GB2169286A

GB2169286A - 4'-Deoxy-4'-halodoxorubicin-14-esters

Info

Publication number: GB2169286A
Application number: GB08500263A
Authority: GB
Inventors: Sergio Penco; Antonino Suarato; Federico Arcamone
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1985-01-05
Filing date: 1985-01-05
Publication date: 1986-07-09
Also published as: GB8500263D0

Abstract

4'-Deoxy-4'-halodoxorubicin-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, and X represents a fluorine, chlorine, bromine or iodine atom have antitumour activity. They may be prepared from 4'-deoxy-4'-halodaunorubicin by 14-bromination and reaction of the resultant 14'-bromo-4'-deoxy-4'-halodaunorubicin with a salt of the desired acid. Pharmaceutical compositions containing the esters are also described.

Description

SPECIFICATION 4'-Deoxy-4'-halodoxorubicin-1 4-esters The invention relates to esters of 4'-deoxy-4'-halodoxorubicin, to a process for their preparation, and to pharmaceutical compositions containing them.

The invention provides 4'-deoxy-4'-halodoxorubicin-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 X represents a fluorine, chlorine, bromine or iodine atom; and further provides pharmaceutically acceptable salts of such 4'-deoxy-4'-halodoxorubicin-14-esters.

4'-deoxy-4'-iododoxorubicin and 4'-deoxy-4'-iododaunorubicin are known antitumoural compounds (BE Patent 892943). The corresponding fluoro, chloro- and bromo-derivatives are also known antitumoural compounds (GB Patent 2144744). 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 cardiotoxicity. Accordingly the invention further provides a pharmaceutical composition comprising a 4'-deoxy-4'-halodoxorubicin-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'-deoxy-4'-halodoxorubicin-14-esters above defined, the process comprising reacting 4'-deoxy-4'-halodaunorubicin (BE Patent 892943, GB Patent 2144744) 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'-deoxy-4'-halodaunorubicin 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'-deoxy-4'-halodaunorubicin 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'-deoxy-4'-halodoxorubicin-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'-deoxy-4'-iododoxorubicin- 14acetate 2.0g of 4'-deoxy-4'-iododaunorubicin hydrochloride were dissolved in 150 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, 1.79 of 14-bromo-4'-deoxy-4'-iododaunorubicin hydrochloride were obtained.

1.0 g of 14-bromo-4'-deoxy-4'-iododaunorubicin was suspended in 650 ml of anhydrous acetone and treated with 2.7 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'-deoxy-4'-iododoxorubicin-14-acetate hydrochloride was obtained.

Example 2 4'-deoxy-4'-iododoxorubicin- 14-octanoate 2.8 g of 14-bromo-4'-deoxy-4'-iododaunorubicin, prepared as described in Example 1, were suspended in 500 ml of anhydrous 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'-deoxy-4'-iododoxorubicin-14-octanoate hydrochloride.

Example 3 4'-deoxy-4'-iododoxorubicin- 14benzoate A suspension of 1.5 g of 14-bromo-4'-deoxy-4'-iododaunorubicin, prepared as described in Example 1, in 800 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 3.0 g of sodium bicarbonate in 100 ml of water and then 200 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'-deoxy-4'-iododoxorubicin-14benzoate hydrochloride.

Example 4 4'-deoxy-4'4odo doxorubicin- 14-nicotinate 1.4 g of 14-bromo-4'-deoxy-4'-iododaunorubicin, prepared as described in Example 1, suspended in 700 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 1.0 g of 4'-deoxy-4'-iododoxorubicin-14-nicotinate hydrochloride.

Operating as described in the previous Examples, but employing suitable salts of other acids the following esters of 4'-deoxy-4'-iododoxorubicin were prepared: 14-formate, 14-propionate, 14-glycinate, 14hemisuccinate and 14-cyclopentylpropionate.

Claims

1. A 4'-deoxy-4'-halodoxorubicin-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 substitutent(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 X represents a fluorine, chlorine, bromine or iodine atom; or a pharmaceutically acceptable salt of such a 4'-deoxy-4'-halodoxorubicin-14-ester.

2. 4'-deoxy-4'-iododoxorubicin-14.acetate.

3. 4'-deoxy-4'-iododoxorubicin-14-octanoate.

4. 4'-deoxy-4'-iododoxoru bicin-1 4benzoate.

5. 4'-deoxy-4'-iododoxorubicin-14-nicotinate.

6. A process for the preparation of a 4'-deoxy-4'-halodoxorubicin-14-ester according to claim 1, the process comprising reacting 4'-deoxy-4'-halodaunorubicin or a salt thereof with bromine at room temperature in an anhydrous organic solvent, isolating the resultant 14-bromo-4'-deoxy-4'-halodaunorubicin, 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'-deoxy-4'-halodoxorubicin-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'-deoxy-4'-halodoxorubicin-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.