CA1043807A - Pharmacologically active derivatives of bis-(p-alkanoylbenzyl) acetic and malonic acids - Google Patents
Pharmacologically active derivatives of bis-(p-alkanoylbenzyl) acetic and malonic acidsInfo
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- CA1043807A CA1043807A CA192,776A CA192776A CA1043807A CA 1043807 A CA1043807 A CA 1043807A CA 192776 A CA192776 A CA 192776A CA 1043807 A CA1043807 A CA 1043807A
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- compound
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/88—Unsaturated compounds containing keto groups containing halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the disclosure The invention provides novel bis-(benzyl) acetic acid of derivatives, useful as hypolipidemic agents.
They have the general formula:
They have the general formula:
Description
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 , .
,. ` "''~''~' ; :.
., ~ .
`` ~"''' : ~k ' -. ` .
Case 600-6543 CA~ADA
10~3~7~ ~
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 .
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 , .
,. ` "''~''~' ; :.
., ~ .
`` ~"''' : ~k ' -. ` .
Case 600-6543 CA~ADA
10~3~7~ ~
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, .
,:
Case 600-6543 CANADA
s 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 .
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
,:
Case 600-6543 CANADA
s 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 .
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 ?` . ~: :
. , ,: . '. .
,1 ,, . ;
,:
. :
Case 600-65~3 `
CANADA
~ ~3~07 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- ~
,:
,~ ~. '.
.. ' ' .
- . -Case 600-6543 CANA~A
1~438~7 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, R3 - C - C ~ CH3 V
in whlch Rl, R2 and R3 are a~ defined above, ' ., - ,, .~`~ , . . ' ~.
i ~ . . . . . . .
~ ~ Case 600-6543 CAN'ADA
~0~3807 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 ' .. ' ' ' '"''' .
, ..
'' ~
- ~.
Case 600-6543 CANADA
~438a7 ~
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 ., ~ '.
;. ' ' ' , ' ', ' '~' - Case 600-6543 CANADA
~438~ :
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 8 -- ~ ~
, , ,,:
.
-- .
Case 600-6543 CANADA
3~07 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.
9 ~,:
,'.
; :
..
.
.
.. . . . . . . .
Case 600~6543 CANA~
10~3807 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 ~- -10 - '' ';
, '. .
. . .
Case 600-6543 CANh~A
J ~3~07 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 11 , '` , ' ' ,~
.
: ~ ' ' ' ' - . --. , : ,.. . ~ .. . : .
Case 600-6543 CAN,~DA
1~4;~0~
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- ;
1 2 ~
~.; ~. ,.
. ~
, ~ . - ` ~
Case 600~6543 CANA~A
1V43~07 tallised from ether/petroleum ether to give bis-(~-pi-valoylbenzyl)acetic acid, m.p. 107-109C.
' .:
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, . ~ . .
' , .. . .
. ~:
. , ,: . '. .
,1 ,, . ;
,:
. :
Case 600-65~3 `
CANADA
~ ~3~07 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- ~
,:
,~ ~. '.
.. ' ' .
- . -Case 600-6543 CANA~A
1~438~7 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, R3 - C - C ~ CH3 V
in whlch Rl, R2 and R3 are a~ defined above, ' ., - ,, .~`~ , . . ' ~.
i ~ . . . . . . .
~ ~ Case 600-6543 CAN'ADA
~0~3807 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 ' .. ' ' ' '"''' .
, ..
'' ~
- ~.
Case 600-6543 CANADA
~438a7 ~
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 ., ~ '.
;. ' ' ' , ' ', ' '~' - Case 600-6543 CANADA
~438~ :
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 8 -- ~ ~
, , ,,:
.
-- .
Case 600-6543 CANADA
3~07 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.
9 ~,:
,'.
; :
..
.
.
.. . . . . . . .
Case 600~6543 CANA~
10~3807 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 ~- -10 - '' ';
, '. .
. . .
Case 600-6543 CANh~A
J ~3~07 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 11 , '` , ' ' ,~
.
: ~ ' ' ' ' - . --. , : ,.. . ~ .. . : .
Case 600-6543 CAN,~DA
1~4;~0~
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- ;
1 2 ~
~.; ~. ,.
. ~
, ~ . - ` ~
Case 600~6543 CANA~A
1V43~07 tallised from ether/petroleum ether to give bis-(~-pi-valoylbenzyl)acetic acid, m.p. 107-109C.
' .:
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, . ~ . .
' , .. . .
. ~:
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of compounds of formula I, I
in which the R1's are the same or different and each signifies hydrogen, fluorine or chlorine, the R2's are the same or different and each signifies methyl or ethyl, the R3's are the same or different and each signifies 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 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, characterised by a) producing a compound of formula Ia, Ia in which R1, R2 and R3 are as defined above, and salt forms thereof, by a process comprising the step of decarboxylating a compound of formula II, II
in which R1, R2 and R3 are as defined above, or b) producing a compound of formula Ib, Ib in which R1, R2, R3 and R4 are as defined above, by reacting a compound or compounds of formula III, III
in which R1, R2 and R3 are as defined above, and X signifies chlorine or bromine, with a compound of formula IV, IV
in which R4 is as defined above, and D signifies an alkali metal, in the presence of a strong base, and in an inert organic solvent.
in which the R1's are the same or different and each signifies hydrogen, fluorine or chlorine, the R2's are the same or different and each signifies methyl or ethyl, the R3's are the same or different and each signifies 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 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, characterised by a) producing a compound of formula Ia, Ia in which R1, R2 and R3 are as defined above, and salt forms thereof, by a process comprising the step of decarboxylating a compound of formula II, II
in which R1, R2 and R3 are as defined above, or b) producing a compound of formula Ib, Ib in which R1, R2, R3 and R4 are as defined above, by reacting a compound or compounds of formula III, III
in which R1, R2 and R3 are as defined above, and X signifies chlorine or bromine, with a compound of formula IV, IV
in which R4 is as defined above, and D signifies an alkali metal, in the presence of a strong base, and in an inert organic solvent.
2. A process according to claim 1 which comprises producing a compound of Formula Ia, Ia in which R1, R2 and R3 are as defined in claim 1 and salt forms thereof, by a process comprising the step of decarboxylating a compound of formula II, II
in which R1, R2 and R3 are as defined above.
in which R1, R2 and R3 are as defined above.
3. A process according to claim 1 which comprises producing a compound of formula Ib, Ib in which R1, R2, R3 and R4 are as defined in claim 1 by reacting a compound or compounds of formula III, III
in which R1, R2 and R3 are as defined above, and X signifies chlorine or bromine, with a compound of formula IV, IV
in which R4 is as defined above, and D signifies an alkali metal, in the presence of a strong base, and in an inert organic solvent.
in which R1, R2 and R3 are as defined above, and X signifies chlorine or bromine, with a compound of formula IV, IV
in which R4 is as defined above, and D signifies an alkali metal, in the presence of a strong base, and in an inert organic solvent.
4. A process according to claim 2 in which the decarboxylation is carried out in aqueous medium in the presence of a mineral acid.
5. A process according to claim 2 in which the reaction temperature is from 90° to 180°C.
6. A process according to claim 3 in which a com-pound or compounds of formula III in which X is bromine is reacted with a compound of formula IV in which D is sodium or potassium.
7. A process according to claim 3 in which the reaction is carried out in dimethyl acetamide solution at a temperature of 20° to 30°C.
8. A compound of Formula I, stated in claim 1, or a pharmaceutically acceptable salt thereof, whenever produced by a process according to claim 1 or an obvious chemical equivalent.
9. A compound of formula Ia, stated in claim 2, or a pharmaceutically acceptable salt thereof, whenever produced by a process according to claim 2, 4 or 5 or an obvious chemical equivalent.
10. A compound of formula Ib, stated in claim 3, whenever produced by a process according to claim 3, 6 or 7 or an obvious chemical equivalent.
11. A process for the preparation of bis-(p-piv-aloylbenzyl) malonic acid diethyl ester according to claim 1, in which diethyl malonate is reacted with sodium hydride in cold dimethyl acetamide, and the pro-duct is then reacted with .alpha.-bromo-p-pivaloyltoluene in dimethyl acetamide at 20° to 30°C.
12. Bis-(p-pivaloylbenzyl)malonic acid diethyl ester whenever prepared by a process according to
11. A process for the preparation of bis-(p-piv-aloylbenzyl) malonic acid diethyl ester according to claim 1, in which diethyl malonate is reacted with sodium hydride in cold dimethyl acetamide, and the pro-duct is then reacted with .alpha.-bromo-p-pivaloyltoluene in dimethyl acetamide at 20° to 30°C.
12. Bis-(p-pivaloylbenzyl)malonic acid diethyl ester whenever prepared by a process according to
claim 11.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33389273A | 1973-02-20 | 1973-02-20 | |
| US40322573A | 1973-10-03 | 1973-10-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1043807A true CA1043807A (en) | 1978-12-05 |
Family
ID=26988943
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA192,776A Expired CA1043807A (en) | 1973-02-20 | 1974-02-18 | Pharmacologically active derivatives of bis-(p-alkanoylbenzyl) acetic and malonic acids |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5029534A (en) |
| AT (1) | AT346308B (en) |
| CA (1) | CA1043807A (en) |
| CH (1) | CH591418A5 (en) |
| CS (1) | CS170510B2 (en) |
| DD (1) | DD110033A5 (en) |
| DE (1) | DE2406881A1 (en) |
| ES (1) | ES423376A1 (en) |
| FR (1) | FR2218106B1 (en) |
| GB (2) | GB1453644A (en) |
| HU (1) | HU168102B (en) |
| IE (1) | IE39419B1 (en) |
| IL (1) | IL44224A (en) |
| NL (1) | NL7402093A (en) |
| PH (1) | PH10682A (en) |
| SE (1) | SE399554B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3607728A1 (en) * | 1986-01-25 | 1987-07-30 | Telefonbau & Normalzeit Gmbh | TERMINAL OF A TELECOMMUNICATION SYSTEM |
-
1974
- 1974-02-08 CH CH176774A patent/CH591418A5/xx not_active IP Right Cessation
- 1974-02-11 SE SE7401786A patent/SE399554B/en unknown
- 1974-02-13 DE DE19742406881 patent/DE2406881A1/en not_active Withdrawn
- 1974-02-15 GB GB2533876A patent/GB1453644A/en not_active Expired
- 1974-02-15 NL NL7402093A patent/NL7402093A/xx not_active Application Discontinuation
- 1974-02-15 GB GB695374A patent/GB1453643A/en not_active Expired
- 1974-02-18 CS CS1168A patent/CS170510B2/cs unknown
- 1974-02-18 AT AT125874A patent/AT346308B/en not_active IP Right Cessation
- 1974-02-18 DD DD176622A patent/DD110033A5/xx unknown
- 1974-02-18 JP JP49018655A patent/JPS5029534A/ja active Pending
- 1974-02-18 ES ES423376A patent/ES423376A1/en not_active Expired
- 1974-02-18 HU HUSA2595A patent/HU168102B/hu unknown
- 1974-02-18 CA CA192,776A patent/CA1043807A/en not_active Expired
- 1974-02-18 IL IL44224A patent/IL44224A/en unknown
- 1974-02-19 IE IE333/74A patent/IE39419B1/en unknown
- 1974-02-20 PH PH15530A patent/PH10682A/en unknown
- 1974-02-20 FR FR7405671A patent/FR2218106B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2218106B1 (en) | 1978-01-13 |
| GB1453644A (en) | 1976-10-27 |
| DE2406881A1 (en) | 1974-08-29 |
| DD110033A5 (en) | 1974-12-05 |
| AU6577274A (en) | 1975-08-21 |
| HU168102B (en) | 1976-02-28 |
| NL7402093A (en) | 1974-08-22 |
| AT346308B (en) | 1978-11-10 |
| IL44224A0 (en) | 1974-05-16 |
| IE39419B1 (en) | 1978-10-11 |
| CH591418A5 (en) | 1977-09-15 |
| PH10682A (en) | 1977-08-10 |
| ATA125874A (en) | 1978-03-15 |
| ES423376A1 (en) | 1976-09-16 |
| JPS5029534A (en) | 1975-03-25 |
| GB1453643A (en) | 1976-10-27 |
| CS170510B2 (en) | 1976-08-27 |
| SE399554B (en) | 1978-02-20 |
| IE39419L (en) | 1974-08-20 |
| FR2218106A1 (en) | 1974-09-13 |
| IL44224A (en) | 1977-11-30 |
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