JPS6028961A - N-1-adamantylmaleimide and its preparation - Google Patents

Abstract

NEW MATERIAL:N-1-Adamantylmaleimide of formula I . USE:Carcinostatic agent, antivirus agent. PREPARATION:The reaction between equimolar amounts of maleic acid or its anhydride of formula II and amandazine (=1-aminoadamantane) of formula IIIis carried out in a solvent such as dioxane under heating to form N-1-adamantyl- aminomaleic acid almost quantitatively, then the product is heated with a few moles, per mole of the maleic acid, of a condensation agent such as polyphosphoric acid, acetic anhydride or anhydrous sodium acetate for a relatively short time to give the compound of formula I in good yield.

Description

Detailed Description of the Invention The present invention involves the condensation of maleic anhydride or maleic acid with amantadine (1-aminoadamantane) IJII,
N-1-adamantylmaleimide, which is characterized in that the intermediate N-1-adamantylaminomaleic acid is produced, and this intermediate is ring-closed by heating in the presence of a dehydration condensing agent to obtain the target product N-1-adamantylmaleimide. It takes a manufacturing method. The purpose is to easily produce new compounds useful as anticancer agents and antiviral agents, and to provide them as clinical therapeutic drugs.

As a result of research, the present inventor discovered that N-1-adamantylmaleimide is a new compound that has not been described in any literature or references, and has strong anticancer and anti-inflammatory and anti-inflammatory effects.

The synthetic route for this compound is shown in the following steps.

Second step The first step is an equivalent amount of maleic anhydride or maleic [rf
By mixing T-sold amantadine (1-aminoadamantane) and heating and reacting in a suitable solvent, the reaction proceeds easily and yields intermediate-1, N-1-adamantylaminomaleic acid, almost quantitatively. be able to. Suitable solvents may include dioxane, tetrahydrofuran, and the like. This intermediate can be recrystallized from ethanol and is a white crystal with a melting point of 2030 (decomposed). The elemental analysis values were in good agreement with the molecular formula 014H1903N as shown below.

Calculated value-C7. t7% Experimental value C7.3g%H7
, Otsu 3 Curse H7J/% N 3.62% N 3.6! r% Examples of the condensing agent used in the second step include polyphosphoric acid and a mixture of acetic anhydride and sodium acetate anhydride. Several moles of these condensing agents are mixed with the intermediate N-1-adamantylaminomaleic acid/mop obtained in the first step, and the desired product N- 1-Adamantyl/maleimide can be obtained in good yield. This compound can be purified by recrystallization from dilute ethanol, and the purified product has a melting point of
It is a white to pale yellow crystal of g, and its infrared spectrum chart is as shown in Fig. 7. Moreover, its elemental analysis values were in good agreement with the molecular formula (314H1702N) as shown below.

Calculation [C72,70% Experimental value C72,1, O%H7,
lI/% H7, lIO% N Otsu, 06% N Otsu, 77% The value was 230 mg/g by intraperitoneal administration. In anticancer experiments on transplanted cancers in mice, it was effective against P3Kg and L/210, and was particularly effective against ascites breast cancer MM2 and Lewis lung cancer, with many cured cases. Also in vitr.

In experiments, strong inhibition of the growth of Herpes 8 complex was observed.

Reaction Example 1, Process for producing N-1-adamantylaminomaleic acid (1
) 2 maleic anhydride, lAgC0.3 mol) toamantadine l15.3'g < o, 3 mol)'f,
Mix well and so.

m! Add dioxane and heat on a water bath to completely dissolve the crystals. Continue heating and refluxing for 60 minutes.

After cooling, the precipitated crystals are dried in a suction furnace. The intermediate N-1-adamantylaminomaleic acid was obtained as white crystals (2 g% of the theoretical amount).

(2) Maleic acid 33gC0.3 mol) Toamantadine ll! N-
1-adalanthi l rare amino maleic acid f l-3,0g
(7% of theoretical amount) was obtained.

2. Process for producing N-1-adamantylmaleimide (1) N-
1-adamantylaminomaleic acid Otsu 7゜3gC0-3
Add 230 g of polyphosphoric acid to mol V), heat for 30 minutes in an oil bath at a liquid temperature of 2000, allow to cool, and pour the contents into a large amount of ice water. Suction the precipitate, wash with water, and dry. Yield of crude crystals 3, LA g (57% of theoretical amount) This was reduced to 50%
Recrystallization from ethanol-I yields white to pale yellow crystals with a melting point of //O~//g0.

(2) N-1-adamantylmaleic acid, 3g<0
．． A mixture of 3 mol of acetic anhydride and 20 g of anhydrous sodium acetate was added to the mixture and heated on a boiling water bath for 60 minutes. Pour the cold contents into a large amount of ice water. Suck up the precipitate, wash with water, and dry.

Yield of crude crystals: 3 o, s g (17 g% of theory).

[Brief explanation of drawings]

FIG. 1 is an infrared spectrum chart. patent applicant Takatori Kotabu

Claims (1)

[Claims] 1. N-1-adamantylmaleimide represented by the following structural formula. N'2, a method for producing N-1-adamantylmaleimide represented by the following structural formula.