Note: Descriptions are shown in the official language in which they were submitted.
10~309S
The present invention relates to new amines havingJ~-receptor
blocking activity and being useful in treating cardiovascular diseases and
of the general formula I
Rl OH R5
2 > ArocH2cH~H2NH-c~l(cH2)n-y ~
R ~ 9
(CH2) mR
wherein Rl is in 2 or 3 position and is selected from the group consisting of
-CH2CH=CH2, -OCH2CH-CH2, -OCH2C--CH, alkoxyalkyl, having up to 7 carbon atoms
in each alkyl moiety, HOCH2CH2NHCOCH20-, CH30CH2CH2NH-COCH20-, and -CH=NOR,
wherein R is selected from the group consisting of hydrogen and alkyl having
1 to 6 carbon atoms, R is se]ected from the group consisting of hydrogen,
halogen, alkyl, having 1 - 4 carbon atoms, and alkoxy, having 1 - 4 carbon
atoms, R5 is selected from the group consisting of hydrogen and alkyl,
having 1 - 4 carbon atoms, R9 is selected from the group consisting of
hydrogen and -CONH2, Y is selected from the group consisting of -O-, and
-CH2, n is an integer from O to 5, m is an integer from O to 2 and Ar is
phenylnucleus.
Alkoxyalkyl Rl has up to 7 carbon atoms in each alkyl chain,
preferably up to 4 carbon atoms in each and each of them may be straight
and/or branched. Alkoxyalkyl Rl is thus e.g., methoxymethyl, methoxyethyl,
ethoxyethyl, isopropoxyethyl, n-propoxymethyl, and t-butyloxymethyl.
R1 bein~ -CH=NOR, wherein R is hydrogen, and alkyl with 1 to 6
carbon atoms is e.g., isonitrosomethyl, methylisonitrosomethyl, ethyl-
isonitrosomethyl, n-propylisonitrosomethyl, isopropylisonitrosomethyl.
Halogen R is e.g., chloro, fluoro or bromo.
Alkyl R has up to 4 carbon atoms, and is straigh* or branched
and is e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-
butyl.
Alkoxy R has up to 4 carbon atoms and is straight or branched
and is e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
,~
1093095
Alkyl R has the same meaning as alkyl R and is e.g., methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and t-butyl.
The new compounds have valuable pharmacological properties.
Thus they block cardial js-receptors, which is shown at the determination of
the antagonism of tachycardia after an intravenous injection of 0.5,ug/kg
of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose
of 0.002 to 2 mg/kg. Thus they block the vascular ~6-receptors which is shown
at the determination of the antagonism of vasodilation after an intravenous
injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anaesthetized cat
at an intravenous dose of 3 mg/kg or more. They are thus heart selective.
The new compounds can be used as cardioselective antagonists
of adrenergic ~-receptor-stimulators, e.g., at the treatment of exogenously
or endogenously caused arrythmias and angina pectoris. One may also use
them as intermediates at the preparation of other valuable pharmaceutical
compounds.
Outstanding amines are also those of formula Ia
OHR3aR5a
(Rla) (R2a)Ar-OCH2CHCHNCH~cH2)n-Y - ~ (Ia)
R a (CH2)mR
wherein R is -CH2CH=CH2, R is selected from the group consisting of
hydrogen, halogen, alkyl, and alkoxy, R3a is hydrogen, R~a is hydrogen,
R5a is the group consisting of hydrogen and alkyl, R9a is selected from
the group consisting of hydrogen and -CONH2, Y is a divalent member sel-
ected from the group consisting of -0-, and -CH2-, n is an integer from
0 to 5, m is an integer from 0 to 2, and Ar is phenyl, or a therapeutically
acceptable salt thereof.
Of the compounds of the formula Ia, such compounds are especially
advantageous, wherein R is o-CH2CH=CH2 or m-CH2CH=CH2, R is hydrogen,
chloro, bromo, methyl, ethyl, methoxy and ethoxy, R is hydrogen, R is
hydrogen, R a is hydrogen, methyl or ethyl,
-2-
1~93~95
R9a is hydro~en~ carbamyl, yla is -0- and -C~12-, n is an integer from 0 to 5
m is an integer from 0 to 2~ Ar is phenyl whereby when ya is CH2, n is 1-5,
or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned of formula Ia,
wherein Rla is o-CH2CH=CH2, R a is hydrogen, chloro, methylJ and methoxy,
R a is hydrogen, R a is hydrogen, R a is hydrogen or methyl, R a is hydrogen
or carbamyl, ya is -0-, n is l or 2~ m is 0, 1 or 2J Ar is phenyl, or a thera-
peutically acceptable salt thereof.
Outstanding amines are also those of the formula Ib
(Rlb~ (R )ArOCH2CHCHI-CH(CH2)n ~ (Ib)
(CH2) mR
wherein Rlb is selected from the group consisting of -OCH2CH=CH2 and
-OCH2C--CHJ R2b is selected from the group consisting of hydrogenJ halogenJ
alkyl and alkoxyJ R b is hydrogenJ R b is hydrogenJ R5b is selected from
the group consisting of hydrogenJ and alkylJ R b is selected from the group
consisting of hydrogen and -CONH2J Y is a divalent member selected from the
group consisting of -O-J and -CH2-J n is an integer from 0 to 5J m is an
integer from 0 to 2J and Ar is phenylJ whereby yb is -CH2-J n is 1-5J and
whereby Rl is bound in 2 or 3 position to the phenyl, or a therapeutically
acceptable salt thereof.
Of the compounds of the formula Ib such compounds are especially
advantageousJ wherein R is -OCH2CH=CH2 or -OCH2C--CHJ R b is hydrogenJ
chloroJ bromoJ methyl, ethyl, methoxy and ethoxy, R3b is hydrogen, R4b is
hydrogen, R5b is hydrogen, methyl or ethyl, R9b is hydrogen, carbamyl,
yb is -0-, and CH2, n is an integer from 0 to 5, m is an integer from 0 to 2
Ar is phenylJ whereby when Y is CH2 n is 1-5, and whereby R b is bound in
2 or 3 position to the phenyl, or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned of formula Ib,
wherein Rlb is o-OCH2CH=CH2 or o-OCH2C-CH, R b is hydrogen, chloro, methyl and
-3-
30~5
methoxy, R is hydrogen, R is hydrogen, R5b is hydrogen or methyl,
R is hydrogen or carbamyl, yb is -O-, n is 1 or 2, m is 0, 1 or 2, Ar is
phenyl or therapeutically acceptable salts thereof.
Outstanding amines are also those of formula Ic
oHR3c R5C
(R ) (R )~rOCH2CHCHN-lH(CH2) _yC ~ (Ic)
R4C ( 2)m
wherein RlC is alkoxyalkyl, R2C is selected from the group consisting of
hydrogen, halogen, alkyl, and alkoxy, R3c is hydrogen, R4c is hydrogen,
R5c is selected from the group consisting of hydrogen and alkyl, R9c is
selected from the group consisting of hydrogen and -CONH2, yC is a divalent
member selected from the group consisting of -O-, and -CH2, n is an integer
from O to 5, m is an integer from 0-2 and Ar is phenyl, whereby when Y is
-CH2- n is 1-5, and whereby RlC is bound in 2 or 3 position to the phenyl.
Of the compounds of the formula Ic such compounds are especially
advantageous, wherein RlC is alkoxyalkyl, R2C is hydrogen, chloro, bromo,
methyl, ethyl, methoxy and ethoxy, R3c is hydrogen, R4c is hydrogen,
R5c is hydrogen, methyl or ethyl, R9c is hydrogen or carbamyl, yC is -O-,
and -CH2, n is an integer from O to 5, m is an integer from O to 2, Ar is
phenyl whereby when yC is CH2 n is 1-5, and whereby RlC is bound in 2 or 3
posltion to the phenyl.
Preferably those compounds will be mentioned of formula Ic,
wherein RlC is methoxymethyl, methoxyethyl, or ethoxyethyl, R2C is hydrogen,
chloro, methyl and methoxy, R3c is hydrogen, R4c is hydrogen, R5c is hydrogen
or methyl, R9c is hydrogen or carbamyl, yC is -O-, n is l or 2, m is 0, 1
or 2, Ar is phenyl or therapeutically acceptable salts thereof.
-4-
~ *,~, .,
10~3~9S
Outstanding amines are also those according to formula Ig
OH~3g R5g
(R g)(R g)ArOCH2CHCH~ CH(CH2) -Yg ~ (Ig)
( CH2 ) mR
wherein R g is selected from the group consisting of HOCH2CH2NHCOCH2O- and
CH3OCH2NHCOCH20-, R g is selected from the group consisting of hydrogen,
halogen, alkyl and alkoxy, R3g is hydrogen, R4g is hydrogen, R5g is selected
from the group consisting of hydrogen, and alkyl, R g is selected from the
group consisting of hydrogen and -CONH2, Yg is a divalent member selected
from the group consisting of -0-, and -CH2-, n is an integer from 0 to 5,
m is an integer from 0 to 2, and Ar is phenyl, whereby Rlg is bound in 2 or 3
position to the phenyl, whereby when Yg is -CH2- n is 1-5.
Of the compound of the formula Ig such compounds are especially
advantageous, wherein R g is HocH2cH2~ocH2o- or CH30CH2CH2NHCOCH20, R2g
is hydrogen, chloro, bromo, methyl, ethyl, methoxy and ethoxy, R3g is hydrogen,
R4g is hydrogen, R5g is hydrogen, methyl or ethyl, R9g is hydrogen or
carbamyl, Yg is -0-, and -CH2-, n is an integer from 0 to t,~m is an integer
from 0 to 2, Ar is phenyl, whereby when Yg is CH2 n is 1-2, and whereby R g
is bound in 2 or 3 position to the phenyl or a therapeutically acceptable
salt thereof.
Preferably those compounds will be mentioned according to form-
ula Ig, wherein R g is HOCH2CH2NHCOCH2O- or CH3OCH2CH2NHCOCH2O-, R2g is
hydrogen, chloro, methyl and methoxy, R3g is hydrogen, R4g is hydrogen,
R5g is hydrogen or ~ethyl, R9g is hydrogen or carbamyl, Yg is -0-, n is
1 or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts
thereof.
~'~ -5-
~ ~j5
~)93(~95
Outstanding amines are also those according to formula Ik
oHR3k R5k
(Rlk~ (R2k)ArOCH2CHCHN-CH~CH2)n-Y ~ (Ik)
R4k (CH2)mR
wherein R is -CH=NOR, wherein R is selected from the group consisting of
hydrogen and alkyl having l to 6 carbon atoms, R k is selected from the
group consisting of hydrogen, halogen, alkyl, and alkoxy, R is hydrogen,
R is hydrogen, R k is selected from the group consisting of hydrogen, and
alkyl, R is selected from the group consisting of hydrogen and -CONH2, yk
is a divalent member selected from the group consisting of -0-, and -CH2, n is
an integer from 0 to 5, m is an integer from 0 to 2, and Ar is phenyl,
whereby Rlk is bound in 2 or 3 position to the phenyl, whereby when yk is
-CH2 n is 1-5.
Of the compound of the formula Ik such compounds are especially
advantageous, wherein Rlk is -CH=NOR, wherein Rk is hydrogen or alkyl having
1 to 6 carbon atoms, R2k is hydrogen, chloro, bromo, methyl, ethyl, methoxy,
and ethoxy, R3k is hydrogen, R4k is hydrogen, R5k is hydrogen, methyl or
ethyl, R9k is hydrogen or carbamyl, yk is -0-, and -CH2-, n is an integer
from O to 5, m is an integer from O to 2, Ar is phenyl, whereby when Y is
CH2 n is 1-5 and whereby R k is bound in 2 or 3 position to the phenyl or a
therapeutically acceptable salt thereof,
Preferably those compounds will be mentioned according to form-
ula Ik, wherein Rlk is isonitroso methyl, methylisonitrosomethyl, ethyl-
isonitrosomethyl, propylisonitrosomethyl, or t-butylisonitrosomethyl,
R is hydrogen, chloro, methyl and methoxy, R is hydrogen, R is hydrogen,
R5k is hydrogen or methyl, R9k is hydrogen or carbamyl, yk is -O-, n is
1 or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts
thereof.
, ~ -6-
09S
The following compounds are especially mentioned:
1) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-allylphenoxy)propanol-2.
2) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-methoxyethylphenoxy)propanol-2.
3) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-allylphenoxy)propanol-2.
4) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-methylisonitrosomethyl-
phenoxy)propanol-2.
5) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(3-allylphenoxy~propanol-2.
The new compounds are obtained in accordance to methods known
~ se. Thus (a) a compound of formula II
Xl 3
(R )(R )ArOCH21H HZ II
wherein Ar, Rl, R and R3 have the meanings given above, Xl is a hydroxy
group and Z is a reactive, esterified hydroxy group, or Xl and Z together
form an epoxy group, is reacted with an amine of the formula (III)
R5
HN - CH(CH2) ~ III
~ 2)m
wherein R4, R5, R9, Y, m and n have the same meanings as given above.
A reactive, esterified hydroxy group is particularly a hydroxy
group esteritied with a strong, ~norganic or organic acid, preferably a
hydrohalogen acid, as hydrochloric acid, hydrobromic acid, or hydroiodic
acid, further sulphuric acid or a strong organic sulphonic acid as a strong
aromatiC sulphonic acid, e.g., benzenesulphonic acid, 4-bromoben~ene-
sulphonio acid or 4-toluenesulphonic acid. Thus, Z is preferably chloro,
bromo or iodo.
This reaction is carried out in a common way. At the use of a
reactive ester as a starting material the preparation takes place preferably
in the presence of a basic condensating agent and/or with an excess of an
, ~ -7
~0~33V95
amine. Suitable basic condensating agents are e.g., alkalimetal hydroxides
as sodium or potassium hydroxide, alkalimetal carbonates as potassium
carbonate and alkalimetal alcoholates as sodium methylate, potassium ethyl-
ate and potassium tert.butylate.
~urther, (b) a compound of formula IV
R3
(R )(R )ArOCH2CHOHCHN(R )H (IV)
wherein Ar, Rl, R , R3 and R have the same meanings as given above, is
reacted with a compound of the formula V
Z - CH (CH2)m - Y ~ (V)
(C 2)n
wherein R J R9, Y, m, n and Z have the same meanings as given above.
This reaction is carried out in a common way, preferably in the
presence of a basic condensating agent and/or an excess of an amine. Suit-
able basic condensating agents are e.g., alkaline alcoholates, preferably
sodium or po~assium alcoholate, or also alkaline carbonates as sodium or
potassium carbonate.
ThusJ for example, basic, neutral or mixed salts may be obtained
as well as hemiamino, sesqui- or polyhydrates. The acid addition salts
of the new compounds may in a manner known ~ se be transformed into free
compounds using e.g., basic agents as alkali or ion exchanger. On the other
hand, the free bases obtained may form salts with organic or inorganic acids.
In the preparation of acid addition salts preferably such acids are used
which form suitable therapeutically acceptable salts. Such acids are e.g.,
hydrohalogen acids, sulphuric acid, phosph~ric acid, nitric acid, perchloric
acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulphonic
acids, as formic, acetic, propionic, succinic, glycolic, lactic, malic,
tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, phenyl-
-8-
r~
l~g3095
acetic, benzoic, p-aminobenzoic, antranilic, p-hydroxyhenzoic, salicyclic or
p-aminosalicyclic acid, embonic acid, methanesulphonic, ethanesulphonic,
hydroxyethanesulphonic, ethylenesulphonic acids, halogenbenzenesulphonic,
toluenesulphonic, naphthylsulphonic acids or sulphanilic acid: methionine,
tryptophane, lysine or arginine.
These or other salts of the new compounds as e.g., picrates may
serve as purifying agents of the free bases obtained as the free bases are
transformed into salts, these are separated and the bases are then set free
from the salts again. According to the close relationship between the new
compounds in free form and in the form of their salts it will be understood
from the above and the below that, if possible, the corresponding salts are
included in the free compound.
Further, one may in a manner known per se react a phenol of form-
ula V
~Rl)(R2~ A OH (V)
; with an acetidinol of the formula XXXIX
CH2-N-CH-(CH2)n ~ (XXXIX)
HO-CH-CH2 ( 2)m 2
wherein R5, Y, m and n have the meanings to the formation of a compound
of formula I.
This reaction is carried out in a common way. Thus the reaction
is carried out under alkaline conditions in a suitable solvent, as benzyl-
alcohol by boiling the reaction mixture for some hours. Thereby the phenol
is primarily converted to its metalphenolate as alkalimetalphenolate before
it ïs added to the acetidinol of formula XXX.
The new compounds may, depending on the choice of starting mat-
erial and process, be present as optical antipodes or racemate, or, if they
contain at least one asymmetric carbon atom, be present as an isomer mixture
(racemate mixture~.
_9_
6~ ~
1093095
The isomer mixtures (racemate mixtures) obtained may, depending
on physical-chemical differences of the components, be separated into the
both stereoisomeric ~diastereomeric) forms e.g., by means of chromatography
and/or fractionated crystallisation.
The racemates obtained can be separated according to known methods,
e.g., by means of recrystallisation from an optically active solvent, by
means of microorganisms, or by a reaction with optically active acids form-
ing salts of the compound and separating the salts thus obtained, e.g., by
means of their different solubility in the diastereomers-. from which the
antipodes by the influence of a suitable agent may be set free. Suitably
useable optically active acid are e.g., the L- and D-forms of tartaric acid,
di-o-tolyltartaric acid, malic acid, mandelic acid, camphersulphonic acid or
china acid. Preferably the more active part of two antipodes is isolated.
Suitably such starting materials are used for carrying out the
reactions of the invention, which material leads to groups of end products
primarily especially desired and especially to the specifically described
and preferred end products.
The starting materials ~re known or may, if they should be new,
be obtained according to processes known ~ se.
In clinical use the compounds of the invention are administered
normally orally, rectally or by injection in the form of a pharmaceutical
preparation, which contains an active component either as free base or as
pharmaceutically acceptable non-toxic acid additions salts, as e.g., the
hydrochloride lactate, acetate, sulphamate or the like in combination with
a pharmaceutically acceptable carrier. Thereby the mentioning of the new
compounds of the invention is here related to either the free amine base
or the acid addition salts of the free base, even if the compounds are gen-
erally or specifically described, provided that the context in which such
expressions are used, e.g., in the examples, with this broad meaning should
not correspond. The carrier may be a solid, semisolid or liquid diluent
- 1 0 -
109309, j
or a capsule. These pharmaceutical preparations are a further object of the
invention. Usually the amount of active compound is between 0.1 to 95% by
weight of the preparation, suitably between 0.5 to 20% by weight in prep-
arations for injection and between 2 to 50% by weight in preparations for
oral administration.
In the preparation of pharmaceutical preparations containing a
compound of the present invention in the form of dosage units for oral ad-
ministration the compound selected may be mixed with a solid, pulverulent
carrier, as e.g., with lactose, saccharose, sorbitol, mannitol, starch,
as potato starch, corn starch amylopectin, cellulose derivatives or gel-
atine, as well as with an antifriction agent as magnesium stearate, calcium
stearate, polyethyleneglycol waxes or the like, and be pressed into tablets.
If coated tablets are wanted, the above prepared core may be coated with con-
centrated solution of sugar, which solution may contain e.g., gum arabicum,
gelatine, talc, titandioxide or the like. Furthermore, the tablets may be
coated with a lacquer dissolved in an easily volatile organic solvent or
mixture of solvents. To this coating a dye may be added in order to easily
distinguish between tablets with different active compounds or with differ-
ent amounts of the active compound present.
In the preparation of soft gelatine capsules (pearl-shaped, closed
capsules), wh;ch consist of gelatine and e.g., glycerine or in the preparat-
ion of similar closed capsules the active compound is mi~ed with a vegetable
oil. Hard gelatine capsules may contain granules of the active compound in
combination with a solid, pulverulent carrier as lactose, saccharose,
sorbitol, mannitol, starch, (as e.g., potato starch, corn starch or amylo-
pectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form
of suppositories, which contain the active substance in a mixture with a
neutral fat base, or they may be prepared in the form of gelatine-rectal
capsules which contain the active substance in a mixture with a vegetable
oil or paraffin oil.
--1 1 -
,;.~,'
10~?3095
Liquid preparations for oral administration may be present in the
form of syrups or suspensions, e.g., solutions containing from about 0.2% by
weight to about 20% by weight of the active substance described, whereby
the residue consists of sugar and a mixture of ethanol, water, glycerol and
propylene glycol. If desired, such liquid preparations may contain colouring
agents, flavouring agents, saccharine and carboxymethylcellulose as a thick-
ening agent.
Solutions for parenteral administration by injection may be pre-
pared as an aqueous solution of a watersoluble pharmaceutically acceptable
salt of the active compound, preferably in a concentration from about 0.5%
by weight to about 0.10% by weight. These solutions may also contain stab-
ilizing agents and/or buffering agents and may suitably be available in
different dosage unit ampoules.
The preparation of pharmaceutical tablets for peroral use is
carried out in accordance with the following method:
The solid substances included are ground or sieved to a certain
particle size. The binding agent is homogenized and suspended in a certain
amount of solvent. The therapeutic compound and necessary auxiliary agents
are mixed during a continuous and constantly mixing with the binding agent
solution and are moistened so that the solution is uniformly divided in the
mass without overmoistening any parts. The amount of solvent is usually
so adapted that the mass obtains a consistency reminding of wet snow. The
moistening of the pulverulent mixture with the binding agent solution causes
the particles to gather together slightly to aggregates and the real gran-
ulating process is carried out in such a way that the mass is pressed through
a sieve in the form of a net of stainless steel having a mesh size of about
1 mm. The mass is then placed in thin layers on a tray to be dried in a
drying cabinet. This drying takes place during lO hours and has to be stand-
ardized carefully as the damp degree of the granulate is of utmost importance
for the following process and for the feature of the tablets. Drying in a
-12-
r ~
. ~, ~ .
1~9309S
fluid bed may possibly be used. In this case the mass is not put on a tray
but is poured into a container having a net bottom.
After the drying step the granules are sieved so that the particle
size wanted is obtained. Under certain circumstances powder has to be re-
moved.
To the so called final mixture, disintegrating, antifriction
agents and antiadhesive agents are added. After this mixture the mass
shall have its right composition for the tabletting step.
The cleaned tablet punching machine is provided with a certain
set of punches and dies, whereupon the suitable adjustment for the weight of
the tablets and the degree of compression is tested out. The weight of the
tablets is decisive for the size of the dose in each tablet and is calculated
starting from the amount of therapeutic agent in the granules. The degree
of compression affects the size of the tablet, its strength and its ability
to disintegrate in water. Especially as regards the two latter properties
the choice of compression pressure (0.5 to 5 ton~ means something of a bal-
ancestes. When the right adjustment is set, the preparation of tablets
is started, which is carried out with a rate of 20,000 to 200,000 tablets
per hour. The pressing of the tablets requires different times and depends
on the size of the batch.
The tablets are freed from adhering powder in a specific apparatus
and are thon stored in closed packages until they are delivered.
Many tablets, especially those which are rough or bitter, are
coated with a coating. This means that these are coated with a layer of
sugar or some other suitable coating.
The tablets are usually packed by machines having an electronic
counting device. The different types of packages consist of glass or
plastic gallipots, but also boxes, tubes and specific dosage adapted pack-
ages.
-13-
i U~ '
~.0930'35
The daily dose of the active substance varies and is dependent
on the type of administration, but as a general rule it is 100 to 400 mg/day
of active substance at peroral administration and 5 to 20 mg/day at intra-
venous administration.
The following illustrates the principle and the adaptation of
invention, however, without being limited thereto. Temperature is given
in degree Celsius.
Example 1
1.9 g of 1,2-epoxy-3-(2-allylphenoxy)-propane and 1.8 g of
4-(2-aminoethoxy)-benzamide were refluxed in 25 ml of isopropanol for 1.5
hours. The reaction mixture was evaporated in vacuo, whereupon the residue
was dissolved in acetone and the hydrochloride of 1[2-(4-carbamoylphenoxy)-
ethylamino]-3-(2-allylphenoxy)propanol-2 was precipitated by introducing
ether containing HCl. Mp. 211C. The structure was verified with NMR.
Example 2
2.1 g of 1,2-epoxy-3-[2-(2~ethoxyethyl)phenoxy]-propane and 1.8 g
of 4-(2-aminoethoxy)benzamide were reacted with each other in accordance
with Example 1. The melting point of 1-[2-(4-carbamoylphenoxy)ethylamino]-
3-[2-~2-methoxyethyl)phenoxy]propanol-2 hydrochloride was 105C. The
structure was verified with NMR.
Example 3
1.9 g of 1,2-epoxy-3-~2-allylphenoxy)propane and 2,5 g of
4-~2-aminopropoxy)benzamide were reacted in accordance with Example 1. The
hydrochloride of l-[l-methyl-2-~4-carbamoylphenoxy)-ethylamino]-3-(2-allyl-
phenoxy)propanol-2 melted at 94C. The structure was verified using NMR.
Example 4
1.8 g of 1-amino-3-~2-methylisonitrosomethylphenoxy)-propanol-2
and 1.55 g of 4-methylcarbonylmethoxybenzamide were dissolved in 25 ml of
methanol and cooled to 0C. 1.8 g of NaBH4 were then added during 1/2 hour.
50 ml of water were added and the product was extracted with ethylacetate.
-14-
10'33095
The ethylacetate phase is evaporated in vacuo and the substance, l-[l-methyl-
2-(4-carbamoylphenoxy~ethylamino]-3-(2-methylisonitrosomethylphenoxy)-
propanol-2, is washed with ether and ethylacetate. Mp. 106C. (HCl)
Example 5
1-[2-(4-carbamoylphenoxy)ethylamino]-3-(3-allylphenoxy)propanol-2
was prepared in accordance with Example 1 starting from 1,2-epoxy-3-(3-allyl-
phenoxy)propane and 4-aminoethoxybenzamide. Mp. 228C. as hydrochloride.
Example 6
A syrup containing 2% (weight per volume) of active substance was
0 prepared from the following ingredients:
1-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-allyl-
phenoxy)propanol-2 HCl 2.0 g
Saccharine 0.6 g
Sugar 1 30.0 g
Glycerine 5.0 g
Plavouring agent 0.1 g
Ethanol 96% 10.0 ml
Distilled water ad 100.0 ml
Sugar, saccharine and the hydrochloride salt were dissolved in
60 g of warm water. After cooling,glycerine and a solution of flavouring
agents dissolved in ethanol were added. To the mixture water was then added
to 100 ml.
The above given active substance may be replaced with other pharma-
ceutically acceptable acid addition salts.
Example 7
1-[2-~4-carbamoylphenoxy)ethylamino]-3-~2-chloro-5-methylphenoxy)
propanol-2-hydrochloride (250g) was mixed with lactose ~175.8g), potato
starch ~169,7 g~ and colloidal silicic acid ~32 g). The mixture was moist-
ened with a 10% solution of gelatine and was granulated through a 12-mesh
sieve. After drying potato starch (160 g), talc (50 g) and magnesium stear-
-15-
io930gs
ate (5 g) were admixed and the mixture thus obtained was pressed into
tablets (lO,000) which contain 25 mg of substance. The tablets are sold
on the market provided with a breaking score to give another dose than 25 mg
or to give ~mlltiples thereof when broken.
Example 8
Granules were prepared from 1-[2-~4-carbamoylphenoxy)ethylamino]-
3-(2-(2-methoxyethyl)phenoxy-propanol-2-hydrochloride ~250 g), lactose
(175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After
drying step the granules were mixed with talc (25 g), potato starch (40 g)
and magnesium stearate (2.50 g) and was pressed into 10,000 tablets being
biconvex. These tablets are primarily coated with a 10% alcoholic solution
of shellac and thereupon with an aqueous solution containing saccharose
(45%), gum arabicum (5%), gelatine (4%) and dyestuff (0.2%). Talc and
powder sugar were used for powdering after the first five coatings. The
coating was then coated with a 66% sugar syrup and polished with a 10%
carnauba wax solution in carbon tetrachloride.
Example 9
1-~2-(4-carbamoylphenoxy)ethylamino]-3-(4-chloro-3-thiazoloxy)
propanol-2-hydrochloride (1 g), sodiumchloride (0.8 g) and ascorbic acid
(0.1 g) were dissolved in sufficient amount of distilled water to give
100 ml of solution. This solution, which contains lO mg of active sub-
stance on each ml, was used in filling ampoules, which were sterilized
by heating at 120C. for 20 minutes.
16-
.: .
10~33095
The following compounds have also been prepared:
~Arocl1zcH~ 2~c}l~cH2)n ~3~CH2~mR9
-
Example Ar Rl R R n m R Mp.
C
10 Phenyl 2-CH2=CH-CH2- H H 1 04-NH2C0136-7 (HCl)
11 " 2-CH-C-CH20- H H 1 04-NH2CO-215 (HCl)
12 2-HCH2CH2NHCCH2- H H 1 0~-NH CO-66 (p-OH-
2 benzoate
13 " 2-CH2=CH-CH20- H H 2 04-NH2CO-200 (HCl)
14 " 2-CH2=CH-CH20 H H 4 04-NH2CO-oil (HCl)
Biological effects
The~-receptor blocking agents of the present invention were
tested as regards their biological properties. All compounds uere thereby
tested inana~sthetized cats (males and females weighing 2.5-3.5 kg) pre-
treated with reserpine (5 mg/kg bodyweight administered intra musculary)
about 16 hours before the experiments. The animals were pretreated with
reserpine in order to eliminate the endogenous sympathetic control of heart
rate and vascular smooth muscle tone. The cats wereanaesthetized wlth
pentobarbital (30 mg/kg bodyweight administered i.p.) and artificially
ventilated with room air. A bilateral vagotomy was performed in the neck.
Blood pressure was obtained from a cannulated carotid artery and heart rate
was registered from a cardiotachometer, triggered by the electrocardiogram.
(ECG) Intrinsic beta-mimetic activity on the heart was seen as increased
heart rate after drug administration. The test compounds were given intra-
venously in logarithmically increasing doses. The values obtained were
plotted on dose-response curves~ from which affinity values (ED50) were
estimated. At the end of each experiment high doses of isoprenaline were
. -17-
3{)9S
given in order to obtain the maximal heart rate response.
The compounds were also tested on conscious dogs. Beagle dogs
were trained to be lying quietly and to be lifted to an erect position by
placing their forelegs on a table for 2 minutes. Arterial blood pressure
was registered via a blood pressure transducer attached to the dog at the
heart level. Heart rate was triggered from the ECG. All dogs were pre-
treated with methylscopolamine to avoid vagal influences. Recordings were
taken before and 15 and 75 minutes after administration of the test compound,
first in supine position for 2 minutes and then in the erect position for
2 minutes. The test compounds were given in increasing doses with 2 hour int-
ervals.
Table 1 below shows affinity values and intrinsic ~-mimetic
activity in reserpinized cats and effects on blood pressure in conscious
dogs of compounds of the present invention. Corresponding values for
propanolol, (l-isopropylamino-3-(1-naphthoxy)-propanol-2), practolol,
(4-(2-hydroxy-3-isopropylaminopropoxy)acetanilide), metoprolol, (l-iso-
propylamino-3-[4-(2-methoxyethyl)phenoxy]-propanol-2), tolamolol,
(4-[2-(2-hydroxy-3-o-tolyloxypropylamino)ethoxy]-benzamide) and AH 5158
(5-[1-hydroxy-2-l(l-methyl-3-phenylpropyl)-amino[ethyl]salicylamide), are
shown for comparison.
1093095
~- __ __
, v ~ o t~ N 1` u~ ~ `D
t~O h I ~ `O ~ ~ q
L ~ n
O C O
a~ r1 n n ~ oo co
L $~ ~ + I N L~ N e~ N
~ a
n o a- ~ o o n oo
h ~rl ~ ,_1 N ~1 ~ '
~ ~ ~d + + + + + + +
~ ~d _ I
~ ; ~ _I ~ n ~ n N Ln ~ n
E~ b h O n ~ ~ O ~ oO O --~ O ~0
CC L~
~ ~.
~ ~o n ~ ~
O u~ _I t~ N--I N ~ I O --I O O
~a Ll O 0 ~0 0 0 0 '-i O O O O
. . _ _ .... _ .. _._._.. _
~ _l
O ,t O ~
.~ ~ ~ ~ 3 ~ ~ N t~ O ~ N
~ h ~ O ~ X X X X X X
. .
19 -
.,.~"~,,
93~95
The experiments demonstrate that the compounds tested are potent
~receptor antagonists with or without intrinsic ~6-mimetic activity. The
compounds also decrease blood pressure in conscious dogs significantly more
than propranolol, practolol and metoprolol and the same extent as tolamolol.
The orthostatic effects of the new compounds are not as pronounced as that
of AH 5158, i.e., the blood pressure does not decrease markedly from supine
to erect position.
-20-
~ ;.
,,~ , .
