GB2169285A - 4'-Deoxydoxorubicin-14-esters - Google Patents
4'-Deoxydoxorubicin-14-esters Download PDFInfo
- Publication number
- GB2169285A GB2169285A GB08500262A GB8500262A GB2169285A GB 2169285 A GB2169285 A GB 2169285A GB 08500262 A GB08500262 A GB 08500262A GB 8500262 A GB8500262 A GB 8500262A GB 2169285 A GB2169285 A GB 2169285A
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- GB
- United Kingdom
- Prior art keywords
- deoxydoxorubicin
- acid
- deoxydaunorubicin
- alkyl
- pharmaceutically acceptable
- 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.)
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
4'-Deoxydoxorubicin-14-esters of the formula:- <IMAGE> wherein R represents an acyl radical of a unsubstituted or substituted, aliphatic, aromatic, cycloaliphatic arylaliphatic or heterocyclic mono- or dicarboxylic acid having from 1 to 20 carbon atoms, the substituent(s), if present being halogen atoms, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino or nitro groups, or R represents an acyl radical of an alkyl- or aryl-carbonic acid, of carbamic or alkylcarbamic acid or of sulphonic acid have antitumour activity. They may be prepared from 4'-deoxydaunorubicin by 14-bromination and reaction of the resultant 14'-bromo-4'-deoxydaunorubicin with a salt of the desired acid. Pharmaceutical compositions containing the esters are also described.
Description
SPECIFICATION 4'-Deoxydoxorubicin-14-Esters
The invention relates to esters of 4'-deoxydoxorubicin, to a process for their preparation, and to pharmaceutical compositions containing them.
The invention provides 4'-deoxydoxorubicin-14-esters of the general formula
wherein R represents an acyl radical of a unsubstituted or substituted, aliphatic, aromatic, cycloaliphatic arylaliphatic or heterocyclic mono- or dicarboxylic acid having from 1 to 20 carbon atoms, the substituent(s), if present, being halogen atoms, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino or nitro groups, or R represents an acyl radical of an alkyl- or aryl-carbonic acid, of carbamic or alkylcarbamic acid or of sulphonic acid; and further provides pharmaceutically acceptable salts of such 4'-deoxydoxo ru bici 4-esters.
4'-deoxydoxorubicin and 4'-deoxydaunorubicin are known antitumoural compounds (US Patent 4067969). It has surprisingly been found that the esters according to the invention show not only an antitumour activity in some cases higher than that of the parent compound, but also a reduced toxicity. Accordingly the invention further provides a pharmaceutical composition comprising a 4'deoxydoxorubicin-14-ester according to the invention or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
The invention also provides a process for the preparation of the 4'-deoxydoxorubicin-14-esters above defined, the process comprising reacting 4'-deoxydaunorubicin (US Patent 4067969) or a salt thereof (preferably the hydrochloride) with bromine at room temperature in an anhydrous organic solvent (such as methanol, chloroform or a mixture thereof), isolating the resultant 14-bromo-4'-deoxydaunorubicin and reacting it or one of its salts in an inert polar solvent (such as acetone) with a compound of the formula ROM or (RO)2M', wherein R is as above defined, M represents an alkali metal atom, a quaternary ammonium radical or a quaternary ammonium radical substituted by alkyl groups and M' represents an alkaline earth metal atom.
The reaction of 14-bromo-4'-deoxydaunorubicin or one of its salts with ROM or (RO)2M' may be carried out at the boiling temperature of the inert polar solvent for a short time or in the cold for a protracted reaction time. The resultant 4'-deoxydoxorubicin-14-esters may be isolated as such or salified with a pharmaceutically acceptable organic or inorganic acid and isolated.
The following Examples illustrate the invention.
Example 1
4'-deoxydoxorubicin- 14-acetate
1.8 g of 4'-deoxydaunorubicin hydrochloride were dissolved in 200 ml of chloroform and treated with 9.25 ml of a 2% bromine solution in chloroform. The reaction mixture was allowed to stand for one night at room temperature; the crystalline product formed was filtered off. By recrystallization from ethyl acetate, 1.4 g of 14-bromo-4'-deoxydaunorubicin hydrochloride were obtained.
1.0 g of 14-bromo-4'-deoxydaunorubicin was suspended in 650 ml of anhydrous acetone and treated with 3.0 g of potassium acetate finely subdivided. The solution was refluxed under stirring for 50 minutes and the solvent was filtered off in vacuo. The residue was taken up with 0.1 N hydrochloric acid and the solution was extracted 3 times with 40 ml of chloroform and then with butanol. After concentration, 0.70 g of 4'-deoxydoxorubicin-14-acetate hydrochloride was obtained.
Example 2 4'-deoxydoxorubicin- 14-octanoate
2.8 g of 14-bromo-4'-deoxydaunorubicin, prepared as described in Example 1, were suspended in 500 ml of an hydros acetone and 4 g of dried sodium octanoate were added. The reaction mixture was refluxed for 100 minutes and then filtered. The solvent was evaporated off in vacuo. The residue was taken up with 150 ml of chloroform and 50 ml of methanol and acidified with a methanolic solution of hydrogen chloride. The solution was concentrated and the precipitate so obtained was recrystallized from methanol: chloroform to obtain 1.8 g of 4'-deoxydoxorubicin-14-octanoate hydrochloride.
Example 3 4tdeoxydoxorubicin- 14benzoate
A suspension of 1 g of 14-bromo-4'-deoxydaunorubicin, prepared as described in Example 1, in 750 ml of anhydrous acetone was treated with 3.5 g of sodium benzoate. The solution was refluxed under stirring for 3 hours and the solvent was filtered off in vacuo. A solution of 2.5 g of sodium bicarbonate in 100 ml of water and then 150 ml of chloroform were added to the residue and after stirring the aqueous phase was separated and extracted again with chloroform. The combined organic extracts were evaporated to a small volume and acidified with 1N hydrogen chloride in methanol. The obtained precipitate yielded, by reacrystallization from methanol:chloroform, 0.9 g of 4'-deoxydoxorubicin-14-benzoate hydrochloride.
Example 4 4'-deoxydoxorubicin- 14-nicotinate
1.2 g of 14-bromo-4'-deoxydaunorubicin, prepared as described in Example 1, suspended in 650 ml of anhydrous acetone was treated with 3.5 g of sodium nicotinate and the mixture was refluxed for 3 hours under stirring. it was then cooled, filtered and evaporated to dryness in vacuo.
The residue was taken up with 100 ml of chloroform and 100 ml of 2% sodium bicarbonate solution.
After stirring, the aqueous phase was separated and re-extracted with chloroform and the combined chloroformic extracts were washed and evaporated to a small volume. 1N hydrogen chloride in methanol was added and the precipitate, crystallized from methanol:chloroform, yielded 0.7 g of 4'-deoxydoxorubicin-14-nicotinate hydrochloride.
Operating as described in the previous Examples, but employing suitable salts of other acids the following esters of 4'-deoxydoxorubicin were prepared: 14-formate, 14-propionate, 14-glycinate, 14-hemisuccinate and 14-cyclopentylpropionate.
Claims (8)
1. A 4'-deoxydoxorubicin-14-ester of the formula
wherein R represents an acyl radical of a unsubstituted or substituted, aliphatic, aromatic, cycloaliphatic arylaliphatic or heterocyclic mono- or dicarboxylic acid having from 1 to 20 carbon atoms, the substituent(s), if present being halogen atoms, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino or nitro groups, or R represents an acyl radical of an alkyl- or aryl-carbonic acid, of carbamic or alkylcarbamic acid or of sulphonic acid; or a pharmaceutically acceptable salt of such a 4'-deoxydoxorubicin-14-ester.
2. 4'-deoxydoxorubicin-14-acetate.
3. 4'-deoxydoxorubicin-14-octanoate.
4. 4'-deoxydoxorubicin-14-benzoate.
5. 4'-deoxydoxorubicin-14-nicotinate.
6. A process for the preparation of a 4'-deoxydoxorubicin-14-ester according to claim 1, the process comprising reacting 4'-deoxydaunorubicin or a salt thereof with bromine at room temperature in an anhydrous organic solvent, isolating the resultant 14-bromo-4'-deoxydaunorubicin, and reacting it or one of its salts in an inert polar solvent with a compound of the formula ROM or (RO)2M', wherein R is as defined in claim 1, M represents an alkali metal atom, a quaternary ammonium radical or a quaternary ammonium radical substituted by alkyl groups and M' represents an alkaline earth metal atom.
7. A process for the preparation of a 4'-deoxydoxorubicin-14-ester according to claim 1, the process being substantially as described herein with reference to any of the Examples.
8. A pharmaceutical composition comprising a 4'-deoxydoxorubicin-14-ester according to any of claims 1 to 5 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08500262A GB2169285A (en) | 1985-01-05 | 1985-01-05 | 4'-Deoxydoxorubicin-14-esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08500262A GB2169285A (en) | 1985-01-05 | 1985-01-05 | 4'-Deoxydoxorubicin-14-esters |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8500262D0 GB8500262D0 (en) | 1985-02-13 |
| GB2169285A true GB2169285A (en) | 1986-07-09 |
Family
ID=10572456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08500262A Withdrawn GB2169285A (en) | 1985-01-05 | 1985-01-05 | 4'-Deoxydoxorubicin-14-esters |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2169285A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1217133A (en) * | 1968-04-12 | 1970-12-31 | Farmaceutici Italia | Adriamycin and adriamycinone |
| GB1368680A (en) * | 1972-12-09 | 1974-10-02 | Farmaceutici Italia | Adriamycin derivatives |
| US4067969A (en) * | 1975-09-26 | 1978-01-10 | Societa Farmaceutici Italia S.P.A. | Anthracycline glycosides, their preparation and use |
| GB1499026A (en) * | 1975-06-20 | 1978-01-25 | Farmaceutici Italia | Adriamycin esters |
| GB1511680A (en) * | 1975-11-18 | 1978-05-24 | Farmaceutici Italia | Daunosaminyl anthracyclinones |
| GB1525180A (en) * | 1975-11-12 | 1978-09-20 | Rhone Poulenc Ind | Daunorubicin derivatives |
| EP0014853A1 (en) * | 1979-02-03 | 1980-09-03 | Zaidanhojin Biseibutsu Kagaku Kenkyukai | Anthracycline derivatives, a process for their preparation and pharmaceutical compositions containing them |
-
1985
- 1985-01-05 GB GB08500262A patent/GB2169285A/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1217133A (en) * | 1968-04-12 | 1970-12-31 | Farmaceutici Italia | Adriamycin and adriamycinone |
| GB1368680A (en) * | 1972-12-09 | 1974-10-02 | Farmaceutici Italia | Adriamycin derivatives |
| GB1499026A (en) * | 1975-06-20 | 1978-01-25 | Farmaceutici Italia | Adriamycin esters |
| US4067969A (en) * | 1975-09-26 | 1978-01-10 | Societa Farmaceutici Italia S.P.A. | Anthracycline glycosides, their preparation and use |
| GB1525180A (en) * | 1975-11-12 | 1978-09-20 | Rhone Poulenc Ind | Daunorubicin derivatives |
| GB1511680A (en) * | 1975-11-18 | 1978-05-24 | Farmaceutici Italia | Daunosaminyl anthracyclinones |
| EP0014853A1 (en) * | 1979-02-03 | 1980-09-03 | Zaidanhojin Biseibutsu Kagaku Kenkyukai | Anthracycline derivatives, a process for their preparation and pharmaceutical compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8500262D0 (en) | 1985-02-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |