JPS59199674A - Pyridoxine derivative and blood platelet coagulation inhibitor containing the same - Google Patents

Abstract

NEW MATERIAL:A pyridoxine derivative of formula I (R is acyl derived from triene or pentaene-higher fatty acid). EXAMPLE:2-Methyl-3-hydroxy-4-hydroxymethyl-5-(9, 12, 15-octadecatrienoyl)oxymethylpyridine. USE:Blood platelet coagulation inhibitor. PREPARATION:The reaction between a triene- or pentaene-higher fatty acid and isopropylidene pyridoxine is conducted in the presence of a condensation reagent such as N,N'-dicyclohexyl carbodiimide, then the product is hydrolyzed to form the compound of the formula 1.

Description

DETAILED DESCRIPTION OF THE INVENTION 11. Background Technical Field of the Invention The present invention relates to pyridoxine derivatives and platelet aggregation inhibitors using the same. The pyridoxine conductor 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. Platelet aggregation is also said to be involved in cancer metastasis, and the compounds of the present invention also have a preventive effect on cancer metastasis.

Prior Art Triene higher fatty acid 9,12.15-octatecatrienoic acid (α-lylunic acid is an essential fatty acid, 8.
11.14-Eicosatrienoic acid is a precursor of glosstaglandin E1 and is an important compound. For pentaene higher fatty acids, 5, 8.11, 14.17
- Niicosapentaenoic acid is contained in large amounts in fish oil.
LDL is getting worse.

The present inventors synthesized various esters of pyridoxine and pentaene higher fatty acid esters of pyridoxine, and as a result of intensive research on their pharmacological activity in 7-year-olds, they found that they exhibited excellent platelet Sfe* inhibitory effects. The present invention has been completed.

(2) Purpose of the present invention The object of the present invention is to provide a platelet aggregation inhibitor using a triene higher fatty acid ester of pyridoxine and a pentaene higher fatty acid ester of bi-1 nodoxin, which have a platelet aggregation inhibiting action. Thrombosis, such as acute myocardial infarction and cerebral thrombosis, has become the most common adult disease in recent years, and pharmacology to effectively prevent these diseases is needed.
The town's departure is strongly desired.

A further object of the present invention is to provide a triene higher fatty acid ester of pyridoxine and a pentaene higher fatty acid ester of pyridoxine, which are useful as an agent for preventing translocation.

Detailed Description of the Invention The first object of the present invention is to use a pyridoxine derivative represented by the general formula % (where I't is an acyl group derived from a triene higher fatty acid l or a pentaene higher fatty acid). achieved.

Preferably, R1d14 to 20 carbon atoms of the acyl group b''Eh from the triene high N && vj acid.

Further, R of the acyl group derived from the pentaene higher fatty acid preferably has 18 to 22 carbon atoms.

The second object of the present invention is to provide a platelet aggregation inhibitor using a pyridoxine inducer represented by the formula (wherein R is an acyl group derived from a triene higher fatty acid or a pentaene higher fatty acid). achieved by.

In the pyridoxine derivative represented by the above general formula provided by the present invention, R is defined as a triene, a fatty acid, an acyl group, and an acyl group represented by I.
5. A stone in which the 3@ chain has a 5" di-stop bond in the carbon chain, the hydroxyl group is removed from the fat cough, and the acyl group derived from the pentaene aliphatic acid is derived from the carbon face. It is a group obtained by removing the hydroxyl group from a fatty acid having five cis-conductor double bonds.Among such pyridoxine derivatives, the most preferred one is 2-methyl-3-hydroxy-4-
Hydroxymethyl-5-(9,12,1,5-oftatetrienoyl)oxymethylbilysine, 2-methyl-
3-hydroxyl 4-hydroxymethyl-5-(s,
8.11,14. ．． 17-Nicobentaenoyl)oxymethyl biricin can also be prepared as Ml.

The ester represented by the above formula of the present invention can be obtained by reacting triene higher fatty acid or benquene higher fatty acid and impropylidene pyridoxine in the presence of a condensing agent, followed by hydrolysis with an acid. Examples of condensing agents include N,N'-cyclohexylpodiimide, 2-
Examples include chloro0-1-methylpyridinium p-to-jbenesulfonate. As the acid used for hydrolysis, aqueous acetic acid is preferably mentioned.

The pyridoxine derivative of the present invention is used as a thrombosis preventive agent or a cancer metastasis preventive agent, and the daily dose for adults is approximately 50
~1500 ml, administered in 1 to 3 doses if necessary. Oral administration is preferable, but intravenous injection is also possible.

The compound 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, starch, etc. Yoko sugar, lactose, talc, stearin powder Magui column, etc. can be opened. The compound of the present invention can be used as an oil suspension in addition to the solid formulation described in 2.

It can be made into a syrup-like powder, and α-tocopherol and α-tocotrienol can be added to the drug 1b for stabilization purposes.

The compound of the present invention is wrapped in phocyclodextrin (・phosphorus, etc.)
L. It can also be stabilized.

Next, menu examples and test examples will be shown, and A. Invention 4': More specifically, sushi. I will clarify.

EXAMPLE In an argon stream, α-lino J-k (490~) was dissolved in 20 ml of anhydrous nonaref chloride, and improvilitene bilidoki/n (369 m9) known in the literature was dissolved.

N,N'-dicyclohexylcarbodiimide (390~
],4-dimethylaminopyridine (1 shri) were added one after another, and the mixture was reacted at room temperature for 2 hours. Petroleum ether (15 m6) was added to the reaction solution, stirred for 15 minutes, and then filtered. The P solution was concentrated under reduced pressure to obtain a residue of 940 μm. This product was subjected to 7-silica gel column chromatography, and methylene chloride-
The desired acetonide (692 q) was obtained from the acetic acid ethyl ester (4:1) i4 output. The physicochemical data of this product are as follows.

Engineering R shi11'σ-': 1738, 1603
, 1567, 865.

NMR (CDC73)δ(pPm):
0.97 (3H, t.

J=7.5Hz), 1.56(6H,s), 2.3
7 (3H.

S), 4.86(2H,s), 4.93(
2H,s).

7, 97 (, tn, s).

The above Filj acetonide (640 my) was dissolved in 80% aqueous acetic acid (3M) and stirred at 60°C under argon for 30 hours. After the reaction was completed, the reaction solution was diluted with water, neutralized with sodium carbonate, extracted with ether, and washed with water.

After drying the Glauber's salt, the solvent was distilled off to obtain residue 547. This was subjected to column chromatography using Sephatex LH-20 (309), and 2-methyl-3-hydroxy-4-hydroxymethyl-5-(9) was extracted from the methylene chloride eluate.

12,15-octatecatrienoyl)oinemethylhyridine (338-) was obtained. The physicochemical take of this product is as follows.

IRv2′::”cm′: 1.730
, 164.2, 156ONMR (CDC L3
) δ(1)T)m) : 0.90 ( 31( ,
t.

J=7.5Iiz), 2.40(3T(,s
), 7.85 (LH.

S) Example 2 In a stream of alcon, 5, B, 11, 14, 17-nicoben chloride (396~) was dissolved in 1.5 ml of anhydrous mebulene chloride, and 1 ml of isophylchloride was added.

Lidoxin (274m?), N,N''-di/clofodiimide (297m?), 4-dimethyl7minobirin (], omp) C)x+ *-
, and reacted at room temperature for 3 hours. Add n-pentane (
Add 15mi and stir for 5 minutes then l'M!・\L,,δ
- "After combining the liquids, calculate the solvent under reduced pressure, 9), '
Ii706m? is published. The residue was subjected to silica gel column chromatography using methylene chloride-ethyl acetate (4:1). :． b The desired acetate compound (516Tnr) was obtained. The physicochemical take of this product is as follows.

ClIC13-1・IRν,, xcm, 1730, 160
0, 141ONMR (CDC73) δ (ppm)
: 0.97 (3H, t.

J=7.5Hz), 1.56 (6H, s), 2.42
(3H.

s ), 4.87 (2H, s), 5.00 (2I (,
s) 8.01 (ll-1, S), the above atonide V form (510 my) was dissolved in 80% aqueous acetic acid (
25-) and stirred at 60° C. for 28 hours under argon. After the reaction is complete, pour the reaction solution into ice water 100-N
After neutralization with a2CO3 and extraction with ether, washing with water and drying with Glauber's salt, the solvent was distilled off to obtain a residue of 416 square meters. This was subjected to column chromatography using Sephatex LH-20 (30f), and the methylene chloride eluate was separated from 2-methyl-3-hydroxy-4-hydroxymethyl-
5-(5,8,11,14,17-nicosapentaenoyl)oxymethylpyridine (251). The physicochemical data of this product are as follows.

f RvcB"rrn-": 1725, 1
380, 1290J near, 6H2), 2.30 (
21-1, t, J=7.3l-Iz), 2.43
(31(,s), 4.98(2n,s),
5.04 (2H.

S), 7.85 (IH, S), 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 solution, 1'4). 1. Separate the heart from the blood and collect platelet-rich plasma (P
RP: 505 cells/μl).

250 μt of the PRP was placed in a cuvette, heated in a 37°C constant temperature bath for 2 minutes [)4”, and diluted with the sample bath solution (1.4
After adding 20 µt of M emenol common solution with 1 ml of diluted saline solution - physiological saline (1:3) and incubating for 3 minutes, GI: 10 µt + L of arachidonic acid (50 µM), which is an attracting agent. In addition, platelet aggregation was measured. 2-Methyl-3-hydroxy-4-hydroxymethyl- on platelet aggregation induced by arachidonic acid
The 50% inhibition temperature of 5-(9,12,15-octatecarryenoyl)oxymethylpyridine is 3.8XIF'M
Adashi, 2-methyl-3-hydroxy-4-hydroxymethyl-5-(5,s.

The 50% inhibitory concentration of oxymethylpyridine (11, 14, 17-nicosahentaenoyl) is 4.4X10'M
Met.

(2) Effects of the Invention The present invention provides a triene higher fatty acid ester of pyridoxine and a pentaene higher fatty acid ester of pyridoxine, which have a thrombosis preventive effect and a cancer metastasis preventive effect.

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 coagulation of saliva, 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, according to the present invention, a method for producing the above-mentioned higher fatty acid pyridoxine ester is provided.

Procedural amendment filed June 1980 by Kazuo Wakasugi, Commissioner of the Japan Patent Office1, Indication of the case, Patent Application No. 73312 of 1982, Title of the invention: Pyridoxine derivatives and platelet aggregation inhibitors using the same3, Person making the correction - 4. Correct the date of the correction order by +dt to spontaneous rPRP: 5 x 10' pieces/μnJ.

Claims (1)

[Scope of Claims] (A pyridoxine derivative represented by the general formula (where R is an acyl group derived from a triene higher fatty acid or a pentaene higher fatty acid). (2) R of an acyl group derived from a triene higher fatty acid. is 14 to 20 carbon atoms.
The hyridoxin analyte according to claim 1, wherein 18 to 22 carbon atoms. (4) Blood thinning & 8X i) inhibitor using a pyridoxine conductor represented by the general formula (wherein R is an acyl group derived from a triene higher fatty acid or (d) a pentaene higher fatty acid). (5) R of acyl group derived from triene higher fatty acid
The platelet aggregation inhibitor using a pyridoxine agonist according to claim 4, wherein 14 to 20 carbon atoms. (6) R of the aryl group derived from pentaene higher fatty acid has 18 to 22 carbon atoms '+I revision 31'
2. A platelet aggregation inhibitor using pyridoxine UQ 28 according to item 4.