WO2024172001A1 - Anti-trypanosomal drug - Google Patents
Anti-trypanosomal drug Download PDFInfo
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- WO2024172001A1 WO2024172001A1 PCT/JP2024/004697 JP2024004697W WO2024172001A1 WO 2024172001 A1 WO2024172001 A1 WO 2024172001A1 JP 2024004697 W JP2024004697 W JP 2024004697W WO 2024172001 A1 WO2024172001 A1 WO 2024172001A1
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- 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
Definitions
- the present invention relates to a novel antitrypanosomal drug that is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
- N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide and N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide are known to be useful in preventing or improving various diseases and to be useful as various preparations (see Patent Documents 1 to 22 and Non-Patent Documents 1 to 5).
- N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide and N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide were useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
- the present invention aims to provide a novel antitrypanosomal drug that is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
- N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide known as a prodrug of N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide, is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa, and thus completed the present invention.
- the present invention relates to an antitrypanosomal drug that contains N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide or a pharmacologically acceptable salt thereof, or N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide as an active ingredient.
- the present invention provides a novel antitrypanosomal drug that is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
- the antitrypanosomal drug of the present invention contains, as an active ingredient, N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide or a pharmacologically acceptable salt thereof, or N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide (hereinafter, these compounds are simply referred to as "compounds of the present invention").
- antitrypanosomiasis refers to drugs (particularly pharmaceuticals) that are useful for preventing or ameliorating diseases caused by infection with protozoa of the Trypanosomatidae family.
- diseases include, but are not limited to, Chagas disease caused by infection with the protozoa Trypanosoma cruzi and sleeping sickness caused by infection with the protozoa Trypanosoma brucei.
- Amelioration of the disease does not only mean curing the symptoms of the disease, but also means improving the symptoms, inhibiting the progression of the symptoms, preventing the symptoms from appearing, and reducing the number of protozoa that cause the disease.
- the antitrypanosomal drug of the present invention is useful not only for humans who are at high risk of developing the above diseases or who have developed the above diseases, but also for animals other than humans, such as cows, horses, pigs, goats, sheep, mules, chickens, ducks, geese, turkeys, quails, mice, rats, guinea pigs, dogs, monkeys, and cats.
- N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide and N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide can be produced, for example, based on the methods described in U.S. Patent Application Publication No. 2004/0259877 and U.S. Patent Application Publication No. 2006/0094718.
- Pharmacologically acceptable salts of N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide can be produced by methods commonly used in the art.
- salts include metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts such as ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, and dicyclohexylammonium salts; and the like.
- the antitrypanosomal drug of the present invention may be used in combination with, for example, benznidazole, nifurtimox, etc. When used in combination, these may be administered together or separately to animals at high risk of developing the above-mentioned diseases or animals that have developed the above-mentioned diseases.
- the antitrypanosomal drug of the present invention may consist of only the compound of the present invention, but may also be a composition further containing one or more additives.
- the additives that can be used include, for example, existing additives such as excipients, binders, lubricants, disintegrants, flavorings, solvents, stabilizers, bases, wetting agents, preservatives, buffers, and osmotic pressure regulators.
- the antitrypanosomal drug of the present invention may be in any dosage form, such as tablets, capsules, granules, powders, liquids, fine granules, powders, syrups, injections, liniments, sprays, patches, suppositories, etc.
- the antitrypanosomal drug of the present invention may be administered by any method, such as oral administration or parenteral administration, such as intravenous administration.
- the antitrypanosomal drug of the present invention may be administered to a subject in a required amount all at once, intermittently, or continuously.
- An example of a method of continuous administration is intravenous administration.
- Subjects of administration include the animals listed above.
- the amount of the compound of the present invention administered as an antitrypanosomal drug of the present invention varies depending on the subject (e.g., body weight, age, etc.), symptoms, administration method, etc., but is usually 0.0001 to 10 g per administration.
- qPCR For qPCR, a probe (SEQ ID NO: 1: 5'-TTGGTGTCCAGTGTGTG-3') and primers (SEQ ID NO: 2: 5'-ASTCGGCTGATCGTTTTCGA-3', SEQ ID NO: 3: 5'-AATTCCTCCAAGCAGCGGATA-3') targeting Trypanosoma cruzi satellite DNA were used. qPCR was performed under the following conditions. After holding at 95°C for 20 seconds, 60 cycles of 95°C x 1 second ⁇ 60°C x 20 seconds were performed. As a result, it was revealed that the amount of protozoa in the heart tissue was reduced by more than half in the compound administration group compared to the control group.
- left ventricular posterior wall thickness (LVPW;d, LVPW;s) was measured by cardiac ultrasound (echocardiography). As a result, it was found that the thinning of the left ventricular posterior wall observed in the control group due to protozoan infection was significantly suppressed in the compound-administered group.
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Abstract
Description
本発明は、トリパノソーマ科原虫の感染に起因する疾患の予防又は改善に有用な新規抗トリパノソーマ薬に関する。 The present invention relates to a novel antitrypanosomal drug that is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
Ｎ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－ヒドロキシベンズアミド及びＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミドは、様々な疾患の予防又は改善に有用であり、また、様々な製剤として有用であることが知られている（特許文献１～２２及び非特許文献１～５を参照）。 N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide and N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide are known to be useful in preventing or improving various diseases and to be useful as various preparations (see Patent Documents 1 to 22 and Non-Patent Documents 1 to 5).
しかしながら、Ｎ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－ヒドロキシベンズアミド及びＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミドが、トリパノソーマ科原虫の感染に起因する疾患の予防又は改善に有用であることは知られていなかった。 However, it was not known that N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide and N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide were useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
本発明は、トリパノソーマ科原虫の感染に起因する疾患の予防又は改善に有用な新規抗トリパノソーマ薬を提供することを目的とする。 The present invention aims to provide a novel antitrypanosomal drug that is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
本発明らは、上記課題を解決するために鋭意検討した結果、Ｎ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－ヒドロキシベンズアミドのプロドラッグとして知られているＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミドが、トリパノソーマ科原虫の感染に起因する疾患の予防又は改善に有用であることを見出し、本発明を完成するに至った。 As a result of extensive research to solve the above problems, the inventors discovered that N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide, known as a prodrug of N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide, is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa, and thus completed the present invention.
すなわち、本発明は、Ｎ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－ヒドロキシベンズアミド若しくはその薬理学的に許容される塩又はＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミドを有効成分として含有する抗トリパノソーマ薬などである。 In other words, the present invention relates to an antitrypanosomal drug that contains N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide or a pharmacologically acceptable salt thereof, or N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide as an active ingredient.
本発明によれば、トリパノソーマ科原虫の感染に起因する疾患の予防又は改善に有用な新規抗トリパノソーマ薬を提供することができる。 The present invention provides a novel antitrypanosomal drug that is useful for preventing or ameliorating diseases caused by infection with Trypanosomatidae protozoa.
以下、上記知見に基づき完成した本発明の実施の形態を、実施例を挙げながら詳細に説明する。実施例において特に説明がない場合には、市販の試薬キットや測定装置はそれらに添付のプロトコールを用いる。なお、本発明の目的、特徴、利点、及びそのアイデアは、本明細書の記載により、当業者には明らかであり、当業者であれば本明細書の記載から容易に本発明を再現できる。以下に記載された発明の実施の形態及び具体的な実施例などは、本発明の好ましい実施態様を示すものであり、例示又は説明のために示されているものであって、本発明をそれらに限定するものではない。本明細書で開示されている本発明の意図並びに範囲内で、本明細書の記載に基づき、様々な改変並びに修飾ができることは、当業者にとって明らかである。 Below, the embodiment of the present invention completed based on the above findings will be described in detail with examples. Unless otherwise specified in the examples, commercially available reagent kits and measuring devices use the protocols attached thereto. The objectives, features, advantages, and ideas of the present invention will be clear to those skilled in the art from the description in this specification, and those skilled in the art will be able to easily reproduce the present invention from the description in this specification. The embodiment and specific examples of the invention described below show preferred embodiments of the present invention and are shown for illustrative or explanatory purposes, and do not limit the present invention thereto. It will be clear to those skilled in the art that various modifications and alterations can be made based on the description in this specification within the intent and scope of the present invention disclosed in this specification.
本発明に係る抗トリパノソーマ薬は、Ｎ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－ヒドロキシベンズアミド若しくはその薬理学的に許容される塩又はＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミド（以下、これらの化合物を単に「本発明に係る化合物」と称する。）を有効成分として含有する。 The antitrypanosomal drug of the present invention contains, as an active ingredient, N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide or a pharmacologically acceptable salt thereof, or N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide (hereinafter, these compounds are simply referred to as "compounds of the present invention").
本発明において、抗トリパノソーマ薬とは、トリパノソーマ科原虫の感染に起因する疾患の予防又は改善に有用な薬剤（特に医薬品）を意味する。また、当該疾患（トリパノソーマ症）とは、例えば、原虫Ｔｒｙｐａｎｏｓｏｍａ ｃｒｕｚｉの感染に起因するシャーガス病、原虫Ｔｒｙｐａｎｏｓｏｍａ ｂｒｕｃｅｉの感染に起因する睡眠病などを挙げることができるが、これらに限定されるものではない。前記疾患の改善とは、当該疾患の症状を根治することを意味するだけでなく、その症状を改善すること、その症状の進行を抑制すること、その症状が現れるのを防ぐこと、当該疾患の発症原因である原虫の数を減少させることなどをも意味する。なお、本発明に係る抗トリパノソーマ薬は、上記疾患の発症リスクが高い又は上記疾患を発症したヒトだけでなく、例えば、ウシ、ウマ、ブタ、ヤギ、ヒツジ、ラバ、ニワトリ、アヒル、ガチョウ、シチメンチョウ、ウズラ、マウス、ラット、モルモット、イヌ、サル、ネコ等のヒト以外の動物にも有用である。 In the present invention, antitrypanosomiasis refers to drugs (particularly pharmaceuticals) that are useful for preventing or ameliorating diseases caused by infection with protozoa of the Trypanosomatidae family. Examples of the disease (trypanosomiasis) include, but are not limited to, Chagas disease caused by infection with the protozoa Trypanosoma cruzi and sleeping sickness caused by infection with the protozoa Trypanosoma brucei. Amelioration of the disease does not only mean curing the symptoms of the disease, but also means improving the symptoms, inhibiting the progression of the symptoms, preventing the symptoms from appearing, and reducing the number of protozoa that cause the disease. The antitrypanosomal drug of the present invention is useful not only for humans who are at high risk of developing the above diseases or who have developed the above diseases, but also for animals other than humans, such as cows, horses, pigs, goats, sheep, mules, chickens, ducks, geese, turkeys, quails, mice, rats, guinea pigs, dogs, monkeys, and cats.
Ｎ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－ヒドロキシベンズアミド及びＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミドは、例えば米国特許出願公開第２００４／０２５９８７７号明細書や米国特許出願公開第２００６／００９４７１８号明細書に記載の方法に基づいて製造することができる。また、Ｎ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－ヒドロキシベンズアミドの薬理学的に許容される塩は、当業界で汎用されている方法により製造することができる。当該塩としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩、カルシウム塩などの金属塩；アンモニウム塩、メチルアンモニウム塩、ジメチルアンモニウム塩、トリメチルアンモニウム塩、ジシクロヘキシルアンモニウム塩などのアンモニウム塩；などを挙げることができる。 N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide and N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide can be produced, for example, based on the methods described in U.S. Patent Application Publication No. 2004/0259877 and U.S. Patent Application Publication No. 2006/0094718. Pharmacologically acceptable salts of N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide can be produced by methods commonly used in the art. Examples of such salts include metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts such as ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, and dicyclohexylammonium salts; and the like.
本発明に係る抗トリパノソーマ薬は、例えば、ベンズニダゾール、ニフルチモックスなどと併用してもよい。併用する場合、上記疾患の発症リスクが高い又は上記疾患を発症した動物に対して、これらを一緒に投与してもよいし、別々に投与してもよい。 The antitrypanosomal drug of the present invention may be used in combination with, for example, benznidazole, nifurtimox, etc. When used in combination, these may be administered together or separately to animals at high risk of developing the above-mentioned diseases or animals that have developed the above-mentioned diseases.
本発明に係る抗トリパノソーマ薬は、本発明に係る化合物のみからなるものであってもよいが、１又は２以上の添加物をさらに含む組成物であってもよい。前記添加物としては、例えば、賦形剤、結合剤、滑沢剤、崩壊剤、矯味矯臭剤、溶剤、安定剤、基剤、湿潤剤、保存剤、緩衝剤、浸透圧調整剤などの既存の添加物を用いることができる。 The antitrypanosomal drug of the present invention may consist of only the compound of the present invention, but may also be a composition further containing one or more additives. The additives that can be used include, for example, existing additives such as excipients, binders, lubricants, disintegrants, flavorings, solvents, stabilizers, bases, wetting agents, preservatives, buffers, and osmotic pressure regulators.
本発明に係る抗トリパノソーマ薬はいかなる剤形であってもよく、例えば、錠剤、カプセル剤、顆粒剤、散剤、液剤、細粒剤、粉末剤、シロップ剤、注射剤、塗布剤、噴霧剤、貼付剤、坐剤などを挙げることができる。また、本発明に係る抗トリパノソーマ薬はいかなる方法で投与してもよく、例えば、経口投与、静脈投与などの非経口投与などを挙げることができる。 The antitrypanosomal drug of the present invention may be in any dosage form, such as tablets, capsules, granules, powders, liquids, fine granules, powders, syrups, injections, liniments, sprays, patches, suppositories, etc. The antitrypanosomal drug of the present invention may be administered by any method, such as oral administration or parenteral administration, such as intravenous administration.
本発明に係る抗トリパノソーマ薬は、投与対象に対して、必要量を一度に投与されてもよいし、間歇的に投与されてもよいし、持続的に投与されてもよい。持続的な投与方法としては、例えば、点滴投与を挙げることができる。投与対象としては、上記動物を挙げることができる。 The antitrypanosomal drug of the present invention may be administered to a subject in a required amount all at once, intermittently, or continuously. An example of a method of continuous administration is intravenous administration. Subjects of administration include the animals listed above.
本発明に係る抗トリパノソーマ薬として投与する本発明に係る化合物の量は、投与対象（例えば、体重や年齢など）、症状、投与方法などによって異なるが、通常、１回の投与で０．０００１～１０ｇである。 The amount of the compound of the present invention administered as an antitrypanosomal drug of the present invention varies depending on the subject (e.g., body weight, age, etc.), symptoms, administration method, etc., but is usually 0.0001 to 10 g per administration.
以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されるものではない。 The present invention will be explained in more detail below with reference to examples, but the scope of the present invention is not limited to the following examples.
５週齢の雄のＣ５７ＢＬ／６マウスにＴｒｙｐａｎｏｓｏｍａ ｃｒｕｚｉ Ｙ株（１×１０5原虫）を腹腔内投与し、該マウスを感染させた（感染０日）。感染４週後から、５０ｍｇ／ｋｇ（体重）の投与量となるようにＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミドを週に３回、感染マウス（ｎ＝５）に経口投与した。コントロールとして、化合物を投与していない感染マウスを準備した（ｎ＝５）。感染１２週後に、化合物投与群又は非投与群におけるマウスの心臓組織を取り出し、ｑＰＣＲにより原虫量を測定した。ｑＰＣＲには、Ｔｒｙｐａｎｏｓｏｍａ ｃｒｕｚｉサテライトＤＮＡをターゲットとしたプローブ（配列番号１：５’－ＴＴＧＧＴＧＴＣＣＡＧＴＧＴＧＴＧ－３’）及びプライマー（配列番号２：５’－ＡＳＴＣＧＧＣＴＧＡＴＣＧＴＴＴＴＣＧＡ－３’、配列番号３：５’－ＡＡＴＴＣＣＴＣＣＡＡＧＣＡＧＣＧＧＡＴＡ－３’）を用いた。ｑＰＣＲの条件は以下の条件で行った。９５℃で２０秒間ホールドした後、９５℃×１秒間→６０℃×２０秒間というサイクルを６０サイクル行った。その結果、コントロール群に比べ、化合物投与群では心臓組織における原虫量が半数以上減少することが明らかとなった。 Trypanosoma cruzi Y strain (1 x 105 protozoa) was intraperitoneally administered to 5-week-old male C57BL/6 mice to infect them (day 0 after infection). From 4 weeks after infection, N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide was orally administered to the infected mice (n=5) three times a week at a dose of 50 mg/kg (body weight). As a control, infected mice not administered with the compound were prepared (n=5). After 12 weeks after infection, cardiac tissues were taken from mice in the compound-administered or non-administered groups, and the amount of protozoa was measured by qPCR. For qPCR, a probe (SEQ ID NO: 1: 5'-TTGGTGTCCAGTGTGTG-3') and primers (SEQ ID NO: 2: 5'-ASTCGGCTGATCGTTTTCGA-3', SEQ ID NO: 3: 5'-AATTCCTCCAAGCAGCGGATA-3') targeting Trypanosoma cruzi satellite DNA were used. qPCR was performed under the following conditions. After holding at 95°C for 20 seconds, 60 cycles of 95°C x 1 second → 60°C x 20 seconds were performed. As a result, it was revealed that the amount of protozoa in the heart tissue was reduced by more than half in the compound administration group compared to the control group.
感染２週後から、５０ｍｇ／ｋｇ（体重）の投与量となるようにＮ－［２，５－ビス（トリフルオロメチル）フェニル］－５－ブロモ－２－［（モルフォリノカルボニル）オキシ］ベンズアミドを週に３回、上記感染マウス（ｎ＝５）に経口投与した。コントロールとして、化合物を投与していない感染マウスを準備した（ｎ＝５）。感染１６週後に、心臓超音波検査（心エコー）により、左室後壁厚（ＬＶＰＷ；ｄ、ＬＶＰＷ；ｓ）を計測した。その結果、原虫の感染によってコントロール群で確認された左室後壁の菲薄化が、化合物投与群において有意に抑制されることがわかった。 Starting two weeks after infection, N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide was orally administered to the infected mice (n=5) at a dose of 50 mg/kg (body weight) three times a week. As a control, infected mice not administered the compound (n=5) were prepared. Sixteen weeks after infection, left ventricular posterior wall thickness (LVPW;d, LVPW;s) was measured by cardiac ultrasound (echocardiography). As a result, it was found that the thinning of the left ventricular posterior wall observed in the control group due to protozoan infection was significantly suppressed in the compound-administered group.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009054439A1 (en) * | 2007-10-23 | 2009-04-30 | Institute Of Medicinal Molecular Design, Inc. | Pai-1 production inhibitor |
| JP2010018562A (en) * | 2008-07-11 | 2010-01-28 | Kitasato Institute | Infection prevention-treatment agent for trypanosomatid protozoans |
| JP2012025671A (en) * | 2010-07-20 | 2012-02-09 | Gunma Univ | Anti-trypanosoma agent and trypanosomiasis therapeutic agent |
| WO2014076965A1 (en) * | 2012-11-16 | 2014-05-22 | 学校法人北里研究所 | 1-indane derivative having anti-protozoal activity |
| WO2021086567A1 (en) * | 2019-11-01 | 2021-05-06 | University Of Notre Dame Du Lac | Compounds and methods for potentiating colistin activity |
-
2024
- 2024-02-12 WO PCT/JP2024/004697 patent/WO2024172001A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009054439A1 (en) * | 2007-10-23 | 2009-04-30 | Institute Of Medicinal Molecular Design, Inc. | Pai-1 production inhibitor |
| JP2010018562A (en) * | 2008-07-11 | 2010-01-28 | Kitasato Institute | Infection prevention-treatment agent for trypanosomatid protozoans |
| JP2012025671A (en) * | 2010-07-20 | 2012-02-09 | Gunma Univ | Anti-trypanosoma agent and trypanosomiasis therapeutic agent |
| WO2014076965A1 (en) * | 2012-11-16 | 2014-05-22 | 学校法人北里研究所 | 1-indane derivative having anti-protozoal activity |
| WO2021086567A1 (en) * | 2019-11-01 | 2021-05-06 | University Of Notre Dame Du Lac | Compounds and methods for potentiating colistin activity |
Non-Patent Citations (4)
| Title |
|---|
| BOBBA VIHARIKA; NANAVATY VISHAL; IDIPPILY NETHRIE D.; ZHAO ANRAN; LI BIBO; SU BIN: "Synthesis and biological evaluation of selective tubulin inhibitors as anti-trypanosomal agents", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 12, 8 April 2017 (2017-04-08), AMSTERDAM, NL, pages 3215 - 3222, XP085030772, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2017.04.009 * |
| FERRINS LORI, GAZDIK MICHELLE, RAHMANI RAPHAËL, VARGHESE SWAPNA, SYKES MELISSA L., JONES AMY J., AVERY VICKY M., WHITE KAREN L., R: "Pyridyl Benzamides as a Novel Class of Potent Inhibitors for the Kinetoplastid Trypanosoma brucei", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 57, no. 15, 14 August 2014 (2014-08-14), US , pages 6393 - 6402, XP093201196, ISSN: 0022-2623, DOI: 10.1021/jm500191u * |
| ROBERT URICH, RAFFAELLA GRIMALDI, TORSTEN LUKSCH, JULIE A. FREARSON, RUTH BRENK, PAUL G. WYATT: "The Design and Synthesis of Potent and Selective Inhibitors of Trypanosoma brucei Glycogen Synthase Kinase 3 for the Treatment of Human African Trypanosomiasis", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 57, no. 18, 25 September 2014 (2014-09-25), US , pages 7536 - 7549, XP055354230, ISSN: 0022-2623, DOI: 10.1021/jm500239b * |
| TADA YUKIYO, SHOICHIRO KOKABU, GORO SUGIYAMA, CHIHIRO NAKATOMI, KAZUHIRO AOKI, HIDEFUMI FUKUSHIMA, KENJI OSAWA, YASUTAKA SUGAMORI,: "The novel IκB kinase β inhibitor IMD-0560 prevents bone invasion by oral squamous cell carcinoma", ONCOTARGET, IMPACT JOURNALS LLC, UNITED STATES, vol. 5, no. 23, 1 January 2014 (2014-01-01), United States , pages 12317 - 12330, XP093201198, ISSN: 1949-2553 * |
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