GB2174387A - 6-Deoxyanthracycline glycosides - Google Patents
6-Deoxyanthracycline glycosides Download PDFInfo
- Publication number
- GB2174387A GB2174387A GB08601671A GB8601671A GB2174387A GB 2174387 A GB2174387 A GB 2174387A GB 08601671 A GB08601671 A GB 08601671A GB 8601671 A GB8601671 A GB 8601671A GB 2174387 A GB2174387 A GB 2174387A
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- United Kingdom
- Prior art keywords
- demethyl
- deoxy
- hydrogen atom
- trifluoroacetyl
- daunorubicin
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
6-Deoxyanthracycline glycosides I <IMAGE> (R1=H, or OH, R2=H or OH, R3=H or OH, R2+R3 NOTEQUAL 2OH, X=H or COCF3, R1=H if X=COCF3) are prepared from 6-demethyl-6-deoxy-daunomycinone. They have antitumour properties and pharmaceutical compositions containing them are also described.
Description
SPECIFICATION 6-Deoxyanthracycline glycosides
DESCRIPTION:
The invention relates to 6-deoxyanthracycline glycosides, to a process for their preparation and to pharmaceutical compositions containing them.
The invention provides anthracycline glycosides having the general formula I
wherein R, represents a hydrogen atom or a hydroxy group, one of R2 and R3 represents a hydrogen atom, the other of R2 and R3 represents a hydrogen atom or a hydroxy group, and X represents a hydrogen atom or a trifluoroacetyl group, with the proviso that if X represents a trifluoroacetyl group then R, represents a hydrogen atom. These compounds may be named as follows:
I: Rt=R3=H, R2=OH, X=COCF3 4-demethyl-6-deoxy-N-trifluoroacetyl-daunorubicin.
Ib: R1=R3=H, R2=OH, X=H
4-demethyl-6-deoxy-daunorubicin.
Ic: R,=R2=OH, R3=H, X=H
4-demethyl-6-deoxy-doxorubicin.
!d: R,=R7=H, R3=OH, X=COCF3
4-demethyl-6-deoxy-N-trifluoroacetyl-4'-epi
daunorubicin.
le: R,=R2=H, R3=OH, X=H
4-demethyl-6-deoxy-4'-epi-daunorubicin
If: R,=R3=OH, R2=H, X=H
4-demethyl-6-deoxy-4'-epi-doxorubicin Ig: R1=R2=R,=H, X=COCF3
4-demethyl-6 ,4'-dideoxy-N-trifluoroacetyl-daunorubicin Ih: R1=R2=R3=X=H 4-demethyl-6,4'-dideoxy-daunornbicin Ii: R,=OH, R2=R3=X=H 4-demthyl-6,4'-dideoxy-doxorubicin.
The invention also provides pharmaceutically acceptable salts of those anthracycline glycosides of the general formula I in which X represents a hydrogen atom.
The anthracycline glycosides I may be prepared from 4-demethyl-6-deoxy-daunomycinone, also known as 6-deoxycarminomycinone. This compound is described and claimed in our British
Patent Application NO. 2142022, from which this Application is divided. The 4-demethyl-6deoxydaunomycinone is condensed with a protected halosugar having the general formula II
wherein one of R2 and R3 represents a hydrogen atom and the other of R2 and R3 represents a hydrogen atom or a trifluoroacetoxy group, and Hal represents a halogen atom, preferably a chlorine atom. This condensation proceeds in the presence of silver trifluoromethane sulphonate according to the method described in United States Patent Specification No. 4107423, giving an easily separable mixture of 7S:9S and 7R:9R glycosides. The 4'-0-trifluoroacetyl protecting group, if present, is removed by methanolysis.The diastereoisomeric mixture is then chromatographically separated to give the compound la, Id or lg according to the halosugar II selected for the reaction. This, by mild alkaline hydrolysis, can be converted to the glycoside Ib, le or Ih respectively. This, by 14-bromination and treatment with aqueous sodium formate in accordance with the method described in United States Patent Specification No. 3803124 gives the corresponding doxorubicin derivatives Ic, If or li. These processes are within the scope of the invention.
The anthracycline glycosides I have anti-tumour properties and accordingly the invention additionally provides a pharmaceutical composition comprising an anthracycline glycoside having the general formula I or a pharmaceutically acceptable salt of such a glycoside in which X represents a hydrogen atom in admixture with a pharmaceutically acceptable diluent or carrier.
The invention is illustrated by the following Examples.
EXAMPLE 1 6-Deoxy-4-demethyl-daunorubicin (Ib)
90 mg (0.024 mmol) of racemic 6-deoxy-carminomycinone was dissolved in anhydrous dichloromethane and the solution was cooled to 5-10"C. A solution of 2.4 mg (0.6 mmol) of 1 chloro-N,0-ditrifluoroacetyl-daunosamine, prepared following the procedure described in Cancer
Chemotherapy Reports, Part 3, Vol. 6, No. 2, p. 123, in diethyl ether and a solution of 154 mg (0.06 mmol) of silver trifluoromethanesulphonate in dichloromethane were added simultaneously and rapidly under vigorous stirring.
After 5 minutes, a further 0.03 mmol of the halosugar and 0.3 mmol of silver trifluoromethane suiphonate were added. After 5 minutes, the reaction was quenched with collidine. The mixture was filtered, washed with a saturated aqueous solution of sodium bicarbonate and with water, dried and concentrated under vacuum. The reddish oil obtained was diluted with 100 ml of methanol and allowed to stand overnight at room temperature to remove the O-trifluoroacetyl group. The resulting crude product was purified by flash chromatography on silica gel with dichloromethane:methanol:acetone 20:1:1 by volume to afford the anthracycline a-glycosides la.
7S:9S, 20 mg, m.p. 210-212"C.
TLC on kieselgel plates (Merck F254), using as eluent methylene-dichloride:acetone 4:1 by volume,
Rf=0.27.
m/z 593 (M').
PMR (200 MHz, CDCl3): inter alia J 1.44 (d, J=6.6Hz, 3H, CH2-5'), 2.42 (s, 3H, COCH3), 3.25-3.05 (two d, J=t9Hz, 2H, H-10), 4.22 (s, 1H, OH-9), 5.01 (t, J=3.6Hz, 1H, H-7), 5.20 (t, J=2.7Hz, 1H, H-1'), 6.66 (bd, J=9Hz, 1H, NH), 7.80 (s, 1H, H-6), 12.62 (s, 1H, OH-4), 13.06 (s, 1H, OH-il); m/z 593 (M') 7R:9R 25 mg, m.p. 174-178"C.
TLC on kieselgel plates (Merck F254) using an eluent methylene dichloride:acetone 4:1 by volume,
Rf=0.23.
m/z 593 (M).
PMR (200 MHz, CDCI3): inter alia a 1.44 (d, J=6.5Hz, 3H, CH3-5'), 2.41 (s, 3H, COCH3), 2.96 (d, J=19Hz, 1H, H-10 ax), 3.30 (dd, J=1, 19Hz, 1H, H-10 eq), 4.25 (s, 1H, OH-9), 5.07 (t,
J=3.3Hz, 1H, H-7), 5.27 (t, J=1.8Hz, 1H, H-1'), 6.64 (bd, J=9Hz, 1H, NH), 7.74 (s, 1H,
H-6), 12.66 (s, 1H, OH-4), 13.10 (s, 1H, OH-11).
Mild alkaline hydrolysis of la removes the N-trifluoroacetyi group to give the title compound in quantitative yield. TLC on kieselgel plate (Merck F254) using as eluent methylene dichlororide:methanol:acetic acid:water 80:20:7:3 by volume, Rf 0.47.
EXAMPLE 2 6-deoxy-4-demethyl-doxorubicin (Ic)
A solution of 6-deoxy-4-demethyl-daunorubicin, prepared as described in Example 1, in a mixture of methanol and dioxan was treated with bromine to form the 14-bromo derivative.
Treatment of the 14-bromo derivative with an aqueous solution of sodium formate at room temperature for 100 hours gave 6-deoxy-4-demethyl-doxorubicin. m.p. 167-170"C.
TLC in kieselgel plates (Merck F254) using as eluent methylene dichloride:methanoi:acetic acid:water 80:20:7:3 by volume, Rf 0.47.
Claims (13)
1. An anthracycline glycoside having the general formula I
wherein R1 represents a hydrogen atom or a hydroxy group, one of R2 and R2 represents a hydrogen atom, the other of R2 and R3 represents a hydrogen atom or a hydroxy group, and X represents a hydrogen atom or a trifluoroacetyl group, with the proviso that if X represents a trifluoroacetyl group then R, represents a hydrogen atom; or a pharmaceutically acceptable salt of such an anthracycline glycoside in which X represents a hydrogen atom.
2. 4-Demethyl-6-deoxy-N-trifluoroacetyl-daunorubicin.
3. 4-Demethyl-4-deoxy-daunorubicin.
4. 4-Demethyl-6-deoxy-doxorubicin.
5. 4-Demethyl-6-deoxy-N-trifluoroacetyl-4'-epidaunorubicin.
6. 4-Demethyl-6-deoxy-4'-epi-daunorubicin.
7. 4-Demethyl-6-deoxy-4'-epi-doxorubicin.
8. 4-Demethyl-6,4'-dideoxy-N-trifluoroacetyl-daunorubicin.
9. 4-Demethyl-6,4'-dideoxy-daunorubicin.
10. 4-Demethyl-6,4'-dideoxy-doxorubicin.
11. A process for the preparation of an anthracycline glycoside according to claim 1, the process comprising condensing 4-demethyl-6-deoxy-daunomycinone with a protected halosugar having the general formula II as herein defined in the presence of silver trifluoromethanesulphonate, removing the 4'-0-trifluoroacetyl protecting group, if present, from the glycoside in the resultant diastereomeric mixture by methanolysis, and chromatographically separating the resultant 7S:9S and 7R:9R glycosides to obtain a compound of the formula la, Id or lg as herein defined; and, if desired, removing the N-trifluoroacetyl protecting group by mild alkaline hydrolysis to obtain a compound of the formula Ib, le or Ih as herein defined; and, if desired, treating that compound with bromine and hydrolysing the resultamt 14-bromo derivative with an aqueous solution of sodium formate to obtain a compound of the formula Ic, If or li as herein defined.
12. A process according to claim 11, the process being substantially as described herein with reference to Example 1 or Examples 1 and 2.
13. A pharmaceutical composition comprising an anthracycline glycoside according to claim 1 or a pharmaceutically acceptable salt of such a glycoside in which X represents a hydrogen atom in admixture with a pharmaceutically acceptable diluent or carrer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08601671A GB2174387B (en) | 1983-06-23 | 1986-01-23 | 6-deoxyanthracycline glycosides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838317037A GB8317037D0 (en) | 1983-06-23 | 1983-06-23 | 6-deoxyanthracyclines |
| GB08601671A GB2174387B (en) | 1983-06-23 | 1986-01-23 | 6-deoxyanthracycline glycosides |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8601671D0 GB8601671D0 (en) | 1986-02-26 |
| GB2174387A true GB2174387A (en) | 1986-11-05 |
| GB2174387B GB2174387B (en) | 1987-04-08 |
Family
ID=26286458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08601671A Expired GB2174387B (en) | 1983-06-23 | 1986-01-23 | 6-deoxyanthracycline glycosides |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2174387B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0573976A1 (en) * | 1992-06-10 | 1993-12-15 | Kyowa Hakko Kogyo Co., Ltd. | Anthracyclin analogue, compound UCEG |
-
1986
- 1986-01-23 GB GB08601671A patent/GB2174387B/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0573976A1 (en) * | 1992-06-10 | 1993-12-15 | Kyowa Hakko Kogyo Co., Ltd. | Anthracyclin analogue, compound UCEG |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8601671D0 (en) | 1986-02-26 |
| GB2174387B (en) | 1987-04-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19960620 |