JPH0224270B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION Technical Field The present invention relates to a novel pyridine derivative and a platelet aggregation inhibitor containing 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, such as thrombosis. It is also known that platelet aggregation is involved in cancer metastasis.
The compounds of the present invention also have a preventive effect on cancer metastasis. Prior Art Thrombosis such as myocardial infarction and cerebral thrombosis has come to account for a large proportion of adult diseases in recent years, and there is a strong desire for the emergence of a drug that can effectively prevent this. Among pyridine derivatives, compounds such as nicotinic acid that exhibit antiplatelet aggregation effects have been found, but it is difficult to say that they exhibit antithrombotic effects that are clinically satisfactory. Purpose of the invention The present inventors synthesized various pyridine derivatives,
As a result of intensive research into their pharmacological activities, they discovered that the pyridine derivatives of the present invention have excellent platelet aggregation inhibiting effects, leading to the completion of the present invention. Therefore, an object of the present invention is to provide a novel pyridine derivative having a platelet aggregation inhibitory effect and a platelet aggregation inhibitor containing the same. The pyridine derivative according to the present invention has a strong platelet aggregation inhibiting effect and is useful as a preventive agent for diseases caused by platelet aggregation, such as thrombosis and cancer metastasis. The object of the present invention is achieved by the configuration shown below. That is, the present invention is based on the general formula () (wherein R is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms). In addition, the second invention of the present application is based on the general formula () (wherein R is a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms) is a platelet aggregation inhibitor containing a pyridine derivative. still,
In the present invention, a platelet aggregation inhibitor refers to a preparation that has the effect of inhibiting platelet aggregation. Specific Description of the Invention The pyridine derivative of the present invention represented by the above formula () is represented by the following formula () In tetrahydrofuran, benzene or dimethoxyethane, or in a mixed solvent obtained by appropriately mixing these solvents, an aldehyde compound represented by the general formula () is added. (In the formula, R ¹ represents a straight or branched alkyl group having 1 to 6 carbon atoms.) It can be obtained as an ester by reacting the phosphonate derivative represented by the formula with sodium hydrogen (NaH). . Further, if desired, the ester can be hydrolyzed to obtain a carboxylic acid derivative. Of course, the carboxylic acid derivative can also be used as a sodium, potassium or calcium salt for the purpose of the present invention. The pyridine derivative of the present invention can be used as an active ingredient or one of the active ingredients of a platelet aggregation inhibitor, and is effective for diseases caused by platelet aggregation, but is particularly effective as an antithrombotic agent, angina pectoris, or cancer. Used as a metastasis prevention agent, the dosage is generally 1 for adults.
The daily dose is approximately 60 to 1000 mg, which is preferably administered in 1 to 3 divided doses as necessary. The method of administration can take any form suitable for administration, with oral administration being particularly preferred, although intravenous injection is also possible. The compound of the present invention may be formulated into tablets, powders, capsules, or granules either alone or mixed with pharmaceutical carriers or excipients in a conventional manner. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, and the like. In addition to the solid formulations mentioned above, the compounds of the present invention can also be formulated into liquid formulations such as oily suspensions and syrups. The compound of the present invention can also be stabilized by inclusion with cyclodextrin. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. Example Under an argon atmosphere, 7.15 ml of ethyl orthoformate and 16 mg of ammonium chloride were added to a solution of 5.551 g of 4-bromobenzaldehyde in dry ethanol (15 ml), and the mixture was heated under reflux for 1 hour. Add water to the reaction solution,
Extraction was performed with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 6.824 g of 4-bromobenzaldehyde diethyl acetal. Under an argon atmosphere, 2.58 ml of a 1.55Mn-butyllithium hexane solution was added to a solution of 1.036 g of the compound in 12 ml of dry ether at -70°C, and
Allowed time to react. Nicotinaldehyde at -30℃
429 mg was added, the temperature was gradually raised, and the mixture was allowed to react at room temperature for 20 minutes. Water was added to the reaction solution under ice cooling, and extraction was performed with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue.
1.142g was subjected to silica gel column chromatography, and 4-[(3-pyridyl)hydroxymethyl]benzaldehyde diethyl acetal was extracted from the chloroform:methanol (99:1) elution fraction.
Obtained 698mg. Under an argon atmosphere, a mixture of 4 ml of tetrahydrofuran and 4 ml of 2N hydrochloric acid was added to 786 mg of the compound and reacted at room temperature for 1 hour. After adjusting the reaction solution to pH 10 with a saturated aqueous sodium hydrogen carbonate solution under ice cooling,
Extraction was performed with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 624 mg of the resulting residue was subjected to silica gel column chromatography, and 4- [(3
571 mg of pyridyl)hydroxymethyl]benzaldehyde was obtained. 60% oily sodium hydride under argon atmosphere
Suspend 100 mg in 2 ml of dry tetrahydrofuran,
Under ice-cooling, add 332μ of triethyl-4-phosphonocrotonate and stir for 20 minutes.
pyridyl)hydroxymethyl]benzaldehyde
A solution of 213 mg of dry tetrahydrofuran (2 ml) was added and the mixture was allowed to react at room temperature for 40 minutes. After the reaction under ice cooling, a saturated aqueous ammonium chloride solution was added, and extraction was performed with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, resulting in a residue of 354 mg.
was subjected to silica gel column chromatography,
Chloroform to methanol (99:1 to 98:2)
From the elution fraction, 161 mg of ethyl 5-[4-(3-pyridyl)hydroxymethylphenyl]-2,4-pentadienoate was obtained. Under an argon atmosphere, 1 ml of thionyl chloride was added to 158 mg of the compound, and the mixture was heated at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the resulting residue, followed by extraction with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue.
2 ml of acetic acid was added to 173 mg to dissolve it, and 67 mg of zinc powder was added to this solution and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue (251 mg) was subjected to silica gel column chromatography, and from the chloroform elution fraction, 91 mg of ethyl 5-[4-(3-pyridyl)methylphenyl]-2,4-pentadienoate was obtained.
I got it. The physicochemical data of this product support the structure of the following formula (). MS (m/s): 293 (molecular ion peak), 220 ¹ H-NMR (deuterated chloroform) δppm: 1.28 (3H,
t, J=7Hz), 3.97 (2H, br.s), 4.25 (2H,
q, J = 7 Hz), 5.95 (1H, d, J = 15 Hz) Under an argon atmosphere, add 90 mg of the compound () to 0.3 ml of a 2N aqueous sodium hydroxide solution and ethanol.
1.5 ml of the mixture was added and reacted at room temperature for 5 hours.
Under ice-cooling, the reaction solution was adjusted to pH 4.5 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration. By recrystallizing these crystals from ethanol, 5-[4-(3-pyridyl)methylphenyl]-2,4-pentadienoic acid
Got 50 mg. The physicochemical data of this product support the structure of the following formula (). MS (m/z): 265 (molecular ion peak), 220 IRν ^KBr _nax cm ^-1 : 1685 ¹ H-NMR (heavy pyridine) δppm: 3.91 (2H, br.
s), 6.28 (1H, d, J = 15Hz) Test Example Platelet aggregation inhibitory effect 9 volumes of blood are collected from the rabbit carotid artery using a syringe containing 3.8% sodium citrate (1 volume). The blood is centrifuged to obtain platelet-rich plasma (PRP: 560,000 cells/μ). 250μ of the PRP was placed in a cuvette, heated for 2 minutes in a constant temperature bath at 37°C, added with 20μ of a Tris-buffered isotonic saline solution of the pyridine derivative to be tested, and incubated for 3 minutes. In addition, platelet aggregation was measured using Born's turbidimetry [for example, Journal of Physiology (J. Physiol. Vol. 168,
178, published in 1968)]. Table 1 shows the 50% inhibitory concentrations for platelet aggregation induced by arachidonic acid (100 μM) and collagen (12 μg/ml), using aspirin as a comparative example. As a result of the test, significant anti-platelet aggregation activity was found as shown in Table 1 below as a representative example. Furthermore, it was confirmed that pyridine derivatives according to the present invention not shown in Table 1 also have similar anti-platelet aggregation activity. In addition, the 50% inhibitory concentration in the table means that the platelet aggregation ability is suppressed to 50% by introducing the pyridine derivative according to the present invention, assuming that the platelet aggregation ability without introducing the pyridine derivative is 100%. It means the concentration of pyridine derivative solution required for

[Table] Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (6 weeks old). The LD ₅₀ values of the compounds of the present invention were all 200 mg/Kg or more, confirming high safety. Effects of the Invention According to the present invention, a novel pyridine derivative and a platelet aggregation inhibitor containing the same are provided. The above-mentioned compounds of the present invention significantly inhibit platelet aggregation induced by arachidonic acid or collagen, thereby preventing diseases caused by platelet aggregation.
Especially myocardial infarction, angina pectoris, ischemic attack after cerebral hemorrhage,
It can be used as a preventive agent for thrombosis involving platelet aggregation, such as cerebral infarction. 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.

Claims (1)

[Claims] 1 General formula () A pyridine derivative represented by (wherein R is a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms). 2 General formula () A platelet aggregation inhibitor containing a pyridine derivative represented by the formula (wherein R is a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms).