JPS5967263A - Pentaenoic higher fatty acid pyridyl alcohol ester and its preparation - Google Patents

Abstract

NEW MATERIAL:The pentaneoic higher fatty acid pyridyl alcohol ester. EXAMPLE:5,8,11,14,17-Eicosapentaenoic acid 3-pyridylmethanol ester. USE:Preventive for thrombosis caused by the coagulation of blood such as myocardial infraction, cerebral thrombosis, etc. and preventive for metastasis of cancer. Remarkably suppresses the blood platelet coagulation activity. Dose: 30- 1,500mg of the active component daily for adult, if necessary in several divided doses. PROCESS:The objective novel substance can be prepared either by reacting a pentaenoic higher fatty acid (having five double bonds in the carbon chain and preferably 18-24 carbon atoms) with pyridyl alcohol in a solvent in the presence of dimethylaminopyridine and a condensation agent such as N,N'-dicyclohexacarbodiimide, or by reacting a reactive derivative of a pentaenoic higher fatty acid with pyridyl alcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION 10. Background Technical Field of the Invention The present invention relates to a four-terminal higher fatty acid pyrinol alcohol ester and a process for producing the same.

Benquene higher fatty acid pyrinol alcohol ester provided by the present invention is a new compound and has the effect of significantly inhibiting platelet aggregation. Therefore, it is effective in preventing diseases caused by platelet aggregation, that is, thrombosis. Also,
It is said that the aggregation effect of platelets is also related to cancer metastasis, and the compounds of the present invention also have a preventive effect on cancer metastasis.

Prior Art Dyerberg et al. showed that Greenland skimos, which eat a lot of marine animal meat, rarely suffer from acute myocardial infarction, and that low-density lipotan augments (
Acta Medica Scandinavica (Acta Medica 5can)
di-navica), 192.85 (1972)]
.

Since the meat of marine animals is rich in 5,8,11,14.17-eicosapentaenoic acid, the amount of the above acid contained in the blood plasma of Greenlandic skimo and Danes is very high. When the amount of 5, 8, 11, 1.4.
It was found that it contained 17-eicosapentaenoic acid [American Glossy
Nutrition (American Journal
of C11nical Nutrition), 2
8°958 (1975)].

Therefore, the present inventors believed that unsaturated higher fatty acids have the effect of suppressing platelet aggregation, and completed the present invention as a result of intensive research to find a derivative with even better pharmacological effects.

(2) Purpose of the Invention The object of the present invention is to provide a novel pyridyl alcohol ester of higher fatty acids useful as a preventive agent for thrombosis. Thrombosis, such as acute myocardial infarction and cerebral thrombosis, has come to account for a large proportion of adult diseases in recent years.
There is a strong desire for the emergence of a drug that can effectively prevent this.

A further object of the present invention is to provide pyrinol alcohol esters of higher fatty acids useful as agents for preventing cancer metastasis.

A further object of the present invention is to provide a method for producing dipentaene higher fatty acid pyridyl alcohol ester.

(1) Detailed Description of the Invention The objects of the present invention are achieved by the configurations shown in the following sections.

(1) Henta, T-ton high 111 fat e l-”)
Dyl alcohol ester.

(2) The ester according to item 1 above, wherein the benquene higher fatty acid has 18 to 24 carbon atoms.

(3) -e entaene high ff/i The ester of item 2 above which is the fatty acid caleicosabentaenoic acid.

(4) Eicosapentaenoic acid is 5.8, 11, 14
．． The ester according to item 3 above, which is 17-eicosapentaenoic acid.

(5) The ester according to any one of the above items 1 to 4, wherein the pyridyl alcohol is a pyridyl lower alcohol.

(6) The ester according to item 5 above, wherein the pyridyl lower alcohol is 3-pyridyl lower alcohol.

(7) The ester according to item 6 above, wherein the 3-pyrinol lower alcohol is 3-pyridylmethanol.

(8) The ester according to item 1 above, wherein the higher fatty acid pyridyl alcohol ester is a 5.8,11,14.17-eicosa-encyclopedic acid 3-pyridylmethanol ester.

(9) Pentaene higher fatty acid pyrinol alcohol ester, which is characterized by reacting benquene higher fatty acid and pyrinol alcohol in the presence of a condensing agent, or reacting a reactive derivative of pentaene higher fatty acid with pyrityl alcohol. Manufacturing method.

θ0) The condensing agent is N, N'-dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium p-
1-Luenesulfone salt '1 TaId N, N'
- The method according to item 9 above, which is nosuccinimidyl tribamate.

0]) The method according to item 9 above, wherein the reactive derivative of pentaene higher fatty acid is a located product of pentaene higher fatty acid.

(la-"Location compound of pentaene higher fatty acid) is chloride or bromide of pentaene higher fatty acid."
The manufacturing method described in double item 11.

The benquene higher fatty acid pyrityl alcohol ester provided by the present invention means an ester of a higher fatty acid having five double bonds in its carbon chain and pyrinol alcohol having a hydroxyalkyl group bonded to the pyridine nucleus. The preferred higher fatty acids are those having 18 to 24 carbon atoms, and the hydroxyalkyl group is preferably 18 to 24 carbon atoms.
Those having 4 to 4 carbon atoms are preferred. The hydroxyalkyl group can be bonded to any of the 2- to 6-positions of the pyridine nucleus, but is most preferably bonded to the 3-position.

Among these pentaene higher fatty acid pyridyl alcohol esters, the most preferred are 5, 8, 11.1
4.17-eicosa citrate 3-pyridylmethanol ester, but other examples include 7,10.13,
1.6.19-docosapentaenoic acid-3-pyridylmethanol ester may be mentioned.

The double ester of the present invention is produced by reacting pentaene higher fatty acid and pyridyl alcohol in the presence of a condensing agent, or
Alternatively, it can be obtained by reacting a reactive derivative of pentaene higher fatty acid with pyridyl alcohol. Examples of condensing agents include N,N'-dicyclohexylcarbodiimide, 2-chloro-1-mer-5fi IJ-dinium p-1-luenesulfonate, 2-promo1
-Methylpyridinium iodide, N,N'-disuccinimidyl rubbermate, and the like. N, N
'-Dicyclohexylcarbodiimide is usually used in the coexistence of dimethylaminopyrinone, and 2-chloro-1-methylpyridinium p-1-luenesulfonate
D"'27"como-1-methylpyridinium iodide is used in the presence of a tertiary amine such as triethylamine or l-butylamine. When using these condensing agents, aprotic solvents such as methylene chloride, 1,2-nochloroethane, tetrahydrofuran, and benzene are used.

Reactive derivatives of pentaene higher fatty acids include acid halides, such as acid chlorides and acid bromides.

When using the above-mentioned reactive derivatives, the solvent is not particularly limited, and organic solvents such as methylene chloride, chloroform, trimethylformamide, dimethyl sulfoxide, tetrahydrofuran, benzene, and toluene are widely used. The reaction is usually carried out at -200 to 100°C for about 5 to 8 hours. After the reaction is complete, the desired product is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the entire residue is subjected to column chromatography to obtain the desired ester as crystals.

The pentaene higher fatty acid pyridyl alcohol ester of the present invention is used as a thrombosis preventive agent or cancer metastasis preventive agent, and the dosage is approximately 30 to 150 per day for adults as an active ingredient.
0m9, and the membrane strength is divided into several times as necessary. Oral membranous administration is preferred, but intravenous injection is also possible.

The compounds of the present invention are mixed with pharmaceutical carriers or excipients in a conventional manner and formulated into tablets, powders, capsules, or granules. Examples of carriers or excipients include calcium carbonate, calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate, gum arabic, and the like. Tablets may be coated according to conventional methods. The compound of the present invention is
In addition to the solid formulations mentioned above, liquid formulations such as oily suspensions, syrups, and elixirs can also be used.

Since the compound of the present invention has five double bonds in its molecule, alpha-tocopherol, 2,6-di-tert-butyl-p-cresol (BHT) is added to the formulation for stabilization purposes.
It is also possible to mix the following. The compound of the present invention can also be stabilized by inclusion with cyclodextrin or the like. Alternatively, the compound falsifier of the present invention can also be used as a salt of hydrochloric acid, bromic acid, tartaric acid, or the like.

Next, the present invention will be explained in more detail with reference to Examples and Test Examples.

Example 1 5, 8, 11, ], 4. , 17-eicosapentaenoic acid (151 mg) and trimethylaminopyrinone (67 mg) were dissolved in dichloromethane (lornl). To this solution was added N,N'-dicyclohexacarboimide (11,3m9) and then 3-pyrinnormethanol (3-hydroxymethylpyridine) (60mg).
! , 1 was added, and the mixture was stirred at room temperature for 3 hours. N-penkune (10ml) was added to the reaction solution, and after stirring for 10 minutes, the reaction mixture was filtered. After concentrating the P solution under reduced pressure, the residue was filtered with silica gel (
30F-'), and the solvent was distilled off from the methylene chloride-ethyl acetate (9:1) eluate to give oily compounds 5, 8, 11, 14. , 17
-Eicosapentaenoic acid 3-pyritulmethanol ester (14.7 mg, yield 75 cm) was obtained. The physicochemical data of this product are shown below.

IR (CHCL3) νmax"-': 1710, 14
25,1145NMR (CDCA6) δ (ppm)
:096(31(ItIJ-7,6■IZl-C■)2
-CH5)5.37 (10H, m, -CH-CH
-) Test Example 38 Collect 9 volumes of blood from the rabbit auricular vein using a syringe containing sodium citrate solution (1 volume). The blood was centrifuged at 90 Orpm for 10 minutes, and platelet-rich plasma (Platelet Rich P
lasma (hereinafter referred to as PRP). 3 of the supernatant
/4 was collected, centrifuged at 3000 rpm for 15 minutes,
Platelet poor plasma was added to the supernatant.
Plasma.

(hereinafter referred to as PPP). To measure platelet aggregation ability,
Dilute with PRP k PPP to reduce the platelet count to approximately 500,000/
The one adjusted to μt was used. The adjustment PR of 250μt
P was placed in a key pet and heated for 3 minutes in a 37℃ thermostat, and then heated for 5 minutes.
,8.11,14.17-eicosapentaenoic acid 3-pyridylmethanol ester solution (1,2X10-2M
Ethanol solution - io, 05M+ - diluted with Lys buffer)
After adding 25 μt-q and incubating for 5 minutes, a solution of arachidonic acid, an aggregation inducer (3,2×10′M ethanol solution diluted with Tris-buffered isotonic saline solution)25
μL was added to measure the inhibition rate of platelet aggregation. 5, 8, 11.14. on platelet aggregation induced by arachidonic acid (3X10'M). ．． The inhibition rate of 17-nicosahentaene 3-pyridylmethanol ester was 194% at a 5×10 M dose of the ester and 38.5% at a 1×10 M dose. On the other hand, 5, 8, 1
1, 14. , the inhibition rate of 17-eicosapentaenoic acid was 4.9% at the 1×10′M dose.

(1) Effects of the Invention According to the present invention, a pentaene higher fatty acid pyridyl alcohol ester having a thrombosis preventive effect and a cancer metastasis preventive effect is provided.

Since the above-mentioned compound of the present invention significantly suppresses the platelet aggregation effect induced by arachidonic acid, it can be used as a prophylactic agent for various thromboses caused by blood coagulation, such as myocardial infarction and cerebral thrombosis. 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, the present invention provides a method for producing the pentaene higher fatty acid pyridyl alcohol ester.

Claims (9)

[Claims] (1) Benquene higher fatty acid pyridyl alcohol ester. (2) The ester according to claim 1, wherein the pentaene higher fatty acid has 18 to 24 carbon atoms. (3) -! ! The ester according to claim 2, wherein the higher fatty acid is eicosaben citric acid. (4) Eicosaben citric acid is 5.8.11.14
The ester according to claim 3, which is 17-eicosa-4-citric acid. (5) The ester according to any one of claims 1 to 4, wherein the bilinol alcohol is a pyridyl lower alcohol. (6) The ester according to claim 5, wherein the bilinol lower alcohol is 3-bilinol lower alcohol. (7) The ester according to claim 6, wherein the 3-pyridyl lower alcohol is 3-pyridylmethanol. (8) Benquene higher fatty acid bilinol alcohol ester is 5.8,11.14-. The ester according to claim 1, which is 17-eicosa wave citric acid 3-H+J silmethanol ester. (9) A method for producing a pentaene higher fatty acid pyridyl alcohol ester, which comprises reacting a benquene higher fatty acid with bilinol alcohol in the presence of a condensing agent, or reacting a reactive derivative of a benquene higher fatty acid with pyridyl alcohol. 00 Condensing agent is N, N'-dicyclohequinylcarbonimide, 2-chloro-1-methylvirisonium p
-Toluenesulfonate-i Iti N, N'
- The manufacturing method according to claim 9, which is nosuccinimisollupamate. 0]) The method according to claim 9, wherein the reactive derivative of pentaene higher fatty acid is a halocarnide of pentaene higher fatty acid. 12. The production method according to claim 11, wherein the halo-8 compound of the α-pentaene higher fatty acid is a chloride or bromide of the pentaene higher fatty acid.