BACKGROUND OF THE INVENTION Up to date, 6,7- (diaziridin-1-yl)-5, 8-quinolinedione (German Patent No.

1, 089, 762), and 6-(aziridin-1-yl)-5, 8-quinolinedione (Great Britain Patent No.

765, 658) have known as an aziridinylquinolinedione compound to have anti- tumor activity.

The present invention has been completed to prove that not only disubstituted aziridinylquinolinediones at 6-and 7-position but also monosubstituted aziridinylquinolinediones at 6-or 7-position have significant

anti-cancer activity compared to 6,7- (diaziridin-1-yl)-5, 8-quinolinedione disclosed in the German Patent No. 1,089,762.

SUMMARY OF THE INVENTION In accordance with one aspect of the invention, there are provided novel aziridinylquinolinedione derivatives.

Another object of the present invention is to provide use of the aziridinylquinolinedione derivatives as an anti-tumor agent effective to tumor cells of human.

Further object of the present invention is to provide a process for preparing the aziridinylquinolinedione derivatives selectively and effectively.

Detailed Description of the Invention The present invention provides aziridinylquinolinedione derivatives of formula (1) having an aziridinyl group at one of 6-and 7-position and a different substituent at the other position: wherein RI is a hydrogen atom or Ci-C4 alkyl ; one of 2 and R3 is an aziridinyl or 2-methylaziridinyl and the other one is a halogen atom, C1-C4 alkoxy, azido, or amino.

Particularly preferred compounds of the present invention are the compounds selected from the group consisting of 6-chloro-7-(aziridin-1-yl)-5,8-quinolinedione <BR> <BR> <BR> <BR> <BR> 7-chloro-6-(aziridin-1-yl)-5, 8-quinolinedione<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 7-methoxy-6- (2-methylaziridin-1-yl)-5, 8-quinolinedione 6-methoxy-7- (2-methylaziridin-l-yl)-5, 8-quinolinedione 6-azido-7-(aziridin-1-yl)-5, 8-quinolinedione 6-amino-7-(aziridin-1-yl)-5,8-quinolinedione <BR> <BR> <BR> <BR> <BR> 7-azido-6-(aziridin-1-yl)-5, 8-quinolinedione<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 7-amino-6- (aziridin-1-yl)-5, 8-quinolinedione 6-bromo-7-(aziridin-1-yl)-5,8-quinolinedione <BR> <BR> <BR> <BR> <BR> 6-chloro-7-(2-methylaziridin-1-yl)-5,8-quinolinedione<BR& gt; <BR> <BR> <BR> <BR> <BR> <BR> <BR> 6-bromo-7- (2-methylaziridin-1-yl)-5, 8-quinolinedione<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 6-azido-7-(2-methylaziridin-1-yl)-5, 8-quinolinedione<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 6-amino-7-(2-methylaziridin-1-yl)-5, 8-quinolinedione<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 7-bromo-6-(aziridin-1-yl)-5,8-quinolinedione 7-chloro-6-(2-methylaziridin-1-yl)-5,8-quinolinedione 7-bromo-6-(2-methylaziridin-1-yl)-5, 8-quiulolinedione 7-azido-6-(2-methylaziridin-1-yl)-5, 8-quinolinedione 7-amino-6-(2-methylaziridin-1-yl)-5,8-quinolinedione 7-bromo-6-(aziridin-1-yl)-2-methyl-5,8-quinolinedione 6-bromo-7-(aziridin-1-yl)-2-methyl-5, 8-quinolinedione 7-bromo-6- (2-methylaziridin-1-yl)-2-methyl-5, 8-quinolinedione 6-bromo-7-(2-methylaziridin-1-yl)-2-methyl-5,8-quinolinedion e

7-methoxy-6-(2-methylaziridin-1-yl)-2-methyl-5,8-quinolinedi one<BR> <BR> 6-methoxy-7-(2-methylaziridin-1-yl)-2-methyl-5,8-quinolinedi one 7-azido-6-(aziridin-1-yl)-2methyl-5, 8-quinolinedione 6-azido-7-(aziridin-1-yl)-2-methyl-5,8-quinolinedione 7-azido-6-(2-methylaziridin-1-yl)-2-metllyl-5,8-quinolinedio ne 6-azido-7- (2-methylaziridin-l-yl)-2-methyl-5, 8-quinolinedione 7-amino-6- (aziridin-l-yl)-2-methyl-5, 8-quinolinedione 6-amino-7-(aziridin-1-yl)-2-metllyl-5,8-quinolinedione 7-amino-6- (2-methylaziridin-1-yl)-2-methyl-5, 8-quinolinedione 6-amino-7-(2-methylaziridin-1-yl)-2-methyl-5, 8-quinolinedione and physiologically acceptable salts thereof.

The salts can be formed with organic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid, and tartaric acid.

According to the present invention, a process for preparing aziridinylquinolinedione derivatives of formula (1) is provided.

Among aziridinylquinolinedione derivatives, to prepare a compound of formula (1a), the compound of formula (2) may be reacted with the compound of formula (3) as shown below in Scheme 1: Scheme 1

wherein Rl is a hydrogen atom or Cl-C4 alkyl ; R4 is a hydrogen atom or Ci-C4 alkyl ; and X is a halogen atom.

The reaction of 6,7-dihaloquinolinedione of formula (2) and aziridine compound of formula (3) is usually carried out at 0-20 oC in a non-polar solvent such as benzene and dioxane in the presence of an organic base such as triethylamine and diisopropylethylamine to produce 6-halo-7- aziridinylquinolinedione of formula (la).

To prepare a compound of formula (lb), the compound of formula (2) may be reacted with the compound of formula (3) as shown below in Scheme 2 : Scheme 2 wherein R1 is a hydrogen atom or Cl-C4 alkyl ; R4 is a hydrogen atom or Ci-C4 alkyl ; and X is a halogen atom.

The reaction of 6, 7-dihaloquinolindione of formula (2) and aziridine compound of formula (3) is usually carried out at 0-30 °C in a polar solvent such as ethanol and 2-propanol in the presence of an organic base such as triethylamine and diisopropylethylamine and Lewis acid such as cerium chloride (CeCls) to produce 7-halo-6-aziridinylquinolinedione of formula (1b).

The compounds of formula (1c) and formula (1d) may be also produced from the compound of formula (2) as shown below in Scheme 3: Scheme 3

wherein R1 is a hydrogen atom or C1-C4 alkyl ; R4 is a hydrogen atom or C1-C4 alkyl ; and X is a halogen atom.

The 6, 7-dihaloquinolinedione of formula (2) is first reacted with sodium methoxide in methanol to obtain dimethoxyquinolinedione of formula (4) and further reacted with the compound of formula (3) in methanol in the presence of an organic base such as triethylamine and diisopropylethylamine to produce 6-methoxy-7-aziridinylquinolinedione of formula (1c) and 7-methoxy-6- aziridinylquinolinedione of formula (1d) that can be separated easily with general column chromatography.

The compounds of formula (le) and formula (If) may be also produced from the compound of formula (2) as shown below in Scheme 4: Scheme 4

wherein Rl is a hydrogen atom or Cl-C4 aLkyl ; R4 is a hydrogen atom or Cl-C alkyl ; and X is a halogen atom.

The 6, 7-dihaloquinolinedione of formula (2) is first reacted with sodium methoxide in benzene to obtain 6-halo-7-methoxyquinolinedione of formula (5) and further reacted with sodium azide in aqueous tetrahydrofuran to obtain 6- azido-7-methoxyquinolinedione of formula (6). The compound (6) is then reacted with the compound of formula (3) in methanol in the presence of an organic base such as triethylamine and diisopropylethylamine to produce 6- azido-7-aziridinylquinolinedione of formula (le). The compound (le) is reduced with sodium borohydride in a mixed solvent of tetrahydrofuran and methanol to 6-amino-7-aziridinylquinolinedione of formula (1f).

The compounds of formula (1g) and formula (1h) may be also produced from the compound of formula (5) as shown below in Scheme 5: Scheme 5

wherein RI is a hydrogen atom or C1-C4 alkyl ; R4 is a hydrogen atom or Cl-C4 alkyl ; and X is a halogen atom.

The 6, 7-dihaloquinolinedione of formula (2) is first reacted with sodium azide in aqueous tetrahydrofuran to obtain 6,7-diazidoquinolinedione of formula (7) and further reacted with the compound of formula (3) in methanol in the presence of an organic base such as triethylamine and diisopropylethylamine to obtain 7-azido-6aziridinylquinolindione of formula (1g). The compound (1g) is reduced with sodium borohydride in a mixture solvent of tetrahydrofuran and methanol to 7-amino-6-aziridinylquinolinedione of formula (1h).

The resulting aziridinylquinolinedione derivatives of this invention represented by formula (1) can be separated and purified by appropriate conventional methods such as column chromatography and recrystallization.

The present invention provides the pharmacological use as an anti- cancer agent of the compound of formula (1) defined above. According to the present invention, a pharmaceutical composition is provided which comprises a pharmacologically effective amount of a compound of formula (1) and a pharmacologically acceptable salt thereof. Compounds of the invention may be administered by any suitable route such as parenteral administration and the like. For parenteral administration, the compound of formula (1) is used in the form of a sterile solution, a non-aqueous solvent, a suspension, an emulsion, a freezing dried preparation and the like. Vegetable oils such as propylene glycol, polyethylene glycol, and olive oil and esters such as ethyl oleate are used as non-aqueous solvent and suspending agent. For parenteral administration, the compound of formula (1) is mixed with pharmaceutically acceptable stabilizer or buffer solution and water to form a solution or suspension which is further formulated to an ample or vial for a unit dose. For administration to man, dosages of the compound of formula (1) will vary with the age, weight, sex, type of administration, health condition and response of the particular patient. Dosages will typically be within the range of from 0.01 to 100 mg/kg, preferably from 0.01 to 10 mg/kg and can be administered once or several times per day.

Further, the aziridinylquinolinedione derivatives of formula (1) of the invention provide significant activity against tumor cells separated from human compared to the conventional diaziridinylquinolinedione, Mitomycin C, Doxorubicin.

The present invention is further illustrated in the following

Examples and Experimental Examples, which should not be taken to limit the scope of the invention.

Example 1: 6-chloro-7- (aziridin-1-yl)-5, 8-quinolinedione 6, 7-Dichloro-5, 8-quinolinedione 228 mg (1 mmol) was dissolved in 10 mL of dry benzene under N2 atmosphere at 0 °C and 0.2 mL (1.4 mmol) of triethylamine was added and stirred. After adding 0.2 mL of aziridine at the same temperature, the temperature was increased slowly to the room temperature and stirred for 2 hrs. The reaction mixture was evaporated under the reduced pressure and the residue was purified by column chromatography on silica gel (eluent: 4/1 ethyl acetate/hexane) to afford 6-chloro-7- (aziridin-l- yl)-5,8-quinolinedione as quantitative yield. mp : 170-171°C IH NMR (CDCl3) : 6 8.91 (dd, 1, t=4. 4 Hz, C2H), 8.37 (dd, 1, J=7. 8 Hz, C4 H), 7.62 (dd, 1, C3H), 2.57 (s, 4, 2XCH2) Anal. Calcd. for CnH7ClN202 : C, 56.31; H, 3.01; N, 11. 94. Found: C, 56.62; H, 2. 78; N, 11.49.

Example 2: 7-chloro-6-(aziridin-1-yl)-5, 8-quinolinedione 6, 7-Dichloro-5, 8-quinolinedione 100 mg (0.44 mmol) and CeCl3-7H20 200 mg (0.53 mmol) were added into 25 mL of 95% ethanol and the mixture was stirred under N2 at the room temperature for 40 min. To the reaction mixture were added triethylamine 0.07 mL (0.53 mmol) and aziridine 0.03 mL (0.53 mmol) and stirred for 1 hr. The reaction mixture was evaporated under the

reduced pressure and the residue was purified by column chromatography on silica gel (eluent: 1/1 ethyl acetate/hexane) to afford 7-chloro-6- (aziridin-1-yl)- 5, 8-quinolinedione 94 mg (91%). m p : 171-172 °C 1H NMR (CDCIs) : 6 8.93 (dd, 1, C2 H), 8.35 (dd, 1, C4H0, 7.62 (dd, 1. C3 H), 2.57 (s, 4, 2#CH2) Anal. Calcd. for C11H7ClN2O2 : C, 56.31; H, 3.01; N, 11.94. Found: C, 56.57; H, 2.95; N, 11.64.

Example 3: 6, 7-dimethoxy-5,8-quinolinedione 6, 7-Dichloro-5, 8-quinolinedione 1.20 g (4.39 mmol) and sodium methoxide 780 mg (14.3 mmol) were added into 100 mL of dry methanol and stirred at the room temperature for 4 hrs. 200 g of ice was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under the reduced pressure.

The residue was purified by column chromatography on silica gel (eluent: 3/1 ethyl acetate/hexane) to afford 6, 7-dimethoxy-5, 8-quinolinedione 89 mg (41%). mp: 122-123 °C H NMR (CDCls) : Fi 8.60 (dd, 1, C2 H), 7. 98 (dd, 1, C4 H), 7.37 (dd, 1, Cs H), 3.79 (s, 3, OCH3), 3.77 (s, 3, OCh3).

Anal. Calcd. for C11H9NO4 : C, 60.27; H, 4.14; N, 6. 39. Found: C, 60.30; H, 4.08; N, 6.28.

Example 4: 7-methoxy-6- (2-methylaziridin-1-yl)-5, 8-quinolinedione

6, 7-Dimethoxy-5, 8-quinolinedione 45 mg (0.24 mmol) was dissolved in 10 mL of methanol at 0 °C and triethylamine 0.05 mL (0.35 mmol) was added thereto and stirred. After adding 2-methylaziridine 0.05 mL (0.64 mmol) at the same temperature, the reaction temperature was slowly increased to the room temperature and then stirred for 24 hrs. The reaction mixture was evaporated under the reduced pressure and the residue was purified by column chromatography on silica gel (eluent: 2/1 ethyl acetate/hexane) to afford 7- methoxy-6- (2-methylaziridin-1-yl)-5, 8-quinolinedione and 6-methoxy-7-(2- methylaziridin-1-yl)-5, 8-quinolinedione as a ratio of 3: 1 (90%). mp : 76-77 °C zu NMR (CDCI3) : 6 8.64 (dd, 1, C2 H), 8.00 (dd, 1, C4H),7. 36 (dd, 1, C3 H), 3.82 (s, 3, OCHs), 2.13 (m, 1, CH), 2.05 (dd, 2, CH2), 1.18 (d, 3, CHs).

Anal. Calcd. for C13H12N2O3 : C, 63.93; H, 4.95; N, 11.47. Found : C, 63.98; H, 4.94; N, 11.48.

Example 5: 6-methoxy-7-(2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 4 by column chromatography on silica gel (eluent: 2/1 ethyl acetate/hexane). mp : 85-86 °C H NMR (CDCIs) : 6 8.81 (dd, 1, C2 H), 8.23 (dd, 1, C4H), 7.52 (dd, 1, C3 H), 3.96 (s, 3, OCHs), 2.32 (m, 1, CH), 2.25 (dd, 2, CH2), 1.38 (d, 3, CH3).

Anal. Calcd. for C13H12N2O3 : C, 63.93; H, 4.95; N, 11.47. Found: C, 64.20; H, 5.16; N, 11.05.

Example 6: 7-methoxy-6-chloro-5,8-quinolinedione 6,7-Dichloro-5,8-quinolinedione 1.20 g (5.3 mmol) and sodium methoxide 1.70 g (31.5 mmol) were added into 100 mL of dry benzene at 0 °C and stirred for 1 hr. The reaction mixture was filtered and the filtrate was evaporated under the reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 2/1 ethyl acetate/hexane) to afford 7- methoxy-6-chloro-5, 8-quinolinedione 174 mg (78%). mp : 145-146 C 'H NMR (CDCIs) : # 8.99 (dd, 1, C2H), 8.42 (dd, 1, C4 H), 7.68 (dd, 1, C3 H), 4.35 (s, 3, OCH3).

Anal. Calcd. for CloH6ClN03 : C, 53.71; H, 2.70; N, 6.26. Found: C, 53.90; H, 2.54; N, 6.23.

Example 7 : 6-azido-7-methoxy-5,8-quinolinedione 7-Methoxy-6-chloro-5, 8-quinolinedione 674 mg (3 mmol) and sodium azide 195 mg (3 mmol) were dissolved in 57 mL of THF and 3 mL of water and stirred at the room temperature for 1 hr. The reaction mixture was evaporated under the reduced pressure and extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under the reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 3/1 ethyl acetate/hexane) to afford 6-azido-7-methoxy-5,8-quinolinedione 203 mg (88%). mp : 106-107 °C H NMR (CDCls) : b 8. 95 (dd, 1, Cz H), 8.33 (dd, 1, C4H0,7. 63 (dd, 1, Cs H), 4.21

(s, 3, OCHs).

Anal. Calcd. for CloH6N403 : C, 52.18; H, 2.63; N, 24.34. Found: C, 52.49; H, 2.52; N, 23.86.

Example 8: 6-azido-7-(aziridin-1-yl)-5,8-quinolinedione 6-Azido-7-methoxy-5, 8-quinolinedione 85 mg (0.37 mmol) was dissolved in 10 mL of methanol. After adding 0.08 mL (0.56 mmol) of triethylamine under N2, the reaction mixture was stirred and further 0.03 mL (0.56 mmol) of aziridine was added and stirred for 1.5 hrs. The reaction mixture was evaporated under the reduced pressure and the residue was purified by column chromatography on silica gel (eluent: 1.5/1 ethyl acetate/hexane) to afford 6-azido-7-(azilidin-1-yp-5, 8-quinolinedione 135 mg(56%). mp: > 250 °C 1H NMR (CDCl3) : # 8.94 (dd, 1, C2 H), 8.34 (dd, 1, C4H), 7.62 (dd, 1, C3 H), 2.46 (s, 4, #CH2).

Anal. Calcd. for C11H7N5O2 : C, 54.77; H, 2.93; N, 29.03. Found: C, 54.74; H, 2.75; N, 29.06.

Example 9: 6-amino-7-(aziridin-1-yl)-5, 8-quinolinedione 6-Azido-7-(aziridin-1-yl)-5,8-quinolinedione 426 mg (1.77 mmol) and sodium borohydride 669 mg (17. 7 mmol) were dissolved in 150 mL of THF- methanol (4: 1) under N2 and stirred for 1.5 hrs. Ice was added to the reaction mixture which was further extracted with ethyl acetate. The reaction mixture

was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under the reduced pressure and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to afford 6-amino-7- (aziridin-1-yl)-5, 8-quinolinedione 49 mg (23%). mp: 179-180 °C H NM1t (CDCl3) : 8 8.91 (dd, 1, C2 H)-/8. 27 (dd, 1, C4H), 7.51 (dd, 1, C3 H), 5.04 (br s, 2, NH2), 2.32 (s, 4,2XCH2).

Anal. Calcd. for C11H9N3O2 : C, 61.39; H, 4.22; N, 19.53. Found: C, 61.34; H, 4.18; N, 19.58.

Example 10: 6, 7-diazido-5, 8-quinolinedione 6,7-Dichloro-5, 8-quinolinedione 228 mg (1 mmol) and sodium azide 195 mg (3 mmol) were dissolved in 20 mL of THF and 1 mL of water and the mixture was stirred for 2 hrs. The reaction mixture was evaporated under the reduced pressure and the residue was extracted with water and ethyl acetate.

The organic layer was dried over anhydrous sodium sulfate and filtered. The fi;trate was evaporated under the reduced pressure and the residue was purified by column chromatography on silica gel (eluent: 1/1 ethyl acetate/hexane) to afford 6,7-diazido-5,8-quinolinedione 183 mg (76%). nip : 112-113 °C IH NMR (CDCls) : 6 9.02 (dd, 1, C2 H), 8.41 (dd, 1, C4 H), 7.70 (dd, 1, C3 H).

Anal. Calcd. for C9H3N4O2 : C, 44.82; H, 1.25; N, 40.66. Found: C, 44.87; H, 1. 01; N, 40.64.

Example 11 : 7-azido-6-(aziridin-1-yl)-5,8-quinolinedione 6,7-Diazido-5,8-quinolinedione 188 mg (0.78 mmol) was dissolved in 20 mL of methanol under N2. After adding 0.14 mL (1.10 mmol) of triethylamine to the reaction mixture, further 0.05 mL (1.10 mmol) of aziridine was added thereto and stirred for 4 hrs. The reaction mixture was evaporated under the pressure and the residue was purified by column chromatography on silica gel (eluent: 1/1 ethyl acetate/hexane) to afford 7-azido-6-(aziridin-1-yl)-5, 8- quinolinedione 96 mg (40%). nip : >250 °C IH NMR (CDCl3) : 6 8.95 (dd, 1, C2 H), 8.35 (dd, 1, C4H), 7.61 (dd, 1, C3H), 2.44 (s, 4,2XCH2).

Anal. Calcd. for CliH7N502 : C, 54.77; H, 2.93; N, 29.03. Found: C, 54. 76 ; H, 2.90; N, 29.01.

Example 12: 7-amino-6-(aziridin-1-yl)-5, 8-quinolinedione 7-Azido-6-(aziridin-1-yl)-5,8-quinolinedione 400 mg (1.66 mmol) and sodium borohydride 628 mg (16.6 mmol) were dissolved in 100 mL of THF- methanol (4: 1) under N2 and stirred for 1 hr. Ice was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under the reduced pressure and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to afford 7-amino-6- (aziridin-1-yl)-5, 8- quinolinedione 108 mg (50%). mp : >250 °C

IH NMR (CDCIs) : 6 8.83 (dd, 1, C2 H), 8.30 (dd, 1, C4 H), 7. 55 (dd, 1, C3H), 5.22 (br s, 2, NH2), 2.28 (s, 4,2XCH2).

Anal. Calcd. for CllH9N302 : C, 61.39; H, 4.22; N, 19.53. Found: C, 61.40; H, 4.11; N, 19.60.

Example 13: 6-bromo-7-(aziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 1 by using 6, 7-dibromo-5,8-quinolinedione as a starting material. mp : 166-167 °C IH NMR (CDC13) : # 8.94 (dd, 1, Cz H), 8.41 (dd, 1, C4H), 7.63 (dd, 1, C3 H), 2.64 (s, 4, 2#CH2).

Anal. Calcd. for C11H7BrN2O2 : C, 47.34; H, 2.53; N, 10.04. Found: C, 47. 28; H, 2.63; N, 10.11.

Example 14: 6-chloro-7-(2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 1 by using 6,7-dichloro-5,8-quinolinedione and 2-methylaziridine as starting materials. mp: 101-102 °C H NMR (CDCl3) : 6 8.91 (dd, 1, C2H), 8.38 (dd, 1, C4 H), 7. 62 (dd, 1, C3 H), 2.64 (m, 1, CH), 2.54 (dd, 2, CH2), 1.50 (d, 3, CHs).

Anal. Calcd. for C12H9ClN202 : C, 57. 96; H, 3.65; N, 11.27. Found: C, 57. 99; H, 3.69; N, 11.20.

Example 15: 6-bromo-7-(2-methylaziridin-1-yl)-5,8-quinolinedione

The titled compound was prepared as described in Example 1 by using 6,7-dibromo-5,8-quinolinedione and 2-methylaziridine as starting materials. mp : 83-84 °C H NMR (CDC13) : S 8.82 (dd, 1, C2H), 8.28 (dd, 1, C4H), 7.55 (dd, 1, C3H), 2 61 (m, 1, CH), 2.48 (dd, 2, CH2), 1.45 (d, 3, CH3).

Anal. Calcd. for Ci2H9BrN202 : C, 49. 17; H, 3.09; N, 9.56. Found: C, 49.21; H, 3.11; N, 9.58.

Example 16: 6-azido-7- (2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 8 by using 6-azido-7-methoxy-5, 8-quinolinedione and 2-methylaziridine as starting materials. mp : 105-106 °C 1H NMR (CDCl3) : 6 8.95 (dd, 1, C2 H), 8.36 (dd, 1, C4H0, 7.62 (dd, 1, C3 H), 2.50 (m, 1, CH), 2.42 (dd, 2, CH2), 1.50 (d, 3, CH3).

Anal. Calcd. forCl2H9N502 : C, 56.47; H, 3.55; N, 27.44. Found : C, 56.79; H, 3.56; N, 27. 35.

Example 17: 6-amino-7- (2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 9 by using 6-azido-7-(2-methylaziridin-1-yl)-5,8-quinolinedione as a starting material. mp : 122-124 °C IH NMR (CDCIs) : 6 8. 88 (dd, 1, C2H), 8.24 (dd, 1, C4H), 7. 49 (dd, 1, C3H), 4.92 <BR> <BR> <BR> (br s, 2, NH2), 2.42 (m, 1, CH), 2.21 (d, 1, one of CH2), 2.20 (d, 1, one of CH2), 1.@ 49

(d, 3, CH3).

Anal. Calcd. for C12H11N3O2 : C, 62. 87 ; H, 4.84; N, 18.33. Found: C, 62.52; H, 5.34; N, 18.65.

Example 18 : 7-bromo-6-(aziridin-1-yl)-5,8-quinolinedione The titled compound was prepared as described in Example 2 by using 6,7-dibromo-5, 8-quinolinedione as a starting material. mp : 166-167 °C H NMR (CDCl3) : 6 8.97 (dd, 1, C2H), 8.37 (dd, 1, C4H0, 7. 63 (dd, 1, C3H), 2.62 (s, 4, 2#CH2).

Anal. Calcd. for C11H7BrN2O2 : C, 47.34; H, 2.53; N, 10.04. Found: C, 47. 37; H, 2. 52; N, 10.11.

Example 19: 7-chloro-6- (2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 2 by using 6, 7-dichloro-5, 8-quinolinedione and 2-methylaziridine as starting meterials. mp : 141-143 °C H NMR (CDCls) : 6 8.96 (dd, 1, C2H), 8.35 (dd, 1, C4H), 7. 62 (dd, 1, Cs H), 2.62 (m, 1, CH), 2.52 (dd, 2, CH2), 1.50 (d, 3, CH3).

Anal. Calcd. for C12H9ClN202 : C, 57.96; H, 3.65; N, 11.27. Found: C, 57.95; H, 3.82; N, 11. 17.

Example 20: 7-bromo-6- (2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 2 by using

6, 7-dibromo-5, 8-quinolinedione and 2-methylaziridine as starting materials. mp : 133-134 °C IH NMR (CDCIs) : # 8.85 (dd, 1, C2 H), 8.25 (dd, 1, C4H), 7.55 (dd, 1, C3 H), 2.60 (m, 1, CH), 2.46 (dd, 2, CH2), 1.44 (d, 3, CH3).

Anal. Calcd. for C12H9BrN202 : C, 49.17; H, 3.09; N, 9.56. Found : C, 49.13; H, 3.10; N, 9.55.

Example 21: 7-azido-6- (2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 11 by using 6,7-diazido-5, 8-quinolinedione and 2-methylaziridine as starting materials. mp: 109-110 °C <BR> <BR> <BR> <BR> <BR> IH NMR (CDC13) : 6 8.85 (dd, 1, C2H), 8.24 (dd, 1, C4H), 7.55 (dd, 1, C3H), 2.@ 40 (m, 1, CH), 2.30 (dd, 2, CH2), 1.39 (d, 3, CH3).

Anal. Calcd. for C12H9N5O2 : C, 56.47; H, 3.55; N, 27.44. Found : C, 56.60; H, 3.51; N, 27. 31.

Example 22: 7-amino-6-(2-methylaziridin-1-yl)-5, 8-quinolinedione The titled compound was prepared as described in Example 12 by using 7-azido-6- (2-methylaziridin-1-yl)-5, 8-quinolinedione as a starting material. mp : 151-153 °C H NMR (CDC13) : 6 8.84 (dd, 1, C2H), 8.30 (dd, 1, C4H), 7.55 (dd, 1, C3 H), 5.07 (br s, 2, NH2), 2.42 (m, 1, CH), 2.18 (d, 1, one of CH2), 2.17 (d, 1, one of CH2), 1. 49 (d, 3, CH3).

Anal. Calcd. for C12H11N3O2 : C, 62. 87; H, 4.84; N, 18.33. Found: C, 62.91; H,

4.84; N, 18.27.

Example 23: 7-bromo-6-(aziridin-1-yl)-2-methyl-5, 8-quinolinedione The titled compound was prepared as described in Example 2 by using 6, 7-dibromo-2-methyl-5, 8-quinolinedione as a starting material. mp : 173-174 °C IH NMR (CDC13) : 6 8. 18 (d, 1, C4H), 7.43 (d, 1, C3H), 2.70 (s, 3, CH3), 2.58 (s, 4, 2XCH2).

Anal. Calcd. for C12H9BrN202 : C, 49.17; H, 3.09; N, 9.56. Found: C, 49.15; H, 3.13; N, 9.59.

Example 24: 6-bromo-7-(aziridin-1-yl)-2-methyl-5, 8-quinolinedione The titled compound was prepared as described in Example 1 by using 6, 7-dibromo-2-methyl-5, 8-quinolinedione as a starting material. mp : 182-183 °C zu NMR (CDC13) : 6 8.34 (d, 1, C4H0, 7.50 (d, 1, C3 H), 2.76 (s, 3, CH3), 2.64 (s, 4, 2#CH2).

Anal. Calcd. for C12H9BrN2O2 : C, 49.17; H, 3.09; N, 9.56. Found: C, 49.20 ; H, 2.97; N, 9.57.

Example 25: 7-bromo-6-(2-methylaziridin-1-yl)-2-methyl-5,8-quinolinedion e The titled compound was prepared as described in Example 2 by using 6, 7-dibromo-2-methyl-5, 8-quinolinedione and 2-methylaziridine as starting materials.

mp : 140-141 °C IH NMR (CDC13) : # 8.15 (d, 1, C4 H), 7.41 (d, 1, C3 H), 2.67 (s, 3, CH3), 2.64 (m, 1, CH), 2.50 (dd, 2, CH2), 1.49 (d, 3, CHCHs).

Anal. Calcd. for C13H11BrN2O2 : C, 50. 84 ; H, 3.61; N, 9.12. Found: C, 50.82; H, 3.68 ; N, 9.20.

Example 26 : 6-bromo-7-(2-methylaziridin-1-yl)-2-methyl-5,8-quinolinedion e The titled compound was prepared as described in Example 1 by using 6,7-dibromo-2-methyl-5,8-quinolinedione and 2-methylaziridine as starting materials. mp: 155-156 °C IH NMR (CDCIs) : # 8.24 (d, 1, C4H), 7.44 (d, 1, C3 H), 2.70 (s, 3, CH3), 2.64 (m, 1, CH), 2.52 (d, 2, CHz), 1.52 (d, 3, CHCHs).

Anal. Calcd. for C13H11BrN2O2 : C, 50.84; H, 3.61; N, 9.12. Found : C, 50.84; H, 3.85; N, 9.06.

Example 27: 7-methoxy-6- (2-methylaziridin-1-yl)-2-methyl-5, 8- quinolinedione The titled compound was prepared as described in Example 4 by using t 6, 7-dibromo-2-methyl-5, 8-quinolinedione as a starting material. mp : 93-94 °C 1H NMR (CDCl3) : # 8.21 (d, 1, C4H), 7. 43 (d, 1, C3H), 4.09 (s, 3, OCH3), 2.74 (s, 3, CH3), 2.38 (m, 1, CH), 2.33 (dd, 2, CH2), 1.48 (d, 3, CHCH3).

Anal. Calcd. for C14H14N2O3 : C, 65.11; H, 5.46; N, 10.85. Found: C, 65.17; H,

5.43; N, 10.85.

Example 28: 6-methoxy-7- (2-methylaziridin-1-yl)-2-methyl-5, 8- quinolinedione The titled compound was prepared as described in Example 4 by using 6,7-dibromo-2-methyl-5, 8-quinolinedione as a starting material. alp : 106-108 °C IH NMR (CDC13) : 6 8.24 (d, 1, C4H0, 7.46 (d, 1, C3 H), 4.07 (s, 3, OCHs), 2.74 (s, 3, CH3), 2.36 (m, 1, CH), 2.32 (dd, 2, CH2), 1.50 (d, 3, CHCHs).

Anal. Calcd. for C14H14N2O3 : C, 65.11 ; H, 5.46; N, 10.85. Found : C, 65. 10; H, 5.50; N, 10.89.

Example 29: 7-azido-6-(aziridin-1-yl)-2-methyl-5, 8-quinolinedione The titled compound was prepared as described in Example 10 and 11 by using 6,7-dibromo-2-methyl-5,8-quinolinedione as a starting material. mp : 132-132.5 °C H NMR (CDCl3) : 6 8.14 (d, 1, J=8. 1 Hz, C4H), 7.40 (d, 1, J=8. 1 Hz, C3H), 2. 68 (s, 3, CH3), 2.38 (s, 4,2XCH2).

Anal. Calcd. for C12H9N5O2 : C, 56.47; H, 3.55; N, 27.44. Found: C, 56.46; H, 3.57; N, 27. 46.

Example 30: 6-azido-7- (aziridin-1-yl)-2-methyl-5, 8-quimolinedione The titled compound was prepared as described in Example 6,7, and 8 by using 6, 7-dibromo-2-methyl-5, 8-quinolinedione as a starting material.

mp : 123-124 C 1H NMR (CDC13) : # 8. 18 (d, 1, J=8. 1 Hz, C4H), 7.44 (d, 1, J=8. 1 Hz, Cs H), 2.70 (s, 3, CH3), 2.41 (s, 4, 2XCH2).

Anal. Calcd. for C12H9N5O2 : C, 56. 47 ; H, 3.55; N, 27. 44. Found : C, 56.49; H, 3.48; N, 27. 36.

Example 31: 7-azido-6- (2-methylaziridin-1-yl)-2-methyl-5, 8-quinolinedione The titled compound was prepared as described in Example 10 and 11 by using 6, 7-dibromo-2-methyl-5, 8-quinolinedione and 2-methylaziridine as starting materials. mp : 121-122 °C H NMR (CDC13) : 8 8.20 (d, 1, C4H), 7.44 (d, 1, C3 H), 2.73 (s, 3, CH3), 2.46 (m, 1, CH), 2.38 (dd, 2, CH2), 1.47 (d, 3, J=5. 5 Hz, CHCH3).

Anal. Calcd. for C13H11N5O2 : C, 57.99; H, 4.12; N, 26.01. Found: C, 58.00; H, 4.05; N,. 25. 98.

Example 32: 6-azido-7-(2-methylaziridin-1-yl)-2-emethyl-5,8-quinolinedio ne The titled compound was prepared as described in Example 6,7, and 8 by using 6, 7-dibromo-2-methyl-5, 8-quinolinedione and 2-methylaziridine as starting materials. mp : 124. 5-125 °C IH NMR (Cell3) : # 8.21 (d, 1, C4H), 7.45 (d, 1, C3H), 2.72 (s, 3, CH3), 2.46 (m, 1, CH), 2.38 (dd, 2, CH2), 1.48 (d, 3, CHCHs).

Anal. Calcd. for eC13H11N5O2 : C, 57.99; H, 4.12; N, 26.01. Found: C, 57. 95; H,

4.24; N, 25.93.

Example 33: 7-amino-6- (aziridin-1-yl)-2-methyl-5, 8-quinolinedione The titled compound was prepared as described in Example 12 by using 7-azido-6-(aziridin-1-yl)-2-methyl-5, 8-quinolinedione as a starting material. mp : 173-175 °C I H NMR (CDCB) : 6 8.12 (d, 1, C4 H), 7.35 (d, 1, C3 H), 5.17 (br s, 2, NH2), 2.64 (s, 3, CH3), 2.24 (s, 4, 2#CH2).

Anal. Calcd. for C12H11N3O2 : C, 62.87; H, 4.84; N, 18.33. Found: C, 62.83; H, 4.86; N, 18.39.

Example 34: 6-amino-7-(aziridin-1-yl)-2-methyl-5, 8-quinolinedione The titled compound was prepared as described in Example 12 by using 6-azido-7- (aziridin-1-yl)-2-methyl-5, 8-quinolinedione as a starting material. mp : 180-181 °C 1H NMR (CDCl3) : 6 8.13 (d, 1, GH), 7.34 (d, 1, Cash), 5.00 (br s, 2, NH2), 2.71 (s, 3, CH3), 2.29 (s, 4, 2#CH2).

Anal. Calcd. for C12H11N3O2 : C, 62.87; H, 4.84; N, 18.33. Found: C, 62.98; H, 4.87; N, 18.25.

Example 35: 7-amino-6-(2-methylaziridin-1-yl)-2-methyl-5, 8-quinolinedione The titled compound was prepared as described in Example 12 by using 7-azido-6-(2-methylaziridin-1-yl)-2-methyl-5,8-quinolinedion e as a starting material.

mp : 144. 5-146 °C IH NMR (CDCIs) : 6 8.08 (d, 1, C4 H), 7.32 (d, 1, Cs H), 5. 04 (br s, 2, NH2), 2.62 (s, 3, CH3), 2.36 (m, 1, CH), 2.11 (d, 1, one of CH2), 2.09 (d, 1, one of CH2), 1.47 (d, 3, CHCH3).

Anal. Calcd. for C13H13N3O2 : C, 64.19; H, 5.39; N, 17. 27. Found: C, 64.23; H, 5.42; N, 17. 22.

Example 36: 6-amino-7-(2methylaziridin-1-yl)-2-methyl-5,8-quinolinedione The titled compound was prepared as described in Example 12 by using 6-azido-7-(2-methylaziridin-1-yl)-2-methyl-5, 8-quinolinedione as a starting material. mp : 155-156 °C 1H NMR (CDC13) : 8 8.09 (d, 1, C4H), 7. 31 (d, 1, C3H), 4.92 (br s, 2, NH2), 2.67 (s, 3, CHs), 2.39 (m, 1, CH), 2.15 (d, 1, one of CH2), 2.14 (d, 1, one of CH2), 1.45 (d, 3, CHCH3).

Anal. Calcd. for C13H13N3O2 : C, 64.19 ; H, 5.39; N, 17. 27. Found: C, 64.16; H, 5.38; N, 17.21.

The structures of the compounds prepared in Examples 1-36 are shown in Tables la and 1b.

Table la Category R1 R2 R3 Example 1 H Cl aziridinyl Example 2 H aziridinyl Cl Example 3 H OCH3 OCH3 Example 4 H 2-methylaziridinyl OCH3 Example 5 H OCH3 2-methylaziridinyl Example 6 H Cl OCH3 Example 7 H N3 OCH3 Example 8 H N3 aziridinyl Example 9 H NH2 aziridinyl Example10 H N3 N3 Example11 H aziridinyl N3 Example12 H aziridinyl NH2 Example 13 H Br aziridinyl Example 14 H Cl 2-methylaziridinyl Example 15 H Br 2-methylaziridinyl Example 16 H N3 2-methylaziridinyl Example 17 H NH2 2-methylaziridinyl Example 18 H aziridinyl Br Example 19 H 2-methylaziridinyl Cl Example 20 H 2-methylaziridinyl Br Example 21H2-methylaziridinylN3 Example 22 H 2-methylaziridinyl NH2 Table lb Category R1 R2 R3 Example23 CHs aziridinyl Br Example24 CH3 Br aziridinyl Example25 CH3 2-methylaziridinyl Br Example26 CH3 Br 2-methylaziridinyl Example27 CH3 2-methylaziridinyl OCH3 Example 28 CH3 OCH3 2-methylaziridinyl Example 29 CH3 Aziridinyl N3 Example 30 CH3 N3 aziridinyl Example 31 CH3 2-methylaziridinyl N3 Example 32 CH3 N3 2-methylaziridinyl Example 33 CH3 aziridinyl NH2 Example 34 CH3 NH2 aziridinyl Example 35 CH3 2-methylaziridinyl NH2 Example 36 CH3 NH2 2-methylaziridinyl

Experimental Example: 1 Cytotoxicity test of tumor cell lines The cell culture test was performed to test the cytotoxicity of the compounds of formula (1) on A549 (human lung cancer cell), SK-OV-3 (human ovarian cancer cell), SK-MEL-2 (human melanoma cell), XF-498 (human CNS

cancer cell), and HCT15 (human colon cancer cell) by the SRB (sulforhodamine B) assay in vitro. The control group was mitomycin C, doxorubicin, and 6, 7- (diaziridin-1-yl)-5, 8-quinolinedione. The dose therapeutically effective in 50% of population (EDso) was determined and the result was shown in Tables 2a and 2b.

Table 2a Cell toxicity (ED50, µg/ml) Test material A549 SKOV3 SKMEL2 XF498 HCT15 Example 1 0. 97 0. 42 0. 30 0. 68 0. 47 Example 2 0. 67 0. 24 0. 03 0. 29 0. 02 Example 4 0. 27 0. 35 0. 21 0. 12 0. 37 Example 5 0.44 1.20e 0.23 0.16 0. 87 Example 8 0. 11 1. 00 0. 27 0. 15 0. 30 Example 9 0.07 0.34 0.12 0.09 0. 09 Example 11 0. 38 0. 24 0. 18 0. 23 0. 11 Example 12 0. 02 0. 17 0. 09 0. 03 0. 02 Example 13 1. 14 0. 30 0. 16 1. 39 0. 14 Example 14 0. 92 0. 48 0. 18 0. 40 0. 29 Example 15 0. 77 0. 29 0. 16 0. 58 0. 17 Example 16 0. 22 0. 34 0. 19 0. 25 0. 22 Example 17 0. 22 0. 87 0. 25 0. 17 0. 97 Example 18 1. 06 0. 69 0. 16 1. 71 0. 08 Example 19 1. 13 0. 18 0. 09 0. 09 0. 06 Example 20 1. 53 0. 27 0. 16 1. 74 0. 04 Example 21 0. 43 0. 18 0. 15 0. 26 0. 12 Example 22 1. 10 1. 54 0. 19 0. 13 0. 23 Control 0. 09 0. 14 0. 11 0. 07 0. 12 Mitomycin C 0.08 0.12 0.17 0.07 0. 89 Doxorubicin 0.11 0.16 0.15 0.18 0. 24 Control compound : 6, 7- (diaziridin-1-yl)-5, 8-quinolinedione Table 2b Cell toxicity (EDso, llg/ml) Test material A549 SI<OV3 SI<MEL2 XF498 HCT15 Example 23 1.07 0.15 0.10 0.88 0. 11 Example 24 0. 27 0. 14 0. 12 0. 15 0. 12 Example 25 1.27 0.13 0.14 1.18 0. 13 Example 26 0. 29 0. 14 0. 13 0. 13 0. 11 Example 27 1. 14 1. 04 0. 95 1. 00 0. 18 Example 28 1.17 0.70 0.94 0.87 0. 38 Example 29 0. 26 0. 13 0. 14 0. 14 0. 10 Example 30 0. 25 0. 96 0. 48 0. 18 0. 15 Example 31 1. 08 0. 13 0. 14 0. 17 0. 14 Example 32 0. 27 0. 14 0. 14 0. 15 0. 15 Example 33 0. 15 1. 59 1. 47 0. 32 0. 05 Example 34 0. 93 1. 74 1. 64 7 0. 31 Example 35 1.12 1.34 1.37 0.97 1. 04 Example 36 1. 30 1. 57 1. 62 1. 55 1. 38 Mitomycin C 0. 08 0. 12 0. 17 0. 07 0. 89 Doxorubicin 0. 11 0. 16 0. 15 0. 18 0. 24

Experimental Example 2: Acute toxicity test Acute toxicity test for the compound of formula (1) was performed on 10 mice (5 for male and 5 for female). The compound with dosages of 25,50, 100, and 200 mg/kg was administered intravenously in single dose. After administration for 1 week, mortality was observed. As a result, the compound

of Example 14 showed 125 mg/kg of LDso (the dose lethal to 50% of population) and that of Example 16 did 54 mg/kg which were lower toxicity than doxorubicin having 21 mg/kg of LD5o.

As describe above, the aziridinylquinolinedione derivatives of the present invention has excellent anti-cancer activity with little toxicity and thus can be widely used for anti-cancer agent.