JPS60248641A - Caffeic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 and R2 are H, alkoxy or OH; X is -O-CH2-CH=CH-, -NH-CH2-CH=CH-, -CH2-CH2-CH=CH- or -NH-(CH2)n- (n is 1-4)]. EXAMPLE:Caffeic acid 3,4-dihydro-cinnamyl ester. USE:Useful as a remedy and preventive for allergic disorder, asthma, inflammation, etc. It has lipoxygenase-inhibiting activity. PREPARATION:The compound of formula I can be prepared by reacting caffeic acid or its derivative with the compound of formula II (Y is OH, NH2, or CH2- halogen in a solvent such as THF at a temperature between room temperature and about 50 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to novel caffeic acid derivatives having 5-lipoxygenase inhibitory activity.

[Background of prior art/invention]

Riboquingenase contains 1 koikotrienes, 5 koikotrienes, and 5
- It is an enzyme involved in the in vivo synthesis of hydroxyeicozatetraenoic acid (5-METE).

Therefore, compounds with lipoxygenase inhibitory action are
It is useful for treating and preventing allergies, asthma, inflammation, etc.

As such lipoxygenase inhibitory substances, caffeic acid and its methyl ester are known;
, A. Sheep 12.92 (1984)), but its lipoxygenase inhibitory action cannot be said to be sufficient.

From this point of view, the present inventors have conducted various studies in order to obtain a compound with even better boxygenase inhibitory action, and found that the general formula [wherein R1 and R2 are a hydrogen atom, an alkoxy group, or a hydroxyl group, and X is A group represented by the formula -0-CH2CH=CH-1 -NH-CH2-CH=CH-1 -CH2-CH2-CH=CH-1 or -NH-(CH2)n- (n-1 to 4) represents. The present inventors have completed the present invention by discovering that caffeic acid derivatives represented by the following have particularly excellent poxygenase inhibitory effects.

[Disclosure of the invention]

The present invention provides a caffeic acid derivative (1).

When R1 and R2 in general formula (1) are hydroxyl groups, the substitution positions are preferably m-position and p-position.

As for the alkoxy group regarding R and R2.

A lower alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, and propoxy is preferable.

The caffeic acid derivative (1) of the present invention is, for example, caffeic acid or a reactive derivative thereof with the general formula (R+ and R2 have the same meanings as above, Y is OH, NH2 or c H2-halogen (
Example, Br)] or the general formula (R+ and R2 have the same meanings as above, n-1 to
It can be produced by reacting with the compound represented by 4).

Examples of reactive derivatives of caffeic acid include acid halides (acid chloride, acid bromide, etc.), mixed acid anhydrides (
Examples include chloroethyl carbonate, triethylamine, etc.).

In this reaction, it is preferable to use dicyclohexylcarbodiimide. When compound (U) is allyl alcohol-based, the phenolic hydroxyl group in compound (II) is preferably protected with a protecting group (eg, tetrahydrol, l-branyl group, etc.).

This reaction is preferably carried out in a solvent such as tetrahydrofuran or acetonitrile, and the reaction temperature is room temperature to 50°C.
It is desirable that the

Pharmacological experiment 1 Using polymorphonuclear leukocytes collected from guinea pigs as an enzyme source, the enzyme and 14C-laminated aracitonic acid were added to the reaction solution and allowed to react for a certain period of time. Acid derivative (1) was added. 14c ~ 5 synthesized from arachidonic acid by 5-lipoxygenase
-HETE and leukotriene B were separated by thin layer chromatography, and the enzyme activity was determined by measuring their counts, and ID5o was determined from the enzyme activity inhibition curve. The results are shown in FIG.

Toxicity experiment Regarding the toxicity of the compounds of the present invention to mice, the LDso value is 100 mg/kg or more when administered orally, which is extremely large compared to the administered dose, and the compounds have a wide safety margin.

Thus, the caffeic acid derivative (1) has a 5''-lipoxygenase inhibitory effect, and inhibits leukotrienoic acid, 5-HIiTE in vivo in mammals such as humans, horses, dogs, guinea pigs, mice, and rats. It has a synthesis inhibitory effect and is useful as a therapeutic/preventive agent for allergies, asthma, inflammation, etc.

The caffeic acid derivative (1) is administered orally or parenterally in the form of a pharmaceutical formulation with a suitable and conventional pharmaceutically acceptable carrier.

Pharmaceutical formulations may take conventional forms such as tablets, capsules, powders, suppositories, injections and the like.

For example, caffeic acid derivative (1) is usually administered orally at a dose of 10 to 300 mg once or several times a day, but depending on age, body weight, and/or severity of the disease to be treated and response to treatment. The dosage may vary depending on the dose.

Formulation Example 1 Caffeic acid derivative according to any one of Examples 1 to 5 50-g Magnesium stearate 50 mg Lactose 50B Each of the above components was blended to obtain a tablet weighing 150+I1 g.

Example 1: Preparation of caffeic acid-3,4-dihydro-cinnamyl ester 111 Caffeic acid-3,4-dihydro-cinnamyl ester. lI88mg (7) Tetra! In 6 ml of Ni FD7 run, 106 mg of dicyclohexylcarbodiimide and 155+ ng of 3.4-bistetrahydrobyranyloxycinnamyl alcohol (synthesized from caffeic acid in 3 steps: (a) Esterification (HCI-CH
aO)I), protection of fbl catechol (dihydropyran, para-toluenesulfonic acid L, (C1 reduction (diisobutylaluminum hydride)) was added. The mixture was stirred at room temperature for 17 hours and at 50°C for 3 hours. , the reaction solution was filtered. The filtrate was concentrated and subjected to column chromatography [silica gel/hexane:ethyl acetate (3:
2)) to produce oily caffeic acid-3,4-
Bistetrahydropyranyloxycinnamyl ester 5
Obtain 5 mg.

IR: vmax 3520.3200.1700.
1630.1600 cm-'NMR: δCDCl3 0.9-2.1 (m, 12H) 3.4-4.3 (m, 4B) 4.75 (d, J=6Hy,, 2H) 5.4 (
s, '2H) 6.15 (d, J=15Hz, 7H) 6.2~7
．． 3 (m, 8H) 7.55 (d, J=15Hz, 18) (21(1
5511 Ig of Caffee M-3,4-bistetrahydride biranyloxycinnamyl ester obtained in 1 was dissolved in 2 ml of anhydrous methanol, a catalytic amount of para-toluenesulfonic acid was added at 0°C, and the mixture was stirred at the same temperature for 1 hour. do. After the reaction, add 1 drop of triethylamine and concentrate to obtain a crude product. This material can be used for thin layer chromatography [silica gel/
Purified with hexane:ethyl acetate (1:3)),
15 mg of pure product is obtained.

IR: vmax 3300.1680.1600
cm 'NMR: δ D4-MeOH 4,3-4.6 (m, 21+) 5.9 (d, 15Hz, LH) 5.85-6.7 (m, 8H) 7.2 (d, 15Hz, IH,) Example 2: Preparation of caffeic acid benzylamide To 180+ng of caffeic acid in 5 ml of tetrahydrofuran are added 1, 206 mg of dicyclohexylcarbodiimide and 107 mg of benzylamine. This mixture was stirred at 50° C. for 6 hours, and the reaction solution was filtered. The filtrate was concentrated and recrystallized from ethyl acetate-hexane to give 100 granular crystals.
Get mg.

Melting point: 161-167°C IR: vmax 3250.1640.1585
am-'NMR: δDe-DMSO, CDCl34.4
5 (d, J=6Hz, 28)6.38 (d,
J=14To, IH)6.7~7.5 (+m,
9H) Examples 3 to 5 According to Example 1 or 2, compounds represented by the following general formula were obtained.

n

[Brief explanation of the drawing]

FIG. 1 is a graph showing the enzyme activity inhibitory effect of the compounds of the present invention. Patent Applicant Midori Juji Co., Ltd. Figure 1 Procedure Neichi Masayo: (Voluntary) July 27, 1980 Director General of the Patent Office 1982 Patent Application No. 104999 2, Title of Invention Caffeic Acid Derivative 3, Amendment Relationship with the case of the person who filed the patent application Patent applicant name Mitri Co., Ltd.+Aza4, Agent ■541 Address 406 New Life Hirano-cho, 4-53 Ike-3, Hirano-cho, Higashi-ku, Osaka Telephone: (06) 227-1156 Column 6 of “Detailed Description of the Invention” of the specification, Contents of amendment (1) [-Arachidonic acid” on page 5, line 11 of the specification]
Next, add "various caffeic acid derivatives (■) at various concentrations". (2) On page 5, line 11 of the same book, the text is corrected to ``Made -1 changed to 1.'' (3) Delete "Various concentrations of various caffeic acid derivatives (1) were added to this reaction solution." on page 5, lines 11 to 13 of the same book. that's all

Claims (1)

[Claims] Represents a group represented by the general formula (wherein R and R2 are a hydrogen atom, an alkoxy group or a hydroxyl group, and X is a formula %) (n-1 to 4). ] A caffeic acid derivative represented by