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Title:
4-AMINO-QUINOLINE OUINOLIZIDINYL-AND QUINOLIZIDINYLALKYL-DERIVATIVES WITH ANTIMALARIAL ACTIVITY
Document Type and Number:
WIPO Patent Application WO/2005/037833
Kind Code:
A1
Abstract:
The present invention relates to 4-amino-quinoline quinolizidinyl- and quinolizidinylalkyl-derivatives with antimalarial activity, in particular compounds of the general formula (I), in which R and n are as defined in the description,pharmaceutically acceptable salts thereof, complexes thereof with gold, rhodium or ruthenium and pharmaceutical compositions containing them. The compounds of the invention are active also on chloroquine-resistant strains of Plasmodium falciparum.

Inventors:
Sparatore, Anna c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Taramelli, Donatella c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Basilico, Nicoletta c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Parapini, Silvia c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Sparatore, Fabio c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Boido, Vito c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Canu Boido, Caterina c/o Universita', Degli Studi Di Milano (Via Festa delé Perdono 7, Milano, I-20122, IT)
Application Number:
PCT/IB2004/003393
Publication Date:
April 28, 2005
Filing Date:
October 18, 2004
Export Citation:
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Assignee:
NEED PHARMACEUTICALS S.R.L. (Via Ariberto 17, Milano, I-20127, IT)
Sparatore, Anna c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Taramelli, Donatella c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Basilico, Nicoletta c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Parapini, Silvia c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Sparatore, Fabio c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Boido, Vito c/o Universita', Degli Studi Di Milano (Via Festa del Perdono 7, Milano, I-20122, IT)
Canu Boido, Caterina c/o Universita', Degli Studi Di Milano (Via Festa delé Perdono 7, Milano, I-20122, IT)
International Classes:
A61K31/4709; C07D471/04; C07F1/12; C07F9/60; C07F9/6558; C07F15/00; (IPC1-7): C07D471/04; A61K31/4709; A61P33/06; C07F1/12; C07F9/60; C07F15/00
Other References:
BOIDO CANU ET AL.: "Preparazione e attività antileucemica di chinolizidinil-alchil derivati della 4-amminochinolina e della 9-amminoacridina" BOLLETTINO CHIMICO FARMACEUTICO, vol. 128, 1989, pages 212-215, XP009043694 cited in the application
SPARATORE ET AL.: "Quinolizidine derivatives with antimicrobial activity" FARMACO, EDIZIONE SCIENTIFICA, vol. 42, no. 3, 1987, pages 159-174, XP009043709
CHAUHAN P M S ET AL: "ANTIPARASITIC AGENTS: PART 5-SYNTHESIS OF 4-(SUBSTITUTED ARYL)AMINO-7-CHLOROQUINOLINES AS POTENTIAL ANTIMALARIAL AGENTS" INDIAN JOURNAL OF CHEMISTRY, JODHPUR, IN, vol. 25B, November 1986 (1986-11), pages 1142-1145, XP009037752
BOIDO ET AL.: "Synthesis of quinolizidiyl derivatives as possible antineoplastic agents" STUDI SASSARESI, SEZIONE 2, ARCHIVIO BIMESTRALE DI SCIENZE MEDICHE E NATURALI, vol. 57, no. 5-6, 1979, pages 811-816, XP001205179 cited in the application
Attorney, Agent or Firm:
Trupiano, Federica (Marietti, Gislon e Trupiano S.r.l. Via Larga 16, Milano, I-20122, IT)
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Claims:
CLAIMS
1. Compounds of the general formula (I) in which: R is selected from chlorine, bromine and trifluoromethyl; and n is an integer from 0 to 3; with the proviso that, when R is chlorine and n is 1, 2 and 3, the hydrogen atoms at the 1and 9apositions of the quinolizidinyl nucleous are in the trans conformation; and pharmaceutically acceptable salts thereof.
2. Compounds as claimed in claim 1 wherein R is selected from chlorine, bromine and trifluoromethyl and n is 0.
3. A compound as claimed in claim 2 selected from: (Ia') : R = Cl (la") : R = Cl (Ib') : R= CF3 (Ib") : R = CF3.
4. Complexes of the general formula (II) in which: R is selected from chlorine, bromine and trifluoromethyl; n is an integer from 0 to 3; M is a metal selected from gold, rhodium and ruthenium; Lig is a ligand selected from: PR'3, wherein R'is selected from phenyl or C2C4 alkyl, when M is gold; cyclooctadiene, when M is rhodium; another molecule of formula (1) when M is ruthenium; X is PF6when M is gold and Clwhen M is rhodium or ruthenium; Y is not present when M is gold or rhodium and is chlorine when M is ruthenium.
5. Complex as claimed in claim 4 in which: R is chlorine; n is 1 ; M is gold; Lig is triphenylphosphine; X is PF6 ; Y is not present.
6. Use of compounds of formula (I) : in which: R is selected from chlorine, bromine; and trifluoromethyl and n is an integer from 0 to 3; and of the pharmaceutically acceptable salts thereof and of the complexes of claims 4 and 5 for the preparation of antimalarial medicaments.
7. The use as claimed in claim 6 in which the compound of formula (I) is selected from: (la') : R = Cl (la") : R = Cl (Ib') : R = CF3 (Ib") : R = CF3 either as single enantiomers or in admixture with the corresponding optical antipodes.
8. Pharmaceutical compositions containing the compounds of formula (I) as defined in claim 6, the pharmaceutically acceptable salts thereof or the complexes of claims 4 or 5 in admixture with suitable excipients and/or carriers.
Description:
4-AMINO-OUINOLINE QUINOLIZIDINYL-AND QUINOLIZIDINYLALKYL-DERIVATIVES WITH ANTIMALARIAL ACTIVITY Field of the invention The present invention relates to antimalarial compounds, in particular to 4-amino-quinoline derivatives.

Background of the invention Malaria is an infectious disease caused by protozoa of the Genus Plasmodium. In humans, it is caused by four different parasite species: Plasmodium vivax, P. malariae, P. ovale and P. falciparum, the most virulent and the only lethal one. Malaria is considered, together with tubercolosis and AIDS, one of the most serious and diffused pathologies in the world.

Nowadays, few antimalarial drugs are available due both to worldwide diffusion of drug-resistant strains of P. falciparum and to the scarce number of compounds developed in the last 25 years (only 4 antimalarials out of about 1400 registered drugs in the world) (Olliaro P & Taylor WRJ, J. Exp. Biol., 206,3753, 2003).

The resistance of P. falciparum to quinoline-type drugs, such as chloroquine, and antifolates, such as sulfadoxine/pyrimethamine, is ubiquitous and a number of multi-drug resistant strains have developed. There is therefore the urgent need for antimalarial drugs that are effective, cheap and easy to use in endemic areas, such as sub-Saharian Africa.

Strategies aimed at reaching this goal include: 1) optimisation of combined therapy with the available anti-malarial drugs in association with artemisine- derivatives (the only still active medicaments towards which resistance is not observed); 2) development of analogues of known compounds; 3) identification of new synthetic or natural substances (Rosenthal PJ, J. Exp. Biol. 2003,206, 3735).

Identification and study of compounds belonging to the class of 4-aminoquinoline, such as chloroquine, [7-chloro-4- (4-diethylamino-1- methylbutylamino) quinoline], is a still valid approach, due to their efficacy, low toxicity and low cost. However, there is the need for chloroquine analogues which are also effective towards chloroquine-resistant strains of P. falciparum.

Among the 4-aminoquinoline chloroquine analogues synthesised so far, there are some derivatives whose dialkylaminoalkylamino chain at the 4-position of the quinoline nucleus is modified. In particular, Studi Sassaresi, 57 (1979) pp. 811-816 and Bollettino Chimico Farmaceutico (June 1989, vol.

128, pp. 212-215) report the following compounds: wherein, n is 1,2 o 3, in the form of pure enantiomers, in which the hydrogen atoms at the 1-and 9a-positions of the quinolizidinyl nucleous are in the cis conformation.

Despite the authors'hypotheses, the claimed antimalarial activity of these compounds has not been demonstrated.

Detailed description of the invention It has now been found that 4-amino-quinoline quinolizidinyl-and (o- (quinolizidinyl-1-yl) alkyl-derivatives have antimalarial activity and are active also towards chloroquine-resistant P. falciparum strains.

The present invention relates to the use of compounds of the general formula (I)

wherein: R is selected from chlorine, bromine and trifluoromethyl; and n is an integer from 0 to 3; and pharmaceutically acceptable salts thereof for the preparation of medicaments for malaria therapy.

A further object of the invention are the compounds of the general formula (I) in which: R is selected from chlorine, bromine and trifluoromethyl; and n is an integer from 0 to 3; with the proviso that, when R is chlorine and n is 1,2 or 3, the hydrogen atoms at the 1-and 9a-positions of the quinolizidinyl nucleous are in the trans conformation; and pharmaceutically acceptable salts thereof.

Unless otherwise indicated, the term"compounds of formula (I)"also comprises all the possible stereoisomers.

The term"pharmaceutically acceptable salts"comprises salts of the

compounds of formula (I) with physiologically compatible acids, such as hydrochloric, phosphoric, sulfuric, tartaric and citric acid, as well as other acids commonly used in the pharmaceutical technique.

In particular, the following compounds are preferred, either as single enantiomers or in admixture with the corresponding optical antipodes: (Ia') : R = Cl (la") : R = Cl (Ib') : R = CF3 (Ib") : R = CF3 The invention also comprises the complexes of the general formula (II)

in which: R is selected from chlorine, bromine, and trifluoromethyl; n is an integer from 0 to 3; M is a metal selected from gold, rhodium and ruthenium; Lig is a ligand selected from: PR'3, wherein R'is phenyl or C2-C4 alkyl, when M is gold; cyclooctadiene, when M is rhodium; another molecule of formula (1) when M is ruthenium; X is PF6-when M is gold and Cl-when M is rhodium or ruthenium;

Y is not present when M is gold or rhodium and is chlorine when M is ruthenium.

Particularly preferred is complex (IIa), wherein: R is chlorine; n is 1 ; M is gold; Lig is triphenylphosphine; X is PF6 ; and Y is not present.

The compounds of formula (I) wherein R is chlorine, n is an integer from 1 to 3 and the hydrogen atoms at the 1-and 9a-positions are in the cis conformation, are known and can be prepared by reaction between suitable co- (quinolizidinyl-la-yl) alkylamines and 4,7-dicloroquinoline, as described in Bollettino Chimico Farmaceutico, 128 (1989), pp. 212-215.

Analogously, compounds of formula (I) with the same steric configuration, in which R is bromine or trifluoromethyl and n is an integer from 1 to 3, can be prepared from the corresponding 7-substituted 4-chloro-quinolines.

The compounds of formula (1) in which R is chlorine, bromine or trifluoromethyl, n is an integer from 1 to 3 and the hydrogen atoms at the 1-and 9a-positions are in the trans configuration, can be prepared in the same way starting from the corresponding co- (quinolizidinyl-l 3-yl) alkylamines.

As for the quinolizidinylilalkylamines, (-) lupinylamine (n = 1) was prepared according to Sparatore, F. et al., Farmaco, Ed. Sci, 24 (1969) 587-621, whereas 2-(quinolizidinyl-1'a-yl) ethylamine (n=2) and 3-(quinolizidinyl-1'a- yl) propylamine (n=3) were prepared as described by Boido, V. et al., Farmaco, Ed. Sci. , 34 (1979) 673-687. In all cases, I-lupinine (extracted from Lupinus luteus or Lupinus hispanicus seeds) was used as the starting material.

From racemic lupinine and epi-lupinine, obtained by synthesis (for

example according to A. Sparatore et al., Farmaco, 44 (1989) 1193-1203) all the above mentioned compounds are obtained in the racemic form.

The preparation of epimeric quinolizidinylalkylamines is carried out in a similar way starting from d-epi-lupinine, which in turn can be obtained from l-lupinine by treatment with NaH in hot xylene (see, for example Iusco, G. et al., Farmaco, 51 (1996) 159-174).

The preparation of some quinolizidinylamines is illustrated in Scheme 1. CH20H CH20H H = = H NaH (xylene) CN5 (-) Lupinine (+) epi-Lupinine I SOCI2/PBr SOCI=/PBr3 1 CH2CI/Br CH2CI/Br K-phtalimide NaCH (COOEt) 2 COOED NaCN H COOEt K-phtalimide H O <f ; CN N OX O i o .- UJ- Hf'0 LJLJ, r- N H CHICS Ins 0 N HCI (6N) « r O I LiAIH ^ CH30H/HCI J I H CH2CH2NH2 1/\COOCH3 | HCI (6N) H CH2CH2NH2 Z' H CH : NH : H CHzNHx N 1 L N J H ~ CONH2 CS H = rt k I LiAIH, LiAlH, r H CI-ICH=CI-I2NHz Scheme 1

As for the compounds in which n is 0, 1-quinolizidinylamine was entirely synthesized, as shown in Scheme 2.

Scheme 2 The pipecoline ester is alkylated with y-chlorobutyric ester (Clemo, G. R., et al., J. Chem. Soc. (1931) 437-442 and W. A. Reckow, et. Al., J. Am.

Chem. Soc. 74 (1952) 4960-4962), submitted to a Dieckmann condensation followed by decarboxylative hydrolysis, which leads to 1-quinolizidinone (nor-lupinone). The ketone is then converted to oxime, which is finally reduced to 1-quinolizidinylamine (Hadley, M. S. et al., J. Med. Chem. 28, (1985) 1843-1847). A mixture of diastereomers is obtained which, by reaction with an appropriate 7-substituted 4-chloro-quinoline, affords the corresponding compounds (I), always in the form of a diastereoisomeric mixture, which is subjected to chromatographic separation (Scheme 3).

Scheme 3

The complexes of formula (II) can be prepared according to the method described by Navarro, M. et al., J. Med. Chem. 40 (1997) 1937-1939 for the synthesis of the complex gold-chloroquine and Sanchez-Delgado, R. A. et al, J. Med. Chem. 39 (1996) 1095-1099 for the synthesis of the complexes rhodium-chloroquine and ruthenium-chloroquine.

The compounds of the invention were tested in vitro on chloroquine- sensitive and chloroquine-resistant strains of P. falciparum. IC50 values ranging from 15 to 30 nM were observed on chloroquine-sensitive P. falciparum strains; these values are comparable to those observed with chloroquine (chloroquine-sensitive ICso= 27. 8i9 nM). Surprisingly, ICso values ranging from 18 to 39 nM-significantly different from those of chloroquine (chloroquine-resistant ICso= 150-300 nM) -, were also observed on chloroquine-resistant P. falciparum strains, with a 10-20 fold increase in activity compared to chloroquine, depending on the compounds and strains tested. As shown in the figure, compounds (Ia') and (Ia") proved 6-8 times more active than chloroquine on the W2 strain (chloroquine-resistant), with mean ICso values ranging from 10 to 25 nM. In particular, the figure shows the antimalarial effect of different doses of compounds (Ia') and (Ia") on the W2 P. falciparum strain, in comparison with the same doses of chloroquine (CQ).

Parasites'growth was evaluated with a colorimetric assay for pLDH at 72 hours.

The compounds of the invention proved also effective in vivo, after intraperitoneal and oral administration in the experimental murine malaria model induced with P. berghei : the efficacy was comparable to that of chloroquine. Moreover, the toxicity of the compounds towards mammalian cells is low (ICSo=15. 000-18.000 nM). Therefore, object of the present invention are also pharmaceutical compositions containing compounds of formula (I), salts or complexes thereof, in admixture with suitable excipients

and/or carriers. The compositions will be suitable for administration through the oral or parenteral route and will be prepared, for example, according to the techniques and methods described in Remington's Pharmaceutical Sciences Handbook, XVII Ed. Mack Pub. , N. Y. , U. S. A.. The compounds of formula (I) and (II) will be contained at doses ranging from 1 to 1000 mg.

The invention will be hereinafter illustrated in more detail by means of some examples.

EXAMPLES Example 1-Synthesis of 4- (quinolizidinylalkyl) amino-quinoline A mixture of 4,7-dichloro-quinoline or 7-bromo-4-chloroquinoline or 4-chloro-7-trifluoromethyl-quinoline (8 mmoles), quinolizidinylalkylamine (8 mmoles) and phenol (5 g) is heated for 4 hours at 180°C under magnetic stirring, using a reflux condenser with a KOH trap.

After cooling, the mixture is adjusted to strongly basic pH with NaOH and is extracted three times with ether. The ether solution is washed with 2N NaOH, then with water and finally extracted twice with 5% acetic acid. The acetic solution is then alkalized with 2N NH3 and extracted with ether.

After evaporation of the solvent, a crystalline residue is obtained which is washed with some anhydrous ether and recrystallized from a dichloromethane-diethyl ether mixture or an ethanol-ether mixture.

The mother liquors are evaporated and the residue is purified by chromatography on a silica gel column eluting with a 98: 2-93: 7 CH2Clz/MeOH gradient.

Example 2-Synthesis of 4-(quinolizidinyl) amino-7-chloroquinolines A mixture of 4,7-dichloroquinoline (9.44 mmoles), 1-quinolizidinylamine (9.44 mmoles, diastereomeric mixture) and 6 g of phenol is heated for 4 hours at 180°C under magnetic stirring, using a reflux condenser with a KOH trap.

After cooling, the mixture is adjusted to strongly basic pH with NaOH and extracted four times with ether. The ether solution is washed with 2N NaOH, then with water and finally extracted twice with 5% acetic acid. The acetic solution is then alkalized with 2N NH3 and extracted with ether.

After evaporation of the solvent a solid residue is obtained, which is chromatographed on silica gel eluting with a 99: 1-92: 8 CH2CI2/MeOH gradient.

By evaporation of the fractions eluted with CH2Cl2/1-2% CH30H and washing of the residue with ether, a compound with a melting point of 168-169. 2°C (Ia") is obtained, whereas by evaporation of the fractions eluted with CH2Cl2/3-8% MeOH and washing of the residue with ether a compound with a melting point of 235-238°C (dec. ) (Ia') is obtained.

Example 3-Synthesis of compound (IIa) 200 mg (0.4 mmoles) of triphenylphosphine gold chloride dissolved under reflux in 20 ml of acetonitrile are added with 148.8 mg (0.8 mmoles) of potassium hexafluorophosphate (KPF6) and heating is continued for 30 minutes.

266.7 mg (0.81 mmoles) of 4-[(quinolizidinylmethyl) amino]-7- chloroquinoline is added, the mixture is refluxed under nitrogen for 48 hours, then allowed to cool; the resulting precipitate is filtered off (172 mg).

The filtrate is concentrated, added with ethyl ether (a few drops) and stored in the refrigerator. The separated solid is filtered and washed with anhydrous ether/acetonitrile (1: 3). The solution is concentrated again, treated with ether and stored again in the refrigerator.

This procedure is carried out several times, each one filtering off the precipitate. Finally, the solution is evaporated to dryness and the residue, i. e. compound of formula (IIa), is washed and dried. Yield: 200 mg.