Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1084S04
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_
C5H4N-C00-
CH2
~3 oCO-~C5H4
5 4
~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-
.
~ ~08450~
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
C5H4N-COO--~,,~ .
fH2 : :,
~ -OCO-~C5N4
OCO-NC5H4
- - . . . . .
- . . . . -
. .
- 1084504
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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`
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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
: . .
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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
- 5 - -
,
: - , - : - :-. ...................... . .. .
. - -: ~, : ~ - : ,
` 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
OH 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
-- 6 --
''' ' ` ' ' ' . - : ' '
:
84~
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
-- 8
.
. . .
" ` ''' ,
1084504
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
! . .
9 _
''
.,_, ,, , ,, , , , :.
1084504
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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