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Патент USA US3051718

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Patented Aug. 28, 1962
2
4-aminobenzoic acid-2’-diethylamino-ethylamide is the
therapeutic compound hitherto most widely used for the
3,051,796
present indication.
NEW PHENYLOXY AN1) PMNYLALKOXY
BENZOIC ACE
ES
4-phenylethoxybenzoic acid-2'ediethylaminoethylamide
Hans Suter and Hans Zutter, Scha?hausen, Switzerland,
assignors to Eprova Limited, Scha?'hansen, Switzerland
No Drawing. Filed June 3, 1960, Ser. No. 33,643
Claims priority, application Switzerland June 11, 1959
7 Claims. (Cl. 260-2472)
The present invention relates to a group of new com
(see Example 3) is on average quite 100 times more
active than procainamide.
4~‘benzyloxy-benzoic acid - 2’ - diethylaminoethylamide
10
(Example 3).
pounds consisting of phenyloxy and phenylalkoxy ben
The acute toxicity of the compounds according to the
invention is fairly low. It is only about twice as high
zoic acid aminoalkyl amides, which are suitable for and
eifective in the treatment of disturbances of the heart
rhythm (heart arrhythmia).
as that of the very much less active 4-aminobenzoic acid
15
The new compounds of this invention may be repre
consisting of
2'-diethylaminoethylamide.
As a result, a therapeutic index is produced for the
compounds according to the invention which is several
times higher by comparison with the therapeutic com
sented by the vfollowing general formula:
wherein n is an integer selected from zero to four, pref
erably 1 to 4, Am is a member selected from the group
(Example 2) shows about half, and 4-phenoxy-benzoic
acid-2’-diethylaminoethylamide (Example 1) shows one
third of the activity of the 4-phenylethoxy derivative
20
pound most used at the present time.
The compounds according to the invention are suitable
both for oral administration, for example in the ‘form of
the free bases or their crystallized salts, and also for
introduction into the organism by injection in the form
lower alkyl
/
—lII—alkylene—N\
R1
lower alkyl
of aqueous solutions of the acid addition salts.
The compounds according to the invention are most
easily prepared by conversion of a reactive ‘derivative of
a phenylox-y or phenylalkoxy benzoic acid, advantageous
ly by conversion of a mixed acid anhydride thereof and
an inorganic or organic acid, for example hydrochloric
30 acid or a semi-ester carbonic acid, for example the ethyl
carbonic acid, see Helv. 'chim. Acta 34 (1951), page 874,
with a diamine of the formula
—N (H) N—Ra
in which R, is selected from the group consisting of 35 wherein Am has the meaning de?ned above, and recover
ing the amide thus ‘formed.
hydrogen and a lower alkyl radical, alkylene is a lower
As mixed acid anhydride, it is advantageous to use the
alkylene radical containing at least 2 carbon atoms,
A
—N
R;
V
corresponding acid chloride.
The reaction itself is preferably carried out in a solvent
which is neutral with respect to acid chlorides, advanta
geously in a halogenated hydrocarbon (for example
is a radical selected from the group consisting of piper
chloroform). The diamine is used in at least the equiva~
idino, pyrrolidino and morpholino radicals and R3 is se
lent quantity, but preferably in excess, this particularly
lected from the group consisting of a lower alkyl and
simplifying the working up.
a lower hydroxy alkyl radical.
The temperature at which the reaction is carried out
The invention also includes the acid addition salts of 45
can vary Within fairly wide limits, from less than 0° C.
the above free bases with pharmacologically acceptable
up to the boiling point of the solvent being used. The
inorganic and organic acids, such as for example hydro
compounds according to the invention are generally iso
chloric acid, sulphuric acid, lactic acid, citric acid or
oxalic acid.
lated initially as a free base when using an excess of di—
The preferred compounds of the invention are the di 50 amine, and as a “hydrochloride addition salt” when using
exactly the equivalent quantity of diamine.
alkylaminoethyl amides of the 4-phenyloxy and 4-phenyl
alkoxy benzoic acid.
However salts with other acids which form addition
salts with amines may be prepared by reaction of the free
The phenylalkoxy derivatives generally show a higher
e?icacy than the phenyloxy ‘derivatives, and they are con 55 base, or the hydrohalide salts after conversion to the
vfree base by treatment with a basic reagent such as so
sequently the compounds Which are of particular value.
dium hydroxide or potassium carbonate, with the desired
It has been found that the compounds with the struc
acid (e.g. sulphuric acid, nitric acid, lactic acid, tartaric
ture de?ned above are excellently suitable for the treat
ment of heart arrhythmia as so-called “antiarrhythmics”
or “anti-?brillation agents.” They are particularly char
acterised by an unusually high activity.
acid, citric acid or oxalic acid, a pharmacologically ac
ceptable acid being employed where the salt is to be the
60 ?nal compound). The above mentioned method is, how
ever, not the only method which yields the desired
The anti-arrhythmic activities of the compounds ac
compounds.
cording to the invention, as established in pharmacologi
In addition to using any desired mixed acid anhydride
cal test experiments and for example determined on the
electrically stimulated isolated top of the right ventricle 65 as reactive derivative of a phenyloxy and phenylalkoxy
benzoic acid, it is also possible to use an ester thereof,
of the rat, showed activity values with rheobase, maxi
mum frequency and excitation which are up to 100 times
for example a methyl or cyanomethyl ester (see for ex
greater than those measured in concurrently conducted
ample Helv. Chimica Acta 38 (1955) pages ‘69, 80, 83,
different type of action vmechanism.
acted to form the amides.
1508; 39 (1956) page 872). The actual reaction condi
comparison experiments with procainamide (4-aminoben
tions must of course be adapted to the particular case.
zoic acid-2’-diethyl-aminoethyl amide).
70 It is also in ‘certain circumstances possible for the phenyl
This extraordinary difference can be attributed to a
oxy and phenylalkoxy benzoic acids to be directly re
3,051,706
4
The hydrochloride of this aminoalkylamide is obtained
by dissolving the base in dry ether and adding one quiva
lent of ethereal hydrogen chloride. The hydrogen chlo
‘Finally, the reaction with the amine of the general
formula
.
H—Am
ride initially precipitates in the form of an oil. The
ether is decanted and the oily salt is triturated with ethyl
wherein H—Am is a diamine of the formula
H2N—alkylene—B
acetate, whereupon it crystallizes. After recrystallization
in which formula B is a member selected from the group
from ethyl acetate with addition of some i-propanol or
from benzene, the hydrochloride melts at 114 to 116°
consisting of
lower alkyl
__N/\
C. It is readily soluble in Water, alcohols and chloro
10 form, but is less soluble in cold ethyl acetate, benzene
and petroleum ether.
lower alkyl
can also be carried out in stages, by
(1) a reactive derivative of a phenyloxy and phenyl
alkoxy benzoic acid being ?rst of all reacted with NH3
1 EXAMPLE 2
4-Benzyl0xy Benzoic Acid-Z'-Diethwlaminoethylamide
15
to an amide of the general formula
for about 4 hours under re?ux. The excess thionyl chlo
ride is evaporated. The evaporation residue is taken up in
chloroform and the solution again concentrated by evapo
ration. The 4-benzyloxy benzoyl chloride thus obtained
is ‘dissolved in 70 parts by volume of chloroform, and
added dropwise over a period of approximately 1 hour
and while stirring to a solution of 30 parts by weight of
2-diethylamin0ethylamine in 150 parts by volume of
chloroform. The reaction solution is concentrated by
evaporation, the residue is taken up in ether and water,
the ether solution is separated, washed with water and
and this thereafter being converted by reaction with a
reactive ester of an aminoalcohol of the general vformula
'
25 parts by weight of 4benzyloxy benzoic acid and
100 parts by weight of thionyl chloride are gently boiled
H—O—alkylene—B
into a compound of the Formula I, or by
(‘2) a reactive derivative of a phenyloxy or phenyl—
alkoxy benzoic acid being ?rst of all transformed by re
action with a reactive ester of an alcohol of the general
formula
evaporated.
H2N-alkylene—OH
The evaporation residue crystallizes after
a short time. It can be recrystallized from ya large quan
tity of petroleum ether (RP. 60 to ‘90° C.) or from a
small quantity of i-propylether or from a mixture of both.
reaction with a free aminoalcohol of the formula
H2N-——alkylene—OH and subsequent esteri?cation into a
reactive ester of a hydroxy alkyl amide of the general
formula
The 4-‘benzyloxy benzoic acid-2'-diethylaminoethyl
amide obtained in this manner melts at 64 to ‘65 ° C. It is
readily soluble in most organic solvents and in aqueous
dilute ‘mineral acids, but is scarcely soluble in water.
Microanalysis, calculated for C20H26O2N2 (molecular
weight 326.42)
and thereafter this reactive ester is converted by further
reaction with an amine of the general formula
C calculated 73.59%; found 73.89%.
!
H calculated 8.03%; found ‘8.00%.
40 N calculated 8.58%; found 8.57%.
into a compound of the general Formula I.
The invention is further illustrated by the following
1 EXAMPLE 3
4-Phenylethoxy Benzoic Acid-2'-Diethylamin0ethylamide
examples:
18.1 parts by weight of 4~phenylethoxybenzoic acid and
EXAMPLE 1
40 parts by volume of thionyl chloride are boiled under
re?ux for 6 hours. The solution is then concentrated by
evaporation and the residue is treated with chloroform
as described in Example 1. The 4-phenylethoxybenzyl
chloride thus obtained is dissolved in 60 parts by volume
of alcohol-free chloroform and added dropwise in about
1 hour to a solution of 18.6 parts by weight of 2'-diethyl—
4-Phen0xy-Benz0ic Acid-2'-Diethylaminoethylamide
25.7 parts by weight of 4-phenoxy benzoic acid and
60 parts by volume of thionyl chloride are boiled under
re?ux for ‘6 hours. The excess thionyl chloride is dis
tilled o? in vacuo. The resultant residue is taken up in
a little alcohol-free chloroform and again evaporated.
This operation is repeated once more.
aminoethylamine in 150 parts by volume of chloroform.
' ‘In this way, there are obtained ‘28 parts by weight
After another hour, the reaction solution is concentrated
(i.e. about 100% of the theoretical) of 4-phenoxybenzoyl
, by evaporation and the residue is taken up in diethyl ether
and a large quantity of Water and shaken. The ethereal
chloride.acid
chloride is dissolved in 60 parts by volume
solution is separated, repeatedly washed in water, dried
of chloroform and added dropwise over a period of 1
hour and while stirring to a solution of 29 parts by
weight of Z-diethylaminoethylamine in 150 parts by vol
ume of chloroform. The reaction solution is then con
centrated by evaporation in vacuo.
The evaporation residue is taken up in diethylether and
a large quantity of water and shaken. The ethereal solu
tion is separated out and repeatedly washed with water.
and evaporated.
,
~ The residue (23.4 parts by weight, i.e. 92% of the theo
60
retical), consisting of 4-phenylethoxybenzoic acid-2’-di
ethylaminoethylamide, crystallises on being triturated with
petroleum ether. It can be recrystallized from petroleum
ether (HP. 60 to 90° C.).
Melting point: 65 to 66° C.
Microanalysis, calculated for C21H28O2N2 (molecular
After evaporating the dried ether solution, there remain 65 weight 340.45)
35 parts by weight of a thickly liquid oil, consisting of
C calculated 74.08%; found 74.29%.
4-phenoxybenzoic acid'-2'-diethylaminoethylamide, which
H calculated 8.29%; found 8.19% .
is scarcely soluble in‘ water, but is readily soluble in dilute
N calculated 8.23%; found 8.26%. '
aqueous mineral acids and organic solvents.
Micro-analysis, calculated for C19H24O2N2 (molecular
weight 312.40)
C calculated 73.04%; found 73.09%.
H calculated 7.74%; found 7.57%.
N calculated 8.97%; found ‘8.73%.
4—phenylethoxy benzoic acid-2’(-diethylamino)ethy1amide
is sparingly soluble in water.
A form of the compound which is suitable for use as
an injection solution is obtained by converting the free
75 base into one of its pharmacologically acceptable water
3,051,706
5
6
soluble salts, in which case the procedure is for example
ethyl-N'-methylamide melts at 107 to 108° C. ‘It is
as follows:
readily soluble in lower alcohols, chloroform, ethyl ace
(a) 5.0 g. of the free base (molecular weight 340.45)
tate and dilute mineral acids, but scarcely soluble in water
and benzines.
are dissolved in 14.7 cc. of extremely pure normal hydro
chloric acid solution (the exactly equivalent quantity),
Equivalent weight: calculated for C22H23O3N2
brought to the desired concentration by adding extremely
calculated: 368.46; found 370.
pure twice distilled water, ?ltered until sterile after con
The
hydrochloride of this compound melts after re
trol of the pH value, placed in ampoules and if necessary
sterilized again.
crystallization from i-propanol at 184 to 185° C. It is
(12) 5.0 g. of the free base are mixed with 14.7 ccm. 10 readily soluble in water, chloroform and in lower al
cohols, but is less soluble in benzine.
of a pure normal ‘aqueous lactic acid solution and the
Microanalysis calculated for C22H29O3N2Cl (molecular
solution which is obtained is further treated as in the
weight 404.93)
above Example (:1).
EXAMPLE 4
Cl calculated 8.76%; found 8.76% .
4-Phenyleth0xy Benzoz'c Acid-3’-Dimethylamino-n-Propyl
15
Amide
Replacement of 2-diethylaminoethylamine in Example 3
by 163 parts by weight of 3'-dimethylamino-n-propyl
amine provides in exactly the same wayx4-phenylethoxy 20
benzoic acid-3’-dimethylamino—n-propylamide, which is re
crystallized from petroleum ether.
(RP. 60 to 90° C.)
It is scarcely soluble in Water but readily soluble in dilute
EXAMPLE 8
C calculated 73.59%; found 73.30%.
N (4-Phenylethoxy-Benzoyl ) —N'-Methylpiperazine
5 parts by weight of 4-phenylethoxy-benzoyl chloride
N calculated 8.58%; found 8.37%.
amide is scarcely soluble in water but is more readily
soluble in dilute mineral acids, dilute aqueous lactic acid,
citric acid, tartaric acid and oxalic acid and is very readily
soluble in most organic solvents with the exception of
30 are dissolved in about 10 parts by volume of chloroform
and added dropwise while stirring to a solution’ of 4.5
parts by weight of N-methyl-piperazine in 20 parts by
volume of CHCl3. The reaction solution is evaporated
to dryness. The residue is taken up in water and diethyl
ether and shaken. The etheral solution is separated out,
cold petroleum ether, diisopropyl ether and cold benzine.
EXAMPLE 5
washed with water, dryed and evaporated. The resultant
residue —N(4 - phenylethoxy~benzoyl)-N’-methyl-pipera
zine —— (7.3 parts by weight) is a viscous oil, which is
4-Phenyleth0xybenzoic Acid-2'-N(pz'perz'dino)—Ethylamide
The replacement of Z-diethylaminoethylamine of Ex
ample 3 by 205 parts by Weight of N(2-aminoethyl)
piperidine provides in analogous manner the 4~phenyl
in Example 6 by about 6 parts by weight of N(2-amino
ethyl)-pyrrolidine provides in analogous manner the 4
25 mineral acids and lower alcohols.
H calculated 8.03 %; found 7.84% .
4-phenylethoxy-benzoic acid - 3' - dimethylamino - propyl
Ethylamide
Replacement of N(N'-methy1aminoethyl)—morpholine
phenyl-ethoxy-benzoic acid-2’-N (pyrrolidino) —ethyl amide.
Melting point 70 to 72° C.
Microanalysis, calculated for C2oH26O2N2 (molecular
weight 326.43)
EXAMPLE 7
4-Phenylethoxy-Benzoic Acid-Z’N-(Pyrrolidino) -
40
ethoxy-benzoic acid-2'-N(piperidino)—ethylamide, which
scarcely soluble in Water but readily soluble in aqueous
dilute mineral acids and in most organic solvents.
The hydrochloride melts after recrystallization from a
mixture of ethyl acetate and i-propanol at 204° C.
immediately crystallizes in the impure form. It can be
Microanalysis, calculated for C20H29O2N2Cl (molec
ular Weight 360.88)
successfully recrystallized from a relatively large volume
of petroleum ether (B.P. 60 to 90° C.) or from i-propanol 45 C calculated 66.56%; found 66.79%.
diluted with a little water.
H calculated 6.94%; found 7.08%.
Melting point 111 to 112° C.
N calculated 7.77%; found 7.82%.
Microanalysis calculated for C22H28O2N2 (molecular
weight 352.46)
C calculated 74.96%; found 75.08% .
H calculated 8.01%; found 7.97% .
50
Cl calculated 9.83%; found 9.60%.
The hydrochloride is readily soluble in water, chloro
form, methanol, ethanol and hot i-propanol, but sparingly
soluble in cold ethyl acetate and benzine.
EXAMPLE 9
4-phenylethoxy-benzoic acid - 2' - N(piperidino) - ethyl
N (4—Phenylethoxy-Benzoyl ) ~N'-( 2’-Hydroxyethyl ) amide is scarcely soluble in water and cold petroleum 55
Piperazine
ether, more readily soluble in aqueous mineral acids, aque
ous lactic acid, citric acid, tartaric acid and oxalic acid
5 parts by weight of 4-phenylethoxy-benzoyl chloride in
and very readily soluble in ethanol, acetone and ethyl
10 parts by volume of chloroform are added dropwise
N calculated 7.95%; found 7.86%.
acetate.
EXAMPLE 6
4-Phenyleth0xy-Benzoic Acid-2 ’-N- (Morpholino) —Ethyl
N’-Methylamide
6.4 parts by weight of 4-phenylethoxy benzoic acid chlo
while stirring to 6 parts by weight of N-(2’-hydroxyethyl)
piperazine in 20 parts by volume of chloroform. The
reaction mixture is diluted With chloroform and repeat
edly washed with water, dryed and evaporated. The
viscous oily residue (6.3 parts by weight) -— free N(4
phenylethoxy-benzoyl - N’ - 2' - (hydroxyethyl-pipera
ride are dissolved in about 20 parts by volume of chloro 65 zine -- is sparingly soluble in water and diethyl ether. It
form and added dropwise in about 11 hour to a solution of
is dissolved in ethyl acetate and converted by addition of
7.4 parts by weight of N(N’-methylaminoethyl)mor
etheric hydrochloric acid to the hydrochloride, which
pholine in 35 parts by volume of chloroform. The reac
melts after ‘twice recrystallization from i-propanol at
tion solution is then concentrated by evaporation. The
183° C.
residue is taken up in ether and water. The ethereal solu 70 Microanalysis, calculated for C21H2703N2C1 (molecular
tion is separated out, washed with water and evaporated.
weight 390.94)
The residue (8.1 parts by weight, i.e. 88% of the theo
N calculated 7.16%; found 7.00%.
retical) crystallizes on standing and can be recrystallized
Cl calculated 9.06%; found 9.13%.
from di-i-propylether or a few ethyl acetate. The ob
tained 4-phenylethoxy-benzoic acid-2’ - N - (morpholino) 75 The hydrochloride is readily soluble in water, acetic
3,051,706
7
5%
acid, hot ethanol. and i-propanol and- soluble in’ chloroform, but scarcely soluble in other solvents.
.
is- the radical selected from the group consisting of piperi
dino, pyrrolidino and morpholino radicals, and R3 is se
. As stated above, the herewith described, new amino-
lected- from-the group consisting of the lower alkyl and
alkylamine compounds have proved to be effective agents,
lower hydroxyalkyl .radical, and acid addition salts of
which are useful in the treatment of disturbances of the 5 said amino alkyl amide with pharmacologically acceptable
heart rhythms. They are very well tolerated and do not
inorganic and organic acids.
show undesired secondary effects. In pharmacological ex_ 2. The 4-benzyloxy-benzoic acid-2’-diethylaminoethyl
periments in vitro and the dog, an excellent antiarrhythmic
amide of the’ formula
activity of the new compounds was disclosed against eX-
-
perimental induced pathogenic arrhythmias. I For oral 10
-
application the compounds can be given in capsules of
~
7
/
®CHPO_®‘CONH_OHFGEPN
0.5 g. and for intravenous use they can be applied as salt
02H;
solutions in ampoules. The preferred daily dose is be-
3 The
tween 0.3 g. and 3.0 g. (in most cases 0.5 to 2 g.).
The antiarrhythmic activity in men and the therapeutic 15
effect with regard to its safe, e?‘ective and reliable use-
4~phenylethoxybenzoic acid-2'-diethylamino
‘
ethyl-amide
of the formula
0135
fulness
were veri?ed in clinical tests, for instance with
4-phenyl-ethoxybenzoic acid - 2’ - diethylaminoethylamide
@OHTOHrWQCONECHFCHTN/
'
\
(see Example 3). In most cases a prompt and continual
disappearance of the pathological arrhythmic phenomena 20
could be obtained.
C 2H5
4. The 4-phenylethoxy-benzoic acid-3'-diethylamino
propyl-arnide of the formula
.
CH3
@O?y-OlIz-O—©~CONH—CH2—CHz—CHz—-N/\GHQ
What we claim is: V
i
5. The 4-phenylethoxy benzoic acid-2'-N(piperidino)
1. A chemical compound selected from the group con-
ethylamide of the formula
®orn~oHP0_@-o0—NH-om—om-N\‘ (11) >
sisting of 4-phenyloxy and 4-phenylalkoxy benzoic acid
6. The 4-phenylethoxy benzoic acid—2’-N-(m0rpho
amino alkyl amide of the formula
CH n-O-
@< 2>
Q
lino)-ethyl-N’-methyl-amide of the formula
00-11
35
m
/—'\
wherein n is an integer selected from zero to four, Am is
QOHTOHTOQCOMMM
(H) 0
a
\—/
a member selected from the group consisting of
.
3
lower alkyl
_l?_a1ky1ene_N
~
'
~
~
'
'
7. The N(4-pheny1ethoxybenzoyl) - N’ - methyl-pipera
40 zine oVf/the formula V
—N—alkylene-N R:
|
V
R1
45
' References Cited in the ?le of this patent
and
UNITED STATES PATENTS
-'-N (H) N~R3
¥—/
in which R1 is selected from the group consisting of hy- 50
drogen and the lower alkyl radical, alkylene is the lower
alkylene radical of at least 2 carbon atoms,
N/-\R
_
1
V
2,504,617
Anish ________________ _._ Apr. 18, 1950
- 2,629,737
Krimmel _____________ __ Feb. 24, 1953
2,688,026
2,865,911
2,870,145
Krimmel _____________ __ Aug. 31, 1954
Nielsen et a1. .-'_ ________ __ Dec. 23, 1958
Perron ____________ __'___ Ian. 20, 1959
2,948,736
Martin __‘_____' ________ _V___ Aug. 9, 1960
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