Note: Descriptions are shown in the official language in which they were submitted.
~`~ ~ ~ 4 ~
The present invention relates toanovel substituted
propionic acid, the use of such acid as a medicine, the prepara-
tion thereof and the intermediaries which are necessary in this
preparation.
The novel compound of the invention is the 2-[4-(3-
thenoyl)-phenyl]-propionic acid of the formula
CH - COOH (I)
~ 'his compound has an asymmetrical carbon and, as a
consequence, can be split by utilising the techniques which are
well known to the experts, particularly by crystallisation of the
salts obtained with an optically active organic base. the active -
forms which are obtained form an integral part of the invention.
This compound is prepared
a) by the condensation of 3-thenoyl chloride with fluorobenzene
under the conditions of the Friedel Crafts reaction,~ -
b) the alkylation of the fluorophenylthenyl methanone by ethyl 2-
methyl malonate, in a dipolar aprotic solvent and in the presence
of a strong base,
c) then alkali hydrolysis of the ethyl 2-methyl-2-[4-(3-thenoyl)-
phenyl] malonate and decarboxylation.
Similarly, the salts which are obtained with an orga-
nic or mineral base capable of being used in human therapeutics
also form part of the invention.
~ his acid can be prepared by alkali hydrolysis of
ethyl 2-methyl~2-[4-(3-thenoyl)-phenyl]malonate of the formula
~ ~ C ~ COOC2H5 (II)
COOC2H5
.,,~ ' '~
~ ~ -2-
23~3
and decarboxylation.
This novel intermediate compound forms part of the
invention. It is preferably obtained by alkylation of the
fluorophenyl thenyl methanone by ethyl 2-methyl-malonate in a
dipolar aprotic solvent, in the presence of a strong base.
The fluorophenyl thenyl methanone of formula
~ . ~
~,.. ~.: ' .
-2a-
.
` 11(:~2343
is a novel intermediate compound which forms part of the
invention. It can be obtained by condensation of 3-thenoyl
chloride on fluorobenzene under the conditions of the Friedel-
Crafts reaction.
Furthermore, the 2-[4-(3-thenoyl)-phenyl]-propionic
acid i9 proved to be of particular interest as an analgesic,
anti-inflammatory agent and anti-aggregating agent for blood
platelets.
The analgesic activity is proved by the test using
acetic acid on the mouse (Siegmund method modified by Koster, ~ -
Anderson and Debeer). The active dose 50 (mg/kg) is equal
to 9 for the 2-~4-(3-thenoyl)-phenyl~-propionic acid,
whereas aspirin (acetylsalicylic acid) in this test has a
DA50 of 130, Pyramidon (phenyl dimethylamino dimethylpyra-
zolone) ha~ a DA~o of 32 and Pethidine (ethyl-l-methyl-4-
phenyl-4-piperidine carboxylate hydrochloride) has a DA50
of 17.
The anti-inflammatory activity which is determined,
among other methods, by the oedema test using carrageenin
in the rat (Winter, and Coll-Proc-Soc Exp. Biol. Med. 1972
III, 544-547) has proved to be excellent. The active dose
30 (mg/kg) of the 2-[4-(3-thenoyl)-phenyl]-propionic acid is
5, while that of phenyl butazone (1,2-diphenyl-3,5-dioxo-
4n-butyl pyrazolidine) is 50 and that of Pyramidon is 82.
In connection with the inhibition of erythema
due to ultraviolet in the guinea pig (C.V.Winder, J. Wax,
V. Burr et al, Arch. Int. Pharm. (1958), 116-261), the
2-[4-(3-thenoyl)-phenyl]-propionic acid is proved to be
thirty times more active than aspirin. At 5 mg/kg, the
protection of the animal is complete and is of the same
order as that provided by Indomethacine [1-(4-chlorobenzoyl)-
`:
-3-
'
~23~3
5-methoxy-2-methyl indole 3-acetic acid]or Ketoprofene [2-
(3'-benzoyl-phenyl)-propionic acid].
The 2-[4-(3-thenoyl)-phenyl~-propionic acid has
the property of inhibiting, in vitro and in vivo, the aggre-
gation of the plasma platelets of a rabbit, which aggrega- -
tion is induced by 5-adenosine diphosphate (A D P) and
collagen. The method which is used for proving this phar- ~-
macological pxoperty is based on that described by
Born (Journal of Physiology - 1962) and with the assistance
of a Mustard aggregometer. The result is expressed by a
coefficient resulting from the ratio: the smallest active
concentration(in micromolesj of the standard over the
weakest active concentration of the product. (What is called
. .
active concentration is that which provides an inhibition
of the aggregation equal to or higher than 50%).
.. :
~ A D P Collagen
, -.
- Aspirin
- Phenergan (10-(~2-dimethylamino
; propyl) phenthiazine
- 2-[4-(3-thenoyl)-phenyl]- -
propionic acid 4 60 ~,
The pharmaceutical compositions which~contain the
compound of the invention as active prlnciple, either in
the form of a base, or in the form of an organic or mineral
salt, may be in the form of tablets, pills, capsules, sugar- ;
coated pills, aqueous suspensions, injectable solutions,
aerosols, syrups and the like. The tablets may possibly be
made gastro-resistant by being lacquered with a cellulose
derivative.
The pharmaceutical compositions which contain the
acid compound of the invention as active principle and a
~ ~4~
34,~ :
physiologically acceptable solid or liquid pharmaceutical
support or diluent, permit the daily administration of doses
of active principle which are between 20 and 1000 mg.
Certain pharmaceutical compositions may be formulated
in the following manner.
Compressed tablet of 400 mg
active principle150 mg
.: .
lactose 100 mg
wheat starch139 mg
gelatine 5 mg
talcum 5 mg
magnesium stearate 1 mg
The tablets are coated with a gastro-soluble film
based on cellulose polymers, such as hydropropyl methyl
cellulose and ethyl cellulose.
CapsuIe: Size No. 2 of I80 mg
actlve princlple~ 50 mg
lactose 60~mg
wheat starch 68 mg
magneslum stearate 2 mg
Ointment
active principle5 g
"Emulgade F" *25 g
'iEutanol G" *13 g
Propylene glycol10 g
purified water47 g
Lyophilis_ble injectable_preparation
including the sodium-containing product corresponding to
50 mg of active principle.
The lyophilisate is dissolved, at the moment of
use, in 5 ml of water, for an injectable preparation.
*Trademark
~ ~5-
343
S uppos i torY
active principle 400 mg
semi-synthetic glyceride q.s. for 2 g.
One example which illustrates the different stayes
in the process of the preparation of the new acid according
to the invention, but without any limiting effect, is given
below.
EXAMPLE
____ :
Stage 1:
[4-fluorophenyl~ - [3-thenylJ methanone (formula III) ~-
CllH7 FOS MW = 206.17.-
To a solution of 42.5 g (0.29 mole) of 3-thiophene
carbonyl chloride in 315 ml of fluorobenzene are added in ;
small fractions, and while stirring and cooling on an ice
bath, 57 g (0.42 mole) of anhydrous alumlnium chloride. The
:
reaction is slightly exothermic and tbe temperature rises
to 10C. The mixture is then broughtfor;45~mlnutes to 60C
and then refluxed for 15 minutes. Cooling takes place and
it is poured into iced water, followed by extraction with
chloroform. The organic phase is washed with a 5% solution
of sodium bicarbonate and dried over Na2S04. After evapo-
ration of the solvent and distillation under vacuum, 18.3 g
are obtained (yield: 30%), Bpo 25 mm' 125-130, Mp: 74C
(hexane). IR: C = 0 1660 cm
Staqe II:
Diethyl 2-methyl-2[ 4-(3-thenoyl)-phenyl]-malonate (formula II)
Cl9H205S MW = 360.35.
To a sodium hydride suspension: 4 g of 50% suspen-
sion (0.083 mole) in 83 ml of freshly distilled hexamethyl
phosphorotriamide, are added dropwise, at room temperature, -~
14.4 g (0.083 mole) of diethyl 2-methyl-malonate. The reaction
; is slightly exothermic. 17.1 g (0.083 mole) of [4-fluoro-
-6-
~'
3gL3
phenyl~ -r 3-thienyl]-methanone are then added in small ,~ -
fractions. The temperature is khen brought for 10 hours
to 100C. Dilution is then carried out with 300 ml of
benzene, followed by washing with H20 and drying over Na2S04.
After evaporation of the solvent and vacuum distillation, a ---
yellow oil is obtained.
Weight: 12.1 g (yield 40.6%), Bpo 4 mm: 190-200C
IR: VC = 01660cm (ketone)
VC = 01750cm 1 (esters)
NMR (CC14) :
(ppm): 6 protons at 1.25 (triplet J = 7 cps)
3 protons at 1.95 ~singlet)
4 protons at 4.3 (quatet J = 7 cps)
7 protons from 7.3 to 8 (peak)
Staqe III~
2-~4-(3-thenoyl3-phenyl~-propioni~c acid (formula I)
C11H1203S MW = 260-30~
12.1 g (3.3xlO 2mole) of diethyl-2-methyl-2-[(3,4-
khenoyl-phenyl~-malonate and 80 ml of a 5% aqueous sodium
hydroxyde solution are r fluxed for 6 hours. After cooling -
and washing the solution with benzene, the aqueous phase
is acidified wikh 1/2 HCl. The oil which forms is extracted
with chloroform. After drying over ~a2S04 and evaporation
of the solvent, 9 g of a thick oil are obtained, and this is
recrystallised: 3.4 g of a white solid are obtained:
Mp = 99-105C~ -0----<), yield: 39.5%
IR: vC=0: 1650 cm (ketone)
Vc=0: 1730 cm 1 (acid).
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