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WO2000050404A1 - 4-aminoquinolines utilisees comme antipaludeens - Google Patents

4-aminoquinolines utilisees comme antipaludeens Download PDF

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Publication number
WO2000050404A1
WO2000050404A1 PCT/GB2000/000678 GB0000678W WO0050404A1 WO 2000050404 A1 WO2000050404 A1 WO 2000050404A1 GB 0000678 W GB0000678 W GB 0000678W WO 0050404 A1 WO0050404 A1 WO 0050404A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
group
alkyl
planar
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/GB2000/000678
Other languages
English (en)
Inventor
Kaylene Joy Raynes
Paul Anthony Stocks
Steve Andrew Ward
Paul Michael O'neill
Brian Kevin Park
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.)
University of Liverpool
Original Assignee
University of Liverpool
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 University of Liverpool filed Critical University of Liverpool
Priority to AU28145/00A priority Critical patent/AU2814500A/en
Publication of WO2000050404A1 publication Critical patent/WO2000050404A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • 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

  • the present invention relates to 4-aminoquinolines and derivatives
  • Amodiaquine differs chemically from chloroquine in that it contains a 4- hydroxy anilino function in its side chain. Both amodiaquine and chloroquine do however have four carbon atoms between the secondary and tertiary nitrogen atoms. The presence of a basic side chain (dialkylamino) has previously been considered an essential element in giving both chloroquine and amodiaquine their antimalarial activity.
  • W is Cl or CF 3 ;
  • R is selected from: i) R 2 - NH - R, - Z - where:
  • Z is NH, S, O or CH 2 ;
  • R t is a Cj to C 4 alkyl group; such as, for example, methyl, ethyl, propyl or butyl, most preferably methyl or ethyl; and
  • R 2 -NH- is a group resistant to dealkylation in vivo (by, for example, P450
  • oxidation such as, for example, a secondary amine such as, for example, a
  • Ar is a substituted or unsubstitited aromatic ring structure; such as, for
  • R-j is a planar or non planar, alkyl or cycloalkyl substituent on the 5' position of
  • aromatic ring Ar such as, for example, a C,-C 4 alkyl group, a secondary
  • alkyl group a tertiary alkyl group or a cycloalkyl group, such as, for example, a methyl, ethyl, propyl, iso-propyl, s-butyl, t-butyl or cyclohexyl group.
  • the aromatic ring is a six membered ring and includes substituents, most preferably a hydroxyl group, preferably in the 4' position, and a group which is less susceptible to metabolism than a diethyl amino group, preferably in the 3' position, such as, for example, a 3' tert nitrogen group, such as, for example, a N-tert butyl amino methyl group.
  • substituents most preferably a hydroxyl group, preferably in the 4' position, and a group which is less susceptible to metabolism than a diethyl amino group, preferably in the 3' position, such as, for example, a 3' tert nitrogen group, such as, for example, a N-tert butyl amino methyl group.
  • R groups of the formula (iii) R 4 - Ar - Z - are exemplified by the general formula shown below:
  • Z is NH or a group less susceptible to undergo oxidation to a quinone-imine
  • « is a lipid solubilizing group, for example, a planar alkyl group, such as, for
  • methyl ethyl or propyl
  • a non planar group for example, t-butyl
  • Y is a group less susceptible to metabolism than a 3' diethyl amino group, such
  • N-tert-alkyl amino alkyl group such as, for example, that given below:
  • W is Cl or CF 3 ;
  • Z is NH, S, O or CH 2 ;
  • R is a C, to C 4 alkyl group
  • R 2 -NH- is a group resistant to dealkylation in vivo
  • Ar is a substituted or unsubstitited aromatic ring structure
  • R 4 is a planar or non planar, alkyl or cycloalkyl substituent on the 5' position of the aromatic ring Ar.
  • Z is NH
  • Rj is a Ci - C 4 alkyl group; and R 2 is a secondary amine.
  • Z is NH
  • R is a C, - C 4 alkyl group
  • R N - is a cyclic amine
  • R group is: Formula VIII
  • Z is NH
  • R 4 is a planar or non planar alkyl group; and Y is a N - tert alkyl alkyl amino group.
  • amodiaquine and have the general formula identified below:
  • the first series of compounds investigated contained the structural
  • diethylamino function of AQ has been replaced by a N-terr-butyl-i-nino group to prevent the
  • alkyl substituted Mannich base compounds were prepared using a modified
  • Antimalarial activity The capacity of AQ (Formula III), N-ter/-butyl amodiaquine (TBAQ,) and the 5 '-alkyl
  • N-terf-butyl (Formula XXI) or cyclohexyl (Formula XXII) group substantially decreased antimalarial activity. While alkyl groups which contained a 3 carbon backbone with no greater
  • CAR cellular accumulation ratio
  • accumulation being dependant on the ability of drug to bind to an intraparasitic receptor, whether or not that be firee haem and/or an active exchanger. Whatever the accumulation
  • lipophilicity may be able to overcome the decreased affinity for a receptor, as shown by the WO 00/50404 - 2 3 - PCT/GBOO/00678
  • a non-planar group such as a N-te/7-butyl (Formula XXII) or a cyclophenol group (Formula
  • erythrocytes (2-5%) with parasitemia in the range of 1% to 10% suspended in RPMI 1640
  • Desjardins et al. Desjardins, R E.; Canfield, C. J.; Haynes, J. D.; Chulay,
  • hypoxanthine was added to each well. Cultures were incubated for a further 24 h before they

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (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)

Abstract

La présente invention concerne des 4-aminoquinolines et leurs dérivés. La présente invention concerne, en particulier, des 4-aminoquinolines, ainsi que leurs dérivés, destinés à être utilisés dans le traitement et la prophylaxie de la malaria. Les composés selon l'invention sont représentés par la formule (IV), dans laquelle: W représente Cl ou CF3; X représente N ou N=O; R est choisi parmi: i) R2-NH-R1-Z-, où Z représente NH, S, O ou CH2; R1 représente un groupe alkyle en C1-C4; et R2-NH- représente un groupe résistant à la désalkylation in vivo; ou ii) (a) où Z et R1 sont tels que définis au (i) ci-dessus, et représente un groupe résistant à la désalkylation in vivo ; ou iii) R4-Ar-Z-, où Z est tel que défini au (i) ci-dessus ; Ar représente une structure cyclique aromatique substituée ou non substituée ; et R4 représente un substituant alkyle ou cycloalkyle planaire ou non planaire situé en position 5' du cycle aromatique Ar.
PCT/GB2000/000678 1999-02-25 2000-02-25 4-aminoquinolines utilisees comme antipaludeens Ceased WO2000050404A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU28145/00A AU2814500A (en) 1999-02-25 2000-02-25 4-aminoquinolines as antimalarials

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9904419.0A GB9904419D0 (en) 1999-02-25 1999-02-25 4-aminoquinolines
GB9904419.0 1999-02-25

Publications (1)

Publication Number Publication Date
WO2000050404A1 true WO2000050404A1 (fr) 2000-08-31

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PCT/GB2000/000678 Ceased WO2000050404A1 (fr) 1999-02-25 2000-02-25 4-aminoquinolines utilisees comme antipaludeens

Country Status (3)

Country Link
AU (1) AU2814500A (fr)
GB (1) GB9904419D0 (fr)
WO (1) WO2000050404A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092232A1 (fr) * 2000-05-27 2001-12-06 Ufc Ltd. 4-aminoquinolines utilisees comme agents anti-infectieux
WO2002072554A1 (fr) * 2001-03-14 2002-09-19 The University Of Liverpool Composes anti-malaria
EP1589004A1 (fr) * 2004-04-22 2005-10-26 Universite Pierre Et Marie Curie Paris Vi Composées alcaloides et leur utilisation en tant qu'antipaludéens
WO2006034235A3 (fr) * 2004-09-20 2006-12-21 Serenex Inc Inhibiteurs quinoline et quinazoline a substitution inhibant la quinone reductase 2
US8481543B2 (en) 2008-11-18 2013-07-09 Oregon Health & Science University Compounds for treating parasitic disease

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3136769A (en) * 1961-03-28 1964-06-09 Parke Davis & Co Quinoline nu-oxides
EP0256985A2 (fr) * 1986-08-15 1988-02-24 Ciba-Geigy Ag Thiourées, isothiourées et carbodiimides substituées
EP0326330A2 (fr) * 1988-01-29 1989-08-02 DowElanco Quinoléines, quinazolines et cinnolines fongicides
EP0656353A1 (fr) * 1993-10-28 1995-06-07 F. Hoffmann-La Roche Ag Dérivés d'aminoquinoleines utiles pour le traitement de la malaria

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3136769A (en) * 1961-03-28 1964-06-09 Parke Davis & Co Quinoline nu-oxides
EP0256985A2 (fr) * 1986-08-15 1988-02-24 Ciba-Geigy Ag Thiourées, isothiourées et carbodiimides substituées
EP0326330A2 (fr) * 1988-01-29 1989-08-02 DowElanco Quinoléines, quinazolines et cinnolines fongicides
EP0656353A1 (fr) * 1993-10-28 1995-06-07 F. Hoffmann-La Roche Ag Dérivés d'aminoquinoleines utiles pour le traitement de la malaria

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
ASIAN J. PHARM., vol. 2, no. 2, - 1972, pages 22 - 25 *
AUST. J. CHEM., vol. 47, no. 6, - 1994, pages 1143 - 1154 *
AUST. J. CHEM., vol. 47, no. 8, - 1994, pages 1553 - 1560 *
BIORG. MED. CHEM. LETT., vol. 7, no. 21, - 1997, pages 2741 - 2746 *
CHEMICAL ABSTRACTS, vol. 103, no. 17, 28 October 1985, Columbus, Ohio, US; abstract no. 134346w, OHTOMO, HIROSHI ET AL.: "Pharmacokinetics of antimalarial Fansidar in healthy Japanese." XP002139019 *
CHEMICAL ABSTRACTS, vol. 121, no. 15, 10 October 1994, Columbus, Ohio, US; abstract no. 179466y, BARLIN, GORDON B. ET AL.: "Potential antimalarials. XX. Mannich base derivatives of 2-(7-(chloroquinolin-4-ylamino) and ..." XP002139022 *
CHEMICAL ABSTRACTS, vol. 121, no. 21, 21 November 1994, Columbus, Ohio, US; abstract no. 255609q, BARLIN, GORDON B. ET AL.: "Potential antimalarials. XXI. Mannich base derivatives of 4-(7-chloro (and 7-trifluoromethyl)quinolin-4-ylamino)phenols." XP002139021 *
CHEMICAL ABSTRACTS, vol. 128, no. 5, 2 February 1998, Columbus, Ohio, US; abstract no. 48119j, SRIVASTAVA, SANDHYA ET AL.: "Synthesis of 7-chloro-4-substituted aminoquinolines and their in vitro ability to produce methemoglobin in canine hemolyzate." XP002139020 *
CHEMICAL ABSTRACTS, vol. 80, no. 7, 18 February 1974, Columbus, Ohio, US; abstract no. 33754d, NATARAJAN, P.N.: "Antimalarial activity and decomposition studies od 4-(7-chloro-4'-quinolylamino)-alpha-phenyl-alpha-piperidino-2-cresol." XP002139023 *
DATABASE CHEMICAL ABSTRACTS XP002139024 *
DATABASE CHEMICAL ABSTRACTS XP002139025 *
DATABASE CHEMICAL ABSTRACTS XP002139026 *
DATABASE CHEMICAL ABSTRACTS XP002139027 *
DATABASE CHEMICAL ABSTRACTS XP002139028 *
KAYLENE J. RAYNES ET AL.: "New 4-aminoquinoline Mannich base antimalarials.1. Effect of an alkyl substituent in the 5'-position of the 4'-hydroyanilino side chain", JOURNAL OF MEDICINAL CHEMISTRY., vol. 42, no. 15, - 29 July 1999 (1999-07-29), AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 2747 - 2751, XP002139018, ISSN: 0022-2623 *
SHIN'YAKU TO RINSHO, vol. 34, no. 3, - 1985, pages 415 - 423 *
STEPHEN J. KESTEN ET AL.: "Synthesis and antimalarial effects of 4-((7-chloro-4-quinolinyl)amino)-2-((dietylamino)methyl)-6-alkylphenols and their N-oxides", JOURNAL OF MEDICINAL CHEMISTRY., vol. 30, no. 5, - 1987, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 906 - 911, XP002139017, ISSN: 0022-2623 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092232A1 (fr) * 2000-05-27 2001-12-06 Ufc Ltd. 4-aminoquinolines utilisees comme agents anti-infectieux
WO2002072554A1 (fr) * 2001-03-14 2002-09-19 The University Of Liverpool Composes anti-malaria
JP2004533418A (ja) * 2001-03-14 2004-11-04 ザ・ユニヴァーシティ・オヴ・リヴァプール 抗マラリア化合物
US7132431B2 (en) 2001-03-14 2006-11-07 The University Of Liverpool Anti-malarial compounds
EP1589004A1 (fr) * 2004-04-22 2005-10-26 Universite Pierre Et Marie Curie Paris Vi Composées alcaloides et leur utilisation en tant qu'antipaludéens
WO2005103008A1 (fr) * 2004-04-22 2005-11-03 Universite Pierre Et Marie Curie (Paris Vi) Composes alcaloides et leur utilisation en tant que medicaments contre la malaria
WO2005103009A1 (fr) * 2004-04-22 2005-11-03 Universite Pierre Et Marie Curie (Paris Vi) Composes alcaloides et leur utilisation comme medicaments antipaludiques
US7943633B2 (en) 2004-04-22 2011-05-17 Universite Pierre Et Marie Curie (Paris Vi) Alkaloid compounds and their use as anti-malarial drugs
WO2006034235A3 (fr) * 2004-09-20 2006-12-21 Serenex Inc Inhibiteurs quinoline et quinazoline a substitution inhibant la quinone reductase 2
US8481543B2 (en) 2008-11-18 2013-07-09 Oregon Health & Science University Compounds for treating parasitic disease

Also Published As

Publication number Publication date
AU2814500A (en) 2000-09-14
GB9904419D0 (en) 1999-04-21

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