JPS6026387B2 - Cinnamyl moranoline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present inventors previously discovered and isolated the substance represented by Z=day in the formula [B] below in the minato drug "Mulberry Peel" from the natural world, and named it moranolin. ,reported.

(Yagi et al.: Journal of the Japanese Society of Agricultural Chemistry, Section 5, 571 pages, (1
976)). Subsequently, the present inventors conducted repeated research on the physiological effects of moranolin, and discovered that moranolin has an extremely useful action as a pharmaceutical drug, suppressing the rise in blood pressure in sugar-loaded animals. Invented a blood sugar increase suppressant and applied for a patent.

After that, the present inventors continued their research on various new derivatives of moranoline, and as a result, they discovered a new molanolin derivative of the - group, which has much stronger activity than moranoline, and completed the present invention. .

All of the compounds included in the present invention are new compounds, and can be structurally considered to be N-cinnamyl moranoline derivatives.

The hypoglycemic activity of various N-aralkyl or aralkenyl derivatives of moranoline largely depends on the number of carbon chains between the aromatic nucleus and the nitrogen atom of moranoline, and those with one or two carbon chains have no activity at all. It shows activity only when the number of carbon chains is 3 or more. It shows a long activity when the number of carbon chains is 3 or 4, and the activity of N-cinnamyl moranoline is particularly strong. In addition, y-methylcinnamyl, y-ethylcinnamyl derivatives, etc., which have a hawk substituent group at the y-position of the cinnamyl group, are as active as cinnamyl derivatives, and also have various alkoxy groups on the aromatic nucleus. Cinnamyl derivatives used as substituents generally have high activity.

In particular, the compounds having glycol ether type substituents included in the present invention have high activity and low toxicity, and are particularly useful as pharmaceuticals. In addition to the substances included in the present invention, cinnamyl derivatives having glycol ether-type pupil substituents include cinnamyl derivatives having ethoxy groups or propoxy groups having various alkoxy substituents having 1 to 18 carbon atoms. In addition, some compounds have two or more of these glycol ether-type groups, and it goes without saying that there are many isomers based on their positional values. The useful physiological effects of the substances included in the present invention are properties that generally exist in these glycol ether type cinnamyl moranoline derivatives, and are not limited to the substances included in the present invention. Now, all of the substituted cinnamylmoranoline derivatives included in the present invention not only have much stronger activity than moranoline, but also have much stronger activity than N-alkylmoranolines and unsubstituted cinnamylmoranoline/phosphorus. It has even stronger activity.

Table 1 compares the activities of representative substances included in the present invention with those of N-penzylmolanoline, N-phenethylmoranoline, N-cinnamylmolanoline, and moranoline, N-methylmoranoline. show. Activity is test substance 1 female/
When ko was orally administered to rats at the same time as sucrose/k9, the increase in blood sugar after 120 minutes was compared with the control group.
It is expressed as the suppression rate. Table 1 As described above, all the substances included in the present invention have a strong effect of suppressing blood elevation, and are effective against hyperglycemic symptoms and various diseases caused by blood sugar in humans and animals, such as diabetes,
It is extremely useful as a prophylactic and therapeutic agent for arteriosclerosis, obesity, gastritis, gastric hyperplasia, duodenal hyperplasia, etc.

All of the compounds included in the present invention are N-substituted cinnamyl derivatives, and can be synthesized by various synthetic methods commonly used for N-aralkenylation reactions of amines.

That is, a conventional cough substitution reaction using a compound having an activated substituted cinnamyl group, such as a substituted cinnamyl halide, sulfonate, phosphonate, etc., or a so-called reductive alkylation reaction using a substituted cinnamaldehyde, etc. are generally advantageously carried out. It is possible. Alternatively, it can be synthesized by a method in which the desired compound is obtained by forming an amide type compound with a directly expected cinnamic acid, etc., and then reducing the carbonyl group. Of course, moranoline itself can be used as a raw material for one of these reactions, but the hydroxyl group of moranoline can be protected by an appropriate protecting group, such as an acetyl group, benzyl group, benzyl group, etc.
Using intermediates protected with tetrahydropyranyl groups,
The desired product can also be obtained by removing the protecting group after performing the N-substitution reaction. In addition, as represented by compounds 5 and 7,
Compounds having a hydroxyl group as a substituent on an aromatic ring can be synthesized in addition to the above-mentioned method by first synthesizing an intermediate having a phenolic hydroxyl group, and then synthesizing it with ethylene oxide under alkaline conditions. It can be synthesized by reacting with an epoxy reagent such as or glycidol. In the following, an example of a method for synthesizing typical compounds included in the present invention will be described with reference to Examples.

Example 1 Synthesis of Compound 1 m-B-methoxybentaldehyde obtained by reacting m-oxybennaldehyde with methoxyethoxybromide in the presence of anhydrous potassium carbonate in DMF 12.
Dissolve 7 g of anhydrous tetrahydrofuran in 50' of anhydrous tetrahydrofuran containing about 20% vinylmagnesium bromide.
Drop ice cold light into the furan solution.

After the dropwise addition, it was left to stand at room temperature for 30 minutes, and then treated by a conventional method to obtain a colorless oily carbinol type compound 12. Get the key. The carbinol compound 1 obtained above was melted in 50' of water, cooled with ice, 8.1 g of phosphorus tribromide was added, and the mixture was heated for 5 minutes.

After washing with 100 ml of cold water, the ether layer was dried over anhydrous magnesium sulfate, and the ether was removed under reduced pressure at 30°C or less. A pale yellow oily cinnamyl furomide derivative was obtained. Meanwhile, 30% of moranolin was dissolved in 50% of ethylene glycol and 50% of sodium bicarbonate. Add the cinnamyl bromide derivative obtained above for about 20 minutes under a rope at room temperature, and stir at room temperature for 3 hours.

After the reaction, the reaction solution was diluted with water, acidified with hydrochloric acid, washed with ether, made alkaline with ammonia, and extracted with n-butanol. Butanol was distilled off, and the remaining crystalline material was recrystallized from a mixed solvent of isopropanol and methanol. Yield.
1g.

Melting point: 136-1°C. [Q] Color 4 = -39.70 (methanol) Example 2 Synthesis of Compound 2 m-B-methoxyethoxyacetophenone prepared from m-oxyacetophenone and methoxyethoxyfuromide was prepared in the same manner as in Example 1. The resulting carbinol compound (14) was subjected to a Grignard reaction, and the resulting carbinol compound was mixed with ether (50%) and phosphorus tribromide (9%) under ice-cooling. Treat with him for 5 minutes, cinnamylfuromide type substance 16. get a place

Dissolve 3.1 g of moranoline in DMS050' and 5.1 g of sodium bicarbonate. Add the female and the obtained belomide 1 on top
Bet on the room lamp Azusa 1. Drips in insect time. Rope Azusa for 30 minutes after dripping. The following treatment was carried out in the same manner as in Example 1, and the butanol extract was treated with isopropanol to crystallize. Recrystallized from ethanol. Yield 3.1 total. Melting point 116-119°C. [Q] Yong = Kazuhiro. 90 (meth/-) Example 3 Synthesis of Compound 3 Using p-oxybenaldehyde as a starting material, the reaction was carried out in the same manner as in Example 1, and 7.1 g of the resulting bromide was mixed with 3 moranolin and 3.0 g of sodium bicarbonate. Bamboo and DMS030 were reacted underground at room temperature for 1 hour, followed by the same treatment as in Example 1, and the resulting butanol extract was recrystallized from ethanol.

Yield 1. Spots & melting point 1~I74℃.

[Q] Color 4 = -48.60 (methanol) Examples 1 and 2
, 3 were used to synthesize compounds 4 and 6.

Compound 4 Melting point 166-160 [Q].

24 = -43r (methanol) Compound 6 Eagle & Point 118-12ro [Q] Color 4 = -37-70 (methanol) Example 4 Synthesis of compounds 5 and 7 Dissolve p-oxybenzaldehyde 2 in DMF 200' Then, 4 cycles of anhydrous potassium carbonate and 45 g of 8-methoxyethoxymethyl chloride were added, and the mixture was heated at room temperature for 3 hours.

Dilute with water, extract with ether, and distill the extract under reduced pressure. b.
p. Obtain 2 demons of distillate of 150-15 chi 0/5 Cape Hg. This was subjected to a Grignard reaction with the same vinyl magnesium bromide as in Examples 1, 2, and 3, and the resulting carpinol compound was treated with an equimolar amount of thionyl chloride in 10 qo in ether for 1 minute to form cinnamyl chloride. This compound is reacted with moranoline in DMSO in the presence of sodium bicarbonate in the same manner as in Examples 2 and 3 to obtain p-8-methoxyshethoxymethoxycinnamyl moranoline. Melting point 111-11
04:00. Dissolve the crystals obtained above in 50% methanol, add 2M concentrated hydrochloric acid and 5% water; 2. Heat to reflux for an hour. The reaction product was dried under reduced pressure, the residue was washed with ether, and the insoluble matter was treated with a mixed solvent of ethanol and ethyl acetate to crystallize. Yield 3. Crude crystals obtained in the synthesis of Xg (p-hydroxycinnamyl moranoline hydrochloride) compound 5 1. Females were treated with caustic potassium 1. Dissolve the solution in 30' of methanol, add 2' of ethylene oxide, and heat in a sealed tube at 8 to 0 for 3 hours.

The reaction product was dried under reduced pressure, and the residue was dissolved in water and passed through a column of ion-exchange resin DOWEX 50Wx4 (Japanese model). After washing the column with water, the adsorbate was eluted with 50% aqueous methanol containing 1% ammonia, and the eluate was evaporated under reduced pressure.
Add 0.0% p-toluenesulfonic acid to the remaining pale yellow sticky oil-like reaction product. It crystallizes when added to the hull and treated with isopropanol. Recrystallized from ethanol. Yield 0.8, melting point 131~
1 pine ℃. [Q] poly=-29.60 (methanol) Crude p-hydroxycinnamyl moranoline hydrochloride obtained before synthesis of compound 7 1. Dissolve the cough in 30' of methanol and 1.0' of caustic potassium. Add females, add glycidol 2 and heat under reflux for 4 hours.

Thereafter, compound 5 was treated in the same place and the resulting reaction product was
-Toluenesulfonate and recrystallized from isopropanol. Yield: 0.81g. Melting point 126-130q○. [Q]
Huan = 125-80 Example 5 Synthesis of compound 3 Tetra-○-benzylmolanoline (melting point 44-46°C,
[Q] Volume = 3 (ethanol))5. DM Shigeru ``Dissolved in 30 screams.

3. Add 3.0 g of anhydrous potassium carbonate, and add p-methoxychetoxycinnamyl furomide described in Example 3 under Azusa.
Cough and heat at 60℃~70qo for 6 hours. After the reaction, the reaction solution was diluted with water, made acidic with dilute hydrochloric acid, washed with n-hexane, made alkaline with ammonia, and extracted with benzene.
24% of the crystalline substance remaining after removing benzene
Treated for 3 hours with hydrobromic acid 50% and 90-90%. The residue was dried under reduced pressure, dissolved in water, purified with ether, ammonia alkali, and extracted with n-butanol. The extract was purified by column chromatography on a silica gel column using a 3:1 mixture of chloroform and methanol, and then recrystallized from ethanol. Yield 1.
83, melting point 172-174°C.

Claims (1)

[Scope of Claims] 1. A substituted cinnamyl moranoline derivative represented by the following general formula [A] and acid addition salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R_1 represents hydrogen or a methyl group, R_2 represents hydrogen or a hydroxymethyl group, and R_3 represents hydrogen, a methyl group, an ethyl group, or a methoxyethyl group. 2. The compound according to claim 1, wherein R_1 is hydrogen. 3. The compound according to claim 2, wherein R_2 is hydrogen. 4. The compound according to claim 3, wherein R_3 is hydrogen. 5. The compound according to claim 3, wherein R_3 is a methyl group. 6. The compound according to claim 3, wherein R_3 is an ethyl group. 7. The compound according to claim 3, wherein R_3 is a methoxyethyl group. 8. The compound according to claim 2, wherein R_2 is a hydroxymethyl group. 9. The compound according to claim 8, wherein R_3 is hydrogen. 10. The compound according to claim 1, wherein R_1 is a methyl group. 11. The compound according to claim 10, wherein R_2 is hydrogen. 12. The compound according to claim 11, wherein R_2 is a methyl group.