WO1999006372A1 - Bis-acridinecarboxamides ayant une activite antitumorale - Google Patents

Bis-acridinecarboxamides ayant une activite antitumorale Download PDF

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Publication number
WO1999006372A1
WO1999006372A1 PCT/EP1998/004755 EP9804755W WO9906372A1 WO 1999006372 A1 WO1999006372 A1 WO 1999006372A1 EP 9804755 W EP9804755 W EP 9804755W WO 9906372 A1 WO9906372 A1 WO 9906372A1
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WO
WIPO (PCT)
Prior art keywords
ppm
ethyl
methyl
dimethylamino
bis
Prior art date
Application number
PCT/EP1998/004755
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English (en)
Inventor
Ippolito Antonini
Sante Martelli
Paolo Polucci
Original Assignee
Universita' Degli Studi Di Camerino
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universita' Degli Studi Di Camerino filed Critical Universita' Degli Studi Di Camerino
Priority to EP98939644A priority Critical patent/EP1001936A1/fr
Priority to JP2000505131A priority patent/JP2001512104A/ja
Priority to AU88080/98A priority patent/AU8808098A/en
Publication of WO1999006372A1 publication Critical patent/WO1999006372A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to bis- acridinecarboxamides and the derivatives thereof substituted with aminoalkyl chains.
  • 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
  • DNA intercalating agents comprises acridines [Atwell G.J. et al . , J. Med. Chem.,
  • novel class of bis-acridine derivatives which show a marked antitumor activity, predominantly in solid tumors such as the colon tumor, compared with the compounds of the prior art.
  • novel bifunctional derivatives are distinguished in that they have acridine, acridone, pyrazole-acridone, pyrimido-acridone and pyrazole- pyrimidoacridone systems bearing alkylamino side chains at the para position to the polyamino chain linking the two units .
  • the present invention relates to compounds of general formula (I):
  • Z is a (C2-C ) alkylene chain or a group of formula (CH 2 ) n -N(B)-(CH 2 ) q -N(B , )-(CH 2 )m-(CH 2 ) n -N(B)-X-(CH 2 ) m wherein: n and are independently an integer from 2 to 4,
  • B is hydrogen or (C- ⁇ -C ⁇ -alkyl
  • X is a single bond or a group of formula
  • a and A' which are the same or different, are selected from:
  • R is hydrogen, or one or more substituents which are the same or different, selected from straight or branched (C ⁇ -Cg)alkyl, -OH, -NH , (C ⁇ -C ⁇ )alkoxy , mono- and di-(C 1 -C ⁇ )alkylamino, chlorine, bromine, iodine and fluorine, nitro, mono- and poly-fluoro( C.,-C 4 )alkyl, (C ⁇ -C 4 )alkylsulfonyl, (C ⁇ -C 4 )alkylaminosulfonyl;
  • Y is a -(CH ) D ⁇ T group; p is the integer 2, 3 or 4; - T is selected from -NH , -OH, mono- or di-(C ⁇ -C 4 )- alkylamino, hydroxyethylamino , N-morpholinyl , N-pi- perazinyl, N-thiomorpholinyl , N-pyrrolidinyl, N-pipe- ridinyl, 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 related pharmaceutical formulations as antitumor agents.
  • Preferred compounds of formula (I) are those in which n and m are the integer 3.
  • Said reaction can be carried out in the presence of a condensing agent, such as dicyclohexylcarbodiimide, or after activation of the carboxylic group of the intermediate of formula (III), for example via imidazolide (by reaction with 1,1'- carbonyldii idazole) , mixed anhydride (by reaction with ethyl chloroformate in the presence of triethylamine) or N-hydroxysuccinimidoester (by reaction with N- hydroxysuccinimide in the presence of morpholinoethyl isonitrile) .
  • a condensing agent such as dicyclohexylcarbodiimide
  • the compounds of formula (I)-(c) can be prepared according to the synthetic scheme reported in Figure 3, which comprises reacting at least two equivalents of the intermediate of formula (V) with an equivalent of the polyamine of formula (II) in a solvent such as ethoxyethanol, in the presence of a base such as triethylamine and at a temperature up to 150°C.
  • the compounds of formula (I)-(a) can be prepared according to the synthetic scheme reported in Figure 4, by reducing the corresponding compounds of formula (I)- (c) with aluminum amalgam in ethanol/water .
  • the compounds of formula (I)-(f) can be prepared by reduction of the compounds of formula (I)-(b) with aluminum amalgam in ethanol/water.
  • the compounds of formula (I) in which A and A' are different are prepared by a reaction sequence involving a first condensation between, for instance, a compound of formula A-W wherein A is as defined above and W is a halogen atom or a carboxy-activating group, and a diamine of formula NH 2 -Z-NH 2 , wherein Z is as defined above, followed by a second reaction between the product resulting from the first reaction and a compound of formula A'-W, wherein A' and W are as defined above.
  • the first reaction is usually carried out using an at least 1:2 excess of the diamine compound in a solvent such as 2-ethoxyethanol, ethanol, methanol, ethyl acetate, dimethylsulfoxide, dimethylformamide .
  • a solvent such as 2-ethoxyethanol, ethanol, methanol, ethyl acetate, dimethylsulfoxide, dimethylformamide .
  • the intermediates of formula (III) and (V) can be prepared according to the synthetic scheme reported in Figure 6, which comprises the following synthetic steps: (5) condensation of a 2-halocarboxylic acid with 5- chloro-2-carboxy aniline (or the corresponding methyl carboxylate ) in the presence of copper or of the salts thereof and in basic medium.
  • Examples of said reactions 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.
  • Said reaction can be carried out in the presence of condensing agents such as carbodiimides or after activation of the carboxylic group, for example by formation of the imidazolide (by reaction with carbonyldii idazole ) , of the acid chloride (by reaction with thionyl chloride) or of the hydroxysuccinimido ester (by reaction with N-hydroxy- succinimide in the presence of morpholinoethylisonitrile) .
  • polyamines of formula (II) are compounds widely known and described for example in the already cited Cholody W.M. et al . , J. Med. Chem., 38, 3043-52 (1995) and Hernandez L. et al., Cancer Res., 55, 2338-45
  • the compounds of formula (I) can also be salified by reaction of the free base with pharmaceutically acceptable acids, preferably with hydrochloric acid.
  • the compounds of the invention were tested for their antitumor activity on the human HT 29 cell line of colon adenocarcinoma.
  • the cells were incubated for 144 hours with the test compound, then cytotoxicity was evaluated using the "MTT Assay" (Mosman, T. "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay”; J. Immunol. Methods, (1983), 65, 66-63; Green, L.M., “Rapid Colorimetric Assay for Cell Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines", J. Immunol. Methods, (1984), 70, 257-268).
  • the results are expressed as IC 50 ( ⁇ g/ml), i.e. the concentration of the test compound causing the death of 50% of the cell population.
  • IC 50 ⁇ g/ml
  • the effective dosage of the compounds of the invention can be determined by the expert clinician with conventional, known methods.
  • the relationship between the dosages used for animals of various species and those for humans (on the basis of mg/m2 of body area) is described by Freirich,
  • Tumors which can be treated with the compounds of the present invention are those sensitive to the therapy with DNA intercalating agents.
  • colon tumor can advantageously be treated.
  • compositions containing the compounds of formula (I) are comprised in the invention.
  • compositions can contain any amounts of compounds of formula (I) capable of exerting in mammals 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, subcutaneous 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.
  • Tablets, pills, capsules and similar compositions can contain the following ingredients (in addition to the active ingredient): a ligand, such as microcrystalcell lineulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegration agent such as alginic acid, primogel, maize starch, and the like; a lubricant such as magnesium stearate; a fluidifier such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin or a flavour such as mint essence, methyl salicylate or orange flavour.
  • a liquid carrier such as a fatty oil.
  • Other compositions can contain various materials which modify their physical state, for example coating agents (for tablets and pills) such as sugar or shellac. The materials used in the preparation of the compositions will be pharmaceutically pure and non toxic at the used dosages.
  • the active ingredient can be incorporated in solutions or suspensions, which can also include the following components: a sterile diluent such as water for injections, physiological saline, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterials such as benzyl alcohol; antioxidizers such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamino tetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity of the solution, such as sodium chloride or dextrose.
  • the parenteral preparation can be included in glass or plastic ampoules, mono-dose syringes or vials.
  • 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 suspended in 150 ml of isopentyl alcohol. After refluxing the reaction mixture under stirring for about 20 minutes, an orange-red mass precipitates. The reaction is continued for 4-5 hours, then 150 ml of a 1M potassium carbonate aqueous solution are added and insolubles are filtered off while hot.
  • the aqueous phase is separated, acidified to pH 5 with 2M hydrochloric acid to precipitate the product, which is filtered, suspended in boiling methanol (100 ml), filtered, resuspended in boiling water (200 ml), filtered again and washed with ethanol.
  • the resulting diacid is dissolved in xylene (55 ml), added with 55 ml of phosphorous oxychloride and refluxed for 2 hours.
  • 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.
  • Example 1 - 1 ,7-Bis(l-chloro-9-oxo-9 ,10-dihydro- acridine-4-carbonyl)-4-methyl-l ,4, 7-triazaheptane l-Chloro-9-oxo-9 , 10-dihydroacridine-4-carboxylic acid (500 mg) is suspended in CHCI3 (20 ml), added with Et 3 N (0.26 ml), cooled to 0°C, then added drop by drop with ClCOOEt (0.26 ml) in CHCI3 (10 ml).
  • JV4- 3- ⁇ [ ( l-Chloro-9-oxo-9 , 10-dihydro-4-acridinyl )- carbonyl] amino ⁇ propyl )-l-chloro-9-oxo-9 , 10-dihydro-4- acridinecarboxamide: 0.42 g, 97.6%): m.p.
  • the bis-derivative 1 , 7-Bis ( l-chloro-9-oxo-9 ,10- dihydroacridine-4-carbonyl )-4-methyl-l , 4 , 7-triazaheptane hydrochloride (150 mg) is refluxed in 2- (dimethylamino)ethylamine (2 ml) for 1 hour, then cooled to room temperature and the reaction mixture is partitioned between CHCI3 and IM a 2 C0 3 . The organic phase is worked up to give a residue which is suspended in ethyl ether (10 ml) to give the product, pure by TLC (130 mg), m.p. 116-117°C; hydrochloride m.p.
  • Example 8 1, 7-Bis[4-(N-( 2- ( dimethylamino )ethyl ) )- carboxamido ⁇ 7-hydroxy-9-oxo-9,10-dihydroacridine-l-yl]-
  • Example 11 - 1 9-Bi ⁇ [2-( 2- (dimethylamino )ethyl )-9- nitro-l,3,7-trioxo-[lH,2H,3H,7H,12H]pyrimido[5,6,l-de]- acridine-6-yl]-5-methyl-l , 5 , 9-triazanonane
  • a suspension of pyrimidoacridine from preparation 10 (0.35 g, 0.814 mmol), 3 , 3 ' -diamino-JV- methyldipropylamine (0.071 mL, 0.41 mmol) and triethylamine (0.5 mL ) in 2-ethoxyethanol (10 mL ) is stirred at 80°C for 2 h. After cooling, the mixture is partitioned between CHCI3 and aqueous 1 M a 2 C0 3 . The organic layer is worked up to give a residue that is purified by column chromatography on silica gel using CHCI3/CH3OH (9:1 v/v).
  • Example 14 2-[2-(Dimethylamino)ethyl]-6- ⁇ [3-( ⁇ 2- [2- ( imethylamino ) ethyl ]-1 , 3 , 7-trioxo-2 , 3-dihydro-lff, 1H- pyrimido [5,6, 1-de]acridin-6-yl ⁇ amino )propyl ] amino ⁇ -2 , 3- dihydro-1#, 7J ⁇ -pyrimido[5,6, 1-de]acridine-1 , 3 , 7-trione

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Cette invention concerne des bis-acridinecarboxamides ainsi que les dérivés de ces derniers substitués par des chaînes aminoalkyle. Ces bis-acridinecarboxamides ainsi que leurs dérivés présentent une remarquable activité antitumorale particulièrement dans le cas de tumeur du colon.
PCT/EP1998/004755 1997-08-01 1998-07-30 Bis-acridinecarboxamides ayant une activite antitumorale WO1999006372A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98939644A EP1001936A1 (fr) 1997-08-01 1998-07-30 Bis-acridinecarboxamides ayant une activite antitumorale
JP2000505131A JP2001512104A (ja) 1997-08-01 1998-07-30 抗腫瘍活性を有するビス−アクリジンカルボキサミド
AU88080/98A AU8808098A (en) 1997-08-01 1998-07-30 Bis-acridinecarboxamides having antitumor activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT97MI001852A IT1293525B1 (it) 1997-08-01 1997-08-01 Bis-acridincarbossiammidi aventi attivita' antitumorale
ITMI97A001852 1997-08-01

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WO1999006372A1 true WO1999006372A1 (fr) 1999-02-11

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EP (1) EP1001936A1 (fr)
JP (1) JP2001512104A (fr)
AU (1) AU8808098A (fr)
IT (1) IT1293525B1 (fr)
WO (1) WO1999006372A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6114332A (en) * 1996-10-18 2000-09-05 Xenova Limited Bis(acridinecarboxamide) and bis(phenazinecarboxamide) as antitumor agents
EP3070078A1 (fr) * 2015-03-20 2016-09-21 Politechnika Gdanska Disszmetrique antitumorale bisacridine at leur utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2879598B1 (fr) * 2004-12-17 2007-03-30 Sod Conseils Rech Applic Inhibiteurs de phosphatases cdc25

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0502668A1 (fr) * 1991-03-05 1992-09-09 Btg International Limited Imidazoacridines et leur utilisation comme agents antinéoplastiques
WO1995025093A1 (fr) * 1994-03-14 1995-09-21 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Composes intercalaires bifonctionnels derives d'acridone utilises en tant qu'agents chimiotherapeutiques
WO1997038999A1 (fr) * 1996-04-12 1997-10-23 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Composes derives de l'acridone utiles en tant qu'agents antineoplasiques et antiretroviraux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0502668A1 (fr) * 1991-03-05 1992-09-09 Btg International Limited Imidazoacridines et leur utilisation comme agents antinéoplastiques
WO1995025093A1 (fr) * 1994-03-14 1995-09-21 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Composes intercalaires bifonctionnels derives d'acridone utilises en tant qu'agents chimiotherapeutiques
WO1997038999A1 (fr) * 1996-04-12 1997-10-23 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Composes derives de l'acridone utiles en tant qu'agents antineoplasiques et antiretroviraux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHOLODY W M ET AL: "BISIMIDAZOACRIDONES AND RELATED COMPOUNDS: NEW ANTINEOPLASTIC AGENTS WITH HIGH SELECTIVITY AGAINST COLON TUMORS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 16, 1995, pages 3043 - 3052, XP002035814 *
LIDIA HERNANDEZ ET AL: "MECHANISM OF ACTION OF BISIMIDAZOACRIDONES,NEW DRUGS WITH POTENT,SELECTIVE ACTIVITY AGAINST COLON CANCER", CANCER RESEARCH., vol. 55, no. 11, 1995, MD US, pages 2338 - 2345, XP002035886 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6114332A (en) * 1996-10-18 2000-09-05 Xenova Limited Bis(acridinecarboxamide) and bis(phenazinecarboxamide) as antitumor agents
EP3070078A1 (fr) * 2015-03-20 2016-09-21 Politechnika Gdanska Disszmetrique antitumorale bisacridine at leur utilisation
WO2016150799A1 (fr) * 2015-03-20 2016-09-29 Politechnika Gdańska Bis-acridines asymétriques ayant une activité antitumorale et leurs utilisations
US10202349B2 (en) 2015-03-20 2019-02-12 Gdansk University of Technology Asymmetric bis-acridines with antitumour activity and their uses

Also Published As

Publication number Publication date
AU8808098A (en) 1999-02-22
ITMI971852A1 (it) 1999-02-01
JP2001512104A (ja) 2001-08-21
EP1001936A1 (fr) 2000-05-24
IT1293525B1 (it) 1999-03-01

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