JPS6355508B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION Technical Field The present invention relates to a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same. 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 ), a factor that causes allergies
Leukotrienes such as D ₄ (LTD ₄ ) are biosynthesized in vivo from arachidonic acid by the action of 5-lipoxygenase. Therefore, the amide derivatives of the present invention having 5-lipoxygenase action inhibiting activity 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 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-inhibiting activity, they discovered that the amide derivative according to the present invention has a strong 5-lipoxygenase action-inhibiting activity, and the present invention I was able to complete it. OBJECTS OF THE INVENTION An object of the present invention is to provide a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same. The present invention, which meets the above objectives, is based on the general formula () [In the formula, (R) ^m is a 3,4-dihydroxy group, 3
-Methoxy-4-hydroxy group, 3,4-dimethoxy group, 3,5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4-toluoyloxy group or 3,4,5-trimethoxy group.
n represents the number of double bonds in trans configuration, and is an integer of 1 or 2. Y is (In the formula, X is a hydrogen atom, a halogen atom, or a methoxy group, and n is 4) Narumoto (), (in the formula, n represents 2 or 3) and (In the formula, n represents 2 or 3) It is an amide derivative represented by a group selected from the group (). Furthermore, the present invention also relates to the general formula () [In the formula, (R) ^m is a 3,4-dihydroxy group, 3
-Methoxy-4-hydroxy group, 3,4-dimethoxy group, 3,5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4-toluoyloxy group or 3,4,5-trimethoxy group.
n represents the number of double bonds in trans configuration, and is an integer of 1 or 2. Y is (wherein, X is a hydrogen atom, a halogen atom, or a methoxy group, and n is 4), and Narumoto (), (in the formula, n represents 2 or 3) and It is a 5-lipoxygenase action inhibitor containing an amide derivative represented by the following group (in the formula, n represents 2 or 3). In the present invention, the halogen atom represented by the above formula () is preferably furor, chloro or brome. In the present invention, the 5-lipoxygenase action inhibitor means a preparation that has the action of suppressing the action of 5-lipoxygenase. 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. (In the formula, (R) ^m is a 3,4-dihydroxy group, 3
-Methoxy-4-hydroxy group, 3,4-dimethoxy group, 3,5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4-toluoyloxy group or 3,4,5-trimethoxy group.
n represents the number of double bonds in trans configuration, and is an integer of 1 or 2. ) or, for example, its reactive derivative () (In the formula, the definitions of (R) ^m and n are the same as the definitions of the formula ()) It is obtained by performing a condensation reaction and a deprotecting group reaction. 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 10 to 2000 mg, preferably 20 to 600 mg, and may be administered as needed 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 compound of the present invention can be used as an active ingredient or one of the active ingredients alone or mixed with a pharmaceutical carrier or excipient in a conventional manner, and can be used as a tablet, sugar-coated tablet, powder, capsule, granule, suspension, emulsion, or injection. It can be applied in various forms such as liquid formulations. 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 Under an argon atmosphere, 1.48 g (5.25 mmol) of N-(4-bromobutyl)phthalimide was added to a solution of 2.25 g (7.83 mmol) of N-(p-chlorobenzhydryl)piperazine in dry xylene (20 ml).
Refluxed for an hour. After cooling, dilute aqueous sodium carbonate solution was added and extraction was performed with chloroform. The organic layer was washed with water and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. 1.46 g (2.99 mmol) of N-(p-chlorobenzhydryl)-N-(4-phthalylaminobutyl)piperazine was obtained from the chloroform elution fraction. To an ethanol solution (5 ml) of 555 mg (1.14 mmol) of the phthalimide compound was added 85 mg (1.36 mmol) of an 80% aqueous hydrazine hydrate solution, and the mixture was refluxed for 3.5 hours. After the reaction, the reaction solution was filtered, the solution was distilled off under reduced pressure, and 5 ml of dry N,N-dimethylformamide was added to the resulting residue. In this solution, N-[3-
[3,4-di-(β-methoxyethoxymethoxy)
[phenyl]-2-propenoyl]thiazolidine-
A solution of 620 mg (1.36 mmol) of 2-thione in dry N,N-dimethylformamide (4 ml) was added. After reacting at room temperature for 17 hours, the solvent was distilled off under reduced pressure, and chloroform was added to the resulting residue to remove insoluble matter.
The solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and N-
[4-[3-[3,4-di-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]
661 mg (0.95 mmol) of aminobutyl]-N'-(p-chlorobenzhydryl)piperazine was obtained. To a solution of 630 mg (0.91 mmol) of the amide compound in methanol (10 ml) was added 190 mg (1 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 2.5 hours.
The reaction solution was concentrated under reduced pressure, water was added to the resulting residue,
After adjusting the pH to 10 with a saturated aqueous sodium carbonate solution, extraction was performed with chloroform-methanol (20:1), the organic layer was concentrated under reduced pressure, and the resulting residue was subjected to Sephadex column chromatography, and the methanol eluted fraction was extracted. From, N-[4-[3-(3,4-dihydroxy)phenyl]-2-propenoyl]aminobutyl]-N'-(p-chlorobenzhydryl)
446 mg (0.77 mmol) of piperazine was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3220, 1660, 1600 ¹ H-NMR (CD ₃ OD) δ: 1.30-1.90 (4H, m), 2.10-2.80 (10H,
m), 3.10-3.73 (2H, m), 4.15 (1H,
S), 6.31 (1H, d, J = 15Hz), 6.60-
7.90 (13H) Example 2 Under an argon atmosphere, N-
2.09 g of benzhydrylpiperazine was added, and the mixture was heated and refluxed for 23 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture for extraction, the organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography using chloroform-methanol (100:1,
50:1) N-benzhydryl from the elution fraction
N'-4-phthalylaminobutylpiperazine 2.00g
I got it. 500 mg of the piperazine compound under argon atmosphere
Add 138 mg (2.21 mmol) of 80% hydrazine hydrate to an ethanol solution (10 ml) of (1.10 mmol),
The mixture was heated to reflux for 2 hours. The reaction solution was filtered, and the solution was concentrated under reduced pressure. To the resulting residue, 5 ml of dry tetrahydrofuran was added, and to this solution was added N-[3-{3,
A solution of 620 mg (1.36 mmol) of 4-di-(methoxyethoxymethoxy)phenyl}-2-propenoyl]thiazolidine-2-thione in dry tetrahydrofuran (6 ml) was added, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, chloroform was added to the obtained residue, insoluble matter was removed by filtration, the liquid was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. 50:1) N- [4-
{3-(3,4-dimethoxyethoxymethoxyphenyl)-2-propenoyl]aminobutyl-
750 mg (1.0 ml) of N'-benzhydrylpiperazine was obtained. To a solution of 750 mg (1.0 mmol) of the amide compound in methanol (10 ml) was added 225 mg (1.18 mmol) of p-toluenesulfonic acid monohydrate, 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, the pH was adjusted to 10 with a saturated aqueous sodium carbonate solution, and then extracted with chloroform. The organic layer was concentrated under reduced pressure, the resulting residue was subjected to Sephadex LH-20 column chromatography, and N-[4-{3-(3,4-dihydroxyphenyl)-2-propenoyl} was extracted from the methanol elution fraction. Aminobutyl]-N′-benzhydrylpiperazine 423mg
(0.87 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3220, 1660, 1600 Example 3 800 mg (20 mmol) of 60% sodium hydride,
After washing several times with n-hexane, 10 ml of dimethyl sulfoxide is added and heated to 70° to 75° C. for 45 minutes under an argon atmosphere. Add 3.6 g (20 mmol) of theophylline to this reaction solution and add dimethyl sulfoxide.
After adding the suspension to 50 ml and stirring at room temperature for 1 hour, 5.08 g (20 mmol) of bromoethyl phthalimide was added.
A dimethyl sulfoxide solution was added thereto, and the mixture was allowed to react at room temperature overnight. Water was added to the reaction solution, the resulting precipitate was collected, recrystallized from methanol, and 7-(2
-phthalyl aminoethyl)-theophylline 3.95g
(11.2 mmol) was obtained. 706 mg (2 mmol) of the theophylline derivative was suspended in 50 ml of ethanol, 500 mg (8 mmol) of 80% hydrazine hydrate was added, and under an argon atmosphere,
The mixture was heated under reflux for 2 hours. n-butanol in the reaction solution
After adding 100 ml and cooling to room temperature, the formed crystals were removed by filtration, and the liquid was concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of dimethylformamide, and N-[3-{3,4-di-(β-
Methoxyethoxymethoxy)phenyl}-2-propenoyl]-thiazolidine-2-thione 914mg
(2 mmol) in dimethylformamide (5 ml) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and 7-[2-[3-{3,
861 mg (1.53 mmol) of 4-di-(β-methoxyethoxymethoxy)phenyl}-2-propenoyl]aminoethyl]-theophylline was obtained. 861 mg (1.53 mmol) of the amide was dissolved in 50 ml of methanol, 760 mg (4 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 1 hour. After adding a saturated aqueous sodium bicarbonate solution to the reaction solution and adjusting the pH to 10, water was added, the resulting precipitate was collected, and recrystallized from methanol to give 7-[2-{3-
(3,4-dihydroxy)phenyl-2-propenoyl}-aminoethyl]-theophylline 410
mg (1.06 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). ¹ H-NMR (d ₆ -DMSO) δ: 3.22 (3H, S), 3.42 (3H, S), 3.75 (2H,
m), 4.33 (2H, m), 6.17 (1H, d, J=
16Hz), 6.85 (1H, bs), 6.72 (2H, bs),
7.17 (1H, d, J = 16Hz), 7.85 (1H, s) IRν ^KBr _nax (cm ^-1 ): 3350, 1702, 1650, 1640, 1600 Example 4 3.00 g of benzhydryl 2-chloroethyl ether under argon atmosphere (12.2 mmol), 4 ml of ethyl N-piperazinocarboxylate
(27.3 mmol) was added and reacted at 160°C for 1 hour.
After cooling, water was added to the reaction solution, and the pH was adjusted to 10 with an aqueous sodium carbonate solution, followed by extraction with ethyl acetate.
The organic layer was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and 4.12 g of N-(2-benzhydroxyethyl)-N'-ethoxycarbonylpiperazine ( 11.2 mmol) was obtained. Potassium hydroxide was added to a solution of the piperazine derivative 4.12 (11.2 mmol) in methanol (20 ml) and water (10 ml).
13.2g (235mmol) was added and refluxed for 19 hours. Water was added to the reaction solution, extracted with n-butanol, and the organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to Sephadex column chromatography, and 3.15 g of N-(2-benzhydroxyethyl)piperazine was obtained from the methanol elution fraction.
(10.6 mmol) was obtained. To a solution of 265 mg (0.894 mmol) of the amine compound in dry dimethyl formamide (5 ml) was added N-[3
620 mg (1.36 mmol) of -[3,4-bis(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]thiazolidine-2-thione was added and reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and N-[3-[3,4-bis(β-methoxyethoxymethoxy)phenyl] was extracted from the fraction eluted with chloroform-methanol (100:1). ]-2-propenoyl]-N′-(2-benzhydroxyethyl)
561 mg (0.884 mmol) of piperazine was obtained. To a solution of 561 mg (0.884 mmol) of the amide compound in methanol (10 ml) was added p-toluenesulfonic acid.
178 mg (0.936 mmol) of monohydrate was added and the mixture was refluxed for 4 hours. Concentrate the reaction solution under reduced pressure, add water to the resulting residue, adjust the pH to 10 with an aqueous sodium carbonate solution, perform extraction with n-butanol, wash the organic layer with water, and concentrate the organic layer under reduced pressure. 242 mg of N-[3-(3,4-dihydroxyphenyl)-2-propenoyl]-N'-(2-benzhydroxyethyl)piperazine was extracted from the methanol eluted fraction.
(0.528 mmol) was obtained. This spectroscopic data supports the structure (XI) of the following formula. IRν ^KBr _nax (cm ^-1 ): 3100, 1640, 1600, 1585 ¹ H-NMR (heavy methanol) δ: 2.47 (6H, m), 3.53 (6H, m), 5.30 (1H,
S), 6.57-7.60 (15H, m), Example 5 0.8 g of concentrated sulfuric acid is added to a dry benzene solution (3.5 ml) of 3.27 g of 2-chloroethanol and heated to 50° C. under an argon atmosphere. This is benzhydrol
Slowly add 5.0 g of dry benzene solution (6.5 ml), and after 30 minutes, heat under reflux for 1.5 hours. After cooling, the benzene layer was washed with water, dried over anhydrous Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure to obtain 6.7 g of benzhydryl-2-chloroethyl ether. Potassium phthalimide was added to a solution of 3.7 g of the ether compound in dry dimethyl formamide (30 ml).
Add 3.4g and react at 100°C for 2 hours. The reaction solution was filtered and the solvent was distilled off under reduced pressure, followed by recrystallization from methanol to obtain 4.4 g of benzhydryl-2-phthalyl aminoethyl ether. Add 80% to an ethanol solution (10 ml) of 536 mg of benzhydryl-2-phthalyl aminoethyl ether.
150 mg of an aqueous hydrazine hydrate solution was added and heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended in 20 ml of dry tetrahydrofuran, and N-3-(3,4-di-β-methoxyethoxymethoxy)phenyl-2-propenoylthiazolidine-2- 460 mg of thione was added, and the mixture was stirred at room temperature under an argon atmosphere for 20 hours. The reaction solution was concentrated under reduced pressure, and a 2N aqueous sodium hydroxide solution 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 silica gel column chromatography, and 2-[3-(3,4
433 mg of -di-β-methoxyethoxymethoxy)phenyl-2-propenoyl]aminoethylbenzhydryl ether was obtained. Methanol solution (15ml) of 430mg of the amide compound
15.2 mg of p-toluenesulfonic acid monohydrate was added to the mixture, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The resulting residue was subjected to silica gel column chromatography, and 2-[3-(3,4) -dihydroxy)
162 mg of phenyl-2-propenoyl]aminoethylbenzhydryl ether was obtained. Spectroscopic data of this product support the structure of formula (XII) below. ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.63 (4H, m), 5.40 (1H, S), 6.13 (1H,
d (J=15Hz)), 6.40 (1H, bs), 6.63―
7.80 (16H, m) IRν ^KBr _nax (cm) 3300, 1650, 1600, 1510, 1280 Example 6 N-benzhydryl under argon atmosphere
N'-(4-phthalylaminobutyl)piperazine
500 mg (1.10 mmol) in ethanol solution (10 ml)
80% hydrazine hydrate aqueous solution 138mg
(2.21 mmol) was added and refluxed for 2.5 hours. After the reaction, the reaction solution was filtered, the solution was distilled off under reduced pressure, and 5 ml of dry tetrahydrofuran was added to the resulting residue. Add N-[3-[3-methoxy-4-(β-
methoxyethoxymethoxy)phenyl]-2-propenoyl]thiazolidine-2-thione 492mg
(1.28 mmol) in dry tetrahydrofuran solution (86
ml) was added. After reacting for 23.5 hours at room temperature,
The solvent was distilled off under reduced pressure, chloroform was added to the resulting residue to remove insoluble matter, the liquid was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and chloroform-methanol (100:1-50:
1) From the elution fraction, N-[4-[3-[-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]aminobutyl]-
N′-benzhydrylpiperazine 640mg
(1.09 mmol) was obtained. 630mg of the amide compound
(1.07 mmol) of p-toluenesulfonic acid monohydrate in methanol (10 ml) 225 mg (1.18 mmol)
was added and refluxed for 4.5 hours. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, the pH was adjusted to 10 with a saturated aqueous sodium carbonate solution, and then extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was subjected to sepadex column chromatography.
From the methanol elution fraction, N-[4-[3-(3
-Methoxy-4-hydroxy)phenyl]-2-
461 mg (0.92 mmol) of propenoyl]aminobutyl]-N'-benzhydrylpiperazine was obtained. The spectroscopic data of this product is the structure of the following formula ()
support. IRν ^KBr _nax (cm ^-1 ): 3220, 1660, 1600 ¹ H-NMR (heavy chloroform) δ: 1.30-1.90 (4H, m), 2.10-2.90 (10H,
br, S), 3.10-3.60 (2H, m), 3.75 (3H,
S), 4.20 (1H, S), 6.27 (1H, d, J=
16Hz), 7.80-6.60 (14H) Example 7 353 mg (1 mmol) of 7-(2-phthalylaminoethyl)-theophylline was suspended in 20 ml of ethanol, and 250 mg of 80% hydrazine hydrate was added.
(4 mmol) was added thereto, and the mixture was heated under reflux for 2 hours under an argon atmosphere. After the reaction, add 50ml of n-butanol,
After cooling to room temperature, the formed crystals were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of dimethylformamide, and this solution was added with N.
A dimethylformamide solution (2 ml) containing 383 mg (1 mmol) of -{3-(3-methoxy-4-β-methoxyethoxymethoxy)phenyl-2-propenoyl}thiazolidine-2-thione was added, and the
Allowed time to react. The reaction product was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and 7-[2-{3-(3-methoxy-4-β)
-methoxyethoxymethoxy)phenyl-2-propenoyl}aminoethyl]-theophylline 365
mg (0.75 mmol) was obtained. Dissolve 365 mg (0.75 mmol) of the amide in 30 ml of methanol to obtain p-toluenesulfonic acid monohydrate.
380 mg (2 mmol) was added, and the mixture was heated under reflux for 1 hour.
Add saturated aqueous sodium hydrogen carbonate solution to the reaction solution,
After setting the pH to 10, add water and generate. Collect the precipitate and recrystallize it from methanol to give 7-[2-{3-
(3-methoxy-4-hydroxy)phenyl-
209 mg (0.52 mmol) of 2-propenoyl}aminoethyl]-theophylline was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3300, 1705, 1660, 1645, 1610 Example 8 Under an argon atmosphere, a solution of 625 mg (2.11 mmol) of N-(2-benzhydroxyethyl)piperazine in dry dimethylformamide (2 ml) was added. N-[3
A solution of 998 mg (2.60 mmol) of -[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]thiazolidine-2-thione in dry dimethylformamide (4 ml) was added, and the mixture was allowed to react at room temperature for 2 hours. Ta. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and N-[3-[3-methoxy-4-(β
-methoxyethoxymethoxy)phenyl] -2-
813 mg (1.45 mmol) of propenoyl]-N'-(2-benzhydroxyethyl)piperazine was obtained. To a solution of 813 mg (1.45 mmol) of the amide compound in methanol (16 ml) was added 288 mg (1.51 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was reacted for 1 hour. Add water to the reaction solution and add sodium carbonate aqueous solution.
The pH was adjusted to 10 and extraction was performed with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The resulting residue was subjected to Sephadex column chromatography, and the methanol eluted fraction was purified with N-[3-(3-methoxy-
4-hydroxyphenyl)-2-propenoyl]
556 mg (1.18 mmol) of -N'-(2-benzhydroxyethyl)piperazine was obtained. This spectroscopic data supports the structure () of the following formula. IRν ^KBr _nax (cm ^-1 ): 3300, 1645, 1600, 1590 ¹ H-NMR (heavy methanol) δ: 2.48 (6H, m), 3.63 (6H, m), 3.80 (3H,
S), 5.32 (1H, S), 6.75-7.72 (15H,
m) Example 9 Under an argon atmosphere, concentrated sulfuric acid (0.5 ml) was added to a solution of 3.85 g (40.7 mmol) of 3-chloro-1-propanol in benzene (4 ml), and 5 g (27.2 mmol) of benzhydrol was added to this solution. Benzene (6ml)
The solution was added and refluxed for 0.8 hours. The reaction solution was diluted with benzene, washed with water, the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give 6.80 g of benzhydryl-3-chloropropyl ether.
(26.1 mmol) was obtained. Under argon atmosphere, 6.80 g of the ether compound
(26.1 mmol), add 9.77 g (61.8 mmol) of ethyl-N-piperazinocarboxylate, and
The reaction was carried out at ℃ for 23 hours. The reaction solution was diluted with chloroform, washed with an aqueous sodium bicarbonate solution and water, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. 9.47 g (24.8 mmol) of N-(3-benzhydroxypropyl)-N'-ethoxycarbonylpiperazine was obtained from the benzene (1:5 to 1:1) elution fraction. Under argon atmosphere, 9.47 g of the piperazine derivative
(24.8 mmol) in methanol (20 ml) was added with a solution of 28 g (0.5 mol) of potassium hydroxide in water-methanol (1:260 ml) and refluxed for 21 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 7.5 g (24.2 mmol) of N-(3-benzhydroxypropyl)piperazine. 620 mg of the piperazine derivative under argon atmosphere
(2 mmol) in dry tetrahydrofuran (5 ml) to 766 mg of N-[3-[3-methoxy-4-(β-methoxyethoxymethoxy)-phenyl]-2-propenoyl]-thiazolidine-2-thione.
(2.0 mmol) of dry tetrahydrofuran (5 ml)
The solution was added and allowed to react overnight at room temperature. The reaction solution was concentrated under reduced pressure, diluted with chloroform, washed with 2N aqueous sodium hydroxide solution and water, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. From the chloroform-methanol (50:1) elution fraction, N-[3-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]-N'-(3-benzhydroxypropyl) 1.08 g (1.88 mmol) of piperazine was obtained. 1.08 g (1.88 mmol) of the amide compound was dissolved in 10 ml of methanol, 380 mg (2 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 1 hour under an argon atmosphere. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extraction was performed with ethyl acetate. After drying the organic layer over sodium sulfate, it was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and the N-
[3-[3-methoxy-4-hydroxy)phenyl-2-propenoyl]-N'-(3-benzhydroxypropyl)piperazine 603mg
(1.24 mmol) was obtained. This spectroscopic data supports the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3400, 1640, 1585 ¹ H-NMR (heavy methanol) δ: 1.98 (2H, m), 2.38 (6H, m), 3.58 (6H,
m), 3.82 (3H, S), 5.28 (1H, S), 6.67
~7.78 (15H, m) Example 10 80% solution of 471 mg of benzhydryl-2-phthalyl aminoethyl ether (6.5 ml)
132 mg of an aqueous hydrazine hydrate solution was added and heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was suspended in 20 ml of dry tetrahydrofuran, and N-3-(3-methoxy-4-β-methoxyethoxymethoxy)phenyl-2-propenoylthiazolidine-2- 460.2 mg of thione was added, and the mixture was stirred at room temperature under an argon atmosphere for 20 hours. The reaction solution was concentrated under reduced pressure, and a 2N aqueous sodium hydroxide solution 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 silica gel column chromatography to obtain 2-[3-(3-methoxy-4-β) from the chloroform elution fraction.
548 mg of -methoxyethoxymethoxy)phenyl-2-propenoyl]aminoethylbenzhydryl ether was obtained. Methanol solution (20ml) of 545mg of the amide compound
21 mg of p-toluenesulfonic acid monohydrate was added to the mixture, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting residue was subjected to silica gel column chromatography. From the fraction eluted with chloroform-methanol (50:1), 2-[3-(3-methoxy-) 334 mg of 4-hydroxy)phenyl-2-propenoyl]aminoethylbenzhydryl ether was obtained. Spectroscopic data of this product support the structure of the following formula (). ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.53 (4H, m), 3.68 (1H, S), 6.30 (1H,
S), 6.25 (1H, d (J = 15Hz)), 6.50 (1H,
bs), 6.67-7.40 (14H, m), 7.50 (1H, d
(J=15Hz) IRν ^KBr _nax (cm ^-1 ): 3300, 1660, 1585, 1508, 1270 Example 11 Benzhydryl-3-chloropropyl ether
2 g potassium phthalimide in a solution of 2.6 g (10 mmol) in dry dimethylformamide (20 ml)
(10.8 mmol) and react at 100°C for 2 hours. After filtering the reaction solution and distilling off the solvent under reduced pressure, it was recrystallized from methanol to give benzhydryl-
3-phthalyl aminoethyl ether 3.04g
(8.2 mmol) was obtained. To an ethanol solution (10 ml) of 371 mg (1 mmol) of the ether compound was added 125 mg (2 mmol) of an 80% aqueous hydrazine hydrate solution, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was suspended in 10 ml of dry tetrahydrofuran, and N-[3-
A dry tetrahydrofuran solution (10 ml) containing 490 mg (1.2 mmol) of [3methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]thiazolidine-2-thione was added, and the mixture was reacted for 18 hours at room temperature under an argon atmosphere. I let it happen. The reaction solution was concentrated under reduced pressure, and chloroform was added to the resulting residue.
The organic layer was washed with 2N sodium hydroxide and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 3-[3-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]aminopropylbenzhydryl ether was extracted from the chloroform elution fraction. 378
mg (0.75 mmol) was obtained. 19 mg (0.1 mmol) of p-toluenesulfonic acid monohydrate was added to a methanol solution (10 ml) containing 378 mg (0.75 mmol) of the amide compound, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure.
The obtained residue was subjected to silica gel column chromatography, and chloroform-methanol (50:
1) 3-[3-(3-methoxy-4
-Hydroxyphenyl)-2-propenoyl]aminopropylbenzhydryl ether 230mg
(0.55 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3300, 1655, 1610 Example 12 N-benzhydryl under argon atmosphere
Ethanol solution (10ml) of N′-(4-phthalylaminobutyl)-piperazine 500mg (1.10mmol)
80% hydrazine hydrate aqueous solution 138mg
(2.21 mmol) was added and heated under reflux for 2 hours. The reaction solution was filtered, concentrated under pressure, and 5 ml of dry tetrahydrofuran was added to the resulting residue. In this solution, N-{3-(3,4-dimethoxyphenyl)-
2-propenoyl}-thiazolidine-2-thiene
A solution of 372 mg (1.2 mmol) in dry tetrahydrofuran (5 ml) was added, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, chloroform was added to the resulting residue, insoluble matters were removed by filtration, the liquid was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. -[4-{3-(3,4-dimethoxyphenyl)-2-propenoyl}aminobutyl]-
N′-benzhydrylpiperazine 500mg
(0.97 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3300, 1660 Example 13 7-(2-phthalylaminoethyl)-theophylline 706 mg (2 mmol) was suspended in 50 ml of ethanol, and 500 mg of 80% hydrazine hydrate was added.
(8 mmol) was added, and the mixture was heated under reflux for 2 hours under an argon atmosphere. 100 ml of n-butanol was added to the reaction solution, and after cooling to room temperature, the formed crystals were removed by filtration, and the solution was concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of dimethylformamide, and N-{3-(3,4-dimethoxyphenyl)-2
-propenoyl}-thiazolidine-2-thione
A solution of 620 mg (2 mmol) in 5 ml of dimethylformamide was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under pressure, the resulting residue was subjected to silica gel column chromatography, and 7-[2-{3-
(3,4-dimethoxyphenyl)-2-propenoyl}-aminoethyl]-theophylline 610mg
(1.48 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). ¹ H-NMR (d ₆ -DMSO) δ: 3.18 (3H, S), 3.32 (2H, m), 3.56 (2H,
m), 3.67 (6H.S), 4.27 (2H, m), 6.23
(1H, d, J = 16Hz), 7.20 (1H, d, J
= 16Hz), 6.80-7.03 (3H, m), 7.87 (1H,
d, J=4Hz) IRν ^KBr _nax (cm ^-1 ): 3300, 1702, 1660, 1655, 1615 Example 14 Under an argon atmosphere, 296 mg (1 mmol) of N-(2-benzhydroxyethyl)piperazine was dissolved in dry dimethylformamide ( 2 ml) solution, add N-[3-
(3,4-dimethoxyphenyl)-2-propenoyl]thiazolidine-2-thione 372 mg
(1.2 mmol) of dry dimethylformamide (4 ml)
The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:1), N-[3 ―
(3,4-dimethoxyphenyl)-2-propenoyl]-N'-(2-benzhydroxyethyl)
-348 mg (0.72 mmol) of piperazine was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 1640, 1600 Example 15 Add 80% to an ethanol solution (65 ml) of 472 mg of benzhydryl-2-phthalyl aminoethyl ether.
132 mg of hydrazine hydrate aqueous solution was added and heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended in 20 ml of dry tetrahydrofuran, and N-3-(3,4-dimethoxy)phenyl-2-propenolthiazolidine-2-thione was added to the suspension in 20 ml of dry tetrahydrofuran.
371.3 mg was added, and the mixture was stirred at room temperature under an argon atmosphere for 13 hours. The reaction solution was concentrated under reduced pressure, and a 2N aqueous sodium hydroxide solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and 2-[3-(3,4
465 mg of -dimethoxyphenyl-2-propenoyl]aminoethylbenzhydryl ether was obtained.
Spectroscopic data of this product support the structure of formula (XII) below. ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.55 (4H, m), 3.80 (6H, m), 5.32 (1H,
S), 6.33 (1H, b (J = 15.5Hz)), 6.63
(1H, bs), 6.67-7.27 (12H, m), 7.53
(1H, d (J=15.5Hz) IRν ^KBr _nax (cm ^-1 ): 3250, 1650, 1508, 1270 Example 16 N-benzhydryl-N'- under argon atmosphere
To an ethanol solution (10 ml) of 0.50 g of 4-phthalylaminobutylpiperazine was added 137.8 mg of an 80% aqueous hydrazine hydrate solution, and the mixture was heated under reflux for 2.5 hours.
The reaction solution was filtered, the solution was concentrated under reduced pressure, and dry tetrahydrofuran (5 ml) was added to the resulting residue. Add N-3-(3,5-dimethoxy-4-β-methoxyethoxymethoxy)phenyl-2-propenoylthiazolidine-2-thione to this suspension.
500.8mg dry tetrahydrofuran solution (5ml)
was added, and the mixture was stirred at room temperature for 22 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, filtered with chloroform, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. From the chloroform-methanol (50:1, 20:1) elution fraction. N-benzhydryl-N'-3-(3,5
549.2 mg of -dimethoxy-4-β-methoxyethoxymethoxy)phenyl-2-propenoylaminobutylpiperazine was obtained. A methanol solution of 549.2 mg of the amide compound (815
ml) of p-toluenesulfonic acid monohydrate 253.6
mg was added thereto, and the mixture was heated under reflux for 1.2 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution 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 silica gel column chromatography, and chloroform-
From the methanol (50:1, 20:1) elution fraction, N-
463.8 mg of benzhydryl-N'-3-(3,5-dimethoxy-4-hydroxy)phenyl-2-propenoylaminobutylpiperazine was obtained. Spectroscopic data of this product support the structure of the following formula (). ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.50 (4H, m), 2.43 (10H, m), 3.67 (6H,
S), 4.12 (1H, S), 6.27 (2H, m), 6.28
(1H, d (J=15.5Hz)), 6.60 (2H, S),
6.83-7.63 (11H, m) IRν ^KBr _nax (cm ^-1 ): 3200, 2880, 2760, 1660, 1600 Example 17 Drying of 424 mg (1.43 mmol) of N-(2-benzhydroxyethyl)piperazine under argon atmosphere In dimethylformamide (2 ml) solution, N-[3
-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]thiazolidine-2-thione 475mg
(1.15 mmol) was added and reacted at room temperature for 2 hours.
The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to remove chloroformate.
From the methanol (100:1) elution fraction, N-[3-
[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl-
588 mg (0.995 mmol) of N'-(2-benzhydroxyethyl)piperazine was obtained. To a solution of 588 mg (0.995 mmol) of the amide compound in methanol (10 ml) was added 190 mg (0.999 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 1 hour. Water was added to the reaction solution, and the pH was adjusted to 10 with an aqueous sodium carbonate solution, followed by extraction with ethyl acetate. After washing the organic layer with water, the resulting residue was concentrated under reduced pressure and subjected to sepadex column chromatography, and N-[3-(3,5-
375 mg (0.746 mmol) of dimethoxy-4-hydroxyphenyl)-2-propenoyl]-N'-(2-benzhydroxyethyl)piperazine was obtained.
The spectroscopic data of this substance is the structure of the following formula (
). IRν ^KBr _nax (cm ^-1 ): 3350, 1650, 1610 ¹ H-NMR (heavy methanol) δ: 2.53 (6H, m), 3.67 (6H, m), 3.83 (3H,
S), 5.33 (1H, S), 6.62-7.70 (14H,
m) Example 18 Under an argon atmosphere, 160 mg (0.52 mmol) of N-(3-benzhydroxypropyl)piperazine was added to a solution of N-[3-
(3,5-dimethoxy-4-(β-methoxyethoxymethoxy)-phenyl]-2-propenoyl]-thiazolidine-2-thione 206 mg
A solution of (0.5 mmol) in dry tetrahydrofuran was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was concentrated under reduced pressure, diluted with chloroform, washed with a 2N aqueous sodium hydroxide solution and water, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. From the chloroform-methanol (50:1) elution fraction, N-[-
270 mg (0.45 mmol) of [3,5-di-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl-N'-(3-benzhydroxypropyl)piperazine was obtained. 270 mg (0.45 mmol) of the amide compound was dissolved in 5 ml of methanol, and p-toluenesulfonic acid was dissolved.
Add 95 mg (0.5 mmol) and add 1
The mixture was heated to reflux for an hour. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extraction was performed with ethyl acetate. After drying the organic layer with sodium sulfate, it was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and chloroform-
From the methanol (20:1) elution fraction, N-[3-
(3,5-dimethoxy-4-hydroxyphenyl)
-2-propenoyl]-N'-(3-benzhydroxypropyl)piperazine 200 mg (0.38 mmol)
I got it. The spectroscopic data of this item is expressed by the following formula (
) supports the structure. IRν ^KBr _nax (cm ^-1 ): 3400, 1642, 1600 ¹ H-NMR (heavy methanol) δ: 1.80 (2H, m), 2.40 (6H, m), 3.67 (6H,
m), 3.80 (3H, S), 5.28 (1H, S), 6.7
~7.7 (14H, m) Example 19 125 mg of 80% hydrazine hydrate aqueous solution in 247 mg (1 mmol) of benzhydryl-2-phthalyl aminoethyl ether in ethanol (10 ml)
(2 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was suspended in 10 ml of dry tetrahydrofuran, and N-[3-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)]
[phenyl]-2-propenoyl]thiazolidine-
A solution of 495 mg (1.2 mmol) of 2-thione in dry tetrahydrofuran (10 ml) was added, and the mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform, washed with 2N aqueous sodium hydroxide solution, and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2-[3-[3,5-dimethoxy-
350 mg (0.67 mmol) of 4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]aminoethylbenzhydryl ether was obtained. To a solution of 350 mg (0.67 mmol) of the amide compound in methanol (10 ml) was added 20 mg (0.1 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2-[3-[3,5-dimethoxy-4-hydroxy]phenyl-2-propenoyl]aminoethyl was extracted from the chloroform-methanol (50:1) elution fraction. benzhydryl ether
182 mg (0.42 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3400, 1660, 1600 Example 20 N-(p-chlorobenzhydryl)-N'-(4-phthalylaminobutyl)piperazine 555 mg (1.14 mmol) in ethanol under argon atmosphere (5
ml) 85mg of 80% hydrazine hydrate in solution
(1.36 mmol) was added and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and dry dimethylformamide (2 ml) was added to the resulting residue. Add N-[5
A solution of 685 mg (1.2 mmol) of -(3,4-di-β-methoxyethoxymethoxy)phenyl-2.4pentadienoyl]thiazolidine-2-thione in dry dimethylformamide (2 ml) was added. After reacting at room temperature for 3 hours, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and N-(p-chlorobenzhydryl)- was obtained from the chloroform-methanol (50:1) elution fraction.
N'-[4-[5-[3,4-di-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]aminobutyl]piperazine 563 mg
(0.78 mmol) was obtained. To a solution of 563 mg (0.78 mmol) of the amide compound in methanol (10 ml) was added 152 mg (0.8 mmol) of p-toluenesulfonic acid monohydrate, 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, the pH was adjusted to 10 with an aqueous sodium carbonate solution, and extraction was performed with chloroform. The organic layer was concentrated under reduced pressure, the resulting residue was subjected to Sephadex LH-20 column chromatography, and N-(p-chlorobenzhydryl)- was extracted from the methanol elution fraction.
284 mg (0.52 mmol) of N'-[4-[5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl)aminobutyl]piperazine was obtained. The spectroscopic data of this item is the following formula ()
supports the structure of IRν ^KBr (cm ^-1 ): 3300, 1660, 1600 Example 21 N-benzhydryl-N′- under argon atmosphere
(4-phthalylaminobutyl)piperazine 0.05g
To an ethanol solution (10 ml) was added 137.8 mg of an 80% aqueous hydrazine hydrate solution, and the mixture was heated under reflux for 2.5 hours. The reaction solution was filtered, the solution was concentrated under reduced pressure, and dry tetrahydrofuran (5 ml) was added to the resulting residue. In this suspension, N-[5-(3,4-di-
β-methoxyethoxymethoxy)phenyl-2,
A solution of 571.1 mg of 4-pentadienoylthiazolidine-2-thione in dry tetrahydrofuran (5 ml)
was added, and the mixture was stirred at room temperature for 20 hours under an argon atmosphere. The reaction solution is concentrated under reduced pressure, filtered with chloroform, the solution is concentrated under reduced pressure, and the resulting residue is subjected to silica gel column chromatography. N-benzhydryl-N'-5-(3,4-
Di-β-methoxyethoxymethoxy)phenyl-
622.6 mg of 2,4-pentadienoylaminobutylpiperazine was obtained. A methanol solution of 622.6 mg of the amide compound (15
ml) p-toluenesulfonic acid monohydrate 392.5
mg was added and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and N-benzhydryl-
N'-5-(3,4-dihydroxy)phenyl-
334.0 mg of 2,4-pentadienoylaminobutylpiperazine was obtained. Spectroscopic data of this product support the structure of the following formula (). ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.48 (4H, m), 2.42 (10H, m), 4.17 (1H,
s), 5.98 (1H, d (J = 15.5Hz)), 6.52―
7.50 (16H, m) IRν ^KBr _nax (cm ^-1 ): 2880, 2760, 1655, 1600 Example 22 Under an argon atmosphere, 690 mg (2.33 mmol) of N-(2-benzhydroxyethyl)piperazine was dissolved in dry dimethylformamide (2 ml). ) solution, N-[5
1.75 g (3.26 mmol) of -[3,4-bis(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine-2-thione was added and reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (100:1) was extracted with N-[5-[3,4-bis(β-methoxyethoxymethoxy)phenyl].
-2,4-pentadienoyl]-N'-(2-benzhydroxyethyl)piperazine 856mg
(1.30 mmol) was obtained. To a solution of 856 mg (1.30 mmol) of the amide compound in methanol (17 ml) was added 257 mg (1.35 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 4 hours. Saturated brine was added to the reaction solution, the pH was adjusted to 10 with an aqueous sodium carbonate solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The resulting residue was subjected to Sephadex column chromatography, and N-[5-(3,
439 mg (0.906 mmol) of 4-dihydroxyphenyl)-2,4-pentadienoyl]-N'-(2-benzhydroxyethyl)piperazine was obtained. The spectroscopic data of this substance is the structure of the following formula (
). IRν ^KBr _nax (cm ^-1 ): 3200, 1640, 1610, 1590 ¹ H-NMR (heavy methanol) δ: 2.43 (6H, m), 3.52 (6H, m), 5.30 (1H,
S), 6.35 (1H, d, J = 15Hz), 6.67~
7.57 (16H, m) Example 23 N-[5-[3,4-di-
(β-methoxyethoxymethoxy)phenyl]-
2,4-pentadienoyl]-thiazolidine-2
- A solution of 966 mg (2.0 mmol) of thione in dry tetrahydrofuran (6 ml) was added, and the mixture was reacted at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform, washed with 2N aqueous sodium hydroxide solution and water, the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. From the 1% methanol-chloroform elution fraction, N-[5-[3,4-di-(β-
methoxyethoxymethoxy)phenyl]-2,4
-Pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine 1.09g (1.6mmol)
I got it. Under argon atmosphere, 901mg of the amide compound
(1.33 mmol) of p-toluenesulfonic acid monohydrate in methanol (10 ml) 279 mg (1.47 mmol)
was added and refluxed for 1.5 hours. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.
From the 5% methanol chloroform elution fraction, N-
[5'-[3,4-hydroxyphenyl]-2,4
-Pentadienoyl]-N'-(3-banzhydroxypropyl)piperazine 330mg (0.66mmol)
I got it. This spectroscopic data supports the structure () of the following formula. IRν ^KBr _nax (cm ^-1 ): 3190, 1630, 1565 ¹ H-NMR [deuterochloroform-deuterypyridine (1:1)] δ: 1.50-2.05 (2H, m), 2.10-2.67 (6H,
m), 3.30-3.80 (6H, m), 5.30 (1H,
s), 6.30 (1H, d, J = 15Hz), 6.50―
7.50 (16H, m) Example 24 N-(p-chlorobenzhydryl)-N'-(4-phthalylaminobutyl) under argon atmosphere
An 80% aqueous hydrazine hydrate solution (82 mg, 1.31 mmol) was added to a 95% aqueous ethanol solution (10.5 ml) containing 527 mg (1.08 mmol) of piperazine, and the mixture was refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, and dry dimethylformamide (2 ml) was added to the resulting residue. N to this
-[5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine-2-thione 475 mg
(1.16 mmol) of dry dimethylformamide (2
ml) solution was added. After reacting at room temperature for 4 hours, the mixture was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography. From the chloroform-methanol (50:1) elution fraction, N-(p-chlorobenzhydryl)-N'-[4-[5-[3-methoxy-4-(β-methoxyethoxymethoxy)]
464 mg (0.716 mmol) of phenyl]-2,4-pentadienoyl]aminopropyl]piperazine was obtained. To a solution of 464 mg (0.716 mmol) of the amide compound in methanol (10 ml) was added 137 mg (0.720 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and water was added to the resulting residue, and the pH was adjusted to 10 with an aqueous sodium carbonate solution. Extraction was performed with chloroform, the organic layer was concentrated under reduced pressure, and the resulting residue was subjected to sepadex column chromatography. From the methanol elution fraction, N-(p
-chlorobenzhydryl) -N'-[4-[5-
(3-methoxy-4-hydroxy)phenyl]-
289 mg (0.516 mmol) of 2,4-pendadienoyl]aminobutyl]piperazine was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3220, 1660, 1600 ¹ H-NMR (deuterated chloroform) δ: 1.55 (4H, bs), 2.45 (10H, bs), 3.32 (2H,
bs), 3.83 (3H, S), 4.17 (1H, bs), 5.83
(1H, d, J = 15Hz), 6.50~7.53 (15H,
m) Example 25 N-benzhydryl under argon atmosphere
N'-(4-phthalylaminobutyl)piperazine
500 mg (1.1 mmol) in ethanol solution (10 ml),
80% hydrazine hydrate aqueous solution 128mg
(2.21 mmol) was added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was filtered, the solution was concentrated under reduced pressure, and 5 ml of dry tetrahydrofuran was added to the resulting residue. Add N-[5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine-2-thione 475 to this solution.
mg (1.16 mmol) in dry tetrahydrofuran (6 ml) was added. After reacting overnight at room temperature,
The solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and N-benzhydryl-
N′-[4-[5-[3-methoxy-4-(β-
methoxyethoxymethoxy)phenyl]-2,4
450 mg (0.73 mmol) of -pentadienoyl]aminopropyl]piperazine was obtained. To a solution of 450 mg (0.73 mmol) of the amide compound in methanol (10 ml) was added 152 mg (0.8 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water was added, and the pH was adjusted to 10 with an aqueous sodium carbonate solution. Extraction was performed with chloroform, the organic layer was concentrated under reduced pressure, and the resulting residue was subjected to Sephadex LH-20 column chromatography, and N-benzhydryl-N'-[4-[5-(3 -Methoxy-4-
Hydroxyphenyl)-2,4-pentadienoyl]aminobutyl]piperazine 236mg
(0.45 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3300, 1655, 1600 Example 26 706 mg (2 mmol) of 7-(2-phthalylaminoethyl)-theophylline was suspended in 50 ml of ethanol, and 500 mg (8 mmol) of 80% hydrazine hydrate was added.
was added and heated under reflux for 2 hours under an argon atmosphere. 100 ml of n-butanol was added to the reaction solution, and after cooling, the formed crystals were filtered and the solution was concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of dimethylformamide, and N-[5-(3-methoxy-4
-β-methoxyethoxymethoxyphenyl)-
2,4-pentadienoyl]-thiazolidine-2
- A solution of 820 mg (2 mmol) of thione in dimethylformamide (5 ml) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and 7-
[2-[5-(3-methoxy-4-β-methoxyethoxymethoxyphenyl)-2,4-pentadienoyl]aminoethyl]-theophylline 660mg
(1.28 mmol) was obtained. 660 mg (1.28 mmol) of the amide compound methanol 50
p-toluenesulfonic acid monohydrate 500ml solution
mg (2.63 mmol) was added, and the mixture was heated under reflux for 39 minutes.
After cooling the reaction solution, a saturated sodium bicarbonate aqueous solution was added to adjust the pH to 10, and then water was added to collect the resulting crystals. Recrystallized from methanol to give 7-
340 mg (0.80 mmol) of [2-[5-(3-methoxy-4-hydroxyphenyl)-2,4-pentadienoyl]aminoethyl]theophylline was obtained.
The spectroscopic data of this item is the following formula ()
supports the structure of ¹ H-NMR (d ₆ -DMSO) δ: 3.23 (3H, S), 3.42 (3H, s), 3.62 (2H,
m), 3.80 (3H, s), 4.35 (2H, m), 5.92
(1H, d, J=15Hz), 6.56~7.28 (6H,
m), 7.86 (1H, s), 7.98 (1H, t, J=
4Hz), 9.17 (1H, s) IRν ^KBr _nax (cm ^-1 ): 3302, 1710, 1660, 1650, 1610 Example 27 Under an argon atmosphere, 261 mg (0.881 mmol) of N-(2-benzhydroxyethyl)piperazine Add N- to a solution of dry dimethyltaformamide (5 ml).
[5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine-2-thione 480 mg
(1.17 mmol) was added and reacted at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (100:1) was purified with N-[5
515 mg (0.878 mmol) of -[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-(2-benzhydroxyethyl)piperazine was obtained. 515 mg (0.878 mmol) of the amide compound in methanol (10 ml)
178mg of p-toluenesulfonic acid monohydrate in solution
(0.936 mmol) was added and refluxed for 1 hour. The reaction solution was concentrated under reduced pressure, and water was added to the resulting residue, and the pH was adjusted to 10 with an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. After washing the organic layer with water, the resulting residue was concentrated under reduced pressure and subjected to sepadex column chromatography, and N-
[5-(3-methoxy-4-hydroxyphenyl)
-2,4-pentadienoyl]-N'-(2-benzhydroxyethyl)piperazine 386 mg
(0.774mmol) was obtained. This spectroscopic data supports the structure () of the following formula. IRν ^KBr _nax (cm ^-1 ): 3350, 1640, 1585 ¹ H-NMR (deuterated chloroform) δ: 2.57 (6H, m), 3.58 (6H, m), 3.83 (3H,
m), 5.30 (1H, S), 6.32 (1H, d, J=
15Hz), 6.63-7.60 (16H, m) Example 28 A solution of 650 mg (2.1 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added with N-[5-[3-methoxy-4
-(β-methoxyethoxymethoxy)phenyl]
-2,4-pentadienoyl]-thiazolidine-
A solution of 818 mg (2.1 mmol) of 2-thione in dry tetrahydrofuran (6 ml) was added, and the mixture was reacted at room temperature for 14 hours. After concentrating the reaction solution under reduced pressure, it was diluted with chloroform, washed with 2N aqueous sodium hydroxide solution and water, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. , N-[5-[3-methoxy-4-
(β-methoxyethoxymethoxy)phenyl]-
2,4-Pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine 1.106g
(1.8 mmol) was obtained. Under argon atmosphere, 1.064g of the amide compound
(2.1 mmol) of p-toluenesulfonic acid monohydrate in methanol (10 ml) 370 mg (1.95 mmol)
was added and refluxed for 1.5 hours. After concentrating the reaction solution under reduced pressure,
Diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and water, dried the organic layer over sodium sulfate, concentrated under reduced pressure, and subjected the resulting residue to silica gel column chromatography, diluted with 1-2% methanol-chloroform. From the elution fraction, N-[5-
(3-methoxy-4-hydroxyphenyl)-2,
4-Pentadienoyl-N'-(3-benzhydroxypropyl)piperazine 730mg (1.42mmol)
I got it. This spectroscopic data supports the structure () of the following formula. IRν ^KBr _nax (cm ^-1 ): 1635, 1580 1H-NMR (heavy chloroform) δ: 1.50-2.10 (2H, m), 2.20-2.66 (6H,
m), 3.31-3.73 (6H, m), 3.82 (3H,
s), 5.27 (1H, s), 6.30 (1H, d, J=
16Hz), 6.52-7.70 (16H, m) Example 29 80% methanol solution (10ml) of 697mg of benzhydryl-2-phthalyl aminoethyl ether
Add 195 mg of hydrazine hydrate aqueous solution, 1.5
The mixture was heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, the resulting residue was suspended in 20 ml of dry tetrahydrofuran, and N-5-(3-methoxy-4-β-
methoxyethoxymethoxy)phenyl-2,4-
Pentadienoylthiarizolidine-2-thione
533 mg was added and stirred at room temperature under argon atmosphere for 18 hours. The reaction solution was concentrated under reduced pressure, and a 2N aqueous sodium hydroxide solution 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 silica gel column chromatography to obtain 2-[5-(3-methoxy-4-β-methoxyethoxymethoxy)phenyl-2,4- from the chloroform elution fraction. 623 mg of pentadienoyl]aminoethylbenzhydryl ether was obtained. Methanol solution (15ml) of 620mg of the amide compound
23 mg of p-toluenesulfonic acid monohydrate was added to the mixture, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting residue was subjected to silica gel column chromatography, and 2-[5-(3-) methoxy-4-hydroxy)phenyl-2,4-pentadienoyl]
342.3 mg of aminoethylbenzhydryl ether was obtained. The spectroscopic data of this item is expressed by the following formula (
) supports the structure. 1H-NMR (CDCl ₃ ) δ (ppm): 3.55 (4H, m), 3.77 (6H, s), 5.32 (1H,
S), 5.89 (1H, d (J = 15Hz)), 6.40 (1H,
bs), 6.53-7.77 (17H, m) IRν ^KBr _nax (cm ^-1 ): 3300, 1650, 1585, 1508, 1280 Example 30 371 mg (1 mmol) of benzhydryl-3-phthalaminoethyl ether in ethanol under an argon atmosphere 125 mg (2 mmol) of an 80% aqueous hydrazine hydrate solution was added to the solution (10 ml), and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was suspended in 10 ml of dry tetrahydrofuran, and N-[5-
[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine-2-thione 490 mg (1.2 mmol)
Add a dry tetrahydrofuran solution (10 ml) of
The reaction was allowed to proceed for 18 hours at room temperature under an argon atmosphere.
The reaction solution was concentrated under reduced pressure, chloroform was added to the resulting residue, washed with 2N sodium hydroxide, and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 3-[5-[3-methoxy-4-(β
-methoxyethoxymethoxy)phenyl]-2,
362 mg (0.68 mmol) of 4-pentadienoyl]aminopropylbenzhydryl ether was obtained. To a methanol solution (10 ml) of 362 mg (0.68 mmol) of the amide compound was added 19 mg (0.1 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, the organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and chloroform-methanol (50:
1) 3-[5-(3-methoxy-4
-Hydroxyphenyl)-2,4-pentadienoyl]aminopropylbenzhydryl ether
200 mg (0.45 mmol) was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3300, 1660, 1610 Example 31 N-benzhydryl under argon atmosphere
N'-(4-phthalylaminobutyl)piperazine
500 mg (1.10 mmol) in ethanol solution (10 ml)
80% hydrazine hydrate 138mg (221mmol)
was added and heated under reflux for 3 hours. The reaction solution was filtered, the solution was concentrated under reduced pressure, and 5 ml of dry tetrahydrofuran was added to the resulting residue. In this solution, N-
[5-(3,4-dimethoxyphenyl)-2,4
-pentadienoyl]thiazolidine-2-thione
A solution of 402 mg (1.2 mmol) in dry tetrahydrofuran (6 ml) was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and chloroform-
From the methanol (50:1) elution fraction, N-benzhydryl-N'-[4-[5-(3,4-cymethoxyphenyl)-2,4-pentadienoyl]-aminobutyl]piperazine 460 mg (0.85 mmol) I got it. The spectroscopic data of this item is expressed by the following formula (
) supports the structure. IRν ^KBr _nax (cm ^-1 ): 1660, 1600 Example 32 Under an argon atmosphere, N-[5-
(3,4-dimethoxyphenyl)-2,4-pentadienoyl]-thiazolidine-2-thione 483
mg (1 mmol) dry tetrahydrofuran (5 ml)
The solution was added and allowed to react overnight at room temperature. The reaction solution was concentrated under reduced pressure, diluted with chloroform, washed with 2N-sodium hydroxide aqueous solution and water, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Then, N-[5-3,4-dimethoxyphenyl] was extracted from the chloroform-methanol (50:1) elution fraction.
-2,4-pentadienoyl]-N-(3-benzhydroxypropyl)piperazine 470mg
(0.89 mmol) was obtained. The spectroscopic data of this item is expressed by the following formula (
) supports the structure. IRν ^KBr _nax (cm ^-1 ): 1635, 1575 Example 33 176 mg (0.5 mmol) of 7-(2-phthalylaminoethyl)-theophylline was suspended in 20 ml of ethanol, and 125 mg of 80% hydrazine hydrate was added.
(2 mmol) was added, and the mixture was heated under reflux for 2 hours under an argon atmosphere. 25 ml of n-butanol was added to the reaction solution, and after cooling, the formed crystals were removed by filtration, and the solution was concentrated under reduced pressure. The obtained residue was dissolved in 3 ml of dimethylformamide, and N-[5-
(3,4,5-trimethoxyphenyl)-2,4
-Pentadienoyl]thiazolidine-2-thione
183 mg (0.5 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.
210 mg (0.45 mmol) of -[2-[5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoyl]aminoethyl]-theophylline was obtained.
The spectroscopic data of this item is the following formula ()
supports the structure of ¹ H-NMR (heavy methanol) δ: 3.25 (3H, S), 3.40 (3H, S), 3.72 (3H,
S), 3.80 (6H, S), 3.75 (2H, m), 4.38
(2H, m), 5.91 (1H, d, J=14Hz),
6.50-7.30 (5H, m), 7.70 (1H, S) IRν ^KBr _nax (cm ^-1 ): 3260, 1702, 16651610 Example 34 N-(p-chlorobenzhydryl)-N'- under argon atmosphere To an ethanol solution (5 ml) of 550 mg of 4-phthalylaminobutylpiperazine was added 85 mg of an 80% aqueous hydrazine hydrate solution, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and dry dimethylformamide (20 ml) was added to the resulting residue.
Add N-5-(3,5-dimethoxy-4-
β-methoxyethoxymethoxy)phenyl-2,
4-Pentadienoylthiazolidine-2-thione
594.4mg was added. At room temperature under argon atmosphere
After reacting for 16 hours, the resulting residue was concentrated under reduced pressure and subjected to silica gel column chromatography, and N-p-chlorobenzhydryl-N'-5- was extracted from the chloroform-methanol (50:1) elution fraction. (3,
346.8 mg of 5-dimethoxy-4-β-methoxyethoxy)phenyl-2,4-pentadienoylaminobutylpiperazine was obtained. A methanol solution of 346.8 mg of the amide compound (15
ml) p-toluenesulfonic acid monohydrate 205.4
mg was added and heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and N-p-chlorobenzhydryl-N'-5-( 304.0 mg of 3,5-dimethoxy-4-hydroxy)phenyl-2,4-pentadienoylaminobutylpiperazine was obtained. The spectroscopic data of this item is expressed by the following formula (
XI) supports the structure. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.53 (4H, m), 2.42 (10H, m), 3.30 (2H,
m), 3.83 (6H, S), 4.15 (1H, S), 4.33
(2H, bs), 5, 86 (1H, d (J=15Hz)),
6.62 (4H, m), 7.23 (10H, m) IRν ^KBr _nax (cm ^-1 ): 3220, 2880, 2760, 1650, 1620, 1518 Example 35 N-benzhydryl under argon atmosphere
N'-(4-phthalylaminobutyl)piperazine
500 mg (1.10 mmol) in ethanol solution (10 ml)
80% hydrazine hydrate 138mg (2.21mmol)
was added and heated under reflux for 3 hours. The reaction solution was filtered, the solution was concentrated under reduced pressure, and 5 ml of dry tetrahydrofuran was added to the resulting residue. In this solution, N-
[5-(3,5-dimethoxy-4-β-methoxyethoxymethoxy)phenyl-2,4-pentadienoyl]thiazolidine-2-thione 527 mg
(1.2 mmol) in dry tetrahydrofuran solution (6
ml) and allowed to react at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and N-benzhydryl-N'-[4-[5-(3,5) -dimethoxy-4
-β-methoxyethoxymethoxy)phenyl-
580 mg (0.90 mmol) of 2,4-pentadienoyl]aminobutyl]piperazine was obtained. 580 mg (0.90 mmol) of the amide compound was dissolved in 10 ml of methanol, 380 mg (2.0 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 10 with a saturated aqueous sodium carbonate solution, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, the resulting residue was subjected to Sephadex (H-20 column chromatography), and N-benzhydryl-N'-[4-[5-
(3,5-dimethoxy-4-hydroxy)phenyl-2,4-pentadienoyl]aminobutyl]
420 mg (0.75 mmol) of piperazine was obtained. Spectroscopic data of this product support the structure of formula (XII) below. IRν ^KBr _nax (cm ^-1 ): 3220, 1660, 1600 Example 36 Under an argon atmosphere, N-[5-
A solution of 1.15 g (2.61 mmol) of [3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine in dry dimethylformamide (4 ml) was added.
After reacting at room temperature for 17 hours, the mixture was concentrated under reduced pressure to obtain a residue. This was subjected to silica gel column chromatography using chloroform-methanol (100:1).
N-[5-[3,5-dimethoxy-
4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-(2
-benzhydroxyethyl)piperazine 413mg
(0.670mmol) was obtained. To a solution of 413 mg (0.670 mmol) of the amide compound in methanol (10 ml) was added 148 mg (0.778 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 1 hour. Saturated brine was added to the reaction solution, and the pH was adjusted to 10 with sodium carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure, and the resulting residue was subjected to Sephadex column chromatography, and the methanol elution fraction was N-[5-(3,5-dimethoxy-4-hydroxyphenyl)-2,4- 194 mg (0.367 mmol) of pentadienoyl]-N'-(2-benzhydroxyethyl)piperazine was obtained. This spectroscopic data supports the structure () of the following formula. IRν ^KBr _nax (cm ^-1 ): 3300, 1640, 1620, 1590 ¹ H-NMR (heavy methanol) δ: 2.50 (6H, m), 3.53 (6H, m), 3.80 (3H,
S), 5.33 (1H, S), 6.42 (1H, d, J=
Example 37 Under an argon atmosphere, a solution of 310 mg (1 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added with N-[5-
[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine-2-thione 440 mg
(1 mmol) in dry tetrahydrofuran solution (5
ml) and allowed to react at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with chloroform, washed with 2N aqueous sodium hydroxide solution and water, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. ,
From the chloroform-methanol (50:1) elution fraction, N-[5-[3,5-dimethoxy-4-(β-
methoxyethoxymethoxy)phenyl]-2,4
-Pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine 540mg (0.85mmol))
I got it. 540 mg (0.85 mmol) of the amide compound was dissolved in 10 ml of methanol, 190 mg (1 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 1 hour under an argon atmosphere. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extraction was performed with ethyl acetate. After drying the organic layer with sodium sulfate, it was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and the N-
[5-(3,5-dimethoxy-4-hydroxy-
phenyl)-2,4-pentadienoyl]-
350 mg (0.65 mmol) of N'-(3-benzhydroxypropyl)piperazine was obtained. Spectroscopic data of this product support the structure of the following formula (). IRν ^KBr _nax (cm ^-1 ): 3300, 1640, 1600 Example 38 80% solution of 440 mg of benzhydryl-2-phthalyl aminoethyl ether (6 ml)
Add 123.2 mg of hydrazine hydrate aqueous solution to 1.5
The mixture was heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, the resulting residue was suspended in 20 ml of dry tetrahydrofuran, and N-5-(3,5-dimethoxy-
4-β-methoxyethoxymethoxy)phenyl-
Add 491 mg of 2,4-pentadienoylthiazolidine-2-thione, and stir at room temperature under an argon atmosphere.
Stir for hours. The reaction solution was concentrated under reduced pressure, and a 2N aqueous sodium hydroxide solution 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 silica gel column chromatography to obtain 2-[5-(3,5-dimethoxy-4-) from the fraction eluted with chloroform-methanol (50:1).
β-methoxyethoxymethoxy)phenyl-2,
593 mg of 4-pentadienoyl]aminoethylbenzhydryl ether was obtained. Methanol solution (20ml) of 590mg of the amide compound
41 mg of p-toluenesulfonic acid monohydrate was added to the mixture, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The resulting residue was subjected to silica gel column chromatography, and 2-[5-(3,5 -dimethoxy-4-hydroxy)phenyl-2,4-pentadienoyl]aminoethylbenzhydryl ether 249mg
I got it. The spectroscopic data of this item is expressed by the following formula (
) supports the structure. ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.57 (4H, m), 3.83 (6H, S), 5, 32
(1H, S), 6.23 (1H, d (J=15Hz), 6.60
-6.75 (3H, m), 7.10 - 7.63 (11H, m) IRν ^KBr _nax (cm ^-1 ): 3300, 1650, 1610, 1508, 1340, 1110 Test example 5 - Lipoxygenase action inhibition activity Mouse-derived mastocytoma Cell line P-815 is diluted to 5×10 ⁴ cells/ml in a culture solution containing 90% Eagle's basal medium (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. 20μ 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 the above enzyme solution were added to the test tubes.
0.45ml, _8mMCaCl2 (calcium chloride) solution 0.1ml
and react at 37°C for 5 minutes. IN after ice cooling
Add 60μ of HCl (hydrochloric acid) and add 8μ of ethyl acetate.
Extract in ml. 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-
5-HETE (5-(s)-hydroxy-6,8,11,14-eicosatetraenoic acid), a 5-lipoxygenase product detected with Scanner LB 2723, Berthold, LTB ₄ (leukotriene B ₄ ) is collected and the radioactivity is measured using a liquid scintillation counter. The inhibitory 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 inhibitory 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】

【table】

【table】

【table】

【table】

[Table] The 50% inhibitory concentration in the table refers to the amount of 5-GETE and LTB ₄ produced when no amide derivative is introduced.
When it is set as 100%, the production amount of the 5-lipoxygenase product is reduced by 50% by introducing the amide derivative.
It means the concentration of amide derivative required to suppress the Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks). 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 are provided. It was 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, (R) ^m is a 3,4-dihydroxy group, 3
-Methoxy-4-hydroxy group, 3,4-dimethoxy group, 3,5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4-toluoyloxy group or 3,4,5-trimethoxy group.
n represents the number of double bonds in trans configuration, and is an integer of 1 or 2. Y is (In the formula, X is a hydrogen atom, a halogen atom, or a methoxy group, and n is 4) Narumoto (), (in the formula, n represents 2 or 3) and (In the formula, n represents 2 or 3.) An amide derivative represented by the following formula. 2 General formula () [In the formula, (R) ^m is a 3,4-dihydroxy group, 3
-Methoxy-4-hydroxy group, 3,4-dimethoxy group, 3,5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4-toluoyloxy group or 3,4,5-trimethoxy group.
n represents the number of double bonds in trans configuration, and is an integer of 1 or 2. Y is (In the formula, X is a hydrogen atom, a halogen atom, or a methoxy group, and n is 4) Narumoto (), (in the formula, n represents 2 or 3) and A 5-lipoxygenase action inhibitor containing an amide derivative represented by the following group (in the formula, n represents 2 or 3).