Note: Descriptions are shown in the official language in which they were submitted.
~o74338
NOVEL ARYLOXYAMINOBUTANOL DERIVATIVES AND A PROCESS
FOR THE PREPARATION THEREOF
This invention relates to novel aryloxyaminobutanol
derivatives and pharmaceutical compositions containing the
same, furthermore to a process for the preparation thereof.
Se~eral B -sympatholitics containing l-aryloxy-3-alkylamino-
propane-2-ol moieties are utilized for the treatment of the
disorders of cardiac rhythm, as well as to suppress the
symptoms of angina pectoris. These compounds cannot be utilized,
1~ however, for the treatment of patients suffering from asthma,
since they may cause asthmatic attacks by inhibiting the
-receptors of the bronchial smooth musculature. Due to
their ability to cause cardiac weakness these compounds
may not be administered in decompensation or infarction con-
ditions either.
The aim of our research work performed in the
field of ~-receptor blocking agents has been to prepare
pharmacologically active substances which retain ~he anti-
arrhythmic and other pharmaceutically advantageous activities
or even have increased activites, but are practically free
of the above undesired side effects. We have found that
certain novel aryloxyaminobutanols meet these requirements.
Accordingly, this invention r01ates to novel aryl-
oxyaminobutanols of the general formula (I~
R-G-cH2-cH-cH2-cH2-NH-R (I)
OH
or their stereoisomers or non-toxic acid addition salts, wherein
R stands for an optionally substituted aryl group, and R1 stands for
an alkyl cycloalkyl or an optionally ring-substituted aralkyl group.
-1- ~
1074338
The invention also relates to a process for the preparation
of a compound of the general formula ~I),
R-O-CH2-fH-CH2-CH2-NH-R (I)
OH
or a stereoisomer or a non-toxic acid addition salt thereof, wherein R
stands for optionally halogeno or alkyl or alkoxy substituted phenyl or
naphthyl group, and Rl stands for a C5 9 cycloalkyl-, Cl 7 alkyl- or
phenyl-Cl 6 alkyl group in which
a) a compound of the general formula ~II).
R O CH2 ICH CH2 CH2 N C \ R3 (II)
OH
wherein R has the same meanings as defined above, R2 stands for hydrogen,
alkyl, aralkyl or aryl and R stands for alkyl, aralkyl or aryl, or
R2 and R3 may form together an alkylene chain, is reduced, or
b) a compound of the general formula ~III),
R-O-CH2-fH-CH2-CH2-NH2 (III)
OH
wherein R has the same meanings as defined above is reacted with a com-
pound of the general formula (IV),
X - R (IV~
wherein Rl has the same meanings as defined above, and X stands for
halogen atom or sulphate or phosphate or alkylarysulphonate group, or
c) a compound of the general formula (V),
R
C= O (V)
R3 /
wherein R2 and R3 each have the same meanings as defined above, is re-
acted with a compound of the general formula (III),
R-O-CH -CH-CH2-CH2-NH2 ~III)
OH
--2--
1074338
wherein R has the same meanings as defined above, and the
obtained product is reduced simultaneously with or after
the reactionJ and, if desired, a compound of the general
formula CI) is converted into its non-toxic acid addition
salt, or a salt of a compound of the general formula (I)
is converted into the free base.
If R stands for an aryl group, this group is
preferably naphthyl or phenyl. As mentioned above, this
aryl group may optionally be substituted e.g. with a
halogen atom, an alkyl, alkoxy, amino or nitro group.
If R stands for alkyl, this group may contain 1 to 7
carbon atoms Csuch as methyl, ethyl, propyl or
isopropyl). The cycloalkyl groups mentioned in the
definition of Rl may contain 5 to 9 carbon atoms, such
as cyclohexyl, cyclopentyl or cycloheptylO If Rl stands
.
1~74338
for aralkyl this group may be e.g. benzyl, phenethyl or phenylpropyl. R2
may stand for a Cl 7 alkyl (such as methyl, ethyl, propyl or isopropyl), a
C5 9 cycloalkyl (such as cyclohexyl, cycloheptyl or cyclooctyl) or an
aryl (such as phenyl or naphthyl)group. If R3 stands for alkyl, this group
may contain preferably 1 to 7 carbon atoms, such as methyl, ethyl, propyl
or isopropyl. Of the aralkyl groups mentioned in the definition of R3
reference is made to benzyl, phenethyl and phenylpropyl. If R3 stands for
aryl, this group may be e.g. phenyl or naphthyl. As mentioned above, R2
and R3 may be attached to form an optionally substituted C5 9 alkylene chain.
X stands for a leaving group, preferably a group promoting alkylation, such
as a halogen atom (e.g. chlorine, bromine or iodine), a sulfate, phosphate
or alkylarylsulfonate group (e.g. tosylate or mesylate group).
In process variant a) of the invention the compounds of the
general formula (II) are reduced preferably with nascent hydrogen, a metal
borohydride, such as potassium or calcium borohydride, preferably sodium
borohydride, or by catalytic hydrogenation. As catalyst, preferably palladium
or nickel is used. The reduction can equally be carried out in aqueous or
organic media. As organic solvent preferably a Cl 3 alkanol is applied. The
compounds of the general formula (II), used as starting substances, can be
prepared by condensing a compound of the general formula (III) with a com-
pound of the general formula (V). The condensation can be performed by heat-
ing the mixture of the reactants in the absence of solvent, or in an organic
solvent medium, preferably benzene or toluene, at the boiling point of the
mixture. A dehydrating agent, such as potassium carbonate can be added to
the reaction mixture, if necessary. This Schiff-base formation can be pro-
moted by adding a catalytic amount of an amine salt, e.g. an amine hydrochlo-
ride, to the reaction mixture.
In process variant b) of the invention a cornpound of the general
formula (III) is condensed with a compound of the general formula (IV) in an
organic solvent medium, preferably in an alkanol or dimethyl formamide, at
the boiling point of the reaction mixture. According to a preferred method
a substance is added to the reaction mixture which can bind the molecule
--4--
1074338
split off during the condensation. If this molecule is a hydrohalide, a
basic substance, preferably an alkali metal carbonate (such as potassium or
sodium carbonate, or sodium hydrocarbonate) is added to the system.
In process variant c) of the invention a compound of the general
formula (III) is reacted with a compound of the general formula (V) in an
organic solvent medium, preferably an alkanol, by reducing the intermediate
simultaneously with or after the condensation. The reduction is carried out
by shaking the mixture in the presence of hydrogen and a catalyst a~ room
temperature and under atmospheric pressure. As catalyst, a platinum-on-
carbon or palladium-on-carbon system, or nickel is used.
The compounds of the general formula (III~, used as starting sub-
stances according to process variants b) and c) of the invention, can be
prepared by reducing a compound of the general formula (VI),
R-O-CH2-CH-CH2 C = N ~VI)
OH
wherein R has the same meanings as given above. This reduction can be pre-
formed with a metal hydrode or by catalytic hydrogenation. In the latter
case the process is conducted preferably in an alkanol medium under a
pressure of 5 to 8 atmospheres. As catalyst platinum, or, more preferably,
Raney-nickel can be used.
The non-toxic acid addition sal~s of the compounds having the
general formula (I) are prepared by conventional reactions with organic
or mineral acids. The maleates of the compounds of the general formula (I)
possess particularly favourable properties.
The compounds according to the invention are excellent heart-specific
~-sympatholitics. The pharmacological effects of these new compounds were
compared with those of the three well-known ~-receptor blocking agents
widely used ih the t~erapy: l-isopropylamino-3-~1-naphthyloxy)-propane-1-ol
hydrochloride ~Propranolol hydrochloride, InderalR), l-isopropylamino-3-
(2-allyl-oxyphenoxy)-propane-2-ol hydrochloride (Oxprenolol hydrochloride,
TrasicorR) and ~-~2-hydroxy-3-isopropyl-aminopropoxy)-acetanilide CPractolol,
Dalzic ).
1~74338
Several new compounds of the invention exhibited excellent activit-
ies in ths pharmacological tests. Of these compounds l-(l-naphthyloxy)-
4-cyclohexylamino-butane-2-ol maleate, referred to in the following as
Compound A, proved to be outstandingly preferable. The acute toxicity of
Compound A, determined on mice after intravenous administration, is LD5~ =
50 mg./kg., the corresponding toxicities of Propranolol. Oxprenolol and
Practolol are 37.5 mg./kg., 45.5 mg./kg., and 132.5 mg./kg., respectively.
Compound A, like the three reference substances, showed negative
chronotropic and negative inotropic effects on frog heart isolated according
to the method of Straub. The positive chronotropic and inotropic effects
of isoproterenol cannot be inhibited with Oxprenolol and Propranolol, whereas
Compound A is able to inhibit this harmful effect as well.
Compound A exerts a vasodilatating effect on Trendellenburg frogs
~a 20 to 28% increase of the droplet number occurs), while the reference
substances do not influence the droplet number.
Compound A, like the reference substances, decreases the pulse
number on Langendorff rat heart preparates. Of the four substances tested
Compound A and Propranolol proved to be the most active ones in reducing the
increase of pulse rate caused by isoproterenol.
Compound A, like the reference substances, does not influence the
breath number and breath volume of rabbits.
With respect to the coronaria circulation of open-chest, artificial-
ly breathing dogs the action of Compound A is similar to that of Inderal,
Trasicor and Dalzic, that is in small dosages it does not influence the
coronary flow, and even in high dosages it decreases the coronary flow ~o
only a minor extent.
Compound A has no cardiac weakening effect on Starling cat heart-
lung prepara~es. This compound, when examined on cats, inhibits the arrhyth-
mia caused by Strophantine, and decreases the toxicity of Strophantine. In
this respect the activity of Compound A is superior to that of Oxprenolol and
Practolol, and about equal to that of Propranolol.
It is a very important feature that the blocking activity of Compound
--6--
1074338
A supersedes those of all the three reference substances with respect to the
suppression of aconitine arrhythmia. A significant advan~age of the novel
compounds according to the invention in comparison with the known substances
is that they are heart-specific, being therefore more widely applicable in
the therapy, and that their undesirable side-effects are notably weaker.
This specificity is indicated characteristically, for instance, by the
fact that Compound A, while possessing essentially similar or even stronger
activities in the various anti-arrhythmic tests than the reference substances,
provokes bronchial spasm to a considerably lower extent than the known sub-
stances.
The extent of bronchial spasm, provoked by the compounds under
examination, can be delermined as follows:
A spray containing 0.3% of histamine is made inhalated by Guinea
pigs. This treatment causes bronchial spasm with the control animals within
112 seconds. When the animals are pre-treated with Propranolol, Oxprenolol
and Practolol, respectively, the bronchial spasm appears already 20 to 25
seconds after the inhalation, whereas with the animals pre-treated with
Compound A this effect appears only 75 to 80 seconds after the histamine
treatment.
Similar results were obtained in the self-control tests performed
on Guinea pigs with respect to the bronchial spasm provoked by histamine.
According to this test Inderal, Trasicor and Dalzic decrease the period
elapsed until the appearance of bronchial spasm by about 25 to 45%, whereas
Compound A has no effect on this period.
The compounds of the invention can be converted into pharmaceutical
compositions by admixing them with inert, non-toxic solid or liquid diluents
or carriers usable in the pharmaceutical industry. The pharmaceutical com-
positions can be formulated into solid compositions, e.g. tablets~ film-coated
tablets, enterosolvent dragees, pills, capsules, or into liquid compositions,
such as suspensions, solutions or emulsions. These compositions may contain
optionally other therapelltically active substances as well.
The most advantageous representatives of the novel compounds accord-
--7--
1074~3~
ing to the invention are as follows:
l-(l-naphthyloxy)-2-hydroxy-4-cyclohexylaminobutane maleate,
l-(l-naphthyloxy)-2-hydroxy-4-isopropylaminobutane maleate,
l-(l-naphthyloxy)-2-hydroxy-4-~phenylprop-2-yl)-aminobutane maleate,
1-(2,3-dichlorophenoxy)-2-hydroxy-4-isopropylaminobutane maleate,
l-phenoxy-2-hydroxy-4-~1-phenyl-prop-2-yl~-aminobutane maleate, and
l-phenoxy-2-hydroxy-4-cyclohexylaminobutane maleate.
The invention is elucidated in detail by the aid of the following
non-limiting Examples.
ExamPle 1
A mixture of 34.6 g. ~0.15 moles~ of 3-hydroxy-4-~1-naphthyloxy)-
butylamine, 14.7 g. ~0.15 moles) of cyclohexanone and 400 ml. of dry benzene
is refluxed for 80 minutes. Thereafter the benzene is evaporated under
reduced pressure, the Schiff-base obtained as a residue is dissolved in 400 ml.
of methanol, and reacted with 5.8 g. of sodium borohydride for one hour
under shaking and cooling with water ~at a temperature not exceeding 40C).
After 3 hours of standing the mixture is diluted with 200 ml. of water,
extracted with 4x50 ml. of chloroform, the chloroform extracts are combined,
dried and evaporated. The base obtained as a residue is dissolved in 100 ml.
of ethanol and reacted with 16 g. of maleic acid under gentle heating. 52.4
g. of l-~l-naphthyloxy)-2-hydroxy-4 -cyclohexylaminobutane maleate are
obtained; m.p.: 163-165C ~after recrystallization from ethanol). LD50 =
50 mg./kg.
Example 2
A mixture of 3.46 g. ~0.015 moles) of 1-(1-naphthyloxy)-2-hydroxy
-4-aminobutane, 1.47 g. of cyclohexanone, 2 g. of 8% palladium-on-carbon and
20 ml. of ethanol is hydrogenated at room temperature under atmospheric
pressure with shaking. When the hydrogen uptake ceases the catalyst is
removed by filtration, and 1.6 g. of maleic acid are added to the filtrate
under gentle heating. Upon cooling, crystalline l-~l-naphthyloxy)-2-hydroxy
-4-cyclohexylaminobutane maleate separates from the reaction mixture; m.p.
164-165C.
--8--
1~433~
Example 3
A mixture 5.78 g. (0.025 moles) of 1-~1-naphthyloxy)-2-hydroxy-4-
aminobutane, 4 g. of dry acetone and 60 ml. of benzene is refluxed for one
hour, and the mixture is evaporated. The residueJ obtained with 100% yield,
is dissolved in 60 ml. of methanol, and 1 g. of sodium borohydride is added
to the shaken solution in small portions within one hour. The mixture
is allowed to stand for several hours, diluted with water to the twofold
of the original volume, and extracted with 4x25 ml. of choroform. The com-
bined extracts are dried, then the solvent is evaporated. The residue is
dissolved in 20 ml. of methanol, and treated with 2.27 g. of maleic acid.
7.2 g. of 1-(1-naphthyloxy)-2-hydroxy-4-isopropylaminobutane maleate are
obtained; m.p.: 147-149C (after recrystallization from isopropanol).
Example 4
A solution of 9.2 g. ~0.04 moles) of 1-(1-naphthyloxy)-2-hydroxy-
4-aminobutane and 5.36 g. (0.04 moles) of phenylacetone in 100 ml. of benzene
is refluxed for one hour. The mixture is evaporated, the residue is dis-
solved in 100 ml. of methanol, and reduced with 2 g. of sodium borohydride
as described above. The obtained base is treated with 4.3 g. of maleic acid
to obtain l-(l-naphthyloxy)-2-hydroxy-4-(1-phenyl-prop-2-yl)-aminobutane
maleate; m.p.: 152-155C (after recrystallization from ethanol).
Example 5
A mixture of 1.56 g. ~0.0068 moles) of l-(1-naphthyloxy)-2-hydroxy
-4-aminobutane, 3.7 g. (0.03 moles) of isopropylbromide, 0.7 g. (0.007 moles)
of sodium carbonate, 200 ml. of potassium iodide and 15 ml. of ethanol is
stirred and refluxed for 30 hours. The solvent is evaporated, the residue
is taken up in dilute hydrochloric acid, and this solution is washed once
with ether. The acidic solution is rendered alkaline with a 20% aqueous
sodium hydroxide solution, and the obtained mixture,is extracted with ether.
The extract is washed with water, dried over magnesium sulfate, and evaporated.
The residual oil is converted into its salt by treating it with 0.0067 moles
of maleic acid. The thus-obtained l-(l-naphthyloxy)-2-hydroxy-4-isopropyl-
aminobutane maleate melts at 147-149C ~after recrystallization from isopro-
panol).
1074338
Example 6
A mixture of 18.1 g. ~0.1 moles) of 1-phenoxy-2-hydroxy-4-aminobut-
ane, 9.8 g. (0.1 ~oles~ of cyclohexanone and 180 ml. of dry benzene is re-
fluxed for 1.5 hours. The benzene is evaporated, the residue is dissolved
in 170 ml. of methanol, and 2.5 g. of sodium borohydride are added in port-
ions to the shaken solution under cooling. The mixture is allowed to stand
for one day, thereafter it is diluted with water to the twofold of its origi-
nal volume, and extracted with ether. The etheral phase is dried and evapor-
ated. The free base, obtained as a residue ~m.p.: 92C) is reacted in ethanol
with maleic acid. This way l-phenoxy-2-hydroxy-4-cyclohexylaminobutane male-
ate, melting at 110-112C is obtained. The product can be crystallized from
dioxane.
Example 7
A solution of 9.05 g. ~0.05 moles~ of 1-phenoxy-2-hydroxy-4-
aminobutane and 6.7 g. ~0.05 moles) of phenylacetone in 125 ml. of benzene
is refluxed for one hour. The solvent is evaporated, and the Schiff-base,
obtained as a residue, is dissolved in 80 ml. of methanol. Thereafter 2.5 g.
of sodium borohydride are added to the solution in small portions within one
hour, and the mixture is allowed to stand for one day. Then the mixture is
diluted with 100 ml. of water and extracted with 3x50 ml. of ether. The
etheral extracts are combined, dried and evaporated. The residue is dissolved
in 50 ml. of ethanol and treated with 4.45 g. of maleic acid. This way 1-
phenoxy-2-hydroxy-4-(1-phenyl-propyl-2-amino)-butane maleate, melting at
123-124C, is obtained.
Example 8
A mixture of 5 g. of 1-~2,3-dichlorophenoxy)-2-hydroxy-4-aminobut-
ane, 4 g. of dry acetone and 50 ml. of benzene is refluxed for one hour, there-
after the solvent and the excess of acetone are evaporated. The Schiff-base,
obtained as a residue, is dissolved in 50 ml. of methanol and reduced by
adding 0.76 g. of sodium borohydride in small portions to the mixture. The
reaction mixture is diluted with water and extracted with chloroform. The
chloroform solution is dried and evaporated, and the residue is dissolved in
-10-
~7433~
lO ml. of ethanol. This solution is treated with 2.14 g. of maleic acid
to obtain 5.9 g. of 1-~2,3-dichlorophenoxy)-2-hydroxy-4-isopropylaminobutane
maleate; m.p. 127C (after recrystallizaticn from ethyl acetate~.
Example 9
A mixture of 92.4 g. (0.406 moles) of 3-~1-naphthyloxy)-3-hydroxy-
butyronitrile, 500 ml. of 10% methanolic ammonia and 20 g. of Raney-nickel is
hydrogenated with shaking in a pressure bomb under a pressure of 6 to 7
atmospheres. When the hydrogen uptake ceases the mixture is filtered, and
the filtrate is evaporated under reduced pressure. The residue is extracted
with 100 ml. of ether to obtain 8.46 g. ~90%) of 1-(1-naphthyloxy)-2-hydroxy-
-4-aminobutane; m.p.: 73-75C.
Exanple 10
88.6 g. (0.5 moles) of 4-phenoxy-3-hydroxybutyronitrile are hydro-
genated with shaking in 500 ml. of 10% methanolic ammonia in the presence
of 20 g. of Raney-nickel. The reduction is conducted under a pressure of
6 to 7 atmospheres. The mixture is filtered, and the filtrate is evaporated
to obtain 85 g. ~94%) of 1-phenoxy-2-hydroxy-4-aminobutane in the form
of a viscous oil. This substance solidifies slowly upon standing and can
be processed directly.
Example 11
A mixture of 42.7 g. ~0.174 moles) of 1-~2,3-dichlorophenoxy)-2-
hydroxy-3-cyanopropane, 200 ml. of 10% methanolic ammonia and Raney-nickel
catalyst is hydrogenated under a pressure of 5 atmospheres. The reaction
mixture is filtered, and the filtrate is evaporated to obtain a viscous
slbwly solidifying residue with almost quantitative yield. Having recry-
stallized from ethyl acetate, the product melts at 102-104C. The crude
1-(2,3-dichlorophenoxy)-2-hydroxy-4-aminobutane can be processed further
without purification.
Example 12
1000 tablets, each weighing 445 mg. and containing 40 mg. of active
agent are prepared from the following ingredients:
l-(l-naphthyloxy)-2-hydroxy-4-cyclohexylamino-
-11-
107433~
butane maleate 40 g.
corn starch 164 g.
calcium phosphate 240 g.
magnesium stearate 1 g.
total445 g.
The ingredients are thoroughly blended, granulated, and then com-
pressed into tablets.
