JPS61172892A - Ester of 4'-haloanthracycline - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to tr-specific Fca tumor aphanto 2 cyclins.

More specifically, the present invention relates to compounds of the formula Cyclic acids, arylaliphatic acids, heterocyclic acids (substituents include halogen atoms, hydroxyl groups, alkyl groups, alkyloxy groups, free amino groups,
monoalkyl- or dialkyl-substituted amino groups and nitro groups), alkyl carbonates or aryl carbonates, carbamic acids or acids selected from alkyl carbamic acids and sulfonic acids. Acyl group %X is F, 0β, Br
and esters of 4'-deoxy-4'-halodoxorubicin at the 14-position.

Belgian patent No. 892,945 of the applicant discloses 4'-deoxy-4'-iodo-daunorubicin and 4'-deoxy-4'-iodo-doxorubicin, which have significant anti-inflammatory activity. A patent has been claimed.

During the inventor's experimental operations, *< 41- of formula I
It has been found that some derivatives of deoxy-41-iototequin rubicin exhibit reduced cardiotoxicity and, at the same time, higher antitumor activity than cryo-compounds in which the primary alcohol group is free. .

It has also been found that other halogen atoms, such as fluorine, bromine and chlorine, may also be present in the 4'-position besides iodine. However, it has been found that the 4'-iodo conductor is of particular interest from a pharmacological point of view.

Another object of the present invention is a process for backtracking the 14-esters of 4'-deoxy-4'-halo-daunorubicin having the formula I above starting from 4'-deoxy-4'-halo-daunorubicin. .

The starting products of the process according to the invention are known products which are the subject of the applicant's invention. In more detail.

4'-Deoxy-4'-iodo-daunorubicin is disclosed and claimed in Belgian Patent No. 892,943] and the corresponding 4-bromo, 4-fluoro and 4'-chloro have been filed. Earlier British Patent No. 83 relating to
No. 21,676.

salt in a suitable anhydrous organic solvent such as methanol and chloroform or a mixture thereof at room temperature;
4'-deoxy-4, preferably in the form of #L2 salt
'-Halo-daunorubicin is reacted with bromine to produce the corresponding 14-bromo-4'-deoxy-4'-halo-daunorubicin, which is isolated as a salt, eg, the hydrochloride salt, according to known methods.

The ester of 4'-deoxy-4'-halodine rubicin of the present invention having the formula (1) is 14-7'romo4'-
A is prepared by reacting 7'oxy-4'-halo-daunorubicin or one of its salts, preferably the hydrochloride salt, with the desired lily salt. More specifically, the method of the present invention comprises preparing 14-bromo-4'-deoxy-4'-halo-daunorubicin hydrochloride with the formula ROM (wherein R has the meaning given above and 1M is an alkali metal or alkaline earth metal II4 or a quaternary ammonium group optionally substituted by an alkyl group. It is carried out in the presence of an inert polar solvent.

The 14-esters of 4'-deoxy-4'-norodequinrubicin thus obtained are isolated up to their t or converted into salts of organic rR or inorganic acids and then purified by extraction and purification.

EXAMPLES The present invention will be explained below using examples, but they are not intended to limit the invention.

Example 1 4'-deoxy-41-iototequin rubicin-14
- Acetate 2, OP of 42-deoxy-41-iodo-daunorubicin hydrochloride was dissolved in 15011ffi of chloroform and treated with 2% bromine solution in chloroform.

The reaction mixture was left overnight at room temperature and the resulting crystalline product was removed and recrystallized from ethyl acetate to give t7p of 14
-bromo-4'-deoxy-4'-iodo-daunorubicin hydrochloride was obtained.

Tonight's worth of 14-bromo-4'-deoxy-4'-iodo-daunorubicin was suspended in 650 ml of anhydrous acetone and treated with 2.7 Jl of finely divided potassium acetate.

The solution was refluxed under stirring for 50 minutes and the solvent was removed in vacuo. 0. Combined with IN hydrochloric acid solution, the solution was extracted three times with 40 μm of chloroform and then with butanol. %0.65P of 41-deoxy-4 after concentration
'-Iodo-doxorubicin-14-acetate hydrochloride was obtained.

Example 2 4'-7'oxy-4'-iodo-doxorubicin-1
4-Octanoate 14 of 2,8 days prepared as described in Example 1
-Bromo-4'-deoxy-4'-iodo-daunorubicin was suspended in 500 g of anhydrous acetone and to this was added 42 g of sodium octoate. The reaction mixture was refluxed for 1 hour 40 minutes, filtered and the solvent was evaporated in vacuo.

The residue was combined with 15,011,111 ml of chloroform and 50 ml of methanol and clarified with a methanol solution of hydrochloric acid. The solution was concentrated and the resulting precipitate was recrystallized from methanonyl-chloroform to yield 1.89 4'-deoxy-4'-iodo-doxorubicin-14-octanoate hydrochloride.

Example 3 4'-deoxy-41-iototequin rubicin-14
A suspension of 15 14-bromo-4'-deoxy-4'-iodo-daunorubicin in anhydrous acetone was treated with &;5 Ii of sodium benzoate. The solution was refluxed under stirring for 3 hours and the solvent was removed in vacuo. 5,01 in water of 100 to the residue
A solution of 1 part sodium bicarbonate was then added with 200 parts of chloroform, stirred, the aqueous phase was separated, extracted again with chloroform, the 9 organic extracts were combined, evaporated to reduce the volume, and dissolved in methanol. The mixture was made acidic with 1N hydrochloric acid. The resulting precipitate was recrystallized from methanol-chloroform to yield 12N 4'-deoxy-4'-iodo-doxorubicin-14-benzoate hydroxychloride.

Example 4 4'--F'oxy-4'-iodo-doxorubicin-
14-Nicotinate suspended in 700 g of anhydrous acetone, 1 of 49
4-Bromo-4'-deoxy-4'-iodo-daunorubicin was treated with 3.5 Jl of sodium nicotinate and the mixture was refluxed under stirring for 3 hours, then cooled, filtered and evaporated to dryness in vacuo. hardened.

The residue was dissolved in 10 Qmj of chloroform and 10011
11 of 2% sodium bicarbonate solution.

After stirring, the aqueous phase was separated and re-extracted with chloroform, the chloroform extracts were combined and washed and evaporated to reduce the volume.

A methanol solution of 1N hydrochloric acid was added, and the precipitate was crystallized from methanol-chloroform to yield 1.0 μl of 4'-deoxy-4'-iodo-doxorubicin-14-nicotinate hydrochloride.

The following esters of 4'-deoxy-4'-halodoquin rubicin were prepared as described in the previous examples, except that appropriate salts of other acids were used: 14-formate, 14
-propionate, 14-glycinate, 14-emisuccinate and 14-cycloantylpropionate were prepared.

Claims (1)

[Claims] 1) 4 in an anhydrous organic solvent or a mixture thereof at room temperature.
'-Deoxy-4'-halo-daunorubicin is reacted with bromine to form the corresponding 14-bromo-derivative, which 14-bromo-derivative or one of its salts is prepared in an inert polar solvent with the formula ROM (formula where R is a substituted or unsubstituted aliphatic monocarboxylic acid or aliphatic dicarboxylic acid having 1 to 20 carbon atoms,
Aromatic acids, cycloaliphatic acids, arylaliphatic acids, and heterocyclic acids (substituents include halogen atoms, hydroxyl groups, alkyl groups, alkyloxy groups, free amino groups, monoalkyl- or dialkyl-substituted amino groups, and nitro M is an acyl group of an acid selected from the group consisting of alkyl carbonates or aryl carbonates, carbamic acids or alkyl carbamic acids and sulfonic acids; M is an alkali metal, an alkaline earth Class metal, 4th
quaternary substituted by ammonium group and alkyl group
(selected from the group consisting of ammonium groups) and isolation of the resulting product ▲ Numerical formulas, chemical formulas, tables, etc. ▼ I (wherein R has the above meaning and X is selected from the group consisting of F, Cl, Br and I). 2) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ I (wherein R is a substituted or unsubstituted aliphatic monocarboxylic acid or aliphatic dicarboxylic acid having 1 to 20 carbon atoms, Aromatic acids, alicyclic acids, arylaliphatic acids, heterocyclic acids (substituents include halogen atoms, hydroxyl groups, alkyl groups, alkyloxy groups, free amino groups,
mono- or dialkyl-substituted amino groups and nitro groups), alkyl or aryl carbonates, carbamic acids or acyl groups of acids selected from alkylcarbamic acids and sulfonic acids; and X is selected from the group consisting of F, Cl, Br and I). 3) 4'-deoxy-4'-iodo-doxorubicin-
14-Acetate. 4) 4'-deoxy-4'-iodo-doxorubicin-
14-octanoate. 5) 4'-deoxy-4'-iodo-doxorubicin-
14-benzoate. 6) 4'-deoxy-4'-iodo-doxorubicin-
14- Nicotinate.