COMPOSE PHARMACEUTIQUE CONTENANT UN PHENYL-AMINO- ALCOOL SUBSTITUE ET PROCEDE DE PREPARATION

PHARMACEUTICAL COMPOSITIONS COMPRISING SUBSTITUTED PHENYL-AMINO-ALCOHOL AND PROCESS FOR PREPARING THESE COMPOSITIONS

Abrégé anglais

"Continental Pharma"
"Pharmaceutical compositions comprising substituted phenyl-amino-
alcohol and process for preparing these compositions"
ABSTRACT OF THE DISCLOSURE.
A hydrosoluble pharmaceutical composition based
on a substituted phenyl-amino-alcohol as active ingredient,
wherein said amino-alcohol is provided in association with
glucuronic acid.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for preparing a hydrosoluble pharmaceutical
composition based on substituted phenyl-amino-alcohol as active
ingredient, comprising reacting glucuronic acid with a sub-
stituted phenyl-amino-alcohol in a solvent.
2. A process according to claim 1 wherein said substituted
phenyl-amino-alcohol has the formula:
<IMG>
wherein R1 is an alkyl radical of 1 to 4 carbon atoms, R2 is
an alkyl radical of l or 2 carbon atoms and R3 is an alkyl
radical of 4 to 16 carbon atoms.
3. A process as claimed in claim 1 wherein an at least
equimolecular amount of said substituted phenyl-amino-alcohol
is gradually added to an aqueous solution of glucuronic acid,
and the mixture is stirred until a clear solution is obtained.
4. A process as claimed in claim 1 wherein an aqueous
solution of glucuronic acid is added to said substituted phenyl-
amino-alcohol in suspension or solution in a solvent.
5. A process as claimed in claim 3 wherein water or a
mixture of water and water miscible organic solvents, such as
alcohols, more particularly methanol, ethanol, isopropanol,
dioxan and tetrahydrofuran, is used as solvent.
6. A process as claimed in claim 1 wherein glucuronic
acid is heated before contacting it with said substituted
phenyl-amino-alcohol to a temperature of 40-60°C.
7. A process as claimed in claim 1 wherein the solvent
is eliminated after reaction between glucuronic acid and said
substituted phenyl-amino-alcohol until reaction products are
obtained as a powder.

8. A process as claimed in claim 1 wherein a salt of
glucuronic acid is reacted with a salt of said substituted
phenyl-amino-alcohol and then the residual salt resulting from
the double decomposition is eliminated.
9. A process according to claim 1 wherein glucuronic
acid is D-glucuronic acid.
10. A process according to claim 2 wherein R1 is an
isopropyl radical, R2 is a methyl radical and R3 is an alkyl
radical of 6 to 14 carbon atoms.
11. A process according to claim 10 wherein the substituted
phenyl-amino-alcohol is 1-(4-isopropylthiophenyl)-2-n-octylamino-
1-propanol.
12. A hydrosoluble pharmaceutical composition based on
substituted phenyl-amino-alcohol as active ingredient, wherein
said amino-alcohol is provided in association with glucuronic
acid, the composition having been prepared by the process of
claim 1 or any obvious chemical equivalent thereof.
13. A hydrosoluble pharmaceutical composition prepared
by the process of claim 2 or any obvious chemical equivalent
thereof.
14. A hydrosoluble pharmaceutical composition prepared
by the process of claim 3 or any obvious chemical equivalent
thereof.
15. A hydrosoluble pharmaceutical composition prepared
by the process of claim 4 or any obvious chemical equivalent
thereof.
16. A hydrosoluble pharmaceutical composition prepared
by the process of claim 5 or any obvious chemical equivalent
thereof.

17. A hydrosoluble pharmaceutical composition prepared
by the process of claim 6 or any obvious chemical equivalent
thereof.
18. A hydrosoluble pharmaceutical composition prepared
by the process of claim 7 or any obvious chemical equivalent
thereof.
19. A hydrosoluble pharmaceutical composition prepared
by the process of claim 8 or any obvious chemical equivalent
thereof.
20. A hydrosoluble pharmaceutical composition prepared
by the process of claim 9 or any obvious chemical equivalent
thereof,
21. A hydrosoluble pharmaceutical composition prepared
by the process of claim 10 or any obvious chemical equivalent
thereof.
22. A hydrosoluble pharmaceutical composition prepared
by the process of claim 11 or any obvious chemical equivalent
thereof.
11

Description

109~416
This invention relates to a hydrosoluble pharmaceu-
tical composition based on a substituted phenyl-amino-alcohol.
The advantage of having hydrosoluble forms of medi-
caments is multiple. As a matter of fact, in addition to the
possibility of administering such medicaments parenterally, a
hydrosoluble form has several other advantages, namely to
allow an optimum distribution of the medicament to be obtained
surely when screening tests are made and also to allow in
vitro tests to be carried out. In therapeutics, an injectable
form also allows to obtain a quick medicament action.
To administer medicaments orally, it is also some-
times interesting to have rather hydrosoluble compounds with
the object of accelerating or modifying the active product
absorption.
An object of the invention is to provide a pharma-
ceutical composition based on a substituted phenyl-amino-
alcohol having a substantially unlimited water solubility.
According to the invention, the substituted phenyl-
amino-alcohol is provided in the pharmaceutical composition in
20 association with a glucuronic acid.~ The phenyl-amino-alcohol ~:
advantageously has the general formula:
RlS ~ - CHOH-CH-NHR3 (I)
R2
wherein Rl is an alkyl radical of 1 to 4 carbon atoms, R2 is
an alkyl radical of 1 or 2 carbon atoms and R3 is an alkyl
radical of 4 to 16 carbon atoms.
The hydrosoluble pharmaceutical composition is
prepared by reacting glucuronic acid with the substituted
phenyl-amino-alcohol in a solvent.
~k
~l ,

10~5416
This invention also provides a method of use of
said pharmaceutical composition in which this composition is
administered intravenously or orally in doses between 1 and
50 mg/day.
The invention is based on the fact that it has been
found that glucuronic acid, and more particularly D-glucuronic
acid, is able to give such substituted phenyl-amino-alcohols a
quite remarkable hydrosolubility which is impossible to reach
with other kinds of acids. Such amino-alcohols have been
10 described in Belgian Patent 799,379.
Other details and particularities of the invention
will become apparent from the following description given by way
of a non limitative example of several embodiments of the com-
position, the process for preparing this composition and its use.
Amino-alcohols which are of a particular interest for
the hydrosoluble pharmaceutical composition according to the
invention are more particularly those of formula (I) wherein
Rl is an isopropyl radical, R2 is a methyl radical and R3 is an
alkyl radical of 6 to 14 carbon àtoms.
More particularly for compound 1-(4-isopropylthio-
phenyl)-2-n-octylamino-1-propanol, the water solubility of the
glùcuronate is unlimited while it is only of 1510 mg/l for
hydrochloride, of 550 mg/l for succinate, of 1505 mg/l for
citrate and of 4720 mg/l for lactate.
In general, it is known that these amino-alcohols
have a very high therapeutical interest and have activities
on cardiovascular system, as antihypertensive agent, antispas-
modic agent, peripheral vasodilatator, protecting agent against
myocardium anoxia, bronchodilatator, ~-lytic agent, normolipi-
demient agent, normolipoproteinement agent, inhibitor of

1095416
platelet aggregation and stimulator of cerebral energetic
metabolism. Moreover, these compounds allow to act on the
central nervous system, for example as tranquillizer.
The acute toxicity with an i.v. administration was
studied on mice for l-(4-isopropylthiophenyl)-2-n-octylamino-
l-propanol glucuronate.
DL50 is 20 mg/kg (confidence limits for p = 0,95
: 18-22 mg/kg).
The oral toxicity on mice is similar to that of
1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol(~ 4000 mg/
kg).
The tolerance after repeated i.v. administrations
(5 successive days) was studied on rabbits. No anomaly was
observed till the dose of 0,03 mg/kg/ml.
The effects of 1-(4-isopropylthiophenyl)-2-n-octyla-
mino-1-~opanolgl~curonate are atleast thesame as those of the
1-(4-isoprophylthiophenyl)-2-n-octylamino-1-propanol itself).
The antispasmodic activity was compared on guinea
pig ileum (inhibition of the contractions caused by histamine)
and on rat aorta (inhibition of the contactions caused by
calcium on depolarized bands).
The results are at least similar for both compounds.
The activity is of the musculatrope type, comprising a 6pecific
inhibition of movements of calcium ions. On guinea pig
ileum, the PD~2 values (logarithm of the molar concentration
reducing maximum concentration by 50%) are 6.42 (- 0.19) and
6.66 (- O.O9)respectively for glucuronate and 1-(4-isopropyl-
thiophenyl)-2-n-octylamino-1-propanol. These two values are
significantly different.
On rat aorta, the PA2 values in relation to calcium
(logarithm of the molar concentration for which the effect of
a double antagonist dose is reduced to that of a simple dose)
are 7.52 ~ - 0.08) and 7.46 (- 0.19) respectively for 1-(4-
isopropylthiophenyl)-2-n-octylamino-1-propanol glucuronate
and for l-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol.
The anti-platelet and antithrombotic activity was
studied under various conditions.

1095416
The 1-(4-isopropylthiophenyl)-2-n-octylamino-1-
propanol was tested relating to its antithrombotic activity
on thromboses induced in rats by applying ADP on mesenteric
arteries having previously received a standard electric sti-
mulation.
Formation of thrombus is significantly reduced
(by 80%) at a dose of lmg/kg i.v. It is also found that the
latency period before a thrombus appears is increased and that
the formation rate is decreased. The duration of the protec-
tion effect of the product is 1 hour.
By using the filter loop technique, it is remar-
ked that the product, at a dose of lmg/kg i.v. inhibits the
platelet aggregation induced by ADP by 70% and is ten times
as active as a reference drug such as dipyridamole.
The stability of 1-(4-isopropylthiophenyl)-2-n-
octylamino-l-propanol glucuronatein aqueous solu~ion ~asrevealed as
bein~ exce~ent;a so~fn ~ lm~ does n~ shcw any detectaole varia-
tion of the product content after 110 days at 20 C and 40 C.
Compatibility of 1-(4-isopropylthiophenyl)-2-n-
octylamino-l-propanol glucuronate with the most current clini-
cally used perfusion solutions (Ringer lactate and glucidic
Trophysan 100 for example) has also revealed very favourable.
The hydrosoluble pharmaceutical composition accor-
ding to the invention can be prepared by reacting glucuronic
acid and substituted phenyl-amino-alcohol in a preferably
aqueous solvent.
This reaction can be for example carried out by
slowly adding an equimolecular amount of phenyl-amino-alcohol
to an aqueous solution of glucuronic acid, this mixture being
stirred until a clear solution is obtained.
The obtained aqueous solution can be directly used
for therapeutical uses or can be brought to the desired concen-
tration by concentration or dilution.
In some cases, it may be advantageous to heat the
aqueous solution of glucuronic acid before addition of phenyl-
amino-alcohol, preferably to a temperature of 40-60C.
A low excess of glucuronic acid may be optionally
used.

lO~t~4~6
Inversely, it is possible to add the aqueous so-
lution of glucuronic acid to the substituted phenyl-amino-
alcohol, the latter being optionally suspended in water.
According to the invention, the eompound can also
be diss~ved and suspended in water or in a mixture of water
miscible organic solvent, such as alcohols, more particular-
ly methanol, ethanol, isopropanol, dioxan and tetrahydrofuran.
After addition of glucuronic acid, the solution
may be still evaporated under reduced pression or lyophilised
in the case of aqueous solutions.
So a water soluble powder is obtained, which can be
used for preparing aqueous solutions having wished dilution
(extemporaneous preparation).
In some eases, it may be useful to prepare hydroso-
luble pharmaceutical compositionsaccording to the invention ^-
from a phenyl-amino-aleDhol salt, sueh as for example hydro~
ehloride, by double decomposition with a glueuronie aeid salt,
for example barium glucuronate, most advantageously in aqueous
solution. The residual salt resulting from this double deeom-
position, for example barium ehloride, is then filtered out.
Although the pharmaeeutieal eomposition aeeording
to the invention may be administered orally, due to its very
high water solubility, it is more pa~tieularly suitable for
administration by intravenous injeetion or perfusion.
Due to the low toxieity of glueuronie aeid, it is
possible to obtain eompositions having a very favourable the- 3
rapeutieal index.
The invention is still illustrated by a number of
preparation examples of speeifie eompositions aeeording to
the invention.
Example 1
20 g (0.103 mole) of D-glueuronie aeid and 30.9 g
( ~.l mole) of 1-(4-isopropylthiophenyl)-2-n-hexylamino-1-
propanol are mixed with 20 ml of water. A elear syrup is
formed, which can be diluted with distilled water at will.
By lyophilisation of the solution, 52 g of dry product is
obtained (comprising 2.1% of water).

10C~S4~6
Example 2.
24 g (0.127 mole) of D-glucuronic acid and 41.9 g
(o.l mole) of 1-(4-isopropylthiophenyl)-2-n-tetradecylamino-
1- propanol are mixed with 50 ml of water. Stirring is made
until complete solution (a few minutes). So a clear solution,
which can be diluted with distilled water at will is obtained.
Example 3.
20.4 g (0.105 mole) of D-glucuronic acid are dissol-
ved in 283.5 g of water and 33.76 g(0.1 mole) of 1-(4-isopro-
pylthiophenol)-2-n-octylamino-1-propanol are added to this
solution with stirring . Stirring is continued until complete
solution, which requires about 1/2 hour. A clear solution
containing 10% of 1-(4-isopropylthiophenyl)-2-n-octhylamino-
l-propanol is so obtained.
Instead of treating at room temperature, as in the
present example, higher temperaturesare used according to a
variant, more particularly in water heated to about 60C.
Example 4.
To 33.76 g (0.1 mole) of 1-(4-isopropylthiophenyl)-
2-n-octylamino-1-propanol dissolved in 330 ml of tetrahydro-
furan, l9r 41 g (0.1 mole) of D-glucuronic acid and 50 ml of
water are added and stirring is continued until complete
solution of glucuronic a~d, which requires about 2 hours.
Solvents are evaporated under vacuum and 53.3 g of dry pro-
duct are obtained.
The preparation of injectable solutions or of aque-
ous solutions for oral administration can be made directly
from a solution prepared according to Example 2 or from a so-
lid product prepared according to Example 1 after dissolution
in water.
Hereinafter two typical galenic formulations are
still given for in~ectable compositions.
1 l-(4-isopropylthiophenyl)-2-n-octylamino-1-
p~opanol 1 m~
D-glucuronic acid 0.6 mg
Anhydrous dextrose 55.1 mg
~idist. water, q.s. 1 ml
2 l-(4-isopropylthiophenyl)-2-n-octylamino-
l-propanol 20 mg

8 1o954l6
D-glucuronic acid 12 mg
Anhydrous dextrose
Bidist, water, q.s. 1 ml
The da~y doses of substituted phenyl-amino-
alcohols in association with glucuronic acid, proposed for
humans, are about 1 to 50 mg, preferably 0.001 to 1 mg/kg.
Application is preferably made by intravenous in-
jection or perfusion.