JPS604181B2 - Synthesis method of 6-aminochroman derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the following general formula (W) [wherein R,, R2, and R3 are hydrogen or a methyl group, and R4
represents hydrogen or a lower alkyl group, m, n' represents an integer of 0 to 3;

Further, A and B represent hydrogen atoms or a bond may be formed between A and B. This invention relates to a method for synthesizing a novel unsaturated fatty acid amide of a 6-aminochroman compound represented by the following.

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

That is, the cholesterol-lowering effect of compound (1) is clear from the results of the following pharmacological test.Pharmacological test (1) Sample compound: The following compound was selected.

N-(2,2,5,7,8-pentamethyl-chromanyl-6)-geranoylamide (hereinafter referred to as compound A) N-(2,2,5,7,8-pentamethyl-chromanyl-6)
)-alnesiroylamide (hereinafter referred to as compound B) N
-Methyl-N-(2,2,5,7,8-bentamethyl-chromaniru-6)-farnesilylamide (hereinafter referred to as compound C)N-[2-(4,8,12-trimethyl -tridecyl)-2-methyl-chromanyl-6]-farnesilylamide (hereinafter referred to as compound D) N-methyl-
N-[2-(4',8,12-trimethyl-tridecyl)-2,5,7,8-tetramethyl-chromaniru6]
-Falnesiroylamide (hereinafter referred to as compound E) N-
Methyl-N-[2-(4,8,12'-trimethyl-tridecyl)-2,5,7,8-tetramethyl-chromaniru-6]-phitenoylamide (hereinafter referred to as compound F)
■ Animals used: Wistar male rats (weight 140~
170 days) were used for each test compound.

'3} Test item i) Effect on animals administered normal diet 'A' Administration method, dosage and measurement method Test compounds A to F were suspended in a 5% aqueous gum arabic solution and administered at 200 9/k on 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.

{0) 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 administration.

Therefore, the higher the number is 4, the better the cholesterol-lowering effect (average value for 5 animals).

Table 1 il1 Effects on animals administered with cholesterol-loaded feed Administrative method, dosage and measurement method Cholesterol 2 % by weight and feed containing 1% by weight of cholic acid, and at the same time test compounds A to F.
was suspended in a 5% aqueous gum arabic solution and orally administered for 5 consecutive days at a dose of 200 females/k91 days each.

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

‘Ro’ 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 higher the numerical value, the better the cholesterol-lowering effect (average value for 5 animals).

Table 2 iii) Acute toxicity test Administration method, dose Test compounds A to F were suspended in a 5% aqueous gum arabic solution, and 500 9/k9 was added for each test compound.
, 2000 at a dose of 9/k9.

After administration, there was an observation period of 4 days for the 500 females/k9 and 2000 female'kg administration groups, and a 7 day observation period for the 10,000 nails 9/kg administration group. (Mouth) Observation Results For all test compounds, only temporary diarrhea was observed for the first time at a dose of 10,000 females/kg, and weight gain was steady.

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 9/k9 (oral) or more.

(2) Results This pharmacological test revealed that all of Compounds A to F had excellent cholesterol-lowering effects, and their toxicity (acute toxicity) was also extremely low.

From the results of the above pharmacological tests, the compound (1) of the present invention represented by Compounds A to F can be used to treat diseases caused by increased blood cholesterol levels, particularly so-called adult diseases such as arteriosclerosis, diabetes, and liver disease. It is thought to have great utility in prevention and treatment.

The present invention is based on the following general formula (m [wherein R,, R2, R3, R4 and m represent the above-mentioned meanings.

] 6-aminoc.

Mann compound has the following general formula (m) [wherein A, B and n
represents the above meaning.

It can be carried out according to a conventional acid amide formation method in which an unsaturated fatty acid represented by the following formula or a reactive derivative thereof is reacted. Examples of reactive derivatives of the compound (blood) include acid anhydrides, acid chlorides, mixed acid anhydrides, active esters, and the like. When the compound (m) is used as it is, for example, N.N'-dicyclocarbodiimide, diphenyl phosphite, triphenyl phosphite, polyphosphoric acid, polyphosphoric acid ester [Yuichi Kanaoka et al.
See Chemical Pharmaceutical Bulletin, No. 19, No. 9, pp. 1065-1072 (1960 Wang)]
．． 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; diethyl ether, diisof. Ether solvents such as propyl ether, tetrahydrofuran, dioxane; n-hexane,
Saturated hydrocarbon solvents such as ligroin and petroleum ether; Ester solvents such as ethyl acetate and methyl acetate; Acetone,
The reaction can be carried out more smoothly by appropriately selecting an organic solvent such as a ketone solvent such as methyl ethyl ketone or a tertiary amine solvent such as triethylamine or pyridine and using it alone or in the form of a mixed solvent. The points are also appropriate. Next, the present invention will be explained with reference to examples. Example
1 Synthesis of N-(2,2,5,7,8-bentamethyl-chromaniru6)-geranoylamide In a solution of 45 parts of polyphosphoric acid ethyl ester and 23 parts of trimethylamine dissolved in 120 parts of chloroform, 6 parts were dissolved. -Amino 2, 2, 5, 7
- 23 hours of 8-bentamethyl-chroman and 15 hours of gellanic acid were added, and the mixture was refluxed at 65 qo for 5 hours under condensation.

After refluxing, the reaction mixture was concentrated under reduced pressure, and the residue was dispersed in an aqueous sodium bicarbonate solution and extracted with benzene. After washing the benzene extract with water and drying with trinitrate, the benzene was distilled off, and the residue was purified by silica gel column chromatography using n-hexane ether mixed solvent as the effluent solvent, and the solvent was removed to form a pale yellowish brown powder. Obtained the object. Yield 23
．． 5 days (yield 93%) Melting point 100-103℃ Elemental analysis value C as 024 5N02 Days N Implied value (%) 78.00 9.55 3.7
9 Actual measurement value (Tsutomu) 78.01 9.53 3.7
71R spectrum measurement value (Cm-1) 3250 (shiNH
), 1660 (shi C ni.

) MAS spectrum measurement value M+: 369 NMR spectrum measurement value (7: CDC13) NH; 3
．． 35 (IH) AromCH3; 7,92 (group) Chroman-3 position C ratio; 8.12 (group) Chroman-4 position C is; 7.40 (ga) CH=; 4.22 (IH), 4. 80 (IH) Example
2N-(2,2,5,7,8-bentamethyl-chromanyl-6)-furnesylamide 6-amino-
2, 2, 5, 7, 8-bentamethyl-chroman 11th evening,
Farnesylic acid 15%, polyphosphoric acid ethyl ester 33%
One day, 15 minutes of triethylamine and 150 minutes of chloroform were reacted according to Example 1.

The desired product was obtained as a pale yellow oil. Yield 20 days (yield 91%) Elemental analysis value C day N (as 43N02 theoretical value) 79.58 9.90 3.20
Actual value moxibustion) 79.50 9.81 3.2
41R spectrum measurement value (Cm-1) 3250 (WaNH
), 1660 (shi C ni.

) MAS spectrum measurement value M+: 437 NM old spectrum measurement value (D: CDC13) NH; 3
．． 22 (IH) AromCH3; 7.94 (group) Chroman-3 position C is; 8.14 (2H) Chroman-4 position C ratio; 7.42 (2H) CH=; 4.22 (IH), 4.90 (2H) Example
Synthesis of 3N-methyl-N-(2,2,5,7,8-bentamethyl-chromanyl-6)-farnesiroylamide 6-N-methylamino-2,2,5,7,8-bentamethylchroman After 10 days, to a solution obtained by dissolving 2 times of triethylamine in 100 times of ethyl ether, 9 times of phalnesylic acid chloride was added dropwise at room temperature and under a saucepan.

After the addition was completed, the mixture was further incubated at room temperature for 8 hours. The reaction mixture was dispersed in water and extracted with benzene. The benzene extract was purified in the following order: 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water.
Then, it was dried over young salt and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethyl ether as the eluent, and the solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow oil.

Yield 16.32 (yield 84%) Elemental analysis value C day N theoretical value as C day 4bu02 *) 79.77 10.04 3.6
5 actual measurement value) 79.81 9.98 3.
711R spectrum measurement value (Cm-1) 1650 (yC
=0) MAS spectrum measurement value M+: 451 NM old spectrum measurement value (D: CDC13) N-C ratio;
6.92 (9H) AromCH3; 7.98 (group) Chroman-3 position C expansion; 8.19 (pan) Chroman-4 position C ratio; 7.39 (2H) CH=; 4.69 (IH), 5 .00 (2H) Example
Synthesis of 4N-[2-(4,8,12'-trimethyl-tridecyl) 2-methyl-chromanyl-6]-farnesilylamide 2-(4',8,12'-trimethyl-tridecyl) (decyl) 2-2-methyl-6-aminochroman, 17 units of phalnesylic acid, 4 units of polyphosphoric acid ethyl ester
5 minutes, triethylamine for 20 hours, and chloroform for 100 hours were reacted according to Example 1.

The desired product was obtained as a pale yellow oil. Yield 29 days (yield 85%) Elemental analysis value C4, day 67N02 C day N theoretical value (%) 81.26 11.15 2.31
Actual value (many) Otsu 1.06 10.91 2.37
1R spectrum measurement value (Cm-1) 3300 (shiNH)
, 1655 (shiC=.

) MAS spectrum measurement value M: 605 NM old spectrum measurement value (7: CDC13) N-H; 2
．． 56 (IH) AromH; 3.00 (fine) Chroman-3 position CQ; 8.18 (ga) Chroman-4 position C ratio; 7.34 (ga) CH=; 4.34 (IH), 4.92 (2H) Example
2-(
4,8,12-trimethyl-tridecyl)-6-N-methylamino-2,517,8-tetramethyl-chroman 11, farnesylic acid 7, polyphosphate ester 16
One evening, 7 hours of triethylamine and 100 minutes of chloroform were reacted according to Example 1.

The desired product was obtained as a pale yellowish brown oil.

Yield 14.5 evenings (yield 88%) Elemental analysis value C day N as 75N02 Theoretical value (%) 81.63 11.42 2
．． 12 Actual measurement value (many) 81.69 11.35
2.271R spectrum measurement value (Cm-1) 1650
(ShiC=.

) MAS spectrum measurement value M+: 661 NM eye spectrum measurement value (7: CDC13) N-CH3
;6.90 (Aim) AromCH3: 7.98 (Phantom) Chroman-3rd CQ; 8.36 (2H) Chroman-4th CH2; 7.38 (bait) CH=; 4.68 (IH), 4 .90 (2H) Example
Synthesis of 6N-methyl-N-[2-(4',8,12-trimethyl-tridecyl)-2,5,7,8-tetramethyl-chromanyl-6]-phitenoylamide 21(4'
・8,12'-trimethyl-tridecyl)-6-N-methylamino-2,5,718-tetramethyl-chroman 11 times, phythenic acid 10 times, polyphosphate ester 10 times, triethylamine 79 times, chloroform 100 times as an example. The reaction was carried out according to 1.

The desired product was obtained as a pale yellow oil.

Yield 16.5 evenings (yield 90%) Elemental analysis value C same day 8 as 02 C day N Theoretical value (grandchild) 81.57 12.19 1.
90 Actual value (%) 81.56 12.09
1.981R spectrum measurement value (Cm-1) 1660 (
Shi C Ni.

) MAS spectrum measurement value M+: 735 NM old spectrum measurement value (7: CDC13) N-C &;
6.92 (general) Ar.

mCH3; 7-96 (Kong H) chroman-3 position C day; 8.
20 (2H) Chroman-4-position C ratio; 7.40 (2H) CQ =; 5.20 (IH) Example 7 N-[2-methyl-2-(4'.8.IZ-trimethyl-tridecyl)-k Synthesis of 2-methyl-2-(4',8,12-trimethyl-tridecyl)-chroman, 10 parts of phythenic acid ethyl ester, 3 parts of sodium ethylate and 75 parts of ethanol. and heated under reflux for 5 hours.

After completion of reflux, the reaction mixture was dispersed in water and extracted with benzene. The benzene extract was washed with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, dried over sulfur, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethylenal as the eluent, and the solvent was removed under reduced pressure to obtain the desired product as a pale yellow oil. yield
15.3 evening (yield 79%) Elemental analysis value C later 8, C day N as N02 Theoretical value (poly) 81.23 12.00 2.
06 actual measurement value) 81.35 11.97 1.
981R spectrum measurement value (Cm-1) 3260 (ShiN
H), 1650 (shi C ni.

) MAS spectrum measurement value M: 679 NM Nagi spectrum measurement value (7: CDC13) N-H; 2
．． 91 (IH) AromH; 3.01 (lees) Chroman-3 position CH2; 8.22 (2H) Chroman-4
Position C ratio; 7.20 (2H) C=H; 4.50 (IH) Example 8 N-[2-(4,8,12-trimethyl-tridecyl)
12,5,7,8-tetramethyl-chromanilu6]-
Synthesis of phytenolamide 2 -(4',8,12-trimethyl-tridecyl)-6-aminochroman 3 is dissolved in 50' of toluene, and anhydrous phyten 4. A solution of 50% 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 regularly with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, dried with bitter salt, and then concentrated under reduced pressure. Zanwan was purified by silica gel chromatography using a mixed solvent of n-hexane and ethyl ether as the eluent, and the solvent was distilled off under reduced pressure to obtain the desired product as a pale brown oil. Yield: 4.1 evening (yield: 81%) Elemental analysis value: C: 87N20 (C day: N) Theoretical value (poly): 81.49 12.14 1.
94 actual measurement value) 81.46 12.21 1
．． 961R spectrum measurements (Cm-1) 3260 (HiNH), 1655 (Cm-1).

) MAS spectrum measurement value M+: 721 NMR spectrum measurement value (D: CDC13) N day; 2
．． 87 (IH) AromCH3; 7.90 (group) Chroman - 3rd position CH2; 8.15 (ga) Chroman - 4th position C ratio; 7.38 (pan) C=H; 4.45 (IH) Next, this Compounds obtained by the method of the invention are shown as examples.

column e ink Ku.

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 6-aminochroman compound represented by the following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A and B are hydrogen atoms or may form a bond between A and B. represents. Further, n represents an integer from 0 to 3. ] is characterized by reacting unsaturated fatty acids or reactive derivatives thereof. The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula,
R_1, R_2, R_3, R_4, A, B, m, and n have the above meanings. A method for synthesizing an unsaturated fatty acid amide of a 6-aminochroman compound represented by