JPS604182B2 - Method for producing linoleic acid amide of 6-aminochroman compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the following general formula (1) [wherein R,, R2, and R3 are hydrogen or a methyl group, and R4
represents hydrogen or a lower alkyl group.

Moreover, m represents an integer of 0 to 3. This invention relates to a method for producing linoleic acid amide of a 6-aminochroman compound represented by the following.

Compound (1) according to the present invention has an excellent blood and liver cholesterol lowering effect.

That is, the cholesterol-lowering effect of compound (1) is clear from the results of the following pharmacological tests.

Pharmacological testing '11 Sample compound: The following compound was selected.

N-(2,2,5,7,8-bentamethyl-chromaniru-6)-linoleic acid amide (hereinafter referred to as compound A)N-
Methyl-N-(2,2,5,7,8-bentamethyl-chromanyl)-linoleic acid amide (hereinafter referred to as compound B)
N-Methyl-N-[2-(4', 8, 12-trimethyl-trideral)-2, 5, 7, 8-tetratylchromaniru-6]-linoleic acid amide (hereinafter referred to as compound C)
N-[2-methyl-2-(4', 8, 12'-trimethyl-tridecyl)-chromaniru-6]-linoleic acid amide (hereinafter referred to as compound D) ■ Animals used: Wistar male rats (body weight 140-170 mm) Five animals were used for each test compound.

'3} Test item i) Effect on animals administered with normal diet (A) Administration method, dosage and measurement method Test compounds A to D were suspended in a 5% aqueous gum arabic solution, and each was administered at 200 9/k on 91 days. The dose was orally administered for 8 consecutive days.

On the other hand, a Planck test was conducted by administering only a 5% aqueous gum arabic solution in the same manner as a control.

On the 8th day of administration, the total amount of cholesterol and the amount of ester-type cholesterol in the blood and liver were measured.

‘0} Measurement result The results are shown in the table below.

The values are the remaining amounts of total cholesterol and ester-type cholesterol after 8 days of administration.

Therefore, the lower the number, the better the cholesterol-lowering effect (average of 5 animals).

Table 1 ii) Effects on animals administered with cholesterol-loaded feed Administrative method, dosage and measurement method Cholesterol was administered to the animals according to the method described in Pharmaceutical Journal, Vol. 92, No. 7, pp. 879-885 (1972). Feed a mixture of 2% by weight and 1% by weight of cholic acid, and at the same time feed test compounds A to D.
were suspended in a 5% aqueous gum arabic solution and administered orally for 5 consecutive days at a dose of 200 9'k91 days each.

On the other hand, a blank test was conducted by administering only a 5% aqueous gum arabic solution in the same manner as a control.

On the 5th day of administration, the total cholesterol amount and ester type cholesterol amount in the blood and liver were measured.

'0) Measurement result The results are shown in the table below.

The values are the remaining amounts of total cholesterol and ester-type cholesterol after 5 days of administration.

Therefore, the lower the number, the greater the cholesterol-lowering effect (average value for 5 animals).

Table 2 iii} Acute toxicity test [A' Administration method, dosage Test compounds A to D were suspended in a 5% aqueous gum arabic solution, and 500 9/k9 was added for each test compound.
, administered orally at a dose of 2000 Ta'k9.

After administration, there was an observation period of 4 days for the 500 9/k9 and 2000 9/k9 administration groups, and a 7 day observation period for the 10000 9/k9 administration group. 'Low Observation Results For all test compounds, only temporary diarrhea was observed for the first time at the dose of 10,000 9/k9, and weight gain was also normal.

No deaths were observed.

From the above results, the oral acute toxicity of the test compound is considered to be extremely low.

Furthermore, the lethal dose (LD) is estimated to be 10,000 females/k9 (oral) or more.

(2) Results These pharmacological tests revealed that compounds A to D all have significant cholesterol-lowering effects, and their toxicity (acute toxicity) is also extremely low.

From the results of the above pharmacological tests, the compound (1) of the present invention, represented by compounds A to D, is effective for the prevention and treatment of diseases caused by an increase in blood cholesterol, especially so-called adult diseases such as arteriosclerosis and diabetes. It is thought that it has great utility value. The present invention relates to the following general formula (b) [wherein R,, R2, R3, R4 and m represent the above-mentioned meanings.

This can be carried out according to a conventional acid amide formation method in which a 6-aminochroman compound represented by the following formula is reacted with IJ/oleic acid or a reactive derivative thereof.

Examples of reactive derivatives of linoleic acid include acid anhydrides,
Examples include acid chloride, mixed acid anhydride, and active ester. When the compound (m) is used as it is, for example, N.N'-zine chlorocarbodiimide, diphenyl phosphite, triphenyl phosphite, polyphosphoric acid, polyphosphate ester [Yuichi Kanaoka et al., Chemical Pharmaceutical Co., Ltd.]・Refer to Bulletin, Vol. 13, No. 9, pp. LO65-LO72 (1965)], P-toluenesulfonic acid, P-toluenesulfonic acid chloride, sulfuric acid, and other condensation catalysts commonly used in the formation of acid amides. can be used. Although the reaction proceeds without a solvent, for example, halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride, dichloromethane, dichlorolethane, and trichlorethylene; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; methanol, ethanol, Lower alcohol solvents such as propanol; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; saturated hydrocarbon solvents such as n-hexane, ligroin, and petroleum ether; ethyl acetate,
Ester solvents such as methyl acetate; organic solvents such as acetone, ketone solvents such as methyl ethyl ketone, or tertiary amine solvents such as triethylamine and pyridine are selected as appropriate and used alone or in the form of a mixed solvent to facilitate the reaction. It can be carried out smoothly and is suitable for post-processing. Next, the present invention will be explained with reference to examples.

Example 1 Synthesis of N-(2.2.5.7.8-bentamethyl-chromanyl-6)-linoleic acid amide In 100% chloroform, 13.0% polyphosphoric acid ester and 6.0% triethylamine were dissolved. 6-amino-2.2.
A solution of 4.4 ml of 5,7,8-bentamethyl-chroman and 8.4 ml of linoleic acid dissolved in 30 ml of chloroform was added to the undercoat and refluxed at 64° C. for 3 hours.

After refluxing, the reaction mixture was concentrated under reduced pressure, and the residue was dispersed in 5% aqueous sodium bicarbonate solution. This solution was extracted with benzene, and the benzene extract was washed with water, dried with bitter salt, and then the benzene was removed. The residue was purified by silica gel chromatography using n-hexane/ethylenal mixed solvent as an eluent. The desired product was obtained as a pale yellow powder. Yield 8
．． 0 (yield 83%) Melting point 59-60k Elemental analysis value C Shiji 5, N02 as C day N Theoretical value (%) 79.78 10.67 2.9
1 actual measurement value) 79.73 10.75 2.
811R spectrum measurement value (Ka-1) 3225 (shiNH
), 1640 (shiC=.

) MAS spectrum measurement value M+: 481 NM old spectrum measurement value (7: CDC13) NH; 3.
05 (IH) CH of linoleic acid: 4.60 (4H) Chroman-3 position C: 8.22 (pan) Chroman-4 position C ratio: 7.50 (2H) Aromatic CH3: 7.86 ( 3H), 7.92 (3H),
7.94 (3H) Terminal CH3 of linoleic acid; 9.10 (
9H) Example 2N-methyl-N-(2.2.5.7.
Synthesis of 8-bentamethyl-chromanyl-6)-linoleic acid amide N・N'-dicyclohexylcarbodiimide 1
To the solution obtained by adding 0.5 parts of toluene to 50 parts of toluene, 6.5 parts of 6-N-methylamino-2,2,5,7,8-bentamethyl-chroman and 11.8 parts of linoleic acid were added. A solution obtained by dissolving 50% of toluene was added dropwise.

After the addition, the reaction mixture was heated at room temperature for 8 hours, filtered in an oven,
The furnace solution was washed successively with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, dried with ramie, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of n-hexane and ethyl ether as an eluent. The desired product was obtained as a pale yellow oil. Yield 11.1 days (Yield 80%) Elemental analysis value C8 days 53N02 (C days N Theoretical value) 79.94 10.78 2.83
Actual measurement value) 79.77 10.81 2.8
2IR spectrum measurement value (skin-1) 1650〈C=.

) MAS spectrum measurement value M+: 495 NM old spectrum measurement value (7: CDC13) N-C ratio;
6.87 (group) CH= of linoleic acid; 4.62 (Misaki) Chroman-3 position CQ; 8.15 (ga) Chroman-4 position C ratio; 7.35 (2H) Aromatic CH3: 7.87 ( Pan), 7.92 (spot), 7.
95 (fine) linoleic acid terminal CH3; 9.10 (3H) Example 3 N-methyl-N-[2-(4,8,12-trimethyl-tridecyl)-2,517,8-tetramethyl-chromanyl] 6]-Synthesis of linoleic acid amide 2-(4.8.1
Anhydrous linoleic acid was added to a solution obtained by dissolving 4.5% of 2-trimethyl-tridecyl)-6-N-methylamino-2,5,7,8-tetramethyl-chroman in 50% toluene at room temperature. A solution obtained by dissolving 5.5 parts of acid in 50 parts of toluene was added dropwise.

After the dropwise addition was completed, the mixture was heated under reflux for 5 hours. After refluxing, the reaction mixture was washed with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution and water, dried with ramie, and then concentrated under reduced pressure.The residual light was purified by silica gel chromatography using a mixed solvent of n-hexane and ethyl ether as an eluent. The desired product was obtained as a pale yellow oily substance. Yield: 6.5% (92%) Elemental analysis value: C: 83N02 (C: theoretical value) 81.64 11.85 1.98 Actual value (%) ) 81.73 11.89 2.251
R spectrum measurement value (Ka-1) 1660 (shiC=.

) MAS spectrum measurement value M+: 705 NM yield spectrum measurement value (D: CDC13) N-CH3
: 7.00 (pan) CH of linoleic acid =; 4.72 (calm) Chroman-3 position C ratio: 8.28 (pan) chroman-4 position C is; 7.29 (pan) Aromatic CH3; 7 .90 (wide), 7.96 (fine), 7.
98 (pan) linoleic acid terminal CH3: 9.10 (spotted) Example 4 Synthesis of N-[2-methyl-2-(4',8,12-trimethyl-tridecyl)-chromaniru6]-linoleic acid amide 2-methyl-2- (4',8-IZ-trimethyl-tridecyl)-16-amino-chroman 17.0 times and triethylamine 6 times were dissolved in 150 times ethyl ether to dissolve 150 times linoleic acid chloride at room temperature under Takaazusa, 150 times linoleic acid chloride was added. was added dropwise.

After the dropwise addition was completed, Takaazusa was kept at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 150ml of ice water and extracted with benzene. The benzene extract was sequentially washed with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, and then dried with sheep's salt to remove the solvent. The remaining bamboo was purified by silica gel chromatography using a mixed solvent of n-hexane and ethyl ether as an eluent. The desired product was obtained as a pale yellow oil. Yield: 20 yen (yield: 70
%) Elemental analysis value C as Sasabi 75N02 C day N Theoretical value (multi) 81.29 11.63 2.1
5 Actual measurement value) 81.56 11.65 2.1
71R spectrum measurement value (skin-1) 3300 (State H),
1650 (Shi C Ni.

) MAS spectrum measurement value M+: 649 NM old spectrum measurement value (Month: CDC13) NH; 2.
20 (IH) Linoleic acid CH =: 4.66 (Mountain H) Chroman-3 position C ratio: 8.25 (pan) Chroman-4 position C ratio: 7.24 (criminal) Aromatic H; 2.66 (IH), 2.96 (IH), 3.
34 (IH) Terminal C ratio of linoleic acid; 9.10 (spotted) Example 5 N1 [21 (4,8,12-trimethyl-tridecyl)
Synthesis of 12,5,7,8-tetramethyl-chromanyl-6]-linoleic acid amide 21-(4',8,12-trimethyl-tridecyl)-6-amino-2,5,7,8-tetramethyl-chromantri Nolic acid chloride was reacted according to Example 4.

The desired product was obtained as a pale yellowish brown oil. Elemental analysis value C
47th day 8, N02 as C day N theoretical value) 81.55 11.79 2.02
Actual measurement value) 81.26 11.74 2.19
1R spectrum measurement value (skin-1) 3250 (shiNH),
1645 (Shi C Ni.

) MAS spectrum measurement value M: 691 NM old spectrum measurement value (7: CDC13) NH; 3.
30 (IH) Linoleic acid CH =; 4.62 (Misaki) Chroman-3 position C4; 8.23 (2H) Cuman-4 position C ratio; 7.28 (ga) Aromatic CH3; 7.88 (Spot), 7.93 (Spot), 7.
95 (pan) linoleic acid terminal CH3; 9.10 (pan) Example 6 N-methyl-N-[2-methyl-2-(4.8.12-trimethyl-tridecyl)-chromanyl-6]-linoleic acid Synthesis of amide 2-methyl-2-(4', 8, 12'
-trimethyl-tridecyl)161N-methyl-aminochroman, linoleic anhydride was reacted according to Example 3.

The desired product was obtained as a pale yellow oil. Elemental analysis value C Day N Theoretical value (%) 51.38 11.69 2.1
1 Actual value (me 81.45 11.56 2.2
11R spectrum measurement value (Ki-1) 1660 (shic=.

) MAS spectrum measurement value M+: 663 NM old spectrum measurement value (7: CDC13) N-C;
6.80 (pan) CH of linoleic acid; 4.68 (4H) Cuman-3-position C ratio; 8.20 (pan) chroman-4-position CQ; 7.26 (pan) Aromatic H; 3 .20 (group)

Claims (1)

[Claims] 1. The following general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1, R_2, R_3 represent hydrogen or a methyl group, and R_4 represents hydrogen or a lower alkyl group. Moreover, m represents an integer of 0 to 3. ] The following general formula ▲ mathematical formula, which is characterized by reacting linoleic acid or its reactive derivative with a 6-aminochroman compound represented by
There are chemical formulas, tables, etc.▼ [In the formula, R_1, R_2, R_3, R_4 and m represent the above meanings. ] A method for producing linoleic acid amide of a 6-aminochroman compound represented by