JPH0353291B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to dienecarbonyl compounds. Furthermore, the present invention relates to a platelet aggregation inhibitor and a 5-lipoxygenase action inhibitor containing the above dienecarbonyl compound. The dienecarbonyl compound provided by the present invention is a new compound and has a strong platelet aggregation effect. Therefore, it is effective in preventing diseases caused by platelet aggregation, such as thrombosis. Furthermore, platelet aggregation is known to be involved in cancer metastasis, and the compounds of the present invention also have a preventive effect on cancer metastasis. Furthermore, the dienecarbonyl compound provided by the present invention has an activity of inhibiting the action of 5-lipoxygenase. Leukotriene C ₄ (LTC ₄ ) and leukotriene D ₄ are factors that cause allergies.
Since leukotrienes such as (LTD ₄ ) are biosynthesized in vivo from arachidonic acid by the action of 5-lipoxygenase, the above-mentioned dienecarbonyl compounds that have inhibitory activity on the action of this enzyme are important for the development of allergies. It inhibits biosynthesis and can be used as an antiallergic agent. [Prior art and its problems] Thrombosis such as myocardial infarction and cerebral thrombosis has come to account for a large proportion of adult diseases in recent years, and there is a strong desire for the emergence of antithrombotic agents that can effectively prevent this. There is. Various substances having antiplatelet aggregation effects are known, but their effects are weak and unsatisfactory as antithrombotic agents. In addition, some compounds are known that have inhibitory activity on the action of 5-lipoxygenase, but their activity is not necessarily sufficient, and there has been a desire for a better antiallergic agent. [Means for Solving the Problems] The present inventors synthesized various diene carbonyl compounds and conducted intensive research on their pharmacological activities. As a result, the present inventors found that certain diene carbonyl compounds have excellent platelet aggregation inhibiting effects and 5-lipoxygenase inhibition. The present inventors have discovered that the present invention has a certain effect and have completed the present invention. Accordingly, an object of the present invention is to provide a novel dienecarbonyl compound and a platelet aggregation inhibitor and a 5-lipoxygenase action inhibitor containing the same. The dienecarbonyl compound according to the present invention is useful as a preventive agent for diseases caused by platelet aggregation, such as thrombosis and cancer metastasis, and as an antiallergic agent. The present invention achieves this object by the general formula () [In the formula, R ¹ and R ² are the same or different and represent a hydroxyl group,
Represents a lower alkoxy group, a lower alkoxycarbonyloxy group, R ³ represents a hydrogen atom, R is a linear or branched alkyl group having 2 to 21 carbon atoms or a formula

[Formula] or

[Formula] (In the formula, n and l are the same or different and represent integers of 1 to 5, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a halogen atom, or a lower alkoxy group) . ] Consists of a dienecarbonyl compound having the following. Furthermore, the present invention comprises a platelet aggregation inhibitor containing a dienecarbonyl compound represented by the above formula (). The present invention further comprises a 5-lipoxygenase action inhibitor containing a dienecarbonyl compound represented by the above formula (). In the definition of the substituent in the above formula (), the lower alkoxy group means a linear or branched alkoxy group having 1 to 4 carbon atoms, preferably a methoxy or ethoxy group. Examples of halogen atoms include chlorine, bromine, fluorine, and iodine. In the above formula (), when R is an alkyl group, preferable examples include methyl, ethyl, propyl, hexyl, octyl, decyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, heneicosyl, and the like. R is the formula

In the case of a group having the formula: R ⁴ and R ⁵ are the same or different and are preferably hydrogen, chlorine, bromine, methoxy, ethoxy, etc., and n is preferably 1 or 2. R
is the formula

When it is a group having the formula, the thienyl group may be either 2- or 3-thienyl, and l is preferably 1 or 2. In the compound represented by the above formula (), R
A compound where is a hydrogen atom has the formula () [In the above formula, R ¹ , R ² and R ³ are the same as those mentioned above, and R ⁶ represents an alkyl group] The diene carboxylic acid ester represented by the following is reduced to a diene alcohol compound, and then oxidized with an oxidizing agent. and the expression ()′ [In the above formula, R ¹ , R ² and R ³ are the same as those described above]. A compound in which R in the above formula () is other than a hydrogen atom is a diene aldehyde compound represented by the above formula ()', or a diene aldehyde compound represented by the above formula () or ().

【formula】 [R in the above formula has the same meaning as described above]

It is produced by a condensation reaction with a carbonyl compound represented by the formula and, if necessary, a deprotection reaction. The compound () is reduced to a diene alcohol compound using a reducing agent such as diisobutylaluminum hydride in a solution using toluene as a solvent, for example. The obtained diel alcohol compound is oxidized with an oxidizing agent such as activated manganese dioxide in a solvent (eg, benzene, toluene, methylene chloride) to give a diene aldehyde compound represented by formula ()'. The condensation of a dienaldehyde compound and a carbonyl compound represented by formula () is
Using methylene chloride and water as a solvent, using a caustic alkali (e.g., sodium hydroxide) as a base, and using a quaternary ammonium salt (e.g., tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate) as a phase transfer catalyst. It is done. This condensation reaction can also be carried out using tetrahydrofuran, 1,2-dimethoxyethane, benzene, etc. as a solvent and sodium hydride, potassium butoxide, etc. as a base. Furthermore, the dienaldehyde compound and the carbonyl compound represented by the formula () can be prepared using an alcoholic solvent (e.g., methanol, ethanol) alone or mixed with water, and a caustic alkali (e.g., sodium hydroxide) as the base. It is done. The dienecarbonyl compound represented by the above formula () of the present invention can be used as an active ingredient or one of the active ingredients of a platelet aggregation inhibitor, and is effective in treating diseases caused by platelet aggregation, particularly cerebral thrombosis. It is used as a cancer metastasis prevention agent. The dienecarbonyl compound of the present invention represented by the above formula () is further used as a 5-lipoxygenase action inhibitor, that is, an antiallergic agent. The dosage is approximately 10 to 600 mg per day for adults when used as a platelet aggregation inhibitor, and 10 to 2000 mg per day for adults when used as an anti-allergy agent.
mg, preferably 20-600 mg. The above-mentioned dosage is appropriately increased or decreased depending on the patient's weight, age, symptoms, etc., and is administered in 1 to 3 divided doses if necessary. 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 may be formulated into tablets, powders, capsules, or granules either alone or mixed with pharmaceutical carriers or excipients in a conventional manner. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, and the like. In addition to the solid formulations mentioned above, the compounds of the present invention can also be formulated into liquid formulations such as oily suspensions and syrups. The compound of the present invention can also be stabilized by inclusion with cyclodextrin. Next, the present invention will be explained in more detail with reference to Examples and Test Examples. Example 1 266 mg of 3-(3,4-dimethoxymethyloxyphenyl)-2-propenal under argon atmosphere
(0.95 mmol) in tetrahydrofuran (10 ml) were added 235 µ (1.9 mmol) of methyl butyl ketone and 2 ml of water, and then 24 µ (0.06 mmol) of 10% sodium hydroxide was added under ice cooling and allowed to react overnight at room temperature. Under ice cooling, an aqueous hydrochloric acid solution was added to the reaction mixture to adjust the pH to 7, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and the fraction eluted with benzene:ethyl acetate (100:1→10:1) From 4-
(3,4-dimethoxymethyloxyphenyl)-
1,3-butadienyl butyl ketone 194 mg (0.56
mmol) was obtained. Under an argon atmosphere, 194 mg (0.56 m
mol) was added with 10 ml of 80% acetic acid, and the mixture was heated under reflux for 5 hours. Acetic acid was distilled off under reduced pressure, the resulting residue was subjected to Sephadex LH-20 column chromatography, and 4-(3,4-dihydroxyphenyl)-1,3-butadienylbutyl was extracted from the methanol elution fraction. 76 mg (0.31 mmol) of ketone was obtained. Spectroscopic data of this product support the structure of the following formula (). PMR (heavy methanol) δ: 0.92 (3H, t, J = 7Hz), 1.50 (4H, m),
2.56 (2H, t, J = 7Hz), 6.21 (1H, d, J =
15Hz), 6.5-7.5 (6H, m) MS (m/z): 246, 189, 161 Example 2 Under argon atmosphere, 3-(3-methoxy-4-
methoxymethyloxyphenyl)propenal
7.00 g and 12.50 g of 2-tridecanone were dissolved in a mixed solvent of 120 ml of tetrahydrofuran, 30 ml of water, and 30 ml of ethanol, and 15.1 ml of a 10% aqueous sodium hydroxide solution was added at room temperature. After reacting at room temperature for 16 hours, 37 ml of 1N hydrochloric acid was added under ice cooling. After the reaction mixture was concentrated under reduced pressure, the residue was poured into ice-cooling, and extracted three times with ethyl acetate. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 19.4 g of an extracted residue. The residue was subjected to silica gel column chromatography, and 1-(3-methoxy-4-methoxymethyloxyphenyl)-5-oxo-1,3-hexadeca was extracted from the fraction eluted with benzene/ethyl acetate (98:2). 9.15 g of diene was obtained. 4.75 g of the compound was dissolved in 100 ml of 80% acetic acid aqueous solution and reacted under heating under reflux for 5 hours. The reaction mixture was dried under reduced pressure to obtain 4.80 g of a residue. The residue was recrystallized from ether/hexane (1:1) to give 1-(3-
2.15 g of methoxy-4-hydroxyphenyl)-5-oxo-1,3-hexadecadiene was obtained. Spectroscopic data of the compound supports the structure of formula () below. ^1H -NMR ( _CDCl3 ) δ (ppm): 2.55 (2H, t, J = 7Hz), 3.88 (3H, S),
6.18 (1H, d, J = 15Hz) MS (m/): 358 (molecular ion peak) Example 3 By the same reaction procedure as in Example 2, 3-(3,
1- from 8.00 g of 4-dimethoxymethyloxyphenyl) propenal and 18.9 g of 2-tridecanone.
(3,4-dimethoxymethyloxyphenyl)-5
-Oxo-1,3-hexadecadiene (9.98g) was obtained, and then 1-(3,4-
dihydroxyphenyl)-5-oxo-1,3-
1.36 g of hexadecadiene was obtained. Spectroscopic data of the compound supports the structure of formula () below. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.77 (2H, t, J = 7Hz), 6.18 (1H, d, J =
15Hz) MS (m/): 344 (molecular ion peak) Example 4 Dimethyl methyl phosphate under argon atmosphere
Dissolve 2.804g in 60ml of dry tetrahydrofuran,
The mixture was cooled in a dry ice/methanol bath, and 16.0 ml of n-butyllithium-n-hexane solution (1.55M) was added dropwise. After 5 minutes, 4.073 g of methyl 4-phenylbutanoate was added, and the mixture was reacted for 1.5 hours in a cold bath. After adding 5 ml of methanol to the reaction mixture, the mixture was brought to room temperature, 30 ml of water was added, and extraction was performed three times with chloroform. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.448 g of an extracted residue. The residue was subjected to silica gel column chromatography, and (2-oxo-5-phenylpentyl) was extracted from the fraction eluted with methylene chloride.
-3.951 g of dimethyl phosphonate were obtained. the compound
1.081 g and 0.845 g of 3-(3-methoxy-4-methoxymethyloxyphenyl) propenal were dissolved in 2 ml of methylene chloride, and the solution was mixed with 2.2 ml of 50% aqueous sodium hydroxide solution, 65 mg of tetrabutylammonium hydrogen sulfate, and methylene chloride. It was added dropwise to 4.4 ml of the mixed solution and stirred at room temperature. After reacting for 20 minutes at room temperature, water
60 ml was added, and extraction was performed three times with methylene chloride. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an extraction residue of 1.411 g.
I got it. The residue was subjected to silica gel column chromatography, and 1-(3-methoxy-4-methoxymethyloxyphenyl)-5-oxo-8-phenyl- was obtained from the benzene/ethyl acetate 19:1 elution fraction.
0.765 g of 1,3-octadiene was obtained. the compound
0.490g was dissolved in 10ml of methanol, and 1.3g of acidic ion exchange resin (DOWEX50W x 8) was added thereto. After reacting overnight at room temperature, the ion exchange resin was removed and the mother liquor was dried under reduced pressure to give 1-(3-methoxy-4-hydroxyphenyl)-5-oxo-8.
0.384 g of -phenyl-1,3-octadiene was obtained. The spectroscopic data of this compound is expressed by the following formula ()
supports the structure of IRν ^CHCl3 _nax (cm ^-1 ): 3540, 1670 ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.87 (3H, S),
6.17 (1H, d, J = 15Hz) Example 5 By the same reaction procedure as in Example 4, 4-(3,
Methyl 4-dimethoxyphenyl)butanoate 1.165
g from dimethyl [2-oxo-5-(3,4-dimethoxyphenyl)pentyl]phosphonate 1.255
1-(3-methoxy-4-hydroxyphenyl) was obtained by condensation of 1.000 g of the compound with 0.672 g of 3-(3-methoxy-4-methoxymethyloxyphenyl)propenal and subsequent deprotection reaction. 0.630 g
I got it. The spectroscopic data of this compound is expressed by the following formula (
) supports the structure. IRν ^CHCl3 _nax (cm ^-1 ): 3550, 1675 ¹ H−NMR (CDCl ₃ ) δ (ppm): 2.00 (2H, q,
J=7Hz), 3.83 (6H, S), 3.88 (3H3HS),
6.17 (1H, d, J = 15Hz) Example 6 By the same reaction procedure as in Example 4, (3,4-
2 from 3.980g of methyl acetate (dimethoxyphenyl)
-oxo-3-(3,4-dimethoxyphenyl)
2.004 g of dimethyl propylphosphonate was obtained, followed by 1.449 g of the compound and 3-(3-methoxy-4-
methoxymethyloxyphenyl)propenal
Condensation of 1.013 g and subsequent deprotection reaction yielded 0.752 g of 1-(3-methoxy-4-hydroxyphenyl)-5-oxo-6-(3,4-dimethoxyphenyl)-1,3-hexadiene. Obtained. Spectroscopic data of the compound supports the structure of formula () below. IRν ^CHCl3 _nax (cm ^-1 ): 3550, 1675 ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.93 (2H, S),
3.83 (3H, S), 3.88 (6H, S), 6.23 (2H, d,
J=15Hz) Example 7 2-oxo-4 was prepared from 4.005 g of methyl 3-phenylpropionate by the same reaction procedure as in Example 4.
-2.543 g of dimethyl phenylbutylphosphonate were obtained, followed by 1.024 g of the compound and 3-(3,4-dimethoxymethyloxyphenyl)propenal.
1 by condensation of 1000 g and subsequent deprotection.
-(3,4-dihydroxyphenyl)-5-oxo-7-phenyl-1,3-heptadiene 0.507g
I got it. The spectroscopic data of the compound is expressed by the following formula (
) supports the structure. IRν _nax (cm ^-1 ): 3550, 1660 ¹ H-NMR (C ₅ D ₅ N) δ (ppm): 2.83 (4H, bs), 6.08 (1H, d, J = 15Hz) Test example (1) Platelets Aggregation inhibitory effect Collect 9 volumes of blood from the rabbit carotid artery using a syringe containing 3.8% sodium citrate solution (1 volume). The blood is centrifuged to obtain platelet-rich plasma (PRP: 7×10 ⁵ cells/μg). The PRP268μ was placed in a cuvette, heated for 2 minutes in a 37°C constant temperature bath, 2μ of an ethanol solution of the diene carbonyl compound to be tested was added, and incubated for 3 minutes. A solution is added and platelet aggregation is measured using Born's nephelometric method [for example, Journal of Physiology (J. Physiol. Vol. 168, Vol.
178, published in 1968)]. The 50% inhibitory concentrations for platelet aggregation induced by arachidonic acid (100 micromoles) and collagen (10 μg/ml) are shown in Table 1 with cinnamaldehyde, acetylsalicylic acid, and dipyridamole as comparative examples. As a result of the test, significant anti-platelet aggregation activity was found as shown in Table 1 below as a representative example. Furthermore, it was confirmed that dienecarbonyl compounds according to the present invention not shown in Table 1 also have similar platelet aggregation activity. In addition, the 50% inhibitory concentration in the table means that the platelet aggregation ability is suppressed to 50% by introducing the enone derivative, assuming that the platelet aggregation ability without introducing the diene carbonyl compound according to the present invention is 100%. It means the concentration of diene carbonyl compound solution required for this purpose.

【table】

【table】

[Table] (2) Inhibitory activity of 5-lipoxygenase Mouse-derived mastocytoma cell line P-815
Eagle basic medium [manufactured by Gibco Laboratories]
Dilute to 5 x 10 ⁴ cells/ml in a culture medium containing 90%. 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 are resuspended in phosphate buffer at pH 7.4 to a concentration of 2×10 ⁷ cells/ml. After treating the suspension with an ultrasonic cell disrupter, for 10 minutes
Centrifuge at 10,000 rpm and use the supernatant as a 5-lipoxygenase enzyme solution. 20 μ of radiolabeled arachidonic acid (10 μ Kyrie/ml), indomethacin (2×10 ⁻⁸ mol) and the enone derivative used in the present invention to be tested were placed in test tubes, respectively.
Add 0.45ml of phosphate buffer to this and 0.45ml of the above enzyme solution.
ml, 8 mmol CaCl ₂ (calcium chloride) solution
Add 0.1 ml and react at 37°C for 5 minutes. After cooling on ice, add 60μ of 1N HCl (hydrochloric acid) and extract with 8ml of ethyl acetate. 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 (Dunnschicht-Scanner LB2723, manufactured by Berthold).
- 5-HETE, a lipoxygenase product
(5-(s)-hydroxy-6,8,11,14-eicotetraenoic acid), LTB ₄ (leukotriene
This is done by collecting the portion corresponding to B ₄ ) and measuring the radioactivity 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 inhibitory activity was found as shown in Table 2 below. Furthermore, it was confirmed that diene carbonyl compound 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 in the table refers to the 5-
When the production amount of HETE and LTB ₄ is taken as 100%,
By introducing the dienecarbonyl compound, the above 5
- Means the concentration of diene carbonyl compound required to suppress the production of lipoxygenase product by 50%. Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). The LD ₅₀ values of the dienecarbonyl compounds of the present invention were all 400 mg/Kg or more, confirming high safety compared to the effective dose. [Effects of the Invention] According to the present invention, a novel dienecarbonyl compound, a platelet aggregation inhibitor containing the same, and 5
- Lipoxygenase action inhibitors are provided. The compound of the present invention significantly suppresses the platelet aggregation effect induced by arachidonic acid ADP or collagen. It can be used as a prophylactic agent for thrombosis involving aggregation. Furthermore, since platelet aggregation is involved in cancer metastasis, the above compounds of the present invention can also be used as agents for preventing cancer metastasis. Furthermore, since the compound of the present invention inhibits the action of 5-lipoxygenase, LTC ₄ , an allergy-inducing factor produced by the action of this enzyme,
The production of leukotrienes such as LTD ₄ can be suppressed. Therefore, the dienecarbonyl compound can be effectively used as a 5-lipoxygenase action inhibitor for allergic asthma, allergic rhinitis, and the like.

Claims (1)

[Claims] 1 General formula () [In the formula, R ¹ and R ² are the same or different and represent a hydroxyl group,
It represents a lower alkoxy group or a lower alkoxycarbonyloxy group, R ³ represents a hydrogen atom, and R represents a linear or branched alkyl group having 2 to 21 carbon atoms or the formula [Formula] or [Formula] (Formula n and l are the same or different and represent an integer of 1 to 5, and ^R4 and ^R5 are the same or different and represent a hydrogen atom, a halogen atom, or a lower alkoxy group] Compound. 2 General formula () [In the formula, R ¹ and R ² are the same or different and represent a hydroxyl group,
It represents a lower alkoxy group or a lower alkoxycarbonyloxy group, R ³ represents a hydrogen atom, and R represents a linear or branched alkyl group having 2 to 21 carbon atoms or the formula [Formula] or [Formula] (Formula n and l are the same or different and represent an integer of 1 to 5, and ^R4 and ^R5 are the same or different and represent a hydrogen atom, a halogen atom, or a lower alkoxy group] A platelet aggregation inhibitor characterized by containing a compound. 3 General formula () [In the formula, R ¹ and R ² are the same or different and represent a hydroxyl group,
It represents a lower alkoxy group or a lower alkoxycarbonyloxy group, R ³ represents a hydrogen atom, and R represents a linear or branched alkyl group having 2 to 21 carbon atoms or the formula [Formula] or [Formula] (Formula n and l are the same or different and represent an integer of 1 to 5, and ^R4 and ^R5 are the same or different and represent a hydrogen atom, a halogen atom, or a lower alkoxy group] A 5-lipoxygenase action inhibitor comprising a compound.