JP4553355B2 - トリパノソーマ原虫寄生感染症の予防又は治療用医薬組成物 - Google Patents
トリパノソーマ原虫寄生感染症の予防又は治療用医薬組成物 Download PDFInfo
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- JP4553355B2 JP4553355B2 JP2004292002A JP2004292002A JP4553355B2 JP 4553355 B2 JP4553355 B2 JP 4553355B2 JP 2004292002 A JP2004292002 A JP 2004292002A JP 2004292002 A JP2004292002 A JP 2004292002A JP 4553355 B2 JP4553355 B2 JP 4553355B2
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- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
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- 230000002285 radioactive effect Effects 0.000 description 1
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- 150000004671 saturated fatty acids Chemical class 0.000 description 1
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- 229940054269 sodium pyruvate Drugs 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/84—Naphthothiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
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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
- A61P33/06—Antimalarials
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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
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Description
1−1.薬剤感受性熱帯熱マラリア原虫の培養
本例では、Plasmodium Falciparum FCR-3株の原虫を用いた。実験に用いた培地は、ろ過滅菌したRPMI−1640培地で、pHを7.4に合わせ、ヒト血清を10%となるように添加した。マラリア原虫の培養は、O2濃度5%、CO2濃度5%、N2濃度90%、温度は36.5℃で行った。
培養したマラリア原虫感染赤血球を遠心分離で集め、血清を含む培地で洗浄を行った後、非感染赤血球を加え、初期感染率0.3%とした。このときのヘマトクリット値は3%とした。試験に用いる本発明化合物、陽性対象薬(クロロキン、キニーネ)は、ジメチルスルホキシド(DMSO)に溶解し、所定濃度の試験液とした。24穴培養プレートに試験液を5〜10μLずつ加えた。コントロールはDMSOを10μL/ウェル加えた。試験液はデュープリケートにとった。次に、あらかじめ所定濃度に調製した熱帯熱マラリア原虫培養液を加え、静かにピペッティングを行い培地に一様に懸濁させた。培養プレートは、CO2−O2−N2(5%,5%,90%)インキュベーター中で72時間培養した後、それぞれのウェルについて薄層塗抹標本を作成し、Diff−Quik染色を行った後、顕微鏡(油浸、1,000×)下で計測し、試験液添加群及びコントロールのマラリア原虫感染率を算出した。上記で求めたマラリア原虫感染率から次式によって増殖阻害率を算出し、50%増殖阻害濃度(EC50)を求めた。
a:初期感染率
b:試験液添加時の感染率
c:コントロールの感染率
マウス乳癌由来FM3A細胞の野生株であるF28−7株を用いた。培地はES培地に非動化した胎児牛血清を2%となるように添加し、CO2濃度5%、37℃で培養した。この条件下でのFM3A細胞の倍加時間は約12時間であった。前培養を行い、対数増殖期に入った細胞を5×104cells/mLになるように培地で希釈した。サンプルはマラリア活性測定時に調製したものを用いた。24穴培養プレートにサンプル溶液を5〜10μLずつ加えた(培地等を加えると最終濃度は1×10−4〜1×10−5Mとなった。)。化合物はデュープリケートにとり、コントロールとしてDMSOを10μL加えたウェルも同時に用意した。次に、用意しておいた培養細胞浮遊液を990〜995μLずつ加え、静かにピペッティングを行い培地に一様に懸濁させた。48時間培養した後、それぞれのウェルについて細胞数をセルコントローラー(CC-108,Toa.Medical Electrics社製)で計数し、下記式により増殖率を算出し、50%増殖阻害率(EC50)を算出した。
A:初期細胞数
B:2日後のコントロールの細胞数
C:サンプル添加した2日後の細胞数
薬剤感受性熱帯熱マラリア原虫とマウスFM3A細胞に対するサンプルのEC50値からサンプルの抗マラリア作用を評価した。薬剤感受性マラリア原虫に対する選択毒性の指標として用いられる化学療法係数を下記式により算出し、薬効判定を行った。
=(マウスFM3A細胞に対するサンプルのEC50値)
÷(薬剤感受性熱帯熱マラリア原虫に対するサンプルのEC50値)
2−1.クロロキン耐性熱帯熱マラリア原虫の培養
本例では、Plasmodium Falciparum K1株の原虫を用いた。実験に用いた培地は、ろ過滅菌したRPMI−1640培地で、ヒト血清を5%となるように添加した。マラリア原虫の培養は、O2濃度3%、CO2濃度4%、N2濃度93%、温度は37℃で行った。
試験に用いる本発明化合物、陽性対象薬(クロロキン)は、DMSOに溶解し、所定濃度の試験液とした。培養したマラリア原虫感染赤血球を遠心分離で集め、非感染赤血球で希釈し、初期感染率0.15%とした。このときのヘマトクリット値は2.5%とした。96穴培養プレートのウェルに、200μLのマラリア感染培養液を加え、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加え調整した。試験液はデュープリケートにとった。37℃で48時間培養した後、0.5μCiの放射性のトリチウム(3H)表指揮されたヒポキサンチンを各ウェルに加えた。さらに24時間同条件で培養した後、グラスファイバーフィルター上に採取し蒸留水で洗浄した。ベータプレート液体シンチレーションカウンター(Wallac社製)で放射線強度を計測し、試験液添加群及びコントロールのマラリア原虫感染率を算出した。上記で求めたマラリア原虫感染率から次式によって増殖阻害率を算出し、50%増殖阻害濃度(EC50)を求めた。
a:初期感染率
b:試験液添加時の感染率
c:コントロールの感染率
ラット由来L6細胞(rat skeletal myoblast cell)を用いた。培地はRPMI1640培地に、L−グルタミン(200mM)が1%、胎児牛血清が10%となるように添加し、CO2濃度5%、37℃で培養した。試験に用いる本発明化合物または対象薬をDMSOに溶解し、所定濃度の試験液とした。前培養を行い、対数増殖期に入った細胞を含む培地を96穴培養プレートのウェルにとり、次に所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加えた。試験液はデュープリケートにとった。培養プレートをインキュベーター中で72時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。
A:初期細胞数
B:3日後のコントロールの細胞数
C:サンプル添加した3日後の細胞数
クロロキン耐性熱帯熱マラリア原虫とラットL6細胞に対するサンプルのEC50値からサンプルの抗マラリア作用を評価した。クロロキン耐性マラリア原虫に対する選択毒性の指標として用いられる化学療法係数を下記式により算出し、薬効判定を行った。
=(ラットL6細胞に対するサンプルのEC50値)
÷(クロロキン耐性熱帯熱マラリア原虫に対するサンプルのEC50値)
3−1.アフリカ・トリパノソーマ原虫の培養
本実施例では、Trypanosoma brucei rhodensiense(STIB900株)の原虫の血流棲息型トリポマスチゴート体を用いた。実験に用いた培地は、ろ過滅菌したMEM培地に、25mMのN−2−ヒドロキシエチルピペラジン−2−エタンスロホン酸(HEPES)、1g/Lのグルコース、1%のMEM非必須アミノ酸、0.2mMの2−メルカプトエタノール、2mMのピルビン酸ナトリウム炎、0.1mMのヒポキサンチン及び15%熱処理ウマ血清を加えたものを用いた。原虫の培養はCO2濃度を5%とした空気中で、温度は37度で行った。
試験に用いる本発明化合物、陽性対象薬(メラルソプロール)は、ジメチルスルホキシド(DMSO)に溶解し、所定濃度の試験液とした。96穴培養プレートのウェルに、原虫の個数が8×103個を含む培地と、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加え、それぞれ100μLになるよう培地を加え調整した。試験液はデュープリケートにとった。培養プレートをインキュベーター中で72時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。それぞれのウェルに10μLのAlamar Blue水溶液を加え、さらに2時間培養した。次に、培養プレートを蛍光マイクロプレートリーダー(Spectramax Gemeni XS;米国モレキュラー・デバイス社製)に装着し、536nmの励起波長で照射し、588nmの蛍光強度を測定し、試験液添加群及びコントロールのトリパノソーマ原虫感染率を算出した。上記で求めた原虫感染率から次式によって増殖阻害率を算出し、50%増殖阻害濃度(EC50)を求めた。
a:初期感染率
b:試験液添加時の感染率
c:コントロールの感染率
アフリカ・トリパノソーマ原虫に対する選択毒性の指標として用いられる選択毒性係数を下記式により算出し、薬効判定を行った。
=(ラットL6細胞に対するサンプルのEC50値)
÷(アフリカ・トリパノソーマ原虫に対するサンプルのEC50値)
4−1.アメリカ・トリパノソーマ原虫の培養
本実施例では、Trypanosoma cruzi (Tulahuen C2C4株)の原虫のラットL6細胞に感染したアマスチゴート体及びトリポマスチゴート体を用いた。実験に用いた培地は、L6細胞を含むRPMI1640培地に、L−グルタミン(200mM)が1%、胎児牛血清が10%となるように添加し、CO2濃度5%、37℃で培養した。
試験に用いる本発明化合物、陽性対象薬(ベンズニダゾール)は、DMSOに溶解し、所定濃度の試験液とした。96穴培養プレートのウェルに、原虫の個数が5x103個を含む培地を加え48時間前培養を行った。培地を交換後、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加えた。試験液はデュープリケートにとった。培養プレートをインキュベーター中で96時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。
a:初期感染率
b:試験液添加時の感染率
c:コントロールの感染率
アメリカ・トリパノソーマ原虫に対する選択毒性の指標として用いられる選択毒性係数を下記式により算出し、薬効判定を行った。
=(ラットL6細胞に対するサンプルのEC50値)
÷(アメリカ・トリパノソーマ原虫に対するサンプルのEC50値)
5−1.リーシュマニア原虫の培養
本例では、Leishmania donovani (MHOM/ET/67/L82株)を用いた。原虫はSyrian Goldenハムスターで継代し、そこからアマスチゴート体を得た。実験には、10%の加熱処理したウシ胎児血清を加えたSM培地を用い、pH5.4に調整し、CO2濃度5%の空気下、37℃で培養した。
試験に用いる本発明化合物、陽性対象薬(ミルテフォシン)は、DMSOに溶解し、所定濃度の試験液とした。96穴培養プレートのウェルに所定の個数の原虫を含む培地を加え前処理をほどこした後、CASYセル分析システム(ドイツ・Scharfe社製)でアマスチゴートの濃度を計測した。その後、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加えた。試験液はデュープリケートにとった。培養プレートをインキュベーター中で72時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。
a:初期感染率
b:試験液添加時の感染率
c:コントロールの感染率
リーシュマニア原虫に対する選択毒性の指標として用いられる選択毒性係数を下記式により算出し、薬効判定を行った。
=(ラットL6細胞に対するサンプルのEC50値)
÷(リーシュマニア原虫に対するサンプルのEC50値)
Claims (2)
- 下記一般式(2)で表される化合物を有効成分として含有することを特徴とするトリパノソーマ原虫寄生感染症の予防又は治療用医薬組成物。
(式中、Rは、ビニル基で置換されていてもよい炭素数1〜7のアルキル基を表し、
R 2 は、炭素数1〜7のアルキル基を表し、
R 3 は、水酸基若しくはカルボキシル基で置換されていてもよい炭素数1〜7のアルキル基、又は−C 2 H 4 −O−C 2 H 4 −O−C 2 H 4 −OMeを表し、
X 1 は、S、−CH=CH−、又は−CR 4 R 5 −(R 4 及びR 5 は、それぞれ独立して、炭素数1〜7のアルキル基を表す。)を表し、
X 2 は、S、О、又は−CH=CH−を表し、
Yは、Sを表し、
Z 1 は、ベンゼン環又はナフタレン環が縮合していてもよい5〜6員環を形成するための原子群であり、該5〜6員環は、炭素数1〜7のアルキル基で置換されていてもよく、
Z 2 は、ベンゼン環又はナフタレン環が縮合していてもよい5〜6員環を形成するための原子群であり、該5〜6員環は、炭素数1〜7のアルキル基で置換されていてもよく、
L 1 ,L 2 ,L 3 ,L 4 及びL 5 は、メチン基を表し、
mは0、nは0又は1を示し、
pは1、qは0を示し、
Qは、生理学的に許容しうるアニオンを表し、
kは、分子全体の電荷をゼロにするのに必要な0〜2の整数を示す。) - Qが、ハロゲンイオン、スルホン酸イオン、又はカルボン酸イオンであることを特徴とする請求項1に記載のトリパノソーマ原虫寄生感染症の予防又は治療用医薬組成物。
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PCT/JP2005/018093 WO2006038550A1 (ja) | 2004-10-04 | 2005-09-30 | 原虫寄生感染症の予防又は治療用医薬組成物 |
CN2005800331728A CN101031295B (zh) | 2004-10-04 | 2005-09-30 | 原生动物感染病的预防或治疗用药物组合物 |
EP05787692.2A EP1800682B1 (en) | 2004-10-04 | 2005-09-30 | Medicinal composition for prevention or treatment of parasitic protozoan infection |
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