CH633446A5 - Long-acting papaveroline derivative and process for obtaining it - Google Patents

Description

The present invention relates to a papaverolinic derivative, endowed with effective pharmacological properties and long-lasting actions, and the relative process for obtaining it, and in particular the tetra-nicotinic ester of papaveroline, having the formula of structures:

C H N-COO 5 4

CrH N-COO-l. 5 4

CH,

(THE)

OCO-NC H „5 4

OCO-NC H 5 4

As is known, papaveroline is a tetraphenol, structurally made up of an isokinolinic nucleus and a benzene nucleus, condensed by means of a methylene bridge. Papaveroline can be easily prepared by total demylation of papaverine.

the latter has proven, in practice, a vector system of therapeutically active papaverolin radicals.

According to a non-limiting interpretation, the "ready-delay" action of the tetra-nicotinic ester of 45 papaveroline is thought to be due to the fact that the esterified phenolic groups of nicotinic acid belong to different nuclei (isokinolinic nucleus and benzene nucleus ).

Therefore, their hydrolysis will take place at different times and is linked to the pH of the medium.

50 It has also been discovered that the tetra-nicotinic ester of papaveroline, object of the present invention, in the therapy of arteriopathic forms, combines the action of papaveroline with that characteristic of nicotinic acid, with the advantage of not operating limitedly to the deep circle, as in the case of papaveroline, but also to the superficial and cutaneous one, typical of nicotinic acid.

The tetra-nicotinic ester of papaveroline, object of the present invention, can be obtained by reaction of 60 nicotyl chloride hydrochloride with papaveroline.

The reaction is slightly exothermic and takes place, preferably at 20-30 ° C, by direct introduction of the nicotyl chloride hydrochloride into the papaveroline.

From the reaction mixture, the ester can be separated, 65 by suitable dilution with water and ice and subsequent neutralization with sodium bicarbonate.

The precipitate, separated, is washed with acetone and dried.

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The crude product thus obtained is purified by dissolution in dioxane, hot filtering and precipitation for long rest.

The ester, separated, washed, dried, was recognized through the tests of papaveroline and nicotinic acid and, quantitatively, it was determined by spectrophotometric method.

The composition and structure of the ester obtained were determined by centesimal composition tests, N.M.R., I.R. and U.V., determination of nicotinic groups, thin layer chromatography and melting point, as detailed in the following example.

Pharmacological tests were also carried out, such as LD50, total and partial vascular resistance, central and peripheral, deep, medial and superficial flowmetry, skin thermometry, acute and chronic toxicity, which allowed to determine that:

a) papaveroline tetranicotinate maintains qualitatively the pharmacodynamic characteristics of the ester components, ie papaveroline and nicotinic acid;

b) the nicotinic activity is evident just after the administration of the ester and is maintained for 6-12 hours;

c) skin hyperemia, due to the nicotinic action, is less marked, compared to the compounds in which the nicotinic acid is free or in the form of salt, but unlike these it has a more prolonged action (ready-action delay);

d) with the same weight, the ester has a lower toxicity than that of the components administered in combination.

From the above, it is evident that the nicotinic radicals are not hydrolyzed and therefore made free at the same time, but at different times, thus realizing the desired "ready-delay" action.

To better illustrate the inventive concept of the present invention and to implement the same, the following example is reported, for purely exemplifying but not limitative purposes.

Example

The preparation of the tetranicotylpapaveroline, object of the present invention, is carried out in two successive steps: A) preparation of the nicotyl chloride hydrochloride; B) reaction of the latter with papaveroline.

A) Preparation of the nicotyl chloride hydrochloride:

In a 500 cc flask, equipped with reflux refrigerant, 60.5 g (0.5 moles) of nicotinic acid are heated to reflux in an anhydrous environment for 3 hours with 300 g (2.5 moles) of SOCl2.

The acid dissolves quickly and at the end of the dissolution the precipitation of the chloride hydrochloride begins.

After a 1 hour rest, the excess of SOC1 is removed by distillation under reduced pressure and the solid residue is washed repeatedly with petroleum ether and placed in a dryer.

B) Preparation of the poppy tetranicotinic ester

lina:

In a 500 cc three-necked flask equipped with stirrer, reflux condenser and thermometer, 15 g (0.078 moles) of papaveroline are dissolved in 200 cc of pyridine.

Maintaining the temperature between 20-30 ° C, 43 g (0.2415 moles) of nicotyl chloride hydrochloride prepared in A are slowly added.

The dissolution of the latter is slow and a strong stirring is necessary.

The mixture is left to react for 8 hours at room temperature and is heated for 1 hour to 60 ° C to complete the reaction.

After cooling, the reaction mixture is poured into water and ice and the solution is neutralized with sodium bicarbonate.

After filtration, the precipitate is washed with ace-5 tone and dried. Thus 23 g of product are obtained.

23 g of the crude product are dissolved in reflux in dioxane (200 cc), filtered hot and allowed to precipitate due to a long rest.

18.5 g of crystallized product are obtained with an io yield of 50%.

Reaction scheme

OCO-C, H. 5 4

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Physical and chemical characteristics

The product thus obtained is presented as a crystalline white powder, insoluble in water, methanol, ethanol and soluble in dioxane.

so It is altered by prolonged treatment with acid and alkaline solutions.

Tetranicotilpapaveroline hydrolyzes in an acid and alkaline medium; the hydrolytic reaction involves the intervention of 4 water molecules; 4 moles of nicotinic acid and one mole of papaveroline originate from a mole of tetranicotinate.

This process allows the qualitative and quantitative recognition of the ester components.

The product, after recrystallization from dioxane, has a melting point of 214-215 ° C.

Elementary analysis

The substance dried in a stove at 110 ° C, up to constant weight, gave the following analytical values:

65 found: C% 67.97 - H% 3.68 - N% 10.12 corresponding to a brute formula: C40H25O8N5.

The calculated values are: C% 68.28 - H% 3.55 - N% 9.96, that is, in excellent agreement with the experimental ones.

633446

Thin layer chromatography

Thin layer chromatography was carried out on a 5 X 20 glass plate, GF2S4 Merck silica gel layer; thickness 0.2 mm; activation at 120 ° C for 1 hour; development time 180 min .; stroke 10 cm.

A mixture of:

- 60% n-butanol,

- 20% 96% acetic acid e

- 20% of water.

The relief was made with U.V. 360 mu, while 0.1-0.2 cc of a 0.2% solution in tetranicotylpapaveroline dioxane, obtained above, is deposited in a stain on the aforementioned glass plate.

After the development, an oblong blue / violet spot with Rf of 0.62 is observed on the plate.

By leaving the slab exposed to air at room temperature, the stain takes on a yellow-brown color.

Chemical structure

To confirm the presence of 4 nicotinic groups, steps were taken as follows: 0.12-0.15 g of the product were placed in a 250 ml flask equipped with a funnel with taps, a reflux condenser with a thermometer.

150 ml of 85% phosphoric acid at 155 g and ml of water are introduced into the reaction flask.

It heats up on a flame, directly, initially moderating the heating; when the internal temperature of the flask reaches 160 ° C, 50 ml of water is fed through the tap funnel at the rate of 6 drops per minute; finally it boils for 30 minutes.

It is left to cool and is titrated potentiometrically with 0.1 N NaOH.

Ml 1 of 0.1 N NaOH corresponding to 0.01231 g of C5H4N-COOH.

We worked on 0.1246 g of tetranicotinic ester; 7.05 ml of NaOH 0.1 N were consumed. Found 0.08678 g, theoretical 08678 g, error 0.14% less.

Therefore, the compound, object of the present invention, has the structure of:

6-7 dinicotinossi- 1 (3'-4 'dinicotinossibenzil) isochinoline, i.e.

• eoo eoo

CS.

oco.

co -

Brute formula: C40H25O8N5 P.M. = 705.708

Papaveroline base = 39.57% Nicotinic acid = 60.33%

Spectrophotometric analysis of the UV spectrum

The compound has two significant maxima in dioxane: at 231 mjx (e = 57 000 ± 1%) characteristic of the nicotinic nucleus, at 258 mp, (e = 28 000 ± 1%), practically referable to the papaverolinic nucleus (papaveroline base max. abs. 250 m [t in HCl 1 N).

The slippage of the maximum is probably due to the different solvent used.

The presence of maximum absorptions in the UV obviously, it allows the dosage of the compound by spectrophotometric method.

I.R. spectrum

The I.R. in suspension (nujol) of the compound it has characteristic absorption areas and precisely: at 1740 cm-1, characteristic of the ester group C = 0; at 1590 cm-1, characteristic of the groups C — C C = N; and at 1225-1070 cm-1 characteristic of the nucleus 1, 2, 3, 4 replaced.

N.M.R. spectrum

They have been recorded in chloroform. They are very complex; in fact, the test substance is not soluble, like papaveroline, in dimethylsulfoxide, therefore it is difficult to be able to make a safe assignment of the signals. However, it can be obtained with a good approximation that it is tetranicotilpapaveroline, since the ratio of aromatic protons to benzyl protons was equal to 11.56, theoretical 11.5, in good agreement with the structure of tetranicotinate.

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Claims (5)

633446 2. Process for the preparation of the tetra-nicotinic ester of papaveroline, as in claim 1, characterized in that it consists in reacting the chloride of nicotyl chloride with papaveroline. 2 CLAIMS 1. Papaverolinic derivative, endowed with effective pharmacological properties and having therapeutic activity not limited to the time of administration, consisting of the tetra-tinic ester of papaveroline, having formula of structures: w- Eous C_H N-COO S 4 (THE) OCO-NC H 5 4 OCO-NC H 5 4 3. Process according to claim 2, characterized in that the reaction is carried out at a temperature comprised between 20 ° and 30 ° C. Method according to claim 2 or 3, characterized in that the poppy-liner tetra nicotine ester is separated from the reaction medium by dilution with water and ice and subsequent neutralization with sodium bicarbonate. 5. Process according to claim 2, characterized in that the papaveroline is fed to the reaction medium in the form of a pyridine solution. 6. Process according to claim 2, characterized in that the poppy-line tetra nicotinic ester is purified by crystallization from dioxane. The therapeutic use of this compound is also known, but it had been very limited due to its poor solubility in water and in harmless solvents. To overcome this drawback, it has been proposed to translate a sulfonic group HSO 3 into the benzene ring and the sulphonated product thus obtained has been effectively administered for the treatment of particular arteriopathic forms. An attempt was then made to obtain, in medicine: drugs for me, an increasingly targeted therapy with activities not only linked to the time of administration, but with a guarantee of duration, commonly known as the "ready-delay" action. The various attempts made, by producing metal derivatives with less solubility or by resorting to particular excipients which allow the slow release of the medicinal substance, have not given satisfactory results in practice. Therefore, the object of the present invention is to provide a derivative of papaveroline which, in addition to having its own instantaneous pharmacological action, has a therapeutic activity, which is not limited to the time of administration (ready-delay action). This purpose is achieved by using the tetra-nicotinic ester of papaveroline, having the structural formula: 25 C_II „N-COO- 5 4 C H N-COO 5 4 30 CH 35 œ oco- 40 OCO-NC 5 4 ■ NC5H4