JPS6035346B2 - 6-aminochroman derivative - Google Patents

Description

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

More specifically, the present invention is based on the following general formula [1] (where R, R2 and R3 are hydrogen or a methyl group, R4 is hydrogen or a lower alkyl group, and m and n are integers of 0 to 3). represent.

Further, A and B represent hydrogen atoms or a bond may be formed between A and B. ) relates to unsaturated fatty acid amides of 6-aminochroman compounds. Compound [1] according to the present invention has an excellent blood and liver cholesterol-lowering effect and is useful as a therapeutic agent for hyperlipidemia.

Conventionally, drugs with cholesterol-lowering effects include:
For example, highly unsaturated fatty acids, heparin, sitosterol,
There are drugs such as egg 8-pack hormone, but there is nothing definitive, and this drug awaits future development.

As a result of various studies on therapeutic agents for hyperlipidemia, the present inventors found that the compound [1] of the present invention was effective and developed it.

That is, the compound [1] of the present invention is effective in the prevention and treatment of diseases caused by an increase in the amount of cholesterol in dishes, such as arteriosclerosis, diabetes, and adult diseases such as 80-year-old diseases. Therefore, an object of the present invention is to provide a novel therapeutic agent for hyperlipidemia. A further object of the present invention is to provide a novel method for producing a therapeutic agent for hyperlipidemia.

Next, pharmacological experiments using animals will be shown to demonstrate the cholesterol-lowering effect of the compounds of the present invention.

{1' Test 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-bentamethyl-chromanyl-6)-farnesiroylamide (hereinafter referred to as compound B) N-methyl-N-(2,2,5,7,8-pentamethyl-chromanyl) -6)-Falnesylylamide (hereinafter referred to as compound C) N-[2-(4',8,12-trimethyl-tridecyl)-2-methyl-chromaniru6]-Falnesylylamide (hereinafter referred to as compound D) N-methyl-N-[2
-(4.8.12-trimethyl-tridecyl)-2.5
・7,8-tetramethyl-chromanyl-6]-farnesiroylamide (hereinafter referred to as compound E) N-methyl-N
- [2-(4,8,12-trimethyl-tridecyl)-
2,5,7,8-Tetramethyl-chromanyl-6]-phitenoylamide (hereinafter referred to as compound F)'2} Animals used: Wistar male rats (body weight 140-170 mm) were administered 50% of each sample compound. I used two.

{3) Test items {i) Effects on animals fed normal diet {i} Administration method, dosage and measurement method Sample compounds A to F were suspended in a 5% aqueous gum arabic solution, and each was administered for 200 9'k91 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.

‘.

) The measurement 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, those with lower values have excellent cholesterol-lowering effects (average value for 5 animals).

Table 1 'ii) Effects on animals administered with cholesterol-loaded feed (ii) 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
% by weight and 1% by weight of cholic acid, and at the same time test compounds A to F were suspended in a 5% aqueous Arabic solution.
Each was administered orally for 5 consecutive days at a dose of 200 9/kg/day.

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 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 5 days of administration.

Therefore, those with lower numbers have better cholesterol-lowering effects (average value for 5 animals).

Table 2 'iii Acute toxicity test' Administration method, dosage Test compounds A to F were suspended in a 5% aqueous gum arabic solution, and 500 μ9/k9 were administered for each test compound.
, 2000 doses of 9'k9 were administered orally.

After administration, there was an observation period of 4 days for the 500 m9/k9 and 2000 m9/k9 administration groups, and a 7 day observation period for the 10000 m9/k9 administration group. 'o} Observation Results For all test compounds, only temporary diarrhea was observed for the first time at a dose of 9'kg of 10,000, 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.

The lethal dose (LD) is 10,000 9'kg (oral).
It is estimated that this is the above.

(4'Results) This pharmacological test revealed that Compounds A to F all have excellent cholesterol-lowering effects and are safe drugs with extremely low toxicity (acute toxicity).

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 considered to have high utility value for prevention and treatment.

In the present invention, the method for producing compound (1) is, for example, as follows.

That is, the following general formula (0) [wherein R,, R2, R3, R4 and m represent the above-mentioned meanings].

A normal acid amide in which a 6-aminochroman compound represented by the following formula (m) is reacted with an unsaturated fatty acid or a reactive derivative thereof represented by the following general formula (m) [wherein A, B and n represent the above-mentioned meanings] It can be carried out according to the formation method.

Examples of the reactive conductor of compound (m) include acid anhydrides, acid chlorides, mixed acid anhydrides, and active esters. When using the compound (m) as it is, for example, N.N'-dicyclocarbodiimide, diphenyl phosphite, triphenyl phosphite, polyphosphoric acid, polyphosphoric acid ester [Yuichi Kanaoka et al.], chemical/pharmaceutical Condensation catalyst used in the formation of ordinary 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, dioxane; Saturated hydrocarbon solvents such as n-hexane, ligroin, petroleum ether; Ester solvents such as methyl acetate; acetone, methyl ethyl ketone, etc. The reaction can be carried out more smoothly by appropriately selecting an organic solvent such as a ketone solvent or a tertiary amine solvent such as triethylamine or pyridine and using it alone or in the form of a mixed solvent. Appropriate. Another method is as follows.

That is, the following general formula (W) [wherein A, B and n represent the above-mentioned meanings].

] The following general formula (V) [wherein R,, R2, R3, R4 and m represent the above-mentioned meanings and X represents a halogen atom] is added to the ketone compound represented by the following general formula (V). ] 6-
A Wittig reagent derived from a haloacetamide form of an aminochroman compound is reacted to form the following general formula (1) [wherein R,, R2, R3, R4, A, B, m, and n represent the above-mentioned meanings.

The process consists of synthesizing an unsaturated fatty acid amide of a 6-aminochroman compound represented by

In the present invention, as a Wittig reagent derived from compound (V), compound (V) can be converted into, for example, triphenylphosphine [(C6day5)3P] phenyldialkoxyphosphine [6day55(AIKO)2P]] or trialkylphosphine. Neighboring compounds such as phosphite [P(OAIK)3] (where NK is a lower alkyl group) were prepared by Wadsworth et al.
worth, etal) [J.Am.Chem.
．． Soc. ) No. 8, p. 1733 (1961)], Homer et al. (Ber)
Vol. 95, p. 581 (1962)], Green World et al., Journal of the Organic Chemistry (J.○rg.Ch
Em) Vol. 28, p. 1128 (1963)].

P-(N-6-chromaniluacetamido)-dialkylphosphonate (following formula)P-(N-6-chromaniluacetamido)-triphenylphosphonium salt (following formula)P
-(N-chromaniluacetamide)-alkyl phenylphosphonate (the following formula) [wherein R,, R2, R3, R
4 and n have the above meanings.

AIK represents lower alkyl. ] The reaction between compound (W) and the Wittig reagent derived from compound (V) is carried out by reacting according to the usual Wittig reaction (see the above-mentioned literature).

During the reaction, an alkaline reagent such as butyllithium, sodium amide, sodium hydride, sodium methylate, potassium t-footoxide, caustic potash, sodium carbonate, triethylamine, etc. is usually added.

The reaction also proceeds without a solvent*, but the solvents usually used in the Wittig reaction, such as benzene, toluene, xylene, hexane, petroleum ether, ligroin cyclohexane, ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, and harsh acid ethyl ester By using , dimethylformamide, etc., the reaction can be carried out even more smoothly and the post-treatment can be carried out more easily. Starting material 6-ha. Acetamide-chroman compound (V)
is a new compound, for example, when using triethylamine, pyridine, etc. as a solvent, the following formula [wherein R,, R2, R3, R4
and m have the above meanings.

It can be easily obtained by reacting a 6-aminochroman compound represented by the following with a haloacetyl halide.

Next, the present invention will be explained with reference to Examples.

Example 1 Synthesis of N-(2,2,5,7,8-pentamethyl-chromanyl-6)-geranoylamide 6-amino- 2, 2, 5, 7
- Added 239 g of 8-bentamethyl-chroman and 15 g of gellanic acid, and refluxed at 65 qo for 5 hours.

After refluxing, the reaction mixture was concentrated under reduced pressure, the residual light was dispersed in an aqueous sodium bicarbonate solution, the benzene extract was washed with water, and dried with E-nitrogen, the benzene was removed by chlorination, and the n-hexane-ether mixed solvent was drained from the residue. The product was purified using silica gel column chromatography as a solvent, and the solvent was removed to obtain the desired product as a light brown powder. Yield: 23.5 evenings (yield: 93%)
) Melting point 100-10300 Elemental analysis value C24 day 35N02 C day N Theoretical value (%) 78.009.553.79 Actual value (%
) 78.019.533.771R spectrum measurement value (skin-1) 3250 (shiNH), 1660 (shiC=.

) MAS spectrum measurement value M+: 369 NMR spectrum measurement value (7: CDC13) NH; 3
．． 35 (IH) ~ omCH3; 7.92 (spot) Kuman - 3rd place CH2; 8.12 (ga) Kuman - 4th place C side; 7.40 (group) CH=; 4.22 (IH ), 4.80 (IH) Example
Synthesis of 2N-(2,2,5,7,8-pentamethyl-chromanyl-6)-farnesiroylamide 6-amino-2,2,5,7,8-pentamethyl-chromanyl-6)
Farnesylic acid 159, polyphosphoric acid ethyl ester 33
9. Triethylamine 15%, chloroform 150% [
was reacted according to Example 1.

The desired product was obtained as a pale yellow oil. Yield 20 days (yield 91%) Elemental analysis value C29 days 43N02 C days N Theoretical value (%) 79.589.903.20 Actual value (%
) 79.509.813.201R spectrum measurement (cm-1) 3250 (NH), 1660 (ratio=.

) MAS spectrum measurement value M+: 437 NMR spectrum measurement value (7: CDC13) NH; 3
．． 22 (IH) ~ omCH3; 7,94 (team) Chroman - 3rd position CH2; 8.14 (team) Chroman - 4th position C4: 7.42 (2H) CH=: 4.22 (IH), 4.90 ( ) Example 3
Synthesis of N-methyl-N-(2,2,5,7,8-bentamethyl-chromaniru6)-farnesiroylamide 6
-N-Methylamino-2,2,5,7,8-Pentamethylchroman 10 times and triethylamine 2 times were dissolved in ethyl ether to form a solution, and 9 times phalnesylic acid chloride was added dropwise at room temperature under stirring. added.

After the addition was completed, the mixture was further worshiped at room temperature for 8 hours. The reaction mixture was dispersed in water and extracted with benzene. The benzene extract was washed vertically in the following order: 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, then dried over reed 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 pressure to obtain the desired product as a pale yellow oil.

Yield 16.3 days (yield 84%) Elemental analysis value C3 mountain 45N02 C day N Theoretical value (%) 79.7710.043.65 Actual value (
%) 79.81 9.983.711R spectrum measurement value (Suppression-1) 1650 (ShiC Ni.

) MAS spectrum measurement value M: 451 NMR spectrum measurement value (7: CDC13) N-CH3
;6.92 (proto) ~〇mCH3;7-98■H) Chroman-3 position CH2; 8.19 (2H) Chroman-4
Position CH2; 7.39 (2H) CH=; 4.69 (IH)
, 5.00 (2H) Example 4N-[2-(4'・8・
Synthesis of 12-trimethyl-tridecyl)-2-methyl-chromanyl-6]-farnesilylamide 2-(4.
8,12-trimethyl-tridecyl)-2-methyl-6
- Aminochroman 22 days, falnesylic acid 1.7 days,
Ethyl polyphosphate ester 45%, triethylamine 2%
0 evening, black.

Form 100 was 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 (%) 81.2611.152.31 Actual value (
%) 81.0610.912.371R spectrum measurement value (arc-1) 3300 (shiNH), 1655 (shiC=
.

) MAS spectrum measurement value M: 605 NMR spectrum measurement value (7: CDC13) N-H; 2
．． 56 (IH) ~ omH: 3.00 (female 1) Chroman-3 position CH2; 8.18 (pan) Chroman-4 position CH2; 7.34 (2H) CH; 4.
34 (IH), 4.92 (phantom) Example 5N-methyl-N-[2-(4.8.12-trimethyl-tridecyl)
-2,5,718-tetramethyl-chromanyl-6]-
Synthesis of farnesiroylamide 2-(4', 8, 12-
trimethyl-tridecyl)-6-N-methylamino-2
・11 parts of 5,7,8-tetramethyl-chroman, 7 parts of phalnesylic acid, 16 parts of polyphosphate, 7 parts of triethylamine, and 100 parts of chloroform were reacted according to Example 1.

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

Yield 14.5 days (yield 88%) Elemental analysis value C45 days 75N02 C days N Theoretical value (%) 81.6311.422.12 Actual value (
%) 81.6911.352.271R spectrum measurement (c-1) 1650 (shi.

Engineering. ) MAS spectrum measurement value M+: 661 NMR spectrum measurement value (7: CDC13) N-CH3
: 6.90 (3H) ~ omCH3; 7.98 (3H) Chroman-3 position CQ: 8.36 (2H) Chroman-4 position CH2; 7.38 (2H) CH=; 4.
68 (IH), 4.90 (2H) Example 6N-methyl-N-[2-(4'.8.IZ-trimethyl-tridecyl)-2.5.7.8-tetramethyl-chromanyl-6
]-Synthesis of phytenoylamide) 2-(4, 8, 12-
trimethyl-tridecyl)-6-N-methylamino-2
- 5,7,8-tetoramethyl-chroman 11 times, phythenic acid 10 times, polyphosphate ester 10 times, triethylamine 7 times, and chloroform 100 times were reacted according to Example 1.

The desired product was obtained as a pale yellow oil.

Yield: 16.5 days (yield 90%) Elemental analysis value: C as C5-8-02 Days N Theoretical value (%) 81.5712.191.90 Actual value (
%) 81.5612.091.981R spectrum measurement (arc-1) 1660 (C=.

>MAS spectrum measurement value M+: 735 NMR spectrum measurement value (7: CDC13) N-C&:
6.92 (9H) ~ omOH3; 7.96 (9H) Chroman-3 position CH2; 8.20 (2H) Chroman-4
CH2:7.40(2H)CH2=;5.20(IH
) Example 7 Synthesis of N-[2-(methyl-2-(4,8,12-trimethyl-tridecyl)-chromaniru-6]-phytenolamide 2-methyl-2-(4',8,12-trimethyl- 11 parts of (tridecyl)-chroman, 10 parts of phythenic acid ethyl ester, and 3 parts of sodium ethyl ester were dissolved in 75 parts of ethanol, and the mixture was 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 ethyl chloride as the eluent, and the solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow substance. Yield 1
5.3 days (yield 79%) Elemental analysis value C46 days 8, C days N as N02 Theoretical value (%) 81.2312.002.06 Actual value (
%) 81.3511.971.981R spectrum measurement value (inhibition-1) 3260 (hiNM), 1650 (shiC=
.

) MAS spectrum measurement value M+: 679 NMR spectrum measurement value (7: CDC13) N day; 2
．． 91 (IH) ~ omH; 3.01 (9H) chroman-3 position CH2; 8.22 (2H) chroman-4
Position C; 7.20 (ga) C=H; 4.50 (IH) Example 8 N-[2-(4', 8, 12-trimethyl-tridecyl)-2, 517, 8-tetramethy Synthesis of 2-(4',8,12-trimethyl-tridecyl)-6-aminochromanyl]-phitenoylamide was dissolved in toluene 50, and added to this solution at room temperature. A solution of 4.5 liters of phytic anhydride dissolved in 50 ml of toluene was added dropwise to the bottom.

After the dropwise addition was completed, the mixture was heated under reflux for 5 hours. After the reflux was completed, the reaction mixture was washed successively with 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, dried over 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 the soot, and the solvent was evaporated under reduced pressure to obtain the desired product as a pale yellowish brown substance. Yield 4.19 (yield 8
1%) Elemental analysis value C as C46HB7N20 Theoretical value (%) 81.4912.141.94 Actual value (
%) 81.4612.211.961R spectrum measurement value (inhibition-1) 3260 (shiNH>, 1655 (shiC:
.

) MAS spectrum measurement value M+; 721 NMR spectrum measurement value (month: CDC13) N-H: 2
．． 87 (IH) ~ omCH3; 7.90 (group) Chroman-3 position CH2; 8.15 (2fl) Chroman-
4-position CH2: 7.38 (panic) C=H; 4.45 (IH) Next, compounds obtained by the method of the present invention are shown as examples.

Satoshi Example 19 Synthesis step of N-(2,2,5,7,8-bentamethyl-chromanyl-6)-phyte/ylamide 16-Chloracetamide-2,2,517,8-pentamethylchroman synthesis 6-amino-2,2,5,7,8-pentamethyl-chroman 51, pyridine 40, benzene 1.5
The resulting solution was heated at 155 to 20°C under stirring.
45 minutes of chloracetyl chloride was added dropwise.

After the completion of the dropping, touzasa was continued for 3 hours while maintaining the do of 15 to 20. After the reaction is completed, the reaction mixture is dispersed in ice water and 5%
The residue was sequentially purified with hydrochloric acid, a 5% aqueous sodium bicarbonate solution, and water, dried over trinitric nitrate, and concentrated under reduced pressure to obtain the desired product as brown plate-shaped crystals. Yield 69 days Melting point 158-160q○ Elemental analysis value C, 6 days C as 22N02CI day N
Theoretical value (%) 64.967.504.74 Actual value (%
) 64.957.554.75 Step 2N-(2・21
5.7.8-pentamethyl-chromanyl-6)-phytenolamide 6-chloroacetamide-2.2.5.7.8-besotamethyl-chroman obtained in step 1 of synthesis 5.
P obtained from 9 days and triethyl phosphite 8.3 days
20 oo
After adding 2.7 evenings of sodium ethylate,
6.10.14-trimethyl-2-pentadecanone8.
I instilled it overnight.

After the completion of the dropping, the sabotage was continued for 8 hours at 20°C. After the reaction was completed, the reaction mixture was dispersed in water, washed with water, dried over bitter salt, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of n-hexane and ethyl ether as an elution solvent, and the solvent was distilled off to obtain the desired product as a pale yellow oil. Yield: 9.3 evenings (yield 91%)
) Elemental analysis value C34 day 57N02 C day N Theoretical value (%) 79.7911.232.74 Actual value (
%) 79.81 11.222.75 IR spectrum measurement value (skin-1) 3260 (yNH), 1660 (shic
=.

) MAS spectrum measurement value M: 511 NMR spectrum measurement value (D: CDC13) N-H; 2
．． 85 (IH) Aromatic CH3: 8.98 (group) Chroman 3-position - CH2: 8.21 (2H) Chroman 4-position -CW; 7.41 (2H) CH=; 4.80 (lH) Example 20 Synthesis of N-(2,2,5,7,8-pentamethyl-chromanyl-6)-geranoylamide 6-chloroacetamide-2,2,5,7,8-pentamethyl-chroman7.
P prepared from triethyl phosphite and triethyl phosphite.
-[N-(2,2,5,7,8-bentamethyl-chromanyl)-acetamido]-diethylphosphonate and 3.89 g of methylheptenone were reacted according to Example 19, Step 2.

The desired product was obtained as a pale yellowish brown powder. Yield 8
．． 4 days (yield 91%) Melting point 100-10 is ○ Elemental analysis value C24 days 35N02 C days N Theoretical value (%) 78.009.553.79 Actual value (%
) 78.049.483.761R spectrum measurement value (skin-1) 3250 (shi NH), 1660 (shi C2).

) MAS spectrum measurement value M+: 369 NMR spectrum measurement value (7: CDC13) NH; 3
．． 35 (IH) ~〇mCH3; 7-92 (split H) Chroman-3 position CH2: 8.12 (2H) Chroman-4
Position C ratio; 7.40 (2H) CH =; 4.22 (IH), 4.80 (IH)) chroman - 3rd position CH2: 8.14 (2H) chroman - 4th position CH
2:7.42(2H)CH=;4.22(IH),4.
90(2H) Example 21N-methyl-N-(2.2.
Synthesis of 5,7,8-pentamethyl-chromanyl-6)-farnesiroylamide 6-chloroacetamide-2.
2,5,7,8-P-[N-
(2,2,5,7,8-bentamethyl-chromanyl)-acetamido]-diethylphosphonate and 9.7 hours of geranylacetone were reacted according to Example 19, Step 2.

The desired product was obtained as a pale yellow oil. Yield 16.8 days (yield 96%) Elemental analysis value C3 as 45N02 Theoretical value (%) 79.7710.043.65 Actual value (
%) 79.53 9.873.231R spectrum measurement value (arc-1) 3250 (Lito JH), 1660 (Shi C
=.

) MAS spectrum measurement value M+: 437 NMR spectrum measurement value (7: CDC13) NH; 3
．． 22 (IH) to omCH3; 7.94 (field) Compounds obtained by the same method as Example 19 are shown below.

Ship Example 37 Powder N-(2,2.5,7,8-pentamethyl-chromanyl-6)geranoylamide 50 parts by weight Silicic anhydride 300 Silicic anhydride hydrate 200 The above components were mixed and prepared by obtained the drug.

Example 38 Jaw granules N-(2,2.5,7,8 pentamethyl-chromanyl-6)-falnesilylamide 40 parts by weight Silicic anhydride 200 Silicic anhydride hydrate 200 Lactose
150 polyvinylpyrrolidoso
50 The above components were brazed and extruded into granules.

This was dried and sized to obtain jaw granules. Example 39 Capsule N-Methyl-N-(2.2.5.7.8-pentamethyl-chromanyl-6)-falnesylamide 10 Hiroshige military silicic anhydride 50 Silicic anhydride hydrate 50 microcrystalline cellulose
20 polyvinylpyrrolidone
5 The above ingredients were granulated and filled into No. 2 capsules.

1 capsule 225/9.

Example 40 Tablet N-[2-(4.8.12-trimethyl-tridecyl)-2-methyl-chromanyl-6]-farnesilylamide 50 parts by weight Silicic anhydride 40 Silicic anhydride hydrate 20 lactose
40 microcrystalline cellulose
50 The above ingredients were granulated and compressed into tablets.

9 out of 200 per tablet.

Example 41 Soft capsule N-methyl-N(2-(4,8,12-trimethyl-tridecyl)-2,5,7,8--tetramethyl-chromaniru6)-farnesiroylamide 10 Part by Weight Octyl Tesyl Triglyceride 1005 The above components were mixed and filled into soft capsules.

1 capsule 200/9.

Claims (1)

[Claims] 1 The following general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ ~
Represents an integer of 3. Further, A and B represent hydrogen atoms or a bond may be formed between A and B. ) 6-aminochroman derivative represented by. 2. The 6-aminochroman derivative according to claim 1, wherein n is 3 and A and B are hydrogen atoms. 3. The 6-aminochroman derivative according to claim 1, wherein n is 3, R_1, R_2, and R_3 are methyl, and A and B are hydrogen atoms. 4. The 6-aminochroman derivative according to claim 1, wherein n is 2, and A and B form a bond between A and B. 5. The 6-aminochroman derivative according to claim 1, wherein n is 2, R_1, R_2, and R_3 are methyl, and A and B form a bond between AB. 6. The 6-aminochroman derivative according to claim 1, wherein n is 1 and A and B form a bond between A and B. 7. The 6-aminochroman derivative according to claim 1, wherein n is 1, R_1, R_2, and R_3 are methyl, and A and B form a bond between A and B. 8. The 6-aminochroman derivative according to claim 1, wherein n is 3, R_1, R_2, and R_3 are methyl, A and B are hydrogen atoms, and m is 0. 9. The 6-aminochroman derivative according to claim 1, wherein n is 3, R_1, R_2, R_3, and R_4 are methyl, A and B are hydrogen atoms, and m is 0.