DK149750B - METHOD OF ANALOGUE FOR THE PREPARATION OF N-ALKENYL MORANOLINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. - Google Patents

Description

in 149750

The present invention relates to an analogous process for the preparation of novel N-alkenylmoroline derivatives of the general formula I shown in the preamble of claim 1, wherein R is as defined herein or pharmaceutically acceptable acid addition salts thereof, and the process of the invention is characterized by the method of claim 1. characteristic part stated.

The inventor of the present process has previously isolated a naturally occurring substance having the general formula II

OH

"" "Ly" ^ Jr \ CHo0H 11

L

from a Chinese drug, Cortex Mori, and has reported this drug under the name moranolin (M. Yagi et al., Nippon Nogeika-gaku Kaishi 5j), 571 (1976)).

Later extensive studies on the pharmacological effects of moranolin have shown that this drug has a very useful drug effect, namely the effect of inhibiting rise in blood sugar in sugar-laden animals, and a Japanese patent application has been filed (Japan Kokai Sho-52-83951).

Further studies on various new derivatives of moranolin have shown that certain novel N-alkenyl derivatives of moranolin of the general formula I are substances whose effect in the stated respect far exceeds the effect of moranolin. The object of the invention is therefore to provide a technical process for the preparation of N-alkenyl-ylmoranoline derivatives substituted on the N atom by a group - (CH-CH = C-CH ~) -H where n is an integer 1 to 3 , or δ j δ n CH3 a phytyl group, ie. a group? H3? H3 CH3 CH3 (CH3CH (CH2) 3CH (ch2) 3CH (ch2) 3c = chch2-).

149750 2

The compounds of the present invention were administered orally to rats at doses of 10 mg / kg together with 2 g / kg of sucrose, and one hour later the percent inhibition of blood sugar levels was measured; it was found, as can be seen from Table 1 below, that the compounds prepared by the process of the invention have significantly more potent inhibitory effect than moranolin.

Table 1

Compound% Inhibition n = 1014% _

Ax n = 2__76% _ n = 3 108% _

Moranolin 28% xr = - (CHOCH = C-CHO) -H 2 in 2 n ch 3

As mentioned, the compounds of the present invention have far more potent inhibitory effects on blood sugar rise than moranolin and are very useful as prophylactic agents and drugs for various diseases caused by hyperglycemic symptoms as well as hepatic glycemia.

Compounds of general formula I, but wherein n has a value of 4 or more, i. which are N-substituted with a higher alkenyl group are also novel compounds, and their physiological effect is similar to that of the compounds where n is 1, 2 or 3. Most of these compounds, except the compound where R is a phytyl group, however, is of little practical importance as drugs because of the great difficulty of synthesis and purification thereof and because of their instability.

149750 3

The alkenylation of moranolin occurs by reaction with an alkenyl halide or alkenyl sulfonate, preferably in a polar solvent such as water, an alcohol, dimethylsulfoxide, dimethylformamide or mixtures thereof, or in a suspension medium consisting of such a polar solvent and a non-polar solvent such as benzene or hexane. , at room temperature or under heating and in the presence of an acid-binding agent such as an alkali metal hydroxide, alkali metal carbonate or alkali metal bicarbonate. When the reaction is carried out in a suspension medium, the yield is sometimes improved by the addition of a phase transfer catalyst such as a cationic surfactant.

If one or more of the hydroxyl groups in the moranoline during the reaction is protected by protecting groups, the protecting group is removed after the alkenylation.

The process according to the invention will be illustrated in the following by some examples.

Example 1

Synthesis of the compound where n = 1.0 g of tetra-O-benzylmoranoline (the hydrochloride, mp 185-189 ° C, [α] D = 27.5 ° (ethanol)) is dissolved in 20 ml of DMF (dimethylformamide) and then 5.4 g of anhydrous potassium carbonate and 5.4 g of isoprenyl bromide are added and the mixture is stirred at 60-70 ° C for 4 hours. After cooling, dilution with water and extraction with benzene is done and the extract is subjected to column chromatography on silica gel with a mixture of equal parts benzene and ethyl acetate for purification. 5.4 g of a pale yellow oily substance are obtained. It is heated together with 50 ml of 47% HBr at 80-85 ° C with stirring for 2 hours. After completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in methanol and the solution washed with hexane. The methanol layer is evaporated to dryness under reduced pressure, the (S) residue dissolved in water and passed down through a "Dowex" w 1x2 (OH) ion exchange column and the eluate further passed through a "Dowex" 50W x 4 (H) ion exchange column. After washing the column with water, the adsorbed substance is eluted with 1% s of ammonia water. Evaporation to dryness of the eluate under reduced pressure gives a 4

14975O

Qlieajtlyt product. This is purified by column chromatography on silica gel with a solution of chloroform / methanol 3: 1.

The crystalline substance thus obtained is recrystallized from acetone. Mp. 140-142 ° C, [α] 24 = -28.7 ° (methanol), yield 0.84 g.

Example .2

Synthesis of the compound where n = 1 1.0 g of Moranolin is dissolved in 10 ml of DMSO and 4.0 g of anhydrous potassium carbonate and 4.0 g of isoprenyl bromide are added and the mixture is heated to 60-65 ° C with stirring for 6 hours.

After completion of the reaction, the mixture is passed through a "Dowex" 50W x 4 ion exchange column. After washing the column with water and then with methanol, the adsorbed is eluted with 1% ammonia water, the eluate is evaporated to dryness under reduced pressure, the residue is treated with hot acetone to remove insoluble matter and the crystalline substance obtained from the acetone solution is recrystallized from acetone. . Mp. 140-142 ° C, Ca1 4 =: -28.7 ° (methanol), yield 0.26 g.

Example 3

Synthesis of the compound where n = 2 5.0 g of Moranolin is dissolved in 30 ml of 50S aqueous methanol and then 17 g of potassium carbonate and 15 g of geranyl chloride are added and heating is carried out at 55-60 ° C with stirring for 6 hours. After completion of the reaction, dilute with water and acidify with hydrochloric acid followed by washing with hexane and alkalinization with ammonia, and the basic substance is extracted with butanol. The resulting pale yellow oily reaction product (5.4 g) is added to 2.9 g of p-toluenesulfonic acid to convert the substance into salt which is recrystallized from ethanol. Mp. 133-135 ° C, [α] 25 = -0.5 ° (methanol), yield 4.3 g.

Example 4

Synthesis of the compound where n = 3. In 50 ml of DMF, 3.26 g of moranolin are dissolved and then 5.6 g of anhydrous potassium carbonate and 10.5 g of farnesyl bromide are added; then heated to 55-65 ° C with stirring for 6 hours «

After completion of the reaction, dilute with water and acidify by adding hydrochloric acid, then wash with hexane, make alkaline with ammonia and extract with butanol.

To purify the resulting reaction product, it is subjected to column chromatography on silica gel using a 3: 1 chloroform / methanol mixture. Yield 0.87 g. Crystallization is difficult. A colorless, viscous, oily substance is obtained.

It is readily soluble in methanol and ethanol, heavily soluble in ether, chloroform and water and insoluble in benzene and hexane. = 0.5 (silica gel / chloroform-methanol 3: 1). The p-Toluenesulfonic acid salt 24 o is a colorless powder. Crystallization difficult. [a) D = -3.0 (methanol).

Example 5

Synthesis of the compound where R is a phytyl group Similar to Example 4, but using phytyl bromide instead of farnesyl bromide as in Example 4, corresponding N-phytyl derivative is obtained. This appeared as a colorless viscous substance and was insoluble in water and soluble in ethanol. R f = 0.57 (silica gel / chloroform-methanol 3: 1).

Calculated for C26H5NO4 (Molecular Weight 441.70): C 70.70 H 11.64 N 3.17

Found: C, 70.34; H, 11.87; N, 2.98%.