NZ535791A - 9-aminoacridine derivatives and process for the preparation thereof - Google Patents

Abstract

A dibenzocyclooctane lignan derivative of formula (I) for prevention and treatment of neurodegenerative disease.

Description

New Zealand Paient Spedficaiion for Paient Number 535791 5791 - 1 [description] [Title of the Invention] 9-Aminoacridine derivatives and process for the preparation thereof [Technical Field] The present invention relates to a new 9-aminoacridine derivative of the general formula (I) H II wherein Y is ;a bond or N Z (I) H N.

CH- (wherein X is oxygen or sulfur, Ri, R2, R3, R4 and Rg are independently hydrogen, halogen, nitro, amino, hydroxy, C1-C4 lower alkylamino, C1-C4 alkyl or CrC4 lower alkoxy, R* and R" are independently C1-C4 alkyl or C1-C4 lower alkoxy, and Z is C1-C4 lower alkyl, C1-C4 lower alkoxy or Ci-C4 lower alkylamino.

In the above definitions, C1-C4 alkyl means straight or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl 30 or the like.

Intellectual Property Office of N.Z- - 3 AUG 2005 Dcrcu/pn C1-C4 lower alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy or the like.

C1-C4 lower alkylamino means methylamino, ethylamino, propylamino, butylamino or the like.

[Back ground of the technology] WO 00/37447 describes 9-amnoacridine derivatives and process for the preparation thereof of the compounds of the formula (1) wherein A is hydrogen or (wherein X is oxygen or sulfur, Rl, R2, R3, R4 and R5 are independently hydrogen, halogen, nitro, amino, hydroxy, C1-C4 lower alkylhydroxy, C1-C4 lower alkylamino, C1-C8 alkyl, C1-C4 lower alkoxy or C1-C4 lower alkyloxycarbonyl and m and n are independently an integer of 0, 1 or 2.), R6, R7, R8 and R9 are independently C1-C8 alkyl or C1-C4 lower alkoxy, and Y is hydrogen, amino, -N=CHRV (wherein Rx is hydrogen, benzyl, o hnA^r- C1-C8 alkyl or C1-C6 lower alkylamino), JHR™ Intellectual Property Office of N.Z. - 3 AUG 2005 received (wherein R,x is hydrogen, benzyl, C1-C8 alkyl or C1-C6 lower alkylamino, and RMV is hydrogen, benzyl, C1-C8 alkyl or amino protecting group) or w R1\ A. ,R,' 'q v)r y R4* Rb (wherein, X is as defined above, Rl\ R2\ R3\ R4' and R5X are independently hydrogen, halogen, nitro, amino, hydroxy, C1-C4 lower alkylhydroxy, C1-C4 lower alkylamino, C1-C8 alkyl, C1-C4 lower alkoxy or C1-C4 lower alkyloxycarbonyl, and q and r are independently an integer of 0, 1 or 2) or its pharaiaceutically acceptable salt, and process for the preparation thereof.

-JVR" In the above compounds of the formula (1) wherein Y is NHI? (R" and Rx" are as defined above.), there may be isomers of I-form, d-form or racemic form.

However, the compound of the present invention is not described in the 25 WO 00/37447.

[Detailed description of the invention] The inventors had studied for a long time to find new compounds having intensive antitumor activities. As a result, the inventors have found out 30 that the compounds of the general formula (I), or acid addition salts Intellectual Property Office of N.Z. - 3 AUG 2005 thereof as defined above have not only prominent antitumor activities but also very low toxicities.

R' (I) wherein Y is a bond or H N CH; (wherein X is oxygen or sulfur, Ri, R2, R3, R4 and R5 are independently hydrogen, halogen, nitro, amino, hydroxy, C1-C4 lower alkylhydroxy, C1-C4 lower alkylamino, Ci-Cs alkyl or C1-C4 lower alkoxy, R' and R" are 20 independently Cr-Cs alkyl or C1-C4 lower alkoxy, and Z is C1-C4 lower alkyl, C1-C4 lower alkoxy or C1-C4 lower alkylamino.

Accordingly, an object of the invention is to provide a compound of the general formula (I) or add addition salt thereof having not only prominent 25 antitumor activity but also very low toxicity, and/or to provide a process for the preparation of the compound of the general formula (I) or acid addition salt thereof; or at least to provide the public with a useful choice.

The compounds of the present invention can be mixed with 30 pharaiaceutically acceptable vehicles by a conventional method to give Intellectual Property Office of N.Z. - 3 AUG 2005 Dcrci \/ c n pharmaceutical preparations to be used for prevention or treatment of various kinds of tumors.

Therefore, the other object of the present invention is to provide 5 pharmaceutical preparations containing an effective amount of a compound of the general formula (I) or add addition salt thereof as an active ingredient Adds which can be reacted with the compound of the general formula (I) 10 to form acid addition salt thereof are pharmaceutically acceptable inorganic acids, organic adds, amino adds or sulfonic adds; for example, inorganic adds such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric add; organic adds such as formic acid, acetic add, propionic add, succinic add, citric add, maleic add and malonic add; 15 amino adds such as serine, cysteine, cystine, asparagine, glutamine, lysine, arginine, tyrosine and proline; sulfonic acids such as methanesulfonic add, ethanesulfonic add, benzenesulfonic acid and toluenesulfonic acid.

Vehicles used in formulating pharmaceutical preparations containing the 20 compound of the general formula (I) as an active ingredient are sweetening agents, binding agents, dissolving agents, aids for dissolution, wetting agents, emulsifying agents, isotonic agents, adsorbents, degrading agents, antioxidents, preservatives, lubricating agents, fillers, perfume or the like; for example may include lactose, dextrose, sucrose, mannitol, 25 sorbitol, cdlulose, glycine, silica, talc, stearic add, stearin, magnesium stearate, caldum stearate, magnesium aluminum silicate, starch, gdatine, tragacanth gum, alginic add, sodium alginate, methyl cdlulose, sodium carboxy methyl cdlulose, agar, water, ethanol, polyethylenglycol, polyvinyl pyirolidone, sodium chloride, potassium 30 chloride, orange essence, strawberry essence and vanilla aroma.

Intellectual Property Office of N.Z. - 3 AUG 2005 received Daily dosage of the compound of the general formula (I) may be varied depending on age, sex and degree of disease, but preferably lmg to 5,00Qmg per day may be administered by once to several times.

The compound of the general formula (I) according to the present invention may be prepared by following schemes I, II.

Scheme I (a) + JL _/ v R" N"^Z (b) condensing agent XM (I) wherein Ri, R2, R3, R4, R5, R', R", X, Y and Z are as defined above and Yi is hydrogen or the group of Jv^NH2 The compound of the general formula (a) and (b) are reacted under the presence of condensing agent and acid in a conventional organic solvent to 30 give effectively a comound of the general formula (I).

Intellectual Property Office of N.Z. -3 AUG 2005 received The reaction may be carried out preferably in a conventional organic solvent such as tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethylformamide, pyridine, etc.

The reaction may be carried out preferably under the presence of 5 condensing agent such as dicyclohexylcarbodiimide(DCC), HOBT or WSCD in a conventional acid such as inorganic acid or organic acid.

A compound of the general formula (a) or (b) is a known compound in J. Med. Chem., 1995, 38, 3226 or in PCT/KR99/00787 or can be prepared and used by a analogy method thereof.

The reaction may be carried out at a temperature between 3*C and a boiling point of a solvent, preferably 25*0 and 50t: for a time between 5 and 24hours, preferably for a time between 10 and 24hours.

Acid may be used 1 ~ 1.5equivalent, preferably 1 —1.1 equivalent.

Scheme II (c) condensing agent ^ (d) .OH RJ ,r2 •s-7 F4 R4 Intellectual Property Office of N.Z. - 3 AUG 2005 received WO 03/074490 PCT/KR02/00392 8 - wherein Ri, R2, R3, R4, Rs, R', R", X, Y and Z are as defined above and O ho- Y2 is -OH or the group of ch 3 —1 The compound of the general formula (c) and (d) are reacted under the presence of condensing agent and acid in a conventional organic solvent to give effectively a comound of the general formula (I).

The reaction may be carried out preferably in a conventional organic solvent such as tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethylformamide, pyridine, etc.

The reaction may be carried out preferably under the presence of condensing agent such as dicyclohexylcarbodiimide(DCC), HOBT or WSCD in a conventional acid such as inorganic acid or organic acid.

A compound of the general formula (c) or (d) is a known compound in J. Med. Chem., 1995, 38, 3226 or in PCT/KR99/00787 or can be prepared and used by a analogy method thereof.

The reaction may be carried out at a temperature between 3°C and a boiling point of a solvent, preferably 25 °C and 50 °C for a time between 5 and 24hours, preferably for a time between 10 and 24hours.

Acid may be used 1 — 1.5equivalent, preferably 1 —1.1 equivalent. pct/kr02/00392 - 9 [Examples] Compounds of the general formula (I) were prepared according to the above-mentioned processes of the invention.

.OH ^ R'"^N^Z (I) Examples 1—17 : Compound of the general formula (I) wherein Y = h n. ch3 Ex. No.

R' R" Ri Rz Rs R4 Rs X z 1 H CH2CH3 H H H H H O OCHs 2 H CH2CH3 H CHs H CHs H O OCHs 3 H CH2CH3 H OCHs H OCHs H O OCHs 4 H CH2CH3 H F H F H O OCHs H CH2CH3 H CI H CI H O OCHs 6 H CH2CH3 H F H H H O OCHs 7 H CH2CH3 H OH H OH H O OCHs 8 H CH2CH3 H OCH3 OCHs OCHs H O OCHs 9 H CH2CH2CH3 H OCH3 H OCHs H O OCHs H CH2CH2CH3 H CH3 H CHs H 0 OCHs 11 H CHs H OCHs H OCHs H s OCHs 12 H CH2CH3 H OCH3 H OCHs H s OCHs 13 H CH2CH2CH3 H OCHs H OCHs H s OCHs 14 H CH2CH3 H CHs H CHs H s OCHs 2-CHs CH2CH3 H CHs H CHs H 0 OCHs 16 3,4-CHs CH2CH3 H CHs H CHs H 0 OCHs 17 4-OCH3 CH2CH3 H CHs H CHs H 0 OCHs Example 18~29 : Compound of the general formula (I) wherein Y = 0(zero) Ex. No. r' r" ri r2 rs Ri R5 X z 18 H CH2CH3 H H H H H O OCHs 19 H CH2CH3 H CHs H CHs H O OCHs H CH2CH3 H OCHs H OCHs H O OCHs 21 H CHbCHs H F H F H O OCHs 22 H CH2CH3 H CI , H CI H O OCHs 23 H CH3CH3 H F H H H O OCHs 24 H CH2CH3 H OH H OH H O OCHs H CH2CH3 H OCHs OCHs OCHs H O OCHs 26 H CH2CH3 H OCHs H OCHs H S OCHs 27 H CH2CH3 H CHs H CHs H s OCHs 28 H CH2CH3 H F H H H s OCHs 29 H CH2CH3 H CI.

H CI H s OCHs Example 1 4-phenylpiperazine-l-carboxylic acid (5-{l-[3-(acridine-9-yl-amino)~5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-methyl-2-methoxypyridi ne-3-yl)amide 2-ethyl-6-methoxy-5-[(4-phenylpiperazine-l-carbonyl)amino]nicotinic acid(0.5g, 1.24mmole) was dissolved in pyridine(30mL) and thereto DCC(0.26g, 1.24mmole), DMAP(0.15g, 1.24mmole) and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide were added. After stirring the resulting mixture for 24 hours at the room temperature. The resulting product was purified by column chromatography to give the titled compound. yield : 68.2% m.p. : 218-220°C !H NMR(DMSO-de) : 1.20(3H,t), 1.38(3H,d), 2.79(2H,q), 3.19(4H,m), 3.61(4H,m), 3.96(3H,s), 445(2H,s), 4.53(lH,m), 6.50(lH,m), 6.85(lH,t), 7.01(4H,d), 7.28(4H,m), 5 7.62(4H,m), 8.00(3H,d), 8.51(lH,d), 9.97(lH,s) Example 2 4-(3,5-dimethylphenyl)piperazine-l-carboxylic acid (5-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-ethyl-2-10 methoxypyridine-3~yl)amide The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethylphenyl)-piperazine-l-carbonyl]-amino}-6-metho xy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 52.3% m.p. : 205 - 207 °C XH NMR(DMSO-de) : 1.20(3H,t), 1.38(3H,d), 2.79(2H,q), 3.19(4H,m), 3.59(4H,m), 3.75(6H,s), 3.96(3H,s), 4.45(2H,s), 4.53(lH,m), 5.18(lH,m), 6.03(lH,s), 6.14(2H,s), 20 6.48(lH,s), 7.01 (2H,m), 7.30(3H,m), 7.56(3H,m), 7.96(2H,d), 8.18(lH,m), 8.50(lH,d), 9.95(lH,s) Example 3 4-(3,5-dimethoxyphenyl)piperazine-l-carboxylic acid (5-{l-[3~(acridine-25 9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-ethyl-2-methoxypyridine-3-yl)arnide The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-l-carbonyl]-amino}-6-meth oxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-30 phenyl]-2-aminopropaneamide to give the titled compound. 12 - yield : 49.1% m.p. : 231—233 °C XH NMR(DMSO-d6) : 1.13(3H,t), 1.38(3H,d), 2.12(lH,s), 2.79(2H,q), 3.19(4H,m), 3.59(4H,m), 3.75(6H,s), 3.96(3H,s), 5 4.46(2H,s), 4.53 (1H,m), 5.19(lH,m), 6.03(lH,s), 6.15(2H,s), 6.50(lH,s), 7.04(2H,m), 7.32(2H,s), 7.60(4H,m), 7.96(lH,s), 8.00(lH,s), 8.25(lH,m), 8.51 (lH,d), 9.97(lH,s) Example 4 4-(3,5~difluorophenyl)piperazine~l-carboxylic acid (5-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-ethyl-2-methoxypyridine-3-yl)amide The same reaction procedure to the example 1 were carried out using 15 2-ethyl-5-{[4-(3,5-difluorophenyl)-piperazine-l-carbonyl]-amino}-6-methox y-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 48.7% m.p. : 202-204°C XH NMR(DMSO-de) : 1.20(3H,t), 1.38(3H,d), 2.78(2H,q), 3.30(4H,m), 3.59(4H,m), 3.96(3H,s), 4.45(2H,s), 4.53(lH,m), 5.20(lH,s), 6.54(2H,m), 6.69(2H,d), 7.09(2H,m), 7.33(2H,s), 7.61 (4H,m), 7.94(lH,s), 8.04(lH,s), 8.25(lH,s), 8.51(lH,d), 9.99(lH,s) Example 5 4-(3,5-dichlorophenyl)piperazine-l-carboxylic acid (5~{l-[3-(aciidine-9-yl~amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-ethyl-2-methoxypyridine-3-yl)amide 30 The same reaction procedure to the example 1 were carried out using - 13 " 2-ethyl-5-{[4-(3,5-c3ichlorophenyl)-piperazine-l-carbonyl]-amino}-6-methox y-mcotinic acid and N-[3-(acridine-9-yl-amino)H5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 47.8% m.p. : 184-186°C :H NMR(DMSO-de) : 1.20(3H,t), 1.38(3H,d), 2.79(2H,q), 3.32(4H,m), 3.59(4H,m), 3.96(3H,s), 4.46(2H,s), 4.54(lH,m), 5.18(lH,s), 6.45(lH,s), 6.92(lH,s), 7.02(3H,s), 7.34(3H,m), 7.50(3H,m), 7.94(lH,s), 8.04(lH,s), 10 8.22(lH,m), 8.50(lH,m), 9.96(lH,s) Example 6 4-(3-fluorophenyl)piperazine-l-carboxylic acid (5-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-ethyl-2-metho 15 xypyridine-3-yl)amide The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3-fluorophenyl)-piperazine-l-carbonyl]-amino}-6-methoxy-n icotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 53.4% m.p. : 208 - 210°C XH NMR(DMSO-de) : 1.16(3H,t), 1.48(3H,d), 2.80(2H,q), 3.09(4H,s), 3.48(4H,m), 3.96(3H,s), 4.34(2H,s), 4.81(lH,m), 6.41(lH,m), 6.53(3H,m), 6.86(lH,m), 6.98(2H,m), 25 7.15(lH,m), 7.17(2H,m), 7.38(3H,m), 7.86(3H,m), 8.35(lH,m), 9.49(lH,s) Example 7 4-(3-hydroxyphenyl)piperazine-l-carboxylic acid (5-{l-[3-(acridine-9-yl-30 amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-ethyl-2-metho xypyridine-3-yl)amide The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3-hydroxyphenyl)-piperazine-l-carbonyl]-amino}-6-methoxy -nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-5 phenyl]-2~aminopropaneamide to give the titled compound. yield : 41.9% m.p. : 207- 209 °C NMR(DMSO-de) : 1.21(3H,t), 1.49(3H,d), 2.81(2H,q), 3.18(4H,m), 3.60(4H,m), 4.02(3H,s), 4.52(2H,s), 4.75(lH,m), 10 6.41 (3H,m), 6.67(lH,s), 7.06(2H,m), 7.16(2H,m), 7.24(lH,s), 7.35(lH,s), 7.47(lH,d), 7.58(2H,m), 7.86(2H,m), 8.08(2H,d), 8.36(lH,s), 9.55(lH,s) Example 8 4-(3,4,5-trimethoxyphenyl)piperazine-l-carboxylic acid (5-{l-[3-(acridine -9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-ethyl-2 -methoxypyridine-3-yl)amide The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,4,5-trimethoxyphenyl)-piperazine-l-carbonyl]-amino}-6-me 20 thoxy-nicotinic acid and N-[3-(acridine-9-yl-arnino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 44.3% m.p. : 205-207°C XH NMR(DMSOde) ■: 1.23(3H,t), 1.50(3H,d), 2.81(2H,q), 3.76(3H,s), 25 3.83(6H,s), 4.05(3H,s), 4.54(2H,s), 4.73(lH,m), 6.75(2H,m), 7.20(2H^n), 7.37(lH,s), 7.41(lH,s), 7.50(lH,d), 7.66(2H,m), 7.88(2H,m), 8.09(lH,s), 8.14(2H,m), 8.48(lH,s), 9.01(lH,s), 9.77(lH,s) Example 9 4-(3,5-dimethoxyphenyl)piperazine-l-carboxyEc acid (5-{l-[3-(acridine-9-yl-aimno)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-2-methoxy -6-propylpyridine-3-yl)-amide The same reaction procedure to the example 1 were carried out using 5 2-propyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-l-carbonyU-amino}-6-met hoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 41.2% m.p. : 220~222 °C XH NMR(DMSO-de) : 0.88(3H,t), 1.38(3H,d), 1.68(2H,m), 2.76(2H,q), Example 10 4-(3,5-dimethylphenyl)piperazine-l-carboxylic acid (5-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-2-methoxy-6 20 -propylpyridine-3-yl)-amide The same reaction procedure to the example 1 were carried out using 2-propyl-5-{[4-(3,5-dimethylphenyl)-piperazine-l-carbonyl]-amino}-6-meth oxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 42.3% m.p. : 195-197°C NMR(DMSO-ds) : 0.88(3H,t), 1.38(3H,d), 1.67(2H,m), 2.25(6H,s), 3.19(4Hrm), 3.59(4H,m), 3.75(6H,s), 3.95(3H,s), 4.45(2H,s), 4.54(lH,m), 5.19(lH,s), 6.04(lH,s), 6.15(2H,s), 6.50(lH,s), 7.04(2H,m), 7.31(2H,s), 7.59(4H,m), 7.98(3H,d), 8.25(lH,m), 8.50(lH,d), 9.56(lH,s) 2.76(2H,m), 3.15(4H,m), 3.36(6H,s), 3.59(4H,m), 3.95(3H,s), 4.45(2H,s), 4.54(lH,m), 5.19(lH,m), 6.49(2H,s), 6.62(2H,s), 7.05(2H,m), 7.31(2H,s), 7.58(3H,m), 7.96(3H,d), 8.23(lH,m), 8.50(lH,d), 9.96(lH,s) Example 11 N-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]ethyl}-5-{ [4-(3,5-dimethoxyphenyl)piperaane-l-carbothionyl]amino}-6-methoxy-2-me thylnlcotineamide The same reaction procedure to the example 1 were carried out using 5-{[4-(3,5-dimethoxy-phenyl)-piperazine-l-carbothionyl]-amino-2-methyl-6 10 -methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxy-methyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 58.2% m.p. : 181—183 °C !H NMRCDMSO-de) : 1.40(3H,d), 2.54(3H,s), 3.28(4H,m), 3.75(6H,s), 15 3.90(3H,s), 4.07(4H^m), 4.45(2H,s); 4.55(lH,m), .18(lH,m), 6.03(lH,s), 6.15(2H,s), 6.49(lH,m), 7.03(2H,m), 7.31(3H,m), 7.60(2H,m), 7.67(2H,m), 8.25(2H,m), 8.52(lH,d), 9.08(lH,s), 9.99(lH,s) Example 12 N-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]ethyl}-5-{ [4-(3,5-dimethoxyphenyl)piperazine-l-carbothionyl]amino}-2-ethyl-6-methox ynicotineamide The same reaction procedure to the example 1 were carried out using 25 5-{[4-(3,5-dimethoxy-phenyl)-piperazine-l-carbothionyl]-amino-2-ethyl-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound. yield : 43.9% m.p. : 177-179°C XH NMR(DMSO-de) : 1.20(3H,t), 1.43(3H,d), 2.82(2Htm), 3.19(2H,m), 3.29(2H,m), 3.79 (6H,s), 3.93(3H,s), 4.12(4H,m), 4.38(lH,m), 4.45(lH,m), 4.60(lH,m), 6.25(lH,s), 6.58(3H,d), 7.08(3H,m), 7.45(2H,m), 7.84(6H,m), 8.34(lH,m), 8.72(lH,s), 9.77(lH,s) Example 13 N-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]ethyl}-5-{ [4-(3,5-dimethoxyphenyl)piperazine-l-carbothionyl]amino}-6-methoxy-2-pro pylnicotineamide The same reaction procedure to the example 1 were carried out using 5-{[4-(3,5-dimethoxy-phenyl)-piperazine-l-carbothionyl]-amino-2-propyl-6 -methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)~5-hydroxy-methyl-phenyl]~2-aminopropaneamide to give the titled compound. yield : 46.5% m.p. : 168-170 °C XH NMR(DMSO-de) : 0.90(3H,t), 1.38(3H,d), 1.69(2H,m), 2.83(2H,m), 3.28(4H,m), 3.75(6H,s), 3.91(3H,s), 4.13(4H,m), 4.46(2H,s), 4.55(lH^n), 6.03(lH,s), 6.15(2H,s), 6.53(lH,s), 7.08(3H,m), 7.31(2H,s), 7.60(3H,m), 20 7.66(2H,m), 7.76~8.35(2H,m), 8.53(lH,d), 9.07(lH,s), 9.99(lH,s) Example 14 N-{l-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]ethyl}-5-{ 25 [4- (3,5-dimethylphenyl)piperazine-l-carbothionyl]amino}-2-ethyl-6-methoxy nicotineamide The same reaction procedure to the example 1 were carried out using 5-{ [4- (3,5-dimethyl-phenyl)-piperazine-l-carbothionyl]-amino-2-methyl-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl~amino)-5-hydroxymethyl-30 phenyl]-2-aminopropaneamide to give the titled compound. yield : 47.7% m.p. : 198-200 °C XH NMR(DMSO-de) : 1.21 (3H,t), 1.41(3H,d), 2.30(6H,s), 2.82(2H,q), 3.17(2H,m), 3.27(2H,m), 3.90(3H,s), 4.07(4H,m), 4.32(2H,s), 4.45 (lH,m), 4.60(lH,m), 6.25(lH,s), 6.58(3H,d), 7.08(3H,m), 7.45(2H,m), 7.84(6H,m), 8.34(lH,m), 8.72(lH,s), 9.77(lH,s) Example 15 4-(3,5-dimethylphenyl)-piperazine-l-carboxylic acid (6—ethyl—5—{1—[3— hydroxymethyl-5-(2-methylacridine-9-yl-amino)-phenylcarbamoyl]-ethylcar bamoyl}-2-methoxypyridine-3-yl)amide The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethylphenyl)-piperazine-l-carbonyl]-amino}-6-metho 15 xy-nicotinic acid and 2-amino-N- [3-hydroxymethyl-5- (2-methyl-acridine-9-yl-amino)-phenyl]-propioneamide to give the titled compound. yield : 51.3% m.p. : 164—166°C XH NMR(DMSO-de) : 1.18(3H,t), 1.52(3H,d), 2.05(lH,s), 2.17(2H,m), 20 2.22(lH,s), 2.28(6H,s), 2.82(2H,m), 3.10(4H,m), 3.63(4H,m), 4.00(3H,s), 4.42(2H,s), 4.85(lH,m), 6.51(3H,m), 6.56(lH,s), 7.00(3H,m), 7.43(2H;m), 7.78(4H,m), 8.48(lH^n), 9.53(lH,s) Example 16 4-(3,5-dimethylphenyl)piperazine-l-carboxylic acid (5—{1—[3— (3,4-dimeth-ylacridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-etibiylcarbamoyl}-6-ethyl~2-methoxypyridine-3-yl)amide The same reaction procedure to the example 1 were carried out using 30 2-ethyl-5-{[4-(3,5-dimethylphenyl)-piperazine-l-carbonyl]-amino}-6-metho xy-nicotinic acid and 2-amino-N-[3-(3,4~dimethyl-acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-propioneamide to give the titled compound. yield : 53.9% m.p. : 176~178°C !H NMR(DMSO-de) : 1.21(3H,t), 1.52(3H,d), 2.28(6H,s), 2.39(3H,s), 2.74(3H,s), 2.83(2H,q), 3.05(4H,m), 3.48(4H,m), 3.99(3H,s), 4.30(2H,s), 4.89(lH,m), 6.41(lH,m)) 6.49(2H,s), 6.56(lH,s), 6.85(lH,m), 7.05(4H,m), 7.54(lH,m), 7.73(lH,m), 7.92(2H,m), 8.42(lH,s), 10 9.31 (lH,s) Example 17 4-(3,5-dimethylphenyl)piperazine-l-carboxy]ic acid (5-{l-[3-(4-methoxy-acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-ethylcarbamoyl}-6-15 ethyl-2-methoxypyridine-3-yl)amide The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethylphenyl)-piperazine-l-carbonyl]-amino}-6-metho xy-nicotinic acid and 2-amino-N-[3-(4-methoxy-acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-propioneamide to give the titled compound. 2o yield '■ 50.8% m.p. : 178-179°C XH NMR(DMSO-de) : 1.18(3H,t), 1.50(3H,t), 2.27(6H,s), 2.82(2H,q), 3.12(4H,m), 3.53(4H,m), 3.98(3H,s), 4.14(lH,m), 4.42(2H,s), 4.81(lH,m), 6.52(4H,m), 6.89(4H,m), 25 7.18(2H,m), 7.41(3H,m), 7.93(lH,m), 8.37(lH,s), 9.33(lH,s) Example 18 4-phenyl-piperazine-l-carboxylic acid{5- [3- (acridine-9-yl-amino)-5-hy-droxy- methylphenylcarbamoyl]-6-ethyl-2-methoxy-pyridine-3-yl}amide ou 2-ethyl-6-methoxy-5- [(4-phenylpiperazine-l-carbonyl)amino3nicotinic acid(6.48g, 15.7mmole) was dissolved in DMF(lOQmL), thereto WSCD(3g, 15.7mmole) HOBT(2.12g, 15.7mmole) and [3- (acridine-9-yl-amino)- -aminophenyl]-methanol were added. The resulting mixture was stirred 5 for 24 hours at the room temperature and the solvent used was removed under the reduced pressure. Then, the resulting product was purified by column chromatography to give the titled compound. yield : 73.2% m.p. : 187-1891: *H NMR(DMSO-db) : 1.24(3H,t), 2.82(2H,q), 3.Q2(4Hm), 3.62(4H,m>, 3.99(3H,s), 4.49(2H,s), 5.28(lH,t), 6.85(2H,m), 7.02(2H,m), 7.27(4H,m), 7.45(lH^n), 7.55(2H>m)J 7.77(4H,m), 8.03(2H,s), 8.09(2H,m), 10.39(lH,s) Example 19 4-(3,5-dimethylphenyl)-piperazine-l-carboxylic acid{5~ [3- (acridine-9-yl-amino)-5-hydroxymetiiylphenylcarbamoyl]-6-ethyl-2-niethoxy-pyridine-3-yl }amide The same reaction procedure to the example 18 were carried out using 20 2-ethyl-5- {[4- (3,5-dimethylphenyl) -piperazine-l-carbonyl]-amino} - 6-methoxynicotinic add and [3- (acridine-9-yl-amino) -5-aminophenyl] -methanol to give the titled compound. yield : 69.5% m.p. : 178—180"C !H NMR(DMSO-cfe) : 1.89(3H,t), 2.28(6H,s), 2.70(2H,q), 3.3H4HM 3.7K4HM 3.99(3H,s), 4.51(2H,s), 5.28(lH,t), 6.69(lH,s), 6.89(lH,s), 7.08(lH,s), 7.53(2H,m), 7.71 (lH,s), 7.87(lH,s), 8.04(3HM 8.18(3H,m), 8.37(2H^n), 10.46(lH,s), 11.55(lH,s), 12.28(lH,s), 14.88(lH,s) Intellectual Property Office of N.Z. -3 AUG 2005 received Example 20 4- (3,5-dimethoxyphenyl)-piperazine-l-carboxylic acid{5~[3~ (acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-6-ethyl-2-methoxy-pyridine-3 -yl}amide Hie same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-dimethoxyphenyl)-piperazihe-l-carbonyl]-amino} -6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound. yield : 70.2% m.p. : 170 ~ 172 "C NMR(DMSO-de) 1.25(3H,t), 2.84(2H,q), 3.24(4H>m)) 3.66(4H,m), 3.76(6H,s) 4.04(3H,s), 4.58(2H,s), 5.28(lH,t), 6.02(lH,s), 6.08(lH,s), 6.90(lH,s), 7.26(2H,m), 7.34(llim), 7.42(lH,m), 7.58(lH,s), 7.62(2H^n), 7.75(2E^m), 7.88(lH,d), 8.03(2H^n), 8.23(2HM 8.37(lH,s), 10.06(lH,s) Example 21 4-(3,5-difluorophenyl)-piperazine-l-carboxylic acid{5- [3- (acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-6-ethyl-2-methoxy-pyridine-3-yl }amide The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{ [4- (3,5-difluorophenyl)-piperazine-l-carbonyl]-amino}-6-methox 25 ynicotinic acid and [3-(acridine-9-yl~amino)-5-aminophenyl]-methanol to give the titled compound. yield : 68.8% m.p. : 184—18610 lH NMR(DMSO-cfe) : 1.24(3H,t), 2.79(ZH,q), 3.31(4H^n), 3.59(4H,m), 30 3.98(3H,s), 4.47(2H,s), 5.19(lH,t), 6.53(2H^n), Intellectual Property Office of N.Z. - 3 AUG 2005 RPrcit/cn " 3 AUG 2005 received 6.70(2H,d), 7.07(lH,m), 7.38(3H^n), 7.bl(3H,mJ,' 8.05(3H,m), 10.23(lH,s), 10.93(lH,s) Example 22 4-(3,5-dichlorophenyl)-piperaane-l-carboxylic acid{5-[3- (acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-6-ethyl-2-methoxy-pyri.dine-3-yl >amide The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-dichlorophenyl)-piperazine-l-carbonyl]-amino}-6-methox 10 ynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound. yield : 71.2% m.p. : 210-212 £ 2H NMR(DMSO-db) : 1.25(3H,t), 2.83(2H,q), 3.30(4H,m), 3.66(4H,m), 15 4.03(3H,s), 4.53(2H,s), 5.41(lH,t), 6.63(lH,s), 6.79(3Hfm), 7.11(2H>m), 7.23(lH,m), 7.42(lH,m), 7.55(4Hjn), 7.71(lH,s), 8.09(2H,m), 8.32(lH,s), 9.74(lH,s) Example 23 4-(3-fluorophenyl)-piperazine-l-carboxylic acid{5~ [3- (acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl3-6-ethyl-2-methoxy-pyridine~3-yl }amide The same reaction procedure to the example 18 were carried out using 25 2-ethyl-5-{[4-(3-fluorophenyl)-piperazine-l-carbonyl]-amino>-6-methoxynicotinic acid and [3- (acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound. yield : 72.1% m.p. : 186-188"C *H NMRCDMSO-de) : 1.25(3H,t), 2.84(2H,q), 3,28(4H,m), 3.67(4H,m), 4.04(3H,s), 4.55(2H,s), 5.39(lH,t), 6.63(2H,m), 6.69(2Htm), 7.22(4H,m), 7.33(lH,m), 7.44(lH,m), 7.63(4H,m), 8.17(2H,m), 8.37(lH,s), 9.66(lH,s) Example 24 4-(3-hyc3roxyphenyl)-piperazine--l-carboxylic acid{5- [3- (acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl]-6-ethyl-2-methoxy-pyridine-3-yl }amide The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3-hydroxyphenyl)-piperazine-l-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound. yield : 70.6% m.p. : 196-1981 NMR(DMSO-cfe) : 1.25(3H,t), 2.80(2H,q>, 3.14(4H,m), 3.59(4H,m), 3.98(3H,s), 4.47(2H,s), 5.21(lH,t), 6.28(lH,d), 6.37(lH,s), 6.45(lH,d), 6.61(lH,m), 7.04(lH,t), 7.22(2HM 7.44(2H^n), 7.58(lH^n), 7.71(2H,m), 7.75(lH^n), 8.06(3HM 9.20(lH,s), 10.27(lH,s) Example 25 4-(3,4,5-trimethoxyphenyl)-piperazine-l-carboxylic acid{5-[3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyU-6-ethyl-2-methoxy-pyridine -3-yl}amide The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,4,5-trimethoxyphenyl)-piperazine-l-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminoph-enyl]-methanol to give the titled compound. yield : 66.8% m.p. : 190-1921: XH NMR(DMSO-cfe) 1.26(3H,t), 2.85(2H,q), 3.14(4H,m), 3.59(4H,m), 3.78(3H,s), 3.84(6H,s), 4.11(3H,s), 4.57(2H,s), 5.34(lH,t), 6.71(lH,s), 6.77(2H,s), 7.21(2H,s), 7.35(lH,m), 7.65(4h,m), 7.88(3HM 8.04(lH,s), 8.14(2H,m), 8.56(lH,s), 8.92(lH,s), 9.07(lH,s) Example 26 N-(3-(acridine-9-yl-amino)-5-hydroxymethylphenyl]-5-{[4-(3,5-dimethoxyp henyl)-piperazine-l-carbotMonyl]-amino}-2-ethyl-6-methoxynicotineamide 10 The same reaction procedure to the example 18 were carried out using 5-{[4-(3,5-dimethoxyphenyl)-piperazine-l-carbonyl]-amino-2-methyl-6-met hoxynicotinic acid and [3-(acridine~9-yl-amino)-5-aminophenyl]-methanol to give the titled compound. yield : 69.8% m.p. : 176—178"C NMR(DMSO-cfe) : 1.27(3H,t), 2.90(2H,q), 3.32(4H,m), 3.99(3H,s), 4.10(4H,m), 4.53(2H,s), 5.35(lH,s), 6.03(lH,s), 6.05(2H,d), 6.61(lH,s), 7.19(3H,m), 7.39(lH,m), 7.55(2H,m), 7.72(2HM 8.11(4H,m), 9.16(lH,s) Example 27 N-(3-(acridine-9-yl-amino)-5-hydroxymethylphenyl]-5-{[4-(3,5-dimethylph enyl)-piperazine-l-carbothionyl]-amino}-2-eihyl-6-methoxynicotmeamide The same reaction procedure to the example 18 were carried out using 25 5-{[4-(3,5-dimethylphenyl)-pipera2ane-l-carbothionyl]-amino-2-methyl-6-m ethoxynicotinic acid and [3- (acridme-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound. yield : 71.2% m.p. : 170—172*0 XH NMR(DMSO-de) : 1.28(3H,t), 2.27(6H,s), 2.90(2H,q), 3.28(4HM 3.99(3H,s), 4.11(4H,m), 4.55(2H,s), 5.39(lH,t), 6.54(3H^m), 6.70(lH,s), 7.15(2H,m), 7.32(lH^n), 7.47(1HM 7.60(2H,m), 7.76(2H,m), 8.02(lH,s), 8.13(2H,m), 8.42(lH,s), 9.70(lH,s) Example 28 N- (3- (acridine-9-yl-amino)-5-hydroxymethylphenyl] -5-{ [4- (3-fluorophenyl) -piperazine-l-carbythionyl]-amino}-2-ethyl-6-methoxynicotineamide The same reaction procedure to the example 18 were carried out using 10 5-{[4-(3-fluorophenyl)-piperazine-l-carbonyl]-amino-2-methyl-6-methoxyni cotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound. yield : 70.8% m.p. : 176 ~ 178 "C NMR(DMSO-de) : 1.26(3H,t), 2.87(2H,q), 3.36(4H^n), 3.94(3H,s), Example 29 N-(3-(acridine-9-yl-amino)-5~hydroxymethylphenyl]-5-{[4-(3,5-dichlorophe nyl)-piperazine-l-carbytJiionyl]-amino}-2-ethyl-6-methoxynicotineamide The same reaction procedure to the example 18 were carried out using 5-{[4-(3,5-dichlorophenyl)-piperazine-l-carbothionyl]-armno-2-methyl-6-me 25 thoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aininophenyl]- methanol to give the titled compound. yield : 69.8% m.p. : 174-176°C XH NMR(DMSO-cfe) : 1.26(3H,t), 2.86(2H,q), 3.42(4HM 3.93(3H,s), 4.09(4H,m), 4.46(2H,s), 5.21(lH,t), 6.61(2HJm), 6.82(2H^n), 7.26(4H,m), 7.46(lH,s), 7.66(3HUn), 7.71(lH,s), 8.05(2HM 9.10(lH,s), 10.27(lH,s) 4.07(4HM 4.47(2H,s), 5.2(lH,t), 6.54(lH,s), 6.91(lH,s), 6.99(2H,m), 7.11(2H,m), 7.43(2H,s), 7.58(3H,m), 7.72(2H,m), 8.03(2H,m), 9.09(lH,s), 10.24(lH,s) The compounds prepared in the examples according to the present invention were tested for pharmacological activities against tumors. Antitumor activities of the compounds were tested in vitro against 5 kinds of human tumor cell lines and 2 kinds of leukemia tumor cell lines. 5 Methods and results of the tests are as follows.

Experimental 1 : In vitro antitumor effect against human tumor cell lines. A Tumor cell lines : A549 (human non-small lung cell) SKOV-3 (human ovarian cell) 10 HCT-15 (human colon cell) XF-498 (human CNS cell) SKMEL-2 (human melanoma cell) B. Method : SRB Assay 15 a. Human solid tumor cell lines, A549(non-small lung cell), SKMEL-2(melanoma), HCT-15(colon), SKOV-3(ovarian) and XF-498(CNS) were cultured in 5% CO2 incubators using the RPMI 1640 media containing 10% FBS at 37*0, while with transfer-culturing successively once or twice per week. Cell cultures were dissolved in a 20 solution of 0.25% trysin and 3 mmol CDTA PBS(-) to separate the cells sticked on the culture media b. 5x103~2x104 cells were added into each well of 96-well plate and cultured in 5% CO2 incubator at 37*0 for 24 hours. c. Each sample drug was dissolved in a little DMSO and diluted with the 25 used medium to a prescribed concentration for experiment, while the final concentration of DMSO was adjusted below 0.5%. d. Medium of each wdl cultured for 24 hours as above b. was removed by aspiration. Each 200/tf of drug samples prepared in c. was added into each well and the wells were cultured for 48 hours. Tz(time zero) plates were collected at the point of time drugs were added.

I '3 AUG 2005 I iR P r* 1— 11. — e. According to the SRB assay method, cell fixing with TCA, staining with 0.4% SRB solution, washing with 1% acetic acid and elution of dye with lOmmol Tris solution were carried out on Tz plates and culture-ended plates, and then, OD values were measured at 520 nm.

C. Calculation of result a. Time zero(Tz) value was determined with measuring the SRB protein value at the point of time drugs were added. b. Control value(C) was determined with the OD value of an well 10 untreated with drug. c. Drug-treated test value(T) was determined with the OD value of drug-treated well. d. Effects of drugs were estimated with growth stimulation, net growth inhibition and net killing calculated from Tz, C and T values. e. If T > Tz, cellular response function was calculated by 100x(T-Tz)/(C-Tz), and, if T < Tz, by 100 (T-Tz)/Tz. The results are shown in the next table 1.

* REFERENCE 1) P. Skehan, R. Strong, D Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenney and M. R. Boyd • Proc. Am. Assoc. Cancer Res., 30, 612 (1989). 2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. Boyd ; J. Natl. Cancer Inst., 82, 1113 (1990). 3) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd ; J, Natl. Cancer Inst, 82, 1107 (1990).

D. Results.

It was found that the compounds of the present invention have the even or superior antitumor activities ED5o(ng/nil) [than that of cisplatin, the control against human solid cancer cell lines.

Table 1. EDsoGag/me) Ex. No.

A549 SK-OV-3 SK-MEL-2 XF-498 HCT-15 2 0.12 0.12 0.01 0.18 0.19 3 0.12 0.19 0.03 0.18 0.13 9 0.24 0.19 0.15 0.15 0.15 16 0.08 0.14 0.02 0.09 0.07 19 0.21 0.17 0.18 0.38 0.27 Cisplatin 0.81 0.71 0.71 0.77 3.03 Experimental 2 : In vitro antitumor effects against animal leukemia cells.

A. Material : Tumor cell lines : P388 (mouse lymphoid neoplasma cell) B. Method : Dye Exclusion Assay. 1) The concentration of P388 cells being cultured in PPMI 1640 media containing 10% FBS was adjusted to lxlO6 cells/ml. 2) Each sample drug of a concentration diluted in the ratio of log dose was added into cell culture media and cultured at 37 "C for 48 hours in 50% CO2 incubator, and then viable cell number was measured by dye exclusion test using trypan blue. 3) The concentration of each sample compound showing 50 % cell growth 25 inhibitionGCso) compared with the control was determined and listed in the table 2 below.

♦ REFERENCE 1) P. Skehan, R. Strong, D. Scudiero, A Monks, J. B. Mcmahan, D. T. 30 Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. : Proc. Am. tofe//ectual Office Property of N.Z. 3 AUG 2005 Assoc. Cancer Res., 30, 612 (1989). 2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A Monks and M. R. Boyd. : J. Natl. Cancer Inst, 82, 1113 (1990) 3) P. Skehan, R. Strong, D. Scudiero, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd : J. Natl. Cancer Inst, 82, 1107(1990) C. Results As the result of measurement of antitumor activities IC5o(^g/ml) against P388 cancer cells of the compounds according to the present invention, it was found that the compounds tested have equal to or higher antitumor activities than those of the control drug, mitomycin C. j,- Table 2 Ex. No.

P388 (Hg/ml) 2 0.3 3 1.0 4 0.9 9 0.4 16 0.3 Mitomycin C 1.1 Experimental 3 : in vivo antitumor effects against mouse leukemia P388 cells A. Material of experiment BDF1 mice were used B. Method of experiment 1) Leukemia P388 cells being transfer-cultured successively in DBA/2 30 mouse, were grafted into each mouse of a group comprising 8 mice of 6 'ntelfectiiarpTopertv— Office of N.Z. - 3 AUG 2005 RPP. Clv/rn week old BDF1 mouse with the dose of lxl06cells/0.1ml 2) Sample drugs were dissolved in PBS or suspended in 0.5% tween 80, and then injected into abdominal cavity of mouse at each prescribed concentration on days 1, 5, 9, respectively. 3) With observation everyday, survival times of tested mice were measured. Antitumor activities was detemimed in such a manner that the increasing ratio(T/C%) of average survival days of drug-treated groups compared with the control group was calculated using the mean survival times of each tested groups.

The results are shown at the next table 3.

Table 3 Experimental 4. Acute toxicity test (LDso) : a) Method : Litchfield-Wilcoxon method. 6-week-old ICR mice(male 30±2.0g) were fed freely with solid feed and water at room temperature, 23±1°C and at humidity 60+5%. Sample drugs were injected into the abdominal cavities of mice. Each group comprised 6 mice. Observed during 14 days, external appearances and life or death thereof were recorded, and also, visible lesions were observed from dead 30 mice by dissection. LDso value was calculated by Litchfield-wilcoxon Intellectual Property Office of N.Z. - 3 AUG 2005 □ crciwcn Ex. No.

Dose (mg/kg) MST (days) T/C (%) 100 22.0 200.0 2 50 >60.0 >545.5 >60.0 >545.5 100 11.6 100.0 3 50 >60.0 >545.5 17.0 154.5

Claims (1)

1. WO 03/074490 PCT/KR02/00392 - 32 - method. b) Results As shown in the following table, the compounds according to the present invention are predominantly safe in comparison with cisplatin, whereby 5 much problems of known compounds such as restriction of dosage, unfavorable side effects by toxicity, etc. may be overcome considerably. Table 4 10 Ex. No. LDso (mg/kg) ip iv 2 80 3 80 Cisplatin 9.7 [Industrial applicability] 15 As described above, the compounds according to the present invention are much more safer and also have much superior antitumor activities to known anticancer drugs, and accordingly the compounds are expected to be useful as a new anticancer drug. 20 25 30 WO 03/074490 - 33 - 10 What we claim is: [claim 1] A compound of the general formulaCD JOH (i) 15 wherein Y is a bond or o ch wherein X is oxygen or sulfur, Ri, R2, R3, R4 and R5 are independently hydrogen, halogen, nitro, amino, hydroxy, C]-C4 alkylamino, 20 C1-C4 alkyl or C1-C4 alkoxy, R' and R" are independently C1-C4 alkyl or C4-C4 alkoxy, and Z is C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkylamino or a pharmaceutically acceptable salt thereof. 25 WO 03/074490 10 - 34 - [claim 2] A process for the preparation of a compound of the following general formula (I) or apharmaceutically acceptable salt thereof, comprising reacting a compound of the following general formula(a) with a compound of the following general formula(b) to give a compound of the following general formula (I) and if necessary converting the compound of the general formula (I) into a pharmaceutically acceptable salt thereof; ,oh « X X (I) 15 20 (a) (b) wherein Ri, R2, R3, R4, Rs, R', R", X, Y and Z are as defined above and ,JL^NH2 25 Yi is hydrogen or the group of ' WO 03/074490 - 35 - [claim 3] A process for the preparation of a compound of the following general formula (I) or apharmaceutically acceptable salt thereof, comprising reacting a compound of the following general formula(c) with a compound of the 5 following general formula(d) to give a compound of the following general formula (I) and if necessary converting the compound of the general formula (I) into a pharmaceutical^ acceptable salt thereof; ^OH 10 (I) 15 20 ivj—\l r" n z R« R4 25 (d) wherein Ri, R2, R3, R4, Rs, R', R", X, Y and Z are as defined above and O HO" Y2 is -OH or the group o# CH I— 3-1 30 toteliectuai Office Property' of N.Z. " 3 AUG 2005 Becf IV Ed [claim 4] A compound of the general formula (I), as defined in claim 1, when prepared by a process as claimed in claim 2 or claim 3. [claim 5] A pharmaceutical preparation comprising a compound as claimed in claim 1 and a pharmaceutical^ acceptable vehicle. [claim 6] A use of a compound as claimed in claim 1 in the manufacture of a medicament for the treatment of cancer. [claim 7] A compound, as claimed in claim 1 or claim 4, substantially as herein described with reference to any example thereof. [claim 8] A pharmaceutical preparation, as claimed in claim 5, substantially as herein described with reference to any example thereof. [claim 9] A use, as claimed in claim 6, substantially as herein described with reference to any example thereof. 259260-1