JPS61172891A - Production of anthracycline ester - 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 novel anti-inflammatory anthracyclines.

More specifically, the present invention relates to an aliphatic monocarboxylic acid aliphatic dicarboxylic acid, an aromatic acid having the structural formula (wherein R has 1 to 20 substituted or unsubstituted carbon atoms).

From alicyclic acids, arylaliphatic acids, and heterocyclic eR (substituents are) halogen atoms, hydroxyl groups, alkyl groups, alkyloxy groups, free amino groups, monoalkyl- or dialkyl-substituted amino groups, and nitro groups. 4'-epi-acyl groups of acids selected from alkyl leg acids or aryl carbonates, carbamic acids or alkyl carbamic acids and sulfonic acids; Concerning esters at the 14-position of doxorubicin.

4'-Epidoxorubicin is US%IF by the applicant.
It is a known anti-tumor compound which is described and claimed in US Pat. No. 4,058,519.

During the experimental operations of the present inventors, it was found that the esters at the 14-position of 4'-epidoxorubicin having the above formula (1) not only exhibit higher antitumor activity than the frozen compound in some cases. It was also found to exhibit reduced toxicity.

In another aspect, the invention is directed to U.S. Pat.
4'-dipidoquine rubicin-14 starting from 4'-dipidoquine rubicin described in , 345,068.
-Providing a method for producing esters.

A suitable anhydrous organic solvent, such as methanol and chloroform, in a mixture thereof at room temperature;
4'-Dibiedaunorubicin, preferably in the form of the hydrochloride salt, is reacted with bromine to form the corresponding 14-bromo-4'
- Epidaunorubicin gold is produced and isolated as a salt according to known methods, e.g.

The ester of 4'-evidoquin rubicin of the present invention bearing the above formula I comprises 1a [%] of 14-7'lomo-4'-epidaunorubicin or a salt thereof, preferably the desalted salt with the salt of the desired acid. (by reacting). More specifically, the process of the invention comprises preparing 14-bromo-41-dipidunorubicin salt with the formula ROM (wherein R has the meaning given above and M is an alkali metal or alkaline earth metal or optionally an alkyl a quaternary ammonium group substituted by a group). The reaction is carried out in the presence of an inert polar solvent, such as acetone, at boiling temperatures for short periods of time or at cooling temperatures for extended reaction times.

The 14-esters of 4'-evidoquin rubicin thus obtained are either isolated to their 14-esters or converted into salts of acetic acid or inorganic acids, and then extracted and extracted).
M is accepted.

The present invention will be explained below with reference to examples, but these are not intended to explain the present invention.

Example 1 4'-epidoxorubicin-14-acetate ts) and 4'-epidoxorubicin hydrochloride [is.

2 in chloroform.
% bromine solution 9.25ml! Processed with.

The reaction mixture f was left overnight at room temperature in the car, and the resulting crystalline product was removed and recrystallized from ethyl acetate.
4-bromo-4'-dipidacunorubicin hydrochloride was obtained.

tOPO14-bromo-4'-epidaunorubicin 6
2, finely divided, suspended in anhydrous acetone of 50
72 of potassium acetate.

The solution was refluxed under stirring for 50 minutes and the solvent was removed in vacuo. The residue was combined with the t-alN salt solution and the solution was extracted three times with t-40Tnl of chloroform and then with butanol. After concentration, 0.655 i of 4'-epidoxorubicin-14-acetate salt was obtained.

Example 2 4'-Epidoxorubicin-14-octanoate 450! If1 was suspended in anhydrous acetone, and to this was added 4j1 dried sodium octoate. The reaction mixture was refluxed for 1 hour and 40 minutes to a % concentration and the solvent was evaporated in vacuo. 150ml of residue! of chloroform and 50 grams of methanol and acidified with a saline solution of methanol. The solution was concentrated and the resulting precipitated IR was recrystallized from methanol-chloroform to yield 1.39 4'-epidoxorubicin-14-octanoate hydrochloride.

Example 3 4'-Epidoxorubicin-14-benzoate 700
A suspension of 14-bromo-4'-epidaunorubicin of 1j+ in anhydrous acetone of 3.5 jl
of sodium benzoate. The solution was poured under stirring for 3 hours and the solvent was removed in vacuo. To the residue were added 2.5 jl of sodium bicarbonate solution in 100 ml of water and then 150+d of chloroform, and after stirring the aqueous phase was separated off and extracted again with chloroform. The organic extracts were combined, evaporated to reduced volume and acidified with 1N hydrochloric acid in methanol. The resulting precipitate was recrystallized from dimethanol-chloroform to yield 0.79 4'-evidoxorubicin-14-penzoate hydroxycroside.

Example 4 4'-Epidoxorubicin-14-nicotinate 650
1,02 of 14-bromo-4'-dihytaunorubicin suspended in anhydrous acetone was treated with 3.52 of sodium nicotinate, and the mixture was refluxed under stirring for 3 hours, then cooled. It was filtered and evaporated to dryness in vacuo.

The residue was dissolved in 1001111 chloroform and 100 m
1 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 obtain 0.62 of 41-epidoxorubicin-14-nicotinate hydrochloride.

The following esters of 4'-epidoquin rubicin were prepared as described in the previous examples except using appropriate salts of other acids: 14-formate, 14-propionate % 14-glycinate, 14 -Emisuccinate and 14-cyclopentylpropionate were produced.

Claims (1)

[Claims] 1) 4 in an anhydrous organic solvent or a mixture thereof at room temperature.
'-epi-daunorubicin is reacted with bromine to form the corresponding 14-bromo-derivative, and this 14-bromo-
The derivative or one of its salts is dissolved in an inert polar solvent in an aliphatic monocarboxylic acid, an aliphatic dicarboxylic acid having the formula ROM, in which R has 1 to 20 carbon atoms, substituted or unsubstituted. acids, aromatic acids, alicyclic acids,
Aryl aliphatic acids, and heterocyclic acids (substituents selected from the group consisting of 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 alkylcarbamic acids, and sulfonic acids; M is an alkali metal, an alkaline earth metal, a quaternary ammonium group, and an alkyl group; (selected from the group consisting of quaternary ammonium groups substituted by a group) and isolation of the resulting product. , R has the above-mentioned meaning). 2) Formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ I (wherein R is a substituted or unsubstituted aliphatic monocarboxylic acid, 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, monoalkyl- or dialkyl-substituted amino groups, and nitro alkyl or aryl carbonates, carbamic acids or acyl groups of acids selected from alkylcarbamic acids and sulfonic acids). 3) 4'-Epidoxorubicin-14-acetate. 4) 4'-Epidoxorubicin-14-octanoate. 5) 4'-Epidoxorubicin-14-benzoate. 6) 4'-Epidoxorubicin-14-nicotinate.