CA1084504A - Tetra-nicotinic ester of papaveroline and process for the production thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

As a new product, tetra-nicotinic ester of papav-eroline having pharmacological activities. The process for producing the compound involves the reaction of nicotyl chloride chlorohydrate and papaveroline.

Description

The present invention relates to a derivative of papaveroline,having effective pharmacological properties of long duration, and to a process for preparing same. Particular-ly,the invention relates to the tetra-nicotinic ester of papaveroline having the following structural formula:

C5H4N-C00_ ~3 oCO-~C5H4 ~s is known, papaveroline is a tetraphenol, struc~ur-ally consisting of an isoquinolinic nucleus and of a benzyl nucleus, condensed through a methylenic bridge. Papaveroline can be easily prepared by the total demethylization of papaverine.
The therapeutic use of such compound was also known, such use, however, being greatly limited because of its low solubility in water and in acceptable solvents.
To overcome this disadvantage, it has been proposed to introduce in the benzyl ring a sulfonic group HS03 and the sulfonated product thus obtained has been effectively admini-.

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stered for the treatment of particular arteriopathic condi-tions. ~:
It has then been tried to arrive, in medicine, to pharmaceutical compounds suitable for a more selective therapy, and with an activity tied not only to the-time of -administration, but with a controlled period of activity, .:-~
commonly known as a "fast-delayed" action.
The various tentatives which have been made, utilizing metallic derivatives of lower solubility or using ~ :
particular excipients which permitted the slow release of the active substance have not, in practice, given satisfactory results.
Therefore, an object of the present invention is to realize a papaveroline derivative which, in addition of having an immediate pharmacological action, also has a therapeutic activity not limited with respect to the time of administration (fast-delayed action).
This object is obtained utilizing the tetra-nicotinic ester of papaveroline, having the structural formula:

C5H4N-COO--~,,~ .

fH2 : :, ~ -OCO-~C5N4 - - . . . . .

- . . . . -. .

The latter compound has proved to be, in practice, a carrier system for therepeutically active papaverolinic ra-dicals.
According to a non-limitative interpretation, it is felt that the "fast-delayed" action of the tetra-nicotinic ester of papaveroline is due to the fact that the esterified phenolic groups of the nicotinic acid belong to different nuclei (isoquinolinic nucleus and benzyl nucleus). Therefore their hydrolysis will take place at different rates and is dependent on the medium pH value.
It has been further discovered that the tetra-nicotinic acid of papaveroline, object of the present invention, in the therapy of arteriopathic forms, combines to the action of papaveroline that action characteristic of nicotinic acid, with the advantage of not operating only upon the deep stratus, as is the case with papaveroline, but also upon the superfi-cial and cutaneous stratus, characteristic of nicotinic acid.
The tetra-nicotinic ester of papaveroline, object of the present invention, can be obtained by the reaction of nicotyl chloride chlorohydrate with papaveroline. The reaction is slightly exothermic and takes place preferably at 20-30C.
by the direct addition of the nicotyl chloride chlorohydrate the papaveroline.
The ester may be separed from the reaction mixture by suitable dilution with water and ice followed by neutraliza-tion with sodium bicarbonate.
The precipitate, after separation, is washed with acetone and dried.
The raw product thus obtained is purified by dissolv-ing it in dioxane, filtering while hot, and allowing it toprecipitate after long standing.

The ester, separated, washed and dried, has been -`
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recognized by means of the tests for papaveroline and nicotinic acid and, quantitatively, by spectrophotometric means.

The composition and the structure of the ester thus obtained have been determined by elemental analysis, N.M.R., I.R. and U.V. spectra, determination of the nicotinic groups, thin layer chromatography and melting point, as reported in detail in the following example.

There have also been effected pharmacological tests, such as LD50, total and partial vascular resistances, central and partial vascular resistances, central and peripheric, deep level fluximetry, medial and superficial, cutaneous thermome-try, acute and chronic toxicity, which have permitted to determine that:

a) the tetra-nicotinate of papaveroline maintains inaltered, quantitatively, the pharmacodynamic characteristics of the components of the ester, i.e., papaveroline and nicotinic acid;

b) the nicotinic activity shows itself as soon as the ester is administered and continues for 6-12 hours;

c) the cutaneous hyperemia, due to the nicotinic action, i9 less pronounced, as compared to those compounds in which the nicotinic acid is in a free state or in the form of a salt, but, as compared to the latter, presents a more prolonged action (fast-delayed action):

d) on an equal weight basis, the ester shows a lower toXlCity than that of the two components administered separately.

As can be seen above, it is evident that the nicotinic radicals are not hydrolized and therefore freed on the same moment but rather at separate times, thus obtaining the desired "fast-delayed" action.

To better illustrate the inventive concept of the present invention and the actuation of the same, there is set : . .
-- 4 _ -'' 1084~04 forth the following example, merely by the way of illustration and not cf limitation.
Example The preparation of the tetranicotylpapaveroline, object of the present invention, is effected in two successive steps: A) preparation of the nicotyl chloride chlorohydrate;
B) reaction of the latter with papaveroline.
A) - Preparation of the nicotvl chloride chlorohydrate.
In a 500cc round bottom flask, equipped with a reflux condenser, there is heated under reflux conditions and under ~;
anhydrous conditions for 3 hours 60.5g (0.5 mol) of nicotinic acid with 300g (2.5 mol) of SOC12.
The acid dissolves rapidly and, when the solution is complete, there begins the precipitation of the chloride chlorohydrate. After allowing the reaction mixture to stand for one hour, the excess of SOC12 is removed by distillation under reduced pressure and the solid residue is washed repeat-edly with petroleum ether and placed in a desiccator.
B) - Pre~aration of the tetranicotinic ester of papaveroline.
In a 500cc three-necked round bottom flask, equipped with stirrer, reflux condenser and thermometer, there is dissolved 15g (0.078 mol) of papaveroline in 500cc of pyridine.
Maintaining the temperature between 20-30C, there is showly added 43g (0.2415 mol) of the nicotyl chloride chlorohydrate prepared in part A). -~
The rate of solution of the latter is slow and it is -necessary to maintain a strong stirring action.
The mixture is allowed to react for 8 hours at ambient .:
temperature and it is then heated for one hour at 60C to complete the reaction.
After cooling, the reaction mixture is poured in , : - , - : - :-. ...................... . .. .
. - -: ~, : ~ - : , ` 188~504 water and ice and the solution is neutralized with sodium -~
bicarbonate.
After filtration, the precipitate is washed with acetone and dried. There is thus obtained 23g of product.
The 23g of the raw product are then dissolved under reflux conditions in 200cc of dioxane, filtered while hot and the solution allowed to stand for a long period to obtain a precipitate.
There is obtained 18.5g of crystallized product with a yield of 50%.
Reaction scheme.

HO ~ C5H4N-COO-HO ~ C5H4N-COO-HCI. ~ COCI I I
4 ~ ~ fH2 NaHCO3 1 2 ~ ~ -OCO-NC5H4 .
PhYsical and chemical characteristics.
The product thus obtained is a while crystalline powder, insoluble in water, methanol, ethanol and soluble in dioxane. -Its characteristics change after prolonged treatment with acid and alkaline solutions.
The tetranicotylpapaveroline hydrolizes in acid and alkaline environments, the hydrolitic reaction involves the reaction of 4 molecules of water' from one mole of tetranicoti-nate there are obtained 4 mols of nicotinic acid and one mole ''' ' ` ' ' ' . - : ' ' :

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of papaveroline.
Such process permits the qualitative and quantitative determination of the components of the ester.
The product, after recrystallization from dioxane, shows a melting point of 214-215C.
Elemental AnalYsis.
The compound, dried to constant weight in an oven at 110C, gave the following analytical values:
Found: C : 67.97% H : 3.68%; N : 10.12.% corresponding to an empirical formula: C40H25O8N5.
The calculated values are: C : 68.28% H : 3.55%
N : 9.96% which agree fully with the experimental values.
Thin Layer Chromatoara~hY.
The thin layer chromatography has been performed on glass plate 5x20: silica gel layer G~254 Merck, thickness 0.2 mm:
activation at 120C for 1 hour: development time 180 min.:
travel 10 cm.
As eluent there has been used a mixture of:
60% n-butanol 20% acetic acid (96%) 20% water The determination was made under U.V. light of 360 m,u while 0.1-0.2 cc of a 0.2% solution in dioxane of the tetra-nicotylpapaveroline obtained above is deposited as a sport on the above-deccribed glass plate.
After development, on the plate there is observed an oblong spot of blue/purplish color having an Rf of 0.62.
Leaving the plate exposed to the air at ambient temperature, the spot assumes a yellow-brown coloration.
Chemical Structure.
To conf~rm the presence of 4 nicotinic groups, the following procedure was followed.

* Tradbmark : . :: . . . - . : . :- ~ . - : -.

:;,............. . . . :: . .. . - - . ~ :

108~504 . ` `` ' .
In a 250cc round bottom flask equipped with a stop-cockcontrolled funnel, reflux condenser and thermometer there was introduced 0.12-0.15g of the product.
` In the reaction flask there are introduced 150 ml.
of 85% phosphoric acid (equivalent to 155g) and 20 ml. of water.
It is then heated over a direct flame controlling initially the rate of heating: when the temperature inside the flask reaches 160C, there is added through the funnel 50 ml.
~0 of water at the rate of 6 drops per minute. The mixture is then .
heated io the boiling point for 30 minutes.
The mixture is allowed to cool and it is titered potentiometrically with 0.1 N NaOH, 1 ml of 0.1 N NaOH
corresponding to 0.01231g of C5H4N-COOH.
We have used 0.1246g of tetranicotinic ester, there have been utilized 7.05 ml of 0.1N NaOH. Found: 0.08678g;
theorical: 0.07678, error: minus 0.14%.
Therefore the compound object of the present inven-tion has the following structure:
607 dinicotinoxy-l (3'-4' dinicotinoxybenzyl) isoquinoline, l.e.

.
~ COO

CO
C~2 ~/ OCO~ "~
l~COf ~

EmPiriCal formula: C40H25O8N5 M.W. : 705.708 .

. . .

" ` ''' , Papaveroline base: 39.57%
Nicotinic acid: 60.33%
S~ectrophotometric Analysis.
U.V. Spectrum.
~.
The compound presents, in dioxane, two significative maxima: at 231 m~u (~ = 57000 + 1%) characteristic of the nicotinic nucleus, at 258 mJu ( = 28000 + 1%), practically referrable to the papaverolinic nucleus (papaveroline base max. ass. 250 mu in 1 N HClj.
- The drop in the maximum is probably due to the different solvents employed.
The presence of maximum absorptions in the U.V.
consents, as is obvious, the determination of dosage of the compound for spectrophotometric determinations.
I.R. Spectrum.
The I.R. spectrum in suspension (nujol) of the compound ~;
presents characteristic zones of absorption and precisely:
at 1740 cm 1, characteristic of the ester group C=0 ` at 1590 cm 1, characteristic of the group C=C, C=N, and at 1225-1070 cm 1, characteristic of the 1,2,3,4 substituted nucleus. y N.M.R. Spectrum.
.
They have been determined in chloroform. They prove to be very complex: in fact, the substance under examination i8 not soluble, as is papaveroline, in dimethylsulfoxide, there-fore it is difficult to make an exact evaluation of the data.
However, it is possible to predict with good certainty that the test product is tetranicotylpapaveroline inasmuch as the relationship aromatic protons/benzylic protons results equal to 11.56 (theoretical 11.5) in good agreement with the struc-ture of tetranicotinate.
The process for the preparation of the tetra-nicotinic ! . .

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ester of papaveroline has been described above merely by way of illustration and not of limitation. It is understood that in the practice of the present invention various abvious modi-fications thereto may be made by one skilled in the art with-out departing from the ambit of the invention.
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Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of the tetra-nicotinic ester of papaveroline wherein nicotyl chloride chlorohydrate is reacted with papaveroline, and the resulting product separated from the reaction mixture.

2. A process as claimed in claim 1, wherein the reaction is conducted at a temperature of from about 20 to about 30°C.

3. A process as claimed in claim 2, wherein the product is isolated from the reaction mixture by diluting said mixture with water and ice and subsequently neutralizing the resulting mixture with sodiumbicarbonate.

4. A process as claimed in claim 2, wherein the papaveroline reactant is fed to the reaction vessel as a pyridine solution.

5. A process as claimed in claim 2, wherein the raw product is purified by crystallization from dioxane.

6. As a novel compound, the tetra-nicotinic ester of papaveroline of the structural formula:

whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.