CA2089165A1 - Diphenylurea derivatives - Google Patents
Diphenylurea derivativesInfo
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- CA2089165A1 CA2089165A1 CA002089165A CA2089165A CA2089165A1 CA 2089165 A1 CA2089165 A1 CA 2089165A1 CA 002089165 A CA002089165 A CA 002089165A CA 2089165 A CA2089165 A CA 2089165A CA 2089165 A1 CA2089165 A1 CA 2089165A1
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- urea
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
-
- 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
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- 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
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- 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
- C07C323/23—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/42—Y being a carbon atom of a six-membered aromatic ring
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- 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
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Diphenylurea derivatives of formula (I), wherein R1 represents alkyl, X1 represents oxygen, -OCH2- or -S(O)n-, wherein n is zero, 1 or 2, R2 and R3 each represents hydrogen, methyl or ethyl, R4 represents alkyl, dimethylamino, -OR6 or -S(O)mR6, wherein m is zero, 1 or 2 and R6 represents alkyl optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, and R5 represents -NR7R8 or -OR9, wherein R7 and R8 each represents hydrogen or alkyl optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, and R9 represents alkyl optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms possess useful pharmacological properties.
Description
WO92/0~13 . PCT/GB91/01383 & ~
"DIPHENYLUREA DERIVATIVES"
This invention relates to new, therapeutically useful diphenylurea derivatives, to a process for their production and to pharmaceutical compositions containing them, and methods for their use.
The new diphenylurea derivatives of the present invention are the compounds of formula I, hereinafter depicted, wherein R1 represents a straight- or branched-chain alkyl group containing from about 4 to about 18 carbon atoms, X1 represents an oxygen atom, or a group of the formula -OCH2- or ~S(O)n~, wherein n represents zero, 1 or 2, R and R may be the same or different and each represents a hydrogen atom or a methyl or ethyl group, R4 represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, a dimethylamino group or a group of the formula -OR or -S(O)mR , wherein m represents zero, 1 or 2 and R6 represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkenyl, alkoxyalkyl, alkylthioaIkyl, alkyla~x~kyl or dialkylamiYY~Xyl group containing up to about 6 carbon atoms, and R5 represents a group of the formula -NR7R8 or -OR9, , . :
.:
- . :
W092/0~13 PCT/GB91iO~383 ~ 2 -wherein R7 and R8 may be the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms~
preferably an alkyl, alkenyl, alkoxyalkyl, alkylthioaIkyl, aLkylam~Y~Xyl or dialkyl~mu~YIXyl gn containing up to about 6 carbon atoms, and R9 represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero ato~s, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl or dialkylaminoalkyl group containing up to about 6 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-containing . . , - ~ ,: : . .
'~ , ' ` , . ':
WO92/0~13 PCT/~ 3 ~8916~
from 8 to l2, e.g. 9, lO or ll, carbon atoms; -((i) Xl represents an oxygen atom;
(iii) R2 and R3 each represents a hydrogen atom;
(iv) R4 represents an alkyl, alkoxy or alkylthio grvup containing l or 2, preferably l, carbon atoms;
(v) R7 represents a hydrogen atom;
(vi) R8 represents a straight- or branched-chain alkyl group containing up to 5, preferably 3 or 4 carbon atoms, optionally interrupted by an oxygen or sulphur atom, preferably an alkyl, alkoxyalkyl or alkylthioalkyl group containing u~ to 5, preferably 3 or 4 carbon atoms; and/or (vii) R represents an alkyl group containing up to 3 carbon atoms, e.g. a methyl group;
the other symbols being as hereinbefore defined.
Important compounds according to the invention include:-A N-(4-decyloxyphenyl~-N'-t2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl~urea;
B N-(4-decyloxyphenyl)-N'-(2-methoxy-5-methoxy-carbonylphenyl)urea;
C N-(4-decyloxyphenyl)-N'-t2-methoxy-5-(2-methoxy-ethylcarbamoyl)phenyl]urea;
, . . . . .
, .'. ~ ,. ''' ' ' .
,. . . : :
.
-. . .
.
.
W092/0~13 PCT/GB91/01~3 1 6 ~ 4 _ D N-(4-decyloxyphenyl)-N'-[2-methoxy-5-(2-methyl-thioethylcarbamoyl)phenyl]urea;
E N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4- .
decyloxyphenyl)urea;
F N-(5-N-butylcarbamoyl-2-methylthiophenyl)-N'-(4-decyloxyphenyl)urea;
G N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-undecyloxyphenyl)urea;
H N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-nonyloxyphenyl)urea;
I N-(5-methoxycarbonyl-2-methylthiophenyl)-N'-(4-nonyloxyphenyl)urea;
J N-[2-methylthio-5-(2-methylthioethylcarbamoyl)-phenyl]-N'-(4-nonyloxyphenyl)urea;
K N-t2-methylthio-5-(2-methylthioethylcarbamoyl)-phenyl]-N'-(4-undecyloxyphenyl)urea; and L N-(5-N-butylcarbamoyl-2-methylphenyl)-N~-(4-undecyloxyphenyl)urea.
The letters A to L are allocated to compounds for easy reference later in this specification.
The compounds according to the invention are 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, .. . . . ~ , . . . . ........................ ~
~, . .: , ~ ~ . -. .
WO92/03413 PCT/G~91/01383 ~: ' _ 5 _ ~0~-16~
c:holesterol ester storage disease and atheroma in vein grafts.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following n 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 9~$.
Compounds of formula I can be prepared by the 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, - compounds of general formula I wherein R2 represents a hydrogen atom, Rl, R3, R4, R5 and Xl being as hereinbefore defined, are prepared by the reaction of a compound of general formula II hereinafter depicted, wherein R3, R4 and R5 are as hereinbefore defined, with a compound of general formula III, hereinafter .. ~ ~ .' ' . ' , ': ' ' . : ' ~ .
WO92/0~13 PCT~GB~ 83 ~?,!
., ,A .
depicted, wherein R1 and X1 are as hereinbefore defined, optionally prepared in ~i~, by the application or adaptation of known methods.
The reaction between the compound of formula II
and the compound of formula III preferably takes place in a suitable solvent, for example dichloromethane, toluene, or a mixture thereof. The reaction preferably takes place at an elevated temperature, for example at or near 100C.
Preparation of the intermediate of formula III
in situ can be carried out by the reaction of a compound such as bis(trichloromethyl) carbonate with a compound of the general formula IV, hereinafter depicted, wherein R1 and X1 are as hereinbefore defined. The reaction is preferably carried out in a solvent such as toluene, in the presence of a tertiary amine, e.g. triethylamine, preferably at an elevated temperature.
According to a further feature of the invention, compounds of formula I are prepared by reacting a compound of general formula:
R OH (V~
wherein R9 is as hereinbefore defined, or a compound of general formula:
HNR7R8 (VI) . .
. ' ' ~ : .
WO92/0~13 PCT/GB~
~; .-, - 7 - ~u o~ ~ ~3 wherein R7 and R8 are as hereinbefore defined, with a compound of formula VII, hereinafter depicted, wherein R , R , R , R4 and Xl are as hereinbefore defined and zl represents a halogen, e.g. chlorine, atom, preferably in the presence of a base, such as a tertiary amine and optionally in a solvent, e.g.
toluene, optionally with heating.
According to a further feature of the invention, compounds of formula I wherein at least one of m and n is zero may be converted into a compound of formula I wherein m and/or n is greater than in the starting material, the other symbols being as hereinbefore defined, by oxidation using a conventional oxidant, such as a percarboxylic acid (e.g. m-chloroperbenzoic acid), in an inert solvent, such as dichloromethane, at or below room temperature.
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 of formula I wherein R2 and/or R3 and/or R7 and/or R8 is other than a hydrogen atom may be prepared from compounds of formula I wherein R2 and/or R3 and/or R7 and/or R8 represents a hydrogen atom by the application or adaptation of known methods of alkylation.
` :' . . . ':
W O 92/03413 PC~r/GB91/01383 6 S ;~
Compounds of formulae II, III, IV, V, VI and VII
may be prepared by the application or adaptation of known methods. , ?
'., ; ~ ' ' -. ~ ' ", ' '. :
.` : ~ ` . `:, : `. : :: . - . . i .
.: . .- . ` ` .. . : ` . ` ~
.. `-"' . ` ' . . , ~ , . ~
: . , . , ., ` ,. . ` ,,. ~` .
WO 92/03413 PCI`/GB91/01383 ~'.` I
9 ~ 9 1 ~ J
COR
RlXl~ -N J~N~
coR5 HR3N~
R X ~3--NCO III
. . . - ' :
R Xl~ N~2 IV
R X ~3_ N~ l~OZ
','': . . . '': , ~ ' , . ' ,;
.~ .. . . . .
:' . ' ~
W092/0~13 PCT~GB9~rR~ 3 ..,.
1 6 5 - lo -The following Examples illustrate the preparation of the compounds according to the invention and the Reference Example illustrates the preparation of the intermediates.
Compounds A and B
A stirred solution of bis(trichloromethyl) carbonate (0.49g) in toluene (lOOml) was treated with a suspension of 4-decyloxyaniline (1.24g) and triethyl-amine (0.7ml) in toluene (150ml) at the ambient temperature under an inert atmosphere. The mixture was stirred for 30 minutes and then was heated at lOO~C for 2 hours. The mixture was then cooled and evaporated, and the resulting residue was dissolved in dichloromethane (200ml). This solution was treated with 3-amino-4-methylthio-N-(2-methylthioethyl)-benzamide (l.lg) and the mixture was heated at reflux `
for 1 hour. The mixture was then allowed to stand at the ambient temperature for 18 hours, and then it was washed with water (lOOml), dried over magnesium sulphate, and concentrated under reduced pressure to a volume of about 50ml when a solid separated. This solid was filtered off and recrys~allised from ethanol, to give N-(4-decyloxyphenyl)-N'-[2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl]urea (1.3g) in the form of small colourless needles, m.p. 126-128C.
, :`
' ' ' ' ' ' :. , - - . . ' W092/0.~413 PCI/G~g~ 3~ !
!`:` . I
8916~ .
Elemental analysis:- C,63.5j~,7.9;N,8.10;S,12.00%;
calculated:- C,63.24;H,7.77;N,7.90;S,12.06%;~.
By proceeding in a similar manner, but using methyl 3-amino-4-methoxybenzoate in place of the 3-amino-4-methylthio-N-(2-methylthioethyl)benzamide, there was prepared N-(4-decyloxyphenyl)-N'-(2-methoXy~
5-methoxycarbonylphenyl)urea in the form of colourless crystals, m.p. 115-116C. [Elemental analysis:-C,68.50;H,8.1;N,5.98~; caloulated:- C,68.39;H,7.95 N,6.13~].
Compounds C. D and E
A mixture of N-(5-carboxy-2-methoxyphenyl)-N'-(4-decyloxyphenyl)urea (1.55g; prepared as described in Reference Example 1) and thionyl chloride (0.27ml) in toluene (60ml) was heated at reflux for 30 minutesO
The mixture was then chilled and added dropwise, with cooling, to a stirred solution of 2-methoxyethylamine (0.8g) in toluene (20ml). The mixture was allowed to stand at the ambient temperature for 18 hours, and then it was evaporated and the resulting residue was extracted with hot dichloromethane (3x50ml). The extract was evaporated and the residue was recrystall-ised from acetone, to give N-(4-decyloxyphenyl)-N'-:... :. .. . ...
, . .
W092/0~13 PCT~GB9l/013~
~8'~ 16~
[2-methoxy-5-(2-methoxyethylcarbamoyl)phenyl]urea (0.75g) in the form of a colourless powder, m.p.
126-128C. tElemental analysis:- C,67.70;H,8.4;
N,8.50%; calculated:- C,67.31;H,8.27;N,8.41%].
~ y proceeding in a similar manner, but using the appropriate quantities of 2-methylthioethylamine and butylamine in place of the 2-methoxyethylamine, there were prepared:-N-(4-decyloxyphenyl)-N'-t2-methoxy-5-(2-methylthio-ethylcarbamoyl)phenyl]urea in the form of colourless crystals, m.p. 105-107C (from methanol) [Elemental analysis:- C,65.20;H,8.00;N,8.2;S,6.10%; calculated:-C,65.21;H,8.01;N,8.15;S,6.22%]; and N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-decyloxy-phenyl)urea, in the form of off-white crystals, m.p.
62-63C [purification by mplc on silica gel, eluting with a mixture of diethyl ether and methanol (l9:lv/v)]
[Elemental analysis:- C,69.80;H,8.80;N,8.40%;
calculated:- C,69.99;H,8.71;N,8.44%]. - -EXAMP~E 3 Compound F
A stirred solution of bis(trichloromethyl) carbonate (0.49g) in toluene (lOOml) was treated with a suspension of 4-decyloxyaniline (1.24g) and triethylamine (0.7ml) in toluene (150ml) at the ambient temperature under an inert atmosphere and stirred for ,~.~ . . . . . .
.
: . . . . . ..
.
:: . -~ . : - :
. . : , :. :-- :
. .
. .
W092/0~13 PCT/CB91/01383 ~ ~. 8 ~ i J
30 minutes. The mixture was heated at 100C for 5 hours. The mixture was treated with 3-amino-N-butyl-4-(methylthio)benzamide (1.19g) and stirring was continued at 100C for a further period of 2 hours.
The mixture was allowed to stand at the ambient temperature for 18 hours, and then it was diluted with dichloromethane (500ml), washed with hydrochloric acid (2xlOOml;2N~, dried over magnesium sulphate, and then evaporated. The resulting residue was dissolved in a hot mixture of ethyl acetate and ethanol (150ml;1:1v/v).
Upon cooling, a solid separated out and was discarded.
The remaining filtrate was concentrated under reduced pressure to a volume of about 50ml, when a second solid separated. This second solid was recrystallised from ethanol, to qive N-(5-N-butylcarbamoyl-2-methylthio-phenyl)-N'-(4-decyloxyphenyl)urea-(0.65g), in the form of a colourless solid, m.p. 110-112C. [Elemental analysis:- C,67.60;~,8.5;N,7.90%; calculated:- C,67.80;
H,8.44;N,8.18%].
ComDounds G. H I J. K and L
A stirred solution of bis(trichloromethyl) carbonate (0.99g) in toluene (200ml) was treated with 4-undecyloxyaniline (2.63g) at the ambient temperature under an inert atmosphere. The suspension was then treated with triethylamine (2.79ml), resulting in a , .
: - .
W~92/0~13 PCT/GB91/~3~
6~ 14 -thick slurry. It was then heated at 100C 2 hours, with vigorous stirring. The suspension was then filtered and the filtrate was treated with 3-amino-N~
butyl-4-(methoxy)benzamide (2.24g). This mixture was then stirred at 100C for 2 hours, allowed to stand at the ambient temperature for 18 hours, and then evaporated. The resulting residue was dissolved in ethyl acetate (300ml) and the solution was washed with hydrochloric acid (2xlOOml;4N). The organic solution was dried over magnesium sulphate and treated with activated charcoal. After filtration, the colourless solution was evaporated and the residue recrystallised from aqueous ethanol, to give N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-undecyloxyphenyl)urea (3.2g) in the form of a colourless solid, m.p. 84-86C.
tElemental analysis:- C,68.30;H,8.80;N,8.00;H20,306%~
calculated for C30H45N304:H20 H20,3-4%]-By proceeding in a similar manner, but using theappropriate quantities of the corresponding aniline derivatives, there were prepared:-N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-nonyloxy-phenyl)urea in the form of a colourless solid, m.p.
171-172C (from ethyl acetate) lElemental analysis:-C,71.80;H,8.90;N,8.80%; calculated:- C,71.91;H,8.84;
N,8.99%];
' ~ .
., ' ~ - ~ . ' ' :
: . .
.~ : .. .
WO92/0~13 PCT/GB91~3 (. ~
~8916~ !
N-(5-methoxycarbonyl-2-methylthiophenyl)-N'-(4-nonyl-oxyphenyl)urea in the form of tiny colourless needles~
m.p. 155-157C (from ethanol) tElemental analysis~
C,65.10;H,7.50;N,5.80%; calculated:- C,65.47;H,7~47 N,6.11%~;
N-t2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl]~
N'-(4-nonyloxyphenyl)urea in the form of a colourless solid, m.p. 120-123C (from ethyl acetate) tElemental analysis:- C,62.40;H,7.80;N,7.70%; calculated:-C,62.63;H,7.59;N,8.12%];
N-t2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl~- -N'-(4-undecyloxyphenyl)urea in the form of a colourless solid, m.p. 130-131C (from ethanol) tElemental analysis:- C,64.1;H,8.2;N,7.4~; calculated:- C,63.82;
H,7.94;N,7.70%]; and N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-undecyl oxyphenyl)urea in the form of a colourless solid, m.p.
159-164C (from ethyl acetate) tElemental analysis:-C,72.25;H,9.2;N,8.3~; calculated:- C,72.69;H,9.15;
N,8.48~].
A suspension of N-(4-decyloxyphenyl)-N'-(2-methoxy-5-methoxycarbonylphenyl)urea (10.67g) and sodium hydroxide (1.02g) in a mixture of ethanol (250ml) and water (25ml) was heated at reflux for 90 minutes. The mixture was then cooled, acidified by : , - , . ~
:
., : , ' , ' ~ :
. ~ . .
, WO92/0~13 PCT/GB91/013~ .
~0~)16~ --treatment with hydrochloric acid (2N) and diluted with water (50ml). The solid which separated was recrystallised from a mixture of tetrahydrofuran and dimethylformamide, to give N-(5-carboxy-2-methoxy-phenyl)-N'-(4-decyloxyphenyl)urea in the form of colourless crystals, m.p. 261-263C.
:, ~ . . : , .- .. -. . . . . . . . . . ..
': . .. . . . ~ ' :
, , ~.
,; . .. . ..
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WO9~/03413 PCT/GB9l/013~
'~, ~V8Yl~
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 administered parenterally, rectally or orally.
Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium 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 ~0~2/~13 PCT/GB9~0138~ ¦
'~``''''''`` ! ' ~3~16~ - 18 -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 also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositlons of sterilising agents, by irradiation or by heating. They may also be manufactured in the for~
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 .
.. . : . :
W092/0~13 PCT/GB9~ 3 ( -~ D~91 ~
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 1 to about 10, mg/kg body weight per day by oral administration.
The following Example illustrates pharmaceutical compositions according to the present invention.
No. 2 size gelatin capsules each containing:
N-(4-decyloxyphenyl)-N'-~2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl]urea 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
' ~' . .
'~
-
"DIPHENYLUREA DERIVATIVES"
This invention relates to new, therapeutically useful diphenylurea derivatives, to a process for their production and to pharmaceutical compositions containing them, and methods for their use.
The new diphenylurea derivatives of the present invention are the compounds of formula I, hereinafter depicted, wherein R1 represents a straight- or branched-chain alkyl group containing from about 4 to about 18 carbon atoms, X1 represents an oxygen atom, or a group of the formula -OCH2- or ~S(O)n~, wherein n represents zero, 1 or 2, R and R may be the same or different and each represents a hydrogen atom or a methyl or ethyl group, R4 represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, a dimethylamino group or a group of the formula -OR or -S(O)mR , wherein m represents zero, 1 or 2 and R6 represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkenyl, alkoxyalkyl, alkylthioaIkyl, alkyla~x~kyl or dialkylamiYY~Xyl group containing up to about 6 carbon atoms, and R5 represents a group of the formula -NR7R8 or -OR9, , . :
.:
- . :
W092/0~13 PCT/GB91iO~383 ~ 2 -wherein R7 and R8 may be the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms~
preferably an alkyl, alkenyl, alkoxyalkyl, alkylthioaIkyl, aLkylam~Y~Xyl or dialkyl~mu~YIXyl gn containing up to about 6 carbon atoms, and R9 represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero ato~s, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl or dialkylaminoalkyl group containing up to about 6 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-containing . . , - ~ ,: : . .
'~ , ' ` , . ':
WO92/0~13 PCT/~ 3 ~8916~
from 8 to l2, e.g. 9, lO or ll, carbon atoms; -((i) Xl represents an oxygen atom;
(iii) R2 and R3 each represents a hydrogen atom;
(iv) R4 represents an alkyl, alkoxy or alkylthio grvup containing l or 2, preferably l, carbon atoms;
(v) R7 represents a hydrogen atom;
(vi) R8 represents a straight- or branched-chain alkyl group containing up to 5, preferably 3 or 4 carbon atoms, optionally interrupted by an oxygen or sulphur atom, preferably an alkyl, alkoxyalkyl or alkylthioalkyl group containing u~ to 5, preferably 3 or 4 carbon atoms; and/or (vii) R represents an alkyl group containing up to 3 carbon atoms, e.g. a methyl group;
the other symbols being as hereinbefore defined.
Important compounds according to the invention include:-A N-(4-decyloxyphenyl~-N'-t2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl~urea;
B N-(4-decyloxyphenyl)-N'-(2-methoxy-5-methoxy-carbonylphenyl)urea;
C N-(4-decyloxyphenyl)-N'-t2-methoxy-5-(2-methoxy-ethylcarbamoyl)phenyl]urea;
, . . . . .
, .'. ~ ,. ''' ' ' .
,. . . : :
.
-. . .
.
.
W092/0~13 PCT/GB91/01~3 1 6 ~ 4 _ D N-(4-decyloxyphenyl)-N'-[2-methoxy-5-(2-methyl-thioethylcarbamoyl)phenyl]urea;
E N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4- .
decyloxyphenyl)urea;
F N-(5-N-butylcarbamoyl-2-methylthiophenyl)-N'-(4-decyloxyphenyl)urea;
G N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-undecyloxyphenyl)urea;
H N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-nonyloxyphenyl)urea;
I N-(5-methoxycarbonyl-2-methylthiophenyl)-N'-(4-nonyloxyphenyl)urea;
J N-[2-methylthio-5-(2-methylthioethylcarbamoyl)-phenyl]-N'-(4-nonyloxyphenyl)urea;
K N-t2-methylthio-5-(2-methylthioethylcarbamoyl)-phenyl]-N'-(4-undecyloxyphenyl)urea; and L N-(5-N-butylcarbamoyl-2-methylphenyl)-N~-(4-undecyloxyphenyl)urea.
The letters A to L are allocated to compounds for easy reference later in this specification.
The compounds according to the invention are 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, .. . . . ~ , . . . . ........................ ~
~, . .: , ~ ~ . -. .
WO92/03413 PCT/G~91/01383 ~: ' _ 5 _ ~0~-16~
c:holesterol ester storage disease and atheroma in vein grafts.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following n 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 9~$.
Compounds of formula I can be prepared by the 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, - compounds of general formula I wherein R2 represents a hydrogen atom, Rl, R3, R4, R5 and Xl being as hereinbefore defined, are prepared by the reaction of a compound of general formula II hereinafter depicted, wherein R3, R4 and R5 are as hereinbefore defined, with a compound of general formula III, hereinafter .. ~ ~ .' ' . ' , ': ' ' . : ' ~ .
WO92/0~13 PCT~GB~ 83 ~?,!
., ,A .
depicted, wherein R1 and X1 are as hereinbefore defined, optionally prepared in ~i~, by the application or adaptation of known methods.
The reaction between the compound of formula II
and the compound of formula III preferably takes place in a suitable solvent, for example dichloromethane, toluene, or a mixture thereof. The reaction preferably takes place at an elevated temperature, for example at or near 100C.
Preparation of the intermediate of formula III
in situ can be carried out by the reaction of a compound such as bis(trichloromethyl) carbonate with a compound of the general formula IV, hereinafter depicted, wherein R1 and X1 are as hereinbefore defined. The reaction is preferably carried out in a solvent such as toluene, in the presence of a tertiary amine, e.g. triethylamine, preferably at an elevated temperature.
According to a further feature of the invention, compounds of formula I are prepared by reacting a compound of general formula:
R OH (V~
wherein R9 is as hereinbefore defined, or a compound of general formula:
HNR7R8 (VI) . .
. ' ' ~ : .
WO92/0~13 PCT/GB~
~; .-, - 7 - ~u o~ ~ ~3 wherein R7 and R8 are as hereinbefore defined, with a compound of formula VII, hereinafter depicted, wherein R , R , R , R4 and Xl are as hereinbefore defined and zl represents a halogen, e.g. chlorine, atom, preferably in the presence of a base, such as a tertiary amine and optionally in a solvent, e.g.
toluene, optionally with heating.
According to a further feature of the invention, compounds of formula I wherein at least one of m and n is zero may be converted into a compound of formula I wherein m and/or n is greater than in the starting material, the other symbols being as hereinbefore defined, by oxidation using a conventional oxidant, such as a percarboxylic acid (e.g. m-chloroperbenzoic acid), in an inert solvent, such as dichloromethane, at or below room temperature.
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 of formula I wherein R2 and/or R3 and/or R7 and/or R8 is other than a hydrogen atom may be prepared from compounds of formula I wherein R2 and/or R3 and/or R7 and/or R8 represents a hydrogen atom by the application or adaptation of known methods of alkylation.
` :' . . . ':
W O 92/03413 PC~r/GB91/01383 6 S ;~
Compounds of formulae II, III, IV, V, VI and VII
may be prepared by the application or adaptation of known methods. , ?
'., ; ~ ' ' -. ~ ' ", ' '. :
.` : ~ ` . `:, : `. : :: . - . . i .
.: . .- . ` ` .. . : ` . ` ~
.. `-"' . ` ' . . , ~ , . ~
: . , . , ., ` ,. . ` ,,. ~` .
WO 92/03413 PCI`/GB91/01383 ~'.` I
9 ~ 9 1 ~ J
COR
RlXl~ -N J~N~
coR5 HR3N~
R X ~3--NCO III
. . . - ' :
R Xl~ N~2 IV
R X ~3_ N~ l~OZ
','': . . . '': , ~ ' , . ' ,;
.~ .. . . . .
:' . ' ~
W092/0~13 PCT~GB9~rR~ 3 ..,.
1 6 5 - lo -The following Examples illustrate the preparation of the compounds according to the invention and the Reference Example illustrates the preparation of the intermediates.
Compounds A and B
A stirred solution of bis(trichloromethyl) carbonate (0.49g) in toluene (lOOml) was treated with a suspension of 4-decyloxyaniline (1.24g) and triethyl-amine (0.7ml) in toluene (150ml) at the ambient temperature under an inert atmosphere. The mixture was stirred for 30 minutes and then was heated at lOO~C for 2 hours. The mixture was then cooled and evaporated, and the resulting residue was dissolved in dichloromethane (200ml). This solution was treated with 3-amino-4-methylthio-N-(2-methylthioethyl)-benzamide (l.lg) and the mixture was heated at reflux `
for 1 hour. The mixture was then allowed to stand at the ambient temperature for 18 hours, and then it was washed with water (lOOml), dried over magnesium sulphate, and concentrated under reduced pressure to a volume of about 50ml when a solid separated. This solid was filtered off and recrys~allised from ethanol, to give N-(4-decyloxyphenyl)-N'-[2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl]urea (1.3g) in the form of small colourless needles, m.p. 126-128C.
, :`
' ' ' ' ' ' :. , - - . . ' W092/0.~413 PCI/G~g~ 3~ !
!`:` . I
8916~ .
Elemental analysis:- C,63.5j~,7.9;N,8.10;S,12.00%;
calculated:- C,63.24;H,7.77;N,7.90;S,12.06%;~.
By proceeding in a similar manner, but using methyl 3-amino-4-methoxybenzoate in place of the 3-amino-4-methylthio-N-(2-methylthioethyl)benzamide, there was prepared N-(4-decyloxyphenyl)-N'-(2-methoXy~
5-methoxycarbonylphenyl)urea in the form of colourless crystals, m.p. 115-116C. [Elemental analysis:-C,68.50;H,8.1;N,5.98~; caloulated:- C,68.39;H,7.95 N,6.13~].
Compounds C. D and E
A mixture of N-(5-carboxy-2-methoxyphenyl)-N'-(4-decyloxyphenyl)urea (1.55g; prepared as described in Reference Example 1) and thionyl chloride (0.27ml) in toluene (60ml) was heated at reflux for 30 minutesO
The mixture was then chilled and added dropwise, with cooling, to a stirred solution of 2-methoxyethylamine (0.8g) in toluene (20ml). The mixture was allowed to stand at the ambient temperature for 18 hours, and then it was evaporated and the resulting residue was extracted with hot dichloromethane (3x50ml). The extract was evaporated and the residue was recrystall-ised from acetone, to give N-(4-decyloxyphenyl)-N'-:... :. .. . ...
, . .
W092/0~13 PCT~GB9l/013~
~8'~ 16~
[2-methoxy-5-(2-methoxyethylcarbamoyl)phenyl]urea (0.75g) in the form of a colourless powder, m.p.
126-128C. tElemental analysis:- C,67.70;H,8.4;
N,8.50%; calculated:- C,67.31;H,8.27;N,8.41%].
~ y proceeding in a similar manner, but using the appropriate quantities of 2-methylthioethylamine and butylamine in place of the 2-methoxyethylamine, there were prepared:-N-(4-decyloxyphenyl)-N'-t2-methoxy-5-(2-methylthio-ethylcarbamoyl)phenyl]urea in the form of colourless crystals, m.p. 105-107C (from methanol) [Elemental analysis:- C,65.20;H,8.00;N,8.2;S,6.10%; calculated:-C,65.21;H,8.01;N,8.15;S,6.22%]; and N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-decyloxy-phenyl)urea, in the form of off-white crystals, m.p.
62-63C [purification by mplc on silica gel, eluting with a mixture of diethyl ether and methanol (l9:lv/v)]
[Elemental analysis:- C,69.80;H,8.80;N,8.40%;
calculated:- C,69.99;H,8.71;N,8.44%]. - -EXAMP~E 3 Compound F
A stirred solution of bis(trichloromethyl) carbonate (0.49g) in toluene (lOOml) was treated with a suspension of 4-decyloxyaniline (1.24g) and triethylamine (0.7ml) in toluene (150ml) at the ambient temperature under an inert atmosphere and stirred for ,~.~ . . . . . .
.
: . . . . . ..
.
:: . -~ . : - :
. . : , :. :-- :
. .
. .
W092/0~13 PCT/CB91/01383 ~ ~. 8 ~ i J
30 minutes. The mixture was heated at 100C for 5 hours. The mixture was treated with 3-amino-N-butyl-4-(methylthio)benzamide (1.19g) and stirring was continued at 100C for a further period of 2 hours.
The mixture was allowed to stand at the ambient temperature for 18 hours, and then it was diluted with dichloromethane (500ml), washed with hydrochloric acid (2xlOOml;2N~, dried over magnesium sulphate, and then evaporated. The resulting residue was dissolved in a hot mixture of ethyl acetate and ethanol (150ml;1:1v/v).
Upon cooling, a solid separated out and was discarded.
The remaining filtrate was concentrated under reduced pressure to a volume of about 50ml, when a second solid separated. This second solid was recrystallised from ethanol, to qive N-(5-N-butylcarbamoyl-2-methylthio-phenyl)-N'-(4-decyloxyphenyl)urea-(0.65g), in the form of a colourless solid, m.p. 110-112C. [Elemental analysis:- C,67.60;~,8.5;N,7.90%; calculated:- C,67.80;
H,8.44;N,8.18%].
ComDounds G. H I J. K and L
A stirred solution of bis(trichloromethyl) carbonate (0.99g) in toluene (200ml) was treated with 4-undecyloxyaniline (2.63g) at the ambient temperature under an inert atmosphere. The suspension was then treated with triethylamine (2.79ml), resulting in a , .
: - .
W~92/0~13 PCT/GB91/~3~
6~ 14 -thick slurry. It was then heated at 100C 2 hours, with vigorous stirring. The suspension was then filtered and the filtrate was treated with 3-amino-N~
butyl-4-(methoxy)benzamide (2.24g). This mixture was then stirred at 100C for 2 hours, allowed to stand at the ambient temperature for 18 hours, and then evaporated. The resulting residue was dissolved in ethyl acetate (300ml) and the solution was washed with hydrochloric acid (2xlOOml;4N). The organic solution was dried over magnesium sulphate and treated with activated charcoal. After filtration, the colourless solution was evaporated and the residue recrystallised from aqueous ethanol, to give N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-undecyloxyphenyl)urea (3.2g) in the form of a colourless solid, m.p. 84-86C.
tElemental analysis:- C,68.30;H,8.80;N,8.00;H20,306%~
calculated for C30H45N304:H20 H20,3-4%]-By proceeding in a similar manner, but using theappropriate quantities of the corresponding aniline derivatives, there were prepared:-N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-nonyloxy-phenyl)urea in the form of a colourless solid, m.p.
171-172C (from ethyl acetate) lElemental analysis:-C,71.80;H,8.90;N,8.80%; calculated:- C,71.91;H,8.84;
N,8.99%];
' ~ .
., ' ~ - ~ . ' ' :
: . .
.~ : .. .
WO92/0~13 PCT/GB91~3 (. ~
~8916~ !
N-(5-methoxycarbonyl-2-methylthiophenyl)-N'-(4-nonyl-oxyphenyl)urea in the form of tiny colourless needles~
m.p. 155-157C (from ethanol) tElemental analysis~
C,65.10;H,7.50;N,5.80%; calculated:- C,65.47;H,7~47 N,6.11%~;
N-t2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl]~
N'-(4-nonyloxyphenyl)urea in the form of a colourless solid, m.p. 120-123C (from ethyl acetate) tElemental analysis:- C,62.40;H,7.80;N,7.70%; calculated:-C,62.63;H,7.59;N,8.12%];
N-t2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl~- -N'-(4-undecyloxyphenyl)urea in the form of a colourless solid, m.p. 130-131C (from ethanol) tElemental analysis:- C,64.1;H,8.2;N,7.4~; calculated:- C,63.82;
H,7.94;N,7.70%]; and N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-undecyl oxyphenyl)urea in the form of a colourless solid, m.p.
159-164C (from ethyl acetate) tElemental analysis:-C,72.25;H,9.2;N,8.3~; calculated:- C,72.69;H,9.15;
N,8.48~].
A suspension of N-(4-decyloxyphenyl)-N'-(2-methoxy-5-methoxycarbonylphenyl)urea (10.67g) and sodium hydroxide (1.02g) in a mixture of ethanol (250ml) and water (25ml) was heated at reflux for 90 minutes. The mixture was then cooled, acidified by : , - , . ~
:
., : , ' , ' ~ :
. ~ . .
, WO92/0~13 PCT/GB91/013~ .
~0~)16~ --treatment with hydrochloric acid (2N) and diluted with water (50ml). The solid which separated was recrystallised from a mixture of tetrahydrofuran and dimethylformamide, to give N-(5-carboxy-2-methoxy-phenyl)-N'-(4-decyloxyphenyl)urea in the form of colourless crystals, m.p. 261-263C.
:, ~ . . : , .- .. -. . . . . . . . . . ..
': . .. . . . ~ ' :
, , ~.
,; . .. . ..
... ..
' . :. .
, ,, , : :
WO9~/03413 PCT/GB9l/013~
'~, ~V8Yl~
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 administered parenterally, rectally or orally.
Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium 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 ~0~2/~13 PCT/GB9~0138~ ¦
'~``''''''`` ! ' ~3~16~ - 18 -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 also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositlons of sterilising agents, by irradiation or by heating. They may also be manufactured in the for~
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 .
.. . : . :
W092/0~13 PCT/GB9~ 3 ( -~ D~91 ~
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 1 to about 10, mg/kg body weight per day by oral administration.
The following Example illustrates pharmaceutical compositions according to the present invention.
No. 2 size gelatin capsules each containing:
N-(4-decyloxyphenyl)-N'-~2-methylthio-5-(2-methylthioethylcarbamoyl)phenyl]urea 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 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 18 carbon atoms, X1 represents an oxygen atom, or a group of the formula -OCH2- or -S(O)n-, wherein n represents zero, 1 or 2, R2 and R3 may be the same or different and each represents a hydrogen atom or a methyl or ethyl group, R4 represents a straight-or branched-chain alkyl group containing up to 6 carbon atoms, a dimethylamino group or a group of the formula -OR6 or -S(O)mR6, wherein m represents zero, 1 or 2 and R6 represents a straight- or branched-chain alkyl group containing up to 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, and R5 represents a group of the formula -NR7R8 or -OR9, wherein R7 and R8 may be the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing up to 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, and R9 represents a straight- or branched-chain alkyl group containing up to 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms.
2. A compound according to claim 1 wherein R6 and R9 each independently represents an alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, or dialkylaminoalkyl group containing up to 6 carbon atoms and R7 and R8 each independently represents a hydrogen atom or an alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, or dialkylaminoalkyl group containing up to 6 carbon atoms.
3. A compound according to claim 1 or 2 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 and R3 each represents a hydrogen atom;
(iv) R4 represents an alkyl, alkoxy or alkylthio group containing 1 or 2 carbon atoms;
(v) R7 represents a hydrogen atom;
(vi) R8 represents a straight- or branched-chain alkyl group containing up to 5 carbon atoms, optionally interrupted by an oxygen or sulphur atom; and/or (vii) R9 represents an alkyl group containing up to 3 carbon atoms;
the other symbols being as hereinbefore defined.
4. A compound according to claim 3 wherein R1 represents an alkyl group containing 9, 10 or 11 carbon atoms; R4 represents an alkyl, alkoxy or alkylthio group containing 1 carbon atom and R8 represents a straight- or branched-chain alkyl group containing up to 5 carbon atoms optionally interrupted by an oxygen or sulphur atom; and R9 represents methyl.
5. A compound according to any one of the preceding claims wherein R8 represents an alkyl, alkoxyalkyl or alkylthioalkyl group containing 3 or 4 carbon atoms.
6. A compound according to claim 1 which is N-(4-decyloxyphenyl)-N'-[2-methylthio-5-(2 methylthioethylcarbamoyl)phenyl]urea;
N-(4-decyloxyphenyl)-N'-(2-methoxy-5-methoxy-carbonylphenyl)urea;
N-(4-decyloxyphenyl)-N'-[2-methoxy-5-(2-methoxy-ethylcarbamoyl)phenyl]urea;
N-(4-decyloxyphenyl)-N'- [2-methoxy-5-(2-methyl-thioethylcarbamoyl)phenyl]urea;
N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-decyloxyphenyl)urea;
N-(5-N-butylcarbamoyl-2-methylthiophenyl)-N'-(4-decyloxyphenyl)urea;
N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N'-(4-undecyloxyphenyl)urea;
N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-nonyloxyphenyl)urea;
N-(5-methoxycarbonyl-2-methylthiophenyl)-N'-(4-nonyloxyphenyl)urea;
N-[2-methylthio-5-(2-methylthioethylcarbamoyl)-phenyl]-N'-(4-nonyloxyphenyl)urea;
N-[2-methylthio-5-(2-methylthioethylcarbamoyl)-phenyl]-N'-(4-undecyloxyphenyl)urea; or N-(5-N-butylcarbamoyl-2-methylphenyl)-N'-(4-undecyloxyphenyl)urea.
7. A process for the preparation of a diphenylurea derivative according to claim 1 which comprises:
(A) when R2 represents a hydrogen atom and the other symbols are as defined in claim 1, the reaction of a compound of the general formula:
II
wherein R3, R4 and R5 are as defined in claim 1 with a compound of the general formula :
III
wherein R1 and X1 are as defined in claim 1, which compound is optionally prepared in situ;
(B) the reaction of a compound of the general formula:
wherein R9 is as defined in claim 1, or a compound of the general formula :
wherein R7 and R8 are as defined in claim 1, with a compound of the general formula :
VII
wherein R1, R2, R3, R4 and X1 are as defined in claim 1 and Z1 represents a halogen atom;
(c) the oxidation of a compound of formula (I) wherein at least one of m and n is zero into a compound of formula (I) wherein m and/or n is greater than in the starting material;
optionally followed by the conversion of a compound of formula (I) thus obtained into another compound of formula (I).
8. A pharmaceutical composition which comprises a diphenylurea derivative according to claim 1 in association with a pharmaceutically acceptable carrier or coating.
9. 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 diphenylurea derivative according to claim 1 in association with a pharmaceutically acceptable carrier or coating.
10. 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 diphenylurea derivative according to
claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9017892.2 | 1990-08-15 | ||
| GB909017892A GB9017892D0 (en) | 1990-08-15 | 1990-08-15 | New compositions of matter |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2089165A1 true CA2089165A1 (en) | 1992-02-16 |
Family
ID=10680688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002089165A Abandoned CA2089165A1 (en) | 1990-08-15 | 1991-08-14 | Diphenylurea derivatives |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0543891A1 (en) |
| JP (1) | JPH06500095A (en) |
| AU (1) | AU8411591A (en) |
| CA (1) | CA2089165A1 (en) |
| GB (1) | GB9017892D0 (en) |
| IE (1) | IE912889A1 (en) |
| IL (1) | IL99174A0 (en) |
| PT (1) | PT98684A (en) |
| WO (1) | WO1992003413A1 (en) |
| ZA (1) | ZA916412B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL110151A (en) * | 1993-06-30 | 1998-10-30 | Sankyo Co | Amide derivatives and pharmaceutical compositions containing them |
| DE19624155A1 (en) * | 1996-06-18 | 1998-01-08 | Hoechst Ag | Substituted benzoic acid derivatives, process for their preparation and the use of the compounds for the treatment of diseases |
| US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| ES2377847T3 (en) | 1999-01-13 | 2012-04-02 | Bayer Healthcare Llc | Diphenyl ureas substituted with omega-carboxy aryl as kinase inhibitors p38 |
| US6290478B1 (en) * | 1999-07-16 | 2001-09-18 | Scroll Technologies | Eccentric back chamber seals for scroll compressor |
| SI1478358T1 (en) | 2002-02-11 | 2013-09-30 | Bayer Healthcare Llc | Sorafenib tosylate for the treatment of diseases characterized by abnormal angiogenesis |
| AU2003209119A1 (en) | 2002-02-11 | 2003-09-04 | Bayer Pharmaceuticals Corporation | Pyridine, quinoline, and isoquinoline n-oxides as kinase inhibitors |
| DK1626714T3 (en) | 2003-05-20 | 2007-10-15 | Bayer Pharmaceuticals Corp | Dirarylurine drugs for diseases mediated by PDGFR |
| RS52625B (en) | 2003-07-23 | 2013-06-28 | Bayer Healthcare Llc | Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
-
1990
- 1990-08-15 GB GB909017892A patent/GB9017892D0/en active Pending
-
1991
- 1991-08-13 IL IL99174A patent/IL99174A0/en unknown
- 1991-08-14 ZA ZA916412A patent/ZA916412B/en unknown
- 1991-08-14 IE IE288991A patent/IE912889A1/en unknown
- 1991-08-14 AU AU84115/91A patent/AU8411591A/en not_active Abandoned
- 1991-08-14 WO PCT/GB1991/001383 patent/WO1992003413A1/en not_active Application Discontinuation
- 1991-08-14 PT PT98684A patent/PT98684A/en not_active Application Discontinuation
- 1991-08-14 EP EP91914898A patent/EP0543891A1/en not_active Withdrawn
- 1991-08-14 CA CA002089165A patent/CA2089165A1/en not_active Abandoned
- 1991-08-14 JP JP3513968A patent/JPH06500095A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU8411591A (en) | 1992-03-17 |
| JPH06500095A (en) | 1994-01-06 |
| IL99174A0 (en) | 1992-07-15 |
| GB9017892D0 (en) | 1990-09-26 |
| EP0543891A1 (en) | 1993-06-02 |
| ZA916412B (en) | 1992-04-29 |
| PT98684A (en) | 1992-07-31 |
| IE912889A1 (en) | 1992-02-26 |
| WO1992003413A1 (en) | 1992-03-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |