JPS6323188B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION Technical Field The present invention relates to pyridine derivatives and platelet aggregation inhibitors using the same. The pyridine derivative provided by the present invention is a new compound and has a strong platelet aggregation inhibiting effect. Therefore, it is effective in preventing diseases caused by platelet aggregation, that is, thrombosis.

Prior Art Alpha-linolenic acid, which is a triene higher fatty acid, is an essential fatty acid, and 8,11,14-eicosatrienoic acid is a precursor of prostaglandin _E1 , and each is an important compound. Regarding pentaene higher fatty acids, it has been reported that 5,8,11,14,17-eicosapentaenoic acid is contained in large amounts in fish oil and has the effect of lowering low-density lipoprotein (LDL).

The present inventors synthesized various triene higher fatty acid esters of 2-hydroxymethyl-4-butylpyridine and pentaene higher fatty acid esters of 2-hydroxymethyl-4-butylpyridine, and as a result of intensive research on their pharmacological activities, they found that The present inventors discovered that the present invention has a platelet aggregation inhibiting action.

Purpose of the Invention The present invention provides novel pyridine derivatives having platelet aggregation inhibiting activity, particularly 2-hydroxymethyl-4-
The object of the present invention is to provide a triene higher fatty acid ester of butylpyridine, a pentaene higher fatty acid ester of 2-hydroxymethyl-4-butylpyridine, and a platelet aggregation inhibitor using the same. Thrombosis such as myocardial infarction and cerebral thrombosis has recently come to account for a large proportion of adult diseases, and there is a strong desire for the emergence of a drug that can effectively prevent this.

DETAILED DESCRIPTION OF THE INVENTION The objects of the present invention are achieved by the configuration shown below.

In other words, the first invention of the present application is based on the general formula (wherein R is an acyl group derived from a triene higher fatty acid or a pentaene higher fatty acid).

The triene higher fatty acid is 9,12,15-
Octadecatrienoic acid (α-linolenic acid) or 8,11,14-eicosatrienoic acid (dihomoγ
-linolenic acid) is desirable, and as the pentaene higher fatty acid, 5,8,11,14,17-eicosapentaic acid is desirable.

In addition, the second invention of the present application is a general formula This is a platelet aggregation inhibitor using a pyridine derivative represented by the formula (wherein R is an acyl group derived from a triene higher fatty acid or a pentaene higher fatty acid).

The triene higher fatty acid is 9,12,15-
Octadecatrienoic acid (α-linolenic acid) or 8,11,14-eicosatrienoic acid (dihomoγ
-linolenic acid) is desirable, and as the pentaene higher fatty acid, 5,8,11,14,17-eicosapentaenoic acid is desirable.

In the pyridine derivative represented by the above general formula provided by the present invention, the acyl group derived from a triene higher fatty acid as defined by R is 9,
It is a group obtained by removing the hydroxyl group from 12,15-octadecatrienoic acid (α-linolenic acid) or 8,11,14-eicosatrienoic acid (dihomoγ-linolenic acid), and is an acyl group derived from pentaene higher fatty acid. is a group obtained by removing the hydroxyl group from 5,8,11,14,17-eicosapentaenoic acid.

The ester represented by the above formula of the present invention can be combined with a triene higher fatty acid or a pentaene higher fatty acid.
-hydroxymethyl-4-butylpyridine in the presence of a condensing agent.

Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide and 2-chloro-1-methylpyridinium p-toluenesulfonate.

The pyridine derivative of the present invention is used as a thrombosis preventive agent, and the daily dose for adults is 50 to 1500 mg, divided into 1 to 3 doses if necessary. Oral administration is preferable, but intravenous injection is also possible.

The pyridine derivative of the present invention is mixed with a pharmaceutical carrier or excipient in a conventional manner and formulated into a tablet, powder, capsule, or granule. Examples of the carrier or excipient include calcium carbonate, calcium phosphate, starch, Examples include sucrose, lactose, talc, and magnesium stearate. The pyridine derivatives of the present invention can also be made into liquid preparations such as oily suspensions, syrups, and injections.

Furthermore, the platelet aggregation inhibitor using the pyridine derivative of the present invention can also be used to prevent blood coagulation from collected blood.

Next, the present invention will be explained in further detail by showing production examples and test examples.

Production example 1 α-linolenic acid 169mg under argon atmosphere
(0.61 mmol of dry 1,2-dichloroethane (5
8 mg (0.065 mmol) of 4-dimethylaminopyridine and 150 mg (0.73 mmol) of N,N'-dicyclohexylcarbodiimide at room temperature.
was added. Next, 2-hydroxymethyl-4
- Drying 100 mg (0.61 mmol) of butylpyridine 1,
A solution dissolved in 2-dichloroethane (1 ml) was added and reacted overnight at room temperature. After separating the resulting precipitate, the mother liquor was concentrated to obtain 380 mg of residue. This was subjected to silica gel column chromatography, and the target pyridine derivative, 2-(9,12,15-octadecatrienoyl)hydroxymethyl-4-butylpyridine, was extracted from the eluate fraction of benzene/ethyl acetate 9:1. 257 mg (0.60 mmol) was obtained. The physicochemical data of this product are shown below.

IRν ^neat _nax (cm ^-1 ): 1745, 1710, 1655 mass (m/e): 425 (molecular ion peak), 356,
330, 316, 207, 165, 149 PMR (CDCl ₃ ) δ: 5.19 (2H S) 2.61 (2H t, J = 7.6Hz) 2.40 (2H t, J = 7.6Hz) 0.97 (3H t, J = 7.8Hz ) 0.93 (3H t, J = 7.2Hz) Production example 2 Dry 185 mg (0.61 mmol) of 5,8,11,14,17-eicosapentaenoic acid in an argon atmosphere.
In a solution dissolved in 2-dichloroethane (5 ml),
8 mg of 4-dimethylaminopyridine at room temperature
(0.065 mmol) and 150 mg (0.73 mmol) of N,N'-dicyclohexylcarbodiimide were added. Subsequently, a solution of 100 mg (0.61 mmol) of 2-hydroxymethyl-4-butylpyridine dissolved in dry 1,2-dichloroethane (1 ml) was added, and the mixture was allowed to react overnight at room temperature. After separating the resulting precipitate, the mother liquor was concentrated to obtain a residue of 366 mg. This was subjected to silica gel column chromatography, and the target pyridine derivative 2-(5,8,11,14,17-eicosapentaenoyl)hydroxy 242 mg (0.54 mmol) of methyl-4-butylpyridine was obtained. The physicochemical data of this product are shown below.

IRν ^neat _nax (cm ^-1 ): 1745, 1710, 1650 mass (m/e): 449 (molecular ion peak), 380,
354, 340, 207, 165, 149 PMR (CDCl ₃ ) δ: 5.20 (2H S) 2.62 (2H t, J = 7.6Hz) 2.42 (2H t, J = 7.4Hz) 0.97 (3H t, J = 7.6Hz) ) 0.93 (3H t, J=7.2Hz) Test Example Platelet aggregation inhibitory effect 9 volumes of blood are collected from the rabbit carotid artery using an injection solution containing 3.8% sodium citrate solution (1 volume). The blood is centrifuged to obtain platelet-rich plasma (PRP: 5×10 ⁵ cells/μ).

Place 250μ of the PRP in a cuvette, warm it for 2 minutes in a 37℃ constant temperature bath, and add 2μ of the sample solution [1.4×10 ^-2μ ethanol-dimethyl sulfoxide (1:1) solution diluted with ethanol] and Tris-buffered isotonic saline. 2-(9,12,15-octadecatrienoyl)hydroxymethyl-4 against platelet aggregation induced by adding 18μ of an aqueous solution and incubating for 3 minutes, then adding 10μ of collagen (15μg/ml) as an aggregation inducing agent. -50 of butylpyridine
The % inhibitory concentration (IC ₅₀ ) is 1.0×10 ^-3 M and 2−(5,
The IC ₅₀ of 8,11,14,17-eicosapentaenoyl)hydroxymethyl-4-butylpyridine is 7.5
It was ×10 ^-4 M.

Acute toxicity An acute toxicity test was conducted using ICR male mice (5 weeks old) by intravenous administration. 2-(9,
The LD ₅₀ of 12,15-octadecatrienoyl)hydroxymethyl 4-butylpyridine is 512.4 mg/Kg, and 2-(5,8,11,14,17-eicosapentaenoyl)hydroxymethyl 4-butyl The LD ₅₀ of pyridine was 541.5 mg/Kg, indicating high safety.

Effects of the Invention According to the present invention, a pyridine derivative having a thrombosis preventive effect is provided.

The above compounds of the present invention significantly inhibit platelet aggregation induced by collagen,
It can be used as a prophylactic agent for various thromboses caused by myocardial infarction and cerebral thrombosis.

Claims (1)

[Claims] 1. General formula (wherein R is an acyl group derived from a triene higher fatty acid or a pentaene higher fatty acid). 2. The pyridine derivative according to claim 1, wherein the acyl group derived from the triene higher fatty acid is an acyl group derived from α-linolenic acid or dihomoγ-linolenic acid. 3. The pyridine derivative according to claim 1, wherein the acyl group derived from the pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid. 4 General formula A platelet aggregation inhibitor using a pyridine derivative represented by the formula (wherein R is an acyl group derived from a triene higher fatty acid or a pentaene higher fatty acid). 5. The platelet aggregation inhibitor using a pyridine derivative according to claim 4, wherein the acyl group derived from the triene higher fatty acid is an acyl group derived from α-linolenic acid or dihomoγ-linolenic acid. . 6. The platelet aggregation inhibitor using a pyridine derivative according to claim 4, wherein the acyl group derived from the pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid.