WO1998023618A1

WO1998023618A1 - 2,3,4,7-tetrahydropyridoindazole[1,4] benzodiazepine derivatives having antitumor activity

Info

Publication number: WO1998023618A1
Application number: PCT/EP1997/006355
Authority: WO
Inventors: Ambrogio Oliva; Ernesto Menta
Original assignee: F.Hoffmann-La Roche Ag
Priority date: 1996-11-29
Filing date: 1997-11-14
Publication date: 1998-06-04
Also published as: ITMI962497A0; IT1286509B1; ITMI962497A1

Abstract

The present invention relates to new 2,3,4,7-tetrahydropyridoindazole[1,4]benzodiazepines 4,7 disubstituted of formula (I) and to salts thereof with pharmaceutically acceptable acids. These compounds showed a high antitumor activity.

Description

2.3.4.7-TETRAHYDROPYRIDOINDAZOLEΠ .41BENZODIAZEPINE DERIVATIVES HAVING ANTITUMOR ACTIVITY

The present invention relates to new 2,3,4,7- tetrahydropyridoindazole-[l ,4]benzodiazepines 4,7- disubstituted and to salts thereof with pharmaceutically acceptable acids. These compounds showed a high antitu or activity. State of the art

Some 1,4-bist (aminoalkyl)amino]anthracene-9, 10- diones showed antitumor activity in clinical trials. Particularly interesting are ametantrone, 1 ,4-bis[ [2-(2- hydroxyethylamino)ethyl]amino]anthracene-9,10-dione, and mitoxantrone , 5 , 8-dihydroxy-l , 4-bis[ [2-( 2-hydroxyethyl- amino)ethyl]amino] anthracene-9,10-dione [[Zee-Cheng et al., J. Med. Chem. 21. 291-4 (1978); Cheng et al., "Progress in Medicinal Chemistry", Ellis, G.P. and West, G.B. , eds . Elsevier, Amsterdam, 1983, vol. 20, pp. 83 and references cited therein] .

Mitoxantrone is a broad spectrum antitumor agent, whose activity is similar to that of the anthracycline antibiotic doxorubicin. Clinical experiments have demonstrated that mitoxantrone has a particularly promising activity in the treatment of the advanced breast tumor, of the acute leukemia and of the lymphoma [Legha, Druos of Today. 20. 629 (1984)].

The limiting aspect of these drugs is the cardiotoxicity , particularly for mitoxantrone, and for both a myelodepressive toxic effect. Moreover, both compounds show cross resistance against cellular hystotypes which already developed resistance with doxorubicin, being said resistance mediated by hyperexpression of glycoprotein P. Such a resistance, named mul tidrug resistance (MDR), is common to several antitumor antibiotics, among which amsacrine and podofyllotoxin and derivatives thereof, and it is one of the main reasons of the failing of the treatment of solid tumors with such antibiotics.

In an attempt to overcome these drawbacks anthracenediones with a modified chromophore have been prepared. For example, European Pat. Appln. 103,381 claims 2-aminoalkyl-5-aminoalkylamino anthra[l,9- cd]pyrazole-6(2H)-ones (anthrapyrazoles) with antitumor activity. The antitumor activity of said compounds in preclinical models have been reported by H.D. Hollis Showalter et al. ( J . Med. Chem.. 30. 121-131 (1987))..

However, the anthrapyrazoles are not devoid of toxic side effects, such as severe leukopenia (W.H.O. grade 3 and 4) and neutropenia (W.H.O. grade 4) which resulted dose limiting in Phase I and II clinical trials with the anthrapyrazole CI-941 [I.E. Smith et al., J. Clin. Oncol.. 9. 2141-2147 (1991)]. Moreover a marked nephrotoxicity is associated to the treatment with CI- 941 in the rat [D. Campling and M.E.C. Robbins, Nephrotoxicity. Peter H. Dekker Bach ed., Pages 345-352 (1991), New York: see Chem. Abstracts life: 294n (1992)] and these authors suggest that the renal damages may be a clinical problem in the therapy with anthrapyrazoles. Furthermore recent papers rDruαs of the Future, 17. 725 (1992); Judson, I.R. et al., Proc. Amer. Assoc. Cancer Res.. 32. abstr . 1059 (1991)] indicate that the anthrapyrazole CI-941 induces irreversible cardio- toxicity in the human (a lethal cardiac event has been reported in Can. J. Cardiology, 11/5. 415-22, 1995).

For what said above, the research for new active analogues is still highly desirable. Aza-analogues of anthrapyrazoles, in which a nitrogen has been inserted in positions 8 and 9, are described in PCT/US93/08241

(published 31-03-1994, WO94/06795).

We have found that new benzodiazepine derivatives of aza-anthrapyrazoles are endowed with a high antitumor activity, especially with respect to leukemias. Description of the invention

The present invention relates to compounds of formula ( I ) :

in which: at least one and not more than two X, Y, Z or T groups are nitrogen (=N-) and the others are carbon (=CH-=, with the proviso that X and Z or Y and T , respectively, cannot be simultaneously nitrogen;

R and R-, are the same or different and are selected from the group consisting of (C₁-C₁₀)alkyl, C₂-C₁₀)alkyl substituted by one or two substituents selected from the group consisting of ^{and ~NR}3^N4'

interrupted by one or two oxygen atoms or by a -NR group and being said (C₂-C₁₀ )alkyl optionally substituted by one or two hydroxy (OH) or -NRgR₄ groups;

R₂ is selected from the group consisting of hydrogen,

(C₁-C₆)alkyl, -S(0₂)R₆, (C₂-C₆)alkyl optionally substituted by a -NR R₄ group; R, and R^ can be the same or different and are selected from the group consisting of hydrogen, (C^-C^_Q )alkyl ,

(C₂-C^_Q )alkyl substituted by one or two hydroxy (OH) groups, or R_β and R^, taken together with the nitrogen atom to which are linked, form a 5- or 6-membered heterocyclic aromatic or not-aromatic ring, optionally containing another heteroatom selected from the group consisting of sulfur, oxygen and nitrogen;

R^ is selected from the group consisting of hydrogen,

(C₁-C₁₀)alkyl, (C₂-C₁₀ )hydroxyalkyl, (C₂-C₁₀ )alkyl substituted with a -NR₃R₄ group;

Rg is selected from the group consisting of (^c ~

C₁₀)alkyl, phenyl, phenylalkyl, as free bases and the salts thereof with pharmaceutically acceptable acids. We have found that the compounds of formula (I) have a high antitumor activity especially on the leuke ias and therefore are candidates for the treatment of such pathologies.

The present invention encompasses also the tautomeric forms, the single enantio ers and diastereoisomers of the compounds of formula (I), as well as mixtures thereof.

Examples of pharmaceutically acceptable acids are: inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, pyrophosphoric acid or organic acids such as acetic, trifluoroacetic , propionic, citric, benzoic, lactic, maleic, malic, fumaric, succinic, tartaric, glutamic, aspartic, gluconic, ascorbic, p-toluenesulphonic, methanesulphonic acid or other acids usually employed. Preferred compounds of formula (I) are those in which Z is nitrogen and X, Y and T are carbon.

Particularly preferred compounds of formula (I) are those in which Z is nitrogen and X, Y and T are carbon and R and R., , which can be the same or different, are selected from the group consisting of:

- (C₁-C₁₀)alkyl;

- residue of formula -(CH₂ )_n-NR₃R₄ , wherein n is the integer 2 or 3 and R3 and R are independently hydrogen or a (C., -C5 )alkyl group; - residue of formula -(CH₂)_n-OR₂, wherein n is as above defined and R₂ is hydrogen or a (C^-Cg)alkyl group;

- residue of formula -(CH₂ )_n~NH-(CH₂ )_m-OH, wherein n and m are independently the integer 2 or 3.

Even more particularly preferred compounds of formula (I) are:

7- [ 2- ( dimethylamino )ethyl]-4- («2-hydroxyethyl )-

2,3,4, 7-tetrahydropyrido[4 ' , 3 ' -6 , 7 ] indazole[5,4, 3-efg]-

[1 ,4]benzodiazepine;

7- [ 2- ( dimethylamino )ethyl]-4-methyl-2 ,3,4, 7-tetra- hydropyrido[4' , 3 ' -6 ,7]indazole[ 5 ,4 , 3-efg] [1 ,4]benzo- diazepine .

The compounds of formula (I) can be prepared starting from the intermediates of formula (II):

in which R, X, Y, Z and T are as above defined and U is a chlorine or para-toluenesulphonyloxy (-OTs) group.

In particular, when X and T are contemporaneously a carbon atom, then U is preferably a -OTs group.

The intermediates of formula (II) are reacted with an amine of formula (III):

G-NH-CH₂-CH₂-NH-R₁ (III) wherein R-^ is as above defined and G is a suitable protecting group of a primary amine which can be removed in acidic conditions, to give the intermediates of formula (IV):

The intermediates of formula (IV), once the G protecting group has been removed, are cyclized to give the compounds of formula (I).

The reaction of a compound of formula (II) with an amine of formula (III) can be performed by heating the compound (II) with a stoichiometric amount or with an excess of amine (III). The reaction is usually performed in an inert solvent such as methylene chloride, chloroform, 1 ,1 , 1-trichloroethane , dimethoxyethane, tetrahydrofuran, di ethylsulfoxide , dimethylformamide , pyridine, picoline or mixtures thereof or, if desired, using the same amine (III) as a solvent, optionally in the presence of an inorganic base such as a carbonate or hydrogencarbonate of an alkali or alkaline-earth metal or of an organic base such as trialkyl amine, at a temperature comprised between 40^βC and the boiling temperature of the solvent.

Preferably the reaction is performed in a solvent such as pyridine, chloroform or dimethylsulfoxide, using from 2 to 10 equivalents of amine (III) and working at a temperature ranging from 50^βC to 100"C.

The reaction of an intermediate of formula (II) in which U is OTs with an amine of formula (III) can be performed in solvents such as pyridine or dimethylsulfoxide and at temperatures ranging from 50 "C to 100^βC.

In the case the R^ residue contains some primary or secondary amino groups which may interfere with the reaction, these groups shall be protected with a suitable protecting group which can be the same or different from the G group. In the case the protecting groups are the same, they will be removed in one step during the subsequent reaction. Examples of G protecting groups are: (C-,-C₄ )alkoxycarbonyl derivatives (preferably tert-butoxycarbonyl) and (C₇-C^g )aralkyloxy- carbonyl derivatives (preferably benzyloxycarbonyl ) . The removal of the G protecting group can be performed following procedures well known to the expert of the art, such as for example those described in

Green, T.W., Wuts, P.G.M., "Protective Groups in Organic Synthesis", second edition, John Wiley & Sons, 1991.

For example, the removal of a N-tert-butoxycarbonyl group may be preferably obtained by treating the protected intermediate with trifluoroacetic acid, in an inert solvent such as dichloromethane, chloroform o mixtures thereof, at a temperature ranging from 20°C to 50°C and for a reaction time span ranging from few minutes to several hours.

The cyclization reaction of the intermediate (IV), once the G protecting group has been removed, can be performed in an inert solvent and at temperatures ranging from room temperature to 50°C. The cyclization reaction can also occur directly during the previous reaction of removal of the protecting group, without need of separation of the deprotected intermediate. In this case, the reaction time span could be longer in comparison with that necessary to remove the G group, so that to allow the cyclization reaction to go to completeness.

The intermediate of formula (II) in which U is a -OTs group and X and Y are carbon atoms are known compounds and can be prepared according to what is described in WO 95/24407. For example, its synthesis pattern can encompass the following steps: a) Friedel-Craft acylation of 1 ,4-difluorobenzene with a compound of formula (V):

followed by reaction of the mixtures of the ketoacids obtained in the previous step with sodium methoxide in methanol and subsequent reduction of the keto group with zinc/copper in 75% aqueous formic acid. b) chromatographic separation of the wanted isomer and cyclization thereof by heating at 110 - 120°C in the presence of polyphosphoric acid; c) oxidation of the cyclized compound obtained in the previous step to the corresponding dione by means of cerium ammonium nitrate in water/acetonitrile mixture, followed by removal of the methyl group by reaction with aluminium trichloride in methylene chloride; d) functionalization of the free hydroxy group by means of para-toluenesulphonyl chloride. The compounds of formula (II) in which U is a chlorine atom are known compounds as well and can be prepared following what is described in WO 95/24407. Their synthesis pattern can for example encompass the following steps: a) Friedel-Craft acylation of l-chloro-4-fluorobenzene with a compound of formula (V) in the presence of aluminium trichloride and separation of the wanted regioisomer; b) reduction of the ketoacid regioisomer obtained at step a) with zinc in 75% aqueous formic acid; c) oxidative cyclization of the compound obtained at step b) by means of 30% oleum at 130 - 140°C to give the wanted intermediate. The salts of the compound of formula (I) may be converted one in each other following conventional methods, well known to the expert of the art.

Biological activity of the compounds of the invention

The evaluation of the biological activity of the compounds of the invention has been performed "in vitro" and "in vivo" following protocols developed by the U.S. National Cancer Institute.

The evaluation of the "in vitro" cytotoxic activity has been performed using a human colon adenocarcinoma (LoVo) cell line isolated from a metastatic nodule. The compounds have been tested according to the "MTT assay" (Mosman, T. "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay", J. Immunol. Methods, (1983), 65 , 55-63; Green, L.M., "Rapid Colorimetric Assay for Cell Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines" , J. Immunol. Methods, (1984), 10, 257-268).

Studies of the "in vivo" biological activity have been performed using the P 388 murine leukemia model. The P 388 murine leukemia cells have been injected intravenously (i.v.) in CD2F1 rats. The treatment has been started approximately 24 hours after the tumor transplantation and the doses of the product have been injected i.v. (P 388 i.v. /i.v.) according to pre- established protocols, usually at 3 day-intervals. The studies have been conducted for a period of 60 days and the date of death of each animal has been recorded. The

T/C % has been determined using the mean survival time

(MST) for each group, according to the formula: T/C% = [(MST_treated)/(MST_controls)] x 100

Tables I and II show the data of some representative compounds of formula (I) in comparison with the known anthrapyrazole CI-941.

As it can be seen, the compounds of the invention evidence "in vivo" a marked activity on the P 388 murine leukemia, a model which is considered by the expert of the art as predictive of the activity on the human.

Therefore, on the base of the showed results, the compounds of the invention are expected to be active on the human, especially on leukemias susceptible of treatment with antitumor antibiotics, anthracenediones and anthrapyrazoles.

The compounds of the invention may therefore be employed as active ingredients in therapeutical compositions to induce regression and/or stopping of tumors in mammals when administered in dosages ranging from 0.5 to 20 mg/kg of body weight. A preferred daily dosage regimen in the human could vary from 5 to 200 mg/m² of body area. The dosage may be adjusted in order to be compatible with other regimens of treatment, such as for example the radiotherapy.

The pharmaceutical compositions containing the compounds of formula (I) are encompassed in the invention. These pharmaceutical compositions may contain any amount of one or more compounds of formula (I) able to exert an antitumor activity in the mammals on the tumors susceptible to the therapy with doxorubicin, anthracenediones and anthrapyrazoles.

The pharmaceutical compositions may contain, in addition to the compounds of formula (I), pharmaceutically compatible excipients, so that to allow the administration by any route, such as oral, parenteral, intravenous, intradermic, subcutaneous or topical route, in liquid or solid form. An administration route of the compounds of formula (I) is the oral route. Oral compositions will generally include an inert diluent or an edible carrier. They may be included in gel capsules or compressed into tablets. Other forms suitable for oral administration are capsules, pills, elixirs, suspensions or syrups.

The tablets, pills, capsules and similar compositions may contain the following ingredients (in addition to the active substance): a binder such as a microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel, corn starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharine or a flavoring agent such as peppermint, methyl salicylate or orange flavor. When the chosen composition is in form of capsules, it may contain in addition a liquid carrier such as a fatty oil. Other compositions may contain other various materials which modify the physical form, such as coating agents (for tablets and pills) such as sugar or shellac. The materials used in the preparation of the compositions should be pharmaceutically pure and not toxic at the employed dosages.

For the preparation of pharmaceutical compositions by parenteral administration route, the active ingredient may be incorporated into solutions or suspensions, which may include in addition the following components: a sterile diluent such as water for injection, saline solution, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediamminotetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the solution tonicity such as sodium chloride or dextrose. The parenteral preparation may be included in ampoules, disposable syringes or glass or plastic vials.

The invention is further described by the following examples . PREPARATION 1 - Synthesis of t .2-ethanediamine . N^-(2- aminoethyl )-N^ .N^-dimethyl

The method described in J. Am. Pharm. Assoc, 1955 , 44 , 654-7 is followed.

To a flask containing ethylenediamine (203 ml), kept under stirring and in nitrogen atmosphere, are added portionwise in a span of two hours 73 g of (2- chloroethyl )dimethylamine hydrochloride , keeping the temperature below 55°C. At the end of the addition, the reaction mixture is heated ar about 90°C for 5 hours, then it is brought to room temperature and 85 ml of 35% solution of sodium hydroxide are added. A white precipitate is formed (sodium chloride), which, after adding 100 ml of absolute ethanol and concentrating the mixture to a 185 g weight, is separated by filtration.

The filtrate is concentrated to a 60 g weight, then it is added with 100 ml of ethanol and then it is filtered.

The mixture is again concentrated to dryness and then again filtered. The residue is fractionated by distillation under reducing pressure through a Vigreux column. 21.55 g of the product are obtained. !H NMR in CDC1₃: 2.82-2.72 ppm (m, 2H); 2.70-2.58 ppm (m, 4H); 2.37 ppm (t, 2H); 2.17 ppm (s, 6H). PREPARATION 2 - Synthesis of 1.2-ethanediamine . M2-T2-

To a suspension of 1.31 g of 1,2-ethanediamine, N²- (2-aminoethyl)-N¹,N¹-dimethyl in 10 ml of tetra- hydrofuran and 5 ml of 1 N sodium hydroxide, kept under vigorous stirring, a solution of 1.09 g of ditert-butyl dicarbonate in 4 ml of tetrahydrofuran is added dropwise during about 5 minutes. After about 2 hours 30 minutes the reaction mixture is diluted with 10 ml of ethyl acetate and 5 ml of saturated solution of sodium chloride. The layers are separated and the aqueous phase is further extracted with ethyl acetate (2x10 ml). The organic layers are collected, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue (1.2 g) is purified by silica gel chromatography (65 g; eluent: chloroform/methanol/conc. ammonia from 90:10:0.5 to 80:20:1). 505 mg of the product as an oil are obtained. !H NMR in CDCI3: 5.07 ppm (br s, 1H); 3.22 ppm (q, 2H); 2.74 ppm (t, 2H); 2.68 ppm (t, 2H); 2.40 ppm (t, 2H); 2.22 ppm (s, 6H); 1.44 ppm (s, 9H).

Analogously, 1 ,2-ethanediamine, N²-( 2-hydroxyethyl J-N¹- ( tert-butoxycarbonyl ) is prepared,

¹H NMR in CDC1₃: 5.10 ppm (br t, 1H); 3.65 ppm (t, 2H); 3.22 ppm (q, 2H); 2.80-2.67 ppm (m, 4H); 1.42 ppm (s, 9H) .

EXAMPLE 1 - Synthesis of 2-r2-(dimethylaminoiethv1 ^{^}l-f- ^N-T2-T f ( 1. -dimethvlethoxv)carbonvl1 mino1ethvl1-N- ( 2- hydroxyethvl )a ino1 indazoleT4.3-α l isoσuinoline-6( 2H - oe

A mixture of 2-[2-(dimethylamino)ethyl]-5-[ [ (4- methylphenyl )sulphonyl ]oxy] indazole[4 , 3-gh] isoquinoline- 6(2H)-one (0.623 g), 1 ,2-ethanediamine, N²-(2-hydroxy- ethyl)-N¹-( tert-butoxycarbonyl) (1.652 g) and diisopropylamine (0.47 ml) in anhydrous dime- thylsulphoxide is kept at 60°C under stirring for 16 hours and at 100^βC for additional 5 hours, under nitrogen atmosphere. The reaction mixture is cooled to room temperature and partitioned between dichloromethane (50 ml) and water (80 ml). The layers are separated and the aqueous phase is extracted with dichloromethane (3x50 ml). The organic layers are washed with water (2x50 ml), then they are combined, dried over sodium sulfate and concentrated to dryness. The dark red residue is purified by silica gel chromatography (60 g; eluent: chloroform/methanol/conc . ammonia from 95:5:0.25 to 92:8:0.4). The chromatographic fractions containing the product are collected and evaporated to dryness. The crystallization from methyl-tert-butylether yields red crystals which are recovered by filtration, washed with methyl, tert-butylether and dried under vacuum at 50 ^βC, obtaining 0.29 g of the product, m.p. 100-104'C.

¹H NMR in d6-DMSO: 9.45 ppm (d, 1H); 8.76 ppm (d, 1H)

8.14 ppm (dd, 1H); 8.10 ppm (d, 1H); 7.51 ppm (d, 1H).

6.65 ppm (br t, 1H); 4.69 ppm (t, 2H ) ; 4.60 ppm (t, 1H ) 3.70-3.45 ppm (m, 6H); 3.11 ppm (br q, 2H); 2.81 ppm (t,

2H); 2.21 ppm (s, 6H); 1.22 ppm (s, 9H).

EXAM£L£ 2 7-F2-(dimethYlaminp)ethyl1-4-( 2-hydro- xyethyl )-2 , 3.4.7-tetrahvdropyridoT4 ' .3 ' -6.71indazole- r 5.4.3efσl T1.41benzodiazepine 2 ml of trifluoroacetic acid are added to a solution of 2-[2-(dimethylamino)ethγl]-5-[N-[2-[[(l,l- dimethylethoxy)carbony1] amino]ethyl]-N-( 2-hydroxyethyl )- amino]indazole[4, 3-gh]isoquinolin-6(2H)-one (0.28 g) in anhydrous dichloromethane (2 ml). The mixture is kept under stirring at room temperature for 6 hours, then it is concentrated almost to dryness. The residue is redissolved in ethanol (10 ml) and the resulting solution is concentrated almost to dryness; the procedure is repeated twice. The residue is partitioned between brine (15 ml) and dichloromethane (15 ml). The aqueous phase is brought to strongly basic pH (pH > 11) with 6 N sodium hydroxide. The layers are separated and the aqueous phase is extracted with dichloromethane (4x15 ml). The combined organic layers are dried over sodium sulfate and concentrated to dryness. The foamy residue is purified by silica gel chromatography (35 g; eluent: chloroform/methanol/conc . ammonia from 95:5:0.25 to 85:15:0.75). The chromatographic fractions containing the product are collected and concentrated to dryness. The residue is triturated in a dichloromethane- ethyltert-butylether mixture, to give, after elimination of the solvents by distillation under reduce pressure, the pure product as a yellow-brown solid

(0.108 g).

!H NMR in CDC1₃: 9.33 ppm (d, 1H); 8.52 ppm (d, 1H) 8.27 ppm (dd, 1H); 7.42 ppm (d, 1H); 7.33 ppm (d, 1H)

4.52 ppm (t, 2H); 4.21 ppm (br s, 2H); 4.02 ppm (t, 2H)

3.62 ppm (t, 2H); 3.24 ppm (br s, 2H); 2.87 ppm (t, 2H)

2.32 ppm (s, 6H) .

EXAMPLE 3 = 7-T2- di ethvlamino )ethvl1-4-( 2-hvdroxv- ethyl12.3.4.7-tetrahvdropyridof4 ' .3 ' -6.71 indazoleT 5.4.3- efqiri,41benzQdiazepin.e maleate

A solution of maleic acid (0.073 g) in absolute ethanol (1 ml) is added under stirring to a solution of

7-[2-(dimethylamino )ethyl]-4-( 2-hydroxyethyl )-2 , 3 , 4 , 7- tetrahydropyrido[4" ,3 '-6,7]indazole[5,4,3-efg][l,4]- benzodiazepine (0.199 g) in absolute ethanol (3 ml) heated at 78^DC in nitrogen atmosphere. After addition of methyltert-butylether (2 ml) the reaction mixture is allowed to reach room temperature, under stirring. The red crystals are separated by filtration, washed with methyltert-butylether and dried under vacuum at 40^*C, obtaining 0.211 g of the product.

¹H NMR in d6-DMSO: 9.60 ppm (d, 1H); 8.81 ppm (d, 1H)

8.45 ppm (dd, 1H); 8.12 ppm (d, 1H); 7.61 ppm (d, 1H) 6.02 ppm (s, 4H); 4.91 ppm (t, 2H); 4.14 ppm (br s, 2H)

4.00-3.80 ppm (m, 4H); 3.72 ppm (br s, 2H); 3.43 ppm (t,

2H); 2.67 ppm (s, 6H) .

EXAMPLE 4 -

Starting from the suitable intermediates of formula (II) and by reacting them with the suitable amines of formula (III), according to the procedures described in examples 1-3, the following compounds are prepared:

4,7-bis[2-(dimethylamino)ethyl]-2,3,4,7-tetrahydro- pyrido[4 ' ,3 ' -6 ,7 ] indazole [5 ,4, 3-efg] [1 ,4]benzodiazepine dimaleate , H NMR in d6-DMS0, 333^βK: 9.51 ppm (s, IH); 8.75 ppm

(d, IH); 8.43 ppm (d, IH); 8.07 ppm (d, IH); 7.51 ppm

(d, IH); 6.05 ppm (s, 4H); 4.95 ppm (t, 2H); 4.19 ppm

(br s, 2H); 4.00 ppm (t, 2H); 3.65-3.50 ppm (m, 4H);

3.31 ppm (t, 2H); 2.80 ppm (s, 6H); 2.77 ppm (s, 6H); - 7-[2-(dimethylamino)ethyl]-4-methyl-2,3,4,7-tetra- hydropyrido[ 4 ' , 3 ' -6 , 7 ] indazole [5,4, 3-efg] [ 1 , 4]benzodia- zepine maleate,

^XH NMR in d6-DMSO, 343^βK: 9.15 ppm (s, IH); 8.84 ppm

(d, IH); 8.46 ppm (d, IH); 8.20 ppm (d, IH); 7.50 ppm (d, IH); 6.02 ppm (s, 2H); 4.98 ppm (t, 2H); 4.17-4.05 ppm (m, 2H); 3.82-3.70 ppm ( , 2H); 3.56 ppm (t, 2H);

3.55 ppm (s, 3H); 2.73 ppm (s, 6H);

7-[2-(diethylamino)ethyl]-4-(2-hydroxyethγl)-

2,3,4, 7-tetrahydropyrido[4 ' , 3 ' -6 , 7 ] indazole[ 5 , 4 , 3-efg]- [l,4]benzodiazepine;

7- [2- (dimethylamino)ethyl]-4-decy1-2, 3,4,7-tetra- hydropyrido[4 ' , 3 ' -6 , 7 ] indazole [5,4,3-efg][l,4]benzo- diazepine;

7-methyl-4-[2-(dimethylamino)ethyl] -2 ,3 ,4,7-tetra- hydropyrido[4' ,3 ' -6,7]indazole[5,4,3-efg] [1 ,4]benzodi- azepine;

7-decyl-4-[2-(diethylamino)ethyl] -2,3,4,7-tetrahy- dropyrido[4 ' , 3 ' -6 , 7 ] indazole[5,4,3-efg][l,4]benzodiaze- pine; - 7-(2-hydroxyethyl)-4-[2-(dipenthylamino)ethyl]-

2,3,4, 7tetrahydropyrido[4 ' , 3 ^• -6 , 7 ] indazole [ 5 , 4 , 3-efg]- [l,4]benzodiazepine;

7-[2-( 2-hydroxyethyl )aminoethyl] -4- [2- (dimethylamino )ethyl ] -2 , 3 , 4 , 7-tetrahydropyrido[4 ' , 3 ' -6 , 7 ] indazole- [5,4,3efg][l ,4]benzodiazepine; - 7-methyl-4-[2-(2-hydroxyethyl)aminoethyl] -2,3,4,7- tetrahydropyrido[4 ' ,3 ' -6 ,7]indazole[5 ,4,3-efg] [l,4]ben- zodiazepine;

7- [2- ( dimethylamino )ethyl ]-4- ( 2-hydroxyethyl )- 2,3,4, 7-tetrahydropyrido[2 ' , 3 ' -6 , 7 ] indazole [5,4, 3-efg]- [1 ,4]benzodiazepine;

4, 7-bis[2- (dimethylamino)ethyl]-2,3,4, 7-tetra- hydropyrido[2 ' ,3 ^,-6,7]indazole[5,4_/3-efg] [l,4]benzodi- azepine;

7-[2- ( dimethylamino )ethyl]-4-methγl-2 ,3,4,7- tetrahydropyrido[2* ,3 '-6,7]indazole[5,4,3-efg] [1,4]- benzodiazepine;

7-[2-(dimethylamino)ethyl ]-4-decy1-2, 3, 4, 7-tetrahydropyrido[2 ' ,3 ' -6, 7] indazole[5, 4, 3-efg] [1,4]- benzodiazepine; - 7-methγl-4-[2-(dimethylamino)ethγl]-2,3,4,7-tetra- hydropyrido[2 ' , 3 ' -6 , 7 ] indazole[5,4,3-efg][l,4]benzo- diazepine;

7-decyl-4- [2- (diethyla ino)ethyl]-2,3,4, 7-tetra- hydropyrido[2 ' ,3 ' -6,7]indazole[5,4,3-efg] [l,4]benzo- diazepine;

7- ( 2-hydroxyethyl )-4- [ 2- (dipenthylamino )ethyl ]- 2,3,4 , 7-tetrahydropyrido[ 2 ' , 3 ' -6 , 7 ] indazole [ 5 , 4 , 3-efg]- [l,4]benzodiazepine;

7- [2- (2-hydroxyethyl )aminoethyl]-4- [2- (dimethylami- no)ethyl]-2,3,4,7-tetrahydropyrido[2' ,3 ' -6,7]indazole- [5,4, 3-efg] [1 ,4]benzodiazepine; 7-methy1-4-[ 2- ( 2-hydroxyethy1 ) aminoethyl]-2 ,3,4,7- tetrahydropyrιdo[3 ' ,4 ' -6 , 7] indazole [5 ,4,3-efg] [1 ,4]ben- zodiazepine;

7- [ 2- ( dimethylamino ) ethyl ] -4- ( 2-hydroxyethy1 )- 2,3,4,7-tetrahydropyrιdo[3 ' ,4 ' -6 , 7] indazole [ 5 , , 3-efg]- [1 , 4]benzodιazepιne;

4 ,7-bis [2- (dimethylamino) ethyl]-2, 3, 4, 7-tetrahy- dropyrιdo[3 ' ,4 ' -6 ,7]mάazole[ 5 ,4 ,3-efg] [l,4]benzo- diazepine; - 7-[2-(dιmethylammo)ethyl]-4-methyl-2,3,4,7-te- trahydropyrιdo[3 ' ,4 ' -6 , 7 ] indazole[ 5 , , 3-efg] [1 , ]ben- zodiazepme;

7-[2-(dιmethylammo)ethyl]-4-decyl-2 ,3,4,7-tetra- hydropyπdo[3 ' ,4 ' -6 , 7] indazole [5 ,4 , 3-efg] [l,4]benzo- diazepme;

7-methy1-4- [ 2- (direthylamino) ethyl]-2, 3 ,4,7-tetra- hydropyrιdo[3 ' ,4 ' -6 , 7 ] indazole [5 ,4 ,3-efg] [1 ,4]benzodι- azepme;

7-decyl-4- [2- (diethylamino)ethyl]-2,3,4, 7-tetrahy- dropyπdo[3' ,4 ' -6 ,7]mdazole[ 5 ,4 , 3-efg] [1 ,4]benzodιaze- pme;

7-( 2-hydroxyethy1)-4-[2- (dipenthylamino)ethyl]- 2,3,4,7-tetrahydropyrιdo[3 ' ,4 ' -6 , 7] indazole [ 5 ,4, 3-efg]- [1 , ]benzodιazepιne; - 7-[2-( 2-hydroxyetnyl)ammoethyl]-4- 2-(dιmethylamι- no ) ethyl] -2 , 3 ,4 ,7-tetrahydropyrιdo[3 ' , ' -6 ,7]mdazole- [5,4,3efg][l, 4]benzodιazepιne;

7-[2-(dιmethylamιno)ethyl]-4-( 2-hydroxyethyl )- 2,3,4, 7-tetrahydropyrιdo [ 3 ' , 2 ' -6 , 7 ] indazole [ 5 , 4 , 3-efg] - [l,4]benzodιazepιne;

4 ,7-bis [2- (dimethylamino )ethyl]-2,3,4 , 7-tetrahydro- pyrido[3 ' ,2 ' -6 , 7] indazole [ 5,4 , 3-efg] [1 , 4]benzodiazepine;

7-[2-(dimethylamino)ethyl]-4-methyl-2,3,4,7-tetra- hydropyrido [ 3 ' , 2 ' -6 , 7 ] indazole [5,4,3-efg][l,4]benzodi- azepine; - 7-[2-(dimethylamino)ethyl]-4-decyl-2,3,4,7-tetra- hydropyrido[ 3 ' , 2 ' -6 , 7 ] indazole [5,4, 3-efg] [1,4]benzodi- azepine;

7-methyl-4- [2- ( dimethylamino )ethyl ]-2 , 3 , 4 , 7-tetra- hydropyrido[ 3 ' , 2 ' -6 , 7 ] indazole [ 5 , 4 , 3-efg] [1 , 4]benzodi- azepine;

7-decy1-4-[2-(diethylamino)ethyl]-2, 3,4,7-tetra- hydropyrido[ 3 ' , 2 ' -6 , 7 ] indazole[5,4, 3-efg] [1,4]benzodi- azepine;

7-(2-hydroxyethyl)-4-[2-(dipenthγlamino)ethyl]- 2,3,4,7-tetrahydropyrido[3' ,2'-6,7]indazole[5,4,3-efg]- [1 ,4]benzodiazepine;

7- [2- ( 2-hydroxyethyl )aminoethyl]-4-[2- (dimethyl- amino )ethyl]-2 , 3 , 4 , 7-tetrahydropyrido[3 ' , 2 ' -6 , 7 ] indazole[5,4, 3-efg][l ,4]benzodiazepine ; - 7-methyl-4-[2-(2-hydroxyethyl)aminoethyl]-2,3,4,7- tetrahydropyrido[ 3 ' , 2 ' -6 , 7 ] indazole [5,4, 3-efg] [1 , 4]ben- zodiazepine.

Table I -"in vitro" biological evaluation of the compounds of the invention and of CI-941 in a human colon adenocarcinoma (LoVo) cell line after 1 hour from the exposure to the drug compound

LoVo IC₅₀ (μg/ml)

CI-941

0.039 Table II - "in vivo" biological evaluation of the compounds of the invention and of CI-941 on a P 388 murine leukemia model compound P388 iv/iv + 1,4,7 dose T/C Tox . mg/kg

6 133 0/8

CI-941 9 144 0/8

13.5 133 0/8

Claims

Compounds of general formula ( I )

R and R^ are the same or different and are selected from the group consisting of (C^-C-^alkyl, C₂-C₁₀)alkyl substituted by one or two substituents selected from the group consisting of -OR₂ and -NR₃N₄, (C₂-C₁₀)alkyl interrupted by one or two oxygen atoms or by a -NR₅ group and being said (C₂-C₁₀ )alkyl optionally substituted by one or two hydroxy (OH) or -NR₃R₄ groups; R is selected from the group consisting of hydrogen, (C₁-C₆)alkyl, -S(0₂)Rg, (C₂-Cg)alkyl optionally substituted by a -NR₃R₄ group;

R₃ and R can be the same or different and are selected from the group consisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C_;LQ )alkyl substituted by one or two hydroxy (OH) groups, or R₃ and R₄, taken together with the nitrogen atom to which are linked, form a 5- or 6-membered heterocyclic aromatic or not-aromatic ring, optionally containing another heteroatom selected from the group consisting of sulfur, oxygen and nitrogen;

R₅ is selected in the group consisting of hydrogen, (C^-

C₁₀)alkyl, (C₂-C₁₀ )hydroxyalkyl, (C₂-C₁₀ )alkyl substi- tuted with a -NR₃R₄ group;

Rg is selected from the group consisting of (^cι^_

C₁₀)alkyl, phenyl, phenylalkyl, their tautomeric forms and their enantiomers and diastereoisomers, as free bases and the salts thereof with pharmaceutically acceptable acids.

2. Compounds of claim 1, in which Z is nitrogen and X, Y and T are carbon.

3. Compounds of claim 2, in which R and R^, which can be the same or different, are selected from the group consisting of:

- (C₁-C₁₀)alkyl;

- residue of formula -(CH₂)_n-NR₃R₄, wherein n is the integer 2 or 3 and R₃ and R are independently hydrogen or a (C₁-C₅)alkyl group; - residue of formula -(CH₂)_n-OR₂, wherein n is as above defined and R₂ is hydrogen or a (C₁-Cg)alkyl group;

- residue of formula -(CH₂)_n-NH-(CH₂)_m-OH, wherein n and m are independently the integer 2 or 3.

4. Compounds of claim 1, wherein such compounds are: - 7-[2-(dimethylamino)ethyl]-4-(2-hydroxyethyl)-2,3,4,7- tetrahydropyrido[4' ,3' -6 ,7]indazole[5 ,4,3- efg] [1 ,4]benzodiazepine;

4 , 7-bis [2- ( dimethylamino )ethyl]-2 ,3,4, 7-tetrahydropyrido[4 ' , 3 ' -6, 7] indazole[5, 4, 3-efg] [1 ,4]benzodiazepine di aleate;

7-[2-(dimethylamino)ethyl]-4-methyl-2,3,4,7-tetra- hydropyrido[4 ' , 3 ' -6 , 7 ] indazole [5,4, 3-efg] [1 , 4]benzodi- azepine maleate;

7-[2-(diethylamino)ethyl]-4-(2-hydroxyethyl)- 2,3,4,7-tetrahydropyrido[4' , 3 ' -6 , 7 ] indazole [5, 4 , 3-efg]- [1 ,4]benzodiazepine;

7- [2- (dimethylamino)ethyl]-4-decy1-2, 3,4,7-tetrahydropyrido[4 ' , 3 ' -6 , 7 ] indazole[ 5 , 4 , 3-efg] [1 , 4]benzodi- azepine;

7-methy1-4-[ 2- (dimethylamino) ethyl ]-2, 3,4,7- tetrahydropyrido[4' , 3 ' -6 , 7]indazole[5 ,4 ,3-efg] [1 ,4]ben- zodiazepine;

7-decyl-4-[2-(diethylamino)ethyl]-2,3,4,7-tetrahγ- dropyrido[4' ,3 '-6, 7] indazole [5 ,4 , 3-efg] [1 ,4]benzodi- azepine; - 7-(2-hydroxyethyl)-4-[2-(dipenthylamino)ethyl]-

2,3,4, 7-tetrahydropyrido[4 ' , 3 ' -6 , 7 ] indazole[ 5 , 4 , 3-efg] - [1 ,4]benzodiazepine;

7- [2- (2-hydroxyethyl)aminoethyl]-4-[2- (dimethylamino )ethyl] -2 , 3 , 4 , 7-tetrahydropyrido[4 ' , 3 ' -6 , 7 ]indazole- [5,4,3efg][l , 4]benzodiazepine;

7-methy1-4- [ 2- ( 2-hydroxyethyl ) aminoethyl ]-2 ,3,4,7- tetrahydropyrido[4' ,3 ' -6 ,7]indazole[5 ,4 ,3-efg] [l,4]ben- zodiazepine;

7- [2- (dimethylamino)ethyl]-4- ( 2-hydroxyethyl )- 2,3,4,7tetrahydropyrido[2^! ,3 ' -6 , 7 ] indazole [ 5 , , 3-efg]- [1 ,4]benzodiazepine;

4 ,7-bis [2- (dimethylamino) ethyl]-2 ,3,4 , 7-tetrahydropyrido [2 ' , 3 ' -6 , 7] indazole [5 ,4,3-efg][l ,4]benzodiazepine;

7- [ 2- (dimethylamino )ethyl]-4-methy1-2, 3 ,4 ,7-tetra- hydropyrido[2 ' ,3 ' -6 , 7 ] indazole [ 5 , 4 , 3-efg] [1 ,4]benzodi- azepine; 7- [ 2- ( dimethylamino ) ethyl ] -4-decyl-2 , 3 , 4 , 7-tetrahy- dropyrido[2 ' , 3 ' -6 , 7] indazole [ 5 ,4 , 3-efg] [1 , 4]benzodiaze- pine;

7-methy1-4- [2- (dimethylamino)ethyl ]-2, 3, 4, 7-tetra- hydropyrido[2' , 3 ' -6 , 7]indazole[5, 4 , 3-efg] [1 ,4]benzodi- azepine;

7-decyl-4- [ 2- ( diethylamino )ethyl]-2 ,3,4, 7-tetrahy- dropyrido[2 ' ,3 * -6, 7] indazole [5, 4, 3-efg] [l,4]benzodiaze- pine; - 7-(2-hydroxyethyl)-4-[2-(dipenthylamino)ethyl]-

2,3,4, 7tetrahydropyrido[ 2 ' , 3 ' -6 , 7 ] indazole[5,4, 3-efg]- [1 ,4]benzodiazepine;

7- [2- ( 2-hydroxyethyl )aminoethyl]-4- [2-(dimethylami- no )ethyl]-2 , 3 , 4 , 7-tetrahydropyrido[2 ' , 3 ' -6 , 7 ] indazole- [5 ,4,3-efg] [1 ,4]benzodiazepine;

7-methyl-4- [2-( 2-hydroxyethyl )aminoethyl]-2 , 3 , 4 , 7- tetrahydropyrido[3' ,4 '-6,7]indazole[5 ,4,3-efg] [l,4]ben- zodiazepine;

7-[2-(dimethylamino)ethyl]-4-(2-hydroxyethyl )- 2,3,4,7tetrahydropyrido[3' ,4 ' -6,7]indazole[5,4,3-efg]- [l,4]benzodiazepine;

4, 7-bis[ 2-(dimethylamino)ethyl]-2,3,4, 7-tetrahydro- pyrido[3 ' ,4 '-6,7] indazole[5,4, 3-efg] [l,4]benzodiazepine;

7- [2- ( dimethylamino )ethyl ]-4-methyl-2 ,3,4 , 7-tetra- hydropyrido[ 3 ' , 4 ' -6 , 7 ] indazole [5,4, 3-efg] [1 ,4]benzodi- azepine;

7-[2- (dimethylamino)ethyl ]-4-decy1-2, 3, 4, 7-tetrahydropyrido [3 ' ,4 '-6 ,7]indazole[ 5,4, 3-efg] [1 ,4]benzodi- azepine; - 7-methyl-4-[2-(dimethylamino)ethyl]-2,3,4,7-te- trahydropyrido[ 3 ' , 4 ' -6 , 7 ] indazole[ 5 , 4 , 3-efg] [1 , 4]ben- zodiazepine;

7-decy1-4- [2- (diethylamino)ethyl]-2,3,4, 7-tetrahy- dropyrido[3 ' ,4 ' -6 , 7 ]indazole[5 ,4 , 3-efg] [1 ,4]benzodiaze- pine; - 7-(2-hydroxyethyl)-4-[2-(dipenthylamino)ethyl]-

2,3,4, 7tetrahydropyrido[ 3 ' , 4 ' -6 , 7 ] indazole [5,4, 3-efg]- [1 ,4]benzodiazepine;

7- [ 2- ( 2-hydroxyethyl ) aminoethyl]-4-[2- ( dimethylamino ) ethyl]-2 , 3 , 4 , 7-tetrahydropyrido[ 3 ' , 4 ' -6 , 7 ] indazole- [5,4,3efg] [1 , 4]benzodiazepine;

7-[2-(dimethylamino)ethyl]-4-(2-hydroxyethyl)- 2,3,4 , 7tetrahydropyrido[3 ^■ , 2 ' -6 , 7]indazole[5,4, 3-efg]- [l,4]benzodiazepine;

4 , 7-bis [ 2- (dimethylamino )ethyl]-2 , 3 , 4 , 7-tetrahy- dropyrido[3' ,2' -6,7]indazole[5,4,3-efg] [l,4]benzodiaze- pine;

7-[2-(dimethylamino)ethyl]-4-methyl-2 ,3,4, 7-tetra- hydropyrido[ 3 * , 2 ' -6 , 7 ] indazole[5,4, 3-efg] [1 , 4 ]benzodi- azepine; - 7-[2-(dimethylamino)ethyl]-4-decyl-2,3,4,7-tetra- hydropyrido[3 ' ,2 ' -6 ,7]indazole[5,4,3-efg] [l,4]benzodi- azepine;

7-methγl-4-[ 2- ( dimethylamino )ethyl ]-2 ,3,4 , 7-tetrahydropyrido[ 3 ' , 2 ' -6 , 7 ] indazole [5,4, 3-efg] [1 , 4]benzodi- azepine;

7-decy1-4- [2- (diethylamino )ethyl]-2 ,3,4, 7-tetrahydropyrido[ 3 ' , 2 ' -6 , 7 ] indazole [5,4, 3-efg] [1,4]benzodiaze- pine;

7-( 2-hydroxyethyl )-4-[2-( dipenthylamino)ethyl]- 2,3,4,7tetrahydropyrido[3' ,2' -6,7]indazole[5 ,4 ,3-efg]- [1,4]benzodiazepine ; 7-[2-(2-hydroxyethyl )aminoethyl ] -4- [2- (dimethylamino )ethyl ] -2 , 3 , 4 , 7-tetrahydropyrido[ 3 * , 2 ' -6 , 7 ] indazole- [5,4,3efg] [l,4]benzodiazepine ;

7-methyl-4- [ 2- ( 2-hydroxyethyl )aminoethyl ]-2 ,3,4,7- tetrahydropyrido[3 ' ,2 '-6,7]indazole[5,4,3-efg] [l,4]ben- zodiazepine.

5. Compounds of claim 1, wherein such compounds are: 7-[2-(dimethylamino)ethyl]-4-(2-hydroxyethyl)-

2,3,4, 7tetrahydropyrido[4 ' , 3 ' -6 , 7 ] indazole [5,4, 3-efg]- [l,4]benzodiazepine;

4, 7-bis[ 2- (dimethylamino)ethyl]-2,3,4, 7-tetrahy- dropyrido[4' ,3 ' -6,7]indazole[5,4,3-efg] [l,4]benzodiaze- pine dimaleate;

7- [2- ( dimethyla ino )ethyl]-4-methyl-2 ,3,4, 7-tetra- hydropyrido[4' ,3'-6,7]indazole[5,4, 3-efg] [l,4]benzodi- azepine maleate.

6. A process for the preparation of the compounds of formula ( I ) :

in which: at least one and not more than two X, Y, Z or T groups are nitrogen (=N-) and the others are carbon (=CH-=, with the proviso that X and Z or Y and T , respectively, cannot be simultaneously nitrogen; R and R-, are the same or different and are selected from the group consisting of (C^-C-_j^alkyl, C₂-C₁₀)alkyl substituted by one or two substituents selected from the group consisting of -OR₂ and -NR₃N₄, (C₂-C₁₀ )alkyl interrupted by one or two oxygen atoms or by a -NR₅ group and being said (C₂-C₁₀ )alkyl optionally substituted by one or two hydroxy (OH) or -NR₃R₄ groups;

R₂ is selected from the group consisting of hydrogen,

(C₁-C₆)alkyl, -S(0₂)Rg, (C₂-Cg)alkyl optionally substituted by a -NR₃R₄ group;

R₃ and R₄ can be the same or different and are selected from the group consisting of hydrogen, (C^-C^_Qjalkyl, (C₂-C₁₀ )alkyl substituted by one or two hydroxy (OH) groups, or R and R₄, taken together with the nitrogen atom to which are linked, form a 5- or 6-membered heterocyclic aromatic or not-aromatic ring, optionally containing another heteroatom selected from the group consisting of sulfur, oxygen and nitrogen; Rt_j is selected from the group consisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)hydroxyalkyl, (C₂-C₁₀)alkyl substituted with a -NR₃R₄ group; Rg is selected from the group consisting of (^cι~ C^₀)alkyl, phenyl, phenylalkyl, which process encompasses the following steps: a) reaction of the intermediates of formula (II):

wherein R, X, Y, Z and T are as above defined and U is a chlorine or a para-toluenesulphonyloxy (-OTs) group, with an amine of formula (III):

G-NH-CH₂-CH₂-NH-R₁ (III) wherein R.^ is as above defined and G is a suitable protective group of a primary amine which can be removed in acidic conditions, to give the intermediates of formula (IV):

b) removal of the G protective group from the intermediate of formula (IV); c) cyclization of the intermediate obtained in step b) to give the compounds of formula (I); d) optional salification of the compounds of formula (I) with pharmaceutically acceptable acids; e) optional conversion of a salt of one compound of formula (I) in another salt of a pharmaceutically acceptable acid.

7. Pharmaceutical composition containing at least one compound of formula (I) in admixture with pharmaceutically acceptable excipients.

8. Use of the compounds of formula (I) as antitumor agents.

9. Use of claim 8, wherein the tumor to be treated is a leukemia.