NO152412B - ANALOGY PROCEDURE FOR THE PREPARATION OF TERMINAL BIFUNCTIONAL SUGAR COALS - Google Patents

Abstract

Novel anticarcinogenic compounds of formula (I). where. R '' 'is halogen,. R is hydroxy, or. 1 2. R and R together form an oxygen bridge,. R3 is methyl ,. R 4 is hydrogen, methyl or acyl. n is 1 or zero, with the proviso that if n is 1,. 2 3 4. the groups -R, OR and -OR have configurations corresponding to dulcitol, mannitol or sorbitol, if n is zero. 2 has the groups -R and -OR configuration corresponding to xylitol. Preparation of the compounds is described. The new compounds can be used as antitumor agents as such or formulated as pharmaceutical preparations.

Description

The present invention relates to an analogous method for the production of therapeutically active compounds of formula I

where R1 is halogen,

2

R is hydroxy or

1 2

R and R together form an oxygen bridge,

2

and the steric positions of the -R and -OCH^ groups correspond to xylitol configuration.

Compounds of formula I have not previously been described. Analogous Cg-polyols containing a cyclic ether (a dioxolane ring) in the 3,4-positions have been described, but the terminal diepoxy and dihalogen derivatives of 3,4-0-isopropyl-ydenhesitols have no antitumor activity (Arzneimittel Forschung, 17, 145-149 (1967)).

It has been found that the cytostatic effect of 1,5-dihalogen and 1,2-4,5-dianhydroxylitol can be modified by transferring the secondary hydroxy groups to ethers by reacting these with alkoxy groups to a small extent.

Compounds of formula I can be prepared by methylating 1,2-4,5-dianhydroxylitols of formula VII (see the reaction scheme on page 3) with a suitable methylating agent under appropriate conditions without destroying the oxirane rings in the starting material. The obtained 3-methoxy-1,2-4,5-dianhydroxylitols of formula VIII can be converted into compounds of formula IX by reacting them with a hydrohalide or an alkali halide if desired. Compounds of formula (VIII) can be prepared by treating a dihalogen compound of formula IX with a suitable acid substituting agent of basic

J

character. Compounds of formulas VIII and IX fall under formula I and constitute special subgroups thereof.

Dianhydroxylitols of formula VII can be methylated without destroying the oxirane rings if diazomethane, dimethyl sulfate or a methyl halide is used as the methylating agent in the absence of water.

a) If the methylating agent is diazomethane, a solution or a suspension of a dianhydroxylitol can be treated with

this in the presence of a catalyst. The reaction mixture can be treated with diazomethane in gaseous form which is introduced into the mixture or in the form of a solution which is added dripwise. Preferred catalysts are fluoroboric acid, boron trifluoride, oxides of alkali metals or alkaline earth metals, aluminum chloride or selenium dioxide, and the most preferred catalyst is

•boron trifluoride etherate.

b) The methylation can also be carried out by reacting a dianhydroxylitol of formula VII with dimethyl sulfate in the presence of

a base under anhydrous conditions. If a metal hydride base can be used, the preferred base is sodium hydride. Ether compounds can be used as solvents, and the preferred solvents are the ethers used in the methylation method which is carried out with diazomethane.

c) Alkyl halides can also be used as methylating agents, and preferably methyl iodide or methyl bromide is used, and

as catalyst a metal oxide and/or metal hydride, preferably silver oxide, calcium oxide, strontium oxide, barium oxide and/or hydroxide. The preferred solvents are dimethylformamide and dimethylsulfoxide.

Compounds of formula VIII can in themselves be used as cytostatic agents, but they can also be transferred in other cytostatic sugar alcohol derivatives according to the invention.

The compound VIII can be converted into the compound of formula IX by treating it with a hydrohalide or an alkali halide in which the halogen atom is chlorine, bromine or iodine. Two reaction routes are possible for this transfer. Either a dianhydro compound is reacted with a concentrated aqueous solution of a halogen acid, or the reaction is carried out under milder conditions by dissolving a dianhydro compound VIII in the aqueous solution of an alkali salt of the appropriate halogen acid, then adding the concentrated solution of a strong acid, e.g. . sulfuric acid or perchloric acid to the solution under vigorous stirring, the addition being carried out so that the reaction mixture remains mainly neutral (approx. pH 6.5-7). The compound of formula IX obtained by de

above stated methods fall under formula I.

If desired, the compound of formula IX can be transferred into the compound of formula VIII by reacting them with an acid substitute of a basic nature. Any strong organic or inorganic base can be used in the above reaction as an acid substituting agent. Preferred organic bases are e.g. alcoholates of alkali or alkaline earth metals, or organic nitrogenous bases; preferred inorganic bases are e.g. hydroxides, carbonates or bicarbonates of alkali or alkaline earth metals.

The reactions according to the invention are illustrated below, and the most characteristic reactants for the individual transformations are indicated by the arrows.

Biological business

Cytopharmacological activity of the compounds of formula I, which compounds can be prepared according to the invention. is illustrated by giving the experimental results obtained from experiments with the compound indicated below: 1,2-4,5-dianhydro-3-methoxy-xylitol (our brand is MMDAX).

Toxicological tests

LDj-Q values in mice after intraperitoneal administration:

MMDAX 500 mg/kg

Activity against Walker intramuscular carcinosarcoma

MMDAX 1 x 100 mg/kg/ip 90%

Activity against S-180 subcutaneous sarcoma

MMDAX 8 x 50 mg/kg/ip 75%.

Comparative experiments performed on other tumors ^ 1210 '^- eu~ chemistry in mice, Yoshida sc. sarcoma, P^gg i.p. leukemia) gave

similar results to those stated above, and on the basis of these results it has been found that the compounds of formula I show clear cytostatic activity and their cytostatic effect is better than that of the base molecules.

The new anticarcinogenic compounds of formula I can be used therapeutically in various forms.

Per os: the pure active ingredient without carriers or the pure active ingredient mixed together with excipients generally used in the manufacture of tablets (e.g. starch, lactose, talc) formulated in the form of tablets.

Intravenous: dissolved in water or in a pharmacologically inert organic solvent (various glycols, etc).

Intramuscularly: in the form of the above solutions or as suspensions.

Intraperitoneally: in the form of the aforementioned solutions or as suspensions.

Intracavitally: the pure active ingredient without carriers or the pure active ingredient in the form of the aforementioned solutions or as suspensions.

Locally (in loco): the pure active ingredient is applied to the skin or to parts of the body that were operated on without carriers or mixed together with generally used antibacterial agents and compounds used for the treatment of wounds (sulfonamides, corticoids, vitamins, etc.).

Content of preferred active ingredient in different preparations:

The production and formulation of the anticarcinogenic compounds according to the invention are illustrated by the following examples.

Example 1

1, 2- 5, 6- dianhydro- 3- methoxyxylitol

20 g (0.17 mol) of 1,2-4,5-dianhydroxylitol was dissolved in 1500 ml of dry ether and the solution was saturated with diazomethane gas while stirring at room temperature. A few drops of boron trifluoride in ether in ether solution were added to the reaction mixture while simultaneously introducing permanent diazomethane gas. Addition of boron trifluoride etherate solution was constantly repeated when the reaction mixture was saturated with diazomethane. When the original 1,2-5,6-dianhydroxylitol was completely reacted, saturated aqueous solution of sodium bicarbonate was added to the reaction mixture in an amount sufficient to decompose the entire amount of the added boron trifluoride etherate, the reaction mixture was stirred for half an hour and dried over a caustic soda -bonnet. The filtered clear solution was evaporated and the residue was distilled in vacuo. 15 g of the title compound were obtained in the form of a colorless oil. Boiling point: 48°C/1.5 mmHg. Yield: 67%.

Example 2

1, 5- dibromo- 1, 5- dideoxy- 3- methoxyxylitol

1 g (0.0077 mol) of 1,2-5,6-dianhydro-3-methoxyxylitol was dissolved in 2 ml of acetone and the solution was added dropwise at a temperature below 0°C with stirring to 6 ml of hydrobromic acid cooled below 0° C, and the mixture was stirred for half an hour at a temperature below 0°C. The pH of the solution was adjusted to six by adding sodium bicarbonate. The precipitate formed was filtered and mixed without drying with 50 ml of dichloroethane. The dichloroethane was dried over burnt sodium sulfate, concentrated to

about. 10 ml and hexane was added so that the solution became turbid. The product which precipitates on cooling was filtered off and recrystallized from a 1:1 mixture of dichloroethane and hexane. 1.4 g of the title product were obtained in the form of colorless crystals. Melting point: 78-30°C. Yield: 62%. Rf is 0.59

(with the same solvent mixture as in example 1).

Example 3

1, 5- dichloro- 1, 5- dideoxy- 3- methoxyxylitol

1 g (0.0077 mol) of 1,2-5,6-dianhydro-3-methylxylitol was dissolved in 2 ml of acetone and the solution was added dropwise at a temperature below 0°C with stirring to 8 ml of concentrated hydrochloric acid solution cooled below 0°C. The reactive ion mixture was stirred for half an hour at a temperature below 0°C. The solution was evaporated in vacuo and the remaining oil was placed on a silica gel chromatography column with a volume twenty times that of the residue and eluted with a 1:1 mixture of benzene and ethyl acetate. Fractions containing the title product were combined and evaporated. 0.8 g of the title compound was obtained in the form of a colorless oil. R f is 0.52 (with a 1:1 mixture of benzene and ethyl acetate as solvent). Yield: 51%.

Example 4

1, 5- diiodo- 1, 5- dideoxy- 3- methoxyxylitol

1 g (0.0077 mol) of 1,2-5,6-dianhydroxylitol was dissolved in 2 ml of acetone and the solution was added dropwise at a temperature below 0°C with stirring to 8 ml of concentrated hydrochloric acid cooled under 0°C. The reaction mixture was stirred for half an hour, the formed crystals were filtered off and recrystallized from ethyl acetate. 1.5 g of the title compound was obtained in the form of colorless crystals. Melting point: 105-106°C. Yield: 50.5%.

Claims (2)

1. Analogy method for the production of therapeutically active compounds of formula I where R"*" is halogen, 2 R is hydroxy or 1 2 R and R together form an oxygen bridge, 2 and the steric positions of the -R and -OCH^ groups correspond to the xylitol configuration, characterized by reacting a dianhydroxylitol of formula VII with diazomethane, dimethyl sulfate or a methyl halide in the presence of a catalyst, and optionally reacts the compound of formula VIII formed i with a hydrohalide which gives a compound with for flour IX where X is halogen and, if desired, a compound of formula IX in which the meanings and spatial positions of the substituents are as defined above can be reacted with a basic compound to a compound of formula VIII. 2. Process according to claim 1 for the production of 1,2-4,5-dianhydro-3-methoxyxylitol, characterized in that 1,2-4,5-dianhydroxylitol is used as starting material with formula VII.