JPH08325154A - Benzoic acid derivative and phospholipase a2 inhibitor containing the same - Google Patents

Abstract

PURPOSE: To obtain a benzoic acid derivative which has strong inhibitory action against PLA2 type I and type II, and is useful as a preventive and/or therapeutic agent for inflammatory diseases such as pancreatitis, rheumatism, allergy, ischemic angiopathy, bronchitic asthma or ulcers and an PLA2 inhibitor. CONSTITUTION: The objective compound is represented by formula I (X is O, S; R1 is H, a lower alkyl; R2 is a 10-30C alkyl; R3 -R6 are each H, hydroxy group, nitro, amino, cyano, a lower alkylamino), for example, 2-(pentadecyloxy) benzoic acid. A benzoic acid derivative of formula II (X is O, S; R9 is H, lower alkyl; R10 is a 10-30C alkyl; R11 and R12 are each H, nitro, amino, a lower alkylsulfonyl-amino) is an unknown compound among the derivatives of formula I. The compound of formula I or formula II is obtained by adding a compound of the formula: R2 -OH, then triphenylphosphine to a compound of formula III, dissolving or suspending them in a solvent and dropping a diethyl azodicarboxylate to effect the reactions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to phospholipase A ₂ (hereinafter, referred to as P) containing a benzoic acid derivative as an active ingredient.
(Abbreviated as LA ₂ ) inhibitor. More specifically, P which is useful as a prophylactic and / or therapeutic drug for inflammatory diseases such as pancreatitis, rheumatism, allergy, ischemic vascular disorder, bronchial asthma, ulcer, arthritis, dermatitis, gout, and trauma-induced inflammation.
It relates to LA ₂ inhibitors.

[0002]

2. Description of the Related Art Steroid drugs and non-steroid drugs have been known as therapeutic drugs for various inflammatory diseases. The former exhibits a strong anti-inflammatory effect by inhibiting the biosynthetic pathways of both prostaglandins and leukotrienes, but at the same time, in many cases, side effects appear and pose a problem. Further, the latter is desired to have a more effective drug with a weaker anti-inflammatory effect than the former.

On the other hand, PLA ₂ is drawing attention as a rate-limiting enzyme for a series of in vivo reactions of prostaglandins and leukotrienes. This PLA ₂ inhibitor can suppress the biosynthesis of both prostaglandins and leukotrienes,
It is expected to be a drug having a strong anti-inflammatory effect with few side effects. The anti-inflammatory effect of PLA ₂ inhibitors has already been described in numerous domestic and foreign literature [Drug o
f the Future , 15 , 140 (1990); Arthritis and Rheumatis
m , 36 , 190 (1993); Immunology Today , 12 , 143 (1991).
etc]. Various PLA ₂ inhibitors such as p-bromophenacyl bromide have been known so far, but there are problems such as insufficient inhibitory activity, and none have been marketed as pharmaceuticals.

The compounds represented by the general formula (1) include known compounds, and their use is known as a coupler raw material [CS265355, DE21].
14577, EP423764, DD255999], anthelmintic material [Collect.C
zech.Chem.Commun. 41 , 3628 (1976)], anti-tuberculosis drug [Pharmaceutical magazine, 79 , 1378 (1959)], etc., and the compound represented by the general formula (1) exerts a PLA ₂ inhibitory action. Nothing is known to show.

[0005]

It is known that PLA ₂ has type I, which is exocrine as a digestive enzyme from the pancreas, and endocrine type II, which is present in cells and is involved in the initial process of arachidonic acid metabolism. Type II is considered to be important in normal inflammation. However, in pancreatitis, unlike normal inflammation, I
The first problem is autolysis by type I enzymes, and the proteases, amylase, lipase, and I that escape from the pancreas into the blood
Type PLA _{2 and the} like act on each organ to cause inflammation, and type II PLA ₂ is activated at that site, which is considered to cause multiple organ damage [Scand. J. Gastroent. , 15 , 519 (198
0); Digestion , 52 , 232 (1992); International Journal
of Pancreatology , 8 , 187 (1991)]. Accordingly, to be useful for inflammatory diseases by including pancreatitis, it is necessary PLA ₂ inhibitor together strongly inhibit type I and type II, which until PLA ₂ inhibitors from this point of view The search for is unknown. That is, the present invention includes type I and II
The object is to provide a PLA ₂ inhibitor that strongly inhibits both types.

[0006]

The present inventors have synthesized and evaluated many compounds in order to solve the above problems. Among them, the benzoic acid derivatives shown below have strong P
The present invention has been completed by finding that it has LA ₂ inhibitory activity and is useful as a preventive and / or therapeutic drug for inflammatory diseases such as pancreatitis. That is, the present invention provides: [1] General formula (1) [Chemical formula 3]

[0007]

[Chemical 3](In the formula, X represents an oxygen atom or a sulfur atom, and₁Is hydrogen
Atom, lower alkyl group,-(CH₂)_nC (= O) O
R₇,-(CH₂)_nOC (= O) R₇Or- (CH₂)_n
N (R₇) (R₈), And R₂Is a halogen atom, phenyl
Group, substituted phenyl group or hydroxyl group
Well, one -O-, -S-, -S at any position on the way
(O)-, -S (O)₂-, -N (R₇)-, -C (=
O)-, -C (= O) O-, -OC (= O)-, -C
(= O) N (R₇)-, -N (R₇) C (= O)-, double
It may have a bond selected from a bond and a triple bond.
10 to 3 carbon atoms that may be branched in a chain or ring structure
Represents an alkyl group of 0, R₃, R_Four, R _FiveAnd R₆Are the same
Or differently, hydrogen atom, hydroxyl group, nitro group, amino
Group, cyano group, lower alkylamino group, hydroxy lower
Alkylamino group, lower alkanoylamino group, lower alkanoylamino group
Lucanoyloxy group, lower alkylsulfonylamino
Group, lower alkylsulfonyloxy group, lower alkoxy
Group, hydroxy lower alkoxyl group, lower alkyl
Group, lower alkanoyl group, carboxyl group, carbamoy
Group, halogen atom or halogenated lower alkyl group
Show, R₇And R₈Are the same or different hydrogen atoms,
Lower alkyl group or -CH₂CH₂OH, n is 1
Indicates an integer from 1 to 6. ) Is characterized by
Effective with benzoic acid derivatives or their pharmaceutically acceptable salts
Phospholipase A contained as a component₂An inhibitor,
[2] General formula (2) [Chemical formula 4]

[0008]

[Chemical 4] (In the formula, X is an oxygen atom or a sulfur atom, R ₉ is a hydrogen atom, a lower alkyl group or-(CH ₂ ) n-N
(R ₁₃ ) (R ₁₄ ), wherein R ₁₀ may be substituted with a halogen atom, a carboxyl group, a hydroxyl group, a phenyl group or a substituted phenyl group, and one —O— bond or 1 at any position on the way. And an alkyl group having 10 to 30 carbon atoms and optionally having a double bond, which may be linear or branched, and R ₁₁ and R ₁₂ are the same or different and each is a hydrogen atom or a nitro group. , An amino group, a lower alkylsulfonylamino group, a hydroxyl group, a lower alkoxyl group or a hydroxy lower alkoxyl group. R ₁₃ and R ₁₄ are the same or different and each represents a hydrogen atom or a lower alkyl group.
n represents an integer of 1 to 6. Provided that when R ₁₁ and R ₁₂ are both hydrogen atoms, R ₁₀ has 12, 14 carbon atoms,
The case where 16 or 18 is an unsubstituted straight chain alkyl group or a branched alkyl group is excluded. ) Is a benzoic acid derivative or a pharmacologically acceptable salt thereof,

[3] X in the general formula (2) is an oxygen atom, R
The alkoxybenzoic acid derivative according to claim 2, wherein ₁₀ is a linear alkyl group having 10 to 22 carbon atoms, and R ₁₁ and R ₁₂ are hydrogen atoms, or a pharmaceutically acceptable salt thereof. However,
Except when R ₁₀ has 12, 14, 16 or 18 carbon atoms, and

[4] Pancreatitis, rheumatism, allergy, ischemic vascular disorder, bronchial asthma, ulcer, arthritis, dermatitis, which contains the phospholipase A ₂ inhibitor according to any one of [1] to [3] as an active ingredient. A prophylactic and / or therapeutic agent for inflammatory diseases such as gout or trauma-induced inflammation, and

[5] The preventive and / or therapeutic drug according to [4], wherein the inflammatory disease is acute or chronic pancreatitis.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below. In the general formula (1), O is present at the ortho position of -CO ₂ R _1.
In the general formula (2), R ₂ group and SR ₂ group are —CO ₂
It is important that OR ₁₀ and SR ₁₀ groups are present at the ortho position of R _{9 and} the inhibitory activity against type I PLA ₂ is low when a substituent is present at the meta or para position.

R ₂ and R ₁₀ have 10 to 30 carbon atoms, preferably 10 to 22 carbon atoms. Carbon number 1
When it is less than 0, the inhibitory activity against type I and type II PLA ₂ is remarkably reduced, and when the number of carbon atoms exceeds 30, the type I PLA ₂ is reduced.
Decreased inhibitory activity against ₂ . R ₂ may be substituted with a halogen atom or a hydroxyl group, but in the case of a hydroxyl group, 2 or less is preferable. Further, R ₂ may have one ether bond or the like at any position of its substituent, but the presence of two or more shows a decrease in activity. It is preferable that both R ₄ and R ₅ are hydrogen atoms, and further that R ₃ and R ₆ are the same or different and each is a hydrogen atom, a hydroxyl group or a nitro group.

The main PLA ₂ inhibitory activity in vitro is a carboxylic acid compound or a salt thereof in which R ₁ or R ₉ of the general formula (1) or (2) is a hydrogen atom. Can also be used as a prodrug by conventional techniques for the purpose of prolonging the solubility, reducing toxicity, improving water solubility, improving physical properties, and the like. In addition to hydrogen atom as R ₁ , a lower alkyl group, — (CH ₂ ) _n C (= O) OR ₇ ,-(C
_{H 2) n OC (= O} ) R 7 or _{- (CH 2) n N (} R 7)
R _{9 in} (R ₈ ) may be in the form of a hydrogen atom, a lower alkyl group, or — (CH ₂ ) _n —N (R ₁₃ ) (R ₁₄ ).

The lower alkyl group used in the description of the general formula (1) or (2) means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and a specific example is a methyl group. , Ethyl group, propyl group, butyl group, 2-methylpropyl group, hexyl group and the like.

In the general formula (1) or (2),
Specific examples of R ₂ or R ₁₀ include decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group,
Pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, docosyl group, tricosyl group, hexacosyl group, icosyl group, triacosyl group, 2
-Methyldecyl group, 2-hexyldecyl group, 6-ethyldecyl group, 12-methyltetradecyl group, 14-ethylhexadecyl group, cholesteryl group, 12-cyclohexyldodecyl group, 1H, 1H, 2H, 2H-heptadecafluorodecyl group Group, 2-hydroxyhexadecyl group, 18
-Hydroxyoctadecyl group, 16-methoxyhexadecyl group, 14-butoxytetradecyl group, 12- (hexylthio) dodecyl group, 12- (hexylsulfinyl) dodecyl group,

12- (hexylsulfonyl) dodecyl group, 14- (N, N-dimethylamino) tetradecyl group, 14- (N-hexylamino) tetradecyl group, 2
-Oxodocosyl group, hexadecyloxycarbonylmethyl group, 16- (ethoxycarbonyl) hexadecyl group, 16- (hexanoyloxy) hexadecyl group, 2
-(Dodecanoyloxy) ethyl group, 12- (butanoylamino) dodecyl group, 12- (N-hexyl (hexanoylamino)) dodecyl group, 16- (N, N-dibutylaminocarbonyl) hexadecyl group, oleyl group , Hexadec-2-ynyl group, 2- (12-chlorododecyloxy) ethyl group, 10- (isopropyloxy) decyl group, 1-ethyl-2- (dodecyloxy) butyl group,
Examples thereof include farnesyl group, geranyl group and geranylgeranyl group.

Specific examples of the lower alkylamino group represented by R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ and R _{12 in} the general formulas (1) and (2) include a methylamino group and an ethyl group. Amino group, propylamino group, butylamino group, hexylamino group, dimethylamino group, methylethylamino group, 2
-Methylpropylamino group and the like, and specific examples of the hydroxy lower alkylamino group include hydroxymethylamino group, 2-hydroxyethylamino group, and 3
-Hydroxypropylamino group, 4-hydroxybutylamino group, 6-hydroxyhexylamino group, N, N-
And a bis (2-hydroxyethyl) amino group, an N, N-bis (4-hydroxybutyl) amino group, an N- (2-hydroxyethyl) -N- (4-hydroxybutyl) amino group, and the like.

Specific examples of the lower alkanoylamino group include acetylamino group, propanoylamino group, butanoylamino group and hexanoylamino group. Specific examples of the lower alkanoyloxy group include:
Acetoxyl group, propanoyloxy group, butanoyloxy group, hexanoyloxy group and the like, specific examples of the lower alkylsulfonylamino group, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, Butylsulfonylamino group, hexylsulfonylamino group and the like, and specific examples of the lower alkylsulfonyloxy group include a methylsulfonyloxy group, an ethylsulfonyloxy group,
Examples thereof include a butylsulfonyloxy group and a hexylsulfonyloxy group, and specific examples of the lower alkoxyl group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a hexyloxy group, and a 2-methylpropoxy group. ,

Specific examples of the hydroxy lower alkoxyl group include hydroxymethoxy group, 2-hydroxyethoxy group, 2-hydroxypropoxy group, 3-hydroxypropoxy group, 2-hydroxybutoxy group, 4-hydroxybutoxy group, 6 -Hydroxyhexyloxy group and the like, and specific examples of the lower alkyl group include:
Examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a 2-methylpropyl group, and a hexyl group. Specific examples of the lower alkanoyl group include an acetyl group, a propanoyl group, a butanoyl group, and a hexanoyl group. Specific examples of the halogen atom include fluorine, chlorine, bromine and iodine, and specific examples of the halogenated lower alkyl group include chloromethyl group, bromomethyl group, methyl iodide group and trifluoro group. Examples thereof include a methyl group.

In the pharmacologically acceptable salt of the compound represented by the above general formula (1), the term "pharmacologically acceptable" means that no significant side effect or toxicity appears when administered to a human body. , And its pharmacological activity are not lost. Specific examples of these pharmaceutically acceptable salts include lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts when the compound of the general formula (1) has an acidic functional group such as carboxylic acid. Examples thereof include metal salts such as ammonia, salts with organic bases such as ammonia, ethylamine, diethylamine, triethylamine, triethanolamine, piperidine, aniline, and pyridine. The compound of the general formula (1) exhibits basicity such as amine. When it has a functional group, hydrochloric acid, hydrobromic acid,
Examples thereof include salts with inorganic or organic acids such as phosphoric acid, sulfuric acid, methanesulfonic acid, maleic acid, fumaric acid, succinic acid, citric acid and tartaric acid.

Specific examples of the compound represented by the general formula (1) of the present invention are shown below, but the ester which is a prodrug thereof is also included. Furthermore, the present invention is not limited to these. (1) 2- (decyloxy) benzoic acid (2) 2- (dodecyloxy) benzoic acid (3) 2- (tridecyloxy) benzoic acid (4) 2- (tetradecyloxy) benzoic acid (5) 2- (Pentadecyloxy) benzoic acid (6) 2- (hexadecyloxy) benzoic acid (7) 2- (heptadecyloxy) benzoic acid (8) 2- (octadecyloxy) benzoic acid (9) 2- (nonadecyloxy) Benzoic acid (10) 2- (docosyloxy) benzoic acid

(11) 2- (hexacosyloxy) benzoic acid (12) 2- (triacosyloxy) benzoic acid (13) 2- (oleyloxy) benzoic acid (14) 2- (cholesteryloxy) benzoic acid Acid (15) 2- (14-Ethylhexadecyloxy) benzoic acid (16) 2- (1H, 1H, 2H, 2H-heptadecafluorodecyloxy) benzoic acid (17) 2- (16-Hydroxyhexadecyloxy) )
Benzoic acid (18) 2- (16-methoxyhexadecyloxy) benzoic acid (19) 2- (3-hydroxyhexadecyloxy) benzoic acid (20) 2- (octadecyloxy) -3-nitrobenzoic acid

(21) 2- (hexadecyloxy) -3
-Nitrobenzoic acid (22) 2- (hexadecyloxy) -3-aminobenzoic acid (23) 2- (hexadecyloxy) -3- (methylamino) benzoic acid (24) 2- (hexadecyloxy)- 3- (2-hydroxyethylamino) benzoic acid (25) 2- (hexadecyloxy) -3- (acetylamino) benzoic acid (26) 2- (hexadecyloxy) -3- (methylsulfonylamino) benzoic acid (27) 2- (Hexadecyloxy) -3-hydroxybenzoic acid (28) 2- (Hexadecyloxy) -3-methoxybenzoic acid (29) 2- (Hexadecyloxy) -3- (2-hydroxyethoxy) ) Benzoic acid (30) 2- (hexadecyloxy) -3-acetylbenzoic acid

(31) 2- (hexadecyloxy) -6
-Hydroxybenzoic acid (32) 2- (octadecyloxy) -6-hydroxybenzoic acid (33) 2- (hexadecyloxy) -6-methoxybenzoic acid (34) 2- (hexadecyloxy) -6- (2 -Hydroxyethoxy) benzoic acid (35) 2- (hexadecyloxy) -6- (4-hydroxybutoxy) benzoic acid (36) 2- (hexadecyloxy) -3-cyanobenzoic acid (37) 2- (hexa Decyloxy) -3-carboxybenzoic acid (38) 2- (hexadecyloxy) -6-carbamoylbenzoic acid (39) 2- (hexadecyloxy) -3-acetoxybenzoic acid (40) 2- (hexadecyloxy) ) -3- (Methylsulfonyloxy) benzoic acid

(41) 2- (hexadecyloxy)-
3,5-Dichlorobenzoic acid (42) 2- (hexadecyloxy) -3-hydroxy-6-methylbenzoic acid (43) 2- (hexadecyloxy) -3-chlorobenzoic acid (44) 2- (hexa Decyloxy) -3-methylbenzoic acid (45) 2- (hexadecyloxy) -4-hydroxybenzoic acid (46) 2- (hexadecyloxy) -5-chlorobenzoic acid (47) 2- (hexadecyloxy ) -5-Fluorobenzoic acid (48) 2- (hexadecyloxy) -5-methylbenzoic acid (49) 2- (hexadecyloxy) -5-aminobenzoic acid (50) 2- (hexadecyloxy)- 5-hydroxybenzoic acid

(51) 2- (hexadecyloxy) -5
-Nitrobenzoic acid (52) 2- (hexadecyloxy) -5- (chloromethyl) benzoic acid (53) 2- (hexadecyloxy) -3- (trifluoromethyl) benzoic acid (54) 2- (hexa Decyloxy) -6-hydroxybenzoic acid (55) 2- (octadecyloxy) -6-nitrobenzoic acid (56) 2- (2- (dodecyloxy) ethoxy) benzoic acid (57) 2- (18-hydroxy ( Octadecyloxy)) benzoic acid (58) 2- (12- (hexylthio) dodecyloxy) benzoic acid (59) 2- (12- (hexylsulfonyl) dodecyloxy) benzoic acid (60) 2- (14- (N, N-dimethylamino) tetradecyloxy) benzoic acid

(61) 2- (2-oxodocosyloxy) benzoic acid (62) 2- (hexadecyloxycarbonylmethoxy) benzoic acid (63) 2- (16- (ethoxycarbonyl) hexadecyloxy) benzoic acid (64) 2- (16- (hexanoyloxy) hexadecyloxy) benzoic acid (65) 2- (12- (butanoylamino) dodecyloxy) benzoic acid (66) 2- (16- (N, N- Dibutylaminocarbonyl) hexadecyloxy) benzoic acid (67) 2- (hexadec-2-ynyloxy) benzoic acid (68) 2- (2- (decanoyloxy) ethoxyethoxy) benzoic acid (69) 2- (2- (Hexadecyloxy) ethoxy)
-3-Hydroxybenzoic acid (70) 2- (2- (hexadecyloxy) ethoxy)
-3-Nitrobenzoic acid

(71) Isobutyl 2- (hexadecyloxy) benzoate (72) 2-Ethoxycarbonylmethyl benzoate (hexadecyloxy) benzoate (73) Hexanoyloxyethyl 2- (hexadecyloxy) benzoate (74) 2- (Hexadecyloxy) benzoic acid N, N-
Dibutylaminoethyl (75) 2- (hexadecyloxy) benzoic acid N, N-
Bis (2-hydroxyethyl) aminoethyl (76) 2- (geranyloxy) benzoic acid (77) 2- (farnesyloxy) benzoic acid (78) 2- (geranylgeranyloxy) benzoic acid (79) 2- (10- Phenyldecyloxy) benzoic acid (80) 2- (hexadecylthio) benzoic acid (81) 2- (octadecylthio) benzoic acid or salts thereof. These compounds may be used alone or in combination of two or more.

As described in the section of the prior art,
Known compounds are included in the compounds represented by the general formula (1), but none of them are known to exhibit a PLA ₂ inhibitory action. Further, the compound groups of claims 2 and 3 represented by the general formula (2) are novel compounds. The compounds of the general formulas (1) and (2) are produced, for example, by the following general method. General formula (3) [Chemical formula 5]

[0031]

Embedded image (In the formula, X, R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are represented by the general formula (1)
Same as for. ) To the compound represented by the general formula (4)
[Chemical 6]

[0032]

Embedded image A compound represented by R ₂ —OH (4) (wherein R ₂ is the same as in the case of the general formula (1)) relative to the compound represented by the general formula (3).
2 to 10.0 mol amount, more preferably 0.5 to 2.0 mol amount, further preferably 0.8 to 1.5 mol amount, and further triphenylphosphine compound represented by the general formula (3). 0.8 to 2.0 mol amount, more preferably 1.0 to 1.2 mol amount, and dissolved or suspended in a suitable solvent to give diethyl azodicarboxylate represented by the general formula (3). A compound represented by the general formula (1) can be obtained by adding 0.8 to 2.0 mols, more preferably 1.0 to 1.2 mols, of the compound dropwise and reacting. it can.

This reaction is carried out at a temperature from -30 ° C to the reflux temperature of the reaction mixture or less, preferably -5 to 50.
The reaction temperature is selected from the range of 20 ° C, more preferably 20 to 40 ° C. As a suitable solvent used in this reaction, any solvent inert to this reaction can be used without limitation,
For example, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, ethyl acetate, dioxane, benzene, dimethyl sulfoxide and the like can be used.

When the compounds represented by the general formulas (3) and (4) have an active functional group other than the main reaction site, it is preferable to deprotect after reacting with an appropriate protecting group. . The target product can be purified by a general method such as column chromatography, recrystallization and distillation. The compound of the general formula (2) is similarly produced.

Further, when synthesizing a carboxyl group ester of benzoic acid as a prodrug, the corresponding carboxylic acid is converted to an acid chloride with thionyl chloride or the like, and then the corresponding alcohol (eg, N, N). -Dimethylaminoethanol or the like) or reacting the corresponding carboxylic acid and alcohol with dicyclohexylcarbodiimide (hereinafter abbreviated as DCC), carbodiimidazole (hereinafter C
The desired ester form can be easily obtained by reacting in the presence of a condensing agent such as DI) and diethyl azodicarboxylate. At this time, the molar ratio of the reaction product may be any ratio, but it is preferably 0.8 to 1.2 equivalents. The solvent is also not particularly limited, but an aprotic organic solvent such as THF, ethyl ether, dioxane, toluene, pyridine, triethylamine, chloroform, methylene chloride or ethyl acetate is used. The reaction temperature is allowed from 0 ° C. to the boiling point of the solvent used, but is preferably around room temperature.

Further, the compounds represented by the general formulas (1) and (2) can be converted into pharmacologically acceptable salts by adding an appropriate acid or base.

When the anti-inflammatory agent of the present invention is used as a therapeutic agent for inflammatory diseases, the dose and dosage form are the physical properties of the compounds represented by the general formulas (1) and (2) used as the active ingredient, and the administration target. It varies depending on the symptoms, age, and sex, but for example, 10-5,000 mg, preferably 10-1,000 mg per day for an adult
As such or as a pharmaceutical composition to which a therapeutically inactive excipient is added, orally in the form of powders, granules, tablets, capsules or the like, or parenterally as suppositories, injections, infusions. It can be administered in the form of isotonic solutions, inhalants or patches.

The content of the active ingredient in the preparation is not particularly limited, but is usually 1 to 90%. The PLA of the present invention
The toxicity of ₂ inhibitors is at a level that is not problematic for use as a therapeutic drug for inflammatory diseases.

[0039]

[Examples] Hereinafter, examples of the present invention will be described in detail with reference to compound production examples, pharmaceutical preparation production examples, and pharmacological test examples. The present invention is not limited to the following examples. (Production Example of Compound) Example 1 Methyl 2- (decyloxy) benzoate Methyl salicylate 1.00 g, decanol 1.09 g,
1.81 g of triphenylphosphine was dissolved in 10 ml of THF, and 1.30 g of diethyl azodicarboxylate was added to THF.
A 3 ml solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add 50 ml of n-hexane to the residue, sludge to remove insoluble matter by filtration, and concentrate the filtrate to give crude 2-
Methyl decyloxybenzoate was obtained and subjected to silica gel column chromatography (developing solvent: ethyl acetate / n
-Hexane = 1/5) and purified with 2- (decyloxy)
1.78 g of methyl benzoate was obtained. NMR (CDC
l ₃ ) δppm: 7.77 (1H, dd), 7.42
(1H, dt), 6.89 to 7.02 (2H, m),
4.00 (2H, t), 3.88 (3H, s), 1.7
6 to 1.89 (2H, m), 1.27 to 1.60 (14
H, m), 0.87 (3H, t). Properties: Oily substance.

Example 2 2- (decyloxy) benzoic acid 1.75 g of the compound obtained in Example 1 was added to methanol 30
Dissolve in ml, and add 10% sodium hydroxide aqueous solution 5
After adding ml, the mixture was stirred at 50 ° C. for 3 hours for hydrolysis. The reaction solution was neutralized with hydrochloric acid and then concentrated under reduced pressure, and the precipitate was washed with water,
Collected by filtration. This was recrystallized from a small amount of methanol to obtain 1.54 g of 2- (decyloxy) benzoic acid.
NMR (CDCl ₃ ) δ ppm; 8.20 (1H, d
d), 7.54 (1H, dt), 7.13 (1H, d
t), 7.04 (1H, dd), 4.25 (2H, dd)
t), 1.87 to 1.97 (2H, m), 1.01
1.79 (14H, m), 0.88 (3H, t). Properties: Oily substance.

The following Example 3 was applied according to Examples 1 and 2.
To 17 compounds were synthesized. Example 3 Methyl 2- (tridecyloxy) benzoate NMR (CDCl ₃ ) δppm; 7.80 (1H, d
d,), 7.43 (1H, dt), 6.91 to 6.98.
(2H, m), 4.03 (2H, t), 3.89 (3
H, s), 1.78 to 1.88 (2H, m), 1.23
~ 1.51 (20H, m), 0.88 (3H, t). Properties: Oily substance.

Example 4 2- (Tridecyloxy) benzoic acid NMR (CDCl ₃ ) δ ppm; 8.19 (1H, d
d), 7.54 (1H, dt), 7.07 (1H, d
t), 6.89 (1H, dd), 4.23 (2H,
t), 1.90 to 1.95 (2H, m), 0.91
1.88 (20H, m), 0.87 (3H, t). Melting point: 43-44 [deg.] C.

Example 5 Methyl 2- (pentadecyloxy) benzoate NMR (CDCl ₃ ) δppm; 7.79 (1H, d
d), 7.46 (1H, dt), 6.91 to 7.00
(2H, m), 4.02 (2H, t), 3.89 (3
H, s), 1.77 to 1.88 (2H, m), 1.26
~ 1.51 (24H, m), 0.88 (3H, t). Melting point: 33-34 ° C.

Example 6 2- (pentadecyloxy) benzoic acid NMR (CDCl ₃ ) δ ppm; 8.20 (1H, d
d), 7.56 (1H, dt), 7.13 (1H, dt)
t), 7.05 (1H, d), 4.26 (2H, t),
1.87 to 1.97 (2H, m), 1.43 to 1.49
(2H, m), 1.23 to 1.33 (22H, m),
0.88 (3H, t). Melting point: 54-56 ° C.

Example 7 2- (Hexadecyloxy) benzoic acid NMR (CDCl3) δ ppm; 0.88 (t, 3)
H), 1.26-1.68 (m, 22H), 1.87-
2.01 (m, 2H), 4.25 (t, 2H), 7.0
4 (dd, 1H), 7.14 (dt, 1H), 7.55
(Dt, 1H), 8.20 (dd, 1H). Melting point: 56
~ 58 ° C.

Example 8 Methyl 2- (heptadecyloxy) benzoate NMR (CDCl ₃ ) δppm; 7.77 (1H, d
d), 7.40 to 7.46 (1H, m), 6.85
6.98 (2H, m), 4.03 (2H, t), 3.8
9 (3H, s), 1.80 to 1.88 (2H, m),
1.26 to 1.50 (28H, m), 0.88 (3H,
t). Melting point: 39-40 [deg.] C.

Example 9 2- (heptadecyloxy) benzoic acid NMR (CDCl ₃ ) δ ppm; 8.20 (1H, d
d), 7.55 (1H, dt), 7.14 (1H,
t), 7.04 (1H, d), 4.25 (2H, t),
1.87 to 1.97 (2H, m), 1.42 to 1.52
(2H, m), 1.22 to 1.36 (26H, m),
0.88 (3H, t, J = 7.3). Melting point: 61-64
° C.

Example 10 Methyl 2- (nonadecyloxy) benzoate NMR (CDCl ₃ ) δppm; 7.76 to 7.80
(1H, m), 7.37 to 7.47 (1H, m), 6.
93 to 7.00 (2H, m), 4.03 (2H, t),
3.89 (3H, s), 1.80 to 1.88 (2H,
m), 1.26 to 1.49 (32H, m), 0.88
(3H, t). Melting point: 44-46 [deg.] C.

Example 11 2- (Nonadecyloxy) benzoic acid NMR (CDCl ₃ ) δppm; 8.20 (1H, d
d), 7.55 (1H, dt), 7.14 (1H,
t), 7.05 (1H, d), 4.25 (2H, t),
1.87 to 1.97 (2H, m), 1.46 to 1.58
(2H, m), 1.22 to 1.44 (30H, m),
0.88 (3H, t). Melting point: 67-68 ° C.

Example 12 Methyl 2- (docosyloxy) benzoate NMR (CDCl ₃ ) δppm; 7.58 to 7.93
(1H, m), 7.39 to 7.46 (1H, m), 6.
93 to 6.98 (2H, m), 4.02 (2H, t),
3.88 (3H, s), 1.77 to 1.87 (2H,
m), 1.25 to 1.53 (38H, m), 0.88
(3H, t). Melting point: 64-65 ° C.

Example 13 2- (docosyloxy) benzoic acid NMR (CDCl ₃ ) δppm; 8.20 (1H, d
d), 7.55 (1H, dt), 7.14 (1H,
t), 7.05 (1H, d), 4.25 (2H,
t), 1.87 to 1.97 (2H, m), 1.46 to
1.58 (2H, m), 1.22 to 1.44 (36H,
m), 0.88 (3H, m). Melting point: 74-75 ° C.

Example 14 2- (Octadecyloxy)
Methyl-3-nitrobenzoate NMR (CDCl ₃ ) δppm; 8.00 (1H, d
d), 7.88 (1H, dd), 7.14 to 7.28.
(1H, m), 4.07 (2H, t), 3.95 (3
H, s), 1.75 to 1.85 (2H, m), 1.39
~ 1.45 (2H, m), 1.26 ~ 1.39 (28
H, m), 0.88 (3H, t). Melting point: 46-48
° C.

Example 15 2- (Octadecyloxy)
-3-Nitrobenzoic acid NMR (CDCl ₃ ) δppm; 8.33 (1H, d
d), 8.05 (1H, dt), 7.38 (1H,
t), 4.17 (2H, t), 1.83 to 1.93 (2
H, m), 1.41 to 1.44 (2H, m), 1.26
~ 1.38 (28H, m), 0.88 (3H, t). Melting point: 66-67 ° C.

Example 16 2- (docosyloxy) -3
-Methyl nitrobenzoate NMR (CDCl ₃ ) δppm; 8.00 (1H, d
d), 7.88 (1H, dd), 7.14 to 7.28.
(1H, m), 4.07 (2H, t, J = 6.5),
3.95 (3H, s), 1.75 to 1.85 (2H,
m), 1.39 to 1.45 (2H, m), 1.26 to
1.39 (36H, m), 0.88 (3H, t, J =
7.3). Melting point: 58-60 ° C.

Example 17 2- (docosyloxy) -3
- nitrobenzoic acid _{NMR (CDCl 3) δppm; 8.32} (1H, d
d), 8.04 (1H, dt), 7.37 (1H,
t), 4.17 (2H, t), 1.82 to 1.93 (2
H, m), 1.40 to 1.44 (2H, m), 1.25
~ 1.39 (36H, m), 0.88 (3H, t). Melting point: 73-75 ° C.

Example 18 2- (Hexadecyloxy)
Methyl-3-hydroxybenzoate 1.00 g of methyl 2,3-dihydroxybenzoate was dissolved in 1.5 g of pyridine, 0.67 g of acetic anhydride was added dropwise thereto, and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water to stop the reaction, and the precipitated crystals were separated by filtration. Recrystallization from methanol gave 0.99 g of methyl 3-acetoxy-2-hydroxybenzoate. The obtained methyl 3-acetoxy-2-hydroxybenzoate (0.99 g), hexadecanol (1.14 g) and triphenylphosphine (1.23 g) were added to TH.
Dissolve in F10 ml, diethyl azodicarboxylate 0.9
A solution of 8 g of THF in 3 ml was added dropwise and stirred at room temperature for 1 hour.

After concentration under reduced pressure, 50 ml of n-hexane was added to the residue.
Was added to sludge to remove insoluble matter by filtration, and the filtrate was concentrated to obtain crude methyl 2- (hexadecyloxy) -3-acetoxybenzoate, which was subjected to silica gel column chromatography (developing solvent: Purification with ethyl acetate / n-hexane = 1/5) gave 1.74 g of methyl 2- (hexadecyloxy) -3-acetoxybenzoate. Dissolve this in 10 ml of methanol and add 28%
8 ml of a methanol solution of sodium methoxide was added, and the mixture was stirred at room temperature for 1 hour. Dilute hydrochloric acid was added to this to acidify it, and the mixture was poured into a large amount of water and extracted with ethyl acetate.
1.57 g of methyl (hexadecyloxy) -3-hydroxybenzoate was obtained. NMR (CDCl ₃ ) δ ppm; 7.38 (1H, d
d), 7.14 (1H, dd), 7.03 (1H,
t), 5.92 (1H, s), 3.98 (2H, t),
3.91 (3H, s), 1.76 to 1.87 (2H,
m), 1.26 to 1.45 (26H, m), 0.88
(3H, t). Properties: Oily substance.

Example 19 2- (Hexadecyloxy)
-3-Hydroxybenzoic acid 1.55 g of the compound obtained in Example 18 was added to methanol
It was dissolved in 0 ml, 5 ml of 10% sodium hydroxide aqueous solution was further added, and the mixture was stirred at 60 ° C. for 4 hours for hydrolysis. Concentrated hydrochloric acid was added to the reaction solution to make it acidic, and the precipitate was filtered, washed with water,
After drying, 1.37 g of 2- (hexadecyloxy) -3-hydroxybenzoic acid was obtained. NMR (CDCl ₃ ) δ ppm; 7.63 (1H, d
d), 7.13 to 7.17 (2H, m), 4.11 (2
H, t), 1.81-1.92 (2H, m), 1.25
~ 1.46 (26H, m), 0.88 (3H, t). Melting point: 92-98 ° C.

Example 20 2- (Hexadecyloxy)
3- (Methylsulfonylamino) benzoic acid Methyl 3-nitrosalicylate 1.00 g, hexadecanol 1.23 g, and triphenylphosphine 1.33 g were dissolved in THF 10 ml, and a solution of diethyl azodicarboxylate 0.88 g in THF 3 ml was added dropwise. Then, the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add 50 ml of n-hexane to the residue, sludge to remove insoluble matter by filtration, concentrate the filtrate, add 20 ml of methanol to the residue, stir, and cool with ice-cooling to filter 2- (hexadecyl). 1.97 g of methyl (oxy) -3-nitrobenzoate was obtained. This compound was dissolved in ethyl acetate, 10% Pd / C (0.06 g) was added, and the mixture was hydrogenated under normal pressure. After 1.6 hours the catalyst was filtered off and
After concentration under reduced pressure, 1.88 g of methyl 2- (hexadecyloxy) -3-aminobenzoate was obtained.

To this, 0.66 g of triethylamine was added, and 25 ml of chloroform was added thereto to dissolve it, followed by cooling with ice. 0.66 g of methanesulfonic acid chloride was dissolved in 10 ml of chloroform and added dropwise, followed by stirring for 30 minutes. The reaction solution was washed with water and then concentrated under reduced pressure to obtain methyl 2- (hexadecyloxy) -3- (methylsulfonylamino) benzoate. Dissolve this in 30 ml of methanol, add 5 ml of 10% aqueous sodium hydroxide solution, and add 50 ° C.
And stirred for 3 hours for hydrolysis. Concentrated hydrochloric acid was added to the reaction solution to make it acidic, and the precipitate was filtered, washed with water and dried to obtain 2.18 g of 2- (hexadecyloxy) -3- (methylsulfonylamino) benzoic acid. NMR (CDCl ₃ ) δ ppm; 7.80 (1H,
d), 7.78 (1H, t), 7.23 (1H, d),
4.03 (2H, t), 3.08 (3H, s), 1.8
0 to 1.90 (2H, m), 1.20 to 1.60 (26
H, m), 0.88 (3H, t). Melting point: 92-94
° C.

Example 21 2- (Hexadecyloxy)
Methyl-3-methoxybenzoate 1.00 Methyl 2-hydroxy-3-methoxybenzoate
g, hexadecanol 1.33 g, and triphenylphosphine 1.44 g were dissolved in THF 10 ml, a solution of diethyl azodicarboxylate 1.20 g in THF 3 ml was added dropwise, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add 50 ml of n-hexane to the residue, sludge to remove insoluble matter by filtration, concentrate the filtrate, add 20 ml of methanol to the residue, stir, and cool with ice-cooling. 1.76 g of methyl decyloxy) -3-methoxybenzoate was obtained. NMR (CDCl ₃ ) δ ppm; 7.32 (1H,
q), 7.01 to 7.23 (2H, m), 4.01 (2
H, t), 3.89 (3H, s), 3.86 (3H,
s), 1.73 to 1.84 (2H, m), 1.26 to
1.56 (26H, m), 0.88 (3H, t). Melting point: 32-33 [deg.] C.

Example 22 2- (Hexadecyloxy)
-3-Methoxybenzoic acid 1.70 g of the compound obtained in Example 20 was added to methanol 3
It was dissolved in 0 ml, 5 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 60 ° C. for 5 hours for hydrolysis.
Concentrated hydrochloric acid was added to the reaction solution to make it acidic, and the precipitate was filtered, washed with water, and dried to obtain 1.69 g of 2- (hexadecyloxy) -3-methoxybenzoic acid. NMR (CDCl ₃ ) δ ppm; 11.59 (1H, b
s), 7.74 (1H, q), 7.13 to 7.20 (2
H, m), 4.26 (2H, t), 3.91 (3H,
s), 1.78 to 1.91 (2H, m), 1.06 to
1.54 (26H, m), 0.88 (3H, t). Melting point: 62-63 [deg.] C.

Example 23 2- (hexadecyloxy)
TH 3- (2-Hydroxyethoxy) benzoic acid 1.18 g of methyl 2- (hexadecyloxy) -3-hydroxybenzoate, 0.31 g of monoacetylethylene glycol, 0.79 g of triphenylphosphine
Dissolve in F10 ml, diethyl azodicarboxylate 0.6
A solution of 3 g of THF in 3 ml was dropped, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure and then silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 15 /
1 → 10/1) to give methyl 3- (2-acetoxyethoxy) -2- (hexadecyloxy) benzoate 1.41 g. This was dissolved in 30 ml of methanol, 5 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 60 ° C. for 5 hours for hydrolysis. Concentrated hydrochloric acid was added to the reaction solution to make it acidic, and the precipitate was filtered, washed with water and dried,
0.64 g of 2- (hexadecyloxy) -3- (2-hydroxyethoxy) benzoic acid was obtained. NMR (CDCl ₃ ) δ ppm; 7.77 (1H,
m), 7.19 (2H, m), 4.29 (2H, t),
4.18 (2H, t), 4.03 (2H, t), 1.8
0 to 1.91 (2H, m), 1.26 to 1.46 (26
H, m), 0.88 (3H, t). Melting point: 71-74
° C.

Example 24 2- (hexadecyloxy)
Methyl-6-hydroxybenzoate 2,6-dihydroxybenzoate 1.00 g, hexadecyl alcohol 1.44 g and triphenylphosphine 1.56 g were dissolved in THF 10 ml, and a solution of diethyl azodicarboxylate 1.20 g in THF 3 ml was added dropwise. did. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/5) to give methyl 2- (hexadecyloxy) -6-hydroxybenzoate 1. 53 g were obtained. NMR (CDCl ₃ ) δ ppm; 7.30 (1H, d
d), 6.57 (1H, d), 6.38 (1H, d),
3.98 (2H, t), 3.93 (3H, s), 1.7
8 to 1.83 (2H, m), 1.42 to 1.60 (2
H, m), 1.20 to 1.40 (24H, m), 0.8
8 (3H, t). Melting point: 52-53 [deg.] C.

Example 25 2- (hexadecyloxy)
-6-Hydroxybenzoic acid 1.5 g of the compound obtained in Example 24 was added to methanol 30
Dissolve in ml, and add 10% sodium hydroxide aqueous solution 5
After adding ml, the mixture was stirred at 70 ° C. for 4 hours for hydrolysis. The reaction solution was made acidic by adding concentrated hydrochloric acid, and the precipitate was filtered, washed with water,
After drying, 0.89 g of 2- (hexadecyloxy) -6-hydroxybenzoic acid was obtained. NMR (CDCl ₃ ) δ ppm; 7.39 (1H,
t), 6.71 (1H, d), 6.47 (1H, d),
4.23 (2H, t), 1.88 to 1.91 (2H,
m), 1.40 to 1.60 (2H, m), 1.20
1.50 (24H, m), 0.88 (3H, t). Melting point: 92-95 ° C.

Example 26 2- (octadecyloxy)
-6 g of methyl-6-hydroxybenzoic acid 2,6-dihydroxybenzoate, 1.61 g of octadecyl alcohol and 1.87 g of triphenylphosphine were dissolved in 10 ml of THF, and a solution of 1.24 g of diethyl azodicarboxylate in 3 ml of THF was added dropwise. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, 50 ml of n-hexane was added to the residue, and insoluble matter was removed by filtration, and the filtrate was concentrated. 20 ml of methanol was added to the residue and stirred, and after ice cooling. Filtration gave crude methyl 2- (octadecyloxy) -6-hydroxybenzoate. This was dissolved in 30 ml of methanol, 5 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was heated and stirred at 70 ° C. for 5 hours for hydrolysis. The reaction solution was made acidic by adding concentrated hydrochloric acid, and the precipitate was filtered, washed with water, dried and purified by silica gel column chromatography (developing solvent: chloroform / n-hexane = 2/5) to give 2- (octadecyloxy)-.
Obtained 0.59 g of 6-hydroxybenzoic acid NMR (CDCl ₃ ) δ ppm; 7.37 (1H,
t), 6.71 (1H, d), 6.47 (1H, d),
4.23 (2H, t), 1.85-1.97 (2H,
m), 1.20 to 1.70 (30H, m), 0.88
(3H, t). Melting point: 59-61 ° C.

Example 27 1.00 g of methyl salicylate 2- (3-hydroxy-pentadecyloxy) benzoate, 1.61 g of 3-hydroxy-pentadeca-1-ol and 1.81 g of triphenylphosphine were dissolved in 10 ml of THF. A solution of diethyl azodicarboxylate (1.30 g) in THF (3 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add 50 ml of n-hexane to the residue, sludge to remove insoluble matter by filtration, concentrate the filtrate to obtain crude methyl 2- (3-hydroxy-pentadecyloxy) benzoate. This was purified by silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/5), and methyl 2- (3-hydroxy-pentadecyloxy) benzoate 1.07 g
I got 1.00 g of this ester compound was added to methanol 3
It was dissolved in 0 ml, 5 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. for 3 hours for hydrolysis.

The reaction solution was neutralized with hydrochloric acid and then concentrated under reduced pressure.
The precipitate was washed with water and then collected by filtration. This was recrystallized from a small amount of methanol to obtain 0.92 g of 2- (3-hydroxy-pentadecyloxy) benzoic acid. NMR (CDCl ₃ ) δ ppm: 8.18 (1H, d
d), 7.55 (1H, dt), 7.11 (1H,
t), 7.05 (1H, d), 4.43 to 4.47 (1
H, t), 4.30-4.36 (1H, m), 3.86
~ 3.95 (1H, m), 2.00-2.11 (1H,
m), 1.52 to 1.62 (2H, m), 1.26 to
1.42 (22H, m), 0.88 (3H, t). Melting point: 80-82 ° C.

Example 28 2- (2- (dodecyloxy) ethoxy) benzoic acid methyl salicylate 1.00 g, 2- (dodecyloxy)
Ethanol 1.51 g, triphenylphosphine 1.8
1 g was dissolved in 10 ml of THF, and a solution of 1.30 g of diethyl azodicarboxylate in 3 ml of THF was added dropwise to
Stir for hours. Concentrate under reduced pressure and add 50 m of n-hexane to the residue.
l was added to sludge, insoluble matter was removed by filtration, and the filtrate was concentrated to obtain crude methyl 2- (2- (dodecyloxy) ethoxy) benzoate, which was subjected to silica gel column chromatography (developing solvent). : Ethyl acetate / n-hexane = 1/5) for purification to obtain methyl 2- (2- (dodecyloxy) ethoxy) benzoate (0.79 g).

0.75 g of this ester compound was dissolved in 30 ml of methanol, 5 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. for 3 hours for hydrolysis. The reaction solution was neutralized with hydrochloric acid and then concentrated under reduced pressure. The precipitate was washed with water and then collected by filtration. This was recrystallized from a small amount of methanol to obtain 0.69 g of 2- (2- (dodecyloxy) ethoxy) benzoic acid. NMR (CDCl ₃ ) δ ppm: 8.18 (1H, d
d), 7.55 (1H, dt), 7.15 (1H,
t), 7.05 (1H, d), 4.33 to 4.39 (2
H, m), 3.82 to 3.85 (2H, m), 3.53
(2H, m), 1.59 to 1.64 (4H, m), 1.
25 to 1.29 (16H, m), 0.88 (3H,
t). Melting point: 44-46 ° C.

Example 29 2- (Hexadecylthio) benzoate 20 ml of a THF solution containing 1.68 g of methyl thiosalicylate.
To 5.25 g of triphenylphosphine (1.0 equivalent),
7.27 g (3.0 equivalents) of 1-hexadecanol was dissolved therein, and diethyl azodicarboxylate 3.48 was added thereto at room temperature.
A solution of g (2.0 equivalents) in 12 ml of THF was slowly added dropwise. After completion of dropping, the mixture was stirred at room temperature and left overnight. This reaction liquid was sludged with n-hexane to remove insoluble matter by filtration, the filtrate was concentrated, and after concentration, silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 10).
/ 1) to obtain 4.67 g of the desired product (yield 76%).

4.67 g of this ester compound was added to methanol 4
It was dissolved in a mixed solution of 0 ml and 60 ml of dioxane, 5.7 ml of 2N sodium hydroxide aqueous solution was added thereto, and the mixture was stirred and left overnight. To this, 1N hydrochloric acid was added for neutralization, diluted with a large amount of water, extracted with ethyl acetate, concentrated, and purified by column (developing solvent: n-hexane / ethyl acetate = 5/1).
→ Chloroform was added to obtain 0.50 g of the desired product (yield 17
%) Was obtained. NMR (CDCl ₃ ) δppm: 0.88 (t, 3
H), 1.22-1.35 (m, 26H), 1.40-
1.55 (m, 2H), 1.68-1.78 (m, 2
H), 2.93 (t, 2H), 7.21 (t, 1H),
7.37 (d, 1H), 7.49 (dt, 1H), 8.
14 (dd, 1H)

Example 30 2- (pentadecylthio) benzoic acid 2- (pentadecylthio) benzoic acid was synthesized in the same manner as in Example 2 except that 1-pentadecanol was used for the corresponding alkole. . NMR (CDCl ₃ ) δ ppm; 0.88 (t, 3
H), 1.25-1.35 (m, 24H), 1.40-
1.50 (m, 2H), 1.66-1.78 (m, 2)
H), 2.93 (t, 2H), 7.23 (t, 1H),
7.38 (d, 1H), 7.49 (dt, 1H), 8.
14 (dd, 1H).

Example 31 2- (1H, 1H, 2H, 2
H, heptadecafluorodecaoxy) benzoic acid By the same procedure as in Example 27, 1 equivalent alcohol was prepared.
2- (1H, 1H, 2H, 2H, heptadecafluorodecaoxy) benzoic acid was synthesized using H, 1H, 2H, 2H, heptadecafluorodecanol. NMR (CDCl ₃ ) δppm; 2.68-2.86
(M, 2H), 4.56 (t, 2H), 7.06 (d,
1H), 7.19 (t, 1H), 7.60 (dt, 1
H), 8.20 (dd, 1H). Melting point: 79-81.5
° C.

Example 32 Methyl 2-oleyloxybenzoate Methyl salicylate 1.00 g THF solution 10 ml
1.81 g (1.05 equivalent) of triphenylphosphine, 3.00 g of oleyl alcohol (purity 60%)
(1.05 equivalent) was dissolved, and 3 ml of a THF solution of 1.38 g (1.21 equivalent) of diethyl azodicarboxylate was slowly added dropwise thereto at room temperature. After completion of dropping, stir at room temperature,
I left it overnight. This reaction liquid was sludged with n-hexane to remove insoluble matter by filtration, and the filtrate was concentrated and then subjected to silica gel column chromatography (developing solvent: n-hexane /
Ethyl acetate = 50/1) and the title compound 1.67.
g (63% yield) was obtained. NMR (CDCl ₃ ) δ ppm; 0.88 (t, 3
H), 1.2-2.1 (m, 31H), 3.88 (s,
3H), 4.02 (t, 2H), 5.34 (t, 2)
H), 6.9-7.0 (m, 2H), 7.4-7.5.
(T, 1H), 7.75-7.80 (dd, 1H). Properties: Oily substance.

Example 33 2- (phytoxy) benzoic acid methyl salicylate 1.00 g in a THF solution 13 m
1.81 g (1.05 equivalents) of triphenylphosphine and 2.06 g (1.06 equivalents) of phytol were dissolved in 1 to dissolve 1.38 g of diethyl azodicarboxylate at room temperature.
5 ml of a THF solution of (1.21 equivalent) was slowly added dropwise. After completion of the dropping, the mixture was stirred at room temperature and left overnight. This reaction solution was sludged with n-hexane, concentrated, and purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 15/1), and further ethyl acetate 5
It was dissolved in 0 ml, washed with 10% aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate.
The mixture was concentrated to dryness and dried under reduced pressure to give 2.05 g (yield 72%) of a pale yellow liquid of an ester form.

10 ml of a 10% sodium hydroxide aqueous solution was added to 10 ml of a methanol solution of 1.50 g of this ester compound, and the mixture was heated and stirred at an oil temperature of 70 ° C. for 3 hours. After allowing to cool to room temperature, it was neutralized with 1.2N hydrochloric acid, diluted with a large amount of water, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, it was concentrated to dryness and dried under reduced pressure to give 1.45 g of the target yellow liquid.
(Yield 72%) was obtained. NMR (CDCl ₃ ) δ ppm; 0.86 (t, 12
H), 1.00-1.57 (m, 19H), 1.77.
(S, 3H), 2.07 (t, 2H), 4.79 (d,
2H), 5.53 (t, 1H), 7.06 (d, 1)
H), 7.13 (t, 1H), 7.55 (dt, 1
H), 8.20 (dd, 1H). Properties: Oily substance.

Then, the same reaction as in Example 33 was carried out to obtain the target compound. Example 34 2- (farnesyloxy) benzoic acid NMR (CDCl ₃ ) δppm; 1.60-2.20
(M, 20H), 4.78 (t, 2H), 5.08-
5.11 (br, 2H), 5.53 (t, 1H), 7.
05 (dd, 1H), 7.13 (t, 1H), 7.55
(Dt, 1H), 8.20 (dd, 1H). Properties: Oily substance.

Example 35 2- (10-phenyl-n-
Decanoxy) benzoic acid NMR (CDCl ₃ ) δ ppm; 1.22-1.64
(M, 14H), 1.86-1.97 (m, 2H),
2.60 (t, 2H), 4.25 (t, 2H), 7.0
4 (d, 1H), 7.10-7.30 (m, 6H),
7.55 (dt, 1H), 8.20 (dd, 1H). Properties: Oily substance.

Example 36 2- (15-carboxyl-
Pentadecanoxy) benzoic acid NMR (DMSO) δ ppm; 1.23 (m, 24
H), 1.6-1.75 (m, 2H), 2.18 (t,
2H), 4.01 (t, 2H), 6.97 (t, 1
H), 7.09 (d, 1H), 7.46 (t, 1H),
7.59 (dd, 1H). Melting point: 84-86.5 [deg.] C.

Example 37 2- (12- (p-Carboxylphenoxy) dodecyloxy) benzoic acid NMR (DMSO) δ ppm; 1.20-1.50
(M, 16H), 1.65 to 1.80 (m, 4H),
3.95-4.05 (m, 4H), 6.90-7.05
(M, 3H), 7.09 (d, 1H), 7.43 (d
t, 1H), 7.60 (dd, 1H), 7.87 (d,
2H). Melting point: 146-147.5 [deg.] C.

Example 38 2- (12- (o-Carboxylphenoxy) dodecyloxy) benzoic acid NMR (DMSO) δ ppm; 1.20-1.50
(M, 16H), 1.60-1.80 (m, 4H),
4.00 (t, 4H), 6.96 (t, 2H), 7.0
9 (d, 2H), 7.45 (dt, 1H), 7.60
(Dd, 1H). Melting point: 136.5-138.5 [deg.] C.

Example 39 N, N dimethylaminoethyl 2- (1-hexadecyloxy) benzoic acid ester hydrochloride 0.5 g of 2- (1-hexadecyloxy) benzoic acid obtained in Example 7 (1. 38 mmol) was dissolved in 1.6 g (13.8 mmol) of thionyl chloride, stirred at room temperature, and left overnight. Thionyl chloride was distilled off and 2
-(1-Hexadecyloxy) benzoic acid chloride was obtained as crystals. This was used as it was for the next reaction.
0.13 g of N, N-dimethylaminoethanol (1.5
1 mmol) was dissolved in 5 ml of pyridine, and under a nitrogen stream,
Cool with water and add 5 ml of the above chloride to methylene chloride.
And was added dropwise in 10 minutes. It was gradually returned to room temperature and stirred for 3 hours.

Pyridine was distilled off and ethyl ether / Na was added.
The mixture was neutralized and extracted with an aqueous HCO ₃ solution, the ethyl ether layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 0.57 g of a crude prodrug. This is subjected to column chromatography (developing solvent: CHCl ₃ →
CHCl ₃ / MeOH = 50/1 → 20/1) to obtain 0.5 g of a purified product. (Yield 84.7%) NMR (DMSO) δ ppm; 0.85 (t, 3H),
1.23-1.43 (m, 26H), 1.65-1.7.
2 (m, 2H), 2.19 (s, 6H), 2.56
(T, 2H), 4.01 (t, 2H), 4.27 (t,
2H), 6.99 (t, 1H), 7.11 (d, 1)
H), 7.49 (dt, 1H), 7.60 (dd, 1)
H). Properties: Oily substance.

To 14.00 g of the above ester compound, 8.9 ml of 4N-dioxane hydrochloric acid was added. The mixture was shaken while cooling with ice water, and the precipitated solid was separated by filtration, washed with ethyl acetate and dried under reduced pressure to give 12.32 g of the desired hydrochloride (yield 81.
1%) was obtained. NMR (DMSO) δ ppm; 0.85 (t, 3H),
1.24-1.42 (m, 26H), 1.66-1.7.
6 (m, 2H), 2.83 (s, 6H), 3.47
(T, 2H), 4.03 (t, 2H), 4.55 (t,
2H), 7.01 (t, 1H), 7.15 (d, 1
H), 7.54 (dt, 1H), 7.81 (dd, 1)
H). Melting point: 84-88 ° C.

Example 40 N, N dimethylamino 2-
(Phytoxy) benzoic acid ester hydrochloride 2- (phytoxy) benzoic acid obtained in Example 33
To 5 ml of a THF solution of 5 g was added 1 ml of a THF solution of 0.22 g (1.05 equivalent) of diethyl diethyl azacarboxylate, and N, N-dimethylaminoethanol of 0.
12 g (1.12 equivalent) of THF solution (4 ml) was added dropwise over about 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated,
A small amount of ethyl acetate was added, insoluble matter was filtered off by sludging with n-hexane, and the filtrate was concentrated and then subjected to silica gel column chromatography (developing solvent: CHCl ₃ / Me.
OH = 100/0 to 100/1) to obtain 0.27 g (yield 46.6%) of a yellow liquid of a prodrug form.

4N-dioxane hydrochloric acid 0.17 was added to the total amount.
ml was added, and the mixture was shaken at room temperature for about 10 minutes, concentrated to dryness and dried under reduced pressure to obtain 0.29 g (yield: almost quantitative) of a target yellow liquid. NMR (DMSO) δ ppm; 0.85 (t, 12
H), 1.05-1.55 (m, 19H), 1.69
(S, 3H), 2.00 (t, 2H), 3.33 (s,
6H), 3.47 (t, 2H), 4.55 (t, 2)
H), 4.64 (d, 2H), 5.38 (t, 1H),
7.02 (t, 1H), 7.15 (d, 1H), 7.5
4 (dt, 1H), 7.79 (dd, 1H). Properties: Oily substance.

(Production Example of Pharmaceutical Formulation) Example 41 Production of Injectable Solution of Sodium 2- (pentadecyloxy) benzoate 20-m Sodium 2- (pentadecyloxy) benzoate
g and 0.85 g of sodium chloride, and an appropriate amount of distilled water for injection is added to dissolve the solution to make the total amount 100 ml,
Sterilization filtration was performed with a membrane filter to obtain an injection.

Example 42 2- (Pentadecyloxy)
Production of tablets of benzoic acid 2- (pentadecyloxy) benzoic acid 1 g, lactose 123
g and corn starch 20 g were mixed well, and hydroxypropyl cellulose 5 g was added to water 100 ml.
The mixture was granulated with the liquid dissolved in, and dried at 50 ° C. for 4 hours.
To this, 1 g of magnesium stearate was added and mixed well, and the tablets were tableted using a tableting machine at a weight of 150 mg per tablet.

(Pharmacological Test Example) Example 43 PLA ₂ Inhibitory Action The inhibitory action against the type I PLA ₂ of the representative compound represented by the general formula (1) can be determined by the method of Katsumata et al. [Analytical Bio
Chemistry, 154 , 676 (1986)]. The measuring method is as follows. Test tube with screw cap has a final concentration of 1
00 mM tris-hydrochloric acid buffer solution (pH = 8.0),
0.01 mg / ml bovine serum albumin and 2 mM calcium chloride were added to a solution prepared so as to have concentrations of 10, 100, and 500 μM in purified water or 10 μl of dimethyl sulfoxide. PLA ₂ (Boehringer derived from porcine pancreas)
Mannheim) 50mU per test tube 1m
10 ml tri containing g / ml bovine serum albumin
Dissolve in s-hydrochloric acid buffer (pH = 8.0) and add,
Pre-incubation was performed for 30 minutes at 7 ° C.

[0091] After that, the per tube 1mM of 1-palmitoyl -2- [1- ¹⁴ C] arachidonyl phosphatidylcholine (manufactured by Du pont Co.), 80% ethanol solution 50μl containing deoxycholate Na salt of 25mM addition, 37 Incubated at 0 ° C for 5 minutes. 200 mM
5% Triton X-10 containing ethylenediaminetetraacetic acid
100 μl of 0 was added to stop the reaction. 0.1% acetic acid /
5 ml of n-hexane and about 0.2 of anhydrous sodium sulfate were added.
5 g was added and shaken for 10 minutes. After centrifugation at 3,000 rpm for 10 minutes, 1 ml of the upper n-hexane layer was transferred to a vial and the radioactivity was measured with a liquid scintillation counter.

Next, the inhibitory effect on type II PLA ₂ is as follows:
The measurement was carried out by the following method based on the method of Dehaas et al. [Biochemistry, 13 , 1146, (1974)]. 0.1M Tris-containing 10 mM calcium chloride in an Eppendorf tube
Samples dissolved in purified water or 50 μl of dimethylsulfoxide in hydrochloric acid buffer (pH 7.5) were added to give final concentrations of 10: 1.
00, 500 μM, and partially purified PLA ₂ derived from human rheumatoid arthritis fluid (specific activity 0.
128 nmol / 30 minutes / 50 ng protein),
Preincubation was carried out at 37 ° C for 30 minutes. Then, 0.71n of E. coli cells (manufactured by Dupont) labeled with tritium-labeled arachidonic acid were added per tube.
Mol Pi, about 30,000 dpm, was suspended in 50 μl of physiological saline and added, and the mixture was incubated at 37 ° C. for 30 minutes. The reaction was stopped by adding 100 ml of 2.5 N-hydrochloric acid, and 30 mg of bovine serum albumin at 33.3 mg / ml was added.
After adding 0 μl, the mixture was centrifuged at 14,000 rpm for 5 minutes, 450 μl of the centrifugation supernatant was transferred to a vial, and the radioactivity was measured with a liquid scintillation counter. When the inhibitory activity against type I and type II is strong, the sample concentration should be 0.1, 1, 10
It was adjusted to μM or a lower concentration and measured.

PLA _{2 of} the compounds measured by these methods
The IC ₅₀ value of the inhibitory activity is shown in Table 1 [Table 1]. In this table, the compounds of Examples Nos. 39 and 40 are so-called prodrugs, and the PLA ₂ inhibitory activity value in this test is low. However, when the drug is administered into the body, the ester site is rapidly hydrolyzed by an enzyme such as esterase and converted into the corresponding active form (Example Nos. 7 and 33),
It shows a strong PLA ₂ inhibitory activity.

[0094]

[Table 1]

Example 44 Anti-Pancreatitis Action (Cerulein-Induced Acute Pancreatitis Model) In the experiment, male SD rats (Japan SLC, 9 weeks old, body weight 280-300 g) were used. The femoral vein was cannulated the day before the experiment and fasted the evening before. Cerulein (purchased from Bachem) was dissolved in physiological saline, and 20 μg / kg (2 ml / kg) was subcutaneously administered to the back of the neck 4 times every 1 hour. Specimens are suspended in 5% mannitol aqueous solution and then suspended in sodium acetate or 1NKOH.
Was added, dissolved and administered. Other control compounds were also dissolved in 5% mannitol, and then sodium acetate or 1NKOH was added in the same manner as for the test substance to adjust the pH to the same value as the test solution for administration.

Only the solvent (sodium acetate or 1 NKOH added to 5% mannitol to adjust the pH to the same as the sample solution) was administered to the pathological control group. The drug administration was started at the same time as the start of administration of cerulein through the cannula, and the infusion was performed for 5 hours at a flow rate of 0.8 ml / hr.
n. Before the administration of cerulein, each drug was dissolved in a solvent alone for 1 hour for the purpose of increasing the blood concentration of the drug.

Five hours after the administration of the drug cerulein was sacrificed by excessive administration of Nembutal, and the pancreas was excised.
The wet weight was measured. It is considered that the smaller the wet weight value in the drug administration group, the stronger the anti-pancreatitis effect. The results of representative samples are shown in [FIG. 1], and the compounds of the present invention generally have these actions.

[0098]

INDUSTRIAL APPLICABILITY The benzoic acid derivative represented by the general formula (1) is a type I or type II PL as described in detail in the examples.
It has a strong inhibitory activity against A _2, and has pancreatitis, rheumatism, allergy, ischemic vascular disorder, bronchial asthma, ulcer,
It is useful as a prophylactic and / or therapeutic agent for inflammatory diseases such as arthritis, dermatitis, gout, and trauma-induced inflammation.

[Brief description of drawings]

FIG. 1 is a graph showing an anti-pancreatitis action in a rat pancreatin-induced acute pancreatitis model.

[Explanation of symbols]

 * Significance level p <0.01 *** Significance level p <0.001 I Standard deviation

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/60 ACD A61K 31/60 ACD ACJ ACJ ACL ACL ADA ADA ADM ADM C07C 65/21 9450-4H C07C 65/21 D 205/57 9450-4H 205/57 219/14 7457-4H 219/14 229/62 9450-4H 229/62 233/54 233/54 235/46 9547-4H 235/46 311/08 7419-4H 311/08 317/44 7419-4H 317/44 321/24 7419-4H 321/24 323/50 7419-4H 323/50 (72) Inventor Hiroe Yoda 1144 Togo, Mobara-shi, Chiba Mitsui Toatsu In the chemical company (72) Inventor Nobuyuki Fukasawa 1144 Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Kengo Otsuka 1144, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. Hirokawa Kawachi Prefecture Mobara Togo 1900 address of 1 Mitsui Toatsu in the Chemical Co., Ltd. (72) inventor Yuichiro Kokubun Mobara City, Chiba Prefecture Togo 1900 address of 1 Mitsui Toatsu in the Chemical Co., Ltd.

Claims (5)

[Claims] 1. General formula (1) [Chemical formula 1](In the formula, X represents an oxygen atom or a sulfur atom, and₁Is hydrogen
Atom, lower alkyl group,-(CH₂)_nC (= O) O
R₇,-(CH₂)_nOC (= O) R₇Or- (CH₂)_n
N (R₇) (R₈), And R₂Is a halogen atom, phenyl
Group, substituted phenyl group or hydroxyl group
Well, one -O-, -S-, -S at any position on the way
(O)-, -S (O)₂-, -N (R₇)-, -C (=
O)-, -C (= O) O-, -OC (= O)-, -C
(= O) N (R₇)-, -N (R₇) C (= O)-, double
It may have a bond selected from a bond and a triple bond.
10 to 3 carbon atoms that may be branched in a chain or ring structure
Represents an alkyl group of 0, R₃, R_Four, R _FiveAnd R₆Are the same
Or differently, hydrogen atom, hydroxyl group, nitro group, amino
Group, cyano group, lower alkylamino group, hydroxy lower
Alkylamino group, lower alkanoylamino group, lower alkanoylamino group
Lucanoyloxy group, lower alkylsulfonylamino
Group, lower alkylsulfonyloxy group, lower alkoxy
Group, hydroxy lower alkoxyl group, lower alkyl
Group, lower alkanoyl group, carboxyl group, carbamoy
Group, halogen atom or halogenated lower alkyl group
Show, R₇And R₈Are the same or different hydrogen atoms,
Lower alkyl group or -CH₂CH₂OH, n is 1
Indicates an integer from 1 to 6. ) Is characterized by
Effective with benzoic acid derivatives or their pharmaceutically acceptable salts
Phospholipase A contained as a component₂Inhibitor. 2. General formula (2) [Chemical formula 2] (In the formula, X is an oxygen atom or a sulfur atom, R ₉ is a hydrogen atom, a lower alkyl group or-(CH ₂ ) n-N
(R ₁₃ ) (R ₁₄ ), wherein R ₁₀ may be substituted with a halogen atom, a carboxyl group, a hydroxyl group, a phenyl group or a substituted phenyl group, and one —O— bond or 1 at any position on the way. And an alkyl group having 10 to 30 carbon atoms and optionally having a double bond, which may be linear or branched, and R ₁₁ and R ₁₂ are the same or different and each is a hydrogen atom or a nitro group. , An amino group, a lower alkylsulfonylamino group, a hydroxyl group, a lower alkoxyl group or a hydroxy lower alkoxyl group. R ₁₃ and R ₁₄ are the same or different and each represents a hydrogen atom or a lower alkyl group.
n represents an integer of 1 to 6. Provided that when R ₁₁ and R ₁₂ are both hydrogen atoms, R ₁₀ has 12, 14 carbon atoms,
The case where 16 or 18 is an unsubstituted straight chain alkyl group or a branched alkyl group is excluded. ) A benzoic acid derivative or a pharmaceutically acceptable salt thereof. 3. The alkoxybenzoic acid derivative according to claim 2, wherein X in the general formula (2) is an oxygen atom, R ₁₀ is a linear alkyl group having 10 to 22 carbon atoms, and R ₁₁ and R ₁₂ are hydrogen atoms. A pharmacologically acceptable salt thereof. However, the case where R ₁₀ has 12, 14, 16 or 18 carbon atoms is excluded. 4. Pancreatitis, rheumatism comprising the phospholipase A ₂ inhibitor according to claim 1 as an active ingredient.
A preventive and / or therapeutic drug for inflammatory diseases such as allergy, ischemic vascular disorder, bronchial asthma, ulcer, arthritis, dermatitis, gout or trauma-induced inflammation. 5. The preventive and / or therapeutic drug according to claim 4, wherein the inflammatory disease is acute or chronic pancreatitis.