IL44224A - Bis-(4-alkanoylbenzyl) acetic acid derivatives their production and pharmaceutical compositions containing them - Google Patents

Bis-(4-alkanoylbenzyl) acetic acid derivatives their production and pharmaceutical compositions containing them

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Publication number
IL44224A
IL44224A IL44224A IL4422474A IL44224A IL 44224 A IL44224 A IL 44224A IL 44224 A IL44224 A IL 44224A IL 4422474 A IL4422474 A IL 4422474A IL 44224 A IL44224 A IL 44224A
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Israel
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formula
compound
bis
signifies
hydrogen
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IL44224A
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IL44224A0 (en
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Sandoz Ag
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Publication of IL44224A0 publication Critical patent/IL44224A0/en
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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)

Description

44224/2 I-HIK o» '3Dn n npm *τ»»3ητ †nrs** B»a-e-«-»B«s»a»-:-3»-!»e-3e3-3ea Bls-(4-alkanoylbeniRyl)acetic acid derivatives, their production and pharmaceutical compositions containing them SANDOZ A.G.
C. 42215 Case 600-6543 -IIirnOVEIlENGJC IN ΟΠ RELA ING TO ORGANIC COMPOUMDO This invention relates to bis- (benzyl) acetic acid derivatives.
More particularly, this invention provides compounds of formula I, different, signify hydrogen, fluorine, chlorine, or straight chain alkoxy of 1 to 4 carbon atoms, the R2'S/ which maY be tne same or different, signify methyl or ethyl, the R-j'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 - COOR , - 2 - Case 600-6543 in which signifies alkyl of 1 to 4 carbon atoms , and salt forms of the compounds in which X is hydrogen and Y is -COOH.
The invention also provides . processes for the production of compounds of formula I, characterised by a) producing a compound of formula la, in which R^, R2 and are as defined above, and salt forms thereof, by a process comprising the step of decarboxylating a compound of formula II, in which R^, R2 and 3 are as defined above, or b) producing a compound of formula ib, in which R^, R^, R^ and are as defined above by reacti in which R^, R2 and are as defined above, and X signifies chlorine or bromine, with a compound of formula 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.
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 - 4 - Case 600-6543 of 1 to 4 carbon atoms, such as methanol or ethanol, The decarboxylation is suitably effected by acidification, for example with a mineral acid, such as sulphuric, hydro-bromic or, preferably, hydrochloric acid. The process is conveniently effected at a temperature of from 90° to 180°C, preferably at the reflux temperature of the reaction medium, and suitable reaction times vary, for example from 12 to 36, more typically 15 to 20, hours.
Process b) is conveniently effected at a temperature of from 20° to 30°C, preferably about 25°C.
Suitable strong bases include alkali metal hydrides, such as sodium or potassium hydride, and alkali metal alkoxides such as sodium or potassium ethoxide, preferably potassium ethoxide. Suitable solvents 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 where the R-^'s, R2 ' s and/or R3's, in the desired compound of formula lb, differ, then a mixture of compounds of formula III is employed. In the compounds, cf formula IV, D suitably signifies sodium or potassium, and in the compounds of formula III, X is preferably bromine.
The resulting compounds of formula I may be isolated and purified using conventional techniques.
Where required, the compounds of formula la may be con- - 5 - Case 600-6543 / verted into salt forms, eg alkali 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 lb.
The hydrolysis is conveniently effected at a temperature of from 70° to 150°C, preferably at the reflux temperature of the reaction medium, and suitably employing an alkali metal base, such as sodium or, preferably, potassium hydroxide, 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 a lower alkanol, eg methanol or ethanol..
The resulting compounds of formula II are preferably subjected directly, v/ithout isolation, to process a) .
The compounds of formula III may suitably be produced by treating a compound of formula V, in which R 1' R_ and R are as defined above, - 6 - Case 600-6543 Ψ with a chlorinatinq or brominating agent, in the presence of a free radical initiator and in an inert organic solvent .
Suitable brominating agents include bromine / N-bromophthalimide , N-bromoacetamide and , preferably , N-bromosuccinimide. Suitable chlorinatinq aqents include N-chlorosucci-nimide. Suitable free radical initiators include inorganic and organic peroxides, although the process may. alternatively, be carried out under ultraviolet light for this purpose. The process is conveniently effected at the reflux temperature of the reaction medium, and suitably solvents include halogenated 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 purif ied using conventional reaction techniques .
The compounds of formulae IV and V are either known or may be produced in conventional manner from available materials .
The compounds of formula I possess pharmacological activity . In particular , they possess hypolipidemic , especially hypolipoproteinemic activity as indicated by the fall in cholesterol and triglyceride levels in male - 7 - Case 600-6543 albino Wistar rats weighing 110-130 g initially. The rats are maintained on drug-free 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 er diem of the compound fcr six days. At the end of this period, the animals are anaesthetised with sodium hexobarbital 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. A Two jfutoanalyser cupgfulsof a mixture of zeolite-copper hydroxide and Lloydd's reagent [(Kessler, 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 determined simultaneously on the same sample by Technicon N24 A (cholesterol) and N-78 (triglyceride) methodology. The mean total serum cholesterol levels are then computed and the hypocholesterolemic activity is expressed as the fall in cholesterol levels as a percentage of the control level. The change in serum triglyceride levels induced by the drug is computed as a percentage of the control triglyceride levels.
The compounds are therefore indicated for use - 8 - Case 600-6543 as hypolipidemic/ particularly, hypolipoproteinemic agents. An indicated suitable daily dosage is from 150 to 3000 mg, preferably 700 to 3000 mg, suitably administered in divided dosages of from 37.5 to 1500 mg, preferably 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 excipients, and administered in such forms as tablets or capsules.
The compounds of formula la may be used in the form of the free acids or in pharmaceutically acceptable 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 intended to be limited to any particular form of the compounds.
The preferred compounds of formula I include the compounds of formula lb, particularly those in which 1*2 and R3 are each methyl. More preferably each R^ is ethyl. The most preferred compound of formula lb is bis-(£-piva-loylbenzyDmalonic acid diethyl ester.
The following Examples illustrate the invention. - 10 - Case 600-6543 EXAMPLE 1 : Bis- (p-pivaloylbenzyl) malonic acid diethyl ester (process b) ) To a suspension of 28.5 g (1.17 g atoms) of magnesium turnings 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, dropwise, at a rate that maintains a moderate reflux. After the addition is complete, the mixture is 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 -5°C. The solution is stirred for an additional 1 1/2 hours at 0°C 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 organic phase which is then washed successively with 100 ml of 2N hydrochloric acid, 100 ml of 10% sodium bicarbonate solution and 100 ml of saturated sodium chloride. The resulting organic phase is dried over - 11 - Case 600-6543 anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p_-pivaloyltoluene (b.p. 80-84°C/0.7 mm, n^1 1.5108). A mixture of 156.3 g (0.886 mole) of the resulting p_-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 precipitate is washed with carbon tetrachloride. The solvents are removed in vacuo and the resulting oil is distilled in vacuo to give a-bromo-p_-pivaloyltoluene, b.p. 124-132°/ 22 0.7 mm, nQ 1.5546-V.P.C. (96% monobromo, 4%-dibromo). §i§11EIEiY-Ϊi2 §.5Yii ^ To a cold suspension of 4.66 g (0.194 mole) of sodium hydride in 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 5°C. The mixture is stirred for two hours at room temperature and there is then added 40.8 g (0.16 mole) of a-bromo-p_-pivaloyltoluene in 200 ml of dimethylacetamide while maintaining the reaction temperature at 20° to 30°C. Stirring is continued overnight at room temperature. Water is then - 12 - Case 600-6543 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. The residue is then distilled in vacuo and crystallised from petroleum ether at -50°C to give bis- (p_-pivaloyl- benzyl) malonic acid diethyl ester, m.p. 65° to 67°C.
EXAMPLE 2 : Bis- (p-pivaloylbenzyl) acetic acid [process a) ] To a solution of 10 g (0.03 mole) of bis-(p_-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 5 hours. The solvents are removed in vacuo and the residue partitioned between ether and water. The aqueous layer is made acidic at 0°C with concentrated hydrochloric acid, extracted with ether, dried and evaporated. The resulting oil is treated with 200 ml of concentrated hydrochloric acid and the mixture is refluxed for 20 hours. The cooled mixture is extracted with ether, the ether phase extracted with 2N sodium hydroxide and the basic solution is made acidic at 0°C with concentrated hydrochloric acid, extracted with ether, and the ether phase is then dried and evaporated. The resulting residue is crys- - 13 - Case 600-6543 tallised from ether/petroleum ether to give bis-(p_-pi-valoylbenzyl) acetic acid, m.p. 107-109°C.
EXAMPLE 3 : [process b) ] In manner analogous to Example 1, employing appropriate starting materials in approximately equivalent amounts, the following compounds may be obtained: bis- (2-chloro-p_-pivaloylbenzyl) malonic acid diethyl ester, bis- (2-methoxy-p_-pivaloylbenzyl) malonic acid diethyl ester, bis- (2-fluoro-p_-pivaloylbenzyl) malonic acid diethyl ester ,m.p.62?- 63.5°C. and bis- (p_-pivaloylbenzyl) malonic acid dimethyl ester m.p. 106.5° - 108°C.
EXAMPLE 4 : [process a) ] In manner analogous to Example 1, employing appropriate starting materials in approximately equivalent amounts, the follov/ing compounds may be obtained: bis- (2-chloro-p_-pivaloylbenzyl) acetic acid, bis- (2-methoxy-p_-pivaloylbenzyl) acetic acid, and bis- (2-fluoro-p_-pivaloylbenzyl) acetic acid,

Claims (14)

- 14 - Case 600-6543 What we claim is
1. A process for the production of compounds formula I , in which the R-^'s, which may be the same or different, signify hydrogen, fluorine, chlorine, or straight chain alkoxy of 1 to 4 carbon atoms, the R2's' which maY be the same or different, signify methyl or ethyl, the R-j'3' 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 in which R^ signifies alkyl of 1 to 4 carbon atoms, - 15 - Case 600-6543 and 'salt forms of the compounds in which X is hydrogen and Y is -COOH, characterised by a) producing a compound of formula la, in which R^, and are as defined above, and salt forms thereof, by a process comprising the step of decarboxylating a compound of formula II, in which R , R and R are as defined above, - 16 - Case 600-6543 or b) producing a compound of formula lb, in which ^, R^ r Rg and R^ are as defined above by reacting a compound or compounds of formula III, in which R^, R2 and ^ are as defined above, and X signifies chlorine or brdmine, with a compound of formula IV, in which ^ 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 for the production of a compound of formula I, stated in claim 1, or a salt form of a compound of formula I, in which X is hydrogen and Y is 44224/2 - 17 - -COOH, substantially as herein described with reference to any one of the Examples.
3. A compound of formula I, stated in claim 1, or a salt form of a compound of formula I, in which. X is hydrogen and Y is -COOH, whenever produced by a process according to claim 1 or 2,
4. A compound of formula I, stated in claim 1.
5. A compound of formula la, stated in claim 1.
6. Bis- (£-pivaloylbenzyl) acetic acid.
7. A Compound of formula lb, stated in claim 1.
8. Bis- (p_-pivaloylb'enzyl) malonic acid diethyl ester.
9. Bis- (p-pivaloylbenzyl) malonic acid dimethyl ester.
10. Bis- (2-fluoro-p_-pivaloylbenzyl) malonic acid diethyl ester.
11. A compound according to claim 5 or 6, in salt form.
12. A compound according to claim 5 or 6 , in alkali metal or alkaline earth metal salt form. 18 - 44224/2
13. A pharmaceutical composition comprising a compound of formula I, stated in claim 1, or a pharmaceutically acceptable salt form of a compound of formula I, in which X is hydrogen and Y is -COOH, in association with a pharmaceutically acceptable diluent or carrier.
14. A pharmaceutical composition according to claim 13, substantially as herein described. For the AppL ND:dn
IL44224A 1973-02-20 1974-02-18 Bis-(4-alkanoylbenzyl) acetic acid derivatives their production and pharmaceutical compositions containing them IL44224A (en)

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 (2)

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IL44224A0 IL44224A0 (en) 1974-05-16
IL44224A true IL44224A (en) 1977-11-30

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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)

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DE3607728A1 (en) * 1986-01-25 1987-07-30 Telefonbau & Normalzeit Gmbh TERMINAL OF A TELECOMMUNICATION SYSTEM
US6323060B1 (en) 1999-05-05 2001-11-27 Dense-Pac Microsystems, Inc. Stackable flex circuit IC package and method of making same
US6262895B1 (en) 2000-01-13 2001-07-17 John A. Forthun Stackable chip package with flex carrier
US7485951B2 (en) 2001-10-26 2009-02-03 Entorian Technologies, Lp Modularized die stacking system and method
US6914324B2 (en) 2001-10-26 2005-07-05 Staktek Group L.P. Memory expansion and chip scale stacking system and method
US6940729B2 (en) 2001-10-26 2005-09-06 Staktek Group L.P. Integrated circuit stacking system and method
US7371609B2 (en) 2001-10-26 2008-05-13 Staktek Group L.P. Stacked module systems and methods
US7081373B2 (en) 2001-12-14 2006-07-25 Staktek Group, L.P. CSP chip stack with flex circuit
US7309914B2 (en) 2005-01-20 2007-12-18 Staktek Group L.P. Inverted CSP stacking system and method

Also Published As

Publication number Publication date
FR2218106A1 (en) 1974-09-13
NL7402093A (en) 1974-08-22
CH591418A5 (en) 1977-09-15
IE39419L (en) 1974-08-20
FR2218106B1 (en) 1978-01-13
DE2406881A1 (en) 1974-08-29
SE399554B (en) 1978-02-20
AT346308B (en) 1978-11-10
ATA125874A (en) 1978-03-15
JPS5029534A (en) 1975-03-25
IE39419B1 (en) 1978-10-11
AU6577274A (en) 1975-08-21
PH10682A (en) 1977-08-10
IL44224A0 (en) 1974-05-16
CS170510B2 (en) 1976-08-27
ES423376A1 (en) 1976-09-16
GB1453644A (en) 1976-10-27
GB1453643A (en) 1976-10-27
DD110033A5 (en) 1974-12-05
HU168102B (en) 1976-02-28
CA1043807A (en) 1978-12-05

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