JPH0798788B2 - Hydroxamic acid derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to an aromatic derivative useful as a medical product. More specifically, it relates to a hydroxamic acid derivative having an action for treating a disease caused by an arachidonic acid cascade metabolite and a method for producing the same.

<Prior Art> Arachidonic acid is converted into various leukotrienes (LTs) in vivo by the action of lipoxygenase.
These leukotrienes have various physiological activities, for example, LTB ₄ is chemotactic activity of leukocytes, infiltration, aggregation, degranulation, superoxide anion production, to participate in the adhesive increased the like to the vascular endothelium, LTC ₄ Ya LTD ₄ exhibits physiological activities such as ileum, smooth muscle contraction of respiratory system, cutaneous vasoconstriction, vascular hyperpermeability, and hypotension (The Leukotrienes, A Biological Council
Symposium, PJPiper, Raven Pres (New York)). Currently, leukotrienes showing various physiological activities are allergic diseases such as bronchial asthma, nasal allergy, eye inflammation and atopic dermatitis, and circulatory organs such as edema, ischemic disease, hypertension and ischemic brain injury. It is known to cause systemic diseases. On the other hand, recent studies have also revealed that LTB ₄ is abundant in psoriatic lesions.

Therefore, it is considered that inhibiting lipoxygenase is effective in treating the above-mentioned allergic diseases, cardiovascular diseases, psoriasis and the like and inflammations related thereto.

<Purpose of the Invention> The inventors of the present invention have found that the hydroxamic acid derivative of the present invention can achieve such an object as a result of intensive studies on substances that inhibit the biosynthesis of chemical mediators produced by lipoxygenase. It has been reached and an object of the present invention is to provide such an aromatic derivative and a method for producing the same.

<Structure and Effect of the Invention> That is, the present invention provides the following formula [I]: And a hydroxamic acid derivative represented by the following formula [II] A hydroxylamine derivative represented by the following formula or a hydrochloride compound thereof, and the following formula [III] The following formula [I-a] is obtained by reacting the acid chloride compound represented by Is a method for producing a hydroxamic acid derivative.

In hydroxamic acid derivative represented by the formula [I], A is - (CH ₂₎ m-or (m is a is an integer of 1 to 8) represents the _{- (CH 2) m 1 -0-} (CH 2) represents m ₂ − (m ₁ and m ₂ are the same or different and is 1 or 2), or (M ₃ is 0 or 1). Preferably, m is an integer of 2 to 5, m ₁ and m ₂ are 1, and when an aromatic group is inserted, there are ortho, meta and para-substituted ones, but a meta-substituted phenylene group. Is preferred.

R ¹ represents a hydrogen atom, a C _{1 to} C ₅ alkyl group, or a non-toxic salt thereof when R ¹ is a hydrogen atom. When R ¹ is an alkyl group, examples thereof include groups such as methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl and the like, with preference given to the methyl group. Also, when R ¹ is a hydrogen atom, it can be a non-toxic salt formed with a suitable inorganic or organic base. The following can be mentioned as such a base. That is, examples of the inorganic base include hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals such as sodium, potassium, calcium and magnesium. Examples of the organic base include primary amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine and trimethylamine,
Secondary or tertiary alkylamines; primary, secondary or tertiary alkanolamines such as ethanolamine, diethanolamine, triethanolamine; diamines such as ethylenediamine, hexamethylenediamine; pyrrolidine, piperidine, Examples include cyclic saturated or unsaturated amines such as morpholine, piperazine, N-methylmorpholine and pyridine.

The compound represented by the above formula [Ia] is a compound represented by the above formula [II] and the above formula [III] in the presence of a basic compound.
It is obtained by reacting with a compound represented by

The reaction between the compound of the above formula [II] and the compound of the above formula [III] is carried out by reacting a hydroxylamine derivative represented by [II] or its hydrochloride compound with a base, for example, an organic base such as triethylamine or pyridine 4-dimethylaminopyridine. Alternatively, it is carried out by adding the acid chloride represented by the above formula [III] to a mixture of an inorganic base such as sodium carbonate or sodium hydrogen carbonate. The base used at this time is not limited to the above. As the solvent used in the reaction, for example, methylene chloride, carbon tetrachloride, tetrahydrofuran, dicrime, dimethylformamide, dimethyl sulfoxide, benzene, or a mixed solvent thereof is used, and the reaction may be carried out by adding water to the reaction system. .

The base is 0.1 to 1 with respect to the hydroxyamine derivative [II].
The amount is 0 times equivalent, preferably 0.9 to 1.4 times equivalent, and the acid chloride compound [III] is 0.1 to 10 times equivalent, preferably 0.9 to 1.4 times equivalent. The reaction temperature is 0 ° C to 150 ° C, preferably 10 ° C to 80 ° C. The reaction time varies depending on the compound, but is about 10 minutes to 24 hours. After completion of the reaction, the hydroxamic acid derivative [Ia] can be obtained by a usual post-treatment such as extraction or column chromatography.

Such hydroxamic acid derivatives can then be optionally subjected to a hydrolysis reaction.

That is, the ester group [COOR ¹¹ ] in the formula [Ia]
Can be subjected to a hydrolysis reaction. As the hydrolysis reaction, a method known per se, for example, a method of hydrolyzing in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. is adopted to obtain a corresponding carboxylic acid body.

The desired product can be isolated and purified by a conventional method such as extraction, chromatography and recrystallization.
The non-toxic salt of a carboxylic acid derivative is obtained by a salt forming reaction, and the salt forming reaction is carried out in a suitable solvent with the carboxylic acid obtained by the above-mentioned method and a base such as the above-mentioned alkali metal hydroxide or carbonate. , Ammonium hydroxide, ammonium carbonate, ammonia, amine or the like.

The hydroxylamine derivative [II] used for the synthesis of the hydroxamic acid derivative can be synthesized, for example, by a method known per se according to the route shown in Chart 1.

Specific examples of the hydroxamic acid derivative of the present invention include the following compounds.

(1) N-hydroxy-N- (1-hydroxy-2-naphthyl) -3-methoxycarbonylpropionamide (2) N-hydroxy-N- (1-hydroxy-2-naphthyl) -4-methoxycarbonylbutana Mido (3) N-hydroxy-N- (1-hydroxy-2-naphthyl) -5-methoxycarbonylpentanamide (4) N-hydroxy-N- (1-hydroxy-2-naphthyl) -6-methoxycarbonyl Hexanamide (5) N-hydroxy-N- (1-methoxy-2-naphthyl) -3-methoxycarbonylpropionamide (6) N-hydroxy-N- (1-methoxy-2-naphthyl) -4- Methoxycarbonylbutanamide (7) N-hydroxy-N- (1-methoxy-2-naphthyl) -5-methoxycarbonylpentanamide (8) N- Hydroxy-N- (1-methoxy-2-naphthyl) -6-methoxycarbonylhexanamide (9) N-hydroxy-N- (2-naphthyl) -3-methoxycarbonylpropionamide (10) N-hydroxy- N- (2-naphthyl) -4-methoxycarbonylbutanamide (11) N-hydroxy-N- (2-naphthyl) -5-methoxycarbonylpentanamide (12) N-hydroxy-N- (2-naphthyl) -6-Methoxycarbonylhexanamide (13) N-hydroxy-N- (1-hydroxy-2-naphthylmethyl) -3-methoxycarbonylpropionamide (14) N-hydroxy-N- (1-hydroxy-2) -Naphthylmethyl) -4-methoxycarbonylbutanamide (15) N-hydroxy-N- (1-hydroxy-2-naphthylmethyl) -5-me Toxycarbonylpentanamide (16) N-hydroxy-N- (1-hydroxy-2-naphthylmethyl) -6-methoxycarbonylhexanamide (17) N-hydroxy-N- (1-methoxy-2-naphthylmethyl) ) -3-Methoxycarbonylpropionamide (18) N-hydroxy-N- (1-methoxy-2-naphthylmethyl) -4-methoxycarbonylbutanamide (19) N-hydroxy-N- (1-methoxy-2) -Naphthylmethyl) -5-methoxycarbonylpentanamide (20) N-hydroxy-N- (1-methoxy-2-naphthylmethyl) -6-methoxycarbonylhexanamide (21) N-hydroxy-N- (2 -Naphthylmethyl)-
3-Methoxycarbonylpropionamide (22) N-hydroxy-N- (2-naphthylmethyl)-
4-Methoxycarbonylbutanamide (23) N-hydroxy-N- (2-naphthylmethyl)-
5-Methoxycarbonylpentanamide (24) N-hydroxy-N- (2-naphthylmethyl)-
6-Methoxycarbonylhexanamide (25) N-hydroxy-N- (1-hydroxy-2-naphthyl) -3-methoxycarbonylbenzamide (26) N-hydroxy-N- (1-hydroxy-2-naphthyl) 2-Methoxycarbonylbenzamide (27) N-hydroxy-N- (1-hydroxy-2-naphthyl) -4-methoxycarbonylbenzamide (28) N-hydroxy-N- (1-hydroxy-2-naphthyl) -3 -Methoxycarbonylmethylbenzamide (29) N-hydroxy-N- (1-hydroxy-2-naphthyl) -2-methoxycarbonylmethylbenzamide (30) N-hydroxy-N- (1-hydroxy-2-naphthyl) -4 -Methoxycarbonylmethylbenzamide (31) N-hydroxy-N- (1-hydroxy-2-na (Chyl) -3-methoxycarbonylphenylacetamide (32) N-hydroxy-N- (1-hydroxy-2-naphthyl) -2-methoxycarbonylphenylacetamide (33) N-hydroxy-N- (1- Hydroxy-2-naphthyl) -4-methoxycarbonylphenylacetamide (34) N-hydroxy-N- (1-methoxy-2-naphthyl) -3-methoxycarbonylbenzamide (35) N-hydroxy-N- (1 -Methoxy-2-naphthyl) -2-methoxycarbonylbenzamide (36) N-hydroxy-N- (1-methoxy-2-naphthyl) -4-methoxycarbonylbenzamide (37) N-hydroxy-N- (1-methoxy -2-Naphtyl) -3-methoxycarbonylmethylbenzamide (38) N-hydroxy-N- (1-methoxy- -Naphthyl) -2-methoxycarbonylmethylbenzamide (39) N-hydroxy-N- (1-methoxy-2-naphthyl) -4-methoxycarbonylmethylbenzamide (40) N-hydroxy-N- (1-methoxy-2) -Naphthyl) -3-methoxycarbonylphenylacetamide (41) N-hydroxy-N- (1-methoxy-2-naphthyl) -2-methoxycarbonylphenylamide (42) N-hydroxy-N- (1-methoxy (2-naphthyl) -4-methoxycarbonylphenylacetamide (43) N-hydroxy-N- (2-naphthyl) -3-methoxycarbonylbenzamide (44) N-hydroxy-N- (2-naphthyl) -2 -Methoxycarbonylbenzamide (45) N-hydroxy-N- (2-naphthyl) -4-methoxycarbonyl ester (46) N-hydroxy-N- (2-naphthyl) -3-methoxycarbonylmethylbenzamide (47) N-hydroxy-N- (2-naphthyl) -2-methoxycarbonylmethylbenzamide (48) N-hydroxy- N- (2-naphthyl) -4-methoxycarbonylmethylbenzamide (49) N-hydroxy-N- (2-naphthyl) -3-methoxycarbonylphenylacetamide (50) N-hydroxy-N- (2-naphthyl) ) -2-Methoxycarbonylphenyl acetamide (51) N-hydroxy-N- (2-naphthyl) -4-methoxycarbonylphenyl acetamide (52) N-hydroxy-N- (1-hydroxy-2-naphthyl) ) -4-Methoxycarbonyl-3-oxabutanamide (53) N-hydroxy-N- (1-methoxy-2-na (Chyl) -4-methoxycarbonyl-3-oxabutanamide (54) N-hydroxy-N- (2-naphthyl) -4-methoxycarbonyl-3-oxabutanamide (55) N-hydroxy-N- (1-hydroxy-2- Naphthylmethyl) -4-methoxycarbonyl-3-oxabutanamide (56) N-hydroxy-N- (1-methoxy-2-naphthylmethyl) -4-methoxycarbonyl-3-oxabutanamide (57) N-hydroxy-N- ( 2-naphthylmethyl)-
4-Methoxycarbonyl-3-oxabutanamide (58) (1) to (57) carboxylic acid compounds (59) (58) sodium salt (60) (58) potassium salt The thus obtained aromatic derivative of the present invention. Was shown to have inhibitory activity against lipoxygenase and had anti-SRS-A activity.

Therefore, the compound of the present invention is an allergic disease such as bronchial asthma, nasal allergy, allergic eye inflammation, atopic dermatitis, edema, ischemic disease, hypertension, cardiovascular disease such as ischemic encephalopathy, or diseases such as psoriasis. Treatment or prevention of
It is useful for treating or preventing viral diseases.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 Synthesis of N-hydroxy-N- (1-hydroxy-2-naphthyl) -3-methoxycarbonylpropionamide 1-Hydroxy-2-naphthylhydroxylamine hydrochloride 1.68 g (-7.9 mmol) was made into a solution of THF (10 ml) water (2 ml), and triethylamine 1.7 ml (12 mmol) was added thereto,
Then a solution of 300 mg (2 mmol) of acid chloride of 3-methoxycarbonylpropionic acid in THF (2 ml) was added. 30 at room temperature
After stirring for minutes, KHSO ₄ water was added to terminate the reaction. The organic layer was extracted with methylene chloride and dried over anhydrous magnesium sulfate.

The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 202 mg (35%) of the desired product, hydroxamic acid.

NMR (δppm, CDCl ₃ ) 2.75 (s, 4H), 3.70 (s, 3H), 6.95 (d, 1H, J = 9.0Hz), 7.2 to 7.8 (m, 4H) 8.1 to 8.5 (m, 2H), 8.35 (m, 1H) Example 2 Synthesis of N-hydroxy-N- (1-hydroxy-2-naphthyl) -4-methoxycarbonylbutanamide To a solution of 1-hydroxy-2-naphthylhydroxylamine hydrochloride 2 g (9.5 mmol) in THF (10 ml) water (2 ml) was added triethylamine 2 ml (14.2 mmol), and the mixture was cooled to 0 ° C. to give 4-methoxycarbonylbutanoic acid. Acid chloride 395mg
(2.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. KHSO ₄ water was added, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. 405m hydroxamic acid
g (56%) was obtained.

NMR (δ ppm, CDCl ₃ ) 1.9 to 2.2 (2H, m), 2.3 to 2.6 (m, 4H) 3.65 (3H, s), 6.95 (1H, d, J = 9Hz), 7.2 to 7.8 (m, 4H) , 8.0 (1H, m), 8.4 (1H, m), 9.55 (1H, m) Example 3 Synthesis of N-hydroxy-N- (1-hydroxy-2-naphthyl) -4-carboxybutanamide Methyl ester form 214 mg methanol (2 ml) THF (4 ml)
A 4N LiOH aqueous solution was added, and the mixture was stirred at room temperature for 14 hours. After the reaction, water and ether were added, and after extraction, the aqueous layer was acidified and extracted with AcOEt. The organic layer was dried, the solvent was concentrated and then crystallized with benzene to obtain a carboxylic acid compound.

184 mg (90%) NMR (δ ppm, CDCl ₃ -CD ₃ OD) 2 to 2.3 (m, 2H), 2.3 to 2.75 (m, 4H) 7.0 to 7.6 (m, 4H), 7.6 to 7.8 (m, 1H) , 7.1-7.4 (m, 1H) Example 4 Synthesis of N-hydroxy-N- (1-hydroxy-2-naphthyl) -5-methoxycarbonylpentanamide Adipic acid monomethyl ester 500mg (3.12mmol) and DMF
To 240 μl (3.12 mmol) of 25 ml methylene chloride solution was added oxalyl chloride (613 μl, 7.02 mmol) at 0 ° C., and the mixture was stirred for 1 hour. 1-Hydroxy-2
-Naphthylhydroxylamine hydrochloride 3.4 g (16 mmol) and triethylamine 3.3 ml (24 mmol) in THF (25 ml) water (5 m
l) Added to the solution at 0 ° C. After stirring at 0 ° C. for 1 hour and at room temperature for 1 hour, the reaction was terminated with KHSO ₄ water, and the mixture was extracted with methylene chloride. The organic layer was washed with 4N.HCl and then with saturated aqueous NaCl. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 762 mg (77%) of the desired product.

NMR (δ ppm, CDCl ₃ ) 1.75 (4H, m), 2.35 (4H, m), 3.70 (3H, s), 6.95 (d, 1H, J = 9Hz), 7.2 to 7.55 (m, 3H), 7.7 ( 1H, m), 8.05 (1H, m), 8.45 (1H, m), 9.70 (1H, S Like) Recrystallization (benzene) mp.111-113 ° C Example 5 N-hydroxy-N- (1-hydroxy) Synthesis of 2-naphthyl) -6-methoxycarbonylhexanamide 6-Methoxycarbonylhexanoic acid 500mg (2.87mmol)
And 564 μl (6.46 mmol) of oxalyl chloride were added to a 25 ml methylene chloride solution of 222 μl (2.87 mmol) of DMF at 0 ° C,
The mixture was stirred as it was for 1 hour. This mixture was mixed with 1-hydroxy-2-naphthylhydroxylamine hydrochloride 3.17 g (15 mmo
l) and triethylamine 3.1 ml (23 mmol) THF (25 ml)
A solution of water (5 ml) was added at 0 ° C. After stirring at 0 ° C. for 1 hour and at room temperature for 1 hour, the reaction was terminated with KHSO ₄ water, and the mixture was extracted with methylene chloride. The organic layer was washed with 4N HCl, then saturated N 2
It was washed with aCl water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 738 mg (78%) of the desired product.

NMR (δppm, CDCl ₃ ) 1.2 to 2.0. (M, 6H), 2.25 to 2.6 (m, 4H), 3.7 (s, 3H), 7.05 (d, 1H, J = 9Hz), 7.2 to 8.0 (m, 5H), 8.4 (m, 1H), 9.7 (m, 1H) Example 6 Synthesis of N-hydroxy-N- (1-hydroxy-2-naphthyl) -4-methoxycarbonyl-3-oxabutanamide Adipic acid monomethyl ester 500mg (3.38mmol) and DMF
Oxalyl chloride 660 μm (7.60 mmol) was added to 200 μl (3.38 mmol) of 25 ml methylene chloride solution at 0 ° C., and the mixture was stirred for 1 hour as it was. 1-Hydroxy-2
-Naphthylhydroxylamine hydrochloride 3.6g (17mmol) and triethylamine 3.5ml (25mmol) in THF (25ml) water (5m
l) Added to the solution at 0 ° C. After stirring at 0 ° C. for 1 hour and at room temperature for 1 hour, the reaction was terminated with KHSO ₄ water, and the mixture was extracted with methylene chloride. The organic layer was washed with 4N.HCl and then with saturated aqueous NaCl. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 710 mg (69%) of the desired product. NMR (δpp
m, CDCl ₃ ) 3.70 (s, 3H), 4.29 (s, 2H), 4.30 (s, 2H), 7.15 ~ 7.90 (m, 5H), 8.4 ~ 8.6 (m, 1H), 9.35 (m, 1H) , 9.85 (m, 1H) Example 7 Synthesis of N-hydroxy-N- (2-naphthylmethyl) -3-methoxycarbonylpropionamide 2-Naphthylmethylhydroxylamine 52mg (0.3mmo
l) in THF (5 ml), water (1 ml) solution with triethylamine 30
mg (0.3 mmol), then 40 mg (0.3 mmol) of the acid chloride of 3-methoxycarbonylpropionic acid in THF (1 m
l) The solution was added and stirred at room temperature for 30 minutes. 1N-HCl (5 ml) was added, and the target substance was extracted with methylene chloride. Extract the water, N
It was washed successively with aCl water and dried over anhydrous magnesium sulfate to obtain 82 mg (95%) of a crude product. This was recrystallized from methylene chloride and n-hexane to obtain 50 mg (58%) of colorless crystals.

_{mp91.5~92 ℃ 1 H-NMR (δppm} , CDCl 3): 2.73 (s, 4H), 3.63 (s, 3H), 4.95 (s, 2H), 7.3~8.0 (m, 8H) IR (cm - ¹ , KBr): 3180,2940,1730,1605,1230,1170,830,750 Example 8 Synthesis of N-hydroxy-N- (2-naphthylmethyl) -4-methoxycarbonylbutanamide 2-Naphthylmethylhydroxylamine 52mg (0.3mmo
l) in THF (5 ml), water (1 ml) solution with triethylamine 30
mg (0.3 mmol) was added, then a solution of 4-methoxycarbonylbutanoic acid acid chloride 49 mg (0.3 mmol) in THF (1 ml) was added, and the mixture was stirred at room temperature for 30 minutes. 1N-HCl (5 ml) was added,
The target substance was extracted with methylene chloride. The extract was washed successively with water and aqueous NaCl and dried over anhydrous magnesium sulfate to obtain a purified product, which was then subjected to silica gel column chromatography to obtain 58 mg (64%) of the desired product.

NMR (δppm, CDCl ₃ ): 1.98 (q, 2H, J = 6.0Hz) 2.2 to 2.6 (m, 4H), 3.60 (s, 3H) 4.93 (s, 2H), 7.3 to 8.0 (m, 8H) IR (Cm ^-1 , KBr): 3150,2900,1730,1600,1460,1340,1270 recrystallized (methylene chloride n-hexane) mp 109-110 ° C Example 9 N-hydroxy-N- (1-methoxy-2-) Synthesis of naphthylmethyl) -4-methoxycarbonylbutanamide 1-methoxy-2-naphthylhydroxylamine 267mg
(1.33 mmol) and triethylamine 185 μl (1.33 mmol)
In a solution of THF (15 ml) and water (3 ml) at 0 ° C under acid chloride of 4-methoxycarbonylbutanoic acid 219 mg (1.33 mmol)
THF solution (3 ml) was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour. After the reaction, an aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 279 mg (64%) of the desired product.

NMR (δ ppm, CDCl ₃ ): 1.8 to 2.1 (m, 2H), 2.2 to 2.7 (m, 4H), 3.60 (s, 3H), 3.95 (s, 3H), 5.0 (s, 2H), 7.25 to 8.15 (M, 6H) Example 10 Synthesis of N-hydroxy-N- (1-hydroxy-2-naphthyl) -3-methoxycarbonylbenzamide Isophthalic acid monomethyl ester 500 mg (2.78 mmol) D
To 25 ml of dry methylene chloride solution containing 215 μl of MF (2.78 mmol),
_{2 In the} air, add 546 μl (6.26 mmol) of oxalyl chloride to 0 ° C.
Was added, and then the mixture was brought to room temperature and stirred for 1 hour. This one
-Hydroxy-2-naphthylhydroxylamine hydrochloride
1.76 g (8.34 mmol) and triethylamine 2.9 ml (21 mmol)
Was added dropwise to a THF (25 ml) and water (5 ml) solution under N ₂ atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction was terminated by adding 4N hydrochloric acid, and the mixture was extracted with methylene chloride. The organic layer was washed with 4N hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate 6: 1 → 4: 1) to give 513 mg of hydroxamic acid (55
%)Obtained.

NMR (δ ppm, CDCl ₃ ): 3.97 (s, 3H), 7.1 to 7.8 (m, 6H), 8.1 to 8.6 (m, 5H), 9.4 (br, s, 1H) Example 11 N-hydroxy-N- Synthesis of (1-hydroxy-2-naphthyl) -2-methoxycarbonylmethylbenzamide Homophthalic acid monomethyl ester 830 mg (4.27 mmol) D
N in 30 ml dry methylene chloride solution of 330 μl MF (4.27 mmol)
_{2 In the} air, add 840 μl (9.6 mmol) of oxalyl chloride at 0 ° C.
Was added, and then the mixture was brought to room temperature and stirred for 1 hour. This one
-Hydroxy-2-naphthylhydroxylamine hydrochloride
1.80 g (8.53 mmol) and triethylamine 4.24 ml (30.5 mmo
l) in THF (30 ml) and water (6 ml) was added dropwise under N ₂ atmosphere and the mixture was stirred at room temperature for 1 hour. The reaction was terminated by adding 4N hydrochloric acid, and the mixture was extracted with methylene chloride. Organic layer
The extract was washed with 4N hydrochloric acid, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane:
Subjected to ethyl acetate 6: 1 → 4: 1), hydroxamic acid 776 mg (5
2%) obtained.

NMR (δ ppm, CDCl ₃ ): 3.70 (s, 3H), 3.90 (s, 2H), 7.0 to 7.8 (m, 9H), 8.3 to 8.45 (m, 1H), 9.3 (br, s, 1H), 9.55 (Br, s, 1H) Example 12 Evaluation of lipoxygenase production inhibitory activity in whole human blood First to 1 ml of heparinized venous blood of untreated healthy subjects.
Add 1 μl of DMSO solution of each compound listed in the table (final
10 ^-5 M) at 37 ° C. for 5 minutes, then add 5 μl of A23187 in DMSO (final 25 μm), and treat at 37 ° C. for 15 minutes.
Chilled with ice. 15-HETE 100ng D as an internal standard for quantification
After adding 10 μl of MSO solution, 0.8 ml of acetonitrile was added, and the formed precipitate was removed by centrifugation. LTB ₄ , 5 in the supernatant
-HETE was separated and quantified by HPLC, and the results are shown in Table 1 as the production inhibition rate (%) of LTB _{4 and the} like.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI technical display location A61K 31/215 ABF 9454-4C 31/235 ABE 9454-4C

Claims (6)

[Claims] 1. The following formula [I]: A hydroxamic acid derivative represented by: Wherein A is - (CH ₂₎ m when it is m- is 2
The hydroxamic acid derivative according to claim 1, which is an integer of 5. 3. A is a metaphenylene group The hydroxamic acid derivative according to claim 1. Wherein A is _{- (CH 2) m 1 -0-} (CH 2) m 2 - hydroxamic acid derivative according to claim 1, wherein m _1, m ₂ is 1 when it is. 5. The hydroxamic acid derivative according to claim 1, wherein R ¹ is a methyl group. 6. The following formula [II] A hydroxylamine derivative represented by the following formula or a hydrochloride compound thereof, and the following formula [III] The following formula [Ia] is obtained by reacting the acid chloride compound represented by A method for producing a hydroxamic acid derivative represented by: