Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to new alkaline-earth
metal salts of the monophosphoric acid ester of 2,2'-
dihydroxy-3,3',5,5'-te~rabromobiphenyl, to the production
of the new salts, to compositions containing ~he new
salts as active ingredients, as well as to the use of
the new salts for the control of liver flukes (Fasciola
hepatica),
The monophosphoric acid ester of 2,2'-dihydroxy-3,3',
5,5'-tetrabromobiphenyl is already known. In this
connection reference is made to the French Patent Specifi-
cation No. 1,485,647, to the British Patent Specification
No. 1,122,244, to the US Patent Specifications Nos.
3,482,016 and 3,662,035, and to the German Patent Specifi-
cation No. 1,543,792. In these patent specifications there
lS is a general mention also of salts of the monophosphoric
acid ester of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl;
however, only alkali metal salts are specifically described.
`~The monophosphoric acid ester of 2,2'-dihydroxy-3,3',
5,5'-tetrabromobiphenyl and the alkali metal salts ~hereof that
have hitherto become known have an excellent action against
liver flukes. The possibility of application of these known
substances for the control of liver flukes is however
impaired by the poor stability in storage, under the usual
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: conditions, of the substan~es themselves and of the
preparations containing ~hem.
- It has now been found that, surprisingly, the acid
alkaline-earth metal salts of the monophosphoric acid
es~er of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl
of the formula
Br ~ OH
~ ~ r 1H ~ 2
wherein Me represents magnesium or calcium, which salts
have not been described hitherto, as well as compositions
containing these acid alkaline earth metal salts, have
excellent storage stability both under the normal
storage conditions and in the physiological pH~range.
With regard to their action against liver flukes, the
new alkaline-earth metal salts are at l.east equally as
good as the monophosphoric acid ester of 2,2'-dihydroxy-
3,3',5,5'-tetrabromobiphenyl and the alkali metal salts
thereof that have hitherto become known, and are furthermore
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characterised by good physiological compatibility.
The new alka]ine-earth metal salts of 2,2'-
dihydroxy-3,3',5,5'-tetrabromobiphenyl are obtained
by reacting the monophosphoric acid ester of 2,2'-
dihydroxy-3,3',5,5'-tetrabromobiphenyl, or o-F an
alkali-metal salt thereof, in an inert solvent at
a pH-value of 5 to 6 with a magnesium or calcium salt
soluble in the reaction medium.
Suitable inert solvents are, in yarticular, water
and mixtures of water and ethanol. Where the reaction
is performed in an aqueous medium it is essential that
a pH-range of 5 to 6 be maintained. This desired
pH-range can be obtained by the addition of a buffer
substance, for example sodium acetate~
Suitable calcium and magnesium salts soluble in
the reaction medium are, in particular, ~he chlorides
and the acetates.
The new alkaline-earth metal salts of the
monophosphoric acid ester of 2,2'-dihydroxy-
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3,3',5,5'-tetrabromobiphenyl can be obtained in an
advantageous manner by, ~or example, reacting at room
temperature a monoalkali metal salt of the monophosphoric
acid es~er of 2,2'-dihydroxy-3,3~,5,5'-tetrabromo-
S biphenyl in an aqueous medium with a soluble calcium ormagnesium salt in the molar ratio of 2:1. Furthermore,
the new alkaline-earth metal salts of the formula I are
obtainable by treatment of a suspension of the mono-
phosphoric acid ester in water with an aqueous solution
of excess calcium chloride or magnesium chloride in a
pH-range of 5 to 6 at room temperature or at slightly
elevated temperature. In order to be able to adjust to the
desired pH-range, the reaction is performed in the presence
of a buffer substance, e.g. sodium acetate. The new alkaline-
earth metal salts of the formula I can however be obtainedalso by reaction of the monophosphoric acid ester of
2,2~-dihydroxy-3,3~,5,5~-tetrabromobiphenyl with calcium
chloride or magnesium ch'loride in the molar ratio of 1:1
' in 95% ethanol, and subsequent precipitation of the formed
a~id salt with water. A further possibility for producing
'the new alkaline-earth metal salts of the formula I consists
in reacting the monophosphoric acid ester of 2,2'-dihydroxy-'
3~3',5,5'-tetrabromobiphenyl in 60% ethanol with calcium
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acetate in ~he molar ratio of 2:1. Finally, the new
alkaline-earth metal salts can be produced by reacting
an alkali-metal salt of the monophosphoric acid ester
of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl in an
aqueous medium at pH 5 to 6 with the equivalent amount
of a soluble calcium or magnesium salt.
The monophosphoric acid ester of 2,2'-dihydroxy-3,3'g
5,5'-tetrabromobiphenyl used for the production of the
compounds of the invention can be obtained by reac~ion of
tetrabromobiphenyl with phosphoryl chloride, in the
presence of pyridine, to give the cyclic phosphoric acid
ester chloride; the conversion thereof into the cycllc
phosphate by means of sodium hydroxide solution; and
subsequent treatment with concentrated hydrochloric acid
(see German 'Ausleges~hrift' No. 1,543,792).
The compositions of the invention are characterised
in that they contain an acid alkaline-earth metal salt
of the monophosphoric acid ester of 2,2'-dihydroxy-3,3',
5,5'-tetrabromobiphenyl together with customary carriers
and additivPs.The compositions of the invention can be in the
solid, liquid or paste form. They are produced in a manner
known per se by the intimate mixing of the new alkaline-earth
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metal salts of the formula I with suitable carriers,
optionally with the addition of dispersing agents inert
to the active ingredients. Because of the greater ease
of applying them, the preferred formulations among those
of the invention are the formulations in liquid form,
e.g. suspensions, and in paste form. The new alkaline-
earth metal salts of the formula I are suitable, in
particular, for the production of suspensions and pastes
having excellent stability in storage.
For the production of suspensions, it is possible to
use vegetable oils, paraffin oils, ethylene glycol
stearate, silicone oils, butylhydroxyanisole, aluminium-
monostearate, cetyl alcohol, sorbitol-fatty acid esters
and stearyl alcohol; and for the production of pastes
it is possible to use vegetable oils, paraffin oils,
ethylene glycol stearate, silicone oils, butylhydroxy-
anisole, aluminium~monostearate, cetyl alcohol, æorbitol-
fatty acid esters, stearyl alcohol and cured vegetable oils
and waxes.
In addition, the new alkaline earth metal salts of
the formula I can be processed, with varying degrees of
concentration, with additions of surfactants and carrier
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materials, such as highly dispersed silicic acid, bolus
alba, talcum and polyvinylpyrrolidone, into the form of
wettable powders that are readily suspendible in water.
Po~ders produced in this manner can be administered in
the form of drenches. Furthermore, the active ingredients
can be processed wîth the use of auxiliaries such as
microcrystalline cellulose, highly dispersed silicic acid,
gelatine, maize starch, mannitol and magnesium stearate
into the form of tablets.
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Example 1
6.2 g o~ monophosphoric acid ester of 2,2'-dihydroxy-
3,3',5,5'-te~rabromobiphenyl is suspended in 100 ml of
water. After the additlon of 25 ml of a 10% aqueous
calcium chloride solution, there is added dropwise~ with
vigorous stirring, a 25% aqueous sodium acetate solution
until the reaction mixture has a pH-value of S - 6.
Stirring is subsequently maintained for 8 hours at room
temperature, and during this time the pH-value is
repeatedly corrected to 5-6 by further additions of
sodium acetate solution.
The reaction mixture is stirred for a further lS hours;
the reaction product is then filtered off with suction,
and washed several times with water. After drying, there
is obtained S.6 g of monocalcium salt of 2,2-dihydroxy-
3,3',5,5'-tetrabromobiphenyl, m.p. 210-212C.
Analysis: C X Br 0 P Ca . 2 H20
24 12 8 10 2
calculated: 23.25% C 1.29% H 51.57% Br
ound: 23.70% C 1.40% H 51.80% Br
calculated: 3.23% Ca 2.91% H 0
_ _ 2
found: 3.15% Ca 3.10% X20.
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Example 2
6.2 g of monophosphoric acid ester of 2,2'-dihydroxy-
3,3',5,5'-tetrabromobiphenyl is suspended in 120 ml of
water. There is added 25 ml of a 10% calciuM chloride
solution as well as 8.2 g of solid sodium acetate
(anhydrous). Stirring is maintained for 8 hours at room
temperature; filtration with suction is then performed
and the residue is repeatedly washed on the suction filter
with water. After drying, there is obtained 5.5 g of
monocalcium salt of 2,2-dihydroxy-3,3'~5,5'-tetrabromo-
biphenyl, m.p. 203C, which is identical to the productobtained in Example 1 (mixed mel~ing point).
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Example 3
5.82 g (0.01 mole) of monophosphoric acid ester of
2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl is dissolved
in 100 ml of O.lN NaOH at room tempera~ure with stirring.
The small amount of undissolved impuri.ties is removed
S by filtration, and to the filtrate there is slowly added,
wi~h stirring, 25 ml of a 10% calcium chloride solution.
After stirring for one hour, the resulting precipitate
is filtered off under suction, repeatedly washed with
water and then dried. There is obtained 5.5 g of mono-
calcium salt of 2,2~-dihydroxy-3,3~,5,5~-tetrabromo-
bi.phenyl, which is identified by mixed melting point with
the product produced according to Example 1.
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Example 4
24.0 g of monophosphoric acid ester of 2,2'-dihydroxy-
3,31,5,5'-te~rabromobiphenyl dissolved in 200 ml of
60% ethanol is added dropwise at room tempera~ure, with
continuous stirring, to a solution of 3.2 g of calcium
acetate in 200 ml of 60~/o ethanol. Stirring is subsequently
continued until completion of the reaction, and a further
30 ml of 60% ethanol is added. After one hour, the precipi~ate
is filtered off under suction and dried at 45C.
Yield: 22.13 g Melting point: 204C
C24H12Br8loP2Ca 2
Analysis: C H BrCa H20
calculated: 23.25% 1.29V/o 51.57~/o 3.23% 2.91%
found: 23.13% 1.39% 51.86% 2.94% 3.09%
The products obtained in the Examples 1 to 4 are converted,
w;th partial melting, at 183-185C. A clear melt is then
obtained at the respective temperatures given.
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Example 5
600.0 g of monophosphoric acid ester of 2,2'-
dihydroxy-3,3',5,5'-tetrabromobiphenyl dissolved in
850 ml of 95% ethanol and 11.1.0 g of CaC12 dissolved
in 1300 ml of ethanol are filtered and mixed together;
there is then slowly added, with continuous stirring,
about 20 litres of water. After the precipitate has
settled out, the liquid on top is decanted and the
precipitate is washed with water. Recrystallisation from
dimethylformamide; m.p.: 210C.
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E~ample 6
6,2 g of monophosphoric acid ester of 2,2'-dihydroxy-
3,3',5,5'-tetrabromobiphenyl is suspended in 100 ml of
water. After the addition of 20 ml of a 20% aq~leous
solution. of magnesium chloride, the procedure is carried
out in a manner analogous to that described in Example 1.
There is obtained 5.3 g of the acid magnesium salt
having a rnel~ing point of 190-195C. The composition
corresponds ~o 2 moles of monophosphoric acid es~er per
Mg atom.
AnalYsis: C24H12BrgloP2Mg 2
calculated: 23.59% C 1.32% H 52.32% Br 5.07% P
found: 23.50% C 1~40~/o H 50.90% Br 5.10% P
calculated: 1.99% Mg 2.95% H20
found: 2.05% Mg 3.20% H20
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Example 7
Production of a 15~/~ suspension
15.0 g of aluminium monosteara~e, 494.8 g of peanut
oil and 50.0 g of ethylene glycol stearate are placed
into a heatable vessel and heated at 150C until an
opalescent solution is formed. The solution is then
allowed to cool to about 40C, and there are subsequently
added, with stirring, 260.0 g of silicone oil 556,
0.2 g of butylhydroxyanisole, 30.0 g of sorbitan monolaurate
as well as 150.0 g of the active ingredient. The mixture
is vigorously stirred for about 15 minutes with a turbulent~
chamber mixer until a homogeneous suspension is obtained.
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Example g
Production of a Lo~ SUS~DSi~n
7.5 g of aluminium monostearate, 339.6 g of peanut
oil and 40.0 g o~ hydrogenated peanut oil are placed into
a heatable vessel and heated at 150~C until an opales~ent
solution is formed. The solution is then allowed to
cool to about 40C, and there are subsequently added,
with stirring, 200.0 g of silicone oil 556, 0.2 g of
butylhydroxyanisole as well as the active ingredient.
The mixture is vigorously stirred for about 15 minu~es
with a turbulent-chamber mixer until a homogeneous
suspension is obtained.
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Example 9
Production of a 1.5% paste
669.~ g of a viscous paraffin oil, 100.0 g of cured
castor oil and 80.0 g of hydrogenated peanut oil are
heated in a hea~able steel vessel at about 90C. A~ter
complete melting of the constituents, the mixture is
allowed to cool to about 50C; there are then worked into
the mixture firs~ly 0.2 g of butylhy~roxyanisole and finally
the active ingredient until a homogeneous paste is obtained.
Example 10
- Production of a 40% paste
467.1 g of viscous paraf~in oil, 34.0 g of cured
castor oil and 86.0 g of hydrogenated peanut oil are
heated in a heatable steel vessel at about 90Co After
compl~te melting of the constituents, the mixture is
allowed to cool to about 50C, there are then worked into
lS the mixture firstly 0 D 2 g of ~utylhydroxyanisole and
finally the active ingredien~ until a homogeneous paste
is obtained.
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Example 11
Production of a powder suspendible in water
2.7 g of highly dispersed silicic acid and 0.13 g
of polyoxyethylalkyl e~her/urea mixture are mixed
together with a suitable mixing device. There are
subsequently worked in~o the mixture, in the given
sequence, 5.4 g of polyvinylpyrrolidone K 30, 15.0 g
of active ingredient, 20.57 g of talcum as well as
56.2 g of white clay. The homogeneous mixture is ground
in a suitable mill (e.g. dowelled disc mill) until the
desired particle size is obtained.
For application with water, the iinished powder mixture
can be converted into a suspension; and this can be
administered with an applicator (such as a drench pistol)
to ~he animal.
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Example 12
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Production of tab]ets
120.0 g of active ingredient, 42.0 g of microcrystalline
cellulose and 2.0 g of highly dispersed silicic acid
are mixed together; the mixture is then put through a
sieve having a mesh size of 0.7 mm, and the sieved
material is subsequently moistened with the solution of
8.0 g of gelatine in 200.0 g of water.
To this mixture there is added in small portions,
wi.th continuous mixing and kneading, 25.0 g of maize
starch. The moist mixture is passed through a sieve with
a mesh siæe of 1.1 ~n, and subsequently dried.
There is added to the dried granulate 3.0 g of magneseum
stearate, and the mixture is pressed to form ~ablets, wi~h
the total weight being so chosen that the amount o active
lS ingredient is in proportion to the body weight o the
intended animal species.
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le 13
Production of tablets
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30.0 g of active ingredient and 137.0 g of mannitolare mixed together; the mixture is put through a sieve
having a mesh size of 0.7 mm, and the sieved material
is subsequently moistened with a solution of 5.0 g of
gelatine in 150.0 g of water.
To this mixture there is added in small portions~
with continuous mixing and kneading, 25.0 g of maize
starch. The wet mixture is passed through a sieve with
a mesh size of 1.1 mm, and afterwards dried.
There is added to the dried granulate 3.0 g of
magnesium stearate, and the mixture is processed into the
form of tablets, with the total weight being so chosen
that the amount of active ingredient is in proportion to
the body weight of the intended animal species.
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Production o~
120.0 g of active substance, 42.0 g of microcrystalli.ne
cel.lulose and 2.0 g of highly dispersed silicic acid
are mixed together; the mixture is put through a sieve
of 0.7 mm mesh size, and t.he sieved material is then
moistened with the solution of 8.0 g of gelatine in
200.0 g of wa~er.
To this mixture there is added in small portions, with
continuous mixing and kneading, 25.0 g of maize starch.
The wet mixture is then passed through a sieve having a
mesh size of 1.1 mm and the material obtained is subsequently
dried.
There is added to the dried granulate 3.0 g of
magnesium stearate, and the mixture is processed into
tablets, with the total weight being so adjusted that the
amount of active ingredient is in proportion to the
body weight of the intended animal species.
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