JP2011102308A - 1−(2−ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−シトシンのb型肝炎治療への使用 - Google Patents
1−(2−ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−シトシンのb型肝炎治療への使用 Download PDFInfo
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- JP2011102308A JP2011102308A JP2010290612A JP2010290612A JP2011102308A JP 2011102308 A JP2011102308 A JP 2011102308A JP 2010290612 A JP2010290612 A JP 2010290612A JP 2010290612 A JP2010290612 A JP 2010290612A JP 2011102308 A JP2011102308 A JP 2011102308A
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- hepatitis
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Classifications
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、1-(2-ヒドロキシメチル)-1,3-オキサチオラン-5-イル)-シトシン誘導体およびそれらの生理学的機能性誘導体の、B型肝炎ウィルス感染の治療への使用に関する。
B型肝炎ウィルス(HBV)は、世界的に非常に重要な病原ウィルスである。HBVは、アジア諸国においては非常に一般的で、アフリカのサハラ周辺[sub-Saharan Africa]においてはよくみられる。このウィルスは、病因学的には、主要な肝細胞カルシノーマと関連しており、世界の肝臓癌の8割を引き起こしていると考えられている。合衆国においては、毎年 1万人以上の人々が、HBV疾病のために入院しており、平均 250人の人々が劇痛を伴う疾病で亡くなっている。現在、感染性保菌者は、合衆国に50万人から 100万人存在するものと見積もられている。慢性活動型肝炎は、保菌者の25%以上の人々にみられ、しばしば硬変症へと進行する。合衆国では、毎年、HBV関連の硬変症で5000もの人々が、そしておそらく1000人がHBV関連の肝臓癌で死去しているものと見られている。普遍的なHBVワクチンが存在したとしても、効果的な抗HBV化合物の必要性はなくならないであろう。世界中で 2億 2千万人と見積もられている、感染持続性保菌者の大きなレザバーは、予防接種からは何ら益を受けず、HBV誘発肝臓疾病に対し高い危険性を負い続けている。この保菌者の集団は、感受性の高い人々の感染源となる。そしてそれは特に特定の地域内に住む人々やホモセクシャルもしくは静注薬物濫用者のような高い危険性を有する集団における症例を永続的なものとする。
R1 OCH2 CHO (III)
から得られる。式IIIの化合物を、この分野で公知(Chem.Ber.85:924-932,1952) )のメルカプトアセタール
HSCH2 CH(OR)2
(ここで、Rは、HSCH2 CH(OC2 H5 )2 のようなC1-4 アルコシル基である)と反応させることにより、LがOR(アルコキシ)、例えば、メトキシもしくはエトキシである式IIAの化合物が得られる。代わりに、Lがアルコシルである式IIAの化合物を、炭化水素化学の分野において公知の方法により、Lがハロゲンもしくはアシルである式IIAの化合物に転換してもよい。
方法A:(±)-シスおよび(±)-トランス 2-ベンゾイルメチル-5-(N4 -アセチル-シトシン-1-イル)-1,3-オキサチオランを、ヨーロッパ特許(EP)明細書 0 382 526に記載されているように調製し、(±)-シスおよび(±)-トランス異性体に分離する。(±)-シス異性体を、Robinsら、Nucleic Acisd Chemistry, part 2, 895-900, 1978に従って、 -78℃で、フルオロトリクロロメタン(CCI3 F)およびクロロホルム中において、トリフルオロメチルヒポフルオライトを用いてフッ素化する。エタノール中において、ジメチルアミンを用いて、N4 -アセチルおよび2-ベンゾイル基を除去し、その生成物である(±)-シス-1-(2-(ヒドロキシメチル)-1,3-オキサチオラン-5-イル)-5-フルオロシトシンを単離する。
以下の製剤例において、「活性成分」はシス-1-(2-(ヒドロキシメチル)-1,3-オキサチオラン-5-イル)-5-フルオロシトシンである。
錠剤製剤
以下の製剤A、BおよびCは、顆粒状成分をポビドン溶液で湿らせ、次いでステアリン酸マグネシウムを添加して圧縮することにより調製する。
mg/錠剤 mg/錠剤
(a) 活性成分 250 250
(b) ラクトースB.P. 210 26
(c) ポビドン B.P 15 9
(d) デンプンナトリウム
グリコラート 20 12
(e) ステアリン酸マグネシウム 5 3
500 300
製剤B
mg/錠剤 mg/錠剤
(a) 活性成分 250 250
(b) ラクトース 150 −
(c) アビセルPH 101 60 26
(d) ポビドン B.P. 15 9
(e) デンプンナトリウム
グリコラート 20 12
(f) ステアリン酸マグネシウム 5 3
500 300
製剤C
mg/錠剤
活性成分 100
ラクトース 200
デンプン 50
ポビドン 5
ステアリン酸マグネシウム 4
359
以下の製剤DおよびDは、混合した成分の直打により調製する。製剤Eのラクトースは、直打型のものである(Dairy Crest-「ゼパロックス[Zeparox ]」)。
mg/錠剤
活性成分 250
予めゲル状にしたデンプンNF15 150
400
製剤E
mg/錠剤
活性成分 250
ラクトース 150
アビセル 100
500
製剤F(放出を制御された製剤)
この製剤は、顆粒状成分(下記)をポビドン溶液で湿らせ、次いでステアリン酸マグネシウムを添加して圧縮することにより調製する。
(a) 活性成分 500
(b) ヒドロキシプロピルメチルセルロース 112
(メトセルK4Mプレミアム
[Methocel K4M premium])
(c) ラクトース B.P. 53
(d) ポビドン B.P. 28
(e) ステアリン酸マグネシウム 7
700
薬剤の放出は、約6−8時間にわたって起こり、12時間後に完了する。
カプセル製剤
製剤A
カプセル製剤は、上記例2における製剤Dの成分を混合し、2分割硬ゼラチンカプセルに充填することにより調製する。製剤B(下記)は、同様の方法で調製する。
mg/カプセル
(a) 活性成分 250
(b) ラクトース B.P. 143
(c) デンプンナトリウムグリコラート 25
(d) ステアリン酸マグネシウム 2
420
製剤C
mg/カプセル
(a) 活性成分 250
(b) マクロゴール 4000 B.P. 350
600
製剤D
mg/カプセル
活性成分 250
レシチン 100
落花生油 100
450
製剤Dのカプセルは、レシチンおよび落花生油に活性成分を分散させ、この分散物を、軟らかい、弾性ゼラチンカプセル内に充填することにより調製する。
以下の徐放性カプセル製剤は、押出成形機を用いて成分a、bおよびc成分を押出し、次いでこの押出物を急浄化[spheronization]して乾燥することにより調製する。その後、この乾燥ペレットを、放出制御膜(d)で被覆し、2分割硬ゼラチンカプセルに充填する。
(a)活性成分 250
(b) 微結晶セルロース 125
(c) ラクトース B.P. 125
(d) エチルセルロース 13
513
例4 注入製剤
製剤A
活性成分 0.200g
pH 4.0 -7.0とするに十分な量の塩酸溶液、 0.1M
または水酸化ナトリウム溶液、 0.1M
滅菌水 10mLとするに十分な量
活性成分を大部分の水(35℃ないし40℃)に溶解し、塩酸もしくは水酸化ナトリウムで適当に、 4.0ないし7.0にpHを調製する。次いで、このバッチを水でボリュームアップし、滅菌済みの微孔性フィルターを通して滅菌済みの琥珀色の10mL容ガラスバイアル(タイプ1)に入れ、滅菌済みのクロージャー[closures]およびオーバーシール[overseals ]で密閉する。
活性成分 0.125
滅菌したパイロジェンフリーの
pH 7リン酸緩衝液 25mLとするに十分な量
例5
筋肉内注入
活性成分 0.20g
ベンジルアルコール 0.10g
グリコフロール 75 [Glycofurol 75 ] 1.45g
ベンジルアルコール 3.00mLとするに十分な量
活性成分をグリコフロールに溶解する。次いで、ベンジルアルコールを添加して溶解し、 3mLまで水を加える。その後、この混合物を滅菌済みの微孔性フィルターに通し、滅菌済みの 3mL容の琥珀色のガラスバイアル(タイプ1)内に密閉する。
シロップ
活性成分 0.25g
ソルビトール溶液 1.50g
グリセロール 2.00g
安息香酸ナトリウム 0.005g
フレーバー、ピーチ 17.42.316 9 0.0125mL
精製水 5.00mLとするに十分な量
活性成分をグルセロールおよび大部分の水の混合物に溶解する。その後、この溶液に安息香酸ナトリウム水溶液を添加し、次いでソルビトール溶液を添加して、最後にフレーバーを加える。精製水を加え体積を合わせ、よく混ぜ合わせる。
坐剤 mg/坐剤
活性成分 250
硬脂、B.P (ワイテプソールH15
[Witepsol H15] -Dynamit Nobel) 1770
2020
ワイテプソールH15の5分の1を、最高45℃で、蒸気ジャケットパンにおいて溶解する。活性成分を 200Mのふるいに通し、カッティングヘッドを備えたシルバーソン[silverson ]を用いて滑らかに分散されるまで、撹拌しつつ溶融基材に加える。混合物を45℃に維持し、残ったワイテプソールH15をこの懸濁液に加えて均一な混合が確かなものとなるよう撹拌する。この懸濁液の全てを 250Mステンレス鋼スクリーンに通し、連続的に撹拌しながら40℃になるまで冷す。38℃ないし40℃の温度で、この混合物2.02gを適切な 2mL容のプラスチック型に充填する。坐薬を室温まで冷却する。
ペッサリー
mg/ペッサリー
活性成分 250
デキストロース無水物 380
ジャガイモデンプン 363
ステアリン酸マグネシウム 7
1000
上記成分を直接混合し、生じた混合物を直接圧縮することによりペッサリーを調製する。
B型肝炎ウィルス(HBV)に対する抗ウィルス活性
化合物シス-1-(2-(ヒドロキシメチル)-1,3,-オキサチオラン-5-イル)-5-フルオロシステインを、以下の通りに試験した。
Claims (10)
- 式(I)の化合物がシス異性体の形態にある請求項1に記載の使用。
- 生理学的機能性誘導体が、式(I)の化合物の医薬上許容し得る塩もしくはエステルである請求項1に記載の使用。
- 前記医薬が単位投与剤形をとる先の請求項に記載の使用。
- 前記投与単位が、式(I)の化合物もしくはそれらの生理学的機能性誘導体を10ないし1500mg含む請求項4に記載の使用。
- 前記投与単位が錠剤もしくはカプセルである請求項4または5に記載の使用。
- B型肝炎ウイルス感染の治療または予防に用いられる、請求項1に記載の式(I)の化合物またはそれらの生理学的機能性誘導体。
- B型肝炎ウイルス感染の治療または予防に用いられる、シス-1-(2-(ヒドロキシメチル)-1,3-オキサチオラン-5-イル)-5-フルオロシトシン。
- B型肝炎ウイルスに感染したヒトの治療方法であって、該ヒトに、請求項1に記載の化合物もしくはそれらの生理学的機能性誘導体の有効B型肝炎治療量を投与することを具備する治療方法。
- 前記式(I)の化合物がシス-1-(2-(ヒドロキシメチル)-1,3-オキサチオラン-5-イル)-5-フルオロシトシンである請求項1に記載の方法。
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GB9104741.5 | 1991-03-06 | ||
GB919104741A GB9104741D0 (en) | 1991-03-06 | 1991-03-06 | Therapeutic nucleosides |
GB919109505A GB9109505D0 (en) | 1991-05-02 | 1991-05-02 | Therapeutic nucleosides |
GB9109505.9 | 1991-05-02 |
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JP50582592A Expired - Lifetime JP3479068B2 (ja) | 1991-03-06 | 1992-03-05 | 5−フルオロ−2’−デオキシ−3’−チアシチジンのb型肝炎治療への使用 |
JP2001378640A Expired - Lifetime JP3987335B2 (ja) | 1991-03-06 | 2001-12-12 | シス−1−(2−(ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−5−フルオロシトシンのl−鏡像体 |
JP2007123881A Expired - Lifetime JP4399478B2 (ja) | 1991-03-06 | 2007-05-08 | 1−(2−(ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−5−フルオロシトシンのb型肝炎治療への使用 |
JP2009204044A Withdrawn JP2010013466A (ja) | 1991-03-06 | 2009-09-03 | 1−(2−ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−シトシンのb型肝炎治療への使用 |
JP2010290612A Active JP4891435B2 (ja) | 1991-03-06 | 2010-12-27 | 1−(2−ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−シトシンのb型肝炎治療への使用 |
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JP50582592A Expired - Lifetime JP3479068B2 (ja) | 1991-03-06 | 1992-03-05 | 5−フルオロ−2’−デオキシ−3’−チアシチジンのb型肝炎治療への使用 |
JP2001378640A Expired - Lifetime JP3987335B2 (ja) | 1991-03-06 | 2001-12-12 | シス−1−(2−(ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−5−フルオロシトシンのl−鏡像体 |
JP2007123881A Expired - Lifetime JP4399478B2 (ja) | 1991-03-06 | 2007-05-08 | 1−(2−(ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−5−フルオロシトシンのb型肝炎治療への使用 |
JP2009204044A Withdrawn JP2010013466A (ja) | 1991-03-06 | 2009-09-03 | 1−(2−ヒドロキシメチル)−1,3−オキサチオラン−5−イル)−シトシンのb型肝炎治療への使用 |
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HUE033832T2 (en) | 2002-11-15 | 2018-01-29 | Idenix Pharmaceuticals Llc | 2'-methyl nucleosides in combination with interferon and Flaviviridae mutation |
KR101813721B1 (ko) | 2008-06-30 | 2017-12-29 | 토카겐 인크. | 5-플루오르시토신 제제 및 이의 용도 |
WO2013004658A1 (en) * | 2011-07-01 | 2013-01-10 | Transgene Sa | Formulations of 5-fluorocytosine and uses thereof. |
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JPH037282A (ja) * | 1989-02-08 | 1991-01-14 | Iaf Biochem Internatl Inc | 抗ウィルス性置換1,3‐オキサチオラン |
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US5204466A (en) * | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
NZ241625A (en) * | 1991-02-22 | 1996-03-26 | Univ Emory | 1,3-oxathiolane derivatives, anti-viral compositions containing such and method of resolving racemic mixture of enantiomers |
ATE219366T1 (de) * | 1991-03-06 | 2002-07-15 | Univ Emory | Verwendung von 5-fluoro-2'-deoxy-3'-thiacytidin zur behandlung von hepatitis b |
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