Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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BACKGROUND OF TEIE INVENTION
The invention relates to new quaternary sand-
wicine derivatives, processes and starting materials for
their preparation,and pharmaceutical compositions thereof.
Sandwicine is an indole alkaloid from the group
of rauwolfia alkaloids. This alkaloid is described in
detail by M. Gorman et al, Tetrahedron 1, 328 (1957). It
is an isomer of the rauwolfia alkaloid ajmaline.
Quaternary salts of ajmaline are known to possess anti-
arrhythmic properties,but also undesirable negative
inotropic pxoperties,and sedative side effects.
SUMMARY OF THE INVENTION
It is an object of the present invention to
provide new pharmacologi~ally active sandwicine derivatives
which exhibit strong antiarrhythmic properties and are
low in toxicityO
It is a further object of the present invention
to provide new antiarrhythmic compounds which are low in
side effects,especially low in negative inotropic side
effects.
It is a further object of the present invention
to provide new sandwicine derivatives which exhibit
adrenolytic properties, especially antihypertensive
pxoperties.
It is a further object of the present invention
to provide processes for the preparation of such quaternary
sandwicine derivatives.
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It is still a further object of the present
invention to provide pharmaceutical solid or liquid
formulations containing quaternary sandwicine derivatives.
It is a further object of the present invention
to provide a method of treatment or prevention of diseases
of the coronary and circulary system,especially heart
rhythm disorders.
In order to accomplish the foregoing objects
according to the present invention there are provided new
quat~rnary sandwicine derivatives of the formula (I)
,H3 R X
HO H
wherein R represents an alkyl group containing 1 to 5
carbon atoms,and ~ represents an anion of a physiologi-
cally acceptable acid.
According to the present invention there are
further provided processes for preparing the compounds of
formula tI) and of the intermediate aldehydes of formula
(II~
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9Sg
HO ~ ~ H
wherein R is as as defined above,and which are useful for
their production.
The new compounds of formula Ia
~H3 X
I ~ ; ~ (Ia)
~0 \ H
wherein R is as defined above,and X ~ represents a halide
anion~ are prepared by reacting sandwicine of formula
(III)
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IIII)
HO ' ` H
with an alkyl halide R-Xl,wherein R and Xl are as defined
above. The resulting quaternary compounds of formula (Ia)
are treated with an alkaline agent whereby the corresponding
aldehydes of formula (II) are formed by opening of a
piperidine cyclus. Compounds of formula (I) are prepared
by reacting an aldehyde base of formula (II) with a
physiologically acceptable acid H~X~.
The new compounds of formula I exhibit valuable
pharmacological properties,especially antiarrhythmic
properties.
According to the present invention there are
further provided pharmaceutical compositions comprising the
above described compounds of formula I and inert diluents.
Further objects, features and advantages of the
present invention will become apparent from the detailed
description of the invention which follows.
DETAILED DESCRIPTION OF THE INVENTION
Within the formula ~I) R may represent a branched
or unbranched alkyl group. Preferably it contains 1 to 3
- 5 -
'
107~959
carbon atomsland especially represents methyl, ethyl or
propyl. The anion X~ can be a physiologically acceptable
anion of an inorganic acid such as a hydrogen halide, e.g ,
hydrochloric acid, hydrobromic and hydroiodic acid,
sulfuric acid or,preferably phosphoric-acidj~r an organic
acid such as preferably tartaric acid~citric acid or
oxalic acid, or also alkyl- or arylsulfonic acids.
The quaterni~ation of the sand~icine o~ formula
tIII) can be performed in any con~entional manner. Preferably
equimolar amounts of the starting materials are used. Also
an excess of the alkyl halide may be used, whereby this
alkyl halide simultaneously serves as a solvent. It i5
advisable to effect the quaternizing reaction in the
presence of an organic-solvent which is inert towards the
reacting compounds,and at elevated temperatures,
preferably at reflux tempexature of the solvent. Suitable
601vents are, for example, acetonitrile,chloroform,or
dimethylformamide. The reaction may also be performed at
temperatures below the reflux temperature of the reaction
mixture. The corresponding aldehyde bases of formula
SII ) are prepared by treating a compound of formula (Ia)
with an alkaline agent,preferably an aqueous solution of
an alkaline compound, e.g., as described in Examples lB
or 2B hereafter. Suitable aIkaline solutions are alkali
hydroxide solutions, especially a 10~ sodium hydroxide
solution, or a solution of soaium ~ydrogen carbonate or
sodium carbonate. It îs a~visable to effect the reaction
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in the presence of a suitable extracting solvent. ~11
inert solvents which are not water-miscible are appropriate
such as chloroform, ether,and the like, wherein the
aldehyde bases are sufficiently soluble.
After distilling off the extracting solvent,
advantageously under vacuum, the basic aldehyde bases are
recovered in amorphous form.
Finally, the thus prepared aldehyde bases are
reacted with a physiologically acceptable acid, e.g., one
of the above cited organic or inorganic acids, preferably
tartaric acid, oxalic acid, citric acid, or phosphoric
acid.
The new quaternary compounds of formula (I),
which are prepared from sandwicine according to the present
invention,exhibit valuable pharmacological properties
and therefore are useful in medical treatment. In particu-
lar, they are useful in the treatment and prophylaxis of
diseases of the coronary and circulary system, e.g.,
they are useful as antiarrhythmics in the treatment of heart
xhythm disorders, since they exhibit adrenolytic and
antiarrhythmic activities,as is indicated in standard
te~ts, e.g., measurement of the functional refractory
period and the contraction force in the dissected left
papillary muscle of a guinea pig ~from male or female
guinea pigs weighing 300 to 350 grams).
For the above-mentioned uses,the administered
doses can vary considerably depending on the type of the
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compound, the animal, the mode of administration, the
treated conditions and the therapy which is desired.
Usually satisfactory results are obtained with dosages
between 0.05 and 5 mg/kg boay weight. These doses
can be administered er.terally , preferably orally, or
parenterall~. For example, daily oral doses for larger
mammals can be chosen betweenO.5 andlOO mg.
Surprisingly, the new compounds of formula II)
are considerably more active~and physiologically better
acceptable than the known epimeræ of these sandwicine
derivatives. Thus, in comparison with corresponding known
ajmaline derivatives~the effect of the new sandwicine
; compounds on the isolated papillary muscle of the guinea
pig is similar to that of the ajmaline derivatives at
considerably lower, e.g., 10 times lower dosages. Further-
more, the undesirable negative inotropic effect, which is
observed with the ajmaline compounds, i8 reduced,and at the
same time the new compounds of formu~a ~I) exhibit an
; increased therapeutic range.
From these results it can ~e concluded that the
~teric position of the hydroxy group at the C17 atom is
particularly important for the pharmacological activity of
the sandwicine compounds,since this is the only ~onfigura-
tional difference between the new compounds and their
epimer~.
According to a further feature of the invention,
there are provided pharmaceutical compositions containing
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., .. , . ., . . ~. . .
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at least one of the compounds of formula (I). The
compounds of formula ~) are stable and storable in aqueous
solution,as well as in the solid statP. The compositions
may take the form of solid or liquid formulations for
enteral, preferably oral, or for parenteral administration.
Thus, the formulations may be in the form of capsules,
tablets, coated tablets, suppositories, emulsions or
solutions. These formulations may comprise conventional
pharmaceutical carriers, e.g., solids, such as starch,
lactose, mannit, polyvinyl pyrrolidone or liquids such as
sterile water, pharmaceutically acceptable alcohols or
fatty oils, and may further comprise pharmaceutical
adjuvants, e.g., binders or lubricants for tabletting,
qtabilizing, flavoring or emulsifying agents.
The invention will now be further illustrated
by the following examples:
EXAMPLE 1
A: N-methyl sandwicinium iodide.
A mixture of 12 grams of sandwicine,12 ml of
methyl iodide and 500 ml of acetonitrile is heated to
reflux for about 7 to 9 hours and subsequently evaporated
to dryness. 16.0 gr. of N-methyl sandwicine iodide are
recovered as a yellow amorphous product. Yield: 93% of
the theoretical amount.
B: N-methyl substituted aldehyde base (opened ring).
16.0 gr. of N-methyl sandwicinium iodide are
suspended in 500 ml of water, 12 ml of a 10% solution of
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sodium hydroxide and 1000 ml of chloroform are added,and
the mixture is stirred for 30 minutes. After the chloro-
form phase is removed,the aqueous phase is once more stirred
with 500 ml of chloroform. The chloroform phases are
unified, dried over sodium sulfate,and evaporated to
dryness. 11.5 gr. of an amorphous residue, the aldehyde
base, are recovered. Yield: quantitative.
C: N-methyl-sandwicinium hydrogentartrate.
11.5 gr. of the above aldehyde base are dissolved
in 150 ml of methanol, a solution of 4.1 gr. of L-tartaric
acid in a small amount of methanol is added,and the
solution is introduced into 1500 ml of acetic acid ester
under thorough stirring. The pale precipitate is filtered
by ~uction, washed with acetic acid ester~and dried to
constant weight at 50C.
Melting point: 135-137C. (under decomposition).
Yield: 11.4 gr. = 69% of the theoretical amount.
EXAMPLE 2
A: N-propyl sandwicinium bromide.
A mixture of 22.0 gr. of sandwicine, 22 ml of
propyl bromide and 1000 ml of acetonitrile are heated to
reflux for about 7 to 9 hoursJwhereby a yellow precipitate
is formed. The precipitate is filtered by suction, washed
with acetonitrile,a~d dried at 50C. 20.8 gr. of N-propyl
sandwicinium bromide are reco~ered.
Melting point: 314-316C.
Yield: 69% of the theoretical amount.
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B: N-propyl substituted aldehyde base (opened ring).
20.8 gr. of N-propyl sandwicinium bromide are
suspended in 200 ml of water, 20 ml of a 10% solution of
sodium hydroxide and 200 ml of chloroform are added,and
the mixture is stirred for 30 minutes. After removing the
chloroform phase~the aqueous phase is stirred once more
with 200 ml of chloroform. The unified chloroform phases
are dried over sodium sulfate and evaporated under vacuum.
Residue: 16.2 gr. of the amorphous aldehyde base.
Yield: quantitative.
C: N-propyl sandwicinium hydrogentartrate.
16.2 gr. of the above aldehyde base are
dissolved in 50 ml of methanol, a solution of 7.0 gr. of
L-tartaric acid in a small amount of methanol is added,and
the solution is introduced into 2000 ml of acetic acid
ester under thorough stirring. After allowing the
mixture to stand for a short period of time, the white
precipitate is filtered by suction, washed with acetic
acid ester,and dried to constant weight at 50C. 21.5 gr.
of N-propyl sandwicinium hydrogentartrate are recovered.
Melting point: 205-207C. (The obtained N-propyl-
sandwicinium hydrogentartrate contains small amounts of
the corresponding iso-form compound).
Yield: 94% of theoretical amount.
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EXAMPLE 3
CAPSULES FOR ORAL APPLICATION
N-methyl sandwicinium hydrogentartrate 10 gr.
lactose 70 gr.
starch 18.5 gr.
magnesium stearate 1.5 gr.
The components are thoroughly mixed,and the
mixture is filled into gelatine capsules in portions of
100 mg per capsule.
EXAMPLE 4
One capsule, which is prepared according to
Example 3 is administered to an adult person 3 times per
day for the treatment of heart rhythm disorders.
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