JP2001240581A - Aminobenzamide derivative and application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aminobenzamide derivative that activates the proteikinase C. SOLUTION: The compound and its salt which is permitted in pharamaceutical study are shown by formula I. [In the formula, R1 shows an alkyl group or alkenyl group which can be substituted by hydroxy, R2 shows a carbonyl group or formula (II): -SO2R4 which can be substituted by an alkyl group or alkenly group. (In formula (II), R4 shows a substitutable alkyl group, or alkenyl group, or aromatic hydrocarbon which can be substituted by nitro or amino, or a thiazolyl group having a substituent) R3 shows a hydroxylmethyl group or carboxyl group which can be substituted by hydroxylamino group, or esterified.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an aminobenzamide derivative and a pharmaceutically acceptable salt thereof, and a medicament containing an aminobenzamide derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Protein kinase C (hereinafter referred to as PKC)
Abbreviated) was published in 1977 by Nishizuka et al. [J. Biol. Chem., 2
52, 7603 (1977)]
Ca ²⁺And phospholipid-dependent protein kinase
Important for intracellular signal transduction and cell proliferation
It is known to have a role. PKC is a cancer promotion
Has recently been considered as a PKC activator
Availability for Alzheimer's disease
[Shigebu Nakamura, History of Medicine, 145, 291 (1
998), F. Casamenti, C. Scali, and G. Pepeu,
Eur. J. Pharmacol., 194, 11 (1991)
A), L. Amaducci et al., Psychopharmacology Bulletin,
24, 130 (1998)].
Relationship between synaptic plasticity and channel modification [Yasu Nishizuka
Beauty, Chemistry and Industry, 44, 123 (1991)],
Stimulation of superoxide production from neutrophils [Gilbert
Et al., Biochemistry, 34, 3916 (1995).
Year)], antitumor activity [Yoshida et al., Int. J. Cancer, 7
7, 243 (1998)] and intraocular pressure lowering
[Nagata et al., Jpn. J. Ophthalmol., 37, 339
(1993), Mittag et al., Invest. Ophthalmol. Vi.
s. Sci., 28, 2057 (1987)]
Possibilities for various pharmaceutical applications are being reported
Was. However, the potential use of PKC activators in pharmaceutical applications is
It is still in the research and development stage. Therefore, for medical use
In order to develop a highly effective PKC activator, the present inventors
Diligent research was conducted.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a PK
An object of the present invention is to provide a novel aminobenzamide derivative having a C-activating action and a pharmaceutically acceptable salt thereof.

[0004]

Means for Solving the Problems The present inventors have found that a newly created aminobenzamide derivative has a PKC activating effect, and completed the present invention.

That is, the present invention relates to (1) a compound represented by the general formula (I)

[0006]

Embedded image [In the formula, R ¹ represents an alkyl group or an alkenyl group which may be substituted with a hydroxyl group, and R ² represents a carbonyl group substituted with an alkyl group or an alkenyl group or a compound represented by the formula (II)

[0007]

Embedded image (In the formula, R ⁴ represents an alkyl group which may be substituted, or an alkenyl group, an aromatic hydrocarbon group which may be substituted with a nitro group or an amino group, or a thiazolyl group having a substituent.) R ³ represents a hydroxymethyl group or a carboxyl group which may be substituted or esterified with a hydroxyamino group.] Or a pharmaceutically acceptable salt thereof, 2) a medicament comprising the compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient; and (3) a compound of the above (1) or a pharmaceutically acceptable salt thereof. The present invention relates to a PKC activator comprising a salt as an active ingredient, and (4) the medicament according to the above (2), which is an intraocular pressure reducing agent.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I), R ¹
The alkyl group which may be substituted with a hydroxyl group represented by is usually a group having 1 to 20 carbon atoms, preferably a group having 3 to 3 carbon atoms.
18 represents a linear or branched alkyl group, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-
Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
Examples include a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group and an icosyl group. Preferably, they are an isopropyl group, an n-butyl group, and an octadecyl group.

The hydroxyl group substituted by the alkyl group may be bonded to any carbon of the above alkyl group.
It is preferable that two hydroxyl groups be bonded to carbons adjacent to the alkyl group, for example, a 2,3-dihydroxybutyl group, a 2,3-dihydroxypentyl group, a 3,4-dihydroxypentyl group, a 2,3-dihydroxyhexenyl group A 3,4-dihydroxyhexenyl group, a 4,5-dihydroxyhexenyl group, a 2,3-dihydroxyheptyl group, a 3,4-dihydroxyheptyl group, a 4,5-dihydroxyheptyl group, a 5,6-dihydroxyheptyl group,
2,3-dihydroxyoctyl group, 3,4-dihydroxyoctyl group, 4,5-dihydroxyoctyl group, 5,
6-dihydroxyoctyl group, 6,7-dihydroxyoctyl group, 2,3-dihydroxynonyl group, 3,4-dihydroxynonyl group, 4,5-dihydroxynonyl group,
5,6-dihydroxynonyl group, 6,7-dihydroxynonyl group, 7,8-dihydroxynonyl group, 2,3-dihydroxydecyl group, 3,4-dihydroxydecyl group,
4,5-dihydroxydecyl group, 5,6-dihydroxydecyl group, 6,7-dihydroxydecyl group, 7,8-dihydroxydecyl group, 8,9-dihydroxydecyl group,
2,3-dihydroxyundecyl group, 3,4-dihydroxyundecyl group, 4,5-dihydroxyundecyl group, 5,6-dihydroxyundecyl group, 6,7-dihydroxyundecyl group, 7,8-dihydroxy Undecyl group, 8,9-dihydroxyundecyl group, 9,10-
Dihydroxyundecyl group, 2,3-dihydroxydodecyl group, 3,4-dihydroxydodecyl group, 4,5-dihydroxydodecyl group, 5,6-dihydroxydodecyl group, 6,7-dihydroxydodecyl group, 7,8-dihydroxy Dodecyl group, 8,9-dihydroxydodecyl group,
9,10-dihydroxydodecyl group, 10,11-dihydroxydodecyl group, 2,3-dihydroxytridecyl group, 3,4-dihydroxytridecyl group, 4,5-dihydroxytridecyl group, 5,6-dihydroxytridecyl Group, 6,7-dihydroxytridecyl group, 7,8-dihydroxytridecyl group, 8,9-dihydroxytridecyl group, 9,10-dihydroxytridecyl group, 10,
11-dihydroxytridecyl group, 11,12-dihydroxytridecyl group, 2,3-dihydroxytetradecyl group, 3,4-dihydroxytetradecyl group, 4,5-
Dihydroxytetradecyl group, 5,6-dihydroxytetradecyl group, 6,7-dihydroxytetradecyl group,
7,8-dihydroxytetradecyl group, 8,9-dihydroxytetradecyl group, 9,10-dihydroxytetradecyl group, 10,11-dihydroxytetradecyl group,
11,12-dihydroxytetradecyl group, 12,13
-Dihydroxytetradecyl group, 2,3-dihydroxypentadecyl group, 3,4-dihydroxypentadecyl group, 4,5-dihydroxypentadecyl group, 5,6-dihydroxypentadecyl group, 6,7-dihydroxypentadecyl group A 7,8-dihydroxypentadecyl group,
8,9-dihydroxypentadecyl group, 9,10-dihydroxypentadecyl group, 10,11-dihydroxypentadecyl group, 11,12-dihydroxypentadecyl group, 12,13-dihydroxypentadecyl group, 13,
14-dihydroxypentadecyl group, 2,3-dihydroxyhexadecyl group, 3,4-dihydroxyhexadecyl group, 4,5-dihydroxyhexadecyl group, 5,6-
Dihydroxyhexadecyl group, 6,7-dihydroxyhexadecyl group, 7,8-dihydroxyhexadecyl group,
8,9-dihydroxyhexadecyl group, 9,10-dihydroxyhexadecyl group, 10,11-dihydroxyhexadecyl group, 11,12-dihydroxyhexadecyl group, 12,13-dihydroxyhexadecyl group, 13,
14-dihydroxyhexadecyl group, 14,15-dihydroxyhexadecyl group, 2,3-dihydroxyheptadecyl group, 3,4-dihydroxyheptadecyl group, 4,
5-dihydroxyheptadecyl group, 5,6-dihydroxyheptadecyl group, 6,7-dihydroxyheptadecyl group, 7,8-dihydroxyheptadecyl group, 8,9-dihydroxyheptadecyl group, 9,10-dihydroxyheptadecyl Group, 10,11-dihydroxyheptadecyl group, 11,12-dihydroxyheptadecyl group, 12,
13-dihydroxyheptadecyl group, 13,14-dihydroxyheptadecyl group, 14,15-dihydroxyheptadecyl group, 15,16-dihydroxyheptadecyl group, 2,3-dihydroxyoctadecyl group, 3,4-dihydroxyoctadecyl group, 4,5-dihydroxyoctadecyl group, 5,6-dihydroxyoctadecyl group,
6,7-dihydroxyoctadecyl group, 7,8-dihydroxyoctadecyl group, 8,9-dihydroxyoctadecyl group, 9,10-dihydroxyoctadecyl group, 1
0,11-dihydroxyoctadecyl group, 11,12-
Dihydroxyoctadecyl group, 12,13-dihydroxyoctadecyl group, 13,14-dihydroxyoctadecyl group, 14,15-dihydroxyoctadecyl group, 1
5,16-dihydroxyoctadecyl group and 16,1
Examples thereof include a 7-dihydroxyoctadecyl group. Particularly, a 9,10-dihydroxyoctadecyl group is preferred.

The alkenyl group represented by R ¹ is preferably a linear alkenyl group having 16 to 20 carbon atoms, for example, 1-hexadecenyl group, 2-hexadecenyl group, 3-hexadecenyl group, 4-hexadecenyl group, 5-hexadecenyl group. Group, 6-hexadecenyl group, 7-hexadecenyl group, 8-hexadecenyl group, 9-hexadecenyl group, 1
0-hexadecenyl group, 11-hexadecenyl group, 12
-Hexadecenyl group, 13-hexadecenyl group, 14-
Hexadecenyl group, 15-hexadecenyl group, 1-heptadecenyl group, 2-heptadecenyl group, 3-heptadecenyl group, 4-heptadecenyl group, 5-heptadecenyl group, 6-heptadecenyl group, 7-heptadecenyl group, 8
Heptadecenyl group, 9-heptadecenyl group, 10-heptadecenyl group, 11-heptadecenyl group, 12-heptadecenyl group, 13-heptadecenyl group, 14-heptadecenyl group, 15-heptadecenyl group, 16-heptadecenyl group, 1-octadecenyl group, 2 -Octadecenyl group, 3-octadecenyl group, 4-octadecenyl group, 5
-Octadecenyl group, 6-octadecenyl group, 7-octadecenyl group, 8-octadecenyl group, 9-octadecenyl group, 10-octadecenyl group, 11-octadecenyl group, 12-octadecenyl group, 13-octadecenyl group, 14-octadecenyl group, 15 -Octadecenyl group, 16-octadecenyl group, 17-octadecenyl group, 1-nonadecenyl group, 2-nonadecenyl group, 3-nonadecenyl group, 4-nonadecenyl group, 5-nonadecenyl group, 6-nonadecenyl group, 7-nonadecenyl group, 8 -Nonadecenyl group, 9-nonadecenyl group, 10-nonadecenyl group, 11-nonadecenyl group, 12-nonadecenyl group,
13-nonadecenyl group, 14-nonadecenyl group, 15-
Nonadecenyl group, 16-nonadecenyl group, 17-nonadecenyl group, 18-nonadecenyl group, 1-icosenyl group,
2-icosenyl group, 3-icosenyl group, 4-icosenyl group, 5-icosenyl group, 6-icosenyl group, 7-icosenyl group, 8-icosenyl group, 9-icosenyl group, 10-
Icosenyl group, 11-icosenyl group, 12-icosenyl group, 13-icosenyl group, 14-icosenyl group, 15-
Examples include an icosenyl group, a 16-icosenyl group, a 17-icosenyl group, an 18-icosenyl group and a 19-icosenyl group. Particularly, a 9-octadecenyl group is preferable.

A carbonyl group substituted with an alkyl group represented by R ² (sometimes referred to as an alkylcarbonyl group)
Is preferably a linear or branched lower alkyl group having 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, and a
c-butyl group and tert-butyl group. Particularly, a methyl group is preferable.

The alkenyl group of the carbonyl group (also referred to as an alkenylcarbonyl group) substituted with an alkenyl group represented by R ² is preferably a straight-chain alkenyl group having 16 to 18 carbon atoms, for example, 1-hexadecenyl group, 2-hexadecenyl group, 3-hexadecenyl group, 4
-Hexadecenyl group, 5-hexadecenyl group, 6-hexadecenyl group, 7-hexadecenyl group, 8-hexadecenyl group, 9-hexadecenyl group, 10-hexadecenyl group, 11-hexadecenyl group, 12-hexadecenyl group, 13-hexadecenyl group, 14 -Hexadecenyl group, 15-hexadecenyl group, 1-heptadecenyl group,
2-heptadecenyl group, 3-heptadecenyl group, 4-heptadecenyl group, 5-heptadecenyl group, 6-heptadecenyl group, 7-heptadecenyl group, 8-heptadecenyl group, 9-heptadecenyl group, 10-heptadecenyl group,
11-heptadecenyl group, 12-heptadecenyl group, 1
3-heptadecenyl group, 14-heptadecenyl group, 15
-Heptadecenyl group, 16-heptadecenyl group, 1-octadecenyl group, 2-octadecenyl group, 3-octadecenyl group, 4-octadecenyl group, 5-octadecenyl group, 6-octadecenyl group, 7-octadecenyl group, 8
-Octadecenyl group, 9-octadecenyl group, 10-octadecenyl group, 11-octadecenyl group, 12-octadecenyl group, 13-octadecenyl group, 14-octadecenyl group, 15-octadecenyl group, 16-octadecenyl group, 17-octadecenyl group and the like. And a 9-octadecenyl group is particularly preferred.

The alkyl group represented by R ⁴ in the formula (II) represented by R ² is preferably a linear or branched lower alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group and a propyl group. , Isopropyl group, n-butyl group, se
Examples thereof include a c-butyl group and a tert-butyl group.

The alkyl group may be substituted by a phenyl group or a halogen group. The phenyl group may be substituted by a nitro group or an amino group. Examples of the substituted phenyl group include a benzyl group, a 2-nitrobenzyl group, a 3-nitrobenzyl group, a 4-nitrobenzyl group, -Aminobenzyl group, 3-aminobenzyl group and 4-aminobenzyl group. Particularly, a benzyl group, a 2-nitrobenzyl group and a 2-aminobenzyl group are preferred. Halogen groups include chlorine, bromine,
Fluorine and the like. The halogen group may be bonded to any carbon of the alkyl group, for example, a chloromethyl group,
Dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 1,2-dichloroethyl group, 1-chloropropyl group, 2-chloropropyl group, 3-chloropropyl group,
Examples include a bromomethyl group, a 1-bromoethyl group, a 2-bromoethyl group, a 1,2-dibromoethyl group, a 1-bromopropyl group, a 2-bromopropyl group, and a 3-bromopropyl group. Particularly, a 1-chloropropyl group and a 1,2-dibromoethyl group are preferable.

The alkenyl group represented by R ⁴ includes a linear or branched lower alkenyl group having 2 to 4 carbon atoms, such as a vinyl group, a 1-propenyl group, a 2-propenyl group and a 1-butenyl group. 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group and 2-methyl-
A 2-propenyl group is preferred, and a vinyl group is particularly preferred.

As the aromatic hydrocarbon represented by R ⁴ ,
Examples include a phenyl group and a naphthyl group. The nitro group or amino group which may be substituted by the aromatic hydrocarbon may be bonded to any carbon of the aromatic hydrocarbon, and the amino group may be substituted by a methyl group. For example, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitronaphthyl, 3-nitronaphthyl, 4 -Nitronaphthyl group, 5
-Nitronaphthyl group, 6-nitronaphthyl group, 7-nitronaphthyl group, 8-nitronaphthyl group, 2-aminonaphthyl group, 3-aminonaphthyl group, 4-aminonaphthyl group, 5-aminonaphthyl group, 6-amino Naphthyl group, 7
-Aminonaphthyl group, 8-aminonaphthyl group, 2-N,
N-dimethylaminophenyl group, 3-N, N-dimethylaminophenyl group, 4-N, N-dimethylaminophenyl group, 2-N, N-dimethylaminonaphthyl group, 3-
N, N-dimethylaminonaphthyl group, 4-N, N-dimethylaminonaphthyl group, 5-N, N-dimethylaminonaphthyl group, 6-N, N-dimethylaminonaphthyl group, 7
-N, N-dimethylaminonaphthyl group and 8-N, N
-Dimethylaminonaphthyl group and the like. Especially, 2-nitrophenyl group, 3-nitrophenyl group, 4-
Nitrophenyl group, 2-aminophenyl group, 3-aminophenyl group, 4-aminophenyl group and 5-N, N-
A dimethylaminonaphthyl group is preferred.

The substituent of the thiazolyl group represented by R ⁴ is bonded to the 2-position and / or 4-position of the thiazolyl group, and the substituent bonded to the 2-position is a lower acyl group having 1 to 4 carbon atoms (eg, acetyl). Group, propionyl group, butyryl group, isobutyryl group, etc.), and the substituent bonded to the 4-position is a linear or branched lower alkyl group having 1 to 4 carbon atoms (for example, methyl group , Ethyl group,
Propyl group, isopropyl group, n-butyl group, sec-
Butyl, tert-butyl and the like). As the thiazolyl group having a substituent, for example, a 2-acetamido-4-methyl-5-thiazolyl group can be suitably used.

R ³ is a group having a hydroxyl group at a terminal,
For example, a hydroxymethyl group and a carboxyl group can be suitably used. The carboxyl group may be substituted with a hydroxyamino group, and is esterified with a lower alkyl group having 1 to 3 carbon atoms (for example, a methyl group, an ethyl group, a propyl group and an isopropyl group, particularly preferably a methyl group). May be.

As R ¹ , R ² and R ³ , those described above can be appropriately combined. When R ² is the above-mentioned alkylcarbonyl group, R ¹ is preferably an alkyl group substituted with the above-mentioned hydroxyl group or a combination of the above-mentioned alkenyl group, and when R ² is the above-mentioned alkenylcarbonyl group, R ¹ is the above-mentioned Combinations of alkyl groups are preferred. In particular, the alkyl group or alkenyl group substituted for the carbonyl group of R ² has a short chain (having 1 to 3 carbon atoms,
The same applies hereinafter) and the above-mentioned optionally substituted alkyl group and the above-mentioned alkenyl group represented by R ¹ are substituted by a combination of long chains (having 16 to 18 carbon atoms, the same applies hereinafter) or the carbonyl group of R ² It is preferable that the above-mentioned alkyl group or the above-mentioned alkenyl group has a long chain, and the above-mentioned optionally substituted alkyl group or alkenyl group represented by R ¹ has a short chain. When R ² is the above-mentioned formula (II), R ¹ can be preferably combined with any of the above-mentioned groups, but, above all, R ¹ may be an alkyl group optionally substituted with the above-mentioned long-chain hydroxyl group or Combinations of the above long-chain alkenyl groups are preferred. R ³ can be suitably combined with any of the combinations of R 1 and R 2 described above.

The compounds of the present invention include, for example, the compounds in the following table.

[Table 1]

The compound represented by the general formula (I) of the present invention can be appropriately synthesized, for example, by the following synthetic route or according to the synthetic route.

[0022]

Embedded image

[Wherein R ^{1 ′} represents an alkyl group or an alkenyl group, and R ^{2 ′} represents a carbonyl group substituted with an alkyl group or an alkenyl group or a compound represented by the formula (II ′)

Embedded image (In the formula, R ^{4 ′} represents an alkyl group which may be substituted, an alkenyl group, an aromatic hydrocarbon group which may be substituted with a nitro group, or a thiazolyl group having a substituent.) Formula (III) )

[0024]

Embedded image

[In the formula (III), R ^{1 ′} is as defined above. Can be synthesized by condensing 1-methyl-2-terephthalic acid ester and alkylamine or alkenylamine in an organic solvent with a condensing agent. Examples of the condensing agent that can be used in this reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, -Cyclohexyl-N '-(4-
Diethylaminocyclohexyl) carbodiimide, N,
N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, N, N'-carbonylbis (2-methylimidazole), pentamethyleneketene-N- Cyclohexylimine, diphenylketene-N
Conventional condensing agents such as cyclohexylimine and the like. Condensation is carried out using an inorganic base such as an alkali metal bicarbonate, or tri (lower) alkylamine, pyridine,
It may be carried out in the presence of an organic base such as N- (lower) alkylmorpholine and 1-hydroxybenzyltriazole. A combination of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzyltriazole is preferred. Examples of the organic solvent include a conventional solvent such as methylene chloride, chloroform, N, N-dimethylformamide, and tetrahydrofuran, or a mixed solvent thereof. Preferred is a mixed solvent of methylene chloride and N, N-dimethylformamide. The reaction temperature is generally in a range from cooling to heating, and preferably in a range of 0 ° C to 30 ° C. Next, the compound represented by the formula (III) is reacted with an acyl halide or a sulfonyl halide in the presence of an organic base, and purified by recrystallization or column chromatography to obtain a compound represented by the formula (IV).

[0026]

Embedded image

[In the formula (IV), R ^{1 ′} and R ^{2 ′} are as defined above. ] Can be obtained.
The acyl group of the acyl halide used in this reaction is R ^{2 ′}
Has the same meaning as the carbonyl group substituted with an alkyl group or an alkenyl group, and the sulfonyl group of the sulfonyl halide has the same meaning as that of the formula (II ′) represented by R ^{2 ′} . Any halide (eg, fluoride, chloride, bromide, iodide, etc.) in which a halogen atom is bonded to an acyl group or a sulfonyl group can be used, but chloride and bromide are preferred. The organic base is triethylamine,
Tri (lower) alkylamines (such as diisopropylethylamine), pyridine, lutidine, picoline and 4-
Dimethylaminopyridine and the like can be used. The organic base is preferably triethylamine or pyridine in an amount equivalent to twice that of the acyl halide or the sulfonyl halide. The reaction is usually carried out, for example, with anhydrous dichloromethane, chloroform,
The reaction can be carried out in a conventional solvent such as N, N-dimethylformamide or tetrahydrofuran which does not adversely affect the reaction, or a mixed solvent thereof, but is preferably used in anhydrous tetrahydrofuran or dichloromethane. The reaction temperature is generally in a range from cooling to heating, and preferably in a range of 0 ° C to 30 ° C.

Next, the compound represented by the formula (IV) is reduced by reducing the alkoxycarbonyl group of the compound represented by the formula (IV) with a reducing agent and purifying the compound by recrystallization or column chromatography.

[0029]

Embedded image

[In the formula (V), R ^{1 ′} and R ^{2 ′} are as defined above. Is obtained. As the reducing agent at this time, lithium aluminum hydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and tris ( Sodium methoxy) boron can be used, but lithium borohydride is preferred. The reaction can be carried out in a conventional solvent such as methanol, ethanol, propanol, isopropanol, butanol, dichloromethane, chloroform, dimethoxybenzene, benzene, toluene, ethylbenzene, diethyl ether, dioxane or tetrahydrofuran which does not adversely influence the reaction. And tetrahydrofuran. The reaction temperature is usually in a range from cooling to heating.
Preferably it is in the range of 0 ° C to 30 ° C.

By hydrolyzing the alkoxycarbonyl group of the compound represented by the formula (IV) with an alkali or an acid, the compound of the formula (VI)

[0032]

Embedded image

[In the formula (VI), R ^{1 ′} and R ^{2 ′} are as defined above. Is obtained. Alkaline hydrolysis uses an aqueous alkali solution such as an aqueous sodium hydroxide and potassium hydroxide solution. In order to increase the solubility of the compound represented by the formula (IV), methanol, ethanol, propanol, isopropanol, butanol, A solution to which dioxane, tetrahydrofuran or the like is added can also be suitably used. The alkaline hydrolyzate is then treated with a mineral acid such as hydrochloric acid and sulfuric acid to give the free carboxylic acid. The reaction temperature is usually in a range from cooling to heating, and preferably in a range from 20 ° C to 50 ° C. As the conditions for acid hydrolysis, inorganic acids such as hydrochloric acid and sulfuric acid are generally used, but Lewis acids such as boron trichloride can also be used. The reaction is preferably performed in an acetic acid or formic acid solution. The reaction temperature is usually in the range from room temperature to under heating, and preferably in the range of 30C to 100C.

The compound represented by the formula (VII) is reacted with hydroxyamine in the presence of an organic base and purified by recrystallization to obtain the compound represented by the formula (VII).

[0035]

Embedded image

[In the formula (VII), R ^{1 ′} and R ^{2 ′} are as defined above. ] Can be obtained. Examples of the reactive derivative of the compound represented by the formula (VI) include an acid halide of a carboxyl group, for example, an acid chloride. The acid chloride can be made to act on the corresponding carboxylic acid by a chlorinating agent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride and oxalyl chloride.
As the organic base in this reaction, trialkylamines such as triethylamine and diisopropylethylamine, pyridine, lutidine, picoline, 4-dimethylaminopyridine and the like can be used, and triethylamine is preferable. The reaction can be carried out in acetone, tetrahydrofuran, water, dioxane or the like, or in a mixed solvent thereof, but is preferably in a mixed solvent of tetrahydrofuran and water. The reaction temperature is generally in a range from cooling to heating, and preferably in a range of 0 ° C to 30 ° C.

The alkyl group represented by the general formula (I) in which R ¹ is substituted with a hydroxyl group is prepared by first synthesizing a compound represented by the formula (V) or (VII) wherein R ^{1 ′} is an alkenyl group. It can be obtained by oxidizing the olefin bond of the alkenyl group with an oxidizing agent. As oxidizing agents, silver acetate-iodine and organic peracids (such as peracetic acid, formic acid and pertrifluoroacetic acid) can be used. Organic peracids are usually prepared by adding 30% aqueous hydrogen peroxide to organic acids (such as acetic acid, formic acid and trifluoroacetic acid). Preferred is an organic peracid prepared by adding 30% aqueous hydrogen peroxide to formic acid. The reaction temperature is usually in a range from cooling to heating, and preferably in a range from 25 ° C to 45 ° C.

In R ^{2 represented} by the general formula (I), the compound represented by the formula (I)
The aromatic hydrocarbon in which R ⁴ represented by I) is substituted with an amino group is first represented by the R represented by the formulas (V) to (VII).
It can be obtained by synthesizing a compound in which ^{4 ′} is substituted with a nitro group, and then reducing the nitro group. For the reduction, a known method such as catalytic reduction or reduction with zinc-acetic acid, iron-acetic acid and stannic chloride can be used, but catalytic reduction or stannic chloride is preferred. Examples of the catalyst for the catalytic reduction include palladium-carbon, Raney-nickel and platinum oxide, but palladium-carbon is preferred. The hydrogen pressure is from 1 to 50 atm, preferably from 1 to 5 atm. As the solvent, alcohols (such as methanol and ethanol), ethers (such as tetrahydrofuran), organic acids (such as acetic acid), and a mixed solvent thereof can be used. The reaction temperature is usually in the range from room temperature to heating. Reduction with stannic chloride is usually
In an ethanol solvent, the reaction temperature is preferably in the range of room temperature to reflux temperature.

The pharmaceutically acceptable salts of the compound represented by the general formula (I) thus obtained include, for example, alkali metal salts such as sodium salt and potassium salt, and alkali salts such as calcium salt and magnesium salt. These include inorganic acid salts such as earth metal salts, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates, and organic acid salts such as acetates, citrates, and toluenesulfonates. It is not limited to.

The present invention further includes various solvates and polymorphs of the compound represented by the general formula (I) and a pharmaceutically acceptable salt, and prodrugs thereof.
For example, in the compound of the present invention having a carboxyl group in which R ^{3 of the} compound represented by the general formula (I) is esterified, the ester site is hydrolyzed by a living body esterase to form free carboxy, and PKC activity is exerted or stronger. Since it exhibits PKC activity, it can be regarded as the prodrug of the present invention.

Since the compound of the present invention represented by the general formula (I) and a pharmaceutically acceptable salt thereof have a PKC activating effect, they can be used in warm-blooded animals (eg, human, rabbit, guinea pig, rat, dog, cat). And the like, such as ocular hypertension, glaucoma, central nervous system disorders, senile dementia, Alzheimer's disease, tumors, etc., and immunostimulants by superoxide from neutrophils, etc. Can be used orally or parenterally as appropriate.

The compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof may be in the form of a solid preparation such as a tablet, granule, powder, capsule, ointment and injection. And liquid preparations such as eye drops and eye drops. Any of the preparations can be appropriately prepared by a known method. These preparations include commonly used excipients (starch, glucose, fructose, sucrose, calcium phosphate, etc.), binders (starch, gum arabic, gelatin solution, sodium alginate, carmellose solution, etc.), disintegrants (starch, calcium carbonate, etc.). , Crystalline cellulose, etc.), lubricants (stearic acid, magnesium stearate, talc, etc.), absorption enhancers (thioglycolic acid, capric acid,
Caprylic acid, etc.), buffers (boric acid, borax, sodium acetate, citrate buffer, phosphate buffer, etc.), surfactants (sodium lauryl sulfate, polysorbate 80,
Polyoxyethylene hydrogenated castor oil, etc.), dissolution aids (sodium lauryl sulfate, sodium benzoate, ethylenediamine, potassium iodide, etc.), preservatives (benzalkonium chloride, parabens, chlorobutanol, etc.), emulsifiers (gum arabic, Tragacanth, gelatin,
Tonics such as polyvinylpyrrolidone, etc. (sodium chloride, glycerin, mannitol, etc.), stabilizers (sodium edetate, sodium pyrosulfite, etc.), pH adjusters (hydrochloric acid, citric acid, sodium hydroxide, etc.) are used as appropriate. May be.

When the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a prophylactic / therapeutic agent for Alzheimer's disease, the dose is determined by the type of the disease to be treated, Although it depends on the type of compound used, the age, weight, and condition of the patient, and its dosage form, for example, in the case of oral administration, it is preferable that the dose is about 1 to 100 mg once a day for an adult several times a day. In the case of an injection, for an adult, it is preferable to administer about 0.1 to 30 mg once a day. Further, when used as a topical ophthalmic dosage form for glaucoma diseases, the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof may be used in an amount of about 0.04%.
1 w / v% to 1.0 w / v%, preferably about 0.05 w
It is preferable to instill 1 to several drops of eye drops containing / w% to 0.5 w / v% at a time, about 1 to 6 times a day.

The compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof may be used, if necessary, in combination with one or more of the compounds of the present invention. You can also.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used in combination with other pharmaceutically active ingredients, as long as the object of the present invention is not adversely affected.

[0046]

The present invention will be described in more detail with reference to the following production examples, examples and test examples, but the present invention is not limited thereto. In the physical properties of the compounds described in Production Examples and Examples, the nuclear magnetic resonance spectrum was measured using a Varian Gemini 2000 with proton ( ¹ H-
NMR) was measured at 300 MHz, carbon ( ¹³ C-NMR) was measured at 75 MHz, elemental analysis was measured using a Perkin Elmer CHNS / 02400, mass spectrum was measured using a JEOL JMS-AX505W, and melting point was measured using a Yanaco trace melting point MP 500V. It was done.

Production Example 1 Methyl 2-amino-4- (cis-9-octadecenylcarbamoyl) benzoate 1-methyl-2-aminoterephthalate (1.0
g, 5.124 mmol) and cis-9-octadecenylamine (3.289 g, 12.297 mmol) with N,
In an N-dimethylformamide (2 mL) solution under ice-cooling,
N-ethyl-N ′-(3
-Dimethylaminopropyl) carbodiimide (1.17
A solution in which 9 g, 6.148 mmol) and 1-hydroxybenzotriazole (0.831 g, 6.148 mmol) were dissolved was added dropwise, and the mixture was stirred as it was for 30 minutes, and further stirred at room temperature for 24 hours. Water (20 m
L), extracted with ethyl acetate (100 mL),
The organic phase was washed with a 1N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in that order, and dried over anhydrous sodium sulfate. After removing the inorganic salt by filtration, the solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane (10 mL) to give 2-amino-4- (cis-9-octadecenylcarbamoyl) benzoic acid as a colorless solid. Methyl ester (2.04 g, 9
0%). ¹ H-NMR (DMSO-d ₆ ): δ 0.80-0.82 (3H, m), 1.20-1.21
(22H, m), 1.46-1.52 (2H, m), 1.90-1.96 (4H, m), 3.1
4-3.20 (2H, m), 3.77 (3H, s), 5.24-5.33 (2H, m),
6.75 (2H, br s), 6.90 (1H, dd, J = 8.4, 1.5 Hz),
7.20 (1H, d, J = 1.5 Hz), 7.70 (1H, d, J = 8.4 Hz),
. 8.45 (1H, t, J = 5.4 Hz) 13 C-NMR (DMSO-d 6): δ 13.9, 22.1, 26.5, 26.6 (2C),
28.5, 28.6, 28.7, 28.8, 28.9, 29.0 (2C), 29.1, 3
1.3, 31.9, 33.5, 51.5, 110.2, 112.8, 115.8, 129.6,
130.0, 130.6, 139.9, 151.0, 165.8, 167.4.

Preparation Example 2 2-Amino-4-octadecanylcarbamoylbenzoic acid methyl ester The same operation as in Preparation Example 1 was carried out except that octadecanylamine was used instead of cis-9-octadecenylamine in Preparation Example 1. Thereby, colorless solid 2-amino-4-octadecanylcarbamoylbenzoic acid methyl ester was obtained. 96% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.81-0.85 (3H, m), 1.20-1.21
(30H, m), 1.44-1.56 (2H, m), 3.14-3.21 (2H, m), 3.7
8 (3H, s), 6.75 (2H, m), 6.89 (1H, dd, J = 8.4, 1.5
Hz), 7.19 (1H, d, J = 1.5 Hz), 7.70 (1H, d, J =
8.4 Hz), 8.43 (1H, m).

Preparation Example 3 2-Amino-4-isopropylcarbamoylbenzoic acid methyl ester Solid 2-amino-4-isopropylcarbamoylbenzoic acid methyl ester was obtained. Yield 88
%. ¹ H-NMR (DMSO-d ₆ ): δ 1.12 (6H, d, J = 6.6 Hz), 3.7
8 (3H, s), 4.04 (1H, m), 6.74 (2H, br s), 6.89 (1H,
dd, J = 8.4, 1.5 Hz), 7.18 (1H, d, J = 1.5 Hz),
7.71 (1H, d, J = 8.4 Hz), 8.19 (1H, d, J = 7.8 H
z). ¹³ C-NMR (DMSO-d ₆ ): δ 22.2 (2C), 40.9, 51.5, 110.
1, 113.0, 115.9, 130.5, 140.1, 151.0, 165.2, 167.
Four.

Production Example 4 2-Amino-4-butylcarbamoylbenzoic acid methyl ester A colorless solid was obtained by operating in the same manner as in Production Example 1 using butylamine instead of cis-9-octadecenylamine in Production Example 1. To give 2-amino-4-butylcarbamoylbenzoic acid methyl ester. 86% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.87 (3H, t, J = 7.2 Hz), 1.2
5-1.32 (2H, m), 1.44-1.49 (2H, m), 3.16-3.23 (2H,
m), 3.78 (3H, s), 6.75 (2H, br s), 6.88 (1H, dd, J
= 8.4, 1.5 Hz), 7.19 (1H, d, J = 1.5 Hz), 7.71 (1
. H, d, J = 8.4Hz ), 8.38 (1H, m) 13 C-NMR (DMSO-d 6): δ 13.7, 19.6, 31.1, 51.5, 110.
2, 112.9, 115.8, 130.6, 140.0, 151.0, 165.9, 167.
Four.

Example 1 Methyl 2-methylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoate 2-amino-4- (cis-9-octadecenylcarbamoyl) synthesized in Production Example 1 Methylsulfonyl chloride (1.546 g, 13.494 mm) was added to a solution of benzoic acid methyl ester (3.0 g, 6.747 mmol) and triethylamine (6.827 g, 67.471 mmol) in anhydrous tetrahedrofuran (20 mL) under ice-cooling.
ol) was added dropwise and stirred at room temperature overnight. Water (1
After adding 0 mL), the mixture was extracted with ethyl acetate (100 mL), and the organic phase was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution in that order, and then dried over anhydrous sodium sulfate. After removing the inorganic salt by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: a mixed solvent of ethyl acetate and hexane, v / v = 1: 3) to give a colorless solid. 2-methylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (0.998 g, 28%;
Compound 62) was obtained. Melting point: 149.0-150.9
° C. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.25 (22H,
m), 1.49 (2H, m), 1.94 (4H, m), 3.17 (3H, s), 3.1
9-3.24 (2H, m), 3.88 (3H, s), 5.28-5.31 (2H, m),
7.59 (1H, dd, J = 8.1, 1.5 Hz), 7.93 (1H, d, J =
1.5 Hz), 7.99 (1H, d, J = 8.1 Hz), 8.65 (1H, m), 1
0.06 (1H, s). ¹³ C-NMR (DMSO-d ₆ ): δ 13.9, 22.1, 26.4, 26.5, 26.
6, 28.4, 28.6, 28.7,28.8, 28.9 (3C), 29.0, 29.1, 2
9.2, 31.3, 31.9, 52.8, 118.4, 119.4, 121.6, 129.6,
. 130.0, 131.1, 139.3, 140.1, 164.8, 167.1 Elemental analysis _{(C 28 H 46 N 2 O} 5 S) theory: C, 64.34;
H, 8.87; N, 5.36, found: C, 64.07; H, 9.00;
N, 5.49.

Example 2 Methyl 2-acetylamino-4- (cis-9-octadecenylcarbamoyl) benzoate The same operation as in Example 1 was carried out except that acetyl chloride was used instead of methylsulfonyl chloride in Example 1. Thereby, methyl 2-acetylamino-4- (cis-9-octadecenylcarbamoyl) benzoate (compound 63) was obtained as a colorless solid. Yield 30%. ¹ H-NMR (DMSO-d ₆ ): δ 0.80-0.84 (3H, m), 1.21-1.25
(22H, m), 1.46-1.52 (2H, m), 1.89-1.96 (4H, m), 2.1
0 (3H, s), 3.18-3.25 (2H, m), 3.84 (3H, s), 5.28-
5.33 (2H, m), 7.56 (1H, dd, J = 8.4, 1.5 Hz), 7.89
(1H, d, J = 8.4 Hz), 8.47 (1H, d, J = 1.5 Hz), 8.
56 (1H, t, J = 5.1 Hz), 10.46 (1H, s) 13 C-NMR (DMSO-d 6):. Δ 13.9, 22.1, 24.3, 26.4, 26.5,
26.6, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9 (2C), 2
9.0, 29.1, 31.2, 31.9, 52.4, 120.8, 121.5,129.6 (2
C), 130.0, 130.2, 139.0, 139.3, 165.1, 167.0, 168.
Four.

Example 3 2-Ethylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester As in Example 1, methylsulfonyl chloride was used instead of methylsulfonyl chloride in Example 1. By operation, colorless solid 2-ethylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (Compound 64) was obtained. Melting point: 74.9-77.0C. Yield 7%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.18 (1H, t, J
= 7.5 Hz), 1.21-1.25 (22H, m), 1.49 (2H, m), 1.90-
1.97 (4H, m), 3.18-3.26 (2H, m), 3.29 (2H, m), 3.89
(3H, s), 5.30-5.36 (2H, m), 7.58 (1H, dd, J = 8.
1, 1.5 Hz), 7.95 (1H, d, J = 1.5 Hz), 8.00 (1H, d,
. J = 8.1 Hz), 8.65 (1H, m), 10.12 (1H, br s) 13 C-NMR (DMSO-d 6): δ 7.80, 13.8, 22.0, 26.3, 26.
4, 28.5, 28.5, 28.6, 28.7, 28.8 (4C), 28.9, 29.0, 3
1.2, 31.8, 46.1, 52.8, 118.0, 118.7, 121.3, 129.5,
. 130.0, 131.1, 139.4, 140.1, 164.7, 167.2 Elemental analysis _{(C 29 H 48 N 2 O} 5 S) theory: C, 64.89;
H, 9.01; N, 5.22, found: C, 65.00; H, 9.09;
N, 5.32.

Example 4 4- (cis-9-octadecenylcarbamoyl) -2-
Vinylsulfonylaminobenzoic acid methyl ester Instead of methylsulfonyl chloride of Example 1, 2
By using -chloroethylsulfonyl chloride and operating in the same manner as in Example 1, colorless solid 4- (cis-9-octadecenylcarbamoyl) -2-vinylsulfonylaminobenzoic acid methyl ester (compound 65)
I got Melting point: 93.9-97.5C. Yield 21%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.22-1.25 (22H,
m), 1.49 (2H, m), 1.90-1.97 (4H, m), 3.18-3.28 (2
H, m), 3.82 (3H, s), 5.30-5.38 (2H, m), 6.20 (1H,
d, J = 16.5 Hz), 6.37 (1H, d, J = 9.9 Hz), 7.16 (1
H, dd, J = 16.5, 9.9 Hz), 7.81 (1H, d, J = 1.5 H
z), 8.00 (1H, d, J = 8.1 Hz), 8.08 (1H, dd, J = 8.
1, 1.5 Hz), 8.77 (1H, t, J = 5.4 Hz), 10.18 (1H,
^{. s) 13 C-NMR (} DMSO-d 6): δ 13.4, 21.6, 25.9, 26.0, 27.
9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5 (3C), 28.6, 3
0.8, 31.4, 52.3, 118.6, 119.6, 121.3, 128.5, 129.
1, 129.6, 130.5, 135.3, 138.1, 139.2, 164.1, 166.
6. Elemental analysis _{(C 29 H 46 N 2 O} 5 S · 0.2 H 2 O) theory: C, 6
4.70; H, 8.68; N, 5.20, found: C, 64.32;
8.54; N, 5.23.

Example 5 2-isopropylsulfonylamino-4- (cis-9
-Octadecenylcarbamoyl) benzoic acid methyl ester By using isopropylsulfonyl chloride in place of methylsulfonyl chloride in Example 1 and operating in the same manner as in Example 1, 2-isopropylsulfonylamino-4- (cis) as a colorless solid was obtained. -9-octadecenylcarbamoyl) benzoic acid methyl ester (compound 6
6) was obtained. Yield 2%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.16 (1H, d, J
= 6.9 Hz), 1.20-1.24 (22H, m), 1.50 (2H, m), 1.90-
1.97 (4H, m), 3.15-3.29 (3H, m), 3.89 (3H, s), 5.29
(2H, m), 7.49 (1H, dd, J = 8.4, 1.5 Hz), 7.83 (1
H, d, J = 1.5 Hz), 8.01 (1H, d, J = 8.4 Hz), 8.70
. (1H, m), 9.92 (1H, s) 13 C-NMR (DMSO-d 6): δ 13.8, 13.9, 20.6, 21.9, 25.
8, 25.9, 26.3, 26.4, 28.3, 28.4, 28.5, 28.6, 28.7,
28.8, 28.9, 29.0, 31.1, 31.8, 52.6, 59.6,115.0, 11
6.0, 119.7, 129.4, 129.9, 131.3, 140.2, 144.3, 16
4.4, 167.3.

Example 6 2- (3-chloropropylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid methyl ester In place of methylsulfonyl chloride in Example 1, 3
Using 2-chloropropylsulfonyl chloride as in Example 1, 2- (3
-Chloropropylsulfonylamino) -4- (cis-
9-octadecenylcarbamoyl) benzoic acid methyl ester (compound 67) was obtained. Yield 84%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.25 (24H,
m), 1.50 (2H, m), 1.92-1.96 (2H, m), 2.16-2.25 (2
H, m), 3.23-3.27 (2H, m), 3.77 (2H, t, J = 6.3 Hz),
3.85 (3H, s), 3.86 (2H, t, J = 6.6 Hz), 5.28-5.33
(2H, m), 8.01 (1H, s), 8.02 (1H, d, J = 8.4 Hz),
8.09 (1H, d, J = 8.4 Hz), 8.77 (1H, d, J = 5.4 Hz) 13 C-NMR (DMSO-d 6):. Δ 13.8, 21.9, 25.7, 26.3, 26.
4, 26.5, 28.4, 28.5,28.6, 28.7, 28.8 (3C), 28.9, 2
9.0, 31.1, 31.8, 42.8, 52.5, 52.8, 129.0,129.5, 12
9.9, 131.2, 131.8, 131.9, 133.0, 138.1, 163.3, 16
4.8.

Example 7 2-Benzylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester As in Example 1, benzylsulfonyl chloride was used instead of methylsulfonyl chloride in Example 1. By operation, colorless solid 2-benzylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (Compound 68) was obtained. Yield 33%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22-1.26 (22H,
m), 1.52 (2H, m), 1.95 (4H, m), 3.21-3.26 (2H,
m), 3.81 (3H, s), 4.69 (2H, s), 5.30 (2H, m), 7.16
-7.39 (4H, m), 7.56-7.61 (2H, m), 7.98-8.00 (2H,
m), 8.63 (1H, m), 10.07 (1H, br s).

Example 8 2- (2-nitrobenzylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid methyl ester Instead of methylsulfonyl chloride of Example 1, 2
By using -nitrobenzylsulfonyl chloride and operating in the same manner as in Example 1, 2- (2
-Nitrobenzylsulfonylamino) -4- (cis-
9-octadecenylcarbamoyl) benzoic acid methyl ester (compound 69) was obtained. Yield 15%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.29 (24H,
m), 1.51 (2H, m), 1.94 (2H, m), 3.22-3.24 (2H,
m), 3.85 (3H, s), 5.13 (2H, s), 5.24-5.33 (2H, m),
7.47 (1H, d, J = 7.2 Hz), 7.58-7.66 (3H, m), 7.88
(1H, s), 7.96-8.00 (2H, m), 8.58 (1H, m), 10.20
(1H, s). ¹³ C-NMR (DMSO-d ₆ ): δ 13.9, 22.1, 26.4, 26.5, 26.
6, 28.4, 28.6, 28.7,28.8, 28.9, 29.0 (4C), 31.3, 3
1.9, 52.8, 54.0, 118.6, 119.4, 122.0, 122.9, 125.
3, 129.6, 130.1, 130.4, 131.0, 133.5, 134.4, 138.
7, 140.1, 149.2, 164.7, 167.1.

Example 9 4- (cis-9-octadecenylcarbamoyl) -2-
Phenylsulfonylaminobenzoic acid methyl ester By using phenylsulfonyl chloride in place of methylsulfonyl chloride in Example 1 and operating in the same manner as in Example 1, 4- (cis-9-octadecenylcarbamoyl)-as a colorless solid is obtained. 2-Phenylsulfonylaminobenzoic acid methyl ester (Compound 70) was obtained. Yield 81%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.24 (22H,
m), 1.46 (2H, m), 1.92-1.96 (4H, m), 3.14-3.21 (2
H, m), 3.78 (3H, s), 5.28-5.33 (2H, m), 7.53-7.65
(6H, m), 7.85 (1H, d, J = 8.1 Hz), 7.90 (1H, s),
8.61 (1H, m), 10.33 (1H, s).

Example 10 2- (2-nitrophenylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid methyl ester Instead of methylsulfonyl chloride of Example 1, 2
By using -nitrophenylsulfonyl chloride and operating in the same manner as in Example 1, 2- (2
-Nitrophenylsulfonylamino) -4- (cis-
9-octadecenylcarbamoyl) benzoic acid methyl ester (Compound 71) was obtained. Yield 71%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21 (22H, m),
1.47 (2H, m), 1.95 (4H, m), 3.17 (2H, m), 3.78 (3
H, s), 5.30 (2H, m), 7.51-7.55 (2H, m), 7.84-8.11
(5H, m), 8.65 (1H, m), 10.78 (1H, s).

Example 11 2- (3-nitrophenylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid methyl ester In place of methylsulfonyl chloride in Example 1, 3
By using -nitrophenylsulfonyl chloride and operating in the same manner as in Example 1, 2- (3
-Nitrophenylsulfonylamino) -4- (cis-
9-octadecenylcarbamoyl) benzoic acid methyl ester (Compound 72) was obtained. Yield 69%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.20 (22H, m),
1.46 (2H, m), 1.96 (4H, m), 3.19 (2H, m), 3.78 (3
H, s), 5.30 (2H, m), 8.01 (2H, m), 8.28-8.51 (5H,
m), 8.60 (1H, m).

Example 12 2- (4-nitrophenylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid methyl ester Instead of methylsulfonyl chloride of Example 1,
By using -nitrophenylsulfonyl chloride and operating in the same manner as in Example 1, 2- (4
-Nitrophenylsulfonylamino) -4- (cis-
9-octadecenylcarbamoyl) benzoic acid methyl ester (Compound 73) was obtained. Yield 71%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.20-1.24 (22H,
m), 1.47 (2H, m), 1.95 (4H, m), 3.18 (2H, m), 3.7
8 (3H, s), 5.29 (2H, m), 8.10-8.13 (2H, m), 8.22-
8.25 (2H, m), 8.46-8.50 (3H, m), 8.72 (1H, m).

Example 13 2- (1-Naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester Instead of methylsulfonyl chloride in Example 1, 1
By using -naphthylsulfonyl chloride and operating in the same manner as in Example 1, colorless solid 2- (1-naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (Compound 74) ) Got. Yield 81%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.20-1.24 (22H,
m), 1.46 (2H, m), 1.94 (4H, m), 3.18 (2H, m), 3.7
8 (3H, s), 5.29 (2H, m), 7.49-8.52 (10H, m), 8.56
(1H, m), 10.76 (1H, s).

Example 14 2- (5-Dimethylamino-1-naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester Instead of methylsulfonyl chloride of Example 1, 5
Using dimethylamino-1-naphthylsulfonyl chloride as in Example 1, a colorless solid 2- (5-dimethylamino-1-naphthylsulfonylamino) -4- (cis-9-octadecyl) was obtained. (Cenylcarbamoyl) benzoic acid methyl ester (Compound 75) was obtained. Yield 93%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21 (22H, m),
1.47 (2H, m), 1.95 (4H, m), 2.80-2.82 (6H, m), 3.1
7 (2H, m), 3.78 (3H, s), 5.30 (2H, m), 7.52-7.57
(3H, m), 7.95 (1H, m), 8.10-8.20 (3H, m), 8.45-8.4
7 (2H, m), 8.59 (1H, m), 10.78 (1H, s).

Example 15 Methyl 2- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoate Methyl ester of methylsulfonyl chloride of Example 1 2 instead
By using -acetamido-4-methyl-5-thiazolylsulfonyl chloride in the same manner as in Example 1, colorless solid 2- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) was obtained. 4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (Compound 76) was obtained. Yield 61%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.20 (22H, m),
1.46 (2H, m), 1.94 (4H, m), 2.13 (3H, s), 2.41 (3
H, s), 3.19 (2H, m), 3.78 (3H, s), 5.29 (2H, m),
7.89-7.95 (3H, m), 8.63 (1H, m), 10.43 (1H, s), 1
2.46 (1H, s).

Example 16 Methyl 4-isopropylcarbamoyl-2- (cis-9-octadecenoylamino) benzoate Methyl 2-amino-4-isopropylcarbamoylbenzoate synthesized in Production Example 3 and cis-9 By using -octadecenoyl chloride and operating in the same manner as in Example 1, colorless solid 4-isopropylcarbamoyl-2- (cis-9-octadecenoylamino) benzoic acid methyl ester (Compound 77) was obtained. Obtained. Yield 93%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.14 (6H, d, J
= 6.6 Hz), 1.21-1.27 (20H, m), 1.59 (2H, m), 1.92-
1.97 (2H, m), 3.57-3.60 (2H, m), 3.82 (3H, s), 4.03
(1H, m), 5.30-5.34 (2H, m), 7.56 (1H, d, J = 8.1
Hz), 7.89 (1H, d, J = 8.1 Hz), 8.36 (1H, d, J = 7.
5 Hz), 8.51 (1H, s), 10.49 (1H, s).

Example 17 Methyl 4-butylcarbamoyl-2- (cis-9-octadecenoylamino) benzoate Methyl 2-amino-4-butylcarbamoylbenzoate synthesized in Production Example 3 and cis-9 Using colorless solid 4-butylcarbamoyl-2- (cis-9-octadecenoylamino) benzoic acid methyl ester (Compound 78), the same operation as in Example 1 was performed using -octadecenoyl chloride. Obtained. Yield 59%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83-0.91 (6H, m), 1.22-1.28
(24H, m), 1.49 (2H, m), 1.60 (2H, m), 1.93 (2H, m),
2.35 (2H, t, J = 7.5 Hz), 3.23-3.27 (2H, m), 3.84
(3H, s), 5.34 (2H, m), 7.56 (1H, d, J = 8.1 Hz),
7.91 (1H, d, J = 8.1 Hz), 8.54-8.57 (2H, m), 10.50
(1H, s).

Example 18 4-Hydroxymethyl-3-methylsulfonylamino-N- (cis-9-octadecenyl) benzamide 2-methylsulfonylamino-4 synthesized in Example 1
-(Cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (9.0 g, 17.217 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium tetrahydroborate (750 mg, 34.434) was cooled with ice.
(mmol) was added and stirred at 60 ° C. for 12 hours. Water (10 mL) was added, and the mixture was further stirred for 1 hour. The mixture was extracted with ethyl acetate (100 mL). And dried. After removing the inorganic salt by filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of ethyl acetate and hexane, v / v = 1: 2; 1: 1; 2: 1). ) To give a colorless solid, 4-hydroxymethyl-3.
-Methylsulfonylamino-N- (cis-9-octadecenyl) benzamide (2.098 g, 25%; compound 1) was obtained. Melting point: 63.4-66.1C. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.25 (24H,
m), 1.48 (2H, m), 1.95 (2H, m), 3.00 (3H, s), 3.1
8-3.24 (2H, m), 4.63 (2H, s), 5.28-5.35 (2H, m),
7.51 (1H, d, J = 7.8 Hz), 7.69 (1H, dd, J = 7.8,
1.8 Hz), 7.71 (1H, d, J = 1.8 Hz), 8.43 (1H, m),
9.06 (1H, s). ¹³ C-NMR (DMSO-d ₆ ): δ 13.9, 22.1, 26.4, 26.5, 26.
6, 28.5, 28.6, 28.7,28.8, 29.0 (4C), 29.1, 29.2, 3
1.3, 31.9, 59.5, 124.1, 124.5, 127.4, 129.6, 130.
1, 134.0, 134.2, 140.7, 165.4. FABMS: m / z theoretical: 495 (MH ⁺ ), found: 495. elemental analysis (C ₂₇ H ₄₆ N ₂ O ₄ S.0.25 H ₂ O) theoretical: C,
H, 9.38; N, 5.61, found: C, 65.02;
9.63; N, 5.68.

Example 19 3-acetamido-4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide 2-acetylamino-4- (cis-
Using 9-octadecenylcarbamoyl) benzoic acid methyl ester and performing the same operation as in Example 18,
3-acetamido-4-hydroxymethyl- as a colorless solid
N- (cis-9-octadecenyl) benzamide (Compound 2) was obtained. Melting point: 120.5-122.4C. 90% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.81-0.85 (3H, m), 1.22-1.25
(22H, m), 1.44-1.50 (2H, m), 1.92-1.97 (4H, m), 2.0
4 (3H, s), 3.17-3.23 (2H, m), 4.48 (2H, d, J = 5.4
Hz), 5.28-5.32 (2H, m), 7.46 (1H, d, J = 8.1 Hz),
7.61 (1H, dd, J = 8.1, 1.2 Hz), 7.87 (1H, d, J =
. 1.2 Hz), 8.35 (1H , t, J = 5.1 Hz), 9.37 (1H, s) 13 C-NMR (DMSO-d 6): δ 13.8, 22.0, 23.2, 26.4, 26.5
(2C), 28.4, 28.5 (2C), 28.6, 28.7 (2C), 28.8, 28.
9, 29.0 (2C), 31.2, 31.8, 59.4, 123.3, 123.5, 129.
5, 130.0, 133.3, 134.8, 138.5, 165.5, 168.2. Elemental analysis (C ₂₈ H ₄₆ N ₂ O ₃ .0.25 H ₂ O) theoretical value: C, 7
2.61, H, 10.11; N, 6.05, found: C, 72.52;
10.29; N, 6.22.

Example 20 3- (3-chloropropylsulfonylamino) -4-
Hydroxymethyl-N- (cis-9-octadecenyl)
Benzamide Using 2- (3-chloropropylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester synthesized in Example 6, and operating in the same manner as in Example 18, a colorless solid was obtained. To give 3- (3-chloropropylsulfonylamino) -4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide (Compound 3). Yield 74%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.49 (28H,
m), 2.04-2.15 (2H, m), 2.84-2.91 (2H, m), 3.20-3.3
0 (4H, m), 4.64 (2H, d, J = 4.8 Hz), 5.31-5.39 (3
H, m), 7.51 (1H, d, J = 7.8 Hz), 7.68-7.71 (2H,
m), 8.65 (1H, m), 9.23 (1H, s).

Example 21 3-benzylsulfonylamino-4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide 2-benzylsulfonylamino-synthesized in Example 7
The same operation as in Example 18 was carried out using methyl 4- (cis-9-octadecenylcarbamoyl) benzoate to give 3-benzylsulfonylamino-4-hydroxymethyl-N- (cis-9) as a colorless solid. (Octadecenyl) benzamide (compound 4) was obtained. Yield 73
%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22-1.25 (24H,
m), 1.50 (2H, m), 1.92 (2H, m), 3.21-3.27 (2H,
m), 4.47 (2H, s), 4.57 (2H, s), 5.30-5.33 (2H, m),
7.33 (5H, m), 7.48 (1H, d, J = 8.1 Hz), 7.64 (1H,
d, J = 8.1, 1.5 Hz), 7.75 (1H, d, J = 1.5 Hz), 8.4
1 (1H, m). ¹³ C-NMR (DMSO-d ₆ ): δ 21.9, 26.4, 28.5, 28.7, 28.9
(9C), 29.0, 31.1, 31.8, 57.7, 59.6, 123.0, 123.7,
123.8, 127.1, 128.0, 128.2 (2C), 129.4, 129.5, 12
9.9, 130.7 (2C), 134.0, 139.6, 165.4.

Example 22 4-Hydroxymethyl-3- (2-nitrobenzylsulfonylamino) -N- (cis-9-octadecenyl)
Benzamide Using 2- (2-nitrobenzylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester synthesized in Example 8, the same operation as in Example 18 was carried out to obtain a colorless solid. Of 4-hydroxymethyl-3- (2-nitrobenzylsulfonylamino) -N- (cis-9-octadecenyl) benzamide (Compound 5). Yield 26%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.29 (24H,
m), 1.50 (2H, m), 1.89-1.96 (2H, m), 3.21-3.24 (2
H, m), 4.40 (2H, s), 4.97 (2H, s), 5.34-5.38 (3H,
m), 6.56 (1H, d, J = 7.5 Hz), 6.70 (1H, d, J = 8.1
Hz), 6.96-7.11 (2H, m), 7.71-7.77 (2H, m), 8.00
(1H, dd, J = 8.1, 1.2 Hz), 8.40 (1H, m), 9.43 (1H,
s).

Example 23 4-Hydroxymethyl-N- (cis-9-octadecenyl) -3-phenylsulfonylaminobenzamide 4- (cis-9-octadecenylcarbamoyl) -2-phenylsulfonyl synthesized in Example 9 By using the same procedure as in Example 18 using aminobenzoic acid methyl ester, 4-hydroxymethyl-N- as a colorless solid was obtained.
(Cis-9-octadecenyl) -3-phenylsulfonylaminobenzamide (compound 6) was obtained. Yield 51
%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21 (24H, m),
1.45 (2H, m), 1.92 (2H, m), 3.16 (2H, m), 4.37 (2
H, d, J = 5.1 Hz), 5.06 (1H, m), 5.33 (2H, m), 7.37
(1H, d, J = 8.1 Hz), 7.47-7.67 (5H, m), 7.75-7.78
(2H, m), 8.30 (1H, m).

Example 24 4-Hydroxymethyl-3- (2-nitrophenylsulfonylamino) -N- (cis-9-octadecenyl)
Benzamide Example 18 using methyl 2- (2-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoate synthesized in Example 10.
By performing the same operation as described above, colorless solid 4-hydroxymethyl-3- (2-nitrophenylsulfonylamino) -N- (cis-9-octadecenyl) benzamide (compound 7) was obtained. Yield 60%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22 (22H, m),
1.46 (2H, m), 1.95 (4H, m), 3.16 (2H, m), 4.37 (1
H, d, J = 5.4 Hz), 5.30 (3H, m), 7.23 (1H, m), 7.41
-7.46 (2H, m), 7.55-7.59 (3H, m), 7.76 (1H, m), 8.
92 (1H, m).

Example 25 4-hydroxymethyl-3- (3-nitrophenylsulfonylamino) -N- (cis-9-octadecenyl)
Benzamide Example 18 was obtained using 2- (3-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester synthesized in Example 11.
By performing the same operation as described above, 4-hydroxymethyl-3- (3-nitrophenylsulfonylamino) -N- (cis-9-octadecenyl) benzamide (compound 8) was obtained as a colorless solid. Yield 65%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.24 (22H,
m), 1.46 (2H, m), 1.95 (4H, m), 3.18 (2H, m), 4.38
(2H, s), 5.30 (3H, m), 6.86-7.23 (6H, m), 7.71 (1
H, d, J = 8.4 Hz), 8.37 (1H, m).

Example 26 4-hydroxymethyl-3- (1-naphthylsulfonylamino) -N- (cis-9-octadecenyl) benzamide 2- (1-naphthylsulfonylamino) -4- (synthesized in Example 13) By using cis-9-octadecenylcarbamoyl) benzoic acid methyl ester and operating in the same manner as in Example 18, colorless solid 4-hydroxymethyl-3- (1-naphthylsulfonylamino) -N-
(Cis-9-octadecenyl) benzamide (compound 9) was obtained. Yield 62%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (24H, m),
1.46 (2H, m), 1.95 (2H, m), 3.16 (2H, m), 4.21 (2
H, s), 4.93 (1H, s), 5.29-5.34 (2H, m), 7.46-7.78
(5H, m), 8.00-8.30 (5H, m), 8.65 (1H, m).

Example 27 3- (5-Dimethylamino-1-naphthylsulfonylamino) -4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide 2- (5-dimethylamino-synthesized in Example 14) 1-
The same operation as in Example 18 was carried out using naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester to give a colorless solid, 3- (5-dimethylamino-1-naphthylsulfonyl). Amino) -4-hydroxymethyl-N- (cis-9-
Octadecenyl) benzamide (compound 10) was obtained.
Yield 70%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (24H, m),
1.43 (2H, m), 1.95 (4H, m), 2.80-2.81 (6H, m), 3.1
7 (2H, m), 4.28 (2H, s), 5.34 (3H, m), 7.14-7.32
(1H, m), 7.51-7.59 (4H, m), 7.55-7.59 (5H, m), 8.4
5 (1H, m).

Example 28 3- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) -4-hydroxymethyl-N-
(Cis-9-octadecenyl) benzamide Methyl 2- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoate synthesized in Example 15 By operating in the same manner as in Example 18 to give 3- (2-acetamido-4-methyl-) as a colorless solid.
5-Thiazolylsulfonylamino) -4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide (Compound 11) was obtained. Yield 73%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (22H, m),
1.46 (2H, m), 1.95 (4H, m), 2.14 (2H, s), 2.41 (2
H, s), 3.18 (2H, m), 4.37 (2H, d, J = 5.1 Hz), 5.0
6 (1H, m), 5.30 (2H, m), 7.55-7.78 (3H, m), 8.37
(1H, m), 12.47 (1H, s).

Example 29 3- (2-aminobenzylsulfonylamino) -4-
Hydroxymethyl-N-octadecylbenzamide 4-hydroxymethyl-3- (2
-Nitrobenzylsulfonylamino) -N- (cis-
9-octadecenyl) benzamide (0.20 g, 0.
325 mmol) was dissolved in ethyl acetate (5 mL), and a catalytic amount (2-5 mg) of palladium carbon (Pd 10%) was added, followed by stirring under a hydrogen gas atmosphere at normal pressure and room temperature.
When no intense absorption of hydrogen was observed, the completion of the reaction was confirmed by thin-layer chromatography. ) -4-Hydroxymethyl-N-
Octadecylbenzamide (0.137 g, 72%; compound 12) was obtained. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.29 (30H,
m), 1.49 (2H, m), 3.19-3.24 (2H, m), 4.35 (2H, s),
4.58 (2H, s), 5.34 (1H, m), 6.55 (1H, d, J = 8.1
Hz), 6.70 (1H, d, J = 6.6 Hz), 6.95-7.05 (2H, m),
7.45 (1H, d, J = 8.4 Hz), 7.59 (1H, d, J = 8.4 H
z), 7.76 (1H, s), 8.35 (1H, m).

Example 30 3- (2-aminophenylsulfonylamino) -4-
Hydroxymethyl-N-octadecylbenzamide 4-Hydroxymethyl-3- (2
-Nitrophenylsulfonylamino) -N- (cis-
Example 29 using (9-octadecenyl) benzamide
By performing the same operation as described above, colorless solid 3- (2-aminophenylsulfonylamino) -4-hydroxymethyl-N-octadecylbenzamide (Compound 13) was obtained. Yield 92%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (28H, m),
1.46 (2H, m), 3.16 (2H, m), 4.37 (2H, d, J = 5.4 H
z), 5.06 (1H, m), 6.94-7.22 (4H, m), 7.41-7.59 (3
H, m), 8.12 (1H, m).

Example 31 3-Benzylsulfonylamino-4-hydroxymethyl-N-octadecylbenzamide Using 3-benzylsulfonylamino-4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide synthesized in Example 21. In the same manner as in Example 29, colorless solid 3-benzylsulfonylamino-4-hydroxymethyl-N-octadecylbenzamide (Compound 14) was obtained. Yield 92%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.25 (28H,
m), 1.48 (2H, m), 3.20-3.28 (4H, m), 4.48 (2H,
s), 4.57 (2H, s), 7.34 (5H, m), 7.49 (1H, m), 7.66
(1H, m), 7.76 (1H, s), 8.42 (1H, m).

Example 32 4-Hydroxymethyl-3-methylsulfonylamino-N-octadecylbenzamide Using 4-hydroxymethyl-3-methylsulfonylamino-N- (cis-9-octadecenyl) benzamide synthesized in Example 18. By operating in the same manner as in Example 29, colorless solid 4-hydroxymethyl-3-methylsulfonylamino-N-octadecylbenzamide (Compound 15) was obtained. Melting point: 81.6-83.0
° C. 90% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.25 (30H,
m), 1.49 (2H, m), 3.00 (3H, s), 3.18-3.24 (2H,
m), 4.63 (2H, d, J = 5.1 Hz), 5.36 (1H, t, J = 5.1
Hz), 7.51 (1H, d, J = 7.8 Hz), 7.69 (1H, dd, J =
7.8, 1.5 Hz), 7.71 (1H, d, J = 1.5 Hz), 8.43 (1H,
. m), 9.06 (1H, s) 13 C-NMR (DMSO-d 6): δ 13.9, 22.1, 26.5, 28.7, 28.
8, 29.0 (12C), 29.1, 31.3, 59.5, 124.1, 124.5, 127.
3, 134.0, 134.2, 140.7, 165.4. FABMS: m / z theoretical: 497 (MH ⁺ ), found: 497. elemental analysis (C ₂₇ H ₄₈ N ₂ O ₄ S.0.5 H ₂ O) theoretical: C, 6
4.12; H, 9.76; N, 5.54, found: C, 64.23;
9.57; N, 5.79.

Example 33 N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3-methylsulfonylaminobenzamide 4-Hydroxymethyl-3-methylsulfonylamino-N- (synthesized in Example 18) (Cis-9-octadecenyl) benzamide (0.88 g, 1.779 mmol)
Was suspended in 90% formic acid (5 mL), and the reaction temperature was lowered to 40-
While maintaining the temperature at 45 ° C., a 30% hydrogen peroxide solution (0.3 m
L, 2.668 mmol) was added dropwise, and the mixture was further stirred at 40 ° C. for 1 hour and left at room temperature overnight. Formic acid and water were distilled off under reduced pressure, and a 6N aqueous sodium hydroxide solution was added to the residue.
After adding little by little at 5 ° C or less, the mixture was stirred at 45 ° C for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution in that order, and then dried over anhydrous sodium sulfate. After filtering off the inorganic salts,
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: mixed solvent of ethyl acetate and hexane, v / v = 2: 1; 4: 1) to give a colorless solid N -(Trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3-methylsulfonylaminobenzamide (0.282 g, 30
%; Compound 16) was obtained. Melting point: 93.5-93.9
° C. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22-1.25 (22H,
m), 1.38 (2H, m), 1.49 (4H, m), 3.00 (3H, s), 3.1
0-3.24 (4H, m), 4.63 (2H, d, J = 5.4 Hz), 5.36 (1H,
t, J = 5.4 Hz), 7.51 (1H, d, J = 8.1 Hz), 7.69 (1
(H, d, J = 8.1Hz), 7.71 (1H, s), 8.43 (1H, m), 9.06
^{. (1H, s) 13 C} -NMR (DMSO-d 6): δ 13.9, 22.1, 25.4, 25.7, 26.
5, 28.7, 28.8, 29.0 (4C), 29.1, 29.2, 29.3, 31.3,
32.2, 32.6, 59.5, 73.1, 73.8, 124.1, 124.5, 127.4,
. 134.0, 134.2, 140.7, 165.4 Elemental analysis _{(C 27 H 48 N 2 O} 6 S · 0.02 H 2 O) theory: C,
H, 9.15; N, 5.29, found: C, 60.89;
9.26; N, 5.18.

Example 34 3- (3-chloropropylsulfonylamino) -N-
(Trans-9,10-dihydroxyoctadecyl)-
4-hydroxymethylbenzamide 3- (3-chloropropylsulfonylamino) -4-hydroxymethyl-N- (cis-
Example 33 using (9-octadecenyl) benzamide.
By operating in the same manner as described above, 3- (3-chloropropylsulfonylamino) -N- (trans-
9,10-Dihydroxyoctadecyl) -4-hydroxymethylbenzamide (Compound 17) was obtained. Yield 65
%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22-1.47 (28H,
m), 2.15-2.20 (2H, m), 2.80-2.89 (2H, m), 3.11-3.4
3 (4H, m), 3.64-3.82 (2H, m), 4.52 (2H, s), 5.20
(1H, s), 7.48 (1H, d, J = 8.1 Hz), 7.64-7.66 (2H,
m), 8.49 (1H, m).

Example 35 3-benzylsulfonylamino-N- (trans-
9,10-Dihydroxyoctadecyl) -4-hydroxymethylbenzamide Using 3-benzylsulfonylamino-4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide synthesized in Example 21, operating in the same manner as in Example 33 As a result, colorless solid 3-benzylsulfonylamino-N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethylbenzamide (compound 18) was obtained. Yield 26%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (26H, m),
1.49 (2H, m), 3.24 (2H, m), 3.57-3.60 (2H, m), 4.6
9 (2H, s), 5.22 (1H, s), 7.34 (5H, m), 7.92-8.24
(3H, m), 8.63 (1H, m), 10.07 (1H, br s).

Example 36 N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (2-nitrobenzylsulfonylamino) benzamide 4-hydroxymethyl-3- (2) synthesized in Example 22
-Nitrobenzylsulfonylamino) -N- (cis-
Example 33 using (9-octadecenyl) benzamide.
By performing the same operation as described above, N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (2-nitrobenzylsulfonylamino) benzamide (compound 19) was obtained as a colorless solid. Yield 31
%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (26H, m),
1.48 (2H, m), 3.10-3.23 (4H, m), 4.59 (2H, s), 4.
97 (2H, s), 5.39 (1H, m), 7.51-7.81 (4H, m), 7.89-
8.02 (3H, m), 8.59 (1H, m), 10.21 (1H, m).

Example 37 N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3-phenylsulfonylaminobenzamide 4-hydroxymethyl-N- (cis-9-octadecenyl) synthesized in Example 23 By using -3-phenylsulfonylaminobenzamide and operating in the same manner as in Example 33, a colorless solid N- (trans-9,10-
Dihydroxyoctadecyl) -4-hydroxymethyl-
3-Phenylsulfonylaminobenzamide (Compound 20) was obtained. Yield 41%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (26H, m),
1.47 (2H, m), 3.14-3.40 (4H, m), 4.31 (2H, s), 7.
40-7.66 (6H, m), 7.75-7.78 (2H, m), 8.34 (1H, m).

Example 38 N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (2-nitrophenylsulfonylamino) benzamide 4-Hydroxymethyl-3- (2) synthesized in Example 24
-Nitrophenylsulfonylamino) -N- (cis-
Example 33 using (9-octadecenyl) benzamide.
By performing the same operation as described above, N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (2-nitrophenylsulfonylamino) benzamide (compound 21) was obtained as a colorless solid. Yield 41
%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.49 (28H,
m), 3.11-3.28 (4H, m), 4.10-4.15 (2H, m), 4.86 (1
H, m), 7.53-7.72 (4H, m), 7.76-7.92 (3H, m), 8.27
(1H, m).

Example 39 N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (3-nitrophenylsulfonylamino) benzamide 4-Hydroxymethyl-3- (3) synthesized in Example 25
-Nitrophenylsulfonylamino) -N- (cis-
Example 33 using (9-octadecenyl) benzamide.
By performing the same operation as described above, N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (3-nitrophenylsulfonylamino) benzamide (compound 22) was obtained as a colorless solid. Yield 39
%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.49 (28H,
m), 3.12-3.29 (4H, m), 4.10 (2H, m), 4.74 (1H, m),
7.69-8.12 (4H, m), 8.24-8.36 (3H, m), 8.73 (1H,
m).

Example 40 N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (1-naphthylsulfonylamino) benzamide 4-hydroxymethyl-3- (1) synthesized in Example 26
Using -naphthylsulfonylamino) -N- (cis-9-octadecenyl) benzamide, the same procedure as in Example 33 was carried out to obtain a colorless solid N- (trans-
9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- (1-naphthylsulfonylamino) benzamide (Compound 23) was obtained. 43% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.20 (26H, m),
1.46 (2H, m), 3.12-3.28 (4H, m), 4.11-4.16 (2H, m
m), 4.22 (1H, s), 7.47-7.79 (5H, m), 7.85-8.37 (5
H, m), 8.54 (1H, m).

Example 41 4-hydroxymethyl-3- (5-dimethylamino-1
-Naphthylsulfonylamino) -N- (trans-
9,10-dihydroxyoctadecyl) benzamide 3- (5-dimethylamino-1-) synthesized in Example 27
Using naphthylsulfonylamino) -4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide, a colorless solid 4-hydroxymethyl-3- (5-dimethylamino-
1-naphthylsulfonylamino) -N- (trans-
9,10-Dihydroxyoctadecyl) benzamide (Compound 24) was obtained. Yield 20%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (26H, m),
1.49 (2H, m), 1.95 (4H, m), 3.18-3.34 (8H, m), 4.1
8 (2H, m), 4.79-4.85 (2H, m), 5.36 (1H, m), 7.68-
7.92 (6H, m), 8.07 (1H, d, J = 8.1 Hz), 8.19 (1H,
d, J = 8.1 Hz), 8.26 (1H, s), 8.48 (1H, m).

Example 42 3- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) -N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethylbenzamide Synthesized in Example 28. Using 3- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) -4-hydroxymethyl-N- (cis-9-octadecenyl) benzamide, the same procedure as in Example 33 was carried out to obtain a colorless color. Solid 3- (2-acetamido-4-methyl-
5-Thiazolylsulfonylamino) -N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethylbenzamide (Compound 25) was obtained. Yield 2
5%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.48 (28H,
m), 2.14 (3H, s), 2.41 (3H, s), 3.12-3.27 (4H,
m), 4.37 (2H, m), 7.45-7.76 (3H, m), 8.17 (1H, m).

Example 43 4-Hydroxymethyl-N-isopropyl-3- (cis-9-octadecenoylamino) benzamide 4-Isopropylcarbamoyl-synthesized in Example 16
By using 2- (cis-9-octadecenoylamino) benzoic acid methyl ester and operating in the same manner as in Example 18, colorless solid 4-hydroxymethyl-N-isopropyl-3- (cis-9- (Octadesenoylamino) benzamide (compound 26) was obtained. Yield 59%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.14 (6H, d, J
= 6.6 Hz), 1.22 (20H, m), 1.57 (2H, m), 1.93 (2H,
m), 3.57-3.60 (2H, m), 4.05 (1H, m), 4.47 (2H, d, J
= 5.4 Hz), 5.28-5.60 (3H, m), 7.46 (1H, d, J = 8.
1 Hz), 7.63 (1H, d, J = 8.1 Hz), 7.85 (1H, s), 8.1
4 (1H, d, J = 7.5 Hz), 9.34 (1H, s).

Example 44 N-butyl-4-hydroxymethyl-3- (cis-9-
Octadecenoylamino) benzamide 4-butylcarbamoyl-2-synthesized in Example 17
Using (cis-9-octadecenoylamino) benzoic acid methyl ester and the same operation as in Example 18, a colorless solid N-butyl-4-hydroxymethyl-3 was obtained.
-(Cis-9-octadecenoylamino) benzamide (compound 27) was obtained. Yield 42%. ¹ H-NMR (DMSO-d ₆ ): δ 0.81-0.90 (6H, m), 1.22 (24H,
m), 1.43-1.50 (2H, m), 1.58 (2H, m), 1.92 (2H, m),
2.29 (2H, m), 3.21-3.27 (2H, m), 4.47 (2H, d, J =
5.1 Hz), 5.30-5.35 (3H, m), 7.46 (1H, d, J = 8.1
Hz), 7.61 (1H, d, J = 8.1 Hz), 7.86 (1H, s), 8.36
(1H, m), 9.34 (1H, s).

Example 45 3- (2-aminobenzylsulfonylamino) -N-
(Trans-9,10-dihydroxyoctadecyl) -4
-Hydroxymethylbenzamide N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3- synthesized in Example 36
By using (2-nitrobenzylsulfonylamino) benzamide and operating in the same manner as in Example 29, colorless solid 3- (2-aminobenzylsulfonylamino) -N- (trans-9,10-dihydroxyoctadecyl)- 4-Hydroxymethylbenzamide (compound 28) was obtained. 94% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22 (26H, m),
1.50 (2H, m), 3.10-3.23 (4H, m), 4.40 (2H, s), 4.
61 (2H, s), 6.96-7.06 (4H, m), 7.51-7.77 (3H, m),
8.39 (1H, m).

Example 46 3- (2-aminophenylsulfonylamino) -N-
(Trans-9,10-dihydroxyoctadecyl)-
4-Hydroxymethylbenzamide N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3-synthesized in Example 38
By using (2-nitrophenylsulfonylamino) benzamide and operating in the same manner as in Example 29, colorless solid 3- (2-aminophenylsulfonylamino) -N- (trans-9,10-dihydroxyoctadecyl)- 4-Hydroxymethylbenzamide (Compound 29) was obtained. Yield 93%. ¹ H-NMR (DMSO-d ₆ ): δ 0.84 (3H, m), 1.22-1.49 (28H,
m), 3.11-3.28 (4H, m), 4.10-4.15 (2H, m), 7.44-7.6
0 (4H, m), 7.76-7.79 (3H, m), 8.24 (1H, m).

Example 47 3- (3-aminophenylsulfonylamino) -N-
(Trans-9,10-dihydroxyoctadecyl)-
4-Hydroxymethylbenzamide N- (trans-9,10-dihydroxyoctadecyl) -4-hydroxymethyl-3-synthesized in Example 39
By using (3-nitrophenylsulfonylamino) benzamide and operating in the same manner as in Example 29, colorless solid 3- (3-aminophenylsulfonylamino) -N- (trans-9,10-dihydroxyoctadecyl)- 4-Hydroxymethylbenzamide (Compound 30) was obtained. 94% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.49 (28H,
m), 3.12-3.29 (4H, m), 4.73 (2H, m), 7.85-7.58 (4
H, m), 8.24-8.29 (3H, m), 8.61 (1H, m).

Example 48 2-methylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid 2-methylsulfonylamino-4 synthesized in Example 1
-A 6N potassium hydroxide solution (0.1 mL, 0.6 mmol) was added dropwise to a tetrahydrofuran solution (5 mL) of-(cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (0.11 g, 0.214 mmol), Stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and after extraction with ethyl acetate (100 mL), the obtained aqueous phase was acidified with a 2N aqueous hydrochloric acid solution. The precipitated solid was filtered, washed sequentially with water and hexane, and dried at room temperature to give 2-methylsulfonylamino-4- as a colorless solid.
(Cis-9-octadecenylcarbamoyl) benzoic acid (0.006 g, 56%; compound 31) was obtained. Melting point:
180.9-183.0 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22-1.25 (22H,
m), 1.50 (2H, m), 1.96 (4H, m), 3.20-3.21 (2H,
m), 5.30 (2H, m), 7.54 (1H, dd, J = 8.1, 1.5 Hz),
7.93 (1H, d, J = 1.5 Hz), 8.05 (1H, d, J = 8.1 H
. z), 8.63 (1H, m), 10.68 (1H, br s) 13 C-NMR (DMSO-d 6): δ 13.9, 22.0, 26.4, 26.5, 28.
5, 28.7, 28.8, 28.9,29.0 (7C), 31.2, 31.9, 116.7,
118.2, 120.9, 129.6, 131.6, 140.2, 140.4, 156.9, 16
. 5.0, 169.2 Elemental analysis _{(C 27 H 44 N 2 O} 5 S · 0.25 H 2 O) theory: C,
H, 8.74; N, 5.46, found: C, 63.05;
8.76; N, 5.56.

Example 49 2-acetylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid 2-acetylamino-4- (cis-benzoic acid synthesized in Example 2)
Using 9-octadecenylcarbamoyl) benzoic acid methyl ester and performing the same operation as in Example 48,
2-acetylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid (compound 32) was obtained as a colorless solid. Yield 69%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22 (22H, m),
1.49 (2H, m), 1.96 (4H, m), 2.12 (3H, s), 3.22 (2
H, m), 5.31 (2H, m), 7.52 (1H, m), 7.96-8.06 (2H,
m), 8.56 (1H, m), 10.95 (1H, s).

Example 50 4- (cis-9-octadecenylcarbamoyl) -2-
Vinylsulfonylaminobenzoic acid Using 4- (cis-9-octadecenylcarbamoyl) -2-vinylsulfonylaminobenzoic acid methyl ester synthesized in Example 4 and operating in the same manner as in Example 48, a colorless solid was obtained. 4- (cis-9-octadecenylcarbamoyl) -2-vinylsulfonylaminobenzoic acid (Compound 33) was obtained. Yield 20%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.25 (22H,
m), 1.48 (2H, m), 1.95 (4H, m), 3.20-3.26 (2H, m),
5.30 (2H, m), 6.13 (1H, d, J = 9.9 Hz), 6.22 (1H,
d, J = 16.5 Hz), 6.94 (1H, dd, J = 16.5, 9.9 Hz),
7.54 (1H, dd, J = 8.1, 1.5 Hz), 7.86 (1H, d, J =
1.5 Hz), 8.02 (1H, d, J = 8.1 Hz), 8.59 (1H, m), 1
0.17 (1H, s).

Example 51 2-benzylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) benzoic acid 2-benzylsulfonylamino-synthesized in Example 7
The same operation as in Example 48 was carried out using methyl 4- (cis-9-octadecenylcarbamoyl) benzoate to give 2-benzylsulfonylamino-4- (cis-9-octadecenylcarbamoyl) as a colorless solid. ) Benzoic acid (compound 34) was obtained. Yield 13%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21 (22H, m),
1.51 (2H, m), 1.95 (2H, m), 3.23 (2H, m), 4.69 (2
H, s), 5.30 (2H, m), 7.17 (1H, dd, J = 6.9,1.2 H
z), 7.28-7.34 (4H, m), 7.57 (1H, dd, J = 8.1, 1.2
Hz), 7.98-8.01 (2H, m), 8.63 (1H, m), 10.07 (1H, b
rs).

Example 52 2- (2-nitrobenzylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid Example using 2- (2-nitrobenzylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester synthesized in Example 8 By performing the same operation as in 48, colorless solid 2- (2-nitrobenzylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid (Compound 35) was obtained. Yield 17%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21 (22H, m),
1.52 (2H, m), 1.94 (4H, m), 3.23 (2H, m), 3.85 (3
H, s), 5.13 (2H, s), 5.30 (2H, m), 7.49 (1H, m),
7.59-7.68 (3H, m), 7.89 (1H, s), 7.96-8.06 (2H,
m), 8.59 (1H, m), 10.20 (1H, s).

Example 53 2- (2-nitrophenylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid Example using 2- (2-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester synthesized in Example 10 48
By operating in the same manner as described above, colorless solid 2- (2-nitrophenylsulfonylamino) -4- (cis-9-
Octadecenylcarbamoyl) benzoic acid (compound 36)
I got Yield 18%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.25 (22H,
m), 1.46 (2H, m), 1.95 (4H, m), 3.19 (2H, m), 5.30
(2H, m), 7.51 (1H, m), 7.84 (2H, m), 7.95-8.12
(4H, m), 8.55 (1H, m), 10.79 (1H, s).

Example 54 2- (3-nitrophenylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid Example using 2- (3-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester synthesized in Example 11 48
By operating in the same manner as described above, 2- (3-nitrophenylsulfonylamino) -4- (cis-9-
Octadecenylcarbamoyl) benzoic acid (compound 37)
I got Yield 29%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.24 (22H,
m), 1.47 (2H, m), 1.95 (4H, m), 3.18 (2H, m), 5.30
(2H, m), 7.52 (1H, m), 7.80-7.91 (3H, m), 8.13 (1
H, m), 8.42-8.46 (2H, m), 8.56 (1H, m).

Example 55 2- (4-nitrophenylsulfonylamino) -4-
(Cis-9-octadecenylcarbamoyl) benzoic acid Example using 2- (4-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester synthesized in Example 12 48
By operating in the same manner as described above, colorless solid 2- (4-nitrophenylsulfonylamino) -4- (cis-9-
Octadecenylcarbamoyl) benzoic acid (compound 38)
I got Yield 17%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.24 (22H,
m), 1.46 (2H, m), 1.95 (4H, m), 3.17 (2H, m), 5.28
-5.33 (2H, m), 7.86-8.02 (2H, m), 8.23 (1H, d, J =
8.4 Hz), 8.31-8.39 (3H, m), 8.47 (1H, m).

Example 56 2- (1-Naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid 2- (1-Naphthylsulfonylamino) -4- (cis) synthesized in Example 13 Using -9-octadecenylcarbamoyl) benzoic acid methyl ester and the same operation as in Example 48, a colorless solid 2- (1-naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) was obtained. ) Benzoic acid (compound 39) was obtained. Yield 2%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.24 (22H,
m), 1.46 (2H, m), 1.96 (4H, m), 3.17 (2H, m), 5.30
(2H, m), 7.51-7.84 (8H, m), 8.06 (1H, m), 8.22 (1
H, m), 8.52 (1H, m), 10.75 (1H, s).

Example 57 2- (5-dimethylaminonaphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl)
Benzoic acid 2- (5-dimethylamino-1-) synthesized in Example 14
The same operation as in Example 48 was performed using naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester to give a colorless solid, 2- (5-dimethylaminonaphthylsulfonylamino)-. 4- (cis-9-octadecenylcarbamoyl)
Benzoic acid (compound 40) was obtained. Yield 18%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.24 (22H,
m), 1.47 (2H, m), 1.94 (4H, m), 2.80 (3H, s), 2.82
(3H, s), 3.15-3.21 (2H, m), 5.28-5.33 (2H, m), 7.
50-7.58 (3H, m), 8.13 (1H, d, J = 7.5 Hz), 8.33-
8.37 (2H, m), 8.46 (1H, d, J = 8.4 Hz), 8.58 (1H,
m).

Example 58 2- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid Synthesized in Example 15 2- (2 -Acetamido-4-methyl-5-thiazolylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester was used to give a colorless solid 2 -(2-acetamido-4-methyl-
5-thiazolylsulfonylamino) -4- (cis-9
-Octadecenylcarbamoyl) benzoic acid (compound 4
1) was obtained. Yield 22%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.20-1.24 (22H,
m), 1.48 (2H, m), 1.94 (4H, m), 2.10 (3H, s), 2.33
(3H, s), 3.19 (2H, m), 5.29 (2H, m), 7.94-7.99 (3
H, m), 8.59 (1H, m), 10.43 (1H, s), 12.56 (1H, s).

Example 59 2-Amino-4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester of 2-amino-4- (cis-9-octadecenylcarbamoyl) benzoic acid synthesized in Production Example 1 By using the same procedure as in Example 48, colorless solid 2-amino-4- (cis-9-octadecenylcarbamoyl) benzoic acid (Compound 42) was obtained. Yield 58%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.24 (22H,
m), 1.46 (2H, m), 1.90-1.96 (4H, m), 3.14-3.21 (2
H, m), 5.28-5.31 (2H, m), 6.86 (1H, dd, J = 8.1, 1.
5 Hz), 7.15 (1H, d, J = 1.5 Hz), 7.69 (1H, d, J =
. 8.1 Hz), 8.35 (1H , t, J = 5.4 Hz) 13 C-NMR (DMSO-d 6): δ 13.9, 22.1, 26.4, 26.6, 28.
6, 28.7, 28.8, 28.9,29.0 (4C), 29.1, 29.2, 31.3, 3
1.9, 111.2, 112.7, 115.6, 129.6, 130.1, 131.1, 13
9.7, 151.1, 165.9, 169.1.

Example 60 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-ethylsulfonylaminobenzoic acid 2-ethylsulfonylamino-4 synthesized in Example 3
-(Cis-9-octadecenylcarbamoyl) benzoic acid methyl ester (1.75 g, 3.26 mmol) was suspended in 90% formic acid (5 mL) and the reaction temperature was raised to 40-4.
While maintaining the temperature at 5 ° C., a 30% hydrogen peroxide solution (0.55 m
L, 4.89 mmol) was added dropwise, and the mixture was further stirred at 40 ° C. for 1 hour and left at room temperature overnight. Formic acid and water were distilled off under reduced pressure, and a 6N aqueous solution of sodium hydroxide was added to the residue for 45 minutes.
The mixture was added little by little at a temperature of not more than 0 ° C, and then stirred at 45 ° C for 1 hour.
Water (100 mL) was added to the reaction mixture, and ethyl acetate (1
00 mL) and the aqueous phase was acidified with 2N aqueous hydrochloric acid. The precipitated solid was filtered, washed successively with water and hexane, further recrystallized from ethanol: water (6: 5, v / v, 6 mL), and dried at room temperature to give a colorless solid 4-
(Trans-9,10-dihydroxyoctadecylcarbamoyl) -2-ethylsulfonylaminobenzoic acid (1.162 g, 64%; compound 43) was obtained. Melting point:
82.0-82.5 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.17 (3H, t, J
= 7.5 Hz), 1.21-1.49 (28H, m), 3.19-3.34 (6H, m),
7.53 (1H, d, J = 8.1 Hz), 7.95 (1H, s), 8.04 (1H,
. d, J = 8.1 Hz) , 8.63 (1H, m), 10.72 (1H, s) 13 C-NMR (DMSO-d 6): δ 7.89, 13.9, 22.1, 25.5, 25.
7, 26.5, 28.7, 28.8,28.9, 29.0 (4C), 29.1, 29.2, 3
1.3, 32.2, 45.9, 73.1, 73.8, 116.6, 117.8,120.9, 1
. 31.7, 140.3, 140.5, 165.0, 169.4 Elemental analysis _{(C 28 H 48 N 2 O} 7 S) theory: C, 60.41;
H, 8.69; N, 5.03, found: C, 60.22; H, 8.78;
N, 5.07.

Example 61 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-methylsulfonylaminobenzoic acid 2-methylsulfonylamino-4 synthesized in Example 1
By using-(cis-9-octadecenylcarbamoyl) benzoic acid methyl ester and operating in the same manner as in Example 60, colorless solid 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-methylsulfonyl is obtained. Aminobenzoic acid (compound 44) was obtained. Yield 7
8%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (26H, m),
1.49 (2H, m), 3.19 (3H, s), 3.23-3.26 (4H, m), 7.5
3 (1H, dd, J = 8.1, 1.5 Hz), 7.91 (1H, d, J = 1.5 H
. z), 8.03 (1H, d, J = 8.1 Hz), 8.63 (1H, m) 13 C-NMR (DMSO-d 6): δ 22.1, 25.7, 26.4, 26.5, 28.
7, 28.8, 28.9, 29.0 (5C), 29.2, 29.3, 31.3, 32.2,
37.2, 73.1, 73.8, 116.6, 118.4, 120.8, 131.6, 140.
1, 140.5, 165.1, 169.2.

Example 62 2-acetylamino-4- (trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid 2-acetylamino-4- (cis-
Using 9-octadecenylcarbamoyl) benzoic acid methyl ester and performing the same operation as in Example 60,
Colorless solid 2-acetylamino-4- (trans-9,
10-Dihydroxyoctadecylcarbamoyl) benzoic acid (compound 45) was obtained. Yield 58%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22 (22H, m),
1.36 (2H, m), 1.49 (2H, m), 2.11 (3H, s), 3.12-3.2
2 (4H, m), 4.14 (2H, m), 7.47 (1H, dd, J = 8.1 Hz),
7.97 (1H, d, J = 8.1 Hz), 8.51 (1H, m), 8.76 (1H,
. s), 11.40 (1H, br s) 13 C-NMR (DMSO-d 6): δ 14.0, 22.1, 24.5, 24.9, 25.
5, 25.7, 26.4, 26.5, 28.7, 28.8, 29.0 (2C), 29.1, 2
9.3, 31.3, 32.6, 33.7, 73.1, 73.8, 119.2,120.1, 12
0.7, 130.8, 139.2, 140.4, 165.6, 168.3, 168.9.

Example 63 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-vinylsulfonylaminobenzoic acid 4- (cis-9-octadecenylcarbamoyl) -2-vinylsulfonyl synthesized in Example 4 A colorless solid of 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-vinylsulfonylaminobenzoic acid (Compound 46) was obtained by the same operation as in Example 60 using aminobenzoic acid methyl ester. . Yield 6
8%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.49 (28H,
m), 3.18-3.23 (2H, m), 6.15 (1H, d, J = 9.9 Hz), 6.24 (1H, d, J = 16.5 H
z), 6.95 (1H, dd, J = 16.5, 9.9 Hz), 7.56 (1H, dd,
J = 8.4, 1.5 Hz), 7.87 (1H, d, J = 1.5 Hz), 8.02 (1
H, d, J = 8.4 Hz), 8.62 (1H, t, J = 5.7 Hz), 10.80
(1H, s). ¹³ C-NMR (DMSO-d ₆ ): δ 13.9, 22.1, 25.5, 25.7, 26.
5, 28.7, 28.8, 28.9,29.0 (3C), 29.1, 29.2, 31.3, 3
2.2, 32.6, 73.1, 73.8, 117.2, 118.5, 121.1, 129.4,
131.5, 135.7, 139.7, 140.0, 164.8, 169.3.

Example 64 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-isopropylsulfonylaminobenzoic acid 2-isopropylsulfonylamino-4- (cis-9-octadecenylcarbamoyl synthesized in Example 5 ) A colorless solid of 4- (trans-9,10) was obtained in the same manner as in Example 60, using benzoic acid methyl ester.
-Dihydroxyoctadecylcarbamoyl) -2-isopropylsulfonylaminobenzoic acid (Compound 47) was obtained. Yield 25%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.46 (34H,
m), 3.17 (2H, m), 3.62 (3H, m), 6.85 (1H, d, J =
8.1 Hz), 7.15 (1H, d, J = 1.5 Hz), 7.70 (1H, dd, J
= 8.1, 1.5 Hz), 8.35 (1H, d, J = 5.7 Hz) 13 C-NMR (DMSO-d 6):. Δ 13.9, 22.0, 25.6, 26.3, 26.
4, 28.6, 28.7, 28.9 (4C), 29.0, 29.2, 29.3, 31.2,
32.1, 32.5, 42.6, 73.0, 73.7, 111.1, 112.6, 115.5,
131.0, 139.6, 151.1, 165.9, 169.0.

Example 65 2- (3-chloropropylsulfonylamino) -4-
(Trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid Using methyl 2- (3-chloropropylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoate synthesized in Example 6, By operating in the same manner as in Example 60, colorless solid 2- (3-chloropropylsulfonylamino) -4- (trans-
9,10-dihydroxyoctadecylcarbamoyl) benzoic acid (compound 48) was obtained. Yield 29%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.50 (28H,
m), 2.04-2.13 (2H, m), 3.18-3.44 (6H, m), 3.68 (2
H, t, J = 6.6 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.98
(1H, s), 8.04 (1H, d, J = 8.1 Hz), 8.63 (1H, m),
10.75 (1H, s). ¹³ C-NMR (DMSO-d ₆ ): δ 14.0, 22.1, 25.7, 26.6, 28.
7, 28.8 29.0 (8C), 29.1, 29.3, 31.3, 32.2, 42.9, 4
8.8, 73.1, 73.8, 117.2, 118.5, 121.2, 131.7, 140.
1, 140.2, 164.9, 169.4.

Example 66 2-benzylsulfonylamino-4- (trans-
9,10-dihydroxyoctadecylcarbamoyl) benzoic acid 2-benzylsulfonylamino- synthesized in Example 7
The same operation as in Example 60 was carried out using methyl 4- (cis-9-octadecenylcarbamoyl) benzoate to give 2-benzylsulfonylamino-4- (trans-9,10-dihydroxyoctadecyl) as a colorless solid. Carbamoyl) benzoic acid (compound 49) was obtained. Yield 50%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.52 (28H,
m), 3.21-3.31 (4H, m), 4.27 (2H, s), 7.27-7.38 (5
H, m), 7.57 (1H, d, J = 8.4 Hz), 7.98-8.00 (2H, m),
8.63 (1H, m), 10.07 (1H, br s).

Example 67 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2- (2-nitrobenzylsulfonylamino) benzoic acid 2- (2-nitrobenzylsulfonylamino) -4 synthesized in Example 8 The same operation as in Example 60 was carried out using-(cis-9-octadecenylcarbamoyl) benzoic acid methyl ester to give 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) as a colorless solid.
-2- (2-Nitrobenzylsulfonylamino) benzoic acid (compound 50) was obtained. Yield 57%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.50 (28H,
m), 3.17-3.24 (4H, m), 4.41 (2H, s), 7.45-7.66 (4
H, m), 7.75-7.91 (3H, m), 8.01 (1H, m).

Example 68 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-phenylsulfonylaminobenzoic acid 4- (cis-9-octadecenylcarbamoyl) -2-phenylsulfonyl synthesized in Example 9 A colorless solid of 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-phenylsulfonylaminobenzoic acid (Compound 51) was obtained by the same operation as in Example 60 using aminobenzoic acid methyl ester. . Yield 78%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (26H, m),
1.39 (2H, m), 3.10-3.19 (4H, m), 7.56-7.62 (3H,
m), 7.70-7.82 (3H, m), 8.30 (1H, m).

Example 69 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2- (4-nitrophenylsulfonylamino) benzoic acid 2- (4-nitrophenylsulfonylamino) -4 synthesized in Example 12 Example 60 was prepared using-(cis-9-octadecenylcarbamoyl) benzoic acid methyl ester.
By operating in the same manner as described above, colorless solid 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2- (4-nitrophenylsulfonylamino)
Benzoic acid (compound 52) was obtained. Yield 84%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.45 (28H,
m), 3.11-3.22 (4H, m), 7.81-7.99 (2H, m), 8.13-8.2
8 (3H, m), 8.37-8.49 (3H, m).

Example 70 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2- (1-naphthylsulfonylamino) benzoic acid 2- (1-naphthylsulfonylamino) -4- (synthesized in Example 13) By using cis-9-octadecenylcarbamoyl) benzoic acid methyl ester and operating in the same manner as in Example 60, colorless solid 4- (trans-
9,10-dihydroxyoctadecylcarbamoyl)-
2- (1-Naphthylsulfonylamino) benzoic acid (compound 53) was obtained. Yield 80%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22 (26H, m),
1.38 (2H, m), 3.19-3.37 (4H, m), 7.54-7.69 (3H,
m), 7.84-8.21 (7H, m), 8.64 (1H, m).

Example 71 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2- (5-dimethylamino-1-naphthylsulfonylamino) benzoic acid Synthesized in Example 14 2- (5-dimethylamino- 1-
The same operation as in Example 60 was carried out using naphthylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester to give 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) as a colorless solid. ) -2- (5-Dimethylamino-1-naphthylsulfonylamino) benzoic acid (Compound 54) was obtained. Yield 76%. ¹ H-NMR (DMSO-d ₆ ): δ 0.82 (3H, m), 1.21-1.49 (28H,
m), 2.77-2.82 (6H, m), 3.18-3.41 (4H, m), 7.08-7.
42 (2H, m), 7.51-7.70 (2H, m), 7.90-8.16 (3H, m),
8.31-8.61 (3H, m).

Example 72 2- (2-acetamido-4-methyl-5-thiazolylsulfonylamino) -4- (trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid Synthesized in Example 15 Using 2-acetamido-4-methyl-5-thiazolylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid methyl ester, the same procedure as in Example 60 was carried out to give a colorless solid. 2- (2-acetamido-4-methyl-
5-thiazolylsulfonylamino) -4- (trans-9,10-dihydroxyoctadecylcarbamoyl)
Benzoic acid (compound 55) was obtained. Yield 26%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21 (26H, m),
1.35 (2H, m), 2.08 (3H, s), 2.38 (3H, s), 3.10-3.2
0 (4H, m), 5.29 (2H, m), 7.67-7.85 (3H, m), 8.10
(1H, m).

Example 73 2- (2-aminobenzylsulfonylamino) -4-
(Trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid Example 29 was obtained using 2- (2-nitrobenzylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid synthesized in Example 52. By performing the same operation as described above, colorless solid 2- (2-aminobenzylsulfonylamino) -4- (trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid (Compound 56) was obtained. 94% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22-1.49 (28H,
m), 3.17-3.25 (4H, m), 4.54 (2H, s), 7.11-7.20 (4
H, m), 7.82-7.93 (3H, m), 8.37 (1H, m).

Example 74 2- (2-aminophenylsulfonylamino) -4-
(Trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid Example 29 was obtained using 2- (2-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid synthesized in Example 53. By performing the same operation as described above, colorless solid 2- (2-aminophenylsulfonylamino) -4- (trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid (compound 57) was obtained. 94% yield. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.47 (28H,
m), 3.15-3.22 (4H, m), 7.19-7.25 (2H, m), 7.42-7.
54 (3H, m), 7.86-7.88 (2H, m), 8.55 (1H, m).

Example 75 2- (3-aminophenylsulfonylamino) -4-
(Trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid Example 29 was obtained using 2- (3-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid synthesized in Example 54. By performing the same operation as described above, colorless solid 2- (3-aminophenylsulfonylamino) -4- (trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid (compound 58) was obtained. Yield 99%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.48 (28H,
m), 3.19-3.23 (4H, m), 7.10-7.40 (3H, m), 8.24-8.
29 (2H, m), 8.59-8.65 (2H, m), 8.78 (1H, m).

Example 76 2- (4-aminophenylsulfonylamino) -4-
(Trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid Example 29 was obtained using 2- (4-nitrophenylsulfonylamino) -4- (cis-9-octadecenylcarbamoyl) benzoic acid synthesized in Example 55. By the same operation as described above, 2- (4-aminophenylsulfonylamino) -4- (trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid (compound 59) was obtained as a colorless solid. Yield 98%. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.22-1.46 (28H,
m), 3.11-3.28 (4H, m), 7.51-7.55 (3H, m), 7.67-7.7
1 (2H, m), 7.94-7.98 (2H, m), 8.51 (1H, m).

Example 77 2- (1,2-dibromoethylsulfonylamino)-
4- (trans-9,10-dihydroxyoctadecylcarbamoyl) benzoic acid 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-vinylsulfonylaminobenzoic acid synthesized in Example 63 (0.2 g, 0.361 mmol)
l) in chloroform (5 mL) solution under ice cooling, 3.4
8M bromine-chloroform solution (0.12 mL, 0.4
33 mmol) was added dropwise, and the mixture was stirred for 1 hour, and further stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained brown solid was recrystallized from ethanol: water (1: 1, v / v, 1 mL) and dried at room temperature to give 2- (1,2-dibromoethylsulfonyl). Amino) -4- (trans-
9,10-dihydroxyoctadecylcarbamoyl) benzoic acid (0.2 g, 78%; compound 60) was obtained. ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.21-1.49 (28H,
m), 3.14-3.26 (2H, m), 3.91 (1H, dd, J = 12.0, 8.4
Hz), 4.24 (1H, dd, J = 2.0, 4.2 Hz), 5.92 (1H, d
d, J = 8.4, 4.2 Hz), 7.61 (1H, dd, J = 8.1, 1.5 H
z), 7.99 (1H, d, J = 1.5 Hz), 8.03 (1H, d, J = 8.1
Hz), 8.62 (1H, m), 11.23 (1H, br s).

Example 78 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2-ethylsulfonylaminobenzenecarbohydroxamic acid 4- (trans-9,10-dihydroxyoctadecylcarbamoyl) -2 synthesized in Example 60 -Ethylsulfonylaminobenzoic acid (1.14 g, 2.048 mm
ol) and dimethylformamide (0.15 g, 2.0
4 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and tetrahydrofuran (30 mL), and oxalyl chloride (1.3 g, 10.238 mmol) was added under ice-cooling.
Was added dropwise and stirred for 40 minutes. The obtained reaction solution was treated with hydroxyamine hydrochloride (1.138 g, 16.381 m).
mol) and triethylamine (2.486 g, 24.5).
(71 mmol) in a solution of tetrahydrofuran (10 mL) and water (2 mL). After stirring at room temperature for 30 minutes,
The reaction mixture was poured into 2N aqueous hydrochloric acid (10 mL),
After extraction with ethyl acetate (100 mL), the organic phase was washed with saturated saline and dried over anhydrous sodium sulfate. After removing the inorganic salt by filtration, the solvent was distilled off under reduced pressure, and the obtained yellow solid was recrystallized from ethanol: water (6: 5, v / v, 6 mL) and dried at room temperature to obtain a yellow solid. 4- (Trans-
9,10-dihydroxyoctadecylcarbamoyl)-
There was obtained 2-ethylsulfonylaminobenzenecarbohydroxamic acid (0.55 g, 47%; compound 61). ¹ H-NMR (DMSO-d ₆ ): δ 0.83 (3H, m), 1.14 (2H, t, J
= 7.2 Hz), 1.22-1.49 (28H, m), 3.15-3.24 (6H, m),
7.42 (1H, dd, J = 8.1, 1.5 Hz), 7.70 (1H, d, J =
8.1 Hz), 7.88 (1H, d, J = 1.5 Hz), 8.51 (1H, m),
9.48 (1H, br s), 11.72 (1H, br s).

Test Example 1 PKC Activity (Method of Measuring PKC Activation) PKC activity was measured by a kit for measuring non-radioimmuno PKC activity [PepTag, manufactured by Promega Corporation]
(Registered trademark)]. That is, a peptide phosphorylated by PKC is labeled with a fluorescent light, and the peptide phosphorylated by PKC is separated by agarose electrophoresis. The electrophoresis image of the agarose gel after electrophoresis was imported into a computer, and the fluorescence intensity was analyzed by image analysis (NIH Im
age 1.61). The analysis is performed using the plot profile (Plot
Using the profile, the band peak areas of the phosphorylated peptide and the non-phosphorylated peptide were measured. From this area value, the ratio of phosphorylated peptide (P ratio) was calculated. The PKC activation rate was based on the following equation. PKC activation rate (%) = [(P ratio of subject−P of base material)
Ratio) / base P ratio] × 100

(Test Results) The PKC activation rates of the compounds of the present invention are shown in Table 2. This result indicates that the compound represented by the general formula (I) of the present invention
Shows that the compound shown by has a PKC activating effect.

[0131]

[Table 2]

[0132]

The compound of the present invention represented by formula (I) and a pharmaceutically acceptable salt thereof involve PKC of a warm-blooded animal (eg, human, rabbit, guinea pig, rat, dog, cat, etc.). It is useful as a prophylactic / therapeutic agent for diseases such as ocular hypertension, glaucoma, central nervous system disorders, senile dementia, Alzheimer's disease, and tumors, and as an immunostimulant by superoxide from neutrophils.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 27/06 A61P 27/06 43/00 111 43/00 111 C07C 311/08 C07C 311/08 311/09 311/09 311/11 311/11 311/13 311/13 311/21 311/21 311/35 311/35 311/44 311/44 C07D 277/44 C07D 277/44 // C07C 237/30 C07C 237 / 30 F-term (reference) 4C033 AD05 AD13 AD17 AD20 4C086 AA01 AA02 AA03 BC82 MA01 MA04 NA14 ZA02 ZA16 ZA33 ZB09 ZB26 ZC19 4C206 AA01 AA02 AA03 JA16 KA01 MA01 MA04 MA12 NA14 ZA02 ZA16 ZA33 ZB26 AB ZAB ZB26 AB ZAB ZAB ZAB ZAB ZAB ZAB ZAB ZAB ZA26

Claims (4)

[Claims] 1. A compound of the general formula (I) [In the formula, R ¹ represents an alkyl group or an alkenyl group which may be substituted with a hydroxyl group, and R ² represents a carbonyl group substituted with an alkyl group or an alkenyl group or a compound represented by the formula (II). (In the formula, R ⁴ represents an alkyl group which may be substituted, or an alkenyl group, an aromatic hydrocarbon group which may be substituted with a nitro group or an amino group, or a thiazolyl group having a substituent.) And R ³ represents a hydroxymethyl group or a carboxyl group which may be substituted or esterified with a hydroxyamino group.] Or a pharmaceutically acceptable salt thereof. 2. A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. An activator of protein kinase C comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The medicament according to claim 2, which is an intraocular pressure reducing agent.