JPWO2015133280A1 - Antimalarial active compounds and antimalarials - Google Patents

Abstract

It is an object to provide a novel compound effective for malaria and its use. An asymmetric group of compounds synthesized based on molecular design aimed at interfering with the heme toxicity avoidance mechanism of malaria is provided.

Description

  The present invention relates to a novel compound exhibiting antimalarial activity and use thereof. This application claims the priority based on the Japan patent application 2014-040616 for which it applied on March 3, 2014, The whole content of the said patent application is used by reference.

  Malaria is the largest parasitic protozoan infection of mankind that is estimated to infect 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, and the like are used as antimalarial drugs, 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.

  In addition, the research group of the inventors of the present application reported that a compound group designed by paying attention to affinity for heme exhibits antimalarial activity (Patent Documents 1 and 2 and Non-Patent Document 1). On the other hand, Patent Document 3 discloses an N, N′-bis (quinolin-4-yl) diamine derivative as a compound exhibiting antimalarial activity (Patent Document 3). Patent Document 4 discloses a compound that exhibits antimalarial activity against both chloroquine sensitivity and strain resistance in a quinoline skeleton.

International Publication No. 2007/097450 Pamphlet International Publication No. 2012/032952 Pamphlet International Publication No. 95/35287 Pamphlet US Patent Application Publication No. 2008-262031

Chubu Public 3 University New Technology Briefing Material Collection (November 2, 2007), pages 63-67

  An object of the present invention is to provide a compound effective for malaria (that is, a novel compound having high antimalarial activity) and use thereof.

但し、非対称性の構造であり、式中のmは1〜5であり、nは1〜5であり、RはH、CH₃、CH₂CH₃又はCH₂NH₂を表し、Arは芳香族ヘテロ環基を表す。
［２］前記芳香族ヘテロ環基が含窒素芳香族ヘテロ環基である、［１］に記載の化合物。
［３］前記芳香族ヘテロ環が二環芳香族ヘテロ環基である、［２］に記載の化合物。
［４］二環芳香族ヘテロ環基が非置換又は置換のキノリル基、イソキノリル基又はベンゾイミダゾリル基である、［３］に記載の化合物。
［５］以下の化学式２〜９のいずれかで表される、［１］に記載の化合物。

［６］抗マラリア活性を示す、［１］〜［５］のいずれか一項に記載の化合物。
［７］［６］に記載の化合物又はその薬学的に許容可能な塩を有効成分として含有する抗マラリア薬。
［８］［７］に記載の抗マラリア薬を対象に投与するステップを含む、マラリアの予防又は治療方法。
［９］抗マラリア薬を製造するための、［６］に記載の化合物の使用。Under the above problems, the inventors proceeded with research. As a result, they succeeded in finding a novel compound with high antimalarial activity. Among 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.
[1] A compound represented by the following 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.
[2] The compound according to [1], wherein the aromatic heterocyclic group is a nitrogen-containing aromatic heterocyclic group.
[3] The compound according to [2], wherein the aromatic heterocyclic ring is a bicyclic aromatic heterocyclic group.
[4] The compound according to [3], wherein 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.
[7] An antimalarial drug containing the compound according to [6] or a pharmaceutically acceptable salt thereof as an active ingredient.
[8] A method for preventing or treating malaria, comprising a step of administering the antimalarial drug according to [7] to a subject.
[9] Use of the compound according to [6] for producing an antimalarial drug.

Synthesis method of compounds 2Q (n = 2) and 3Q (n = 3). Antimalarial activity of each compound. The antimalarial activity of each compound was compared using a chloroquine (CQ) resistant strain (K1) and a sensitive strain (FCR3). Toxicity was also evaluated comparatively. Hemin protective effect of each compound. The novel compound 2-quino-3Q (■) showed a much higher hemin protecting effect than chloroquine (●) and quinine (+).

但し、非対称性の構造であり、式中のmは1〜5であり、nは1〜5であり、RはH、CH₃、CH₂CH₃又はCH₂NH₂を表し、Arは芳香族ヘテロ環基を表す。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.

In a preferred embodiment, the aromatic heterocyclic ring is a bicyclic aromatic heterocyclic group. Specific examples of 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 compounds of the present invention exhibit antimalarial activity. The presence or absence and / or degree of antimalarial activity can be evaluated by the evaluation method described below. Although not bound by theory, the compound of the present invention has a high affinity for heme, and polymerizes heme by π-π 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.

  Here, considering the pharmacokinetics when used as an active ingredient of a medicine (that is, an antimalarial drug), a low molecular weight compound is preferable, so that the numerical values of m and n are preferably small. Therefore, m and n are preferably 1 to 3, more preferably 1 or 2. Moreover, it is preferable to make m and n equal so that the amine as a linker has symmetry. This design is advantageous for synthesis.

IsoQ-2QSpecific examples of novel compounds provided by the present application are shown below (chemical formulas 2 to 11). In addition, the detail of the synthesis | combining method of the said compound and the result of activity evaluation is mentioned later.

IsoQ-2Q

IsoQ-3Q

IsoQ-3Q

2-quino-2Q

2-quino-2Q

2-quino-3Q

2-quino-3Q

BzIm-2Q

BzIm-2Q

BzIm-3Q

BzIm-3Q

2-(8-Cl)quino-3Q

2- (8-Cl) quino-3Q

2-(8-Cl)quino-2Q

2- (8-Cl) quino-2Q

  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. In the case of formulating, other pharmaceutically acceptable ingredients (for example, carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological Saline solution and the like). As the excipient, lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used. As the disintegrant, starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer. As the emulsifier, gum arabic, sodium alginate, tragacanth and the like can be used. As the suspending agent, glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used. As the soothing agent, benzyl alcohol, chlorobutanol, sorbitol and the like can be used. As the stabilizer, propylene glycol, diethylin sulfite, ascorbic acid or the like can be used. As preservatives, phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used. As 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. The “subject” here is not particularly limited, and includes humans and non-human mammals (including pet animals, domestic animals, laboratory animals. Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, Goats, sheep, dogs, cats, chickens, quails, etc.). Preferably, 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 (prophylactic use). Thus, 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% by weight to about 95% by weight so that a desired dose can be achieved.

  In another aspect of the present invention, a prophylactic method or a therapeutic method for malaria using the above antimalarial drug (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. For example, the dose can be set so that the amount of the 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). As 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.

  A molecular group aimed at interfering with the heme toxicity avoidance mechanism of malaria (considering its affinity with heme) was synthesized, and a compound group in which two large π planes were bound to triamine was synthesized as follows.

1. Synthesis of each compound (1) Preparation of aminoquinoline (FIG. 1)
4,7-Dichloroquinoline and triamines having different carbon chain lengths were used as raw materials, and the mixture was stirred at 70 ° C. without solvent. The mixture was separated and purified by column chromatography, and n = 2 aminoquinoline (2Q) was obtained in a yield of 57%. Similarly, n = 3 aminoquinoline (3Q) was obtained in a yield of 50%.
2Q: ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.37 (d, J = 5.7 Hz 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.9, 2.0 Hz 1H), 6.59 (d, J = 5.7 Hz 1H), 3.53 (t, J = 6.6 Hz, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.89 (t , J = 6.6 Hz, 2H), 2.71 (t, J = 6.2 Hz, 2H), 2.38 (s, 3H). FAB, m / z (NBA) 279 (M + 1) ⁺
3Q: ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.37 (d, J = 5.4 Hz, 1H), 7.85 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 6.28 (d, J = 5.4 Hz), 3.33 (t, J = 6.3 Hz, 2H), 2.91-2.93 (m, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.54 (t, J = 6.3 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.39 (t, J = 7.0 Hz, 2H), 1.86-2.17 (m, 2H), 1.63-1.71 (m, 2H)
FAB, m / z (NBA) 207 (M + 1) ⁺

(2) Synthesis of 2-PYM-2Q
Put 1-methylpyrrolidone (0.25 ml), 2Q (94.3 mg, 0.338 mmol) and 2-chloropyrimidine (80.3 mg, 0.701 mmol) in a sample tube tube, seal it under vacuum and heat at 110 ° C for 5 hours did. After cooling to room temperature, separation and purification were performed by alumina column chromatography (AcOEt: CH ₃ OH = 97: 3), and the solvent was distilled off under reduced pressure to obtain the desired product (8.7 mg, 7.2%). ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.51 (d, J = 5.2 Hz, 1H), δ 8.24 (t, J = 5.6 Hz, 2H), δ 7.93 (d, J = 2.4 Hz, 1H), δ 7.70 (d, J = 8.8 Hz, 1H), δ 7.32 (dd, J = 2.0, 9.0 Hz, 1H), δ 6.50 (t, J = 4.8 Hz, 1H), δ 6.35 (d, J = 5.2 Hz , 1H), δ 3.57 (dd, J = 5.8,11.8 Hz, 2H), δ 3.31 (dd, J = 5.0, 11.4 Hz, 2H), δ 2.82 (t, J = 5.8 Hz, 2H), δ 2.74 ( t, J = 6.2 Hz, 2H), δ 2.37 (s, 3H). FAB, m / z (glycerin) 357 (M + 1) ⁺ , 359 (M + 3) ⁺

(3) Synthesis of 2-Py-2Q
2Q (47.7 mg, 0.172 mmol) and 2-fluoropyridine (29.5 mg, 0.304 mmol) were placed in a sample tube tube, sealed under vacuum and heated at 100 ° C. for 27 hours. After cooling to room temperature, separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 94: 5: 1), and the solvent was distilled off under reduced pressure to obtain the desired product (26.0 mg, 42.6 %). ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.48 (d, J = 5.4 Hz, 1H), δ 8.11 (tt, J = 1.0, 2.4 Hz, 1H), δ 7.12 (d, J = 2.2 Hz, 1H ), δ 7.75 (d, J = 9.0 Hz, 1H), δ 7.38-7.34 (m, 1H), δ 7.24 (dd, J = 2.2, 9.0 Hz, 1H), δ 6.59-6.55 (m, 1H), δ 6.36-6.30 (m, 2H), δ 3.42 (dd, J = 5.3, 11.5 Hz, 2H), δ 3.32-3.27 (m, 2H), δ 2.82 (t, J = 5.8 Hz, 2H) δ 2.74 ( t, J = 5.9 Hz, 2H), δ 2.36 (s, 3H). FAB, m / z (glycerin) 357 (M + 1) ⁺ , 359 (M + 3) ⁺

(4) Synthesis of 3BQ
4,7-Dichloroquinoline (3.00 g, 15.15 mmol) was placed in a 50 ml eggplant flask and dried under vacuum. The mixture was filled with Ar, N-methyl-2,2′-diaminodiethylamine (1.00 g, 6.88 mmol) was added thereto while flowing Ar, and the mixture was heated and stirred at 130 ° C. for 3 hours. After cooling to room temperature, separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ 100%), and the solvent was distilled off under reduced pressure to obtain the desired product (821.6 mg, 25.4%). ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.48 (d, J = 5.4 Hz, 2H), δ 7.95 (d, J = 2.0 Hz, 2H), δ 7.55 (d, J = 9.3 Hz, 2H), δ 7.32 (dd, J = 2.2, 9.0 Hz, 2H), δ 6.27 (d, J = 5.4 Hz, 2H), δ 3.36 (dd, J = 6.2, 10.6 Hz, 4H), δ 2.66 (t, J = 6.6 Hz, 4H), δ 2.46 (s, 3H), δ 1.99 (t, J = 6.4 Hz, 4H). FAB, m / z (glycerin) 469 (M + 1) ⁺ . EI-HRMS Calcd for C ₂₅ H ₂₇ Cl ₂ N ₅ 467.16436, Found 467.16560.

(5) Synthesis of nor-2BQ
Put 4,7-dichloroquinoline (1.52 g, 7.7 mmol), N-Boc-2,2'-diethylamine (2.35 g, 11.6 mmol) and NaHCO ₃ (0.73 g, 8.64 mmol) in a 20 ml eggplant flask. Vacuum dried. After Ar substitution, the mixture was heated and stirred at 100 ° C. for 3 hours. Separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 97.5: 1.5: 1), and the solvent was distilled off under reduced pressure to obtain N-Boc-2BQ (135.7 mg, 3.4%). N-Boc-2BQ (135.7 mg, 0.26 mmol) was placed in a 10 ml eggplant flask and dried under vacuum. After Ar substitution, trifluoroacetic acid (1.4 ml, 18.9 mmol) was added with a syringe and stirred at room temperature for 2.5 hours. . The mixture was shaken with (CH ₂ Cl ₂ : isopropanol = 1: 1) and an aqueous Na ₂ CO ₃ solution, the organic layer was dried over Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure to obtain the desired product. (61.7 mg, 56.1%) ¹ H NMR (CD ₃ OD, 400 MHz), δ 8.30 (d, J = 5.5 Hz, 2H), δ 7.94 (d, J = 9.1 Hz, 2H), δ 7.73 (d, J = 2.2 Hz, 2H), δ 7.27 (dd, J = 2.2, 9.0 Hz, 2H), δ 6.53 (d, J = 5.6 Hz, 2H), δ 3.51 (t, J = 6.0 Hz, 4H), δ 3.02 (t, J = 6.2 Hz, 4H). FAB, m / z (glycerin) 427 (M + 1) ⁺ . FAB-HRMS Calcd for C ₂₂ H ₂₂ N ₅ Cl ₂ 426.12523, (M + 1) ⁺ , Found 426.12510 (M + 1) ⁺ .

(6) Synthesis of IsoQ-2Q
1-Chloroisoquinoline (18.0 mg, 1.10 mmol), 2Q (30.0 mg, 1.08 mmol) and NaHCO ₃ (11.3 mg, 1.35 mmol) were placed in a 5 ml eggplant flask and vacuum dried. Thereto was filled with Ar, 0.2 ml of DMF was added while flowing Ar, and the mixture was heated and stirred at 100 ° C. for 22 hours. After cooling to room temperature, separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 98: 1: 1), and the solvent was distilled off under reduced pressure. Thereafter, separation and purification were performed by GPC. Further, separation and purification were performed by alumina column chromatography, and the solvent was distilled off under reduced pressure to obtain the desired product. (40 mg, 90.8%) ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.48 (d, J = 5.4 Hz, 1H), δ 7.94 (d, J = 5.9 Hz, 1H), δ 7.89 (d, J = 2.1 Hz, 1H), δ 7.65 (d, J = 7.7 Hz, 1H), δ 7.58-7.52 (m, 2H), δ 7.42 (d, J = 8.9 Hz, 1H), δ 7.18-7.14 (m, 1H), δ 6.91 (d, J = 5.8 Hz, 1H), δ 6.86 (dd, J = 2.2, 9.0 Hz, 1H), δ 6.35 (d, J = 5.4 Hz, 1H), δ 3.76 (q, J = 5.6 Hz, 2H), δ 3.63 (q, J = 7.3 Hz, 2H), δ 3.38-3.34 (m, 2H), δ 2.46 (s, 3H), δ 2.91-2.87 (m, 2H). m / z (glycerin) 406 (M) ⁺ . FAB-HRMS Calcd for C ₂₃ H ₂₅ ON ₅ Cl 406.17985 (M + 1) ⁺ , Found 406.17794 (M + 1) ⁺ .

(7) Synthesis of IsoQ-3Q
1-Chloroisoquinoline (101.1 mg, 0.62 mmol), 3Q (154.2 mg, 0.50 mmol) and NaHCO ₃ (50.4 mg, 0.60 mmol) were placed in a 3 ml eggplant flask and vacuum dried. This was filled with Ar, and heated and stirred at 120 ° C. for 22 hours. After cooling to room temperature, separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH = 99.8: 0.2). The solvent was distilled off under reduced pressure to obtain the desired product (104.9 mg, 48.3%). ¹ H NMR (CD ₃ OD, 400 MHz), δ 8.21 (d, J = 4.5 Hz, 1H), δ 7.95 (d, J = 6.7 Hz, 1H), δ 7.92 (d, J = 7.2 Hz, 1H) , δ 7.69 (d, J = 1.7 Hz, 1H), δ 7.67 (d, J = 4.8 Hz, 1H), δ 7.57 (d, J = 6.5 Hz, 1H), δ 7.51 (t, J = 5.7, 8.0 , 1H), δ 7.38 (t, J = 5.7, 3.6 Hz, 1H), δ 7.26 (dd, J = 1.8, 7.2 Hz, 1H), δ 6.78 (d, J = 4.8 Hz, 1H), δ 6.33 ( d, J = 4.5 Hz, 1H), δ 3.51 (t, J = 5.4 Hz, 2H), δ 3.30-3.28 (m, 2H), δ 2.61-2.57 (m, 4H), δ 2.33 (s, 3H) , δ 1.94-1.87 (m, 4H). FAB-HRMS Calcd for C ₂₅ H ₂₉ N ₅ Cl 434.21115 (M + 1) ⁺ , Found 434.21025 (M + 1) ⁺ .

(8) Synthesis of 2-quino-2Q
2-Chloroquinoline (151 mg, 0.92 mmol), 2Q (221 mg, 0.76 mmol) and NaHCO ₃ (86.0 mg, 1.02 mmol) were placed in a 5 ml eggplant flask and dried in vacuo. After Ar substitution, the mixture was stirred with heating at 110 ° C. for 17 hours. Separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 98.7: 0.3: 1), and the solvent was distilled off under reduced pressure to obtain the desired product. (127.7 mg, 41.4%) ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.48 (d, J = 4.9 Hz, 1H), δ 7.92 (d, J = 2.0 Hz, 1H), δ 7.73 (d, J = 8.8 Hz, 1H), δ 7.66-7.50 (m, 4H), δ 7.24-7.20 (m, 1H), δ 7.14 (dd, J = 2.4, 8.8 Hz, 1H), δ 6.46 (d, J = 8.8 Hz, 1H), δ 6.34 (d, J = 5.4 Hz, 1H), δ 3.68-3.59 (m, 2H), δ 3.32 (dd, J = 4.6, 11.0 Hz, 2H), δ 2.86 (t, J = 5.9 Hz, 2H), δ 2.80 (t, J = 6.1 Hz, 2H), δ 2.42 (s, 1H). FAB, m / z (glycerin) 406 (M) ⁺ . FAB-HRMS Calcd for C ₂₃ H ₂₅ N ₅ Cl 406.17985 (M + 1) ⁺ , Found 406.17777 (M + 1) ⁺ .

(9) Synthesis of 2-quino-3Q
2-Chloroquinoline (85.0 mg, 0.52 mmol), 3Q (132.8 mg, 0.43 mmol) and NaHCO ₃ (46.0 mg, 0.052 mmol) were placed in a 3 ml eggplant flask and dried under vacuum. After Ar substitution, the mixture was heated and stirred at 120 ° C. for 24 hours. Separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH = 99.8: 0.2), and the solvent was distilled off under reduced pressure to obtain the desired product (57.4 mg, 30.8%). ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.49 (d, J = 5.3 Hz, 1H), 7.89 (d, J = 2.3, 1H), δ 7.77 (d, J = 9.3 Hz, 1H), δ 7.59 -7.55 (m, 1H), δ 7.51-7.46 (m, 1H), δ 7.20-7.16 (m, 1H), δ 6.52 (d, J = 9.0 Hz, 1H), δ 6.34 (d, J = 5.4 Hz , 1H), δ 3.55-3.52 (m, 2H), δ 3.45-3.43 (m, 2H), δ 2.64-2.59 (m, 4H), δ 2.37 (s, 3H), δ 1.97-1.89 (m, 4H FAB-HRMS Calcd for C ₂₅ H ₂₉ N ₅ Cl 434.21115 (M + 1) ⁺ , Found 434.21213 (M + 1) ⁺ .

(10) Synthesis of BzIm-2Q
2-Chlorobenzimidazole (197 mg, 1.29 mmol), 2Q (300 mg, 1.08 mmol) and NaHCO ₃ (108 mg, 1.29 mmol) were placed in a 5 ml eggplant flask and dried under vacuum. After Ar substitution, the mixture was stirred with heating at 100 ° C. for 21.5 hours. Separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 98: 1: 1), and the solvent was distilled off under reduced pressure to obtain the desired product (174.5 mg, 40.9%). ¹ H NMR (CD ₃ OD, 400 MHz), δ 8.17 (d, J = 5.8 Hz, 1H), δ 7.80 (d, J = 9.3 Hz, 1H), δ 7.61 (d, J = 2.0 Hz, 1H) , δ 7.09 (dd, J = 2.2, 9.1 Hz, 1H), δ 7.06-7.04 (m, 2H), δ 6.87-6.84 (m, 2H), δ 6.37 (d, J = 5.4 Hz, 1H), δ 3.42-3.35 (m, 4H), δ 2.74-2.66 (m, 4H), δ 2.35 (s, 3H). FAB, m / z (glycerin) 397 (M + 2) ⁺ . FAB-HRMS Calcd for C ₂₁ H ₂₄ N ₆ Cl 395.17510 (M + 1) ⁺ , Found 395.17516 (M + 1) ⁺ .

(11) Synthesis of BzIm-3Q
2-Chlorobenzimidazole (78.8 mg, 0.516 mmol), 3Q (131.1 mg, 0.427 mmol) and NaHCO ₃ (43.5 mg, 0.52 mmol) were placed in a 3 ml eggplant flask and vacuum dried. After Ar substitution, the mixture was stirred with heating at 120 ° C. for 20.5 hours. Separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 99: 1), and the solvent was distilled off under reduced pressure to obtain the desired product. (35.9 mg, 19.9%) ¹ H NMR (CD ₃ OD, 400 MHz), δ 8.27 (d, J = 5.8 Hz, 1H), δ 8.01 (d, J = 9.0 Hz, 1H), δ 7.74 (d, J = 2.3 Hz, 1H), δ 7.15 (dd, J = 2.9, 6.0.1 Hz, 1H), δ 7.16-7.14 (m, 2H), δ 6.95-6.93 (m, 2H), δ 6.49 (d, J = 2.4 Hz, 1H), δ 3.41-3.37 (m, 4H), δ 2.66-2.59 (m, 4H), δ 2.36 (s, 3H), δ 1.97 (t, J = 7.1, 6.8 Hz, 2H) , δ 1.87 (t, J = 7.3 Hz, 2H). FAB-HRMS Calcd for C ₂₃ H ₂₈ N ₆ Cl 423.20640 (M + 1) ⁺ , Found 423.20584 (M + 1) ⁺ .

(12) Synthesis of 2- (8-Cl) quino-3Q
2,8-dichloroquinoline (500 mg, 2.52 mmol), 3Q (645 mg, 2.10 mmol) and NaHCO ₃ (230 mg, 2.73 mmol) were placed in a 10 ml eggplant flask and vacuum dried. After Ar substitution, the mixture was stirred with heating at 130 ° C. for 6 hours. Separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 98.8: 0.2: 1), and the solvent was distilled off under reduced pressure to obtain the desired product (750.1 mg, 76.3%). ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.45 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), δ 7.72 (d, J = 6.8 Hz, 1H), δ 7.58 (dd, J = 1.2, 6.0 Hz, 1H), δ 7.49 (d, J = 7.2 Hz, 1H), δ 7.46 (dd, J = 1.0, 6.2 Hz, 1H), δ 7.12 (dd, J = 1.2 , 7.2 Hz, 1H), δ 7.07 (t, J = 6.2 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 6.29 (d, J = 4.4 Hz, 1H), δ 3.55 (q, J = 4.9 Hz, 2H), δ 3.45-3.43 (m, 2H), δ 2.63-2.60 (m, 4H), δ 2.37 (s, 3H), δ 1.98-1.91 (m, 4H).

(13) Synthesis of 2- (8-Cl) quino-2Q
2,8-dichloroquinoline (500 mg, 2.52 mmol), 2Q (585 mg, 2.10 mmol) and NaHCO ₃ (230 mg, 2.73 mmol) were placed in a 10 ml eggplant flask and vacuum dried. After Ar substitution, the mixture was heated and stirred at 130 ° C. for 4.5 hours. Separation and purification were performed by alumina column chromatography (CH ₂ Cl ₂ : CH ₃ OH: triethylamine = 98.8: 0.2: 1). The solvent was distilled off under reduced pressure to obtain the desired product (662.5 mg, 71.6%). ¹ H NMR (CDCl ₃ , 400 MHz), δ 8.41 (d, J = 4.3 Hz, 1H), 7.91 (d, J = 1.7, 1H), δ 7.62 (d, J = 7.1, 1H), δ 7.59 ( dd, J = 1.1, 6.0 Hz, 1H), δ 7.47 (d, J = 7.1, 1H), δ 7.42 (dd, J = 1.0, 6.4 Hz, 1H), δ 7.14 (dd, J = 1.7, 7.1 Hz , 1H), δ 7.08 (t, J = 6.2 Hz, 1H), δ 6.43 (d, J = 7.1 Hz, 1H), 6.27 (d, J = 4.4 Hz, 1H), δ 3.74 (q, J = 4.7 Hz, 2H), δ 3.32 (dd, J = 4.6, 7.9 Hz, 2H), δ 2.91-2.86 (m, 4H), δ 2.45 (s, 3H).

2. Evaluation of synthesized compounds (1) In vitro drug sensitivity test and toxicity evaluation Using a drug-resistant strain (K1 strain) of cultured Plasmodium falciparum, the method of Makler et al. (Makler, M. et al., Am J. Med. Hyg. 48: 739-741, 1993), an in vitro drug sensitivity test was performed. With 10% human plasma containing RPMII640 medium, culture conditions are mixed gas of _{3% 0 2, 4% C0} 2, 93% N 2, was 37 ° C.. First, the pre-cultured P. falciparum was diluted with non-infected erythrocytes so that the initial infection rate was 0.5 to 1.0%, and 190 μl was dispensed into a 96-well culture plate. Subsequently, 10 μl 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.

On the other hand, a drug sensitivity test using a drug-sensitive strain of malaria parasite (FCR3) was performed for each compound by the same method. In addition, 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. For details of the test method, refer to K. Otoguro et al., J. Antibiot., 54: 658-663 (2001).

  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.

(2) Evaluation of hemin protective effect of each compound (inhibition activity of hemin on hydrogen peroxide decomposition reaction) According to a previously reported method (P. Loria, S. Miller, M. Foley and L. Tilley, Biochem. J. 1999, 339, 363-370), and the hemin protective effect of each compound was evaluated. Compound (final concentration: 0, 5, 10, 30, 50, 100 μM) and BSA (final concentration: 0.8 mg / mL) are added to a solution of hemin (final concentration: 15 μM) in acetate buffer (160 mM, pH 5.2) After shaking at 20 ° C. for 1 hour, hydrogen peroxide (final concentration: 20 mM) was added and shaken, and the absorbance change over time (405 nm) of hemin was measured with an ultraviolet-visible absorption spectrometer. Measurement was performed three times, and the average value of the inhibition rate ((each absorbance-PC) / (NC-PC)) was obtained and plotted (FIG. 3. PC: absorbance at sample concentration 0, NC: sample concentration 0 · H ₂ Absorbance without O ₂ ). The new compound 2-quino-3Q showed the highest inhibition rate. This result suggests the mechanism of action of the new compound and confirms the validity of the strategy (design based on affinity with heme) adopted in the synthesis of the new compound.

  The compounds of the present invention exhibit excellent antimalarial activity. Conventionally, since 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. Among the compounds provided by the present invention, 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, which can be said to be advantageous in terms of safety and cost. On the other hand, considering the assumed mechanism of action of the compound of the present invention (inhibition of heme polymerization by π-π stacking ability and electrostatic interaction with carboxylate), a mechanism for avoiding heme toxicity similar to malaria is not limited to malaria. It can be expected to be effective against schistosomiasis. It is also envisaged that 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.

  The present invention is not limited to the description of the embodiments and examples of the invention described above. Various modifications may be included in the present invention as long as those skilled in the art can easily conceive without departing from the description of the scope of claims. The contents of papers, published patent gazettes, patent gazettes, and the like specified in this specification are incorporated by reference in their entirety.

Claims (9)

A compound represented by the following 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 compound according to claim 1, wherein the aromatic heterocyclic group is a nitrogen-containing aromatic heterocyclic group.   The compound according to claim 2, wherein the aromatic heterocyclic ring is a bicyclic aromatic heterocyclic group.   4. The compound according to claim 3, wherein the bicyclic aromatic heterocyclic group is an unsubstituted or substituted quinolyl group, isoquinolyl group or benzoimidazolyl group. The compound of Claim 1 represented by either of the following chemical formulas 2-9.

  6. A compound according to any one of claims 1 to 5 exhibiting antimalarial activity.   An antimalarial drug comprising the compound according to claim 6 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 claim 7 to a subject.   Use of a compound according to claim 6 for the manufacture of an antimalarial drug.

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