JP3281492B2 - N-hydroxyureas - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel N-hydroxyureas. The compounds of the present invention simultaneously inhibit the action of lipoxygenase and thromboxane synthase, and are useful for treating or alleviating allergic diseases and inflammatory diseases.

[0002]

BACKGROUND ART It is known that arachidonic acid is metabolized via a series of enzyme systems to produce metabolites having various physiological activities. Of these, thromboxane A ₂ or the leukotrienes, asthma, psoriasis, enteritis, nephritis, ulcers, is an important chemical mediators in causative allergic reactions of various diseases, such as ischemia, inhibited these production enzymes simultaneously Thus, there is a demand for a new type of drug that has a considerable effect in treating or alleviating the above-mentioned various diseases. Recently, quinone derivatives (JP-A-63-45257;
JP-A-5-78321), chroman derivatives or dihydrobenzofuran derivatives (JP-A-5-310724), imidazolylphenol derivatives (JP-A-6-9571),
Amino coumaran derivatives (JP-A-6-41123) have become known.

[0003]

The present inventors have conducted various studies in order to find a novel compound that simultaneously inhibits the actions of lipoxygenase and thromboxane synthase. The present inventors have found that novel N-hydroxyureas having different structures have an excellent action and completed the present invention.

[0004]

According to the present invention, there is provided the following formula (I):

[0005]

Embedded image

(Wherein R ₁ is a hydrogen atom, a halogen atom,
A nitro group or a lower alkyl group or a lower alkoxy group which may be substituted with a halogen atom, R ₂ represents a hydrogen atom or a cycloalkyl group, and n represents an integer of 1 to 5. ) Or a pharmacologically acceptable salt thereof.

The N-hydroxyureas represented by the formula (I) belong to a trisubstituted olefin compound, and there are two types of geometric isomers.
Also, a mixture of isomers is included. Further, if necessary, each geometric isomer can be separated from the isomer mixture by a fractional crystallization method, chromatography or the like.

Hereinafter, each substituent of the N-hydroxyureas represented by the formula (I) will be described in more detail. R ₁
A lower alkyl group which may be substituted with a halogen atom means a lower alkyl group which may be substituted with one or more fluorine atoms, chlorine atoms, bromine atoms or iodine atoms,
Specifically, a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, and an isopropyl group and a lower alkyl group substituted by a halogen atom such as a difluoromethyl group, a trifluoromethyl group, and a 2,2,2-trichloroethyl group. Alkyl groups can be mentioned. Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,
Butoxy group and the like. In the present invention, a preferable substituent of R ₁ is a hydrogen atom or a trifluoromethyl group.

R ₂ represents a hydrogen atom or a cycloalkyl group such as a cyclopentyl group or a cyclohexyl group. Among them, in the present invention, a hydrogen atom or a cyclohexyl group is mentioned as a preferable substituent of R ₂ . n represents an integer of 1 to 5, preferably an integer of 1 to 4.

In the present invention, the N-hydroxyureas represented by the formula (I) may be non-toxic acidic salts such as pharmacologically acceptable acidic salts. Specifically, inorganic acid salts formed from hydrochloric acid, hydrobromic acid, sulfuric acid, bisulfite, phosphoric acid, etc., and formic acid, acetic acid, citric acid, fumaric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid And organic acid salts formed from methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like.

In the following, specific examples of preferred compounds of the present invention are shown. (Compound 1) N-hydroxy-N-[(E) -7-phenyl-7- (3-pyridyl) -6-hepten-1-yl] urea (Compound 2) N-hydroxy-N-[(Z) -7-phenyl-7- (3-pyridyl) -6-hepten-1-yl] urea (Compound 3) N'-cyclohexyl-N-hydroxy-
N-[(Z) -7-phenyl-7- (3-pyridyl)-
6-Hepten-1-yl] urea (Compound 4) N-hydroxy-N- [4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-
Buten-1-yl] urea

The compounds of the present invention can be prepared by a number of methods. Compounds in which R ₁ is a hydrogen atom, such as compound 1, are prepared according to the reaction steps described in detail below.

[0013]

Embedded image

The starting materials used in the above reaction steps are synthesized from commercially available compounds or known compounds according to known methods.

Step 1: First, a carboxylic acid (ii) is synthesized from 3-benzoylpyridine (i) by a known standard method (Wittig reaction). In general, the reaction solvent may be any solvent as long as it does not inhibit the reaction, such as aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, Carbon tetrachloride) or ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.). The product obtained from this reaction is isolated by known methods but is used without further purification in the next step.

Step 2: Esters (iii) and (iv) are synthesized from the carboxylic acid (ii) by a known method. For example, a method of reacting a carboxylic acid and an alcohol in the presence of a mineral acid (dry hydrogen chloride, sulfuric acid, etc.), a method of reacting an acid chloride and an alcohol in the presence of a base (dimethylaniline, pyridine, sodium hydroxide, etc.), A method of reacting carboxylic acid with diazomethane can be used. The mixture of (iii) and (iv) obtained here can be isolated and purified by a known simple method, for example, recrystallization or chromatography, and each can be used in the next step.

Step 3: Ester (iii) is converted to alcohol (v) by using various reducing agents. As the reducing agent used here, lithium aluminum hydride,
Sodium borohydride, lithium borohydride, diisobutylaluminum hydride and the like are mentioned, and preferable ones are lithium aluminum hydride.
The reaction solvent used here may be any solvent as long as it does not hinder the reaction, for example, aromatic hydrocarbons (benzene, toluene, xylene, etc.) or ethers (diethyl ether, tetrahydrofuran,
Dioxane). Preferred is tetrahydrofuran. The product obtained from this reaction is isolated by known methods but is used without further purification in the next step.

Step 4: Aldehyde (vi) is synthesized by oxidizing alcohol (v). The oxidation reaction used in this step can be performed, for example, by the method of D. Swern, et al. [Journal of Organic Chemistry, Vol. 43, No. 2480]
P. 1978], but is not limited thereto. The compound obtained here can be easily isolated and purified by a known method such as recrystallization or chromatography.

Step 5: The aldehyde (vi) is reacted with hydroxylamine hydrochloride to synthesize the oxime (vii). This reaction is performed in the presence of a base such as pyridine and triethylamine in an organic solvent that does not inhibit the reaction. As the solvent to be used, for example, aromatic hydrocarbons (benzene,
Examples include alcohols (such as methanol, ethanol, propanol, and isopropanol), and ethers (such as diethyl ether, tetrahydrofuran, and dioxane). Preferred is ethanol. The oxime (vii) obtained here can be easily isolated and purified by known means, for example, recrystallization, column chromatography and the like.

Step 6: Reduction of the oxime (vii) to give hydroxylamine (viii). Examples of the reducing agent include sodium cyanoborohydride, a boron-pyridine complex, a boron-triethylamine complex, and a boron-dimethylsulfide complex, and preferred examples include sodium cyanoborohydride. The product obtained here can be easily isolated and purified by a known method such as recrystallization or chromatography.

Step 7: The final target compound 1 (ix) is obtained by reacting hydroxylamine (viii) with trimethylsilyl isocyanate. The reaction solvent has no adverse effect on the reaction, for example, aromatic hydrocarbons (benzene,
Examples thereof include toluene, xylene and the like, halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride and the like), and ethers (diethyl ether, tetrahydrofuran, dioxane and the like), and tetrahydrofuran is most preferable in this case. The compound obtained here can be easily isolated and purified by a known method such as recrystallization or chromatography.

The compound in which R ₁ is other than a hydrogen atom can be produced by another reaction. The reaction process is shown in detail below using Compound 4 as an example. The starting materials used in this reaction step can be produced from commercially available compounds or known compounds according to known methods.

[0023]

Embedded image

Steps 8 to 13: First, S. Ohkawa, et.
al.) [Journal of Medicinal Chemistry]
34, page 267, 1991], that is, using 3-bromopyridine as a raw material, alkylating (step 8) and trimethylsilyl (TMS) (step 9) to synthesize a ketone (x). Bromide (xi) is added to this (x) (Step 1).
0), deprotection (step 11), dehydration (step 12), and deacetylation (step 13) to give the alcohol (xii)
Can be led to. Steps 14 and 15: At this stage, the reaction with N, O-bis (tert-butoxycarbonyl) hydroxylamine is performed using the conditions of the Mitsunobu reaction from (xii), and the N, O protected hydroxylamine derivative (xiii ) Is synthesized. This is followed by an acid hydrolysis leading to hydroxylamine (xiv) (see WO 92/01682). Step 16: At this stage, the final target compound 4 is obtained by the same method as in Step 7 in the synthesis of compound 1.
(xv).

A pharmacologically acceptable salt of the compound of the present invention can be easily produced by reacting the compound of the present invention with the above-mentioned nontoxic inorganic or organic acid by a conventional method.

When the compound of the present invention is used as a therapeutic drug for allergic diseases or inflammatory diseases, it can be administered by an appropriate method such as oral or parenteral administration. Forms for oral administration include, for example, tablets, granules,
Capsules, pills, powders and the like, and forms for parenteral administration include, for example, injections, solutions, inhalants and the like. When formulating these pharmaceutical administration compositions,
The compound of the present invention or a pharmacologically acceptable salt thereof can be prepared according to a conventional method. For example, in the case of an oral preparation, lactose, glucose, corn starch, excipients such as sucrose, carboxymethylcellulose calcium, disintegrants such as hydroxypropylcellulose, calcium stearate, magnesium stearate, talc, polyethylene glycol, hardened oil and the like Lubricants, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin, gum arabic and other binders, wetting agents such as glycerin and ethylene glycol, and other surfactants and flavoring agents as needed. It can be used to prepare the desired dosage form. In the case of parenteral drugs,
Water, ethanol, glycerin, propylene glycol,
Using a diluent such as polyethylene glycol, agar, or tragarant gum, if necessary, a solubilizing agent, a buffer,
Preservatives, flavors, coloring agents and the like can be used.

When the compound of the present invention is formulated as a therapeutic drug for allergic diseases and inflammatory diseases, the dosage unit is the compound of the present invention per adult, and when administered orally, 5 to 1000 mg per day, preferably 5-100m
g, in the case of parenteral administration, it is administered in the range of 1 to 200 mg, preferably 1 to 20 mg per day, each being 1 to 3 mg per day
Desired therapeutic effects can be expected with multiple divided doses.

[0028]

Next, an embodiment of the present invention will be described. Example 1 Synthesis of N-hydroxy-N-[(E) -7-phenyl-7- (3-pyridyl) -6-hepten-1-yl] urea (Compound 1) (1) (E, Z)- 7-Phenyl-7- (3-pyridyl) -6-heptenoic acid 5-Carboxypentyltriphenylphosphonium bromide (31.00 g, 67.83 mmol) was suspended in tetrahydrofuran (300 mL) under argon, and n- Butyl lithium
(1.47 M, n-hexane solution, 92.30 mL, 135.66 mmol)
Was added dropwise and stirred at the same temperature for 20 minutes. Then, a solution of 3-benzoylpyridine (10.30 g, 56.53 mmol) in tetrahydrofuran (50 mL) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 2 hours. After the reaction, the mixture was extracted twice with water (200 mL). The aqueous layer was adjusted to pH 6 with a 10% aqueous hydrochloric acid solution, and then extracted with ethyl acetate. After washing with saturated saline and drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and (E, Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid (18.74 g) was obtained as white crystals. Obtained. Used for the next reaction without purification. (2) (E) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid ethyl ester and (Z) -7-phenyl-7- (3-pyridyl) -6-
Heptenoic acid ethyl ester (E, Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid (18.7
4 g) in ethanol (200 mL) and concentrated sulfuric acid (40 mL)
Was added dropwise, and the mixture was heated under reflux for 3 hours. After the reaction, the temperature was returned to room temperature, adjusted to pH 8-9 with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. After washing with saturated saline and drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 1 kg, n-hexane: ethyl acetate = 1: 2) to give (E) -7 -Phenyl-7- (3-pyridyl)-
6-heptenoic acid ethyl ester (5.61 g) and (Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid ethyl ester
(4.60 g) were obtained as white crystals.

(3) (E) -7-phenyl-7- (3-pyridyl) -6-
Hepten-1-ol Under argon, a solution of (E) -7-phenyl-7- (3-pyridyl) -6-hepten-1-ol (1.00 g, 3.24 mmol) in tetrahydrofuran (20 mL) was added at 0 ° C. Lithium aluminum hydride (123 mg, 3.24 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, water (5.0 mL) was added, and the mixture was stirred at room temperature for 15 minutes, diluted with tetrahydrofuran (10 mL), and filtered through Celite. After diluting with ethyl acetate, washing with saturated saline, drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and (E) -7-phenyl-7- (3-pyridyl) -6-heptene-1-
All (0.95 g) was obtained as a yellow oil. Used for the next reaction without purification. (4) (E) -7-phenyl-7- (3-pyridyl) -6-heptenal Oxalyl chloride 0.61 mL, 7.12 mmol under argon
Dimethylsulfoxide (1.01 mL, 14.24 mmol) was added dropwise to a dichloromethane (40 mL) solution at −78 ° C., and the mixture was stirred for 30 minutes. Then at the same temperature (E) -7-phenyl-7- (3-pyridyl) -6-hepten-1-ol (0.95 g) in dichloromethane
(10 mL) The solution was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. Further, triethylamine (2.97 mL, 21.37 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction, water is added dropwise at room temperature for 30 minutes.
After stirring for minutes, the mixture was extracted with ether, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 100 g, chloroform: methanol = 9: 1) to obtain (0.83 g) as a yellow oil.

(5) (E) -7-phenyl-7- (3-pyridyl) -6-
Heptenal oxime (E) -7-phenyl-7- (3-pyridyl) -6-heptenal (0.83
g, 3.15 mmol) in ethanol (2.0 mL), pyridine (2.0 mL) and hydroxylamine hydrochloride (0.33 g, 4.7
2 mmol) and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, diluted with ethyl acetate, and washed with water and saturated saline in this order. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel 100 g, chloroform: methanol = 9: 1).
Then, (E) -7-phenyl-7- (3-pyridyl) -6-heptenal oxime (0.78 g) was obtained as white crystals. (6) (E) -7-phenyl-7- (3-pyridyl) -6-heptene-1-
Ilhydroxylamine Under argon, (E) -7-phenyl-7- (3-pyridyl) -6-heptenal oxime (0.78 g, 2.80 mmol) in acetic acid (4.0 m
L) The solution was added at 0 ° C with sodium cyanoborohydride (0.8
8 mg, 13.98 mmol) and stirred at room temperature for 15 minutes. After the reaction, the mixture was adjusted to pH 7 with a 15% aqueous sodium hydroxide solution and then to pH> 9 with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. After washing with saturated saline, drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel 80 g, chloroform: methanol =
9: 1) to give (E) -7-phenyl-7- (3-pyridyl) -6-
Hepten-1-ylhydroxylamine (0.62 g) was obtained as white crystals.

(7) N-hydroxy-N-[(E) -7-phenyl-7
-(3-Pyridyl) -6-hepten-1-yl] urea Under argon, (E) -7-phenyl-7- (3-pyridyl) -6-hepten-1-ylhydroxylamine (623 mg, 2.209 mmol )
Was added to a solution of (8.0 mL) in tetrahydrofuran (0.36 mL, 2.65 mmol), and the mixture was stirred at room temperature for 15 hours. After the reaction, volatiles were distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 120 g, chloroform: methanol = 9: 1) to give N-hydroxy-N-[(E) -7-phenyl-7- (3-pyridyl) -6-heptene-1
[-Yl] urea (552 mg) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): δ 1.32 (m, 2H), 1.44 (m, 2H), 1.6
0 (m, 2H), 2.13 (m, 2H), 3.52 (t, 2H), 6.08 (t, 1
H), 7.12 (m, 1H), 7.17 (m, 1H), 7.26-7.40 (m, 5H),
8.37 (m, 1H), 8.54 (d, 1H).

Example 2 Synthesis of N-hydroxy-N-[(Z) -7-phenyl-7- (3-pyridyl) -6-hepten-1-yl] urea (Compound 2) Using (Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid ethyl ester obtained in 1 (2), it was synthesized in the same manner as in Example 1 below. ¹ H-NMR (CDCl ₃ ): δ 1.32 (m, 2H), 1.47 (m, 2H), 1.
56 (m, 2H), 2.05 (m, 2H), 3.51 (t, 2H), 5.46 (br,
2H), 6.15 (t, 1H), 7.16 (m, 2H), 7.19-7.29 (m, 4
H), 7.33 (m, 1H), 7.49 (m, 1H), 8.43 (d, 1H), 8.47
(m, 1H).

Example 3 N'-cyclohexyl N-hydroxy-N-[(Z) -7-phenyl-7
Synthesis of-(3-pyridyl) -6-hepten-1-yl] urea (Compound 3) The above compound was synthesized by using cyclohexyl isocyanate instead of trimethylsilyl isocyanate in the final step in Example 2. ¹ H-NMR (CDCl ₃ ): δ 1.14-2.04 (m, 18H), 4.10 (m, 2
H), 4.18-4.20 (m, 1H), 6.20 (m, 1H), 6.98 (d, 1H),
7.14-7.29 (m, 5H), 7.38 (m, 1H), 7.57 (m, 1H), 8.3
3 (d, 1H), 8.40 (m, 1H).

Example 4 Synthesis of N-hydroxy-N- [4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-buten-1-yl] urea (Compound 4) (1) 1- (3-pyridyl) -1- (3-trifluoromethylphenyl) -4-trimethylsilyloxybutan-1-ol m-bromobenzotrifluoride (7.8 g, 34.
665 mmol) in tetrahydrofuran (96 mL), magnesium (1.67 g, 69.583 mmol) and iodine (catalytic amount)
Was added, and the mixture was gradually heated to prepare a Grignard reagent.
Next, a solution of 1- (3-pyridyl) -4-trimethylsilyloxybutan-1-one (3.91 g, 17.378 mmol) in tetrahydrofuran (56 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After the reaction, water was added dropwise, extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 1- (3-pyridyl) -1- (3- (Trifluoromethylphenyl) -4-trimethylsilyloxybutan-1-ol (5.69 g) was obtained. Used for the next reaction without purification. (2) 1- (3-pyridyl) -1- (3-trifluoromethylphenyl) butane-1,4-diol 1- (3-pyridyl) -1- (3-trifluoromethylphenyl) -4-
Trimethylsilyloxybutan-1-ol (5.69 g) was dissolved in ethanol (40 mL), 10% HCl (10 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. After washing with saturated saline and drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and crude 1- (3-pyridyl) -1- (3-trifluoromethylphenyl) butane-1,4
-Diol (4.63 g) was obtained. Used for the next reaction without purification.

(3) 4-acetoxy-1- (3-pyridyl) -1- (3
-Trifluoromethylphenyl) -1-butene 1- (3-pyridyl) -1- (3-trifluoromethylphenyl) butane-1,4-diol (4.63 g) was dissolved in acetic acid (50 mL) and concentrated. Sulfuric acid (10 mL) was added dropwise, and the mixture was stirred at 60 ° C for 40 minutes. After the reaction, the mixture was neutralized with sodium hydrogen carbonate, and then water was added, followed by extraction with ethyl acetate. Wash with saturated saline,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 100 g, chloroform: ethyl acetate = 1: 1) to give 4-acetoxy-1- (3-pyridyl) -1- (3-trifluoromethylphenyl)
1-butene (2.21 g) was obtained. (4) 4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-buten-1-ol 4-acetoxy-1- (3-pyridyl) -1- (3-trifluoromethylphenyl ) -1-Butene (0.89 g) in methanol (5 mL)
, And a 15% aqueous sodium hydroxide solution (6 mL) was added dropwise, followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After washing with saturated saline and drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-buten-1-ol. Used for the next reaction without purification.

(5) N, O-bis (tert-butoxycarbonyl) -4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-buten-1-ylhydroxylamine 4- (3 -Pyridyl) -4- (3-trifluoromethylphenyl) -3-
From Buten-1-ol (0.69 g), International Patent No. 92/0
According to the method of M. No. 1682, the N, O-bis (ter
By reacting with (t-butoxycarbonyl) hydroxylamine, N, O-bis (tert-butoxycarbonyl) -4-
(3-Pyridyl) -4- (3-trifluoromethylphenyl) -3-buten-1-ylhydroxylamine (0.98 g) was obtained. (6) 4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-buten-1-ylhydroxylamine N, O-bis (tert-butoxycarbonyl) -4- (3-pyridyl) -Four
From-(3-trifluoromethylphenyl) -3-buten-1-ylhydroxylamine (0.98 g), International Patent No. 92/0
Hydrolysis with trifluoroacetic acid according to the method of 1682 gave 4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-buten-1-ylhydroxylamine (0.33 g)
I got

(7) N-hydroxy-N- [4- (3-pyridyl) -4
-(3-Trifluoromethylphenyl) -3-buten-1-yl] urea 4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3-
From buten-1-ylhydroxylamine (0.33 g), N-hydroxy-N-
[4- (3-pyridyl) -4- (3-trifluoromethylphenyl) -3
[Buten-1-yl] urea (0.27 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 2.30 (q, 2H), 3.46 (t, 3H), 6.
26 (s, 2H), 6.28 (buried t, 0.5H), 6.37 (t, 0.5H),
7.31-7.74 (m, 6H), 8.39-8.58 (m, 2H), 9.21 (s, 1
H) ¹³ C-NMR (CDCl ₃ ): δ 27.60, 27.74, 49.28, 49.32, 7
9.37, 122.97, 123.08, 123.63, 123.90, 124.03, 124.
47, 125.67, 125.98, 129.29, 129.72, 129.79, 129.9
5, 130.52, 131.05, 131.32, 133.94, 134.32, 134.58,
137.27, 137.38, 137.78, 139.83, 142.75, 147.93, 1
48.42, 148.84, 150.18, 161.66.

(Formulation Example) Example 5 (Preparation of tablet) Compound of the present invention (Compound 1) 250 g Lactose 620 g Corn starch 400 g Hydroxypropyl cellulose 20 g Magnesium stearate 10 g The above-mentioned compound of the present invention, lactose and corn starch are mixed until uniform. After that, a 5 W / V% ethanol solution of hydroxypropylcellulose is added and kneaded and granulated. 1
After passing through a 6-mesh sieve and sieving, the tablets are compressed in a conventional manner,
Weight per tablet 130mg, diameter 7mm, active substance content 2
5 mg tablets were obtained.

Example 6 (Preparation of capsule) Compound of the present invention (Compound 3) 250 g Lactose 620 g Avicel 620 g Magnesium stearate 10 g The above-mentioned compound of the present invention, lactose, Avicel and magnesium stearate were thoroughly mixed until uniform. Then, it is filled into No. 3 capsules and the weight of the contents per capsule is 1
The capsules were 50 mg and the active ingredient content was 25 mg.

[0040] Using the Test Example 1 (lipoxygenase inhibitory activity test) rat polymorphonuclear leukocytes, an experiment was conducted as an index the production amount of leukotriene B _4. Male Wister rats (CLEA Japan) were intraperitoneally administered with 12% sodium caseinate, and after 16 hours, intraperitoneal washing was performed to collect polymorphonuclear leukocytes. The obtained polymorphonuclear leukocytes were in a phosphate buffer (137 mM).
NaCl, 3 mM KCl, 8 mM Na ₂ HPO ₄ , 2 mM KH ₂ PO ₄ ), add (2.5 × 10 ⁵ cells / 0.4 mL), test compound (final concentration 10 ^-5 M), and add 10 minutes Further, 0.1 mL of a calcium solution (10 mM CaCl ₂ , 0.86% NaCl) was added, and 3 minutes
After incubation at 7 ° C., the reaction was started with 1.25 μL of calcium ionophore (20 μM A-23187). The reaction time was 5 minutes, and the reaction was stopped with 250 μL of methanol. After stopping the reaction, centrifuge for 20 minutes (4 ℃, 3000
rpm) and the amount of leukotriene B ₄ in the supernatant was determined by the EIA method (Cayman
(Manufacturer's kit).

[0041] Test Example 2 using (thromboxane synthase inhibitory activity test) human platelets microsomes, an experiment was conducted as an index the production amount of thromboxane B ₂ is stable metabolite of thromboxane A _2. Human platelet microsomes (50μg protei
n / mL) and 1 mL of a buffer (20 mM Tris-HCl buffer, 1 mM EDTA, pH 7.5) containing the test compound (final concentration ^10-6 M) were stirred and then incubated at 0 ° C for 30 minutes. Prostaglandin H ₂ (100 ng / 2 μL) was added thereto, and incubated at 23 ° C. for 3 minutes to react. Then, after adding 1M hydrochloric acid and stopping the reaction by making it acidic, 1M Tris-Base
, And centrifuged at 3,000 rpm for 20 minutes, and the amount of thromboxane B ₂ in the supernatant was measured by the EIA method (Cayman kit).

The above-mentioned tests were carried out using the above-mentioned compounds 1 to 4 as test compounds, and the leukotriene B ₄ production inhibitory action (LTBI) of each compound and thromboxane B ₂
Production inhibitory effect of (TxSI) with an IC ₅₀ shown in Table 1 (Table 1). Table 1 shows that the compound of the present invention inhibits the action of both lipoxygenase and thromboxane synthase.

[0043]

[Table 1]

[0044]

Since the compound of the present invention has a strong lipoxygenase inhibitory activity and a strong thromboxane synthase inhibitory activity, it can be used as a therapeutic agent for allergic diseases or inflammatory diseases, specifically, a metabolite of arachidonic acid. It is useful as a therapeutic or prophylactic for various diseases caused by, for example, asthma, psoriasis, enteritis, nephritis, ulcer, ischemia and the like.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int. Cl. ⁷ Identification code FI A61P 43/00 A61P 43/00 (56) References JP-A-8-208607 (JP, A) International Publication 96/23772 (WO, A1) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 213/00-213/42 A61K 31/00-31/4406 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the formula (I) (Wherein, R ₁ represents a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group or a lower alkoxy group which may be substituted with a halogen atom, R ₂ represents a hydrogen atom or a cycloalkyl group, and n represents 1 Or an integer of 5) or a pharmacologically acceptable salt thereof. 2. The N-hydroxyureas or pharmaceutically acceptable salts thereof according to claim 1, wherein R ₁ is a hydrogen atom and R ₂ is a hydrogen atom. 3. The N-hydroxyureas according to claim 1, wherein R ₁ is a halogen atom, a nitro group or a lower alkyl group or a lower alkoxy group optionally substituted with a halogen atom, or a pharmacologically acceptable N-hydroxyurea. Salt. 4. The N-hydroxyurea or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₂ is a cycloalkyl group. 5. The N-hydroxyurea or a pharmaceutically acceptable salt thereof according to claim ₁ , wherein R ₁ is a hydrogen atom or a trifluoromethyl group and R ₂ is a cyclohexyl group. 6. The N-hydroxyurea or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer of 1 to 4.