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WO2007045987A1 - Nouveaux derives antipaludiques de 4-aminoquinoline - Google Patents

Nouveaux derives antipaludiques de 4-aminoquinoline Download PDF

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Publication number
WO2007045987A1
WO2007045987A1 PCT/IB2006/002946 IB2006002946W WO2007045987A1 WO 2007045987 A1 WO2007045987 A1 WO 2007045987A1 IB 2006002946 W IB2006002946 W IB 2006002946W WO 2007045987 A1 WO2007045987 A1 WO 2007045987A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrol
chloro
amine
quinolin
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2006/002946
Other languages
English (en)
Inventor
Fabio Sparatore
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NEED PHARMACEUTICALS Srl
Original Assignee
NEED PHARMACEUTICALS Srl
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 NEED PHARMACEUTICALS Srl filed Critical NEED PHARMACEUTICALS Srl
Priority to EP06809083A priority Critical patent/EP1937686A1/fr
Publication of WO2007045987A1 publication Critical patent/WO2007045987A1/fr
Anticipated expiration legal-status Critical
Priority to AP2008004444A priority patent/AP2008004444A0/xx
Ceased legal-status Critical Current

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Classifications

    • 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)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dérivés 4-aminoquinoline représentés par la formule générale A-X-Y-T dans laquelle A est un espaceur et T représente un cycle azoté ou un groupe amine, substitué le cas échéant. Ce sont de puissant composés actifs antipaludiques pour les souches de Plasmodium falciparum sensibles et résistantes à la chloroquine.
PCT/IB2006/002946 2005-10-21 2006-10-20 Nouveaux derives antipaludiques de 4-aminoquinoline Ceased WO2007045987A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP06809083A EP1937686A1 (fr) 2005-10-21 2006-10-20 Nouveaux derives antipaludiques de 4-aminoquinoline
AP2008004444A AP2008004444A0 (en) 2005-10-21 2008-04-26 New anti-malaria derivatives of 4-aminoquinoline

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2005A002008 2005-10-21
IT002008A ITMI20052008A1 (it) 2005-10-21 2005-10-21 Nuovi antimalarici derivati della 4-aminochinolina

Publications (1)

Publication Number Publication Date
WO2007045987A1 true WO2007045987A1 (fr) 2007-04-26

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Application Number Title Priority Date Filing Date
PCT/IB2006/002946 Ceased WO2007045987A1 (fr) 2005-10-21 2006-10-20 Nouveaux derives antipaludiques de 4-aminoquinoline

Country Status (5)

Country Link
EP (1) EP1937686A1 (fr)
CN (1) CN101346381A (fr)
AP (1) AP2008004444A0 (fr)
IT (1) ITMI20052008A1 (fr)
WO (1) WO2007045987A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481543B2 (en) 2008-11-18 2013-07-09 Oregon Health & Science University Compounds for treating parasitic disease
US9216965B2 (en) 2012-09-13 2015-12-22 Glaxosmithkline Intellectual Property Development Limited Amino-quinolines as kinase inhibitors
US9586953B2 (en) 2012-09-13 2017-03-07 Glaxosmithkline Intellectual Property Development Limited Prodrugs of amino quinazoline kinase inhibitor
US9604938B2 (en) 2011-08-18 2017-03-28 Glaxosmithkline Intellectual Property Development Limited Amino quinazolines as kinase inhibitors
US9604963B2 (en) 2011-03-04 2017-03-28 Glaxosmithkline Intellectual Property Development Limited Amino-quinolines as kinase inhibitors
US9650364B2 (en) 2013-02-21 2017-05-16 GlaxoSmithKline Intellectual Property Development Limted Quinazolines as kinase inhibitors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898369A (zh) * 2012-11-05 2013-01-30 上海书亚医药科技有限公司 3-氨基-7-溴喹啉-2-甲酸乙酯及其制备方法
CN108191829B (zh) * 2016-06-30 2020-07-03 珠海赛隆药业股份有限公司（长沙）医药研发中心 应用富马酸沃诺拉赞中间体ⅳ制备富马酸沃诺拉赞的方法
CN107915720B (zh) * 2016-10-08 2020-09-11 常州市第四制药厂有限公司 沃诺拉赞的新制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072554A1 (fr) * 2001-03-14 2002-09-19 The University Of Liverpool Composes anti-malaria
WO2005037833A1 (fr) * 2003-10-21 2005-04-28 Need Pharmaceuticals S.R.L. Derives de quinolizidinyle de 4-amino-quinoline et d'alkyle de quinolizidinyle a activite antipaludeenne

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072554A1 (fr) * 2001-03-14 2002-09-19 The University Of Liverpool Composes anti-malaria
WO2005037833A1 (fr) * 2003-10-21 2005-04-28 Need Pharmaceuticals S.R.L. Derives de quinolizidinyle de 4-amino-quinoline et d'alkyle de quinolizidinyle a activite antipaludeenne

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481543B2 (en) 2008-11-18 2013-07-09 Oregon Health & Science University Compounds for treating parasitic disease
US9604963B2 (en) 2011-03-04 2017-03-28 Glaxosmithkline Intellectual Property Development Limited Amino-quinolines as kinase inhibitors
US10220030B2 (en) 2011-03-04 2019-03-05 Glaxosmithkline Intellectual Property Development Limited Amino-quinolines as kinase inhibitors
US9604938B2 (en) 2011-08-18 2017-03-28 Glaxosmithkline Intellectual Property Development Limited Amino quinazolines as kinase inhibitors
US9216965B2 (en) 2012-09-13 2015-12-22 Glaxosmithkline Intellectual Property Development Limited Amino-quinolines as kinase inhibitors
US9586953B2 (en) 2012-09-13 2017-03-07 Glaxosmithkline Intellectual Property Development Limited Prodrugs of amino quinazoline kinase inhibitor
US9695161B2 (en) 2012-09-13 2017-07-04 Glaxosmithkline Intellectual Property Development Limited Prodrugs of amino quinazoline kinase inhibitor
US9650364B2 (en) 2013-02-21 2017-05-16 GlaxoSmithKline Intellectual Property Development Limted Quinazolines as kinase inhibitors

Also Published As

Publication number Publication date
CN101346381A (zh) 2009-01-14
EP1937686A1 (fr) 2008-07-02
AP2008004444A0 (en) 2008-04-30
ITMI20052008A1 (it) 2007-04-22

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