Note: Descriptions are shown in the official language in which they were submitted.
`" 11~4556
Benzothiazole derivatives, process for their prepa-
ration and their therapeutic applications
This invention relates to both stereoisomers and to the
racemate of 2-(2-phenyl-6-benzothiazolyl)propionic acid
S having the formula:
and their salts with physiologically acceptable bases,
alkaline cations, alkaline-earth cations, and amines, together
with their salts with inorganic or organic physiologically
accept~le acids, their alkyl esters and the compounds which,
by the metabolic route, generate this acid in humans.
The racemic acids of the formula (I) may be prepared
by reacting aminothiol of the formula (II) or an equivalent
thereof such as the disulfide corresponding to the formula
(III)
HOOC- I H ~`~SH HOOC-CH ~ S-S--~fH-COOii
CH,3 . C~3 CH3
(II ) (III )
with benzoic acid or a derivative such as henzoyl chloride,
a benzoyl ester or benzoic aldehyde, the reaction with
benzoyl chloride leading to the best yield.
In the course of the action of the acid chloride on the
aminothiol of the formula (II) , which occurs preferably in
the presence of an inorganic br organic base, are typically
formed intermediate compounds (IV) and (V)
NP-C ~31 ~ NB-C~)
DDC-CL 5~1 J ~OC-C S-C ~>~
., ~k -
1~4556
Said compounds of the formulae (IV) and (V) are not
isolated, but their mixture is cyclized either by the action
of heat, or by the action of acids or bases.
In the course of the action of benzaldehyde on amino-
thiol of the formula (II), which occurs either in an in~t solvent
such as nitrobenzene, henzene, and the like, or in a basic
solvent such as pyridine or quinoline, may be formed an
intermediate benzothiazine of the formula (VI)
~OOC - c~ ~/L~ ( VI )
CH3
which on oxidation, with FeCl3 or dimethylsulfoxide, for exam-
ple, will produce the desired benzothiazole.
The two enantiomers of the acid of the formula (I) may
be separated by use of a salt of the corresponding acid with
a chiral amine, and more particularly each of the two enan-
tiomers of 2-phenyl-ethylamine. According to a method known
per se , said salts are recrystallized to separate the two
diastereoisomers.
The salts of the acids of the formula (I) may be prepared
by action of a stoichiometric amount of the selected acid or
base on the acids of the formula (I) as a solution in an
alcohol, a ketone or an aliphatic ether.
The esters of the acids of the formula (I) may be prepa-
red by action of an alcohol or a haloalkane on the acid of
the formula (I) or a reactive derivative thereof, according
to methods known Per se.
The aminothiols of the formula (II) may be prepared by
decomposition, in a basic medium, in the presence or the
absence of a reducing agent, of a compound having the formula:
~oo~ -fH--~S~L ~2
CH3
-- 1144S56
Said aminoacids are new chemicals, which may be prepared
by action of bromine and ammonium thiocyanate on a compound
of the formula:
,~,, N~i2
HCOC C~I J~ (VIII )
H3
ln acetic acid solution.
The following non-limiting Examples illustrate the
preparation of the compounds of the formula (I).
_XAMPLE l
a) Preparation of 2-(2-amino-6-benzothiazolyl)propionic
acid
. . _
2-(4-Amino~phenyl)propionic acid (24.7 g), prepared for
example as disclosed in Org. Prep. Proc. Int. pp.303-307
(1977) is dissolved in 300 ml acetic acid followed by 22.8 g
ammonium thiocyanate. Bromine t2A g) dissolved in acetic
acid (60 ml) is added dropwise to this solution at 15C,after
which the mixture is allowed to warm to room temperature for
several hours, with stirring. The solvent is then removed
under reduced pressure and the residual oil is suspended in
an acidic aqueous solution; the resultant precipitate is
removed and the aqueous phase is adjusted to pH 4.5 bv addi-
tion of a sodium hydroxide solution. The resulting precipitate
is filtered off and recrystallized from methanol or ethanol,
to give 26 g %-(2-amino-6-benzothiazolyl)propionic acid (pure)
having a melting point of 234C.
b) Preparation of 2-(2-phenyl-6-benzothiazolyl)propionic
acid with benzovl chloride
. . _
A solution of 45 g 2-(2-amino-6-benzothiazolyl)propionic
acid in 200 ml 40% a~ueous sodium hydroxide solution which
may, if desired, contain 40 g sodium sulfide nonahydrate,
is heated to the refluxing temperature until there is no
more ammonia evolved.About 500 ml water are added to the
solution and, at a temperature of 10C, 70 g benzoyl chloride
in lO~ solution in a water-immiscible solvent, such as
benzene,are slowly added to the above aqueous solution, with
.
11~4556
vigorous stirring. When the addition is complete, the reac-
tion mixture is allowedtowarmtoroomtem~erature ~d stirring is
continued for several hours, after which the organic phase
is separated and the aqueous phase is acidified to pH 4 by
addition of a concentrated aqueous hydrochloric acid solu-
tion. The resulting precipitate comprises benzoic acid,
the uncyclized derivatives of type (IV) and tV) and even,
sometimes, some final benzothiazole.
The cyclization is effected on this mixture, for exam-
ple by heating the gummy solid at 120C for several hours,
or in acidic medium, as followsf the solid is dissolved in
1 litre water containing 7~ ml of a 40% aquecus sodium
hydro~ide solution; the solution is filtered throu~h decolo-
rizing charcoal! and is then added dropwise to an about 2N
hydrochloric acid aqueous solution maintained at about 50C.
The resulting precipitate is filtered off at this temperature.
The final acid, which is thus obtained in a yield of 45g,
is recrystallized from isopropanol/water (2:1.) mixture or
from a 2-butanone/cyclohexanone (1:2) mixture, to give 36 g
of pure product melting at about 160C. According to the
recrystallization solvents and the precipitation rate, the
acid will occur in different crystalline forms, of sometimes
very close melting points, but the solid phase infrared
spectra of which are not superimposable.
The cyclizatlon may also be effec~ed in basic medium:
the resulting solid is thoroughly washed with water and dis-
solved in 350 ml of a 95~ aqueous ethanol solution containing
25 g potassium hydroxide; after heating for several hours,
the reaction medium is made acidic, the ethanol is removed,
and the resulting material is poured over about 1 litre water.
The resulting precipitate of the desired final acid is iso-
lated and recrystallized as previo~sly mentioned.
EXAMLDLE 2
. .
Preparation of 2-(2-phenyl-6-benzothiazolyl)propionic acid
with benzaldehyde _
22 g 2-(2-Amino-6-benzothiazolyl)propionic acid are
dissolved in 100 ml of a concentrated sodium hydroxide solu-
4556
tion and the mixture is heated for 1 hour at the refluxingtemperature (until ammonia is no longer evolved). The solu-
tion is adjusted to pH 4.5, at room temperature, with a
hydrochloric acid solution. The resulting precipitate is
filtered off, to give 16 g material having a melting point
of about 154C.
This solid material and 8 g benzaldehyde are dissolved
in 100 ml pyridine and the mixture is maintained at the
refluxing temperature for 5 hours. The solvent is then remo-
~10 ved under reduced pressure. The residue is dissolved in lOOml ethanol, 200 mg ferric chloride are added thereto and the
solution is maintained for 2 hours at the refluxing tempera-
ture. The preci~itate which appears on cooling is purified
by dissolution in a basic aqueous solution prior to being
recrystallized from a 2-butanone/cyclohexane ~1:2) mixture.
The desired product is obtained pure in a yield of 40~.
EXAMPLE 3
The hygroscopic sodium salt of-2-(2-phenyl-6-benzothia-
zolyl)propionic acid is prepared by action of 0.55 g sodium
hydroxide on 3.7 g acid as a solution in 100 ml methanol.
M.P. = 270C. This salt is watersoluble.
EXAMPLE 4
The pyrrolidine salt of 2- (2-phenyl-6-benzothlazolyl)-
propionic acid is prepared by action of 1 g amine on 4 g acid
dlssolved in methanol. The salt melts at 142C and is water-
soluble.
EXAMPLE 5
The methanesulfonate of 2-(2-phenyl-6-benzothiazolyl)-
propionic acid is prepared by action of 0.1 ~ole sulfonic
30 acid on 0.1 mole acid dissolved in 500 ml acetone. M.p.=182C
EXAMPLE 6
The hydrochloride of 2-(2-phenyl-6-benzothiazolyl)pro-
pionic acid is prepared by action of gaseous hydrochloric
acid on the acid in benzene solution. It melts at 150C with
35 decomposition.
EXAMPLE 7
Preparation of methyl _2- ~2-phenyl-6-benzothiazolyl)propionate
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6 g 2-(2-Phenyl-6-benzothiazolyl)propionic acid are
dissolved in 100 ml anhydrous methanol and the mixture is
refluxed for 6 hours at the-temperature of the solvent after addition
of a few drops of concentrated sulfuric acid. The solution
is concentrated to 1/2 volume and the ester is precipitated
by addition of 1 volume ice-water, to give 5 g of ester
whlch melts at 86C.
EXAMPLE 8
.
Separation of the two enantiomers of 2-(2-phenyl-6-benzo-
thiazolyl)pro ~ from their racemic mixture
a) Dextrorotatory enantiomer (in dimethylformamide solution)
The salt-of the acid with laevorotatory ~-phenylethyl-
amine is prepared in 2-butanone. Addition of 19 g amine dis-
solved in 50 ml 2-butanone to a solution of 50 g acid in 500
ml 2-butanone gives a 51 g salt precipitate. The latter is
recrystallized six times from the minimum amount of 2-buta-
none, to give 10 g of salt having a specific rotation of
~7 22= -22.5 in methanol (c = 2 g/100 ml).
~ The free acid is obtained by addition of hydrochloric
acid to the aqueous solution of this amine salt. The resulting
precipitate is isolated and repeatedly recrystallized from
isopropanol-water (2:1) to give the dextrororatory enantiomer
in a yield of 35~. M.P. = 179C.
b) Leavorotatory enantiomer (in dimethylformamide solution)
The recrystallization solvents of the chiral salt
obtained according to (a) are evaporated and the acid, sliah~y
enriched with some laevorotatory enantiomer, is freed from
its salt, to give 25 g acid with which are prepared 28 g of
salt, by action of 10.3 ~ dextrorotatory ~-phenylethylamine
dissolved in 540 ml 2-butanone.
After three recrystallizations from 2-butanone, the iso-
lated salt has a specific rotation~/22= 23 (c - 2 g/100
ml, methanol).
The acid is then freed from its salt and repeatedly
recrystallized successively from isopropanol-water (2:1) and
2-butanone-cyclohexane (1:2) to give , in a yield of 25%, the
leavorotatory isomer having an optical puritv of about 98%.
1144556
- -22 O
~/D = -81 (C = 0.1 g/ml, ~imethylformamide) . M.P. = 179C.
The compounds of the formula (I) inhibit the biosynthe-
sis of the prostaglandines and exhibit a ~ gesic properties
at the inhibiting dosages. They have also an anti-blood-
platelet aggregating activity, and protect a~ainst thecardiovascular effects of endotoxine-induced shock.
They have a low toxicity (LD50, in mice, per os, in
excess of 1000 mg/kg). The efficient doses determined in the
different tests being markedly lower, the therapeutic index
of said compounds is excellent, which makes them therapeu-
tically useful in humans.
The analgesic activity of the compounds of the formula
(I) was demonstrated in the phenylbenzoquinone-induced
writhing test in mice. Thus, the acid of the formula (I)
(racemate) has in this test an ED50 of 3-6 mg/kg p.o. This
analgesic activity is extended in duration, a dosage of
12.5 mg/kg of this compound still providing an analgesia of
42% 24 hours after its administration.
On the other hand, the compounds of the formula (I)
20 inhibited the blood-platelet aggregation induced in vitro
with ADP on platelet-riched plasma of rats. Thus,
sodium 2-(2-phenyl-6-benzothiazolyl)propionate is active at
a concentration ten times lower than that of acetylsalicyllc
acid.
l'he activlty of the compounds of the formula (I) on the
blosynthesis of the prostaglandines is evidenced by a protec-
tive effect against the toxicity of arachidonic acid, a pre-
cursor of this biosynthesis. Thus, on oral administration at
a dosage of 0.5 mg/kg, the compounds of the formula (I)
decrease the mortality of mice which have been
administered a lethal dose of arachidonic acid.
By the intravenous route, the soluble salts of the
compounds of the formula (I), and particularly the sodium
salt, are active at the same dosages. The dextrorotatory enan-
tiomer of the acid (Example 8) has an activity comparable tothat of the racemate (Example 1) and superior to that of its
- laevorotatory homolog.
- 1144556
Finally, on intravenous administration at a
dosage of 1 mg/kg, the compounds of the formula (I) have
a protective effect, in anesthetized dogs, against the
cardiovascular effects of the shock induced with
Escherichia Coli endotoxine.
The compounds of the formula (I) may be
administered to humans under various pharmaceutical forms,
by the oral, rectal or parenteral routes, at efficient
non-toxic dosages for the treatment of pain, hyperthermia,
dysmenorrhea, shock conditions, and also for the treatment
of diseases in which the decrease of blood-platelet
aggregation is an important factor.
The unit dose depends on the route of
administration and on the nature of the compound selected
as active ingredient of the therapeutic composition. The
solutions for parenteral or intravenous administration are
preferably prepared with aqueous diluents, the active
ingredient being used in a chemical form soluble in such
as a medium, for example as an alkaline cation salt.
For oral administration, the compounds of the formula (I)
may be placed into capsules, or mixed with the usual
excipients to form pills, tablets or cachets, whlch are
gastrosoluble or enterosoluble.
Except for particular cases, the daily dosage
regimen in adults is from 20 mg to 1 g, as a single dose
or in several doses.
