DERIVES DE SUBSTITUTION DE 1-ARYLAMINO-3-AMINO-2- PROPANOLS; PREPARATION ET UTILISATION COMME AGENTS THERAPEUTIQUES

SUBSTITUTED 1-ARYLAMINO-3-AMINO-2-PROPANOLS: PREPARATION AND THERAPEUTIC APPLICATIONS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
Preparation and therapeutic activity of 1-
arylamino-3-amino-2-propanols, of general formula (I)
<IMG> (I)
where R represents an isopropyl group in ring position
2 or a methyl group in ring position 4, or an isopropyl
group in ring position 2 simultaneously with a methyl
group in ring position 5, and where NR1R2 represents an
NHC(CH3)3 group, an NHCH(CH3)2 group, or an N(CH3)2
group, and pharmaceutically suitable salts thereof,
such as the hydrochlorides.
The general preparation of these products is in
two steps: the arylamine (II)
<IMG> (II)
is reacted with epichlorohydrin in a solvent such as
ethanol at the boiling point of the solvent, yielding
the hydrochloride of (III)
<IMG> (III)

This hydrochloride, in a solvent such as ethanol
and at a temperature equal to or greater than the
boiling point of the solvent, yields, with the amine
NR1R2, the product of formula (I).
The inventive products are employed
therapeutically, notably in the treatment of
arrhythmias.
114/map

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A method of preparation of products
of general formula (I)
<IMG> (I)
where R represents an isopropyl group in ring
position 2 or a methyl group in ring position
4, or an isopropyl group in ring position 2 simulta-
neously with a methyl group in ring position
6; and where NR1R2 represents a t-butylamino
group, an isopropylamino group or a dimethylamino
group; with the proviso that R may not represent
a methyl group in ring position 4 when NR1R2
represents a dimethylamino group; and pharmaceuti-
cally suitable salts thereof, characterized in
that an arylamine of general formula (II)
<IMG> (II)
where R represents an isopropyl group in ring
position 2 or a methyl group in ring position
4, or an isopropyl group in ring position 2 simulta-
14

neously with a methyl group in ring position
6, is reacted with epichlorohydrin (III)
<IMG> (III)
in a solvent, at the boiling point of the solvent;
and in that the hydrochloride thus obtained is
reacted with the amine NHR1R2 where NR1R2 represents
an NHC(CH3)3 group, an NHCH(CH3)2 group, or
an N(CH3)2 group, in a solvent such as ethanol,
at temperatures greater than or equal to the
boiling point of the solvent.
2. A method of preparation of pharmaceuti-
cally suitable salt of products of general formula
(I)
<IMG> (I)
where R represents an isopropyl group in ring
position 2 or a methyl group in ring position
4, or an isopropyl group in ring position 2 simulta-
neously with a methyl group in ring position
6; and where NR1R2 represents a t-butylamino
group, an isopropylamino group or a dimethylamino
group; characterized in that an arylamine of
general formula (II)

<IMG> (II)
where R represents an isopropyl group in ring
position 2 or a methyl group in ring position
4, or an isopropyl group in ring position 2 simulta-
neously with a methyl group in ring position
6, is reacted with epichlorohydrin (III)
<IMG> (III)
in a solvent, at the boiling point of the solvent;
and in that the hydrochloride thus obtained is
reacted with the amine NHR1R2 where NR1R2 represents
an NHC(CH3)3 group, an NHCH(CH3)2 group, or an
N(CH3)2 group, in a solvent such as ethanol,
at temperatures greater than or equal to the
boiling point of the solvent, and converting the
product obtained into pharmaceutically suitable
salts thereof.
3. A method according to claim 1, wherein
the hydrochloride is reacted with the amine NHR1R2
where NR1R2 represents NHC(CH3)3.
4. A method according to claim 1, wherein
the hydrochloride is reacted with the amine NHR1R2
where NR1R2 represents N(CH3)2.
16

5. A method according to claim 1,
which comprises reacting 2-isopropylaniline with
epichlorohydrin to give the hydrochloride of
<IMG>
which is reacted with t-butylamine to give 1-(2-
isopropylanilino)-3-t-butylamino-2-propanol,
and optionally converting the latter compound
into pharmaceutically suitable salts thereof.
6. A method according to claim 1,
which comprises reacting 2-isopropyl-6-methylaniline
with epichlorohydrin to give the hydrochloride
<IMG>
which is reacted with t-butylamine to give 1-(2-
isopropyl-6-methylanilino)-3-(t-butylamino)-2-
propanol, and optionally converting the latter
compound into pharmaceutically suitable salts
thereof.
17

7. A product of general formula (I)
<IMG> (I)
where R represents an isopropyl group in ring
position 2 or a methyl group in ring position
4, or an isopropyl group in ring position 2 simulta-
neously with a methyl group in ring position
6; and where NR1R2 represents a t-butylamino
group, an isopropylamino group, or a dimethylamino
group; with the proviso that R may not represent
a methyl group in ring position 4 when NR1R2
represents a dimethylamino group; and pharmaceuti-
cally suitable salts thereof, whenever prepared
by the process of claim 1 or its obvious chemical
equivalents.
8. A pharmaceutically suitable salt
of a product of general formula (I)
<IMG> (I)
where R represents an isopropyl group in ring
position 2 or a methyl group in ring position
4, or an isopropyl group in ring position 2 simulta-
neously with a methyl group in ring position
6; and where NR1R2 represents a t-butylamino
group, an isopropylamino group, or a dimethylamino
18

group, whenever prepared by the process of claim
2 or its obvious chemical equivalents.
9. The product according to claim
7, characterized in that NR1R2 represents NHC(CH3)3,
whenever prepared by the process of claim 3 or
its obvious chemical equivalents.
10. The product according to claim
7, characterized in that NR1R2 represents N(CH3)2,
whenever prepared by the process of claim 4 or
its obvious chemical equivalents.
11. The product according to claim
7 which is 1-(2-isopropylanilino)-3-t-butylamino-2-
propanol, ancl pharmaceutically suitable salts
thereof, whenever prepared by the process of
claim 5 or its obvious chemical equivalents.
12. The product according to claim
7 which is 1-(2-isopropyl-6-methylanilino)-3-t-
butylamino-2-propanol, and pharmaceutically suitable
salts thereof, whenever prepared by the process
of claim 6 or its obvious chemical equivalents.
19

Description

~3~
1052-009-0
114/
TITLE OF THE INVENTIO~
SUBSTIT~T~D l-ARYLAMINO-3-AMINO-2-PROPANOLS:
PR~PARATION AND THERAPEUTIC APPLICATIONS
BACKGROUND O~ THE IN~ENTION
Field of the Invention
The present invention relates to various novel
substituted l-arylamino-3-amino-2-propanols, the
method of preparing these, and their therapeutic
applications, particularly in treatment of arrhythmias.
The general formula of the products comprising the
object of the present invention is:
4 ~ ~ C~l2 ~ Cl~ ~ CH2~R1~2 (I~
where R represents an isopropyl group in position 2 or
a methyl group in position 4/ or an isopropyl group in
position 2 simultaneously with a methyl group in
position 6, and where NRlR2 represents a t-butylamino
qroup, an isopropylamino groupl or a dimethylamino
group. The products may be in the form of the free
. base or of salts which are pharmaceutically suitable
such as the hydrochlorideq.

~?~3i~
Description of_the Prior Art
various substituted l-arylamino-3-amino-2-
propanols are already known. Thus, Ferrari, G.,
Ferrini, R., and C. Casagrande, 1968, Boll. Chim.
Farm., 107:234-247, describe 1-arylamino-3-amino-2-
propanols and reveal their beta-blocking and local
anesthetic properties. The beta-blocking propJerties of
these derivatives are either very weak or very inferior
to the beta-blocking properties of their l-aryloxy
homologs. Accordingly, these authors did not study the
properties of the compounds in more detail.
Sinha, J.N., Rastogi, V.K., and S.S. Parmar
described the specific beta-2 blocking activity of 1-
(2,4-dimethylphenylamino)-3-(1-methylethyl)amino-2-
propanol (1972, Eur. J. Pharmacol., 19:285-287).
SUMMARY OF THE INVENTION
We have discovered that the novel l-arylamino-3-
amino-2-propanols comprising the object of the present
invention have antiarrhythmic properties ~hich enables
their use in treatment of arrhythmias. They also have
local anesthetic activity, antiaggregation activity
with regard to platelets, activity against calcium
deposition or calcification, hypolipemic activity,
diuretic activity, and Hl and H2 antihistaminic
activity, thus enabling said products to be employed
therapeutically for various conditions.

-3-
The general preparation of the inventive product
begins with the arylamine (II)
~ NH2 (II)
which is reacted with epichlorohydrin (III)
Cl - CH2 - CH\-f H2 (III)
in a solvent such as ethanol at the boiling point of
the solvent, leading to the hydrochloride of (IV)
R ~ ~ C~2 ~ C~\ ~C~2 ~IV)
This hydrochloride, in the presence of the amine
NHRlR2 in a solvent such as ethanol at or above the
boiling point of the solvent yields a product of
formula (I)
NH - CH2 CH ~ CH2NRlR2 (I)
OH
where R, Rl, and R2 are as defined supra.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The examples hereinafter serve to describe the
invention in more detail without in any way limiting
its scope.

_4_ ~3~2
Example 1
1-(2-isopropylanilino)-3-(t-butylamino)-2-propanol
dihydrochloride, or COR37 05C, the dihydrochloride of a
product of formula (I) with R = 2-(1-methylethyl), and
NRlR2 = NHC(CH3)3, was prepared as follows~
One mole 2-isopropylaniline and 1.1 mole
epichlorohydrin are refluxed 24 hours in absolute
ethanol, yielding the hydrochloride of (V)
CH3
H ~ CH
NH - CH2 - C \ / H2 (V)
This is dissolved in absolute ethanol and refluxed
24 hours in the presence of a large excess of t-
butylamine. After evaporation of the solvents, the
product obtained is purified in an alumina or silica
column, ~nd recrystallized. The resulting base is
obtained in 70% yield~ Th~ ba~e is then converted to
the dihyclrochloride (COR 37 0~C~.
Physicochemical characteristics: Melting point =
140C. Melting point of the corresponding base =
82~C. NMR spectrum of the base/TMS: ~ = 1.05 ppm (1 s,
9 H, t-Bu), S = 1.25 ppm ~1 d, 6 H, J = 7 Hz; CMe2),
~ = 2.70 ppm ~1 m, 2 H; CH2N(t-Bu)); ~ = 3.2 ppm ~1 ~,

5~ 3~2
3 H, ArNCH2 ~ ArCHMe2) ~ = 3.8 ppm (1 m, 1 H: CHO)
= 6.7 ppm (1 m, 2 H, 2 aromatic protons), ~ = 7.1 ppm
(1 m, 2 H; 2 aromatic protons).
Example 2
1-(2-isopropyl-6-methylanilino)-3-(t-butylamino)-
2-propanol dihydrochloride, or COR37 06C, the
dihydrochloride of formula (I) with R = 2-(1-
methylethyl)-6-methyl, and NRlR2 = NHC(Me)3, was
prepared as follows:
One mole 2-isopropyl-6-methylaniline and 1.1 mole
epichlorohydrin are refluxed 24 hours in absolute
ethanol, yieldiny the hydrochloride of (VI)
CH3
NH ~ CB2 ~ CH ~ CH2 (VI)
C~(CH3)~
This is dissolved in absolute ethanol and refluxed
24 hours in the presence of a large excess of t-
butylamine. After evaporation of the solvents, the
product obtained i~ purified in an alumina or silica
column, and recrystallized. The resulting base is
obtained in 70% yield. The base is then converted to
the dihydrochloride (COR37 06C)~
Physicochemical characteristics: Melting point =

--6--
158DCo NMR spectrum of the base~TMS: ~ = 1.1 ppm (1
s, 9 H, t-Bu), ~ = 1.25 ppm (1 d, 6 H, J = 7 H~, CMe2);
~ = 2.3 ppm (1 s, 3 ~ ArCH3), ~ = 2.7 ppm (1 m, 2 H;
CH2NH(t-Bu)) ~ = 3.0 ppm (1 m, ~ H, ArNCH2); ~ - 3.2
ppm (1 sp, 1 H ArCHMe2), ~ = 3.8 ppm (1 m, 1 H, CHO)
= 6.9 ppm (1 m, 3 H; 3 aromatic protons).
Example 3
1-(4-methylanilino)-3-(t-butylamino)-2-propanol
dihydrochloride, or COR37 O9C, the dihydrochloride of
formula ~I) with R = 4-Me, and NRlR2 = NH(t-Bu), was
prepared as follows:
One mole 4-methylaniline and 1.1 mole
epichlorohydrin are refluxed 24 hours in absolute
ethanol, yielding the hydrochloride of (VII)
H3C { ~ NH CH2 C \ /CH2 (VII)
This is dissolved in absolute ethanol and refluxed
24 hours in the presence of a large excess of t-
butylamine. After evaporation of the solvents, the
product obtained is purified in an a~umina or silica
column, and recrystallized. The resulting base is
obtained ia 60~ yield. The base is th~n converted to
the dihydrochloride (C0~37 O9C).

~7- ~3~2
Physicochemical characteristics: Melting point of
the corresponding base = 82~C. NMR spectrum of the
base/TMS: ~ = 1.1 ppm (1 s, 9 H, t-Bu); ~ = 2.2 ppm (1
s, 3 H; ArCH3) ~ = 2.6 ppm (1 m, 2 H. CH2NH(t-Bu)):~
= 3.1 ppm (1 m, 2 H, ArNCH2); ~ = 3.7 ppm (1 m, 1 H;
CHO); and ~ = 6.5 and 6.95 ppm ~AB, 4 H, J = 8 Hz; 4
aromatic protons~.
Example 4
1-(2-isopropylanilino)-3-dimethylamino-2-propanol,
or COR37 49C, the dihydrochloride of formula (I) with R
= 2-isopropyl, and NRlR2 = NMe2, was prepared as
follows:
The hydrochloride of ~V), prepared according to
Example 1, is dissolved in absolute ethanol and
maintained 24 hours in an autoclave at 100C in the
presence of a large excess of dimethylamine. After
evaporation of the solvents, the product obtained is
purified in an alumina or silica column, and
recrystallized. The resulting base is obtained in 47%
yield. 'rhe ba~e is then converted to the
dihydrochloride (COR37 49C).
Physicochemical properties: MMR spectrum of the
. ba~e/TMS: ~ = 1.15 ppm (l d, 6 H, J = 6 Hz, CMe2). ~ =
1.95 ppm (1 ~, 6 H, NMe2), ~ = 2.5 to 3.3 ppm (1 m, 5
H~ CMe2 ~ 2 CH2N), ~ = 3.8 pp~ (1 m, 1 H; C~10) ~ = 6.

-8- ~D~3
ppm (1 m, 2 H, 2 aromatic protons~' ~ = 6.95 ppm (1 m
2 H, 2 aromatic protons)
Example 5
1-(2-isopropyl~6-methylanilino)-3-dimethylamino-2-
propanol, or COR37 50C, the dihydrochloride of formula
(I) with R = 2-(1-methylethyl)-6-methyl, and NRlR2 =
NMe2, was prepared as follows
The hydrochloride of (VI), prepared according to
Example 2, is dissolved in absolute ethanol and
maintained 24 hours in an autoclave at 110C in the
presence of a large excess of dimethylamine. After
evaporation of the solvents, the product obtained is
purified in an aluminum or silica column, and
recrystallized. The resulting base is obtained in 42%
yield. The base is then conver~ed to the
dihydrochloride (COR37 50C).
Physicochemical characteristics: NMR spectrurn of
the base/TMS: ~ = 1.25 ppm (1 d, 6 Hl J = 6 Hz, CMe2),
~ = 2.25 ppm (1 ~, 9 H. Ar ~ + NMe2), ~ = 2.5 to 3.5
ppm (1 m, 5 H, CHMe2 + 2 NCH2): ~ = 3.85 ppm (1 m, 1 H,
CHO), ~ = 7.0 ppm (1 mJ 3 H, 3 aromatic protons).
The toxicological and pharmacological properties
of the inventive products will now be described:
The acute lethal toxicity W25 determined o~
mice. By oral administration, in solution in Tween,
COR37 05C caused 0% mortality at 500 mg/kg, 40~ at 750,

~L~a~
and 40~ at 1000 mg/kg. ~iortality with COR37 06C was 03
at 100 mg/kg, 10~ at 200, 10~ at 250, 90% at 375, and
100% at 500 ppm (L~50 = 294 mg/kg (261 to 332)).
t~ortality with C0~37 ~9C, COR37 49C, and COR37 50C was
0~ at 300 my/kg. Intraperitoneally, in solution in
'l'ween, COR37 05C caused 0% moetality at 200 mg/kg.
Mortality with CoR37 06C was 0% at 100 mg/kg and 100%
at 200 mg/kg. Mortality with COR37 09C was 0~ at 50
mg/kg and 100% at 100 mg/kg. I~ortalities with COR37
49C and CoR37 50C were 0% at 200 mg/kg. Intravenously,
the LD50 of COR37 05C was 56 mg/kg (53.8 to 59.5).
The antiarrhythmic activity was determined on
various models. COR37 05C and COR37 06C administered
intraperitoneally to mice undee profound chloroEorm
anesthesia had antiarrllythmic activity beginning at a
dose of 25 mg/kg, and COR37 50C at 100 mg/kg. Under
the sama conditions, propranolol is active at a dose of
40 mg/kg, and quinidirle at a dose of 100 mg/kg.
In vitro, on an isolated ateium of a guinea pig,
stimulated electrically, COR37 05C and COR37 06C were
active with Ci30 of 6.22 (4.37 to 8.86) x 10-6
moles/liter and 7.26 (~.68 to 11.2) x 10 6 mole~liter,
re~pectively, compared to 10 5 moles/liter for
procaine, 4 ~ 10 6 moles/liter for quinidine, and 4.5 x
10-6 moles/liter for propeanolol.
*Trademark
~ ~..
; r

~3~
--10--
Tl-ese products were tested on the model of
aconitine induced arrl~ythmia in rats. The results are
expressed as the percellt increase in the amount of
aconitine to produce extrasystoles (E), fibrilloflutter
(F), tachycardia (T), and death (D). When administered
by i.v. prior to infusion of aconitine, 10 mg/kg CoR37
05C showed the following activity: E 78%, T 87~, and D
83~. Activity of 5 mg/ky COR37 06C was E 45%, T 39%,
and D 79%. When administered orally 45 minutes prior
to perfusion of aconitine, the activity of 100 mg/kg
COR37 05C was F, ~3~, T 99%, F 43~, and D 107~, and that
of 100 mg/kg COR37 06C was E 25%, T 32%, F 29~, and D
105~. Further, after oral administration of COR37 05C
and COR37 06C, tlle percent of animals showing no
fibrillofluttering was 70~ and 60%t respectively.
The local anesthetic activity was determined in
tests on guinea pig corneas subjected to tactile
stimulation. COR37 06C employed in a concentration of
0.5~ was active for 30 minutes.
The antiaggregation activity on platelets wa~
determined in vitro. On the model of platelet-rich
plasma (PRP) of rabbits, aggregation induced by 0.05 ml
of a atandardized preparation of bovine collagen was
inhibited 100~ by CoR37 06C at 1 microgram/ml, as
compared ta 10 ~Ig/ml Aspirin or 0.5 ~g/ml
indometllacin. On the same model, aggregation of
~Trademark

3V~
platelets induced by ADP, 100 ~g/ml COR37 09C had
inhibiting activity of 79%, C0~37 50C 80%, and
adenosine 64~.
The products according to the present invention do
not have beta-blocking activity. This was determined
in vitro on guinea pig atriums stimulated electrically,
with activity measured in terms of blocking of the
inotropic action of isoproterenol; and in vivo on
tachycardia induced by isoproterenol in mice, and on
the inhibiting activity on the effects of isoproterenol
on arterial pressure and cardiac frequency in
anesthetized normal rats. COR37 05C is not active with
respect to beta-2 adrenergic receptors' and COR37 06C,
COR37 09C, COR37 49C, and COR37 50C do not have beta-
blocking properties.
The activity against calcium deposition and
calcification was detertnined in vitro on the left
atrium of a guinea pig stimulated electrically at 150
beats/min, with the test compound in a Tyrode's
solution low in calcium (0.6 mM~. COR37 49C and COR37
50C at 100 ~g/l inhibited the increase of the
contractile force induced by the addition of 0~6 mM of
calcium.
The hypolipemic activity was demonstrated in mice
rendered hypercholesterolemic by a regimen rich in
cholesterol and cholic acid administered for 7 days.

-12-
Administration of COR37 49C at 400 mg/kg on days 6 and
7 resulted in a 22% reduction of serum cholesterol.
The diuretic activity was determined on the rat.
COR37 49C administered in an oral dose of 20 mg/kg to a
rat which had been administered excess water, increased
the urinary excretion of sodium by a factor of 2.2.
The anti-H2 antihistaminic activity was
demonstrated in vitro. On the model comprised of the
right atrium of a guinea pig without stimulation, 25
~g/ml COR37 49C produced 50% inhibition of the
chronotropic effect induced by 5 ~g/ml histamine.
The anti-Rl antihistaminic activity was
demonstrated in vitro on guinea pig ileum. 25 ~g/ml
COR37 49C produced 80% inhibition of the contractions
induced by histamine.
Taking into account their pharmacological
activities as well as their moderate toxicity, the
inventive products may be employed in human and
veterinary therapy. Formulated with customary
excipients, they may be used, for example, in treating
cardiac arrhythmias. They may also be employed in
local anesthesia by infiltration or conduction, in
contact anesthesia, in treatment of hyperaggregability
states of platelets, treatment of hyperlipemia,
hyperlipoproteinemia and edematous states, ulcerous
disorder~, allergic or pruritic conditions, and
transport disorders.

~;~3 ~3~
-13-
They may be administered orally in the form, e.g.,
of coated pills, compressed tablets, syrups, or
capsules; rectally in the form of suppositories;
intramuscularly or intravenously, or topically in the
form of an ointment or gel. Dosages will vary
according to the indication and the patient, from 1 to
100 mg/day in one to six oral administrations or one or
two administrations rectally, or from 0.5 to 50 mg per
day parenterally by injection.