CA2089166A1 - Benzanilide derivatives and their use as anti-antherosclerotic agents - Google Patents
Benzanilide derivatives and their use as anti-antherosclerotic agentsInfo
- Publication number
- CA2089166A1 CA2089166A1 CA002089166A CA2089166A CA2089166A1 CA 2089166 A1 CA2089166 A1 CA 2089166A1 CA 002089166 A CA002089166 A CA 002089166A CA 2089166 A CA2089166 A CA 2089166A CA 2089166 A1 CA2089166 A1 CA 2089166A1
- Authority
- CA
- Canada
- Prior art keywords
- decyloxybenzamido
- benzoate
- group containing
- carbon atoms
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
Abstract
Benzanilide derivatives of formula (I) wherein R1 represents alkyl, optionally interrupted by one or more hetero atoms, X1 represents oxygen, sulphur or -NR5- wherein R5 represents hydrogen or alkyl or alkanoyl optionally substituted by halogen, R2 represents hydrogen or alkyl, R3 represents alkyl, alkoxy, alkylthio, dimethylamino or a heterocyclo group containing at least one nitrogen atom and linked via that nitrogen atom to the rest of the molecule, or a halogen atom, and R4 represents alkyl containing up to 10 carton atoms, optionally containing one or more carbon-carbon double or triple bonds, and optionally interrupted by one or more hetero atoms.
Description
W092/0~8 PCT/GB9~/Q13~
~1~8916~ ~
BENZANILIDE DERIVATIVES AND THEIR USE AS ANTI-ANTHER~SCLEROTIC A~ENTS
This invention relates to new, therapeutically useful benzanilide derivatives, to a process for their production and to pharmaceutical compositions containing them, and methods for their use.
The new benzanilide derivatives of the present invention are the compounds of formula I, hereina_ter depicted, wherein Rl represents a straight- or branched-chain alkyl group containing from about 4 to about 20 carbon atoms, optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alb=b~iyl, alkyla=ulx~Xyl or d~Xyl~=Lx~kyl group ooT;L~ng ~u~ about 4 to abcut 20 carbon atoms, Xl represents an oxygen or sulphur atom or a group -NR5- wherein R5 represents a hydrogen atom or a straight- or branched-chain alkyl or alkanoyl group containing up to about 5 carbon atoms, optionally substituted by one or more halogen, e.g. chlorine or fluorine, atoms, R2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms, R3 represents a straight- or branched-chain alkyl, alkoxy or alkylthio group containing from l to about 4 carbon atoms or a dimethyl-amino group or a 5- to 8-membered heterocyclo group containing at least one nitrogen atom and linked via that nitrogen atom to the rest of the molecule, e.g. an ' :. . ~ . , ' ' ' ' ' .' .: ' ~ ' ~ '. ' -W092/0~8 PCT/GB91/01376 -- 2imidazol-l-yl or pyrrolidin-1-yl group, or a halogen, e.g. chlorine or fluorine, atom, and R4 represents a straight- or branched-chain alkyl group containing up to about 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkoxyal~yl, alkylaminoalkyl or dialkylaminoalkyl group containing up to about 10 carbon atoms.
As will be apparent to those skilled in the art, some of the compounds of formula I exhibit optical isomerism. All such forms, and their mixtures, are embraced by the invention.
Especially important compounds of the present invention include those wherein at least one of the symbols has a value selected from the following:-(i) R1 represents an alkyl group containingfrom 8 to 12, e.g. 10, carbon atoms;
(ii) X1 represents an oxygen atom;
(iii) R2 represents a hydrogen atom;
(iv) R3 represents an alkoxy or alkylthio group containing 1 or 2 carbon atoms, a dimethylamino group or a halogen, e.g.
chlorine or fluorine, atom; and/or (v) R4 represents a straight- or branched-: . .
, :' ' ' ' . , , .
' W092/0~8 PCT/CB91/01376 ~'~.'. ,.
~D~916b s chain alkyl group containing up to 5 carbon atoms, optionally containing a carbon-carbon double bond or interrupted by an oxygen atom;
the other symbols being as hereinbefore defined.
- Important compounds according to the invention include:- :
A methyl 3-(4-decyloxybenzamido)-4-methoxy-benzoate;
B 3-methylbutyl 3-(4-decyloxybenzamido)-4-methoxybenzoate;
C 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-methoxybenzoate;
D methyl 4-chloro-3-(4-decyloxybenzamido)benzoate;
E methyl 3-(4-decyloxybenzamido)-4-fluorobenzoate;
F methyl 3-(4-decyloxybenzamido)-4-(methylthio)-benzoate; -:
G 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate;
H butyl 3-(4-decyloxybenzamido)-4-(methylthio)-benzoate;
I ethyl 3-(4-decyloxybenzamido)-4-(ethylthio)-benzoate;
J ethyl 3-(4-decyloxybenzamido)-4-ethoxybenzoate;
K 3-methylbut-3-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate;
.. . . . . .. . . . .. ..
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W~s~/n~s PCTJG~ 376 k~, a'~l6~
L 2-methoxyethyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate; and M methyl 3-(4-decyloxybenzamido)-4-dimethylamino-benzoate.
The letters A to M are allocated to compounds for easy reference later in this specification.
The compounds according to the invention a~e inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase (ACAT;EC 2.3.1.26). They are therefore of value as anti-atherosclerotic agents and have utility in the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the followlng in vitro tests which are believed to correlate to pharmacological activity in humans and other animals.
In assays performed in vitro microsomes (prepared from the livers of rats fed a diet supplemented with 0.5%w/w cholesterol and 0.25%w/w cholic acid for 7 days) were incubated with radiolabelled oleoyl-CoA in the presence of compounds according to the invention at a concentration of l~g/ml. The degree of ACAT inhibition produced was up to 95%.
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Compounds of formula I can be prepared by the i application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
According to a feature of the present invention~ i .
compounds of general formula I are prepared by the reaction of a compound of general formula II ~:
hereinafter depicted, wherein R2, R3 and R4 are as hereinbefore defined, with a compound of general formula III, hereinafter depicted, wherein Rl and X
are as hereinbefore defined and zl represents a halogen, e.g. chlorine, atom.
The reaction may be performed in the presence of a suitable base, such as a tertiary amine, and may be :
carried out in a suitable solvent, e.g. dichloro-methane, optionally with heating.
According to a further feature of the invention, compounds of formula I are prepared by reacting a compound of general formula:
R40H (IV) wherein R4 is as hereinbefore defined, with a compound of formula V, hereinafter depicted, wherein Rl, R2, R3 and Xl are as hereinbefore defined and z2 represents a halogen, e.g. chlorine, atom or a hydroxy group.
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W092/03408 PCT/GB91/013~
!) 1 6 ~
When z2 represents a halogen atom the reaction may be performed in the presence of a suitable base, such as a tertiary amine.
When z2 represents a hydroxy group the reaction is preferably performed in the presence of a condensing agent, such as dicyclohexylcarbodiimide, or a catalytic quantity of an inorganic acid, e.g. hydrochloric acid, optionally prepared n situ.
In each instance the reaction may be carried out in a suitable solvent, e.g. dichloromethane, optionally with heating.
According to a further feature of the invention, compounds of general formula I are prepared by the interconversion of other compounds of formula I. For example, compounds wherein R2 represents a straight- or branched-chain alkyl group containing from l to 4 carbon atoms may be prepared from compounds of formula I wherein R2 represents a hydrogen atom by alkylation by the application or adaptation of known methods.
Compounds of formulae II, III, IV and V may be prepared by the application or adaptation of known methods.
For example, (i) acid halides of formula V
wherein z2 represents a halogen atom may be prepared from the corresponding carboxylic acids of formula V
wherein z2 represents a hydroxy group by known methods, :'` ` ` , . .
.: . ~ , : :
W092/0~08 PCT~GB91/01376 ' ~0~166 e.g., when z2 represents a chlorine atom, by reaction with thionyl chloride;
(ii) the corresponding carboxylic acids of formula V
wherein z2 represents a hydroxy group may be prepared from compounds of formula I by hydrolysis of the ester grouping -CooR4 by known methods, for example by reaction with alkali, e.g. aqueous sodium hydroxide solution, followed by neutralisation by treatment with mineral acid, e.g. dilute hydrochloric acid.
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' . ' , ' ' ' . ~' ' ~ ' ' ' , - -, ~ '. ' '" ' ' ' ' ` - : ' ' , ' '.
" ' ' ' ' :, .~' , .' "
WO92/03408 : PCI/GB91/01376 6~ f~
_ 8 _ CoOR4 R1X 1 ~ CONR2 ~
CoOR4 HR2N ~
RlXl~\ CoZl III
,:
coz2 RlXl ~CONR2~ V
.
WD ~/~8 PCT/GU~If~l~7~
~U~16~
g The following Examples illustrate the preparation of the compounds according to the invention and the Reference Example illustrates the preparation of the intermediates.
Com~ounds A. D. E. F. I and J
A stirred solution of methyl 3-amino-4-methoxy- -benzoate (5.49g) and triethylamine (4.55g) in dichloro-methane (120ml) was treated with 4-decyloxybenzoyl chloride (9.Og; prepared from 4-decyloxybenzoic acid and thionyl chloride) and the mixture was stirred for 2 hours. The reaction mixture was then poured into water, the organic layer was separated and washed with hydrochloric acid (50ml; lN), with aqueous sodium hydroxide solution (50ml; lN), and with water (lOOml), and then it was dried over magnesium sulphate. The solution was concentrated under reduced pressure, to give an oil that solidified on standing. The solid was recrystallised from methanol, to give methyl 3-(4-decyloxybenzamido)-4-methoxybenzoate (3.2g), in the form of colourless needles, m.p. 84-85C.
[Elemental analysis:- C,70.9;H,8.2;N,3.03%;
calculated:- C,70.72;H,7.99;N,3.17%].
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of methyl 3-amino-4-chlorobenzoate, and .
. . .
, .
. .
W092/0~8 PCT/G~1/01376 ~,~ t `2~89166 working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous acetone and then from toluene, there was prepared methyl 4-chloro-3-(4-decyloxybenzamido)benzoate, in the form of colourless crystals, m.p. 106-107C.
[Elemental analysis:- C,67.5;H,7.3;N,2.93;C1,8.0%;
calculated:- C,67.32;H,7.23;N,3.13;Cl,7.95%~.
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of methyl 3-amino-4-fluorobenzoate, stirring at the ambient temperature for 2 hours, heating at reflux for 1 hour and working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous acetone and then from toluene, there was prepared methyl 3-(4-decyloxybenzamido)-4-fluorobenzoate, in the form of colourless crystals, m.p. 105-106C. [Elemental analysis:- C,69.5;H,7.6;
N,3.13;F,4.47%; calculated:- C,69.90;H,7.51;N,3.26;
F,4.42%].
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of methyl 3-amino-4-(methylthio)benzoate, there was prepared methyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate in the form of a cream powder, m.p. 97-99C. [Elemental analysis:- C,67.9;H,7.63;
N,2.9;S,7.1%; calculated:- C,68.27;~,7.66;N,3.07;
,. . : ., - . ~
.
WQ92/0~8 PCT/CB91/01376 ~ ., ~0~91~S
S,7.00%]-By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of ethyl 3-amino-4-(ethylthio)benzoate and working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous ethanol, there was prepared ethyl 3-(4-decyloxy-benzamido)-4-(ethylthio)benzoate in the form of white crystals, m.p. 91-93C. [Elemental analysis:-C,69.4;H,8.09;N,2.85;S,6.3%; calculated:- C,69.24;
H,8.09;N,2.88;S,6.60%].
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of ethyl 3-amino-4-ethoxybenzoate and working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous ethanol, there was prepared ethyl 3-(4-decyloxybenzamido)-4-ethoxybenzoate, in the form of white crystals; m.p.
89-91C. [Elemental analysis:- C,71.3;H,8.3;N,2.9~;
calculated:- C,71.61;H,8.37;N,2.98%~.
Compound B
Ice-cold 3-methylbutan-1-ol (5ml) was treated with acetyl chloride (0.8ml) followed, after 10 minutes, by 3-(4-decyloxybenzamido)-4-methoxybenzoic acid (2.0g). The suspension was warmed on a steam "
,' `' `
W092/0~8 PCT/G~9l/013 ~
~9 16~
- 12 - t bath for 3 hours and then the mixture was partitioned between water (50ml) and dichloromethane (50ml). The organic solution was dried and concentrated under reduced pressure to give a white solid, which was chromatographed on silica gel, eluting with dichloro methane, and recrystallised from methanol, to give 3-methylbutyl 3-(4-decyloxybenzamido)-4-methoxybenzoate (0.97g), in the form of colourless needles, m.p.
66-680C. [Elemental analysis:- C,71.9;H,8.8;N,2.6%;
calculated:- C,72.43;H,8.65;N,2.32~].
Compounds C G and H
A mixture of 3-(4-decyloxybenzamido)-4-methoxy-benzoyl chloride [2.22g; prepared from 3-(4-decyloxy-benzamido)-4-methoxybenzoic acid and thionyl chloride in dichloromethane], 3-methylbut-2-en-1-ol (2.58g) and triethylamine (3ml) in toluene (lOOml) was heated at 100C for 3 hours. The mixture was cooled and then treated with water (50ml), diethyl ether (30ml) and hydrochloric acid (5ml;2N), and the organic layer was removed and dried. Concentration under reduced pressure left an oil which solidified on standing. The solid was chromatographed on silica gel, eluting with dichloromethane, and recrystallised from methanol, to give 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-' ~
W092/0~08 PCT/GB91/01376 ~916~
methoxybenzoate (1.66g), in the form of a colourless solid, m.p. 60-62C. [Elemental analysis:- C,72.6;
H,8.4;N,2.8q%; calculated:- C,72.69;H,8.34;N,2.83%].
By proceeding in a similar manner, but replacing the 3-(4-decyloxybenzamido)-4-methoxybenzoic acid by the appropriate quantity of 3-(4-decyloxybenzamido)-4-(methylthio)benzoic acid and purifying the crude product by crystallisation from ethanol, instead of chromatography, there was prepared 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate in the form of a white solid, m.p. 107-109DC. [Elemental analysis:- c~7o.3;H~8.l;N~2.64;s~6.s%; calculated:-C,70.42;H,8.07;N,2.74;S,6.26%~.
By proceeding in a similar manner, but replacing the 3-methylbut-2-en-1-ol by the appropriate quantity of butan-l-ol and purifying the crude product by crystallisation from aqueous ethanol instead of chromatography, there was prepared butyl 3-(4-decyl-oxybenzamido)-4-(methylthio)benzoate, in the form of a cream-coloured powder, m.p. 89-91C. [Elemental analysis:- C,70.1;H,8.5;N,2.71;S,6.5%; calculated:-C,69.70;H,8.27;N,2.80;S,6.42%].
ComDounds K and L
3-Methylbut-3-en-1-ol (2.Oml) was treated with a solution of 3-(4-decyloxybenzamido)-4-(methylthio)-W092/~8 ~ PCr/GB91/01376 ~.
~3~ 6 ~ - 14 -benzoyl chloride (2.31g) in toluene (20ml) [prepared from 3-(4-decyloxybenzamido)-4-(methylthio)benzoic acid and thionyl chloride in toluene], and the mixture was stirred vigorously. It was then treated with triethylamine (lml) and the mixture was left to stand at the ambient temperature for 18 hours. The mixture was then diluted with dichloromethane (lOOml) and washed with water (lOOml), dried over magnesium sulphate and concentrated under reduced pressure.
The resulting residue was chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol, and recrystallised from diethyl ether, to give 3-methylbut-3-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate (0.45g), in the form of a colourless solid, m.p. 91-93C. [Elemental analysis:- C,70.4;H,8.1;N,2.63;S,6.32~; calculated:-C,70.42;H,8.07;N,2.74jS,6.26%].
By proceeding in a similar manner, but replacing the 3-methyl-but-3-en-1-ol by the appropriate quantity of 2-methoxyethanol and omitting the aqueous wash stage, there was prepared 2-methoxyethyl 3-(4-decyloxy-benzamido)-4-(methylthio)benzoate, in the form of a colourless solid, m.p. 88-90C. ~Elemental analysis:- C,67.3;H,7.8;N,2.76;S,6.56%; calculated:-C,67.03;H,7.84;N,2.79;S,6.39%~.
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W092/0~8 PCT/GB91/01376 f-,' .
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Compound M
By proceeding in a manner similar to that described hereinbefore in Example 1, but replacing the ¦ -methyl 3-amino-4-methoxybenzoate by the appropriate ¦
quantity of methyl 3-amino-4-dimethylaminobenzoate and omitting the acid and base washes from the work-up, there was prepared methyl 3-(4-decyloxybenzamido)-4-dimethylaminobenzoate in the form of a white solid, m.p. 77-78C (recrystallised from a mixture of ethyl acetate and petrol [Elemental analysis:- C,71.7jH,8.5;
N,6.1%; calculated:- C,71.34;H,8.42;N,6.16%].
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W0 92/03408 Pcl`/GB9~ 37~
~a~l6~
A mixture of methyl 3-(4-decyloxybenzamido)-4~
methoxybenzoate (3.31g) and aqueous sodium hydroxide solution (lOml;2N) in ethanol (lOOml) was heated at reflux for 2 hours. The mixture was concentrated under reduced pressure, then diluted with water (150ml) and washed with dichloromethane (50ml). The aqueous fraction was acidified to pH1 by treatment with dilute hydrochloric acid, and extracted with dichloromethane (2x50ml). This extract was dried and concentrated under reduced pressure, and the resulting solid was recrystallised from methanol, to give 3-(4-decyloxy-benzamido)-4-methoxybenzoic acid (l.Sg), in the form of a colourless solid, m.p. 194-196C. [Elemental analysis:- C,69.7;H,7.6;N,3.0%; calculated:- C,70023;
H,7.78;N,3.28%].
The present invention also includes within its scope pharmaceutical formulations which comprise-at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.
In clinical practice the compounds of the present invention may be administe~ed parenterally, rectally or orally.
Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of - : , :, . ,:, .
, - , , :
, . ~ , , - . . . ~: .
- , ..
W092t0~8 PCT/GB91~0~76 2~91~6 the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactoseO
The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesi~m stearate.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may ,.
., , ~ : . .
W092/0~8 PCT/GB91/01376 ~ o ~ 18 -also contain adjuvants such as stabilisi~g, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined - by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.5 to about 70, preferably about l to about l0, mg/kg body weight per day by oral administration.
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W092/0~08 PCT/GB91/01376 ~V891~
The following Example illustrates pharmaceutical compositions according to the present invention.
No. 2 size gelatin capsules each containing:-3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate 20 mg lactose l00 mg starch 60 mg dextrin 40 mg magnesium stearate l mg were prepared in accordance with the usual procedure.
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~1~8916~ ~
BENZANILIDE DERIVATIVES AND THEIR USE AS ANTI-ANTHER~SCLEROTIC A~ENTS
This invention relates to new, therapeutically useful benzanilide derivatives, to a process for their production and to pharmaceutical compositions containing them, and methods for their use.
The new benzanilide derivatives of the present invention are the compounds of formula I, hereina_ter depicted, wherein Rl represents a straight- or branched-chain alkyl group containing from about 4 to about 20 carbon atoms, optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alb=b~iyl, alkyla=ulx~Xyl or d~Xyl~=Lx~kyl group ooT;L~ng ~u~ about 4 to abcut 20 carbon atoms, Xl represents an oxygen or sulphur atom or a group -NR5- wherein R5 represents a hydrogen atom or a straight- or branched-chain alkyl or alkanoyl group containing up to about 5 carbon atoms, optionally substituted by one or more halogen, e.g. chlorine or fluorine, atoms, R2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms, R3 represents a straight- or branched-chain alkyl, alkoxy or alkylthio group containing from l to about 4 carbon atoms or a dimethyl-amino group or a 5- to 8-membered heterocyclo group containing at least one nitrogen atom and linked via that nitrogen atom to the rest of the molecule, e.g. an ' :. . ~ . , ' ' ' ' ' .' .: ' ~ ' ~ '. ' -W092/0~8 PCT/GB91/01376 -- 2imidazol-l-yl or pyrrolidin-1-yl group, or a halogen, e.g. chlorine or fluorine, atom, and R4 represents a straight- or branched-chain alkyl group containing up to about 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkoxyal~yl, alkylaminoalkyl or dialkylaminoalkyl group containing up to about 10 carbon atoms.
As will be apparent to those skilled in the art, some of the compounds of formula I exhibit optical isomerism. All such forms, and their mixtures, are embraced by the invention.
Especially important compounds of the present invention include those wherein at least one of the symbols has a value selected from the following:-(i) R1 represents an alkyl group containingfrom 8 to 12, e.g. 10, carbon atoms;
(ii) X1 represents an oxygen atom;
(iii) R2 represents a hydrogen atom;
(iv) R3 represents an alkoxy or alkylthio group containing 1 or 2 carbon atoms, a dimethylamino group or a halogen, e.g.
chlorine or fluorine, atom; and/or (v) R4 represents a straight- or branched-: . .
, :' ' ' ' . , , .
' W092/0~8 PCT/CB91/01376 ~'~.'. ,.
~D~916b s chain alkyl group containing up to 5 carbon atoms, optionally containing a carbon-carbon double bond or interrupted by an oxygen atom;
the other symbols being as hereinbefore defined.
- Important compounds according to the invention include:- :
A methyl 3-(4-decyloxybenzamido)-4-methoxy-benzoate;
B 3-methylbutyl 3-(4-decyloxybenzamido)-4-methoxybenzoate;
C 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-methoxybenzoate;
D methyl 4-chloro-3-(4-decyloxybenzamido)benzoate;
E methyl 3-(4-decyloxybenzamido)-4-fluorobenzoate;
F methyl 3-(4-decyloxybenzamido)-4-(methylthio)-benzoate; -:
G 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate;
H butyl 3-(4-decyloxybenzamido)-4-(methylthio)-benzoate;
I ethyl 3-(4-decyloxybenzamido)-4-(ethylthio)-benzoate;
J ethyl 3-(4-decyloxybenzamido)-4-ethoxybenzoate;
K 3-methylbut-3-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate;
.. . . . . .. . . . .. ..
.. : :
: - . . .
,:. , .:
.: . : - . . .
:.: . ~ . -. : . .~ .
: -: . . - ~ .~:
W~s~/n~s PCTJG~ 376 k~, a'~l6~
L 2-methoxyethyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate; and M methyl 3-(4-decyloxybenzamido)-4-dimethylamino-benzoate.
The letters A to M are allocated to compounds for easy reference later in this specification.
The compounds according to the invention a~e inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase (ACAT;EC 2.3.1.26). They are therefore of value as anti-atherosclerotic agents and have utility in the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the followlng in vitro tests which are believed to correlate to pharmacological activity in humans and other animals.
In assays performed in vitro microsomes (prepared from the livers of rats fed a diet supplemented with 0.5%w/w cholesterol and 0.25%w/w cholic acid for 7 days) were incubated with radiolabelled oleoyl-CoA in the presence of compounds according to the invention at a concentration of l~g/ml. The degree of ACAT inhibition produced was up to 95%.
.:
.: , - . .. : . . .:
'' .':
:, ......... .
., . . . : :- . . .... -W092/0~8 -PCT/G~91~01376 , 1 ' ~5)'~391~
Compounds of formula I can be prepared by the i application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
According to a feature of the present invention~ i .
compounds of general formula I are prepared by the reaction of a compound of general formula II ~:
hereinafter depicted, wherein R2, R3 and R4 are as hereinbefore defined, with a compound of general formula III, hereinafter depicted, wherein Rl and X
are as hereinbefore defined and zl represents a halogen, e.g. chlorine, atom.
The reaction may be performed in the presence of a suitable base, such as a tertiary amine, and may be :
carried out in a suitable solvent, e.g. dichloro-methane, optionally with heating.
According to a further feature of the invention, compounds of formula I are prepared by reacting a compound of general formula:
R40H (IV) wherein R4 is as hereinbefore defined, with a compound of formula V, hereinafter depicted, wherein Rl, R2, R3 and Xl are as hereinbefore defined and z2 represents a halogen, e.g. chlorine, atom or a hydroxy group.
b~.. . -' ' ' ' , . `
,, `,' ' ' .'` ~' ' ' . '` '' ~ ... : .. '.. ....
`
'' ` . ~ -: ,`" , , :
'`, , ` ` ~ ' : ` `
.
~ ~ . .. ' ' .
W092/03408 PCT/GB91/013~
!) 1 6 ~
When z2 represents a halogen atom the reaction may be performed in the presence of a suitable base, such as a tertiary amine.
When z2 represents a hydroxy group the reaction is preferably performed in the presence of a condensing agent, such as dicyclohexylcarbodiimide, or a catalytic quantity of an inorganic acid, e.g. hydrochloric acid, optionally prepared n situ.
In each instance the reaction may be carried out in a suitable solvent, e.g. dichloromethane, optionally with heating.
According to a further feature of the invention, compounds of general formula I are prepared by the interconversion of other compounds of formula I. For example, compounds wherein R2 represents a straight- or branched-chain alkyl group containing from l to 4 carbon atoms may be prepared from compounds of formula I wherein R2 represents a hydrogen atom by alkylation by the application or adaptation of known methods.
Compounds of formulae II, III, IV and V may be prepared by the application or adaptation of known methods.
For example, (i) acid halides of formula V
wherein z2 represents a halogen atom may be prepared from the corresponding carboxylic acids of formula V
wherein z2 represents a hydroxy group by known methods, :'` ` ` , . .
.: . ~ , : :
W092/0~08 PCT~GB91/01376 ' ~0~166 e.g., when z2 represents a chlorine atom, by reaction with thionyl chloride;
(ii) the corresponding carboxylic acids of formula V
wherein z2 represents a hydroxy group may be prepared from compounds of formula I by hydrolysis of the ester grouping -CooR4 by known methods, for example by reaction with alkali, e.g. aqueous sodium hydroxide solution, followed by neutralisation by treatment with mineral acid, e.g. dilute hydrochloric acid.
' ' , .' ' : , .
' . ' , ' ' ' . ~' ' ~ ' ' ' , - -, ~ '. ' '" ' ' ' ' ` - : ' ' , ' '.
" ' ' ' ' :, .~' , .' "
WO92/03408 : PCI/GB91/01376 6~ f~
_ 8 _ CoOR4 R1X 1 ~ CONR2 ~
CoOR4 HR2N ~
RlXl~\ CoZl III
,:
coz2 RlXl ~CONR2~ V
.
WD ~/~8 PCT/GU~If~l~7~
~U~16~
g The following Examples illustrate the preparation of the compounds according to the invention and the Reference Example illustrates the preparation of the intermediates.
Com~ounds A. D. E. F. I and J
A stirred solution of methyl 3-amino-4-methoxy- -benzoate (5.49g) and triethylamine (4.55g) in dichloro-methane (120ml) was treated with 4-decyloxybenzoyl chloride (9.Og; prepared from 4-decyloxybenzoic acid and thionyl chloride) and the mixture was stirred for 2 hours. The reaction mixture was then poured into water, the organic layer was separated and washed with hydrochloric acid (50ml; lN), with aqueous sodium hydroxide solution (50ml; lN), and with water (lOOml), and then it was dried over magnesium sulphate. The solution was concentrated under reduced pressure, to give an oil that solidified on standing. The solid was recrystallised from methanol, to give methyl 3-(4-decyloxybenzamido)-4-methoxybenzoate (3.2g), in the form of colourless needles, m.p. 84-85C.
[Elemental analysis:- C,70.9;H,8.2;N,3.03%;
calculated:- C,70.72;H,7.99;N,3.17%].
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of methyl 3-amino-4-chlorobenzoate, and .
. . .
, .
. .
W092/0~8 PCT/G~1/01376 ~,~ t `2~89166 working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous acetone and then from toluene, there was prepared methyl 4-chloro-3-(4-decyloxybenzamido)benzoate, in the form of colourless crystals, m.p. 106-107C.
[Elemental analysis:- C,67.5;H,7.3;N,2.93;C1,8.0%;
calculated:- C,67.32;H,7.23;N,3.13;Cl,7.95%~.
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of methyl 3-amino-4-fluorobenzoate, stirring at the ambient temperature for 2 hours, heating at reflux for 1 hour and working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous acetone and then from toluene, there was prepared methyl 3-(4-decyloxybenzamido)-4-fluorobenzoate, in the form of colourless crystals, m.p. 105-106C. [Elemental analysis:- C,69.5;H,7.6;
N,3.13;F,4.47%; calculated:- C,69.90;H,7.51;N,3.26;
F,4.42%].
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of methyl 3-amino-4-(methylthio)benzoate, there was prepared methyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate in the form of a cream powder, m.p. 97-99C. [Elemental analysis:- C,67.9;H,7.63;
N,2.9;S,7.1%; calculated:- C,68.27;~,7.66;N,3.07;
,. . : ., - . ~
.
WQ92/0~8 PCT/CB91/01376 ~ ., ~0~91~S
S,7.00%]-By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of ethyl 3-amino-4-(ethylthio)benzoate and working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous ethanol, there was prepared ethyl 3-(4-decyloxy-benzamido)-4-(ethylthio)benzoate in the form of white crystals, m.p. 91-93C. [Elemental analysis:-C,69.4;H,8.09;N,2.85;S,6.3%; calculated:- C,69.24;
H,8.09;N,2.88;S,6.60%].
By proceeding in a similar manner, but replacing the methyl 3-amino-4-methoxybenzoate by the appropriate quantity of ethyl 3-amino-4-ethoxybenzoate and working-up the reaction by concentrating under reduced pressure and crystallising the residue from aqueous ethanol, there was prepared ethyl 3-(4-decyloxybenzamido)-4-ethoxybenzoate, in the form of white crystals; m.p.
89-91C. [Elemental analysis:- C,71.3;H,8.3;N,2.9~;
calculated:- C,71.61;H,8.37;N,2.98%~.
Compound B
Ice-cold 3-methylbutan-1-ol (5ml) was treated with acetyl chloride (0.8ml) followed, after 10 minutes, by 3-(4-decyloxybenzamido)-4-methoxybenzoic acid (2.0g). The suspension was warmed on a steam "
,' `' `
W092/0~8 PCT/G~9l/013 ~
~9 16~
- 12 - t bath for 3 hours and then the mixture was partitioned between water (50ml) and dichloromethane (50ml). The organic solution was dried and concentrated under reduced pressure to give a white solid, which was chromatographed on silica gel, eluting with dichloro methane, and recrystallised from methanol, to give 3-methylbutyl 3-(4-decyloxybenzamido)-4-methoxybenzoate (0.97g), in the form of colourless needles, m.p.
66-680C. [Elemental analysis:- C,71.9;H,8.8;N,2.6%;
calculated:- C,72.43;H,8.65;N,2.32~].
Compounds C G and H
A mixture of 3-(4-decyloxybenzamido)-4-methoxy-benzoyl chloride [2.22g; prepared from 3-(4-decyloxy-benzamido)-4-methoxybenzoic acid and thionyl chloride in dichloromethane], 3-methylbut-2-en-1-ol (2.58g) and triethylamine (3ml) in toluene (lOOml) was heated at 100C for 3 hours. The mixture was cooled and then treated with water (50ml), diethyl ether (30ml) and hydrochloric acid (5ml;2N), and the organic layer was removed and dried. Concentration under reduced pressure left an oil which solidified on standing. The solid was chromatographed on silica gel, eluting with dichloromethane, and recrystallised from methanol, to give 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-' ~
W092/0~08 PCT/GB91/01376 ~916~
methoxybenzoate (1.66g), in the form of a colourless solid, m.p. 60-62C. [Elemental analysis:- C,72.6;
H,8.4;N,2.8q%; calculated:- C,72.69;H,8.34;N,2.83%].
By proceeding in a similar manner, but replacing the 3-(4-decyloxybenzamido)-4-methoxybenzoic acid by the appropriate quantity of 3-(4-decyloxybenzamido)-4-(methylthio)benzoic acid and purifying the crude product by crystallisation from ethanol, instead of chromatography, there was prepared 3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate in the form of a white solid, m.p. 107-109DC. [Elemental analysis:- c~7o.3;H~8.l;N~2.64;s~6.s%; calculated:-C,70.42;H,8.07;N,2.74;S,6.26%~.
By proceeding in a similar manner, but replacing the 3-methylbut-2-en-1-ol by the appropriate quantity of butan-l-ol and purifying the crude product by crystallisation from aqueous ethanol instead of chromatography, there was prepared butyl 3-(4-decyl-oxybenzamido)-4-(methylthio)benzoate, in the form of a cream-coloured powder, m.p. 89-91C. [Elemental analysis:- C,70.1;H,8.5;N,2.71;S,6.5%; calculated:-C,69.70;H,8.27;N,2.80;S,6.42%].
ComDounds K and L
3-Methylbut-3-en-1-ol (2.Oml) was treated with a solution of 3-(4-decyloxybenzamido)-4-(methylthio)-W092/~8 ~ PCr/GB91/01376 ~.
~3~ 6 ~ - 14 -benzoyl chloride (2.31g) in toluene (20ml) [prepared from 3-(4-decyloxybenzamido)-4-(methylthio)benzoic acid and thionyl chloride in toluene], and the mixture was stirred vigorously. It was then treated with triethylamine (lml) and the mixture was left to stand at the ambient temperature for 18 hours. The mixture was then diluted with dichloromethane (lOOml) and washed with water (lOOml), dried over magnesium sulphate and concentrated under reduced pressure.
The resulting residue was chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol, and recrystallised from diethyl ether, to give 3-methylbut-3-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate (0.45g), in the form of a colourless solid, m.p. 91-93C. [Elemental analysis:- C,70.4;H,8.1;N,2.63;S,6.32~; calculated:-C,70.42;H,8.07;N,2.74jS,6.26%].
By proceeding in a similar manner, but replacing the 3-methyl-but-3-en-1-ol by the appropriate quantity of 2-methoxyethanol and omitting the aqueous wash stage, there was prepared 2-methoxyethyl 3-(4-decyloxy-benzamido)-4-(methylthio)benzoate, in the form of a colourless solid, m.p. 88-90C. ~Elemental analysis:- C,67.3;H,7.8;N,2.76;S,6.56%; calculated:-C,67.03;H,7.84;N,2.79;S,6.39%~.
.
- , - -. : -: . . :::.
~ .
W092/0~8 PCT/GB91/01376 f-,' .
~U8~
Compound M
By proceeding in a manner similar to that described hereinbefore in Example 1, but replacing the ¦ -methyl 3-amino-4-methoxybenzoate by the appropriate ¦
quantity of methyl 3-amino-4-dimethylaminobenzoate and omitting the acid and base washes from the work-up, there was prepared methyl 3-(4-decyloxybenzamido)-4-dimethylaminobenzoate in the form of a white solid, m.p. 77-78C (recrystallised from a mixture of ethyl acetate and petrol [Elemental analysis:- C,71.7jH,8.5;
N,6.1%; calculated:- C,71.34;H,8.42;N,6.16%].
..
~, .: : . . . :
.: .
: . ~
W0 92/03408 Pcl`/GB9~ 37~
~a~l6~
A mixture of methyl 3-(4-decyloxybenzamido)-4~
methoxybenzoate (3.31g) and aqueous sodium hydroxide solution (lOml;2N) in ethanol (lOOml) was heated at reflux for 2 hours. The mixture was concentrated under reduced pressure, then diluted with water (150ml) and washed with dichloromethane (50ml). The aqueous fraction was acidified to pH1 by treatment with dilute hydrochloric acid, and extracted with dichloromethane (2x50ml). This extract was dried and concentrated under reduced pressure, and the resulting solid was recrystallised from methanol, to give 3-(4-decyloxy-benzamido)-4-methoxybenzoic acid (l.Sg), in the form of a colourless solid, m.p. 194-196C. [Elemental analysis:- C,69.7;H,7.6;N,3.0%; calculated:- C,70023;
H,7.78;N,3.28%].
The present invention also includes within its scope pharmaceutical formulations which comprise-at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.
In clinical practice the compounds of the present invention may be administe~ed parenterally, rectally or orally.
Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of - : , :, . ,:, .
, - , , :
, . ~ , , - . . . ~: .
- , ..
W092t0~8 PCT/GB91~0~76 2~91~6 the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactoseO
The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesi~m stearate.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may ,.
., , ~ : . .
W092/0~8 PCT/GB91/01376 ~ o ~ 18 -also contain adjuvants such as stabilisi~g, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined - by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.5 to about 70, preferably about l to about l0, mg/kg body weight per day by oral administration.
. . . , : : - : :
. :. . . ~ ~ : :
: ~ ,: .. :. . : : , ~ . .
W092/0~08 PCT/GB91/01376 ~V891~
The following Example illustrates pharmaceutical compositions according to the present invention.
No. 2 size gelatin capsules each containing:-3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate 20 mg lactose l00 mg starch 60 mg dextrin 40 mg magnesium stearate l mg were prepared in accordance with the usual procedure.
- ::: - . : . : : : : ..
. . . . . : .
: :: . , . . ~- , ": ~ , .
. .. . :, . , :, . ~ :
Claims
I
wherein R1 represents a straight- or branched-chain alkyl group containing from 4 to 20 carbon atoms, optionally interrupted by one or more hetero atoms, X1 represents an oxygen or sulphur atom or a group -NR5- wherein R5 represents a hydrogen atom or a straight- or branched-chain alkyl or alkanoyl group containing up to about 5 carbon atoms, optionally substituted by one or more halogen atoms, R2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, R3 represents a straight- or branched-chain alkyl, alkoxy or alkylthio group containing from 1 to 4 carbon atoms or a dimethylamino group or a 5- to 8-membered heterocyclo group containing at least one nitrogen atom and linked via that nitrogen atom to the rest of the molecule, or a halogen atom, and R4 represents a straight- or branched-chain alkyl group containing up to 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds, and optionally interrupted by one or more hetero atoms.
2. A compound according to claim 1 wherein R1 represents an alkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl group containing from 4 to 20 carbon atoms, the heterocyclo group represented by R3 is an imidazol-1-yl or pyrrolidin-1-yl group; R4 represents an alkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl group containing up to about 10 carbon atoms; and wherein halogen atoms are fluorine or chlorine.
3. A compound according to claim 1 wherein at least one of the symbols has a value selected from the following:
(i) R1 represents an alkyl group containing from 8 to 12 carbon atoms;
(ii) X1 represents an oxygen atom;
(iii) R2 represents a hydrogen atom;
(iv) R3 represents an alkoxy or alkylthio group containing 1 or 2 carbon atoms, a dimethylamino group or a halogen atom; and/or (v) R4 represents a straight- or branched-chain alkyl group containing up to 5 carbon atoms, optionally containing a carbon-carbon double bond or interrupted by an oxygen atom;
the other symbols being as hereinbefore defined.
4. A compound according to any one of the preceding claims wherein R1 represents an alkyl group containing 10 carbon atoms.
5. A compound according to claim 1 which is:
methyl 3-(4-decyloxybenzamido)-4-methoxy-benzoate;
3-methylbutyl 3-(4-decyloxybenzamido)-4-methoxybenzoate:
3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-methoxybenzoate;
methyl 4-chloro-3-(4-decyloxybenzamido)benzoate;
methyl 3-(4-decyloxybenzamido)-4-fluorobenzoate;
methyl 3-(4-decyloxybenzamido)-4-(methylthio)-benzoate;
3-methylbut-2-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate;
butyl 3-(4-decyloxybenzamido)-4-(methylthio) benzoate;
ethyl 3-(4-decyloxybenzamido)-4-(ethylthio)-benzoate:
ethyl 3-(4-decyloxybenzamido)-4-ethoxybenzoate;
3-methylbut-3-enyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate;
2-methoxyethyl 3-(4-decyloxybenzamido)-4-(methylthio)benzoate; or methyl 3-(4-decyloxybenzamido)-4-dimethylamino-benzoate.
6. A process for the preparation of a benzanilide derivative according to claim 1 which comprises:
(A) the reaction of a compound of the general formula:
II
wherein R2, R3 and R4 are as defined in claim 1, with a compound of the general formula :
III
wherein R1 and X1 are as defined in claim 1 and Z1 represents a halogen atom;
(B) the reaction of a compound of the general formula:
wherein R4 is as defined in claim 1 with a compound of the general formula :
V
wherein R1, R2, R3 and X1 are as defined in claim 1 and Z2 represents a halogen atom or a hydroxy group;
optionally followed by the conversion of a compound of general formula (I) into another compound of general formula (I).
7. A pharmaceutical composition which comprises a benzanilide derivative according to claim 1 in association with a pharmaceutically acceptable carrier or coating.
8. A pharmaceutical composition useful in the treatment of a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase which comprises a benzanilide derivative according to claim 1 in association with a pharmaceutically acceptable carrier or coating.
9. A method for the treatment of a condition which can be ameliorated by an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase which comprises the administration of a benzanilide derivative according to
claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909017710A GB9017710D0 (en) | 1990-08-13 | 1990-08-13 | New compositions of matter |
| GB9017710.6 | 1990-08-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2089166A1 true CA2089166A1 (en) | 1992-02-14 |
Family
ID=10680575
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002089166A Abandoned CA2089166A1 (en) | 1990-08-13 | 1991-08-13 | Benzanilide derivatives and their use as anti-antherosclerotic agents |
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| Country | Link |
|---|---|
| EP (1) | EP0543884A1 (en) |
| JP (1) | JPH06500083A (en) |
| AU (1) | AU8337891A (en) |
| CA (1) | CA2089166A1 (en) |
| GB (1) | GB9017710D0 (en) |
| IE (1) | IE912849A1 (en) |
| IL (1) | IL99160A0 (en) |
| PT (1) | PT98665A (en) |
| WO (1) | WO1992003408A1 (en) |
| ZA (1) | ZA916339B (en) |
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| JP2894445B2 (en) * | 1997-02-12 | 1999-05-24 | 日本たばこ産業株式会社 | Compounds effective as CETP activity inhibitors |
| EP1603554A1 (en) | 2003-03-17 | 2005-12-14 | Japan Tobacco Inc. | Method for increasing the oral bioavailability of s-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU79008A1 (en) * | 1978-02-03 | 1979-09-06 | Byk Gulden Lomberg Chem Fab | W- (N-ALKYL-N-BENZOYL-AMINO) -PHENYLALCANIC ACIDS, THEIR USE AND MANUFACTURING AND MEDICINAL PRODUCTS |
| IT1196348B (en) * | 1984-11-29 | 1988-11-16 | Italfarmaco Spa | COMPOUNDS WITH ANTI-INFLAMMATORY ACTIVITY |
| LU86258A1 (en) * | 1986-01-21 | 1987-09-03 | Rech Dermatologiques C I R D S | BENZAMIDO AROMATIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN OR VETERINARY MEDICINE AND IN COSMETICS |
| US4882357A (en) * | 1988-07-15 | 1989-11-21 | Warner-Lambert Company | Novel N-(substituted-phenyl)-5-(substituted-2,5-dimethylphenoxy)-2,2-dimethylpentanamides |
| GB8921792D0 (en) * | 1989-09-27 | 1989-11-08 | May & Baker Ltd | New compositions of matter |
-
1990
- 1990-08-13 GB GB909017710A patent/GB9017710D0/en active Pending
-
1991
- 1991-08-12 IL IL99160A patent/IL99160A0/en unknown
- 1991-08-12 IE IE284991A patent/IE912849A1/en unknown
- 1991-08-12 ZA ZA916339A patent/ZA916339B/en unknown
- 1991-08-13 EP EP91914772A patent/EP0543884A1/en not_active Ceased
- 1991-08-13 PT PT98665A patent/PT98665A/en not_active Application Discontinuation
- 1991-08-13 AU AU83378/91A patent/AU8337891A/en not_active Abandoned
- 1991-08-13 WO PCT/GB1991/001376 patent/WO1992003408A1/en not_active Application Discontinuation
- 1991-08-13 JP JP3513601A patent/JPH06500083A/en active Pending
- 1991-08-13 CA CA002089166A patent/CA2089166A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0543884A1 (en) | 1993-06-02 |
| AU8337891A (en) | 1992-03-17 |
| PT98665A (en) | 1992-06-30 |
| IL99160A0 (en) | 1992-07-15 |
| GB9017710D0 (en) | 1990-09-26 |
| JPH06500083A (en) | 1994-01-06 |
| IE912849A1 (en) | 1992-02-26 |
| ZA916339B (en) | 1992-05-27 |
| WO1992003408A1 (en) | 1992-03-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |