Note: Descriptions are shown in the official language in which they were submitted.
SPECIFICATION
The present invention relates to an anti-inflammatory, analgesic,
antipyretic, water-soluble compound and t~ the process for its prepa-
ratiDn. More particularly the invention concerns the 2'-4'-difluoro-
4-phosphonoxy(l,l'-diyhenyl)-3-carboxy acid (III) characterized by
a strong solubility in water and the process for preparing acid, as
well as the pharmaceutically acceptable salts thereof.
.. . .. . .
The salycilic ocid derivative represented by 2'~4'-difluoro-
4-hydrox~(l,l'-diphenyl)-3-carboxy acicl ("diflunisal") and its use
as an anti-inflammatory and analgesic substance are well known i~
the art especial:Ly in the painful synclromes induced by arthrosis, or-
thopaedic, tooth and surgical operations, etc.
However, we haveto point out that the insolubility in water of
the "diflunisal" limits the administering pharmacologic forms of
said salycilic acid derivative substantially to the iablets and like
so as to exclude its use for an oral or parenteral administration in
the form of syrups, drops, etc.
Therefore it will be well understood that there is an inc~easing
demand of a "diflunisal" derivative characterized by a strong solubi-
lity in watex which permits to prepare solutions suitable, as it
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is known, to a larger application of the therapeutic use and so to
the different administering forms and dosages.
Such a demand is entirely met by tbe product (III) of this
invention and the pharmaceutically acceptoble salts thereof.
As a motter of fnct, the compounds according tothis invention
because of their water-solubility, can be conveniently usedfor
preparing pharmaceutic forms suited to the oral, parenteral or
rectal administration (tablets, capsules, retarded release tablets~
drops, syrups, suppositories) and additionally for external use as
ointments, sqlves, creams, emulsions and solutions.
As a consequence it is the main object of this invention to
provide the water-soluble compound represented by 2',4'-difluoro-
4-phosphonoxy-(1,1'-diphenyl)-3-carboxy acid (III) and the process
for its preparation.
The process a~cording to the invention is characterized by the
steps of:
- treating 2',4'-difluoro-4-hydroxy-(1,1'-diphenyl)-3-carboxy acid
(I) with phosphorl~s pentachloride, and
- hydrolyzing the addition product (II) by means of a stoichiometric
amount of water according to reaction schedule:
S -~ ~LF 4;y --~
F ~ o_ ~3~ 0
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As aforesaid also the pharmqceutically acceptable salts of the
compound (III) are ~cluded in the scope of the invention.
The following specific example is given to illustrate the present
invention, which however is not limited thereto.
EXAMPLE
208.27g(1 mole) of finely powdered phosphorus pentachloride are
added at room temperature, under stirring to 25~.2 g(tmole) of
2',4'-difluoro-4-hydroxy-(1,1'-diphenyl)-3-carboxy acid (I).
These two compo~ents are amalgamated and then heated at 75/80C
for the period oF 1 hr until the mass appears to be Fluified.
2~0ml of acetone ancl 400 ml of benzene are successively added tc the
mass cooled at 5C.
The solution obtained thereby is additioned with 54 ml ~3 moles)
of water at a temperature o~ 5C allowing the temperature to reach
25-30C. The intermediate, chlorirlated derivative (II) is hydroli-
zed in this way.
The solven$ is distilled under reduced pressure and the
residue is recovered with ether and ~iltered~ 285 g (yield 85%)
m.p. 176-178C (decomposition).
,
Th~ analytical and spectroscopic data appear to be in ~ccordance
with the proposed structure. The compound is water-soluble either in
the acid forrn and, for example, as trisodic salt
A.
Swiss male mice, h~ving a weight of 25 g were tested after a
18 hrs fast.
The animals were treated with yradual doses of 2',4'-difluoro-
-4-phosphoxy (l,l'diphenyl)-3-carboxy acid (0.2 ml/10 g of bo~y
weight) dissolved by stoichiometric amounts of NaOH lN up tv a
final pH of the solution of 6.5.
The animals were kept under observation for a period of 7
days/ The DL50 was calculated according to Lithifisld (J. Pharm.
Exp. Ther. ~6, 99; 1949).
Product DL50 mg/~g (acceptable limits)
2',4'-difluoro~4-phosphonoxy - 224 (206-244)
-(l/l'-diphenyl)-3-carboxy acid
Anti-inFlammatory action in rat
_ _
2',4'-difluoro-4-pllosphonoxy-~1,1'-diphenyl)-3-~arboxy ocid was
administered per os to male Wistar rats with a weight of 120 g,
af~er a 18hrs fast, at a dose of 165 mg/ky, 1 ho~r before that -
~oedemo had been induced.
This oedema was induced by a subplantar injection of Carragenin3
1% (0.1 ml) in one of the posterior paws
The oedema growth was cheched after 30' - ~0~ - 180' with a Ba
sile Hg plathysmograph in comparison with a con~rol animal group~
The results are gathered in the graph of ~igure 1 enclosed
with this specification wherein it may be n~ e~ the run of -the
volume increase in mm ~ ~quoted in the axis o~ ordinates~ oF tha
paw against the oedema introduction time in minutes (quoted in the
~xis of abscissas) in cont}ol rats ( --) and in those (~
which have been treated by the 2',4'-difluoro-4-phosphonoxy-(1,1'-di
phenyl~-3-carboxy acid.
This invention has been described with a particular reference
to some specific embodiments, but it will be understood that
changes and alterations may be mnde therein without come out of
its scope.
