RU2269524C2 - Derivatives of 9-aminoacridine and method for their preparing - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of 9-aminoacridine that possess the expressed antitumor effect and low toxicity and correspond to the formula (I):

wherein Y means a bond or represents compound of the formula:

X means oxygen or sulfur atom; R₁-R₅ mean independently hydrogen, halogen atom, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy-group; R' and R'' represent (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy-group; Z means (C₁-C₄)-alkoxy-group, and to their pharmaceutically acceptable salts. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable medicinal properties of compounds.

3 cl, 4 tbl, 29 ex

Description

FIELD OF THE INVENTION

The present invention relates to new derivatives of 9-aminoacridine of General formula (I)

where Y denotes a bond or represents

where X is oxygen or sulfur, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₄ lower alkylamino, C ₁ -C ₄ alkyl or C ₁ -C ₄ lower alkoxy, R 'and R''independently are C ₁ -C ₄ alkyl or C ₁ -C ₄ lower alkoxy, and Z is C ₁ -C ₄ lower alkyl, C ₁ -C ₄ lower alkoxy or C ₁ -C ₄ lower alkylamino.

In the above definitions of C ₁ -C _4, lower alkyl means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or the like. C ₁ -C ₄

Lower alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy or the like.

C ₁ -C ₄ Lower alkylamino means methylamino, ethylamino, propylamino, butylamino or the like.

Prior art

WO 00/37447 describes 9-aminoacridine derivatives and a process for preparing compounds of formula (1)

where a is hydrogen or a group

(where X is oxygen or sulfur, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₄ lower alkyl hydroxy, C ₁ -C ₄ lower alkylamino , C ₁ -C ₈ alkyl, C ₁ -C ₄ lower alkoxy or C ₁ -C ₄ lower alkyloxycarbonyl, and m and n independently represent an integer of 0, 1 or 2), R ₆ , R ₇ , R ₈ and R ₉ independently represent C ₁ -C ₈ alkyl or C ₁ -C ₄ lower alkoxy and Y means hydrogen, amino group, -N = CHR` (where R` means hydrogen, benzyl, C ₁ -C ₈ alkyl or C ₁ -C ₆ lower alkylamino)

(where R`` is hydrogen, benzyl, C <sub>1</sub> -C <sub>8</sub> alkyl or C <sub>1</sub> -C <sub>6</sub> lower alkylamino, and R`` is hydrogen, benzyl, C ₁ -C ₈ alkyl or an amino protecting group) or

(wherein X has the same meanings as given above, R ₁ ', R _2', R ₃ ', R _4' and R ₅ 'independently represent hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₄ lower alkyl hydroxy, C ₁ -C ₄ lower alkylamino, C ₁ -C ₈ alkyl, C ₁ -C ₄ lower alkoxy or C ₁ -C ₄ lower alkyloxycarbonyl, and q and r independently represent an integer of 0, 1 or 2) or its pharmaceutically acceptable salt and method for its preparation.

In the above compounds of formula (1), where Y is a group

(R`` and R``, have the same meanings given above), can be isomers of the l-form and d-form or in racemic form.

However, the compounds of the present invention are not described in WO 00/37447.

DETAILED DESCRIPTION OF THE INVENTION

The inventors conducted lengthy studies to identify new compounds with intense anti-cancer effects. As a result, the authors found that the compounds of general formula (I) or their acid addition salts, as defined above, have not only a noticeable anti-cancer effect, but also very low toxicity.

where Y means a bond or represents a group

(where X is oxygen or sulfur, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, nitro, amino, hydroxy, C ₁ -C ₄ lower alkyl hydroxy C ₁ -C ₄ lower alkylamino, C ₁ -C ₈ alkyl or C ₁ -C ₄ lower alkoxy, R ′ and R ″ independently are C ₁ -C ₈ alkyl or C ₁ -C ₄ lower alkoxy, and Z is C ₁ -C ₄ lower alkyl C ₁ -C ₄ lower alkoxy or C ₁ -C ₄ lower alkylamino.

Accordingly, an object of the present invention is a compound of general formula (I) or an acid addition salt thereof having not only a noticeable anti-cancer effect, but also a very low toxicity.

Another object of the invention is a method for producing a compound of general formula (I) or an acid addition salt thereof.

The compounds of the present invention can be mixed with pharmaceutically acceptable diluents in the usual way to obtain pharmaceutical preparations for use in the prevention or treatment of various types of tumors.

Therefore, another object of the present invention are pharmaceutical preparations containing an effective amount of a compound of general formula (I) or an acid addition salt thereof as an active component.

Acids that can interact with a compound of general formula (I) to form an acid addition salt thereof are pharmaceutically acceptable inorganic acids, organic acids, amino acids or sulfonic acids; for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid; organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid and malonic acid; amino acids such as serine, cysteine, cystine, asparagine, glutamine, lysine, arginine, tyrosine and proline; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

The diluents used in the preparation of pharmaceutical preparations containing a compound of general formula (I) as an active ingredient are sweetening agents, binders, solvents, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, degradation agents, antioxidants, preservatives, softeners, fillers, perfumes or the like; examples may include substances such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silicon dioxide, talc, stearic acid, stearin, magnesium stearate, calcium stearate, magnesium aluminosilicate, starch, gelatin, tragacanth resin, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence and vanilla flavor.

The daily dose of a compound of general formula (I) may vary depending on age, gender and degree of disease, but preferably, 1 mg to 5000 mg per day may be administered once or several times a day.

The compound of General formula (I) according to the present invention can be obtained according to the following schemes I, II.

Scheme I

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ', R'', X, Y and Z are as defined above, and Y ₁ is hydrogen or a group

Compounds of general formula (a) and (b) are reacted in the presence of a condensing agent and an acid in a conventional organic solvent to effectively form a compound of general formula (I).

The reaction can preferably be carried out in a conventional organic solvent, such as tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethylformamide, pyridine and the like.

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

The compound of general formula (a) or (b) is a known compound as described in J. Med. Chem. 1995, 38, 3226 or in PCT / KR99 / 00787, or can be obtained and used in a similar way.

The reaction can also be carried out at a temperature of from 3 ° C to the boiling point of the solvent, preferably at 25-50 ° C, for 5-24 hours, preferably for 10-24 hours.

The acid may be used in an amount of 1-1.5 equivalents, preferably 1-1.1 equivalents.

Scheme II

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ', R'', X, Y and Z are as defined above, and Y ₂ is —OH or a group

Compounds of general formula (c) and (d) are reacted in the presence of a condensing agent and an acid in a conventional organic solvent to successfully produce a compound of general formula (I).

The reaction can preferably be carried out in a conventional organic solvent, such as tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethylformamide, pyridine and the like.

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

A compound of general formula (c) or (d) is a known compound and is described in J. Med. Chem., 1995, 38, 3226, or in PCT / KR99 / 00787, or may be prepared and used in a similar manner.

The reaction can be carried out at a temperature of from 3 ° C to the boiling point of the solvent, preferably at 25 -50 ° C, for 5-24 hours, preferably for 10-24 hours.

The acid may be used in an amount of 1-1.5 equivalents, preferably 1-1.1 equivalents.

Examples

Compounds of general formula (I) are prepared according to the above method of the present invention.

Examples 1-17: Compounds of General formula (I), where

Examples 18-29: Compounds of general formula (I), where Y = 0 (zero)

Example 1

(5- {1- [3- (Acridin-9-ylamino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-methyl-2-methoxypyridin-3-yl) 4-phenylpiperazin-1-carboxylic acid amide

2-Ethyl-6-methoxy-5 - [(4-phenylpiperazine-1-carbonyl) amino] nicotinic acid (0.5 g, 1.24 mmol) was dissolved in pyridine (30 ml) and DCC (0, 26 g, 1.24 mmol), DMAP (0.15 g, 1.24 mmol) and N- [3- (acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide. After the resulting mixture was stirred for 24 hours at room temperature, the resulting product was purified by column chromatography to obtain the title compound.

Yield: 68.2%

Mp: 218-220 ° C.

¹ H NMR (DMSO-d ₆ ): 1.20 (3H, t), 1.38 (3H, d), 2.79 (2H, q), 3.19 (4H, m), 3.61 (4H, m), 3.96 (3H, s), 4.45 (2H, s), 4.53 (1H, m), 6.50 (1H, m), 6.85 (1H, t) 7.01 (4H, d), 7.28 (4H, m), 7.62 (4H, m), 8.00 (3H, d), 8.51 (1H, d), 9.97 ( 1H, s)

Example 2

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-dimethylphenyl) piperazin- 1-carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 52.3%, mp: 205-207 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 5.18 (1H, m) 6.03 (1H, s), 6.14 (2H, s), 6.48 (1H, s), 7.01 (2H, m), 7.30 (3H, m), 7.56 ( 3H, m), 7.96 (2H, d), 8.18 (1H, m), 8.50 (1H, d), 9.95 (1H, s)

Example 3

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-dimethoxyphenyl) piperazine- 1-carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 49.1%, mp: 231-233 ° C;

¹ H NMR (DMSO-d ₆ ): 1.13 (3H, t), 1.38 (3H, d), 2.12 (1H, s), 2.79 (2H, q), 3.19 (4H, m), 3.59 (4H, m), 3.75 (6H, s), 3.96 (3H, s), 4.46 (2H, s), 4.53 (1H, m) , 5.19 (1H, s), 6.03 (1H, s), 6.15 (2H, s), 6.50 (1H, s), 7.04 (2H, m), 7.32 ( 2H, s), 7.60 (4H, m), 7.96 (1H, s), 8.00 (1H, s), 8.25 (1H, m), 8.51 (1H, d), 9.97 (1H, s)

Example 4

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-difluorophenyl) piperazin- 1-carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3,5-difluorophenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 48.7%, mp: 202-204 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 5.20 (1H, s), 6.54 (2H, m) 6.69 (2H, d), 7.09 (2H, m), 7.33 (2H, s), 7.61 (4H, m), 7.94 (1H, s), 8.04 ( 1H, s), 8.25 (1H, s), 8.51 (1H, d), 9.99 (1H, s)

Example 5

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-dichlorophenyl) piperazin- 1-carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3,5-dichlorophenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 47.8%, mp: 184-186 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 5.18 (1H, s), 6.45 (1H, s) 6.92 (1H, s), 7.02 (3H, s), 7.34 (3H, m), 7.50 (3H, m), 7.94 (1H, s), 8.04 ( 1H, s), 8.22 (1H, m), 8.50 (1H, m), 9.96 (1H, s)

Example 6

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3-fluorophenyl) piperazin-1- carboxylic acid

The reaction is carried out in the same manner as in example 1, using 2-ethyl-5 - {[4- (3-fluorophenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- (acridine- 9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 53.4%, mp: 208-210 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 6.41 (1H, m), 6.53 (3H, m) 6.86 (1H, m), 6.98 (2H, m), 7.15 (1H, m), 7.17 (2H, m), 7.38 (3H, m), 7.86 ( 3H, m), 8.35 (1H, m), 9.49 (1H, s)

Example 7

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3-hydroxyphenyl) piperazin-1- carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3-hydroxyphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- (acridine- 9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 41.9%, mp: 207-209 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 6.41 (3H, m), 6.67 (1H, s) 7.06 (2H, m), 7.16 (2H, m), 7.24 (1H, s), 7.35 (1H, s), 7.47 (1H, d), 7.58 ( 2H, m), 7.86 (2H, m), 8.08 (2H, d), 8.36 (1H, s), 9.55 (1H, s)

Example 8

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,4,5-trimethoxyphenyl) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in example 1, using 2-ethyl-5 - {[4- (3,4,5-trimethoxyphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3 - (acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 44.3%, mp: 205-207 ° C;

¹ H NMR (DMSO-d ₆ ): 1.23 (3H, t), 1.50 (3H, d), 2.81 (2H, q), 3.76 (3H, s), 3.83 (6H, s), 4.05 (3H, s), 4.54 (2H, s), 4.73 (1H, m), 6.75 (2H, m), 7.20 (2H, m) 7.37 (1H, s), 7.41 (1H, s), 7.50 (1H, d), 7.66 (2H, m), 7.88 (2H, m), 8.09 ( 1H, s), 8.14 (2H, m), 8.48 (1H, s), 9.01 (1H, s), 9.77 (1H, s)

Example 9

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -2-methoxy-6-propylpyridin-3-yl) amide 4- (3,5-dimethoxyphenyl) piperazin- 1-carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-propyl-5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 41.2%, mp: 220-222 ° C;

¹ H NMR (DMSO-d ₆ ): 0.88 (3H, t), 1.38 (3H, d), 1.68 (2H, m), 2.76 (2H, q), 3.19 (4H, m), 3.59 (4H, m), 3.75 (6H, s), 3.95 (3H, s), 4.45 (2H, s), 4.54 (1H, m) 5.19 (1H, s), 6.04 (1H, s), 6.15 (2H, s), 6.50 (1H, s), 7.04 (2H, m), 7.31 ( 2H, s), 7.59 (4H, m), 7.98 (3H, d), 8.25 (1H, m), 8.50 (1H, d), 9.56 (1H, s)

Example 10

(5- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -2-methoxy-6-propylpyridin-3-yl) amide 4- (3,5-dimethylphenyl) piperazin- 1-carboxylic acid

The reaction is carried out in the same manner as in example 1, using 2-propyl-5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 42.3%, mp: 195-197 ° C;

¹ H NMR (DMSO-d ₆ ): 0.88 (3H, t), 1.38 (3H, d), 1.67 (2H, m), 2.25 (6H, 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 (1H, m), 5.19 (1H, 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 (1H, m), 8.50 (1H, d), 9.96 (1H, s)

Example 11

N- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethyl} -5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbotionyl] amino} -6-methoxy -2-methylnicotinamide

The reaction is carried out in the same manner as in example 1, using 5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbotionyl] amino} -2-methyl-6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 58.2%, mp: 181-183 ° C;

¹ H NMR (DMSO-d ₆ ): 1.40 (3H, d), 2.54 (3H, s), 3.28 (4H, m), 3.75 (6H, s), 3.90 ( 3H, s), 4.07 (4H, m), 4.45 (2H, s), 4.55 (1H, m), 5.18 (1H, m), 6.03 (1H, s), 6.15 (2H, s), 6.49 (1H, m), 7.03 (2H, m), 7.31 (3H, m), 7.60 (2H, m), 7.67 (2H , m), 8.25 (2H, m), 8.52 (1H, d), 9.08 (1H, s), 9.99 (1H, s)

Example 12

N- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethyl} -5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbotionyl] amino} -2-ethyl -6-methoxynicotinamide

The reaction is carried out in the same manner as in example 1, using 5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbotionyl] amino-2-ethyl-6-methoxynicotinic acid and N- [3- (acridine -9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 43.9%, mp: 177-179 ° C;

¹ H NMR (DMSO-d ₆ ): 1.20 (3H, t), 1.43 (3H, d), 2.82 (2H, m), 3.19 (2H, m), 3.29 ( 2H, m), 3.79 (6H, s), 3.93 (3H, s), 4.12 (4H, m), 4.38 (1H, m), 4.45 (1H, m), 4.60 (1H, m), 6.25 (1H, s), 6.58 (3H, d), 7.08 (3H, m), 7.45 (2H, m), 7.84 (6H , m), 8.34 (1H, m), 8.72 (1H, s), 9.77 (1H, s)

Example 13

N- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethyl} -5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbotionyl] amino} -6-methoxy -2-propylnicotinamide

The reaction is carried out in the same manner as in example 1, using 5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbotionyl] amino} -2-propyl-6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 46.5%, mp: 168-170 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 6.03 (1H, s), 6.15 (2H, s), 6.53 (1H, s), 7.08 (3H, m), 7.31 (2H, s), 7.60 (3H , m), 7.66 (2H, m), 7.76 ~ 8.35 (2H, m), 8.53 (1H, d), 9.07 (1H, s), 9.99 (1H, from)

Example 14

N- {1- [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethyl} -5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbotionyl] amino} -2-ethyl -6-methoxynicotinamide

The reaction is carried out in the same manner as in example 1, using 5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbotionyl] amino} -2-methyl-6-methoxynicotinic acid and N- [3- ( acridin-9-yl-amino) -5-hydroxymethylphenyl] -2-aminopropanamide to give the title compound.

Yield: 47.7%, mp: 198-200 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m) 4.60 (1H, m), 6.25 (1H, s), 6.58 (3H, d), 7.08 (3H, m), 7.45 (2H, m), 7.84 ( 6H, m), 8.34 (1H, m), 8.72 (1H, s), 9.77 (1H, s)

Example 15

(6-ethyl-5- {1- [3-hydroxymethyl-5- (2-methylacridin-9-yl-amino) phenylcarbamoyl] ethylcarbamoyl} -2-methoxypyridin-3-yl) amide 4- (3,5-dimethylphenyl ) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and 2-amino-N- [3-hydroxymethyl-5- (2-methylacridin-9-yl-amino) phenyl] propionamide to give the title compound.

Yield: 51.3%, mp: 164-166 ° C;

¹ H NMR (DMSO-d ₆ ): 1.18 (3H, t), 1.52 (3H, d), 2.05 (1H, s), 2.17 (2H, m), 2.22 ( 1H, 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 (1H, m), 6.51 (3H, m), 6.56 (1H, s), 7.00 (3H, m), 7.43 (2H , m), 7.78 (4H, m), 8.48 (1H, m), 9.53 (1H, s)

Example 16

(5- {1- [3- (3,4-Dimethylacridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and 2-amino-N- [3- (3,4-dimethylacridin-9-yl-amino) -5-hydroxymethylphenyl] propionamide to give the title compound.

Yield: 53.9%, mp: 176-178 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 6.41 (1H, m), 6.49 (2H, s), 6.56 (1H, s), 6.85 (1H, m), 7.05 ( 4H, m), 7.54 (1H, m), 7.73 (1H, m), 7.92 (2H, m), 8.42 (1H, s), 9.31 (1H, s)

Example 17

(5- {1- [3- (4-Methoxyacridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] ethylcarbamoyl} -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-dimethylphenyl) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in Example 1, using 2-ethyl-5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and 2-amino-N- [3- (4-methoxyacridin-9-yl-amino) -5-hydroxymethylphenyl] propionamide to give the title compound.

Yield: 50.8%, mp: 178-179 ° C;

¹ H NMR (DMSO-d ₆ ): 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 (1H, m), 4.42 (2H, s), 4.81 (1H, m) 6.52 (4H, m), 6.89 (4H, m), 7.18 (2H, m), 7.41 (3H, m), 7.93 (1H, m), 8.37 ( 1H, s), 9.33 (1H, s)

Example 18

{5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) 4-phenylpiperazin-1-carboxylic acid amide

2-ethyl-6-methoxy-5 - [(4-phenylpiperazine-1-carbonylamino] nicotinic acid (6.48 g, 15.7 mmol) was dissolved in DMF (100 ml), WSCD (3 g, 15.7) was added. mmol) HOBT (2.12 g, 15.7 mmol) and [3- (acridin-9-yl-amino) -5-aminophenyl] methanol. The resulting mixture was stirred for 24 hours at room temperature and the used solvent was removed under reduced Then, the resulting product is purified by column chromatography to give the title compound.

Yield: 73.2%, mp: 187-189 ° C;

¹ H NMR (DMSO-d ₆ ): 1.24 (3H, q), 2.82 (2H, q), 3.02 (4H, m), 3.62 (4H, m), 3.99 (3H, s), 4.49 (2H, s), 5.28 (1H, t), 6.85 (2H, m), 7.02 (2H, m), 7.27 (4H, m) 7.45 (1H, m), 7.55 (2H, m), 7.77 (4H, m), 8.03 (2H, s), 8.09 (2H, m), 10.39 ( 1H, s)

Example 19

4- (3,5-Dimethylphenyl) piperazine-1-carboxylic acid {5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) amide

The reaction is carried out in the same manner as in Example 18 using 2-ethyl-5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and [3- (acridine- 9-yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 69.5%. Mp: 178-180 ° C.

¹ H NMR (DMSO-d ₆ ): 1.89 (3H, t), 2.28 (6H, s), 2.70 (2H, q), 3.31 (4H, m), 3.71 (4H, m), 3.99 (3H, s), 451 (2H, s), 5.28 (1H, s), 6.69 (1H, s), 6.89 (1H, s), 7 08 (1H, s), 7.53 (2H, m), 7.71 (1H, s), 7.87 (1H, s), 8.04 (3H, m), 8.18 (3H, m), 8.37 (2H, m), 10.46 (1H, s), 11.55 (1H, s), 12.28 (1H, s), 14.88 (1H, s)

Example 20

{5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-dimethoxyphenyl) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in Example 18 using 2-ethyl-5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and [3- (acridine- 9-yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 70.2%. Mp: 170-172 ° C.

¹ H NMR (DMSO-d ₆ ): 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 (1H, s), 6.02 (1H, s), 6.08 (1H, s), 6.90 (1H, s), 7.26 (2H, m), 7.34 (1H, m), 7.42 (1H, m), 7.58 (1H, s), 7.62 (2H , m), 7.75 (2H, m), 7.88 (1H, d), 8.03 (2H, m), 8.23 (2H, m), 8.37 (1H, s), 10 , 06 (1H, s)

Example 21

{5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-difluorophenyl) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in Example 18 using 2-ethyl-5 - {[4- (3,5-difluorophenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and [3- (acridine- 9-yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 68.8%. Mp: 184-186 ° C.

¹ H NMR (DMSO-d ₆ ): 1.24 (3H, t), 2.79 (2H, q), 3.31 (4H, m), 3.59 (4H, m), 3.98 (3H, s), 4.47 (2H, s), 5.19 (1H, t), 6.53 (2H, m), 6.70 (2H, d), 7.07 (1H, m) 7.38 (3H, m), 7.51 (3H, m), 8.05 (3H, m), 10.23 (1H, s), 10.93 (1H, s)

Example 22

{5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,5-dichlorophenyl) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in Example 18, using 2-ethyl-5 - {[4- (3,5-dichlorophenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and [3- (acridine- 9-yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 71.2%. Mp: 210-212 ° C.

¹ H NMR (DMSO-d ₆ ): 1.25 (3H, t), 2.83 (2H, q), 3.30 (4H, m), 3.66 (4H, m), 4.03 (3H, s), 4.53 (2H, s), 5.41 (1H, t), 6.63 (1H, s), 6.79 (3H, m), 7.11 (2H, m) , 7.23 (1H, m), 7.42 (1H, m), 7.55 (4H, m), 7.71 (1H, s), 8.09 (2H, m), 8.32 ( 1H, s), 9.74 (1H, s)

Example 23

{5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) 4- (3-fluorophenyl) piperazine-1-carboxylic acid amide

The reaction is carried out in the same manner as in Example 18 using 2-ethyl-5 - {[4- (3-fluorophenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and [3- (acridine-9- yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 72.1%. Mp: 186-188 ° C.

¹ H NMR (DMSO-d ₆ ): 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 (1H, t), 6.63 (2H, m), 6.69 (2H, m), 7.22 (4H, m) 7.33 (1H, m), 7.44 (1H, m), 7.63 (4H, m), 8.17 (2H, m), 8.37 (1H, s), 9.66 ( 1H, s)

Example 24

{5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3-hydroxyphenyl) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in Example 18 using 2-ethyl-5 - {[4- (3-hydroxyphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and [3- (acridine-9- yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 70.6%. Mp: 196-198 ° C.

¹ H NMR (DMSO-d ₆ ): 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 (1H, t), 6.28 (1H, d), 6.37 (1H, s), 6.45 (1H, d) 6.61 (1H, m), 7.04 (1H, t), 7.22 (2H, m), 7.44 (2H, m), 7.58 (1H, m), 7.71 ( 2H, m), 7.75 (1H, m), 8.06 (3H, m), 9.20 (1H, s), 10.27 (1H, s)

Example 25

{5 [3- (Acridin-9-yl-amino) -5-hydroxymethylphenylcarbamoyl] -6-ethyl-2-methoxypyridin-3-yl) amide 4- (3,4,5-trimethoxyphenyl) piperazine-1-carboxylic acid

The reaction is carried out in the same manner as in Example 18 using 2-ethyl-5 - {[4- (3,4,5-trimethoxyphenyl) piperazine-1-carbonyl] amino} -6-methoxynicotinic acid and [3- ( acridin-9-yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 66.8%. Mp: 190-192 ° C.

¹ H NMR (DMSO-d ₆ ): 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 (1H, t), 6.71 (1H, s) 6.77 (2H, s), 7.21 (2H, s), 7.35 (1H, m), 7.65 (4H, m), 7.88 (3H, m), 8.04 ( 1H, s), 8.14 (2H, m), 8.56 (1H, s), 8.92 (1H, s), 9.07 (1H, s)

Example 26

N- (3- (Acridin-9-yl-amino) -5-hydroxymethylphenyl] -5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbotionyl] amino} -2-ethyl-6-methoxynicotinamide

The reaction is carried out in the same manner as in Example 18 using 5 - {[4- (3,5-dimethoxyphenyl) piperazine-1-carbonyl] amino} -2-methyl-6-methoxynicotinic acid and [3- (acridine- 9-yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 69.8%. Mp: 176-178 ° C.

¹ H NMR (DMSO-d ₆ ): 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 (1H, s), 6.03 (1H, s), 6.05 (2H, d), 6.61 (1H, s) , 7.19 (3H, m), 7.39 (1H, m), 7.55 (2H, m), 7.72 (2H, m), 8.11 (4H, m), 9.16 ( 1H, s)

Example 27

N- (3- (Acridin-9-yl-amino) -5-hydroxymethylphenyl] -5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbotionyl] amino} -2-ethyl-6-methoxynicotinamide

The reaction is carried out in the same manner as in Example 18 using 5 - {[4- (3,5-dimethylphenyl) piperazine-1-carbotionyl] amino-2-methyl-6-methoxynicotinic acid and [3- (acridine-9 -yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 71.2%. Mp: 170-172 ° C.

¹ H NMR (DMSO-d ₆ ): 1.28 (3H, s), 2.27 (6H, s), 2.90 (2H, q), 3.28 (4H, m), 3.99 (3H, s), 4.11 (4H, m), 4.55 (2H, s), 5.39 (1H, t), 6.54 (3H, m), 6.70 (1H, s) 7.15 (2H, m), 7.32 (1H, m), 7.47 (1H, m), 7.60 (2H, m), 7.76 (2H, m), 8.02 ( 1H, s), 8.13 (2H, m), 8.42 (1H, s), 9.70 (1H, s)

Example 28

N- (3- (Acridin-9-yl-amino) -5-hydroxymethylphenyl] -5 - {[4- (3-fluorophenyl) piperazine-1-carbionyl] amino} -2-ethyl-6-methoxynicotinamide

The reaction is carried out in the same manner as in Example 18 using 5 - {[4- (3-fluorophenyl) piperazine-1-carbonyl] amino} -2-methyl-6-methoxynicotinic acid and [3- (acridine-9- yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 70.8%. Mp: 176-178 ° C.

¹ H NMR (DMSO-d ₆ ): 1.26 (3H, q), 2.87 (2H, q), 3.36 (4H, m), 3.94 (3H, s), 4.09 (4H, m), 4.46 (2H, s), 5.21 (1H, t), 6.61 (2H, m), 6.82 (2H, m), 7.26 (4H, m) 7.46 (1H, s), 7.66 (3H, m), 7.71 (1H, s), 8.05 (2H, m), 9.10 (1H, s), 10.27 ( 1H, s)

Example 29

N- (3- (Acridin-9-yl-amino) -5-hydroxymethylphenyl] -5 - {[4- (3,5-dichlorophenyl) piperazine-1-carbionyl] amino} -2-ethyl-6-methoxynicotinamide

The reaction is carried out in the same manner as in Example 18 using 5 - {[4- (3,5-dichlorophenyl) piperazine-1-carbotionyl] amino} -2-methyl-6-methoxynicotinic acid and [3- (acridine- 9-yl-amino) -5-aminophenyl] methanol to give the title compound.

Yield: 69.8%. Mp: 174-176 ° C.

¹ H NMR (DMSO-d ₆ ): 1.26 (3H, t), 2.86 (2H, q), 3.42 (4H, m), 3.93 (3H, s), 4.07 (4H, m), 4.47 (2H, s), 5.2 (1H, s), 6.54 (1H, s), 6.91 (1H, 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 ( 1H, s), 10.24 (1H, s)

The compounds obtained in the examples according to the present invention are tested for pharmacological action against tumors. The anticancer effect of the compounds is determined in vitro against 5 types of cell lines of a human tumor and 2 types of cell lines of leukemia.

Test methods and test results are as follows.

Experiment 1: In vitro antitumor activity against human tumor cell rows.

A. Cancer cell series:

A549 (not a small human pulmonary cell)

SKOV-3 (human ovarian cell)

HCT-15 (human colon cell)

XF-498 (human CNS cell)

SKMEL-2 (human melanoma cell)

B. Method: SRB Analysis

but. The cell series of a solid human tumor, A549 (non-small pulmonary cells), SKMEL -2 (melanoma), HCT-15 (large intestine), SKOV-3 (ovarian) and XF-498 (CNS) were cultured in 5% CO ₂ incubators using RPMI 1640 medium containing 10% FBS at 37 ° C, with sequential transfer of culture once or twice a week. Cell cultures were dissolved in a solution of 0.25% tryzin and 3 mmol CDTA PBS (-) to separate cells adhering to the culture medium.

b. 5x10 ³ -2x10 ⁴ cells were added to each well of a 96-cell plate and cultured in a 5% CO ₂ incubator at 37 ° C for 24 hours.

from. Each drug sample was dissolved in a small amount of DMSO and diluted with the medium used to a predetermined concentration for the experiment to reach a DMSO concentration below 0.5%.

d. The medium of each cell cultured for 24 hours, as described above in paragraph b, was removed by suction. Every 200 μl of drug samples prepared in step c was added to each well and the cells were cultured for 48 hours. Plates corresponding to Tz (time zero) were collected at the time of drug addition.

e. According to the SRB analysis method, cell fixation by TLC, manifestation with a 0.4% SRB solution, washing with 1% acetic acid and eluting the dye with 10 mmol Tris solution was carried out on Tz plates and final culture plates, and then OD values were determined at 520 nm

C. Calculation of results

but. Zero time (Tz) values were determined by measuring the SRB protein value at the time of drug addition.

b. The control value (C) was determined by the OD value of the untreated cell.

from. The value of the drug-treated sample (T) was determined by the OD value of the drug-treated cell.

d. The effects of drugs were determined by stimulation of growth, inhibition of net growth and net killing, calculated by the values of Tz, C and T.

e. If T ≥ Tz, the cell response function was calculated by the equation 100x (T-Tz) / (C-Tz), and if T <Tz, then by the equation 100 (T-Tz) / Tz. The results are presented in the following table 1.

* LINKS

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

The compounds of the present invention were found to have an equal or superior antitumor effect of ED ₅₀ (mg / ml) compared to cisplatin, a control drug against cell series of solid human cancer.

Table 1
ED ₅₀ (μg / ml) Project 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

Experiment 2: In vitro antitumor activity against animal leukemia cells.

A. Material:

Tumor Cell Rows: P388 (Mouse Neoplasm Lymphoid Cells)

B. Method: Dye exclusion assay

1) The concentration of P388 cells cultured in RPMI 1640 medium containing 10% FBS was adjusted to 1x10 ⁶ cells / ml.

2) Each drug sample with a concentration diluted with respect to the log dose is added to the cell culture medium, cultured at 37 ° C for 48 hours in a 50% CO ₂ incubator, and then the degree of exclusion of the dye using trypan blue is determined.

3) Determine the concentration of the sample of each compound, showing 50% inhibition of cell growth (IC ₅₀ ) compared with the control, and are presented in table 2 below.

* LINK

1) R. Skehan, R. Strong, D. Scudiero, A. Monks, J.B. Mcmahan, D.T. Vistica, J. Warren, H. Bokesch, 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, J.B. Mcmahan, D.T. Vistica, J. Warren, H. Bokensch, S. Kenney and M.R. Boyd .: J. Natl. Cancer Inst. 82, 1107 (1990).

C. Results

As a result of measurements of the antitumor effect of IC ₅₀ (mg / ml) against mouse cancer cells P388 of the compounds of the present invention, it was found that the tested compounds have an equal or higher anti-cancer effect than the control drug compounds, mitomycin C.

table 2 Project No. .; P388 (mg / ml) 2 0.3 3 1,0 four 0.9 9 0.4 16 0.3 Mitomycin c 1,1

Experiment 3: in vivo anti-cancer effect against mouse leukemia cells P388

A. Experiment Material

Used BDF1 mice.

B. Method of experiment

1) P388 leukemia cells cultured sequentially with transfer of culture to DBA / 2 mice were inoculated into each group of mice, including 8 BDF1 mice 6 weeks old, at a dose of 1 x 10 ⁶ cells / 0.1 ml.

2) The drug samples are dissolved in PBS or suspended in a 0.5% tween 80 solution, and then injected into the abdominal cavity of the mouse with each given concentration on day 1, 5, 9, respectively.

3) During daily observation, determine the survival time of experimental mice. The anticancer effect is determined in such a way that the increasing ratio (T / C%) of the average survival days of the drug-treated groups compared to the control group is calculated using the average survival time of each of the test groups.

The results are presented below in table 3.

Table 3 Etc. No. Dose (mg / kg) MST (days) T / C (%) one hundred 22.0 200,0 2 fifty > 60.0 > 545.5 25 > 60.0 > 545.5 one hundred 11.6 100.0 3 fifty > 60.0 > 545.5 25 17.0 154.5

Experiment 4. Acute toxicity test (LD ₅₀ ):

a) Test method: Litchfield-Wilcoxon method

6-week-old ICR mice (males, 30 ± 2.0 g) were freely fed with solid food and water at room temperature, 23 ± 1 ° C, and relative humidity of 60 ± 5%. Drug samples were injected into the abdominal cavity of mice. Each group included 6 mice. When observing for 14 days, an assessment was made of the appearance, lifespan, or death of animals, and the visible lesions of dead mice during preparation were recorded. LD ₅₀ values were calculated by the Litchfield-Wilcoxon method.

b) Results

As shown in the table below, the compounds of the present invention are predominantly safe compared to cisplatin, and many problems associated with the use of known compounds, such as dose limitation, undesirable side effects due to toxicity, etc., can be significant degrees are overcome.

Table 4 Etc. No. LD ₅₀ (mg / kg) ip iv 2 80 3 80 Cisplatin 9.7

Industrial applicability

As described above, the compounds of the present invention are significantly safer and also have a significantly superior antitumor effect compared to known anticancer drugs, and therefore it is expected that the compounds of the present invention can be used as a new antitumor drug.

Claims (2)

1. Derivatives of 9-aminoacridine of General formula (I)

where Y is a bond or group

where X is oxygen or sulfur, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ independently mean hydrogen, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, R 'and R "independently C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; and Z is C ₁ -C ₄ alkoxy, or pharmaceutically acceptable salts thereof. 2. A method for producing compounds of general formula (I) according to paragraph 1 or their pharmaceutically acceptable salts, comprising reacting a compound of general formula (a) with a compound of general formula (b) to obtain a compound of general formula (I) and, if necessary, converting a compound of general formula (I) in its pharmaceutically acceptable salt

where R ₁ , R ₂ , R ₃ R ₄ , R ₅ , R ', R'', X, Y and Z are as specified in claim 1, a Y ₁ means hydrogen or a group