WO2015133280A1 - Composé ayant une activité antipaludique et médicament antipaludique - Google Patents

Composé ayant une activité antipaludique et médicament antipaludique Download PDF

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Publication number
WO2015133280A1
WO2015133280A1 PCT/JP2015/054491 JP2015054491W WO2015133280A1 WO 2015133280 A1 WO2015133280 A1 WO 2015133280A1 JP 2015054491 W JP2015054491 W JP 2015054491W WO 2015133280 A1 WO2015133280 A1 WO 2015133280A1
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Prior art keywords
compound
antimalarial
mmol
compound according
drug
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PCT/JP2015/054491
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English (en)
Japanese (ja)
Inventor
恒彦 樋口
信樹 加藤
直樹 梅澤
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公立大学法人名古屋市立大学
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Priority to JP2016506416A priority Critical patent/JPWO2015133280A1/ja
Publication of WO2015133280A1 publication Critical patent/WO2015133280A1/fr

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    • 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
    • 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
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, 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 a novel compound exhibiting antimalarial activity and use thereof.
  • This application claims priority based on Japanese Patent Application No. 2014-040616 filed on Mar. 3, 2014, the entire contents of which are incorporated by reference.
  • Malaria is the largest parasitic protozoan infection that is said to kill hundreds of millions of people each year and kill millions of them. This threat has continued since prehistoric times in the tropics, but the tropical and subtropical areas were the main infected areas so far, but there are concerns that it will spread to the temperate zone due to global warming. With the spread of the epidemic, there is an urgent need to develop new and effective medicines.
  • Chloroquine, quinine, mefloquine, artemisinin, etc. are used as a treatment for malaria, but all have strong side effects. Since chloroquine has fewer side effects than other drugs, it is often used as a first-line drug for the prevention and treatment of malaria, but the spread of chloroquine-resistant malaria species has become a major problem in recent years. Recently, resistance to other drugs has also occurred, and it is urgent to cope with multidrug resistance.
  • Patent Documents 1 and 2 discloses an N, N′-bis (quinolin-4-yl) diamine derivative as a compound exhibiting antimalarial activity
  • Patent Document 4 discloses a compound that exhibits antimalarial activity against both chloroquine sensitivity and strain resistance in a quinoline skeleton.
  • An object of the present invention is to provide a compound effective for malaria (that is, a novel compound having high antimalarial activity) and its use.
  • the inventors proceeded with research. As a result, they succeeded in finding a novel compound with high antimalarial activity.
  • the newly synthesized compounds there were those that showed significantly higher activity than previously reported compounds.
  • the compound showed a strong activity against chloroquine resistant strains and an extremely strong activity against chloroquine sensitive strains.
  • One of the characteristics of the novel compound is asymmetry, and at least in this respect, the novel compound is distinguished from the antimalarial active compound reported by the present inventors in the past.
  • the following inventions are provided mainly based on the above findings.
  • a compound represented by the following chemical formula 1 is an asymmetric structure, m in the formula is 1 to 5, n is 1 to 5, R represents H, CH 3 , CH 2 CH 3 or CH 2 NH 2 , Ar is aromatic Represents a heterocyclic group.
  • the aromatic heterocyclic ring is a bicyclic aromatic heterocyclic group.
  • the bicyclic aromatic heterocyclic group is an unsubstituted or substituted quinolyl group, isoquinolyl group, or benzoimidazolyl group.
  • [5] The compound according to [1], represented by any one of the following chemical formulas 2 to 9.
  • [6] The compound according to any one of [1] to [5], which exhibits antimalarial activity.
  • a method for preventing or treating malaria comprising a step of administering the antimalarial drug according to [7] to a subject.
  • the first aspect of the present invention relates to a novel compound.
  • the compound of the present invention is represented by the following chemical formula (Chemical Formula 1). However, it is an asymmetric structure, m in the formula is 1 to 5, n is 1 to 5, R represents H, CH 3 , CH 2 CH 3 or CH 2 NH 2 , Ar is aromatic Represents a heterocyclic group.
  • the aromatic heterocyclic ring is a bicyclic aromatic heterocyclic group.
  • the bicyclic aromatic heterocyclic group are a quinolyl group, an isoquinolyl group, and a benzimidazolyl group.
  • the quinolyl group, isoquinolyl group or benzoimidazolyl group here may be substituted at one or more positions.
  • the substitution position is not particularly limited. Examples of the substituent include Cl, Br, I, CH 3 , CF 3 , OCH 3 and the like.
  • the substitution can be performed for the purpose of, for example, improving activity, improving solubility (particularly water solubility), reducing toxicity, adjusting metabolic rate, and the like.
  • the compound of the present invention exhibits antimalarial activity.
  • the presence or absence and / or degree of antimalarial activity can be evaluated by the evaluation method described below.
  • the compound of the present invention has a high affinity for heme, and polymerizes heme by ⁇ - ⁇ stacking ability and electrostatic interaction with carboxylate. It is thought to show medicinal properties by inhibiting or promoting conversion to a toxic heme monomer structure.
  • m and n are preferably 1 to 3, more preferably 1 or 2.
  • m and n are preferably 1 to 3, more preferably 1 or 2.
  • Another aspect of the present invention relates to an antimalarial drug containing the compound shown above or a salt thereof as an active ingredient.
  • the salt here is not particularly limited as long as it is pharmaceutically acceptable, and salts (inorganic acid salts) with hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, formic acid, acetic acid, lactic acid, fumaric acid Examples thereof include salts (organic acid salts) with maleic acid, tartaric acid, citric acid and the like. These salts can be prepared by conventional means.
  • the active ingredient can be formulated according to a conventional method.
  • other pharmaceutically acceptable ingredients for example, carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological Saline solution and the like.
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • stabilizer propylene glycol, diethylin sulfite, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • the dosage form for formulation is not particularly limited, and can be prepared as, for example, tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and suppositories.
  • the drug of the present invention thus formulated can be applied to a subject by oral administration or parenteral administration (intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal injection, etc.) depending on the form.
  • parenteral administration intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal injection, etc.
  • the “subject” here is not particularly limited, and includes humans and non-human mammals (including pet animals, domestic animals, laboratory animals.
  • mice Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, Goats, sheep, dogs, cats, chickens, quails, etc.
  • the antimalarial drug of the present invention is applied to humans.
  • the antimalarial drug of the present invention is applied to a malaria infected person, a potential malaria infected person (therapeutic use), or a person who may be infected with malaria (preventive use).
  • the antimalarial drug of the present invention can be used for preventive purposes as well as therapeutic purposes.
  • the content of the active ingredient in the antimalarial drug of the present invention generally varies depending on the dosage form, but is, for example, about 0.001 wt% to about 95 wt% so that a desired dose can be achieved.
  • a method for preventing or treating malaria using the antimalarial drug described above (hereinafter, these two methods are collectively referred to as “therapeutic methods”) is provided.
  • the treatment method of the present invention includes a step of administering the antimalarial drug of the present invention to a living body.
  • the administration route is not particularly limited, and examples thereof include oral, intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, and transmucosal. These administration routes are not mutually exclusive, and two or more arbitrarily selected can be used in combination (for example, intravenous injection or the like is performed simultaneously with oral administration or after a predetermined time has elapsed). In addition, oral administration is preferable because administration is easy.
  • the dose of the antimalarial drug varies depending on the symptom, age of the administration subject, sex, weight, etc., but a person skilled in the art can appropriately set an appropriate dose.
  • the dose can be set so that the amount of active ingredient per day is about 1 mg to about 1000 mg, preferably about 20 mg to 500 mg, for an adult (body weight: about 60 kg).
  • the administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted. In setting the administration schedule, it is possible to consider the condition of the administration subject, the duration of effect of the drug, and the like.
  • falciparum pre-cultured was diluted with non-infected erythrocytes so that the initial infection rate was 0.5 to 1.0%, and 190 ⁇ l was dispensed into a 96-well culture plate. Subsequently, 10 ⁇ l of sample solution (DMSO solution of test compound) was added to each well and cultured for 72 hours, and then the culture plate was frozen. On the next day, after freezing and thawing and color-reacting lactate dehydrogenase released from the protozoa with Malstat reagent, the enzyme activity of the protozoa was colorimetrically determined with a plate reader. The growth inhibition activity (IC 50 value) of the protozoa was calculated from the absorbance of the drug added group and the absorbance of the control group.
  • a drug sensitivity test using a drug-sensitive strain of malaria parasite was performed for each compound by the same method.
  • cytotoxicity (IC 50 value) of each compound was evaluated using human fetal lung-derived normal fibroblast MRC-5, and the toxicity ratio (Selectivity index) between malaria parasite and MRC-5 cells was determined.
  • IC 50 value cytotoxicity of each compound was evaluated using human fetal lung-derived normal fibroblast MRC-5, and the toxicity ratio (Selectivity index) between malaria parasite and MRC-5 cells was determined.
  • the test results are shown in FIG.
  • the novel compound showed particularly high activity against a drug (chloroquine) sensitive strain.
  • IsoQ-2Q, IsoQ-3Q, 2-quino-2Q and 2-quino-3Q showed higher activity than chloroquine against both drug-sensitive and drug-resistant strains.
  • the activity of 2-quino-3Q is much higher and far surpasses that of chloroquine.
  • the compound of the present invention exhibits excellent antimalarial activity.
  • chloroquine-resistant malaria is dealt with by using a combination of antimalarial drugs, the risk of side effects and an increase in drug costs due to the combined use of multiple drugs are problematic.
  • particularly effective compounds exhibit strong activity against chloroquine resistant strains. Therefore, there is a possibility that it can be dealt with by single agent administration, and it can be said that it is advantageous in terms of safety and cost.
  • a mechanism for avoiding heme toxicity similar to malaria is not limited to malaria. It can be expected to be effective against schistosomiasis.
  • the compounds of the present invention may be used as an active ingredient of a reagent for studying the mechanism of avoiding heme toxicity in malaria.

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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)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

　La présente invention vise à fournir un nouveau composé efficace contre la malaria et une application pour celui-ci. La présente invention concerne un groupe de composés asymétriques, synthétisés sur la base d'une conception moléculaire visant à interférer avec le mécanisme d'évitement de la toxicité de l'hème de la malaria.
PCT/JP2015/054491 2014-03-03 2015-02-18 Composé ayant une activité antipaludique et médicament antipaludique WO2015133280A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2016506416A JPWO2015133280A1 (ja) 2014-03-03 2015-02-18 抗マラリア活性化合物及び抗マラリア薬

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014-040616 2014-03-03
JP2014040616 2014-03-03

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WO2015133280A1 true WO2015133280A1 (fr) 2015-09-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114133377A (zh) * 2021-11-25 2022-03-04 江苏海洋大学 一种喹啉-1，2，4-三嗪杂合体、制备方法及其应用

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JPH10501540A (ja) * 1994-06-17 1998-02-10 エフ・ホフマン−ラ ロシュ アーゲー Ｎ，ｎ′−ビス（キノリン−４−イル）ジアミン誘導体、それらの製造方法、及び抗マラリア剤としてのそれらの用途
JPH11500749A (ja) * 1995-11-16 1999-01-19 エフ・ホフマン−ラ ロシュ アーゲー キノリン誘導体
WO2007097450A1 (fr) * 2006-02-27 2007-08-30 Nagoya City University Compose ayant une activite antimalarique et medicament antimalarique le contenant en tant que substance active
US20080262031A1 (en) * 2005-02-04 2008-10-23 Ctg Pharma S.R.L. 4-Aminoquinoline Derivatives as Antimalarials
WO2012032952A1 (fr) * 2010-09-06 2012-03-15 公立大学法人名古屋市立大学 Composé ayant une activité antipaludique et médicament antipaludique
WO2012048894A1 (fr) * 2010-10-14 2012-04-19 Julius-Maximilians-Universität Würzburg Composés hybrides à base de 4- et 8-aminoquinoléines pour la prévention et le traitement de la malaria et d'autres maladies parasitaires
WO2012149186A2 (fr) * 2011-04-29 2012-11-01 The Trustees Of The University Of Pennsylvania Nouveaux composés bisaminoquinoléines, compositions pharmaceutiques préparées à partir de ceux-ci et leur utilisation

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JPH10501540A (ja) * 1994-06-17 1998-02-10 エフ・ホフマン−ラ ロシュ アーゲー Ｎ，ｎ′−ビス（キノリン−４−イル）ジアミン誘導体、それらの製造方法、及び抗マラリア剤としてのそれらの用途
JPH11500749A (ja) * 1995-11-16 1999-01-19 エフ・ホフマン−ラ ロシュ アーゲー キノリン誘導体
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WO2007097450A1 (fr) * 2006-02-27 2007-08-30 Nagoya City University Compose ayant une activite antimalarique et medicament antimalarique le contenant en tant que substance active
WO2012032952A1 (fr) * 2010-09-06 2012-03-15 公立大学法人名古屋市立大学 Composé ayant une activité antipaludique et médicament antipaludique
WO2012048894A1 (fr) * 2010-10-14 2012-04-19 Julius-Maximilians-Universität Würzburg Composés hybrides à base de 4- et 8-aminoquinoléines pour la prévention et le traitement de la malaria et d'autres maladies parasitaires
WO2012149186A2 (fr) * 2011-04-29 2012-11-01 The Trustees Of The University Of Pennsylvania Nouveaux composés bisaminoquinoléines, compositions pharmaceutiques préparées à partir de ceux-ci et leur utilisation

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DATABASE REGISTRY 6 December 2011 (2011-12-06), retrieved from STN Database accession no. 1349611-33-1 *
GIRAULT,S. ET AL.: "Antiplasmodial activity and cytotoxicity of bis-, tris- and tetraquinolines with linear or cyclic amino linkers", J.MED.CHEM., vol. 44, no. 11, 2001, pages 1658 - 1665, XP002730047, ISSN: 0022-2623 *
VENNERSTROM,J.L. ET AL.: "Bisquinolines.2. Antimalarial N,N-bis(7-chloroquinolin-4-yl) heteroalkanediamines", J.MED.CHEM., vol. 41, no. 22, 1998, pages 4360 - 4364, XP055135948, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114133377A (zh) * 2021-11-25 2022-03-04 江苏海洋大学 一种喹啉-1，2，4-三嗪杂合体、制备方法及其应用

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