-phenyl-1- (N-tripuloacetate-2-methyl-indolin-5-sulfonyl) -2-imidazolone.

Yield: 68%

Melting Point: 232.9-233.9 ℃

Example 1 4-phenyl-1- (2-methylindolin-5-sulfonyl) -2-imidazolone (Compound D in Scheme 1)

4-Phenyl-1- (N-trifuluroacetate-2-methylindolin-5-sulfonyl) -2-imidazolone (6 g, 13.3 mmol) is suspended in 30 ml of a mixture of water and methane, respectively. Potassium carbonate (3.7 g, 26.6 mmol) is added, and the mixture is stirred at room temperature for 4 hours. The solvent of the reaction solution was concentrated in half, extracted twice with 200 ml of dichloromethane, and concentrated to dryness with anhydrous forget-me-not. The resulting crude product was chromatographed using a mixed solution of dichloromethane and methanol 10: 1 as a developing solvent, and the target compound 4-phenyl-1- (2-methylindolin-5-sulfonyl) -2-imidazolone 4.2 g is obtained. 4-phenyl-1- (indolin-5-sulfonyl) -2-imidazolone can be prepared by the same preparation method using indolin instead of 2-methyl-indolin.

Yield: 87%

Example 2 4-phenyl-1- (N-ethoxycarbonylindolin-5-sulfonyl) -2-imidazolone (Compound 1)

4-phenyl-1- (indolin-5-sulfonyl) -2-imidazolone (150mg, 0.44mmol) prepared in Example 1 was dissolved in 10ml of dichloromethane and pyridine (39ul, 0.484mmol and ethylchloro Formate (46ul, 0.484mmol) was added and stirred for 1 hour at room temperature The reaction solution was diluted with 30 ml of dichloromethane, washed twice with 10 ml of water, dried over anhydrous for concentration and concentrated, and then mixed with dichloromethane and methanol 15: 1. Was purified by column chromatography using a developing solvent to give 173 mg of the target compound.

Yield: 96%

Melting Point: 214-216 ℃

Example 3: 4-phenyl-1- (N-ethylcarbamoylindoline-5-sulfonyl) -2-imidazolone (Compound D)

4-phenyl-1- (indolin-5-sulfonyl) -2-imidazolone (100 mg, 0.29 mmol) prepared in Example 1 was dissolved in 10 ml of toluene and ethylisocyanate (35 ul, 0.435 mmol) was added thereto. Stir at 8 ° C. for 8 hours. The toluene was concentrated under reduced pressure, and the resulting crude product was dissolved in 30 ml of dichloromethane and washed twice with 10 ml of water. The dichloromethane layer was dried over anhydrous forget-me-not, concentrated, and purified by column chromatography using a mixed solution of dichloromethane and methanol 15: 1 as a developing solvent to obtain 113 mg of the target compound. Compounds (3), (4), (5), (6), (7) and (8) can be prepared by the same method.

Yield: 95%

Melting Point: 234.1-234.8 ℃

Compound 3: 4-phenyl-1- (N-ethylcarbamoyl-2-methyl-indolin-5-sulfonyl) -2-imidazolone

Yield: 92%

Melting Point: 239.8-241.4 ℃

Compound 4: 4-phenyl-1- (N-propylcarbamoyl-2-methyl-indolin-5-sulfonyl) -2-imidazolone

Yield: 95%

Melting Point: 137.8-138.2 ℃

Compound 5: 4-phenyl-1- (N-propylcarbamoylindolin-5-sulfonyl) -2-imidazolone

Yield: 95%

Melting Point: 165-167 ℃

Compound 6: 4-phenyl-1- (N-isopropylcarbamoylindolin-5-sulfonyl) -2-imidazolone

Yield: 93%

Melting Point: 214-216.5 ℃

Compound 7: 4-phenyl-1-[(N-carboxy- (t-butylcarbamoyl) indoline-5-sulfonyl)]-2-imidazolone

Yield: 76%

Melting Point: 221.7-223 ℃

Compound 8: 4-phenyl-1- (N-isopropylcarbamoyl-2-methyl-indolin-5-sulfonyl) -2-imidazolone

Yield: 93%

Melting Point: 154.3-156.5 ℃

Example 4: 4-phenyl-1- [N- (4-nitrobenzoyl) -indolin-5-sulfonyl] -2-imidazolone compound 9)

4-phenyl-1- (indolin-5-sulfonylchloride) -2-imidazolone (300 mg, 0.88 mmol) prepared in Example 1 was suspended in dichloromethane to give pyridine (85 ul, 1.05 mmol) and 4- Nitrobenzoyl chloride (163 mg, 0.88 mmol) is added and stirred at room temperature for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated. The resulting crude product was purified by column chromatography using a mixed solution of dichloromethane and methanol 15: 1 as a developing solvent to obtain 400 mg of the target compound.

Yield: 92%

Melting Point: 244.8-246.3 ℃

Compounds (10), (11), (12), (13), (14), (15), (16), (17) and (18) can be prepared by the same method.

Compound 10: 4-phenyl-1- [N- (4-aminobenzoyl) indolin-5-sulfonyl] -2-imidazolone

Yield: 98%

Melting Point: 199-201 ℃

Compound 11: 4-phenyl-1- [N- (4-nitrobenzoyl) -2-methylindolin-5-sulfonyl] -2-imidazolone

Yield: 88%

Melting Point: 168.5-171.8 ℃

Compound 12: 4-phenyl-1- [N- (4-aminobenzoyl) -2-methylindolin-5-sulfonyl] -2-imidazolone

Yield: 68%

Melting Point: 189-190 ℃

Compound 13: 4-phenyl-1- [N-benzoyl-indolin-5-sulfonyl] -2-imidazolone

Yield: 96%

Melting Point: 167.4-170 ℃

Compound 14: 4-phenyl-1- [N- (4-ethoxybenzoyl) indolin-5-sulfonyl] -2-imidazolone

Yield: 89%

Melting Point: 249-252.8 ℃

Compound 15: 4-phenyl-1- [N-nicotinoylindolin-5-sulfonyl] -2-imidazolone

Yield: 82%

Melting Point: 244-245.2 ℃

Compound 16: 4-phenyl-1- [N-furanoylindoline-5-sulfonyl] -2-imidazolone

Yield: 85%

Melting Point: 255.5-257 ℃

Compound 17: 4-phenyl-1- [N-thiophenoylindolin-5-sulfonyl] -2-imidazolone

Yield: 97%

Melting Point: 258.2-259.5 ℃

Compound 18: 4-phenyl-1- [N- (4-chlorobenzoyl) indolin-5-sulfonyl] -2-imidazolone

Yield: 87%

Melting Point: 220.3-221.3 ℃

Example 5: 4-phenyl-1- [N- (4-chloroacetylaminobenzoyl) indolin-5-sulfonyl] -2-imidazolone (Compound 19)

4-phenyl-1- [N- (4-aminobenzoyl) indolin-5-sulfonyl] -2-imidazolone (150 mg, 0.3 mmol) prepared in Example 4 was dissolved in 10 ml of dichloromethane and pyridine ( 73 µl, 0.9 mmol) and chloroacetyl chloride (36 µl, 0.45 mmol) were added and stirred at room temperature for 2 hours. The reaction solution was diluted with 30 ml of dichloromethane, washed twice with 10 ml of water, dried over anhydrous forget-me-not and concentrated. The resultant crude product was column chromatographed using a mixed solution of dichloromethane and methanol 10: 1 as a developing solvent to obtain 130 mg of the target compound.

Yield: 84%

Melting Point: 188-189 ℃

In the same preparation method, Compound 20 can be prepared using 4-phenyl-1- [N- (4-aminobenzoyl) -2-methylindolin-5-sulfonyl] -2-imidazolone.

Compound 20: 4-phenyl-1- [N- (4-chloroacetylaminobenzoyl) -2-methylindolin-5-sulfonyl] -2-imidazolone

Yield: 72%

Melting Point: 245.5-246.4 ℃

Example 6: 4-phenyl-1- (N-chloroacetyl-2-methylindolin-5-sulfonyl) -2-imidazolone (Compound 21)

4-phenyl-1- (2-methylindolin-5-sulfonyl) -2-imidazolone (300 mg, 0.85 mmol) prepared in Example 4 was dissolved in 10 ml of dichloromethane and pyridine (75 μl, 0.93 mmol) ) And chloroacetyl chloride (74 [mu] l, 0.93 mmol) are added and stirred at room temperature for 2 hours. The reaction solution was diluted with 50 ml of dichloromethane, washed twice with 10 ml of water, dried over anhydrous forget-me-not and concentrated. The resulting crude product was column chromatographed using a mixed solution of dichloromethane and methanol 10: 1 as a developing solvent to obtain 342 mg of the target compound.

Yield: 94%

Melting Point: 157-159 ℃

Example 7 4-phenyl-1- (N-allylaminoacetyl-2-methylindolin-5-sulfonyl) -2-imidazolone hydrochloride (Compound 22)

4-phenyl-1- (N-chloroacetyl-2-methylindolin-5-sulfonyl) -2-imidazolone (120 mg, 0.278 mmol) prepared in Example 6 was dissolved in 5 ml of acetone and sodium iodide Id (63 mg, 0.42 mmol) was added and the mixture was stirred at room temperature for 2 hours. Acetone is concentrated under reduced pressure, and the resulting yellow precipitate is dissolved in 10 ml of tetrahydrofuran, and allylamine (208 µl, 2.78 mmol) is added and stirred for 2 hours at room temperature again. The solvent was concentrated under reduced pressure, dissolved in 20 ml of dichloromethane and washed twice with 10 ml of water. The dichloromethane layer was dried over anhydrous forget-me-not, and the crude product obtained was concentrated by column chromatography using a mixed solution of dichloromethane and methanol 10: 1 as a developing solvent to obtain 110 mg of the target compound. To 110 mg of 4-phenyl-1- (N-allylaminoacetyl-2-methylindolin-5-sulfonyl) -2-imidazolone obtained, 5 ml of 25% HClgas / methanol solution was added, stirred at room temperature for 3 minutes, and then a solvent. Concentrated under reduced pressure. The concentrate is dissolved in about 5 ml of water to completely remove excess hydrochloric acid gas, and the water is concentrated under reduced pressure. The obtained material is completely dried and then recrystallized from methanol and ethyl acetate to obtain 4-phenyl-1- (N-allylamino. Acetylindolin-5-sulfonyl) -2-imidazolone hydrochloride (100 mg) is obtained.

Yield: 85%

Melting Point: 220-222 ℃

Compounds (23), (24), (25), (26), (27) and (28) can be prepared by the same preparation method.

Compound 23: 4-phenyl-1- (N-isobutylaminoacetyl-2-methylindolin-5-sulfonyl) -2-imidazolone hydrochloride

Yield: 84%

Melting Point: 197-199 ℃

Compound 24: 4-phenyl-1- (N-isopropylaminoacetyl-2-methylindolin-5-sulfonyl) -2-imidazolone hydrochloride

Yield: 76%

Melting Point: 202-203.6 ℃

Compound 25: 4-phenyl-1- (N-methylaminoacetyl-2-methylindolin-5-sulfonyl) -2-imidazolone hydrochloride

Yield: 65%

Melting Point: 197-199 ℃

Compound 26: 4-phenyl-1- (N-isobutylaminoacetylindolin-5-sulfonyl) -2-imidazolone hydrochloride

Yield: 77%

Melting Point: 225 ℃

Compound 27: 4-phenyl-1- (N-isopropylaminoacetylindolin-5-sulfonyl) -2-imidazolone hydrochloride

Yield: 81%

Melting Point: 205-206 ℃

Compound 28: 4-phenyl-1- [N- (t-butylaminoacetyl) -2-methylindolin-5-sulfonyl] -2-imidazolone hydrochloride

Yield: 65%

Melting Point: 227.2-230 ℃

Experimental Example 1 In Vitro Cytotoxicity Test

In vitro cytotoxicity of DSU (diarylsulfonylurea) derivatives was determined by MTT screening for cancer cell strains at double intervals. The MTT method is an experimental method to determine the extent to which MTT is reduced to formazan crystals by the mitochondrial succinate dehydrogenase of surviving cells with absorbance. The concentration of each test drug that inhibits growth by 50% (IC ₅₀ ) was determined and compared with doxorubicin and cytotoxicity.

Each test drug was dissolved in DMSO (dimethylsulfoxide) at a concentration of 20 mg / ml, filtered through a 0.22 μm filter, and titrated with an azeotropic ratio of 5 from 200 μg / ml to 0.0128 μg / ml using RPMI 1640 medium. Diluted to concentration and used.

A549 human lung cancer cells, KB human skin cancer cells, Colo205 human colon cancer cells, and SK-OV-3 human ovarian cancer cells were used as the test cancer cells. 100 μg (10000 cells / well) of each suspension of cancer cells suspended in RPMI 1640 medium was inoculated in a 96 well microplate, incubated for 24 hours at 37 ° C., 5% CO ₂ , and then diluted in each well. 100 μl was added to a final drug concentration of 100 μg / ml to 0.0064 μg / ml and the control group was inoculated with the same amount of RPMI medium. Here, RPMI 1640 medium containing 10% (v / v) fetal bovine serum, penicillin, and streptomycin was used for cell culture. After exposure of the cancer cells to the drug for 72 hours, 25 μl of MTT solution (2 mg / ml saline solution) was added to each well, followed by incubation for 4 hours, followed by centrifugation (1000 rpm, 10 minutes) to remove the supernatant. The formazan crystals were dissolved in 100 µl of dimethyl sulfoxide.

This was measured by absorbance at 540nm using a microplate reader to calculate the concentration of the test drug (IC ₅₀ ) that inhibits the growth of cancer cells by 50% compared to the control.

Experimental results of phagocytosis of human cancer cells of the compounds by the MTT detection method are described in Table 1 below.

TABLE 1

Compound α = compound 35 of First Patent Application No. 93-937 (= 1- (p-chlorobenzenesulfonyl) -4-phenyl-2-imidazolidinone)

Compound (beta) = Compound 36 (= (1-5-Indansulfonyl) -4-phenyl-2-imidazolidinone) of the prior patent application 93-937

As shown in Table 1, the compounds of the present invention showed cytotoxicity 10 to 100 times more potent than the control drug, sloefenyuer, against the four cancer cell lines tested, the most excellent among the compounds of the prior patent application No. 93-937. And cytotoxicity superior to compound No. 36. Therefore, it can be seen that the compound of the present invention can be used as a stronger anticancer agent than saffron.

Claims (7)

Diarylsulfonylimidazolone derivatives of the general formula (1) and pharmaceutically acceptable salts thereof. [Formula 1] In the above formula, R is chloroacetyl, C ₁ -C ₅ alkylaminoacetyl, C ₁ -C ₄ alkoxy carbonyl, benzoyl, nitrobenzoyl, aminobenzoyl, ethoxybenzoyl, chlorobenzoyl, chloroacetylaminobenzoyl, furanoyl, cheo Phenoyl and alkylcarbamoyl of C ₁ -C ₆ , and R ′ represents hydrogen or lower alkyl of C ₁ -C ₄ . R is ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, 4-nitrobenzoyl, 4-aminobenzoyl, nicotinoyl, thiophenoyl, 4-chloroacetylaminobenzoyl, allylaminoacetyl, t -Butylaminoacetyl, and R 'represents hydrogen or lower alkyl of C ₁ -C ₄ and a pharmaceutically acceptable salt thereof. The compound of formula (1) according to claim 1, wherein R represents isopropylaminoacetyl, isobutylaminoacetyl, t-butylaminoacetyl, and R 'represents hydrogen or lower alkylmethyl of C ₁ -C ₄ , and pharmaceutically Acceptable salts. 4-phenyl-1- (2-methylindolin-5-sulfonyl) -2-imidazolone. An anticancer composition comprising a compound of formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. A method of preparing a compound of formula 1 and a pharmaceutically acceptable salt thereof by reacting a compound of formula A with a compound of formula B. Wherein R is chloroacetyl, C ₁ -C ₅ alkylaminoacetyl, C ₁ -C ₄ alkoxycarbonyl, benzoyl, nitrobenzoyl, aminobenzoyl, ethoxybenzoyl, chlorobenzoyl, chloroacetylaminobenzoyl, furano One, chiphenoyl and C ₁ -C ₆ alkylcarbamoyl, and R ′ represents hydrogen or lower alkyl of C ₁ -C ₄ . A method of preparing a compound of formula 1 and a pharmaceutically acceptable salt thereof by reacting a compound of formula D with formula RX. Wherein R is chloroacetyl, C ₁ -C ₅ alkylaminoacetyl, C ₁ -C ₄ alkoxycarbonyl, benzoyl, nitrobenzoyl, aminobenzoyl, ethoxybenzoyl, chlorobenzoyl, chloroacetylaminobenzoyl, furano ₁ , chiphenoyl and C ₁ -C ₆ alkylcarbamoyl, R 'represents hydrogen or C ₁ -C ₄ lower alkyl, X is halogen atom, alkylsulfonyl, substituted or unsubstituted benzenesulfonyl Or acid anhydride.