JPS5943948B2 - Substituted moranoline derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present inventors previously discovered and isolated a substance represented by the formula [B] below from the Chinese herbal medicine mulberry bark for the first time from natural pruritus, named it moranolin, and reported it.

(Yagi et al.: Journal of the Japanese Society of Agricultural Chemistry, Vol. 50, p. 571, (1
Furthermore, as a result of repeated research into the physiological effects of moranolin, the present inventors discovered that moranolin has an extremely useful effect as a pharmaceutical, suppressing the rise in blood sugar in animals with a sugar load. He invented a blood sugar rise suppressant containing moranoline and filed a patent application (Japanese Patent Application Laid-open No. 83951/1983). After that, the present inventors continued extensive research on various new derivatives of moranolin, and as a result, they gradually discovered a group of new moranolin derivatives that have 10 times more activity than moranolin, and completed the present invention. did. All of the novel moranoline derivatives included in the present invention are structurally N-aralkylmoranoline or N-
It can be characterized as an aralkenyl moranoline, and its activity is far more potent than moranoline itself, as detailed below.

Moreover, among the N-aralkylmoranolines, N-benzylmoranoline and N-phenethylmoranoline, which have simpler structures than the compounds of the present invention, have far greater activity than the N-aralkylmoranolines of the present invention. weak. That is, the substances included in the present invention, in other words those in which the chain between the nitrogen atom and the phenyl group of moranoline has three or more carbon atoms, exhibit extremely strong activity. Note that N-aralkynylmoranoline derivatives having a triple bond between a nitrogen atom and a phenyl group, such as 3-phenyl-2-propynylmoranoline, 3-phenyl-2-butynylmoranoline,
Compounds represented by 4-phenyl-3-butynylmoranoline, 4-phenyl-3-pentynylmoranoline, etc.
Although it similarly has strong activity, its practical value is small due to difficulties in industrial production. Also, a group of substances having various heteroaromatic ring groups in place of the phenyl group in the formula [A],
For example, furan, thiophene, pyrrole, imidazole,
Similar activities are also found among substances having 5- or 6-membered heteroaromatic ring groups containing oxygen, nitrogen, and sulfur, such as pyrazole, thiazole, oxazole, pyridine, pyrimidine, pyridazine, and pyrazine, and fused ring groups containing these. There is something to show.

However, although the synthesis of these substance groups is possible by a method similar to the method described in this specification, it is generally extremely difficult and cannot be realized industrially. Now, when 10 rng/K9 of the compound included in the present invention is orally administered to rats at the same time as sucrose 27/K9 and the rate of inhibition of blood sugar rise is measured 60 minutes later, the rate of inhibition of blood sugar rise is almost 100% or more in all cases. . On the other hand, the inhibition rate of moranoline was only 28% under the same experimental conditions, and conversely, N-benzylmoranoline and N-phenethylmoranoline inhibited blood sugar elevation by 35% and 21%, respectively. showed enhancement. Table 1 lists examples of substances included in the present invention, and shows the rate of inhibition of blood sugar elevation of these substances under the above-mentioned experimental conditions. As described above, all the substances included in the present invention have a strong glycemic control effect, and are effective against hyperglycemic symptoms and various diseases caused by hyperglycemia in humans and animals, such as:
Diabetes, arteriosclerosis, obesity, heart disease, gastritis, gastric ulcer, -
It goes without saying that it is extremely useful as a preventive and therapeutic agent for intestinal ulcers, etc.

All of the substances included in the present invention are new substances that have not been described in any literature, and can be synthesized, for example, by the following method.
The most common and advantageous method is the N-alkylation of moranoline.

That is, moranoline can be mixed with water, various alcohols, DMS, etc.
Various active aralkyl group or aralkenyl group reagents can be mixed with various active aralkyl groups or aralkenyl group reagents in polar solvents such as OLDMF, various seronlubes, glymes, and dioxane, or mixed solvents thereof, or in a suspension medium of these and nonpolar solvents such as benzene and hexane. It can be synthesized by reacting in the presence of a deoxidizing agent. Active reagents include, for example, aralkyl halides,
Examples include aralkenyl halides, aralkyl sulfonic acid esters, aralkenyl phosphoric esters, and the like. It is also possible to obtain the desired product by using moranoline whose hydroxyl group is protected with an appropriate protecting group, such as an acetyl group, benzoyl group, benzyl group, or tetrahydropyranyl group, and removing the protecting group after the N-substitution reaction. can. It can also be synthesized by using a reagent having a carbonyl group as a reaction reagent, such as aralkyl aldehyde or aralkenyl aldehyde, and carrying out a so-called reductive alkylation or aralkenylation reaction. As the reduction method in this case, various metal hydride complex reducing agents may be employed in addition to the catalytic hydrogenation reaction. Furthermore, by applying this reductive alkylation or aralkenylation synthesis method to nojirimycin or its derivatives, -
It is also possible to obtain the desired product by performing reduction and alkylation or aralkenylation. Alternatively, it can be synthesized by first synthesizing N-acylmolanoline derivatives and reducing them to obtain N-alkyl derivatives or N-aralkenyl derivatives. Examples of substances included in the present invention are given below, and their synthesis methods and substances are shown in Examples.

Example 1 Synthesis of Compound 1 3.26 ml of moranoline was mixed with 25 ml of methanol and 2 DMF.
Heat and dissolve in 5 ml of the mixed solution, add 5.0 ml of sodium bicarbonate and 8.5 ml of 4-phenylbutyl bromide, and add 8.5 ml of the mixture.
00 for 4 hours, then heated and stirred at 95 mm for 2 hours.

The reaction solution is diluted with water, made acidic by adding hydrochloric acid, washed with benzene, converted into an ammonia alkali, and extracted with n-butanol. If the butanol is distilled off after washing with water, crystals will remain. Recrystallized from acetone. Melting point 118-119°C. Yield 2.9170 [α] Amanichi 19.01 (methanol).
p-Toluenesulfonate: Recrystallized from isopropanol, melting point 163-164°C, [α]D4 re(water) Example 2 Synthesis of compound Moranoline 3,267 was dissolved by heating in 25 ml of DMF,
Sodium bicarbonate 4.0 and 4-phenyl-3-
Butenyl bromide 7. Add Oku and heat and stir at 800-85°C for 6 hours.

The following treatment was carried out in the same manner as in Example 1, and the resulting reaction product contained p.
-Toluenesulfonic acid 3,5? Add to make salt and recrystallize from ethanol.

Melting point: 160°C to 162°C, [α] 8.0°C (Methanono). Yield: 3.1270 Example 3 Synthesis of Compound Moranoline (1.57%) was dissolved with heating in 20ml of DMF, and potassium carbonate (1.57%) and Add γ-phenylcinnamyl bromide 407 and heat and stir at 600°C for 1 hour.

Thereafter, the same treatment as in Example 1 is carried out, and the resulting reaction product is recrystallized from a mixed solution of ethyl acetate and n-hexane. Melting point 91
Le~94°C1 [α]21) - 57.2 points (methanol). Yield: 0.3970 Example 4 Synthesis of Compound M 2.07 g of moranoline was dissolved in DMF4Om/ and 3.5 g of potassium carbonate was dissolved. Then, 5.5 grams of 4-phenyl-3-pentenyl bromide were added, and the mixture was heated and stirred at 60 liters for 11 hours.

Thereafter, the reaction product obtained by the same treatment as in Example 1 was recrystallized from isopropanol. Melting point: 126°C to 131°C.

[α]-123,2. (Methanono (to).

A yield of 0.4010 or less indicates physical properties of compounds included in the present invention other than those mentioned above.

All of these were synthesized according to the method described above. Compound melting point: 169~170'C1 [α]2d-139.9' (metano(he) compound melting point: 138~141℃, [α] 1-71.41 (metano(he) compound melting point: 1647~166℃, [α] 2♂116.9℃ (methanol) Compound melting point: 1601~162℃, [α] 10.42 (methanol) compound (p-toluenesulfonate) Melting point :190 to 192°C [α]M-12.

79 (water) compound melting point: 1162-118°C, [α]2^-151.7°C (methano(c) compound
(p-toluenesulfonate) Melting point: 223-226°C

Claims (1)

[Scope of Claims] 1. An N-substituted moranoline derivative represented by the following general formula [A]. However, Z in the formula represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼. Here, R represents hydrogen or a phenyl group, and when R is hydrogen, X represents an alkylene group or alkenylene group having 4 or 5 carbon atoms, and when R is a phenyl group, it represents an alkylene group or an alkenylene group having 3.4 carbon atoms.
or represents an alkenylene group of 5. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [A] 2 The N-substituted moranoline derivative according to claim 1, wherein R is a phenyl group and X is an alkenylene group having 3, 4 or 5 carbon atoms. 3. The N-substituted moranoline derivative according to claim 2, wherein X is ▲a numerical formula, a chemical formula, a table, etc.▼. 4. The N-substituted moranoline derivative according to claim 2, wherein X is ▲a numerical formula, a chemical formula, a table, etc. 5. The N-substituted moranoline derivative according to claim 2, wherein X is ▲a numerical formula, a chemical formula, a table, etc.▼. 6. The N-substituted moranoline derivative according to claim 1, wherein R is H and X is an alkylene group or alkenylene group having 4 or 5 carbon atoms. N according to claim 6, wherein T X has 4 carbon atoms
-Substituted moranoline derivatives. 8 Claim 1 in which X is -(CH_2)_4-
N-substituted moranoline derivatives as described in . 9. The N-substituted moranoline derivative according to claim 1, wherein X is -(CH_2)_2-CH=CH-. 10. The N-substituted moranoline derivative according to claim 1, wherein X is -CH_2-C(CH_3)=CH-. 11. The N-substituted moranoline derivative according to claim 7, wherein X is -CH_2-CH=C(CH_3)-. 7. The N-substituted moranoline derivative according to claim 6, wherein 12 X has 5 carbon atoms. 13. The N-substituted moranoline derivative according to claim 12, wherein 13X is -(CH_2)_5-. 14. The N-substituted moranoline derivative according to claim 12, wherein X is -(CH_2)_3-CH=CH-. 15 X is -(CH_2)_2-CH=C(CH_3)
- The N-substituted moranoline derivative according to claim 12. 13. The N-substituted moranoline derivative according to claim 12, wherein 16X is -CH_2-CH=CH-CH=CH-.