PROCESS FOR THE MANUFACTURE OF NEW AMINES

PROCEDE DE FABRICATION DE NOUVELLES AMINES

English Abstract

CIBA-GEIGY AG 4-6930/1+2
Basel Canada
A PROCESS FOR THE MANUFACTURE OF NEW AMINES
Abstract of the Disclosure
Compounds of the formula
<IMG> (I)
wherein R1 represents hydrogen or lower alkyl; R2 represents
lower alkyl; R3 represents lower alkyl, and Ph represents
a meta- or para-phenylene radical, unsubstituted or substi-
tuted once by alkyl or alkenyl with 1 to 4 C-atoms or by
halogen, and pharmaceutically acceptable salts thereof,
which are manufactured by using processes known per se
inhibit cardioselective .beta.-receptors and thus are useful
as cardioselective .beta.-receptor blocking agents.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of new amines of formula I
<IMG> (I)
wherein R1 represents hydrogen or lower alkyl; R2 represents lower alkyl;
R3 represents lower alkyl, and Ph represents a meta- or para-phenylene
radical, unsubstituted or substituted once by alkyl or alkenyl with up to
4 C-atoms or by halogen, and pharmaceutically acceptable salts thereof,
which comprises;
a) reacting a compound of formula V
<IMG> (V)
wherein R1, R2 and Ph have the above significance, X1 represents the hydroxyl
group and Z represents a halogen atom or a reactive esterified hydroxyl group,
or X1 and Z together form an epoxy group, with an amine of the formula
NH2-R3
wherein R3 has the above significance; or
b) reacting a compound of formula VI
<IMG> (VI)
wherein R1, R2 and Ph have the above significance, with a compound of the
formula
21

Z-R3
wherein Z and R3 have the above significance; or
c) reacting a compound of formula VIII
<IMG> (VIII)
wherein R1, R2 and Ph have the above significance, with a compound of
formula IX
<IMG> (IX)
wherein Z, X1 and R3 have the above meanings; or
d) removing from a compound of formula I wherein R1, R2, R3 and
Ph have the above significance and which possesses a removable radical
on the nitrogen atom of the amino group and/or on the hydroxyl group,
said radical or radicals; or
e) reducing a Schiff base of formulae XII or XIII
<IMG> (XII)
or
<IMG> (XIII)
or a ring-tautomer, corresponding to formula XIII, wherein R1, R2, Ph and
R3 have the above significance and R3'H is the same as R3; or
22

f) reducing in a compound of formula XVI
<IMG> (XVI)
wherein R1,R2,R3 and Ph have the above significance, the 2-oxo group to a
hydroxyl group; or
g) reacting a reactive acid derivative of a carbamic acid of
formula XVII
<IMG>
(XVII)
wherein Ph and R3 have the above significance, with an amine of formula
R1 - NH - R2
wherein R1, and R2 have the above significance; and,
when required, resulting racemates are resolved into the optical
antipodes, and/or resulting free bases are coverted into their pharmaceutically
acceptable salts or resulting salts into the free bases or into other salts
which are pharmaceutically acceptable.
2. A process as claimed in claim 1 (a), wherein a compound of formula
V is used, in which Z represents a halogen atom, the -OSO3H group or the
radical of a strong aromatic sulphonic acid and wherein the reaction is
carried out in the presence of a basic condensation agent.
3. A process as claimed in claim 2, wherein a compound of formula V
is used, in which Z represents chlorine, bromine or iodine.
4. A process as claimed in claim 3, wherein the reaction with a compound
of formula V is carried out with an excess of amine.
23

5. A process as claimed in claim 1(b), wherein a compound of formula
Z-R3
is used, in which Z represents a hydroxyl group esterified by a hydrohalic
acid, sulphuric acid or a strong aromatic sulphonic acid and wherein the
reaction is carried out in the presence of a basic condensation agent.
6. A process as claimed in claim 1(c), wherein a compound of formula
IX is used, in which Z is a halogen atom, the .OSO3H group or a radical of a
strong aromatic sulphonic acid and a compound of formula VIII in the form of
its metal phenolate and wherein the reaction is carried out in the presence
of an acid-binding agent.
7. A process as claimed in claim 1(d), wherein the removable radicals
are acyl radicals which are removed by hydrolysis or hydrogenolysis.
8. A process as claimed in claim 1(e), wherein the reduction of a
Schiff base of formulae XII or XIII, or a ring-tautomer corresponding to
formula XIII is carried out with a di-light metal hydride or by catalytic
hydrogenation.
9. A process as claimed in claim 1(f), wherein the reduction of a
compound of formula XVI is carried out with a di-light metal hydride or with
an alkanol and the corresponding metal alcoholate thereof.
10. A process as claimed in claim 1(g), wherein a lower alkyl ester or
phenyl ester, an acid halide or an isocyanate, is used as reactive acid
derivative of a carbamic acid of formula XVII.
24

11. A process as claimed in claims 1 to 3, wherein compounds of
formula III
<IMG> (III)
are prepared in which R? and R? each represents lower alkyl, R? represents
lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with
2 to 4 C-atoms, from corresponding intermediates of the various formulae
given in claim 1 in which R1,R2 and R3 have the same values as given above
for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as
defined above.
12. A process as claimed in claims 4 to 6, wherein compounds of
formula III
(III)
<IMG>
are prepared in which R? and R? each represents lower alkyl, R3 represents
lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with
2 to 4 C-atoms, from corresponding intermediates of the various formulae given
in claim 1 in which R1, R2 and R3 have the same values as given above for
R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as defined
above.

13. A process as claimed in claims 7 to 9, wherein compounds of
formulae III
(III)
<IMG>
are prepared in which R1' and R2' each represents lower alkyl, R3" represents
lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with
2 to 4 C-atoms, from corresponding intermediates of the various formulae
given in claim 1 in which R1, R2 and R3 have the same values as given above
for R1', R2' and R3" and Ph is a p-phenylene radical substituted by R4 as
defined above.
14. A process as claimed in claim 10, wherein compounds of formula
III
(III) :
<IMG>
are prepared in which R1 and R2 each represents lower alkyl, R3 represents
lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with
2 to 4 C-atoms, from corresponding intermediates of the various formulae
given in claim 1 in which R1, R2 and R3 have the same values as given above
for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as
defined above.
15. A process as claimed in claim 1, wherein 1-[p-N',N'-dimethyl-
ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane is prepared from the
corresponding chemical intermediates defined therein in which R1 and R2
26

are methyl groups, R3 is isopropyl and Ph is p-phenylene.
16. A process as claimed in Claim 1, wherein 1-[o-chloro-p-N',N'-
dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane is prepared
from the corresponding chemical intermediates defined therein in which
R1 and R2 are methyl groups, R3 is isopropyl and Ph is o-chloro-p-phenylene.
17. A compound of formula I
<IMG> (I)
wherein R1 represents hydrogen or lower alkyl; R2 represents lower alkyl;
R3 represents lower alkyl, and Ph represents a meta- or para-phenylene radical,
unsubstituted or substituted once by alkyl or alkenyl with 1 to 4 C-atoms or
by halogen, or pharmaceutically acceptable salts thereof, whenever prepared
according to claim 1 to 3 or by an obvious chemical equivalent thereof.
18. 1-[(p-N',N'-Dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-
propane, whenever prepared according to claim 15, or by an obvious chemical
equivalent thereof.
19. 1-[(o-Chloro-p-N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropyl-
amino-propane whenever prepared according to claim 16 or by an obvious
chemical equivalent thereof.
27

Description

38~
The invention relates to a process for the manu-
facture of new amines of the formula
Rl\ OH
/ N-C-NH-Ph-O-CH2-CI-I-CH2-NH-R3 (I~
-R2
wherein Rl represents hydrogen or lower alkyl; R2 represents
lower alkyl; R3 represents lower alkyl, and Ph represents
a meta- or para-phenylene radical, unsubstituted or sub-
stituted once by alkyl or alkenyl withup to 4 C-atoms or
by halogen, and pharmaceutically acceptable salts thereof.
The term lower rad.tcals is used to describe those con-
taining up to 7 C-atoms. .
Lower alkyl radicals are for example methyl, ethyl,
n-propyl or isopropyl, or straight-chain or branched buty~,
pentyl or hexyl, which can be bonded in any desired posi-
tion.
: ` ~
Alkenyl radicals with 2: to 4 C-atoms are for ex- ~.
ample allyl or methallyl. :
: ~alagen atoms are especially fluorine, chlorine :~.
or bromine.
Meta- or para-phenylene radicals Ph can be unsub- .
stituted or have one substituent. Substituents are alkyl
radicals ~ith 1 to ~``C-atoms, or alkenyl~ra~icals with 2 to 4 C-atoms.
~: :
- 2 - ~ :-
.
- : ::.. , . :

~9~
The new compoun~s possess valuable pharmacological
properties. Thus they inhibit cardioselective ~-receptors
as is found in animal experiments, for example on intra-
venous administration of 0.1 - 1 mg~kg to pen-tobarbital
narcotized cats in the isoproterenol-tachycardia test,
on intravenous administration of more than 10 mg/kg in
narcotized cats through inhibition of the isoproterenol
vasodilation, on the isolated guinea pig heart (according
to Langendorff) in a concentration of approximat~ly
0.3 - 3 y~ml through inhibition of the isoproterenol
tachy-cardia (blocking of cardial ~-receptors), as also
on intravenous administration of approximately 5 - 30
mg~kg in narcotized cats through blocking o~ vascular
~-receptors.
The new compounds can there~ore he used as
cardioselective ~-receptor blocking agents. The new com-
pounds are however also valuable intermediate products
for the manufacture of other use~ul substances, especial-
ly pharmaceutically active compounds.
Particularly valuable compounds because o~ theix
outstanding pharmacological properties are l-[(p-N',N'-
dimethyl-ureido)-phenoxy~-2-hydroxy-3-isopropylamino
propane, l-~lm-N',N'-dimethyl-ureido~-phenoxy]-2-hydroxy-
-3-isopropylamino-propane, l-[lo-allyl-p-N',N'-dimethyl-
ureidoj-phenoxy]-2-hydroxy-3-isopropyl-amino-propane,
F
. . . .
` . ~ .`
.

8~
and especially l-[(o-chloro-p-N'-,N'-dimethylureido)-
phenoxy]-2-hydroxy-3-isopropylamino-propane which, for
example, when intravenously administered 0.1 - 1 mg/kg
to pentobarbital-narco-tized cats inhibit the isoproterenol
tachycardia (0.5 Y/kg administered intravenously) and
on intravenous administration of over 10 mg/kg to
pentobarbital-narcotized cats inhibit the isoproterenol-
vasodilatation (0.5 y,~kg administered intravenously) and
also, in concentrations of 0.3 - 3 ~/ml, inhibit the iso-
proterenol-tachycardia (0.005 ~/ml) blocking of cardial
~-receptors) on the isolated
, . . ~ , .
. - ~, . . . ~ , .
- ~ ,
- '
' : '

guinea pig heart (according to Langendorff), and hlock vascular ~-receptors
on intravenous administration of 5-30 mg/kg on narcotized cats.
The new compounds of formula I are obtained according to methods
which are in themselves known, and comprise;
a) reacting a compound of formula V
1 \ " ,1
N - C - NH - Ph - O - CH2 - CH - CH2 - Z ~V)
R2
~herein Rl, R2 and Ph have the above significance, Xl represents the hydroxyl
group and Z represents a halogen atom or a reactive esterified hydroxyl group,
or Xl and Z together form an epoxy group~ with an amine of the formula
2 3
~herein R3 has the above significance; or
b) reacting a compound of formula VI
1 O OH
2.
N - C - NH - Ph - O - CH2 - CH - CH2 - NH2 ~VI)
R2
wherein Rl, R2 and Ph have the above significance, with a compound of the
formula
Z-R3
wherein Z and R3 have the above significance; or
c) reacting a compound of formula VIII
1 \ "
/ N - C - NH - Ph - OH ~VIII)
R2
wherein Rl, R2 and Ph have the above significance, with a compound of
formula IX
- 5 -
~1 .
.
. ~ ~

~L49~
z - CH2 - CH - CH2 - NH 3 (IX)
~herein Z, Xl and R3 have the above meanings; or
d) removing from a compound of formula I wherein Rl, R2, R3 and Ph
have the above significance and which possesses a removable radical on
the nitrogen atom of the amino group and/or on the hydroxyl group, said
radical or radicals; or
e) reducing a Schiff base of formulae XII or XIII
1 \ " OH
N - C - NH - Ph - O - CH2 - CH - CH = N - R3 ~XII)
or
1 O OH
N - C - NH - Ph ~ ~ CH2 ~ CH ~ CH2 ~ N = R3' ~XIII)
or a ring-tautomer, corresponding to formula XIII, wherein Rl, R2, Ph and ~`
R3 have the above significance and R3'H is the same as R3; or
f) reducing in a compound of formula XVI
1 ~ O O
N - C - NH - Ph - O - CH2 - C - CH2 - NH - R3 ~XVI)
wherein R1, R2, R3 and Ph have the above significance, the 2-oxo group to
a hydroxyl group; or
g) reacting a reactive acid derivative of a carbamic acid of formula
XVII OH
HOOC - N~ - Ph - O - CH2 - CH - CH2 - NH - R3 ~XVII)
wherein Ph and R3 have the above significanceJ with an amine of formula
- 6 -
- ,
: :: . : : , : ~

` - -
~4~
Rl - NH - R2
wherein Rl, and R2 have the above significance; and
when required, resulting racemates are resolved in~o the optical
antipodes, and/or resulting free bases are converted into their pharmaceutically
acceptable salts or resulting salts into the free bases or into other salts
which are pharmaceutically acceptable.
Thus it is for example possible to react a compound of formula V
" ,Xl
/ N - C - NH - Ph - O - CH - CH - CH - Z ~V)
wherein Rl, R2 and Ph have the above significance, Xl represents the hydroxyl
group and Z represents a halogen atom or a reactive esterified hydroxyl group,
or Xl and Z together form an epoxy group, with an amine of formula NH2-R3,
wherein R3 has the above significance.
The halogen atoms mentioned with respect to the group Z include
chlorineJ bromine and iodine. A reactive esterified hydroxyl group is
especially a hydroxyl group esterified by a strong inorganic or organic
acid, above all sulphuric acid or a strong organic sulphonic acid, such
as a strong aromatic sulphonic acid, for example benzenesulphonic acid,
4-bromobenzenesulphonic acld or 4-toluenesulphonic acid. Thus Z especially
represents chlorine, bromine, iodine, the -OSO3H group or a strong aromatic
sulphonic acid residue.
This reaction is carried out in the usual manner. When using a
reactive ester as the starting materials, the process is preferably carried
out in the presence of a basic condensation agent and/or ~i~h an excess of
amine .
It is furthermore possible to react a compound of formula VI
- 7 -
:

~ga~9
1 \ " OH
N - C - NH - Ph - O - CH2 - CH - CH2 - NH2 (VI)
R2
wherein Rl, R2 and Ph have the above significance, witll a compound of
formula Z-R3, wherein Z and R3 have the above significance.
This reaction is carried out iTI the usual manner, preferably
in the presence of a basic condensation agent and/or with an excess of
amine. Suitable basic condensation agents are, for example, alkali
alcoholates, especially sodium or potassium alcoholate, or alkali carbonates,
such as sodium or potassium carbonate.
It is furthermore possible to react a compound of formula VIII
10 - 1 N - C - NH - Ph - OH (VIII)
R /
wherein Rl, R2 and Ph have the above significance, with a compound of
f~rmula IX
,1
Z - CH2 - CH - CH2 - NH R3 (IX)
~herein Z, Xl and R3 have the above significance.
This reaction is carried out in the usual manner. If reactive
esters are used as the starting material, the compound of formula VIII
can preferably be used in the form of its metal phenolate, such as alkali
; phenolate, for example sodium phenolate, or the process is carried out in
the presence of an acid-binding agent, especially a condensation agent,
~20 which can form a salt with the compound of formula VIII, such as an
alkali alcoholate.
'`'
.. . . . . ~ .
,. .- , ~ . -
.: - ~ . . . .
' ~. ~ , , ,, ~

It is furthermore possible, in a compound of formula I wherein
Rl, R2, R3 and Ph have the above significance and which possesses a removable
radical on the nitrogen atom of the amino group and/or on the hydroxyl group,
to remove this radical or radicals.
Such removable radicals are especially radicals removable by
hydrolysis or hydrogenolysis.
Radicals removable by hydrolysis are for example acyl radicals,
for example oxycarbonyl radicals, such as alkoxycarbonyl radicals, for
example the tert.-butoxy-carbonyl radical, aralkoxycarbonyl radicals, for
example a carbobenzoxy radicalg and especially lower alkanoyl radicals or
aryloyl radicals, for example the acetyl radical or a benzoyl radical.
Compounds with radicals which can be removed by hydrolysis are
for example also compounds of formula XI
Rl O
N - C - NH - Ph - 0 - CH2 - CH - CH2 ~XI)
R2 O \ N - R3
wherein Rl, R2, R3 and Ph have the above significance and
Y represents a carbonyl or thiocarbonyl radical.
The hydrolysis is carried out in the usual manner by means of
hydrolysing agents and, for example, in the presence of basic agents, or,
especially when using compounds of formula XI as the starting material, of
acid agents. Such acid agents are for example dilute inorganic acids, such
as sulphuric acid or a hydrohalic acid, such as one of those mentioned above.
Radicals removable by hydrogenolysis are for example ~-aralkyl
radicals, such as benzyl radicals, or aryloxycarbonyl radicals, such as
~ . .
., , , . . . :
.

phenoxycarbonyl radicals, which can be split off by hydrogenolysis in the
usual manner, especially by catalytically activated hydrogen, such as by
hydrogen in the presence of a hydrogenation catalyst, for example palladium
or platinum. Further radicals which are removable by hydrogenolysis are for
example ~-halogen-ethoxycarbonyl radicals, such as the 2,2,2-trichlorethoxy-
carbonyl radical or the 2-iodoethoxycarbonyl or 2,2,2-tribromoethoxycarbonyl
radical, which can be removed in the usual manner, especially by nascent
hydrogen. Nascent hydrogen can herein be obtained by the action of metal
or metal alloys on agents which yield hydrogen, such as carboxylic acids,
alcohols or water, and in particular zinc or zinc alloys together with acetic
acid can be used. The hydrogenolysis of ~-halogen-ethoxycarbonyl radicals
can preferably be effected by chromium-II compounds, such as chromium-II
chloride or chomium-II acetate. In carrying out the hydrogenolysis care
must be taken that other reducible groups, above all the urea group, are
not attacked.
It is furthermore possible to reduce a Schiff base of formulae
XII or XIII
1 " OH
R / N - C - NH - Ph - O - CH2 - CH - CH = N - R3 (XII)
or
1 O OH
N - C - NH - Ph - O - CH2 - CH - CH2 - N =R3' ~XIII)
-R2
or a ring-tautomer, corresponding to formula XIII, of formula XIV
1 \ O
N - C - NH - Ph - O - CH2 - fH ICH2 ~XIV)
R2 \ H
~-~ 3
- 10 -
. ~ ~

wherein Rl, R2, Ph and R3 have the above significance and R3'1-1 is the
same as R3.
This reduction is carried out in the usual manner, for example
with a di-light metal hydride, such as sodium borohydride, or by catalytic
hydrogenation, such as with hydrogen in the presence of palladium, platinum
oxide or Raney nickel. During the reduction, care must be taken that other
reducible groups, above all the urea group, are not attacked.
It is furthermore possible to reduce the 2-oxo group in a compound
of formula XVI
" .,
N - C - NH - Ph - O - CH2 - C - CH2 - NH - R3 (XVI)
wherein Rl, R2, R3 and Ph have the above significance, to a hydroxyl group.
This reduction is carried out in the usual manner, especially using
a di-light metal hydride, such as one of those mentioned above, or according
to the method of Meerwein-Pondorf-Verley or a modification thereof,
especially with an alkanol as a reagent and as a solvent, such as isopropanol,
and with a metal alkanolate, preferably a metal alkanolate,correspGnding to
the alkanol, such as a metal isopropanolate, for exam~le aluminium isopropano-
late.
It is furthermore possible to react a reactive acid derivative of
a carbamic acid of formula XVII OH
HOOC - NH - Ph - O - CH2 - CH - CH2 - NH - R3 ~XVII) 1-
wherein Ph and R3 have the above significance with an amine of formula
Rl-NH-R2, wherein Rl and R2 have the above significance.
A reactive acid derivative of such a carbamic acid is for
example a lower alkyl estsr or above all a phenyl ester, an acid halide,
~`
- 11 -
. .
.
- , : ~ , ~ . . :.
.: - . .

~1~9t~9
such as an acid chloride, or especially an internal anhydrlde, such as an
isocyanate.
This reaction is carried out in the usual manner, especially using
an excess of amine, and optionally in a solvent and at elevated temperature,
preferably above 1~0C.
~ epending on the process conditions and starting substances, the
final substances are obtained in the free form or in the form of their acid
addition salts, which are also included in the invention. Thus for example
basic, neutral or mixed salts, and where relevant also hemihydrates, mono-
hydrates, sesquihydrates or polyhydrates thereof, can be obtained. The acid
addition salts of the new compounds can be converted into the free compound in
a manner which is in itself known, for example with basic agents, such as
alkalis or ion exchangers. On the other hand, the resulting free bases can
form salts with organic or inorganic acids. In order to manufacture acid
addition salts, such acids are especially used as are suitable for forming
therapeutically usable salts. As such acids there may for example be mentioned:
hydrohalic acids, sulphuric acids, phosphoric acids, nitric acid, perchloric
acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic
acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic,
tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; phenyl-
acetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or
p-aminosalicylic acid, embonic acid, methanesulphonic, ethanesulphonic,
hydroxyethanesulphonic and ethylenesulphonic acid; halogenobenzenesulphonic,
toluenesulphonic, naphthalenesulphonic or sulphanilic acid; methionine,
tryptophan, lysine or arginine.
These or other salts of the new compounds, such as for example
the picrates, can also serve or the purification of the resulting
- 12 -
,

free bases, by converting the free bases into salts, separating these off
and again liberating the bases from the salts. In view of the close
relationships between the new compounds in the free form and in the form
of their salts, the free compounds are, in the preceding and following
text~ where appropriate also to be understood to include the corresponding
salts as regards sense and purpose.
The invention also relates to those embodiments of the process
in which a reagent is optionally present in the form of its salts.
Thus it is possible to react an aldehyde of formula XVIII
Rl O OH
., ,
N - C - NH - Ph - O - CH2 - CH - CHO (XVIII)
R2
wherein Rl, R2 and Ph have the above significance, with an amine of formula
H2N-R3, wherein R3 has the above significance, in the presence of a suitable
reducing agent such as one of those mentioned above. Here a compound of
formula XII is obtained as an intermediate product and this is then reduced
in accordance with the invention.
It is furthermore possible in a suitable manner to react an amine
of formula VI with an aldehyde or ketone of formula O=R3', wherein R3' has
the above significance, in the presence of a suitable reducing agent, such
as one of those mentioned above. Here a compound of formula XIII or
XIV is obtained as an intermediate product and this is then reduced in
accordance with the invention.
The new compounds can, to the extent that they possess asymetric ?
carbon atoms, and depending on the choice of the starting substances and
working methods, be present as optical antipodes or racemates or, to the
extent that they contain at least two asymmetric carbon atoms, also as
.
- 13 -
- :

-
isomer mixtures (racemate mixtures).
Resulting isomer mixtures (racemate mixtures) can be resolved into
the t~o stereoisomeric (disastereomeric) pure racemates on the basis of the
physico-chemical differences of the constituents in a known manner, for
example bychromatography and/or fractional crystallisation.
Resulting racemates can be resolved according to known methods,
for example by recrystallisation from an optically active solvent, with
the aid of micro-organisms or by reaction with an optically active acid which
forms salts with the racemic compound and separation of the salts obtained
in this manner, for example on the basis of their different solubilities,
into the diastereomers, from which the antipodes can be liberated by the
action of suitable agents. Particularly customary optically active acids are
for example the D- and L-forms of tartaric acid, di-o- toluyltartaric acid,
malic acid, mandelic acid, camphorsulphonic acid or quinic acid. Advantageous-
ly the more active of the two antipodes is isolated.
Appropriately, such starting substances are used for carrying out
the reactions according to the invention as lead to the initially particularly
mentioned groups of final substances and particularly to the final substances
which have been especially described or highlighted.
The starting substances are known or can, if they are new, be
obtained according to methods which are in themselves known.
The new compounds can be used as medicines, for example in the
form of pharmaceutical preparations, in which they or their salts are
present mixed with a pharmaceutical, organic or inorganic, solid or liquid
carriers which is for example suitable for enteral or parenteral
administration. Possible substances for forming the carriers are those
- 14 -
:' .~: :`.
- . .

which do not react with the new compounds, such as for example water,
gelatine, lactose, starch, magnesium stearate, talc vegetable oils, benzyl
alcohols, gum, polyalkylene glycols, white petroleum jelly, cholesterol or
other known medicinal carriers. The pharmaceutical preparations can for
example be in the form of tablets, dragees, capsules, suppositories, ointments
or creams, or in a liquid fo~m as solutions ~for example as an elixir or
syrup), suspensions or emulsions. They are optionally sterilised and/or
contain auxiliary substances, such as preservatives, stabilisers, wetting
agents or emulsifiers, salts for regulating the osmotic pressure or buffers.
They can also contain yet further therapeutically valuable substances. The
preparations, which can also be used in veterinary medicine, are formulated
according to usual methods.
The examples which follow explain the invention without however
restricting it.
Example 1
A solution of 40 g of l-[o-chloro-p-~N',N'-dimethyl-ureido)-
phenoxyJ-2,3-epoxy-propane and 40 g of isopropylamine in 40 ml of ethanol
in heated to boiling for 4 hours. Thereafter the mixture is concentrated
by evaporation in vacuo and the residue is dissolved in 2 N hydrochloric
acid. After extraction with ether, the hydrochloric acid layer is separated
off and rendered alkaline by adding concentrated sodium hydroxide solution.
The base which has separated out is extracted by shaking with methylene
chloride. After evaporation of the solvent and after recrystallisation of
the residue from ethyl acetate, the l-[o-chloro-p-(N',N'dimethylureido)-
phenoxy]-2-hydroxy-3-isopropylamino-propane of formula
,
F
- 15 -
.

(CH3)2NCONH - ~ OCH2CHCH2NIICH \ CH3
Cl 3
is obtained in crystals of melting point 130C.
The cyclohexylsulphamate melts at 146-150C.
The epoxide used as the starting product can be manufactured as
follows:
50 g of dimethylcarbamic acid chloride are added dropwise at room
temperature to a solution of 63 g of 3-chloro-4-hydroxy-aniline to 300 ml
of pyridine, whilst stirring and the mixture is left to stand for 12 hours.
Thereafter 2 N hydrochloric acid is added until a pH value of 5 is reached,
after which the N,N-dimethyl-N'-~3-chloro-4-hydroxy-phenyl)-urea precipitates.
The compound melts at 202-203C.
45 g of the phenol are now heated for 15 hours under reflux with
45 g of epichlorohydrin and 45 g of potassium hydroxide in 450 ml of acetone.
Thereafter the potassium hydroxide is filtered off and the solvent is evaporated
off. The residue is dissolved in methylene chloride and extracted by shaking
with 2 N sodium hydroxide solution. After evaporation of the solvent, the
crude l-[o-chloro-p-~N',N'-dimethylureido)-phenoxy]-2,3-epoxy-propane remains,
which is used for the above reaction.
Example 2
10 g of 1-[p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane are
warmed for 4 hours at 90C with 10 g of isopropylamine in 10 ml of ~hanol.
Thereafter the excess amine as well as the solvent are evaporated off in vacuo.
F
.
- 16 -
... . . . . . .
- ., ~ .: .
, . . - ~ . .

The residue is dissolved in 2 N hydrochloric acid, the undissolved constituents
are filtered off and the solution extracted with methylene chloride. The
aqueous phase is rendered alkaline by adding 2 N sodium hydroxide solution
and is thereafter extracted with methylene chloride. After evaporation of
the solvent, 1-[p-~N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-
propane of formula
(CH3)2NCONH --- ~ 2 H 2NHCH \
CH3
remains, which after recrystallisation from benzene melts at 138-139 C~
The epoxide used as the starting product can be manufactured
as follows:
12 g of dimethylcarbamoyl chloride are added to a solution of 20
g of p-benzyloxy-aniline in 100 ml of pyridine and the mixture is left ~o
stand for 2 days. On addition of water, the N,N-dimethyl-N'-~p-benzyloxy-
phenyl)-urea precipitates; it melts at 155-158C after sublimation.
20 g of this urea are dissolved in 200 ml of ethanol and hydrogenated
after addition of 2 g of palladium-charcoal ~10 per cent strength). When the
uptake of hydrogen has ended, the mixture is concentrated by evaporation in
vacuo and the residue is dissolved in 2 N sodium hydroxide solution. The
undissolved constituents are extracted with ether and the aqueous layer is
rendered acid by adding 5 N hydrochloric acid. N,N-dimethyl-N'-(p-hydroxy-
phenyl)-urea precipitates; it melts at 203-205C after recrystallisation from
isopropanol.
20 g of the phenol are heated for 10 hours with 20 g of potassium
hydroxide and 20 g afepiclilorohydrin in 200 ml of acetone, whilst stirring.
- 17 -
.., . . ~ . , .
.. , :. . . . : . ~ . :

9~
Thereafter the potassium hydroxide is filtered off and the filtrate is
concentrated by evaporation. The residue is dissolved in methylene chloride
and extracted with 2 N sodium hydroxide solution. After evaporation of the
methylene chloride, the crude l-~p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxy-
propane remains as an oil.
Example 3
A solution of l-[o-allyl-p-(N',N'-dimethylureido)-phenoxy]-2,3-
epoxypropane (15 g) and isopropylamine ~15 g) in 20 ml of ethanol is heated
for 4 hours. Thereafter the reaction mixture is evaporated in vacuo, the
residue dissolved in 2N-hydrochloric acid and filtered. The filtrate is
rendered alkaline by addition of concentrated sodium hydroxide solution. An
oil is precipitated that is extracted with methylene chloride. After the
solution has been dried and the solvent evaporated, there remains l-[o-allyl-
p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of
formula
OH 3
)2NcoNH - ~ OCH2CHCH2NHCH /
CH2CH=CH2 CH3
which after recrystallization from benzene-petroleum ether melts at 110-112C.
The epoxide used as starting material can be prepared in the
following way:
To 2-allyl-4-amino-phenol ~15 g) in 50 ml of pyridine is added
dimethyl-carbamoyl chloride (12 g) and the mixture is left to stand for 12
hours at 25C. On addition of 200 ml of 2N hydrochloric acid, extraction
with methylene chloride is effected. The extract is evaporated to dryness
in vacuo. The residue is dissolved in 2N sodium hydroxide solution, the
- 18 -
.
: '
'.'

9~L49~
resulting solution treated with charcoal and adjusted to a pH of 9 by
addition of hydrochloric acid. The precipitated constituents are filtered
off, the filtrate rendered acid. 2-Allyl-4-(N',N'-dimethylureido)-phenol
is precipitated, which after recrystallization from ethyl acetate-pentane
melts at 125-127C.
12 g of the phenol is heated to boiling for 12 hours with 12 g of
epichlorohydrin and 12 g of potassium carbonate in 75 ml of acetone. Thereafter
the solid constituents are filtered off and the filtrate is evaporated in
vacuo. The residue is dissolved in methylene chloride and extracted with
sodium hydroxide solution. After evaporation of the solvent, the crude 1-
[o-allyl-p-~N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane remains as an oil.
Example 4
A mixture of 30 g 1-~m-~N',N'-dimethylureido)-phenoxy]-2,3-epoxy-
propane, 30 g isopropylamine and 30 ml ethanol is heated to 60 for 4 hours
and then evaporated to dryness in vacuo. The residue is dissolved in 2N-acetic
acid and extracted with ether. After separation of the water phase the same
is rendered alkaline by addition of sodium hydroxide solution and extracted
with methylene chloride. After evaporation of the solvent the l-[m-~N',N'-
dimethyl-ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of the formula
IOH / CH3
IOCH2CHCH2NHCH
I CH3
~ .
NHCON~CH3)2
.
remains, which melts after recrystalli~ation from isopropanol at 130.
- ~ .

~14~
Example 5
Tablets containing 20 mg of active substance are manufactured with
the following composition:
l-[o-Chloro-p-~N',N'-dimethylureido)-phenoxy]-
2-hydroxy-3-isopropylamino-propane 20 mg
Starch 60 mg
Lactose 50 mg
Colloidal silica 5 mg
Talc 9 mg
Magnesium stearate 1 mg
145 mg
Tablets containing 20 mg of l-[p-(N',N'-dimethyl-
ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane can be manufactured in
the usual manner with the same composition.
Example 6
The following mixture is used to manufacture capsules:
l-[o-Chloro-p-(N',N'-dimethylureido)-phenoxy-
2-hydroxy-3-isopropylamino-propane 2500 g
Talc 80 g
Colloidal silica 20 g
The active substance isintimately mixed with talc and
colloidal silica, and the mixture is forced through a sieve (0.5mm)
and filled into hard gelatine capsules in portions of 21 mg.
Capsules can be manufactured in the same manner and with the
same composition using l-~p-~N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy
-3-isopropylamino-propane.
- 20 -
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.. .. . ~ . '
:: ' :. , . : ~
- . ~ . .
;'
.