JPS603078B2 - Derivatives of vincamic acid hydrazide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a hybrid hydrazide of vincamic acid and pyridinecarboxylic acid and its acid salts.

The invention also relates to processes for the preparation of said hydrazides and addition salts and their therapeutic applications. Vincamine, the important alkaloid of L. vinucinica, is known to exhibit valuable pharmaceutical properties.

In particular, while it has an antihypertensive effect, it also has an undesirable secondary effect common to most antihypertensive agents. Vincamine is used as a drug, ie essentially as a cerebral oxygenator and a microvascular vascular regulator. However, since the duration of action of vincamine is short, with a view to overcoming this drawback and/or improving the pharmaceutical properties of the alkaloid, acid addition salts (particularly pamoate) or vincanol (see French Patent Specification No. 1 No. 6697) have been proposed. Alternatively, attempts have been made to prepare semi-synthetic products such as amides of avovincamic acid. The present invention is based on the surprising discovery that a hybrid hydrazide of vincamic acid and pyridine carboxylic acid has pharmaceutically valuable properties.

This hydrazide property exists even though vincamic acid hydrazide, which is a base for these and is used as an intermediate in the synthesis of vincanol, does not have such properties. The expression pyridinecarboxylic acid as used herein refers to 2-
It means pyridinecarboxylic acid (picolinic acid), 3-pyridinecarboxylic acid (nicotinic acid) or 4-pyridinecarboxylic acid (isonicotinic acid). The present invention therefore provides compounds of the formula which are hybrid hydrazides of vincamic acid and pyridinecarboxylic acid.

Acid addition salts thereof are also within the scope of this invention. These new compounds are particularly suitable for use as mild antihypertensive agents and vasodilators to treat cerebral and peripheral vascular insufficiency.

Thus, the present invention also provides pharmaceutical compositions that are particularly useful for treating cerebrovascular insufficiency. The composition comprises at least one hybrid hydrazide of formula (1) or a non-toxic acid addition salt thereof in association with physiologically acceptable excipients. A representative compound of the present invention is a hybrid hydrazide of vincamic acid and nicotinic acid of the following formula.

Compounds of formula (1) can be prepared by reacting a vincamic acid hydrazide of the formula with a halide, anhydride or ester of pyridinecarboxylic acid in an inert anhydrous solvent and, if desired, reacting the resulting reaction product by known methods. Can be converted to acid addition salts.

In a preferred method of preparation, the hydrazide of formula (0) is dissolved in an inert anhydrous solvent and then reacted with excess pyridine carboxylic anhydride.

In this case, about 1 mol per 1.5 mol of pyridinecarboxylic anhydride
It is convenient to use mol of hydrazide and the reaction temperature is 3
0°C, sometimes equal to 30°C, and about 15°C
None, preferably 25°C. Suitable inert anhydrous solvents that can be used include pyridine, triethylamine and dimethylformamide.

The reaction time is generally greater than, and in some cases equal to, 2 hours. To obtain acid addition salts, the hybrid hydrazides of formula (1) are reacted with inorganic or organic acids in known manner.

Suitable acids that can be used for this purpose include hydrochloric acid, sulfuric acid, phosphoric acid,
Succinic acid, maleic acid, fumaric acid, citric acid, malic acid, lactic acid, tartaric acid, benzoic acid, salicylic acid, aspartic acid, N-acetyl-aspartic acid, glutamic acid, N
- Acetyl-glutamic acid, nicotinic acid, ascorbic acid and p-toluenesulfonic acid. A typical acid addition salt is the tartrate salt of the formula. Vincamic acid hydrazide (0) used as starting material can be prepared as described in NL-A-302131.

The invention is illustrated by the following examples. Example A describes the preparation of vincamic acid hydrazide used as the starting material. Example A 1.7 pine vincamine (0.005 mol) is combined with 1.7 mol of absolute alcohol and 2 80% hydrazine hydrate (0
．． 05 mol).

The mixture was continued to boil under reflux until the vincamine was completely dissolved (approximately 7 hours) and boiling continued for an additional 15 minutes. The solution was then diluted with water (2 ml), made alkaline with 2 drops of dilute sodium hydroxide solution (10%) and washed.
Extracted with loform. The solution was washed with water (3 times) and then dried with N04. Distillation yielded 1.7 female vincamic acid hydrazide, and iodometric titration revealed that the hydrazide content was 100%). The product was yellowish white.

Its UV spectrum matched that of vincamine, ^max = 275-2 vertical skin (shoulder at 29 m). In the IR spectrum, the vincamine ester band at 1750 skin-1 disappears and is replaced by 1 iso-1.
An amide band was observed in Ka-1. Example 1 Mixture of vincamic acid and nicotinic acid. Hydrazide (formula l
a).

Vincamic acid hydrazide was dissolved in 60' of anhydrous pyridine.

The anhydrous nicotine solution was added in portions while cooling. The solution was continued until completely dissolved and the solution was then left at normal temperature (15-25 qo) for 4 hours. The solution was then poured into 50% water with stirring and made alkaline by addition of dilute sodium hydroxide solution (10%). A precipitate formed and adhered to the container wall. After standing for 15 minutes, the solution was filtered and extracted with chloroform (500-300-200 streams).

The precipitate was also dissolved in chloroform (approximately 200%). All chloroform solutions were washed thoroughly with water (5 times, 1 sleeve each), dried over anhydrous sodium sulfate and distilled in vacuo at temperatures between 30 and 3500°C until a volume of about 60 streams was obtained. Add this concentrated solution to an alumina column (
Chromatography was performed using a Merck Alumina 30 female, activity 2-3 column, starting with chloroform. Collected 100 boxes. The first fractions contained viridine and other less aggressive impurities. The next fraction(s) contained pure hybrid hydrazide.
The polarity of the eluate was gradually increased (up to 10% ethanol in chloroform) until all the product was eluted (approximately 2 ranges in total, with a total edge of approximately 100'). After distilling the eluate in vacuo, approximately 10. A mixed hydrazide of the gunwale was obtained.

The product was yellowish white.

It was insoluble in water and soluble in chloroform, acetone and ethanol. Furthermore, it was found to be the only spot (Rf
= approximately 0.5) and was shown to be pure by chromatography. There was therefore no need to crystallize the hybrid hydrazide. In fact, crystallization of the product was difficult, but nevertheless, by dissolving the product in a minimum amount of acetone and adding hexane (hexane was added until opalescence occurred and the mixture was cooled). It was found that small polymorphic crystals were obtained by precipitation. Melting point: 175-180℃ [Microkeffler (microk6f)
ler)]. Analysis (spectral characteristics) C Foundation Day 2 is 503
=459U. V. : Irimachi 270-26fu 282 and 290 on the shoulder.

1. R. :1560 and 165 ratio double-1.

Mass vector: m/e459 (M+), 441, 41
2,371,333 252,12,106 and 7 Example 2 - Tartrate of mixed hydrazide of pinkamic acid and nicotinic acid [Code number K. 15 (formula m)].

The hybrid hydrazide described in Example 1 was dissolved in approximately 20' alcohol. 9 to 650 (ie equimolar amounts) of tartaric acid dissolved in several cubic centimeters of ethanol was added. The solution was distilled to dryness under reduced pressure to obtain a coagulated crystal residue.

The product was washed with chloroform on a glass frit and thoroughly washed with chloroform. The product is a white pseudocrystal and has a melting point (decomposition) of 180 - 215 qo
Met. It was soluble in methanol and ethanol and insoluble in less polar organic solvents such as ether and chloroform. It is highly soluble in water, the solubility on cooling being over 9/mass of 200 and the pH' of the aqueous solution thus obtained being approximately 6. Purity was checked by chromatography on a thin layer of alumina.

Conditions were as described for the hybrid hydrazide, under which the tartrate decomposed and a spot corresponding to the hydrazide was detected. Pharmacological tests were carried out on the products of the invention.

K. The pharmacological test results for No. 15 are summarized below. In intravenous administration in mice, K. 15's LD-50 is 135 females/ko while Pinkamine's LD-50 is 85-95.
It was him/k9. LD-50 for intraperitoneal administration is 3
It was 3/k9 of 75. When administered orally to mice, K
．． 15, administration of Shigeru/X9 caused less than 10% death in mice, while LD of vincamine administered by the same route
-50 was 9/k9 of 450. K. 15 is a slow antihypertensive agent and this property was demonstrated at higher doses. In dogs, K. has a pronounced anti-hypertensive effect on blood pressure changes caused by carotid artery lead (blockade of the carotid artery by Akiko) or adrenaline or noradrenaline. 15 was not shown. K. 15, the time of blood pressure change was delayed. In mice in anoxic state due to pressure reduction, the ED-50 for intraperitoneal administration was 118 Mo/k9. In mice, K. 15 to LD-50's 1/51/10, and 1/
Even after 20 doses, the effects of DOPA and pan-TP (5-hydroxytryptophan) were not enhanced.

This phenomenon indicates the absence of monoamine oxidase inhibition (IMAO) activity. In dogs, K. No. 15 showed action as a peripheral vasodilator, indicated by an increase in femoral blood flow.

Its action followed the pharmacology (3/k9 of 0.86 - 6.88). High dosage i.e. 9/k of 17.2-34.4
In some cases, a slight drop in blood pressure was observed at doses above 9. At lower doses, an increase in femoral flow was observed with no change in blood pressure. In contrast, administration of 2 o/[9 or more vincamine caused a decrease in blood pressure, and the blood pressure varied variably. K. of 10 to 9/kg of 20 as determined by a 45 minute arterial ischemia test. 15
administration caused an increase in femoral flow and therefore lactate clearance per minute.

Unilateral cerebral edema that affects only one brain hemisphere and is produced by incision and prying of the dura in awake rabbits (edema that causes an increase in slow waves and a decrease in beta-1 waves, i.e. beta-1/slow waves) Regarding a model of edema that lowers the wave ratio, K. Intravenous administration of 15 3M o/k9 caused an increase in this ratio during the first hour.

This ratio peaked at 4 hours and the beneficial effects disappeared after 4 hours. 6. Administration of &o/k9 was effective immediately after intravenous infusion.

The 6th hour was the best.

Regression began at 3q hours and disappearance of the effect was seen after 7 q hours.

As a result, K. 15 showed a long duration of effect. K. Cardiac tolerance to administration of vincamine was superior to that of vincamine.

In rabbits, detectable heart damage was rare and only for a limited period of time. Clinical trials have shown good results when the active ingredient is administered in the form of drops (orally), tablets and injectable ampoules, especially when the formulation contains 0.5 to 50 mg of active ingredient per dose. Obtained.

In these studies, cerebrovascular insufficiency (acute brain injury, cerebral hypoxia, cranial traumatic systemic injury and/or prolonged coma)
to 20 elderly people, both men and women, suffering from
K. each. The patient was given 4 pills a day containing 5 parts of 15 and continued for one month. Very good tolerability and marked improvement was observed in the common syndrome of cerebrovascular insufficiency. In particular, improvements were seen in both physical and mental symptoms. Regarding physical symptoms, headache, dizziness, asthenia, and buzzing in the ears were alleviated.

Claims (1)

[Claims] 1. A compound of the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or an acid addition salt thereof. 2 Vincamic acid hydrazide of the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is reacted with a halide, anhydride or ester of pyridinecarboxylic acid in an inert anhydrous solvent to produce the formula ▲There are mathematical formulas, chemical formulas, tables, etc. A process for preparing the compound and, if desired, converting the resulting reaction product into an acid addition salt by known methods.