JPH07233110A - 1-naphthol derivative - Google Patents

Abstract

PURPOSE:To obtain a new 1-naphthol derivative having strong 5lipoxygenase inhibiting action and useful for the treatment and prevention of respiratory tract diseases, inflammation, thrombosis, ischemic diseases, dermatosis, etc., and the protection of the cells of the gastrointestinal tracts. CONSTITUTION:This compound is expressed by formula I (R<1> is a substituted or unsubstituted aromatic group; R<2> to R<4> each is H, a halogen, an alkyl, an alkoxy, an alkylthio or nitro), e.g. 2-[(4-biphenyl)methyl]-1-naphthol. The compound can be produced by reacting a compound of formula II (e.g. 4- phenylbenzaldehyde) with alpha-tetralone or its corresponding derivative in the presence of a base preferably in a solvent such as alcohol and ether.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 1-naphthol derivative, which has 5-lipoxygenase inhibitory activity.

[0002]

BACKGROUND OF THE INVENTION 5-Lipoxygenase is an enzyme involved in arachidonic acid metabolism, and inhibitors of this enzyme can be used for treating diseases of the respiratory tract such as allergic asthma, bronchitis, inflammation, rheumatism and thrombosis and thromboembolism. It is effective for treating and preventing ischemia, angina, arteriosclerosis, etc., and for skin diseases such as psoriasis, inflammatory skin diseases, and protection of cells in the gastrointestinal tract. Japanese Patent Laid-Open No. 61-26394
No. 3 discloses certain 2-substituted-1-naphthol derivatives, and describes that they have a 5-lipoxygenase inhibitory action. However, in that specification 2
No aromatic-substituted benzyl group is disclosed as a substituent at position 1, and no specific data is described regarding 5-lipoxygenase inhibitory activity. JP-A-2-25664.
5, Japanese Unexamined Patent Publication No. 4-59743, and Japanese Unexamined Patent Publication No. 5-493.
No. 9 discloses 1-hydroxynaphthyl-unsaturated carboxylic acids and their derivatives as compounds having an anti-inflammatory action, but does not describe whether or not they have a 5-lipoxygenase inhibitory action.

[0003]

An object of the present invention is to provide a compound having an excellent 5-lipoxygenase inhibitory action.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a 1-naphthol derivative having an aromatic-substituted benzyl group at the 2-position has a strong 5-lipoxygenase inhibitory action and completed the present invention. Came to do.

That is, the present invention is based on the general formula (1)

[0006]

[Chemical 2]

(In the formula, R ¹ represents a substituted or unsubstituted aromatic group, and R ² , R ³ , and R ⁴ are independently a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkylthio group, or a nitro group. Group is shown)).

In the present invention, the aromatic group represented by R is a phenyl group, a pyridyl group, a pyrazyl group, a pyrimidyl group, a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, Examples thereof include a thiazolyl group, an isothiazolyl group, a triazolyl group and a thiadiazolyl group.

These aromatic groups include halogen atoms such as fluorine atom, chlorine atom and bromine atom; methyl group, ethyl group,
C ₁ -C ₆ alkyl groups such as propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, hexyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group , butoxy group, isobutoxy group, an alkoxy group of C ₁ -C _5, such as isopentyl group, a hydroxyl group, an acetoxy group, propionyloxy group, butyryloxy group, alkylcarbonyloxy group C ₂ -C _5, such as valeryloxy; carboxyl Group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, t
- butoxycarbonyl group, an alkoxycarbonyl group having C ₂ -C ₆ such as a pentyloxycarbonyl group; oxo group; an amino group; an acetyl group, a propionyl group, a butyryl group, an alkylcarbonyl group having C ₂ -C ₆ such as a valeryl group; C ₁ -C such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, s-butylamino group, t-butylamino group, pentylamino group, isopentylamino group, etc. ₅ monoalkylamino group; C ₂ such as acetylamino group, propionylamino group, butyrylamino group and valerylamino group
To C ₆ alkylcarbonylamino group; carbamoyl group; methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group,
Butylcarbamoyl group, isobutylcarbamoyl group, s
-Butylcarbamoyl group, t-butylcarbamoyl group,
C ₂ -C ₆ alkylcarbamoyl group such as pentylcarbamoyl group; methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, s-butylthio group, t-butylthio group, pentylthio group, hexylthio group A C ₁ -C ₆ alkylthio group such as nitro group; a phenyl group, a tolyl group, a p-fluorophenyl group, a m-ethoxyphenyl group, a naphthyl group, a phenanthryl group, or another C ₆ -C ₁₄ aryl group. It may have one or more substituents.

Of the substituents represented by R ² , R ³ and R ⁴ ,
As examples of the halogen atom, alkyl group, alkoxy group and alkylthio group, the same ones mentioned above can be mentioned. Particularly preferred substituents from the viewpoint of 5-lipoxygenase activity include a hydrogen atom, a halogen atom and an alkyl group.

The compound of the present invention can be produced by the following method. That is, the general formula (2)

[0012]

[Chemical 3]

It can be produced by reacting a compound represented by the formula (wherein R ¹ and R ² have the same meanings as described above) with α-tetralone or its corresponding derivative in the presence of a base.

Examples of the base used in the above production method include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as potassium t-butoxide and sodium methoxide, n-butyllithium, lithium N, Examples thereof include lithium compounds such as N-diisopropylamide. In the reaction, it is preferable to use a solvent, and alcohols such as methanol, ethanol, propyl alcohol, t-butyl alcohol and the like, ethers such as diethyl ether, tetrahydrofuran and the like, and any solvent which does not participate in the reaction can be used. The reaction temperature is preferably about -30 to 200 ° C.

[0015]

EXAMPLES The present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to these.

Reference Example 1. 2- (4-formylphenyl) furan

[0017]

[Chemical 4]

4-Bromobenzaldehyde (1.86 g, 10 mmol) and furan (5
ml) in DMA (25 ml), potassium acetate (1.47 g, 15 mmol), tetrakis (triphenylphosphine) palladium (0) (0.58 g, 0.
5 mmol) was prepared, and after sealing, the mixture was stirred at 150 ° C. for 22 hours. After the reaction, DMA was distilled off, extracted with dichloromethane, washed with water, and dried with magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography,
-(4-Formylphenyl) furan (0.90 g) was obtained.

¹ H-NMR (CDCl ₃ ): δ 6.40-6.60 (m, 1H),
6.70-6.90 (m, 1H), 7.30-8.21 (m, 5H), 10.03 (s, 1
H) .MS (m / e): 242 (M ⁺ ).

Reference Example 2. 2- (4-formylphenyl) thiophene

[0021]

[Chemical 5]

4-bromobenzaldehyde (0.37
g), thiophene (10 ml), potassium acetate (0.2
9 (g) and tetrakis (triphenylphosphine) palladium (0) (0.11 g) were reacted in the same manner as in Reference Example 1 to obtain 2- (4-formylphenyl) thiophene (0.29 g). ¹ H-NMR (CDCl ₃ ): δ 7.00-8.00 (m, 7H), 10.02 (s, 1
H).

Reference Example 3-1. 4- (1-pyrrolyl) benzonitrile

[0024]

[Chemical 6]

4-aminobenzonitrile (6.01 g,
50.9 mmol) and 2,5-dimethoxytetrahydrofuran (7.07 g, 53.6 mmol) were dissolved in toluene (65 ml), and the molecular sieves 4A (22
g) was added, and the mixture was heated and stirred for 3.5 days. The reaction solution was filtered and then concentrated, and the residue was purified by column chromatography to give 4- (1-pyrrolyl) benzonitrile (6.23).
g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 6.30-6.50 (m, 2H), 7.00-7.20
(m, 2H), 7.48 (d, J = 10Hz, 2H), 7.73 (d, J = 10Hz, 2
H).

Reference Example 3-2. 4- (1-pyrrolyl) benzaldehyde

[0027]

[Chemical 7]

4- (1-Pyrrolyl) benzonitrile (2.03 g, 12.1 mmol) was added to benzene (17 m).
l), dissolved in diisobutylaluminum hydride solution (12.1 ml, 12.1 mmol), and stirred at 45 ° C. for 6 hours. Methanol (6 ml) and water (5 ml) were added to the reaction solution, 1N hydrochloric acid was added, the mixture was extracted with dichloromethane and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography,
-(1-Pyrrolyl) benzaldehyde (1.92 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 6.30-6.50 (m, 2H), 7.00-7.30
(m, 2H), 7.50 (d, J = 9Hz, 2H), 7.95 (d, J = 9Hz, 2H),
10.02 (s, 1H).

Example 1. 2-[(4-biphenyl) methyl] -1-naphthol

[0030]

[Chemical 8]

Α-Tetralone (0.32 g, 2.2 mm)
ol) and 4-phenylbenzaldehyde (0.40 g,
2.2 mmol) to t-butyl alcohol (20 ml)
And potassium t-butoxide (0.495 g,
(4.4 mmol) was added and the mixture was heated with stirring for 16 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated, adjusted to pH 7 with an aqueous sodium carbonate solution, and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was evaporated and the residue was purified by column chromatography to give 2-[(4-biphenyl) methyl] -1-naphthol (0.52 g). ¹ H-NMR (CDCl ₃ ): δ 4.16 (s, 2H), 6.90-8.30 (m, 16
H) .MS (m / e): 310 (M ⁺ ).

Example 2. 2-[[4- (2-furanyl) phenyl] methyl] -1-naphthol

[0033]

[Chemical 9]

Α-Tetralone (0.31 g, 2.1 mm
ol) and 4- (2-furanyl) benzaldehyde (0.
37 g, 2.1 mmol of t-butyl alcohol (2
0 ml) and potassium t-butoxide (0.48
g, 4.3 mmol) was added and the mixture was heated with stirring for 15 hours.
1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated, adjusted to pH 7 with an aqueous sodium carbonate solution, and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was evaporated and the residue was purified by column chromatography to give 2-[[4- (2-furanyl) phenyl] methyl] -1-naphthol (0.54
g) was obtained.

¹ H-NMR (CDCl ₃ ): δ 4.09 (s, 2H), 6.70-
7.70 (m, 12H), 7.75-7.90 (m, 1H), 7.95-8.20 (m, 1
H) .MS (m / e): 300 (M ⁺ ).

Example 3. 2-[[4- (2-thienyl) phenyl] methyl] -1-naphthol

[0037]

[Chemical 10]

Α-Tetralone (0.24 g, 1.65 m
mol) and 4- (2-thienyl) benzaldehyde (0.29 g, 1.5 mmol) are dissolved in t-butyl alcohol (15 ml), potassium t-butoxide (0.34 g, 3.1 mmol) is added, and the mixture is heated for 15 hours. It was stirred. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated, adjusted to pH 7 with an aqueous sodium carbonate solution, and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was evaporated and the residue was purified by column chromatography to give 2-[[4-
(2-thienyl) phenyl] methyl] -1-naphthol (0.27 g) was obtained.

¹ H-NMR (CDCl ₃ ): δ 4.13 (s, 2H), 6.90-
7.70 (m, 12H), 7.71-8.00 (m, 1H), 8.01-8.30 (m, 1
H) .MS (m / e): 316 (M ⁺ ).

Example 4. 2-[[4- (3-thienyl) phenyl] methyl] -1-naphthol

[0041]

[Chemical 11]

Α-Tetralone (71 mg, 0.49 mm
ol) and 4- (3-thienyl) benzaldehyde (91
mg, 0.48 mmol) to t-butyl alcohol (5
ml) and potassium t-butoxide (116 m)
g, 1.03 mmol) was added, and the mixture was heated with stirring for 17.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated, adjusted to pH 7 with an aqueous sodium carbonate solution, and extracted with ethyl acetate.
After drying over magnesium sulfate, the solvent was evaporated and the residue was purified by column chromatography to give 2-[[4- (3-
Thienyl) phenyl] methyl] -1-naphthol (27
mg) was obtained.

¹ H-NMR (CDCl ₃ ): δ 4.16 (s, 2H), 5.24
(brs, 1H), 6.70-8.00 (m, 12H), 8.01-8.31 (m, 1H). MS (m / e): 316 (M ⁺ ).

Example 5. 2-[[4- (1-pyrrolyl) phenyl] methyl] -1-naphthol

[0045]

[Chemical 12]

Α-Tetralone (0.458 g, 2.68)
mmol) and 4- (1-pyrrolyl) benzaldehyde (0.367 g, 2.51 mmol) are dissolved in t-butyl alcohol (24 ml), potassium t-butoxide (0.600 g, 5.36 mmol) is added, and the mixture is heated for 23 hours. It was stirred. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated, adjusted to pH 7 with an aqueous sodium carbonate solution, and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was evaporated and the residue was purified by column chromatography to give 2-[[4
-(1-Pyrrolyl) phenyl] methyl] -1-naphthol (0.342 g) was obtained.

¹ H-NMR (CDCl ₃ ): δ 4.19 (s, 2H), 6.36
(m, 2H), 7.08 (m, 2H), 7.20-7.70 (m, 9H), 7.80-8.0
0 (m, 1H), 8.01-8.30 (m, 1H). MS (m / e): 299 (M ⁺ ).

Test Example 1. Measurement of 5-lipoxygenase activity The crude enzyme produced from rat basophilic leukemia cells (RBL-1) was incubated with the test compound for 5 minutes,
Linoleic acid was added to start the reaction. 8 more at room temperature
After incubating for a minute, sodium hydroxide was added to stop the reaction, and 5-hydroxyicosatetraenoic acid (5-HETE) (Proc. Natl. Acad. S) was added.
ci. , USA 1985, 81, 689. J .; Bi
ol. Chem. 1985, 260, 11554. ) Was quantified by absorbance (234 nm), and IC ₅₀ value was calculated from the amount of 5-HETE depending on each concentration of the compound of the present invention. Table 1 shows the test results of the 5-lipoxygenase inhibitory activity of the compound of the present invention.

[0049]

[Table 1] Table 1. 5-lipoxygenase inhibitory activity ────────────────────── Example number of test compound IC ₅₀ (μM) ───────────── ────────── Example-1 0.14 Example-2 0.26 Example-3 0.22 Example-5 0.28 ───────────── ──────────

[0050]

The compound of the present invention has a strong lipoxygenase inhibitory action. Therefore, the treatment and prevention of diseases of the respiratory tract, such as allergic asthma, bronchitis, inflammation, rheumatism and thrombosis and thromboembolism, ischemia, angina, arteriosclerosis, etc., and also skin diseases such as psoriasis,
It is expected to be useful for inflammatory skin diseases and protection of cells in the gastrointestinal tract.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 207/333 307/42 333/16 // A61K 31/045 ABG ABX ACB ADA 31/05 ABF 9454 -4C 31/34 ACD 31/38 ABE 31/40 AED

Claims (1)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ represents a substituted or unsubstituted aromatic group,
R ² , R ³ and R ^{4 each} independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkylthio group or a nitro group. ) 1-naphthol derivative represented by.