KR810000382B1 - Process for preparing vincamin-5-pyridoxal phosphate - Google Patents

Abstract

Title compd. (I) was prepd. by reaction of vincamin in the mixt. of H2O and MeOH(50%), and pyridoxal-5-phosphate at 65≰. Thus, 2l MeOH(50%), and 141.75 g (0.4 mol) vincamin in H20 were fed in reactor, stirred and heated to 40≰C. The suspended mixt. was reacted with 106.5 g(0.4 mol) pyridoxal-5-phosphate at 105≰C. The reactant was extracted with MeOH under reduced pressure, removed impurity and dried to give 223 g I(m.p.; 150≰C, yield; 93%).

Description

Preparation of vincarmine-5-pyridoxalphosphate

The present invention relates to a method for producing a novel vincarmine pyridoxal phosphate of the general formula (1).

The novel salts of the present invention are yellow powders, completely soluble in water to form a colorless solution, slightly soluble in ethanol at room temperature, insoluble in chloroform and soluble in dimethylsulfoxide. The novel salt of the present invention has a molecular weight of 601.58, of which 58.92% (weight) is% of vincarmine.

Of particular importance is the fact that the novel salts of the present invention generally have better solubility and more significant therapeutic effects than vincarmine. Tests have shown that the compounds of the present invention are 4-10 times more effective than vincarmine. Moreover, the compounds of the present invention also have some anti-depressive action and are therefore particularly useful for patients suffering from depression syndrome and receiving vincarmine treatment.

The compound of the present invention can be prepared by the present invention by stirring a mixture of bicarmine and pyridoxal-5-phosphate suspended in a mixture of water and ethanol (50%) at about 65 ° C. The obtained stirred solution is lyophilized to obtain vincarmine pyridoxal phosphate in high yield.

The present invention is explained in more detail by the following examples.

EXAMPLE

Into a reactor equipped with a stirrer and a warmer, 2 liters of a methanol solution (50%) and 141.75 g of vincarmine (0.4 mol) dissolved in water were added, stirred, and warmed to 40 ° C to pyridoxal-5-phosphate monohydrate. 106.5 g (0.4 mol) was added. The mixture was heated to 105 DEG C while stirring to obtain a clear solution in which methanol was extracted at 35 DEG C under reduced pressure. The remaining solution was filtered to remove impurities and the solution was lyophilized to yield 223 g of yellow powder. Melting point: 150 ° C (pasty melting), yield: 93%, the analysis results are consistent with the molecular formula C ₂₉ H ₃₆ N ₃ O ₉ P.

Toxicity was determined by administering a compound of the present invention to mice. The oral dose of LD50 was 1.4 g / kg while the intraperitoneal dose (I.P.) was 0.380 g / kg. Compared to vincarmine, the compound of the present invention showed a little more toxicity upon oral administration, but much less upon intraperitoneal administration.

Various pharmacological tests were carried out with the novel compounds of the present invention.

Action on per-hypocapno-anemia cerebral syndrome (dog)

As a result, 0.42 mg / kg of the compound of the present invention (theoretically equivalent to 0.25 mg / kg of vincarmine) was administered intravenously while 1 mg / kg of vincarmine was administered intravenously. As a result, it was found that the vincarmine pyridoxal phosphate of the present invention was four times more effective than the same amount of vincarmine alone.

Actions on functional coronary insufficiency induced by na-pitressine (dog)

The novel salts of the present invention in the test showed a very useful action in the treatment of blood circulation and metabolic disease (dose) 1 mg / kg, whereas vincarmine showed no activity at all.

Action on Developmental Disorders Caused by Multi-Cerebral Hypotension (Rabbit)

In the test, the compound of the present invention showed a very good effect when administered 50-100 μg / kg, and vincarmine showed the same result when administered 1000 μg / kg (intravenously). These tests showed that the action of vincarmine pyridoxalphosphate was at least 10 times that of vincarmine.

Ra-unilateral Cerebral Edema Caused by Electroencephalopathy Disease (Rabbit)

The novel salts of the present invention and vincarmine were administered at various doses. The dose of vincarmine pyridoxalphosphate 4.2 mg / kg (eg, 2.5 mg / kg of vincarmine) showed the same effect as the administration of the vincarmine base 10 mg / kg. In this test, the activity of vincarmine pyridoxalphosphate was also four times better than that of vincarmine.

When the compound of the present invention is orally administered, 5 mg of vincarmine pyridoxal phosphate is preferably administered as enteric skin tablets. At the time of injection, a solution in which 3 mg of the compound of the present invention lyophilized in 2 ml of isotonic solution is placed in an opaque vial.

For oral administration, the daily dose is 2-8 tablets or 1 or 2 bottles per day for intravenous administration.

Claims (1)

As described above, the vincarmine-5-pyri of formula (1) characterized by reacting the vincarmine suspension and 5-pyridoxal phosphate suspended in a water and ethanol mixture at 65 ° C in a stoichiometric ratio. Preparation of poisonous phosphate.

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