JPH11246512A - Sulfur oxyacid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain sulfur oxyacid derivatives suppressing scavenger receptors existing on the surface of macrophage cells or the like deeply concerning to the advance of arteriosclerosis, diabetic complication, Alzheimer's disease or the like. SOLUTION: The derivatives are expressed in formula I (X is a single bond or -OCH2 -; n is 12 to 23; the two acylamino groups are each in metha or para position). For example, sodium salt of 2,4-bisoctadecanoylaminobenzenesulfonic acid. The compound having a single bond as the X of the compounds of the formula I is obtained, for example, reacting 2 to 4 equivalent of carboxylic acid chloride [C1CO(CH2 )n CH3 ] to the compound of formula II and the compound of formula III, in an inert organic solvent such as tetrahydrofuran or the like, in the presence of a base such as diisopropylethylamine or the like at room temperature to the refluxing temperature for 10 minutes to 24 hours to carry out the diacylation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel sulfuric acid derivative and a pharmaceutically acceptable salt thereof. More specifically, the following formula (I) useful as a compound that inhibits a scavenger receptor present on the surface of macrophage cells or the like that is deeply involved in the development of arteriosclerosis, diabetic complications and Alzheimer's disease, etc.

[0002]

Embedded image (Wherein, X represents a single bond or an atomic group —OCH ₂ —,
n represents an integer of any of 12 to 23. However, each of the two acylamino groups is mutually bonded to the benzene ring at the meta or para position. ) And a pharmaceutically acceptable salt thereof.

[0003]

2. Description of the Related Art In recent years, it is well known that cerebrovascular disease and heart disease are important factors of death, and arteriosclerosis is a trigger for such diseases. The pathological feature of early lesions of atherosclerosis is a phenomenon in which foam cells increase in the arterial wall, and these foam cells are known to be caused by macrophages taking up denatured low-density lipoprotein (denatured LDL). Have been. It is known that the scavenger receptor acts when macrophages take up the denatured LDL, and recognizes a molecule having a negative charge.

[0004] Suzuki et al. Found that the area of atherosclerotic foci of a double knockout mouse formed by crossing an apoE-deficient mouse, which is known to develop severe arteriosclerosis, and a scavenger receptor-deficient mouse, ApoE-deficient mice deficient in ApoE alone are reported to be significantly smaller (Nature, 386, 292).
296 pages, 1997).

[0005] Scavenger receptors are also considered to be deeply involved in diabetic complications such as diabetic nephropathy, diabetic retinopathy and diabetic neuropathy. That is, persistent hyperglycemia in vivo causes non-enzymatic saccharification of various proteins, and in particular, the final product of the Maillard reaction late saccharification product (AGE) of the final product in the saccharification process is:
Macrophages, vascular endothelial cells via AGE receptors,
Various changes are caused by binding to liver, kidney mesangial cells and the like. For example, AGE binding to macrophages is determined by TNF (Tumor Necrosi).
s Factor), IL-1 (Interleuki)
ne 1) promotes the secretion of cytokines such as platelet-derived growth factor (PDGF), causing cell damage characteristic of diabetic complications. AGE scavenger receptor
Is one of the receptors involved in the uptake and degradation of E. coli (EJ Biochem., 230, 408-41).
5, p. 1995), it has been reported that the AGE degradation activity in the double knockout mouse is reduced to 1/3.

[0006] Furthermore, scavenger receptors are also thought to be involved in Alzheimer's disease. In other words, the pathological feature of Alzheimer's disease is senile plaque in which β-amyloid is accumulated, and this β-amyloid is known to generate active oxygen by activating microglia and to exhibit neurotoxicity. It has been reported that β-amyloid activates microglia via a scavenger receptor expressed on microglia (Natur)
e, 382, 716-719, 1996).

[0007] As described above, since scavenger receptors are involved in various diseases, compounds that inhibit scavenger receptors are not only required for arteriosclerosis, diabetic complications and Alzheimer's disease, but also for various diseases. It is thought that it can be a prophylactic and therapeutic agent.

[0008]

An object of the present invention is to provide a novel sulfuric acid derivative which inhibits a scavenger receptor and a pharmaceutically acceptable salt thereof.

[0009]

Means for Solving the Problems The present inventors have conducted various studies to achieve the above object, and as a result, have found that the above-mentioned formula (I)
It has been found that a sulfuric acid derivative represented by the formula (I) and a pharmaceutically acceptable salt thereof have an inhibitory effect on a scavenger receptor, and thus completed the present invention.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention has the following formula (I)

[0011]

Embedded image (Wherein, X represents a single bond or an atomic group —OCH ₂ —,
n represents an integer of any of 12 to 23. However, each of the two acylamino groups is mutually bonded to the benzene ring at the meta or para position. ) And a pharmaceutically acceptable salt thereof.

The sulfuric acid derivative and the pharmaceutically acceptable salt thereof in the present invention are a sulfonic acid derivative having a sulfonic acid group directly bonded to a benzene ring, a pharmaceutically acceptable salt thereof and an atomic group on the benzene ring. Refers to a pharmaceutically acceptable salt of a sulfate ester bonded via —OCH ₂ —.

The pharmaceutically acceptable salts of the above formula (I) which are the compounds of the present invention include salts with alkali metals such as sodium and potassium, and salts with organic bases such as pyridine.

The compound of the formula (I), which is a compound of the present invention, and a pharmaceutically acceptable salt thereof also include hydrates thereof.

Specific examples of the compound (I) of the present invention and pharmaceutically acceptable salts thereof are listed below.・ 2,4-bisoctadecanoylaminobenzenesulfonic acid sodium salt ・ 2,4-bistetradecanoylaminobenzenesulfonic acid sodium salt ・ 2,4-bisdocosanoylaminobenzenesulfonic acid sodium salt ・ 2,5-bis Octadecanoylaminobenzenesulfonic acid sodium salt, 2,5-bisoctadecanoylaminobenzyl sulfate sodium salt, 3,5-bisoctadecanoylaminobenzyl sulfate sodium salt, and the like.

The meanings of the abbreviations used in the present specification are shown below. THF: tetrahydrofuran DMSO: dimethyl sulfoxide Hereinafter, a method for producing the sulfuric acid derivative represented by the formula (I), which is a compound of the present invention, and a pharmaceutically acceptable salt thereof, and a synthetic intermediate will be described. (1) Method for producing compound (Ia) in the case where X is a single bond among compound (I):
It can be produced by Method A shown in the following formula (Scheme 1). [Method A] (Where n is the same as above) That is, the compound (Ia) of the present invention can be produced by diacylating the compound (II). The diacylation reaction is carried out in an inert organic solvent such as THF in the presence of a base such as diisopropylethylamine.
The reaction can be carried out by reacting compound (II) with 2 to 4 equivalents of carboxylic acid chloride [ClCO (CH ₂ ) _n CH ₃ ] at a temperature from room temperature to the reflux temperature of the solvent for 10 minutes to 24 hours. The thus-obtained compound (Ia) of the present invention is treated with an inorganic base or an organic base by a conventional method to form a salt, whereby the pharmaceutically acceptable salt of the compound of the present invention (I) can be obtained. Can be manufactured.

Of the compound (II) used as a raw material in the above-mentioned Method A, 2,4- and 2,5-diaminobenzenesulfonic acid can be easily obtained.

On the other hand, 2,6-diaminobenzenesulfonic acid is obtained by converting readily available 2-chloro-1,3-dinitrobenzene, for example, from Biochemistry, 16
Volume, pages 5207-5216, 1977, and then reducing the nitro group according to a conventional method.

3,5-Diaminobenzenesulfonic acid is a readily available chlorobenzene, for example, as described in Org. S
yntheses Coll. 4 volumes, 364-366
Page, 1963, followed by nitration and sulfonation, followed by reduction according to a conventional method. (2) Among the compound (I), X is an atomic group -OCH ₂ - preparation of compounds when it is (Ib): Compound (Ib)
Can be produced, for example, by Method B shown in the following formula (Scheme 2). [Method B] (Where n is the same as above) That is, the compound (Ib) can be produced by reacting the compound (III) with chlorosulfuric acid. This reaction can be performed by reacting 1 to 10 equivalents of chlorosulfuric acid with respect to compound (III) in pyridine at 70 ° C. to the reflux temperature of the solvent for 10 minutes to 2 hours. The compound (Ib) thus obtained is treated with an inorganic base or an organic base by a conventional method to form a salt, whereby a pharmaceutically acceptable salt of the above formula (I), which is a compound of the present invention, is produced. be able to.

The compound (III) used as a starting material in the above-mentioned Method B can be produced, for example, by the following scheme (Scheme 3). (Where n is the same as above) That is, first, in an inert organic solvent such as THF, for example, in the presence of a base such as diisopropylethylamine,
Relative to the compound (IV), to produce the 2-4 equivalents of the carboxylic acid chloride _{[ClCO (CH 2) n CH} 3] a compound by reacting 4 hours 10 minutes at room temperature (V). Then, in an organic solvent such as a mixed solvent of methanol and THF or a mixed solvent of methanol and tert-butanol, the compound (V) is stirred at the reflux temperature of 1 to 20 equivalents of sodium borohydride and the solvent for 10 minutes to 4 hours. By doing so, compound (III) can be produced.

Of the compound (IV) used as a starting material in the scheme 3, the 3,5-diamino compound can be produced by subjecting easily available 3,5-diaminobenzoic acid to methyl esterification according to a conventional method. .

On the other hand, 2,4- and 2,5-diamino compounds are readily available 2-amino-4-nitro and 2-amino-4-nitro compounds.
It can be produced by subjecting -amino-5-nitrobenzoic acid to methyl esterification and further reducing the nitro group according to a conventional method.

The 2,6-diamino compound can be produced by subjecting readily available 2,6-dinitrobenzaldehyde to aldehyde oxidation, methyl esterification, and nitro group reduction sequentially in a conventional manner.

[0024]

The sulfuric acid derivative represented by the above formula (I) and the pharmaceutically acceptable salt thereof, which are the compounds of the present invention, have an inhibitory effect on the scavenger receptor as shown in the following Test Examples. Having. Therefore, the compound of the present invention can be used as a prophylactic and therapeutic agent for various diseases as well as arteriosclerosis, diabetic complications and Alzheimer's disease.

Hereinafter, the action and effect of the compound of the present invention will be specifically described with reference to test examples. [Test Example] The inhibitory action of the compound of the present invention on scavenger receptors was evaluated using the following acetylated LDL binding inhibitory action as an index. (1) Test compound Compound of the present invention a 2,4-bisoctadecanoylaminobenzenesulfonic acid sodium salt (compound of Example 1) (2) Test method First, the method of Havel et al. (J. Clin. Inves)
t. , 34, pp. 1355-1353, 1955). That is, blood is collected from a healthy person and subjected to ultracentrifugation to give a specific gravity of 1.019 to 1.063.
An LDL fraction corresponding to g / ml was prepared. Then, B
asu et al. (Proc. Natl. Acad. Sc.
i. , 73, 3178-3182 (1976)).
ein et al. (Methods in Enzymo)
logy, 98, pp. 241-260, conducted a ^{1 25} I-labeled acetylated LDL according 1983),
¹²⁵ I-acetylated LDL was obtained. Next, the method of Cohn and Morse (J. Explorer. Med., 1
10, p. 419, 1959). That is, after ddY female mice were bled to death, PBS [-] (Ca ⁺ and Mg
²⁺ free physiological phosphate buffer) to give a peritoneal macrophage suspension. Subsequently, after washing the peritoneal macrophages with PBS [-], the peritoneal macrophages were added to each well of a 12-well plastic plate by 2 ×.
10 ⁶ cells were inoculated and cultured overnight at 37 ° C. in 5% CO ₂ in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum. The next day, 10 mM HEPES was added to the wells.
Dulbecco's modified Eagle's medium containing sodium buffer (pH 7.4) and 10% fetal calf lipoprotein-free serum was added and incubated at 4 ° C for 30 minutes. continue,
10 μg / ml ¹²⁵ I-acetylated LDL, 10 m
M HEPES sodium buffer (pH 7.4), 10
Incubation was carried out at 4 ° C for 2 hours in Dulbecco's modified Eagle's medium containing serum containing no fetal bovine lipoprotein and a test compound at a predetermined concentration. After completion of the reaction, the medium was removed, and the cells were washed. The cells were dissolved with a 0.1N aqueous sodium hydroxide solution, and the radioactivity was measured with a gamma counter. Further, the protein concentration of the cell lysate was measured, and the total amount of ¹²⁵ I-acetylated LDL bound per 1 mg of cell protein was calculated. Also, non-specific ¹²⁵ I-acetylated L
To obtain the amount of DL bound, add 400 μl to the reaction medium.
g / ml acetylated LDL was added and the amount of binding was similarly calculated to calculate the amount of non-specific binding. The specific binding amount was calculated from the difference between the total binding amount and the non-specific binding amount. The inhibition rate (%) of acetylated LDL binding was calculated by using D instead of the test compound.
The specific binding amount when MSO was added (A) and the specific binding amount when test compound was added (B) were calculated by the following formula. 2

## EQU1 ## Inhibition rate (%) = (1-B / A) × 100 (3) Test results The results are shown in Table 1.

[0026]

[Table 1] As is clear from Table 1, the compound a of the present invention exhibited an acetylated LDL binding inhibitory action in a concentration-dependent manner.

Therefore, the compounds of the present invention have an inhibitory action on scavenger receptors, and can be used as preventive and therapeutic drugs for various diseases as well as arteriosclerosis, diabetic complications and Alzheimer's disease.

[0028]

The present invention will be described more specifically below with reference to examples and reference examples. Example 1 2,4-bisoctadecanoylaminobenzenesulfone
Acid sodium salt [In the formula (I), X is a single bond, n
Is 16, and two acylamino groups correspond to sulfonic acid.
And the sodium salt of the compound bound at the 2- and 4-positions] : 2,4
-A mixture of 1.88 g of diaminobenzenesulfonic acid, 3.88 g of diisopropylethylamine and 50 ml of THF was added with 6.6 octadecanoyl chloride under ice cooling.
After dropping 6 g, the mixture was further stirred at 70 to 75 ° C for 1 hour. After 1 L of water was added to the reaction mixture, concentrated hydrochloric acid was added until the pH was about 2. 300 ml of chloroform
, And the chloroform layer was washed with 200 ml of water, and the solvent was distilled off under reduced pressure. 50m of methanol in the residue
After adding 10% aqueous solution of sodium carbonate until the pH of the solution reached about 10, 150 ml of water was added.
The precipitated solid was collected by filtration and dried. This solid was heated to a mixed solution of chloroform: methanol = 1: 1: 1.
After stirring with 00 ml, insolubles were removed. After evaporating the solvent under reduced pressure from the filtrate, the residue was stirred with 150 ml of ethyl acetate, and the precipitated crystals were collected by filtration to obtain 3.00 g of the title compound as pale yellow crystalline powder. Melting point: 218.0 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.84
(6H, t, J = 6.5 Hz), 1.10-1.40
(56H, m), 1.40-1.70 (4H, m),
2.20-2.35 (4H, m), 7.44 (1H, d
d, J = 1.8, 8.8 Hz), 7.51 (1H, d,
J = 8.8 Hz), 8.39 (1H, d, J = 1.8H)
z), 9.93 (1H, brs), 10.41 (1H,
brs). Elemental analysis value (as C ₄₂ H ₇₅ N ₂ NaO ₅ S · 0.5H ₂ O): Calculated value (%) C, 67.07; H, 10.18; N, 3.72 Actual value (%) C , 67.02; H, 10.09; N, 3.84.

Example 2 2,4-bistetradecanoylaminobenzenesulfone
Acid sodium salt [In the formula (I), X is a single bond, n
Is 12, and two acylamino groups are
And the sodium salt of the compound bound at the 2- and 4-positions] : 2,4
1.88 g of diaminobenzenesulfonic acid and 5.43 g of tetradecanoyl chloride were treated in the same manner as described in Example 1 to obtain 3.40 g of crude crystals of the title compound. This was recrystallized from chloroform to obtain 2.70 g of the title compound as a pale brown crystalline powder. Melting point: 228.0-230.0 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.84
(6H, t, J = 6.6 Hz), 1.15-1.35
(40H, m), 1.45-1.70 (4H, m),
2.20-2.35 (4H, m), 7.43 (1H, d
d, J = 1.9, 8.6 Hz), 7.52 (1H, d,
J = 8.6 Hz), 8.39 (1H, d, J = 1.9H)
z), 9.90 (1H, brs), 10.43 (1H,
brs). Elemental analysis (as C ₃₄ H ₅₉ N ₂ NaO ₅ S · 0.5H ₂ O): Calculated (%) C, 63.82; H, 9.45; N, 4.38 Found (%) C , 63.64; H, 9.68; N, 4.23.

Example 3 2,4-Bisdocosanoylaminobenzenesulfonic acid
Sodium salt [in the formula (I), X is a single bond, n is 2
0, and two acylamino groups are
Sodium salt of a compound bonded to the 2, 4-position] : 2,4-
1.88 g of diaminobenzenesulfonic acid and 7.90 g of docosanoyl chloride were treated in the same manner as described in Example 1 to obtain 6.70 g of crude crystals of the title compound. 1.50 g of this was taken and recrystallized from chloroform: methanol = 1: 1 to give 0.97 g of the title compound as a pale brown crystalline powder. Melting point: 213.0-215.5 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.84
(6H, t, J = 6.6 Hz), 1.15-1.40
(72H, m), 1.45-1.70 (4H, m),
2.20-2.35 (4H, m), 7.42 (1H, d
d, J = 2.0, 8.6 Hz), 7.52 (1H, d,
J = 8.6 Hz), 8.39 (1H, d, J = 2.0H)
z), 9.89 (1H, brs), 10.43 (1H,
brs). Elemental analysis _{(as C 50 H 91 N 2 NaO 5} S): Calculated (%) C, 70.21; H , 10.72; N, 3.28 Found (%) C, 70.12; H , 10.70; N, 3.21.

Example 4 2,5-bisoctadecanoylaminobenzenesulfone
Acid sodium salt [In the formula (I), X is a single bond, n
Is 16, and two acylamino groups correspond to sulfonic acid.
And a sodium salt of a compound bonded to the 2,5-position] : 2,5
By treating 1.88 g of diaminobenzenesulfonic acid and 6.66 g of octadecanoyl chloride in the same manner as described in Example 1, the title compound 1.
70 g were obtained as a pale yellow crystalline powder. Melting point: 176.0-179.0 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.80 −
0.95 (6H, m), 1.15-1.40 (56H,
m), 1.45-1.70 (4H, m), 2.20-
2.35 (4H, m), 7.55-7.70 (1H,
m), 7.82 (1H, s), 8.15-8.25 (1
H, m), 9.80 (1H, brs), 10.28 (1
H, brs). Elemental analysis value (as C ₄₂ H ₇₅ N ₂ NaO ₅ S · 1.75 H ₂ O): Calculated value (%) C, 65.12; H, 10.21; N, 3.62 Actual value (%) C H, 9.93; N, 3.23.

Embodiment 53,5-bisoctadecanoylaminobenzyl sulf
Sodium salt [In the formula (I), X is an atomic group
—OCH ₂ —, n is 16 and two acylamino groups
Of a compound in which is bonded to the sulfate at positions 3 and 5 with respect to sulfate
Lium salt] (9304) : To 1.5 ml of pyridine, add
150 μl of sulfuric acid is added dropwise at room temperature.
For 30 minutes. After cooling this to room temperature, (3
-Hydroxymethyl-5-octadecanoylaminofe
Nyl) octadecaneamide (see Reference Example 1 below) 350
mg of pyridine solution (5.5 ml),
Stirred at C for 1 hour. Pyridine was distilled from the reaction mixture under reduced pressure.
After removal, 7 ml of methanol was added to the residue. This liquid
Then, add a saturated aqueous solution of sodium carbonate until the pH indicates about 9.
After the addition, 5 ml of water was added. Filtration of precipitated crystals
And dried. The crystals were stirred with 50 ml of chloroform.
After stirring, insolubles were removed. The solvent is distilled off from the filtrate under reduced pressure.
After that, the residue was stirred with ethyl acetate to precipitate crystals.
To afford the title compound as a pale brown crystalline solid.
220 mg were obtained as a powder. Melting point: 205.0-208.0 ° C (decomposition)¹ H-NMR (DMSO-d₆) Δ ppm: 0.84
(6H, t, J = 6.4 Hz), 1.15-1.40
(56H, m), 1.45-1.70 (4H, m),
2.25 (4H, t, J = 7.3 Hz), 4.62 (2
H, s), 7.17 (2H, s), 7.93 (1H,
s), 9.84 (2H, brs). Elemental analysis value (C₄₃H₇₇N₂NaO₆S 1.5H₂O): Calculated (%) C, 64.55; H, 10.08; N, 3.50 Found (%) C, 64.44; H, 9.75; N, 3.64

Embodiment 62,5-bisoctadecanoylaminobenzyl sulf
Sodium salt [In the formula (I), X is an atomic group
—OCH ₂ —, n is 16 and two acylamino groups
Of a compound in which is linked to the sulfate at positions 2 and 5
Lium salt] : (3-Hydroxymethyl-4-octadeca
Noylaminophenyl) octadecanamide (see below)
(See Example 2) 240 mg as in the method described in Example 5
By treating with the method, 204 mg of the title compound was obtained.
Obtained as a brown crystalline powder. Melting point: 120.0-123.0 ° C (decomposition)¹ H-NMR (DMSO-d₆) Δ ppm: 0.84
(6H, t, J = 6.6 Hz), 1.10-1.40
(56H, m), 1.40-1.70 (4H, m),
2.15-2.35 (4H, m), 4.69 (2H,
s), 7.45 (1H, d, J = 2.5 Hz), 7.5
6 (1H, dd, J = 2.5, 8.7 Hz), 7.65
(1H, d, J = 8.7 Hz), 9.28 (1H, br
s), 9.81 (1H, brs). Elemental analysis value (C₄₃H₇₇N₂NaO₆S ・ 2.0H₂O): Calculated (%) C, 63.83; H, 10.09; N, 3.46 Found (%) C, 63.67; H, 9.91; N, 3.49.

Reference Example 1 (3-hydroxymethyl-5-octadecanoylamino
Phenyl) octadecanamide [in the formula (III)
n is 16 and two acylamino groups are
Method for producing compound bound to positions 3 and 5 with respect to tyl group] (1) To a methanol solution (50 ml) of 5.00 g of 3,5-diaminobenzoic acid was added 10.0 g of concentrated sulfuric acid under ice cooling. The mixture was further refluxed for 16 hours. PH of the reaction mixture
After adding a saturated aqueous solution of sodium hydrogencarbonate until the solution showed about 8, the mixture was extracted three times with 100 ml of ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 5.5 g of methyl 3,5-diaminobenzoate as orange crystals. ¹ H-NMR (CDCl ₃ ) δ ppm: 3.66 (4
H, brs), 3.85 (3H, s), 6.17 (1
H, t, J = 2.1 Hz), 6.77 (2H, d, J =
2.1 Hz).

(2) 3.50 g of methyl 3,5-diaminobenzoate, 5.47 g of diisopropylethylamine,
To a mixture of 35 ml of THF was added a solution of 12.8 g of octadecanoyl chloride in THF under ice cooling (35 ml).
Was added dropwise, and the mixture was further stirred at room temperature for 30 minutes. After the solvent was distilled off from the reaction mixture under reduced pressure, 200 ml of chloroform was added to the obtained residue. The solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. By purifying the finally obtained residue by medium pressure column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1), methyl 3,5-bisoctadecanoylaminobenzoate is obtained as a light brown powder. 4.50 g was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.88 (6
H, t, J = 6.6 Hz), 1.15-1.45 (56
H, m), 1.50-1.80 (4H, m), 2.36
(4H, t, J = 7.5 Hz), 3.90 (3H,
s), 7.31 (2H, brs), 7.91 (2H,
d, J = 2.0 Hz), 8.15 (1H, t, J = 2.
0 Hz).

(3) A solution of 4.40 g of methyl 3,5-bisoctadecanoylaminobenzoate in THF (60 ml)
Was added with 1.42 g of sodium borohydride at room temperature,
The mixture was heated to reflux. After 1 ml of methanol was added dropwise at the same temperature over 10 minutes, the mixture was heated under reflux for 30 minutes. Further, 1 ml of methanol was added dropwise at the same temperature over 10 minutes, the mixture was heated under reflux for 30 minutes, and then cooled to room temperature. After evaporating the solvent from the reaction mixture under reduced pressure, water and 1N hydrochloric acid were added to the obtained residue until the pH reached about 2. The precipitated powder was collected by filtration, washed with chloroform and a saturated aqueous solution of sodium hydrogen carbonate, and dried. The powder obtained at the end was recrystallized from 250 ml of a mixed solution of ethyl acetate: methanol = 5: 1 to give 2.60 g of (3-hydroxymethyl-5-octadecanoylaminophenyl) octadecaneamide as yellow crystals. Obtained. Melting point: 149.0-150.5 ° C. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.84
(6H, t, J = 6.6 Hz), 1.15-1.35
(56H, m), 1.45-1.70 (4H, m),
2.25 (4H, t, J = 7.4 Hz), 4.38 (2
H, s), 5.13 (1H, brs), 7.22 (2
H, s), 7.78 (1H, s), 9.76 (2H, b
rs). Elemental analysis (as C ₄₃ H ₇₈ N ₂ O ₃ ): Calculated (%) C, 76.96; H, 11.71; N, 4.17 Found (%) C, 76.74; H, 11.86; N, 4.15

Reference Example 2 (3-hydroxymethyl-4-octadecanoylamino
Phenyl) octadecanamide [in the formula (III)
n is 16 and two acylamino groups are
Method for producing compound bonded to positions 2 and 5 with respect to tyl group] (1) According to the method described in Reference Example 1 (1), 2-amino-5-nitrobenzoic acid is methyl-esterified to give 2 -Methyl -amino-5-nitrobenzoate was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 3.93 (3
H, s), 6.50 (2H, brs), 6.66 (1
H, d, J = 9.1 Hz), 8.13 (1H, dd, J
= 2.7, 9.1 Hz), 8.83 (1H, d, J =
2.7 Hz). (2) Iron 5.59 g, methanol 300 ml, water 50 m
and 1 ml of concentrated hydrochloric acid were heated to reflux, 4.00 g of methyl 2-amino-5-nitrobenzoate was added little by little at the same temperature, and then heated to reflux for 30 minutes. Further, after adding 5.59 g of iron at the same temperature, the mixture was heated under reflux for 4 hours.
After insoluble matter was removed from the reaction mixture by hot filtration, the solvent was distilled off from the filtrate under reduced pressure, 200 ml of water was added, and the mixture was extracted three times with 100 ml of chloroform. The chloroform layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by medium pressure column chromatography (elution solvent: chloroform → chloroform: methanol = 50: 1 → 20: 1) to give methyl 2,5-diaminobenzoate as a brown oil. 1.1 g were obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 2.70-4.
10 (2H, br), 3.85 (3H, s), 4.50
−5.90 (2H, br), 6.56 (1H, d, J =
8.6 Hz), 6.77 (1H, dd, J = 2.8,
8.6 Hz), 7.23 (1H, d, J = 2.8H)
z). (3) According to the method described in Reference Example 1 (2), 2,5-
Methyl 2,5-bisoctadecanoylaminobenzoate was obtained by diacylating methyl diaminobenzoate with octadecanoyl chloride. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.88 (6
H, t, J = 6.4 Hz), 1.15-1.45 (56
H, m), 1.65-1.85 (4H, m), 2.34.
(2H, t, J = 7.5 Hz), 2.42 (2H, t,
J = 7.7 Hz), 3.91 (3H, s), 7.14
(1H, brs), 7.47 (1H, dd, J = 2.
2,9.0 Hz), 8.35-8.45 (1H, m),
8.69 (1H, d, J = 9.0 Hz), 10.91
(1H, brs). (4) According to the method described in Reference Example 1 (3), 2,5-
Reduction of methyl bisoctadecanoylaminobenzoate with sodium borohydride provided (3-hydroxymethyl-4-octadecanoylaminophenyl) octadecaneamide. Melting point: 136.0-138.0 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.88 (6
H, t, J = 6.6 Hz), 1.10-1.45 (56
H, m), 1.55-1.75 (4H, m), 2.20
-2.40 (4H, m), 4.55 (2H, d, J =
5.5Hz), 5.15 (1H, t, J = 5.5H)
z), 7.35-7.50 (1H, m), 7.60 (1
H, d, J = 2.0 Hz), 7.65-7.80 (1
H, m), 9.04 (1H, brs), 9.33 (1
H, brs). Elemental analysis (as C ₄₃ H ₇₈ N ₂ O ₃ .0.25 H ₂ O): Calculated (%) C, 76.45; H, 11.71; N, 4.15 Found (%) C, 76.49; H, 11.68; N, 4.30.

Claims (1)

[Claims] (1) The following formula (I): (Wherein, X represents a single bond or an atomic group —OCH ₂ —,
n represents an integer of any of 12 to 23. However, each of the two acylamino groups is mutually bonded to the benzene ring at the meta or para position. ) And a pharmaceutically acceptable salt thereof.