SE420311B - N-alkenyl-2-hydroxymethyl-3,4,5-TRIHYDROXIPIPERIDIN - Google Patents

Description

1903336-1 Japan ma, nrjgkai 3h0_52-83951. Further studies of new 2-hydroxymethyl-3,4,5-trihydroxypiperidine derivatives have shown that the new N-alkenyl derivatives of 2-hydroxymethyl-3,4,5-trihydroxypiperidine are more useful than 2-hydroxymethyl-3,4. 4,5-trihydroxypiperidine.

The compounds of formula A have been administered orally to rats at a dose of 10 mg / kg together with 2 g / kg of sucrose, and 2 hours later the percentage inhibition of the increase in blood sugar level was measured. Table 1 shows that each compound falling into formula A has a much greater inhibitory effect than 2-hydroxymethyl-3,4,5-trihydroxypiperidine.

Table 1 Compound% inhibition n = 1 104 'k (A) n = 2 - 76 n = 3 A 108 2-hydroxymethyl-3,4,5-trihydro-oxypiperidine 28 * _' lmcn = _ zcn c caünn CH3 p As mentioned above, all the compounds of the invention have much stronger inhibitory activity on blood sugar increase than 2-hydroxymethyl-3,4,5-trihydroxypiperidine, and they are very useful as prophylactic and therapeutic agents in various diseases, caused by hyperglycemia symptoms and hyperglycemia.

Among the substances represented by the general formula A is the group in which n represents 4 or more, e.g. a higher alkenyl group, as novel as the substances covered by the present invention, and their physiological activity is the same. However, most of these compounds, except that in which R represents phytyl, have little practical significance as drugs, for they are very difficult to prepare and purify, and they are unstable. All the substances which fall within the scope of the invention are new substances, which have been described in detail in the literature. The most common method of preparing these substances is by alkenylation of 2-hydroxymethyl-3,4,5-trihydroxypiperidine. Thus, they can be prepared by reacting 2-hydroxymethyl-3,4,5-trihydroxypiperidine with an active alkenyl reagent such as an alkenyl halide or an alkenyl sulfonate in a polar solvent such as water, an alcohol, DMSO, DMF or a mixture thereof, or in a suspension medium, consisting of such polar solvents and a non-polar solvent such as benzene or hexane at room temperature or under heating in the presence of U an acid accepting agent such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal bicarbonate. When the reaction is carried out in a suspension medium, the yield can sometimes be improved by adding a phase transfer catalyst such as a cationic surfactant.

A method of protecting the hydroxyl group with a suitable protecting group, and alkenylating the protected 2-hydroxymethyl-3,4,5-trihydroxypiperidine and then removing the protecting group, can also be used.

It is also possible to reductively alkylate 2-hydroxymethyl-3,4,5-trihydroxypiperidine with an alkenaldehyde or to convert 2-hydroxymethyl-3,4,5-trihydroxypiperidine to an alkenecarboxylic acid amide and then reduce it for preparation of an N-alkenyl product.

The invention is described by the following examples, which describe in detail - one of the synthetic methods for the substances covered by the invention.

At the same time, physical data or other properties of these substances are stated.

Example gel 1 Synthesis of the compound wherein n represents 1.

In 20 ml of DMF is dissolved 5.0 g of tetra-o-benzyl-2-nyaroxymethyl-3,4,5-s-trihyaroxypiperine (hyarochloride, m.p. 185 DEG-199 DEG C., .alpha. ), 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 chromate. the extract is tographed for purification on a silica gel column with a 1: 1 mixture of benzene-ethyl acetate as eluent. 5.4 g of a pale yellow oily substance are obtained. This 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 is washed with hexane. The methanol layer is evaporated to dryness under reduced pressure, the residue is dissolved in water and passed through an ion exchange column, filled with Dowex 1x2 (OH), and the eluate is further passed through an ion exchange column filled with Dowex 50W x 4 (H). After washing the column with water, the absorbed substances are eluted with 1% aqueous ammonia. Evaporation to dryness of the eluate under reduced pressure gives a pale yellow oily product.

This is purified by column chromatography on silica gel with chloroform-methanol 3: 1 as eluent. The substance so crystalline is recrystallized from acetone. Melting point 140-142 ° C, | a | š4 = -28.70 (methanol), yield 0.84 g.

Eåäfßšll Synthesis of the compound where n represents 1 (alternative procedure).

In 10 ml of DMSO are dissolved 1.0 g of 2-hydroxymethyl-3,4,5-trihydroxypiperidine and 4.0 g of anhydrous potassium carbonate and 4.0 g of isoprenyl bromide are added, and the mixture is heated at 60-65 ° C with stirring for 6 hours. After completion of the reaction, the mixture is passed through an ion exchange column, filled with Dowex 50W x 4. After column washing with water and then with methanol, the absorbed substance is eluted with 1% aqueous ammonia, and the eluate is evaporated to dryness under reduced pressure. The remaining substance is treated with hot acetone to remove insoluble material, and the crystalline substance obtained from the acetone solution is recrystallized from acetone. Melting point 140-142 ° C, | u | â4; -28.70, (methanol), yield 0.26 g.

Example 3 Synthesis of the compound where n represents 2.

In 30 ml of 50% aqueous methanol is dissolved 5.0 g of 2-hydroxymethyl-3,4,5-trihydroxypiperidine and then 17 g of potassium carbonate and 15 g of geranyl chloride are added and then heated at 55-60 ° C with stirring for 6 hours. After completion of the reaction, dilute with water and acidify by adding hydrochloric acid. It is then washed with hexane and made alkaline with ammonia. The basic substance is then extracted with butanol. To the resulting pale yellow oily reaction product (5.4 g) is added 2.9 g of p-toluenesulfonic acid for conversion to a salt which is recrystallized from ethanol. Melting point 133 ~ 135 ° C, | a | 24 = 0.5 (methanol), D yield 4.3 g.

Example gel 4 Synthesis of the compound wherein n represents 3.

In 50 ml of DMF is dissolved 3.26 g of 2-hydroxymethyl-3,4,5-trihydroxypiperidine and then 5.6 g of anhydrous potassium carbonate and 10.5 g of farnesyl bromide are added and heated at 55-65 ° C with stirring for 6 hours. After completion of the reaction, dilute with water and acidify with hydrochloric acid. It is then washed with hexane, made alkaline with ammonia and extracted with butanol. The resulting reaction product is purified by column chromatography on silica gel using a 3: 1 mixture of chloroform and methanol as eluent. Yield 0.87 g. The substance is difficult to crystallize. A colorless viscous oil is obtained. It is readily soluble in methanol and ethanol and sparingly soluble in ether, chloroform and water and insoluble in benzene and hexane. Rf = 0.5 (silica gel / chloroform-methanol 3: 1), p-toluenesulfonic acid salt, colorless powder, which is difficult to crystallize {a | š4 = -3.00 (methanol).

Example Gel Synthesis of the compound wherein R represents phytyl.

Using the same procedure as in Example 4 but using phytyl bromide instead of farnesyl bromide, used in Example 4, the corresponding N-phytyl derivatives are prepared. This is a colorless, viscous substance and is insoluble in water and soluble in ethanol, Rf = 0.57 (silica gel / chloroform-methanol 3: 1).

Elemental analysis: For the molecular formula C 26 H 51 NO 4 (molecular weight 441.70) calculated (%) C 70.70; H 11.64; N 3.17 Found (%) C 70.34; H 11.87; N 2.98

Claims (2)

N-alkenylpiperidine derivatives, characterized in that they have the general formula A OH HO OH (A) NH OH å 2 wherein R represents - (CH 2 CH = C-CH 2) n H, n represents an integer 1- 3, in CH 3 or a phytyl group CH 3 CH 3 CH 3 CH 3 IIII (_ (CH 3 CH (CH 2) 3 CH (CH 2) 3 CH (CH 2) 3 C = CHCl 4 I 2 -), and acid addition salts thereof. The present invention relates to N-alkenylpiperidine derivatives of the general formula A OH H0 OH (A) N CH OH, 2 R wherein R represents - (CH 2 CH = ç-CH 2) nH, wherein n represents an integer one of one ena ons 1-3, or a phytyl group (CH 3 CH (CH 2) 3 CH (CH 2) 3 CH (CH 2) 3 C = CHCH 2. -), and acid addition salts thereof. These compounds are useful as prophylactic and therapeutic agents in various diseases, caused by hyperglycemia symptoms and hyperglycemia.