JPS6015626B2 - Linoleic acid amide of 6-aminochroman compound - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel 6-aminochroman derivatives.

・To be more specific, the following general formula [1] (wherein R,, R2, R3 are hydrogen or methyl groups, R4
represents hydrogen or a lower alkyl group.

Moreover, m represents an integer of 0 to 3. ) This relates to the linoleic acid amide of the 6-aminochroman compound represented by

The compound [1] of the present invention has an excellent blood and liver cholesterol lowering effect and is useful as a therapeutic agent for hyperlipidemia.

That is, the cholesterol-lowering effect of compound [1] is clear from the results of the following pharmacological tests. Pharmacological test '1} Test compound: The following compound was selected.

N-(2,2,5,7,8-pentamethyl-chromanyl-6)-linoleic acid amide (hereinafter referred to as compound A) N-methyl-N-(2,2,5,7,8-pentamethyl-chromanyl-6)-linoleic acid amide (hereinafter referred to as compound B)
N-methyl-N-[2-(4', 8', 12-trimethyl-tridecyl)-2, 5, 7, 8-tetramethyl-chromanyl-6]-linoleic acid amide (hereinafter referred to as compound C) N 1 [2-methyl-21 (4', 8, 12-tri*
Methyl-tridecyl)-chromanyl-6]-linoleic acid amide (hereinafter referred to as compound D) '2' Animals used: Five male Wistar rats (body weight 140-170 mm) were used for each compound tested.

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

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

'B1 Measurement results 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 exposure.

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 Administration method, dosage and measurement method Pharmaceutical Journal, Vol. 92, No. 7, pp. 879-885 (1972
Cholesterol 2 was added to the animals used according to the method described in
At the same time, 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. administered.

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

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

[Mouth’ measurement results 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 value, the better the cholesterol-lowering effect (average value for 5 animals).

Table 2 ii.

Acute toxicity test 'I' Administration method, dose Test compounds A to D were suspended in a 5% aqueous gum arabic solution, and 5003 females/k9 were administered for each test compound.
, administered orally at a dose of 9/kg of 2000.

After administration, there was an observation period of 4 days for the 500 females/k9 and 2000 9/k9 administration groups, and a 7 day observation period for the 10,000 females/k9 administration group. {o) Observation results
4 10 for any sample compound
At the dose of 000 fences/k9, only transient diarrhea was observed for the first time, and weight gain was 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 c/k9 (oral) or more.

'41 Results These pharmacological tests revealed that Compounds A to D all have excellent cholesterol-lowering effects, and their toxicity (acute toxicity) is also extremely low.

From the results of the above pharmacological tests, the compounds (1) of the present invention, represented by compounds A to D, are useful for the prevention and treatment of diseases caused by an increase in the amount of cholesterol in dishes, especially so-called adult diseases such as arteriosclerosis and diabetes. It is thought that it has great utility value. When the compound according to the present invention is used as a cholesterol-lowering agent or a therapeutic agent for hyperlipidemia, the daily dosage for adults is 9 to 10 minutes per day.

Although any method of administration may be used, oral administration is preferable because long-term administration is required due to the nature of the disease. The dosage form may be any powder, granule, tablet, capsule, liquid, etc. The present invention has the following general formula [b] (wherein R,, R2, R3, R4 and m represent the above meanings.

It can be carried out according to a conventional acid amide formation method in which a 6-aminochroman compound represented by ) is reacted with linoleic 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 using the compound (m) as it is, for example, N.N'-dicyclocarbodiimide, diphenyl phosphite, triphenyl phosphite, polyphosphoric acid, polyphosphate ester [Yuichi Kanaoka et al., Chemical Pharmaceutical Co., Ltd.]・Butylene, Volume 13, No. 9, . Condensation catalysts commonly used in the formation of acid amides, such as P-toluenesulfonic acid, P-toluenesulfonic acid chloride, and sulfuric acid, 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; Ester solvents such as ethyl acetate and methyl acetate Solvent: Ketone solvent such as acetone, methyl ethyl ketone, or triethylamine,
The reaction can be carried out more smoothly by appropriately selecting an organic solvent such as a tertiary amine solvent such as pyridine and using it alone or in the form of a mixed solvent, and it is also suitable in terms of post-treatment.
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 parts of chloroform, 13.0 parts of polyphosphoric acid methyl ester and 6.0 parts of triethylamine were dissolved. 6-amino2.2 in the solution
- A solution prepared by dissolving 4.4 parts of 5,7,8-bentamethyl-chroman and 8.4 parts of linoleic acid in 30 parts of chloroform was added to the filtrate 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, the benzene extract was washed with water, dried with trachea, and then the benzene was distilled off. Musumumi was purified by silica gel chromatography using n-hexane/ethyl ether mixed solvent as an eluent. The desired product was obtained as a pale yellow powder. Yield 8
0 (total yield %) Melting point 59-60℃ Elemental analysis value C32 days 6, C days N as N02 Theoretical value (%) 79.7810.672.91 Actual value (
%) 79.7310.752.81m Spectral measurements (skin-1) 3225 (shiNH), 1640 (shiC=.

) MAS spectrum measurement value M: 481 NMR spectrum measurement value (7: CDC13) NH; 3.
05 (IH) CH3 of lino-acid: 4.60 (Misaki) Chroman-3 position CQ; 8.22 (ga) Chroman-4 position C ratio: 7.50 (ga) Aromatic CH3; 7.86 ( thin), 7.92 (thin), 7.
94 (Field) Terminal C of linoleic acid; 9.10 (Fine) Example 2 N-methyl-N-(2,2,5,7,8-bentamethyl-chromanyl-6)-linoleic acid amide Synthesis N・N'
6-N-methylamino-2,2,5,7,8-pentamethyl-chroman 6.5
In the evening, a solution obtained by dissolving 11.8 g of linoleic acid in 50 g of toluene was added dropwise.

After the addition was completed, the reaction mixture was incubated at room temperature for 8 hours, filtered in an oven,
The furnace solution was sequentially washed with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, dried with bitter nitrogen, 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 C33 days 53NQ as C days N Theoretical value (%) 79.9410.782.83 Actual value (
%) 79.7710.812.821R spectrum measurement value (K-1) 1650 (ShiC=.

) MAS spectrum measurement value M+: 495 NMR spectrum measurement value (7:CDC13) N-C ratio:
6.87 (ga) CH of linoleic acid =: 4.62 (''H) Chroman-3 position C ratio; 8.15 (phantom) Chroman-4 position C ratio: 7.35 (ga) Aromatic CH3; 7 .87 (9H), 7. Scales (9H), 7
．． 95 (fine) linoleic acid terminal C ratio; 9.10 (9H) Example 3 N-methyl-N-[2-(4', 8, 12-trimethyl-tridecyl)-2, 5, 7, 8- Synthesis of tetramethyl-chromanyl-6]-linoleic acid amide 21 (4',8
・12-trimethyl-tridecyl)-16-N-methylamino-2,5,7,8-tetramethyl-chroman 4.5
A solution obtained by dissolving 5.5 g of linoleic anhydride in 50 g of toluene was added dropwise to the solution obtained by dissolving 5.5 g of linoleic anhydride in 50 g of toluene at room temperature.

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 trisulfuric acid, 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 6.5 days (yield 92%) Elemental analysis value C43 days 83N02 C days N Theoretical value (%) 81.6411.851.98 Actual value (
%) 81.7311.892.25 Melon spectrum measurement value (Suppression-1) 1660 (Shi C Ni.

) MAS spectrum measurement value M: 705 NMR spectrum measurement value (7: CDC13) N-C &;
7.00 (Chihito) CH of ly/-ruic acid:: 4.72 (Mountain) Chroman - C ratio at 3rd position; 8.28 (Ga) Coumaron - CQ at 4th position: 7.29 (Ga) Aromatic CH3 :7.90 (group), 7.96 (fine), 7.
Sea bream (dark blue) Linoleic acid terminal C: 9.10 (general) Example 4 Synthesis of N-[2-methyl-2-(4,8,12-trimethyl-tridecyl)-chromanyl-6]-linoleic acid amide 2 -Methyl-21 (4', 8, IZ-trimethyl-
To a solution obtained by dissolving 17.0 mg of tridecyl-6-aminochroman and 6 mg of triethylamine in 150 mg of ethyl ethyl, add 11.1 mmol of linoleic acid chloride at room temperature under the conditions of ethyl ethyl.
50 ml was added dropwise.

After the dropping was completed, the feeding was continued for 8 hours at room temperature. After completion of the stirring, the reaction mixture was poured into 150 ml of ice water and extracted with benzene. The benzene extract was sequentially washed with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, then dried over ramie salt, and the solvent was distilled off. 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: 20 yen (yield: 70
%) Elemental analysis value C44 day 7 is 02 C day N Theoretical value (%) 81.2911.632.15 Actual value (
%) 81.5611.652.1? IR spectrum measurement value (inhibition-1) 3300 (shiNH>), 1650 (shiCni).

) MAS spectrum measurement value M+: 649 NMR spectrum measurement value (7: CDC13) NH; 2.
20 (IH) Linoleic acid CH =; 4.66 (Misaki) Chroman - 3rd C position; 8.25 (Ga) Chroman - 4th position C base; 7.24 (Ga) Aromatic H; 2.66 ( IH), 2.96 (IH), 3.
3(IH) linoleic acid terminal C&;9.10 (Chichi) Example 5 N-[2-(4',8,12-trimethyl-tridecyl)-2,5,7,8-tetramethyl-chromanyl -6〕
-Synthesis of linoleic acid amide 2-(4', 8, 12'-trimethyl-tridecyl)-6-amino-2, 5, 7, 8
-Tetramethyl-chroman and IJ nolic acid chloride were reacted according to Example 4].

The desired product was obtained as a pale diamond-brown oil. Elemental analysis value C
47 days 8, C days N as NQ Theoretical value (%) 81.5511.792.02 Actual value (
%) 81.2611.742.19m Spectral measurements (H-1) 3250 (NH), 1 I 5 (C=.

) MAS spectrum measurement value M+: 691 NMR spectrum measurement value (T: CDC13) NH; 3.
30 (IH) Linoleic acid CH=: 4.62 (phantom H) Chroman-3 position C ratio: 8.23 (pan) Chroman-4 position CQ: 7.28 (2H) Aromatic CH3: 7. General (Chihito), 7.93 (9H), 7
．． 95 (fine) linoleic acid terminal C melon: 9.10 (Chichi) Example 6 N-methyl-N-[2-methyl-21 (4', 8, 12
Synthesis of 2-methyl-2-(4', 8, 12
-trimethyl-tridecyl)-16-N-methyl-aminochroman and linoleic anhydride were reacted according to Example 3].

The desired product was obtained as a pale yellow oil. Elemental analysis value C4
C day N as phantom 77N02 Theoretical value (%) 81. Total 11.692.11 actual measurement value (%
) 81.5411.562.21m Spectrum measurement value (Sup-1) 1660 (Shi C:.

) MAS spectrum measurement value M 10: 6 muscle NMR spectrum measurement value (T: CDC13) N1C melon;
6.80 (9H) linoleic acid CH=;4. Iso ('H) Chroman-3 position C ratio: 8.20 (ga) Chroman-4 position C ratio: 7.26 (broad) Aromatic H; 3.20 (fine) Example 7 Powder N1 (2. 2,5,7,8-pentamethyl-chromanyl-6)-linoleic acid amide 50 parts by weight silicic anhydride
300 Silicic anhydride hydrocarbon 200 The above components were mixed to obtain a powder.

Example 8 Parent granule N-methyl-N-(2,2,5,7,8-bentamethyl-chromaniru-6)-linoleic acid amide 40 parts by weight Silicic anhydride 200 Silicic anhydride hydrate 200 Lactose 150 Polyvinylpyrrolidone 50 The above components were kneaded and extruded into granules.

This was dried and sized to obtain forehead granules. Example 9 Capsule N-methyl-N-[2-4',8,12-trimethyl-
tridecyl)-2,5,7,8-tetramethyl-chromanyl-6)-linoleic acid amide 10 parts by weight Silicic anhydride 50 Silicic anhydride hydrate 50 Microcrystalline cellulose 20 Polyvinylpyrrolidone 5 parts by weight Above The ingredients were granulated and filled into No. 2 capsules.

1 capsule 225/9.

Example 10 Tablet N-[2-methyl-2-(4',8,12-trimethyl-tridecyl)-chromaniru6]-linoleic acid amide
5 parts by weight of silicic anhydride
40 silicic anhydride hydrate
20 lactose
40 microcrystalline cellulose
50 of the above ingredients were granulated and compressed into tablets.

9 out of 200 per tablet.

Example 11 European capsule N1 [21 (4',8,12-trimethyl-tridecyl)-2,5,7,8-tetramethyl-chromaniru6]
10 parts by weight of linoleic acid amide 100 parts by weight of octyldecyl triglyceride The above components were mixed and filled into European capsules.

1 capsule 200 females.

Claims (1)

[Claims] 1 The following general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ linoleic acid amide of a 6-aminochroman compound represented by (representing an integer of ~3). 2. The linoleic acid amide of the 6-aminochroman compound according to claim 1, wherein R_1, R_2, and R_3 are methyl. The linoleic acid amide of the 6-aminochroman compound according to claim 1, which is 3N-(2.2.5.7.8-pentamethyl-chromanyl-6)-linoleic acid amide. The linoleic acid amide of the 6-aminochroman compound according to claim 1, which is 4 N-methyl-N-(2,2,5,7,8-pentamethyl-chromanyl-6)-linoleic acid amide. 5 The following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, R_3 represent hydrogen or a methyl group, R_4 represents hydrogen or a lower alkyl group, and m represents an integer from 0 to 3. .) A therapeutic agent for hyperlipidemia containing linoleic acid amide of a 6-aminochroman compound.