JP2015180677A - (+)−1,4−ジヒドロ−7−[(3s,4s)−3−メトキシ−4−(メチルアミノ)−1−ピロリジニル]−4−オキソ−1−(2−チアゾリル)−1,8−ナフチリジン−3−カルボン酸の製造方法 - Google Patents
(+)−1,4−ジヒドロ−7−[(3s,4s)−3−メトキシ−4−(メチルアミノ)−1−ピロリジニル]−4−オキソ−1−(2−チアゾリル)−1,8−ナフチリジン−3−カルボン酸の製造方法 Download PDFInfo
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- JP2015180677A JP2015180677A JP2015116753A JP2015116753A JP2015180677A JP 2015180677 A JP2015180677 A JP 2015180677A JP 2015116753 A JP2015116753 A JP 2015116753A JP 2015116753 A JP2015116753 A JP 2015116753A JP 2015180677 A JP2015180677 A JP 2015180677A
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- naphthyridine
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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- Endocrinology (AREA)
- Reproductive Health (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
Description
本出願は、「ボレロキシンの製造方法(METHOD OF PREPARING VORELOXIN)」という題名の2008年12月31日に出願の米国仮出願第61/141,856号に対する優先権を主張する。上述した出願の開示は、その全体が本明細書において参照により組み込まれる。
(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-(メチルアミノ)-1−ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸を製造するための方法、該化合物の製造において有用な中間体を製造するための方法、該化合物を含む組成物、癌の治療のためのこのような組成物の使用方法、及びSNS-595の製造において該中間体を使用する方法が本明細書に提供される。
下記構造:
特定の副生成物がSNS-595製剤に存在することが公知であるが、最終的な薬物生成物におけるそのようなものの量を減少させることが重要である。癌患者は、有意な化学療法、及び放射線を受けて、免疫系を損ない得ることが多いので、癌患者に高度に純粋な薬物を送達することは有益である。更に、非経口的投与については、薬物が直接血流の中に入るので、送達される薬物の純度、及び割合は、極めて重要である。その結果、実質的に純粋なSNS-595を生成することができる方法が本明細書において記述される。加えて、提供される方法は、実質的に純粋なSNS-595を商業的に製造するほどまでスケールアップすることができる。
(5.1 定義)
別途定義されない限り、本明細書において使用される全ての専門用語、及び科学用語は、共通に当業者によって理解されているのと同じ意味を有する。全ての特許、出願、公開された出願、及びその他の刊行物は、これらの全体が参照により組み込まれる。本明細書において用語に対して複数の定義がある場合、明記しない限りこの説におけるものを特に優先する。
チアゾリル)-1,8-ナフチリジン-3-カルボン酸を含むことを意味する。
特定の実施態様において、SNS-595の製造のための方法が本明細書に提供される。特定の実施態様において、本明細書に提供される方法は、SNS-595物質を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、N-デスメチル-SNS-595、及びO-デスメチル-SNS-595を含む組成物を生成する。特定の実施態様において、本明細書に提供される方法は、実質的に純粋なSNS-595を含む組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、N-デスメチル-SNS-595、及びO-デスメチル-SNS-595から本質的になる組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、及びN-デスメチル-SNS-595を含む組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、及びN-デスメチル-SNS-595から本質的になる組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、及びO-デスメチル-SNS-595を含む組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、及びO-デスメチル-SNS-595から本質的になる組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、及びN,O-ビスデスメチル-SNS-595を含む組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、及びN,O-ビスデスメチル-SNS-595から本質的になる組成物を生成する。特定の実施態様において、本明細書に提供される方法は、SNS-595、N-デスメチル-SNS-595、O-デスメチル-SNS-595、及びN,O-ビスデスメチル-SNS-595から本質的になる組成物を生成する。
SNS-595は、実施例3に記載されているように(3S,4S)-4-メトキシ-N-メチルピロリジン-3-アミン・2TsOH、及び7-クロロ-4-オキソ-1-チアゾール-2-イル-1,4-ジヒドロ-[1,8]ナフチリジン-3-カルボン酸エチルエステルから製造することができる。
本明細書において記述される方法に従って製造されたSNS-595物質を投与することを含む、種々の癌を治療し、予防し、及び/又は管理する方法が本明細書に提供される。特定の実施態様において、本方法は、実質的に純粋なSNS-595を投与することを包含する。癌の例は、固形腫瘍、及び血液癌を含む。本明細書に提供される方法は、また前癌状態の治療、又は予防のために使用してもよい。
特定の代表的な実施態様において、本明細書に提供される癌を治療し、予防し、又は管理する方法は、体表面積に基づいて、約10mg/m2〜100mg/m2のSNS-595物質の用量を患者に投与することを含む。特定の代表的な実施態様において、本明細書に提供される癌を治療し、予防し、又は管理する方法は、体表面積に基づいて、約10mg/m2〜110mg/m2のSNS-595物質の用量を患者に投与することを含む。特定の実施態様において、本方法は、実質的に純粋なSNS-595を投与することを包含する。別の実施態様において、本方法は、約20mg/m2〜90mg/m2のSNS-595物質の用量を投与することを含む。別の実施態様において、本方法は、約40mg/m2〜80mg/m2のSNS-595物質の用量を投与することを含む。別の実施態様において、本方法は、約30mg/m2〜50mg/m2のSNS-595物質の用量を投与することを含む。別の実施態様において、本方法は、約50mg/m2〜110mg/m2のSNS-595物質の用量を投与することを含む。
最も一般的なこのような投薬量単位は、体表面積の平方メートル当たりの活性化合物のミリグラム数である(mg/m2)。
本明細書において記述される方法に従って製造されるSNS-595物質、及びSNS-595物質を含む医薬組成物は、その他の活性薬剤、又は医学的手順との相補的併用療法において使用することができることが、また認識されるだろう。特定の実施態様において、実質的に純粋なSNS-595は、併用療法において使用される。
特定の実施態様において、本明細書に提供される方法は、1つ以上の第2の活性薬剤と組み合わせて、及び/又は放射線治療、若しくは外科手術と組み合わせて本明細書に提供される、SNS-595物質又は医薬組成物を投与することを含む。特定の実施態様において、本方法は、1つ以上の第2の活性薬剤と組み合わせて、及び/又は放射線治療、若しくは外科手術と組み合わせて、実質的に純粋なSNS-595を投与することを包含する。
本明細書に提供される方法は、本明細書に提供されるSNS-595物質、及び希釈剤又はアジュバントなどの医薬として許容し得る担体を、又は別の抗癌剤などのその他の活性成分と組み合わせて含む医薬組成物を使用する。特定の実施態様において、本方法は、実質的に純粋なSNS-595を含む医薬組成物の使用を包含する。臨床実務において、SNS-595物質は、経口的、非経口的、直腸、又は吸入(例えば、エアロゾルの形態で)によるものを含むが、限定されない任意の従来の経路によって投与してもよい。非経口的投薬形態は、皮下、静脈内(ボーラス注射を含む)、筋肉内、及び動脈内を含むが、限定されない種々の経路によって患者に投与することができる。これらの投与は、典型的には混入物に対する患者の天然の防御を迂回するので、非経口的投薬形態は、無菌であるか、又は患者への投与の前に滅菌することができる。非経口的投薬形態の例は、注射用の溶液、注射のための医薬として許容し得る媒体に溶解又は懸濁させるための乾燥生成物、注射用の懸濁液、及び乳剤を含むが、限定されない。一つの実施態様において、SNS-595物質は、IV注射によって投与される。
請求された主題の特定の実施態様は、以下の非限定的な実施例によって例証される。
BOC2O=ジ-tert-ブチル-ジカルボナート
KHMDS=カリウムヘキサメチルジシラザン
DBDMH=1,3-ジブロモ-5,5-ジメチルヒダントイン
TsOH=p-トルエンスルホン酸一水和物
CDI=カルボニルジイミダゾール
PGA=ピログルタミン酸
DTTA=ジ-p-トルオイル酒石酸
CSA=カンファースルホン酸
DBTA=ジベンゾイル酒石酸
ACN=アセトニトリル
IPA=イソプロピルアルコール
MeOH=メタノール
THF=テトラヒドロフラン、及び
MTBE=メチルtert-ブチルエーテル。
(Tetrahedron Asymmetry、12(2002)2989-2997)
N-Boc-3-ピロリン1(296g、1.75モル)をアセトニトリル(ACN、1800mL)及び水(296mL)中の1,3-ジブロモ-5,5-ジメチルヒダントイン(270g、0.94モル)のスラリーに添加し、その一方で、0〜10℃にて容器の温度を維持した。添加後、反応混合物を室温に暖めて、反応が完了したと判断されるまで(TLC又はHPLC)撹拌した。反応を5%のチオ硫酸ナトリウム水溶液(600mL)の添加によってクエンチして、生成物をジクロロメタン(2×750mL)で抽出した。合わせた有機層を、水(300mL)及び鹹水(200mL)で洗浄した。有機層を無水Na2SO4(75g)で乾燥して、減圧下で濃縮し、2(450g)を得て、これを次の工程において直接使用した。
10グラム(10g)のブロモヒドリン2を、40%のメチルアミン水溶液(50mL)及び炭酸水素ナトリウム(3.1g)で室温にて処理して、化合物4(8.5g)を得た。
メタノール(MeOH、220mL)中の化合物5A(57g、0.16モル)の混合物に、K2CO3(68.0g、0.49モル)を室温で添加した。Boc無水物(40g、0.18モル)を約1時間にわたって反応混合物に滴下して、反応が完了するまで(約2時間)、反応混合物を撹拌した。メタノールを約55〜60℃にて減圧下で蒸留して、水(150mL)を反応混合物に添加して、生成物をメチルtert-ブチルエーテル(MTBE、2×150mL)で抽出した。合わせた有機層を水(200mL)及び鹹水(100mL)で洗浄し、次いで、無水Na2SO4で乾燥した。減圧下での濃縮により、白色固体(52g)として化合物6を得た。
テトラヒドロフラン(THF、150mL)中の6(52g、0.16mol)の懸濁液を約30分間室温で撹拌して、-10〜-15℃に冷却した。カリウムヘキサメチルジシリルアミド(KHMDS、THF中の40%溶液、144mL、0.256mol)の溶液をゆっくり添加し、一方で、-5〜-15℃の間に温度を制御する。15分後、硫酸ジメチル(18.7mL、1.20mol)を反応混合物に滴加し、一方で-10〜0℃の間に温度を維持して、次いで生じる反応混合物を約30分間この温度にて撹拌した。反応混合物を水(100mL)、続いて酢酸(50mL)の添加によってクエンチした。生成物をメチルtert-ブチルエーテル(2×150mL)で抽出した。合わせた有機層を、水(100mL)、鹹水(50mL)で洗浄して、無水Na2SO4で乾燥した。減圧下での蒸発により、油(54g)として、化合物7を得た。
(±)-3-ヒドロキシ-4-メチルアミノ-ピロリジン-1-カルボン酸、tert-ブチルエステルの分割を種々のキラル酸と塩を形成することによって試みた。表3は、反応の概要を提供する。表において、「化合物4」は、(±)-3-ヒドロキシ-4-メチルアミノ-ピロリジン-1-カルボン酸、tert-ブチルエステルをいう。表3において、キラルHPLCによるエナンチオマー比は、S:Rとして表してある。実験番号72、74、及び75以後において、HPLC分析は、化合物6の段階で行った。
(化合物8の合成)
適切な医薬組成物の例示的な例は、メタンスルホン酸でpH 2.5に調整したソルビトールの4.5%の水溶液のミリリットル(mL)あたり10mgのSNS-595、及び(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-アミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸(SNS-595の量は、少なくとも99.95%であり、かつ(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-アミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸の量は、約0.05%未満である)を含む。このような溶液を作製するための1つのプロトコルは、100mg/10mLプレゼンテーションを作製するために以下を含む:100mgの活性組成物(これは、本質的に少なくとも99.95%のSNS-595、及び0.05%未満の(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-アミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸からなる)、及び450mgのD-ソルビトールを蒸留水に添加し;容積を、10mLの容積までにし;かつ生じる溶液を、メタンスルホン酸でpH 2.5に調整する。生じる組成物は、凍結乾燥にも適する。凍結乾燥された形態は、次いで使用前に適切な濃度に滅菌水で再構成される。
適切な医薬組成物の例示的な例は、メタンスルホン酸でpH 2.5に調整したソルビトールの4.5%の水溶液の1mLあたり10mgの総量のSNS-595、及び不純物(SNS-595の量は、少なくとも99.95%であり、かつ不純物の総量は約0.05%未満である)を含む。このような溶液を作製するための1つのプロトコルは、100mg/10mLプレゼンテーションを作製するために以下を含む:少なくとも約99.95%のSNS-595、及び約0.05%未満の不純物から本質的になる100mgの組成物、並びに450mgのD-ソルビトールを、蒸留水に添加し;容積を、10mLの容積までにし;かつ生じる溶液のpHを、メタンスルホン酸で2.5に調整する。生じる組成物は、凍結乾燥にも適する。凍結乾燥された形態は、次いで使用前に適切な濃度に滅菌水で再構成される。
Claims (44)
- (+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-(メチルアミノ)-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸の製造方法であって、
i)化合物3をメチルアミンでエポキシド開裂して、化合物4を得ること、
v)アミノ基をp-トルエンスルホン酸一水和物で脱保護して、化合物8を得ること、及び
- 前記メチル化剤が硫酸ジメチルである、請求項1記載の方法。
- 前記工程ii)におけるキラル酸が、L-(-)-リンゴ酸である、請求項1記載の方法。
- 約0.25〜2当量の前記L-(-)-リンゴ酸が、工程ii)において使用される、請求項3記載の方法。
- 約0.5〜1.5当量の前記L-(-)-リンゴ酸が、工程ii)において使用される、請求項1〜4のいずれか一項記載の方法。
- 約0.9〜1.1当量の前記L-(-)-リンゴ酸が、工程ii)において使用される、請求項1〜5のいずれか一項記載の方法。
- 前記L-(-)-リンゴ酸が、約40℃で化合物4の溶液に添加されて、反応混合物を形成する、請求項3記載の方法。
- 前記反応混合物が、加熱されて透明な溶液を形成する、請求項7記載の方法。
- 前記透明な溶液が、前記反応混合物を約50〜55℃に加熱することによって得られる、請求項8記載の方法。
- 前記透明な溶液を冷却して、化合物5Aの結晶を得る、請求項9記載の方法。
- 前記化合物5Aの結晶が、前記透明な溶液を段階的に5〜10℃に冷却することによって得られる、請求項10記載の方法。
- 前記化合物5Aの二級アミンをboc-無水物で保護して、化合物6を得る、請求項10記載の方法。
- 化合物3が、水酸化ナトリウムによる3-ブロモ-4-ヒドロキシ-ピロリジン-1-カルボン酸、tert-ブチルエステルのエポキシ化によって製造される、請求項1〜13のいずれか一項記載の方法。
- 3-ブロモ-4-ヒドロキシ-ピロリジン-1-カルボン酸、tert-ブチルエステルが、N-boc-3-ピロリン及び1,3-ジブロモ-5 ,5-ジメチルヒダントインを反応させることによって製造される、請求項14記載の方法。
- 化合物10がカルボニルジイミダゾール、2,6-ジクロロニコチン酸、2-アミノチアゾール、及びマロン酸エチルカリウムを反応させることによって製造される、請求項1〜15のいずれか一項記載の方法。
- 化合物8及び化合物10が、N,N'-ジイソプロピルエチルアミンの存在下において反応される、請求項1〜16のいずれか一項記載の方法。
- 化合物8及び化合物10の反応が、約3時間約45℃で行われる、請求項17記載の方法。
- 前記キラル酸がL-(-)-リンゴ酸である、請求項19記載の方法。
- 前記キラル酸がL-(-)-ピログルタミン酸である、請求項19記載の方法。
- 前記メチル化剤が硫酸ジメチルである、請求項22記載の方法。
- 前記工程ii)におけるキラル酸が、L-(-)-リンゴ酸である、請求項22記載の方法。
- 約0.9〜1.1当量の前記L-(-)-リンゴ酸が、工程ii)において使用される、請求項24記載の方法。
- (+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-(メチルアミノ)-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸の製造方法であって、
i)化合物2をメチルアミン及び塩基と反応させて、化合物4を得ること、
v)アミノ基をp-トルエンスルホン酸一水和物で脱保護して、化合物8を得ること、及び
- 請求項1〜18のいずれか一項記載の方法によって製造された、(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-(メチルアミノ)-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸。
- 組成物の総重量に基づいて、少なくとも99.95%の(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-(メチルアミノ)-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸、及び0.05%未満の(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-アミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸から本質的になる組成物。
- 組成物の総重量に基づいて、0.02%未満の(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-アミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸を有する、請求項29記載の組成物。
- 組成物の総重量に基づいて、0.01%未満の(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-アミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸を有する、請求項29記載の組成物。
- 医薬として許容し得る担体、賦形剤、又はアジュバントを更に含む、請求項29〜31のいずれか一項記載の組成物。
- その必要のある対象に、請求項29〜32のいずれか一項記載の組成物を投与することを含む、癌の治療方法。
- 前記癌が固形腫瘍を含む、請求項33記載の方法。
- 前記癌が卵巣癌である、請求項33記載の方法。
- 前記卵巣癌が、白金耐性の上皮卵巣癌である、請求項35記載の方法。
- 前記癌が血液系悪性腫瘍である、請求項33記載の方法。
- 前記血液系悪性腫瘍が、急性骨髄性白血病である、請求項37記載の方法。
- 前記癌が乳癌である、請求項33記載の方法。
- 第2の薬剤の治療的に有効な用量を投与することを更に含む、請求項33〜39のいずれか一項記載の方法。
- 前記第2の薬剤がシタラビン、カルボプラチン、シスプラチン、ゲムシタビン、抗嘔吐薬、及びこれらの組み合わせから選択される、請求項40記載の方法。
- 1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-アミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸、及び1,4-ジヒドロ-7-[(3S,4S)-3-オキシ-4-メチルアミノ-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸からなる群から選択される不純物を実質的に含まない、(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-(メチルアミノ)-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸。
- ヒトへの使用に適した、少なくとも1キログラムの(+)-1,4-ジヒドロ-7-[(3S,4S)-3-メトキシ-4-(メチルアミノ)-1-ピロリジニル]-4-オキソ-1-(2-チアゾリル)-1,8-ナフチリジン-3-カルボン酸であって、
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PL2295056T3 (pl) | 2004-03-15 | 2016-07-29 | Sunesis Pharmaceuticals Inc | Zastosowanie SNS-595 do leczenia białaczki |
US20100048609A1 (en) * | 2006-08-01 | 2010-02-25 | Jacobs Jeffrey W | Pharmaceutical dosage forms for (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid |
EP2214662B1 (en) | 2007-10-22 | 2016-07-13 | Sunesis Pharmaceuticals, Inc. | (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid in combination with gemcitabine for use in treating cancer |
EP2249831A2 (en) | 2007-12-10 | 2010-11-17 | Sunesis Pharmaceuticals, Inc. | Methods of using (+)-1,4-dihydro-7-ý(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl¨-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment of antecedent hematologic disorders |
UA110465C2 (en) | 2009-09-04 | 2016-01-12 | Sunesis Pharmaceutecals Inc | Stable sns-595 composition |
TW201120037A (en) * | 2009-10-26 | 2011-06-16 | Sunesis Pharmaceuticals Inc | Compounds and methods for treatment of cancer |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02218664A (ja) * | 1989-02-17 | 1990-08-31 | Tokyo Kasei Kogyo Kk | 光学活性な1h−3−アミノピロリジン化合物の製造法 |
JPH07188124A (ja) * | 1993-12-28 | 1995-07-25 | Toray Ind Inc | 光学活性アミンの単離方法 |
JPH11349565A (ja) * | 1998-06-05 | 1999-12-21 | Dainippon Pharmaceut Co Ltd | ピリドンカルボン酸誘導体の製造方法およびその中間体 |
WO2007146335A2 (en) * | 2006-06-12 | 2007-12-21 | Sunesis Pharmaceuticals, Inc. | Compounds and compositions for treatment of cancer |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6233176A (ja) | 1985-08-05 | 1987-02-13 | Toyama Chem Co Ltd | 1,4−ジヒドロ−4−オキソナフチリジン誘導体およびその塩 |
KR0166088B1 (ko) | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
EP0787726B1 (en) | 1994-06-14 | 2001-11-28 | Dainippon Pharmaceutical Co., Ltd. | Novel compound, process for producing the same, and antitumor agent |
JP4323574B2 (ja) | 1995-12-13 | 2009-09-02 | 大日本住友製薬株式会社 | 抗腫瘍剤 |
JPH10173986A (ja) | 1996-12-16 | 1998-06-26 | Sony Corp | 移動体撮影装置 |
JP4178783B2 (ja) | 2001-10-19 | 2008-11-12 | 三菱化学株式会社 | 光学記録媒体 |
PL2295056T3 (pl) | 2004-03-15 | 2016-07-29 | Sunesis Pharmaceuticals Inc | Zastosowanie SNS-595 do leczenia białaczki |
US8580814B2 (en) | 2006-04-03 | 2013-11-12 | Sunesis Pharmaceuticals, Inc. | Methods of using (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4- oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment of cancer |
US20100048609A1 (en) | 2006-08-01 | 2010-02-25 | Jacobs Jeffrey W | Pharmaceutical dosage forms for (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid |
US7790274B2 (en) | 2006-08-02 | 2010-09-07 | High Impact Technology, Llc | Layered panel structure including self-bonded thermoformable and non-thermoformable layer materials |
SI2049109T1 (sl) | 2006-08-02 | 2016-04-29 | Sunesis Pharmaceuticals, Inc. | Kombinirana uporaba(+)-1,4-dihidro-7-((3s,4s)-3-metoksi-4-(metilamino)- 1-pirolidinil)-4-okso-1-(2-tiazolil)-1,8-naftiridin-3-karboksilne kisline in citarabina (ara-c) za zdravljenje levkemije |
EP2214662B1 (en) | 2007-10-22 | 2016-07-13 | Sunesis Pharmaceuticals, Inc. | (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid in combination with gemcitabine for use in treating cancer |
EP2249831A2 (en) | 2007-12-10 | 2010-11-17 | Sunesis Pharmaceuticals, Inc. | Methods of using (+)-1,4-dihydro-7-ý(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl¨-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment of antecedent hematologic disorders |
CN102405045A (zh) | 2009-02-27 | 2012-04-04 | 逊尼希思制药公司 | 利用sns-595 治疗具有降低的brca2 活性的癌症对象的方法 |
UA110465C2 (en) | 2009-09-04 | 2016-01-12 | Sunesis Pharmaceutecals Inc | Stable sns-595 composition |
TW201120037A (en) | 2009-10-26 | 2011-06-16 | Sunesis Pharmaceuticals Inc | Compounds and methods for treatment of cancer |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02218664A (ja) * | 1989-02-17 | 1990-08-31 | Tokyo Kasei Kogyo Kk | 光学活性な1h−3−アミノピロリジン化合物の製造法 |
JPH07188124A (ja) * | 1993-12-28 | 1995-07-25 | Toray Ind Inc | 光学活性アミンの単離方法 |
JPH11349565A (ja) * | 1998-06-05 | 1999-12-21 | Dainippon Pharmaceut Co Ltd | ピリドンカルボン酸誘導体の製造方法およびその中間体 |
WO2007146335A2 (en) * | 2006-06-12 | 2007-12-21 | Sunesis Pharmaceuticals, Inc. | Compounds and compositions for treatment of cancer |
Non-Patent Citations (2)
Title |
---|
TSUZUKI Y: "PRACTICAL SYNTHESIS OF (3S,4S)-3-METHOXY-4-METHYLAMINOPYRROLIDINE", TETRAHEDRON ASYMMETRY, vol. V12 N21, JPN5012005327, 26 November 2001 (2001-11-26), GB, pages 989 - 2997 * |
日本化学会, 実験化学講座18 有機化合物の反応II(上), JPN6014011156, November 1957 (1957-11-01), pages 第531−546頁 * |
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