JPH0154343B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION Technical Field The present invention relates to novel amide derivatives. The amide derivative provided by the present invention has the activity of inhibiting the action of the enzyme 5-lipoxygenase. Leukotriene C ₄ (LTC ₄ ) and leukotriene D ₄ (LTD ₄ ) are factors that cause allergies.
The leukotrienes are biosynthesized in vivo from arachidonic acid by the action of 5-lipoxygenase. Therefore, the amide derivatives of the present invention having the activity of inhibiting the action of 5-lipoxygenase suppress the biosynthesis of the above-mentioned allergy-inducing factors, and are useful as anti-allergic agents. Prior Art Recently, it has been revealed that leukotrienes are produced from arachidonic acid by the action of 5-lipoxygenase, and that these leukotrienes are a factor in the development of allergies [Science No. 220]
Volume, 568 pages, 1983, The American Association for the Advancement
of science (The American Association
Published by For the Advancement of Science). As mentioned above, leukotrienes (LTC ₄ , LTD ₄ ), which are 5-lipoxygenase products of arachidonic acid, are involved as important factors in the onset of allergic diseases such as allergic asthma and allergic rhinitis. There is a strong desire for the emergence of a drug that has the activity of deactivating 5-lipoxygenase and inhibiting its action. The present inventors synthesized various amide derivatives, and as a result of intensive research on their 5-lipoxygenase action inhibitory activity, they discovered that the amide derivative according to the present invention has a strong 5-lipoxygenase action inhibitory activity, and the present invention I was able to complete it. OBJECTS OF THE INVENTION The object of the present invention is to provide a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same as an active ingredient. The present invention, which meets the above objectives, is based on the general formula () [In the formula, n represents the number of double bonds in trans configuration and is an integer of 1 or 2. Y is (In the formula, X represents a hydrogen atom, a halogen atom, or a methoxy group, and p represents an integer of 2 or 3)
group (), and Represents a group selected from the groups (). However, when Y represents a group, n is 2. ] This is an amide derivative represented by The halogen atom in the formula () is preferably fluorine, chlorine or bromine. Detailed Description of the Invention The amide derivative represented by the above formula () of the present invention is a carboxylic acid derivative represented by the following formula (), as shown in the Examples. (wherein n has the above-mentioned meaning) or, for example, a reactive derivative thereof () (wherein n has the abovementioned meaning) with an amino compound having the formula HY (wherein Y has the abovementioned meaning). The amide derivative of the present invention is used as a 5-lipoxygenase action inhibitor, that is, an antiallergic agent, and the dosage varies depending on the symptoms, but the daily dose for adults is generally 30 to 2000 mg, preferably 50 to 600 mg, and as necessary depending on the symptoms. It is best to administer in 1 to 3 doses. The administration method can take any form suitable for administration, and oral administration is particularly preferred, but intravenous injection is also possible. The compounds of the present invention may be used alone or mixed with pharmaceutical carriers or excipients in a conventional manner to form various formulations such as tablets, sugar-coated tablets, powders, capsules, granules, suspensions, emulsions, and injection solutions. It can be applied in Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate, and the like. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. Example 1 3,5-dimethoxy-4- under argon atmosphere
3.00 g (13.4 mmol) of hydroxycinnamic acid was suspended in a sulfuric acid-ethanol (1:115, 50 ml) solution,
Refluxed for 5.5 hours. Water was added to the reaction solution, and extraction was performed with methylene chloride. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, and the organic layer was concentrated under reduced pressure.
3.34 g (13.24 mmol) of ethyl 3,5-dimethoxy-4-hydroxy-cinnamate was obtained. Under argon atmosphere, 2.00 g of the ester compound
(7.9 mmol) of β-methoxyethoxymethyl chloride in dry dichloroethane (60 ml).
ml (15.9mmol), diisopropylethylamine
2.77 ml (15.9 mmol) was added and refluxed for 1.5 hours.
Water was added to the reaction solution, and extraction was performed with chloroform. The organic layer was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and 3,5-dimethoxy-4-
2.60 g (7.6 mmol) of ethyl (β-methoxyethoxymethoxy)cinnamate was obtained. Under argon atmosphere, 2.6 g of the ester compound
(7.6 mmol) water-methanol (1:4, 40 ml)
Add 3.04g (76mmol) of sodium hydroxide to
The reaction was allowed to proceed at room temperature for 1.5 hours. Add water to the reaction solution,
The pH was adjusted to 3 with 6N hydrochloric acid, and extraction was performed with chloroform. The organic layer was concentrated under reduced pressure to obtain 2.148 g (6.9 mmol) of 3,5-dimethoxy-4-(β-methoxyethoxymethoxy)cinnamic acid. Under argon atmosphere, 2.015g of the acid compound
(6.45 mmol) in dry dichloroethane (65 ml) was added with 846 mg of 2-mercaptothiazoline.
(7.10 mmol), 1.46 g (7.10 mmol) of N,N'-dicyclohexylcarbodiimide, and 0.08 g (0.65 mmol) of 4-dimethylaminopyridine were added, and the mixture was reacted at room temperature for 12.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, water was added to the resulting residue, and extraction was performed with methylene chloride. After washing the organic layer with a 1N aqueous sodium hydroxide solution and water, the organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain N-[3-[3,5-dimethoxy-4- (β-methoxyethoxymethoxy)phenyl]propenoyl]-2-thiothiazoline 2.50g
(6.05 mmol) was obtained. Meanwhile, under an argon atmosphere, 5.73 g (20 mmol) of p-chlorobenzhydrylpiperazine and N-
(2-bromoethyl)phthalimide 4.57g
After dissolving (18 mmol) in 50 ml of benzene, 15
The mixture was heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, separated with a chloroform-methanol (100:1) mixed solvent, recrystallized from ethanol,
N-(p-chlorobenzhydryl)-N'-(2-phthalylaminoethyl)piperazine 3.80g
(8.26 mmol) was obtained. Under argon atmosphere, 103 mg of the piperazine derivative
(0.22 mmol) in ethanol solution (4 ml) was added 29 mg (0.46 mmol) of an 80% aqueous hydrazine hydrate solution, and the mixture was refluxed for 2 hours. Concentrate the reaction solution under reduced pressure,
3 ml of dry dimethylformamide was added to the resulting residue. Add 109 mg of N-[3-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]propenoyl]-2-thiothiazoline to this solution.
(0.26 mmol) of dry dimethylformamide (3
ml) solution was added. After reacting for 13.5 hours, the solvent was distilled off under reduced pressure, chloroform was added to the obtained residue, insoluble matter was filtered, the filtrate was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and ethyl acetate was added. From the elution part, N-[2-[3-[3,
33 mg (0.05 mmol) of 5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]2-propenoyl]aminoethyl-N'-p-chlorobenzhydrylpiperazine was obtained. To a solution of 33 mg (0.05 mmol) of the amide compound in methanol (4 ml) was added 20 mg (0.11 mmol) of p-toluenesulfonic acid hydrate, and the mixture was refluxed for 6.5 hours. The reaction solution was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was subjected to Sephadex column chromatography, and N-[2-[3-(3,5-dimethoxy-4-hydroxyphenyl)- 14 mg (0.03 mmol) of 2-propenoyl]aminoethyl-N'-p-chlorobenzhydrylpiperazine was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^CHCl3 _nax cm ^-1 : 3530, 1665, 1620 ¹ H-NMR (deuterated chloroform) δ: 2.43 (10H, brs), 3.83 (6H, s), 4.18 (1H,
s), 6.10 (1H, d, J=15Hz), 6.63 (2H, s),
7.10−7.65 (5H, m) Example 2 3,5-dimethoxy-4- under argon atmosphere
Hydroxybenzaldehyde 10.01g (55mmol)
β in dry methylene chloride (100 ml) solution under ice cooling.
-Methoxyethoxymethyl chloride 7.6ml
(67mmol), diisopropylamine 12.4ml
(71 mmol) was added and reacted at room temperature for 14.5 hours. The reaction solution was diluted with methylene chloride, washed with water, and the organic layer was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. ,5-dimethoxy-4-(β-methoxyethoxymethoxy)
14.5 g (53.7 mmol) of benzaldehyde was obtained. Under an argon atmosphere, 1.3 ml (5.86 mmol) of triethyl 4-phosphonocrotonate was added to a solution of 210 mg (5.25 mmol) of mineral oil containing 60% sodium hydride in dry tetrahydrofuran (20 ml), and the mixture was reacted at 0°C for 1 hour. , 3,5-dimethoxy-4-(β
-methoxyethoxymethoxy)benzaldehyde
A solution of 1.01 g (3.74 mmol) in dry tetrahydrofuran (4 ml) was added, and the mixture was reacted at room temperature for 2 hours.
A saturated ammonium chloride aqueous solution was added to the reaction solution, and extraction was performed with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography using benzene-ethyl acetate (5:1 to
2:1) From the elution fraction, 910 mg of ethyl 5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoate
(2.49 mmol) was obtained. Under argon atmosphere, 880 mg of the ester compound
(2.40 mmol) in methanol (10 ml) was added a solution of 962 mg (2.41 mmol) of sodium hydroxide in water-methanol (1:4, 40 ml), and the mixture was reacted at room temperature for 23.5 hours. Add water to the reaction solution and add 1N hydrochloric acid.
After adjusting the pH to 3.5, chloroform extraction was performed. The organic layer was concentrated under reduced pressure, and 5-[3,5-dimethoxy-
4-(β-methoxyethoxymethoxy)phenyl]
790 mg (2.34 mmol) of -2,4-pentadienoic acid was obtained. Under argon atmosphere, 890mg of the acid compound
(2.63 mmol) in dry dichloroethane (30 ml) was added with 345 mg of 2-mercaptothiazoline.
(2.90mmol), dimethylaminopyridine 32mg
(0.26 mmol), N,N'-dicyclohexylcarbodiimide 596 mg (2.89 mmol) was added, and at room temperature
The reaction was allowed to proceed for 1.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. N-[5-[3,5-dimethoxy] -4-(β-methoxyethoxymethoxy)
1.056 g (2.4 mmol) of phenyl]-2,4-pentadienoyl]-2-thiothiazoline was obtained. Under an argon atmosphere, 35 mg of an 80% aqueous hydrazine hydrate solution was added to an ethanol aqueous solution (4 ml) containing 120 mg (0.28 mmol) of N-(p-chlorobenzhydryl)-N'-(2-phthalylaminoethyl)piperazine.
(0.56 mmol) was added and refluxed for 2.5 hours. After the reaction,
The solvent was distilled off under reduced pressure, and dry dimethylformamide (4 ml) was added to the resulting residue. This solution contains N-
[5-(3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-2-thiothiazoline 147 mg
(0.33 mmol) of dry dimethylformamide (4
ml) solution was added. After reacting at room temperature for 4.2 hours, the solvent was distilled off under reduced pressure, chloroform was added to the resulting residue, insoluble matter was filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was subjected to silica gel column chromatography using methylene chloride-ethyl acetate (10:1).
~1:1) From the elution fraction, N-[2-[5-[3,
5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]
Aminoethyl]-N'-benzhydrylpiperazine
113 mg (0.18 mmol) was obtained. To a solution of 110 mg (0.18 mmol) of the amide compound in methanol (8 ml) was added 34 mg (0.18 mmol) of p-toluenesulfonic acid hydrate, and the mixture was refluxed for 5.6 hours. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 9 with an aqueous sodium carbonate solution. Extraction was performed with chloroform, the organic layer was concentrated under reduced pressure, and N-
[2-[5-(3,5-dimethoxy-4-hydroxyphenyl)-2,4-pentadienoyl]aminoethyl]-N'-benzhydrylpiperazine 90 mg
(0.16 mmol) was obtained. Spectroscopic data of this product support the structure of formula (XI) below. IRν ^KBr _nax cm ^-1 : 3400, 1650, 1580 ¹ H-NMR (methanol-d ₄ ) δ: 2.47 (10H, br, s), 3.77 (6H, s), 4.17 (1H,
s), 6.02 (1H, d, J=14Hz), 6.60−7.60 (15H,
m), 7.80 (1H, s) Example 3 An ethanol solution (4 ml) of 206 mg (0.44 mmol) of N-(p-chlorobenzhydryl)-N'-(2-phthalylaminoethyl)piperazine under an argon atmosphere. 60mg of 80% hydrazine hydrate aqueous solution
(0.92 mmol) was added and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and 5 ml of dry dimethylformamide was added to the resulting residue. This solution contains N-[5-
A solution of 220 mg (0.5 mmol) of {3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl}-2,4-pentadienoyl]-2-thiothiazoline in dry dimethylformamide (4 ml) was added. After reacting at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and N-(p-chlorobenz hydryl)-N'-[2-[5-{3.5-dimethoxy-4
-(β-methoxyethoxymethoxy)phenyl}-
185 mg (0.31 mmol) of 2,4-pentadienoyl]aminoethyl]piperazine was obtained. To a solution of 150 mg (0.25 mmol) of the amide compound in methanol (10 ml) was added 52 mg (0.27 mmol) of p-toluenesulfonic acid hydrate, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 9 with an aqueous sodium carbonate solution. Extract with chloroform, concentrate the organic layer under reduced pressure,
N-(p-chlorobenzhydryl)-N'-[2-
118 mg (0.23 mmol) of {5-(3,5-dimethoxy-4-hydroxyphenyl)-2,4-pentadienoyl}aminoethyl]piperazine was obtained. Spectroscopic data of this product support the structure of formula (XII) below. IRν ^KBr _nax cm ^-1 : 3400, 1660, 1620 Example 4 Under argon atmosphere, N-(benzhydryl)-
N'-(3-phthalylaminopropyl)piperazine
220 mg (0.5 mmol) in ethanol solution (5 ml)
80% hydrazine hydrate aqueous solution 60mg (1mmol)
was added and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and dry dimethylformamide (5 ml) was added to the resulting residue. Add N-[5-{3,5
-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl}-2,4-pentadienoyl]-
A solution of 220 mg (0.5 mmol) of 2-thiothiazoline in dry dimethylformamide (4 ml) was added. After reacting at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and mixed with chloroform-methanol (50:1).
N-(benzhydryl)-N'-[3-
[5-{3.5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl}-2,4-pentadienoyl]aminopropyl]piperazine 204mg
(0.35 mmol) was obtained. To a solution of 204 mg (0.35 mmol) of the amide compound in methanol (10 ml) was added 76 mg (0.4 mmol) of p-toluenesulfonic acid hydrate, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 9 with an aqueous sodium carbonate solution. Extraction was performed with chloroform, the organic layer was concentrated under reduced pressure, and N-
(Benzhydryl)-N'-[2-{5-(3,5-dimethoxy-4-hydroxyphenyl)-2,4-
Pentadienoyl}aminopropyl}piperazine
173 mg (0.35 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax cm ^-1 : 3350, 1660, 1615 Example 5 Under argon atmosphere, 5-{3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl}-2,4-pentadienoic acid 200 mg (0.6 mmol) )
Methyl anthranilate in acetonitrile solution of 90
mg (0.6 mmol), 154 mg (0.6 mmol) of 2-chloro-1-methylpyridinium iodide, and 0.5 ml of triethylamine were added, and the mixture was heated under reflux for 18 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic layer was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and the fraction eluted with benzene-ethyl acetate (10:1) was extracted with N- 5-{3,5-dimethoxy-4-(β-methoxyethoxymethoxy)
66 mg (0.14 mmol) of methyl phenyl}-2,4-pentadienoyl]anthranilate was obtained. 66 mg (0.14 mmol) of the amide compound was dissolved in 4 ml of methanol, 1 ml of water was added, and 100 mg of sodium hydroxide was added, followed by reaction at room temperature for 1 hour. 1N hydrochloric acid was added to the reaction solution to adjust the pH to 4, and the resulting crystals were collected by filtration and converted to N-[5-{3,5-dimethoxy-
4-(β-methoxyethoxymethoxy)phenyl}
-2,4-pentadienoyl]-anthranilic acid
56 mg (0.12 mmol) was obtained. 56 mg (0.12 mmol) of the amide compound was dissolved in 1 ml of dioxane, 4 ml of 80% acetic acid was added, and the mixture was heated under reflux for 2 hours. Water was added to the reaction solution, the resulting crystals were collected by filtration, and recrystallized from methanol to give N-{5-[3,
5-dimethoxy-4-hydroxyphenyl]-
2,4-Pentadienoyl}-anthranilic acid 24
mg (0.65 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3530, 1660, 1620, 1590 ¹ H-NMR (heavy acetone) δ: 3.83 (3H, s), 6.12 (1H, d, J = 14Hz),
6.85 (2H, S), 6.90-7.67 (6H, m), 8.02 (1H,
dd. Dilute to 5 x 10 ⁴ cells/ml in a culture medium containing 90% Gibco Laboratories (manufactured by Gibco Laboratories). After culturing the diluted solution in the air at 37°C for 48 hours with shaking, the culture solution is cooled on ice and centrifuged to collect the cells. The cells were resuspended in phosphate buffer at pH 7.4 at a concentration of 2x.
10 ⁷ pieces/ml. The suspension was treated with an ultrasonic cell disrupter, and then centrifuged at 10,000 rpm for 10 minutes.
The supernatant is used as a 5-lipoxygenase enzyme solution. 20μl of radiolabeled arachidonic acid (10μKyries/ml),
Indomethacin (2 x 10 ^-8 mol) and the amide derivative according to the present invention to be tested were placed in test tubes, and 0.45 ml of phosphate buffer and 0.45 ml of the above enzyme solution were added to the test tubes.
ml, 0.1 ml of 8mMCaCl ₂ (calcium chloride) solution was added, and the mixture was allowed to react at 37°C for 5 minutes. IN−HCl after ice cooling
Add 60μ of (hydrochloric acid) and 8ml of ethyl acetate.
Extract with The concentrated solution obtained by concentrating the extract is spotted on a silica gel thin layer plate (Merck 60F ₂₅₄ ) and developed. The inhibitory activity was measured using a radio thin layer chromatography scanner (Du¨nnschicht-Scanner).
LB 2723, manufactured by Berthold)
5-HETE (5(s)-hydroxy-6,8,11,
14-eicosatetraenoic acid) and LTB ₄ (leukotriene B ₄ ) are collected, and the radioactivity is measured using a liquid scintillation counter. The inhibition activity of 5-lipoxygenase is confirmed by the decrease in the production amount of the 5-lipoxygenase product. As a result of the test, remarkable 5-lipoxygenase action inhibition activity was found as shown in the table below. Furthermore, it was confirmed that amide derivatives according to the present invention not shown in the table also have similar 5-lipoxygenase action inhibiting activity.

【table】

[Table] In addition, the 50% inhibitory concentration or 30% inhibitory concentration in the table refers to 5-HETE when no amide derivative is introduced.
When the production amount of LTB ⁴ is taken as 100%, it means the amide derivative concentration required to suppress the production amount of the 5-lipoxygenase product to 50% or 30% by introducing the amide derivative. Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). of the compounds of the invention
The LD ₅₀ values were all 100 mg/Kg or higher, confirming high safety compared to the effective dose. Effects of the Invention According to the present invention, a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same as an active ingredient are provided. It has been revealed that the above-mentioned compound of the present invention has an activity of inhibiting the action of 5-lipoxygenase.
That is, by inhibiting the action of 5-lipoxygenase, the above compound can suppress the production of leukotrienes such as LTC ₄ and LTD ₄ , which are allergy-inducing factors produced by the action of 5-lipoxygenase. . Therefore, the amide derivative can be effectively used as a 5-lipoxygenase action inhibitor against allergic asthma, allergic rhinitis, etc.

Claims (1)

[Claims] 1 General formula () [In the formula, n represents the number of double bonds in trans configuration and is an integer of 1 or 2. Y is (In the formula, X represents a hydrogen atom, a halogen atom, or a methoxy group, and p represents an integer of 2 or 3)
group (), and Represents a group selected from the groups (). However, when Y represents a group, n is 2. ] An amide derivative represented by.