DE19547958A1 - Anthracyclin-Derivate - Google Patents
Anthracyclin-DerivateInfo
- Publication number
- DE19547958A1 DE19547958A1 DE19547958A DE19547958A DE19547958A1 DE 19547958 A1 DE19547958 A1 DE 19547958A1 DE 19547958 A DE19547958 A DE 19547958A DE 19547958 A DE19547958 A DE 19547958A DE 19547958 A1 DE19547958 A1 DE 19547958A1
- Authority
- DE
- Germany
- Prior art keywords
- deamino
- group
- methoxy
- morpholinyl
- formula
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(A1): 3′-Deamino-3′[2(S)-methoxy-4-morpholinyl)- doxorubic-in-N-oxid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=O, R₉=H, R₁₀=(S)OCH₃, X=O, R₇=OH, R₈=H)
(A2): 3′-Deamino-3′[2(S)-methoxy-4-morpholinyl)- doxorubicin-N-hydroxidchlorid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=OH, R₉=H, R₁₀=(S)OCH₃₁ X=O, R₇=OH, R₈=H]
(A3): 3′-Deamino-3′[2(R)-methoxy-4-morpholinyl]- doxorubicin-N-oxid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=O, R₉=H, R₁₀=(R)OCH₃, X=O, R₇=OH, R₈=H]
(A4): 3′-Deamino-3′[2(R)-methoxy-4-morpholinyl]- doxorubicin-N-hydroxidchlorid
[R₁=OCH₃₁ R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=OH, R₉=H, R₁₀=(R)OCH₃, X=O, R₇=OH, R₈=H]
(A5): 4-Demethoxy-3′-deamino-3′[2(S)-methoxy-4- morpholinyl]-daunorubicin-N-oxid
[R₁=H, R₂=R₃=OH, R₄=H, R₅=COCH₃, R₆=O, R₉=H, R₁₀=(S)OCH₃, X=O, R₇=OH, R₈=H]
(A6): 4-Demethoxy-3′-deamino-3′[2(S)-methoxy-4- morpholinyl]-daunorubicin-N-hydroxidchlorid
[R₁=H, R₂=R₃=OH, R₄=H, R₅=COCH₃, R₆=OH, R₉=H, R₁₀=(S)OCH₃, X=O, R₇=OH, R₈=H]
(A7): 4-Demethoxy-3′-deamino-3′[2(R)-methoxy-4- morpholinyl]-daunorubicin-N-oxid
[R₁=H, R₂=R₃=OH, R₄=H, R₅=COCH₃, R₆=O, R₉=H, R₁₀=(R)OCH₃, X=O, R₇=OH, R₈=H]
(A8): 4-Demethoxy-3′-deamino-3′[2(R)-methoxy-4- morpholinyl]-daunorubicin-N-hydroxidchlorid
[R₁=H, R₂=R₃=OH, R₄=H, R₅=COCH₃, R₆=OH, R₉=H, R₁₀=(R)OCH₃, X=O, R₇=OH, R₈=H]
(A9): 3′-Deamino-3′[4-morpholinyl]-doxorubicin-N-oxid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=O, R₉=R₁₀=H, X=O, R₇=OH, R₈=H]
(A10): 3′-Deamino-3′[4-morpholinyl]-doxorubicin-N- hydroxid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=OH, R₉=R₁₀=H, X=O, R₇=OH, R₈=H]
(A11): 13-Dihydro-3′-deamino-3′[2-methoxy-4- morpholinyl]-doxorubicin-N-oxid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=CH(OH)CH₂OH, R₆=O, R₉=H, R₁₀=OCH₃, X=O, R₇=OH, R₈=H)
(A12): 13-Dihydro-3′-deamino-3′[2-methoxy-4- morpholinyl]-doxorubicin-N-hydroxychlorid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=CH(OH)CH₂OH, R₆=OH, R₉=H, R₁₀=OCH₃, X=O, R₇=OH, R₈=H)
(A13): 3′-Deamino-3′[piperidin]-doxorubicin-N-oxid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=O, R₉=R₁₀=H, X=CH₂₁ R₇=OH, R₈=H]
(A14): 3′-Deamino-3′[piperidin]-doxorubicin-N- hydroxychlorid
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₆=OH, R₉=R₁₀=H, X=CH₂, R₇=OH, R₈=H]
Anthracyclin-N-oxide der Formel A (R₆=O) können durch ein Verfahren hergestellt werden, das die folgenden Schritte umfaßt:
i) Reaktion einer Verbindung der Formel B
(B1): 3′-Deamino-3′[2(S)-methoxy-4-morpholinyl]- doxorubicin
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₉=H, R₁₀=(S)OCH₃, X=O, R₇=OH, R₈=H]
(B2): 3′-Deamino-3′[2(R)-methoxy-4-morpholinyl]- doxorubicin
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₉=H, R₁₀=(R)OCH₃, X=O, R₇=OH, R₈=H]
(B3): 4-Demethoxy-3′-deamino-3′[2(S)-methoxy-4- morpholinyl]-daunorubicin
[R₁=H, R₂=R₃=OH, R₄=H, R₅=COCH₃, R₉=H, R₁₀=(S)OCH₃, X=O, R₇=OH, R₈=H]
(B4): 4-Demethoxy-3′-deamino-3′[2(R)-methoxy-4- morpholinyl]-daunorubicin
[R₁=H, R₂=R₃=OH, R₄=H, R₅=COCH₃, R₉=H, R₁₀=(R)OCH₃, X=O, R₇=OH, R₈=H]
(B5): 3′-Deamino-3′[4-morpholinyl]-doxorubicin
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₉=R₁₀=H, X=O, R₇=OH, R₈=H]
(B6): 13-Dihydro-3′-deamino-3′[2-methoxy-4-morpholinyl]- doxorubicin
(B7): 3′-Deamino-3′[piperidin]-doxorubicin
[R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COCH₂OH, R₉=R₁₀=H, X=CH₂, R₇=OH, R₈=H]
Methylenchlorid, Methanol, Essigsäure, Wasser (30 : 4 : 1 : 0,5, bezogen auf das Volumen) Rf:0,6.
Methylenchlorid, Methanol, Essigsäure, Wasser (30 : 4 : 1 : 0,5, bezogen auf das Volumen) Rf:0,6.
Methylenchlorid, Methanol, Essigsäure, Wasser (30 : 4 : 1 : 0,5, bezogen auf das Volumen) Rf:0,63.
Methylenchlorid, Methanol (20 : 1, bezogen auf das Volumen) Rf:0,28.
Methylenchlorid, Methanol (20 : 1, bezogen auf das Volumen) Rf:0,28.
Methylenchlorid, Methanol, Essigsäure, Wasser (30 : 4 : 1 : 0,5, bezogen auf das Volumen) Rf:0,37.
methoxy-4-morpholinyl]doxorubicin (B1) | |
Verbindung | |
IC50 (ng/ml) | |
A1 | |
5,43 | |
A2 | 0,36 |
B1 | 7,62 |
Claims (18)
3′-Deamino-3′[2(S)-methoxy-4-morpholinyl]- doxorubicin-N-oxid,
3′-Deamino-3′[2(S)-methoxy-4-morpholinyl]- doxorubicin-N-hydroxidchlorid,
3′-Deamino-3′[2(R)-methoxy-4-morpholinyl]- doxorubicin-N-oxid,
3′-Deamino-3′[2(R)-methoxy-4-morpholinyl]- doxorubicin-N-hydroxidchlorid,
4-Demethoxy-3′-deamino-3′[2(S)-methoxy-4- morpholinyl]-daunorubicin-N-oxid,
4-Demethoxy-3′-deamino-3′[2(S)-methoxy-4- morpholinyl]-daunorubicin-N-hydroxidchlorid,
4-Demethoxy-3′-deamino-3′[2(R)-methoxy-4- morpholinyl]-daunorubicin-N-oxid,
4-Demethoxy-3′-deamino-3′[2(R)-methoxy-4- morpholinyl]-daunorubicin-N-hydroxidchlorid,
3′-Deamino-3′[4-morpholinyl]-doxorubicin-N-oxid,
3′-Deamino-3′[4-morpholinyl]-doxorubicin-N- hydroxid,
13-Dihydro-3′-deamino-3′[2-methoxy-4-morpholinyl]- doxorubicin-N-oxid,
13-Dihydro-3′-deamino-3′[2-methoxy-4-morpholinyl]- doxorubicin-N-hydroxychlorid,
3′-Deamino-3′[piperidin]-doxorubicin-N-oxid oder
3′-Deamino-3′[piperidin]-doxorubicin-N- hydroxychlorid ist.
- (a) Reaktion einer Verbindung der Formel B mit einer Peroxid-Verbindung worin R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ und X wie in Anspruch 1 definiert sind, und, falls gewünscht
- (b) Behandlung des resultierenden N-Oxides mit einer organischen oder anorganischen Säure und, falls gewünscht,
- (c) Umwandlung des Anthracyclinanalogons der Formel A, das somit erhalten ist, in ein pharmazeutisch akzeptables Salz davon.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9426075 | 1994-12-23 | ||
GB9426075A GB2296495B (en) | 1994-12-23 | 1994-12-23 | Anthracycline derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
DE19547958A1 true DE19547958A1 (de) | 1996-06-27 |
DE19547958B4 DE19547958B4 (de) | 2015-01-22 |
Family
ID=10766488
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19547958.0A Expired - Lifetime DE19547958B4 (de) | 1994-12-23 | 1995-12-21 | Anthracyclin-Derivate |
Country Status (4)
Country | Link |
---|---|
JP (1) | JP4081148B2 (de) |
DE (1) | DE19547958B4 (de) |
GB (1) | GB2296495B (de) |
IT (1) | IT1277073B1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004082689A1 (en) * | 2003-03-18 | 2004-09-30 | Pharmacia Italia Spa | Combined therapy comprising nemorubicin and a cyclooxygenase-2-inhibitor |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2315067B (en) * | 1996-07-11 | 2000-02-16 | Pharmacia Spa | Morpholinyl anthracycline derivatives |
EP1242438B1 (de) * | 1999-12-29 | 2006-11-08 | Immunogen, Inc. | Doxorubicin- und daunorubicin-enthaltende, zytotoxische mittel und deren therapeutische anwendung |
BRPI0408494A (pt) * | 2003-03-18 | 2006-04-04 | Pharmacia Italia Spa | terapia combinada contra tumores compreendendo nemorubicina com terapia de radiação |
US8742076B2 (en) | 2008-02-01 | 2014-06-03 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
MX2010011079A (es) * | 2008-04-11 | 2012-06-01 | Tianjin Hemay Bio Tech Co Ltd | Derivados antibioticos de antraquinona tetraciclica con alta actividad, proceso para preparar los mismos y uso de estos. |
CN101555264B (zh) * | 2008-04-11 | 2014-09-03 | 天津和美生物技术有限公司 | 具有高活性的四环蒽醌类抗生素的衍生物及其制备和应用 |
WO2010009124A2 (en) | 2008-07-15 | 2010-01-21 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
BR112013013127B1 (pt) | 2010-12-02 | 2021-06-22 | Nerviano Medical Sciences S.R.L. | Processo para a preparação de derivados de morfolinil antraciclina, compostos derivados de morfolinil antraciclina e composição farmacêutica compreendendo estes compostos |
ES2633359T3 (es) * | 2012-03-06 | 2017-09-20 | Tianjin Hemay Oncology Pharmaceutical Co., Ltd. | Derivados de antraquinona tetracíclica |
ES2695162T3 (es) * | 2013-04-29 | 2019-01-02 | Nerviano Medical Sciences Srl | Nuevos derivados de morfolinil antraciclina |
EP3215513B1 (de) | 2014-11-05 | 2019-05-08 | Nerviano Medical Sciences S.r.l. | Funktionalisierte morpholinyl-anthracyclin-derivate |
CN110776501B (zh) * | 2019-08-22 | 2021-04-02 | 联宁(苏州)生物制药有限公司 | 一种用于抗体药物偶联物的药物毒素pnu-159682的制备方法及其中间体 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4301277A (en) * | 1980-10-20 | 1981-11-17 | Sri International | 3-Deamino-3-(4-morpholinyl) derivatives of daunorubicin and doxorubicin |
JPS57163393A (en) * | 1981-03-27 | 1982-10-07 | Microbial Chem Res Found | Novel anthracyclin derivative and its preparation |
JPS59212499A (ja) * | 1983-05-13 | 1984-12-01 | アドリヤ・ラボラトリ−ズ・インコ−ポレ−テツド | 抗腫瘍性抗生物質アントラサイクリンの4−デメトキシ−3′−デアミノ−3′(4−モリホリニル)誘導体 |
US4585859A (en) * | 1983-05-24 | 1986-04-29 | Sri International | Analogues of morpholinyl daunorubicin and morpholinyl doxorubicin |
-
1994
- 1994-12-23 GB GB9426075A patent/GB2296495B/en not_active Expired - Lifetime
-
1995
- 1995-12-13 IT IT95MI002614A patent/IT1277073B1/it active IP Right Grant
- 1995-12-21 DE DE19547958.0A patent/DE19547958B4/de not_active Expired - Lifetime
- 1995-12-22 JP JP33521695A patent/JP4081148B2/ja not_active Expired - Lifetime
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004082689A1 (en) * | 2003-03-18 | 2004-09-30 | Pharmacia Italia Spa | Combined therapy comprising nemorubicin and a cyclooxygenase-2-inhibitor |
Also Published As
Publication number | Publication date |
---|---|
GB2296495B (en) | 1998-04-15 |
GB2296495A (en) | 1996-07-03 |
JPH08231581A (ja) | 1996-09-10 |
JP4081148B2 (ja) | 2008-04-23 |
GB9426075D0 (en) | 1995-02-22 |
IT1277073B1 (it) | 1997-11-04 |
ITMI952614A0 (de) | 1995-12-13 |
ITMI952614A1 (it) | 1997-06-13 |
DE19547958B4 (de) | 2015-01-22 |
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