JP2001512104A - Bis-acridine carboxamide with antitumor activity - Google Patents

Abstract

  (57) [Summary] The present invention relates to bis-acridinecarboxamides and their derivatives substituted with aminoalkyl chains, and has clearly demonstrated significant antitumor activity, especially in colon tumors.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to bis-acridinecarboxamides and their derivatives substituted with aminoalkyl chains.

[0002] The compounds have clearly demonstrated marked antitumor activity, especially in colon tumors.

[0003]

[Prior art]

Treatment of solid tumors is an open question for anticancer therapy. The search for novel molecules that can treat solid tumors has led to the finding that tumor cells become resistant to a number of anticancer drugs (multidrug resistance, MDR), and that drugs have become more susceptible to tumor masses with poorly developed blood vessels. Hindered by a number of factors, such as difficulty in reaching.

A number of compounds currently in preclinical or clinical development or already used in anti-cancer therapy, such as mitoxantrone or doxorubicin, are DN
A belongs to a broad family of intercalating molecules. Although these molecules share a tri- or tetracyclic planar structure, they often belong to completely different classes with different physicochemical and biological properties.

[0005] The nature of the substituents and aromatic rings in the backbone is important because often slight structural changes give analog compounds a completely different biological behavior. Indeed, for example, the change from anthracenedione to the corresponding benzo [g] isoquinoline-5,10-dione is not less than that of the carbocyclic analog, but retains the same antitumor activity while maintaining cardiotoxicity. It is known to produce a reduction (Krapcho, P .;
WO 92/15300; Krapcho et al., US 5,587,382).

However, the molecules currently used in therapy induce the described multidrug resistance,
Therefore, they limit their effective use in long-term treatment.

Another known class of DNA intercalating agents comprises acridine [At
well G. J. J. et al. Med. Chem. , 30, 664-9 (1987).
Bagley B.). C. Et al., Cancer Chemother. and
Pharmacol. Atwell G., 36, 244-8 (1995);
J. J. et al. Med. Chem. , 27, 1481-5 (1984); Rewc.
astle G. W. J. et al. Med. Chem. , 29, 472-7 (198
6); A. J. et al. Med. Chem. , 30, 658-66
3 (1987); Wakelin L. et al. P. G. FIG. J. et al. Med. Chem. ,
30, 855-861 (1987)].

[0008] Examples of bis-imidazoacridones having antitumor activity are known in the literature [Cholody W. et al. M. J. et al. Med. Chem. , 38, 3043-
52 (1995); Hernandez L .; Et al., Cancer Res. , 5
5, 2338-45 (1995)]. However, even within the same kind of molecule,
As the authors themselves suggest, slight structural modifications in bifunctional agents can dramatically affect their activity and selectivity.

We have now found a new class of bis-acridine derivatives that show significant antitumor activity, mainly in solid tumors such as colon tumors, as compared to prior art compounds. In particular, the novel bifunctional derivatives are acridine, acridone, pyrazole-acridone, pyrimido-acridone and pyrazole-pyrimidoacridone in which they possess an alkylamino side chain in the para position to the polyamino chain connecting the two units. It is characterized by having a system.

[0010]

DISCLOSURE OF THE INVENTION

The present invention has the general formula (I): A-NH- Z-NH-A ' formula: - Z is (C ₂ -C ₄₎ alkylene chain or formula _{(CH 2) n -N (B} ) - (CH 2 _{) q -N (B ') -} (CH 2) m - (CH 2) n -N
(B) -X- (CH ₂₎ a group of _m, where, - n and m are integers from 2 independently up to 4, - B is hydrogen or (C ₁ -C ₄₎ - alkyl and a, - X is a single bond or the formula - '- a group, wherein, - q is an integer from 2 to 4, and _{B (CH 2) p -N (} B)' is hydrogen or ( C ₁ -C ₄ ) alkyl,-the same or different A and A ′ are:

[0011]

Embedded image

Wherein: R is hydrogen or linear or branched (C ₁ -C ₆ ) alkyl, —OH, —
_{NH 2, (C 1 -C 4} ) alkoxy, mono - and di - (C ₁ -C ₄₎ alkylamino, chlorine, bromine, iodine and fluorine, nitro, mono- - and poly - fluoro (C ₁ - C ₄₎ alkyl, (C ₁ -C ₄₎ alkylsulfonyl, (C ₁ -C ₄₎ alkylamino same or different one is selected from Nosuruhoniru or more substituents; - Y is - (CH _{2) p} - It is a T group; - p is an integer 2, 3 or 4; - T is -NH _2, -OH, mono- - or di - (C ₁ -C ₄₎ alkylamino, hydroxyaldehyde ethylamino, N- morpholinyl , N-piperazinyl, N-thiomorpholinyl, N-pyrrolidinyl, N-piperidinyl, a possible stereoisomer or a mixture of stereoisomers, and pharmaceutically acceptable acids and salts thereof. To.

Another object of the present invention is a process for preparing a compound of formula (I).

It is a further object of the present invention to provide formulations containing an effective dose of at least one compound of formula (I) in admixture with pharmaceutically acceptable excipients and formula (I) as anticancer agents
)) Use of the compound and related preparations.

Preferred compounds of formula (I) are those wherein n and m are the integer 3.

Particularly preferred compounds are those in which A = A ′ is a group of formula (b), (c) or (e).

Most preferred compounds are those in which B is a methyl group.

Preparation of Compounds of the Invention Compounds of formula (I) wherein A = A 'is a group of formula (b) (hereinafter compound (I)-(b
Formulas (I)-(a), (I)-(c), (I)-(d), (I)-
(E) and (I)-(f) are similarly defined) can be prepared according to the synthetic scheme reported in FIG. 1, which includes the following synthetic steps. (1) One equivalent of the polyamine of the formula (II) is reacted with 2 equivalents of the acridone of the formula (III) to give a compound of the formula (IV). In the presence of a condensing agent such as dicyclohexylcarbodiimide or for example imidazolide (by reaction with 1,1'-carbonyldiimidazole), mixed anhydride (by reaction with ethyl chloroformate in the presence of triethylamine) or N The reaction can be carried out after activation of the carboxyl group of the intermediate of formula (III) with -hydroxysuccinimide ester (by reaction with N-hydroxysuccinimide in the presence of morpholinoethyl isonitrile). (2) at a temperature of up to 0.99 ° C. in the presence of a base such as triethylamine, a dimer obtained in at least 2 equivalents of a step of an amine of the formula Y-NH ₂ in a solvent such as ethoxyethanol (1) To give compounds of formula (I)-(b). Compounds of formula (I)-(d) can be obtained according to the synthetic scheme reported in FIG. 2, which can be obtained in a solvent such as ethoxyethanol at a temperature of up to 150 ° C. in the presence of a base such as triethylamine. even without least hydrazine of formula Y-NH-NH ₂ comprising reacting a compound of 2 equivalents of the formula (IV).

The compounds of formulas (I)-(c) can be prepared according to the synthetic scheme reported in FIG. 3, which can be prepared in the presence of a base such as triethylamine at temperatures up to 150 ° C., such as ethoxyethanol. Reacting one equivalent of the polyamine of formula (II) with at least two equivalents of the intermediate of formula (V) in a suitable solvent.

The compounds of formulas (I)-(a) are prepared according to the synthetic scheme reported in FIG. 4 by reducing the corresponding compounds of formulas (I)-(c) with aluminum amalgam in ethanol / water. be able to.

The compounds of (I)-(e) can be prepared according to the synthetic scheme reported in FIG. 5, which comprises the following synthetic steps: (3) preferably ranging from 0 ° C. to room temperature Reacting the intermediate of formula (V) with phosgene in a solvent in the presence of a base such as triethylamine at a temperature of to give an intermediate of formula (VI); (4) Reaction of one equivalent of the polyamine of formula (II) with at least two equivalents of the intermediate of formula (VI) in a solvent such as ethoxyethanol at a temperature up to 150 ° C. in the presence of the compound of formula (I)-(e ).

The compounds of formulas (I)-(f) can be prepared by reducing the compounds of formulas (I)-(b) with aluminum amalgam in ethanol / water.

For example, a compound of formula AW wherein A is as defined above and W is a halogen atom or a carboxy activating group and a compound of formula NH ₂ when Z is as defined above the first condensation between diamine -Z-NH _2, followed by the compound of the formula A'-W of the first case of the products obtained from the reaction with a 'and W are as defined above To produce compounds of formula (I) wherein A and A 'differ according to a reaction sequence comprising a second reaction between

Usually, the first reaction is carried out in a solvent such as 2-ethoxyethanel, ethanol, methanol, ethyl acetate, dimethylsulfoxide, dimethylformamide using at least a 1: 2 excess of the diamine compound.

The intermediates of formulas (III) and (V) can be prepared according to the synthetic scheme reported in FIG. 6, which comprises the following synthetic steps: (5) in the presence of copper or its salts To condense 5-chloro-2-carboxyaniline (or the corresponding methyl carboxylate) and 2-halocarboxylic acid in a basic medium. Examples of such reactions are the use of copper acetate or the use of copper and alkali metal carbonates in the presence of a tertiary amine. Preferably, the reaction is performed in a solvent such as an alcohol or a dipolar aprotic solvent. Preferred solvents are N-methylpyrrolidone and isopentyl alcohol. (6) cyclizing the intermediate obtained in (5) to give about a 2: 1 ratio of 1-chloro-9-oxo-9,10-dihydroacridine-4-carboxylic acid and 6-chloro-9-oxo This gives a mixture of isomers of -9,10-dihydroacridine-4-carboxylic acid (or the corresponding methyl carboxylate). The cyclization is carried out in the presence of a condensing agent such as polyphosphoric acid or phosphorus oxychloride, the latter preferably in the presence of a solvent such as an aromatic hydrocarbon. (7) Basically hydrolyzing any methyl carboxylate obtained in (6) to obtain a compound of formula (II)
Generates the corresponding acid of I). (8) (6) or (7) the acid derivative obtained in engaged appropriate amine and condensation of the formula H ₂ N-Y give rise to intermediates of formula (V). In the presence of a condensing agent such as carbodiimide, or for example, imidazolide (by reaction with carbonyldiimidazole)
The reaction can be carried out after activation of the carboxyl group by formation of an acid chloride (by reaction with thionyl chloride) or hydroxysuccinimide ester (by reaction with N-hydroxysuccinimide in the presence of morpholinoethyl isonitrile). .

If the group Y present on the amine or hydrazine used in the above synthesis contains, in turn, primary and secondary amino groups or hydroxy groups, the usual reaction with a protecting group allows the condensation reaction to proceed. Protect these before. After the condensation reaction, the protecting group is removed.

Examples of protection and deprotection reactions of primary and secondary amine protecting groups and alcohol protecting groups are described in Green, T .; W. Wuts, P .; G. FIG. M. , "Protective
e Groups in Organic Synthesis ", 2nd edition, J
ohn Wiley & Sons, 1991.

The polyamines of the formula (II) are generally known compounds, for example those disclosed in the previously cited Cholody W. et al. M. J. et al. Med. Chem. , 38, 3043-
52 (1995) and Hernandez L. et al. Et al., Cancer Res. ,
55, 2338-45 (1995), which are incorporated herein by reference.

Deprotection of a protecting group, such as the conversion of a compound of formula (I) with R = methoxyl to a compound with R = hydroxyl by cleavage reaction under acidic conditions (48% hydrobromic acid) Or, for example, when R is a nitro group, the compound of formula (I) obtained by reduction to an amine by reductive alkylation and subsequent functionalization of the amine or by reaction with an alkylsulfonyl chloride is obtained. Formula (I
) Can be converted into other compounds, which are also included within the meaning of formula (I).

Further, the reaction of a free base with a pharmaceutically acceptable acid, preferably hydrochloric acid, yields the formula (
The compound of I) may be changed to a salt.

Biological Activity of Compounds of the Invention Compounds of the invention were tested for their antitumor activity against human HT29 cell line of colon adenocarcinoma. The cells are incubated with the test compound for 144 hours, then "
MTT Assay "(Mosman, T." Rapid Colorimetry "
c Assay for Cellular Growth and Surv
ival: Application to Proliferation an
d Cytotoxicity Assay "; Immunol. Meth
ods, (1983), 65, 66-63; Green, L .; M. , "Rapi
d Colorimetric Assay for Cell Viabil
application; Application to the Quantitation
of Cytotoxic and Growth Inhibitory L
ymphokines ", J.M. Immunol. Methods, (1984)
, 70, 257-268) was used to evaluate cytotoxicity. The result was determined as IC ₅₀ (μg
/ Ml), ie, the concentration of test compound that causes 50% death of the cell population.

Data for some representative compounds of the invention are reported in the table.

[0033]

[Table 1]

The data reported in the tables clearly show that the compounds of the invention have comparable, if not higher, activity than mitoxantrone.

The compounds of formula (I), at a dose ranging from the body area m ² per 1mg to 1200 mg, when administered to humans and animals bearing tumors sensitive to treatment with DNA intercalating agents , Can induce regression of the above tumors.

The expert clinician will be able to determine the effective dose of the compounds of the present invention in the usual manner known.

The relationship between doses used in animals of various species and those in humans (based on mg / m ² body area) is described in Freirich, E. et al. J. Etc., Cancer Chemot
her. Rep. , 50, n. 4, 219-244, May 1966.

Tumors that can be treated with the compounds of the present invention are those that are susceptible to treatment with a DNA intercalating agent.

In particular, colon tumors can be conveniently treated.

The present invention comprises a pharmaceutical composition containing a compound of formula (I). These pharmaceutical compositions can contain any amount of a compound of formula (I) that can exert antitumor activity on a tumor susceptible to treatment with a DNA intercalating agent in a mammal.

The pharmaceutical composition may be in liquid or solid form, and may be administered by any route, such as oral, parenteral, intravenous, intradermal, subcutaneous or topical, so that at least one of the formula (I) can be administered. In addition to the compound, a pharmaceutically compatible excipient can be included.

The route of administration of the compounds of formula (I) is oral. Oral compositions typically include an inert diluent or an edible carrier. They can be included in gelatin capsules or compressed into tablets. Other forms for oral administration are capsules, pills, elixirs, suspensions or syrups.

Tablets, pills, capsules and similar compositions comprise (in addition to the active ingredient) the following ingredients:
Microcrystalline cell lineulose
Excipients such as starch or lactose; disintegrants such as alginic acid, primogel, corn starch, etc .; lubricants such as magnesium stearate; fluids such as colloidal silicon dioxide. Agents may include sweeteners such as sucrose or saccharin or flavors such as mint essence, methyl salicylate or orange flavor. When the selected composition is in the form of a capsule, it may additionally contain a liquid carrier such as a fixed oil. Other compositions may contain various materials that modify their physical state, for example, coatings (for tablets and pills) such as sugars or shellac. The materials used in preparing the compositions are pharmaceutically pure and non-toxic at the dosages employed.

For the preparation of pharmaceutical compositions for parenteral administration, the active ingredient can be incorporated into a solution or suspension, which contains the following ingredients: water for injection, saline, oil, Sterile diluents such as polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminotetraacetic acid Agents; may include buffers such as acetate, citrate or phosphate and agents for adjusting the tonicity of the solution such as sodium chloride or dextrose. Parenteral preparations can be enclosed in glass or plastic ampules, single dose syringes or vials.

The following examples further illustrate the present invention.

Production 1-1-Chloro-7-nitro-9-oxo-9,10-dihydroacridine-4-carboxylic acid 2-amino-4-chlorobenzoic acid (7 g), 2-chloro-5-nitrobenzoic acid The acid (7 g), potassium carbonate (7 g) and copper powder (0.25 g) are suspended in 150 ml of isopentyl alcohol. After refluxing the reaction mixture under stirring for about 20 minutes, an orange-red mass precipitates. The reaction is continued for 4-5 hours, then 150 ml of 1M
An aqueous potassium carbonate solution is added and the insoluble material is filtered off while hot. The aqueous phase was separated and acidified to pH 5 with 2M hydrochloric acid to precipitate the product, which was filtered, suspended in boiling methanol (100 ml), filtered and resuspended in boiling water (200 ml), Filter again and wash with ethanol.

The dibasic acid obtained is dissolved in xylene (55 ml), 55 ml of phosphorus oxychloride are added and refluxed for 2 hours. After cooling, the precipitate was filtered, suspended in boiling methanol, filtered, washed with ethyl ether and dried to give about a 2: 1 ratio of 1-chloro-7-nitro-9-oxo-9, 5.8 g of a mixture of 10-dihydroacridine-4-carboxylic acid and 6-chloro-2-nitro-9-oxo-9,10-dihydroacridine-4-carboxylic acid are obtained.

Production 2--2- (5-chloro-2-methoxycarbonyl-phenylamino)
5-Methoxybenzoic acid Methyl 2-amino-4-chlorobenzoate (0.8 g) in 5 ml N-methylpyrrolidone and 10 ml N, N-diisopropylethylamine, 2-bromo-
A suspension of 5-methoxybenzoic acid (1 g) and copper (II) acetate monohydrate (0.86 g) is heated with stirring at 160 ° C. for 6 hours. After cooling, diluting with water and acidifying to pH 2, a solid separates, which is collected by filtration and dried. The solid is then suspended in ethyl ether under stirring and filtered to give 0.75 g of product, m.p. p.
176-177 ° C. are obtained (crystallized from methanol).

¹ H-NMR in d ₆ -DMSO: 3.80 ppm (s, 3H); 3.88
ppm (s, 3H); 6.87 ppm (d, 1H); 7.03-7.21 ppm
(M, 2H); 7.33-7.57 ppm (m, 2H); 7.89 ppm (d,
1H); 10.42 ppm (s, 1H); 11.29 ppm (brs, 1H).

Preparation 3-1 Methyl 1-chloro-7-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylate 1 g of 2- (5-chloro-2-methoxycarbonylphenylamino) -5-methoxy The benzoic acid is refluxed in 50 ml of chloroform until PPE (40 g) and all solids are dissolved. The chloroform is evaporated off to give an oil, which is heated to 100 ° C. for 1 hour. The mixture is carefully diluted with 5 ml of methanol and 10 ml of water, then extracted with chloroform (3 × 20 ml). The combined organic extracts are dried and the residue is flash chromatographed on silica gel (
Eluent: chloroform / benzene, purified by 3: 2) 0.58 g of product,
m. p. 219-220 ° C are obtained.

¹ H-NMR in CDCl ₃ : 3.92 ppm (s, 3H); 4.01 pp
m (s, 3H); 7.20 ppm (d, 1H); 7.25-7.33 ppm (m
11.2 ppm), 7.81 ppm (m, 1H); 8.24 ppm (d, 1H);
10 ppm (s, 1H).

Preparation 4-1 Methyl 1-chloro-6,7-dimethoxy-9-oxo-9,10-dihydroacridine-4-carboxylate 1-methyl-2-pyrrolidinone (5 mL) and N, N-diisopropylethylamine ( Methyl 2-amino-4-chlorobenzoate (0.7 g, 3 g in 10 mL).
. 83 mmol), commercially available 2-bromo-4,5-dimethoxybenzoic acid (
1 g, 3.83 mmol) and Cu (OAc) ₂ .H ₂ O (0.77 g, 3.83 g)
(mmol) at 160 ° C. for 8 hours. After cooling, diluting with water and acidifying to pH 2, the collected precipitate is stirred with hot MeOH and then with Et ₂ O, filtered and dried. The resulting solid (0.32 g) is refluxed in CHCl ₃ (25 mL) until PPE (15 g) and all solids are dissolved. The reflux condenser is removed and the CHCl ₃ is evaporated off to give an oil, which is heated at 100 ° C. for 1 hour. After cooling, the mixture is carefully diluted with MeOH (5 mL) and water (50 mL), and then extracted with CHCl ₃ (3 × 20 mL). The concentrated chloroform extract is chromatographed on silica gel using CHCl ₃ / C ₆ H ₆ (9: 1 v / v) to give the title product (0.19 g, 63.3%):
_{C 17 H 14 ClNO 5; m} . p. 277-278 ° C; ¹ H-NMR (CDCl ₃ ) δ 3.95-4.00 (m, 6H, 2 x O-CH ₃ ), 6.70 (s, 1H, ar), 7.18 ( d, 1H, ar), 7.75 (s, 1H, ar), 8.20 (
d, 1H, ar), 12.04 (brs, 1H, 10H, ex).

Preparation 5-1-chloro-7-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid 1-chloro-7-methoxy-9 in 100 ml of ethanol and 100 ml of 2M sodium hydroxide A suspension of methyl-oxo-9,10-dihydroacridine-4-carboxylate (1 g) is refluxed for 30 minutes. The reaction mixture is acidified with 4M hydrochloric acid and stirred at room temperature for 20 minutes. The precipitate was collected by filtration and washed with water, methanol and ethyl ether to give 0.72 g of pure product, m.p. p. 340-34
Obtain 1 ° C.

¹ H-NMR in d ₆ -DMSO: 3.89 ppm (s, 3H); 7.28
ppm (d, 1H); 7.43 ppm (m, 1H); 7.59 ppm (d, 1H)
); 7.75 ppm (d, 1H); 8.30 ppm (d, 1H); 12.35p
pm (s, 1H).

Preparation 6-1-Chloro-6,7-dimethoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid The ester prepared in Preparation 4 (0.7 g, 2.01 mmol) was treated with EtOH.
(70 mL) and 2M NaOH (70 mL) and heat under reflux for 30 minutes. After cooling, the resulting mixture was acidified with 4M HCl and stirred at room temperature for 20 minutes; the precipitate was collected, washed with water, MeOH and Et ₂ O to give the crude title compound (0.5 g, 74.6). %) Which is used in the next step without further purification.

Preparation 7 4- [N- [3- (dimethylamino) propyl]]-carboxamide-1-chloro-9-oxo-9,10-dihydroacridine 1 g of (Rewcastle et al., Synt.
a mixture of 1-chloro-9-oxo-9,10-dihydroacridine-4-carboxylic acid and 1.1 g of 1,1'-carbonyldiimidazole is obtained, if necessary. Stir with heating until completely dissolved. The mixture is cooled to 10 ° C. and 1.02 g of 3-dimethylaminopropylamine are added. After 15 minutes at room temperature, the mixture is partitioned between chloroform and 1M sodium carbonate. The organic phase is worked up to give the product, which is ethyl ether (0
. 86 g) solidifies upon treatment with m. p. 150-151 ° C.

¹ H-NMR in CDCl ₃ : 1.85 ppm (m, 2H); 2.38 pp
m (s, &H); 2.63 ppm (t, 2H); 3.60 ppm (q, 2H);
7.16 ppm (d, 1H); 7.22-7.38 ppm (m, 2H); 7.5
9-7.60 ppm (m, 2H); 8.40 ppm (dd, 1H); 8.57p
pm (s, 1H); 13.14 ppm (s, 1H).

The following compounds are prepared analogously: 4- [N- [2- (dimethylamino) ethyl]] carboxamide-1-chloro-7-methoxy-9-oxo-9,10-dihydroacridine, m . p. 1
70-172 ℃, ¹ H-NMR in _{CDCl 3: 2.43ppm (s, 6H} )
2.76 ppm (t, 2H); 3.65 ppm (q, 2H); 3.93 ppm
(S, 3H); 7.19 ppm (d, 1H); 7.25-7.34 ppm (m,
2H); 7.62 ppm (brs, 1H); 7.78-7.89 ppm (m, 2H); 12.77 ppm (s, 1H); 4- [N- [2- (tert-butoxycarbonylamino) ) Ethyl]] carboxamide-1-chloro-9-oxo-9,10-dihydroacridine, m.p.
p. 212-213 ° C., ¹ H-NMR in d ₆ -DMSO: 1.42 ppm (
s, 9H); 3.25 ppm (t, 2H); 3.38 ppm (t, 2H);
7.28-7.42 ppm (m, 2H); 7.60-
7.82 ppm (m, 2H); 8.08-8.25 ppm (m, 2H); 9.0
2 ppm (t, 1H); 12.80 ppm (s, 1H).

Preparation 8-4- {N- [2- (dimethylamino) ethyl] -carbamoyl}
-1-chloro-6,7-dimethoxy-9-oxo-9,10-dihydroacridine: m.p. p. 221-222 ° C; ¹ H-NMR (CDCl ₃ ): δ 2.35 (s,
_{6H, 2 x CH 3),} 2.60 (t, 2H, CH 2), 3.50-3.60 (m
_{, 2H, CH 2), 4.00-4.01} (m, 6H, 2 x O-CH 3), 6.7
1 (s, 1H, ar), 7.18 (d, 1H, ar), 7.30 (br s, 1H, CO-NH, ex), 7.68 (d, 1H, ar), 7. 80 (s, 1H,
ar), 12.72 (br s, 1H, 10-H, ex).

Preparation 9-4- [N- [2- (dimethylamino) ethyl]]-carboxamide-1-chloro-7-nitro-9-oxo-9,10-dihydroacridine hydrochloride Cooled to 0 ° C. 1-Chloro-7-nitro-9-oxo-9,10-dihydroacridine-4-carboxylic acid and 6-chloro-2-nitro-9-oxo-9,10-dihydroacridine in 30 ml of stirred chloroform. Mixture of isomers of -4-carboxylic acid (1 g of mixture; Preparation 1) and triethylamine anhydride (0.31
To 4 g) is added dropwise a solution of ethyl chloroformate (0.34 g) in 20 ml of chloroform. After 1 hour with stirring at room temperature, the mixture was cooled to 0 ° C and N, N-
Dimethylethylenediamine (0.32 g) is added and then kept under stirring at room temperature overnight. The precipitated solid is filtered, washed with methanol, chloroform and finally with ethyl ether, to give 0.58 g of product, m.p. p. 295-297 DEG C. are obtained (crystallized from methanol).

¹ H-NMR in d ₆ -DMSO: 2.88 ppm (s, 6H); 3.34
ppm (t, 2H); 3.75 ppm (q, 2H); 7.33 ppm (d, 1H
); 7.90 ppm (d, 1H), 8.30 ppm (d, 1H); 8.49 pp
m (dd, 1H); 8.93 ppm (d, 1H); 9.47 ppm (t, 1H)
10.03 ppm (brs, 1H); 11.03 ppm (brm, 1H).

Preparation 10-6-Chloro-2- [3- (dimethylamino) propyl] pyrimido [5,6,1- de ] acridine-1,3,7-dione While maintaining the temperature at 0 ° C., 20 ml of A mixture of chloroform and 1-chloro-4- [N- [3- (dimethylamino) propyl]] carboxamide-9-oxo-9,10-dihydroacridine (0.33 g) in 1 ml of triethylamine in 10 ml of chloroform Of phosgene (2 ml of a 20% solution in toluene) is added dropwise. Upon completion of the addition, the mixture is stirred at room temperature for 20 minutes, then the reaction mixture is partitioned between chloroform and 1M sodium carbonate. The organic phase is worked up to give a residue, which is separated by chromatography on a silica gel column (eluent chloroform / methanol 19: 1), 280 mg of product, m.p. p
. 212-214 ° C (dec).

¹ H-NMR in CDCl ₃ : 2.31-2.51 ppm (m, 2H); 2
. 85 ppm (s, 6H); 3.20 ppm (t, 2H); 4.35 ppm (t
7.47-7.80 ppm (m, 3H); 8.28-8.60 ppm
(M, 3H).

Preparation 11-6-chloro-2- [2- (dimethylamino) ethyl] -9-me
Toxi-1,3,7-trioxo [1H, 2H, 3H, 7H, 12H] pyrimido
[5,6,1-deAcridine CHCl_Three4- {N- [2- (dimethylamino) ethyl]} carboxamide-1-chloro-7-methoxy-9-oxo-9,10-dihydro in (10 ml).
Acridine (700mg) and Et_ThreeCHCl in a solution of N (2 ml)_Three(10ml
COCl in)_Two(20% in toluene, 3.7 ml) are added dropwise at 0 ° C. When the addition is complete, the mixture is stirred at room temperature for 20 minutes. The reaction mixture is CHCl _Three And 1M Na_TwoCO_ThreeDistribute between. The organic phase is worked up to give a residue, which is ethyl
Suspend in ether (20 ml), stir for 10 minutes, then filter to 620 mg
Which was slightly impure by TLC and used as such for the next reaction
, Converted to the hydrochloride salt for characterization: m. p. > 300 ° C (crystallized from EtOH
);¹H-NMR (DMSO-d₆): 2.90 ppm (s, 6H), 3
. 43-3.56 ppm (m, 2H), 3.95 ppm (s, 3H), 4.42
ppm (t, 2H), 7.50 ppm (d, 1H), 7.64 ppm (s, 1H
), 7.78 ppm (d, 1H), 8.43 ppm (d, 1H), 8.54 pp
m (d, 1H), 10.16 ppm (brs, 1H).

Preparation 12-6-Chloro-2- [2- (dimethylamino) ethyl] -9,1
4- ｛N- [2- (dimethylamino) in 0-dimethoxy-pyrimido [5,6,1- de ] acridine-1,3,7-trione CHCl ₃ (10 mL) and anhydrous triethylamine (0.5 mL) Ethyl] carbamoyl} -1-chloro-6,7-
Dimethoxy-9-oxo-9,10-dihydroacridine (0.2 g, 0.49
solution COCl ₂ (20% in toluene in CHCl ₃ (10 mL) in mmol),
1.26 mL, 2.52 mmol) are added dropwise at 0 ° C. with stirring. The resulting mixture is stirred at room temperature for 30 minutes, then partitioned between CHCl ₃ and 1M aqueous Na ₂ CO ₃ . The organic phase is worked up to give a residue, which is CHCl ₃ / CH ₃ OH (19: 1
Purification by column chromatography on silica gel using (v / v) gives the title product (0.14 g, 66.7%): C ₂₁ H ₂₀ ClN ₃ O ₅ ; p. 21
4-215 ° C; ¹ H-NMR (CDCl ₃ ) δ 2.35 (s, 6H, 2xCH ₃ ), 2.70 (t, 2H, CH ₂ ), 4.00-4.03 (m, 6H, 2 _{x O- CH 3), 4.34 (} t, 2H, CH 2), 7.57 (d, 1H, ar), 7.7
4 (s, 1H, ar), 8.15 (s, 1H, ar), 8.40 (d, 1H, a
r).

Production 13 −N4-[2- (dimethylamino) ethyl] -1-({3- [(3-aminopropyl)-(methyl) amino] propyl} -amino) -9-oxo
So-9,10-dihydro-4-acridinecarboxamide 2-Jethoxyethanol (10 mL). Med. Chem. , 1995
, 38, 3282-3286, 1-chloro-N-4- [2- (dimene).
Tylamino) ethyl] -9-oxo-9,10-dihydro-4-acridinecal
Boxamide (0.3 g, 0.97 mmol), 3,3'-diamino-N-Methyl
Dipropylamine (0.32 mL, 1.96 mmol) and triethylamine (
(0.5 mL) is stirred at 80 ° C. for 24 hours. After cooling, the mixture was cooled to CH
Cl_ThreeAnd 1M Na_TwoCO_ThreePartition between water. Treat the organic layer to get a residue, which
CHCl_Three/ MeOH (1: 1 v / v) and 32% NH_ThreeWater (2 per liter of eluent)
0mL) and purified by column flash chromatography on silica gel
To give the title product as an oil (0.22 g, 50%): C_{twenty five}H₃₆N₆O_Two; ¹ H-NMR (CDCl_Three) Δ 1.48-1.65 (m, 2H, CH_Two) 1.7 2-1.92 (m, 2H, CH_Two), 2.15 (s, 3H, CH_Three), 2.22 (
s, 6H, 2 x CH_Three), 2.28-2.52 (m, 6H, 3 x CH_Three), 2
. 68 (t, 2H, CH_Two), 3.15-3.28 (m, 2H, CH_Two), 3.4
0-3.51 (m, 2H, CH_Two), 6.10 (d, 1H, ar), 7.00 (brt, 1H, CO-NH, ex), 7.15 (t, 1H, ar), 7.28 (d, 1H, ar). , 7.50 (d, 1H, ar), 7.60 (t, 1H, ar), 8.25 (d, 1H)
H, ar), 10.87 (br t, 1 H, ex), 13.39 (br s, 1 H
, Ex).

Example 1 -1,7-bis (1-chloro-9-oxo-9,10-dihydroacridine-4-carbonyl) -4-methyl-1,4,7-triazaheptane 1-chloro- 9-oxo-9,10-dihydroacridine-4-carboxylic acid (
(500 mg) in CHCl ₃ (20 ml), add Et ₃ N (0.26 ml), cool to 0 ° C., then add a drop of ClCOOEt (0.26 ml) in CHCl ₃ (10 ml). Add each. The mixture is stirred at room temperature for 1 hour, cooled again to 0 ° C., N ² -methyldiethylenetriamine (0.12 ml) is added and stirred at room temperature for 4 hours. The precipitate obtained is filtered, treated with boiling MeOH (20 ml),
230 mg of product, m.p. p. > 300 ° C .; ¹ H-NMR (DMSO-d ₆ ) 2.80-3.11 ppm (m, 7H), 3.53-3.75 ppm (m, 4
H), 7.09 ppm (d, 2H), 7.35 ppm (d, 2H), 7.52 p
pm (t, 2H), 8.00-8.11 ppm (m, 4H), 9.20 ppm (
brt, 2H), 9.68 ppm (brs, 1H), 12.50 ppm (s,
2H).

The following compounds are prepared analogously: 1,9-bis (1-chloro-9-oxo-9,10-dihydroacridine-4
-Carbonyl) -5-methyl-1,5,9-triazanonane, m.p. p. 245-
247 ° C (decomposition);¹H-NMR (DMSO-d₆) 1.92-2.18 ppm (
m, 4H), 2.80 ppm (s, 3H), 3.04-3.30 ppm (m, 4H).
H), 3.40-3.51 ppm (m, 4H), 7.20-7.34 ppm (m
, 4H), 7.55 ppm (d, 2H), 7.70 ppm (t, 2H), 8.0
8-8.21 ppm (m, 4H), 9.28 ppm (brt, 2H), 10. 21 ppm (brs, 1H), 12.80 ppm (s, 2H); 1,7-bis (1-chloro-7-methoxy-9-oxo-9,10-dihydro
Acridine-4-carbonyl) -4-methyl-1,4,7-triazaheptane (
After completion of the reaction, the mixture was washed with CHCl_ThreeAnd Na_TwoCO_Three Distribute between 1M. Process the organic phase
To give a residue, which is_ThreeChromatographically on a silica gel column eluting with 9: 1 MeOH / MeOH), m.p. p. 155-156 ° C; ¹ H-NMR (DMSO-d₆) 2.35 ppm (s, 3H), 2.60-2.7
2 ppm (m, 4H), 3.40-3.56 ppm (m, 4H), 3.79 pp
m (s, 6H), 7.00 ppm (d, 2H), 7.24 ppm (d, 2H),
7.38-7.56 ppm (m, 4H), 7.87 ppm (d, 2H), 8.7
8 ppm (brt, 2H), 12.54 ppm (s, 2H); 1,9-bis (1-chloro-7-methoxy-9-oxo-9,10-dihydro
Acridine-4-carbonyl) -5-methyl-1,5,9-triazanonane (anti
After completion of the reaction, the mixture is_ThreeAnd Na_TwoCO_Three Distribute between 1M. Process organic phase
To give a residue, which is_ThreeSeparation by chromatography on a silica gel column eluted with 4/1 MeOH / MeOH, m.p. p. 158-159 ° C;¹H-NMR (CDCl_Three) 1.90-2.09 ppm (m, 4H), 2.48 ppm (s, 3H), 2.69-2.89 ppm (m, 4H), 3.49-3.67.
ppm (m, 4H), 3.88 ppm (s, 6H), 6.81 ppm (d, 2H
), 7.15-7.24 ppm (m, 4H), 7.57-7.66 ppm (m,
4H), 8.20 ppm (brt, 2H), 12.44 ppm (s, 2H).

[0069] N4 - (3 - {[( 1- Chloro-9-oxo-9,10-dihydro-4-acridinyl) - carbonyl] amino} propyl) -1-chloro-9-oxo-9,
10-dihydro-4-acridinecarboxamide: (0.42 g, 97.6%)
_{: C 31 H 22 Cl 2 N} 4 O 4; m. p. > 300 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 1.90-2.10 (m, 2H, CH ₂ ), 2.91-3.09 (m, 4H, 2 × CH ₂ ), 7. 12-7.28 (m, 4H, ar), 7.48 (d, 2H, ar), 7.70 (t, 2H, ar), 8.02-8.40 (m, 6H, 4a)
r <+> 2xCO-NH, ex), 15.65 (s, 2H, ex).

[0070] N4 - {2 - [{2 - [(2 - {[(1- Chloro-9-oxo-9,10-dihydro-4-acridinyl) carbonyl] amino} - ethyl) (methyl) amino] ethyl {-(Methyl) amino] ethyl} -1-chloro-9-oxo-9,10
-Dihydro-4-acridinecarboxamide Example 2- 1,7-bis [1- (2- (dimethylamino) ethyl) amino-9-oxo-9,10-dihydroacridine-4-carbonyl] -4-methyl- 1,4,7-triazaheptane (compound (I)-(b)) bis derivative 1,7-bis (1-chloro-9-oxo-9,10-dihydroacridine-4-carbonyl) -4-methyl -1,4,7-Triazaheptane hydrochloride (150 mg) was refluxed in 2- (dimethylamino) ethylamine (2 ml) for 1 hour, then cooled to room temperature and the reaction mixture was washed with CHCl ₃ and 1M Na _2. Partition between CO ₃ . The organic phase is worked up to give a residue, which is suspended in ethyl ether (10 ml) to give the pure product by TLC (130 mg), m.p. p. 116-117
° C; hydrochloride m. p. 238-240 ° C .; ¹ H-NMR (CDCl ₃ ) 2.31 pm (s, 12H), 2.50 ppm (s, 3H), 2.60 ppm (t, 4H)
), 2.77-2.87 ppm (m, 4H), 3.54-3.65 ppm (m,
4H), 5.80 ppm (d, 2H), 6.78 ppm (brt, 2H), 10-7.21 ppm (m, 4H), 7.41-7.52 ppm (m, 4H)
, 8.28 ppm (d, 2H), 10.85 ppm (brt, 2H), 13. 18 ppm (s, 2H).

The following compounds are similarly prepared: 1,9-bis [1- (2- (dimethylamino) ethyl) amino-9-oxo-
9,10-dihydroacridine-4-carbonyl] -5-methyl-1,5,9-
Triazanonane, m.p. p. 119-120 ° C; hydrochloride m. p. 226-228 ° C (decomposition);¹H-NMR (CDCl_Three) 1.77-1.99 ppm (m, 4H)
, 2.28 ppm (s, 12H), 2.38 ppm (s, 3H), 2.51-2
. 68 ppm (m, 8H), 3.15-3.31 ppm (m, 4H), 3.46
-3.62 ppm (m, 4H), 6.05 ppm (d, 2H), 7.10-7.
26 ppm (m, 4H), 7.40-7.61 ppm (m, 6H), 8.30 p
pm (d, 2H), 10.91 ppm (brt, 2H), 12.36 ppm (s, 2H); 1,7-bis [1- (2- (dimethylamino) ethyl) amino-7-methoxy
-9-oxo-9,10-dihydroacridine-4-carbonyl] -4-methyl
-1,4,7-Triazaheptane (treatment of the organic phase to give a residue,
l_Three/ MeOH / 38% NH_Three(Separation by flash chromatography on a silica gel column eluted at (1: 1: 0.01) to give the product), m.p. p. 2
17-218 ° C; hydrochloride m. p. 270-273 ° C (decomposition);¹H-NMR (C
DCI_Three2.) 2.28 ppm (s, 12H), 2.40 ppm (s, 3H), 54 ppm (t, 4H), 2.72 ppm (t, 4H), 3.00-3.10p
pm (m, 4H), 3.50-3.63 ppm (m, 4H), 3.88 ppm (
s, 3H), 5.72 ppm (d, 2H), 6.58 ppm (brt, 2H), 7.10-7.20 ppm (m, 4H), 7.41 ppm (d, 2H), 7.
68 ppm (s, 2H), 10.90 ppm (brt, 2H), 13.10 pm (s, 2H); 1,9-bis [1- (2- (dimethylamino) ethyl) amino-7-methoxy
-9-oxo-9,10-dihydroacridine-4-carbonyl] -5-methyl
-1,5,9-Triazanonane (treatment of the organic phase to give a residue, which is _Three / MeOH / 38% NH_Three(Separated by flash chromatography on a silica gel column eluted with (1: 1: 0.01)), m.p. p. 143-144 ° C
Hydrochloride m. p. 250-252 ° C (decomposition);¹H-NMR (CDCl_Three) 1. 82-1.88 ppm (m, 4H), 2.28 ppm (s, 12H), 2.34
ppm (s, 3H), 2.53-2.61 ppm (m, 8H), 3.20-3.
28 ppm (m, 4H), 3.48-3.56 ppm (m, 4H), 3.86 p
pm (s, 3H), 6.01 ppm (d, 2H), 7.13-7.21 ppm (
m, 4H), 7.42 ppm (brt, 2H), 7.49 ppm (d, 2H), 7.69 ppm (s, 2H), 10.96 ppm (brt, 2H), 13. 38 ppm (s, 2H).

[0072] N4 - {3 - {[( 1 - {[2- ( dimethylamino) ethyl] amino} -9-
Oxo-9,10-dihydro-4-acridinyl) -carbonyl] amino {propyl) -1-{[2- (dimethylamino) ethyl] amino} -9-oxo-9,
10-dihydro-4-acridinecarboxamide: (0.11 g, 47.8%)
: M. p. 220-221 ° C; hydrochloride m. p. 198-200 ° C; ¹ H-NMR
_{(DMSO-d 6) δ2.11-2.31 (} m, 14H, 4 x CH 3 + CH 2), 2.47-2.62 (m, 6H, 3 x CH 2), 2.63-2 .75 (m, 6H, 3 x CH 2), 6.20 (d, 2H, ar), 7.19 (t, 2H, ar), 7.40 (d, 2H, ar), 7.60 ( t, 2H, ar), 8.09
-8.21 (m, 4H, ar), 10.41 (brt, 2H, CO-NH, ex), 15.80 (brs, 2H, ex).

[0073] N4 - {2 - [{2 - [(2 - {[(1 - {[2- ( dimethylamino) ethyl] amino} -9-oxo-9,10-dihydro-4-acridinyl) carbonyl] Amino {ethyl) (methyl) amino] ethyl {(methyl) amino] ethyl}-
1-{[2- (dimethylamino) ethyl] amino} -9-oxo-9,10-dihydro-4-acridinecarboxamide: m.p. p. 268-270 ° C .; ¹ H-N MR (DMSO-d ₆ ) δ 2.91 (s, 12H, 4 × CH ₃ ), 3.00 (s)
_{, 6H, 2 x CH 3)} , 3.25-3.59 (m, 8H, 4 x CH 2), 3.
61-4.00 (m, 12H, 6 x CH 2), 6.52 (d, 2H, ar), 7.23 (t, 2H, ar), 7.45 (d, 2H, ar), 7 .64 (t, 2
H, ar), 8.12 (d, 2H, ar), 8.30 (d, 2H, ar), 9.
14 (br s, 2H, ex), 10.90 (br s, 2H, ex), 13.1
2 (br s, 2H, ex), 13.40 (br s, 2H, ex), 13.60
(Brs, 2H, ex).

Example 3-1,7-Bis [1- (2- (dimethylamino) ethyl) amino-7-hydroxy-9-oxo-9,10-dihydroacridine-4-carbonyl] -4-methyl- 1,4,7-Triazaheptane 1,7-bis [1- (2- (dimethylamino) ethyl) amino-7-methoxy-9-oxo-9,10-dihydroacridine-4-carbonyl] -4- Methyl-1,4,7-triazaheptane (130 mg) was refluxed in 48% HBr (3 ml) for 1 hour, then cooled to room temperature and the reaction mixture was partitioned between CHCl ₃ and 1M Na ₂ CO _3. I do. The organic phase is worked up to give a residue, which is CHCl ₃ / MeOH
Separation by flash chromatography on a silica gel column eluted with / 38% NH ₃ (1: 1: 0.01) to give the product (80 mg), m.p. p. 162
-163 ° C; hydrochloride m. p. 262-264 ° C (decomposition); ¹ H-NMR (DMS
_{O-d 6) 2.23ppm (s} , 12H), 2.34ppm (s, 3H), 2. 51-2.74 ppm (m, 8H), 3.17-3.22 ppm (m, 4H),
3.42-3.46 ppm (m, 4H), 6.05 ppm (d, 2H), 7.1
6 ppm (d, 2H), 7.41-7.50 ppm (m, 4H), 7.89 pp
m (d, 2H), 8.22 ppm (br t, 2H), 9.65 ppm (br s
, 2H), 10.83 ppm (brt, 2H), 13.62 ppm (s, 2H).

The following compounds are similarly prepared: 1,9-bis [1- (2- (dimethylamino) ethyl) amino-7-hydroxy-9-oxo-9,10-dihydroacridine-4-carbonyl] -5-methyl-1,5,9-triazanonane, m.p. p. 221-222 ° C; hydrochloride m. p. 250-251 ° C; ¹ H-NMR (DMSO-d ₆ ) 1.69-1.76 ppm
(M, 4H), 2.19-2.21 ppm (m, 15H), 2.40 ppm (t
, 4H), 2.52-2.56 ppm (m, 4H), 3.26-3.46 ppm
(M, 8H), 6.18 ppm (d, 2H), 7.19 ppm (d, 2H), 7
. 40-7.50 ppm (m, 4H), 7.95 ppm (d, 2H), 8.48
ppm (brt, 2H), 9.69 ppm (brs, 2H), 10.83 pp
m (brt, 2H), 13.70 ppm (s, 2H).

Example 4-1,7-Bis [1- (2- (dimethylamino) ethyl) -aminoacridine-4-carbonyl] -4-methyl-1,4,7-triazaheptane (Compound (I )-(F)) 1,7-bis [1- (2- (dimethylamino) ethyl) amino-9-oxo-
9,10-dihydroacridine-4-carbonyl] -4-methyl-1,4,7-
Triazaheptane trihydrochloride (350 mg) and _{EtOH / H 2 O (3:} 1,30m l) is refluxed in. Al pellets (350 mg) placed in a HgCl ₂ ethanol solution (1300 mg in 25 ml of EtOH) for 1 min are added for 30 min. Upon completion of the addition, the mixture was refluxed for 30 minutes, then filtered hot while washing with EtOH (20 ml), diluted with H ₂ O (50 ml), and added FeCl ₃ (120
0 mg) is added. The reaction mixture is partitioned between CHCl ₃ and 1M Na ₂ CO ₃ .
The organic phase was worked up to give a residue, which was separated by flash chromatography on a silica gel column eluted with CHCl ₃ / MeOH / 38% NH ₃ (1: 1: 0.01) to give the product (40 mg). Obtain, m. p. 196-197 ° C; hydrochloride m. p. 248-249 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 2.46 ppm (s, 12H), 2.62 ppm (s, 3H), 2.75-2.90 ppm (
m, 4H), 2.90-3.06 ppm (m, 4H), 3.30-3.44 pp
m (m, 4H), 3.81-3.97 ppm (m, 4H), 5.74 ppm (b
rt, 2H), 6.27 ppm (d, 2H), 7.07 ppm (t, 2H), 7.32 ppm (t, 2H), 7.51 ppm (d, 2H), 7.71 ppm (
d, 2H), 8.32 ppm (s, 2H), 8.50 ppm (d, 2H), 11
. 60 ppm (brs, 2H).

The following compound is similarly prepared: 1,9-bis [1- (2- (dimethylamino) ethyl) aminoacridine-4
-Carbonyl] -5-methyl-1,5,9-triazanonane, m.p. p. 166-
167 ° C; hydrochloride m. p. 240-242 ° C (decomposition);¹H-NMR (CDCl _Three ) 2.01-2.10 ppm (m, 4H), 2.29-2.50 ppm (m, 15H), 2.72-2.88 ppm (m, 8H), 3.31-3.46 ppm
(M, 4H), 3.60-3.73 ppm (m, 4H), 6.14 ppm (br
 , 2H), 6.44 ppm (d, 2H), 7.27 ppm (t, 2H), 7. 60 ppm (t, 2H), 7.74 ppm (d, 2H), 7.90 ppm (d
, 2H), 8.71 ppm (d, 2H), 8.88 ppm (s, 2H), 11.
71 ppm (brs, 2H).

Example 5-1,7-Bis [2- (2- (dimethylamino) ethyl) pyrazole [3,4,5- kl ] acridine-5-carbonyl] -4-methyl-1,4
, 7-Triazaheptane (compound (I)-(d)) 1,7-bis (1-chloro-9-oxo-9,10-dihydroacridine-4
-Carbonyl) -4-methyl-1,4,7-triazaheptane monohydrochloride (270
mg) and 2- (dimethylamino) ethylhydrazine (420 mg) are suspended in 2-ethoxyethanol (10 ml) at 120 ° C for 1 hour. The mixture is cooled to room temperature and partitioned between CHCl ₃ and 1M Na ₂ CO ₃ . The organic phase was worked up to give an oily residue, which was separated by flash chromatography on a silica gel column eluted with CHCl ₃ / MeOH / 38% NH ₃ (1: 1: 0.02) and analyzed by TLC
To give the pure product as an oil (70 mg), which is converted to the hydrochloride in a customary manner for characterization: m.p. p. Trihydrochloride 230-231 ° C; ¹ H-NMR (D
_{MSO-d 6) 2.88ppm (s} , 12H), 3.01ppm (s, 3H), 3.32-4.00ppm (m, 12H), 4.50-4.78ppm (m, 4
H), 6.64 ppm (d, 2H), 7.10 ppm (t, 2H), 7.30 p
pm (t, 2H), 7.44 ppm (d, 2H), 7.68-7.91 ppm (
m, 4H), 8.82 ppm (brt, 2H), 10.40-10.65 ppm (m, 3H), 11.00 ppm (brs, 2H).

The following compounds are prepared similarly: 1,9-bis [2- (2- (dimethylamino) ethyl) pyrazole [3,4
5- kl ] acridine-5-carbonyl] -5-methyl-1,5,9-triazanonane (after chromatography, the product is obtained as a pure solid residue, which is characterized as the free base), m.p. p. 159-160 ° C; hydrochloride m. p. 200-202 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 1.82-1.97 ppm
(M, 4H), 2.27 ppm (s, 12H), 2.37 ppm (s, 3H),
2.53-2.71 ppm (m, 4H), 2.77 ppm (t, 4H), 3.5
0-3.64 ppm (m, 4H), 4.29 ppm (t, 4H), 6.36 pp
m (d, 2H), 6.97-7.12 ppm (m, 4H), 7.15-7.35
ppm (m, 6H), 7.91 ppm (d, 2H), 10.52 ppm (brs, 2H); 1,7-bis [2- (2- (dimethylamino) ethyl) -9-methoxypyrazole [3 , 4,5- kl ] acridine-5-carbonyl] -4-methyl-1,4
, 7-Triazaheptane trihydrochloride, m.p. p. 245-247 ° C; ¹ H-NMR (DMSO-d ₆ ) 2.86 ppm (s, 12H), 3.00 ppm (s, 3H), 3.30-3.75 ppm (m, 12H), 3.84 ppm ( s, 6H), 4
. 60-4.80 ppm (m, 4H), 6.56 ppm (d, 2H), 6.92
ppm (d, 2H), 7.20 ppm (s, 2H), 7.40 ppm (d, 2H)
), 7.78 ppm (d, 2H), 8.71 ppm (brt, 2H), 10. 30-10.54 ppm (m, 4H), 10.88 ppm (brs, 1H); 1,9-bis [2- (2- (dimethylamino) ethyl) -9-methoxypyrazole [3,4,5- kl ] acridine-5-carbonyl] -5-methyl-1,5
, 9-Triazanonane trihydrochloride, m.p. p. 204-205 ° C; ¹ H-NMR (DMSO-d ₆ ) 1.90-2.15 ppm (m, 4H), 2.68-2.92 pm (m, 15H), 3.00-3.50 ppm (M, 8H), 3.51-3.
70 ppm (m, 4H), 3.80 ppm (s, 6H), 4.69-4.85p
pm (m, 4H), 6.81 ppm (d, 2H), 6.97 ppm (d, 2H)
, 7.26 ppm (s, 2H), 7.52 ppm (d, 2H), 7.84 ppm
(D, 2H), 8.56 ppm (brt, 2H), 10.69 ppm (br s
, 2H), 10.83 ppm (brs, 1H), 11.15 ppm (brs,
2H).

Example 6-1,7-bis [2- (2- (dimethylamino) ethyl) -9-
Hydroxypyrazole [3,4,5- kl ] acridine-5-carbonyl] -4
-Methyl-1,4,7-triazaheptane 1,7-bis [2- (2- (dimethylamino) ethyl) -9-methoxypyrazole [3,4,5- kl ] acridine-5-carbonyl]- 4-methyl-1,4
, 7-Triazaheptane trihydrochloride (200 mg) is refluxed in 48% HBr (3 ml) for 1 hour; the mixture is cooled to room temperature and partitioned between CHCl ₃ and 1M Na ₂ CO ₃ . The organic phase is worked up to give a residue, which is CHCl ₃ / MeOH / 38% N
Separation by flash chromatography on a silica gel column eluted with H ₃ (1: 1: 0.01) to give the product (40 mg), m.p. p. 282-283 ° C
Hydrochloride m. p. 255-257 ° C (decomposition); ¹ H-NMR (DMSO-d ₆ ) 2.18 ppm (s, 12H), 2.34 ppm (s, 3H), 2.55-2.
77 ppm (m, 8H), 3.30-3.50 ppm (m, 4H), 4.33 p
pm (t, 4H), 6.54 ppm (d, 2H), 6.80 ppm (d, 2H)
, 7.18 ppm (s, 2H), 7.36 ppm (d, 2H), 7.56 ppm
(D, 2H), 8.03 ppm (brt, 2H), 9.46 ppm (brs,
2H), 10.56 ppm (s, 2H).

The following compounds are prepared analogously: 1,9-bis [2- (2- (dimethylamino) ethyl) -9-hydroxypyrazole [3,4,5- kl ] acridine-5-carbonyl]- 5-methyl-1,
5,9-triazanonane, m.p. p. 239-240 ° C; hydrochloride m. p. ^{260 -261 ℃; 1 H-NMR} (DMSO-d 6) 1.67-1.84ppm (m, 4
H), 2.20 ppm (s, 12H), 2.25 ppm (s, 3H), 2.39
-2.52 ppm (m, 4H), 2.74 ppm (t, 4H), 3.23-3.
42 ppm (m, 4H), 4.36 ppm (t, 4H), 6.63 ppm (d,
2H), 6.81 ppm (d, 2H), 7.18 ppm (s, 2H), 7.37
ppm (d, 2H), 7.62 ppm (d, 2H), 8.21 ppm (brt, 2H), 9.45 ppm (s, 2H), 10.58 ppm (s, 2H).

Example 7-1,7-bis [4- (N- (2- (dimethylamino) ethyl)
) -Carboxamido-9-oxo-9,10-dihydroacridin-1-yl]
-4-Methyl-1,4,7-triazaheptane (compound (I)-(c)) 4- {N- [2- (dimethylamino) ethyl]} carboxamide-1-chloro-9-oxo-9 , 10-dihydro-acridine (500mg), N ² - methyl di ethylene triamine (0.1 ml) and Et ₃ starting product N (0.5 ml) is at 120 ° C. under stirring until disappearance of 2-ethoxyethanol (10ml) Put inside. The reaction mixture is cooled to room temperature and partitioned between CHCl ₃ and 1M Na ₂ CO ₃ .
The organic phase was worked up to give a residue which was separated by flash chromatography on a silica gel column eluted with CHCl ₃ / MeOH / 38% NH ₃ (1: 1: 0.01) to give the product (170 mg). Obtained as a pure solid by TCL, m.p. p
. 135-136 ° C; hydrochloride m. p. 258-260 ° C (decomposition); ¹ H-NMR
(CDCl ₃ ) 2.32 ppm (s, 12H), 2.48 ppm (s, 3H), 2.59 ppm (t, 4H), 2.83 ppm (t, 4H), 3.34-3.4
4 ppm (m, 4H), 3.45-3.55 ppm (m, 4H), 6.16 pp
m (d, 2H), 6.88 ppm (brt, 2H), 7.10 ppm (t, 2H), 7.25 ppm (d, 2H), 7.49-7.60 ppm (m, 4H),
8.20 ppm (d, 2H), 10.97 ppm (brt, 2H), 13.20 ppm (s, 2H).

The following compounds are similarly prepared: 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-9-oxo-9,10-dihydro-acridin-1-yl ] -5-methyl-
1,5,9-triazanonane, m.p. p. 112-113 ° C; hydrochloride m. p. 235-236 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 1.90-2.07 ppm
(M, 4H), 2.30 ppm (s, 12H), 2.40 ppm (s, 3H),
2.59 ppm (t, 4H), 2.70 ppm (t, 4H), 3.24-3.3
9 ppm (m, 4H), 3.50-3.67 ppm (m, 4H), 6.08 pp
m (d, 2H), 7.05-7.20 ppm (m, 4H), 7.28 (d, 2H)
), 7.50 ppm (t, 2H), 7.62 ppm (d, 2H), 8.28 pp
m (d, 2H), 10.89 ppm (brt, 2H), 13.27 ppm (s, 2H); 1,7-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamide-7. -Methoxy-9-oxo-9,10-dihydroacridin-1-yl]-
4-methyl-1,4,7-triazaheptane, m.p. p. 160-162 ° C; hydrochloride m. p. 220-222 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 2.34 pm (s, 12H), 2.53 ppm (s, 3H), 2.60 ppm (t, 4H)
), 2.87 ppm (t, 4H), 3.29-3.45 ppm (m, 4H), 3
. 46-3.60 ppm (m, 4H), 3.88 ppm (s, 3H), 6.04
ppm (d, 2H), 6.85 ppm (brt, 2H), 7.15-7.26 ppm (m, 4H), 7.48 ppm (d, 2H), 7.59 ppm (s, 2H)
), 11.02 ppm (brt, 2H), 13.10 ppm (s, 2H); 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamide-7-methoxy-9-. Oxo-9,10-dihydroacridin-1-yl]-
5-methyl-1,5,9-triazanonane, m.p. p. 160-161 ° C; hydrochloride m. p. 230-233 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 1.90-2. 10 ppm (m, 4H), 2.20-2.38 ppm (m, 15H), 2.5
2-2.68 ppm (m, 8H), 3.18-3.34 ppm (m, 4H), 3
. 45-3.63 ppm (m, 4H), 3.90 ppm (s, 3H), 5.92
ppm (d, 2H), 6.90 ppm (brt, 2H), 7.06-7.28 ppm (m, 4H), 7.48 ppm (d, 2H), 7.61 ppm (s, 2H)
), 10.90 ppm (brt, 2H), 13.17 ppm (s, 2H); 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamide-7-nitro-9-. Oxo-9,10-dihydroacridin-1-yl] -5
-Methyl-1,5,9-triazanonane, m.p. p. 152-153 ° C; hydrochloride m. p. 255-257 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 1.84-2.
04 ppm (m, 4H), 2.51 ppm (s, 15H), 2.48-2.70
ppm (m, 8H), 3.20-3.37 ppm (m, 4H), 3.40-3.
55 ppm (m, 4H), 6.10 ppm (d, 2H), 6.89 ppm (br
, 2H), 7.15 ppm (d, 2H), 7.42 ppm (d, 2H), 21 ppm (d, 2H), 8.91 ppm (s, 2H), 10.57 ppm (
(brt, 2H), 13.58 ppm (brs, 2H).

Example 8 1,7-bis [4- (N- (2- (dimethylamino) ethyl)
) -Carboxamido-7-hydroxy-9-oxo-9,10-dihydroacridin-1-yl] -4-methyl-1,4,7-triazaheptane 1,7-bis [4- (N- (2 -(Dimethylamino) ethyl)) carboxamido-7-methoxy-9-oxo-9,10-dihydroacridin-1-yl]-
4-Methyl-1,4,7-triazaheptane (280 mg) is refluxed in 48% HBr (3 ml) for 1 hour. The reaction mixture was cooled to room temperature and CHCl ₃ and 1M
Partition between Na ₂ CO ₃ . The organic phase was worked up to give a residue, which was separated by flash chromatography on a silica gel column eluted with CHCl ₃ / MeOH / 38% NH ₃ (1: 1: 0.01) to give the product (210 mg) , M. p
. 190-192 [deg.] C; hydrochloride m. p. 254-255 ° C; ¹ H-NMR (DMS
_{O-d 6) 2.25ppm (s} , 12H), 2.38-2.50ppm (m, 7 H), 2.75-2.93ppm (m, 4H), 3.32-3.77ppm (m
, 8H), 6.31 ppm (d, 2H), 7.10 ppm (d, 2H), 7.4
1-7.54 ppm (m, 4H), 7.98 ppm (d, 2H), 8.30 pp
m (brt, 2H), 9.64 ppm (brs, 2H), 10.96 ppm (
(brt, 2H), 13.69 ppm (s, 2H).

The following compounds are prepared analogously: 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-7-hydroxy-9-oxo-9,10-dihydroacridine- 1-yl]
-5-methyl-1,5,9-triazanonane, m.p. p. 186-188 ° C; hydrochloride m. p. 270-271 ° C; ¹ H-NMR (DMSO-d ₆ ) 1.80-1. 90 ppm (m, 4H), 2.22 ppm (s, 15H), 2.42-2.51
ppm (m, 8H), 3.34-3.44 ppm (m, 8H), 6.21 ppm
(D, 2H), 7.21 ppm (d, 2H), 7.42-7.51 ppm (m,
4H), 7.94 ppm (d, 2H), 8.29 ppm (brt, 2H), 9. 12. 62 ppm (brs, 2H), 10.91 ppm (brt, 2H),
67 ppm (s, 2H).

Example 9-1,7-bis [4- (N- (2- (dimethylamino) ethyl)
) -Carboxamidoacridin-1-yl] -4-methyl-1,4,7-triazaheptane (compound (I)-(a)) 1,7-bis [4- (N- (2- (dimethylamino) ) Ethyl)) carboxamido-9-oxo-9,10-dihydroacridin-1-yl] -4-methyl-1
, 4,7-triazaheptane trihydrochloride (190 mg) and _{EtOH / H 2 O (3:} 1,15ml) are refluxed in. Al pellets (190 mg) placed in a HgCl ₂ ethanol solution (760 mg in 18 ml of EtOH) for 1 min are added for 30 min. Upon completion of the addition, the mixture was refluxed for 30 minutes, filtered hot while washing with EtOH (20 ml), diluted with H ₂ O (50 ml), and added FeCl ₃ (60 ml).
0 mg) is added. The reaction mixture is partitioned between CHCl ₃ and 1M Na ₂ CO ₃ .
The organic phase was worked up to give a residue, which was separated by flash chromatography on a silica gel column eluted with CHCl ₃ / MeOH / 38% NH ₃ (1: 1: 0.01) to give the product (90 mg). Obtain, m. p. 138-139 ° C; hydrochloride m. p. 255-257 ° C. (decomposition); ¹ H-NMR (CDCl ₃ ) 2.45 ppm (s, 12H), 2.57 ppm (s, 3H), 2.70 ppm (t, 4H)
, 2.90-3.02 ppm (m, 4H), 3.40-3.53 ppm (m, 4H)
H) 3.68-3.82 ppm (m, 4H), 5.80 ppm (brt, 2H), 6.43 ppm (d, 2H), 6.97-7.17 ppm (m, 4H),
7.58 ppm (t, 2H), 7.78 ppm (d, 2H), 8.28 ppm (
s, 2H), 8.73 ppm (d, 2H), 11.65 ppm (brt, 2H).

The following compounds are similarly prepared: 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-acridin-1-yl] -5-methyl-1,5,5 9-triazanonane, m.p.
p. 130-131 ° C; hydrochloride m. p. 250-252 ° C (decomposition); ¹ H-NM
_{R (CDCl 3) 2.02-2.16ppm (m} , 4H), 2.44ppm (s, 12H), 2.54ppm (s, 3H), 2.65-2.87ppm (m, 8
H), 3.29-3.44 ppm (m, 4H), 3.69-3.82 ppm (m
, 4H), 6.26 ppm (d, 2H), 6.85 ppm (brt, 2H), 7.35 ppm (t, 2H), 7.67 ppm (t, 2H), 7.78 ppm (
d, 2H), 8.02 ppm (d, 2H), 8.68 ppm (d, 2H),
74 ppm (s, 2H), 11.81 ppm (s, 2H).

Example 10-1,7-bis [2- (2- (dimethylamino) ethyl) -1
, 3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6
, 1- de ] Acridin-6-yl] -4-methyl-1,4,7-triazaheptane (compound (I)-(e)) 6-chloro-2- [2- (dimethylamino) ethyl] -1,3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6,1- de ] acridine (300 mg; manufactured by Antonini, I. et al., J. Med. Chem.
Are described in 1995,38,3282-6), N ² - Mechirujiechire Ntoriamin (0.06 ml) and Et ₃ N (2 at 80 ° C. under stirring until 0.5ml) the starting product disappears visible -Place in ethoxyethanol (10 ml).
The reaction mixture is cooled to room temperature and partitioned between CHCl ₃ and 1M Na ₂ CO ₃ . The organic phase was worked up to give a residue, which was chromatographed on a silica gel column eluting with CHCl ₃ / MeOH (4: 1) to give the product (190 mg) in TL
C, obtained as a pure solid, m.p. p. 183-184 <0>C; hydrochloride m. p. 275-277 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 2.42 ppm (s, 12H
), 2.58 ppm (s, 3H), 2.71 ppm (t, 4H), 2.86 pp
m (t, 4H), 3.20-3.30 ppm (m, 4H), 4.25 ppm (t
, 4H), 6.60 ppm (d, 2H), 7.16 ppm (t, 2H), 7.5
2 ppm (t, 2H), 7.91 ppm (d, 2H), 8.08 ppm (d, 2H)
H), 8.52 ppm (d, 2H), 10.90 ppm (brt, 2H).

The following compounds are prepared analogously: 1,9-bis [2- (2- (dimethylamino) ethyl) -1,3,7-trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6,1- de ] acridin-6-yl] -5-methyl-1,5,9-triazanonane, m.p. p. 14
3-144 ° C; hydrochloride m. p. 259-260 ° C (decomposition); ¹ H-NMR (CD
_{Cl 3) 1.90-2.04ppm (m, 4H} ), 2.32ppm (s, 3H), 2.40ppm (s, 12H), 2.60ppm (t, 4H), 2.71pp
m (t, 4H), 3.28-3.40 ppm (m, 4H), 4.28 ppm (t
, 4H), 6.44 ppm (d, 2H), 7.28 ppm (t, 2H), 7.5
2 ppm (t, 2H), 7.96 ppm (d, 2H), 8.20 ppm (d, 2H)
H), 8.74 ppm (d, 2H), 10.75 ppm (brt, 2H); 1,7-bis [2- (2- (dimethylamino) ethyl) -9-methoxy-1,
3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6
1- de ] acridin-6-yl] -4-methyl-1,4,7-triazaheptane, m.p. p. 200-202 <0>C; hydrochloride m. p. 253-254 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 2.40 ppm (s, 12H), 2.60 ppm (s, 3H), 2.70 ppm (t, 4H), 2.85 ppm (t, 4H) ), 3.3
4-3.46 ppm (m, 4H), 3.71 ppm (s, 3H), 4.25 pp
m (t, 4H), 6.54 ppm (d, 2H), 7.08 ppm (d, 2H),
7.26 ppm (s, 2H), 8.10 ppm (d, 2H), 8.52 ppm (
d, 2H), 10.94 ppm (brt, 2H); 1,9-bis [2- (2- (dimethylamino) ethyl) -9-methoxy-1,
3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6
1- de ] acridin-6-yl] -5-methyl-1,5,9-triazanonane, m.p. p. 183-185 ° C; hydrochloride m. p. 258-259 ° C (decomposition); ¹ H
_{-NMR (CDCl 3) 1.90-2.10ppm (m} , 4H), 2.31pp m (s, 3H), 2.40ppm (s, 12H), 2.56-2.78ppm (
m, 8H), 3.25-3.42 ppm (m, 4H), 3.85 ppm (s, 3
H), 4.27 ppm (t, 4H), 6.40 ppm (d, 2H), 7.05 p
pm (d, 2H), 7.58 ppm (s, 2H), 7.98 ppm (d, 2H)
, 8.60 ppm (d, 2H), 10.77 ppm (brt, 2H).

Example 11-1,9-bis [2- (2- (dimethylamino) ethyl) -9
-Nitro-1,3,7-trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6,1- de ] acridin-6-yl] -5-methyl-1,5,9-
Toriazanonan CHCl ₃ (10 ml) solution of 1,9-bis [4- (N- (2- (dimethylaminopyridine Roh) ethyl)) carboxamido 7-nitro-9-oxo-9,10-dihydro-acridine-1-yl] -5-methyl-1,5,9-triazanonane (230 m
g) and Et ₃ N (0.75 ml) at 0 ° C. in CHCl ₃ (10 ml).
OCl ₂ (20% in toluene, 0.7 ml) is added dropwise. When the addition is complete, the mixture is stirred at room temperature for 20 minutes. The reaction mixture is partitioned between CHCl ₃ and 1M Na ₂ CO ₃ . The organic phase is worked up to give a residue, which is CHCl ₃ / MeOH
Product (140 mg) separated by chromatography eluting with (1: 1)
Is obtained by TLC as a pure solid, m.p. p. 148-149 ° C; hydrochloride m. p. 262-263 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 1.90-2.10p
pm (m, 4H), 2.35 ppm (s, 15H), 2.60-2.75 ppm
(M, 8H), 3.32-3.48 ppm (m, 4H), 4.25 ppm (t,
4H), 6.50 ppm (d, 2H), 7.98 ppm (d, 2H), 8.23
-8.33 ppm (m, 4H), 8.79 ppm (d, 2H), 8.96 ppm
(S, 2H), 10.65 ppm (brt, 2H).

Example 12-1,7-bis [2- (2- (dimethylamino) ethyl) -9
-Hydroxy-1,3,7-trioxo- [1H, 2H, 3H, 7H, 12H]
Pyrimid [5,6,1-deAcridine-6-yl] -4-methyl-1,4,4
7-triazaheptane 1,7-bis [2- (2- (dimethylamino) ethyl) -9-methoxy-1,
3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6,
1-deAcridine-6-yl] -4-methyl-1,4,7-triazahepta
(150 mg) is refluxed in 48% HBr (3 ml) for 1 hour. The reaction mixture was cooled to room temperature and CHCl_ThreeAnd 1M Na_TwoCO_ThreeDistribute between. Process the organic phase
To give a residue, which is_Three/ MeOH / 38% NH_Three(1: 1: 0.01) separated by flash chromatography on a silica gel column eluted with
The product (140 mg) is obtained by TLC as a pure solid, m.p. p. 279-28
0 ° C; hydrochloride m. p. 270-272 ° C (decomposition);¹H-NMR (DMSO-d ₆ ) 2.31 ppm (s, 12H), 2.50 ppm (s, 3H), 2.63-2.81 ppm (m, 8H), 3.39-3.54 ppm (m, 4H), 4.0
2-4.20 ppm (m, 4H), 6.69 ppm (s, 2H), 6.79 pp
m (d, 2H), 6.90 ppm (d, 2H), 8.01 ppm (d, 2H),
8.30 ppm (d, 2H), 10.40 ppm (brs, 2H), 10.74 ppm (brt, 2H).

The following compounds are prepared analogously: 1,9-bis [2- (2- (dimethylamino) ethyl) -9-hydroxy-1
, 3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6
, 1- de ] acridin-6-yl] -5-methyl-1,5,9-triazanonane, m.p. p. 263-264 ° C; hydrochloride m. p. 265-267 ° C (decomposition); ¹ H-NMR (DMSO-d ₆ ) 1.80-1.97 ppm (m, 4H), 2.25-2.42 ppm (m, 15H), 2.56-2 .74 ppm (m, 8H),
3.21-3.36 ppm (m, 4H), 4.05-4.20 ppm (m, 4H)
), 6.50 ppm (d, 2H), 7.05 ppm (d, 2H), 7.44 pp
m (s, 2H), 7.76 ppm (d, 2H), 8.46 ppm (d, 2H),
10.01 ppm (brs, 2H), 10.66 ppm (brt, 2H).

Example 13-1,9-bis {2- [2- (dimethylamino) ethyl] -9
, 10-Dimethoxypyrimido [5,6,1- de ] acridin-6-yl} -5
-Methyl-1,5,9-triazanonane Pyrimidoacridine from preparation 10 (0.35 g, 0.814 mmol) in 2-ethoxyethanol (10 mL), 3,3'-diamino-N-methyldipropylamine ( 0.071 mL, 0.41 mmol) and triethylamine (0.
(5 mL) is stirred at 80 ° C. for 2 hours. After cooling, the mixture is partitioned between CHCl ₃ and 1M Na ₂ CO ₃ . The organic layer is treated to give a residue, which is purified by column chromatography on silica gel using CHCl ₃ / CH ₃ OH (9: 1 v / v). The desired product The residue obtained by evaporation of the fractions containing further purified by stirring in Et ₂ O. Filtration of the mixture gives the pure title compound (0.08 g, 21.0%): C ₄₉ H ₅₇ N ₉ O ₁₀ ; p. 190-191 ° C; hydrochloride m. p. 240-242 ° C (decomposition); ¹ H-NMR (
_{CDCl 3) δ1.90-2.10 (m, 4H} , 2 x CH 2), 2.30 (s,
_{3H, CH 3), 2.35 (} s, 12H, 4 x CH 3), 2.58-2.76 (
_{m, 8H, 4 x CH 2} ), 3.24-3.40 (m, 4H, 2 x CH 2), 3
. 93 (s, 6H, 2 x O-CH 3), 4.00 (s, 6H, 2 x O-CH 3), 4.29 (t, 4H, 2 x CH 2), 6.43 (d, 2H, ar), 7. 58 (s, 2H, ar), 7.97 (d, 2H, ar), 8.40 (s, 2H, ar)
ar), 10.85 (brs, 2H, ex).

Example 14-2- [2- (dimethylamino) ethyl] -6-{[3-(｛
2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-di
Hydro-1H, 7H-Pyrimido [5,6,1-deAcridine-6-yldia
Mino) propyl] amino} -2,3-dihydro-1H, 7H-Pyrimido [5, 6
, 1-deAcridine-1,3,7-trione 2-ethoxyethanol (10 mL). Med. Chem. 1995,
38, 3282-3286, 2- [2- (dimethylamino) ethyl
] -6-chloro-2,3-dihydro-1H, 7H-Pyrimido [5,6,1-de Acridine-1,3,7-trione (0.2 g, 0.54 mmol), 1,3
-Diaminopropane (0.023 mL, 0.27 mmol) and triethylamido
(0.5 mL) is stirred at 80 ° C. for 2 hours. After cooling, the mixture is
HCl_ThreeAnd 1M Na_TwoCO_ThreePartition between water. Processing the organic layer to obtain a residue,
To CHCl_Three/ CH_ThreePurify by column chromatography on silica gel with OH (9: 1 v / v) to give the pure title compound (0.1 g, 50%): C ₄₁ H₄₀N₈O₆M. p. 222-224 ° C; hydrochloride m. p. 273-274 ° C;¹H-NMR (CDCl_Three) Δ 2.30 (t, 2H, CH_Two), 2.45 (s, 12H, 4 x CH_Three), 2.70 (t, 4H, 2 x CH_Two), 3.56-3.
69 (m, 4H, 2 x CH_Two), 4.30 (t, 4H, 2 x CH_Two), 6.7
5 (d, 2H, ar), 7.41 (t, 2H, ar), 7.68 (t, 2H, a
r), 8.21-8.30 (m, 4H, ar), 8.70 (d, 2H, ar),
11.00 (brt, 2H, ex).

The following compounds are similarly prepared: 2- [2- (dimethylamino) ethyl] -6-{[6-({2- [2- (dimethylamino) ethyl] -1,3,7-) trioxo-2,3-dihydro - 1H, 7 H - pyrimido [5,6,1- de] acridine-6-yl} amino) hexyl]
Amino} -2,3-dihydro - 1H, 7H - pyrimido [5,6,1- de] _{acridine-1,3,7-trione: 67.7%; C 44 H 46} N 8 O 6; m. p. 275
-276 ° C; hydrochloride m. p. 239-241 ° C; ¹ H-NMR (CDCl ₃ ) δ 1.57-1.73 (m, 4H, 2 x CH ₂ ), 1.74-1.98 (m, 4H
, 2 x CH ₂ ), 2.40 (s, 12H, 4 x CH ₃ ), 2.71 (t, 4H
, 2 x CH ₂ ), 3.31-3.37 (m, 4H, 2 x CH ₂ ), 4.31 (
_{t, 4H, 2 x CH 2} ), 6.68 (d, 2H, ar), 7.41 (t, 2H, ar), 7.68 (t, 2H, ar), 8.20 (d, 2H , Ar), 8.3
0 (d, 2H, ar), 8.71 (d, 2H, ar), 10.90 (brt, 2H, ex).

2- [2- (dimethylamino) ethyl] -6-{[8-({2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-dihydro- 1H , 7 H - pyrimido [5,6,1- de] acridine-6-yl} amino) octyl]
Amino} -2,3-dihydro - 1H, 7H - pyrimido [5,6,1- de] _{acridine-1,3,7-trione: 63.6%; C 46 H 50} N 8 O 6; m. p. 242
-243 ° C; hydrochloride m. p. 185-187 ° C; ¹ H-NMR (CDCl ₃ ) δ 1.41-1.62 (m, 8H, 4 x CH ₂ ), 1.63-1.90 (m, 4H
, 2 x CH ₂ ), 2.35 (s, 12H, 4 x CH ₃ ), 2.68 (t, 4H
, 2 x CH ₂ ), 3.30-3.46 (m, 4H, 2 x CH ₂ ), 4.30 (
_{t, 4H, 2 x CH 2} ), 6.68 (d, 2H, ar), 7.42 (t, 2H, ar), 7.65 (t, 2H, ar), 8.22 (d, 2H , Ar), 8.3
5 (d, 2H, ar), 8.71 (d, 2H, ar), 10.87 (brt, 2H, ex).

2- [2- (dimethylamino) ethyl] -6-{[12-({2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-dihydro- 1H , 7H -pyrimido [5,6,1- de ] acridin-6-yl {amino) dodecyl] amino} -2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridine-1, _{3,7-trione: 80.8%; C 50 H 58} N 8 O 6; m. p. 18
7-189 ° C; hydrochloride m. p. 254-256 ° C; ¹ H-NMR (CDCl ₃ ) δ 1.31-1.59 (m, 14H, 7 x CH ₂ ), 1.64-1.90 (m,
6H, 3 x CH ₂ ), 2.38 (s, 12H, 4 x CH ₃ ), 2.70 (t,
_{4H, 2 x CH 2),} 3.29-3.45 (m, 4H, 2 x CH 2), 4.3
_{0 (t, 4H, 2 x} CH 2), 6.68 (d, 2H, ar), 7.46 (t, 2H, ar), 7.69 (t, 2H, ar), 8.22 (d , 2H, ar), 8
. 40 (d, 2H, ar), 8.71 (d, 2H, ar), 10.87 (brt, 2H, ex).

2- [2- (dimethylamino) ethyl] -6-({2-[{2-[[2- (}
2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridin-6-yl @ amino) ethyl] -(Methyl) amino] ethyl {(methyl) amino] ethyl} amino) -2,3-dihydro- 1H, 7H -pyrimido- [5,6,1- de ] acridine-1,3,7-trione: 23 0.5%; C ₄₆ H ₅₂ N ₁₀ O ₆ ; p. 235-236 ° C; hydrochloride m. p. > 300 ° C; ¹ H-NMR (CDCl ₃ ) δ 2.2 4-2.61 (m, 18H, 6 x CH ₃ ), 2.62-2.74 (m, 8H, 4 x CH ₂ ), 2 _{.76-3.00 (m, 4H, 2 x} CH 2), 3.15-3
. _{31 (m, 4H, 2 x} CH 2), 4.30 (br t, 4H, 2 x CH 2), 5.93 (d, 2H, ar), 7.34-7.59 (m, 4H, ar), 7.
70 (t, 2H, ar), 8.28 (d, 2H, ar), 8.71 (d, 2H,
ar), 10.77 (brs, 2H, ex).

Example 15-N4-[2- (dimethylamino) ethyl] -1-({3- [
[3-({2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-
2,3-dihydro-1H, 7H-Pyrimido [5,6,1-deAcridine-6
-Yl @ amino) propyl] (methyl) amino] propyl @ amino) -9-oxo
So-9,10-dihydro-4-acridine-carboxamide 2-Compound of Preparation 11 in 2-ethoxyethanol (10 mL) (0.21 g, 0
. 46 mmol), pyrimidoacridine used in Example 14 (0.34 g
, 0.92 mmol) and triethylamine (0.5 mL) at 80 ° C.
Stir for 3 hours. After cooling, the mixture was washed with CHCl_ThreeAnd 1M Na_TwoCO_ThreeDistribute among
You. The organic layer was worked up to give a residue, which was_Three/ MeOH (1: 1 v / v
) And 32% NH_ThreeColumn chromatography on silica gel with water (4 mL for 1 L eluent)
Purify by lash chromatography. The fraction containing the desired product
The residue obtained by evaporation is_TwoFurther purification by stirring in O. Filtration of the mixture gives the pure title product (0.3 g, 83.3%): C₄₄H ₅₁ N₉O_FiveM. p. 160-162 ° C; hydrochloride m. p. 233-235 ° C;¹H
-NMR (CDCl_Three) Δ 1.85-2.04 (m, 4H, 2 x CH_Two), 2.
23-2.40 (m, 15H, 5xCH_Three), 2.53-2, 73 (m, 8H, 4 x CH_Two), 3.20-3.40 (m, 4H, 2xCH)_Two), 3.43-
3.55 (m, 2H, CH_Two), 4.30 (t, 2H, CH_Two), 6.00 (d,
1H, ar), 6.45 (d, 1H, ar), 6.78 (brt, 1H, ex), 7.05-7.15 (m, 2H, ar), 7.30-7.54. (M, 3H,
ar), 7.97 (d, 1H, ar), 8.12-8.24 (m, 2H, ar)
, 8.62 (d, 1H, ar), 10.72 (brs, 1H, ex), 10. 84 (br s, 1H, ex), 13.11 (s, 1H, ex).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 471/04 105 C07D 471/04 105C 519/00 311 519/00/00 311 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT , LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Porcci, Paolo Italia I-62032 Camelino Via de Rubastione 2 F term (reference) 4C034 BD01 4C065 AA07 BB05 CC09 DD03 EE02 HH01 JJ01 KK04 LL01 PP18 4C072 MM02 4C086 AA01 AA02 AA03 BC27 CB05 GA07 MA04 NA14 ZB26

Claims (8)

[Claims] 1. General formula (I): A-NH-Z-NH-A 'wherein: -Z is a (C ₂ -C ₄ ) alkylene chain or a formula (CH ₂ ) _n -N (B)-( _{CH 2) -N (B ')} - (CH 2) m - (CH 2) a _{n -N (B) -X- (CH} 2) m group, wherein, - n and m are independently is an integer from 2 to 4, - B is hydrogen or (C ₁ -C ₄₎ - alkyl, - X is a single bond or the formula _{- (CH 2) p -N (} B ') - be a group Wherein q is an integer from 2 to 4 and B ′ is hydrogen or (C ₁ -C ₄ ) alkyl; and the same or different A and A ′ are: Wherein: R is hydrogen or straight or branched (C ₁ -C ₆ ) alkyl, —OH, —
_{NH 2, (C 1 -C 4} ) alkoxy, mono - and di - (C ₁ -C ₄₎ alkylamino, chlorine, bromine, iodine and fluorine, nitro, mono- - and poly - fluoro (C ₁ - C ₄₎ alkyl, (C ₁ -C ₄₎ alkylsulfonyl, (C ₁ -C ₄₎ alkylamino same or different one is selected from Nosuruhoniru or more substituents; - Y is - (CH _{2) p} - It is a T group; - p is an integer 2, 3 or 4; - T is -NH _2, -OH, mono- - or di - (C ₁ -C ₄₎ alkylamino, hydroxyaldehyde ethylamino, N- morpholinyl , N-piperazinyl, N-thiomorpholinyl, N-pyrrolidinyl, N-piperidinyl, the possible stereoisomers or stereoisomeric mixtures and pharmaceutically acceptable acids and salts thereof. 2. The compound according to claim 1, wherein n and m are integers 3. 3. The compound according to claim 1, wherein A = A ′ is a group of formula (b), (c) or (e). 4. The compound according to claim 1, wherein B is a methyl group. 5. A 1,7-bis (1-chloro-9-oxo-9,10-dihydro-acridine-4-carbonyl) -4-methyl-1,4,7-triazaheptane; 9-bis (1-chloro-9-oxo-9,10-dihydroacridine-4
-Carbonyl) -5-methyl-1,5,9-triazanonane; 1,7-bis (1-chloro-7-methoxy-9-oxo-9,10-dihydroacridine-4-carbonyl) -4-methyl -1,4,7-triazaheptane;-1,9-bis (1-chloro-7-methoxy-9-oxo-9,10-dihydroacridine-4-carbonyl) -5-methyl-1,5, 9 Toriazanonan; - N4 - (3 - { [(1- chloro-9-oxo-9,10-dihydro-4-acridinyl) - carbonyl] amino} propyl) -1-chloro-9-oxo-9,
10-dihydro-4-acridine carboxamide; - N4 - {2 - [ {2 - [(2 - {[(1- Chloro-9-oxo-9,10-dihydro-4-acridinyl) carbonyl] amino} - ethyl ) (Methyl) amino] ethyl {-(methyl) amino] ethyl} -1-chloro-9-oxo-9,10
-Dihydro-4-acridinecarboxamide; -1,7-bis [1- (2- (dimethylamino) ethyl) -amino-9-oxo-9,10-dihydroacridine-4-carbonyl) -4-methyl-1 , 4,7
-Triazaheptane;-1,9-bis [1- (2- (dimethylamino) ethyl) amino-9-oxo-
9,10-dihydroacridine-4-carbonyl) -5-methyl-1,5,9-
Triazanonane; -1,7-bis [1- (2- (dimethylamino) ethyl) amino-7-methoxy-9-oxo-9,10-dihydroacridine-4-carbonyl] -4-methyl-1,4,4 7-triazaheptane;-1,9-bis [1- (2- (dimethylamino) ethyl) amino-7-methoxy-9-oxo-9,10-dihydroacridine-4-carbonyl] -5-methyl- 1,5,9 Toriazanonan; - N4 - (3 - { [(1 - {[2- ( dimethylamino) ethyl] amino} -9-
Oxo-9,10-dihydro-4-acridinyl) -carbonyl] amino {propyl) -1-{[2- (dimethylamino) ethyl] amino} -9-oxo-9,
10-dihydro-4-acridinecarboxamide; -N4- {2-[{2-[(2-} [(1-{[2- (dimethylamino) ethyl] amino} -9-oxo-9,10-dihydro -4-acridinyl) carbonyl] amino {ethyl) (methyl) amino] ethyl {(methyl) amino] ethyl}-
1-{[2- (dimethylamino) ethyl] amino} -9-oxo-9,10-dihydro-4-acridinecarboxamide; -1,7-bis [1- (2- (dimethylamino) ethyl) -amino -7-hydroxy-9-oxo-9,10-dihydroacridine-4-carbonyl] -4-methyl-1,4,7-triazaheptane; -1,9-bis [1- (2- (dimethylamino) ) Ethyl) amino-7-hydroxy-9-oxo-9,10-dihydroacridine-4-carbonyl] -5-methyl-1,5,9-triazanonane; -1,7-bis [1- (2- ( Dimethylamino) ethyl) -aminoacridine-
4-carbonyl] -4-methyl-1,4,7-triazaheptane; 1,9-bis [1- (2- (dimethylamino) ethyl) aminoacridine-4
-Carbonyl) -5-methyl-1,5,9-triazanonane; -1,7-bis [2- (2- (dimethylamino) ethyl) -pyrazole [3,4
, 5-kl] acridine-5-carbonyl] -4-methyl-1,4,7-triazaheptane; - 1,9-bis [2- (2- (dimethylamino) ethyl) pyrazole [3,4,
5- kl ] acridine-5-carbonyl] -5-methyl-1,5,9-triazanonane; -1,7-bis [2- (2- (dimethylamino) ethyl) -9-methoxypyrazole [3,4 , 5- kl ] acridine-5-carbonyl] -4-methyl-1,4
, 7-Triazaheptane trihydrochloride;-1,9-bis [2- (2- (dimethylamino) ethyl) -9-methoxypyrazole [3,4,5- kl ] acridine-5-carbonyl] -5 -Methyl-1,5
, 9-Triazanonane trihydrochloride; 1,7-bis [2- (2- (dimethylamino) ethyl) -9-hydroxypyrazole [3,4,5- kl ] acridine-5-carbonyl] -4-methyl -1,
4,7-triazaheptane; 1,9-bis [2- (2- (dimethylamino) ethyl) -9-hydroxypyrazole [3,4,5- k1 ] acridine-5-carbonyl] -5-methyl -1,
5,9-triazanonane; 1,7-bis [4- (N- (2- (dimethylamino) ethyl))-carboxamido-9-oxo-9,10-dihydroacridin-1-yl] -4-methyl −
1,4,7-triazaheptane; 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-9-oxo-9,10-dihydroacridin-1-yl]- 5-methyl-1
, 5,9-Triazanonane; -1,7-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-7-methoxy-9-oxo-9,10-dihydroacridin-1-yl] −
4-Methyl-1,4,7-triazaheptane; 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-7-methoxy-9-oxo-9,10- Dihydroacridin-1-yl]-
5-methyl-1,5,9-triazanonane; 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-7-nitro-9-oxo-9,10-dihydroacridine -1-yl] -5
-Methyl-1,5,9-triazanonane; 1,7-bis [4- (N- (2- (dimethylamino) ethyl))-carboxamide-7-hydroxy-9-oxo-9,10-dihydroacridine -1-yl] -4-methyl-1,4,7-triazaheptane; 1,9-bis [4- (N- (2- (dimethylamino) ethyl)) carboxamido-7-hydroxy-9- Oxo-9,10-dihydroacridin-1-yl]
-5-methyl-1,5,9-triazanonane; 1,7-bis [4- (N- (2- (dimethylamino) ethyl))-carboxamidoacridin-1-yl] -4-methyl-1, 4,7-triazaheptane; 1,9-bis [4- (N- (2- (dimethylamino) ethyl))-carboxamidoacridin-1-yl] -5-methyl-1,5,9-triazanonane -1,7-bis [2- (2- (dimethylamino) ethyl) -1,3,7-trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6,1- de ] acridine; -6-yl] -4-methyl-1,4,7-triazaheptane; 1,9-bis [2- (2- (dimethylamino) ethyl) -1,3,7-trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6,1- e] acridine-6-yl] -5-methyl-1,5,9-Toriazanonan; - 1,7-bis [2- (2- (dimethylamino) ethyl) -9-methoxy-1,
3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6
1- de ] acridin-6-yl] -4-methyl-1,4,7-triazaheptane; -1,9-bis [2- (2- (dimethylamino) ethyl) -9-methoxy-1,
3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6
1- de ] acridin-6-yl] -5-methyl-1,5,9-triazanonane; -1,9-bis [2- (2- (dimethylamino) ethyl) -9-nitro-1,3
, 7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6,1
- de] - acridine-6-yl] -5-methyl-1,5,9-Toriazanonan; - 1,7-bis [2- (2- (dimethylamino) ethyl) -9-hydroxy -
1,3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,
6,1- de ] acridin-6-yl] -4-methyl-1,4,7-triazaheptane; -1,9-bis [2- (2- (dimethylamino) ethyl) -9-hydroxy- 1
, 3,7-Trioxo- [1H, 2H, 3H, 7H, 12H] pyrimido [5,6
, 1- de ] Acridin-6-yl] -5-methyl-1,5,9-triazanonane; -1,9-bis {2- [2- (dimethylamino) ethyl] -9,10-dimethoxy-pyrimido [5,6,1- de ] -acridin-6-yl] -5-methyl-1
, 5,9-Triazanonane; -2- [2- (dimethylamino) ethyl] -6-{[3-({2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2, 3-dihydro - 1H, 7 H - pyrimido [5,6,1- de] acridine-6-yl} amino) propyl]
Amino {-2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridine-1,3,7-trione; -2- [2- (dimethylamino) ethyl] -6-{[ 6 - ({2- [2- (dimethylamino) ethyl] 1,3,7-trioxo-2,3-dihydro - IH, 7 H - pyrimido [5,6,1- de] acridine-6-yl [Amino) hexyl]
Amino {-2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridine-1,3,7-trione; -2- [2- (dimethylamino) ethyl] -6-{[ 8-({2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-dihydro- 1H, 7 H -pyrimido [5,6,1- de ] acridin-6-yl [Amino) octyl]
Amino {-2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridine-1,3,7-trione; -2- [2- (dimethylamino) ethyl] -6-{[ 12-({2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridin-6-yl} Amino) dodecyl] amino} -2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridine-1,3,7-trione; -2- [2- (dimethylamino) ethyl]- 6-(｛2-[｛2-[[2-(｛
2- [2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridin-6-yl @ amino) ethyl] (methyl) amino] ethyl} (methyl) amino] ethyl} amino) -2,3-dihydro - 1H, 7H - pyrimido - [5,6,1- de] acridine-1,3,7-trione; - N4 -[2- (dimethylamino) ethyl) -1-({3-[[3-({2- [
2- (dimethylamino) ethyl] -1,3,7-trioxo-2,3-dihydro- 1H, 7H -pyrimido [5,6,1- de ] acridin-6-yl @ amino)
A compound according to claim 1, selected from propyl] (methyl) amino] propyl @ amino) -9-oxo-9,10-dihydro-4-acridinecarboxamide. 6. Use of a compound according to claims 1 to 5 for the manufacture of a medicament having antitumor activity. 7. The use according to claim 6, wherein the tumor to be treated is a colon tumor. 8. A formulation comprising an effective dose of at least one compound according to claims 1 to 5 in admixture with a pharmaceutically acceptable excipient.