WO1999006405A1 - Pyrazolo-acridine derivatives having antitumour activity - Google Patents

Pyrazolo-acridine derivatives having antitumour activity Download PDF

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Publication number
WO1999006405A1
WO1999006405A1 PCT/EP1998/004781 EP9804781W WO9906405A1 WO 1999006405 A1 WO1999006405 A1 WO 1999006405A1 EP 9804781 W EP9804781 W EP 9804781W WO 9906405 A1 WO9906405 A1 WO 9906405A1
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Prior art keywords
dimethylamino
ethyl
ppm
acridine
pyrazolo
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PCT/EP1998/004781
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French (fr)
Inventor
Ippolito Antonini
Sante Martelli
Paolo Polucci
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Universita' Degli Studi Di Camerino
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Priority to AU97382/98A priority Critical patent/AU9738298A/en
Publication of WO1999006405A1 publication Critical patent/WO1999006405A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • the present invention relates to pyrazolo-acridines and pyrazolo-pyri idoacridines susbtituted with aminoalkyl chains .
  • Said compounds have evidenced a remarkable antitumour activity, in particular in colon tumours.
  • the treatment of solid tumors is a still unresolved problem of the antitumor therapy.
  • the search for new molecules able to cure solid tumors is hindered by a number of factors, such as the development, by the tumor cells, of resistance to many antitumor drugs (Multi-Drug Resistance, MDR ) and the difficulty for the medicament to reach the tumor mass which is scarcely vascularized.
  • MDR Multi-Drug Resistance
  • Another known class of DNA intercalating consists of acridines [Atwell G.J. et al., J. Med. Chem. , 30, 664-9 (1987); Baguley B.C. et al . , Cancer Chemother . and Pharmacol., 36, 244-8 (1995); Atwell G.J. et al., J. Med. Chem., 27, 1481-5 (1984); Rewca ⁇ tle G.W. et al., J. Med. Chem., 29, 472-7 (1986); Denny W.A. et al . , J. Med. Chem., 30, 658-663 (1987); Wakelin L.P.G. et al., J. Med.
  • EP 0 138 302 (Warner - Lambert Co.) reports 5-nitro pyrazolo acridines, whereas in Antonini I. et al., J. Med. Chem., 38, 3282-6 (1995) pyrimido-acridines having antitumour activity are described.
  • the present invention relates to compounds of general formula (I):
  • R is selected from hydrogen, straight or branched
  • a and A* are independently selected from -NH , -OH, mono- or di-(C 1 -C 4 )alkylamino, hydroxyethylamino , N-mor- pholinyl, N-piperazinyl , N-thiomorpholinyl , N-pyrro- lidinyl, N-piperidinyl , possible stereoisomers or stereomeric mixtures and salts thereof with pharmaceutically acceptable acids.
  • a second object of the present invention is a process for the preparation of the compounds of formula
  • a further object of the present invention are pharmaceutical formulations containing an effective dose of at least one compound of formula (I) in admixture with pharmaceutically acceptable excipients, as well as the use of said compounds of formula (I) and of the pharmaceutical formulations containing them as antitumour agents.
  • Preferred compounds of formula (I) are those in which n and m are the integers 2 or 3.
  • More preferred compounds are those in which p is the integer 1.
  • reaction condensation of the acid derivative obtained in (b) or (c) with a ⁇ uitable amine of formula H N-(CH2 ) m ⁇ A' .
  • Said reaction can be carried out in the presence of condensing agents such as carbodimides or after activation of the carboxylic group, for example via imidazolide (by reaction with carbonyldiimidazole ) , acid chloride (by reaction with thionyl chloride) or hydroxy ⁇ uccinimido e ⁇ ter (by reaction with N- hydroxysuccinimide in the presence of morpholinoethyli ⁇ onitrile ) .
  • condensing agents such as carbodimides or after activation of the carboxylic group, for example via imidazolide (by reaction with carbonyldiimidazole ) , acid chloride (by reaction with thionyl chloride) or hydroxy ⁇ uccinimido e ⁇ ter (by reaction with N- hydroxysuccinimi
  • the compound ⁇ of formula (I) can al ⁇ o be ⁇ alified by reaction of the free ba ⁇ e with pharmaceutically acceptable acids, preferably with hydrochloric acid.
  • An alternative method for the preparation of the compounds of formula (I") comprises the reaction of a derivative of formula
  • the compounds of the invention were tested for their antitumor activity on the human HT 29 cell line of colon adenocarc oma .
  • the cells were incubated for 144 hours with the test compound, then cytotoxicity was evaluated using the "MTT Assay" (Mosman, T. "Rapid
  • ICc f ( VQ / MI ) , i.e. the concentration of the te ⁇ t compound cau ⁇ ing the death of
  • the effective dosage of the compounds of the invention can be determined by the expert clinician with conventional, known methods.
  • the relationship between the do ⁇ ages u ⁇ ed for animal ⁇ of variou ⁇ species and tho ⁇ e for humans (on the basis of mg/m ⁇ of body) is described by Freirich, E.J. et al., Cancer Chemother. Rep., 50, n.4, 219-244, May
  • Tumours which can be treated with the compound ⁇ of the pre ⁇ ent invention are tho ⁇ e ⁇ ensitive to the therapy with DNA intercalating agents.
  • colon tumour can advantageously be treated .
  • the pharmaceutical compositions containing the compounds of formula (I) are comprised in the invention.
  • compositions can contain any amounts of compound ⁇ of formula (I) capable of exerting in mammal ⁇ an antitumor activity against tumors sensitive to the therapy with DNA intercalating agents.
  • compositions can contain, in addition to at least one compound of formula ( I ) , pharmaceutically compatible excipients, so as to allow the administration through any route, such as the oral, parenteral, intravenous, intradermal, ⁇ ubcutaneous or topical routes, in the liquid or solid form.
  • An administration route for the compounds of formula (I) is the oral one.
  • Oral compositions will usually include an inert diluent or an edible carrier. They can be included in gelatin capsules or compressed into tablets. Other forms for the oral administration are capsules, pills, elixirs, su ⁇ pen ⁇ ion ⁇ or ⁇ yrup ⁇ .
  • Tablet ⁇ , pill ⁇ , cap ⁇ ules and similar compo ⁇ ition ⁇ can contain the following ingredients (in addition to the active ingredient): a ligand, such as microcrystalcell lineulose, gum tragacanth, or gelatin; an excipient ⁇ uch as ⁇ tarch or lacto ⁇ e; a di ⁇ integration agent ⁇ uch a ⁇ alginic acid, primogel, maize starch, and the like; a lubricant such as magnesium ⁇ tearate; a fluidifier such a ⁇ colloidal silicon dioxide; a sweetening agent such a ⁇ ⁇ ucro ⁇ e or ⁇ accharin or a flavour ⁇ uch a ⁇ mint e ⁇ sence, methyl salicylate or orange flavour.
  • a ligand such as microcrystalcell lineulose, gum tragacanth, or gelatin
  • an excipient ⁇ uch as ⁇ tarch or lacto ⁇ e a di ⁇ integration agent ⁇ uch a ⁇ alginic acid, primo
  • the ⁇ elected compo ⁇ ition i ⁇ in the form of cap ⁇ ules can contain in addition a liquid carrier ⁇ uch as a fatty oil.
  • Other compositions can contain various material ⁇ which modify their phy ⁇ ical state, for example coating agents (for tablets and pill ⁇ ) ⁇ uch a ⁇ sugar or shellac.
  • the material ⁇ used in the preparation of the compo ⁇ itions will be pharmaceutically pure and non toxic at the used dosages.
  • the active ingredient can be incorporated in solutions or ⁇ uspension ⁇ , which can al ⁇ o include the following components: a sterile diluent such as water for injections, phy ⁇ iological ⁇ aline, oil ⁇ , polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterials ⁇ uch a ⁇ benzyl alcohol; antioxidizer ⁇ ⁇ uch as ascorbic acid or sodium bisulfite; chelating agent ⁇ ⁇ uch a ⁇ ethylenedia ino tetraacetic acid; buffers such as acetates, citrates or phosphates and agent ⁇ for adju ⁇ ting the tonicity of the ⁇ olution, ⁇ uch a ⁇ ⁇ odium chloride or dextro ⁇ e .
  • the parenteral preparation can be included in glas ⁇ or plastic ampoules, mono-dose syringe ⁇ or vial ⁇ .
  • 2-Amino-4-chlorobenzoic acid (7 g), 2-chloro-5- nitrobenzoic acid (7 g), potassium carbonate (7 g) and copper powder (0.25 g) are su ⁇ pended in 150 ml of isopentyl alcohol. After refluxing the reaction mixture under ⁇ tirring for about 20 minute ⁇ , an orange-red ma ⁇ precipitate ⁇ . The reaction i ⁇ continued for 4-5 hours, then 150 ml of a 1M potas ⁇ ium carbonate aqueou ⁇ ⁇ olution are added and insolubles are filtered off while hot.
  • aqueous pha ⁇ e is ⁇ eparated, acidified to pH 5 with 2M hydrochloric acid to precipitate the product, which i ⁇ filtered, suspended in boiling methanol (100 ml), filtered, resuspended in boiling water (200 ml), filtered again and washed with ethanol.
  • 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 IM sodium carbonate. The organic phase is worked up to give the product which solidifies by treatment with ethyl ether (0.86 g) , m.p. 150-151°C.
  • Example 1 5-[N-[2- ( dimethylamino )ethyl] ]car- boxamido-2- [2- (dimethylamino) ethyl] yrazolo [3 ,4,5- A-J]acridine
  • reaction mixture is cooled at room temperature, then partitioned between chloroform and IM sodium carbonate.
  • the organic phase gives, after work up, an oily residue which is fla ⁇ h-chromatographed on ⁇ ilica gel column (eluent: chloroform/methanol 1 : 1, then chloroform/methanol/38% ammonia 1 : 1 : 0.01), thereby obtaining 120 mg of a thick oil which i ⁇ directly transformed into the dihydrochloride by treatment with hydrogen chloride, m.p. 211-213"C (dec).
  • Example 2 5-[N-[2-( dimethylamino )ethyl] ]- carboxamido-2-[ 2- (dimethylamino ) ethyl ]-9-hydroxypyrazo- lo[ 3 , 4 , 5- ⁇ VJ]acridine dihydrochloride
  • 0.25 g of 5-[N- [ 2- ( dimethylamino )ethyl] ] -carboxa- mido-2-[ 2- (dimethylamino) ethyl ]-9-methoxypyrazolo[ 3 ,4,5- JcJ]acridine dihydrochloride are ⁇ u ⁇ pended in 2 ml of 48% hydrobromic acid and the mixture i ⁇ refluxed, under ⁇ tirring, until the ⁇ tarting product disappears. The reaction mixture is cooled at room temperature, then partitioned between chloroform and IM sodium carbonate.
  • Example 6 2-[2- ( dimethylamino )ethyl]-6- [2- ( dimethylamino . ) ethyl ]-10-hydroxy-2 ,5,6, 7-tetrahydropyrazo- lo[3 ,4 , 5-/77/3]pyrimido[ 5,6, 1-de] acridine-5 , 7-dione 0.14 g of 2-[2-(dimethylamino)ethyl]-6-[2-(dime- thyla-mino ) ethyl ]-10-methoxy-2 ,5,6, 7-tetrahydropyrazo- lo[3 ,4 , 5-m ⁇ ]pyrimido[5 , 6 , l-de]acridine-5 ,7-dione are suspended in 2 ml of 48% hydrobromic acid and the reaction mixture is refluxed, under stirring, until the starting product disappears (monitoring by TLC).
  • reaction mixture is cooled at room temperature and partitioned between chloroform and IM sodium carbonate.
  • the organic phase is worked up to give a residue which is su ⁇ pended in ethyl ether, filtered, wa ⁇ hed with ethyl ether to give 80 mg of product, which i ⁇ transformed into hydrochloride by treatment with hydrogen chloride, m.p. 289-290°C (m.p. hydrochloride 266-268°C with dec).
  • Example 7 2-[2- (dimethylamino ) ethyl] -6- [2- (dimethylamino )ethyl]-10-amino-2 ,5,6, 7-tetrah ⁇ dropyrazo- lo[3 , 4 , 5-m.n]pyrimido[5 , 6 , l-de]acridine-5 , 7-dione tri- hydrochloride 0.13 g of 2-[2-(dimeth ⁇ lamino)ethyl]-6-[2- ( dimethylamino )ethyl]-10-nitro-2 ,5,6, 7-tetrahydropyrazo- lo[3 , 4 , 5-mn]pyrimido[ 5,6, l-de]acridine-5 , 7-dione are ⁇ u ⁇ pended in 20 ml of methanol and added with 1 ml of 37% hydrochloric acid and 20 mg of 5% palladium-on- carbon.
  • reaction mixture is placed in hydrogen atmo ⁇ phere (30 psi) under stirring at room temperature for 1 hour, then filtered and washed with ethyl ether to obtain 100 mg of product, m.p. 283-285°C (dec).

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Abstract

Pyrazolo-acridines and pyrazolo-pyrimidoacridines susbtituted with aminoalkyl chains, have evidenced a remarkable antitumour activity, in particular in colon tumours.

Description

PVRAZOT. -ACRIDINE DERIVATIVES HAVING ANTTTUMOUR ACTTVTTY
The present invention relates to pyrazolo-acridines and pyrazolo-pyri idoacridines susbtituted with aminoalkyl chains .
Said compounds have evidenced a remarkable antitumour activity, in particular in colon tumours.
PRIOR ART
The treatment of solid tumors is a still unresolved problem of the antitumor therapy. The search for new molecules able to cure solid tumors is hindered by a number of factors, such as the development, by the tumor cells, of resistance to many antitumor drugs (Multi-Drug Resistance, MDR ) and the difficulty for the medicament to reach the tumor mass which is scarcely vascularized.
A number of compounds which are at present in preclinical or clinical development or which are already used in the antitumor therapy, such as mitoxantrone or doxorubicine , belong to the wide family of the DNA intercalating molecules. Although these molecules share a tri- o tetra-cyclic planar structure, they belong to well distinct classes, having frequently different chemico-phyεical and biological properties.
The nature of the substituents and of the aromatic rings in the backbone is critical since often small structure changes give the analogue compounds an altogether different biological behaviour. It is in fact known, for example, that a change from anthracenediones to the corresponding benzo[g]isoquinolin-5 , 10-diones causes a decrease in cardiotoxicity , while maintaining an antitumor activity identical to, if not better than, that of the carbocyclic analogues (Krapcho, P., WO 92/15300; Krapcho et al., US 5,587,382).
However, the molecules presently used in therapy induce the cited multi-drug resistance, limiting therefore their effective use in a long-term therapy.
Another known class of DNA intercalating consists of acridines [Atwell G.J. et al., J. Med. Chem. , 30, 664-9 (1987); Baguley B.C. et al . , Cancer Chemother . and Pharmacol., 36, 244-8 (1995); Atwell G.J. et al., J. Med. Chem., 27, 1481-5 (1984); Rewcaεtle G.W. et al., J. Med. Chem., 29, 472-7 (1986); Denny W.A. et al . , J. Med. Chem., 30, 658-663 (1987); Wakelin L.P.G. et al., J. Med. Chem., 30, 855-861 /1987). EP 0 138 302 (Warner - Lambert Co.) reports 5-nitro pyrazolo acridines, whereas in Antonini I. et al., J. Med. Chem., 38, 3282-6 (1995) pyrimido-acridines having antitumour activity are described.
We have now found a novel class of acridine derivatives which show a marked antitumour activity, predominantly in solid tumours such as the colon tumour, compared with the compounds of the prior art. DISCLOSURE OF THE INVENTION
The present invention relates to compounds of general formula (I):
Figure imgf000004_0001
wherein :
R is selected from hydrogen, straight or branched
(C1-C6 )alkyl, -OH, -NH2, (C1~C4 )alkoxy, mono- and di-
(cl~c4 )alkylamino, chlorine, bromine, iodine and fluorine, nitro, mono- and poly-fluoro(C1-C4)alkyl ,
(C1-C4)alkylsulfonyl , ( 1~C4 )alkylaminosulfonyl; n and are independently the integer 2, 3 or 4; p is 0 or the integer 1;
A and A* are independently selected from -NH , -OH, mono- or di-(C1-C4 )alkylamino, hydroxyethylamino , N-mor- pholinyl, N-piperazinyl , N-thiomorpholinyl , N-pyrro- lidinyl, N-piperidinyl , possible stereoisomers or stereomeric mixtures and salts thereof with pharmaceutically acceptable acids. A second object of the present invention is a process for the preparation of the compounds of formula
(I).
A further object of the present invention are pharmaceutical formulations containing an effective dose of at least one compound of formula (I) in admixture with pharmaceutically acceptable excipients, as well as the use of said compounds of formula (I) and of the pharmaceutical formulations containing them as antitumour agents. Preferred compounds of formula (I) are those in which n and m are the integers 2 or 3.
More preferred compounds are those in which p is the integer 1.
Most preferred compounds are those in which R is a nitro group. PREPARATION OF THE COMPOUNDS OF THE INVENTION
The compounds of the invention of formula (I!l):
in which p is 1 and n, m, R, A and A' have the meanings defined above, can be prepared starting from the corresponding pyrazolo-acridineε-5-carboxamides of formula (I1):
Figure imgf000006_0002
in which p is 0, by reaction with phosgene in an inert solvent and in the presence of a base. Preferred conditions are the use of chloroform as solvent, in the presence of triethyla ine and at temperatures ranging from 0°C to room temperature.
Compounds of formula (I1) can, in their turn, be prepared according to the reaction scheme reported in Figure 1.
In Figure 1, the meanings of R, m, n, A and A' are the same as reported above, R' is hydrogen or a methyl group and Alg is a bromine or chlorine atom. The scheme of Figure 1 comprises the following synthesis steps:
(a) condensation of a 2-halo carboxylic acid with 5- chloro-2-carboxyaniline (or the corresponding methyl carboxylate) in the presence of copper or of the salts thereof and in basic medium. Examples of said reaction are the use of copper acetate in the presence of a tertiary amine or the use of copper and of an alkali metal carbonate. The reaction is preferably carried out in a solvent, such as an alcohol or a dipolar aprotic solvent. Preferred solvents are N-methylpyrrolidone and isopentyl alcohol .
(b) cyclization of the intermediate obtained in (a) to give an isomeric mixture of l-chloro-9-oxo-9 ,10- dihydroacridin-4-carboxylic and 6-chloro-9-oxo- 9 ,10-dihydroacridin-4-carboxylic acids (or of the corresponding methyl carboxylateε) in an about 2 : 1 ratio. The cyclization is carried out in the presence of condensing agents such as polyphosphoric acid or phosphorous oxychloride, the latter preferably in the presence of a solvent such as an aromatic hydrocarbon.
(c) basic hydrolysis of methyl carboxylateε posεibly obtained in (b) to give the corresponding acids.
(d) condensation of the acid derivative obtained in (b) or (c) with a εuitable amine of formula H N-(CH2 )m~A' . Said reaction can be carried out in the presence of condensing agents such as carbodimides or after activation of the carboxylic group, for example via imidazolide (by reaction with carbonyldiimidazole ) , acid chloride (by reaction with thionyl chloride) or hydroxyεuccinimido eεter (by reaction with N- hydroxysuccinimide in the presence of morpholinoethyliεonitrile ) .
(e) reaction of the carboxamides obtained in (d) with the suitable hydrazine of formula
H2 -NH-(CH2 )n~A in a solvent and at a temperature from room temperature to 150βC, preferably from 110 to 130°C, to give the desired pyrazoloacridines of formula ( I ' ) •
When the groups A and A' of the amineε uεed in steps (d) and (e) contain in their turn primary and secondary amino groups or hydroxy groups, these will be protected before the condensation reaction, by conventional reactions with protective groups. After the condensation reaction, εaid protective groups will be removed.
Examples of protection and deprotection reactions of primary and εecondary amines- protective groupε and of alcohols- protective groups are described in Green,
T.W., Wuts, P.G.M., "Protective Groups in Organic
Synthesiε", second edition, John Wiley & Sons, 1991.
The resulting compounds of formula (I1) can be trasformed into other compounds of formula (I'), which are also comprised within the meaningε of formula (I), by deprotection reaction of the protective groupε, such as transformation of compounds of formula (I1) with R = methoxyl into compounds with R = hydroxyl by cleavage reaction in acidic conditionε (48% hydrobromic acid), or, for example, when R iε a nitro group, by reduction to amme and subsequent optional functionalization of the amme via reductive alkylation or by reaction with an alkylsulfonyl chloride.
The compoundε of formula (I) can alεo be εalified by reaction of the free baεe with pharmaceutically acceptable acids, preferably with hydrochloric acid.
An alternative method for the preparation of the compounds of formula (I") comprises the reaction of a derivative of formula
Figure imgf000009_0001
with phosgene m baεic medium (tertiary amme), followed by reaction with a hydrazme of formula
H2N-NH-(CH2)n-A, to give the compoundε of formula (I").
BIOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE IPVENTIQfl
The compounds of the invention were tested for their antitumor activity on the human HT 29 cell line of colon adenocarc oma . The cells were incubated for 144 hours with the test compound, then cytotoxicity was evaluated using the "MTT Assay" (Mosman, T. "Rapid
Colorimetric Aεsay for Cellular Growth and Survival:
Application to Proliferation and Cytotoxicity Aεεay"; J.
Immunol. Methodε, (1983), 65, 66-63; Green, L.M., "Rapid Colorimetric Assay for Cell Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokineε" , J. Immunol. Methodε, (1984), 70, 257-268).
The reεults are expresεed as ICcf) ( VQ / MI ) , i.e. the concentration of the teεt compound cauεing the death of
50% of the cell population.
The data concerning some repreεentative compoundε of the invention are reported in Table I . lϋb_I≤ I - CYtQtQXic activity of the compounds of the invention on £H≤ Imman HI 29 cell line of colon adenocarcinoma
Figure imgf000010_0001
R n m A = A' P IC50 (μg/ml)
H 2 2 N(Me)2 0 0.038
N02 2 2 N(Me)2 0 0.002
H 2 2 N(Me)2 1 1.019
OCH2 2 2 N(Me)2 1 0.006
N02 2 2 N(Me)2 1 0.0004
NH2 2 2 N(Me)2 1 0.003
mitoxantrone 0.005
The compounds of formula (I), when administered to man and animals bearing tumours suceptible of treatment with DNA intercalating agents, at dosages ranging from 1 mg to 1200 g per square metre of body area, are capable of inducing the regresεion of the above mentioned tumours .
The effective dosage of the compounds of the invention can be determined by the expert clinician with conventional, known methods. The relationship between the doεages uεed for animalε of variouε species and thoεe for humans (on the basis of mg/m^ of body) is described by Freirich, E.J. et al., Cancer Chemother. Rep., 50, n.4, 219-244, May
1966. Tumours which can be treated with the compoundε of the preεent invention are thoεe εensitive to the therapy with DNA intercalating agents.
In particular, colon tumour can advantageously be treated . The pharmaceutical compositions containing the compounds of formula (I) are comprised in the invention.
These pharmaceutical compositions can contain any amounts of compoundε of formula (I) capable of exerting in mammalε an antitumor activity against tumors sensitive to the therapy with DNA intercalating agents.
The pharmaceutical compositions can contain, in addition to at least one compound of formula ( I ) , pharmaceutically compatible excipients, so as to allow the administration through any route, such as the oral, parenteral, intravenous, intradermal, εubcutaneous or topical routes, in the liquid or solid form.
An administration route for the compounds of formula (I) is the oral one. Oral compositions will usually include an inert diluent or an edible carrier. They can be included in gelatin capsules or compressed into tablets. Other forms for the oral administration are capsules, pills, elixirs, suεpenεionε or εyrupε .
Tabletε, pillε, capεules and similar compoεitionε can contain the following ingredients (in addition to the active ingredient): a ligand, such as microcrystalcell lineulose, gum tragacanth, or gelatin; an excipient εuch as εtarch or lactoεe; a diεintegration agent εuch aε alginic acid, primogel, maize starch, and the like; a lubricant such as magnesium εtearate; a fluidifier such aε colloidal silicon dioxide; a sweetening agent such aε εucroεe or εaccharin or a flavour εuch aε mint eεsence, methyl salicylate or orange flavour. When the εelected compoεition iε in the form of capεules, it can contain in addition a liquid carrier εuch as a fatty oil. Other compositions can contain various materialε which modify their phyεical state, for example coating agents (for tablets and pillε) εuch aε sugar or shellac. The materialε used in the preparation of the compoεitions will be pharmaceutically pure and non toxic at the used dosages. For the preparation of pharmaceutical compositions for the parenteral administration, the active ingredient can be incorporated in solutions or εuspensionε, which can alεo include the following components: a sterile diluent such as water for injections, phyεiological εaline, oilε, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterials εuch aε benzyl alcohol; antioxidizerε εuch as ascorbic acid or sodium bisulfite; chelating agentε εuch aε ethylenedia ino tetraacetic acid; buffers such as acetates, citrates or phosphates and agentε for adjuεting the tonicity of the εolution, εuch aε εodium chloride or dextroεe . The parenteral preparation can be included in glasε or plastic ampoules, mono-dose syringeε or vialε.
The invention iε further deεcribed by the following examples.
Preparation 1 - l-Chloro-7-nitro-9-oxo-9 ,10- dihydroacridine-4-carboxylic acid
2-Amino-4-chlorobenzoic acid (7 g), 2-chloro-5- nitrobenzoic acid (7 g), potassium carbonate (7 g) and copper powder (0.25 g) are suεpended in 150 ml of isopentyl alcohol. After refluxing the reaction mixture under εtirring for about 20 minuteε, an orange-red maεε precipitateε . The reaction iε continued for 4-5 hours, then 150 ml of a 1M potasεium carbonate aqueouε εolution are added and insolubles are filtered off while hot. The aqueous phaεe is εeparated, acidified to pH 5 with 2M hydrochloric acid to precipitate the product, which iε filtered, suspended in boiling methanol (100 ml), filtered, resuspended in boiling water (200 ml), filtered again and washed with ethanol.
The resulting diacid is disεolved in xylene (55 ml), added with 55 ml of phoεphorouε oxychloride and refluxed for 2 hourε. After cooling, the precipitate iε filtered, suspended in boiling methanol, filtered, washed with ethyl ether and dried to give 5.8 g of a mixture of l-chloro-7-nitro-9-oxo-9 ,10-dihydroacridine- 4-carboxylic acid and 6-chloro-2-nitro-9-oxo-9 , 10- dihydroacridine-4-carboxylic acid in an about 2 : 1 ratio. Preparation 2 - 2-( 5-Chloro-2-methoxycarbonyl- phenylamino)-5-methoxybenzoic acid A suspension of methyl 2-amino-4-chlorobenzoate
(0.8 g), 2-bromo-5-methoxybenzoic acid (1 g) and copper (II) acetate onohydrate (0.86 g) in 5 ml of N- methylpyrrolidone and 10 ml of N,N-diisopropylethylamine iε heated at 160°C under εtirring for 6 hourε. After cooling, dilution with water and acidification to pH 2, a εolid εeparateε, which iε recovered by filtration and dried. The εolid is then suεpended under εtirring in ethyl ether and filtered to give 0.75 g of product, m.p. 176-177°C (crystallized from methanol ) . iH-NMR in d6-DMSO: 3.80 ppm (s, 3H ) ; 3.88 ppm (s, 3H); 6.87 ppm (d, IH); 7.03-7.21 ppm (m, 2H ) ; 7.33-7.57 ppm (m, 2H); 7.89 ppm (d, IH); 10.42 ppm (s, IH ) ; 11.29 ppm (br ε, IH) . Preparation 3 - Methyl l-chloro-7-methoxy-9-oxo- 9 , 10-dihydroacridine-4-carboxylate
1 g of 2-( 5-chloro-2-methoxycarbonylphenylamino)-5- methoxybenzoic acid iε refluxed with PPE (40 g) in 50 ml of chloroform until the whole εolid iε diεεolved. Chloroform iε evaporated off to obtain an oil which iε heated to 100°C for one hour. The mixture is carefully diluted with 5 ml of methanol and 10 ml of water, then extracted with chloroform (3 x 20 ml). The combined organic extracts are dried and the residue is purified by flash-chromatography on εilica gel (eluent chloro orm/benzene 3 : 2 ) to give 0.58 of product, m.p. 219-220°C.
1H-NMR in CDC13: 3.92 ppm (s, 3H ) ; 4.01 ppm (s, 3H); 7.20 ppm (d, IH ) ; 7.25-7.33 ppm ( , 2H ) ; 7.81 ppm (m, IH); 8.24 ppm (d, IH ) ; 12.10 ppm (ε, IH).
Preparation 4 - l-Chloro-7-methoxy-9-oxo-9 , 10- dihydroacridine-4-carboxylic acid
A εuεpenεion of methyl l-chloro-7-methoxy-9-oxo-
9 ,10-dihydroacridine-4-carboxylate (1 g) in 100 ml of ethanol and 100 ml of 2M sodium hydroxide is refluxed for 30 minutes. The reaction mixture is acidified with
4M hydrochloric acid and stirred at room temperature for
20 minutes. The precipitate is recovered by filtration, washed with water, methanol and ethyl ether to give 0.72 g of pure product, m.p. 340-341*C. 1H-NMR in d6-DMS0: 3.89 ppm (s, 3H); 7.28 ppm (d,
IH); 7.43 ppm ( , IH); 7.59 ppm (d, IH); 7.75 ppm (d, IH); 8.30 ppm (d, IH); 12.35 ppm (s, IH ) .
Preparation 5 - 4-[N-[3-(dimethylamino )propyl] ]- carboxamido-l-chloro-9-oxo-9 , 10-dihydroacridine A mixture of 1 g of l-chloro-9-oxo-9 ,10- dihydroacridine-4-carboxylic acid (obtained according to the procedureε described in preparations 1-4) and 1.1 g of 1 , 1 ' -carbonyldiimidazole in 10 ml of dimethylformamide is stirred, if necesεary with heating, until the whole εolid iε diεεolved. 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 IM sodium carbonate. The organic phase is worked up to give the product which solidifies by treatment with ethyl ether (0.86 g) , m.p. 150-151°C. iH-NMR in CDCI3: 1.85 ppm (m, 2H ) ; 2.38 ppm (s, 6H); 2.63 ppm (t, 2H ) ; 3.60 ppm (q, 2H ) ; 7.16 ppm (d, IH); 7.22-7.38 ppm (m, 2H); 7.59-7.69 ppm ( , 2H ) ; 8.40 ppm (dd, IH ) ; 8.57 ppm (ε, IH ) ; 13.14 ppm (ε, IH ) .
The following compoundε are prepared analogously: 4-[N-[2-( dimethylamino )ethyl] Jcarboxamido-1- chloro-7-methoxy-9-oxo-9 ,10-dihydroacridine , m.p. 170-
172°C, 1H-NMR in CDC13: 2.43 ppm (ε, 6H ) ; 2.76 ppm (t,
2H); 3.65 ppm (q, 2H ) ; 3.93 ppm (ε, 3H); 7.19 ppm (d, IH); 7.25-7.34 ppm ( , 2H); 7.62 ppm (br s, IH ) ; 7.78-
7.89 ppm (m, 2H ) ; 12.77 ppm (s, IH ) ;
4-[N-[2-( tert-butoxycarbonylammino) ethyl] ]car- boxamido-l-chloro-9-oxo-9 ,10-dihydroacridine , m.p. 212-
213°C, ^-H-NMR in d6-DMSO: 1.42 ppm (s, 9H); 3.25 ppm (t, 2H); 3.38 ppm (t, 2H ) ; 7.01 ppm (t, IH ) ; 7.28-7.42 ppm (m, 2H); 7.60-7.82 ppm (m, 2H ) ; 8.08-8.25 ppm (m, 2H); 9.02 ppm (t, IH); 12.80 ppm (s, IH ) .
Preparation 6 - 4-[N-[2-(dimethylamino)ethyl] ]car- boxamido-l-chloro-7-nitro-9-oxo-9 , 10-dihydroacridine hydrochloride
An isomeric mixture of l-chloro-7-nitro-9-oxo-9 , 10- dihydroacridine-4-carboxylic acid and 6-chloro-2-nitro- 9-oxo-9 ,10-dihydroacridine-4-carboxylic acid (1 g of mixture; preparation 1) and anhydrous triethylamine (0.314 g) in 30 ml of chloroform, cooled to 0°C and stirred, is dropped into a solution of ethyl chloroformate (0.34 g) in 20 ml of chloroform. After 1 hour under stirring at room temperature, the mixture is cooled to 0°C and added with N,N-dimethylethylenediamine (0.32 g), then kept at room temperature and under stirring overnight. The precipitated solid is filtered and washed with methanol, chloroform and finally with ethyl ether, to give 0.58 g of product, m.p. 295-297°C ( cryεtallized from methanol). 1H-NMR in d6-DMSO: 2.88 ppm (ε, 6H); 3.34 ppm (t,
2H); 3.75 ppm (q, 2H ) ; 7.33 ppm (d, IH); 7.90 ppm (d, IH); 8.30 ppm (d, IH ) ; 8.49 ppm (dd, IH ) ; 8.93 ppm (d,
IH); 9.47 ppm (t, IH ) ; 10.03 ppm ( br s, IH); 11.03 ppm
(br m, IH) .
Preparation 7 - 6-Chloro-2- [ 3- ( dimethylamino )pro- pyl]pyrimido[ 5 , 6 , 1-de] acridine-1 , 3 ,7-dione
A mixture of l-chloro-4-[N-[3-(dimethylamino )pro- pyl] ]carboxamido-9-oxo-9 ,10-dihydroacridine (0.33 g) in
20 ml of chloroform and 1 ml of triethylamine iε added drop by drop with a εolution of phoεgene (2 ml of 20% εolution in toluene) in 10 ml of chloroform, keeping the temperature at 0°C. When the addition is completed, the mixture is εtirred at room temperature for 20 minutes, then the reaction mixture is partitioned between chloroform and IM sodium carbonate. The organic phase is worked up to give a residue which iε chromatographed on a εilica gel column (eluent chloroform/methanol 19 : 1), to give 280 mg of product, m.p. 212-214°C (dec. ) . -H-NMR in CDCI3: 2.31-2.51 ppm (m, 2H); 2.85 ppm (ε, 6H); 3.20 ppm (t, 2H ) ; 4.35 ppm (t, 2H ) ; 7.47-7.80 ppm (m, 3H); 8.28-8.60 ppm ( , 3H).
Example 1 - 5-[N-[2- ( dimethylamino )ethyl] ]car- boxamido-2- [2- (dimethylamino) ethyl] yrazolo [3 ,4,5- A-J]acridine A mixture of 4-[N-[2- (dimethylamino )ethyl] ]car- boxamido-l-chloro-9-oxo-9 , 10-dihydroacridine (0.2 g; obtained according to the procedure deεcribed in preparation 5) and of 2- (dimethylamino )ethylhydrazine (0.3 g) in 10 ml of 2-ethoxyethanol is heated at 120°C under stirring until the starting product disappears (monitoring by TLC). The reaction mixture is cooled at room temperature, then partitioned between chloroform and IM sodium carbonate. The organic phase gives, after work up, an oily residue which is flaεh-chromatographed on εilica gel column (eluent: chloroform/methanol 1 : 1, then chloroform/methanol/38% ammonia 1 : 1 : 0.01), thereby obtaining 120 mg of a thick oil which iε directly transformed into the dihydrochloride by treatment with hydrogen chloride, m.p. 211-213"C (dec). -H-NMR in d6-DMSO: 2.80 ppm (s, 12H); 3.21-3.39 ppm ( , 2H ) ; 3.52-3.80 ppm ( , 4H ) ; 4.80 ppm (t, 2H ) 6.90 ppm (d, IH); 7.15 ppm (t, IH); 7.40 ppm (t, IH) 7.59 ppm (d, IH); 7.84 ppm (d, IH ) ; 7.93 ppm (d, IH) 8.80 ppm (br t, IH ) ; 10.70 ppm ( br s, IH ) ; 10.72 ppm (s, IH); 10.90 ppm ( br ε, IH) . The following compounds are prepared analogously by treatment of the appropriate carboxamide (prepared according to Antonini et al, J. Med. Chem., 1997, 40, 3749-3755) with the suitable alkylhydrazme (obtained according to Eslager et al , J. Med. Chem, 1964, 7, 493- 500):
5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-2- [3- (dimethylamino )propyl ]pyrazolo [3 ,4 , 5- kl ~ acridine dihydrochloride, m.p. 203-206°C (dec), 1H-NMR in d6-DMSO: 2.20-2.40 ppm ( , 2H ) ; 2.72 ppm (d, 6H ) ; 2.83 ppm (d, 6H); 3.02-3.24 ppm (m, 2H ) ; 3.24-3-37 ppm (m, 2H ) ; 3.61- 3.78 ppm ( , 2H ) ; 4.46 ppm (t, 2H ) ; 6.81 ppm (d, IH ) ; 7.14 ppm (t, IH); 7.39 ppm (t, IH); 7.55 ppm (d, IH); 7.80-7.92 ppm (m, 2H ) ; 8.72 ppm (br t, IH); 10.62 ppm (br ε, IH); 10.70 ppm (s, IH ) ; 10.84 ppm ( br ε, IH ) ; - 5-[N-[3-(dimethylamino )propyl] ]carboxamido-2-[3-
( dimethylamino )propyl] pyrazolo [ 3,4,5-'Vi]acridine dihy- drochloride, m.p. 125-128°C (dec), 1H-NMR in d6-DMSO:
1.89-2.09 ppm (m, 2H ) ; 2.20-2.40 ppm (m, 2H ) ; 2.72 ppm
(ε, 12H); 3.00-3.10 ppm (m, 4H); 3.20-3.46 ppm ( , 2H ) ;
4.46 ppm (t, 2H); 6.82 ppm (d, IH); 7.13 ppm (t, IH); 7.38 ppm (t, IH); 7.54 ppm (d, IH); 7.73-7.90 ppm ( ,
2H); 8.58 ppm (br t, IH ) ; 10.62-10.81 ppm (m, 2H ) ; 10.91 ppm (br ε, IH);
5- [N-[ 3- (dimethylamino )propyl] ]carboxamido-2-[2-
( dimethylamino )ethyl]pyrazolo[3 ,4 , 5-<i]acridine dihydro- chloride, m.p. 210-212βC (dec), 1H-NMR in d6-DMSO: 1.88-2.09 ppm (m, 2H); 2.75 ppm (d, 6H); 2.83 ppm (d, 6H); 3.02-3.20 ppm (m, 2H ) ; 3.30-3.49 ppm (m, 2H ) ; 3.53- 3.70 ppm (m, 2H ) ; 4.80 ppm (t, 2H ) ; 6.90 ppm (d, IH); 7.16 ppm (t, IH); 7.40 ppm (t, IH ) ; 7.59 ppm (d, IH); 7.79-7.90 ppm (m, 2H ) ; 8.60 ppm (br t, IH ) ; 10.60 ppm (br ε, IH); 10.70-10.85 ppm (m, 2H).
5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-2- [2- (dimethylamino )ethyl]-9-methoxypyrazolo[3 , 4 , 5- J]acridine dihydrochloride, m.p. 239-241°C (dec), 1H-NMR in d6- DMSO: 2.85 ppm (d, 12H); 3.21-3.36 ppm (m, 2H); 3.55- 3.76 ppm (m, 4H ) ; 3.82 ppm (ε, 3H ) ; 4.80 ppm (t, 2H ) 6.84 ppm (d, IH); 7.04 ppm (d, IH ) ; 7.30 ppm (ε, IH) 7.59 ppm (d, IH ) ; 7.89 ppm (d, IH ) ; 8.68 ppm ( br t , IH) 10.41 ppm (br s, IH ) ; 10.50-10.75 ppm ( , 2H ) ; - 5-[N-[2-(dimethylamino)ethyl] ]carboxamido-2- [ 3- ( dimethylamino )propyl]-9-methoxypyrazolo[ 3 ,4 , 5-Js:J]acridine dihydrochloride, m.p. 182-184°C (dec), 1H-NMR in d6- DMSO: 2.20-2.40 ppm (m, 2H); 2.73 ppm (d, 6H ) ; 2.83 ppm (d, 6H); 3.03-3.20 ppm (m, 2H ) ; 3.22-3.37 ppm ( , 2H); 3.60-3.74 ppm (m, 2H ) ; 3.84 ppm (s, 3H); 4.44 ppm (t, 2H); 6.78 ppm (d, IH ) ; 7.00 ppm (d, IH ) ; 7.29 ppm (s, IH); 7.54 ppm (d, IH ) ; 7.84 ppm (d, IH ) ; 8.64 ppm ( br t,
IH); 10.46-10.68 ppm (m, 2H ) ; 10.79 ppm (br s, IH ) ;
5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-2-[ 2- (dimethylamino ) ethyl ]-9-nitropyrazolo[ 3 ,4 , 5-A:J]acridine di- hydrochloride, m.p. >300°C (free base m.p. 170-171°C), 1H-NMR in d6-DMSO: 2.86 ppm (s, 12H); 3.25-3.39 ppm (m, 2H); 3.60-3.75 ppm (m, 4H); 4.84 ppm (t, 2H ) ; 7.05 ppm (d, IH); 7.83 ppm (d, IH ) ; 7.98 ppm (d, IH); 8.21 ppm (d, IH); 8.56 ppm (ε, IH); 8.90 ppm ( br t, IH); 10.58 ppm (br ε, 2H); 11.14 ppm (ε, IH);
5-[N-[2-( tert-butoxycarbony1amino ) ethyl] ]carboxa- mido-2- [2- (dimethylamino) ethyl]pyrazolo [3 ,4 , 5-A:l]-acri- dine, m.p. 166-167°C, iH-NMR in CDC13: 1.46 ppm (s, 9H); 2.34 ppm (s, 6H ) ; 2.90 ppm (t, 2H ) ; 3.38-3.63 ppm ( , 4H); 4.43 ppm (t, 2H ) ; 5.08 ppm ( br t, IH); 6.50 ppm (d, IH); 7.08 ppm ( br t, IH); 7.12 ppm (d, IH); 7.28- 7.37 ppm (m, 3H ) ; 7.96 ppm (d, IH); 10.55 ppm (ε, IH ) .
5- [N-[ 2- (Dimethylamino) ethyl] ]carboxamido-2-( 2- tetrahydro-lH-1-pyrrolyethyl ) -pyrazolo [3 ,4 , 5-.fcI]acridme dihydrochloride, m.p. 160-162 °C (dec), 1H NMR in DMSO- d6: 5 1.75-2,10 ( , 4H ) ; 2.85 (d, 6H ) ; 2.90-3.10 (m, 2H); 3.22-3.40 (m, 2H ) ; 3.41-3.60 (m, 2H); 3.61-3.80 (m, 4H); 4.80 (t, 2H ) ; 6.92 (d, IH ) ; 7.18 (t, IH ) ; 7.40 (t, IH); 7.59 (d, IH ) ; 7.80-7.97 (m, 2H ) ; 8.70 (br t, IH , exchangeable with D20 ) ; 10.46 (br ε, IH, exchangeable with D20); 10.72 (ε, IH, exchangeable with D20); 11.10 (br ε, IH, exchangeable with D20).
5- [N[ 2- (Dimethylamino) ethyl] ]carboxamido-2-( 2-pipe- ridinoethyl)pyrazolo [3 ,4 , 5-Jc-πacridine dihydrochloride , m.p. 145-148 "C (dec), 1H NMR in DMSO-d5: δ 1.28-1.96 (m, 6H); 2.82 (d, 6H ) ; 2.88-3.07 (m, 2H ) ; 3.20-3.35 (m, 2H); 3.40-3.61 (m, 4H ) ; 3.62-3.78 (m, 2H ) ; 4.82 (t, 2H ) ;
6.92 (d, IH); 7.17 (t, IH ) ; 7.40 (t, IH); 7.54 (d, IH); 7.80 (d, IH); 7.91 (d, IH), 8.78 (br t, IH, H, exchangeable with D20); 10.65-10.84 (m, 2H , exchangeable with D20); 11.16 ( br s, IH, exchangeable with D20).
5-[N-[2-(Diethylamino)ethyl] ]carboxamido-2-[2- (die- thylamino )ethyl]pyrazolo[ 3 ,4 , 5-A-J]acridine dihydrochloride, m.p. 170-171 °C (dec), 1H NMR in DMSO-d6. δ 1.20-1.40 (m, 12H); 3.10-3.30 (m, 10H); 3.51-3.80 ( , 4H); 4.85 (t, 2H ) ; 6.93 (d, IH); 7.18 (t, IH ) ; 7.40 (t, IH); 7.60 (d, IH ) ; 7.80-7.96 ( , 2H ) ; 8.84 ( br t, IH , exchangeable with D20); 10.60-10.78 (m, 2H , exchangeable with D20); 11.00 ( br s, IH, exchangeable with D20).
5-[N-( 2-Piperidinoethyl ) ]carboxamido-2-( 2-piperidi- noethyl)pyrazolo[3 ,4, 5-<l]acridine dihydrochloride, m.p. 140-142 "C (dec), ^-H NMR in DMSO-d6: δ 1.21-2.00 (m, 12H); 2.80-3.10 (m, 4H ) ; 3.20-3.37 (m, 2H ) ; 3.40-3.63 (m, 6H); 3.68-3.72 ( , 2H ) ; 4.87 (t, 2H ) ; 6.90 (d, IH ) 7.16 (t, IH); 7.40 (t, IH ) ; 7.66 (d, IH); 7.81 (d, IH ) 7.94 (d, IH); 8.84 (br t, IH , exchangeable with D20) 10.60-10.80 ( , 2H, exchangeable with D20); 11.10 ( br ε, IH, exchangeable with D20).
5-{N-[2-[ ( 2-Hydroxyethyl )amino]ethyl] }carboxamido- 2- [2- (dimethylamino) ethyl]pyrazolo [3 ,4 , 5-'cJ]acridine dihydrochloride, m.p. 100-102 °C (dec), 1H NMR in DMSO- d6: δ 2.85 (d, 6H); 3.00-3.30 ( , 4H ) ; 3.53-3.80 (m, 6H); 4.80 (t, 2H ) ; 6.90 (d, IH); 7.15 (t, IH ) ; 7.40 (t, IH); 7.59 (d, IH); 7.80-8.00 (m, 2H ) ; 8.71 ( br t, IH, exchangeable with D20); 9.16 ( br s, 2H , exchangeable with D20); 10.70 (s, IH , exchangeable with D20); 10.85 (br ε, IH, exchangeable with D20). 5-{N-[2-[ ( 2-Hydroxyethyl )amino]ethγl] }carboxamido-
2-(2-tetrahydro-lH-l-pyrrolyethyl)pyrazolo[3,4 , 5-kl] - acridine dihydrochloride, m.p. 123-125 °C, 1H NMR in
DMSO-d6: δ 1.73-2.10 (m, 4H ) ; 2.90-3.30 (m, 6H); 3.45- 3.57 (m, 2H); 3.60-3.83 (m, 6H ) ; 4.75 (t, 2H ) ; 6.91 (d,
IH); 7.20 (t, IH); 7.40 (t, IH, ar ) ; 7.59 (d, IH); 7.80-
7.95 (m, 2H); 8.68 (br t, IH , exchangeable with D20);
9.10 (br s, 2H, exchangeable with D20); 10.72 (s, IH, exchangeable with D20); 11.19 (br s, IH, exchangeable with D20) .
5-{N-[2-[( 2-Hy roxyethy1) amino] ethyl] }carboxamido- 2-( 2-piperidinoethyl) pyrazolo [3 ,4, 5-A:J]acridine dihydrochloride, m.p. 110-112 °C, 3-H NMR in DMSO-dg δ 1.22-2.00 ( , 6H); 2.80-3.30 (m, 6H); 3.40-3.62 ( , 2H ) ; 3.67-4.00 (m, 6H); 4.88 (t, 2H ) ; 6.90 (d, IH); 7.15 (t, IH); 7.40 (t, IH); 7.55 (d, IH); 7.75-8.00 (m, 2H ) ; 8.68 ( br t, IH, exchangeable with D20); 9.08 (br ε, 2H, exchangeable with D20); 10.52 (s, IH, exchangeable with D20); 10.92 (br s, exchangeable with D20). - 5-[N-[2-(Dimethylamino)ethyl] ]carboxamido-9-metho- xγ-2-( 2-tetrahydro-lH-1-pyrrolyethy1) pyrazolo [3 ,4 , 5-kl ] - acridine dihydrochloride, m.p. 195-197 °C; 1H NMR in DMSO-d6: δ 1.75-2,10 (m, 4H ) ; 2.85 (d, 6H ) ; 2.91-3.10 ( , 2H); 3.21-3.40 (m, 2H ) ; 3.41-3.59 (m, 2H ) , 3.61-3.78 ( , 4H); 3.85 (ε, 3H ) ; 4.77 (t, 2H); 6.88 (d, IH); 7.04 (d, IH); 7.30 (ε, IH); 7.68 (d, IH ) ; 7.90 (d, IH ) ; 8.75 (br t, IH, exchangeable with D20); 10.58-10.80 (m, 2H, exchangeable with D20); 11.44 (br ε, IH , exchangeable with D20) . - 5-[N-[2-(Dimethylamino )ethyl] ]carboxamido-9-metho- xy-2-( 2-piperidinoethyl )pyrazolo[3 , 4 , 5-iJ]acridine di- hydrochloride, m.p. 205-207 °C (dec), 1H NMR in DMSO-dg: δ 1.30-1.89 ( , 6H); 2.85 (d, 6H ) ; 2.90-3.07 ( , 2H ) ;
3.22-3.34 (m, 2H); 3.41-3.58 (m, 4H ) ; 3.60-3.72 (m, 2H ) ;
3.87 (s, 3H); 4.88 (t, 2H ) ; 6.85 (d, IH); 7.05 (d, IH ) ; 7.30 (s, IH); 7.60 (d, IH ) ; 7.90 (d, IH ) ; 8.72 (br t,
IH, exchangeable with D20); 10.52-10.70 (m, 2H, exchangeable with D20); 11.09 (br ε, IH, exchangeable with D20) .
5-[N-[2-(Dimethγlamino)ethyl] ]carboxamido-9-nitro- 2-( 2-tetrahydro-lH-l-pyrrolyethyl )pyrazolo[3 , , 5-&I]- acridine dihydrochloride, m.p. 249-251 °C, 1H NMR in
DMSO-d6 δ 1.72-2,12 (m, 6H); 2.90-3.23 ( , 6H ) ; 3.25-
3.37 ( , 2H); 3.40-3.57 (m, 2H ) ; 3.65-3.85 (m, 2H ) ;
3.90-4.10 (m, 2H ) , 4.84 (t, 2H ) ; 7.09 (d, IH); 7.75-7.95 (m, 2H); 8.20 (d, IH ) , 8.50 (s, IH ) ; 10.33 (br t, IH, exchangeable with D20); 10.91-11.20 ( , 3H, exchangeable with D20) .
5-[N-[2-( Dimethylamino ) ethyl ] ] carboxamido-9-nitro-
2-( 2-piperidinoethyl )pyrazolo [3 ,4 , 5-ci]acridine dihydro- chloride, m.p. >300 "C , 1H NMR in DMS0-d5: δ 1.30-1.90
( , 6H); 2.87 (d, 6H ) ; 2.90-3.09 (m, 2H ) ; 3.22-3.38 ( ,
2H); 3.43-3.59 (m, 4H); 3.60-3.75 (m, 2H ) ; 4.90 (t, 2H )
7.09 (d, IH); 7.83 (d, IH); 7.93 (d, IH ) ; 8.21 (d, IH)
8.50 (s, IH); 8.80 ( br t, IH , exchangeable with D20) 10.30-10.60 (m, 2H , exchangeable with D20); 11.10 (s,
IH, exchangeable with D20).
Example 2 - 5-[N-[2-( dimethylamino )ethyl] ]- carboxamido-2-[ 2- (dimethylamino ) ethyl ]-9-hydroxypyrazo- lo[ 3 , 4 , 5- <VJ]acridine dihydrochloride 0.25 g of 5-[N- [ 2- ( dimethylamino )ethyl] ] -carboxa- mido-2-[ 2- (dimethylamino) ethyl ]-9-methoxypyrazolo[ 3 ,4,5- JcJ]acridine dihydrochloride are εuεpended in 2 ml of 48% hydrobromic acid and the mixture iε refluxed, under εtirring, until the εtarting product disappears. The reaction mixture is cooled at room temperature, then partitioned between chloroform and IM sodium carbonate.
The organic phase is worked up to give an oily residue which is flaεh-chromatographed on εilica gel column
(eluent chloroform/methanol/38% ammonia 1 : 1 : 0.01), thereby obtaining 120 mg of a thick green oil which iε directly tranεformed into the dihydrochloride by treatment with hydrogen chloride, m.p. 191-193°C (dec).
1H-NMR in d6-DMS0: 2.88 ppm (ε, 12H); 3.15-3.34 ppm ( , 2H); 3.50-3.71 ppm (m, 4H); 4.77 ppm (t, 2H) 6.76 ppm (d, IH); 6.86 ppm (d, IH ) ; 7.20 ppm (s, IH) 7.40 ppm (d, IH); 7.85 ppm (d, IH); 8.65 ppm (br t, IH) 10.48-10-67 ppm (m, 2H ) ; 10.72 ppm (s, IH).
The following compounds are prepared analogously: 5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-2-[ 3- (dimethy1amino )propyl ] -9-hydroxypyrazolo [3,4, 5- kl ] acridine dihydrochloride, m.p. 185-187βC (dec), 1H-NMR in d6- DMSO: 2.20-2.40 ppm (m, 2H ) ; 2.71 ppm (d, 6H ) ; 2.83 ppm (d, 6H); 3.00-3.18 ppm (m, 2H); 3.22-3.36 ppm (m, 2H); 3.57-3.75 ppm (m, 2H ) ; 4.45 ppm (t, 2H ) ; 6.74 ppm (d, IH); 6.88 ppm (d, IH); 7.23 ppm (s, IH ) ; 7.40 ppm (d, IH); 7.83 ppm (d, IH ) ; 8.62 ppm (br t, IH); 10.48-10.65 ppm (m, 2H); 10.73 ppm ( br ε, IH).
5- [N- [ 2- ( Dimethylamino ) ethyl ] ] carboxamido-9-hydro- xy-2-(2-tetrahydro-ltf-l-pyrrolyethyl )pyrazolo[3 ,4 , b-kl] - acridine dihydrochloride, m.p. 235-238 °C, 1H NMR in DMS0-d6 δ 1.70-2,10 (m, 4H ) ; 2.85 (d, 6H ) ; 2.90-3.10 (m, 2H); 3.23-3.38 (m, 2H ) ; 3.40-3.56 (m, 2H ) ; 3.70-3.88 ( , 4H ) ; 4 . 80 ( t , 2H ) ; 6 . 80-6 . 97 ( , 2H ) ; 7 . 25 ( ε , IH ) ; 7 . 44
(d, IH); 7.89 (d, IH ) ; 8.69 (br t, IH exchangeable with D20); 10.45-10.70 (m, 2H , exchangeable with D20); 11.22 (br s, IH, exchangeable with DnO). - 5-[N-[2-(Dimethylamino)ethyl] ]carboxamido-9-hydro- xy-2-( 2-piperidinoethγl )pyrazolo[ 3,4, 5-A:J]acridine dihydrochloride , m.p. 248-250 °C (dec), 1H NMR in DMSO-d6: δ 1.25-2.00 (m, 6H ) ; 2.70-3.10 (m, 8H ) ; 3.20-3.36 (m, 2H); 3.40-3.60 ( , 4H ) ; 3.63-3.75 ( , 2H ) ; 4.85 (t, 2H ) ; 6.77-6.93 (m, 2H); 7.25 (s, IH); 7.44 (d, IH ) ; 7.90 (d, IH); 8.70 (br t, IH , exchangeable with D20); 10.52-10.79 (m, 2H, exchangeable with D20); 11.00 (br ε, IH , exchangeable with D 0).
Example 3 - 5- [N- [2- (dimethylamino )ethyl ] ]- carboxamido-2- [2- (dimethylamino ) ethyl ]-9-aminopyrazo- lo[3 ,4 , 5-<s:I]-acridine trihydrochloride
5- [N-[2- (dimethylamino) ethyl] ] carboxamido-2- [2- (dimethylamino ) ethyl ]-9-nitropyrazolo[ 3 ,4 , 5-<2]acridine dihydrochloride (0.2 g) iε εuεpended in 20 ml of methanol, then added with 1 ml of 37% hydrochloric acid and 20 mg of 5% palladium-on-carbon. The reaction mixture iε placed in hydrogen atmosphere (30 psi) with εtirring at room temperature for 1 hour. The catalyεt iε then filtered off, the εolvent is evaporated and the residue is suspended in 10 ml of boiling ethanol filtration. The reaction mixture is then cooled at room temperature and the solid is recovered by filtration and washed with ether ethyl, to give 180 mg of product, m.p. 250-252°C (dec. ) . iH-NMR in d6-DMSO: 2.86 ppm (ε, 12H); 3.21-3.39 ppm (m, 2H); 3.52-3.78 ppm (m, 4H); 4.84 ppm (t, 2H); 6.94 ppm (d, IH ) ; 7.38 ppm (d, IH); 7.70 ppm (d, IH);
7.83 ppm (ε, IH ) ; 7.94 ppm (d, IH ) ; 8.80 ppm ( br t , IH ) ; 10.10-10.90 ppm ( , 6H ) .
Example 4 - 5-[N-[2-( amino )ethyl] ]carboxamido-2-[2- (dimethylamino)ethyl]pyrazolo[3 ,4 , 5-A-J]acridine dihydrochloride
0.15 g of 5-[N-[2-( tert-butoxycarbonyla mino )- ethyl] ] carboxamido-2-[ 2- (dimethylamino ) ethyl ]pyrazo- lo[3 , 4 , 5-&l]acridine are diεsolved in 20 ml of dioxane and added with 2 ml of 37% hydrochloric acid. The reaction mixture is stirred at room temperature for 1 hour, then the solvent is evaporated and the residue is crystallized from ethanol to give 110 mg of product, m.p. 221-223°C (dec. ) . ÷-H-NMR in d6-DMSO: 2.85 ppm (s, 6H); 2.94-3.15 ppm (m, 2H); 3.50-3.70 ppm ( , 4H ) ; 4.80 ppm (t, 2H); 6.90 ppm (d, IH); 7.18 ppm (t, IH); 7.40 ppm (t, IH ) ; 7.58 ppm (d, IH); 7.80-7.96 ppm ( , 2H ) ; 8.20 ppm (br s, 2H); 8.65 ppm (br t, IH); 10.63 ppm (br ε, 2H); 10.72 ppm (ε, IH).
Example 5 - 2- [2- ( dimethylamino ) ethyl] -6- [2- ( dimethylamino ) ethyl] -2 ,5,6, 7-tetrahydropyrazolo [3,4,5- /π.π]pyrimido[5 , 6 , l-?e]acridine-5 , 7-dione
A mixture of 5-[N- [ 2- ( dimethylamino )ethyl] ]-car- boxamido-2- [2- (dimethylamino) ethyl]pyrazolo [3 , 4 , 5-Jl]- acridine of hydrochloride (0.05 g) in 10 ml of chloroform and 0.2 ml of triethylamine , kept a 0°C, iε added with phoεgene (0.35 ml of 20% solution in toluene) in 10 ml of chloroform drop by drop. When the addition is completed, the mixture is stirred at room temperature for 20 minutes. The reaction mixture is then partitioned between chloroform and IM sodium carbonate. The organic phase is worked up to give a residue which is suspended in ethyl ether (10 ml) and stirred for 10 minutes. By filtration, 20 mg of product are obtained, m.p. 181- 182°C (m.p. hydrochloride 282-284°C with dec).
1H-NMR in CDC13: 2.31 ppm (s, 6H); 2.38 ppm (s,
6H); 2.68 ppm (t, 2H ) ; 2.89 ppm (t, 2H ) ; 4.37 ppm (t,
2H); 4.51 ppm (t, 2H); 7.10 ppm (d, IH ) ; 7.44 ppm (t,
IH); 7.51 ppm (t, IH); 8.00 ppm (d, IH ) ; 8.19 ppm (d, IH); 9.45 ppm (d, IH) .
The following compounds are prepared analogously: 2-[3-(dimethylamino)propyl]-6-[2-(dimethylamino)- ethyl]-2, 5, 6 , 7-tetrahydropyrazolo[3 ,4 , 5-m.ra]pyrimi- do[5 ,6 ,l-?e]acridine-5 ,7-dione , purified by flash- chro atography on silica gel column (eluent chlorofor /methanol 1 : 1), m.p. 154-155°C (m.p. hydrochloride 148-151βC with dec), 1H-NMR in CDC13: 2.10-2.30 ppm (m, 10H); 2.38 ppm (s, 6H); 2.69 ppm (t, 2H); 4.38 ppm (t, 2H ) ; 4.51 ppm (t, 2H ) ; 7.16 ppm (d, IH); 7.40-7.60 ppm ( , 2H); 8.00 ppm (d, IH ) ; 8.20 ppm (d, IH); 9.48 ppm (d, IH);
2- [ 3- ( dimethylamino )propyl ] -6- [ 3- ( dimethylamino ) - propyl]-2 ,5,6 , 7-tetrahydropyrazolo[ 3 ,4 , 5-.mn]pyrimi- do[ 5 , 6 , l-de]acridine-5 ,7-dione , purified by flaεh- chromatography on silica gel (eluent chloroform/methanol/38% ammonia 1 : 1 : 0.01), m.p. 185- 187°C (m.p. hydrochloride 178-180°C with dec), !H-NMR in CDCI3: 1.88-2.10 ppm (m, 2H ) ; 2.10-2.37 ppm (m, 16H); 2.53 ppm (t, 2H ) ; 4.39 ppm (t, 2H ) ; 4.50 ppm (t, 2H); 7.15 ppm (d, IH); 7.39-7.59 ppm ( , 2H ) ; 7.90 ppm (d, IH); 8.20 ppm (d, IH ) ; 9.45 ppm (d, IH ) ; 2- [ 2- ( dimethylamino ) ethyl ] -6- [ 3- ( dimethylamino ) pro- pyl]-2 , 5 , 6 ,7-tetrahydropyrazolo[3 ,4 , 5-/7m]pyrimido[5 ,6,1- de]acridine-5 ,7-dione , purified by flaεh-chromatography on silica gel (eluent 1) chloroform/methanol 1 : 1; 2) chloroform/methanol/38% ammonia 1 : 1 : 0.01), m.p. 161-
162°C (m.p. hydrochloride 283-2850C with dec), 1H-NMR in CDC13: 1.88-2.09 ppm (m, 2H); 2.27 ppm (s, 6H ) ; 2.31 ppm (ε, 6H); 2.45 ppm (t, 2H); 2.90 ppm (t, 2H); 4.39 ppm (t, 2H); 4.53 ppm (t, 2H); 7.12 ppm (d, IH ) ; 7.40- 7.60 ppm ( , 2H); 8.00 ppm (d, IH); 8.20 ppm (d, IH); 9.57 ppm (d, IH ) ;
2- [2- (dimethylamino) ethyl]-6- [2- (dimethylamino )- ethyl]-10-methoxy-2 ,5,6 , 7-tetrahydropyrazolo[3 , 4 , b-mn} - pyrimido[5 , 6 ,l-de]acridine-5 ,7-dione , purified by chromatography on εilica gel (eluent chloroform/methanol 1 : 1), m.p. 186-187βC (m.p. hydrochloride 278-281°C with dec), ^-H-NMR in CDCI3: 2.34 ppm (ε, 6H); 2.55 ppm (ε, 6H); 2.82-3.01 ppm (m, 4H); 3.92 ppm (s, 3H); 4.45 ppm (t, 2H); 4.58 ppm (t, 2H ) ; 7.05 ppm (d, IH ) ; 7.12 ppm (d, IH); 7.60 ppm (s, IH); 8.00 ppm (d, IH ) ; 9.40 ppm ( d , IH ) ;
2- [ 3- ( imethylamino ) ropyl ] -6- [ 2- ( dimethylamino ) - ethyl ]-10-methoxy-2 ,5,6 , 7-tetrahydropyrazolo[ 3 , 4 , 5-mn] - pyrimido[ 5 , 6 , l-de]acridine-5 , 7-dione , purified by flash- chromatography on silica gel (eluent chloroform/methanol 1 : 1), m.p. 200-201°C (m.p. hydrochloride 253-255°C with dec), iH-NMR in CDCI3: 2.10-2.30 ppm (m, 10H) 2.36 ppm (s, 6H); 2.68 ppm (t, 2H ) ; 3.95 ppm (s, 3H) 4.38 ppm (t, 2H); 4.49 ppm (t, 2H ) ; 7.05 ppm (d, IH ) 7.14 ppm (d, IH ) ; 7.62 ppm (ε, IH ) ; 8.00 ppm (d, IH) 9.40 ppm (d, IH ) ; 2- [2- (dimethylamino) ethyl] -6- [2- (dimethylamino )- ethyl]-10-nitro-2 ,5,6 , 7-tetrahydropyrazolo[3 ,4, 5-mn] - pyrimido[5 , 6 , l-de]acridine-5 ,7-dione , m.p. 216-217°C (m.p. hydrochloride 261-263°C with dec), ^-H-NMR in CDC13: 2.33 ppm (s, 6H); 2.43 ppm (s, 6H ) ; 2.75 ppm (t, 2H); 2.93 ppm (t, 2H ) ; 4.39 ppm (t, 2H ) ; 4.54 ppm (t, 2H); 7.19 ppm (d, IH); 8.00 ppm (d, IH ) ; 8.27 ppm (d, IH); 8.95 ppm (s, IH); 9.63 ppm (d, IH ) ;
6-[2-(Dimethylamino)ethyl]-ll-methoxy-2-( 2-tetra- hydro-l#-l-pyrrolyethyl )-2 , 5 , 6 , 7-tetrahydropyrazo- lo[ 3 , 4 , 5-/n.n]pyrimido[ 5,6, l-de]acridine-5 , 7-dione , m.p . 190-191 °C; m.p. hydrochloride 200-202 °C with dec), 1H NMR in CDC13: δ 1.72-1.92 (m, 6H); 2.37 (s, 6H ) ; 2.58 (br t, 2H); 2.70 (t, 2H); 3.08 (t, 2H ) ; 3.94 (ε, 3H); 4.39 (t, 2H); 4.59 (t, 2H ) ; 7.00-7.10 (m, 2H); 7.63 (s,
IH); 8.00 (d, IH); 9.40 (d, IH ) .
Example 6 - 2-[2- ( dimethylamino )ethyl]-6- [2- ( dimethylamino.) ethyl ]-10-hydroxy-2 ,5,6, 7-tetrahydropyrazo- lo[3 ,4 , 5-/77/3]pyrimido[ 5,6, 1-de] acridine-5 , 7-dione 0.14 g of 2-[2-(dimethylamino)ethyl]-6-[2-(dime- thyla-mino ) ethyl ]-10-methoxy-2 ,5,6, 7-tetrahydropyrazo- lo[3 ,4 , 5-m^]pyrimido[5 , 6 , l-de]acridine-5 ,7-dione are suspended in 2 ml of 48% hydrobromic acid and the reaction mixture is refluxed, under stirring, until the starting product disappears (monitoring by TLC). The reaction mixture is cooled at room temperature and partitioned between chloroform and IM sodium carbonate. The organic phase is worked up to give a residue which is suεpended in ethyl ether, filtered, waεhed with ethyl ether to give 80 mg of product, which iε transformed into hydrochloride by treatment with hydrogen chloride, m.p. 289-290°C (m.p. hydrochloride 266-268°C with dec).
1H-NMR in d6-DMSO: 2.20 ppm (s, 6H ) ; 2.25 ppm (s,
6H); 2.53 ppm (t, 2H ) ; 2.78 ppm (t, 2H); 4.16 ppm (t, 2H); 4.56 ppm (t, 2H ) ; 6.96 ppm (d, IH ) ; 7.37-7.45 ppm
(m, 2H); 7.80 ppm (d, IH); 9.21 ppm (d, IH ) .
The following compound iε prepared analogouεly:
2- [ 3- ( dimethylamino )propyl] -6- [ 2- ( dimethylamino )- ethyl ]-10-hydroxy-2 ,5,6 , 7-tetrahydropyrazolo[3 ,4 , b-mn] - pyrimido[5 , 6 ,l-de]acridine-5 ,7-dione, m.p. 241-242βC (m.p. hydrochloride 295-297°C with dec), 1H-NMR in CDC13: 2.00-2.16 ppm (m, 2H ) ; 2.16-2.22 ppm ( , 8H ) ; 2.54 ppm (ε, 6H); 3.00 ppm (t, 2H); 4.30-4.51 ppm (m, 4H); 6.38 ppm (d, IH ) ; 6.60 ppm (ε, IH); 7.11 ppm (d, IH); 8.00 ppm (d, IH); 8.81 ppm (d, IH).
Example 7 - 2-[2- (dimethylamino ) ethyl] -6- [2- (dimethylamino )ethyl]-10-amino-2 ,5,6, 7-tetrahγdropyrazo- lo[3 , 4 , 5-m.n]pyrimido[5 , 6 , l-de]acridine-5 , 7-dione tri- hydrochloride 0.13 g of 2-[2-(dimethγlamino)ethyl]-6-[2- ( dimethylamino )ethyl]-10-nitro-2 ,5,6, 7-tetrahydropyrazo- lo[3 , 4 , 5-mn]pyrimido[ 5,6, l-de]acridine-5 , 7-dione are εuεpended in 20 ml of methanol and added with 1 ml of 37% hydrochloric acid and 20 mg of 5% palladium-on- carbon. The reaction mixture is placed in hydrogen atmoεphere (30 psi) under stirring at room temperature for 1 hour, then filtered and washed with ethyl ether to obtain 100 mg of product, m.p. 283-285°C (dec).
1H-NMR in d6-DMSO: 2.90 ppm (s, 12H); 3.39-3.56 ppm (rn, 2H ) ; 3.62-3.81 ppm (m, 2H ) ; 4.20 ppm (br s, 3H ) ; 4.35-4.50 ppm (m, 2H ) ; 5.00 ppm (t, 2H); 7.10 ppm (d, IH); 7.51-7-67 ppm ( , 2H ) ; 7.97 ppm (d, IH ) ; 9.22 ppm
(d, IH); 10.16 ppm (br s, IH ) ; 10.96 ppm ( br ε, IH ) .
Example 8 - 2-[2-( dimethylamino ) ethyl]-6- [ 3-
( dimethylamino )propyl] -2 ,5,6 ,7-tetrahydropyrazolo[3 ,4,5- /π/3]pyrimido[5 , 6 , l-de]acridine-5 ,7-dione
A mixture of pyrimidoacridine of preparation 7
(0.22 g) and of 2- ( dimethylamino )ethylhydrazine (0.26 g) in ethanol iε heated to 120βC under εtirring for 30 minuteε. The reaction mixture iε partitioned between chloroform and IM sodium carbonate. After work up of the organic phase, the residue is flaεh-chromatographed on silica gel column (eluent: chloroform/methanol 1 : 1, then chloroform/methanol/38% ammonia 1 : 1 : 0.01) to give 100 mg of the product, m.p. 161-162°C (m.p. hydrochloride 283-285°C with dec).
1H-NMR in CDC13: 1.88-2.09 ppm (m, 2H ) ; 2.27 ppm
(s, 6H); 2.31 ppm (s, 6H); 2.45 ppm (t, 2H ) ; 2.90 ppm
(t, 2H); 4.39 ppm (t, 2H ) ; 4.53 ppm (t, 2H ) ; 7.12 ppm
(d, IH); 7.40-7.60 ppm ( , 2H ) ; 8.00 ppm (d, IH ) ; 8.20 ppm (d, IH); 9.57 ppm (d, IH).

Claims

C_LΔIH£
Compounds of general formula (I):
Figure imgf000032_0001
wherein:
R is selected from hydrogen, straight or branched
(C^-Cg )alkyl, -OH, - H2 , (C-^-^ )alkoxy, mono- and di-
(C« -C4 )alkylamino, chlorine, bromine, iodine and fluorine, nitro, mono- and poly-fluoro(C1-C4 )alkyl ,
( C-j-C ) alkylsulfonyl, (C1-C4 )alkylaminosulfonyl; n and m are independently the integer 2, 3 or 4; p i╬╡ 0 or the integer 1;
A and A' are independently selected from -NH2 , -OH, mono- or di-(C^-C4 )alkylamino , hydroxyethylamino , N-mor- pholinyl, N-piperazinyl , N-thiomorpholinyl , N-pyrro- lidinyl, N-piperidinyl , pos╬╡ible stereoisomer╬╡ or ╬╡tereomeric mixtures and salts thereof with pharmaceutically acceptable acids.
2. Compounds according to claim 1, in which n and m are the integer 2.
3. Compounds according to claims 1 and 2, in which p is the integer 1.
4. Compounds according to claims 1 to 3, in which R is a nitro group.
5. Compound╬╡ according to claim 1, selected from: 5- [N-[2- (dimethylamino)ethyl] ] carboxamido-2-[ 2- (dimethylamino )ethyl ]pyrazolo[ 3 ,4 , 5-A-J]acridine;
5- [N-[ 2- (dimethylamino) ethyl] ]carboxamido-2-[ 3- (dimethylamino )propyl]pyrazolo [3 , 4 , 5-Js:i]acridine dihydro- chloride;
5-[N-[3-( dimethylamino )propyl] ] carboxamido-2- [ 3- ( dimethy1amino )propyl]pyrazolo [3 ,4 , 5-A:I]acridine dihydrochloride;
5- [N- [ 3-( dimethylamino )propyl] ]carboxamido-2-[2- (dimethylamino)propyl]pyrazolo[3 ,4 , 5-A:J]acridine dihydrochloride;
5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-2-[ 2- (dimethylamino ) ethyl ]-9-methoxypyrazolo[ 3 , 4 , 5-cI]acridine dihydrochloride; - 5-[N-[2-(dimethylamino)ethyl] ]carboxamido-2-[3-(di- methylamino)propyl]-9-methoxypyrazolo[3 ,4 , 5-<I]acridine dihydrochloride;
5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-2- [2- (dimethylamino ) ethyl ]-9-nitropyrazolo[ 3 , 4 , - kl ] acr idine di- hydrochloride;
5-[N-[2-( tert-butoxycarbonylamino ) ethyl] ] carboxamido-2- [2- (dimethylamino )ethyl]pyrazolo [3 ,4, 5-.fc.Z]-acri- dine;
5-[N-[2- (Dimethylamino ) ethyl] ] carboxamido-2- ( 2-te- trahydro-ltf-1-pyrrolyeth╬│l ) -pyrazolo [3 ,4,5-y-I]acridine dihydrochloride;
5- [N[ 2- (dimethylamino ) ethyl] ]carboxamido-2- ( 2-pipe- ridinoethyl )pyrazolo[3 , 4 , 5-╬╗'2]acridine dihydrochloride; 5-[N-[2- (diethylamino )ethyl] ]carboxamido-2- [2- ( di- ethylamino)ethyl]pyrazolo[3 ,4 , 5-^J]acridine dihydrochloride; 5-[N-( 2-p╬╣per╬╣dmoethyl ) ]carboxam╬╣do-2-( 2-p╬╣per╬╣d╬╣- noethyl)pyrazolo [3 ,4 , 5-il]acr╬╣d╬╣ne dihydrochloride;
5-{N-[2-[( 2-hydroxyethyl ) ammo] ethyl] }carboxam╬╣do- 2- [2- (dimethylamino ) ethyl ] yrazolo[ 3 , 4 , 5- kl ] acridme di- hydrochloride;
5-{N-[2-[ ( 2-hydroxyethyl )ammo]ethyl] }carboxam╬╣do- 2- ( 2-tetrahydro-lf-1-pyrrolyethyl )pyrazolo [ 3 , 4 , 5- kl ] - acridme dihydrochloride;
5-{N-[2-[ ( 2-hydroxyethyl )ammo]ethyl] }carboxam╬╣do- 2-( 2-p╬╣per╬╣dmoethyl)pyrazolo[3 ,4 , 5-A:J]acr╬╣d╬╣ne dihydrochloride;
5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-9-metho- xy-2- ( 2-tetrahydro-lH-l-pyrrolyethyl )pyrazolo[ 3 , 4 , b-kl ] - acridme dihydrochloride; - 5-[N-[2-(d╬╣methylammo )ethyl] ]carboxam╬╣do-9-me- thox╬│-2-( 2-p╬╣per╬╣dmoethyl )pyrazolo [3 , 4 , 5-ci]acr╬╣dme dihydrochloride;
5- [N-[ 2- (dimethylamino) ethyl] ] carboxamido-9-nitro- 2- ( 2-tetrahydro-ltf-l-pyrrolyethyl ) pyrazolo [ 3 , 4 , 5- kl ] - acrid e dihydrochloride;
5- [N-[ 2- (dimethylamino ) ethyl] ] carboxamido-9-n╬╣tro- 2-( 2-p╬╣per╬╣dmoethyl ) pyrazolo [3 , 4 , b-kl ] acridme dihydrochloride;
5- [N-[ 2- (dimethylamino ) ethyl] ]-carboxam╬╣do-2-[2- (dimethylamino) ethyl ]-9-hydroxypyrazolo[ 3 , 4 , 5- kl ] acridme dihydrochloride;
5-[N-[2- (dimethylamino ) ethyl] ] carboxamido-2- [ 3- ( dimethylamino )propyl ]-9-hydroxypyrazolo[ 3 , 4 , 5- kl ] acridme dihydrochloride; - 5-[N-[2-( dimethylamino )ethyl] ]carboxam╬╣do-9-hydro- xy-2-( 2-tetrahydro-l#-l-pyrrolyethyl ) yrazolo [3 ,4 , -kl] - acridine dihydrochloride;
5- [N-[ 2- (dimethylamino ) ethyl] ] carboxamido-9-hydro- xy-2-( 2-piperidinoethyl )pyrazolo[3 ,4, 5 -kl ] acridine dihydrochloride; - 5-[N-[2-(dimethylamino)ethyl] ]carboxamido-2-[2-(di- methylamino)ethyl]-g-aminopyrazolo[3 , , 5- kl] -acridine trihydrochloride ;
5- [N-[ 2- (amino) ethyl] ] carboxamido-2- [2- (dimethylamino ) ethyl]pyrazolo [3 ,4 , 5 -kl ] acridine dihydrochloride; - 2-[2-(dimethylamino)ethyl]-6-[2-(dimethylamino)- ethyl]-2 ,5,6, 7-tetrahydropyrazolo[ 3 ,4 , 5-/rm]pyrimido- [5,6 ,1-de] acridine-5 ,7-dione;
2- [3- (dimethylamino )propyl] -6- [ 2- ( dimethylamino )- ethyl] -2 ,5,6 , 7-tetrahydropyrazolo[3 ,4 , 5-mn]pyrimi- do [5 ,6 ,1-de] acridine-5 , 7-dione; 2-[3- (dimethylamino)propyl]-6-[3-(dimethylamino )- propyl] -2 ,5,6 , 7-tetrahydropyrazolo[ 3 ,4 , 5-/π.n]pyrimi- do[5 , 6 , 1-de] acridine-5 , 7-dione;
2- [2- (dimethylamino) ethyl] -6- [3- (dimethylamino )pro- pyl]-2,5,6, 7-tetrahydropyrazolo[ 3 , 4 , 5-mi3]pyrimido[5 , 6 ,1- de] acridine-5 , 7-dio e,ΓÇó 2-[2-(dimethyla ino)ethyl]-6-[2-(di ethylamino)- ethyl ]-10-methoxy-2 ,5,6 , 7-tetrahydropyrazolo[3 ,4 , b-mn] - pyrimido[5 , 6 , 1-de] acridine- 5 ,7-dione; - 2-[3-(dimethylamino)propyl]-6-[2-(dimethylamino)- ethyl]-10-methoxy-2 ,5,6 , 7-tetrahydropyrazolo[ 3 ,4 , b-mn] - pyrimido[5 ,6 , 1-de] acridine-5 ,7-dione;
2- [2- (dimethylamino ) ethyl ] -6- [2- ( dimethylamino ) - ethyl ]-10-nitro-2 ,5,6 , 7-tetrahydropyrazolo[3 ,4 , -mn] - pyrimido[5 , 6 , 1-de] acridine-5 ,7-dione;
6-[2-(dimethylamino)ethyl -ll-methoxy-2-( 2-tetra- hydro-ltf-1-pyrrolyethyl )-2 , 5 , 6 , 7-tetrahydropyrazo- lo[3 ,4, 5-mΛ]pyrimido[5 , 6 , 1-de] acridine-5 ,7-dione;
2- [2- (dimethylamino ) ethyl]-6- [2- (dimethylamino )e- thyl]-10-hydroxγ-2 ,5,6 , 7-tetrahydropyrazolo[ 3 ,4 , 5-/πn]py- rimido[ 5 , 6 , 1-de]acridine-5 , 7-dione;
2-[3- (dimethylamino )propyl]-6-[2- ( dimethylamino )- ethyl]-10-hydroxy-2 ,5,6, 7-tetrahydropyrazolo[ 3 , 4 , -mn] - pyrimido[5 ,6 , 1-de]acridine-5 ,7-dione;
2- [2- (dimethylamino ) ethyl] -6- [2- (dimethylamino )e- thyl]-10-amino-2 ,5,6, 7-tetrahydropyrazolo[3 ,4, 5-/πn]pyri- mido[ 5 , 6 ,1-de] acridine-5 , 7-dione trihydrochloride;
2- [2- (dimethylamino ) ethyl] -6- [3- (dimethylamino )propyl ] -2 , 5,6 ,7-tetrahydropyrazolo[3 , 4 , 5-/7/τj-]pyrimido[ 5 ,6 ,1- de]acridine-5 ,7-dione , 6. Compounds according to claims 1 to 5 for use as therapeutical agents.
7. Compounds according to claim 6 for use as antitumor agents .
8. Pharmaceutical compositions containing an effective dosage of at least one compound according to claims 1 to
5 in admixture with pharmaceutically acceptable excipient╬╡ .
PCT/EP1998/004781 1997-08-01 1998-07-31 Pyrazolo-acridine derivatives having antitumour activity WO1999006405A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138302A1 (en) * 1983-07-19 1985-04-24 Warner-Lambert Company Pyrazolo(3,4,5-kl)acridine compounds, pharmaceutical compositions comprising the same and processes for their production

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138302A1 (en) * 1983-07-19 1985-04-24 Warner-Lambert Company Pyrazolo(3,4,5-kl)acridine compounds, pharmaceutical compositions comprising the same and processes for their production

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CANCER RES., vol. 47, no. 16, 1987, pages 4299 - 4304 *
CHEMICAL ABSTRACTS, vol. 107, no. 21, 23 November 1987, Columbus, Ohio, US; abstract no. 190463b, JUDITH S. SEBOLT ET AL: "Pyrazoloacridines,a new class of anticancer agents with selectivity against solid tumors in vitro" page 28; XP002056758 *
DAVID B. CAPPS ET AL: "2-(aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines,a new class of anticancer agents.", JOURNAL OF MEDICINAL CHEMISTRY., vol. 35, no. 26, 25 December 1992 (1992-12-25), WASHINGTON US, pages 4770 - 4778, XP002056757 *

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