PRODUCTION D'UN NOUVEAU DERIVE DE LA DIOSMINE

PREPARATION OF A NEW DIOSMINE DERIVATIVE

Abrégé anglais

ABSTRACT
The invention refers to the preparation of
diosmine octakis (hydrogen sulfate) aluminium, a new
derivative of diosmine, by reaction of diosmine with a
sulfating agent, such as sulfur trioxide-pyridine complex,
sulfur trioxide-trimethylamine complex and sulfur
trioxide-triethylamine complex, at a temperature between
40° and 110°C, in an approprlate medium, with preference
pyridine, dimethylformamide and dimethylacetamide, and
final addition of aluminium hydroxychloride. This product
may be used in gastrointestinal diseases.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
followa:
1. Diosmin octakis (hydroyen sulfate)
aluminium, with molecular formula,
<IMG>
in which R represents
SO3 Al2 (OH)5
2. A process for the preparation of the
compound as claimed in claim 1 which comprises reacting
diosmine with a sulfating agent in proper conditions
resulting in the diosmine octasulfate which is isolated as
aluminium salt.
3. A process as claimed in claim 2 in which
the sulfating agent is the sulfur trioxide-pyridine
complex, the sulfur trioxide-trimethyiamlne complex and
the sulfur trioxide-triethylamine complex.
4. A process as claimed in claim 2 in which
the solvent of the sulfating reaction is pyridine,
dimethylformamide and dimethylacetamide.

5. A process as claimed in claim 2 in which
the reaction of diosmine with the sulfating agent takes
place at temperatures between 40° and 110°C.

Description

~3~ ~3~7
P~EPARATION OF A N~W DIOSMINE D~RIVATIV~
Diosmine is a polyhydroxylated flavone with
elght hydro~yl groups, two of them are phenollc and the
other six being ln the sugar rest, and ls able to undergo
dif~erent reactions belng esteriflcatlon one of them.
Diosmlne can glve esters when lt ls treated with
a reactlve derivatlve of organic and lnorganic acids in a
sultable solvent. In partlcular Diosmine forms esters
from sulfuric acld when lt reacts wlth a sulfating agent,
varying the esterificatlon index wlth the conditions of
the reactlons, especially wlth the molar ratio of
dlosmlne/sulfatin~ agent. In certain conditions lt ls
posslble to esterlfy all the hydroxyl groups of the
molecular and to afford the octasulfate of diosmlne.
The sulfur trioxide-pyrldine complex or the
sulfur trloxlda-trialkylamine complexes are u~ed as
sulfatlng agents. The flrst of these 1 obtalned from
chlorosulfonlc acid or from the sulfur trloxlde and the
pyridine, and lt can be prepared and purified prevlous to
lts use or formed ln situ in the reaction vessel. The
sulfur trioxlde-pyrldlne complex sulfates subst~nces such
as hydrazlne, dyethylamine, phenol and naphthalene, and it
'~
~k
--1--
.
~3
.

~L3~31~
has ~een used in preparation of carbohydrate, sterol and
phenol sulfate esters, Th~ sulfur trio~clde-trlalkylamine
complexes, e~peclally those formed wlth trlmethylamlne and
trlethylamine, are also useful to carry out the reaction.
They are mild agents, sulfating alcohols or phenols.
In the present invent lon, thle preparation of a
new dlosmine derlvatlve 1R descrlbed. The dlosmine
derivative ls a dlo~mln octakis ~hydrog~n sulfate)
aluminium which has ~ great pharmacolog~cal interest and
has the followin~ molecular formula.
~, t ~ ~ OR
o~ ~ oc~3
01~ 0~
il OR OR 0
ln whlch R represents
S03 Al2 (OH)5
The product adminlstered orally in doses of ~00
mg/kg to rats with gastric lesions lnduced by pure ethanol
(following the technlque of A. Robert et al., Gastro-
enterology, 77, 433-443 (1979) signiflcantly protected the
ga~tric muco~a.
-la-

131~3~7
In another experiment carried out in accordance
with Shay et al's method (Gastroenterology, 5, 43-61
(1945)) the diosmin octakis (hydrogen sulfate) aluminium
significantly protected the glandular and aglandular
region oE the stomach at doses of 100 and 200 mg~kg, when
it was administered orally immediately after the pilorus
ligation.
Besides the gastric mucosa protective activity and
acid-consuming capacity of the diosmin octakis (hydrogen
sulfate) aluminium, it lacks of undesirable side effects.
The preparation of the diosmin octakis (hydrogen
sulfate) aluminium is carried out by the reaction of the
diosmine with the sulfur trioxide-pyridine complex or with
the sulfur trioxide-trialkylamine complexes, using the
sulfating agents in an excess.
The solvent employed in the sulfation of Diosmine
is chosen among pyridine, dimethylformamide and dimenthyl-
acetamide and the temperature at which the reaction takes
place can oscilate between ~0 and 110C without a substan-
tial variation in the result oE the process, but logically
at low temperatures the completion of the reaction takes
more time.
The aluminium salt of the diosmine octasulfate can
be made from the corresponding sodium salt or from the
corresponding ammonium salt by adding aluminium hydroxy-
chloride in an aqueous solution.
The following examples of the preparation of the
diosmin octakis (hydrogen sulfate) aluminium illustrate
the invention but are not exhaustive.
EXAMPL~ 1
A mixture of 10 g. of diosmine and 25 g. of the
sulfur trioxide-pyridine complex in 100 ml. of pyridine
ls heated at a temperature of 60C for 5 hours with
stirring. The upper layer of pyridine is separated by
,~

- ~3~3~
- 3
,, .
decantation and the lower one is neutralized with
concentrated aqueous sodiu~ hydroxide. Ethyl alcohol is
added dropwise until a precipitate begins to form. This
deposit is filtered off and more ethyl alcohol is added
5, to the liquid part. The new solid formed is separated by
filtration and is washed several times with ethyl alcohol.
It is dried at room temperature in vacum (16,7 g.). It is
dissolved in 200 ml. of distilled water and 130 ml. of a
15% solution of aluminium hydroxychloride is added. The
lO.resulting yellow solid is filtered, washed several times
" with water and is dried in vacuum at room temperature
(26 g.~. M.P. higher than 250QC.
IR (3490, 1640 cm ).
C2~H64All~O79S8, calculated: Al 18,34 S 10,90
15. found : 18,71 10,81
EXAMPLE 2
gO of diosmine and 24 g. of the sulfur
20.trioxide-trimethylamine complex is heated in 40 ml. of
dimethylformamide for 2 hours at a temperature o 90QC.
The mixture is cooled at room temperature and then poured
into 400 ml. of acetone with stirring. The upper layer is
separated by decantation and the lower layer is washed twice
25.with acetone. It is the dissolved in water and 150 ml. of
a 15% solution of aluminium hydroxychloride is added. The
solid which forms is filtered, washed in water and dried.
17 g. of the product described in Example l. are obtained.
30.
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