JPH07588B2 - Polyenoic acid derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel polyenoic acid derivative.

[0002]

[Technical level] 20 to 22 carbons, 3 or more (usually 3
To 6) fatty acids having double bonds (ie polyenoic acid), and examples thereof include arachidonic acid (eicosatetraenoic acid, AA).

[0003]

[Chemical 2]

Eicosapentaenoic acid (EPA)

[0005]

[Chemical 3]

Docosahexaenoic acid (DHA)

[0007]

[Chemical 4]

And the like.

Such polyenoic acid and its derivatives are a group of physiologically active substances called prostaglandins (PG), thromboxane, and leukotrienes (each of which has a characteristic strong physiological activity. For example, PG has a platelet aggregation inhibitory action. , As a precursor (known as arachidonic acid cascade, eicosapentaenoic acid cascade, etc.) that has contraction and dilation effects on the arterial wall, and is expected to have thrombosis, arteriosclerosis prevention, and anticancer effects) It is an important substance that works.

[0010]

[Technical problem] However, since such polyenoic acid and its derivatives cannot be produced in the human body, they must be supplied from the outside of the body in an effective form, which has been particularly noted in recent years. The emergence of effective derivatives is highly anticipated.

[0011]

DISCLOSURE OF THE INVENTION Therefore, the object of the present invention is to provide a novel derivative of polyenoic acid, the gist of which is represented by the general formula RCO-NHR ¹ (I) [wherein RCO-has 20 to 22 carbon atoms. R is a polyenoic acid residue.
¹ is hydroxyl (-OH) or formula

[0012]

[Chemical 5]

The group represented by Here, R ² and R ³ each represent an alkyl group, and n represents an integer of 3 or less. ] It is a polyenoic acid amide derivative represented by these.

In the present specification, the alkyl group is preferably a lower alkyl group having 1 to 4 carbon atoms, and specific examples thereof include methyl, ethyl, n-propyl, iso-propyl and n-butyl. R ² and R ³ may be the same or different from each other.

In the general formula (I), preferred specific examples of the -NHR ¹ moiety include hydroxylamine, 2-dimethylaminoethylamine, 3-diethylaminopropylamine and the like.

In the present specification, the eicosaporienoic acid residue represented by RCO- has 20 carbon atoms as described above,
A fatty acid residue having 3 or more, preferably 3 to 6 double bonds and means an acyl group derived from the fatty acid. Preferred examples thereof include AA residues, EPA residues,
DHA residues and the like are listed. Compound (I) of the present invention
Is usually a reactive derivative of polyenoic acid (for example, an acid anhydride, an ester, an acid halogenide, etc.) and a compound represented by the general formula NHR ¹ (II) (wherein R ¹ is as defined above). It is manufactured by

The acid anhydride, for example, is produced by the method of Seliger et al. [J. Lipid Res., 2 , 174 (1966)] or a method analogous thereto.

This amidation reaction is carried out in the presence or absence of a solvent which does not inhibit the reaction (eg chloroform, carbon tetrachloride, ether, alcohol, water, etc.), and is usually
It is carried out under a condensing agent such as 4- (dimethylamino) pyridine, quinoline or triethylamine. The reaction temperature is usually about -10 ° C to room temperature.

The polyenoic acid derivative (I) thus obtained
Can be isolated and purified by means known per se such as concentration, phase transfer, recrystallization, chromatography and the like.

The polyenoic acid derivative (I) has an inhibitory action on platelet aggregation, a contraction action on an arterial wall, an expansion action and the like, and is useful as a prophylactic / therapeutic agent for thrombus, arteriosclerosis, etc., an anti-inflammatory agent, an anti-cancer agent and the like.

Since the polyenoic acid derivative (I) is chemically unstable, lecithin is added as a stabilizer in an amount of 1-10.
It is preferable to add about 10% and store and use.

Reference Example Synthesis of Sn-1,2-di (5,8,11,14,17-eicosapentaenoyl) glycero-3-phosphorylcholine (1) 5,8,11,14,17-E Synthesis of icosapentaenoic acid (EPA) 10 g of triglyceride of EPA was added to 1 part of potassium hydroxide.
It is dissolved in a 0% methanol solution (methanol: water = 9: 1) and stirred in an argon stream at 30 to 40 ° C. for 2 hours. Methanol is concentrated under reduced pressure, and the residue is neutralized with 5% sulfuric acid. After extraction with ether, washing with water and drying, the ether is distilled off under reduced pressure. A colorless viscous liquid with an EPA content of about 50% is obtained. This product is used in the next reaction without purification.

NMR (CCl ₄ ) δ: 5.38 (t, J =
4 Hz, olefin H) 12.12 (s, COOH) 5.38 and 12.12 proton integration ratio = 5: 1

(2) Synthesis of 5,8,11,14,17-eicosapentaenoic acid 15 g of EPA (content 50%) obtained in the above reaction is dissolved in 250 ml of anhydrous carbon tetrachloride. A solution of 4.9 g of dicyclohexylcarbodiimide in 50 ml of anhydrous carbon tetrachloride is added dropwise to this solution. After completion of the dropping, the resulting dicyclohexylurea is filtered off after stirring at room temperature for 5 hours. The filtrate is concentrated under reduced pressure at room temperature to obtain anhydrous 5,8,11,14,17-eicosapentaenoic acid as a colorless viscous liquid. Yield 13 g (EPA anhydrous content 50%).

[0025]

【Example】

Example 1 N- [2- (N ', N'-dimethylamino) ethyl] -5
Synthesis of Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic amide 6 g (10 mmol) of eicosapentaenoic anhydride was dissolved in 30 ml of anhydrous ether in an argon stream to give 2
-(N ', N'-dimethylamino) ethylamine 1.7 g
(20 mmol) is added dropwise. After stirring at room temperature for 30 minutes, the reaction solution is washed with saturated potassium hydrogen carbonate and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to alumina column chromatography. The column was eluted with ether and then with chloroform, and the fraction colored with the Dragendorff reagent was concentrated under reduced pressure to obtain 3 g (yield 68%) of the target compound as a colorless oil.

IRν ^Nujol _Max cm ⁻¹ : 3300,164
0 NMR (CDCl ₃ ) δ: 2.27 (s, N (CH ₃ ) ₂ ),
3.35 (2H, t, J = 8Hz), 6.45 (1H,
broad, CON H )

Example 2 Synthesis of 5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenohydroxanoic acid NH ₂ OH.HCl 2 g (30 mmol) in methanol (14 ml) 2 g potassium hydroxide (35 mmol) Are dissolved in methanol (5 ml) with heating. When the temperature has dropped to 30-40 ° C., add potassium hydroxide solution to NH ₂ OH.
-Drop to the HCl solution while cooling with ice. To this is added 10 g (16 mmol) eicosapentaenoic anhydride in one portion. After stirring for 5 minutes, acidify with dilute acetic acid and extract with ether. The ether layer is washed with saturated potassium hydrogen carbonate solution and saturated brine, dried and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-petroleum ether (1: 4), then ethyl acetate-petroleum ether (1: 1).
3.2 g (yield 63%) of the target compound is obtained as a colorless oil.

IRν ^Nujol _Max cm ^-1 : 3250,164
_{0 NMR (CDCl 3) δ:} 8.96 (s, N H O H)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/16 ABX 9454-4C ACB 9454-4C ADU 9454-4C AED 9454-4C AEL 9454-4C C07C 231/02 7106-4H

Claims (1)

[Claims] 1. A compound represented by the general formula: RCO-NHR ¹ [RCO- represents a polyenoic acid residue having 20 to 22 carbon atoms,
¹ is hydroxyl (-OH) or the formula Represents a group represented by. Here, R ² and R ³ each represent an alkyl group, and n represents an integer of 3 or less. ] The polyenoic acid derivative represented by these.