1~7793~
The present invention relates to fatty acid derivatives.
More particularly, the invention is concerned with thiocarbamoyl-
thio fatty acid derivatives, a process for the manufacture thereof
and pharmaceutical preparations containing same.
. The thiocarbamoylthio fatty acid derivatives provided
by the present invention are compounds of the general formula
:'
A - NH - C~ S (CH2)n ~I)
:' ,~ :
' R2
, wherein Rl and R2 each independently represent a
~ . :
hydrogen or halogen atom or a methyl, methoxy or
~ 10 p-chlorophenoxy group, at least one of Rl and R2
.. being other than hydrogen, Y represents a cyano group
. or a group of the formula -Cl-R3 in which R3 represents
, ~ O
-~ a hydroxy, lower alkoxy or hydroxy-(lower alkoxy) group
, or a group of the formula -N~R4)(R5) in which R4 re-
presents a hydrogen atom and R5 represents a cyclo-
alkyl group containing up to 6 carbon atoms or R4
and R5 each independently represent a hydrogen atom or
a lower alkyl group or R4 and R5 together with the nitrogen
.. ..
`. atom to which they are attached represent a piperidine or
, .,
' A' ~t
- 2 -
` ,
107793~
morpholine ring, A rcpresents a methylene, ethylene,
propylene or -OC~12C1~2- group and n stands for an
integer of from 2 to 10 inclusive,
and pharmaceutically acceptable salts of compounds of formula I in which Y
represents a carboxy group with bases.
As used in this description and in the claims appended
hereto, the term "lo~er" denotes groups containing from 1 to 7 carbon
atoms. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy,
isopropoxy and butoxy. Examples of groups of the formula -N~R )(R )
: 10 are amino, monomethylamino, dimethylamino, monoethylamino, diethyl-
amino, monocyclopropylamino, monocyclobutylamino, monocyclopentyl-
amino, monocyclohexylamino, piperidino and morpholino.
A preferred class of compounds of formula I hereinbefore
comprises those in which R represents a hydrogen atom, i.e. those
; compounds which are monosubstituted in the phenyl ring. Other pre-
Y ferred compounds of formula I are those in which R2 represents a
halogen atom, especially a chlorine atom, and Y represents a group
of the formula -C-R3, especially a lower alkoxycarbonyl or carboxy
group, as-well a those in which A represents a methylene group and
: 20 n stands for 2, 3 or 4, especially 3. An especially preferred com-
. ..
pound of formula I is 4- [ [(p-chlorobenzyl)thiocarbamoyl~thio7 -
. butyric acid ethyl ester.
Examples of salts of the acids of formula I are alkali
metal salts (e.g. sodium and potassium salts), ammonium salts,
'~.'; 5~
_ - 3 -
:................................... .
.
1~377~3~ 4 -
alkaline earth metal salts (e.g. calcium salts) and salts with
c~ines (e.g. monoalkylamines, dialkylamines or trialkylamines).
According to the process provided by the present invention,
the thiocarbamoylthio fatty acid derivatives aforesaid, i.e. the
compounds of formula I hereinbefore and salts of such compounds
in which Y represents a carboxy group with bases, are manu-
factured by reacting a compound of the general formula
;' .
Rl
A - NH - ~ - S~
:'. ~
`: R
:',
, wherein Rl, R2 and A have the significance
given earlier and M represents Na+, K or
:
NH4 ~
with a compound of the general formula
,~
X(CH2)nY (III)
,~'
, wherein X represents a halogen atom and Y
`~ 15 and n have the slgnificance given earlier,
. . ,
or with an alkali metal salt of a halocarboxylic acid of the
general formula
:'~
X(CH2)nCOOH (IV)
; , wherein X and n have the significance
given earlier,
or reacting an isothiocyanate of the general formula
,' '
:
:.
.. ~ .
.
.:; . ~. : ~ :
;, ~
.: . . .
. , .
~ ~ - 5 - 1~77938
A- N =
~2
1 2
, wherein R , R and A have the significance
given earlier,
with a mercaptan of the general formula
. 5 HS -(CH2)n Y (VI)
, wherein Y and n have the significance
given earlier,
and, if desired, saponifying an ester obtained or an amide
obtaLned to an acid, re-esterifying an ester obtained, esterifying
an acid obtalned or converting same into a salt with a base,
hydrolysing a nitrile obtained to an amide or dehydrating an
amide obtained to a nitrile.
,~:
`The reaction of a compound of formula II with a compound
`- of formula III is conveniently carried out in an inert solvent
such as water, acetone, an alcohol, dimethylformamide, dioxan
or dioxan/water. The reaction can be carrled out at room
temperature, although in certain cases it may be convenient to
warm the reaction mixture.
',
The reaction of an isothiocyanate of formula V with a
mercaptan of formula VI is conveniently carried out in an inert
solvent such as toluene or an ether (e.g. dioxan) at a temperature
.. ,~ .
between about -20C and the reflux temperature of the reaction
` mixture, preferably at about 0C.
~'
.
;; - - . .
, -
'
. . .
- 6 - 1~77938
. .~ ~
The optional subsequent transformations at the group Y can
be carried out in accordance with methods known per se. The
saponification of an ester or amide of formula I to an acid of
formula I can be carried out, for example, with dilute acids
S such as half-concentrated hydrochloric acid, conveniently while
warming. The esterification of an acid of formula I can be
carried out by reacting a suspension or solution of said acid
with excess alcohol and thionyl chloride at a temperature between
about oC and room temperature. The manufacture of an afore-
mentioned salt of an acid of formula I can be carried out by
, reacting the acid with the stoichiometric amount of a base such
as an alkali metal hydroxide, ammonium hydroxide, an alkaline
earth metal hydroxide or an amine. A nltrile of formula I can
be hydrolysed to a corresponding amide of formula I using an
acid such as hydrochloric acid or sulphuric acid. An amide offormula I can be dehydrated to a corresponding nitrile of
;,,
formula I using phosphorus oxychloride or thlonyl chloride and
dimethylformamide.
The compounds of formula II can be prepared by reacting a
compound of the general formula
~A - NH2 (VII)
,';', .
- , wherein R , R and A have the significance
given earlier,
~` with sodium hydroxide, potassium hydroxide or ammonium hydroxide
:,
,.
. .
. .
.',: ,
.~ .
,,
.
~ 7 ~ 1077938
and carbon disulphide. This reaction is preferably carried out
in a water-miscible inert solvent such as acetonitrile at a low
temperature, i.e. about 0C to room temperature.
The compounds of formulae III, IV, V, VI and VII are known
or can be prepared in analogy to known compounds.
The thiocarbamoylthio fatty acid derivatives provided by
.- the present lnvention may be used as medicaments, especially for
lowering the blood fat level. In the case of the repeated
. administration of 4-/ [(p-chlorobenzyl)thiocarbamoyl]thio 7-
10 -butyric acid ethyl ester to rats there was brought about, for
i example, a 30-40% reduction of the triglyceride and a 20-30~i
reductlon of the cholesterol in the serum, this effect being
: achieved with half of the dosage which would have been required
with the use of the known lipid-lowering agent clofibrate
("Merck Index", 1968, page 270). For administration to adul~s
there come into consideration doQages of 0.1-0.2 mmol of an
aforementioned thiocarbamoylthio fatty acid derivative per kg of
--~ body weight.
The thiocarbamoylthio fatty acid derivatives provided by
the present invention can be used as medlcaments; for example,
~ ln the form of pharmaceutical preparatlons whlch contaln them
:`~ in association with a compatible pharmaceutical carrler material.
; This carrier material can be an organic or inorganic inert
............. carrier material which is suitable for enteral or parenteral
~;~ 25 administration such as, for example, water, gelatin, gum arabic,
lactose, starch, magnesium stearate, talc, vegetable oils,
:,
:''
. . .
, . ~ .
", ' .
..
8 - ~7793~
polyalkyleneglycols, petroleum jelly etc. The pharmaceutical
preparations can be made up in a solld form (e.g. as tablets,
dragées or capsules~ or in a liquid form (e.g. as solutions,
suspensions or emulsions). The pharmaceutical preparations may
be sterilised and/or may contain adjuvants such as preserving,
. stabilising, wetting or emulsifying agents, salts for variation
of the osmotic pressure or buffers. The pharmaceutical
preparations may also contain therapeutically valuable substances
other than the thiocarbamoylthio fatty acid derivatives provided
by this invention.
,~
:
'''
':
:.;
'
i,''-
:' - .
. . ~
?`
.
. .
,.,.`
. - .
. . ~
107793~
The following Examples illustrate the process provided
by the present invention:
Example 1
To a solution of 160 g of 4-bromobutyric acid ethyl ester
in 1125 ml of absolute dimethylformamide were added gradually
under argon at 0C while stirring well and cooling 172.3 g of
~- ammonium (N-4-chlorobenzyl)dlthiocarbamate, the temperature
being held constant. The slightly yellow solution was stirred
overnight at room temperature, diluted with 1500 ml of water and
extracted four times with 500 ml of ethyl acetate each time.
The combined organic phases were washed three times with 200 ml
of saturated sodium chloride solutlon each time and dried over
80 g of magnesium sulphate with the addition of carbon, filtered
and evaporated under reduced pressure. The resultlng crystal-
line residue was recrystallised from 700 ml of diisopropyl ether.
There was obtained 218 g of 4- ~ (p-chlorobenzyl)thiocarbamoyl]
thio] -butyric acid ethyl ester of melting point 61 -62C.
The dithiocarbamate used as the starting materlal can be
. prepared as follows:
:,.
260 ml of concentrated ammonia solutlon (ca 3.48 mol) were
treated under argon and while cooling by means of icetmethanol
bath at ~-10C within about 20 minutes with 164.5 g of carbon
disulphide and the mixture was subsequently stirred for a
further 15 mlnutes at the same tem~erature. 245 g of 4-chloro-
benzylamine dissolved inl22 ml of acetonitrile were then slowly
, '
''~'''
. . .
'~.' ' `' ~ ~
:
'''~' '~ ~ '
- iO'77938
-- 10 --
~ . .
a~1ded, the temperature being still maintained at C-10C.
Subsequently, the mixture was stirred overnight at room
temperature and then cooled in an ice-bath to 0C. The
? precipitated crystals were filtered off under suction, washed
successively with acetonitrile and diethyl ether and dried up to
constant weight under reduced pressure at 70-80C. There was
obtained 390 g of ammonium (N-4-chlorobenzyl)dithiocarbamate
of melting point 140-142C
In analogy to the process described earlier there were
manufactured the following thiocarbamoylthio fatty acid
derivatives:
.
. ' ' .
;l 3~ r [(p-chlorobenzyl)thiocarbamoyl]thio /-propionic acid
ethyl ester of melting point 67-68C,
11- r [(p-chlorobenzyl)thiocarbamoyl]thio 7-undecanoic acid
-~ ethyl ester of melting point 51.5-52.5C,
S-r~ (p-chlorobenzyl)thiocarbamoyl]thio 7-valeric acid
.. . . .
. ~ ethyl ester of boiling point 135-137C/0.08 Torr,
. 20 4- r [(2,5-dichlorobenzyl)thiocarbamoyl]thio 7-butyric acid
: ethyl ester of melting point 62-63C,
4~ r [(p-methoxybenzyl)thiocarbamoyl]thio 7-butyric acid
, ethyl ester of melting point 47-48C,
. 4-/ [(p-methylbenzyl)thiocarbamoyl]thio_7-butyric acid
ethvl ester of melting point 61-62C,
.
~, . ; , ...
,
.. . . .
,. .
''''' ' ' -
~,...
l~77g38
4-f~ 2(p-<p-chlorophenoxy>phenoxy)ethyl]thiocarbamoyl~ thio~-
-bu1:yric acid ethyl ester of melting point 72-74C and
4-{r [2-(p-chlorophenoxy)-ethyl]thiocarbamoyl_7thio}-
-butyric acid ethyl ester of melting point 63-64C.
Example 2
20.3 g of ammonium 3-~(p-chlorophenyl)propyl]dithio-
carbamate were added slowly while cooling with ice to a solution
of 12.4 ml of 4-bromobutyrlc acid ethyl ester in 120 ml of
ethanol and the mixture was stirred overnight at room temperature.
After evaporat~on in vacuo, the residue was partitioned between
water and ethyl acetate, the aqueous phase extracted three times
with ethyl acetate, the combined organic phases washed with
saturated sodium chloride solution, dried over magneslum sulphate
and agaln concentrated ln vacuo. The residual oily residue was
chromatographed on sillca gel using toluene/ethyl acetate for
;the elutlon. There w~re thus obtained l9.0 g of 4-{r [3-(p-
-chlorophenyl)propyl]thiocarbamoyl 7thio}-butyric acid ethyl
ester as a colourless viscous oil.
. .
4-/ [(p-Chlorophenethyl)thiocarbamoyl]thio 7-butyrlc acid
`20 ethyl ester was manufactured in the form of an oll ln an analogous
manner to that described in the preceding paragraph.
, .
-Example 3
.' ~
.:
`~lO g of 4-{/ [3-(p-chlorophenyl)propyl]thiocarbamoyl_7-
`thio}-butyric acid ethyl ester dissolved in lO0 ml of acetic
'~
.
j: - . . . :
.~. -
- : . :
.
. . .. ~ ~ ~ ,
,. ~ :
', ' : ' :
~ 12 1~7793~
acid were stirred under slight reflux for 8 hours with 50 ml of
' half-concentrated hydrochloric acid. The mixture was evaporated
in vacuo and the residue recrystallised from carbon tetrachloride.
There were obtained 4.4 g of 4-{/ [(p-chlorophenyl)propyl1-
t:hiocarbamoyl_7thio}-butyric acid of melting point 98-100C.
The following thiocarbamoylthio fatty acid derivatives were
manufactured in a corresponding manner:
~ 4-/ [(p-Chlorophenethyl)thiocarbamoyl]thio 7-butyric acid
-~ of melting point 112-113C,
3~ r [(p-chlorobenzyl)thiocarbamoyl]thio 7-propionic acid
of meltlng point 126-127C and
4- ~ ~(p-chlorobenzyl)thiocarbamoyl]thio_7-butyric acid of
.~ melting point 104-105C.
''"
Example 4
To 37.5 g of 4-bromobutyronitrile in 350 ml of absolute
dimethylformamide w~te added while cooling with ice 53.7 g of
.~.
ammonium (N-4-chlorobenzyl)dithiocarbamate and the mixture was
stirred overnight at room temperature. After evaporation in
- vacuo, the product was taken up in ethyl acetate, washed with
, 20 water, dried, concentrated and the residue crystallised from
diethyl ether/diisopropyl ether. There were thus obtained
-.:
~;, 48.2 g of 3-cyanopropyl(p-chlorobenzyl)dithiocarbamate of
~; melting point 61-63C.
. "
`` ''
~, ~
Example 5
~.,
~ 25 29.2 g of 3-cyanopropyl(p-chlorobenzyl)dithiocarbamate
~, ......
: .. , , . , . : .
;.. ':'. ' ' '
':''~ '" ' ', ' ' .- .' ~ '
:: , .
;; . .
~ ' ' . . ' ~ : '
'.: ' ,
.. ,.. :......................................................... :
- 13 ~ i~77938
were suspended in 150 ml of concentrated hydrochloric acid and
stirred at room temperature for 2 hours. The mixture was
diluted with water and extracted with ethyl acetate. After
washing, drying and concentration of the ethyl acetate phases,
18.1 g of 3-carbamoylpropyl(p-chlorobenzyl)dithiocarbamate were
crystallised from ethyl acetate/diisopropyl ether; melting
point 123-125C.
Exam~le 6
15.8 g of ~-chloro-N-methylbutyric acid amide dissolved in
200 ml of absolute ethanol were treated with 24.8 g of ammonium
(N-4-chlorobenzyl)dithiocarbamate. After a clear solution had
formed, it was stirred at 60C for 1.5 hours, then concentrated
; in vacuo, the residue taken up in water and extracted with ethyl
acetate. The organic phases were washed with saturated sodium
chloride solution, dried over magnesium sulphate, concentrated
and the residue crystallised from ethyl acetate/diisopropyl
ether. There were thus obtained 12.7 g of 3-(methylcarbamoyl)-
propyl(p-chlorobenzyl)dithiocarbamate of melting point
139-141C.
. .
The following thiocarbamoylthio fatty acld derivatives
were manufactured in an analogous manner:
3-(Ethylcarbamoyl)propyl(p-chlorobenzyl)dithiocarbamate of
melting point 117-119C,
3-(diethylcarbamoyl)propyl(p-chlorobenzyl)dithiocarbamate
,s 25 of melting point 71-73C,
3-(cyclohexylcarbamoyl)propyl(p-chlorobenzyl)dithiocar-
bamate of melting point 109-111C,
,. . .
, . ~
.
.' ' ' ' ~
107793~
,.
1~
3-(piperidinocarbonyl)propyl(p-chlorobenzyl)dlthiocar-
bc~mate of melting point 82-86C,
3-(morpholinocarbonyl)propyl(p-chlorobenzyl)dithiocar-
b~mate of melting polnt 102-104C,
:, .
' .
Example 7
:
1.5 g of 4- r t(p-chlorobenzyl)thiocarbamoyl]thio 7-butyric
acid were dissolved in 30 ml of diethyl ether and treated with
. .
an excess of an ethereal diazomethane solution. The resulting
solution was evaporated and the residue recrystallised from
cyclohexane. There were thus obtained 1.2 g Of 4-r [ (p-chloro-
benzyl)thiocarbamoyl]thio 7-butyric acid methyl ester of melting
,....:- ~
,~ point 60-62C.
,. ~ .
Example 8
::
.,~
"., ~
9.15 g of 4-rt (p-chlorobenzyl)thiocarbamoyl]thio 7-butyric
, acld dissolved in 120 ml of ethyleneglycol were treated dropwise
?'~ 5 20 at ~5C with 8.7 ml of thionyl chloride and the mixture was
subsequently stirred at room temperature for 3 hours. The
solution was th n made al~aline with 2-N sodium hydroxide
solution and extracted with chloroform. The chloroform phases
were washed with saturated sodium chloride solution, dried over
; 25 magnesium sulphate and concentrated. Recrystallisation of the
", .
. ~
.,!. . ,
,
.'.. ` , ' '
.~'`` ' , . ' . , ~ '
,~'. .
' . ' ' ~ ' , '
,' ' . '.
~ . . , ' . ' ~
- 15 - 10 7 ~ 3 8
residue from diisopropyl ether gave 8.1 g of 4-/ [(p-chloro-
benzyl~thiocarbamoyl]thio 7-butyric acid 2-hydroxyethyl ester
of meltlng point 77-78C.
The following thiocarbamoylthio fatty acid derivatives
were manufactured in an analogous manner:
4-/ [(p-Chlorobenzyl)thiocarbamoyl]thio 7-butyric acid
isopropyl ester of melting point 76-77C,
4-/ [(p-chloroben~yl)thiocarbamoyl~thio 7-butyric acid
; butyl ester of melting point 66-67C and
4-r [(p-chlorophenethyl)thiocarbamoyl]thio 7-butyric acid
2-hydroxyethyl ester of melting point 69-70C.
Example 9
"
To a solution of 1.06 g of 3-mercaptopropionic acid in 5 ml
;~ of toluene and 2.0 g of triethylamine were added while cooling
; 15 1.83 g of p-chlorobenzylisothiocyanate. Two phases formed.
The mixture was acidiLied with l-N hydrochloric acid and
` extracted with chloroform. The chloroform phases were washed
with water, dried over magnesium sulphate, concentrated and the
residue recrystallised from acetonitrile. There were thus
obtained 2.1 g of 3-/ [(p-chlorobenzyl)thiocarbamoyl]thio 7-
- -propionic acid of melting point 126-127C.
..
3-/ [(p-Chlorophenethyl)thiocarbamoyl]thio 7-propionic
acid of melting point 104.5-105C was manufactured in a
corresponding manner.
;
.
.' ' ' ' . - - : :
.. . . . . .
, ~
,
- 16 - ~077~38
The following Example illustrates a pharmaceutical
preparation containing the thiocarbamoylthio fatty acid
derivatives provided by the present invention:
Example A
Tablets containing the following ingredients were produced
in a manner known per se:
Inqredient Per tablet
: 4~ r [_p-Chlorobenzyl)thiocarbamoyl]-
thio 7-butyric acid ethyl ester 50.00 mg
10 Polyethyleneglycol 200.00 mg
Lactose 70.00 mg
: Microcrystalline cellulose 70.00 mg
; Poly~inylpyrrolidone 100.00 mg
;; Magnesium stearate 10.00 mg
; 15 Total weight500.00 mg
:,j
".
:,,
: ,~
~ . ?
~.,,
.,. .
~,
. ..
;~;'" .
.
. ., ~
.,' .~
I;'.
'." '
.i.'" '
i ;I'
~ ., .
,.~
. .
~'. `" ', , , , , ~
~' , ,
' ' ' ,
.
