Note: Descriptions are shown in the official language in which they were submitted.
W092/0~12 2 0 8 915 1 PCT/GB91/01375
' :.
BENZAMIDE DE~IVATIVES
~ his invention relates to new, therapeutically
useful benzamide derivatives, to a process for their
production and to pharmaceutical compositions
containing them, and methods for their use.
The new benzamide derivatives of the present
invention are the compounds of formula I, hereinafter
depicted, wherein Rl represents a straight- or
branched-chain alkyl group co~taining up to about 20
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, and optionally interrupted
by one or more sulphinyl or sulphonyl groups,
preferab~y an alkylthioalkyl, alkylaminoalkyl or
dialkylaminoalkyl group or more especially an alkyl,
alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, or
alkoxyalkoxyalkoxyalkyl group, optionally carrying one
or more substituents selected from halogen, e.g.
bromine, iodine, fluorine or, preferably, chlorine,
atoms, amino groups, alkoxy, alkylthio and alkylamino
groups each containing up to about 3 carbon atoms, and
groups of the formula -CONR R wherein R6 represents a
hydrogen atom or a methyl group and R7 represents a
methyl, trifluQromethyl or trichloromethyl group, the
symbols R2 are the same or different and each
-
. . : : :
7 ..
WO92/0~12 P~T/GB91/01375
2089~5~ - 2 -
represents a hydrogen atom, a straight- or
branched-chain alkyl group containing up to about
carbon atoms or an optionally substituted phenyl group
or the two groups R2 together with the carbon atom to
which they are attached form a saturated or unsaturated
ring containing from 3 to about 8 carbon atoms and
optionally containing one or-more
hetero atoms selected from oxygen, sulphur and nitrogen
atoms, R3 represents a hydrogen atom or a straight- or
branched-chain alkyl group containing up to about 6
carbon atoms, R4 represents a straight- or
branched-chain alkoxy or alkylthio group containing up
to about 6 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, e.g. an imidazol-1-yl or
pyrrolidin-1-yl group, and R represents a group of the
formula -NR8R9 or -OR1O wherein R8 and R9 may be the
same or different and each represents a hydrogen atom
or a straight- or branched-chain alkyl group containing
up to about lO 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, and optionally
interrupted by one or more sulphinyl or sulphonyl
groups, and RlO represents a hydrogen atom or a
7Q92/03412 2 ~ 8 ~1 51 PCT/GB9t/01375
straight- or branched-chain alkyl group containing up
to about lO 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, and optionally
interrupted by one or more sulphinyl or sulphonyl
groups, and pharmaceutically acceptable salts thereofO
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, and
processes for their preparation and~separation, are
embraced by the invention.
Especially important compounds of the present
invention include those wherein at least one of the
symbo}s has a value selected from the followingo-
(i) Rl represents an alkyl, alkenyl, alkoxyalkyl,
alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl or
haloalkyl, e.g. chloroalkyl, group, containing from 8
to 20 carbon atoms, preferably an alkyl or alkeny~
group containing from 8 to 20, preferably lO to 18,
carbon atoms;
(ii) the symbols R2 each represent a hydrogen atom,
or the two groups R2 together with the carbon
atom to which they are attached form a
cycloalkyl ring containing from 3 to 8,
preferably 5 or 6, e.g. 5, carbon atoms;
. ~ .
.,: : .
.: . . . . .
~. ,
; , ,, .:. : ,: . ~. . . , . . . ;
WO92/0~12 PCT/GB91/01375
~089~
(iii) R3 represents a hydrogen atom;
(iv) R4 represents an imidazol-l-yl group or a
straight- or branched-chain alkoxy or alkylthio
group containing up to 3, preferably l or 2,
carbon atoms, preferably methoxy, methylthio or
ethylthio;
(v) R8 represents a hydrogen atom or a straight- or
branched-chain alkyl group containing up to 3
carbon atoms, e.g. methyl;
(vi) R9 represents a straight- or branched-chain
alkyl or alkenyl group containing up to 6 carbon
atoms, optionally interrupted by one or more ..
oxygen or sulphur atoms or sulphonyl groups,
preferably an alkyl, alkoxyalkyl or
alkylthioalkyl group containing 3 or 4 carbon
atoms, or an alkenyl group containing 5 carbon
atoms, e.g. a butyl, methoxyethyl,
methylthioethyl, methoxypropyl,
methylthiopropyl, methylsulphonylpropyl or
methylbut-2-enyl group;
(vii) RlO represents a hydrogen atom or a straight- or
branched-chain alkyl group containing up to 6
preferably up to 3, carbon atoms, e.g. methyl;
the other symbols being as hereinbefore defined, and
pharmaceutically acceptable salts thereof.
Important compounds according to the invention
include:-
' ' :: - , - ' : : ..
`;''.: . . . ~.,: ~ '` '
~: :. . :: ., . - ,
~,: . , : . ~, .: .. : : : , ...
WO92/03412 2 0 8 9151 PCT/GB91/01375
A (Z)-N-(2-methylthio)ethyl-4-methylthio-3-.
(octadec-9-enamido)benzamide ;
E3 (Z)-N-(2-methoxy)ethyl-4-methylthio-3-(octadec-
9-enamido)benzamide;
C (Z)-methyl 4-methoxy-3-(octadec-9-enamido)-
benzoate;
D N-(2-methylthio)ethyl-3-hexadecanamido-4-
(methylthio)benzamide;
E N-butyl-3-hexadecanamido-4-(methylthio)benzamide; . :
F N-(2-methoxy)ethyl-3-hexadecanamido-4-(methyl-
thio)benzamide;
G N-butyl-3-dodecanamido-4-(methylthio)benzamide;
N-(2-methoxy)ethyl-3-dodecanamido-4-(methyl-
thio)benzamide;
I N-(2-methylthio)ethyl-3-dodecanamido-4-(methyl- ;
thio)benzamide;
J N-butyl-N-methyl-3-hexadecanamido-4-methoxy-
benzamide;
K (Z?-N-butyl-4-methoxy-3-(octadec-9-enamido)-
benzamide;
L N-(2-methylthio)ethyl-3-(l-decylcyclopentane-
carboxamido)-4-(methylthio)benzamide;
M (Z)-sodium 4-methoxy-3-(octadec-9-enamido)- ?
benzoate;
N (Z)-4-methoxy-3-(octadec-9-enamido)benzoic
acid;
. ` ~ . . , - . - , . . . . .
. . ., . . ~ , . . . .,
. .: . ~ . : : :
. ~ . .
.. . . . .
WO92/0~12 PCT~GB91/01375 _ ~
2089151
- 6 -
o N-butyl-3-dodecanamido-4-(ethylthio)benzamide;
P N-butyl-4-ethylthio-3-hexadecanamidobenzamide;
Q N-butyl-4-ethylthio-3-heptadecanamidobenzamide;
R N-butyl-4-ethylthio-3-octadecanamidobenzamide;
S 4-ethylthio-3-hexadecanamido-N-(2-methylthio-
ethyl)benzamide;
T 4-ethylthio-3-heptadecanamido-N-(2-methylthio-
ethyl)benzamide;
U 3-heptadecanamido-4-methylthio-N-(2-methylthio-
ethyl)benzamide;
V 3-heptadecanamido-N-(2-methoxyethyl)-4-(methyl-
thio)benzamide;
W (Z)-N-butyl-3-octadec-9-enamido~4-(methylthio)-
benzamide;
X 4~ethylthio-N-(3-methylthiopropyl)-3-octa-
decanamidobenzamide;
Y 4-ethylthio-3-heptadecanamido-N-(3-methylthio-
propyl)benzamide;
Z 4-ethylthio-3-hexadecanamido-N-(3-methylthio-
propyl)benzamide;
AA 4-methylthio-N-(2-methylthioethyl)-3-octa-
decanamidobenzamide;
AB N-butyl-3-dodecanamido-4-methoxybenzamide;
AC 4-ethylthio-3-hexadecanamido-N-(3-methoxy-
propyl)benzamide;
AD N-butyl-3-octadecanamido-4-(methylthio)-
. : :
.: ... . - .
.:. .
:. ~ . , , , :
WD92/0~12 2 ~ 8 31 ~ ~ PCT/GB9~/01375 ' ~
-- 7
benzamide;
AE 4-methylthio-N-(3-methylthiopropyl)-3-octa-
decanamidobenzamide;
AF 4-ethylthio-N-(3-methoxypropyl)-3-octa-
decanamidobenzamide;
AG N-butyl-3-(5-chloropentanamido)-4-(ethylthio)-
benzamide;
AH 3-(4-chlorobutanamido)-4-ethylthio-N-(3-methyl-
thiopropyl)benzamide;
AI 3-(5-chloropentanamido)-4-ethylthio-N-(3-methyl-
thiopropyl)benzamide;
AJ methyl 3-hexadecanamido-4-methoxybenzoate;
AK 3-hexadecanamido-4-methoxybenzoic acid;
AL sodium 3-hexadecanamido-4-methoxybenzoate;
AM 3-hexadecanamido-4-methoxy-N-(2-methoxyet~yl)-
benzamide;
AN 3-hexadecanamido-4-methoxy-N-(3-methylbut-2-
enyl)benzamide;
AO N-butyl-4-methylthio-3-(5,9-dioxahexadecan-
amido)benzamide;
AP 4-methylthio-N-(3-methylthiopropyl)-3-(5,9-
dioxahexadecanamido)benzamide;
AQ N-butyl-4-ethylthio-3-(5,9,13-trioxahexa-
decanamido~benzamide;
AR 4-ethylthio-N-(3-methylthiopropyl)-3-t5,9-
dioxahexadecanamido)benzamide;
. - . . . , . .:
W092/0~12 PCT/GB9l~Ot375
2~9~
- 8 -
AS N-butyl-4-ethylthio-3-(5,9-dioxahexadec-
anamido)benzamide;
AT 4-ethylthio-N-(3-methoxypropyl)-3-(5,9-dioxa-
hexadecanamido)benzamide;
AU 4-ethylthio-N-(3-methoxypropyl)-3-(5,9,13- 1
trioxahexadecanamido)benzamide;
AV 4-ethylthio-N-(3-methoxypropyl)-3-(5-oxahexa-
decanamido)benzamide;
AW 4-methylthio-N-(3-methylthiopropyl)-i-(5-
oxahexadecanamido)benzamide;
AX N-butyl-4-methylthio-3-(5-oxahexadecanamido)-
benzamide;
AY 4-methoxy-N-(3-methylthiopropyl)-3-(5,9-dioxa-
hexadecanamido)benzamide;
AZ 4-ethylthio-N-(3-methylthiopropyl)-3-(509013
trioxahexadecanamido)benzamide;
BA methyl 3-heptadecanamido-4-(imidazol-1-yl)-
benzoate;
BB N-(3-methylsulphonylpropyl)-4-methylthio-3-
~5,9-dioxahexadecanamido)benzamide;
BC 4-ethylthio-N-(3-methylthiopropyl)-3-(5,9-
dioxaoctadecanamido~benzamide;
BD N-butyl-4-ethylthio-3-(5,10-dioxahexa-
decanamido)benzamide;
BE 4-ethylthio-N-(3-methylthiopropyl)-3-(6,10,14-
trioxahexadecanamido)benzamide;
.. . . .
~ - . .. .
.. .. . . .... ..
' :.. ,' ' . - . , '
WQ92/0~12 2 0 8 9151 PCT/CB91/~1375
_ g
BF 4-imidazol-l-yl-N-(3-methylthiopropyl)-3-(5-
oxahexadecanamido)benzamide; and
BG 3-hexadecanamido-4-imidazol-l-yl-N-(3-
methylthiopropyl)benzamide.
The le~ters A to BG are allocated to compounds
for easy referencP later in this specification.
The compounds according to the invention are
inhibitors of acyl coenzyme-A:cholesterol-O-acyl
transferase (ACATjEC 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 following in vitro andin-vivo
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
0.5~g/ml or l~g/ml. The degree of ACAT inhibition
produced was up to 99%.
.:. , : . ; .. . . ..
,~ . . :
.. , .. : ....... ~ - . : . - :
WO92/0~12 PCT/GB91/01375
~.. '-, ~ .
20~9~1
-- 1 0
In n-vivo tests, using rats fed on a diet
similar to that described above and supplemented
further by 0.01%w.w of test compound, compounds
according to the invention inhibited increases in
plasma cholesterol concentrations, measured after 3
days, relative to control animals fed on the
cholesterol supplemented diet without the drug, by up
to 100%.
; ~ ~ ' ' ', , .
, ; . . ~ ,
::. , , . ... : . . -
:., . ... :
. : . : . . -
~092/0~12 2 a ~ 9 ~ ~ 1 PCT/GB91/01375
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 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 the general
formula:
Rl_C(R2)2cozl (III)
wherein Rl and R2 are as hereinbefore defined and zl
represents a halogen, e.g. chlorine, atom or an
alkoxycarbonyloxy group, for example methoxycarbonyloxy
or ethoxycarbonyloxy, or with the corresponding
anhydride of the general formula:
[R -C(R )2CO]2O ~IV) Z
wherein Rl and R2 are as hereinbefore defined.
When zl represents a halogen atom the reaction
may be performed in the presence of a suitable base,
such as a tertiary amine, e.g. triethylamine or
, pyridine.
r In each instance the reaction may be carried out
in a suitable solvent, e.g. dichloromethane, optionally
with heating.
~ ' ' '
,:.' . . : - '
WO92/0~12 PCl`/GB91/0137~ ~
2~89~
- 12 -
According to a further feature of the invention~
compounds of formula I wherein R10 is other than
hydrogen are prepared by reacting a compound of general
formula:
RlloH (V)
wherein Rll represents a straight- or branched-chain
alkyl group containing up to about lO 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, and optionally interrupted by one or more
sulphinyl or sulphonyl groups, or a compound of general
formula:
HNR8R9 (VI)
wherein R8 and R9 are as hereinbefore defined, with a
compound of formula VII, hereinafter depicted, wherein
Rl, R2, R3 and R4 are as hereinbefore defined and z2
represents a hydroxy group, a halogen, e.g. chlorine,
atom or an alkoxycarbonyloxy group, for example
methoxycarbonyloxy or ethoxycarbonyloxy, or with the
corres.ponding anhydride .
The reaction conditions are similar to those
described above for the reaction between the compounds
of general formulae II and III.
When z2 represents a hydroxy group the reaction
is preferably performed in the presence o~ a condensing
....... ~ , . . .
.
'
.
,
W~92tO~12 2 0 ~ ~151 PCT/GB91/0137s
- 13 -
agent, such as dicyclohexylcarbodiimide, or a catalytic
quantity of an inorganic acid, e.g. hydrochloric acid,
optionally prepared in 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, according to a feature of the invention,
(a) compounds of formula I wherein R3 and/or
R8 and/or R9 is other than a hydrogen atom are prepared
from compounds of formula I wherein R3 and/or R8 and/or
R represents a hydrogen atom by the application or
adaptation of known methods of alkylation; according to
a further feature of the invention, (b) compounds of
formula I containing a sulphonyl group are prepared by
the oxidation of compounds of formula I containing a
sulphinyl or thio group and compounds of formula I -
containing a sulphinyl group are prepared by the
oxidation of compounds of formula I containing a thio
group 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, (c) compounds of formula I wherein RlO
` . `' ', ' . ~ '
-- ' '. ' ' . .
WO92/0~12 PCT/GB91/01375
~9~
14 -
represents a hydrogen atom are prepared from compounds
of formula I wherein R represents a straight- or
branched-chain alkyl group containing up to about lO
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, and optionally interrupted
by one or more sulphinyl or sulphonyl groups, by
hydrolysis of the ester grouping -COORl0 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; and, conversely, according to
a further feature of the invention, (d) compounds of
formula I wherein RlO represents a straight- or
branched-chain alkyl group containing up to about lO
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, and optionally interrupted
by one or more sulphinyl or sulphonyl groups are
prepared by the esterification of compounds of formula
I wherein Rl represents a hydrogen atom, by the
application or adaptation of known methods.
By the term "pharmaceutically acceptable salts"
as used in this specification is meant acid addition
,
: ' ' ' ' , '
WO92/0~12 PCT/G~91~01375
20~9151
salts the anions of which are relatively innocuous to
the animal organism when used in therapeutic doses so
that the beneficial pharmaceutical properties of
the compounds of formula I are not vitiated by
side-effects ascribable to those anions and salts
formed with bases such as alkali metal, e.g. sodium or
potassium, salts and alkaline earth metal, e.g. calcium
or magnesium, salts, the cations of which are
relatively innocuous to the animal organism when used
in therapeutic doses so that the beneficial
pharmaceutical properties of the compounds of formula I
are not vitiated by side-effects ascribable to those
cations.
It is to be understood that, where in this
specification reference is made to the compounds o~
formula I, it is intended to refer also, where the
context so permits, to their pharmaceutically
acceptable salts.
Suitable acid addition salts for use in
pharmaceuticals may be selected from salts derived from
inorganic acids, for example hydrochlorides,
hydrobromides, phosphates, sulphates and nitrates, and
organic acids, for example oxalates, lactates,
tartrates, acetates, salicylates, citrates,
propionates, succinates, fumarates, maleates,
methylene-bis-~-hydroxynaphthoates, gentisates and
di-p-toluoyltartrates.
W092/0~12 PCTtGBgl/01375
2~9~
- 16 -
~ s well as being useful in themselves as active
compounds, salts of the compounds of formula I are
useful for the purposes of purification of the parent
compounds, for example by exploitation of the
solubility differences between the salts and the parent
compound, by techniques well known to those skilled in
the art.
The salts can be prepared from the parent
compounds of formula I by the application or adaptation
of known methods, and the parent compounds of formula I
can be prepared from the salts by the application or
adaptation of known methods.
The compounds of formula I can be purified by
~he usual physical means, for example by
crystallisation or chromatography.
Compounds of formulae II, III, IV, V, VI and VII
may be prepared by the application or adaptation of
known methods.
For example, acid halides of formula VII wherein
zl represents a halogen atom may be prepared from the
corresponding carboxylic acids of formula VII wherein
zl represents a hydroxy group by the application or
adaptation of known methods, e.g., when zl represents a
chlorine atom, by reaction with thionyl chloride or
oxalyl chloride.
... -. :
.
,.
: .. . : -
' .......... :
WO92/0~12 2 ~ PCT/GB91/0137S
- 17 -
Similarly, acid halides of formula III wherein
zl represents a halogen atom may be prepared from the
corresponding carboxylic acids of the general formula~-
Rl-C(R2)2COOH (VIII)
wherein Rl and R2 are as hereinbefore defined, by the
application or adaptation of known methods, e.g., when
zl represents a chlorine atom, by reaction with thionyl
chloride or oxalyl chloride.
Compounds of the general formula:-
Rl2-C(R2)2COOH (IX)
within formula VIII, wherein R 2 represents an
alkoxyalkyl or, more particularly, an alkoxyalkoxyalkyl
or, especially, an alkoxyalkoxyalkoxyalkyl, group, and
R2 is as hereinbefore defined, are key intermediates
and they, a process for their preparation, and their ~ -
use in synthesis of useful pharmaceuticals, e.g.
compounds of formula I, form features of the present
invention.
According to a feature of this invention,
compounds of formula IX are prepared by the oxidation
- of compounds of the general formula:-
R12-C (R2 ) 2CH20H (X)
wherein Rl2 and R2 are as hereinbefore defined, by the
application or adaptation of known methods, for example
by reaction with an alkali metal halite such as sodium
bromite and a free radical such as 2,2,6,6-tetramethyl-
- . ............... ..
' '
-::
WO92/0~12 PCT/GB91/01375
2 ~
- 18 -
1-piperidinyloxy free radical.
This reaction is preferably carried out in the
presence of a base such as an aqueous solution of an
alkali metal carbonate or bicarbonate, and in the
presence of a suitable solvent such as acetonitrile,
preferably at or, more especially below room
temperature.
, : .. ~ ".. ,
.. . . .
,:: : . : . .
' ' .
. . .
W O 92/034t~2 0 8 91 5 1 PC'r/GB91/01375
_ 19 _
coR5 ,,
R1C(R2)2CoWR3 ~ I
~4 ;
~:
CoR5
~R3N ~ II
~4
' ', ' ' .
C~Z
R1C(R2)2CoNR3 ~ VII
:' ~
R4
~ . , . - ~ - .
` :~ , '.- ': '
`:~ . - . . . .
~. .
W092/0~l2 2 ~ 8 9151 PCT/GB91/01375
- 20 -
The following Examples illustrate the
preparation of the compounds according to the
invention. Examples 1 to 16 illustrate the
preparation of compounds of general formula I, Examples
17 and 18 illustrate the preparation of key
intermediates of general formula IX, and the Reference
Examples illustrate the preparation of other
- intermediates.
EXAMPLE 1
Com~ound A
A stirred solution of oleic acid (4.20g) and
triethylamine (1.8g) in dichloromethane (50ml was
treated with methyl chloroformate (1.7g) at -30C.
The mixture was stirred for 2 hours, allowing it to
warm to the ambient temperature. It was then treated
with a solution of N-(2-methylthio)ethyl-4-methylthio-
3-aminobenzamide (4.0g) and triethylamine (2.5g) in
dichloromethane (50ml). The resulting clear solution
was left to stand for 17 hours and was then diluted
with dichloromethane (250ml), washed sequentially with
hydrochloric acid (200ml;1N), aqueous sodium chloride
solution, saturated aqueous sodium hydrogen carbonate
solution (lOOml) and finally with aqueous sodium
chloride solution, dried over magnesium sulphate and
concentrated under reduced pressure. The resulting
residue was dissolved in diethyl ether (250ml) and the
.: . ,: ;
. . , . :.
.
, ~ , .
W092/0~12 2 ~ 8 915 1 PCT/GBgl/01375
- 21 -
solution was washed with hydrochloric acid
(2xl50ml;2N), dried over magnesium sulphate and
concentrated under reduced pressure. The resulting
residue was crystallised from a mixture o~ petrol
(b.p. 40-60C) and diethyl ether, to give a waxy solid~
which was subjected to column chromatography on silica
gel, eluting with ethyl acetate, and recrystallised
from t-butyl methyl ether, to give (Z)-N-(2-methyl-
thio)ethyl-4-methylthio-3-(octadec-9-enamido)benzamide
(0.7g) in the form of a colourless, soft solid, m.p.
84-86C. [Elemental analysis:-C,67.4;H,9.5;N,5.1;
S,12.2%; calculated:- C,66.88;H,9.29;N,5.38;S,12.31%].
EXAMPLE 2
Com~ound B
An ice-cooled solution of N-(2-methoxy)ethyl-3=
amino-4-(methylthio)benzamide (3.99g) in dry dichloro-
methane (50ml) and dry triethylamine (2.79ml) was
slowly treated with a solution of oleoyl chloride (5g)
in dry dichloromethane (3Oml). The mixture was
stirred at the am~ient temperature for 2.5 hours and
was then concentrated under reduced pressure, to leave
a solid. This solid was dissolved in ethyl acetate
and the solution was washed sequentially with
hydrochloric açid (2N), aqueous sodium hydroxide
solution (lN) and with water, dried over magnesium
sulphate and concentrated under reduced pressure.
.:
.
- '
WO92/0~12 2 0 ~ 915 ~ PCT/GB9l~01~75
The resulting residue was crystallised from a mixture
of amyl acetate (65ml) and ethyl acetate (Sml), and
then from toluene, to give (Z)-N-(2-methoxy)ethyl-4-
methylthio-3-(octadec-9-enamido)benzamide (4.81g) in
the form of a soft, white solid, m.p. 110-112Co
[Elemental analysis:- C,69.1;H,9.8;N,5.46;S 6.5%;
calculated:- C,69.00;H,9.58;N,5.55;S,6.35%].
EXAMPLE 3
Com~ound C
A solution of methyl 3-amino-4-methoxybenzoate
(3.0g) in dry dichloromethane (50ml) and dry
triethylamine (2.79ml) was slowly treated with a
solution of oleoyl chloride (5g) in dry dichloromethane
(30ml). The mixture was stirred at the ambient
temperature for 45 minutes and was then concentrated
under reduced pressure. The resulting solid was
crystallised from aqueous ethanol, to give brown
crystals (6.63g), of which a sample (250mg) was
recrystallised from ice-cold petrol (b.p. 40-60C)
containing a trace of methanol, to give (Z)-methyl
4-methoxy-3-(octadec-9-enamido)benzoate (195mg), in the
form of off-white crystals, m.p. 46-47C. tElemental
analysis:- C,72.2;H,9.65;N,3.18%; calculated~- C,72.77;
H,9.72;N,3.14%].
.
W092/0~12 2 a 8 ~1 5 ~ PCT/GB91~01375
EXAMPLE 4
Com~ound K
A stirred, ice-cooled solution of (Z)-4-methoxy-
3-(octadec-9-enamido)benzoyl chloride (1.5g) tprepared
by the reaction of thionyl chloride with (Z)-4-methoxy~
3-(octadec-9-enamido)benzoic acid (itself prepared as
described hereinafter in Example 7)] in dichloromethane
(20ml) was treated with a solution of butylamine (0.5g)
in dry dichloromethane (lOml). The mixture was
stirred at the ambient temperature for 1 hour and was
then concentrated under reduced pressure. The
resulting residue was crystallised from cyclohexane and
then recrystallised from a mixture of diethyl ether and
pentane to give (Z)-N-butyl-4-methoxy-3-(octadec-9-
enamido)benzamide (0.474g) in the form of a grey solid~
m.p. 81-82C. [Elemental analysis:- C,73.9;H,10.4;
N,S.7%; calculated:- C,74.03;H,10.35;N,5.76%].
EXAMPLE S
Com~ounds D E. F. G. H. I and J
A solution of N-(2-methylthio)ethyl-3-amino-4-
(methylthio)benzamide (3.0g) and dry triethylamine
(3.0g) in dry dichloromethane (50ml) was treated with a
solution of hexadecanoyl chloride (3.4g) in dry
dichloromethane (20ml). The solution was stirred at
the ambient temperature for 3 hours and was then
diluted with dichloromethane (250ml). The solution
' '
--
W092/0~l2 2 0 8 91 51 PCT/GB9l/0l375
- 24 -
was washed with hydrochloric acid (lOOml;lN), dried
over magnesium sulphate and concentrated under reduced
pressure, and the resulting solid was recrystallised
from a mixture of t-butyl methyl ether and ethanol
(9:lv/v), to give N-(2-methylthio)ethyl-3-hexadecan-
amido-4-(methylthio)benzamide (5.14g) in the form of
white crystals, m.p. 104-105C. [Elemental
analysis:- C,65. 3 jH,9.4jN,5.6jS, 13.2%; calculatedo-
C,65.54jH,9.37;N,5.66;S,12.96%].
By proceeding in a similar manner, but using the
appropriate acid chloride and the appropriate
aminobenzamide derivative, there were prepared:-
N-butyl-3-hexadecanamido-4-~methylthio)benzamide,in the
form of white crystals, m.p. 125-126C [Elemental
analysis:- C,70.4;H,10.18;N,5.88;S,6.95%; calculatedo~ -
C,70.54;H,10.15;N,5.88;S,6.73%];
N-(2-methoxy)ethyl-3-hexadecanamido-4-(methylthio)-
benzamide in the form of white crystals, m.p. 115-
117C tElemental analysis:- C,68.1;H,9.9;N,5.8;S,6.88%;
calculated:- C,67.74;H,9.69;N,5.85;S,6.70%];
N-butyl-3-dodecanamido-4-(methylthio)benzamide in the
form of white crystals, m.p. 1~26-128C [Elemental
analysis:- C,68.4;H,9.6;N,6.7;S,7.7%; calculated:-
C,68.53;H,9.58;N,6.66;S,7.62%];
N-(2-methoxy)ethyl-3-dodecanamido-4-(methylthio)-
W~92t0~12 PCTtGB~J01375
20~3~5 1 ~
benzamide in the form of white crystals, m.p. 113-115C
[Elemental analysis:- C,65.3;H,9.2;N,6.6;S,7.6%;
calculated:- C,65.37;H,9.06;N,6.63;S,7.59%];
N-(2-methylthio)ethyl-3-dodecanamido-4-(methylthio)-
benzamide in the form of white needles, m.p. 102-104C
[Elemental analysis:- C,63.1;~,8.8;N,6.7;S,14.7%;
calculated:- C,62.97;H,8.73;N,6.39;S,14.62%]; and
N-butyl-N-methyl-3-hexadecanamido-4-methoxybenzamide in
the form of an off-white powder [from petrol (b.p.
100-120C)], m.p. 66-68C [Elemental analysis:- C,73.2;
H,10.8;N,5.61%; calculated:- C,73.37;H,10.62;N,5.90%].
EXAMPLE 6
Compound L
A solution of 1-decylcyclopentanecarboxylic acid
(2.lg) and thionyl chloride (3ml) in dry dichloro~
methane (30ml) was hsated at reflux for 3 hours. The
reaction mixture was concentrated under reduced
pressure and the resulting residue was dissolved in
dichloromethane (30ml) and added to a solution of dry
triethylamine (2.4g) and N-(2-methylthio)ethyl-3-amino-
4-(methylthio)benzamide (2.16g) in dichloromethane
(5Oml). The mixture was stirred at the ambient
temperature for 1 hour, then it was diluted with
dichloromethane (lOOml) and washed sequentially with
hydrochloric acid (lOOml;lN), aqueous sodium chloride
solution (lOOml), aqueous potassium hydroxide solution
W092/0~l2 2 ~ 1 PCTtGB91~01375
(1.5g in lOOml), hydrochloric acid (lOOml;lN) and with
aqueous sodium chloride solution (lOOml), dried over
magnesium sulphate and concentrated under reduced
pressure. The resulting residue was chromatographed
on silica gel, eluting with t-butyl methyl ether~ to
give N-(2-methylthio)ethyl-3-(1-decylcyclopentane-
carboxamido)-4-(methylthio)benzamide (3.15g) in the
form of a waxy solid.
[Elemental analysis:- C,66.2;H,9.4jN,5.24;S,12.3%;
calculated for C27H44N202S2:1/ 5 12
C,65.94;H,9.27;N,5.36;S,12.28%].
EXAMPLE 7
Compounds M and N
A mixture of (Z)-methyl 4-methoxy-3-(octadec-9-
enamido)benzoate (6.12g; prepared as described in
Example 3), sodium hydroxide (0.6g), water (20ml) and
ethanol (200ml) was heated at reflux for l.S hours.
The mixture tcontaining (Z)-sodium 4-methoxy-3-(octa-
dec-9-enamido)benzoate] was cooled to the ambient
temperature and was then poured onto a mixture of
crushed ice and concentrated hydrochloric acid. The
product was collected and recrystallised from methanol,
to give (Z)-4-methoxy-3-(octadec-9-enamido)benzoic
acid (4.14g) in the form of a white powder, m.p.
179-183C. ~Elemental analysis:- C,72.3;H,9.5;
N,3.3%; calculated:- C,72.35;H,9.S7;N,3.24%].
?
:. :
. ~
'' -.:' ~ ' ~ :
W092/n~l2 PCT/GB91/01375
.
2a8~
- 27 -
EXAMPLE 8
Com~ounds O to V
By proceeding in a manner similar to that
described in Example 5, but employing the appropriate
acid chlorides and the appropriate anilines, and simply
removing the solvent under reduced pressure at the end
of the reaction period and crystallising the residue ,
there were prepared:-
N-butyl-3-dodecanamido-4-(ethylthio)benzamide, in the
form of white plates, m.p. 102-104C (from aqueous
ethanol) [Elemental analysis:- C,69.0;H,9.9;N,6.4;
S,7.4%; calculated:- C,69.08;H,9.74;N,6.45;S,7.37%];
N-butyl-4-ethylthio-3-hexadecanamidobenzamide, in the
form of white crystals, m.p. 89-91C (from aqueous
ethanol) [Elemental analysis:- C,70.9;H,10.3;N,5.4;
S,6.57%; calculated:- C,70.97jH,10.27;N,5.71;S,6.53%~;
N-butyl-4-ethylthio-3-heptadecanamidobenzamide, in the
form of white crystals, m.p. 81-83C (from aqueous
ethanol) [Elemental analysis:- C,71.1;H,10.7;N,5.3;
S,6.09%; calculated:- C,71.37;H,10.38;N,5.55;S,6.35%~;
N-butyl-4-ethylthio-3-octadecanamidobenzamide, in the
form of white crystals, m.p. 80-82C (from aqueous
ethanol) [Elemental analysis:- C,71.6;H,10.8;N,5.3;
S,6.02%; calculated:- C,71.76;H,10.49;N,5.40;S,6.18%];
4-ethylthio-3-hexadecanamido-N-(2-methylthioethyl)-
.i .
~ -92/0~12 2 0 8 91~1 PCT/GB9lJ01375
- 28 -
benzamide, in the f~rm of white crystals, m.p. 92 94C
(from aqueous ethanol) [Elemental analysis:- C,66.5;
H,9.7;N,5.5;S,12.5%; calculated:- C,66.09;H,9.51;
N,5.51;S,12.60%];
4-ethylthio-3-heptadecanamido-N-(2-methylthioethyl~
benzamide, in the form of white crystals, m.p. 91-93C
(from aqueous ethanol) tElemental analysis:- C,66.5;
H,9.7;N,5.36;S,12.0%; calculated:- c,66.62;H,9.64;
N,5.36;S,12.26%];
3-heptadecanamido-4-methylthio-N-(2-methylthioethyl)-
benzamide, in the form of white crystals, m.p.
101-102C (from aqueous ethanol and then from ethyl
acetate) tElemental analysis:- C,66.5;H,9.8;N,5.50;
S,12.6%; calculated:- C,66.0g;H,9.51;N,5.51;S,12.60%~;
and
3-heptadecanamido-N-(2-methoxyethyl)-4-(methylthio)-
benzamide, in the form of white crystals, m.p.
115-116C (from aqueous ethanol and then from
isopropanol) [Elemental analysis:- C,68.4;H,10.10;
N,5.65;S,6.50%; calculated:- C,68.25;~,9.82jN,5.69;
S,6.50%].
EXAMPLE 9
Compound W
By proceeding in a manner similar to that
described in Example 2, but replacing the
- ,
''. : ' `~ :
. ' `, ` `: " ' :
:
WO92/0~12 PCT/GB91/01375
2 0 s s ~
- 29 -
N-(2-methoxy)ethyl-;-amino-4-(methylthio)benzamide by
the appropriate quantity of 3-amino-N-butyl-4-(methyl-
thio)benzamide and crystallising the product from
toluene, there was prepared (Z)-N-butyl-3-octadec-9-
enamido-4-(methylthio)benzamide, in the form of a soft~
pale brown solid, m.p. 118-120C [Elemental analysis--
C,71.3;H,lO.O;N,5.59;S,6.37%; calculated:- C,71.66;
H,10.02;N,5.57;S,6.38~].
EXAMPLE 10
Com~ounds X to AJ
By proceeding in a manner similar to that
described in Example 5, but employing the appropriate
acid chlor~des and the appropriate anilines, there were
prepared:-
4-ethylthio-N-(3-methylthiopropyl)-3-octadecanamido-
benzamide, in the form of colourless crystals, m.p.
75-76C (from a mixture of t-butyl methyl ether and
methanol) [Elemental analysis:- C,67.4;H,lO.O;N,5.0;
S,11.6%; calculated:- C,67.59;H,9.88;N,5.08;S,11.64%];
4-ethylthio-3-heptadecanamido-N-(3-methylthiopropyl)-
benzamide, in the form of white crystals, m.p. 74-77C
(from a mixture of t-butyl methyl ether and methanol)
[Elemental analysis:- C,67.5;H,lO.OO;N,5.30;S,11.70%;
calculated:- C,67.11;H,9.76;N,5.22;S,11.95%];
4-ethylthio-3-hexadecanamido-N-(3-methylthiopropyl)-
WO92/0~12 2 0 8 ~ ~ ~1 PCT/GB9ll0l~7~ 1
- 30 -
benzamide, in the form of white crystals, m.p. 75-7~C
(from a mixture of t-butyl methyl ether and methanol~ ,
~Elemental analysis:- C,66.5;H,9.7;N,5.11;S,11.9%;
calculated:- C,66.62jH,9.64jN,5.36jS,12.26%];
4-methylthio-N-(2-methylthioethyl)-3-octadecanamido
benzamide, in the form of white crystals, m.p.
104-106C (from a mixture of t-butyl methyl ether and
methanol) [Elemental analysis:- C,66.6;H,9.9;N,5.2;
S,12.0%; calculated:- C,66.62;H,9.64;N,5.36;S,12.26%~;
N-butyl-3-dodecanamido-4-methoxybenzamide, in the form
of white crystals, m.p. 107-109C (from t-butyl methyl
ether) [Elemental analysis:- C,70.9;H,lO.lO;N,6.72%;
calculated:- C,71.24;H,9.96;N,6.93%];
4-ethylthio-3-hexadecanamido-N-(3-methoxypropyl)-
benzamide, in the form of white crystals, m.p. 78~80~C
(from acetonitrile) tElemental analysis:- C,68.4;
H,9.93,N,5.1;S,6.21%; calculated:- C,68.73;H,9.94;
N,5.53;S,6.33%];
N-butyl-3-octadecanamido-4-(methylthio)benzamide, in
the form of a white powder, m.p. 115-118C (from a
mixtllre of t-butyl methyl ether and methanol)
[Elemental analysis:- C,71.6;H,10.7;N,5.13;S,5.79%;
calculated:- C,71~38;H,10.38;N,5.55;S,6.35%];
4-methylthio-N-(3-methylthiopropyl)-3-octadecanamido-
benzamide in the form of a white powder, m.p. 87-94C
(from toluene) ~Elemental analysis:- C,66.6;H,9.85;
W092/0~l2 PCT/CB91/0137S
2 ~9 ~ 31 -
N,4.83;S,11.65%; calculated:- C,67.12;H,9.76;N,5.22,o
S,11.94%];
4-ethylthio-N-(3-methoxypropyl~-3-octadecanamido-
benzamide, in the form of a white powder, m.p. 80-83OC
tfrom toluene) tElemental analysis:- C,69.7;H,10.3~
N,5.07;S,5.87%; calculated:- C,69.62;H,10.18;N,5.24;
S,5.99%];
N-butyl-3-(5-chloropentanamido)-4-(ethylthio)benzamide,
in the form of a white powder, m.p. 104-105C (from
t-butyl methyl ether) [Elemental analysis:- C,58.2;
H,7.4;Cl,9.6;N,7.5;S,8.6%; calculated:- C,58.28;H,7.34;
Cl,9.56;N,7.55;S,8.64%];
3-(4-chlorobutanamido)-4-ethylthio-N-(3-methylthio-
propyl)benzamide in the form of a white powder, m.p.
80-81C (from a mixture of t-butyl methyl ether and
methanol) [Elemental analysis:- C,52.2;H,6.87jCl,9.5;
N,7.3;S,15.7%; calculated:- C,52.49;H,6.48;Cl,9.11;
N,7.20;S,16.49%];
3-(5-chloropentanamido)-4-ethylthio-N-(3-methylthio-
propyl)benzamide, in the form of a pale yellow powder,
m.p. 95-960C (from a mixture of t-butyl methyl ether
and methanol) [Elemental analysis:- C,53.7;H,6.87;
Cl,8.8;N,6.82;S,15.6%; calculated:- C,53.65;H,6.75;
Cl,8.80;N,6.85;S,15.91%]; and
methyl 3-hexadecanamido-4-methoxybenzoate, in the form
of colourless needles, m.p. 109-110C (from ethanol)
: '
~ -
:- ' ' :
W092/0~12 ~PCT/GB91iOI375
2 ~ ~ 9 ~ 5 1
- 32 -
[Elemental analysis:- C,71.1;H,9.9;N,3.26%;
calculated:- C,71.56;H,9.8S;N,3.34%].
EXAMPLE 11
Com~ounds AK and AL
By proceeding in a manner similar to that
described in Example 7 but replacing the (Z)-methyl
4-methoxy-3-(octadec-9-enamido)benzoate by the
corresponding quantity of methyl 3-hexadecanamido-4-
methoxybenzoate (prepared as described in Example 10)~
there was prepared 3-hexadecanamido-4-methoxybenzoic
acid, in the form of c~lourless needles, m.p. 198-200C
(from ethanol) tElemental analysis:- C,71.1;H,9.8;
N,3.40%; calculated:- C,71.07;H,9.69;N,3.45%], via
sodium 3-hexadecanamido-4-methoxybenzoate.
EXAMPLE 12
ComPound AM
A mixture of 3-hexadecanamido-4-methoxybenzoic
acid (4.04g; prepared as described in Example 11) and
thionyl chloride (1.3ml) was heated in boiling toluene
(lOOml) for 3 hours. The solvent was removed under
reduced pressure. The residual acid chloride was
dissolved in dry dichloromethane (35ml) and was added
to a stirred solution of 2-methoxyethylamine (3ml) and
dry triethylamine (1.6ml) in dichloromethane (115ml).
After standing at the ambient temperature for 2 days,
the solution was washed with hydrochloric acid
: ,~
.:
. .
.
W092/0~12 PCT/GB91/0137~
f~;' !
33 -
(2x200ml;2N) and then with water (2x200ml) and was then
it was dried over potassium carbonate and concentrated
under reduced pressure. The resulting residue was
chromatographed on silica gel, eluting with a mixture
of diethyl ether and dichloromethane, to give
3-hexadecanamido-4-methoxy-N-(2-methoxyethyl)benzamide
(2.0g), in the form of a white powder, m.p. 78-80C
tElemental analysis:- C,69.8;H,10.3;N,5.90%;
calculated:- C,70.09;H,10.02;N,6.06%].
EXAMPLE 13
Com~ound AN
A solution of 3-hexadecanamido-4-methoxybenzoyl
chloride [prepared from 3-hexadecananamido-4-methoxy-
benzoic acid (2.02g; prepared as described in Example
11) and thionyl chloride~ in dichloromethane (50ml) was
added to a stirred solution of 3-methylbut-2-enylamine
hydrochloride (0.98g) in dichloromethane (lOOml) and
triethylamine (lml). The mixture was stirred at the
ambient temperature for 1 hour and was then washed
succesively with water (lOOml), aqueous sodium
hydroxide solution (lOOml;2N), dilute hydrochloric acid
(lOOml;2N) and with water (lOOml), and it was then
dried over magnesium sulphate and concentrated under
reduced pressure . The resulting residue was
chromatographed on silica gel, eluting with a mixture
of methanol and dichloromethane, to give 3-hexadec-
.
-, .
W092/034l2 2 0 ~ 1 PCT/&B9~/0~375
- 34 -
anamido-4-methoxy-N-(3-methylbut-2-enyl)benzamide
(0.6g), in the form of a cream solid, m.p. 109-111C
after crystallisation from a mixture of petrol (b~po
40-600c) and diethyl ether tElemental analysis:-
C,73.2;H,10.3;N,5.60%; calculated:- C,73.68;HtlO~24,o
N,5.93%].
EXAMPLE 14
ComPounds AO to AZ
A solution of 5,9-dioxahexadecanoyl chloride in
dichloromethane [prepared from 5,9-dioxahexadecanoic
acid (2.0g; prepared as described in Example 17) and
oxalyl chloride (2.4ml) in dichloromethane (25ml)] was
added to a stirred suspension of 3-amino-N-butyl-4-
(methylthio)benzamide (1.83g) in dry dichloromethane
(25ml) an,d triethylamine (2.5g), produclng a clear
solution. After standing at the ambient temperature
for 65 hours, the solution was concentrated under
reduced pressure to about lOml. The residue was taken
up in t-butyl methyl ether (300ml) and was washed
sequentially with dilute hydrochloric acid (lOOml;
0.5N), aqueous sodium hydroxide solution (lOOml;2%w/v)
and with dilute hydrochloric acid (lOOml;0.5N) and was
then dried and concentrated under reduced pressure.
The resulting residue was chromatographed on silica
gel, eluting with ethyl acetate, to give N-butyl-4-
.
- ~ .
.
.
W092/0~12 PCT/GB~1/0~37~
2~9~ 35 -
methylthio-3-(5,9-dioxahexadecanamido)benzamide (2O05g)
in the form of a pale yellow, waxy solid [Elemental
analysis:- C,65.4;H,9.6;N,5.93;S,6.42%; calculated~
C,64.96;H,9.23;N,5.83;S,6.67%].
By proceeding in a similar manner, but using the
appropriate acids and the appropriate anilines, there
were prepared:-
4-methylthio-N-(3-methylthiopropyl)-3-(5,9-dioxahexa-
decanamido~benzamide, in the form of a pale yellow,
waxy solid [Elemental analysis:- C,61.0;H,8.9 jN,5.36;
S,12.4%; calculated:- C,60.90;H,8.65;N,5.46;S,12.51%]
N-butyl-4-ethylthio-3-(5,9,13-trioxahexadecanamido)-
benzamide, in the form of an amber oil [Elemental
analysis:- C,62.5;H,9.1;N,5.7;S,6.43%; calculated:-
C,62.87;H,8.93;N,5.64;S,6.46%];
4-ethylthio-N-(3-methylthiopropyl)-3-(5,9-dioxahexa-
decanamido)benzamide, in the form of a pale yellow,
waxy solid (eluting with a mixture of dichloromethane
and methanol) [Elemental analysis:- C,61.4;H,8.91;
N,5.34;S,12.0%; calculated:- C,61.56;H,8.80;N,5.32;
S,12.17%~;
N-butyl-4-ethylthio-3-(5,9-dioxahexadecanamido)-
benzamide, in the form of a pale brown oil (eluting
with a mixturè of dichloromethane and methanol)
[Elemental analysis:- C,65.4;H,9.6;N,5.5;S,6.26%;
calculated:- C,65.55;H,9.37;N,5.66;S,6.48%];
. .
20~ 5~
~92~0~12 PCT/GB91/01375
4-ethylthio-N-(3-methoxypropyl)-3-(5,9-dioxahexa-
decanamido)benzamide, in the form of a pale brown oil
(eluting with a mixture of dichloromethane and
methanol) [Elemental analysis:- C,63.2;H,9.1;N,5.2;
S,6.12%; calculated:- C,63.50;H,9.08;N,5.48;S,6.28%~;
4-ethylthio-N-(3-methoxypropyl)-3-(5,9,13-trioxahexa-
decanamido)benzamide, in the form of a pale brown oil
tElemental analysis:- C,60.5;H,8.7;N,5.16;S,6.08%;
calculated:- C,60.91;H,8.65jN,5.46;S,6.25%];
4-ethylthio-N-(3-methoxypropyl)-3-(5-oxahexadecan-
amido)benzamide, in the form of a pale brown oil that
solidified on standing (eluting with a mixture of
dichloromethane and methanol) ~Elemental analysis:-
C,66.4;H,9.8;N,5.35;S,6.24%; calculated:- C,66.10;
H,9.51;N,5.51;S,6.30%];
4-methylthio-N-(3-methylthiopropyl)-3-(5-oxahexa-
decanamido)benzamide, in the form of a pale brown oil
that solidified on standing (eluting with a mixture of
dichloromethane and methanol) tElemental analysis:-
C,63.6;H,9.3;N,5.48;S,11.9%; calculated:-
Cl63.49;H,9.08;N,5.17;S,12.55%];
N-butyl-4-methylthio-3-(5-oxahexadecanamido)benzamide,
in the form of a pale brown oil that solidified on
standing (eluting with a mixture of dichloromethane and
methanol) [Elemental analysis:- C,68.0;H,9.9;N,5.6;
S,6.24%; calculated:- C,67.74;H,9.69;N,5.85jS,6.70%];
.
.
. ; . ' ~
WO92/0~12 PCT/GB91~0l37~
,~
2~8~ 37 -
4-methoxy-N-(3-methylthiopropyl)-3-(5,9-dioxahexa-
decanamido)benzamide, in the form of a pale brow~ oil
(eluting with a mixture of dichloromethane and
methanol) tElemental analysis:- C,62.5;H,9.2;N,5.48;
S,6.19%; calculated:- C,62.87;H,8.93;N,5.64;S,6.46%]s
and
4-ethylthio-N-t3-methylthiopropyl)-3-(5,9,13-trioxa-
hexadecanamido)benzamide, in the form of a pale brown
oil (eluting with a mixture of dichloromethane and
methanol) [Elemental analysis:- C,58.2;H,8.5;N,4.96;
S,11.3%; calculated:- C,59.06;H,8.39;N,5.30;S,12.13%].
EXAMPLE 1S
Compound BA
Heptadecanoyl chloride (2.79g) was added
dropwise during lo minutes to a stirred solution of
methyl 3-amino-4-(imidazol-1-yl)benzoate (2.0g;
prepared as described in Reference Example 1) in dry
pyridine (60ml). When the reaction was complete
(judging by a thin-layer chromatogram), water (300ml)
was added. The precipitated solid was collected,
washed with water and dried and was then dissolved by
heating in ethyl acetate (60ml) containing hydrochloric
acid (lml). The solid which crystallised on cooling
was collected, was washed with diethyl ether and was
dried at 80C, to give methyl 3-heptadecanamido-4-
: .
~92/0~12 2 ~ 8 9 1 51 PCT/GB91/01375
- 38 -
(imidazol-l-yl)benzoate in the form of white crystals
of the hydrated hydrochloride, m.p. 106-109C
tElemental analysis:- C,64.7;H,8.6;N,7.9;Cl,6.83;water,
3.8~; calculated for C28R43N303.HCl.H20:- C,64.72;
H,8.99;N,7.81;Cl,6.59;water,3.35%].
.~ ~ , . .. . ~ .
. ;.' . . : ' ' ` . , ~. , ~. : ':
.
.
~ .
WO92/0~12 PCT/GB91/01375
208~
- 39
EXAMPLE 16
Com~ounds BB to BG
By the application or adaptation of methods
described hereinbefore, more especially in the
preceding Examples, there were prepared:-
N-(3-methylsulphonylpropyl)-4-methylthio-3-(5,9-dioxa-
hexadecanamido)benzamide, in the form of a pale brown
oil which solidified on standing;
4-ethylthio-N-(3-methylthiopropyl)-3-(5,9-dioxaoctadec-
anamido)benzamide, in the form of a pale brown oil
tElemental analysis:- C,63.1;H,9.5;N,4.37%;
calculated:- C,62.78;H,9.08;N,5.05%];
N-butyl-4-ethylthio-3-(5,10-dioxahexadecanamido)-
benzamide, in the form of a pale yellow solid;
4-ethylthio-N-(3-methylthiopropyl)-3-(6,10,14-
trioxahexadecanamido)benzamide, in the form of a pale
brown oil tElemental analysis:- C,58.0;H,8.5;N,5.30;
S,11.0%; calculated:- C,59.06;H,8.39;N,4.95;S,12.13%~;
4-imidazol-1 yl-N-(3-methylthiopropyl)-3-(5-oxahexa-
decanamido)benzamide, in the form of a white powder,
m.p. 77-79C [Elemental analysis:- C,66.0;H,8.9;
N,10.7~; calculated:- C,65.62;H,8.74;N,}0.56%]; and
3-hexadecanamido-4-imidazol-1-yl-N-(3-methylthio-
propyl)benzamide, in the form of a white powder, m.p.
104-105C [Elemental analysis:- C,68.6;H,9.4;N,10.7%;
calculated:- C,68.14;H,9.15;N,10.60%].
, ~ ` ' '' -, ' ' : ,
.
.
: - :
.
WO92/0~12 PCT/GB91/01375
f^ 208~151
- 40 -
EXAMPLE 17
Compounds INT a INT b and INT c
Sodium bromite trihydrate (35.0g) was added to a
cooled, vigorously stirred mixture of 5,9,13-trioxa-
hexadecan-1-ol (11.5g), 2,2,6,6-tetramethyl-1-piperid-
inyloxy, free radical (0.25g), aqueous sodium hydrogen
carbonate solution (450ml;5%w/v) and acetonitrile
(450ml) maintaining a temperature of from 0C to 10C.
The mixture was stirred at the ambient temperature for
4 hours and then the reaction was quenched by the
careful addition of sufficient hydrochloric acid and
aqueous sodium metabisulphite to give a pH of from 2 to
4 and to consume excess oxidant. The solution was
extracted with t-butyl methyl ether (4x200ml) and the
combined organic solution was washed with aqueous
sodium chloride solution, dried and concentrated under
reduced pressure. The resulting residue was
distilled at an oven temperature of 170C and a
pressure of O.lmmHg, to give 5,9,13-trioxahexadecanoic
acid (10.3g) in the form of a colourless, mobile oil.
tElemental analysis:- C,59.52;H,9.99%; calculated:-
C,59.9;H,10.9~].
By proceeding in a similar manner, but replacing
the 5,9,13-trioxahexadecan-1-ol by the appropriate
quantities of 5,9-dioxahexadecan-1-ol and 5-oxahexa-
. ~...... . .
: . :
. - - ,
WO 92/03412 PCI'/GB91/01375
2~89~
- 41 -
decan-l-ol, respectively, and with the difference that
the residue left after concentrating under reduced
pressure was taken up in t-butyl methyl ether, filtered
to remove solids, and concentrated under reduced
pressure again before distilling, there were prepared
5,9-dioxahexadecanoic acid, in the form of a
colourless, mobile oil [Elemental analysis:- C,64.9;
H,11.3%; calculated:- C,64.58;H,10.84%]; and
5-oxahexadecanoic acid, in the form of a colourless,
mobile oil which solidified, m.p. 28-30C [Elemental
analysis:- C,68.5;H,11.6%; calculated:-
C,69.72;H,11.70%].
W092/034l2 Z O ~ 9 1 5 I PCT/G~9l/01375
- 42 -
EXAMPLE 18
ComDounds INT d INT e and INT f ¦
By proceeding in a manner similar to that
described in Example 17, but using the appropriate
alcohols, there were prepared:- j
6,10,14-trioxahexadecanoic acid, in the form of a
colourless, mobile oil tElemental analysis:- C,5705;
H,10.0%; calculated:- C,59.52;H,9.99~];
5,10-dioxahexadecanoic acid, in the form of a
colourless, mobile oil, b.p. 97-105C/0.lmmHg :
tElemental analysis:- C,66.1;H,11.5%; calculated:-
C,64.58;H,10.84%]; and
5,9-dioxahexadecanoic acid, in the form of a
colourless, mobile oil tElemental analysis:- C,66.2;
H,11.4%;.calculated:- C,66.63;H,11.18%].
.... .
,
.. . . . .
. ~
W092/0~12 PCT/GB91/01375
~,i~;
~~9 ~ - 43 -
REFERENCE EXAMPLE 1
Methyl 4-(imidazol-1-yl)-3-nitrobenzoate (19.3g)
was reduced by reaction with iron powder (22.0g) in
boiling ethanol (150ml) containing water (35ml) and
hydrochloric acid (1.5ml;lN). Recrystallisation from
ethyl acetate gave methyl 3-amino-4-(imidazol-1-yl)-
benzoate (9.7g) in the form of pale yellow crystals,
m.p. 161-165C.
REFERENCE EXAMPLE 2
Methyl 4-fluoro-3-nitrobenzoate (17.0g) was
reacted with imidazole (13.0g) at the ambient
temperature in dry tetrahydrofuran (lOOml), to give
methyl 4-(imidazol-1-yl)-3-nitrobenzoate (14.68g) in
the form of large yellow needles, m.p. 71-74C (from
t-butyl methyl ether).
REFERENCE EXAMPLE 3
- 4-Ethylthio-N-(3-methoxypropyl)-3-nitrobenzamide
(47.0g) was reduced by reaction with iron powder
(55.0g) in boiling ethanol (750ml) containing
hydrochloric acid (95ml;0.5N). Recrystallisation
from t-butyl methyl ether gave 3-amino-4-ethylthio-
N-(3-methoxypropyl)benzamide (32.4g) in the form of
fine cream needles, m.p. 73-75C.
REFERENCE EXAMPLE 4
Reaction of 3-methoxypropylamine with
4-ethylthio-3-nitrobenzoyl chloride and
:
WO9~/0~12 20~3151 PCT/CB91/01375
- 44 -
recrystallisation from toluene gave
4-ethylthio-N-(3-methoxypropyl)-3-nitrobenzamide in
74~ yield in the form of a yellow solid, m.p.
101-103C.
REFERENCE EXAMPLE 5
A solution of 3-(3-propoxypropoxy)propan-1-ol
(25.39g) and dry pyridine (11.47g) in dichloromethane
(30ml) was added during lo minutes to a stirred
solution trifluoromethanesulphonic anhydride (49.lg) in
dichloromethane (9Oml), keeping the temperature below
0C. The mixture was stirred for 3 hours without
further cooling and was then washed with ice-cold water
(lOOml) and dried. The solution was filtered,
diluted with dichloromethane (lSOml) and was then
stirred with potassium carbonate (27.0g) and
4-hydroxybutyl acrylate (25.2g) overnight at ambient
temperature under an atmosphere of argon. The mixture
was then heated at reflux for 8 hours. The mixture
was filtered, the residue was washed with
dichloromethane (300ml) and the filtrate was then
washed with hydrochloric acid (250ml;1N) and with water
(2x250ml). The residue left after drying and
concentrating under reduced pressure was dissolved in
ethanol (300ml) and was stirred with a solution of
sodium hydroxide (11.4g) in water (65ml) for 4 hours.
The solution was concentrated under reduced pressure to
WO92/0~1~ PCT/GB91/01375
20~9~$~ ~
about 180ml, was diluted with t-butyl methyl ether
(llitre) and was washed with water (2x400ml). The
residue left after drying and concentrating under
reduced pressure was distilled under reduced pressure
to give 5,9,13-trioxahexadecan-1-ol (16.9g) in the form
of a colourless, mobile oil, b.p. 109-113C/O.lmmHgO
By proceeding in a similar manner, but using
the appropriate quantity of 3-heptyloxypropan-1-ol
instead of 3-(3-propoxypropoxy)propan-1-ol, there was
prepared 5,9-dioxahexadecan-1-ol, in the form of a
colourless, mobile oil, b.p. 123-125C/O.lmmHg.
REFERENCE EXAMPLE 6
Lithium aluminium hydride (3.Sg) was carefully
added to a stirred solution of aluminium chloride
(38.98g) in diethyl ether (200ml) under a gentle stream
of nitrogen, keeping the temperature below 15C. The
mixture was stirred for 2 hours and then 2-decyl-1,3-
dioxepane (30.7g) was added during 30 minutes. The
mixture was stirred at reflux for 8 hours and was then
cooled to ambient temperature. Water (50ml) was
added dropwise, followed by diethyl ether (300ml). The
aqueous fraction was extracted with diethyl ether
(3x200ml) and the combined organic solution was then
dried. The solvent was removed and the residue was
distilled, to give 5-oxahexadecan-1-ol (25.24g) in the
form of an oil, b.p. 126-127C/O.lmm~g.
WO92/0~12 2 ~ 51 pcT/Gs9~/ol37~ i
- 46 -
The present invention also includes within its
scope pharmaceutical formulations which comprise at
least one of the compounds of formula I, or a
pharmaceutically acceptable salt thereof, in
association with a pharmaceutically acceptable carrLer
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
- . ~ .
W092/0~12 PCT/GB91/01375
( ...
~9 ~ - 47 -
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
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
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
., : , . . .
,, ~ .:
:' ', ' , "': '
. ~ ~
,,
WO92/0~12 2 0 3 ~ ~ 51 PCT/GB91/01375
- 48 -
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 lO,
mg/kg body weight per day by oral administration.
The following Example illustrates pharmaceutical
compositions according to the present invention.
COMPOSITION EXAMPLE 1
No. 2 size gelatin capsules each containing:-
N-butyl-3-hexadecanamido-4-(methylthio)-
benzamide, 20 mg
lactose l00 mg
starch 60 mg
dextrin 40 mg
magnesium stearate l mg
were prepared in accordance with the usual procedure.
