Note: Descriptions are shown in the official language in which they were submitted.
1~3~07 ' ~" '
This invention relates to bis-(benzyl)acetic acid
derivatives.
More particularly, this invention provides compounds
of formula I,
R2 .
11 /~\
CH3 ~ CH2 / X
C
R3 1 ~ Q
Rl .'
in which the Rl's, which may be the same or different,
signify hydrogen, fluorine or chlorine.
the R2's, which may be the same or different, signify
methyl or ethyl, :~ :.
- the R3's, which may be the same or different, signify
methyl or ethyl, and
either (i) X signifies hydrogen and Y signifies -COOH,
or (ii) X and Y are the same or different and each -
signifies a radical - COOR4
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in which R4 signifies alkyl of 1 to
4 carbon atoms,
and salt forms of the compounds in which X is hydrogen
and Y is -COOH.
The invent~on also provides processes for the
production of compounds of formula I, characterised by
a) producing a compound of formula Ia,
R2 l
R3 ~
~ C~----COCH Ia
R3 - 7 ~ ~2
R2 Rl, :
in which Rl, R2 and R3 are as defined above,
and salt forms thereof,
by a process comprising the step of decarboxylating a
, compound of formula II, -
. R~2 ~ t
~H ~ ~ /
R3 - C - ~ ~ ~ C ~ II .
2 - Rl
ln which ~1~ R2 and R3 are as defined above,
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or b) produclng a compound of formula ~b,
C~13 ~ ~ / 4
~3 ~ f \
R3 ~- C - C ~, ~12 C~ 4
? Rl : ~
1~ 2~ R3 and R4 are as defined above
by reacting a compound or compounds of formula III, ~ :
R2 O Rl
R3 - C - C ~ CH2X III .
C 3
in which Rl, R2 and R3 are as defined above, .
and X signifies chlorine or bromine,
with a compound of formula IV, -
.~ / COOR4
D CH IV -
\ COOR4
in which R4 is as defined above, and
D signifies an alkali metal,
in the presence of a strong base, and in an inert
organlc solvent.
Process a) is suitably effected in an aqueous
medium, comprising water alone or in admixture with an
inert, water-miscible organic solvent, eg. an alkanol
-3
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of l to 4 carbon atoms, such as methanol or ethanol,
The decarboxylation is suitably effected by acidification,
fox example with a mineral acid, such as sulphuric, hydro-
bromic or, preferably,hydrochloric acid. The process is
conveniently effected at a t~ature of frcm 90 to 180C, preferably
at the re~lux ~erature of the reaction medium, and suitable reaction
times vary, for example from 12 to 36, more typically lS to 20, hours.
Process b) is conveniently effected at a
temperature of from 20 to 30C, preferably about 25C.
O Suitable strong bases include alkali metal hydrides,
such as sodium or potassium hydride, and alkali metal
alkoxides such as sodium or potassium ethoxide, prefer-
ably potassium ethox.ide. Suitable ~olvents include
~, alkanols of 1 to 4 carbon atoms, eg methanol or ethanol,
dimethylformamide and, preferably, dimethylacetamide.
Suitable reaction times vary, for example from 12 to 24,
more typically 16 to 20, hours. It will be appreciated
that ~Ihere the Rl's, R2's and/or R3's, in the desired
compound of formula Ib, differ, then a mixture of compounds
of formula III is employed. In the compounds ~ formula IV,
D suitably signifies sodium or potassium~ and in the ~unds
of fo~a III, X is preferably bromlne.
; The resulting compounds of formula I may be
isolated and purified using conventional technlques.
Whe~e requircd, the compo nds of formula Ia may be con- ~
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verted into salt forms, eg alXali metal or alkaline earth
metal salt forms, particularly sodium, potassium, calcium
or magnesium salt forms, in conventional manner, for
example by reaction with an appropriate hydroxide or
oxide, and vice versa.
The compounds of formula II may suitably be
produced by hydrolysis of a compound of formula Ib.
The hydrolysis is conveniently effected at a
temperature of from 70 to 150C, preferably at the reflux
t~ature of the reaction ~edium, and suitably employing an alkali
metal base, such as sodium or, preferably, potassium hydroxlde, for the
hydrolysis. The process is conveniently effected in a
aqueous medium comprising water alone or in admixture
with an inert, water-miscible organic solvent, such as
lS a lo~7er alkanol, eg methanol or ethanol
The resulting compounds of formula II are
preferably subjected directly, without isolation, to
process a).
The compounds of formula III may suitably be
produced by treating a compound of formula V,
R2 O
R3 - C - C ~ CH3 V
C 3
in whlch Rl, R2 and R3 are a~ defined above,
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with a chlormat~.g or broN~atinq aqent, m the presence of a f~ee
radical initiator and in an inert organic ~olvent.
Suitable brominating agents include bromine,
N-bromophthalimide, N-bromoacetamide and, preferably,
N-brom~succinimide. Suitable chlorinatLn~ aqents inc~u~e N-chlor~succi-
n ~ de. Suitable free radical initiators include ir.organic ~nd crganic
peroxides al~houqh the ~x~ss ma~, alternati~el~, he carried ~t u~der
ultraviolet liaht for this ~se. The process is conveniently
effected at the xeflux temperature of the reaction q-~
medium, and suitably solvents include haloyenated
hydrocarbons, eg. methylene dichloride, chloroform, and
carbon tetrachloride, and aromatic hydrocarbons, such
as benzene. The reaction time may, for example, vary from
12 to 48, more typically 18 to 25 hours.
The resulting compounds of formula III may be
isolated and purified using conventional reaction tech-
nigues.
The compounds of formulae IV and V are either
kno~n or may be produced in conventional manner from
available materials.
The compounds of formula I possess pharmacological
activity. In particular, they possess hypolipidemic,
especially hypolipopr~e~emic activity as indicated by ~ -
the fall in cholesterol and triglyceride levels in male
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albino Wistar rats weighing 110-130 g initially. The
rats are maintained on drug-~ree laboratory chow diet
for seven days and then divided into groups of 8 to 10
` animals. Each group with the exception of the control is
then given orally 30 milligrams per kilogram of body ~ -
weight per diem of the compound fcr six days. At the end
of this period, the animals are anaesthetised with sodium ~
hexobarhital and bled from the carotid arteries. Serum
or plasma samples are collected, and 1.0 ml samples of
the serum are added to 9.0 ml redistilled isopropanol.
Two autoanalyser cupsful of a mixture of zeolite-copper
hydroxide and Lloydds reagent ~(Xessler, G., and Lederer,
H., Technicon Symposium, Mediad Inc., New York, 345-
347 (1965)~, are added, and the mixture is shaken for
one hour. Cholesterol and triglyceride levels are deter-
mined simultaneously on the same sample by ~echnicon
- N24 A (cholesterol) and N-78 (triglyceride) methodology.
- The mean total serum cholesterol levels are then computed; and the hypocholesterolemic activ$ty is expressed as the ~ -
fall in cholesterol levels as a percentage of the control
level. The change in serum triglyceride levels induced -
by the dxug is computed as a percentage of the control
triglyceride levels.
~ The compounds are therefore lndicated for use
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as hypolipidemic, particularly, hypolipoproteinemic
agents. An indicated suitable daily dosage ls from 150
to 3000 mg, preferably 700 to 3000 mg, suit~b3y admi-
nistered in divided dosages of from 37.5 to 1500 mg, pre-
ferably 175 to 1500 mg, two to four times daily, or in
retard form.
The compounds may be admixed with conventional,
pharmaceutically acceptable diluents or carriers, and,
optionally, other excipie~ts, and administered in such
forms as tablets or capsules.
The compounds of formula Ia may be used in
the form of the free acids or in pharmaceutically accep-
table salt forms, such as those mentioned above, which
. salt forms have the same order of activity as the free
acids.
It will be appreciated that the compounds of
formula I, in which X, Y and the benzyl substituents
differ~ possess an asymetric carbon atom and may therefore
exist in optically active or racemic form. Such forms
may be produced in conventional manner and it is to be
understood that the invention is not intendPd to be
limited to any particular form of the compounds.
The preferred compounds of formula I include
the compounds of formula Ib, particularly those in which
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R2 and R3 are each methyl. More preferabl~v each R~ is ethyl.
The most preferred comp~und of f~rmula I is bis-~-piva- -.
A loylbenzyl) ~ acid diethyl ester.
The follo~ing E~amples illustxate the invention.
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EXP*IPLE 1 : Bi~-(p-pivaloylbenzyl)malonic acid dieth~
ester (process b))
a) a-Bromo--~-~ivaloyltoluene
_ _ _ _ _
To a suspension of 28.5 g (1.17 g atoms~of magnesium
turn~ngs in 150 ml of tetrahydrofuran, under a nitrogen
atmosphere, there is added 10 ml of 4-bromotoluene
(1.17 mole) in 650 ml of dry tetrahydrofuran, the
bromotoluene solution being added, drop~ise, at a
rate that maintains a moderate reflux. After the
addition is complete, the mixture i~ refluxed for an
additional 1 1/2 hours. The resulting Grignard
solution is added, dropwise, to a cold solution of
128.0 g of pivaloyl chloride (1.06 mole) in 500 ml of
dry tetrahydrofuran at a rate that maintains the ;~
temperature at 0 to -5C. The solution is stirred -
fox an additional 1 1/2 hours at 0C and then at
- room temperature for 18 hours. The mixture is then
cooled to 0 C and hydrolysed by the addition of
100 ml of 2N hydrochloric acid. The layers are
separated and 200 ml of ether is added to the organ~c
phase which is then washed successively with 100 ml
of 2N hydrochloric acid, 100 ml of 10% sodium bicar
bonate solution and 100 ml of saturated sodium
chloride. The resulting organic phase is dried over ~- -
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anhydrous sodium sulfate, filtered, and the solvent
is removed in vacuo to give ~-pivaloyltoluene
(b.p. 80-84C/0.7 mm, nD 1.5108). A mixture of
156.3 g (0.886 mole) of the resulting ~-pivaloyl-
toluene is then added to 157.8 g (0.886) mole of
N-bromosuccinimide, 4.0 g (0.016 mole) of benzoyl
peroxide and 150 ml of carbon tetrachloride and the mixture
heated at reflux for 18 hours. The mixture is cooled
and filtered and the resulting preclpitate is washed
with carbon tetrachloride. The solvents are removed -
in vacuo and the resulting oil is distilled in vacuo
to give -bromo-~-pivaloyltoluene, b.p. 124-132/
0.7 mm, n2 1.5546-V.P.C.(96~ monobromo,4~-dibromo).
b) Bls-(~-~ivaloylbenzyl)malonic acld dieth~l ester
_____ _ _____ _____ ____________________ _______
To a cold suspension of 4.66 g (0.194 mole) of sodium ~;
- h~dride ln 200 ml of dimethylacetamide there is added,
dropwise, 28.2 g (0.176 mole) of diethyl malonate in
80 ml of dimethylacetamide, the temperature being
maintained at 0 to 5C. The mixture is stirred for
; 20 two hours at room temperature and there is then added
40.8 g ~0.16 mole) of a-bromo-~-pivaloyltoluene in
200 ml of dimethylacetamide ~hile maintaining the
reaction temperature at 20 to 30C. Stirring is con-
tinued overnight at room temperature. Water is then
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added and the excess dimethylacetamide is removed in
vacuo. The resulting residue is partitioned between
petroleum ether and water. The organic phase is washed
with water, and brine, dried and evaporated in vacuo.
S The residue is then distilled ~n vacuo and crystallised
from petroleum ether at -~0C to give bis~ pivaloyl-
benzyl)malonic acid diethyl ester, m.p. 65to 67C.
.' ~'' '
EXAMPLE 2 : Bis-(~-pivalo~lbenzyl)acetic acid [process a)]
To a solution of 10 g (0.03 mole) of bis~
pivaloylbenzyl)malonic acid diethyl ester in 45 ml of
ethanol and 45 ml of water, there is added 8.4 g (0.15
mole) of potassium hydroxide and the mixture is refluxed
for S hours. The solvents are removed in vacuo and the
residue partitioned between ether and ~7ater. The aqueous
layer is made acidic at 0C with concentrated hydrochloric
acid, extracted with ether, dried and evaporated. The
resulting oil is treated with 200 ml o~ concentrated hy-
drochloric acid and the mixture is refluxed for 20 hours.
. :.
The cooled mixture is extracted with ether, the ether
; 20 phase extracted with 2N sodium hydroxide and the basic
solution is made acidic at 0C with concentrated hydrochlo-
rlc acid, extracted with ether, and the ether phase is
then dried and evaporated. The resulting residue is crys- ;
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tallised from ether/petroleum ether to give bis-(~-pi-
valoylbenzyl)acetic acid, m.p. 107-109C.
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EXAMPLE 3 : [process b)3
In manner analogous to Example 1, employing
approprate starting materials in appxoximately equi-
- ~alent amounts, the following compounds may be obtained:-
bis-(2-chloro-~-pivaloylbenzyl)malonic acid
- diethyl ester,
bis-(2-m~thoxy-~-pivaloylbenzyl)malonic acid
diethyl ester,
bis-(2-fluoro-~-pivaloylbenzyl)malonic acid
diethyl ester, m . p . 62-63 . 5C,
and bis~ pivaloylbenzyl)malonic acid dimethyl ester,
- m.p. 106.5 - 108C.
EXAMPLE 4 : [process a)~
In manner analogous to Example 1, employing
appropriate starting materials in approximately equi-
valent amounts, the follo~ring compounds may be obtained:-
bis-(2-chloro-~-pivaloylbenzyl)acetic acid,
bis-(2-methoxy-~-pivaloylbenzyl)acetic acid~
ànd bis-~2-fluoro-~-pivaloylbenzyl)acetic acid,
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