JPS6048987A - Pyrazinecaroxylic acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The alkylpyrazine-6-carboxylic acid alpha-tocopheryl ester of formula I (R1 and R2 are H or 1-6C alkyl). EXAMPLE:2-Methylpyrazine-6-carboxylic acid alpha-tocopheryl ester. USE:A remedy for hyperlipemia. It can be administered orally without causing the side effects such as gastritis even by the continuous administration for a long period, and has high safety. Dose: 10-100mg/kg-wt. PREPARATION:The alkylpyrazine-6-carboxylic acid of formula II or its reactive derivative is made to react with the alpha-tocopherol of formula III in an inert solvent, preferably methylene dichloride, chloroform, etc. optionally in the presence of a dehydrative condensation agent such as dicyclohexyl carbodiimide, at 0- 20 deg.C for 15-25hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyrazinecarboxylic acid derivative, a therapeutic agent for hyperlipidemia containing the pyrazinecarboxylic acid derivative as an active ingredient, and a method for producing the new compound.
More specifically, the present invention relates to a novel pyrazinecarboxylic acid derivative that has an extremely effective and long-lasting therapeutic effect on hyperlipidemia without causing side effects, and a method for producing the same.

Arteriosclerosis is an important arterial lesion mainly seen in adults, in which lipids such as cholesterol or proteins such as fibrin enter the arterial walls, causing them to thicken, become hard, and lose elasticity. It refers to a state in which the lumen is narrowed. The cause of the deposition of these substances within the arterial wall is not always clear, but it is believed that a diet rich in lipids promotes their appearance, areas of the artery that contract and relax rapidly, areas with relatively rapid blood flow, and trauma and inflammation. It is recognized that the appearance rate is high in areas affected by . Atherosclerosis, in particular, is known to appear in areas where vascular cynic cells have been damaged, and cholesterol present in low-density lipoproteins in plasma is deposited within the vascular wall, causing thickening of the vascular wall. It is allowed to go.

Such circulatory disorders caused by arteriosclerosis can lead to high blood pressure, impaired blood flow, and decreased function of organs and tissues such as the kidneys and heart.Also, blood vessel walls become brittle, which can lead to cerebral hemorrhage.

Therefore, in order to prevent the onset of circulatory disorders due to arteriosclerosis, it is important to prevent damage to vascular iron cells and to lower plasma lipids.

In order to prevent arteriosclerosis caused by lipid deposition, attempts have been made to administer unsaturated fatty acids such as linoleic acid, lilunic acid, and eicosabenitaenoic acid, or to administer various drugs.

Among drugs, α-tocopherol is known to have a peripheral vasodilator effect and is recognized as a good therapeutic agent for frostbite and the like. In addition, 3-methylpyrazine-4-oxide-6-carboxylic acid is
As reported in Publication No. 353.84, 3-methylpyrazine-4-oxide-6-carboxylic acid is known to have a therapeutic effect on lipemia. However, 3-methylpyrazine-4-oxide-6-carboxylic acid is Since it is administered in the form of a drug, it has the disadvantage that if it is continuously taken, gastrointestinal disorders such as gastritis appear as side effects, and it is difficult to administer large amounts or continuously.

The present invention was completed in view of these points, and
A novel compound that is safe even when administered continuously over a long period of time and has an excellent therapeutic effect on hyperlipidemia, a therapeutic agent for hyperlipidemia containing this new compound as an active ingredient, and the above-mentioned novel compound. The purpose is to provide a method for producing compounds.

The novel compound according to the present invention, which has no side effects even when administered continuously over a long period of time and has an excellent therapeutic effect on hyperlipidemia, has a chemical structure represented by the following general formulas (I) and (IT). It is a compound of

(a) General formula CI) H3 [wherein R1 and R2 are a hydrogen atom or an alkyl group of 01 to 6]. ] Alkylpyrazine-6-carboxylic acid-α- represented by
Tocopheryl ester.

(b) General formula (II) [In the formula, R15R2 is a hydrogen atom or an alkyl group of 01 to 6. ] Alkylpyrazine-4-oxide-6-carboxylic acid-α-tocopheryl ester represented by:

The pyrazinecarboxylic acid derivative represented by the general formula (1) is an alkylpyrazine derivative represented by the following general formula (Ill).
It is produced by reacting 6-carboxylic acid or a reactive derivative thereof with α-tocopherol represented by the following structural formula (IV).

General formula (III) [wherein R1 and R2 are a hydrogen atom or an alkyl group of 01 to G]. ] Structural formula■ In addition, the pyrazinecarboxylic acid derivative represented by the general formula (1) is an alkylpyrazine derivative represented by the following general formula (V).
It is produced by reacting 4-oxide-6-carboxylic acid or a reactive derivative thereof with α-tocopherol represented by the above structural formula IJV).

General formula (V) ↓ [In the formula, R1 and R2 are a hydrogen atom or an alkyl group of 01 to 6. ] To produce the novel compound represented by the general formula CI) according to the present invention, as described above, the structural formula [■] is added to the alkylpyrazine-6-carboxylic acid represented by the general formula (I) or a reactive derivative thereof. α-Tocopherol represented by is reacted, and this reaction is carried out as follows.

The esterification reaction between alkylpyrazine-6-carboxylic acid or alkylpyrazine-4-oxide-6-carboxylic acid and α-tocopherol is carried out using an inert solvent used in a normal esterification reaction, that is, an aromatic hydrocarbon such as benzene. , toluene, xylene, halogenated hydrocarbons such as methylene dichloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, hexachloroethane, cyanide hydrocarbons such as acetonitrile, propionitrile, dialkyl substituted fatty acid amides such as dimethyl It can be carried out in porumamide\diethylformamide, in alkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide, and in ethers such as diethyl ether, dipropyl, diisopropyl ether, methyl isopropyl ether, anisole, diphenyl ether, tetrahydrofuran. Any solvent may be used as long as it dissolves the alkylpyrazine-6-carboxylic acid and does not interfere with the reaction, but halogenated hydrocarbons are preferred, and methylene chloroform dichloride and carbon tetrachloride are particularly preferred.

The esterification reaction can proceed by contacting the carboxylic acid and phenol with a compound that releases a small amount of hydrogen cations, preferably a mineral acid, but dehydration condensation can be carried out by depriving the carboxylic acid and phenol of one molecule of water to carry out the esterification reaction. Agents may also be used. The dehydration condensation agent has 2 to 6 carbon atoms, particularly preferably 2 carbon atoms.
~4 alkyl chloroformates, and NN′-substituted carbodiimides, such as dicyclohexylcarbodiimide,
Cyclohexyl and morpholinocarbodiimide.
A tertiary amino compound such as a trialkylamine-
Phenylalkylamine and nitrogen-containing heterocyclic compounds such as pyridine, quinoline, etc. relative to carboxylic acid
1.0 equivalent, preferably 0.1 to 1.0 equivalent, may be added to promote the reaction.

When N N'-substituted carbodiimide is used as a dehydration condensation agent, the temperature is preferably 3000 or less, preferably 08 to 200 (1
! for 10 to 30 hours, preferably 15 to 2 hours at a temperature of
After reacting for 5 hours, the inert compound used as a solvent, such as a halogenated hydrocarbon, is separated by distillation, and the remaining target product, tocopheryl ester, is removed by an appropriate method, such as molecular distillation or using an inert solvent. It was synthesized by purification by recrystallization method etc. Next, the pharmacological activity of the thus synthesized alkylpyrazine-6-carboxylic acid or alkylpyrazine, -4-oxide-6-carboxylic acid α-tocopheryl esters will be shown.

As a compound according to the present invention, 2-methyl-pyrazine-6-
Carboxylic acid-α-tocopheryl ester, 3-methylpyrazine-6-carboxylic acid-α-tocopheryl ester,
2-methylpyrazine-4-oxide-6-carboxylic acid-
α-Tocopheryl ester, 3-methylpyrazine-4-
Using oxide-6-carboxylic acid-α-tocopheryl ester, each of these compounds was uniformly emulsified in a 1.5% by weight aqueous solution of polyoxyethylene hydrogenated castor oil (HOD-, manufactured by 60 Nitscol). On the other hand, as a comparative example, nicotinic acid-α-tocopheryl ester was prepared in the same manner as 1.
A homogeneous emulsion in a 5% by weight polyoxyethylene hardened castor oil aqueous solution was used.

S P FJ Wister rat (male, weight 7
5 to 9094 weeks old) were used in a group of 5 animals, and 1
．． A high-cholesterol diet containing 0% cholesterol was fed. At the same time that high-cholesterol diet was started, an emulsion of the compound was forcibly administered into the stomach using a probe once every morning in the morning.

The concentration of the compound in the emulsion is 1 m9/ml to 5 m9/m
1, and the concentration was such that the administered amount of the compound was contained in the administered liquid volume of 10 mlAcg.

One week and two weeks after the start of administration, the animals were allowed to eat at approximately 17:00, and then the carotid artery was cut under light ether anesthesia to collect blood. It was measured using

The results are shown in Table 1.

(Left below) Table 1 Orally administered rice with high cholesterol diet: 1.5
% polyoxyethylene hardened castor extract oil 15% aqueous solution was provided.

Rice: Used as a comparative drug.

Alkylpyrazine-6-carboxylic acid-α- according to the present invention
As shown in Table 1, tocopheryl ester and alkylpyrazine-4-oxide-6-carboxylic acid-α-toco7eryl ester have excellent therapeutic effects on lipemia, and can be administered continuously over a long period of time. It has been proven to be extremely safe, with no side effects such as gastritis observed.

Pyrazine carboxylic acid derivative according to the present invention, pyrazine-4
-The oxide carboxylic acid derivative can be administered orally. The dosage of this compound is 1 to 50.0 m/g, preferably 5 to 300 m/g, and more preferably 10 m/g/body weight.
It is desirable that it be about 100rn.

The pyrazinecarboxylic acid derivative according to the present invention can be used as a therapeutic agent for hyperlipidemia in the form of a capsule, tablet, granule, or emulsion, for example. In this case, excipients include starch lactose, sucrose, methylcellulose, carboxymethylcellulose, sodium alginate, calcium lactate, magnesium aluminate metasilicate, calcium hydrogen phosphate, aluminum silicate, kaolin, glucose, microcrystalline cellulose, polyvinylpyrrolidone, colloid. silica gel,
Hydroxypropyl starch or the like can be used.

As the binder, agar-argin, dextrin, dextrose, gelatin, lactose, glucose, polyvinylpyrrolidone, sucrose, polyvinyl alcohol, polyvinyl acetate, microcrystalline cellulose, hydroxypropylcellulose, etc. can be used.

As the lubricant, sodium benzoate, boric acid, starch, talc, love wax, stearic acid, aluminum stearate, magnesium stearate, aluminum stearate, etc. can be used.

Emulsifiers include gum arabic, tragacanth, pectin, sodium pectate, saponin, sodium alginate, lecithin, gelatin, casein, egg yolk, lanolin, bentonite, kaolin, aluminum hydroxide,
Magnesium hydroxide, sodium soap, potassium soap,
Triethanolamine oleate, triethanolamine stearate, Rho 1 oil, sodium lauryl sulfate, polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, sorbitan monofatty acid ester, polyoxyethylene sorbitan alkyl ester, etc. may be used. I can do it.

Next, the method for producing the compound according to the present invention will be explained with reference to Examples.

Example 1 5 parts of 2-methyl-pyrazine-6-carboxylic acid, 16 parts of α-tocopherol and 6 parts of dimethylaminopyridine were dissolved in 100 m of dichloromethane.

10.2 dicyclohexylcarbodiimide in the above solution.
A solution of 9 dissolved in 100 ml of dichloromethane was added under stirring and maintained at QOa for 5 hours.

- After standing at room temperature overnight, the precipitated crystals of dicyclohexyl urea were collected, washed successively with 5% hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and after 1 hour, the solvent was distilled off. The residue was purified using silica gel column chromatography to obtain 15.39 oily 2-methyl-pyrazine-6-carboxylic acid-α-tocopheryl ester.

Engineering R (cm”) 723.800, 920, 10
35.1152.1182.1240.1280.13
40, 1380-.

1410.1465.1530.1580, 1650
.

1740.1762.294O NMR (ppm) 0.8.0.9.1.25.2.0
8.267.8.62.9.32 Elemental analysis value 0: 71.83% H: 11.40%
N: 5.91%〃 Theoretical value c: 72.10
%H: 11.59% N: 6.00%Example 2 2-Methyl-pyrazine-6-carboxylic acid 5 in Example 1
5 g of 3-methyl-pyrazine-6-carboxylic acid instead of g
The procedure was carried out in the same manner as in Example 1 except that 14.9 g of oily 3-methyl-pyrazine-6-carboxylic acid-α-tocopheryl ester was obtained.

Engineering R7max 405.723.800.91g, 10
35.1150, 1180, 1240, 1280
, 1340.

1380, 1410, 1465, 1530,
1580.1650, 1740, 1762, 29
4ONMR (ppm) O18,0,9,1,25,2
,08,2,68 elemental analysis value C! : 72.32%
H: 11.41% N: 6.34% theoretical value 0
: 72.10% H: 11.59% N: 6
．． 00% Example 3 2-Methyl-pyrazine-6-carboxylic acid 5 in Example 1
2-methyl-pyrazine-4-oxide-6- in place of g
The procedure was carried out in the same manner as in Example 1 except that carboxylic acid 5 was used.
Oily 3-methyl-pyrazine-4-oxide-6-carboxylic acid-α-tocopheryl ester 15.59 wop+
t,=.

Engineering R (cm-) 640.722.740.781.8
51.880.967.1015.1100.1183
．． 1230.1312.1330.1362.1472
．． 1530.1600.1762.2940□ NMR
(ppm) 0.85.0.93.1.28.2.05
．． 2.57.8.65.9.01 Elemental analysis value 0: 69.98% H: 10.98
% N: 5.51% Theoretical value 0:, 69.71%
H+ 11.20% N: 5.81% Example 4 2-Methyl-pyrazine-6-carboxylic acid 5 in Example 1
3-methyl-pyrazine-4-oxide-6- in place of g
The procedure was carried out in the same manner as in Example 1 except that carboxylic acid 5 was used.
14.39 pieces of oily 3-methyl-pyrazine-4-oxide-6-carboxylic acid-α-toffheryl ester were obtained.

Engineering R7max (cs-1) 590 (w) 640 (w)
682 (w) 722 (w) 738 (m) 780
(m) 850 (m) 878 (m) 965
(m) 1010 (s) 1100 (s) 1180
(s) 1230 (s) 1310 (s) 132
5 (s) 1360 (s) 1470 (s) 15
30(m), 1600(s) 1760(a) 2
940(s) Elemental analysis value 0: 69.34% H:
10.89% N: 6.15% Theoretical value 0: 69
．． 71%H: 11.20%N: 5.81%N
MR (ppm) 0185.0.93.1.28.2.
05.2.57.8.65.9.01

Claims (1)

[Scope of Claims] (]) Alkylpyrazine-6-carboxylic acid-α-tocopheryl ester represented by the following general formula (1) 0 [In the formula, RI and R2 are hydrogen atoms or alkyl groups of 01 to 6] It is. ] (2) Alkylpyrazine-4-oxide-6-carboxylic acid-α-tocopheryl ester represented by the following general formula (1). H3 [In the formula, R1 and R2 are a hydrogen atom or an ai-6 alkyl group. ] (3) Alkylpyrazine-6-carboxylic acid or its reactive derivative represented by the following general formula (]11),
Process for producing alkylpyrazine-6-carboxylic acid-α-tocopheryl ester (7) represented by the following general formula (1), which is characterized by reacting α-tocopherol represented by the following structural formula (IV). . General formula (1) [In the formula, R1 and R2 are hydrogen atoms or 01-6 alkyl groups. ] General formula (11) [In the formula, R1 and R2 are a hydrogen atom or an alkyl group of 01 to 6. ] Structural formula (IV) H3 (4) Alkyl-4 represented by the following general formula [v]
The following general formula (Tl
) A method for producing alkylpyrazine-4-oxide-6-carboxylic acid-α-tocopheryl ester. General formula (Tl) H3 [wherein R1 and R2 are a hydrogen atom or an alkyl group of 01 to 6]. ] General formula (V) ↓ [In the formula, R1 and R2 are a hydrogen atom or an alkyl group of 01 to 6. ] Structural formula (IV) H3 (5) A therapeutic agent for hyperlipidemia containing an alkylpyrazine-6-carboxylic acid-α-tocopheryl ester represented by the following bifurcated formula [■] as an active ingredient. General formula (I) H3 [In the formula, 1 and R2 are a hydrogen atom or an alkyl group of 01 to 6.] (6) Alkylpyrazine-4-oxide-6 represented by the following general formula (n) - Hyperlipidemia therapeutic agent containing carboxylic acid-α-tocopheryl ester as an active ingredient.General formula (n) [In the formula, F1 and R2 are hydrogen atoms or 01-6 alkyl groups.]