JP5315335B2 - トポテカンの製造方法 - Google Patents
トポテカンの製造方法 Download PDFInfo
- Publication number
- JP5315335B2 JP5315335B2 JP2010503051A JP2010503051A JP5315335B2 JP 5315335 B2 JP5315335 B2 JP 5315335B2 JP 2010503051 A JP2010503051 A JP 2010503051A JP 2010503051 A JP2010503051 A JP 2010503051A JP 5315335 B2 JP5315335 B2 JP 5315335B2
- Authority
- JP
- Japan
- Prior art keywords
- topotecan
- group
- base
- dimethylmethyleneiminium
- halide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Separation By Low-Temperature Treatments (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
Description
例えば、米国特許第5,734,056号は、ビス(ジメチルアミノ)メタン;ビス (N-モルホリノ)メタン;ビス(N-メチルピペラジニル)メタン;ビス (4'-ピペリジノピペリジニル)メタン;ビス(シクロプロピルアミノ)メタン;ビス (N-メチルアニリノ)メタン;またはビス(シクロヘキシルアミノ)メタンと10-ヒドロキシ-カンプトテシンとを反応させて、トポテカンを含む9-置換カンプトテシン類を製造する方法を開示している。
のイミニウム塩と、有機溶媒中で塩基の存在下に反応させて、トポテカンまたはその医薬的に許容される塩を有利に製造できることを見出した。
有機の塩基は、アミン、ピリジン、ピコリン、キノリン、ピペリジン、ピロリジン、N-メチルモルホリン、およびこれらの組合せから選択され得る。
無機の塩基は、水酸化アルカリ、炭酸アルカリ、炭酸水素アルカリ、およびこれらの組合せからなる群から選択され得る。好ましい塩基はトリエチルアミンである。
上記のイミニウム塩は、好ましくはN, N-ジメチルメチレンイミニウムハライドであり、より好ましくはN, N-ジメチルメチレンイミニウムクロライドまたはN, N-ジメチルメチレンイミニウムヨウダイドである。
該有機溶媒は、C1〜C4のクロル化された炭化水素から選択された有機ハロゲン化物溶媒、またはC1〜C6のアルコール類から選択されたアルコールであるのが好ましい。より好ましくは、有機溶媒系は、ジクロロメタンとイソプロパノールとの混合溶媒である。
反応は無水条件下に行われるのが好ましい。
あるいは、トポテカン塩酸塩は、10-ヒドロキシ-カンプトテシンと式(I)のイミニウム塩とのマンニッヒ反応により得られる反応混合物に塩酸を加えることによっても製造することができる。
したがって、本発明によって製造されるトポテカンまたはトポテカン塩は、式IIのヒドロキシメチル不純物を実質的に含んでいない。
最終生成物であるトポテカンまたはトポテカン塩が、式IIのヒドロキシメチル不純物を含んでいないのが、より好ましい。
本発明のその他の目的および特徴は、付随した図面とともに考慮される以下の詳細な記述から明らかになるだろう。
さらに、図面は、ここに記載された構造および方法を概念的に示すことだけを意図しているということが理解されるべきである。
以下は、本発明の2つの実施形態により、トポテカンおよびトポテカン塩酸塩を製造する方法の実施例である。
実施例1
工程1a:マンニッヒ反応
10-ヒドロキシ-カンプトテシン(0.1 g)、N,N-ジメチルメチレンイミニウムヨウダイド(約 0.06 g)、ジクロロメタン (約 1.3 g)およびイソプロパノール(約 0.8 g) を適当な反応器中に入れた。得られた混合物を5〜10分間撹拌した。次いで、トリエチルアミン(0.002-0.03 g)を加え、得られた混合物を室温で撹拌した。反応終了後、得られた混合物に、塩酸(37%, 0.003-0.045 g)およびイソプロパノール(約 0.14 g)の混合物を加えた。得られた混合物を4時間にわたって撹拌し、次いで固形物を濾取し、ジクロロメタン(約 1 g)で洗浄し、真空下に乾燥して、約 0.11 g のトポテカンHClを得た。
Claims (15)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US92291807P | 2007-04-11 | 2007-04-11 | |
US60/922,918 | 2007-04-11 | ||
PCT/US2008/004610 WO2008127606A1 (en) | 2007-04-11 | 2008-04-10 | Process for making topotecan |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010523672A JP2010523672A (ja) | 2010-07-15 |
JP5315335B2 true JP5315335B2 (ja) | 2013-10-16 |
Family
ID=39864238
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010503051A Expired - Fee Related JP5315335B2 (ja) | 2007-04-11 | 2008-04-10 | トポテカンの製造方法 |
Country Status (14)
Country | Link |
---|---|
US (1) | US7977483B2 (ja) |
EP (1) | EP2148882B8 (ja) |
JP (1) | JP5315335B2 (ja) |
KR (1) | KR20100015824A (ja) |
CN (1) | CN101679450B (ja) |
AR (1) | AR068970A1 (ja) |
AU (1) | AU2008239680B2 (ja) |
CA (1) | CA2683937C (ja) |
ES (1) | ES2390388T3 (ja) |
HR (1) | HRP20120739T1 (ja) |
IL (1) | IL201455A (ja) |
NZ (1) | NZ580344A (ja) |
TW (1) | TWI360419B (ja) |
WO (1) | WO2008127606A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2373172B1 (es) * | 2010-07-16 | 2012-12-10 | Consejo Superior De Investigaciones Científicas (Csic) | Proceso de obtención de derivados solubles en agua de 20 (s) camptotecina como agentes antitumorales. |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5004758A (en) | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
ATE186461T1 (de) | 1990-09-28 | 1999-11-15 | Smithkline Beecham Corp | Verfahren zur herstellung wasserlöslicher camptothecinanaloge, sowie die verbindungen 10- hydroxy-11-c(1-6)-alkoxycamptothecin |
US6660861B1 (en) | 2003-03-27 | 2003-12-09 | Council Of Scientific And Industrial Research | Process for preparing Topotecan from 10-hydroxy-4-(S) camptothecin |
EP1608660B1 (en) * | 2003-03-31 | 2007-10-10 | Council of Scientific and Industrial Research | Process for preparing topotecan from 10-hydroxy-4-(s) camptothecin |
AR046579A1 (es) | 2003-11-12 | 2005-12-14 | Smithkline Beecham Corp | Compuesto cristalino de topotecan, composicion farmaceutica que lo comprende, procedimiento para prepararlo y su uso para preparar dicha composicion farmaceutica |
US7547785B2 (en) * | 2005-12-26 | 2009-06-16 | Dr. Reddy's Laboratories Limited | Process for preparing topotecan |
-
2008
- 2008-04-09 US US12/082,162 patent/US7977483B2/en not_active Expired - Fee Related
- 2008-04-10 ES ES08742705T patent/ES2390388T3/es active Active
- 2008-04-10 WO PCT/US2008/004610 patent/WO2008127606A1/en active Application Filing
- 2008-04-10 TW TW097113081A patent/TWI360419B/zh not_active IP Right Cessation
- 2008-04-10 NZ NZ580344A patent/NZ580344A/en not_active IP Right Cessation
- 2008-04-10 CA CA2683937A patent/CA2683937C/en not_active Expired - Fee Related
- 2008-04-10 AU AU2008239680A patent/AU2008239680B2/en not_active Ceased
- 2008-04-10 EP EP08742705A patent/EP2148882B8/en not_active Not-in-force
- 2008-04-10 JP JP2010503051A patent/JP5315335B2/ja not_active Expired - Fee Related
- 2008-04-10 CN CN2008800177733A patent/CN101679450B/zh not_active Expired - Fee Related
- 2008-04-10 KR KR1020097022152A patent/KR20100015824A/ko active IP Right Grant
- 2008-04-11 AR ARP080101529A patent/AR068970A1/es unknown
-
2009
- 2009-10-11 IL IL201455A patent/IL201455A/en not_active IP Right Cessation
-
2012
- 2012-09-17 HR HRP20120739AT patent/HRP20120739T1/hr unknown
Also Published As
Publication number | Publication date |
---|---|
WO2008127606A8 (en) | 2013-02-07 |
NZ580344A (en) | 2012-02-24 |
CA2683937A1 (en) | 2008-10-23 |
US7977483B2 (en) | 2011-07-12 |
ES2390388T3 (es) | 2012-11-12 |
JP2010523672A (ja) | 2010-07-15 |
WO2008127606A1 (en) | 2008-10-23 |
AU2008239680A1 (en) | 2008-10-23 |
IL201455A0 (en) | 2010-05-31 |
EP2148882A4 (en) | 2010-05-19 |
EP2148882A1 (en) | 2010-02-03 |
TW200902004A (en) | 2009-01-16 |
IL201455A (en) | 2014-02-27 |
EP2148882B1 (en) | 2012-06-20 |
EP2148882B8 (en) | 2013-02-27 |
AU2008239680B2 (en) | 2013-04-04 |
TWI360419B (en) | 2012-03-21 |
HRP20120739T1 (hr) | 2012-12-31 |
CN101679450B (zh) | 2012-05-02 |
US20090221826A1 (en) | 2009-09-03 |
CN101679450A (zh) | 2010-03-24 |
CA2683937C (en) | 2013-03-26 |
KR20100015824A (ko) | 2010-02-12 |
AR068970A1 (es) | 2009-12-23 |
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