JP2557090B2 - Caffeic acid derivative and pharmaceutical composition containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a compound represented by the general formula (I): (Wherein, X represents a hydrogen atom or a hydroxyl group, R ¹ represents a hydrogen atom, a linear or branched alkyl group or alkenyl group having 1 to 20 carbon atoms), and a caffeic acid derivative represented by the formula and a derivative thereof. It relates to a pharmaceutical composition.

The caffeic acid derivative of the present invention has a 12-lipoxygenase inhibitory action and is useful as a therapeutic agent for cardiovascular diseases such as prevention of arteriosclerosis.

(Prior Art) Leukotrienes, which are considered to be the cause of allergic diseases, especially asthma, include 5-hydroperoxy-icosatetraenoic acid (5-HPETE) and 5-hydroxy-icosietetraenoic acid due to the action of 5-lipoxygenase from arachidonic acid. It is generated through conversion to (5-HETE). Based on such findings, many compounds having 5-lipoxygenase inhibitory activity have been reported for the purpose of developing therapeutic agents for cardiovascular diseases.

On the other hand, it is a conversion enzyme from arachidonic acid to 12-hydroperoxy-icosatetraenoic acid (12-HPETE) and 12-hydroxy-icosatetraenoic acid (12-HPETE).
-For lipoxygenase, see 12-HETE by Tada et al.
Is involved in the development of ischemic heart disease (Card
iovascular Research, Volume 21, No.8, pp.551-558, 1987
, And Muroda et al. Reported that 12-HETE has an endothelial cell-damaging activity and an action of promoting migration of vascular medial smooth muscle cells, which is involved in the exacerbation of vascular lesions such as arteriosclerosis and sickness ( Therapeutics, Vol. 13, No. 6, 785-788 pages, 1984).

(Problems to be Solved by the Invention) From the above findings, a compound having 12-lipoxygenase inhibitory activity is expected to be useful as a cardiovascular disease agent, but as such a compound, a conventional Scutellaria baicalensis (Sc
Baicalen (B isolated from utellaria baicalensis)
Other than aicalein) is not known. Baicalen has the following structure.

(Means for Solving the Problems) In view of such circumstances, the present inventors extensively screened compounds having 12-lipoxygenase inhibitory activity, and as a result, the caffeic acid derivative represented by the general formula (I) was identified as baicalene. The present invention has been completed based on the finding that they have equivalent or higher inhibitory activity.

The caffeic acid derivative of the present invention can be synthesized by the following method. That is, the general formula (II): (In the formula, X represents the meaning defined in the above formula (I).) In a suitable solvent which does not participate in the reaction of the benzaldehyde and the cyanoacetic acid or its alkyl or alkenyl ester, for example, in benzene or toluene. , A base such as pyridine or piperidine as a catalyst can be used to carry out an ordinary Knoevenagel condensation reaction.

The compound of the present invention thus synthesized can be purified by cooling the reaction solution and then filtering out the crystal that crystallizes out, or by using silica gel column chromatography or the like.

In formula (I), examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an n-pentyl group, an n-hexyl group and an icosyl group, and an alkenyl group. Is, for example,
Examples thereof include an allyl group, a 2-butenyl group, a 3-butenyl group, a 4-pentenyl group, a 4-hexenyl group, and an icosa-5,8,11,14-tetraenyl group.

Further, the pharmaceutically acceptable salt referred to in the present invention is a base addition salt which can be used medically, and examples thereof include salts with sodium, potassium and calcium. When the compound of the present invention is used as a therapeutic agent for cardiovascular disease, the compound or a pharmaceutically acceptable salt thereof alone or together with a known harmless excipient, etc., a capsule,
It can be orally or parenterally administered in an appropriate dosage form such as tablets and injections. These formulations are prepared as follows, for example. After pulverizing the drug substance, excipients,
For example, it is mixed with lactose, starch or a derivative thereof, a cellulose derivative, etc., and packed in a gelatin capsule to obtain a capsule. In order to make tablets, in addition to the above excipients, a binder such as sodium carboxymethylcellulose, alginic acid and gum arabic and water are added and kneaded, and then kneaded into granules if necessary, and then lubricants such as talc and stearic acid are further added. Add and adjust the tablets using a conventional compression tableting machine. For parenteral administration by injection, the compound of the present invention is dissolved in sterile distilled water or sterile physiological saline and sealed in an ampoule to give an injection preparation. If necessary, a stabilizer and a buffer substance may be contained.

The effective amount of the therapeutic agent for cardiovascular disease varies depending on the kind of the disease, the intensity of the symptoms, the administration method, and the physical factors of the patient, but in general, an effective amount for suppressing the symptoms of the disease should be used. Administer.

Next, production of the compound of the present invention will be described by way of examples, but the present invention is not limited to these examples.

Example 1 Ethyl 2-cyano-3- (3,4-dihydroxyphenyl) -2-propenoate (Compound 1) 2.0 g of 3,4-dihydroxybenzaldehyde (14.5 mmo
l) in ethanol (10 ml), add 1.6 parts of ethyl cyanoacetate
g (14.5 mmol) and 3 drops of piperidine were added and reacted at room temperature for 20 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized with a mixed solution of ethanol and water to obtain 2.3 g (9.9 mmol) of the title compound. The present invention can also be obtained by using benzene as a solvent and heating under reflux. Compounds 2 to 6 were also synthesized in the same manner.

Compound 2: 2-Cyano-3- (3,4-dihydroxyphenyl) -2-propenoic acid Compound 3: 2-Cyano-3- (3,4,5-hydroxyphenyl) -2-propenoate Compound 4: 2- Cyano-3- (3,4,5-trihydroxyphenyl) -2-propenoic acid Compound 5: Methyl 2-cyano-3- (3,4-dihydroxyphenyl) -2-propenoate Compound 6: Isopropyl 2-cyano- 3- (3,4-Dihydroxyphenyl) -2-propenoate Example 2 (5z, 8z, 11z, 14z) -icosatetraenyl 2-cyano-3- (3,4-dihydroxyphenyl) -2-propenoate ( Compound 7) 90 mg (2.4 mmol) of lithium aluminum hydride was suspended in anhydrous tetrahydrofuran (40 ml), and the suspension was cooled to 0 under a nitrogen stream.
Cooled to ℃, stirred and cooled with arachidonic acid 600mg (2.0mmo
A solution of l) in anhydrous tetrahydrofuran (35 ml) was added dropwise. After stirring at 0 ° C. for 1 hour, the mixture was further stirred at room temperature for 1 hour. Next, 0.1 ml of water was gradually added, then 0.1 ml of 10% aqueous sodium hydroxide solution and 0.3 ml of water were added, and the mixture was allowed to stand for 1 hour. The reaction mixture was dried over magnesium sulfate and concentrated under reduced pressure to give (5z, 8z, 11z, 14z) -icosatetraenol 510mg.
(1.8 mmol) was obtained.

The product was then added to N, N-dimethylformamide (10m
l), cooled to 0 ° C, and dissolved in the same solvent under cooling and stirring 4 ml of cyanoacetic acid 150 mg (1.8 mmol), also 2 ml.
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide of 273 mg (1.8 mmol) and also 2 ml of 4-dimethylaminopyridine 21 mg (0.2 mmol) were sequentially added,
The mixture was stirred for 1 hour and further at room temperature for 3 hours.

Subsequently, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain (5z, 8z, 11z, 14z) -icosatetraenyl cyanoacetate 300 mg (0.8 mmol).

This product was dissolved in 10 ml of benzene, and a solution of 116 mg (0.8 mmol) of 3,4-dihydroxybenzaldehyde in diethyl ether (10 ml) and 1 drop of piperidine were added, and the mixture was refluxed for 1.5 hours while removing water produced. The reaction mixture was cooled and concentrated under reduced pressure to give 240 mg (0.5 mmo) of the title compound.
l) got.

Similarly, icosyl 2-cyano-3- (3,4-dihydroxyphenyl) -2-propenoate (Compound 8) was synthesized by using arachidic acid instead of arachidonic acid.

Table 1 shows yields, properties, etc. of the compounds 1 to 8 synthesized above.

Next, preparation examples of the therapeutic agent of the present invention will be shown.

Formulation Example 1 (Capsule) Compound 1 10 g Lactose 30 g Corn starch 30 g Crystalline cellulose 28 g Magnesium stearate 2 g Total amount 100 g The above components were granulated by a conventional method and filled into 200 gelatin hard capsules. The resulting formulation contains 50 mg of active ingredient in a capsule.

Formulation Example 2 (tablets) Compound 1 20 g Lactose 40 g Corn starch 20 g Hydroxypropyl cellulose 18 g Talc 2 g Total amount 100 g After thoroughly mixing the above ingredients in a kneader, tableting, 50
200 0 mg tablets were produced. Thus, a preparation of the present invention containing 100 mg of the active ingredient in one purified product was obtained.

Example of Pharmacological Test Method The 12-lipoxygenase inhibitory activity of the compound of the present invention was measured by the following pharmacological test.

Citrated blood was collected from the abdominal aorta of the rat. Washed platelets were prepared according to a conventional method and diluted with a phosphate buffer (pH = 8.0) containing 0.45% NaCl to obtain an enzyme solution. A test compound (10 µN) was added to the enzyme solution, 0.2 µCi of [ ¹⁴ C] arachidonic acid and 3 µg of arachidonic acid were further added, and the mixture was reacted at 37 ° C for 3 to 5 minutes. The reaction solution was developed with a thin-layer chromatogram, 12-HETE was identified by a radiochromatographic scanner, and the decrease in the production amount was used as an index of 12-lipoxygenase inhibitory activity.

Results When the amount of 12-HETE produced in the control (without addition of the test drug) was 100%, the amounts of 12-HETE produced were 38.1%, 36.0% and 31.4% when the compounds 1, 5 and 6 of the present invention were added, respectively.
%, A significant 12-lipoxygenase inhibitory activity was observed.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Seiko Murota 3-8-11-301 Koishikawa, Bunkyo-ku, Tokyo (72) Inventor Ikuo Morita 3-12-27-320 Hasune, Itabashi-ku, Tokyo

Claims (2)

(57) [Claims] 1. General formula (I): (In the formula, X represents a hydrogen atom or a hydroxyl group, R ¹ represents a hydrogen atom, a linear or branched alkyl group or alkenyl group having 1 to 20 carbon atoms.) And a pharmaceutically acceptable derivative thereof. Acceptable salt. 2. A therapeutic agent for a circulatory disease comprising the compound according to claim 1 as an active ingredient.