WO2020179902A1 - Inhibiteur de croissance du parasite responsable du paludisme - Google Patents

Inhibiteur de croissance du parasite responsable du paludisme Download PDF

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Publication number
WO2020179902A1
WO2020179902A1 PCT/JP2020/009614 JP2020009614W WO2020179902A1 WO 2020179902 A1 WO2020179902 A1 WO 2020179902A1 JP 2020009614 W JP2020009614 W JP 2020009614W WO 2020179902 A1 WO2020179902 A1 WO 2020179902A1
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Prior art keywords
malaria
growth inhibitor
growth
dif
malaria parasite
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PCT/JP2020/009614
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English (en)
Japanese (ja)
Inventor
敏宏 美田
禅 久保原
晴久 菊地
大島　吉輝
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Juntendo Educational Foundation
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Juntendo Educational Foundation
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Priority to JP2021503662A priority Critical patent/JP7565603B2/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • 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
    • 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 growth inhibitor of malaria parasite and a pharmaceutical composition containing the growth inhibitor as an active ingredient.
  • Malaria is one of the three major infectious diseases in the world and is a parasitic disease caused by the malaria parasite. It is a typical mosquito-borne infection and is transmitted by the blood-sucking of Anopheles mosquito. There are five species of malaria parasites that infect humans, but the most severe and deadly Plasmodium falciparum, such as cerebral malaria, is the most widely distributed in the world, especially in Africa. Malaria parasites are bihostic to humans and mosquitoes, with the liver and erythrocytes as parasites in humans. It adapts to each environment by changing its morphology and metabolism even within the host and parasitic sites. In particular, parasites in erythrocytes (blood-type protozoa) are closely related to the pathophysiology of malaria, and drugs that selectively inhibit the growth and proliferation of blood-type protozoa can be expected to have a large therapeutic effect.
  • the current first-line drug is an artemisininin combination therapy in which one of lumefantrine, mefloquine, piperakin, amodiakin, and fancidal is added to an artemisinin derivative. With this treatment, the protozoa disappears quickly and the symptoms caused by malaria recover.
  • Artemisinin combination therapy is currently being introduced as a first-line treatment in all endemic countries, including Africa, and its effects have led to a decline in malaria deaths since the mid-2000s.
  • DIF-1 Differentiation-inducing factor-1
  • Non-Patent Documents 1 and 2 DIF-3 isolated at the same time has low differentiation-inducing activity and is known to be a degradation product of DIF-1 (Non-Patent Documents 3, 4, and 5).
  • DIF-1 and DIF-3 are originally the differentiation-inducing factors of slime molds that induce the stalk cell differentiation of the slime molds themselves, and the compounds isolated as their degradation products.
  • DIF-1, DIF-3 (hereinafter, these may be collectively referred to as DIF compounds) and their derivatives (hereinafter, may be referred to as DIF derivatives) have tumor cell growth inhibitory activity and glucose metabolism promotion in mammalian cells. It was discovered that it has activity, interleukin-2 production control activity, growth inhibitory activity against tripanosoma protozoa, and antibacterial activity (Patent Documents 1 to 6).
  • JP, 2006-340615 A Japanese Unexamined Patent Publication No. 2006-290810 WO/2010/128663 JP, 2010-180160, A JP 2012-25671 A JP, 2016-37456, A
  • An object of the present invention is to provide an agent for suppressing the growth of malaria parasite.
  • the present inventors have conducted diligent studies to solve the above problems. That is, the effects of DIF compounds and various DIF derivatives on the growth of malaria standard culture strains and wild strains were examined, and it was found that the DIF compounds and DIF derivatives strongly inhibit the growth of malaria standard culture strains and wild strains in vitro. As a result, it was found that a growth inhibitor satisfying the above-mentioned problems was achieved, and the present invention was completed.
  • a growth inhibitor for malaria parasite which comprises a compound represented by the following general formula (I) or (II) or a salt thereof.
  • R 1 represents hydrogen, an alkyl group having 1 to 10 carbon atoms or a phenyl group
  • R 2 represents hydrogen or an alkyl group having 1 to 10 carbon atoms
  • X 1 represents hydrogen or halogen.
  • R 1 represents hydrogen, an alkyl group having 1 to 10 carbon atoms or a phenyl group
  • R 2 represents hydrogen or an alkyl group having 1 to 10 carbon atoms
  • X 1 represents hydrogen or halogen.
  • X 2 represents halogen.
  • a pharmaceutical composition for suppressing the growth of malaria parasite which contains the growth inhibitor according to any one of [1] to [4].
  • the compound represented by the formula (I) or (II) can be suitably used as a growth inhibitor against malaria parasite.
  • the figure which shows the effect of DIF-1 (+2) on a mouse infected with Plasmodium berghei dose 30 mg / kg.
  • the figure which shows the effect of DIF-1 (+2) on the Plasmodium berghei infected mouse dose 30mg / kg or 50mg / kg).
  • the present invention is a compound represented by the following general formula (I) or (II) (hereinafter, may be referred to as a compound of formula (I) or a compound of formula (II)) or a salt thereof. Consists of a malaria parasite growth inhibitor consisting of.
  • R 1 represents hydrogen, an alkyl group having 1 to 10 carbon atoms or a phenyl group
  • R 2 represents hydrogen or an alkyl group having 1 to 10 carbon atoms
  • X 1 represents hydrogen or halogen.
  • R 1 represents hydrogen, a linear, branched or cyclic alkyl group or phenyl group having 1 to 10 carbon atoms, and is preferably 1 to 5 carbon atoms.
  • R 2 represents a hydrocarbon, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, preferably 5 to 10 carbon atoms, and more preferably 5 to 7 carbon atoms.
  • X 1 represents hydrogen or halogen. Examples of the halogen include chlorine (Cl), bromine (Br), iodine (I) and the like, and Cl is preferable.
  • R 1 represents hydrogen, an alkyl group having 1 to 10 carbon atoms or a phenyl group
  • R 2 represents hydrogen or an alkyl group having 1 to 10 carbon atoms
  • X 1 represents hydrogen or halogen.
  • X 2 represents halogen.
  • R 1 represents hydrogen, a linear, branched or cyclic alkyl group or phenyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. It is more preferably 1 to 2 carbon atoms, and even more preferably 1 carbon atom.
  • R 2 represents hydrogen or a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, preferably 5 to 10 carbon atoms, and more preferably 5 to 7 carbon atoms.
  • X 1 indicates hydrogen or halogen
  • X 2 indicates halogen.
  • the halogen include chlorine (Cl), bromine (Br), iodine (I) and the like, and Cl is preferable. More preferably, X 1 and X 2 are chlorine (Cl).
  • the compound of the above formula (I) or (II) can be synthesized by the method described in, for example, Biochem. Pharmacol. 2005, 70, 676-685.
  • the compound of formula (I) or (II) or a salt thereof has an effect of inhibiting the growth of malaria parasite. Therefore, it can be used as an active ingredient of a malaria parasite growth inhibitor, an active ingredient of a pharmaceutical composition for suppressing the growth of malaria parasite, an experimental reagent, daily necessities and the like.
  • the pharmaceutical composition for suppressing the growth of malaria parasite includes not only a drug that cures the symptom caused by the malaria parasite, but also a drug that improves the symptom and a drug that prevents the symptom from appearing.
  • Examples of the malaria parasite in the present invention include malaria parasites (Plasmodium genus parasites) that infect primates and rodents.
  • malaria parasites that infect humans belonging to primates include Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale. ), Preferably Plasmodium falciparum.
  • a malaria parasite that infects monkeys belonging to primates for example, there is a vivax malaria parasite (Plasmodium knowlesi).
  • examples of malaria parasites that infect rodents include Plasmodium berghei and Plasmodium vinckei
  • examples of malaria parasites that infect rodent rats include , Plasmodium berghei, Plasmodium chabaudi, Plasmodium yoelii.
  • a pharmaceutically acceptable salt can be used, and examples thereof include metal salts such as sodium, potassium, magnesium and calcium, and ammonium salts.
  • the compound of the formula (I) or (II) may be a hydrate.
  • the "malaria parasite growth inhibitor” includes an agent that reduces the number of malaria parasites, an agent that suppresses an increase (proliferation) in the number of malaria parasites, an agent that inactivates malaria parasites, and the like.
  • "inactivating the malaria parasite” includes reducing or suppressing the ability of the malaria parasite to regenerate, and examples of the means for inactivating the malaria parasite include killing.
  • the malaria parasite growth inhibitor of the present invention can also be used in combination with a malaria parasite growth inhibitor other than the compound of formula (I) or (II) or a salt thereof.
  • the present invention relates to a pharmaceutical composition containing a growth inhibitor of malaria parasite, which comprises a compound of formula (I) or (II) or a salt thereof.
  • the "malaria parasite growth inhibitor" of the present invention can be used as a pharmaceutical composition for suppressing the growth of malaria parasite, or a pharmaceutical composition used for the prevention and / or treatment of malaria.
  • the subject to which the pharmaceutical composition of the present invention is administered is an animal infected with malaria or an animal developing malaria.
  • animals are, for example, animals belonging to primates, animals belonging to rodents, specific examples of animals belonging to primates are humans, chimpanzees, monkeys, and specific examples of animals belonging to rodents are. It's a mouse.
  • the administration subject can be prophylactically administered to animals that may be infected with malaria, in addition to the animals that have been infected with or have developed malaria as described above.
  • a pharmaceutical composition containing a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is prepared according to a known means generally used in a method for producing a pharmaceutical preparation.
  • the pharmaceutically acceptable salt can be used as is or mixed with a pharmacologically acceptable carrier to form, for example, tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules, (soft capsules).
  • a pharmacologically acceptable carrier to form, for example, tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules, (soft capsules).
  • pharmaceutical preparations such as liquid preparations, injections, suppositories, sustained-release preparations, etc., they can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.).
  • Pharmacologically acceptable carriers include, for example, excipients, lubricants, binders and disintegrants in solid formulations, or solvents, solubilizers, suspending agents, isotonic agents, buffers in liquid formulations. Agents and soothing agents. Further, if necessary, an appropriate amount of additives such as ordinary preservatives, antioxidants, colorants, sweeteners, adsorbents, and wetting agents can be used.
  • the excipient include lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid and the like.
  • the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like.
  • disintegrant examples include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • the suspending agent for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc .; for example, polyvinyl alcohol, polyvinylpyrrolidone, etc.
  • hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
  • examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates and citrates.
  • the pain-relieving agent include benzyl alcohol and the like.
  • preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the pharmaceutical composition of the present invention may be used in combination with other drugs.
  • the content of the compound of formula (I) or (II) or a salt thereof in the pharmaceutical composition is about 0.01 to about 100% by weight of the whole preparation.
  • the dose of the compound of formula (I) or (II) or a salt thereof varies depending on the administration target, the target organ, the symptom, the administration method, and the like, and is not particularly limited. It is about 0.1 to 5 g, preferably about 0.1 to 1 g, and more preferably about 0.1 to 0.5 g per day.
  • Example 1 Evaluation of growth inhibitory effect of DIF compound and DIF derivative (culture strain used) Four malaria parasite standard cultures were selected based on their susceptibility to chloroquine, which was once the first-line therapeutic agent, and artemisinin, which is currently used as the therapeutic agent, and the protozoa from the Malaria Research and Reference Reagent Resource (MR4). Strains were obtained (Table 1). Two types of resistant strains were used to examine the effect on artemisinin-resistant protozoa in detail. IPC3445 and IPC5202 differ in mutations in the Kelch 13 gene involved in artemisinin resistance. IPC3445 is mutated to C580Y and IPC5202 is mutated to Q539T. Both mutations have been verified to be highly associated with artemisinin resistance in clinical specimens by genome-wide association studies and transfection. C580Y is the most resistant type in endemic areas.
  • the medium used was RPMI 1640 (GIBCO), Hypoxanthine with Gentamicin Reagent Solution (GIBCO), Sodium Bicarbonate Solution, AlbuMAX I (GIBCO), and standard Malaria Complete medium (MCM) containing deactivated serum (acquired from the Japanese Red Cross Society). ..
  • the number of protozoa was measured by the ELISA method for HRP-2, which is a malaria-specific antigen.
  • HRP-2 As positive controls, existing antimalaria drugs chloroquine and quinine were used. Chloroquine and quinine were dissolved in methanol.
  • the IC 50 value was determined using the Sigmoid Emax method. The results are shown in Table 2.
  • DIF-1 (+2) showed significantly less an IC 50 value as compared to 0.50 ⁇ 1.20 ⁇ M and other compounds. This value is 1 to 2 orders of magnitude higher than that of existing antimalaria drugs such as chloroquine and quinine, but it satisfies 1 to 2 ⁇ M, which is a guideline for selecting lead compounds as antimalaria drugs.
  • IPC3445 and IPC5202 were artemisinin-resistant culture strains, and DIF-1 (+2) showed almost the same proliferative effect on artemisinin-resistant strains as the susceptible strains.
  • Example 2 Evaluation of growth inhibitory effect of DIF-1 (+2) on wild Plasmodium falciparum strain DIF-1 (+2) on wild Plasmodium falciparum strain directly obtained from malaria patients (47 persons) in the Republic of Kenya The antimalaria effect of +2) was verified in an in-vitro drug resistance assay system as in Example 1.
  • the Republic of Kenya is a highly endemic country of malaria located in East Africa.
  • the average age of the patients was 3.7 years and the average erythroid protozoal infection rate was 2.4%.
  • the results are shown in Figure 1.
  • the average value IC 50 values of patients infected protozoa are 0.50MyuM, it showed comparable growth inhibition in the case of using cultures.
  • the present invention is useful in fields such as medicine.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention aborde le problème de la fourniture d'un inhibiteur de croissance du parasite responsable du paludisme, et résout le problème en fournissant un inhibiteur de croissance du parasite responsable du paludisme comprenant un composé représenté par la formule générale (I) ou (II), ou un sel associé. Dans la formule (I), R1 représente un atome d'hydrogène, un groupe alkyle en C1 à C10 ou un groupe phényle; R2 représente un atome d'hydrogène ou un groupe alkyle en C1 à C10; et X1 représente un atome d'hydrogène ou un atome d'halogène. Dans la formule (II), R1 représente un atome d'hydrogène, un groupe alkyle en C1 à C10 ou un groupe phényle; R2 représente un atome d'hydrogène ou un groupe alkyle en C1 à C10; X1 représente un atome d'hydrogène ou un atome d'halogène; et X2 représente un atome d'halogène.
PCT/JP2020/009614 2019-03-06 2020-03-06 Inhibiteur de croissance du parasite responsable du paludisme Ceased WO2020179902A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022152709A (ja) * 2021-03-29 2022-10-12 学校法人順天堂 マラリア予防治療薬

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012025671A (ja) * 2010-07-20 2012-02-09 Gunma Univ 抗トリパノソーマ剤およびトリパノソーマ症治療薬
JP2013537184A (ja) * 2010-09-10 2013-09-30 ヘルパービー セラピューティクス リミテッド 新規な使用
JP2016037456A (ja) * 2014-08-06 2016-03-22 国立大学法人群馬大学 抗菌剤
WO2020024060A1 (fr) * 2018-08-01 2020-02-06 Mcmaster University Méthodes d'inhibition de la croissance microbienne

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012025671A (ja) * 2010-07-20 2012-02-09 Gunma Univ 抗トリパノソーマ剤およびトリパノソーマ症治療薬
JP2013537184A (ja) * 2010-09-10 2013-09-30 ヘルパービー セラピューティクス リミテッド 新規な使用
JP2016037456A (ja) * 2014-08-06 2016-03-22 国立大学法人群馬大学 抗菌剤
WO2020024060A1 (fr) * 2018-08-01 2020-02-06 Mcmaster University Méthodes d'inhibition de la croissance microbienne

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EATON, L. ALEXANDER ET AL.: "Synthesis and Antimalarial Activity of Mallatojaponin C and Related Compounds", JOURNAL OF NATURAL PRODUCTS, vol. 79, no. 6, 2016, pages 1679 - 1683, XP055736932 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022152709A (ja) * 2021-03-29 2022-10-12 学校法人順天堂 マラリア予防治療薬
JP7742093B2 (ja) 2021-03-29 2025-09-19 学校法人順天堂 マラリア予防治療薬

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JPWO2020179902A1 (fr) 2020-09-10

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