GB2140006A - Anthracycline derivatives - Google Patents
Anthracycline derivatives Download PDFInfo
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- GB2140006A GB2140006A GB08408453A GB8408453A GB2140006A GB 2140006 A GB2140006 A GB 2140006A GB 08408453 A GB08408453 A GB 08408453A GB 8408453 A GB8408453 A GB 8408453A GB 2140006 A GB2140006 A GB 2140006A
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- deamino
- morpholino
- cyano
- daunorubicin
- doxorubicin
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- 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
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Abstract
Anthracycline glycosides of formula <IMAGE> (X = H or OH, R1 = H or CH3O, one of R2 and R3 = H and the other = H or OH, R4 = H or CN) and their pharmaceutically acceptable acid addition salts have antitumour activity. The preparation of the anthracycline glycosides from the corresponding 3'-amino precursors is also described.
Description
SPECIFICATION
Anthracycline derivatives
The invention relates to a nth racycline glycosides, to processes for their preparation and to pharmaceutical compositions containing them.
The invention provides anthracycline glycosides having the general formula A
wherein
X represents a hydrogen atom or a hydroxy group,
R1 represents a hydrogen atom or a methoxy group,
one of R2 and F3 represents a hydrogen atom, the other of R2 and R3 represents a hydrogen atom or a
hydroxy group, and
R4 represents a hydrogen atom or a cyano group.
Pharmaceutically acceptable acid addition salts of these anthracycline glycosides are included in the invention.
The anthracycline glycosides of the general formula A include: 4-demethoxy-3'-deamino-3'-morpholino-daunorubicin (A-l : R1=R2=R4=X=H, R3=OH); 4-demethoxy-3'-deamino-3'-(3-cyano-morpholino)-daunorubicin (A-ll: R=R2=X=H, R3=OH, R4=CN); 4-demethoxy-3'-deamino-3'-morpholino-doxorubicin (A-lll : R1=R2=R4=H, R3=X=OH); 4-demethoxy-3'-deamino-3'-(3-cyano-morpholino)-doxorubicin (A-IV: R1=R2=H, R3=X=OH, R4=CH); 3'-deamino-3'-morpholino-4'-epi-daunorubicin (A-V: R1=OCH3, R3=R4=X=H, R2=OH); 3'-deamino-3'-(3-cyano-morpholino)-4'-epi-daunorubicin (A-VI :R1=OCH3, R3=X=H, R2=OH, R4=CN); 3'-deamino-3'-morpholino-4'-epi-doxorubicin (A-Vll : R1=OCH3; R3=R4=H, R2=X=OH); 3'-deamino-3'-(3-cyano-morpholino)-4'-epi-doxorubicin (A-Vlll : R1=OCH3, R3=H, R2=X=OH, R4=CN); 3'-deamino-3'-morpholino-4'-deoxy-daunorubicin (A-IX: R1=OCH3, R2=R3=R4=X=H); 3'-deamino-3'-(3-cyano-morpholino)-4'-deoxy-daunorubicin (A-X:R1=OCH3, R2=R3=X=H, R4=CN); 3'-deamino-3'-morpholino-4'-deoxy-doxorubicin (A-XI : R1=OCH3, R2=R3=R4=H,X=OH); and 3'-deamino-3'-(3-cyano-morpholino-4'-deoxy-doXorubicin (A-Xll : R=OCH3, R2=R3=H, R4=CN, X=OH).
The invention further provides a process for the preparation of the anthracycline glycosides according to the invention, the process comprising reacting an anthracycline glycoside having the general formula B
wherein R1, R2, R3 and X are as above defined with bis-(2,2-diethoxyethyl) ether in the presence of NaCNBH3.
The 3'-deamino-3'-morpholino and 3'-deamino-3'-(3-cyanomorpholino) derivatives are formed together and are separated by chromatography, suitably on a silica gel column.
Alternatively, but also within the scope of the invention, the anthracycline glycosides according to the invention may be prepared by reacting an anthracycline glycoside having the general formula B with bis(2-iodoethyl) ether or with 3-(ss-iodo-ethoxy)-2-hydroxy-propionitrile.
The anthracycline glycosides according to the invention exert a remarkable cytotoxic activity against human tumour cells cultivated in vitro, and show promising antitumour activity in mice bearing transplanted tumours. Accordingly, the invention also provides a pharmaceutical composition comprising an anthracy dine glycoside having the general formula A or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
The following Examples illustrate the invention. Thin layer chromatography (TLC) measurements were made on Kieselgel plates (Merck F254) using dichloromethane: methanol (6:1 by volume) as eluent. 'Merck' is a Trade Mark. Proton magnetic resonsance (PMR) measurements were made in DMSO-d6, with values given on the 8 scale.
EXAMPLE 1 4-demethoxy-3'-deamino-3'-morpholino-daunorubicin fA-l) and 4demethoxy-3'-deamino-3'-r3-cyano- morpholino)-daunorubicin (A 41) A solution of 1.0 g (4.0 mmol) of bis(2,2-diethoxyethyl) ether in 15 ml of water and 0.15 ml of glacial acetic acid was refluxed under a nitrogen flow for 30 minutes. The completion of the hydrolysis to bis(2-oxoethyl) ether was checked by TLC on Kieselgel plates (Merck F254) using the solvent system dichloromethane:acetone (4:1 by volume) and spraying with concentrated sulphuric acid. The reaction mixture was then adjusted to pH 7 using solid sodium bicarbonate and added to a solution of 0.11 g (0.2 mmol) of 4-demethoxydaunorubicin hydrochloride in 5 ml of water and 5 ml of acetonitrile. After a few minutes a precipitate formed.The mixture was stirred for 45 minutes and the precipitated solid was then dissolved by adding a further amount of acetonitrile and treated with 0.03 g of NaCNBH3 dissolved in 1 ml of water. The reaction mixture was stirred at room temperature for two hours, diluted with 10 ml of water and extracted with dichloromethane until the extracts were colourless. The combined organic extracts were washed with water, dried on anhydrous sodium sulphate and evaporated to dryness under vacuum to give a crude mixture containing the two products A-l and A-ll in the approximate ratio 4:1 by weight.
Their separation was performed by flash chromatography on a column of silica gel using as eluent the solvent mixture dichloromethane: methanol (96:4 by volume). The fractions containing the less polar product were combined and evaporated to dryness under vacuum to give 0.035 g of pure 4-demethoxy-3' deamino-3'-(3-cyano-4-morpholino)-daunorubicin (A-Il).
TLC: Rf 0.65
FD-MS : m/z 592 (M+), miz 368 laglycone) (PMR: interalia at 1.21 (d, CH3-C-5'), 2.35 (s, CH3CO), 1.5-3.0 (m, C-2'-H2, C-8-H2,
(m,
C-4'-H),4.15(m,C-5'-H),4.63 (m,
4.81 (m, C-7-H), 5.21 (m, C-1'-H), 7.8-8.2 (m, 4 aromatic protons), 13.16 and 13.38 (s, two phenolic protons).
The fractions containing the major reaction product were combined to give 0.1 g of pure 4-demethoxy-3'deamino-3'-morpholino-daunorubicin (A-l).
TLC: Rf 0.54.
FD-MS : m/z 567 IM + ), m/z 368 (aglycone).
PMR: interalia at 1.22 (d, CH3-C-5'), 2.30 (s, CH3CO), 1.4-3.1 (m, C-2'-H2, C-8-H2,
C-3'-H), 3.2-3.9
C-4'-H), 4.85 (m, C-7-H); 5.29 (m, C-1'-H).
EXAMPLE 2 4-demethoxy-3'-deamino-3'-morpholino-doxorubicin {A-lil) and 4-demethoxy-3'-deamino-3'-(3-cyano- morpholino)-doxorubicin (A4V) A solution of 1.0 g (4.0 mmol) of bis(2,2-diethoxyethyl) ether in 15 ml of water and 0.15 ml of glacial acetic acid was refluxed under a nitrogen flow for 30 minutes and then evaporated to dryness under vacuum. The residue was dissolved in 3 ml of dimethylformamide and added to a solution of 0.113 g (0.2 mmol) 4-demethoxy-doxorubicin hydrochloride in 5 ml of dimethylformamide. The mixture was stirred for 45 minutes and then treated with 0.03 g of NaCNBH3 dissolved in 1 ml of water.The reaction mixture was stirred at room temperature for five hours, diluted with water and extracted with dichloromethane until the extracts were uncoloured. The combined organic extracts were evaporated to dryness under vaccum to give a crude mixture containing as major components two products. The separation was performed by flash chromatography on a column of silica gel using as fluent the solvent mixture dichloromethane: methanol (95:5 by volume).
The fractions containing the less polar product were combined and evaporated to dryness under vacuum to give 0.01 g of pure 4-demethOxy-3'-deamino-3'-(3-cyanomorpholino)-doXorubicin (A-IV).
TLC : Rf 0.57.
FD-MS : m/z 608 (M'); m/z 384 (aglycone)
PMR: inter alia at 1.15 (d, CH3-C-5'), 1.7-2.6 (m, C-2'-H2, C-8-H2,
(m, C-10-H2,
C-3'-H, C-4'-H), 4.14 (m, C-5'-H), 4.6-4.95 (m, C-14-H2)
C-7-H), 5.25 (m, C-1 '-H), 7.4-7.8 (m, 4 aromatic protons), 13.10 and 13.92 (two s, phenolic protons).
The fractions containing the major component were combined to give 0.07g of pure 4-demethoxy-3'deamino-3'-morpholino-doxorubicin (A-lll).
TLC: Rf 0.51.
FD-MS : m/z 583 (M'), m/z 384 (aglycone)
PMR : interalia at 1.18 (d, CH3-C-5'), 1.6-2.6 (m, C-2'-H2, C-8-H2,
C-3'--H, C-4'-H, C-5'-H), 4.57 (bs, C-14-H2), 4.90 (bs, C-7-H) and 5.27 (bs C-1'-H).
EXAMPLE 3 3'-deamino-3'-morpholino-4'-epi-daunorubicin (A- V) and3'-deamino-3'-/3-cyano-morpholino)-4' epidaunorubicin (A- VI) Following the procedure described in Example 1, 0.25 g of 4-epi-daunorubicin hydrochloride (0.44 mmol) were treated with 1.0 g of bis(2-oxoethyl) ether and 0.06 g of NaCNBH3 to give, after chromatographic separation 0.08 g of pure 3'-deamino-3'-(3-cyano-morpholino)-4'-epi-daunorubicin (A-VI).
TLC: Rf 0.67.
FD-MS m/z 622 (M'); m/z 398 (aglycone).
PMR: interalia at 1.21 (d, CH3-C-5'), 1.6-3.0 (m, C-2'-H2, C-8-H2,
2.23 (s, CH3CO, 3.3-4.2
C-4'-H, C-5'-H, 4.0 (s, OCH3), 4.7-4.9
(bs, C-1'-H), 7.8-8.2 (m, 3 aromatic protons), 13.20 and 13.45 (two s, phenolic protons).
There were also obtained 0.21 g of 3'-deamino-3'-morpholino-4'-epi-daunorubicin (A-V).
TLC: Rf 0.60.
FD-MS: m/z 597 (M'); m/z 398 (aglycone).
PMR: interalia at 1.2 (d, CH3-C-5'), 1.7-3.2 (m, C-2'-H2, C-8-H2,
2.25 (s, CH3CO), 3.3-3.9 (m,
C-4'-H), 3.97 (s, OCH3), 4.85 (bs C-7-H) and 5.35 (C-1 '-H).
EXAMPLE 4 3'-deamino-3 '-moroho/in o-4'-epAdoxorubicin (A-V/I) and 3'-deamino-3'-63-cyano-morpholino)-4'-epi- doxorubicin (A- VIII) Following the procedure described in Example 2, 0.2 9 of 4'-epi-doxorubicin hydrochloride (0.34 mmol) were treated with 1.0 g of bis(2-oxoethyl) ether and 0.06 9 of NaCNBH3 to give, after purification by flash chromatography, 0.015 g of pure 3'-deamino-3'-(3-cyano-morpholino)-4'-epi-doxorubicin (A-Vlll).
TLC: Rf 0.60.
FD-MS m/z 638 (M '); m/z 414 (aglycone).
PMR : interalia at 1.24 (d, CH3-C-5'), 1.7-3.0 (m, C-2'-H2, C-8-H2,
3.4-4.2 (m,
C-4'-H, C-5'-H), aromatic protons), 13.16 and 14.0 (s, two phenolic protons).
There were also obtained 0.15 9 of 3'-deamino-3'-morpholino-4'-epi-doxorubicin (A-Vll).
TLC: Rf 0.54.
FD-MS: m/z 613 (M '); m/z 414 (aglycone).
PMR : interalia at 1.22 (d, CH3-C-5'), 1.7-31 (m, C-2'-H2, C-8-H2,
3.2-3.9
4.01 (s, OCH2), 4.67 (bs, C-14-H2), 4.89 (bs, C-7-H) and 5.31 (bs, C-1'-H).
EXAMPLE 5 3'-deamino-3'-morpholino-4'-deoxy-daunorubicin (A4X) and 3'-deamino-3'-r3-cyano-morpholino-4'-deoxy- daunorubicin rA-X) The treatment of 0.55 g of 4'-deoxy-daunorubicin hydrochloride (1.0 mmol) with 2.0 g of bis (2-oxoethyl) ether and 0.12 g of NaCNBH3 gave, following the procedure described in Example 1,0.15 g of pure 3'-deamino-3'-(3-cyano-morpholino)-4'-deoxydaunorubicin (A-X).
3.98 (s, OCH3), 4:6-4.9 (m, C-14-H2,
5.35 (bs, C-1'-H), 7.5-8.0 (m, 3
TLC: Rf 0.64.
FD-MS : m/z 606 IM 1; m/z 398 (aglycone).
PMR: inter alia at 1.22 (d, CH3-C-5'), 1.2-3.0 (m, C-8-H2, C-2'-H2,
3.98 (s, OCH3, 4.6-4.9 (m, C-7-H and
5.36 (s, C-1'-H), 7.5-8.0 (m, 3 aromatic protons), 13.15 and 13.27 (two s, phenolic protons).
There were also obtained 0.4 g of 3'-deamino-3'-morpholino-4'-deoxy-daunorubicin (A-iX).
TLC: Rf 0.56.
FD-MS: m/z 581 (M '); m/z 398 (aglycone).
PMR : inter alia at 1.24 (d, CH3-C-5'), 1.2-3.0 (m, C-8-H2, C-2'-H2, C-4'-H2,
2.32 (s, CH3CO-), 3.2-4.3 (m, C-3'-H,
C-5'-H), 3.99 (s, OCH3, 4.92 ibis, C-7-H) and and 5.32 (bs, C-1'-H).
EXAMPLE 6 3-deamino-3'-morohollno4'-deoxy-doxorub/cin (A-XI) and 3-deamino-3'-(3-cyano-morpholino)-4'-deoxy- doxorubicin (A -XII) The treatment of 0.2 g of 4'-deoxy-doxorubicin hydrochloride (0.3 mmol) with 1.0 g of bis(2-oxoethyl) ether and 0.06 g of NaCNBH3 gave, after purification by flash chromatography as described in Example 2, 0.01 g of 3'-deamino-3'-(3-cyano-morpholino)-4'-deoxy-doXorubicin (A-XII).
TLC: Rf 0.63.
FD-MS: m/z 622 (M ' ): m,z 414 (aglycone)
PMR: inter alia at 1.14 (d, CH3-C-5'), 1.2-3.0 (m, C-8-H2, C-2'-H2, C-4'-H2,
(m, C-3'-H,
C-5'-H), 3.96 (s, OCH3), 4.5-4.9 (m, C-14-H2
C-7-H), 5.34 (bs, C-1'-H), 7.5-8.0 (m, 3 aromatic protons), 13.20 and 14.02 (two s, phenolic protons).
There were also obtained 0.12 g of 3'-deamino-3'-morpholino-4'-deoxy-doxorubicin (A-XI).
TLC: Rf 0.56.
FD-MS : m/z597(M'); m/z414(aglycone).
PMR : inter alia at 1.21 (d, CH3-C-5'), 1.2-2.8 (m, C-8-H2, C-2'-H2, C-4'-H2,
(m, C-3'-H,
C-5'-H); 4.0 (s, OCH3), 4.55 (bs, C-14-H2); 4.91 (bs, C-7-H) and 5.31 (bs, C-1'-H).
Claims (18)
1. An anthracycline glycoside having the general formula (A) as defined herein, or a pharmaceutically acceptable acid addition salt of such an anthracycline glycoside.
2. 4-Demethoxy-3'-deamino-3'-morpholino-daunorubicin.
3. 4-Demethoxy-3'-deamino-3'-(3-cyano-morpholino)-daunorubicin.
4. 4-Demethoxy-3'-deamino-3'-morpholino-doxorubicin.
5. 4-Demethoxy-3'-deam ino-3'-(3-cyano-morpholino)-doxorubicin.
6. 3'-Deamino-3'-morpholino-4'-epi-daunorubicin.
7. 3'-Deamino-3'-(3-cyano-morpholino)-4'-epi-daunorubicin
8. 3'-Deamino-3'-morpholino-4'-epi-doxorubicin.
9. 3'-deamino-3'-(3-cyano-morpholino)-4'-epi-doxorubicin.
10. 3'-Deamino-3'-morpholino-4'-deoxy-daunorubicin.
11. 3'-Deamino-3'-(3-cyano-morpholino)-4'-deoxy-daunorubicin.
12. 3'-Deamino-3'-morpholino-4'-deoxy-doxorubicin.
13. 3'-Deamino-3'-(3-cyano-morpholino)-4'-deoxydoXorubicin.
14. A process for the preparation of an anthracycline glycoside according to claim 1, the process comprising reacting an anthracycline glycoside having the general formula (B) as defined herein with bis-(2,2-diethoxyethyl) ether in the presence of NaCNBH3.
15. A process according to claim 14 further comprising separating the resultant 3'-deamino-3'- morpholino and 3'-deamino-3'-(3-cyano-morpholino) derivatives by chromatography.
16. A process for the preparation of an anthracycline glycoside according to claim 1,the process comprising reacting an anthracycline glycoside having the general formula (B) as defined herein with bis(2-iodoethyl) ether or with 3-(P-iodo-ethoxy)-2-hyd roxy-propionitrile.
17. A process for the preparation of an anthracycline glycoside according to claim 1, the process being substantially as described herein with reference to any of the Examples.
18. A pharmaceutical composition comprising an anthracycline glycoside according to claim 1 or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08408453A GB2140006A (en) | 1983-05-17 | 1984-04-02 | Anthracycline derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838313651A GB8313651D0 (en) | 1983-05-17 | 1983-05-17 | Anthracycline derivatives |
| GB08408453A GB2140006A (en) | 1983-05-17 | 1984-04-02 | Anthracycline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8408453D0 GB8408453D0 (en) | 1984-05-10 |
| GB2140006A true GB2140006A (en) | 1984-11-21 |
Family
ID=26286154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08408453A Withdrawn GB2140006A (en) | 1983-05-17 | 1984-04-02 | Anthracycline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2140006A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0170820A2 (en) * | 1984-06-15 | 1986-02-12 | Laboratoires Hoechst S.A. | 3-Amino-3,4,6-trideoxyglycals, processes for their preparation and anthracylines obtained with those glycals |
| US4585859A (en) * | 1983-05-24 | 1986-04-29 | Sri International | Analogues of morpholinyl daunorubicin and morpholinyl doxorubicin |
| WO1986004332A1 (en) * | 1985-01-17 | 1986-07-31 | Sri International | Open chain-morpholino adriamycins |
| EP0387661A2 (en) * | 1989-03-13 | 1990-09-19 | FARMITALIA CARLO ERBA S.r.l. | New 3'-(4-morpholinyl)- and 3'-(2-methoxy-4-morpholinyl)-anthracycline derivatives |
| US8877720B2 (en) | 2009-11-03 | 2014-11-04 | Tianjin Hemay Bio-Tech Co., Ltd. | Epirubicin derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2124224A (en) * | 1982-07-20 | 1984-02-15 | Stanford Res Inst Int | Derivatives of daunorubicin and doxorubicin |
-
1984
- 1984-04-02 GB GB08408453A patent/GB2140006A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2124224A (en) * | 1982-07-20 | 1984-02-15 | Stanford Res Inst Int | Derivatives of daunorubicin and doxorubicin |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4585859A (en) * | 1983-05-24 | 1986-04-29 | Sri International | Analogues of morpholinyl daunorubicin and morpholinyl doxorubicin |
| EP0170820A2 (en) * | 1984-06-15 | 1986-02-12 | Laboratoires Hoechst S.A. | 3-Amino-3,4,6-trideoxyglycals, processes for their preparation and anthracylines obtained with those glycals |
| EP0170820A3 (en) * | 1984-06-15 | 1987-07-01 | Laboratoires Hoechst S.A. | 3-amino-3,4,6-trideoxyglycals, processes for their preparation and anthracylines obtained with those glycals |
| WO1986004332A1 (en) * | 1985-01-17 | 1986-07-31 | Sri International | Open chain-morpholino adriamycins |
| GB2181430A (en) * | 1985-01-17 | 1987-04-23 | Stanford Res Inst Int | Open chain-morpholino adriamycins |
| EP0387661A2 (en) * | 1989-03-13 | 1990-09-19 | FARMITALIA CARLO ERBA S.r.l. | New 3'-(4-morpholinyl)- and 3'-(2-methoxy-4-morpholinyl)-anthracycline derivatives |
| WO1990010639A2 (en) * | 1989-03-13 | 1990-09-20 | Farmitalia Carlo Erba S.R.L. | New 3'-(4-morpholinyl)- and 3'-(2-methoxy-4-morpholinyl)- anthracycline derivatives |
| WO1990010639A3 (en) * | 1989-03-13 | 1990-10-18 | Erba Carlo Spa | New 3'-(4-morpholinyl)- and 3'-(2-methoxy-4-morpholinyl)- anthracycline derivatives |
| EP0387661A3 (en) * | 1989-03-13 | 1991-03-06 | FARMITALIA CARLO ERBA S.r.l. | New 3'-(4-morpholinyl)- and 3'-(2-methoxy-4-morpholinyl)-anthracycline derivatives |
| EP0495528A1 (en) * | 1989-03-13 | 1992-07-22 | FARMITALIA CARLO ERBA S.r.l. | New 3'-(4-morpholinyl)-anthracycline derivatives |
| US8877720B2 (en) | 2009-11-03 | 2014-11-04 | Tianjin Hemay Bio-Tech Co., Ltd. | Epirubicin derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8408453D0 (en) | 1984-05-10 |
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