GB1561719A - Anthracyclines - Google Patents
Anthracyclines Download PDFInfo
- Publication number
- GB1561719A GB1561719A GB5345676A GB5345676A GB1561719A GB 1561719 A GB1561719 A GB 1561719A GB 5345676 A GB5345676 A GB 5345676A GB 5345676 A GB5345676 A GB 5345676A GB 1561719 A GB1561719 A GB 1561719A
- Authority
- GB
- United Kingdom
- Prior art keywords
- anhydro
- daunorubicin
- hydrochloride
- doxorubicin
- process according
- 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
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
Description
(54) ANTHRACYCLINES
(71) We, SOCIETA FARMACEUTICI ITALIA S.p.A., a company organised and existing under the laws of Italy, of 1/2 Largo Guido Donegani - 1 20121 Milan, Italy, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
The invention relates to new antitumour glycosides of the anthracycline series and in particular to 9,10-anhydro-daunorubicin I, 9,10-anhydro-doxorubicin II, their hydrochlorides, and their N-trifluoroacetyl derivatives III and IV respectively
I: R=R1=H
II: R=OH, R1=H
III: R=H, Rl=COCF3 TV R=OH, Rl=COCF3 The process of the invention is based on the treatment of daunorubicin or doxorubicin in a weak organic base such as collidine (2,4,6-trimethyl-pyridine), a lutidine (dimethylpyridine), a picoline (methyl-pyridine) or pyridine with trifluoroacetyl anhydride. This treatment is suitably at 0 C for 10 minutes. Subsequent treatment of the reaction mixture with water or an alkanol having from 1 to 3 carbon atoms (such as methanol, ethanol or propanol) gives an unexpectedly stable key intermediate: 9,10-anhydro-N-trifluoroacetyldaunorubicin or 9, 10-anhydro-N-trifluoroacetyl-doxorubicin. The removal of the Ntrifluoro-acetyl group by mild alkaline hydrolysis gives the final product 9,10-anhydrodaunorubicin or 9, 10-anhydro-doxorubicin, isolable as its hydrochloride suitably by treatment with methanolic hydrogen chloride and an amount of diethyl ether sufficient completely to precipitate the hydrochloride. The new compounds display antimitotic activity and are effective in the treatment of certain tumours in experimental animals.
The invention is illustrated by the following Examples:
Example 1 9,10-Anhydro-daunorubicin (IMI 68)
A solution of daunorubicin hydrochloride (2.5 g) in dry collidine (62 ml) is cooled at 0 C.
Trifluoroacetic anhydride (25 ml) is added dropwise, and the mixture is stirred for 10 minutes at 0 C. Crude 9,10-anhydro-N-trifluoroacetyl-daunorubicin is recovered from the reaction mixture by alternative procedures. Following the first, cold water (25 ml) is added to the reaction mixture, and after 10 minutes the whole is poured into iced water. A precipitate of crude product (2.6 g) is filtered off, washed with cold water to neutrality and dried under vacuum over phosphorus pentoxide. Following the second, the reaction mixture is treated with dry methanol and after 20 minutes at 0 C, is evaporated to dryness under vacuum to give crude product (2.7 g). Purification, performed by chromatography on a column of silicic acid, using 9:1 chloroform:acetone as eluent, gives pure intermediate 9, 10-anhydro-N-trifluoroacetyl-daunorubicin (1.7 g): m.p. 1900C;[a= +550 (c=0.05, in methanol); U.V. and visible spectra: MeOH 270 390 and 502 nm (E 30400, 4360, 14700);
I.R. spectrum (KBr): 1725 (C=O amidey, 1669 (o:-t3-unsaturated -C=O), 1620 and 1585 cm-l (quinone C=O and aromatic C=C).
A solution of the intermediate (0.6 g) in acetone (60 ml) is cooled to 0 C, the reaction mixture is adjusted to pH 4 by addition of N hydrochloric acid and then extracted with chloroform to eliminate some starting material. The aqueous phase, adjusted to pH 8.5, is repeatedly extracted with chloroform, and the combined extracts, dried over anhydrous sodium sulphate, are evaporated to a small volume. Addition of a stoichiometric amount of methanolic hydrogen chloride and excess diethyl ether gives 9,10-anhydro-daunorubicin as the hydrochloride (0.4 g): m.p. 185-186 C (with decomposition); [a]D = +530 (c=0.05, in methanol); U.V. and visible spectra: BMma xH 247; 280, 389 and 499 nm ( 20000, 29400 4140, 16670); IR spectrum (KBr): 1665 (aP-unsaturated C=O), 1620 and 1585 cm-i (quinone C=O and aromatic C=C). The pmr spectrum (DMSO-d6) shows absorptions at
1.15 (d, CH3-C-5'), 2.45 s, CH3-CO), 2.51 (m, CH2-8), 3.93 (s, O-CH3), 5.21 (s, CH-7 and
CH-1'), 5.47 (d, OH-C-4' , 7.58 and 7.80 (two d, CH-1 and CH-3), 7.70 (s, CH-10) and 7.87 (t, CH-2).
Example 2 9, 10-Anhydro-doxorubicin The intermediate, 9,10-anhydro-N-trifluoroacetyl-doxorubicin is obtained, starting from
doxorubicin hydrochloride, as in Example 1: m.p. 175 C (with decomposition) [a]D = +510 (c=0.05, in methanol) XMeOH 270, 390 and 500 nm (E30.400, 4350, 14700); IR
spectrum (KBr): 1720 (C=O, amide), 1672 (ass unsaturated C=O), 1617 and 1582 cm- (quinone C=O and aromatic C=C). Subsequent mild alkaline treatment and acidification,
as described in Example 1, gives 9,10-anhydro-doxorubicin as the hydrochloride: m.p.
178-180 C (with decomposition); [a]D =480 (c=0.05 in methanol).
WHAT WE CLAIM IS:
1. A compound of general formula
wherein R represents a hydrogen atom or a hydroxy group and Rl represents a hydrogen atom or a trifluoroacetyl group, or the hydrochloride of either of the compounds in which
R1 represents a hydrogen atom.
2. A process for the preparation of 9,10-anhydro-N-trifluoroacetyl-daunorubicin or 9,10-anhydro-N-trifluoroacetyl-doxorubicin, the process comprising reacting daunorubicin hydrochloride or doxorubicin hydrochloride with trifluoroacetic anhydride in a weak organic base and treating the resultant reaction mixture with water or an alkanol having from 1 to 3 carbon atoms.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (14)
1. A compound of general formula
wherein R represents a hydrogen atom or a hydroxy group and Rl represents a hydrogen atom or a trifluoroacetyl group, or the hydrochloride of either of the compounds in which
R1 represents a hydrogen atom.
2. A process for the preparation of 9,10-anhydro-N-trifluoroacetyl-daunorubicin or 9,10-anhydro-N-trifluoroacetyl-doxorubicin, the process comprising reacting daunorubicin hydrochloride or doxorubicin hydrochloride with trifluoroacetic anhydride in a weak organic base and treating the resultant reaction mixture with water or an alkanol having from 1 to 3 carbon atoms.
3. A process according to claim 2 in which the weak organic base is collidine, a lutidine,
a picoline or pyridine.
4. A process according to claim 2 or claim 3 in which the reaction with trifluoroacetic anhydride is carried out at OOC for 10 minutes.
5. A process according to any of claims 2 to 4 in which the lower alkanol is methanol, ethanol or propanol.
6. A process according to claim 2 substantially as described herein with reference to either of the Examples.
7. 9, 10-Anhydro-N-trifluoroacetyl-daunorubicin or 9,10-anhydro-N-trifluoroacetyldoxorubicin prepared by a process according to any of claims 2 to 6.
8. A process for the preparation of 9,10-anhydro-daunorubicin or 9,10-anhydrodoxorubicin, the process comprising removing the N-trifluoroacetyl group from a compound according to claim 7 by mild alkaline hydrolysis.
9. A process according to claim 8 in which the mild alkaline hydrolysis is effected with 0.1 N aqueous sodium hydroxide at OOC for 90 minutes.
10. A process according to claim 8 substantially as described herein with reference to either of the Examples.
11. 9, 10-anhydro-daunorubicin or 9, 10-anhydro-doxorubicin prepared by a process according to any of claims 8 to 10.
12. A process for the preparation of 9,10-anhydro-daunorubicin hydrochloride or 9,10-anhydro-doxorubicin hydrochloride, the process comprising treating a compound according to claim 11 with methanolic hydrogen chloride and an amount of diethyl ether sufficient completely to precipitate the hydrochloride.
13. A process according to claim 12 substantially as described herein with reference to either of the Examples.
14. 9,10-anhydro-daunorubicin hydrochloride or 9,10-anhydro-doxorubicin hydrochloride prepared by a process according to claim 12 or claim 13.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB5345676A GB1561719A (en) | 1976-12-22 | 1976-12-22 | Anthracyclines |
DE19772757101 DE2757101A1 (en) | 1976-12-22 | 1977-12-21 | NEW ANTHRACYCLINE AND PROCESS FOR THEIR PRODUCTION |
BE183666A BE862104A (en) | 1976-12-22 | 1977-12-21 | NEW ANTHRACYCLINES AND THEIR PREPARATION PROCESS |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB5345676A GB1561719A (en) | 1976-12-22 | 1976-12-22 | Anthracyclines |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1561719A true GB1561719A (en) | 1980-02-27 |
Family
ID=10467881
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB5345676A Expired GB1561719A (en) | 1976-12-22 | 1976-12-22 | Anthracyclines |
Country Status (3)
Country | Link |
---|---|
BE (1) | BE862104A (en) |
DE (1) | DE2757101A1 (en) |
GB (1) | GB1561719A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1098212B (en) * | 1978-05-09 | 1985-09-07 | Farmaceutici Italia | REPLACED ANTI-CANCER ANTHRACIOLINES |
IT1098211B (en) * | 1978-05-09 | 1985-09-07 | Farmaceutici Italia | ANTI-CANCER DEOXYTRACYCLES |
-
1976
- 1976-12-22 GB GB5345676A patent/GB1561719A/en not_active Expired
-
1977
- 1977-12-21 DE DE19772757101 patent/DE2757101A1/en not_active Withdrawn
- 1977-12-21 BE BE183666A patent/BE862104A/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
DE2757101A1 (en) | 1978-07-06 |
BE862104A (en) | 1978-04-14 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed | ||
PCNP | Patent ceased through non-payment of renewal fee |