Note: Descriptions are shown in the official language in which they were submitted.
03;~
The invention relates to new amines of the formula I
Alkl - S - alk2 - O ~ O - CH2 - A ~I)
wherein A represents the group
-CH~OH) - CH2 - NH - R (Ia)
or represents the ~roup
- CH - ICH2
\ X / ~Ib)
wherein Alkl denotes lower alkyl, alk2 denotes lower alkylene, R is lower
alkyl or phenyl-lower-alkyl, wherein phenyl is unsubstituted or mono-
- substituted by lower alkylJ lower alkoxy, halogen or trifluoromethyl, Rl
is hydrogen J lower alkyl, lower alkenyl, lower alkenyloxy, lower alkanoyl,
halogen or trifluoromethyl, X denotes the methylene or carbonyl group,
in the form of isomer mixtures (racemate mixtures) or pure racemates or
optical antipodes or pharmaceutically accep~able acid addition salts
thereof, as well as to processes for their manufacture.
In the preceding and following text, a lower radical is in
particular understood as a radical with up to 7 C atoms, above all with
up to 4 C atoms.
Thus, lower alkyl Alkl preferably has up to 7 C atoms, such
as iso-propyl or n-propyl, straight or branched butyl, pentyl, hexyl
or heptyl, bonded in any desired position, above all up to 4 C atoms,
and especially ethyl and above all methyl.
-- 2 --
, . ~''
~6JS~d
Lower alkylene alk2 is branched or above all straight-chain
lower alkylene, preferably with at least 2 C atoms in the alkylene
chain and ~ith especially 2 or 3 C atoms in the alkylene chain, such
as propylene-1,3 or above all ethylene-1,2.
The Rl-substituted para-phenylene radical is referred to here-
inafter as Ph.
Suitable values for Rl on the para-phenylene radical are,
for example, hydrogen, trifluoromethyl, fluorine, bromine and especially
chlorine, the lower alkyl radicals given for Alkl, vinyl, methallyl
and especially allyl, ethoxy, iso- or n-propoxy and especially methoxy,
methallyloxy and above all allyloxy, butyryl, propionyl and above all
acetyl. It is preferred that the p-phenylene radical is substituted in
the ortho-position to the 2-hydroxy-propoxy radical, or especially that
the p-phenylene radical is unsubstituted.
The lower alkyl R is unbranched or preferably branched, in
particular branched at the a-C atom, and is, for example, sec.-butyl
or especially tert.-butyl or above all isopropyl.
The phenyl-lower alkyl R preferably has up to 12 C atoms,
above all up to 10 C atoms, and is unbranched or preferably branched
in the lower alkyl part, in particular branched at the a-C atom of
the lower alkyl part. The phenyl part is in particular monosubstituted
by lower alkyl as indicated for Alkl, or lower alkoxy, halogen or
trifluoromethyl as indicated, but is preferably unsubstituted. Examples
_ 3 _
, ~
03Z
of phenyl-lower alkyl R are l-methyl-3-phenyl-propyl and especially
l-methyl-2-phenyl-ethyl.
Condensation products of compounds of the formula I wi~h
formaldehyde are those of the formula Iba
Al~l - S - alk2 - O ~ O - CH2 - CH - CH (Iba)
~X /
wherein Alkl, alk2~ Rl and R have the above meanings and X represents
the methylene group.
Condensation products of compounds of the formula I with car-
bonic acid are those of the formula Ibb
- 4 -
.
,
50~)3Z
Rl
Alkl - S - alk2 - 0 ~ O - CH2 - CH - fH2
O ~ - R (Ibb~
wherein Alkl, alk2, Rl and R have the above meanings.
The new compounds possess valuable pharmacological
properties. Thus, they block cardiac ~-receptors, as can be shown
in determining the antagonism of tachycardia after 0.5 ~g/kg of d/l-
isoproterenol sulphate administered intravenously in narcotised cats
on intravenous administration of 0.02 to 2 mg/kg, they block vascular
~-receptors, as can be shown in determining the antagonism of vaso-
dilation after 0.5 ~g/kg of d/l-isoproterenol sulphate administered
intravenously in narco~ised cats on intravenous administration of 3
or more mg/kg, and they block cardiac ~-receptors as can be shown in
determining the tachycardia after O.OOS ~g/ml of d/l-isoproterenol
sulphate on isolated guineapig hearts in vitro at a concentration of
0.02 to 2 ~g/ml.
The new compounds can therefore be used as cardio-
selective antagonistic agents of adrenergic ~-receptor s~imulants,
for example for the treatment of arrhythmias and angina pectoris.
However, they can also be used as valuable intermediate products
for ~he manufacture of other useful substances, especially of phar-
maceutically active compounds.
,1~ - 5 -
1~003;~
Amongst the amines of the formula I, those wherein Alkl
has the above meanings, alk2 is 1,2-ethylene or 1,3-propylene, R
is ~-branched lower alkyl or phenyl-lower alkyl with an a-branched
lower alkyl part and Rl has the above meanings, should be singled out
particularly.
Amines of the formula I to be singled out very especially
are those wherein Alkl is lower alkyl with up to 4 C atoms, especially
me~hyl, alk2 is 1,3-propylene or especially 1,2-ethylene, R is phenyl-
lower alkyl with up to lO C atoms and an ~-branched lower alkyl part,
10especially 1-methyl-2-phenyl-ethyl, or above all ~-branched lower
alkyl with up to 4 C atoms, such as tert.-butyl or above all isopropyl,
and Rl is lower alkyl with up to 4 C atoms, especially methyl) lower
alkenyl with up to 4 C atoms, especially methallyl or above all allyl,
lower alkoxy with up to 4 C atoms, especially methoxy, lower alkenyloxy
with up to 4 C atoms, especially methallyloxy or above all allyloxy,
lower alkanoyl with up t~ 4 C atoms, especially acetyl, halo~en,
" ~
~ . - 6 -
~ ,.
,
.
~6~5i(;~3~
especially chlorine, or above all hydrogen.
The compounds mentioned not condensed with formaldehyde or car-
bonic acid are preferred.
1-[4-(2-Me~hylthio-ethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-
propane and the compounds mentioned in the examples should be mentioned
particularly.
The new compounds can be obtained according to methods which are
in themselves known.
For example, a compound of the formula II
Xl
Alkl - S - alk2 - O ~ 0 - CH2 - CH - CH2 ~ Z (II)
wherein Alkl, alk2 and Rl have the abo~e meanings, Xl represents the hydroxyl
group and Z represents a reactive esterified hydroxyl group, or Xl and Z
together form an epoxy group, can be reacted with an amine of the formula
NH2-R (III), wherein R has the above meaning.
A reactive, esterified hydroxyl group is in particular a hydroxyl
group esterified by a strong inorganic or organic acid, above all a hydrogen
halide acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid,
or sulphuric acid or a strong organic sulphonic acid, such as a strong aro-
matic sulphonic acid, for exam~le benzenesulphonic acid, 4-bromobenzenesul-
phonic acid or 4-toluenesulphonic acid. Thus Z in particular represents
chlorine, bromine or iodine.
This reaction is carried out in the usual manner. If a reactiv~
ester is used as the starting material, the reaction is preferably carried
out in the presence of a basic condensation agent and/or with an excess of
amine. Suitable basic condensation agents are, for example, alkali metal
hydToxides, such as sodium hydroxide or potassium hydroxide, alkali metal
carbonates, such as potassium carbonate, and alkali metal alcoholates, such
as sodium methylateJ potassium ethylate and potassium tertiarybutylate.
It is also possible to react a compound o the formula IIb
- 7 _
105003;~
Rl OH
Alkl - S - alk2 - O - ~ ~ O - CH2 - CH - CH2 - NH2 (IIb)
wherein Alkl, alk2 and Rl have the above meanings, or a condensation product
thereof with formaldehyde, i.e. a compound of the formula IIc
Alk - S - alk - O ~ O - CH2 - IH I 2 (llc)
wherein Alkl, alk2 and Rl have the above meanings, or a condensation product
thereof with carbonic acid, i.e. a compound of the formula IId
.,, ~1
Alk - S - alk - O ~ 2 IH lH2 (IId)
O NH
wherein Alkl, alk2 and Rl have the above meanings, with a compound of the
formula Z-R (IIIa), wherein Z and R have the above meanings.
This reaction is carried out in the usual manner, preferably in
the presence of a basic condensation agent and/or with an excess of amine.
; Examples of suitable basic condensation agen~s are alkali metal alcoholates,
especially sodium alcoholates or potassium alcoholates, or alkali metal car-
bonates, such as sodium carbonate or potassium carbonate.
It is also possible to react a compound of the formula IV
~Ikl - S - alk2 ~ O~OH ~IV)
wherein Alkl, alk2 and Rl have the above meanings, with a compound of the
formula V
Xll
Z - CH2 - CH - CH2 - NH - ~ (V)
wherein ZJ X1 and R have the above meanings, or with a condensation product
of a compound of the formula V, wherein Xl represents hydroxyl and Z repre-
E - 8 -
- : '
~Losv~3~
sents a reactive esterified hydroxyl group, with formaldehyde, for exampLe
a compound of the formula Va
Z - CH - C~ CH
2 1 2
I (Va)
0~ /N - R
CH2
wherein Z and R have the above meanings, or with a condensa-tion product of a
compound of the formula V, wherein Xl represents hydroxyl and Z represents a
reactive esterified hydroxyl group, with carbonic acid, for example a com-
pound of the formula Vb
Z - CH2 - IH f 2 (Vb)
0 ~ N - R
wherein Z and R have the above meaning.
This reaction is carried out in the usual manner. If reactive
esters are used as the starting material, the compound of the formula IV
can preferably be used in the form of its metal phenolate, such as alkali
metal phenolate, for example sodium phenolate, or the reaction is carried out
in the presence of an acid-binding agent, especially of a condensation agent
which can form a salt with the compound of the formula IV, such as an alkali
metal alcoholate.
It is also possible to hydrolyse a compound of the formula VI
1 1
Alkl - S - alk2 - o ~ - CH2 - IH lH2 (VI)
0 N - R
\y/
wherein Alkl, alk2, Rl and R have the meanings defined under formula I and
Y denotes a methylene or a carbonyl or a thiocarbonyl radical or a salt of
such a compound.
The hydrolysis is carried out in the usual manner, for example in
the presence of hydrolysing agents, for example, in the presence of acid
agents such as, for example, aqueous mineral acids, such as sulphuric acid
J - 9 _
32'
or hydrogen halide acid, or in the presence of basic agents, for example,
alkali metal hydroxides, such as sodium hydroxide.
It is also possible to reduce a Schiff's base of the formula
Rl
OH
Alk - S - alk - 0 ~ 30 - CH2 - CH - CH = N - R (VII)
or of the formula
Rl OH
Alkl - S - alk2 - 0 ~ ~ ~ CH2 ~ CH ~ CH2 ~ N - R' (VIIIa)
whèrein Alkl, alk2, Rl and R have the meanings defined under formula (I~
and R'H has the meanings of R.
This reduction is carried out in the usual manner, for example,
with a di-light metal hydride, such as sodium borohydride or lithium aluminum
hydride, with a hydride such as borane, with formic acid or by catalytic
hydrogenation. In carrying out the reduction it is necessary to ensure that
other reducible groups are not attacked.
It is also possible to react a compound of the formula
Alkl - S - alk2 - Z (IX)
with a compound of the formula
Rl
HO ~ O - CH2 - A (X)
wherein Alkl, alk2, Rl and A have the meanings defined under formula (I) and
Z represents a reactive esterified hydroxyl group, or with a salt of such
a compound.
This reaction is carried out in the usual manner, for example, as
indicated for the reaction of compounds of the formula IV and V.
Depending on the process conditions and starting materials, the
end products are obtained in the free form or in the form of their acid addi-
tion salts which is also encompassed by the invention. Thùs, for example,
basic, neutral or mixed salts and possibly also hemihydrates, monohydrates,
~1 10-
.
. .
3Z
sesquihydrates or polyhydrates thereo:f, can be obtalned. ~he 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 resul~ing free bases can
form salts wit~ organic or inorganic acids.
Æ:
~ D~ 3 2
The acids used -or the manufacture of acid addition sa]-ts
are in particular those wlnic~ are su;-rable for forming
therapeu-tically usable salts. hs exa[nples of such acids
there may be mentioned: Hydrogen halide acids, sulphuric
acids, phosphoric acidsg nitric acid and aliphatic, ali-
cyclic, aromatic or heterocyclic carboxylic acids or sul~
phonic acids, such as formic acid, ace-tic acid, propionic
acid, succinic acid, glycollic acid, lactic acid, malic
acid, -tartaric acid, citric acid, ascorbic acid, maleic
acid, hydroxymaleic acid or pyruvic acid, benzoic acid,
p-aminobenzoic acid, an-thranilic acid, p-hydroxybenzoic
acid, salicylic acid or embonic acld, methanesulphonic acid,
ethanesulphonic acid, hydroxyethanesulphonic acid, e~hylene
sulphonic acid, halogenobenzenesulphonic acids, toluene-
sulphonic acid, naphthalenesulphonic acid or sulphanilic
acid.
These or other salts of the new compounds such as,
for example, the picrates, can also be used for the purifi-
cation of the free bases obtained, by converting -the free
bases into salts, isolating -these and again liberating the
bases from the salts. Because of the close relationships
between the new co~pounds in the free form and in the form
o~ their salts, the free co~pounds, in the preceding and
following text, are where appropriate also to be understood
as the corresponding salts, with regard to general sense and
in-tended use.
The invention also relates to those embodimen-ts of
the process in which a compound obtainable as an in~ermediate
Ja
32
product at any stage of the process is used as the starting material and
the missing process steps are carried out, or the process is stopped at any
stage, or in which a starting material is formed under the reaction conditions
or in which a reactant is present in the form of its salts, if appropriate.
Thus it is possible to react an aldehyde of the formula XI
Rl OH
Alkl - S - alk2 - O ~ O - CH2 - CH - CHO (XI)
wherein Alkl, alk2 and Ph have the above meanings, with an amine of the
formula H2N-R, wherein R has the above meaning, in the presence of a suitable
reducing agent, such as one of those mentioned above. This gives, as the
intermediate product, a compound of the formula VII, which is then reduced
in accordance with the invention.
Depending on the choice of the starting materials and procedures
the new compounds can be in the form of optical antipodes or racemates or,
if they contain at least two asymmetrical carbon atoms, also in the form of
isomer mixtures (racemate mixtures~.
- 13 -
5~32
Resulting lsolner mix-tures (racemate mixtures) can
be sep~ra-ted into the ~YiO stereomc-rio (o~ias~tereo}nerlc)
pure racemates in a known marlner on t',le basis of the
physico--che~i^al differencc-s of the corstituen~ts~ for
exal~le by chromatography and/or fractional crystallisation
Resulting racemates can be resolved in-to the dia
sterevmers according to known methods, for exam~le by
recrys-talllsation from an optically active solvent, with
the aid of micro-organisms or by reaction with an optically
active acid which for~s salts with the racemic compound and
separation of the salts obtained in this manner, for example
on the basis of their different solubillties, and the anti-
podes can be liberated from the diastereomers by treatment
with suitable agents. Particularly customary o~tically
active acids are, for example, the D- ~nd L-forms o~
tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic
acid, cam~horsulphonic acid or quinic acid. AdvantageGusly,
the more active o-f the antipodes is isola-ted.
Preferably, those starting materials are used ~or
carrying out the reaccion according to the invention which
lead to the initially particularly mentioned groups of end
products and especially to the end products which have been
particularly described or singled out.
The starting materials are kno~l or can, if they
are new, be obtained according to methcds which are in
themselves known.
The new sompounds can be used as medicaments~ for
example in the form o~ pharm~ceutical preparations, in w~1ich
~Y_
~6~S{~3~2
they or thelr ~salts ~re ~)re en-t as a mixture ~itl1 a pharma-
ceutical, or~a~ic or lno~ganic, solid or li~uid excipient
t~lich is sui-ta~le for, or ex~mple~ enteral or parenteral
administration4 Suitable subs-tances for formlng the
excipien-t are those wllich do not react w~th the ~ew com~
pounds such as, for example, ~ater, gelatine~ lac-tose,
starch, magnesium stearate, talc, vege-table oils, benzyl
alcohols, gum, polyalkylene glycols, white petroleum ~elly,
cholesterol or other kno~l medicinal excipie-rlts. The
pharmaceutical prep~ra-tions can be, for example~ in the
form of tablets, dragees, capsules, suppositories, ointments
or creams, or in a li~u~d form, as solutions (for example as
an elixir or syru)~ suspensio~s or emulsions. ~ne~ are
optionally sterilised and/or contain auxiliaries, such as
preservatives, stabilising agents, wetting agents or emul-
sifiers, salts for regulating the osmo-tic pressure or buffers.
They can also conialn yet other therapeutically valuable
substances. The preparations, ~hich can also be used ln
veterinary medicine, are formulated according to customary
methods.
; The examples which follow explain the inven-tion
without, however, limiting it.
Exam~
A solution of 20 g of 1-[4-(2-methylthioethoxy)-
phenoxy]-2-hydroxy-3-chloro-propane and 30 g o.~ isopropy]-
amine in 50 ml of isopropanol is heated for 12 to 14 hours
under refll~. Tne volatile constituen-ts are then evaporated
off ~nder reduced pressure and the eJaporation residue is
/~ :
_ ~_ . -
. .
105l)(~3Z
dissolved in 300 ~1 of ethyl acetate and the solution is
e~tracted ~iith 50 ml portions of 2 N hydrochloric acid.
The aqueous phase is separa~ted off and rendered s-trongly
alkaline with concen-trated sodium hydroxi(le solution. The
oil wllich precipitates is extracted with about 200 ml of
ethyl acetate and distilled in a bulb tube at 150 to
160C/0.04 mm Hg. 1-[4-(2-me-thylthioethoxy)-phenoxy]-2-
hydroxy-~-isopropylamino-propane is thus o~tained as an
almost colourless oil which solidifies to crystals. Its
hydrochloride melts at 102 to 103C (crystallise~ from
butanone).
Exam~le 2
An analogous method to Example 1, usin~ ~5 g of
t-butyla~ine, gives 1-[4-(2-methylthioethoxy)-phenoxy]-2-
hydroxy-~-t butylamino-propane of melting point 62-63C
(from ether/petroleum ether). Its hydrochloride melts at
131-133C (from acetone-ether).
1-~4-(2-Methylthioethoxy~-phenoxy]-2-hydroxy-3-
chloropropane, required as the starting material can be
obtained as follows:
2-(p-Hydroxyphenoxy)-tetrahydropyrane is reacted
analoOously to ~xample 4 with 2-methylthioethyl chloride and
is hydrolysed for 2 to 3 hours with dilute hydrochloric
acid in e-thanol. p-(2~Methylthioethoxy)-phenol, thus
obtained, is used in the crude form for the next stage.
20 g of crude p (2-methylthioethoxy)-phenol, 30 ml
of epichloroh~drin and 0.2 ml of piperidine are heated for
1 hour ~der reflux. The excess epichlorohydrin is then
~6
3Z
distilled off at 100~ bath temperature and 10 mm Hg. The crude
1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-chloropropane thus
obtained is used direct for the next stage.
Example 3
3.0 g of 3-isopropyl-5-[4-(2-methylthioethoxy)-phenoxy-
methyl]-oxazolidine are dissolved in 20 ml of 2 N hydrochloric acid
and the solution is warmed for 1 hour on a water bath (about 80~C).
After cooling, the solution is render~d alkaline with 10 ml of con-
centrated sodium hydroxide solution and the mixture is extracted with
100 ml of ether. The resulting 1-[4-(2-methylthioethoxy)-phenoxy]-
2-hydroxy-3-isopropylamino-propane is distilled at 150 - 160C/0.04
mm Hg in a bulb tube. Its hydrochloride melts at 102 to 103C
(crystallised from butanone) and is identical with the product de~
scribed in Example 1.
Example 4
4.7 g of 3-isopropyl-5-(4-hydroxyphenoxy-methyl)-oxazolidine,
dissolved in 70 ml of acetone, 3 g of potassium carbonate and 2.2 g
of 2-methylthio-ethyl chloride are heated for 20 hours under reflux
whilst stirring. After addition of a further 1.5 g of potassium car-
bonate and l.l g of 2-methylthio-ethyl chloride, the reaction mixture
is heated for a further 20 to 24 hours. It is then filtered and the
filtrate is evaporated under reduced pressure. The resulting oil is
taken up in 100 ml of ether and extracted three times with 10 ml of
concentrated sodium hydroxide at a time. The ether phase is dried,
filtered and evaporated
:
" ~t- I?
- . . . . . .
~ s~ z
and -the e-~aporation residue is distille~ in a bulb tube at
140 to 150C/0.03 m~l Hg. 3-Isopropyl-5~[4-(2-methylthio-
ethoxy)-phenoxy-methyl]-oxazolidine is thus obtained as a
yellowish oil.
4.5 g of 1-(4-hydrox~phenoxy)-2-hydroxy-3-
isopropylamino-propane are reacted analogously to Example 4
with a total of 3.3 g of 2~methylthio-ethyl chloride and the
reaction mixture is worked up. Tnis gives 1-[4-(2-methyl-
thioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane
of which the hydrochloride melts at 102 to 103C (from
butanone), and is identical with the product described in
Example 1.
xample 6
3.7 g of 4-(2-methylthioethoxy)-phenol, 3.5 g of
l-chloro-2-hydroxy-3-isopropylamino propane and 5 g of
potassium carbonate in 50 ml of acetone are stirred for 5
to 7 hours at 50C. The undissolved matter is filtered off
and the filtrate is evaporated under reduced pressure. The
evaporation residue is taken up in 100 ml of ether and
extracted 3 times with 10 ml of concentrated sodium hydroxide
solution at a time. The organic phase is separated of~,
dried, filtered and evaporated and gives, after distillation
at 150 to 160C/0.04 mm Hg (bulb tube), 1-[4-(2-methylthio-
ethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane,
melting point of the hydrochloride 102 to 103C (from buta-
none). The product is ide~tical with the product described
in Example 1.
: -
)03~
E~ 7
21 g of crude l-C~-chloro-4-(2-methylthioe-thoxy)-
phenoxy]-2,3-epoxy-propane, 21 g of isopropylamine and lO0 ml
of isopropanol are heated for 3 hours under reflux. The
crude 1-[3-chloro 4-(2-methylthioethoxy)-phenoxy3-2-hydroxy-
3-isopropylamino-propane obtained by working up as in
Example l gives, on reaction with half the equivalent
amount of fumaric acid, a crystalline neutral fumarate of
melting point 149-150C (from isopropanol-ether).
The starting material can be prepared as follows:
43.3 g of chlorohydroquinone, 33 g of 2-methylthio-
ethyl chloride ~nd 42 g of potassium hydroxide in 400 ml of
acetone are heated for 20 hours under reflux whilst stirring.
The reaction mixture is cooled and filtered. After
evaporating off the solvent in vacuo, the evaporation residue
is taken up in 500 ml of ethyl acetate and extracted with a
total of 500 ml of 2 N sodium hydroxide solution in portions.
The aqueous phase is acidified with 6 N hydrochloric acid
whilst cooling with ice and the oil which separates out is
extracted with ethyl acetate. The ethyl acetate is
evaporated off in vacuo and the residue is distilled in a
bulb tube. The fraction boiling at 140C bath temperature
and 0.01 mm Hg contains 3-chloro-4-(2-methylthioethoxy)-
phenol.
21.5 g of 3-chloro-4-(2-methylthioethoxy)-phenol,
15 g of epichlorohydrin and ll g of potassium carbonate in
250 ml of acetone are heated for 16 to 20 hours under reflux.
The undissolved salts are then filtered off and the filtrate
:; /q
'S~3~
is evaporated in vaouo. The evaporation residue is taken
up in 300 ml of ethyl acetate and washed with 100 ml of cold
2 N sodium hydroxide solution. After drying and evaporation,
crude 1-[3-chloro-4-(2-methylthioethoxy)-phenoxy~-2,3-epoxy-
propane is o~tained, which can be used without further
purification.
~.~
18.9 g of 1,2-epoxy-3-[2-methyl-4-(2-methylthio-
ethoxy)-phenoxy]-propane, 20 ml of isopropylamine and 100 ml
of isopropanol are heated for 3 hours under refluxO Working
up analogously to Example 1 gives 1-[2-methyl-4-(2-methyl-
thioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane as
an oil which with half the theoretical amount of fumaric acid
forms the neutral fumarate of melting point 134-135C (from
methanol-ether).
The starting material can be ~repared as ~ollows:
50 g of toluhydroquinone, 50 g of 2-methylthio-
ethyl chloride and 45 g of potassium carbonate in 600 ml of
acetone are heated under reflux. After 18, 33 and 55 hours,
a further 9 g of 2-methylthioethyl chloride and 11 g of
.
potassium carbonate are added in each case. The mixture is
then heated for a further 24 hours. The reaction mixture
is worked up analogously to Example 7 and gives 2-methyl-4-
(2-methylthioethoxy) phenol as an oil of boiling point
130C/0.01 mm Hg~ 24 g of 2-methyl-4-(2-methylthioethoxy)-
phenol, 250 ml of diethyl ketone, 18 g of epichlorohydrin and
18 g of potassium carbonate are reacted analogously to Example
7 and worked up to give the oily 1-[2-methyl-4-(2-methylthio-
_ ~ _
1~50~ethoxy)-phenoxy]-2,3-epoxy-propane. This is used in the
crude form for the next stage.
Example 9
12 g ~f 1-[4-(3-methylthio-propoxy)-phenoxy]-2,3-
epoxy-propane, 120 ml of isopropanol and 15 ml of isopropyl-
amine are heated for 3 to 4 hours under reflux. Af-ter
evaporating off the volatile constituents in vacuo, crude
1-[4-(3-methylthio-propoxy)-phenoxy]-2-hydroxy-3-isopropyl-
amino-propane is obtained, which is isolated analo~ously to
Example 1 and then converted into its hydrochloride. After
recrystallisation from acetone-ether, the hydrochloride melts
at 102-103C.
The epoxypropane required as the starting material
can be obtained as follows:
- 18 g of potassium carbonate 9 2602 g of 1,3-dibromo-
propane and 25 g ol~ 2-(p-hydroxyphenoxy)-tetrahydropyrane
;in 500 ml of acetone are heated for 20 hours under reflux.
The 2-[4-(3-bromopropoxy)-phenoxy]-tetrahydropyrane thus
obtained, in 100 ml of ethanol, is left to stand with a
solution of 42 g o~ sodium methylmercaptide in 4~0 ml of
ethanol for 3 hours at 0-5Co
;After addition of concentrated hydrochloric acid
until pH 1 is reached, the reaction mixture is left to stand
for 2 to 3 hours at room temperature and then evaporated in
vacuo, and the residue is partitioned between lOOml of water
and 300 ml of ether. The ether phase lS exhaustively
`extracted with 2 N sodium hydroxide solution, the aqueous
phase is again rendered acid and 4-(3-methylthiopropoxy)-
~ 0 ~ 2
phenol is extracted with ether. It boils at 125-128C/
0.01 mm Hg.
10 g of 4-(3-methylthio-propoxy)-phenol, 100 ml of
acetone, 8 g of epichlorohydrin and 8 g of potassium carbon-
ate are heated for 48 hours under reflux. After cooling,
the insoluble constituents are filtered oIf and the filtrate
is evaporated. Crude 1-[4-(~-methylthio~propoxy)-phenoxy~-
2,3-epoxypropane is thus obtained, which is used further
without additional purification.
Example 10
22 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-tert.-
butyl-amino-propane, 13 g of potassium carbonate and 11 g of
2-methyl-thio-ethyl chloride in 350 ml of acetone are heated
for 16 hours under reflux whilst stirring. After 24 and 48
hours, a further 13 g of potassium carbonate and 11 g of
methylthio-ethyl chloride are added in each case, and heating
is continued. After a total of 60 to 70 hours' reaction
time the suspension is filtered, the filtrate is evaporated
and the residue is dissolved in 300 ml of ether. The
-ether solution is first washed 3 times wi-th 10 ml of concen-
trated sodium hydroxide solution at a time and then extrac-
ted twice with 75 ml of 2 N hydrochloric acid at a time.
The combined hydrochloric acid extracts are rendered alkaline
with concentrated sodium hydroxide so-ution (pH about 10)
and extracted twice with 200 ml of ether at a time. After
distilling off the ether, crude l-C4-(2-methylthioethoxy)-
phenoxy]-2-hydroxy-3-tert.-butylamino-propane is obtained~
which is identical with the product from Example 2.
.!~
- , ,, , ' .
.
l~tj~32
Exam~le 11
A solution of 11.0 g of 1-[4-(2-methyl-thioethoxy)-2-
allylphenoxy]-2,3-epoxy-propane and 28 g of isopropylamine
in 200 ml of isopropanol is heated for 14 hours ~lder reflux.
The volatile constituents are then evaporated off under
reduced pressure and the evaporation residue is dissolved
in ethyl acetate and extracted with 25 ml of 2 N hydrochloric
acid at a time. Tne aqueous phase lS separated off and
rendered strongly alkaline with concentrated sodium hydroxide
solution. The oil which precipitates is extracted with
ethyl acetate and the extract is washed with water, dried
over sodium sulphate, filtered and evaporated. 1-[2-Allyl-
4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-
propane is obtained as an almost colourless oil. Its
hydrogen-oxalate melts at 116-117C (when crystallised from
acetone).
The epoxypropane derivative required as the starting
substance can be obtained as follows:
42.0 g (0.276 mol) of 2-allylhydroquinone, dissolved
in 300 ml of acetone, 39 g of potassium carbonate and 28 ml
of 2-methylthioethyl chloride are heated for 20 hours under
reflux whilst stirring. Filtration and evaporation of the
filtrate gives 67 g of evaporation residue as a brown oil.
This is dissolved in ether, and the solution is extracted
four times with a total of 300 ml of 2 N sodium hydroxide
solution. The alkaline extracts are brought to pH 9 by
passing in carbon dioxide and then extracted three times
with ether. The ether extracts are dried with sodium
~3
~5~ 3'~
sulphate, fil-tered and evaporated and the evapora-tlon resi-
due is distilled in a bulb tube. The fraction o boiling
range 110-150 C/0.05 mm Hg gives 4 (2 methylthioothoxy)-2-
allyl-phenol of melting point 117-119C after crystallis~tion
from carbon tetrachloride.
13.0 g of 4-(2-methylthioethoxy)-2-allyl-phenol,
dissolved in 100 ml of diethyl ketone, are heated with 8.4 g
of potassium carbonate and 6 ml of epichlorohydrin for ~6
hours whilst stirring under reflux. The mixture is then
evaporated to dryness in vacuo and the residue is par-
titioned between water and ethyl acetate. The organic phase
is washed with water, dried over sodium sulphate, filtered
and evapora-ted. 1-[4-(2-Methylthioethoxy)-2-allylphenoxy]-
293 epoxy-propane is obtained as a yellowish oil.
Example 12
22.5 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-iso-
propylamino-propane, 18.7 g of 2-t-butylthio-ethyl chloride
and 17 g of potassium carbonate in 200 ml of acetone are
stirred for 18 hours under refluxO The same amounts of
potassium carbonate and 2-t-butylthio-ethyl chloride are
then added once more and the mixture is heated for a further
24 hours. Working up as described in Example 10 gives
4-(2-t-butylthioethoxy)-phenoxy~ 2 hydroxy-3-isopropyl-
amino-propane as an oil which distils at 150-160C/0.01 mm Hg
in a bulb tube and forms a neutral fumarate of melting point
127~128QC ~from ace-tone~.
, Example 13
22.5 g of 1 ~4~hydroxyphenoxy)-2-hydroxy-3-
~y ~ :
_ ~_
3i3~ `isopropylamino-propane and a total of 40 g of potassium
carbonate and 37 g of 2-ethylthio-ethyl chloride give,
analogously to Example 12, 1-~4-(2-ethylthioethoxy)-phenoxy~-
2-hydroxy-3-isopropylamino-propane as an oll which distils
at 150-155C/0.02 mm Hg in a bulb tubeO Its hydrochloride
melts at 86-88~C (from isopropanol-ether)0
xample 14
Analogously to Example 12, 22.5 g of 1-(4-hydroxy-
phenoxy)-2-hydroxy-3-isopropylamino-propane 5 25 g of
2-chloropropyl methyl, sulphide and 28 g of potassium
carbonate give 1-[4-~1-methyl-2-methyl-thio-ethoxy)-phenoxy]
-2-hydroxy-3-isopropylamino-propane as an oil which distils
at 150-155 C/0.02 mm Hg in a bulb tube. Its neutral
fumarate melts at 113C (from iso~ropanol-ether).
: Tablets containing 50 mg of active substance are
prepared in the usual manner, in the following com~osition:
Composition
1-[4-(2-Methylthioe-thoxy)-phenoxy]~
2-hydroxy-3-isopropylamino-propane 50 mg
Whea-t s-tarch 59 mg
Lactose 70 mg
Colloidal silica 10 mg
Talc 10 mg
Magnesium stearate - ~
200 mg
_r~
The 1-[4-(2-methylthioethoxy)-phenoxy~-Z-hydroxy-
~5~
3-isopropylamino-propane is mlxed with a part of -the wheat
starch, with lactose and with colloidal silica and the
mixture is forced through a sieve a giving a powder mixture.
A further part of the wlleat starch is worked into a paste
with a five-fold amo~lnt of water on a water bath and the
powder mixture is kneaded with this paste until a slightly
plastic mass has been produced.
The plastic mass is pressed through a sieve of
about 3 mm mesh width and dried and the resulting dry gran-
ules are again forced through a sieve. The remaining wheat
starch, talc and magnesium stearate are then mixed in and
the mixture is pressed to give tablets weighing 200 mg and
having a breaking groove.
The daily dose is about -~ to 4 tablets in the case
of a warm-blooded animal of about 75 kg body weight, and the
appropriate dose o~ active substance can also be administered
as a single tablet of appropriate composition.
Example 16
22 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-C(l~
methyl-3-phenyl-propyl)amino]-propane, 8.5 g of 2-chloro-
ethyl methyl sulphide and 11 g of potassium carbonate are
heated for 6 hours at the reflux tempera-ture, whilst
stirring. After adding the same amounts of 2-chloroethyl
methyl sulphide and potassium carbonate, the reaction mixture
is heated for a further 18 hours. Filtrationl and evapora-
tion of the ~iltrate in vacuo, gives an oil ~hich is
chromatographed on 600 g of silica gel. After elution
with benzene containing 5% of methanol~ and subsequent
~ ~ S~ ~ 3 2
elution wlth benzene which contains 20% of methanol, the
latter fraction gives pure 1-[4-(2-methylthioethoxy)-
phenoxy]-2-hydroxy-3-[(3'-phenyl-1'-methylpropyl)-amîno]-
propane, of which the hydrochloride melts at 154-156C
(sintering at 148C) (from methanol/acetone3.
~ '
12 g of 1-[4-(2-methylthioe-thoxy)~henoxy]-2,3-
epoxy-propane~ 7.5 g of 1-methyl-3-phenyl-propylamine and
100 ml of isopropanol are heated for 4 hours under reflux.
After evaporating the volatile constituents, ultimately in
a high vacuum at 130C/0.01 mm Hg, the reaction mixture is
taken up in a mixture of 50 ml of ethyl acetate and 50 ml of
ether, and the solution is clarified by filtration through
Hy~lo and shaken with 100 ml of 2 N hydrochloric acid.
Hereupon 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-
~ methyl-3'-phenyl-propyl)-amino]-propane precipitates
as the crystalline hydrochloride. After recrystallisation
from water, with addition of active charcoal, this substance
melts at 154-156C (sintering from 148C onwards).
The epoxide used as the starting substance can be
prepared as follows:
- 2-(4-Benzyloxy-phenoxy)-tetrahydropyrane is pre-
pared from hydro~uinone monobenzyl ether and 2,3-dihydro-
pyrane in benzene t using p-toluenesulphonic acid as the
catalyst (melting point 67-69C after crystallisation from
petroleum ether).
This substance is debenzylated with the addition of
a palladium/charcoal catalyst, and thus gives 2-(4-hydroxy-
_ ~47
.
3~
phenoxy)--tetrahydropyrane of mel~ting point 90-93C after
recrystallisation from ether/petrole~n ether.
Reaction of the latter phenol with double the
equivalent amount of methylthioethyl chloride and potassium
carbonate in acetone for 3 days at the reflux temperature,
followed by acid hydrolysis, gives 4-(2 methylthioethoxy)-
phenol, an oil which boils at 120-130C/0.03 mm Hg.
A mixture of 142 g of 4-(2-methylthio-ethoxy~-
phenol, 171 g of potassium carbonate and 115 g of epichloro-
hydrin is heated for 40 hours under reflux, whilst stirring.
The dark suspension is cooled and filtered and the filtrate
is evaporated in vacuo. The dark bro~n oil which remains
is dissolved in 1,500 ml of ether and extracted twice with
500 ml of 2 N sodium hydroxide solution at a time. The
ether solution is then washed three times with 500 ml o~
water at a time, dried over magnesium sulphate and evaporated.
Crude oily 1-[4-(2-methylthioethoxy)-phenoxy 3 -2,3-epoxy-
propane is ob-tained, which after recrystallisation from
ether/petroleum ether melts at 53-58C.
Exam~le 18
A solution of 4.2 g of 5-~[4-(2-methylthioethoxy)-
phenoxy]-methyl~ -3-isopropyl-oxazolidin 2-one in 50 ml of
n-butanol is boiled with 10 ml of 2 N sodium hydroxide
solution for 14 hours under reflux. The solution is
evaporated in vacuo, 20 ml of 2 N hydrochloric acid are
added and the mixture is thoroughly shaken with 20 ml of
ether. The aqueous phase is separated off and evaporated
in vacuo. The crystals which precipitate are recrystallised
~osoo3z
from butanone. This gives 1-[4-(2-methylthioethoxy)-
phenoxy]-2-hydrox-y-3-isopropylamino-propane as -the hydro-
chloride of melting point 102-103 C.
Example 19
The Schiff's base obtained from l-amino-2-hydroxy-
3-[4-(2-methylthioethoxy)-phe~oxy~-propane and benzylacetone
is dissolved in 50 ml o~ isopropanol and stirred with 2 g of
sodium borohydride for 16 hours. The reaction mixture is
evaporated in vacuo and the residue is extracted with 50 ml
of ethyl acetate. The ethyl acetate solution is washed with
20 ml of water and then brought to pH 2 with 2 N hydrochloric
acid. The crystals which precipitate are filtered o~f and
recrystallised from water. This gives 1-[4-(2-methylthio-
ethoxy)-phenoxy]-2-hydroxy-3-[(1'-methyl-3'-phenyl-propyl)-
amino~-propane as the hydrochloride of melting point
154-156C.
l-Amino-2-hydroxy-3-[4-(2-methylthioethoxy)-phenoxy]-
propane, used as the starting substance is obtained by reac-
tion of 1-[4-(2-methylthioethoxy)-phenoxy]-2,3-epoxy-
propane and ammonia in methanol. It melts at 74-81C a~ter
distillation in a high vacuum at 180C/0.05 mm Hg.
Example 20
Analogously to Example 4, 5-~4-hydroxy~phenoxy)-
methyl]-3-isopropyl-oxazolidinone-(2), which is obtainable
~. ,
by debenzylation of 5-[(4-benzyloxy-phenoxy~-methyl~-3~iso-
propyl-oxazolidinone-(2) with palladium-charcoal/hydrogen,
and 2-methylthioethyl chloride gives 5-{~4-(2-methylthio-
ethoxy)-phenoxy~-methyl3 -3-isopropyl-oxazolidinone-(2) of
,
melting point 77-78C (from e-thyl ace~tate/petrole~n ether).
. .. . ..
.
