EP1606263A1 - Derives de 8-aminoquinoline a cycle substitue utiles comme agents anti-paludeens - Google Patents

Derives de 8-aminoquinoline a cycle substitue utiles comme agents anti-paludeens

Info

Publication number
EP1606263A1
EP1606263A1 EP03768070A EP03768070A EP1606263A1 EP 1606263 A1 EP1606263 A1 EP 1606263A1 EP 03768070 A EP03768070 A EP 03768070A EP 03768070 A EP03768070 A EP 03768070A EP 1606263 A1 EP1606263 A1 EP 1606263A1
Authority
EP
European Patent Office
Prior art keywords
formula
aminoquinoline
malarial
compounds
substituted
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.)
Withdrawn
Application number
EP03768070A
Other languages
German (de)
English (en)
Inventor
Rahul Jain
Meenakshi Jain
Prati Pal Singh
Savita Singh
Sandeep Sachdeva
Vijai Misra
Poduri Ramarao
Chaman Lal Kaul
Kulbhushan Tikko
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.)
Council of Scientific and Industrial Research CSIR
Original Assignee
Council of Scientific and Industrial Research CSIR
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 Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Priority claimed from PCT/IB2003/006362 external-priority patent/WO2004085402A1/fr
Publication of EP1606263A1 publication Critical patent/EP1606263A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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 is concerned with the development of novel 8-aminoquinoline analogs in the treatment and prevention of malaria and the said compound has broad spectrum of activity against the blood as well as tissue stages of the human malaria parasites that makes these compounds very attractive in the cure and prevention of malaria and also it is expected that development of these compounds as ideal antimalarial agents may lead to suppression as well as radical cure of the malaria infection with single drug therapy.
  • the present invention relates to a ring-substituted 8-aminoquinoline analogs and the preparation thereof which is useful as antimalarial agents.
  • the present invention particularly relates to synthesis of 2-alkyl-4,5-disubstitited-6-methoxyprimaquine analogs having the formula 1, which are expected to offer an improved means for the chemotherapy of malaria.
  • R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain alkyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups
  • Ri represents H, CH 3 , C 2 H 5
  • R 2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyl group containing 3 to 15 carbon atoms
  • R represents various (R)- and (S)- amino acids or L-unnatural amino acids, and pharmacologically acceptable salts thereof, wherein the salt-forming acid may be organic or inorganic in nature.
  • P. falciparum and P. vivax account for more than 95% of malaria cases in the world, and P. falciparum causes most problems as a result of its prevalence, virulence and drag resistance, and nearly all deaths are attributed to this single parasitic species.
  • Malaria infections caused by P. falciparum are prevalent in the major parts of Africa, sub-Saharan Africa and East Asian countries, whereas P. vivax is the causative species primarily of Indian sub-Continent. The disease can be treated in just 48 hours, yet it can cause fatal complications, if the diagnosis and treatment are delayed.
  • Malaria is re-emerging as the biggest infectious killer and is currently the first priority tropical disease of the World Health Organization.
  • Life cycle of malaria parasite has various stages, and each stage has different degree of susceptibility to available antimalarial agents.
  • the currently available antimalarial agents are conveniently divided into following, two categories i.e. blood-schizontocidal antimalarial agents, which exert their biological activity against the erythrocytic asexual (blood) stages of the malaria parasite, and tissue-schizontocidal antimalarial agents, which exert their antimalarial action on the asexual exoerythrocytic (tissue) stages of the human malaria parasite. All of the available antimalarial drugs are losing their power to treat infection and have become inadequate for the treatment of malaria infection. P.
  • the logical lead compound for this research is primaquine and well supported by following observations: (1) 8-aminoquinolines is the only class of compounds proven to be successful for the treatment of relapsing malaria; (2) the 8-aminoquinolines, such as primaquine are easily synthesized and inexpensive to produce; (3) the 8-aminoquinolines, such as primaquine is the only drug available to exhibit activity against all the stages including that of blood- and tissue-stages of the human malaria life cycle; (4) the 8- aminoquinoline, primaquine has been shown to be effective against drug resistant strains of P. falciparum. Despite research efforts of more than 60 years malaria is still one of the major killer of the world.
  • the main object of the present invention is to provide a process for preparation of ring- substituted 8-aminoquinoline analogs.
  • Another main object of the present invention is to provide, 8-aminoquinoline analogs which exhibits superior antimalarial activities against drag-sensitive and multidrug- resistant parasites.
  • Another object of the present invention is to provide the ring substituted 8-aminoquinoline analogs having LD 50 value above 400mg per body weight value.
  • Yet another object of the present invention is to provide the peptide derivatives of 8- aminoquino lines with reduced toxicity.
  • Another object of the present invention is to provide, 8-aminoquinoline analogs which exhibits reduced methemoglobin toxic side effects
  • the present invention relates to a ring-substituted 8-aminoquinoline analogs and their preparation thereof which is useful as antimalarial agents.
  • the present invention particularly relates to synthesis of 2-alkyl-4,5-disubstitited-6-methoxyprimaquine analogs having the formula 1, which are expected to offer an improved means for the chemotherapy of malaria.
  • R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain alkyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups
  • Ri represents H, CH , C 2 H 5
  • R 2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyl group containing 3 to 15 carbon atoms
  • R 3 represents various (R)- and (S)- amino acids or L-unnatural amino acids, and pha ⁇ nacologically acceptable salts thereof, wherein the salt-forming acid may be organic or inorganic in nature.
  • the present invention relates to the development of novel 8-aminoquinoline analogs in the treatment and prevention of malaria and the broad spectrum of the activity against the blood as well as tissue stages of the human malaria parasites makes these compounds very attractive in the cure and prevention of malaria and also it is expected that development of these compounds as ideal antimalarial agents may lead to suppression as well as radical cure of the malaria infection with single drug therapy.
  • R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain alkyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups
  • Ri represents H, CH 3 , C 2 H 5
  • R 2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyl group containing 3 to 15 carbon atoms
  • R 3 represents various (R)- and (S)- amino acids or L-unnatural amino acids.
  • a ring substituted 8- aminoquinoline analogous wherein the said analogous does not produces methemoglobin (MetHb) toxicity.
  • an anti-malarial composition a pharmaceutically effective amount of a ring substituted 8-aminoquinoline analogous wherein, the R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain alkyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups, Ri represents H, CH 3 , C H 5 , R 2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyl group containing 3 to 15 carbon atoms,
  • R represents various (R)- and (S)-amino acids or L-unnatural amino acids and pharmacologically acceptable additive(s).
  • the pharmaceutically acceptable additives are acceptable diluents selected from group of a lactose, mamiitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; binder selected from group of gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; excipients selected from group of agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof; lubricants selected from group of a magnesium stearate, calcium stearate or steorotes, talc, solid polyethylene glycols, sodium lauryl sulphate or
  • an anti-malarial composition wherein the said composition is having a broad spectrum of anti- malarial activity against blood stages, tissue stages of malarial parasite.
  • an anti-malarial composition wherein the said composition is effective against the resistant strains of human malarial parasite.
  • an anti-malarial composition wherein the ring substituted 8-aminoquinoline analogous of formula 1 are active against P. berghei infection at a dose ranging between 10-lOOmg for 4 days.
  • an anti-malarial composition wherein the ring substituted 8-aminoquinoline analogous of formula 1 are active against P. yoelii infection at a dose ranging between 10-100mg for 4 days.
  • an anti-malarial composition wherein the LD 50 compounds of formula 1 is about 400 mg per kg of body weight.
  • a higher dose may be applied according to the degree of the malarial infection.
  • an anti-malarial composition wherein the ring substituted 8-aminoquinoline analogous of formula 1, said analogous does not produces methemoglobin (MetHb) toxicity.
  • composition wherein the composition is in the form of syrup/ tablet/ capsule/ powder/ injectables.
  • the present invention provides a process for preparation of ring- substituted 8-aminoquinoline analogs as of formula 1
  • R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain allcyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups
  • R 1 represents H, CH , C 2 H 5
  • R 2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyl group containing 3 to 15 carbon atoms
  • R 3 represents various (R)- and (S)- amino acids or L-unnatural amino acids, and pharmacologically acceptable salts thereof, wherein the salt-forming acid may be organic or inorganic in nature which comprises; a.
  • step (d) reacting N8-(4-amino-l-methylbutyl)-8-quinolinamine obtained in step (d) with N- protected amino acid and dicyclohexylcarbodimide in chloroalkane solvent at a temperature ranging between 10-50 C, isolating the ring substituted protective amino acid quinoline derivative followed by deprotection of amino acid moiety in the molecule to give compound of formula 1.
  • alkyl carboxylic acid is selected from a group consisting of tri-methyl acetic acid , isobutyric acid, cyclo- hexane carboxylic acid,l-adamantanecarboxylic acid.
  • 8-nitroquinoline is selected from 6-methoxy-8-nitroquinoline, 5, 6 - dimethoxy - 8 - nitroquinoline, 4- ethyl - 5 - pentoxy - 6 - methoxy - 8 -nitroquinoline, 4-ethyl-5-octoxy-6-methoxy-8- nitroquinoline, 4-methyl-5,6-dimethoxy-8-nitroquinoline, Yet in another embodiment of the present invention, wherein the catalyst used for the reduction step (b) is raney-nickel.
  • alcoholic solvent used is ethyl alcohol.
  • chloro-alkane solvent is selected from dichloro-methane.
  • step (e) wherein the deprotection of bezyl-esters in amino acid moiety in the molecule in step (e) is carried out in presence of Pd-C in methanol in presence of hydrogen gas.
  • the LD 50 of compounds of formula 1 is in the range of 400 to 450 mg per kg of body weight.
  • a single drag method of treating a subject in need thereof by administrating pharmaceutically effective dosages of a ring substituted 8-aminoquinoline analogous of formula 1 as defined in claim 1 along with a pharmaceutically acceptable salt(s), earlier or additives to the mammals.
  • the subject is mammals and preferably humans. Still in another embodiment of the present invention, wherein the compounds of formula 1 are active against P. berghei and P. yoelii infection at a dose ranging between 10-lOOmg for 4 days.
  • the LD 50 of compounds of formula 1 is in the range of 400 to 450 mg per kg of body weight. Still in another embodiment of the present invention, wherein the said composition is having a broad spectram of anti- malarial activity against blood stages, tissue stages of malarial parasite.
  • the said composition is effective against the resistant strains of human malarial parasite.
  • Most of the available antimalarial drags are incapable and ineffectual for the treatment of malaria infection.
  • Development of resistance by P. falciparum has been documented against majority of blood-schizontocides.
  • available tissue-schizontocides are highly toxic for human use as causal prophylactics and gametocytocides.
  • Primaquine N 8 -(4-amino-l-methylbutyl)-6-methoxy-8-quinolinamine, is highly effective tissue-schizontocidal agent, and has direct and fast gametocytocidal action on all species of malarial parasite.
  • the drug also has blood-schizontocidal activity but only at dangerously toxic doses for human use. Its high toxicity profile
  • G-6PD glucose-6-phosphate dehydrogenase
  • the present invention describes the utilization of a radical homolytic free radical reaction [Scheme 1] to provide novel 2-alkyl-8-aminoquinoline, 5-alkyl-8- aminoquinoline and 2,5-dialkyl-8-aminoquinoline derivatives and the surprisingly strong broad-spectrum antimalarial activities of the analogs belonging to 2-alkyl-8- aminoquinoline series.
  • Scheme 1 a radical homolytic free radical reaction
  • the rationale for the synthesis of these compound is as follows: One of the main metabolic degradation pathways known for the quinoline moiety results in oxidative biotransformation at the C-2 position, and converts it to iH-2-oxoquinoline. This pathway is supported by the recent studies conducted by Mirghani and coworkers (Mirghani R.
  • a prodrug is a pharmacologically inactive derivative of a parent drag molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drag that may also have improved biological properties over the parent drug molecule. It has, in fact, been shown that linking the primaquine to small peptides resulted in the formation of compounds, which possess reduced toxicity and a longer half-life compared to primaquine. Furthermore, we have earlier demonstrated that linking amino acids to the side chain amino group at C-8 position of the quinoline ring is found to increase the biological activity with reduced toxicity (Jain, R., Jain, S., Gupta, R. C, Anand, N., Dutta, G. P. and Puri, S. K. hid. J.
  • R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain alkyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups
  • Ri represents H, CH 3 , C 2 H 5
  • R 2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyl group containing 3 to 15 carbon atoms
  • R 3 represents various (R)- and (S)- amino acids or L-unnatural amino acids, and pharmacologically acceptable salts thereof, wherein the salt-forming acid may be organic or inorganic in nature which comprises; a.
  • step (d) reacting N8-(4-amino-l-methylbutyl)-8-quinolinamine obtained in step (d) with N- protected amino acid and dicyclohexylcarbodimide in chloroalkane solvent at a temperature ranging between 10-50 C, isolating the ring substituted protective amino acid quinoline derivative followed by deprotection of amino acid moiety in the molecule to give compound of formula 1.
  • the alkyl carboxylic acid is selected from a group consisting of tri-methyl acetic acid, isobutyric acid, cyclo-hexane carboxylic acid,l- adamantanecarboxylic acid.
  • 8-nitroquinoline is selected from 6- methoxy-8-nitroquinoline, 5, 6-dimethoxy-8-nitroquinoline, 4-ethyl-5-pentoxy-6-methoxy- 8-nitroquinoline, 4-ethyl-5-octoxy-6-methoxy-8-nitroquinoline, 4-methyl-5, 6-dimethoxy- 8-nitroquinoline, hi yet another embodiment of the present invention the catalyst used for the reduction step (b) is raney-nickel .
  • the reduction is carried out at a pressure in the range of 40-50 psi in a Parr hydrogenator.
  • alcoholic solvent used is ethyl alcohol.
  • the chloro-alkane solvent is selected from dichloro-methane.
  • the deprotection of bezyl- esters in amino acid moiety in the molecule in step (e) is carried out in presence of Pd-C in methanol in presence of hydrogen gas.
  • the deprotection of t-Boc protected amino acid is carried out in presence of methanolic HC1.
  • the compounds of formula 1 are active in mice against P. berghei, P. yoelii infection at a dose ranging between 10-lOOmg for 4 days.
  • the LD 50 compounds of formula 1 is above 400mg per kg of body weight.
  • Table 1 In vivo, blood-schizontocidal activity of compounds against P. berghei infection in mice
  • Table 2 In vivo blood-schizontocidal activity of compounds against chloroquine and mefloquine drag-resistant P. yoelii nigeriensis strain in mice
  • Table 3 Acute toxicity studies in Swiss Mice (5, 50, 150, 450 mg/kg)
  • Table 4 A comparison of methanoglobin toxicity between commonly used primaquine drag and 2-tert-Butylprimaquine
  • Table 5 hi vitro antimalarial data of 2-tert-butylprimaquine against P. falciparum Biological Activity
  • mice Blood schizontocidal activity evaluation of potential antimalarial compounds against Plasmodium berghei (sensitive strain) and P. yoelii nigeriensis (resistant strain) infection in mice.
  • Test Procedure On day '0', groups of 6 mice each were inoculated, intraperitoneally, with lxlO 7 infected-erythrocytes, from a donor mouse. Four hours later, mice were administered test compounds/chloroquine primaquine/vehicle, orally. A total of 4 doses were given on days DO', D+l, D+2, and D+3. The tail blood smears were made on day D+4 and D+7, stained with Geimsa, and examined microscopically.
  • Protocol Different drag dilutions [test compounds and chloroquine (positive control)] were prepared in complete RPMI (medium RPMI 1640 + 10%> AB + human seram; CRPMI). Fifty ⁇ L of each dilution was transferred to the respective well of a micro titer plate in triplicates. Parasitized erythrocytes ' (PE; mainly rings; 4% parasitaemia; 5% hematokrit) were added to each well. Volume in each well was made up to 200 ⁇ L with CRPMI. The plates were incubated at 37 °C in a candle jar. After 24-48 h of incubation, thin smears from each well were made and stained with Giemsa.
  • PE paraffinized erythrocytes '
  • 6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH 3 CN (5 mL) while reaction mixture was warmed to 70 °C.
  • Silver nitrate (0.6 mmol), trimethylacetic acid (2.5 mmol), and 10%> H 2 SO 4 (10 mL) was then added to the reaction mixture.
  • a freshly prepared solution of ammonium persulfate (3 mmol) in water (10 mL) was added drop wise to the pre-heated (70 °C) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture ' was made alkaline with addition of 30% NH 4 OH.
  • This compound was synthesized using above-mentioned procedure and 4-ethyl-5-pentoxy- 6-methoxy-8-nitroquinoline as the starting material in the presence of trimethyl acetic acid.
  • 6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH CN (5 mL) while reaction mixture was warmed to 70 °C.
  • Silver nitrate (0.6 mmol), 1-adamantanecarboxylic acid (2 mmol), and 10% H 2 SO 4 (10 mL) was then added to the reaction mixture.
  • a freshly prepared solution of ammonium persulfate (3 mmol) in water (10 mL) was added drop wise to the pre-heated (70 °C) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture was made alkaline with addition of 30% NH 4 OH.
  • 6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH 3 CN (5 mL) while reaction mixture was warmed to 70 °C.
  • Silver nitrate (0.6 mmol), 1-adamantanecarboxylic acid (2.5 mmol), and 10% H 2 SO 4 (10 mL) was then added to the reaction mixture.
  • a freshly prepared solution of ammonium persulfate (3 mmol) in water (10 mL) was added drop wise to the pre-heated (70 °C) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture was made alkaline with addition of 30% NH 4 OH.
  • Catalyst was removed by filtration, and solvent was removed under reduced pressure to provide of ring-substituted 8-quinolinamines as oil, which were subjected to nest step reaction without any further purification.
  • the molecule can easily be synthesized and inexpensive to produce
  • the molecule is effective against drag resistant strains of P. falciparum.
  • the most effective molecule is also devoid of methemoblobin toxicity traditionally associated with 8-aminoquinoline class of antimalarial drags.

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le développement de nouveaux analogues de 8-aminoquinoline de formule I, dans laquelle R, R<1>, R<2> et R<3> ont les définitions données dans la description, pour le traitement et la prévention du paludisme. Ces composés ont un large spectre d'activité dans les stades de développement dans le sang et dans les tissus des parasites qui provoquent le paludisme chez des êtres humains, ce qui les rend très attrayants pour le traitement et la prévention du paludisme causé par des souches sensibles à des médicaments et multirésistantes. On s'attend à ce que le développement de ces composés comme agents anti-paludéens idéaux mène à une cure radicale de l'infection par le paludisme avec un thérapie monomédicamenteuse.
EP03768070A 2003-03-27 2003-12-22 Derives de 8-aminoquinoline a cycle substitue utiles comme agents anti-paludeens Withdrawn EP1606263A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
INDE04732003 2003-03-27
IN473DE2003 2003-03-27
IN549DE2003 2003-03-27
INDE05492003 2003-03-27
PCT/IB2003/006362 WO2004085402A1 (fr) 2003-03-27 2003-12-22 Derives de 8-aminoquinoline a cycle substitue utiles comme agents anti-paludeens

Publications (1)

Publication Number Publication Date
EP1606263A1 true EP1606263A1 (fr) 2005-12-21

Family

ID=35351756

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03768070A Withdrawn EP1606263A1 (fr) 2003-03-27 2003-12-22 Derives de 8-aminoquinoline a cycle substitue utiles comme agents anti-paludeens

Country Status (1)

Country Link
EP (1) EP1606263A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004085402A1 *

Similar Documents

Publication Publication Date Title
US5596002A (en) Method of treating chloroquine-resistant malaria with aminoquinoline derivatives
WO1993021919A1 (fr) Hydroxypyridin-4-ones pour le traitement d&#39;infections parasitaires
CN101868447A (zh) 制备和施用作为抗癌剂的喹啉衍生物的方法
US5510356A (en) Bisquinolines and processes for their production and use to treat malaria
DE112012004878T5 (de) Heterocyclische Dihydro-Fünfring-Ketonderivate als DHODH-Inhibitor und ihre Verwendung
Vangapandu et al. 8-quinolinamines and their pro prodrug conjugates as potent blood-schizontocidal antimalarial agents
EP0494754A1 (fr) Dérivés de hydroxy-3-pyridine-4-one comme compositions pharmaceutiques
US6979740B2 (en) Process for preparation of ring-substituted 8-aminoquinoline analogs as antimalarial agents
Jain et al. Synthesis and blood-schizontocidal antimalarial activities of 2-substituted/2, 5-disubstituted-8-quinolinamines and some of their amino acid conjugates
WO2002044133A1 (fr) Preparation d&#39;inhibiteurs de type 1 d&#39;echangeur de sodium-hydrogene
EP1606263A1 (fr) Derives de 8-aminoquinoline a cycle substitue utiles comme agents anti-paludeens
WO2004085402A1 (fr) Derives de 8-aminoquinoline a cycle substitue utiles comme agents anti-paludeens
EP0785924B1 (fr) Bis-2-aminopyridines, leur procede de preparation et leurs applications contre les parasitoses
EP3319940B1 (fr) Nouveaux composés d&#39;indole ayant une activité antiprotozoaire, leur utilisation et procédés pour les produire
Go et al. Synthesis of some novel amodiaquine analogs as potential antimalarial and antifilarial compounds
US4980360A (en) 5-(phenylalkoxy)primaquine compounds and their use for treatment of malaria
JPH10310576A (ja) イソキノリンスルフォンアミド誘導体及びこれを有効成分とする医薬
WO2011068987A2 (fr) Compositions et méthodes pour le traitement de la lambliase
JP2024523881A (ja) 薬学的化合物
EP3649109B1 (fr) Composés d&#39;éthynyl, leur préparation et leur application thérapeutique pour le traitement de la malaria
US20030119873A1 (en) Methods for preparing sodium-hydrogen exchanger type-1 inhibitors
EP1846401A1 (fr) Nouveaux dérivés de 4-aminoquinoléine comme composés antimalaria
WO2012032952A1 (fr) Composé ayant une activité antipaludique et médicament antipaludique
JP4431796B2 (ja) 新規な抗マラリア剤
WO2020206252A1 (fr) Composés antipaludiques

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20051014

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20071213

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20140930