WO2012032952A1 - 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
WO2012032952A1
WO2012032952A1 PCT/JP2011/069392 JP2011069392W WO2012032952A1 WO 2012032952 A1 WO2012032952 A1 WO 2012032952A1 JP 2011069392 W JP2011069392 W JP 2011069392W WO 2012032952 A1 WO2012032952 A1 WO 2012032952A1
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Prior art keywords
antimalarial
chemical formula
drug
compound according
active compound
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PCT/JP2011/069392
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English (en)
Japanese (ja)
Inventor
恒彦 樋口
直樹 梅澤
信樹 加藤
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公立大学法人名古屋市立大学
株式会社セラバリューズ
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Publication of WO2012032952A1 publication Critical patent/WO2012032952A1/fr

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    • 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
    • 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
    • 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 an antimalarial active compound and use thereof.
  • This application claims priority based on Japanese Patent Application No. 2010-198651 filed on Sep. 6, 2010, 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. Chloroquine is often used as a first-line drug for the prevention and treatment of malaria because it has fewer side effects than other drugs, 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 Document 1 discloses an N, N′-bis (quinolin-4-yl) diamine derivative as a compound exhibiting antimalarial activity (Patent Document 2).
  • An object of the present invention is to provide a compound having high antimalarial activity, particularly a compound effective against drug-resistant malaria and its use.
  • the present inventor has advanced research to solve the above-mentioned problems. As a result, the present inventors have found a compound having excellent antimalarial activity and exhibiting activity against chloroquine resistant malaria strains. The antimalarial activity of the compound exceeded that of existing malaria drugs. In addition, notably, the compound showed a tremendous therapeutic effect that dramatically improved the survival rate of mice infected with malaria parasites (infection model).
  • the following inventions are provided mainly based on the above findings.
  • Antimalarial active compound represented by the following chemical formula 1 However, m in the formula is 1 ⁇ 5, n is 1 ⁇ 5, R1 represents an unsubstituted or substituted quinolinyl group, R2 denotes H, a CH 3 or CH 2 NH 2, R3 is less Represented by Chemical Formula 2 or 3; However, R4 in the formula is a cyclic group in which two or more rings are condensed. [2] The antimalarial active compound according to [1], wherein R4 in chemical formulas 2 and 3 is an aromatic group. [3] The antimalarial active compound according to [1], wherein R4 in chemical formulas 2 and 3 is an aromatic group in which two rings are condensed.
  • R5 and R6 in the formula is H, Cl, CH 3 or CF 3 independently of one another.
  • the antimalarial compound according to [8], wherein R1 in the chemical formula 1 is represented by any one of the following chemical formulas 8 to 11.
  • An antimalarial drug comprising the antimalarial active compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a method for preventing or treating malaria comprising a step of administering the antimalarial drug according to [10] to a subject.
  • Use of the antimalarial active compound according to any one of [1] to [9] for producing an antimalarial drug comprising a step of administering the antimalarial drug according to [10] to a subject.
  • sc subcutaneous administration
  • po oral administration
  • sc subcutaneous administration
  • po oral administration.
  • sc subcutaneous administration, po: oral administration.
  • the first aspect of the invention relates to antimalarial active compounds.
  • the antimalarial active compound of the present invention is represented by the following chemical formula (Chemical Formula 1).
  • m is 1 to 5
  • n is 1 to 5
  • R1 represents an unsubstituted or substituted quinolinyl group.
  • R2 represents H, a CH 3 or CH 2 NH 2.
  • R3 is represented by the following chemical formula (Chemical Formula 2 or 3).
  • a compound represented by Chemical Formula 3 is preferable.
  • R4 is a cyclic group in which two or more rings are condensed.
  • substitution position when R1 is substituted is not particularly limited. It may be substituted at two or more positions.
  • substituents include Cl, Br, I, CH 3 , CF 3 , OCH 3 and the like.
  • the substitution is performed, for example, for the purpose of improving activity, improving solubility (particularly water solubility), reducing toxicity, adjusting metabolic rate, and the like.
  • 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.
  • R4 in Formulas 2 and 3 is an aromatic group.
  • aromatic groups an aromatic group in which two or three rings are condensed is preferable, and an unsubstituted or substituted naphthyl group, anthryl group, phenanthryl group, or quinolinyl group is particularly preferable. The reason is that since it has a large ⁇ -electron conjugated system, the interaction with hem having a large ⁇ -electron conjugated system is also strong.
  • R4 is an aromatic group in which two rings are condensed (for example, a naphthyl group or a quinolinyl group).
  • the substitution position in the case of substitution is not particularly limited. It may be substituted at two or more positions.
  • R3 is represented by any of the following chemical formulas 4-6.
  • R1 in Chemical Formula 1 is represented by the following Chemical Formula 7.
  • R5 and R6 in the formula is H, Cl, CH 3 or CF 3 independently of one another.
  • R1 Specific examples of R1 are shown below (chemical formulas 8 to 11).
  • R 1 in Chemical Formula 1 is represented by the following Chemical Formula 12.
  • R6 and R7 in the formula is H, Cl, CH 3 or CF 3 independently of one another.
  • an antimalarial drug comprising the above-described antimalarial active compound or a salt thereof as an active ingredient.
  • the salt here is not particularly limited as long as it is pharmaceutically acceptable, and is a salt (inorganic acid salt) 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.
  • Naph-2Q showed high activity against drug-sensitive and drug-resistant strains.
  • the activity of Naph-2Q is higher than that of chloroquine and is particularly effective against drug resistant strains (FIGS. 3 and 4).
  • Naph-2Q has relatively low toxicity (FIG. 3).
  • ac-quino-2Q also showed good activity and was particularly effective against drug-resistant strains.
  • the structure of the compound used for the comparison is shown below.
  • mice (5 mice / group, number of infected protozoa: 2 ⁇ 10 6 ) intravenously inoculated with erythrocytes infected with murine malaria parasite (P. berghei N, drug-sensitive strain) were treated with 10% DMSO for 3 days.
  • the test compound dissolved in was administered subcutaneously or orally (once / day).
  • the control group received 10% DMSO.
  • the blood was collected from the tail vein the day after the last day of administration, the protozoa-infected erythrocyte rate (parasitaemia) was examined, and ED 50 and ED 90 values were calculated. Moreover, the state of the mouse was observed over time, and the number of days of survival was recorded.
  • Naph-2Q exerted an extremely high therapeutic effect by subcutaneous administration (FIGS. 5 to 7).
  • the therapeutic effect of Naph-2Q surpassed the therapeutic effect of the most effective antimalarial drug Artesunate (Artesunate) (FIG. 5).
  • Artesunate the most effective antimalarial drug Artesunate
  • FIG. 6 the subcutaneous administration of Naph-2Q dramatically improved the survival rate (FIGS. 6 and 7).
  • Naph-2Q is an excellent compound in that it has a relatively low toxicity to human cells.
  • the compound of the present invention has high affinity for heme and exhibits excellent antimalarial activity.
  • the compounds of the present invention are also effective against drug resistant malaria.
  • An antimalarial drug containing the compound of the present invention as an active ingredient can exert a high preventive and therapeutic effect against malaria infection. This antimalarial drug is expected to be applied particularly to malaria that is resistant to existing antimalarial drugs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (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)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

La présente invention a pour objet : un composé qui a une activité antipaludique élevée, en particulier un composé qui est efficace contre le paludisme chimio-résistant ; et l'utilisation du composé. L'invention porte sur un composé ayant une activité antipaludique qui est représenté par la formule chimique AA. Dans la formule chimique AA, m représente un nombre valant 1-5 ; n représente un nombre valant 1-5 ; R1 représente un groupe quinolinyle non substitué ou substitué ; et R2 représente H, CH3 ou CH2NH2.
PCT/JP2011/069392 2010-09-06 2011-08-29 Composé ayant une activité antipaludique et médicament antipaludique WO2012032952A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010198651A JP2013237614A (ja) 2010-09-06 2010-09-06 抗マラリア活性化合物及び抗マラリア薬
JP2010-198651 2010-09-06

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WO2012032952A1 true WO2012032952A1 (fr) 2012-03-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015133280A1 (fr) * 2014-03-03 2015-09-11 公立大学法人名古屋市立大学 Composé ayant une activité antipaludique et médicament antipaludique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2009148659A2 (fr) * 2008-03-05 2009-12-10 Georgetown University Quinoléines antipaludiques et leurs procédés d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2009148659A2 (fr) * 2008-03-05 2009-12-10 Georgetown University Quinoléines antipaludiques et leurs procédés d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KOSUKE YABUNAKA: "Kagaku Shinkateki Gosei Kagaku ni yoru Ko Malaria Yaku o Mezashita Ko Heme Shinwasei Kagobutsu no Kaihatsu", DAI 27 KAI ABSTRACTS OF SYMPOSIUM ON MEDICINAL CHEMISTRY, 10 November 2008 (2008-11-10), pages 316 - 317 *
TSUNEHIKO HIGUCHI: "Heme o Hyoteki to suru Atarashii Ko Malaria Kassei Kagobutsu no Kaihatsu", CHUBU KORITSU 3 DAIGAKU SHIN GIJUTSU SETSUMEIKAI, 2 November 2007 (2007-11-02), pages 12 - 14, Retrieved from the Internet <URL:http://www.jstshingi.jp/abst/p/07/15/chubu7.pdf> [retrieved on 20110920] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015133280A1 (fr) * 2014-03-03 2015-09-11 公立大学法人名古屋市立大学 Composé ayant une activité antipaludique et médicament antipaludique

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