JPS6129952B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing an acyl derivative of 1,2-5,6-dianhydrohexitol that exhibits antitumor properties. Diepoxide types of dianhydro derivatives of alcohols, such as L-1,2-3,4-diepoxybutanol, especially hexaatomic alcohols such as 1,2-5,6-dihanhydro-D-mannitol and 1,2-5,6 -Dianhydro-Durushiru is well known for its antitumor properties. For example, Jarman, M. Rose, WXJ;
formation of epoxides from substituted
hexitols, Carbohydrate Research 9, 139,
1969; Jarman, IM. Ross, W. C. J.: Formation
of 1,2-5,6-dihanhidro-D-mannitol
from 1,6―dibromo―and1,6―
dimethanesulphonoxy 1,6-dideoxy-D-
mannitol, Chem.Ind.42, 1789, 1967.Elson, A.
L., Jarman, M., Ross, wCJ: Toxicity,
haematological effects and antitumor activity of
epoxides perived from disubstitu-ted
hexitols, Eurpo.J.Cancer.4, 617, 1968. The most effective of these is 1,2-5,6-dianhydrodulcitol (N′emeth.L.,
Instito′ris, L., Somfai, S., Ga′l, F.,
Pa′lyi, I., Suga′r, J., Csuka, O.,
Szentirmay, Z., Kellner, B.: Pharmacology
and antitumoral effect of dulcitoldiepoxide),
1,2-5,6-dianhydro-calactitol, NSC-132313 (Cancer Chemotherapy
Rep.I.56, 593, 1972, Instito´ris, L.,
Ne′meth, L., Somfai, S., Ga′lF., Hercsel, I.
, Zaka, S., Kellner, B.: Investigation into
the Ccrrelation of Cytostatic Activity with
the in vitro Diepoxide Formation on some
Terminally Substituted Hexitols,
Neiplasma 17, 1, 15-24, 1970). However, due to the presence of free hydroxyl groups and the reaction between the epoxide rings that takes place in buffer solutions even without biological media, the compounds undergo transformation. These reactions give metabolites that are disadvantageous in terms of cytostatic activity or are toxic. In order to protect the compounds against these undesired transformations, protecting groups can be introduced which are eliminated in the biological environment and give the diepoxy compound as the active metabolite. Extremely aqueous hexitol
The solubility of the diepoxide is advantageously influenced by the protecting group attached to the hydroxyl group, increasing the cytostatic action of the compound. In animal studies carried out with some of these compounds, they additionally show some beneficial effects, such as a significant reduction in toxicity and a change in the tumor spectrum in a favorable direction. Examination of antitumor activity and toxicity of 1,2-5,6-dianhydro-3,4-diacyl-dulcitol compound The antitumor activity of the diepoxy-diacyl-dulcitol derivative provided in the present invention was tested on transplanted animal tumors. The compounds obtained according to the invention inhibit the growth of transplanted tumors, depending on the dose administered. We will compare 4,6-diepoxy-diacyl-dulcitol with the original 1,2-5,6-dianhydro-dulcitol (DAD) in different experimental systems. Compounds are indicated by the following symbols. DAD=1,2-5,6-dianhydro-dulcitol Diac-DAD=1,2-5,6-dianhydro-3,4-di(acetyl)-dulcitol DS-DAD=1,2-5,6-dianhydro ―
3,4-di-(β-carbomethoxypropionyl)-dulcitol FB-DAD=1,2-5,6-dianhydro-
3,4-di-(γ-phenyl-butyryl)-
Dulcitol FB-DAD=1,2-5,6-dianhydro-
3,4-di-(β-phenyl-propionyl)-dulcitol CA-DAD=1,2-5,6-dianhydro-
3,4-di(chloro-acetyl)-dulcitol acute toxicity Acute toxicity was determined in Swiss mice. Mortality was observed for 21 days after each treatment.

[Table] Toxicity is almost inversely proportional to molecular weight. Death occurs 5-9 days after both intraperitoneal and oral treatments. This means that all substances are well absorbed in the gastrointestinal tract. Cumulative Toxicity The dose of the derivative (LD ₈₀ ) that was found to cause death in 80% of treated mice was divided into two equal parts (LD ₈₀ /2), and this dose was administered at various time intervals (0-96 hours). were administered to groups of mice. Mortality was assessed for 21 days after the second injection. Cumulative survival is calculated by the following formula: CR% = 100 (d ₃ - _{d 2} - _{d 4 )} /d ₁ - d where d ₁ = death rate after LD ₈₀ d ₂ = LD ₈₀ /2 (1 d ₃ = LD ₈₀ / 2 (repeat) mortality rate d ₄ = Death rate of terminally treated control group

[Table] LD ₈₀ = drug dose, after treatment, 80% of treated animals
A dose that will cause death within 21 days. LD ₈₀ /2 = 1/2 of LD ₈₀ . 1x, 2x = once, twice (at predetermined time intervals). Antitumor activity against transplanted tumorsa Ehrlichi's ascites carcinoma 5 million cancer cells are inoculated into ascites. Treatment begins 24 hours after vaccination and continues daily for 6 or 8 days.

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[Table] − Control

Claims (1)

[Scope of Claims] 1 General formula including acylation of 1,2-5,6-dianhydrohexitol with an acid halide, acid anhydride, mixed acid anhydride or mixed ester (In the formula, Q′ and Q″ are each independently an optionally substituted alkanoyl group, aroyl group, aralkanoyl group, cycloalkanoyl group, heterocyclic acyl group, or a hydrogen atom, but Q′ and A method for producing a compound having Q'' (both of which do not represent a hydrogen atom).