JPH06102671B2 - Pharmacologically active salt derivative of 3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde phosphate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a novel pharmacologically active salt derivative, namely 4- (1-pyrrolidinyl) -1- (2,4,6-trimethoxyphenyl) -1-butanone 3- having the following structural formula. Hydroxy-
It relates to 5- (hydroxymethyl) -2-methylisonicotinaldehyde-5-phosphate.

The present invention also relates to a method for producing the above salt derivative (I) and a related pharmaceutical composition.

The salt derivative (I) is 3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-5-.
It is obtained by salting phosphoric acid with 4- (1-pyrrolidinyl) -1- (2,4,6-trimethoxyphenyl) -1-butanone.

The pharmacological activity of the above two starting materials is known. In particular, 4- (1-pyrrolidinyl) -1-in the cerebral ring for the treatment of consciousness disorders and the treatment of symptoms attributed to brain trauma
The pharmacological activity of (2,4,6-trimethoxyphenyl) -1-butanone hydrochloride (Buflomedil) is known, and its peripheral vasodilatory properties are also known.

For 3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-5-phosphate (Piridoxal phosphate),
Known as the enzyme cofactor vitamin.

It may be foreseen to obtain a drug that is vasodilatory by the reaction of these two substances and at the same time has vitamin activity useful in the treatment of the pathological conditions of the elderly.

On the contrary, the inventors of the present invention unexpectedly found from the above reaction that a drug having an antithrombotic effect added to the vasodilating property of unmodified bafromedil could be obtained.

It should be noted that none of the agents currently used exhibit a combination of antithrombotic and peripheral vasodilatory properties.

Therefore, the salt derivative (I) of the present invention exhibits platelet aggregation-inhibiting property and vasodilatory property in one molecule, and therefore has a broader and more complete efficacy than baflomedil and is clinically characterized by peripheral injury. It relates to treating symptoms, especially the clinical symptoms that are common in the elderly.

Furthermore, the salt derivatives (I) of the present invention show another advantage of greater solubility in water compared to bafromedil, which is advantageous for bioavailability and allows parenteral and rectal administration.

The salt derivative (I) of the present invention is prepared by reacting 3-hydroxy-5- (hydroxymethyl) -2-methyl-isonicotaldehyde-5-phosphoric acid with 4- (4-) in a reaction medium consisting of an organic solvent in which (I) is soluble. (1-pyrrolidinyl) -1- (2,4,6-trimethoxyphenyl) -1-butanone, and then (I) is crystallized in an insoluble organic solvent. . The characteristics and advantages of the above salt derivative (I) and the related production method will be well shown from the following description of the preferred embodiment.

Regarding the production of the above salt derivative (I), 3-hydroxy-5
-(Hydroxymethyl) -2-methylisonicotinaldehyde-5-phosphate is pre-released from its monosodium salt in a column packed with a strong base ion exchange resin activated as chloride. The aqueous solution of 3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-5-phosphoric acid thus obtained was concentrated and dried to give a yellow oily residue which was treated with a small amount of absolute ethanol. Redisperse 3 times to remove water. Finally, the residue is treated with anhydrous ethyl acetate to give the product, which is filtered and dried in a vacuum desiccator.

The 3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-5-phosphoric acid thus obtained is dispersed in methanol in which it is insoluble and solid 4- (1-pyrrolidinyl) -1- (2,4,6-Trimethoxyphenyl) -1-butanone is added with stirring. The reaction mass is then heated to a temperature in the range of 40 ° C. to solvent reflux temperature, preferably in the range of 45 ° C. to 55 ° C., to give a clear yellow solution which precipitates even after cooling. Does not happen. The above solution was concentrated to completely remove methanol and then redispersed with ethyl ether to obtain the above salt derivative (I) as crystals after shaking, which was filtered, washed with ethyl ether and dried in a vacuum desiccator. To do.

The salt derivative (I) obtained is a yellow crystalline powder, is very soluble in water and aliphatic alcohols, but insoluble in ethyl ether. Crystallization of the crude product is carried out with a mixture of aliphatic alcohol and ethyl ether until the desired purity is reached. The yield of each crystallization is about 90%.

The product was characterized by X-ray diffractometry, IR, UV and NMR spectroscopy and melting and pH measurements.

Crystallographic analysis by X-ray diffraction shows that the product is a single substance derived from the formation of an ionic bond between the two reactants.

In Table 1 below, characteristic peaks (diffraction angle θ and interplanar distance d), λ _Cu = 1.5418Å and relative intensity Irel are shown for the salt derivative (I) of the present invention, and for comparison purposes. Two reactants, baflomedyl and pyridoxal phosphate, are shown.

From this table, it can be seen that the characteristic peak of the reactant did not exist in the above salt derivative (I), and conversely, when the reactant was made into a salt, a new crystal phase was obtained.

In addition, the IR absorption spectrum performed in the Jawl shows characteristic absorption peaks at the following wavelengths.

2720Cm ^-1 aldehyde -CH absorption bands 1,695 cm ^-1 absorption band ketone carbonyl 1665 cm ^-1 aldehyde carbonyl absorption band 1460 cm ^-1 of the absorption spectrum of the absorption band ethanol solution of 1375 cm ^-1 aromatic double bonds 283 Shows absorption spectrum at ± 1 nm.

The following signals are detected in the NMR spectrum.

2.1s 3H (CH ₃ ) Pyr 3.7s 9H (OCH ₃ ) B 3.9s 3H (1CH ₃ ) 5.95s 2H (aromatic) B 4.16q 1H (1CH) 7.22s 1H (aromatic) P 7.95s 1H (aromatic) Group) P 7.16 ~ 8.23m 10H (aromatic) 10.4s 1H (-CH of aldehyde) P 10.5s 1H (1NH) Melting point measured by Kofler block is 77 ℃ ~ 80
Well specified at ° C.

The pH measured in a 2% aqueous solution is 7.0.

A pharmaceutical composition comprising the above salt derivative (I) of the present invention as an active ingredient, for oral and rectal administration, in combination with a conventional excipient and a conventional pharmaceutical medium, and an injection method, because of its large solubility in water. All pharmaceutical forms for both topical methods can be formulated.

The following examples are given for the purpose of illustrating, without limitation, the method of the present invention.

Example 1 Approximately 700 ml (hydrous) strong base ion exchange resin was activated in a column with 5% HCl solution and then the resin was washed to remove excess hydrochloric acid. Then, add 3-hydroxy-5 to the column.
A 20% solution of 50 g of-(hydroxymethyl) -2-methyl-isonicotinaldehyde-5-phosphate-sodium was passed through. Finally, the substance inside the column was washed with water to a neutral pH. 3-Hydroxy-5- (hydroxymethyl) -2-methyl-isonicotinaldehyde-5 thus obtained
-The phosphoric acid was concentrated to an oil which was re-dispersed 3 times in approximately 3 times the absolute weight of the residue in absolute ethanol.
After removal of water, the residue was redispersed in 200 ml of anhydrous ethyl acetate, in which a yellow precipitate was formed under shaking, which was filtered under reduced pressure.

The filtrate was washed with anhydrous ethyl acetate and dried under reduced pressure.

3-hydroxy-5- (hydroxymethyl) for salt formation
2-Methylisonicotinaldehyde-5-phosphate (C ₈
42.5 g (yield 85%) of H ₁₀ NO ₆ P, molecular weight 247.156) were obtained.
3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-5- in 380 ml of methanol
Disperse phosphoric acid, and always under stirring at room temperature under stirring 4- (1-pyrrolidinyl) -1- (2,4,6-trimethoxyphenyl)-
56 g of 1-butanone (C ₁₇ H ₂₆ NO ₄ , molecular weight 307.4) was introduced.

The above system was heated at 50 ° C. until a single phase was obtained. 3-
Considering that hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-5-phosphate is insoluble even at high temperature, it is certain that salt formation occurred.

The resulting solution was cooled and concentrated under reduced pressure until the solvent in which the solubility of the salt derivative (I) interfered with crystallization, ie methanol, was completely removed. After removing the methanol, the residue was dispersed in 480 ml of ethyl ether,
Then, it was filtered and dried under reduced pressure in a desiccator at room temperature.

4- (1-Pyrrolidinyl) -1- (2,4,6) -trimethoxyphenyl-1-butanone 3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-5-phosphate (C ₂₅ H ₃₆ N ₂ O ₁₀ , molecular weight 554.576) 7
6.8 g was obtained with an active salt formation yield of 80%. The salt derivative (I) obtained had a melting point of 77-80 ° C.

Subsequent crystallization from methanol-ethyl ether gave the desired purity product.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location A61K 31:40) 9454-4C (72) Inventor Paolo Colombo Italy, Pavia, Via Magenta 12 (56) References Japanese Patent Publication No. Sho 48-11934 (JP, B1) CHEMICAL ABSTRACT S, 97 [19] (1982) P. 60 CHEMICAL ABSTRACT S, 69 [11] (1968) P. 3933

Claims (1)

[Claims] 1. The following general formula Represented by 4- (1-pyrrolidinyl) -1- (2,4,6
-Trimethoxyphenyl) -1-butanone A pharmacologically active salt derivative consisting of 3-hydroxy-5- (hydroxymethyl) -2-methylisonicotinaldehyde-phosphate.