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Patented Nov. 5, 1946
George _Newbery, Brentwood, and Alexander
Peter Tawse Easson, HornohurchEngland, as
sig’nors to May & Baker Limited, Dagenham,
Essex, England, a British company
No Drawing. Original application April 11,1942,
Serial No. 438,612. Divided and this ‘applica
tion‘ ‘May 11, 1945, Serial No. 593,326. In Can
'La‘da' April 77, .1942
"5 Claims. (Cl. 260-501‘)
This application is a division of application
able salt 'of either of such acids (e. g. the-ammo
Serial No. 438,612, ?led April 11, 1942.
nium salt). Alternatively, the required . Jsalts
This invention relates to new salts of certain
maybe'iformed by‘ producing‘the diamidin'e base
therapeutically-active amidine derivatives and it
in situ and .m the :presencev-o‘flei-ther :one ‘of fthe
has for its principal object the provision of a new CH said acids or a salt of such acid. Thus,ith‘e imino
class of therapeutically active compounds that
ether corresponding to ‘the diamidin'e' ‘base 1may
can be administered in the form of an aqueous
be reacted with the amm'oniumlsalt of hydroxy
solution. A further object is to provideprocesses
or") hydroxy-propane sulphoriic acid.
for the production of such compounds.
Again, the required salts may be obtained by
~It vhas already been shown that valuable thera 10 double decomposition of suitable salt pairs e. g.
peutic properties are possessed 'by‘the symmetrical
using the dihydrochloride of‘the diamidine base
aromatic diamidines ‘possessing the general
and the silver salt of the acid.
formula Am. R. X. R. Am,gin 'which‘Amrepresents
Examples of diamidines of the foregoinggener-al
an amidine group
formula are: 4:4’-diamidino-diphenoxy pentane,
15 4:4’-diamidino-dip'henoxy propane and 4:4’
diamidino-diphenyle'ther, 4 :4 ’i-diamidino-'stilbene
and 4 : 4’ i~diamidino-a,u'-dimethyl-stilbene.
In the following description, there are given,
a linkage which may be a single bond or an alkane
purely byway of illustration, examples of the
manufactureof compounds Within the scope-of
not very readily soluble in water. "It is an ‘ob
droxyethane sulphonate (di-iseth‘ionate) crystal
R represents a benzene radical; and X represents
the present “invention.
chain ,—(C>H2)n (where .n represents 1 to 10_
andjin which also one'or more of the ‘CH2 groups
‘Example I‘
may be replaced by’oxygen, sulphur ‘or the group
4:4’-diamidino-stilbene ‘(7.2 g.) was added to
NH) orX represents a —-.CR1=CR2—- grouping in
6.8 cc. of ‘8N ‘aqueous solution of ,B-hydroxy
which R1 and Breach represent either a'hydrogen .25 ethane-sulphonic acid; the mixture warmed vto
atom or a hydrocarbon group (e. ‘g; an alkyl,
about‘ 40° C. and just sufficient water added'to
aryl or aralkyl group). Generally, the salts of
complete solution. .Acetone was 1then slowly
these diamidines, such as the hydrochlorides, are
added, when ‘4:4’-diamidino-1sti1b'ene di-pehy
vious therapeutic advantage to have ‘available. .30 lised in the form of prisms :(solubilityin water ‘ap
stable salts possessing a high degree of solubility
prox. T1 in Sat 20°C.)
' '
' '
in water and the present invention has, for its
The corresponding di-ql-hydroxy-‘propane-isuh
object the production of such salts. In many in
phonate is similarly prepared (using the theoret
stances, therapeutically useful basic compounds
ical amount of v-hydroxy-propane-sulphonic
have been found to furnish extremely soluble acid) and c-rystallises in prisms (solubility .in
salts with methane-sulphonates; ‘but in the case
of the various therapeutically useful amidine
water approx; 1 in ,4 at 20°C.)
I ’
Example "II
4 :4’ -diamidinodiphenoxyepentane-di-hydroxy
ane-sulphon'ates .are very little more soluble than 40 ethane-sulphonate_prepared by the method of Ex
‘the hydro chlorides.
ample I, using the theoretical amounts of the
We have discovered a new class of salts of the
diamidine-and the acid, crystallised as prisms
symmetrical aromatic diamidines having the fore
on addition of acetone to the ‘aqueous solution.
going general formula, which salts are stable and
contains 21/2‘ H20 and is soluble ‘in water, ap
possess a high degreeof solubility in water, such 45 proX. 1 in ‘8 at 20°C.
salts being the salts with member-s of the group
‘ Example II]
consisting of hydro-xy-ethane sulphonic acid and
hydroxy-propane sulphonic acid.
3.2 grms. of .4:4"-diamidinodiphenoxy propane
compounds, such as 4:-4'-.diamidino-stilbene or
4:74’édiamidinoediphenoxypentane, the dimeth
In general, these new salts can be prepared by
were ‘dissolved ‘in a "slight excess of 4N isethionic
combining ‘the diamidine base or a salt thereof 50 acid. The solution was just acid to litmus. 'It
with hydroxy ethane 'sulphonic acid or hydroxy
was'?ltered with charcoalythe solids washed with
propane sulphonic acid ‘or with a salt (of either of
a little’methanol and the amidine isethionate pre
such acids. Speci?cally, the diamidine base can
cipitated'from the ?ltrate and washings by adding
be directly combined with hydroxy-ethane or
acetone. The yield of the required 4:4'-diamidi
hydroxy-propane sulph‘onicxacid or with a suit 55 nodip'henoxy propane di-isethionatewas 5.2grms.
Example I
til precipitation was complete. The yield ob
tained was 49 grms. of 95% of theory.
67.2 grms. of 4:4'-diamidinodiphenylether were
dissolved in a slight excess of 8N isethionic acid
We claim:
c 1“.- 4:4'—diamidino-diphenylether-di -.-' beta - hy
with su?icient water‘to give complete solution in 5 droxyethane-sulphonate.
2. Process for the production of a symmetrical
the cold. The solution was just acid to litmus,
and to it was added about quarter of its volume
aromatic diamidine salt having the formula
of alcohol. Acetone was then added slowly and
with stirring, so that the amidine isethionate
separated in crystalline form. Addition was con
tinued until precipitation was almost complete.
The mixture was allowed to stand for some time
and the crystals ?ltered o?, washed with acetone
and dried. The yield of the required 4:4'-di
amidinodiphenylether (ii-isethionate was 130
- '
in which X is selected from the group consisting
Example V
of ,hydroxy-ethyl and hydroxy-propyl radicals,
9.0 grins. of 4:4'-diamidino-a,a'-dimethylstil- , _ which comprises reacting a compound of the for
bene dihydrochloride were dissolved in a little
warm water‘ and slight excess of caustic soda so 20
lutionadded. The diamidine base was precipi
tated as an oil which solidi?ed on cooling in ice.
The base was ?ltered off, washed with water: and
then while damp dissolved in a slight excess of
8N isethionic acid. A little alcohol was added and 25
the vrequired 4:4'-diamidino-m,u'-dimethyl-stil
bene di-isethionate precipitated‘ in the form of
buff yellow micro crystals. Yield 9.8 grms.
with a member selected from the group consist
Example VI
26 grms. of 4:4'-diamidino stilbene were added
30 ing of beta-hydroxyethane-sulphonic acid, gam
ma-hydroxy-propane-sulphonic acid, and the am
in small portions to a gently boiling mixture of
28 grms. (2 mole.) of ammonium isethionate and
monium salt of a said acid.
3. A symmetrical compound of the formula
250‘ cos. of 50% alcohol. Ammonia was immedi
ately evolved with the formation of the amidine 35
base which'dissolved completely in a few min
utes. The reaction was completed by boiling off
the ammonia, whereafter the solution was ?ltered
with charcoal. The required 4:4'-diamiclinostil
bene di-isethionate was precipitated by slowly 40
adding acetone.
Yield. aboutv 90% .
in which X is selected from the group consist
ing of hydroXy-ethyl and hydroxy-propyl radi
Example VII
‘ A mixture of stilbene 4:4’-di-iminoethyl-ether
(1.6 g.)‘ and ?nely powdered ammonium e-hy
4. Process for the production of 4:4'-diami
45 dino-diphenylether-di-beta-hydroxy-ethane- sul
droxy-ethane-sulphonate was suspended in 5 cc.
of absolute alcohol to which was added a few
drops of concentrated alcoholic ammonia and the
mixture brought to the boil. Most of the ammo
nium salt dissolved and separation of the amidine 50
phonate, which comprises reacting 4:4'-diami
dino-diphenylether with beta-hydroxy-ethane
sulphonic acid.
. 5. Process for the production of a symmetrical
aromatic diamidine salt having the formula
isethionate followed in a few minutes. _ The tem
perature was maintained at 40° C. for approx.
20 hours with occasional shaking, acetone was
then added and the precipitated solid ?ltered o?
and dissolved in a little Water. The somewhat
turbid solution was charcoaled, ?ltered and again
treated with acetone. The required 4:4'-diami
dino-stilbene-di-c- hydroxy - ethane - sulphonate
crystallised out as in Example I.
Example VIII
‘in which X is selected from the group consist
ing of hydroxy-ethyl and hydroXy-propyl radi-'
60 cals, which comprises reacting a symmetrical
compound of the formula
‘ 37.3 grins. of pure 4:4'-diamidinostilbene .dihy
drochloride dihydrate (33.7 grms. of anhydrous
salt) were dissolved in 400 cos. of
a solution of 46.8 grms. of silver
100 cos. of water was added with
mixture was heated on the steam
hot water and _>
isethionate in
stirring. The
bath for some
time to coagulate the silver ‘chloride which pre
The precipitate was ?ltered olT (char: 7 ..
with a member selected from the group consist
coal can be used if necessary to clarify), and the 70 ing of beta-hydroxy-ethane-sulphonic acid, gam
ma-hydroxy-propane-sulphonic acid, and the am
solids washed with water. The ?ltrate and wash
monium salt of a said acid.
ings. were concentrated by evaporation and the
required diamidine di-isethionate precipitated in
crystalline form by adding a little alcohol, followed ,
by the slow addition of acetone with shaking, un-'
7s '
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