EP1937686A1 - New anti-malaria derivatives of 4-aminoquinoline - Google Patents

New anti-malaria derivatives of 4-aminoquinoline

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Publication number
EP1937686A1
EP1937686A1 EP06809083A EP06809083A EP1937686A1 EP 1937686 A1 EP1937686 A1 EP 1937686A1 EP 06809083 A EP06809083 A EP 06809083A EP 06809083 A EP06809083 A EP 06809083A EP 1937686 A1 EP1937686 A1 EP 1937686A1
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EP
European Patent Office
Prior art keywords
pyrrol
chloro
amine
quinolin
compound
Prior art date
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EP06809083A
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German (de)
French (fr)
Inventor
Fabio Sparatore
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NEED PHARMACEUTICALS Srl
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NEED PHARMACEUTICALS Srl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Malaria remains one of the most serious diseases in the developing countries, responsible for the death of 1-3 million people and 300-500 million cases every year.
  • the most severe forms of malaria are caused by Plasmodium falciparum, i
  • the two most commonly used antimalarial drugs, chloroquine and sulfadoxine-pyrimethamine, are becoming less and less effective in the majority of the regions where malaria is endemic with consequent increase in morbidity and mortality associated with malaria.
  • the main reasons for this lack of activity are connected with the increasingly widespread resistance of the parasite to the common antimalarial drugs and cross-resistance also to drugs not structurally correlated.
  • the present invention relates to new antimalarial compounds, in particular derivatives of 4-aminoquinoline with quinolizidine and pyrrolizidine rings. Description of the invention
  • the new derivatives of 4-aminoquinoline of the present invention are powerful antimalarial drugs also active on the strains of Plasmodium falciparum resistant to chloroquine .
  • the compounds of the present invention have the following general formula:
  • R Cl, Br, trifluoromethyl
  • M is 0 or an atom of Au, Rh, Ru in the presence of a ligand; the ligand is selected from PR' 3 where R' is phenyl or C2-C4 alkyl when M is gold; cyclooctadiene, when M is rhodium; a second identical quinolinic group when M is ruthenium; a PF 6 " or NO 3 " group can be present when M is gold; a Cl " can be present when M is rhodium or ruthenium;
  • R2 and R3 which can be the same or different, can be H or a linear or branched alkyl preferably (CH 2 ) n-
  • n 0-10 preferably 1-3 or a benzene ring mono or bisubstituted with -CH 3 , -OCH 3 , -CF 3 , F, Cl, Br;
  • T can also be
  • T can also be
  • the preferred compounds of the present invention are :
  • the two above- mentioned compounds (7-chloro-quinolin-4-yl) - (3- diethylaminomethyl-2 -methyl-5-phenyl-pyrrol-1-yl ) -amine and (7-chloro-quinolin-4-yl) - (3-diethylaminomethyl-2 ⁇ phenyl-5-methyl-pyrrol -1-yl) -amine can be obtained in a mixture in variable determinable ratios.
  • the above- mentioned compounds can be used advantageously both individually and in a mixture also in variable ratios.
  • the compounds of the present invention were tested in vitro both on strains of Plasmodium falciparum sensitive and resistant to chloroquine with values of IC 50 between 10 and 200 ng/ml .
  • the compounds of the invention were also tested in vivo after intraperitoneal and oral administration and the effectiveness was comparable or superior to that of chloroquine.
  • the toxicity of the compounds in the mammal cells was low with IC 50 >10000 nM.
  • the pharmaceutically acceptable salts such as salts of inorganic and organic acids, aminoacids, are also part of the present invention.
  • Preferred salts are with hydrochloric, phosphoric, sulphuric, tartaric, citric and fumaric acid.
  • the patients can receive the compounds of the present invention in the therapeutically effective and well tolerated quantity which can be determined by a person skilled in the art.
  • the compounds of the present invention can be administered at a daily dose of between approximately 1 and 60 mg/kg, and preferably between 3 and 30 mg/kg.
  • the compounds of the present invention can be administered using adequate formulations, the nature of which depends on the chosen method of administration.
  • These pharmaceutical compositions can be prepared according to conventional methods using compatible and pharmaceutically acceptable excipients or carriers. Examples of these compositions include capsules, tablets, syrups, powders and granulates for the preparation of extemporary solutions, injectable, rectal, nasal preparations etc.
  • the preferred method of administration is oral .
  • the suspension obtained is transferred into a separator funnel and extracted with CH 2 Cl 2 . After anhydrification with Na 2 SO 4 , the organic phases are evaporated and the solid obtained is purified with flash chromatography on silica gel using CH 2 Cl 2 , CH 3 OH and NH 3 cone. (96:3,6:0,4) as the eluant mixture.
  • the product obtained is recovered with cyclohexane/diethyl ether 50:50 and after filtering and evaporation of the solution, the product has a melting point of 101.2-103.5 0 C.
  • EXAMPLE 5 (7-chloro-quinolin-4-yl) - [2 , 5-dimethyl-3 - (pyrrolidin-1-ylmethyl) -pyrrol-1-yl] -amine. 0.13 ml (1.5 mmoles) of pyrrolidine, 0.13 ml (1.5 mmoles) of 37% formaldehyde and 0.5 ml of glacial acetic acid are placed in a 5 ml flask.
  • the solution obtained is left under stirring at 0 0 C and subsequently transferred to a 50 ml reaction round-bottom flask containing 408 mg (1.5 mmoles) of (7-chloro-quinolin-4-yl) - (2 , 5-dimethyl- pyrrolo-1-yl) -amine (prepared as described in example 1) . It is left to react under stirring in a nitrogen atmosphere for 2 hours. 20% NaOH is added to the mixture until basic pH is reached and the product is extracted with CH 2 Cl 2 . The organic phases are evaporated and the crude residue obtained is column-purified eluting with a 5 mixture of CH 2 Cl 2 in methyl alcohol gradient up to a concentration of 20%. The product has a melting point of 164-166 0 C.
  • the crude material is purified by means of flash chromatography on silica gel, performing gradient elution with a mixture of cyclohexane and CH 2 Cl 2 (from 60:40 to 30:70), 2.2 g of a colourless oil are obtained, with a yield equal to 88%.
  • the reflux solution is heated for two hours in a nitrogen atmosphere under stirring .
  • the progress of the reaction is monitored via TLC on silica gel, using ethyl acetate/cyclohexane (7:3) as eluant .
  • the aqueous phases are re-combined, alkalized once again and counter-extracted with plenty of dichloromethane.
  • the organic phases, recombined, are anhydrified on anhydrous Na 2 SO 4 and evaporated to dryness .
  • the crude material thus obtained is purified by means of flash chromatography on silica gel, performing elution with a mixture of cyclohexane/ethyl acetate (60:40) . After recrystallisation from diethyl ether/petroleum ether, 1.98 g of solid, colour cream white, with melting point 165-168 0 C are obtained. The yield of the reaction is equal to 79%.
  • a 3 -neck round-bottom flask provided with reflux condenser protected by calcium chloride valve is cooled in an ice bath. 6 ml of anhydrous toluene and 0.081 ml (0.78 mmoles) of diethylamide are placed in it. 0.4 ml (0.8 mmoles) of a 2M solution of trimethylaluminium in toluene are added to the cold solution dropwise and electromagnetic under stirring.
  • the progress of the reaction is monitored by TLC on silica gel, using CH 2 Cl 2 /methyl alcohol (10/0.5) as eluant . Once the 24 hours have elapsed, the solution is recovered using plenty of ethyl acetate; a solution of cold NaOH IN is added to the organic phase and the aluminium hydroxide that has formed is filtered.
  • the reaction suspension is treated with a solution of NaOH IN and the aluminium hydroxide that has formed is filtered.
  • the organic phase is anhydrified and brought to dryness and the crude material is purified by means of flash chromatography on silica gel performing gradient elution with a mixture of CH 2 Cl 2 containing 1-7% of methyl alcohol.
  • the yield of the reaction is equal to 65.5%.
  • a three-neck round-bottom flask provided ⁇ with reflux condenser protected by calcium chloride valve is cooled in an ice bath. 6 ml of anhydrous toluene and 0.07 ml (0.78 mmoles) of pyrrolidine are placed in it. 0.4 ml (0.8 mmoles) of a 2M solution of trimethylaluminium in toluene are added to the cold solution, dropwise and under electromagnetic stirring.
  • the progress of the reaction is monitored by TLC on silica gel, using CH 2 Cl 2 /methyl alcohol/NH 3 cone.
  • the reaction suspension is treated with a solution of NaOH IN and the aluminium hydroxide formed is filtered.
  • the organic phase is anhydrified and brought to dryness and the crude material is purified by flash chromatography on silica gel, performing gradient elution with a mixture of CH 2 Cl 2 containing 1-6% of methyl alcohol. After washing with diethyl ether, 95 mg of solid are obtained with melting point between 172.5 and 176°C.
  • the yield of the reaction is equal to 51%.
  • the compounds of the present invention were assayed in vitro and found to be active both on strains of chloroquine-sensitive Plasmodium falciparum (CQ-S)DlO and on strains of chloroquine-resistant Plasmodium falciparum (CQ-R) W2. The results are given in the following table.
  • CM7/I and CM8 the biological data relative to the compounds given in examples 6 and 7 and indicated as CM7/I and CM8 respectively are specified below.
  • the cultures of P. falciparum were maintained according to Trager and Jensen with some modifications (Trager, W. ; Jensen, J. B.; Science 1976, 193, 673).
  • the chloroquine- sensitive strain DlO and the chloroquine-resistant strain W2 were kept in 5% hematocrit (group A positive human red blood cells) in RPMI 1640 (EuroClone, Celbio) , NaHCO 3 24 mM, with the addition of 10% heat-inactivated human plasma group A, 20 mM Hepes, 2 mM glutamine .
  • the cultures were kept at 37 0 C in an atmosphere containing 1% O 2 , 5% CO 2 , 94% N 2 .
  • the products were dissolved in water
  • the compounds were distributed on plates with 96 flat- bottom wells (COSTAR) .
  • Asynchronous cultures with parasitemia of 1-1.5% and 1% final hematocrit were distributed in the wells and incubated for 72 hours at 37°C.
  • the growth of the parasites was determined spectrophotometrically (OD 650 ) by measuring the activity of the lactic dehydrogenase of the parasite
  • the antimalarial activity is expressed as the concentration that inhibits 50% of the culture (IC 50 ) ; each IC 50 value is the mean of at least three separate experiments conducted in duplicate. DlO expl exp2 exp3 exp4 MEAN SD

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

New derivatives of 4-aminoquinoline which have a general formula A-X-Y-T where A is a 4-aminoquinolinic nucleus, X and Y are spacers and T represents a nitrogenous ring or an aminic group, substituted if necessary. These are powerful antimalarial compounds active on both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.

Description

"New anti-malaria derivatives of 4-aminoquinoline" .
****
Prior art
Malaria remains one of the most serious diseases in the developing countries, responsible for the death of 1-3 million people and 300-500 million cases every year. The most severe forms of malaria are caused by Plasmodium falciparum, i The two most commonly used antimalarial drugs, chloroquine and sulfadoxine-pyrimethamine, are becoming less and less effective in the majority of the regions where malaria is endemic with consequent increase in morbidity and mortality associated with malaria. The main reasons for this lack of activity are connected with the increasingly widespread resistance of the parasite to the common antimalarial drugs and cross-resistance also to drugs not structurally correlated.
To combat malaria, new drugs are desperately needed and in particular drugs that are effective on the resistant strains of Plasmodium falciparum. Ideally the new malaria drugs should be effective on the strains resistant to the drugs, act within a reasonable time (ideally three days or less) to obtain good adherence to the treatment, be well-tolerated also by children and pregnant women, and above all have a low cost. (D. A. Fidock et al . Antimalarial drug discovery: efficacy models for compound screening, Nature Reviews 3, 509-520 (2004)). Field of the invention The present invention relates to new antimalarial compounds, in particular derivatives of 4-aminoquinoline with quinolizidine and pyrrolizidine rings. Description of the invention
The new derivatives of 4-aminoquinoline of the present invention are powerful antimalarial drugs also active on the strains of Plasmodium falciparum resistant to chloroquine .
The compounds of the present invention have the following general formula:
in which
R= Cl, Br, trifluoromethyl ;
M= is 0 or an atom of Au, Rh, Ru in the presence of a ligand; the ligand is selected from PR'3 where R' is phenyl or C2-C4 alkyl when M is gold; cyclooctadiene, when M is rhodium; a second identical quinolinic group when M is ruthenium; a PF6 " or NO3 " group can be present when M is gold; a Cl" can be present when M is rhodium or ruthenium;
X: is
in which R2 and R3 , which can be the same or different, can be H or a linear or branched alkyl preferably (CH2) n-
CH3 where n = 0-10 preferably 1-3 or a benzene ring mono or bisubstituted with -CH3, -OCH3, -CF3, F, Cl, Br;
Y: is equal to CH2- (NH) n- (CH2) ra where n = 0,1 and m = 0-10 and preferably 1-3;
T:
T can also be
T can also be
,R4 —N<R5 where R4 and R5 , which can be the same or different, can be H or a linear or branched alkyl preferably (CH2) n-CH3 where n = 0-5, or R4 and R5 together can form a cycle, for example a 5-member cycle of the pyrrolidine type. The preferred compounds of the present invention are :
(7-chloro-quinolin-4-yl) - (2 , 5-dimethyl-3- { [ (tetrahydro- pyrrolizin-7a-ylmethyl) -amino] -methyl} -pyrrol -1-yl) - amine .
(7-chloro-quinolin-4-yl) - (2 , 5-dimethyl-3- { [ (octahydro- quinolizin-1-ylmethyl) -amino] -methyl} -pyrrol -1-yl) -amine,
(7-chloro-quinolin-4-yl) - [2 , 5-dimethyl-3- (pyrrol idin-1- ylmethyl) -pyrrol -1-yl] -amine.
(7-chloro-quinolin-4-yl) - (3-diethylaminomethyl-2 , 5- dimethyl -pyrrol -1-yl) -amine.
[3- (tributylamino-methyl) -2 , 5-dimethyl-pyrrol-l-yl] - (7- chloro-quinolin-4-yl) -amine.
(7-chloro-quinolin-4-yl) - (3-diethylaminomethyl-2-methyl- 5 -phenyl-pyrrol-1-yl) -amine .
(7-chloro-quinolin-4-yl) - (3-diethylaminomethyl-2-phenyl- 5-methyl-pyrrol -1-yl) -amine.
According to the present invention, the two above- mentioned compounds (7-chloro-quinolin-4-yl) - (3- diethylaminomethyl-2 -methyl-5-phenyl-pyrrol-1-yl ) -amine and (7-chloro-quinolin-4-yl) - (3-diethylaminomethyl-2~ phenyl-5-methyl-pyrrol -1-yl) -amine can be obtained in a mixture in variable determinable ratios. The above- mentioned compounds can be used advantageously both individually and in a mixture also in variable ratios.
7-Chloro-N- (2 -methyl-5-phenyl-3 - (pyrrolidin-1-ylmethyl) - lH-pyrroI-l-yl)quinoIin-4-amine.
The compounds of the present invention were tested in vitro both on strains of Plasmodium falciparum sensitive and resistant to chloroquine with values of IC50 between 10 and 200 ng/ml .
The compounds of the invention were also tested in vivo after intraperitoneal and oral administration and the effectiveness was comparable or superior to that of chloroquine. In addition, the toxicity of the compounds in the mammal cells (WEHI clone 13 mouse cells) was low with IC50 >10000 nM.
The pharmaceutically acceptable salts such as salts of inorganic and organic acids, aminoacids, are also part of the present invention. Preferred salts are with hydrochloric, phosphoric, sulphuric, tartaric, citric and fumaric acid.
According to the specific conditions or state of the disease to be treated, the patients can receive the compounds of the present invention in the therapeutically effective and well tolerated quantity which can be determined by a person skilled in the art. For example the compounds of the present invention can be administered at a daily dose of between approximately 1 and 60 mg/kg, and preferably between 3 and 30 mg/kg.
The compounds of the present invention can be administered using adequate formulations, the nature of which depends on the chosen method of administration. These pharmaceutical compositions can be prepared according to conventional methods using compatible and pharmaceutically acceptable excipients or carriers. Examples of these compositions include capsules, tablets, syrups, powders and granulates for the preparation of extemporary solutions, injectable, rectal, nasal preparations etc. The preferred method of administration is oral .
The following examples are non-limiting and further describe the invention, making it possible for a person averagely skilled in the art to produce and use the compounds of said invention. EXAMPLE 1. Synthesis of (7-chloro-quinolin-4-yl) - (2, 5- dimethyl-pyrrole-1-yl) -amine.
767 mg (6.72 mmoles) of acetonylacetone are added to a suspension consisting of 5.6 ml of glacial acetic acid and 1.084 g (5.6 mmoles) of 7-chloro-4-hydrazinoquinoline (Aldrich) . The suspension is heated to 65°C for 3 hours. The acetic acid is evaporated and the crude material is recovered with water alkalized with ammonia. The precipitate that separates is filtered, washed with water and purified by flash chromatography on silica gel using CH2Cl2 containing 1% of methyl alcohol as the eluant mixture. The product is washed with diethyl ether and has a melting point of 225.8-227.5°C .
EXAMPLE 2. Synthesis of (7-chloro-quinolin-4-yl) - (2, 5- dimethyl-3-{ [ (octahydro-quinolizin-1-ylmethyl) -amino] - methyl} -pyrrol-1-yl) -amine.
530 mg (2.2 mmoles) of aminolupinane dihydrochloride (prepared according to F. Sparatore et al . Farmaco Ed. Sci. 1969, 24, p. 587-621), 0.19 ml (2.2 mmoles) of 37% formaldehyde and 0.67 ml of glacial acetic acid are placed in a 10 ml round-bottom flask. The mixture is made to react under stirring and then transferred to a 50 ml 2 -neck round-bottom flask containing 544 mg (2 mmoles) of
(7-chloro-quinolin-4-γl) - (2 , 5-dimethylpirrole-l-yl) -amine
(prepared as described in example 1) . The reaction mixture is kept under stirring for 2 hours in a nitrogen atmosphere. The crude material obtained is recovered with
H2O, alkalized with 20% NaOH, and the suspension is extracted with chloroform in a separator funnel . After anhydrification on sodium sulphate, the organic phases are evaporated to dryness. The solid is purified on silica gel, eluting with CH2Cl2, CH3OH and NH3
(96:3.6:0.4) mixture. The fractions evaporated and washed with diethyl ether give a product with melting point of
188-191°C.
EXAMPLE 3. Synthesis of (7-chloro-quinolin-4-yl) - (3- diethylaminomethyl-2, 5-dimethyl-pyrrol-1-yl) -amine
0.16 ml (1.5 mmoles) of diethylamine, 0.13 ml (1.5 mmoles) of 37% formaldehyde and 0.5 ml of glacial acetic acid are placed in a 5 ml flask. The solution obtained is left to react at 00C under stirring and subsequently transferred to a 50 ml flask containing 408 mg (1.5 mmoles) of (7-chloro-quinolin-4-yl) - (2 , 5-dimethyl- pyrrole-1-yl) -amine (prepared as described in example 1) . It is left to react under stirring in a nitrogen atmosphere at 25°C for 2 hours. The mixture is suspended with H2O and NaOH 2N until it reaches basic pH and is extracted with CH2Cl2. After evaporation of the organic phases the residue obtained is purified in a column of
SiO2 eluting with a mixture of CH2Cl2, CH3OH and NH3
(97:2,7:0,3) . The fractions evaporated and washed with a mixture of diethyl ether/petroleum ether 70:30 give a product having a melting point of 248-2510C with decomposition.
EXAMPLE 4. Synthesis of [3- (tributylamino-methyl) -2, 5- dimethyl-pyrrol-1-yl] - (7-chloro-quinolin-4-yl) -amine.
0.17 ml (1.65 mmoles) of t-butylamine, 0.14 ml (1.65 mmoles) of 37% formaldehyde and 0.5 ml of glacial acetic acid are placed in a 5 ml round-bottom flask. The solution is left to react and subsequently transferred to a 50 ml round-bottom flask containing 408 mg (1.5 mmoles) of (7-chloro-quinolin-4-yl) - (2 , 5-dimethyl -pyrrol-1-yl) - amine. It is left to react for 2 hours under stirring in a nitrogen atmosphere. The crude material is recovered with water and alkalized with 20% NaOH. The suspension obtained is transferred into a separator funnel and extracted with CH2Cl2. After anhydrification with Na2SO4, the organic phases are evaporated and the solid obtained is purified with flash chromatography on silica gel using CH2Cl2, CH3OH and NH3 cone. (96:3,6:0,4) as the eluant mixture. The product obtained is recovered with cyclohexane/diethyl ether 50:50 and after filtering and evaporation of the solution, the product has a melting point of 101.2-103.50C.
EXAMPLE 5. (7-chloro-quinolin-4-yl) - [2 , 5-dimethyl-3 - (pyrrolidin-1-ylmethyl) -pyrrol-1-yl] -amine. 0.13 ml (1.5 mmoles) of pyrrolidine, 0.13 ml (1.5 mmoles) of 37% formaldehyde and 0.5 ml of glacial acetic acid are placed in a 5 ml flask. The solution obtained is left under stirring at 00C and subsequently transferred to a 50 ml reaction round-bottom flask containing 408 mg (1.5 mmoles) of (7-chloro-quinolin-4-yl) - (2 , 5-dimethyl- pyrrolo-1-yl) -amine (prepared as described in example 1) . It is left to react under stirring in a nitrogen atmosphere for 2 hours. 20% NaOH is added to the mixture until basic pH is reached and the product is extracted with CH2Cl2. The organic phases are evaporated and the crude residue obtained is column-purified eluting with a 5 mixture of CH2Cl2 in methyl alcohol gradient up to a concentration of 20%. The product has a melting point of 164-1660C.
EXAMPLE 6. Preparation of 7-chloro-N- (3- ( (diethylamino) methyl) -2 -methyl-5-phenyl-lH-pyrrol-1- 0 yl) quinolin-4-amine .
6.1. Ethyl 2-acetyl-4-oxo-4-phenylbutyrate.
5 20 ml of anhydrous diethyl ether and 230 mg (10 mmoles) of finely divided metallic sodium are placed in a 3 -neck round-bottom flask provided with reflux condenser protected by calcium chloride valve. 1.52 ml (12 mmoles) of ethyl acetoacetate dissolved in 2 0 ml of anhydrous diethyl ether are dripped into said solution.
The mixture is heated under reflux, under nitrogen stream and stirring until the metallic sodium completely disappears. Simultaneously the sodium salt of the ethyl 5 acetoacetate forms, which appears as a white solid.
A solution consisting of 2 g (10 mmoles) of bromoacetophenone dissolved in 26 ml of anhydrous diethyl ether is added dropwise to the suspension thus obtained, after cooling it at room temperature. Following the addition, the mixture is heated under reflux for approximately two hours, after which the sodium bromide is filtered and the organic phases are evaporated by reduced-pressure evaporation. The progress of the reaction is monitored by TLC on silica gel, using CH2Cl2/ethylacetate (10:1) as eluant . The crude material is purified by means of flash chromatography on silica gel, performing gradient elution with a mixture of cyclohexane and CH2Cl2 (from 60:40 to 30:70), 2.2 g of a colourless oil are obtained, with a yield equal to 88%.
6.2. Ethyl 1- (7-chloroquinolin-4-ylamino) -2 -methyl-5- phenyl-IH-pyrrol-3 -carboxylate .
1.2 g (6.2 mmoles) of ethyl 2-acetyl-4-oxo-4- phenylbutyrate are added, dropwise, to a solution consisting of 7 ml of glacial acetic acid and 1.2 g (6.2 mmoles) of 7-chloro-4-hydrazinoquinoline, contained in a
25 ml 2 -neck round-bottom flask provided with reflux with calcium chloride valve.
Once the addition has been completed, the reflux solution is heated for two hours in a nitrogen atmosphere under stirring .
The progress of the reaction is monitored via TLC on silica gel, using ethyl acetate/cyclohexane (7:3) as eluant .
During the reaction, the solution, which is initially yellow, turns brown.
At the end of the two hours the solution is recovered with dichloromethane and the organic phase obtained is thoroughly washed with a cold solution of NaOH IN until the aqueous phase used for the washing remains alkaline.
The aqueous phases are re-combined, alkalized once again and counter-extracted with plenty of dichloromethane. The organic phases, recombined, are anhydrified on anhydrous Na2SO4 and evaporated to dryness .
The crude material thus obtained is purified by means of flash chromatography on silica gel, performing elution with a mixture of cyclohexane/ethyl acetate (60:40) . After recrystallisation from diethyl ether/petroleum ether, 1.98 g of solid, colour cream white, with melting point 165-1680C are obtained. The yield of the reaction is equal to 79%.
6.3. 1- (7-chloroquinolin-4-ylamino) -N,N-diethγl-2-methyl- 5-phenyl-lH-pyrrol-3 -carboxyamide .
A 3 -neck round-bottom flask provided with reflux condenser protected by calcium chloride valve is cooled in an ice bath. 6 ml of anhydrous toluene and 0.081 ml (0.78 mmoles) of diethylamide are placed in it. 0.4 ml (0.8 mmoles) of a 2M solution of trimethylaluminium in toluene are added to the cold solution dropwise and electromagnetic under stirring.
Once the addition has been completed, the solution is left to react at room temperature for approximately one hour in a nitrogen atmosphere under stirring. 250 mg (0.62 mmoles) of ethyl 1- (7-chloroquinolin-4- ylamino) -2-methyl-5-phenyl-lH-pyrrol-3-carboxylate are then added and the suspension obtained is heated under reflux for approximately 24 hours in a nitrogen atmosphere and under stirring, during which a yellow solution forms which then changes colour from yellow to brown.
The progress of the reaction is monitored by TLC on silica gel, using CH2Cl2/methyl alcohol (10/0.5) as eluant . Once the 24 hours have elapsed, the solution is recovered using plenty of ethyl acetate; a solution of cold NaOH IN is added to the organic phase and the aluminium hydroxide that has formed is filtered.
After separation from the aqueous phase, the organic phase is anhydrified and brought to dryness. The crude material is purified by means of flash chromatography on silica gel performing gradient elution with a mixture of CH2Cl2 containing 0.5-2% of methyl alcohol . After washing with an ethanol/diethyl ether (7:3) mixture, 135 mg of crystalline solid with a yield of 51% are obtained. 6.4. 7-Chloro-N- (3- ( (diethylamino) methyl) -2 -methyl-5- phenyl-lH-pyrrol-1-yl) quinolin-4-amine. (CM7/I)
120 mg (0.28 mmoles) of 1- (7-chloroquinolin-4-ylamino) - N, N-diethyl-2 -methyl-5 -phenyl- IH-pyrrol -3 -carboxyamide are added in small portions to a suspension of 120 mg (3.16 mmoles) of LiAlH4 in 10 ml of anhydrous diethyl ether, placed in a two-neck round-bottom flask provided with reflux condenser. Once the addition has been completed, the suspension is heated under reflux for approximately four hours in a nitrogen atmosphere under stirring. The progress of the reaction is monitored by TLC on silica gel, using CH2Cl2/methyl alcohol/NH3 cone. (10/1/0,1) as eluant.
Once the 4 hours have elapsed, the reaction suspension is treated with a solution of NaOH IN and the aluminium hydroxide that has formed is filtered. After separation from the aqueous phase, the organic phase is anhydrified and brought to dryness and the crude material is purified by means of flash chromatography on silica gel performing gradient elution with a mixture of CH2Cl2 containing 1-7% of methyl alcohol. After washing with a mixture of diethyl ether/petroleum ether, 76 mg of solid are obtained, with melting point and decomposition between 156.5 and 1600C. The yield of the reaction is equal to 65.5%. The synthesis of (7-chloro-quinolin-4-yl) - (3- diethylaminomethyl-2 -phenyl-5-methyl-pyrrol-1-yl) -amine (CM7/II) is performed analogously, using the appropriate reagents and starting products.
EXAMPLE 7. Preparation of 7-chloro-N- (2 -methyl-5-phenyl- 3- (pyrrolidin-1-ylmethyl) -lH-pyrrol-1-yl) qu.inolin-4- amine.
7.1. (1- (7-chloroquinolin-4-ylamino) -2 -methyl-5-phenyl- lH-pyrrol-3-yl) (pyrrolidin-1-yl)methadone
A three-neck round-bottom flask provided ■ with reflux condenser protected by calcium chloride valve is cooled in an ice bath. 6 ml of anhydrous toluene and 0.07 ml (0.78 mmoles) of pyrrolidine are placed in it. 0.4 ml (0.8 mmoles) of a 2M solution of trimethylaluminium in toluene are added to the cold solution, dropwise and under electromagnetic stirring.
Once the addition has been completed, the solution is left to react at room temperature for approximately one hour in a nitrogen atmosphere and under stirring. 250 mg (0.62 mmoles) of ethyl 1- (7-chloroquinolin-4- ylamino) -2-methyl-5-phenyl-lH-pyrrol-3-carboxylate are then added and the suspension obtained is heated under reflux for approximately 24 hours in a nitrogen atmosphere and under electromagnetic stirring, during which a yellow solution forms which then changes colour from yellow to brown with the formation of a precipitate. The progress of the reaction is monitored by TLC on silica gel, using CH2Cl2/methyl alcohol (10/1) as eluant . Once the 24 hours have elapsed, the solid is filtered and washed with plenty of toluene and diethyl ether; control on TLC confirms that the required product has been obtained . 220 mg of final amide are obtained, with a yield of 86%. 7.2. 7-chloro-N- (2 -methyl-5 -phenyl-3- (pyrrolidin-1- ylmethyl) -lH-pyrrol-1-yl) quinolin-4-amine (CM8)
200 mg (0.28 mmoles) of (1- (7-chloroquinolin-4-ylamino) - 2 -methyl -5-phenyl-lH-pyrrol -3 -yl) (pyrrolidin-1- yl) methadone are added in small portions to a suspension of 230 mg (6.06 mmoles) of LiAlH4 in 20 ml of anhydrous diethyl ether, placed in a two-neck round-bottom flask provided with reflux condenser. Once the addition has been completed, the suspension is heated under reflux for approximately four hours in a nitrogen atmosphere and under stirring.
The progress of the reaction is monitored by TLC on silica gel, using CH2Cl2/methyl alcohol/NH3 cone.
(10/1/0,1) as eluant.
Once the four hours have elapsed, the reaction suspension is treated with a solution of NaOH IN and the aluminium hydroxide formed is filtered. After separation of the aqueous phase, the organic phase is anhydrified and brought to dryness and the crude material is purified by flash chromatography on silica gel, performing gradient elution with a mixture of CH2Cl2 containing 1-6% of methyl alcohol. After washing with diethyl ether, 95 mg of solid are obtained with melting point between 172.5 and 176°C.
The yield of the reaction is equal to 51%.
EXAMPLE 8. Gold complex of compound of example 2
200 mg (0.4 mmoles) of triphenylphosphine gold chloride dissolved under reflux in 20 ml of acetonitrile are added to 148.8 mg (0.8 mmoles) of potassium hexafluorophosphate (KPF6), heating for 30 minutes. 371 mg (0.82 mmoles) of (7-chloro-quinolin-4-yl) - (2 , 5-dimethyl-3- { [ (octahydro- quinolizin-1-ylmethyl) -amino] -methyl} -pyrrol-1-yl) -amine are added, the mixture is kept under reflux for 48 hours and after cooling the resulting precipitate is filtered. The filtrate is concentrated, a few drops of ether are added and it is kept in the refrigerator. The solid that separates is filtered and washed with a mixture of anhydrous ether/acetonitrile (1/3) . The solution is concentrated again, treated with ether and kept in the refrigerator. This procedure is repeated several times, filtering the precipitate each time. At the end the solution is evaporated to dryness and the residue washed with ether and dried. EXAMPLE 9. Biological data
The compounds of the present invention were assayed in vitro and found to be active both on strains of chloroquine-sensitive Plasmodium falciparum (CQ-S)DlO and on strains of chloroquine-resistant Plasmodium falciparum (CQ-R) W2. The results are given in the following table.
n=4 ±SD
Again according to the invention, the biological data relative to the compounds given in examples 6 and 7 and indicated as CM7/I and CM8 respectively are specified below. The cultures of P. falciparum were maintained according to Trager and Jensen with some modifications (Trager, W. ; Jensen, J. B.; Science 1976, 193, 673). The chloroquine- sensitive strain DlO and the chloroquine-resistant strain W2 were kept in 5% hematocrit (group A positive human red blood cells) in RPMI 1640 (EuroClone, Celbio) , NaHCO3 24 mM, with the addition of 10% heat-inactivated human plasma group A, 20 mM Hepes, 2 mM glutamine . The cultures were kept at 370C in an atmosphere containing 1% O2, 5% CO2, 94% N2. The products were dissolved in water
(chloroquine) or DMSO and subsequently diluted in medium until obtaining the required concentrations (final concentration of DMSO <1%, non-toxic for the parasite) .
The compounds were distributed on plates with 96 flat- bottom wells (COSTAR) . Asynchronous cultures with parasitemia of 1-1.5% and 1% final hematocrit were distributed in the wells and incubated for 72 hours at 37°C. The growth of the parasites was determined spectrophotometrically (OD650) by measuring the activity of the lactic dehydrogenase of the parasite
(pLDH) , according to a modified version of the Makler method (Makler, M.; Hinrichs, D.; Am. J. Trop. Med. Hyg.
1993, 48(2), 205; D. Monti, N. Basilico, S. Parapini, E.
Pasini, P. Olliaro & D. Taramelli. FEBS Letters 2002, 522, 3.) The antimalarial activity is expressed as the concentration that inhibits 50% of the culture (IC50) ; each IC50 value is the mean of at least three separate experiments conducted in duplicate. DlO expl exp2 exp3 exp4 MEAN SD
CM7/I 18.8 14.3 15.8 16.30 2.29
CM8 12.8 17.9 26.6 19.10 6.98
CQ 20.4 14.6 8.6 8.3 12.98 5.74
W2
Vari237Vari239Vari245 MEAN SD
CM7/I 18.3 16.7 32.94 22.65 1.13
CM8 15.3 36 73.12 41.47 14.64
CQ 30 72.8 145 82.60 30.26

Claims

1. Compounds having the following formula:
in which R= Cl, Br, trifluoromethyl;
M= is 0 (zero) or one atom of Au, Rh, Ru in the presence of a ligand; the ligand is selected from: PR'3 where R' is phenyl or C2-C4 alkyl when M is gold; cyclooctadiene, when M is rhodium; a second identical quinolinic group when M is ruthenium; optionally a further PF6 " or NO3 ' group is linked to M when M is gold; optionally a further Cl" is linked to M when M is rhodium or ruthenium; X: is
where R2 and R3 , which are the same or different, are H or a linear or branched alkyl preferably (CH2) n-CH3 where n = 0-10 preferably 1-3 or a benzene ring mono or bisubstituted with -CH3, -OCH3, -CF3, F, Cl, Br;
Y: is equal to CH2- (NH) n- (CH2) m where n = 0,1 and m = 0-10 and preferably 1-3;
T:
or
or
,R4 ~N<R5 where R4 and R5 , which be the same or different, are H or a linear or branched alkyl , preferably (CH2) n-CH3 where n = 0-5, or R4 and R5 together are such as to form a cycle.
2. A compound as claimed in claim 1 which is (7-chloro- quinolin-4-yl) - (2, 5-dimethyl-3- { [ (tetrahydro-pyrrolizin- 7a-ylmethyl) -amino] -methyl} -pyrrol-1-yl) -amine.
3. A compound as claimed in claim 1 which is (7-chloro- quinolin-4-yl) - (2 , 5-dimethyl-3- { [ (octahydro-quinolizin-1- ylmethyl) -amino] -methyl} -pyrrol-1-yl) -amine.
4. A compound as claimed in claim 1 which is (7-chloro- quinolin-4-yl) - [2 , 5-dimethyl-3- (pyrrolidin-1-ylmethyl) - pyrrol-1-yl] -amine.
5. A compound as claimed in claim 1 which is (7-chloro- quinolin-4-yl) - (3-diethylaminomethyl-2 , 5-dimethyl-pyrrol- 1-yl) -amine .
6. A compound as claimed in claim 1 which is [3- (terbutylamino-methyl) -2 , 5-dimethyl-pyrrol -1-yl] - (7- chloro-quinolin-4-yl) -amine.
7. A compound as claimed in claim 1 which is (7-chloro- quinolin-4-yl) - (3-diethylaminomethyl-2-methyl-5-phenyl- pyrrol-1-yl) -amine.
8. A compound as claimed in claim 1 which is (7-chloro- quinolin-4-yl) - (3-diethylaminomethyl-2-phenyl-5-methyl- pyrrol- 1-yl ) -amine .
9. A compound as claimed in claim 1 which is 7-chloro-N- (2 -methyl-5-phenyl-3- (pyrrolidin-1-ylmethyl) -lH-pyrrol-1- yl) quinolin-4-amine .
10. Pharmaceutical compositions containing a compound as claimed in claims 1 to 9 as active ingredient and pharmaceutically acceptable excipients or carriers.
11. Use of a compound as described in claims 1-9 for the preparation of a medicament for the treatment of malaria.
12. Use of a compound as described in claims 1-9 for the preparation of a medicament for the treatment of malaria due to chloroquine-resistant strains of Plasmodium falciparum.
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