DE2624973A1 - NEW VINCAMIC ACID HYDRACIDE DERIVATIVES - Google Patents

Description

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MERRELL TORAUDE, PARIS V / FRANCE New vincamic acid hydrazide derivatives

The invention relates to derivatives of vincamine and in particular the mixed hydrazides of vincamic acid (or the acid on which vincamine is based) and pyridinecarboxylic acids, so-, like their acid addition salts, as new industrial products. It also relates to a process for making these hydrazides and of their acid addition salts, as well as their therapeutically applicable forms.

It is known that vincamine, an important alkaloid of Vinca minor L, has interesting pharmacological properties. In particular, it exhibits hypotensive effects along with the undesirable side effects that accompany most hypotensive agents. As a drug, vincamine is mainly used as a cerebral oxygenator (or to improve cerebral oxygen utilization) and vasoregula-

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- 2 gate used for microcirculation.

However, since the effect of vincamine is only brief, attempts are made to eliminate this disadvantage and / or to improve it the pharmacological properties of the alkaloid on the one hand acid addition salts, in particular the pamoate, and on the other hand, semi-synthetic products such as vincanol (cf. French patent 1,586,697) and the amides of apovincamic acid (see French patent specification 2 023 918).

In order to improve the properties of the vincamine, the applicant tries to obtain new derivatives of different structure, the one vincamoyl group and one pyridine carbonyl group exhibit. Surprisingly, it has been found that the mixed hydrazides of vincamic acid and pyridinearboxylic acids are of interest for therapeutic purposes, whereas the vincamic acid hydrazide, from which they are derived, and that as an intermediate is used for the synthesis of vincanol, is not suitable for therapeutic purposes.

In the following, pyridine-2-carboxylic acid is the pyridinecarboxylic acid or picolinic acid, pyridine-3-carboxylic acid or nicotinic acid and pyridine-4-carboxylic acid or isonicotinic acid.

The new compounds according to the invention are characterized by that they are from the group of the mixed hydrazides of vincamic acid and pyridinecarboxylic acid of the formula I and their acid addition salts come.

These new compounds are particularly suitable as drugs used as weak hypotensives and vasodilators in the treatment of cerebral and peripheral vascular Insufficiencies or circulatory insufficiencies are used.

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According to the invention, therapeutic compositions and Administration forms or pharmaceutical compositions created the compounds mentioned, which are particularly suitable for the treatment of cerebro-vascular insufficiencies, characterized in that they together with a physiologically acceptable excipient an effective amount at least a mixed hydrazide of the formula I or one of its addition salts with non-toxic acids.

For the preparation of the mixed hydrazide of the formula-I uses the vincamic acid hydrazide of the formula II with an ester, a halide or an anhydride is carried out in a manner known per se the pyridine carboxylic acid.

According to a preferred embodiment, the hydrazide II, after dissolving in an inert and anhydrous solvent, is reacted with an excess of pyridinecarboxylic anhydride, advantageously 1 mol of hydrazide per about 1.5 mol of pyridinecarboxylic anhydride, the reaction ^{temperature being equal to or below 30 °} C. and preferably at 15 to 25 ^° C.

Examples of inert and anhydrous solvents that can be used are pyridine, triethylamine and dimethylformamide called. The reaction time is generally at or above 24 hours.

To obtain the acid addition salts, the mixed hydrazide of the formula I is left with a mineral acid or inorganic acid Acid or organic acid react. The acids suitable for this purpose include, in particular, 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-acetylaspartic acid, glutamic acid, N-acetyl-glutamic acid, nicotinic acid, ascorbic acid, Call p-toluenesulfonic acid.

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The vincamic acid hydrazide II used as starting material can as described in published Dutch patent application 302 131.

The ■ following examples, which are not intended to represent any restriction, serve to explain the invention and an embodiment of the synthesis of the starting material.

Preparation of vincamic acid hydrazide (formula II):

¹ »77 g (0.005 mol) of vincamine are added to 1.7 ecm of absolute alcohol and 2 ecm (0.05 mol) of hydrazine hydrate (80%). The mixture is refluxed until the vincamine has completely dissolved (about 7 hours) and a further 15 minutes under boiling.

The solution is then diluted with 2 ecm of water that has been made alkaline with two drops of dilute sodium hydroxide solution (10%) and extracted with chloroform. The solution is washed three times with water and then _{dried over Na 2} SOi. Evaporation gives 1.70 g of vincamic acid hydrazide (iodometric titration: 98-100% hydrazide).

The product has a white-yellow color to be _s ultraviolet spectrum is identical to that of vincamine, Λ = 275-283 nm (shoulder of at ^290!); in the IR spectrum the “ester” band of vincamine at 1750 cm ”has disappeared and an“ amide ”band at 1680 cm” is observed instead.

BeisDiel 1

Mixed vincamic acid and nicotinic acid hydrazide. (Formula Ia)

9 g of vincaffic acid = hydrazide are dissolved in 60 ml of anhydrous pyridine solved. 9 g of nicotinic anhydride are added in small portions with stirring and cooling. It will be up to full resolution stirred further, whereupon the solution for 48 hours at room temperature

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- 5 temperature (15-25 ° C) is left to stand.

The solution is then poured into 500 ecm of water with stirring and made alkaline by adding dilute sodium hydroxide solution (10%). A precipitate forms and adheres to the walls of the vessel. After standing for 15 minutes, the solution is decanted and extracted with chloroform (500 + 300 + 200 ecm). The precipitate is also dissolved in about 200 ml of chloroform. The combined chloroform solutions are washed with plenty of water (5 times one liter), dried over anhydrous sodium sulfate and distilled in vacuo at a temperature not exceeding 30-35 ° C. until a volume of about 60 ecm is obtained. This concentrated solution is subjected to column chromatography on aluminum oxide (300 g of Merck aluminum oxide, activity 2-3, ascending column in chloroform). Fractions of 100 ml are obtained. The first fractions contain pyridine and other less polar impurities. The following fractions contain the mixed hydrazide in the pure state. The polarity of the eluent is gradually increased (up to 10% ethanol in chloroform) in order to elute the entire product (a total of about 20 fractions of 100 ml) »

After distilling the eluant, about 10.5 g of the mixed hydrazide is obtained.

This compound has a white-yellow color, is in water insoluble and soluble in chloroform, acetone and ethanol. In addition, it is chromatographically r-in: One Spot (Rf = about 0.5) in the thin layer chromatogram / carrier: aluminum oxide, eluant: chloroform-methanol (95: 5) /.

It is therefore not necessary to crystallize the mixed hydrazide.

In fact, it is difficult to crystallize the compound,

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although one could obtain small polymorphic crystals by dissolving in the minimal amount of acetone and precipitating by adding hexane (adding the hexane until opalescence appeared and cooling). F = 175-180 ⁰ C (Micro-Kofler).

Analysis (spectral characteristics):

Γ ¹ Η 1 \ ΤΠ - Zi ¹ ^ Q

UV spectrum: K _Qx = 270 - shoulder 265, 282, 290

IR spectrum: 1560, 1650 cm " ¹

Mass spectrum: m / e 459 (M +), 441, 412, 371, 338, 252, 122, 106, 78

Example 2

Tartrate of the mixed hydrazide of vincamic acid and nicotinic acid, Code no. K 15 (see formula III).

Dissolve 2 grams of the mixed hydrazide in about 20 ml of alcohol. 650 mg (mol / mol) of tartaric acid dissolved in some are added ecm ethanol, too.

The solution is distilled to dryness under reduced pressure: A pseudocrystalline residue is obtained.

The product is transferred to a glass frit using chloroform and washed abundantly with chloroform.

A white, pseudocrystalline product is obtained with a melting temperature of 180-215 ° C. (with decomposition). It is in Methanol and ethanol are soluble and insoluble in organic solvents that are less polar, such as ether and chloroform. It is very soluble in water: solubility in the cold

-z

over 200 mg / cm; the pH of the aqueous solution obtained in this way is around 6.

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Investigation of the purity: In thin-layer chromatography on aluminum oxide, among those described for the mixed hydrazide Under certain conditions, the tartrate decomposes and a spot that corresponds to the hydrazide is obtained again.

With the fiction like en compounds were pharmacological Investigations carried out. The tests carried out with K 15 are listed below:

In the mouse, the DLc ₀ of K 15 when administered intravenously is 135 mg / kg, that of vincamine is 85-95 mg / kg. The DLc ₀ when administered intraperitoneally is 375 mg / kg. When administered orally to the mouse, it was observed that the dose of 3 g / kg of K 15 caused the death of less than 10% of the animals, whereas the HL of vincamine was 450 mg / kg with the same administration.

The K 15 is a mildly hypotensive agent only at high doses. In the dog it does not have any clearly antagonistic effects Effects on pressure modifications caused by clasps of the carotids (blocking of the carotid arteries with tweezers), through adrenaline and noradrenaline. The connection delays the occurrence of these pressure phenomena in time.

In mice with hypobaric (or negative pressure) anoxia, the ΠΕ, -q is included with intraperitoneal administration 118 mg / kg.

In the mouse, the compound does not potentiate the effects of DOPA and 5-HTP (5-hydroxytryptophan) at doses of 1/5, 1/10 and 1/20 of the DL _50; this phenomenon shows the absence of an IMAO effect.

In the dog, K 15 shows a vasodilatory peripheral effect, which results in an increase in the femoral throughput depending on

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The dosage (0.86-6.88 mg / kg) expresses a lack of flexibility. Observed at higher doses, i.e. starting from 17.2-34.4 mg / kg one has a slight hypotension. At lower doses, an increase in femoral throughput is observed with no changes in pressure. In contrast, at a dose of 2 mg / kg, vincamine causes hypotension with changes in pressure.

According to the investigation of prolonged arterial ischemia For 45 minutes, K 15 at a dose of 10-20 mg / kg causes an increase in the femoral flow and thus the Elimination of lactate per minute.

On a model of unilateral cerebral edema in one hemisphere obtained by incision and removal of the dura mater from a conscious rabbit (an edema which causes the slow waves to increase and the waves with tetrafrequency to decrease _s QLh ₀ a lowering of the Tsta-slow wave ratio) causes K 15 in a dose of 3? 4 mg / kg intravenously an increase in this ratio from the first hour _o This ratio is Eia; iisal in the fourth hour and the beneficial effect disappears in the 48th hour.

At a dose of 6 _S S mg / kg, this effect occurs when intrave- _t nöser injection to "the peak is in the 6" reaches hour. The decrease begins in the 30 _o'clock hour and in the 72nd hour the effect disappears,

3s _s is therefore determine that the compound is a long-term effect has.

The kardial® tolerance for the administration of K 15 appears above the νzn Vincamine In rabbits, the cardiac disorders observed are less numerous and more limited in time.

IiTi course of "clinical investigations, good results were obtained especially when the active substances

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in the form of drops (oral administration), tablets, gel beads or injectable ampoules were used, each conditioned preparation in particular 0.5-50 mg of active Contained in each dose. The observations with K were recorded.

There were 20 old people of both sexes who suffered from cerebral vascular insufficiency (acute cerebral accidents, cerebral Hypoxia, head trauma and / or prolonged coma), treated with 4 gel beads per day for one month, each 5 mg K 15 contained. Very good tolerance and, objectively, considerable improvements over the usual were observed Syndromes of cerebrovascular insufficiency. In particular, you could see improvements in terms of organic as well determine psychological signs.

As for the organic characteristics, improvements have been made in 1.) Cephalaea or persistent headache, 2.) vertigo or dizziness, 3.) asthenia or weakness and 4.) ringing in the ears. As for psychological traits, were Improvements achieved in terms of impaired awareness or attention, mood, memory over longer and shorter periods of time, temporal or spatial Disorientation and disturbances of the mental life. ,

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U O HO. I. C-NH-NH-C
• ι ti
0 O

HO C-NH- NH-C '

Il Il

O O

H N-NH-C

C - NH - NH- C " Il Il O O

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Claims (12)

Claims i./Neue mixed vincamic acid and pyridine carboxylic acid hydrazide \ y from the group of a) Compounds of the general formula HO C-NH-NH-C- ' Il Il 0 0 and b) their acid addition salts. 2. Mixed vincamic acid and nicotinic acid hydrazide der formula and its acid addition salts. 609884/1 134 3. Acid addition salt of mixed vincamic acid and nicotinic acid hydrazide according to claim 2, which is the tartrate of the formula COOH CHOH I CHOH COOH (III) NH-NH-C acts. 4. A process for the preparation of a mixed hydrazide of the formula I according to claim 1 and its acid addition salts, characterized in that in an inert and anhydrous solvent vincamic acid hydrazide of the formula H ₀ N -NH-C * Il II with a compound which is chosen from the halides, anhydrides and esters of pyridinecarboxylic acids and optionally converting the product thus obtained into an acid addition salt. 609884/1 1 34 5. The method according to claim 4, characterized in that one vincamic acid hydrazide II with an excess of pyridinecarboxylic anhydride implements. .- -. "; ._. 6. A process according to any one of claims 4 and 5, characterized in that 1 mole Vincamsäure hydrazide of formula II with about 1.5 moles Pyridincarbonsäureanhydrid at a temperature of 30 C or below 30 ⁰ C and preferably between 15 and 25 ° C implements. 7. The method according to claim 4, characterized in that the inert and anhydrous solvent is pyridine, Triethylamine or dimethylformamide chooses. 8. The method according to any one of claims 4 to 7, characterized in that that the reaction of vincamic acid hydrazide with the pyridine carboxylic acid anhydride for at least 24 Hours. 9. Medicament, characterized in that there is at least one mixed hydrazide according to one of the effective principle Claims 1 to 3 or one of its addition salts with Contains non-toxic acids. 10. Therapeutic or pharmaceutical compositions, suitable in particular for the treatment of cerebral and peripheral vascular insufficiencies, containing an effective Amount of the medicament according to claim 9 together with a physiologically compatible excipient. 11. Therapeutic or pharmaceutical compositions according to claim 10, characterized in that they. 0.5 - 50 mg contain active ingredient per unit dose. 12. Forms of administration of the pharmaceutical or therapeutic Compositions according to one of Claims 10 and 11, optionally together with customary auxiliaries and carriers. 609884/1 134