THIOCARBAMIDE DERIVATIVES AND PROCESS FOR PREPARING THEREOF

DERIVES DU THIOCARBAMIDE; LEUR PREPARATION

English Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates novel thiocarbamide derivatives of the
general formula I
<IMG> (I)
wherein R1, R2 and R3 may stand for identical or different groups, and they
denote each a hydrogen atom, a C1-8 straight or branched-chain, saturated or
unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one or
more halogen atoms, further hydroxy, dialkylamino, or nitro groups or halogen
atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight or
branched-chain C1-8 alkyl a C2-6 straight or branched-chain hydroxyalkyl
a hydroxyl group; R5 denotes a C2-6 straight or branched-chain hydroxyalkyl
group or a C3-6 straight or branched-chain unsaturated alkyl group; R6 denotes
a hydrogen atom, a straight or branched-chain saturated or unsaturated C1-7
alkyl group which may be substituted with a hydroxy group or with one or more
halogen atoms, or a C3-6 cycloalkyl group, with the proviso that R6 must have
a meaning other than hydrogen atom when R1, R2, R3 and R4 each denote a
hydrogen atom and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxy-
butyl or 1,1-dimethyl-2-hydroxyethyl group; or when R2, R3, and R4 each denote
a hydrogen atom, R5 denotes a 2-hydroxyethyl group and R1 denotes a 2-chloro,
4-chloro, 4-bromo or 2-methyl group; or when R1 denotes a 4-bromo group, R2,
R3 and R4 each denote a hydrogen atom and R5 stands for a 4-hydroxybutyl
group; or when R1 denotes a 2-methyl group, R2 a 4-methyl or 5-methyl group,
R3 and R4 each stand for a hydrogen atom, and R5 is a 2-hydroxyethyl group;
or when R1 denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a
hydrogen atom and R5 a 2-hydroxyethyl group; or when R1, R2 and R3 each
denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group and R4 stands
for a 2-hydroxyethyl or 2-methylpropyl group. It also

relates to a process for the preparation of the new compounds of formula 1.
Certain of the compounds of this invention exhibit very favourable diuretic
and saluretic effects even when administered in small doses. Other compounds
of the invention exhibit blood-pressure lowering, analgesic or antidepressant
affects combined with low toxicity. More details of this activity are dis-
closed.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of novel thiocarbamide derivatives
of the general formula I
(I)
<IMG>
wherein R1, R2 and R3 may stand for identical or different groups, and they
denote each a hydrogen atom, a C1-8 straight or branched-chain, saturated
or unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with
one or more halogen atoms, further hydroxy, dialkylamino, or nitro groups,
or halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated
straight or branched-chain C1-8 alkyl or cycloalkyl group which may be
substituted with a hydroxyl group; R5 denotes a C2-6 straight or branched-
chain hydroxyalkyl group or a C3-6 straight or branched-chain unsaturated
alkyl group; R6 denotes a hydrogen atom, a straight or branched-chain
saturated or unsaturated C1-7 alkyl group which may be substituted with a
hydroxyl group or with one or more halogen atoms, or a C3-6 cycloalkyl group,
with the proviso that R6 must have a meaning other than hydrogen atom when
R1, R2, R3 and R4 each denote a hydrogen atom, and R5 stands for a 2-
hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 1,1-dimethyl-2-hydroxyethyl
group; or when R2, R3 and R4 each denote a hydrogen atom, R5 denotes a 2-
hydroxyethyl group, and R1 denotes a 2-chloro, 4-chloro, 4-bromo or 2-methyl
group; or when R1 denotes a 4-bromo group, R2, R3 and R4 each denote a
hydrogen atom, and R5 stands for a 4-hydroxybutyl group; or when R1 denotes
a 2-methyl group, R2 a 4-methyl or 5-methyl group, R3 and R4 each stand for
a hydrogen atom, and R5 is a 2-hydroxyethyl group; or when R1 denotes a
2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a hydrogen atom, and
R5 a 2-hydroxyethyl group; or when R1, R2 and R3 each denote a hydrogen
21

atom, R5 denotes a 2-hydroxyethyl group, and R4 stands for a 2-hydroxyethyl or
2-methylpropyl group, R6 must have a meaning other than hydrogen atom when at
least one or R1, R2 and R3 denotes a C1-4 alkyl or a halo group, R4 denotes a
hydrogen atom or a C1-4 alkyl group and R5 denotes an allyl group, character-
ized in that
a) an isothiocyanate of the general formula
<IMG> (II)
wherein R1, R2, R3 and R6 have the above-specified meanings, is reacted with
an amine of the general formula III
<IMG> (III)
wherein R4 and R5 have the above-specified meanings, in a melt or in an inert
solvent, or
b1) a compound of the general formula IV
(IV)
<IMG>
wherein R1, R2, R3 and R6 have the above-specified meanings, whereas Q denotes
an -SR7 group, wherein R7 denotes a short-chain alkyl, an aryl or an aralkyl
group, is reacted with an amine of the general formula III, wherein R4 and R5
have the above-specified meanings, in a melt or in an inert solvent, or
b2) a compound of the general formula IV, wherein R1, R2, R3 and
R6 have the above-specified meanings, whereas Q denotes a halogen atom, is
reacted with an amine of the general formula III, wherein R4 and R5 have the
above-specified meanings, in a melt or in an inert solvent, or
b3) a compound of the general formula IV, wherein R1, R2, R3 and
R6 have the above-specified meanings, whereas Q denotes an SH group, is reacted
22

with an amine of the general formula III, wherein R4 and R5 have the above-
specified meanings, and then melting the obtained salt, optionally in the
presence of an inert solvent.
2. Thiocarbamide derivatives of the general formula I as defined in
claim 1 whenever prepared by the process of claim 1 or an obvious chemical
equivalent.
3. A process according to claim 1(b3) in which the dithiocarbamic
acids of formula IV are prepared by reacting compounds of the formula
<IMG>
with carbon disulphide.
4. A process according to claim 1(b2) in which the thiocarbamic
acids of formula IV are prepared by reacting compounds of the formula
<IMG>
with thiophosgene.
5. A process according to claim 1 in which two of R1, R2 and R3 are
hydrogen and the remaining radical 4-chloro, R4 and R6 are hydrogen, and
R5 is 2-hydroxypropyl.
6. A process according to claim 1 which comprises reacting 4-chloro-
benzyl isothiocyanate with propanolamine to yield 1-(4-chlorobenzyl)-3-
(3-hydroxypropyl)-thiocarbamide.
23

7. A process according to claim 1 which comprises reacting methyl-
N-(4-chlorobenzyl)-dithiocarbamate with propanolamine to yield 1-(4-chloro-
benzyl)-3-(3-hydroxypropyl)-thiocarbamide.
8. A process according to claim 1 in which two of R1, R2 and R3
are hydrogen and the remaining radical is 4-fluoro, R6 is hydrogen, R4 is
methyl and R5 is 2-hydroxyethyl.
9. A process according to claim 1 which comprises reacting 4-fluoro-
benzyl isothiocyanate with 2-methylaminoethanol to yield 1-(4-fluorobenzyl)-
3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
10. A process according to claim 1 which comprises reacting methyl-N-
(4-fluorobenzyl)-dithiocarbamate with 2-methylaminoethanol to yield 1-(4-
fluorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
11. A process according to claim 1 in which two of R1, R2 and R3 are
hydrogen and the remaining radical 4-chloro, R6 is hydrogen, R4 is methyl
and R5 is 2-hydroxyethyl.
12. A process according to claim 1 which comprises reacting 4-
chlorobenzyl isothiocyanate with 2-methylaminoethanol to yield 1-(4-chloro-
benzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
13. A process according to claim 1 which comprises reacting methyl-N-
(4-chlorobenzyl)-dithiocarbamate with 2-methylaminoethanol to yield 1-(4-
chlorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
14. A process according to claim 1 in which two of R1, R2 and R3 are
hydrogen and the remaining radical is 4-trifluoromethyl, R6 is hydrogen, R4
is methyl and R5 is 2-hydroxyethyl.
15. A process according to claim 1 which comprises reacting 4-tri-
fluoromethylbenzyl isothiocyanate with 2-methylaminoethanol to yield 1-(4-
trifluoromethylbenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
24

16. A process according to claim 1 which comprises reacting methyl-N-
(4-trifluoromethylbenzyl-dithiocarbamate with 2-methylaminoethanol to yield
1-(4-trifluoromethylbenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
17. A process according to claim 1 in which each of R1, R2, R3 and R4
are hydrogen, R6 is ethyl, and R5 is 2-hydroxyethyl.
18. A process according to claim 1 which comprises reacting 1-phenyl-
propyl isothiocyanate with ethanolamine to yield ? 1-(1-phenylpropyl)-3-
(2-hydroxyethyl)-thiocarbamide.
19. A process according to claim 1 which comprises reacting N-(1-
phenylpropyl)-thiocarbamic acid chloride with ethanolamine to yield ? 1-(1-
phenylpropyl)-3-(2-hydroxyethyl)-thiocarbamide.
20. A process according to claim 1 in which two of R1, R2 and R3 are
hydrogen and the remaining radical is 2-fluoro, R4 and R6 are hydrogen and
R5 is 2-hydroxyethyl.
21. A process according to claim 1 which comprises reacting 2-fluoro-
benzyl isothiocyanate with ethanolamine to yield 1-(2-fluorobenzyl)-3-
(2-hydroxyethyl)-thiocarbamide.
22. A process according to claim 1 which comprises reacting methyl-
N-(2-fluorobenzyl)-dithiocarbamate with ethanolamine to yield 1-(2-fluoro-
benzyl)-3-(2-hydroxyethyl)-thiocarbamide.
23. A process according to claim 1 in which each of R1, R2, R3 and
R4 are hydrogen, R6 is methyl and R5 is 2-hydroxyethyl.
24. A process according to claim 1 which comprises reacting l-phenyl-
ethyl isothiocyanate with ethanolamine to yield ? 1-(1-phenylethyl)-3-(2-
hydroxyethyl)-thiocarbamide.

25. A process according to claim 1 which comprises reacting-N-(1-
phenylethyl)-thiocarbamic acid chloride with ethanolamine to yield ? 1-(1-
phenylethyl)-3-(2-hydroxyethyl)-thiocarbamide.
26

Description

93~
Thi.C invention relates to novel thiocarbamide derivatives of the
general formula I ~ :
~ ~,
2 ~ - CH - NH - C - ~ ~ 4
wherein
Rl, R2 and R3 may stand for identical or different groups, and they denote ;~
each a hydrogen atom, a Cl 8 straight or branched-chain, ;
saturated or unsaturated alkyl, or dialkylaminoalkyl groups,
alkyl substituted with one or more halogen atoms, further hydroxy,
dialkylamino, or nitro groups or halogen atoms, ~ ~ .
R~ denotes a hydrogen atom, a saturated or unsaturated straight or
branched-chain Cl 8 alkyl or cycloalkyl group which may be
substituted with a hydroxyl group,
R5 denotes a C2 ~ straight or branched-chain hydroxyalkyl group or
a C3 6 straight or branched-chain unsaturated alkyl group, .
R6 denote5 a hydrogen atom, a straight or branched-chain saturated
or unsaturated Cl 7 alkyl group which may be substituted with a
hydroxy group or with one or more halogen atoms, or a C3 6
cycloalkyl group, with the proviso that R6 must have a meaning
other than hydrogen atom when Rl, R2, R3
-2-

:::
and R~ each denote a hydrogen atom and R5 stands for ~ .
a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or
; 1,1=dimethyls2-hydroxyethyl group; or
when R2, R3 .and R4 each denote a hydrogen atom, R5 de- : ~
notes a 2~hydroxyethyl group and Rl denotes a 2-chloro, :;
4-chlor~j 4-bromo or~2-methyl group; or ~-~
when Rl denotes a 4-bromo group, R2, R3 and R4 each `~
denote a hydrogen atom and R5 s~ands for a 4-hydroxy-
butyl group; or
".
when Rl denotes a 2-methyl group, R2 a 4-methyl or 5- : :
.. ..
methyl group, R3 and R4 each stand for a hydrogen atom, .
and R5 is a 2-hydroxyethyl group; or
when Rl denotes a 2-methoxy group, R2 a 4-hydroxy group,
R3 and R4 each a hydrogen atom and R5 a 2-hydroxyethyl
group; or - :~
when Rl, R2 and R3 each denote a hydrogen atom, R5 ~;~
denotes a 2-hydroxyethyl group and R4 stands for a 2-
hydroxyethyl or 2-methylpropyl group, and R6 must have ` ~
a meaning other than hydrogen atom when at least one of ~ .
:: ,
Rl, R2 and R3 denotes a Cl 4 alkyl or a halo group, R4
.~ ~ denotes a hydrogen atom or a Cl 4 alkyl group and R5 ~ ~
deno~es an allyl group. : .
The invention also relates to a process for the preparation of
;: ::.
novel thiocarbamide derivatives of the general formula I
'.'' ~.
.:
R2 ~ C~ - NH - C - h \ (I)
3 ~ ~1
wherein Rl, R2 and R3 may stand for identical or different groups, and they :~
denote each a hydrogen atom, a Cl 8 straight or branched-chain, saturated or
-~nsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one
~ 3 ~
. .

~69~3~ :
or more halogen atoms, further hydroxy, dialkylamino, or nitro groups, or
halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight ~;
or branched-chain Cl 8 alkyl or cycloalkyl group which may be substituted with ~-
a hydroxyl group; R5 denotes a C2 6 straight or branched-chain hydroxyalkyl
group or a C3 6 straight or branched-chain unsaturated alkyl group; R6 denotes
a hydrogen atom, a straight or branched-chain saturated or unsaturated C
alkyl group which may be substituted with a hydroxyl group or with one or more
halogen atoms, or a C3 6 cycloalkyl group, with the proviso that R6 must have .
a meaning o~her than hydrogen atom when Rl, R2, R3 and R4 each denote a hydro- ~ ,r
gen atom and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl ~ -
or l,l-dimethyl-2-hydroxyethyl group; or when R2, R3 and R4 each denote a
,
hydrogen atom, R5 denotes a 2-hydroxyethyl group, and Rl denotes a 2-chloro,
4-chloro, 4-bromo or 2-methyl group; or when Rl denotes a 4-bromo group, R2
R3 and R4 each denote a hydrogen atom, and R5 stands for a 4-hydroxybutyl
group; or when Rl denotes a 2-methyl group, R2 a 4-methyl or 5-methyl group,
R3 and R4 each stand for a hydrogen atom, and R5 is a 2-hydroxyethyl group;
or when Rl denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a ::
hydrogen atom, and R5 a 2-hydroxyethyl group; or when Rl, R2 and R3 each ~:
denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group, and R4 stands for
a 2-hydroxyethyl or 2-methylpropyl group, ~dR6 must have a meaning other than `;
hydrogen atom when at ieast one o Rl, R2 and R3 denotes a Cl 4 alkyl or a
halo group, R4 denotes a hydrogen atom or a Cl 4 alkyl group and R5 denotes
an allyl group, characterized in that `
a) an isothiocyanate of the general formula II ~ `
2 ~ CH - N = C = S (II)
6 ; ;
3 :
wherein Rl, R2, R3 and R6 have the above-specified meanings, is reacted with
an amine of the general formula III -
.
~ :. ,; ~ - 3a - ::
" ., .~ .., .. " ., . . " ;"" . ....

~9~3~
/ 4
\ (III)
wherein R4 and R5 have the above-specified meanings, in a melt or in an inert -
solvent, or
bl) a compound of the general formula IV
' ~;
2~fH - NH - C \ (IV)
R3
wherein Rl, R2, R3 and R6 have the above-specified meanings, whereas Q de- ;~
notes an -SR7 group, wherein R7 denotes a short-chain alkyl, an aryl or an
aralkyl group, is reacted with an amine of the general formula III, wherein
R4 and R5 have the above-specified meanings, in a melt or in an inert solvent,
or
b2) a compound of the general formula IV, wherein Rl, R2, R3 and
R6 have the above-specifiefd meanings, whereas Q denotes a halogen atom, is - ;
reacted with an amine of the general formula III, wherein R4 and R5 have the
. .. .
above-specified meanings, in a melt or in an inert solvent, or
b3) a compound of the general formula IV, wherein Rl, R2, R3 and
R6 have the above-specified meanings, whereas Q denotes an SH group is re-
acted with an amine of the general formula III, wherein R4 and R5 have the
above-specified meanings, and then melting the obtained salt, optionally in
the presence of an inert solvent.
According to the above statements the ;
~2 ~ CH -
R3
group may denote e.g. a benzyl, a 2-methylbenzyl, a 3-methylbenzyl, a 4-
methylbenzyl, a 2,3-dimethylbenzyl, a 2,4-di-
- 3b

~6~3~ `:
methylbenzyl, a 2~5-dimethylbenzyl, a 2,6-dimethylbenzyl,
a 2-trifluoromethylbenzyl~ a 3-trifluoromethylbenzyl7 a `~
4-trifluoromethylbenzyl, a 4-methoxybenzyl, a 3J4-dimethoxy-
benzyl9 a 2-fluorobenzyl, a 3-fluorobenzyl, a 4-fluorobenzyl~
S a 2-chlorobenzyl, a 3-chlorobenzyl, a 4-chlorobenæyl, a
3,4~dichlorobenzyl~ a l-phenylethyl, a 1~(4-octylphenyl)-
ethyl, a 1-(4-methoxyphenyl)-ethyl, a 1-(2-fluorophenyl)-
ethyl~ a 1-(3-fluorophenyl)-ethyl~ a 1-(4-fluorophenyl)-
~: ,.,.:
ethyl, a l-phenylpropyl, a l~phenyl-2-methylpropyl, a
l-phenylbutyl, a l-phenyloctyl~ a phenyl-cyclopropylmethyl,
a phenyl-cyclohexylmethyl and similar groups, wher~s the
group
R
/ 4
'`' : ~ '
R
may denote e.g. a 2-hydroxyethylamino, a 2-hydroxypropyl~
amino~ a 3-hydroxypropylamino9 a 2-methyl-3-hydroxypropyl-
amino, a 4~hydroxybutylamino, ~n allylamino, a 2-methyl-
allylamino~ a N-methyl-N~(2-hydroxyethyl)-amino~ a M-ethyl- ~
N-(2-hydroxyethyl)-amino, a N-butyl-N-~2-hydroxyethylamino, ~ -
a N cyclohexyl~N-(2-hydroxyethyl)-amino, a N-methyl-N_
(3-hydroxypropyl)-amino and similar groups.
- According to the above~given definition the group of ~ -~
compounds of the general formula I embraces also the
possible stereoisomers and their mixtures.
Only a few repr~sentatives of the compounds of the
general formula I are known in literature, such as
l-benzyl 3-(2-hydroxyethyl)-thiocarbamide (Bull. Soc. Chim.
France 5, 960 /1960); 1-(2-chlorobenzyl)~3-(2-hydroxyethyl)-
thiocarbamide9 1~(4-chlorobenzyl)-3-(2-hydroxyethyl)-thio-
.,
~, ,
~4~

~L~6~3193~L
carbamide, 1-(2~methylbenzyl)-3-(2-hydroxyethyl)-thio~
carbamide, 1-(2,4-dimethylbenzyl)-3-(2-hydroxy~thyl)-thio-
carbamide~ l-)2~5-dimethylbenæyl) 3-(2-hydroxyethyl)-thio-
carbamide (JO Indian Chem. Soc, 37~ 705 /1960); 1-~4-bromo- ~`
benzyl)-3.(2-hydroxyethyl)-thiocarbamide (Helv. Chim. Acta
48~ 1069 /1965); 1-(2-methoxy-4~hydroxybenzyl)-3-(2-
hydroxyethyl)-thiocarbamide (Japanese Patent Appl. No.
7~0179524~ Dec. 24~ 1966); l~benzyl-3-(3-hydroxypropyl)-
thiocarbamide (Acta Chem. Sc~nd. 12, 1746-58 l1958/); l-benzyl-
3-(4~hydroxybutyl)~thiocarbamide, 1-(4-bromobenzyl)-3-(4~
hydroxybutyl)-thiocarbamide (Helv. Chim. Acta 49, 807 /1966);
l-benzyl-3-(2-methylpropyl)-3-(2-hydroxyethyl)~thiocarbamide,
l-benzyl-3~bis-(2-hydroxyethyl)-thiocarbamide, and
l-benzyl-3~ 1-dimethyl-2-hydroxyethyl)-thiocarbamide - ;
(Helv. Chim. Acta 48, 1069 /1965).
~": ' ' '
In the literature no reference to any favourable ~ ;
physiological effects of these known compounds can be found.
Now it has been found~ however, that certain representa- ~-~
tives of the compounds of the general for~ula I exhibit
very favourable diuretic and saluretic effects appearing
even when administered in small doses, whereas other rep~
resentatlves show blood-pressure lowering, analgesic or
antidepressant effects at a low toxicity.
Of the compounds of the general formula I mainly the
1-(4-chlorobenzyl)-3-(3-hydroxypropyl)-thiorarbamide,
1-(4-fluorobenzyl)-3 methyl-3-(2-hydroxyethyl)-thiocarbamide~
4-chlorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thioc2rbamide
and 1-(4-trifluoromethylbenzyl)~3~methyl~3-(2-hydroxyethyl)-
thiocarbamide showed durable blood-pressure lowering effects

3~ ~
,, ~;,
of 20 to 40 % lasting for more than 90 minutes~ when ad-
ministered either intravenouslg or intraduodenal in very low
doses from 0.1 to 1 mg/kg.
The diuretic and saluretic effects of the compounds of
Z 5 the general fonmula I are listed in Table II. The Lipschnitz
method (J. Pharmacol. Ther~ 79, 97-110 /1943/) as modified
by Kagawa, C~M. and Kalm~ J. (Arch. Int. Pharmacodyn. 137,
241-249 /1962/) was applied~
The analgesic effect of the compounds of the general~-~
formula I is presented in Table IIIJ The used methods were
as follows: Z~
Writhing test(Witkin, L.B. et al.: J~ Pharm. exp. Ther. `
: . . .
133~ 400-408 /1961/)~ on mice;
hot-plate test (Porsza'sz~ J. et alD: Acta physiol.
:. :
Acad. Sci. ~ung~ 4~ 107-113 /1953~), on mice;
Randall-Sellito test (Randall~ LØ and Sellito~ J.:
Arch~ Int. Pharmacodyn. 111, 409-419 /1957/), on rats.
The antidepresssnt effect of the compounds of the
general formula I is shown in Table IV. The applied method
was that of Berly No Askew (Life Sci. 10, 725 /1963/).
In addition to the applications mentioned above, the
compounds of the general fonmula I can be used also for
the preparation of other therapeutically valuable
thiazoline, thiazolidine, thiazine, thiazepine or thiazocine
derivatives. ~
The compounds of the general formula I according to the -;
present in~ention can be prepared by the following methods: ~
a) reacting an isothiocyanate of the general fonmula II ~ -Z
R2 ~ ~ CH - N = C - S
-6-

',
.,~" ' '
~06~93~
wherein Rlg R29 R3 and R6 have the above meanings, with ;~ :
an amine of the general fonmula III ;~
/ R4 ;~
HN (III) ~
\ R :
wherein R4 and ~5 have the above meanings9 in a melt or
in an inert solvent, or
bl) reacting a compound of the general form~la IV
R~
R2 ~ CH - NH~C (IV)
: R3 R6 Q
wherein Rl, R2, R3 and R6 have the above-specified meanings~
whereas Q denotes an -SR7 group, wherein R7 denotes a shor~-
chain alkyl~ an aryl or an aralkyl group, with an amine of
; the general formula III, wherein R4 and R5 have the above
meanings, in a melt or in an inert solvent, or `.
: b2) reacting a compound of the general formula IY,
~0 wherein Rl, R2, R3 and R6 have the abo~eOspecified
meanings~ whereas Q denotes a halogen atom~ with an amine
of the general formula III, wherein R4 and R5 have the -
above meanings~ in a melt or in an inert solvent, or
) reacting a compound of the general formula IV~
wherein Rl, R2, R3 and R6 have the above-specified
meanings, whereas Q denotes an SH group, with an amine of ~`:
' t~
the general formula III, wherein R4 and R5 have the above~ ~`
specified meanings, and then melting the obtained salt,
~ optionally in the presence of an inert solvent.
:` 30 Chlorofonm, dichloroethane 9 tetrachloromethane or ~ J
,. .
;'
.

~6993~
benzene may be preerably applied as inert solvent.
Isothiocyanates of the general fonmula II are partly
known from literature and partly they can be prepared
by known methods (Org. SynthO Coll. Vol. 1~ 2nd edition~
p. 447, John Wiley and Sons Inc., New York, 1948; Chem.
Ber. 101, 1746 /1968/).
Secondary amines of the general fo~mula III are mostly
known from literature or they can be prepared by known
methods (Houben-Weyl: Methoden der organischen CheMie~
Vol. XI/l~ pp. 24~ 267 and 10057 Georg Thieme Verlag,
Stuttgart~ 1957)~
Dithiocarbamic esters of the general fonmula IV
(Q ~ SR7) are partly know~ from literature or they can be
: `
prepared by known methods (Canadian Patent specification
No. 317,244; UOS~ patent specifications Nos. 2,997,382 and
3~2113711; Czecho-Slovak patent specification No. 133~718).
Thiocarbamic acid halogenides of the ~eneral-fonmula
IV (Q = halogen3~are partly known from literature or they
can be prepared by known methods (Chem. Rev. 55~ 193
` 20 /1955/). -~
~- Dithiocarbamic acids of the general formula IV ~ -
(Q = SH) are readily formed from the corresponding amine ~
and carbon disulphide in an inert solvent (Chem. Rev. 55~ ~;
189 /1955/), and their salts with inorganic or organic ~ ;
bases can be well identified.
The ne~ compounds according to the in~ention and their
method of preparation are further illustrated by the
following non~limiting Examples.

~0~93~
1~(4-Fluorobenzyl)-3-(2-hydroxyethyl)-thiocarbamide
a) The solution oE 12.6 g. (0.0766 moles) of 4-fluoro- -
benzyl isothiocyanate in 100 ml. of chloroform is dropwise ;~
added under stirring and ice-cooling to the soLution of
4.88 gO (0.08 mcles) of ethanolamine in S0 ml. of chloro- ;~
form. The reaction mixture is refluxed for an hour, then
the solvent distilled off under vacuum~ affording 17.45 g.
~100 %) of yellow, honey-like 1-(4-fluorobenzyl)-3-(2-hydroxy-
; 10 ethyl)-thiocarbamide which crystallizes on standing. After
recrystallizing the product from a 1:1 mixture of ethyl
acetate and cyclohexane~ its m.p. is 58-60 C.
b) The mixture of 21.;5 g. (0.1 moles) of methyl-N-(4-
fluvrobenzyl)-dithiocarbamate and 12.2 g. (0.2 moles) of
ethanolamine is melted for 3 hours at 80 C. During the
~; reaction, methyl mercaptan is liberated from the mixture~
Excess ethanolamine is removed from the reactlon mixture by
distillation under vacuum, then the residual honey-like
product (22.8 g.~ 100 %3 is recrystallized from a 1:1 mixture
: .
of ethyl acetate and cyclohexane. The product melting at
58-60 C is identical with that obtained in Example la.
; c) The solution of 21.5 g. (0.1 moles) of methyl-N-
(4-fluorobenzyl)-dithiocarbamate and 7032 g. (0.12 moles) of
ethanolamine in 40 ml of isopropanol ls boiled for 3 hours. ~
Meanwhile methyl mercaptan is liberated from the reaction 3
mixture. Isopropanol together with ethanolamine applied in
excess is removed from the reaction mixture by vacuum
:: .
distillation, then the residual honey-like product (22.8 g
100 %) is recrystallized from a lol mixture of ethyl
acetate and cyclohexane. The product (m.p. 58-60 C) is
. . . .
9-

~al6~3~
identical with that obtained in Example la~
d) One proceeds in the way specified in Example lc~
~ith the difference that boiling is carried out in
chlorofcrm, instead of isopropanol. The obtained honey~
like product (22.8 g.~ 100 %) is re~rystalllzed from a 1:1
mixture of ethyl acetate and cyclohexane~ affording a --
compound melting at 58~60 C. The produrt is iden~ical -~
with that prepared according to Example la.
e) One proceeds in the way as specified in Example lc~ `
with the difference that boiling is carried out in dloxane~
instead of isopropanolO The obtained honey-like product ~ -
(22.ô g~, 100 %) when recrystalli~ed from a 1:1 mixture of
e~hyl acetate ~nd cyclohexane, melts at 58~60 C. Ihe `
product is identical with that obtained in Example la.
f) To a solution of 3.13 g. (0.025 moles) of 4-fluoro-
benzylamine in 25 ml. of anhydrous ethanol, 3~02 ml.
(0.05 moles) of carbon disulphide are dropwise added at
O C under stirring and cooling with salted ice. The
reaction mi*ture is stirred for half an hour below O C,
then at the same temperature 2539 ml. (0.0~5 moles) of
ethanolamine are dropwise added and the mixture is stirred
for another half an hour a~ O CO The ethanol applied as ~ ~`
solvent is removed fxom the reaction mixture9 together with
excess carbon disulphide, by distillation, then the residual `~
honey-like salt is heated for an hour on a 140 C oil bath.
Meanwhile hydrogen sulphide is beiag liberated from the
reaction mixture~ On cooling, the obtained honey-like
; product is dissolved in 50 ml of benzeae~ shaken with
3 x 50 ml~ of water, dried, and evaporated to dry~ess under
vacuum~ affording 4.85 g. (85 %) of honey-like 1-~4~fluoro-
10-

~L6169~31
benzyl)-3 (2-hydroxyethyl)-thiocarbamide. Recrystallization
of ~he product from a 1:1 mixture of ethyl acetate and
oyclohexane gives a product melting at 57-60 C~ me
product is identical with that obtained in Example la.
~ Phenylbutyl)-3-methy1-3-(2-hydroxyethyl)-thio~
carbamide
a) Th solution of 23.3 g. (0.15 moles) of l-phenyl-
butyl isothiocyanate in 100 ml. of dirhloroethane is drop-
wise added~ under stirring and ice-cooling~ to the solution
o 12.0 g. (0.16 moles) of 2-methylaminoethanol in 50 ml.
of dlchloroethane. l~e reaction mixture is refluxed for an
hour~ then the solvent is evaporated under vacuum~
affording 39.9 g~ (100 %) of honey-like l-(l-phenylbutyl)-
~ 15 3-methyl~3-(2-hydroxyethyl)_thiocarbamide which crystallizes
; on standingO Recrystallization from ethyl acetate affords
a product melting at 74-75 C. -~
b~ The solution of 14.9 gO (0.1 moles) of l-phenyl-
butylamine and 17.2 g. (0.15 moles) of thiophosgene in
100 ml~ of anhydrous 1~2-dichloroethane is stirred for 4
hours at room temperature~ then the reaction mixture is
~; evaporated to dryness under ~acuum. The obtained N~
phenylbutyl)~thiocarbamic acid chloride is dissolved in
50 ml. of anhydrous benzene. The solution is filtered, then ~-
` 25 the fil~rate is dropwise added slowly, under stirring, - ~
to a solution of 16.5 g. (0~22 moles) of 2-methylaminoethanol - -
in 100 ml~ of benzene. me reaotion mixture is refluxed
for 4 hours~ then allowed to cool~ and treated with 100 ml.
of water. The phases are separated. The benzene solution
is shaken with 2 x 100 ml. of water~ dried~ and evaporated

~69~131 :: ~
`.'. .,
to dryness under vacuum. In this way 25~5 g. t95.7 2) oE ;~
a crude honey-like product are obtained which crystallize
on standing. When recrystalli~ed from ethyl acetate the
product melts at 74-75 C, and is completely identical with
the compound obtained in Example 2a.
When applying the methods specified in Example 1 and
2~ also other compounds of the general formula I listed in
Table I can be prepared.
'.";
'"`''"'
... ' !
`' '' `~ '.
,
'. '~
-12- ~ ~

6~ 9 3
-13
Table I
Number M . p .
of C o m p o u n d C ~ x/
Example _ _ f ~; :
3 ~ 1 (1-Phenylethyl)-3~(2-hydroxyethyl)-
-thiocarbamide ~ 94-96 -
4 ~ 1~ Phenylpropyl)-3-(2-hydroxyethyl)~ :
~thiocarbamide 97 98
~ 1~ Phenyl-2-methylpropyl)-3-
-(2-hydroxyethyl)-thiocarbamide 73-75 :~
6 ~ 1-~1 Phenylbutyl)~3 (2-hydroxyethyl)-
-thiocarbamide 95-96
7 ~ 1-(1-Phenyloctyl)-3-(2-hydroxyethyl)- ~ -
~thiocarbamide 82-85
8 ~ l-(l-Phenyl-l-cyclopropylmethyl)-
-3-(2-hydroxyethyl)-thiocarbamide 97-98.5
9 ~ 1~(1-Phenyl-l-cyclohexylmethyl)-3- honey-like
-(2-hydroxyethyl)-thiocarbamide substance 0.45 .
1-(3,4-Dimethoxybenzyl)-3-(2-hydroxy
ethyl)-thiocarbamide 115-117
11 + 1-Ll-(4-~Methoxyphenyl)-ethyl~-3-
~(2-hydroxyethyl)-thiocarbamide 84-87
12 1-(2,6~Dimethylbenzyl)--3-(2-hydroxy-
ethyl)-thiocarbamide 162-164 :~
13 ~ 1-Ll-(4-Octylphenyl)-ethyl~-3- .
-(2-hydroxyethyl)-thiocarbamide 41-43.5
14 1-(2-Fluorobenzyl)-3-(2-hydroxyethyl)- ` ;
-thlocarbamlde 109-110 :
1-(3-Fluorobenzyl)-3-(2-hydroxyethyl)-
~thiocarbamide 92-94
16 1-(4-Fluorobenzyl)-3-(2-hydroxyethyl)-
-thiocarbamide 59-61
17 1--(3,4-Dichlorobenzyl)-3-(2-hydroxy-
ethyl)-thlocarbamide 91.5-92.5 -.
18 1-(2-Trifluoromethylbenzyl)-3- :.
-(2-hydroxyethyl)-thiocarbamide 88~90
,:,
-13- `
,
,

~L~6~93~
-14~
~ , . .
Table I (continued)
Number C o m p o u n d M.p. -
C ~f x/
Example
:
19 1-(3-Trifluoromethylbenzyl)-3-
-(2-hydroxyethyl)-thiocarbamide 48-50
1-(4-Trifluoromethylbenzyl)-3~
-~(2-hydroxyethyl)~thiocarbamide 80-84
21 ~ 1-tl-Phenylethyl)~3-(3-hydroxypropyl)-
-thiocarbamide 129-131
22 1-~1-(2-Fluorophenyl)-ethy~ -3-
-(2-hydroxyethyl)-thioGarbamide 103-105.5
23 1-~ (3-Fluorophenyl)-ethy ~ -3- honey-like
-(2-hydroxyethyl)-thiocarbamide substance 0.25 :
23a 1-Ll-(4-Fluorophenyl)-ethyl3-3-
-(2-hydroxyethyl)-thiocarbamide 91.5-92
24 1~ Phenyl-2,2,2-tri~luoroethyl)-
~ -3-(2-hydroxyethyl)-thiocarbamide 115-116.5
1 25 ~ 1-(1-Phenylpropyl)-3-(3-hydroxypropyl)-
~ -thiocarbamide 120.5-122
: .,
26 ~ 1-(1-Phenyl-2-methylpropyl)-3-
-(3-hydroxypropyl)-thiocarbamide 108-110
27 1-(3,4-Dimethoxybenzyl)-3-(3-hydroxy--
; propyl)-thiocarbamide 70-73
28 ~rl-~1-(4-Methoxyphenyl)-ethy~ -3- ~-`
` -(2-hydroxyethyl)-thiocarbamide 117-118 ;~
29 1-(2-Fluorobenzyl)-3-(3-hydroxy-
; propyl)-thiocarbamide 100-102
1-(3-Fluorobenzyl)-3-(3 hydroxy-
propyl)-thiocarbamide 99-100.5 ;
31 1-(4-Fluorobenzyl)-3-(3-hydroxy-
~
i propyl)-thiocarbamide 117-119
32 1-(4-Chlorobenzyl)-3-(3-hydroxy
propyl)-thiocarbamlde 124-125.5
33 1-(3,4-Vichlorobenzyl)-3-(3-hydroxy-
propyl)-thiocarbamide 128.5-130.5
` :
~: , ,..-~.
~ : '

~6g93~L
:
Table I (continued)
Number No.p. R x/
of Compound C f
Example
34 1-Benzyl~3_m~thyl-3-(2-hydroxy-
ethyl)-thiocarbamide 54-56
~ Phenylethyl)~3-methyl-3- honey-like
~(2-hydroxyethyl)-thiocarbamide substance 0.51
36+ 1-(1-Phenylpropyl)-3-methyl-3- ~;
_(2-hydroxyethyl)-thiocarbamide 80 82
37+ 1-(l~Phenyl-2-methylpropyl)-3-methyl- ;
-3_(2-hydroxyethyl)-thiocarbamide 71-76 ;~
38+ 1-(1-Phenylbutyl)-3~methyl-3-
-(2-hydroxyethyl)-thiocarbamide 74-75
391~ Phenyloctyl)-3-methyl-3-
-(2-hydroxyethyl)-thiocarbamide 72-73.5
40~ 1-(1-Phenyl-l-cyclopropylmethyl~-3- ` -
_methyl-3-(2~hydroxyethyl)~
_thiocarbamide 114-116
41l-(394-Dimethoxybenzyl)-3-methyl~
-3-(2-hydroxyethyl)-thiocarbamide 89-91
42~ 1~ (4~Nethoxyphenyl)-ethyl7-3-
-methyl-3-(2-hydroxyethyl~
_thiocarbamide 62-65
431-(2-Nethylbenzyl~-3-methyl-3-
-(2-hydroxyethyl)-thiocarbamide 74-76
441-(2~6-Dimethylbenzyl)-3-methyl-3-
-(2-hydroxyethyl)-thiocarbamide 120-121.5
451-Ll-(4~0ctylphenyl)-ethyl/-3-methyl-
-3-(2-hydroxyethyl)-thiocarbamide 52-55
.,
461-(2-Fluorobenzyl)-3-methyl-3-
-(2-hydroxyethyl)-thiocarbamide 63-65
471~(3-Fluorobenzyl)-3-methyl-3
~(2-hydroxyethyl)-thiocarbamide 61-63
481-(4-Fluorobenzyl)-3-methyl-3
-(2-hydroxyethyl)-thiocarbamide 103-105
. . ~
::
-15-

3L~6~931 ;. -
Table I (continued
Number M~po R x/
of Compound C f/
Example
491-(2-Chlorobenzyl~-3-methyl-3- honey-like
-(2~hydroxyethyl~ thiocarbamide substance 0~40 : :.
501-(4-Chlorobenzyl~-3-methyl-3- ~
-(2-hydroxyethyl)-thiocarbamide 147-148 .
511-(3~4~Dichloxobenzyl)-3-methyl-3
-(2-hydroxyethyl)-thiocarbamide 104-106 ;
521-(2-Trifluoromethylben~.yl)-3-methyl- ;
-3-(2-hydroxyethyl)-thiocarbamide 93-94.5
531-(3-Trifluoromethylbenzyl)-3-methyl-
-3-(2-hydroxyethyl)-thiocarbamide 78-80 ;
541-(4-Dimethylaminobenzyl)-3-methyl-3_ ::
-(2-hydroxyethyl)-thiocarbamide 108-110
551-(4-Nitrobenzyl)-3-methyl~-3-
-(2-hydroxyethyl)~thiocarbamide 135-13~.5
56 1-(4-Fluorophenylethyl)-3-methyl-3- honey-like
-(2-hydroxyethyl)-thiocarbamide substance 0.88
57l-(l-Phenyl-2j292-trifluoroethyl)-3-. ~
~methyl-3-(2-hydroxyethyl~-thio- ~:
carbamide 107-110 :~
S81-(4-Trifluoromekhylbenzyl)-3-methy~
-3-(2~hydroxyethyl)-thiocarbamide 91~92
S9~ 1-(l~Phenyl-2-methylpropyl)-3-ethyl~
-3-~2 hydroxyethyl)-thiocarbamide 82-84
+ 1-(1-Phenyl-2-methylpropyl)-3-butyl- honey-like
-3-(2~hydroxyethyl)-thiocarbamide substance 0.71
61+ 1-(1-Phenylethyl)-3~cyclohexyl-3- ~-
-2_hydroxyethyl)-thiocarbamide 89-90.5
62+ 1-(1-Phenylethyl)-3~3-bis- ~ .
-(2-hydroxyethyl~-thiscarbamide 67-69 :.
63+ 1-(1-Phenylethyl)-3-allyl-thlo-
carbamLde 56-59
;
;
_ 16 -

~6993'~
-17- ~.
Table I (continued)
Number C o m p o u n d M.p. x/ "~
Example C Rf s
, ::
64 ~ 1-(1-Phenylpropyl)-3-allyl- honey-like
-thiocarbamide substance 0.75
1-(2-Fluorobenzyl)-3-allyl- ~ i
-thiocarbamide 50-53 ;
66 1-(4-Fluorobenzyl)-3-allyl- honey-like
-thiocarbamide substance o.68 ~,
:~
67 1-(3,4-Dimethoxybenzyl)-3-allyl- -
-thiocarbamide 117-119 ;i
68 t 1-(1-Phenylpropyl)-3-(2-methyl-
allyl)-thiocarbamide 68-69 - -
x/ R~ values are given in a 6:1 mi.xture of benzene and
pyridine. The determination was carried out on a thin
(0.1-0.2 mm~) layer o~ silica gel tMerck).
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- 1 8_

3~
Table III
Analgesic effect ol some compounds o~ the general formula I,
on mice and ra~s
Compound Writhing test Hot plate Randall-Sellito test
test
ED50 mg/kg ED50 mg/kg s~imulation threshold
+ l-(Phenylethyl)-3- 3-10, oral 10-30, oral 200 mg/kg oral: 198 %
-~2-hydroxyethyl~- , lO0 mg/kg oral: 78 %
-thiocarbamide S0 mg/kg oral: 56 %
+ l-(Phenylpropyl)-3- 3-10, oral 10-30, oral 200 mg/kg oral: 593 % - ;;
-~2-hydroxyethyl)- 100 mg/kg oral: 199 %
-thiocarbamide 50 mg/kg oral: 103 %
+ l-~Phenyl, cyclopropyl)-
-methyl-3-~2-hydroxy-
ethyl)-thiocarbamide 10-30, i.p. -- - - `
+ l-(l-Phenylethyl)-3- 10-30, oral 10-30, oral 200 mg/kg oral: 88 %
-methyl-3-(2-hydroxy- 100 mg/kg oral: 24 %
et~yl)-thiocarbamide 50 mg/kg oral: 5 %
Morphine 1.65 s.c. 2.50 s~c. 10 mg/kg s.c.: lO00 %
3 mg/kg s.c.: 90 %
1 mg/kg s.c.: 9 %
Propoxyphene 22.5 oral 70, oral100 mg/kg oral: 1000 %
( -(~)-1,2-dlphenyl- 30 mg/kg oral: 534 %
-3-methyl-2-propio- 10 mg/kg oral: 33 % ` ~;
n~loxy-4-dimethyl-
aminobutane)
Amidazophene 180 oral 60, oral200 mg/kg oral: 100 %
C l-Phenyl-2,3- 100 mg/kg oral: 69 %
-dimethyl-5- 50 mg/kg oral: 8 %
-~Yrazolone) :
; ':.
- 19 -

~C16~D3~ -~
Table IV
Antidepressant effect of some compounds of the general
formula I on mice
Antagonization of the temperature~
lowering action of reserpine
C o m p o u n d
Dose Change in rectal ~
TempeOrature :,'
mgtkg ' C : ''
+ 1-(2-Fluorobenzyl)-3-
-(2-hydroxyethyl)-
-thiocarbamide 30 + 3.4 :~
Phenylethyl)D3_ ~ ;
-methyl-3-(2-hydroxy-
ethyl~-thiocarbamide 30 + 3.5
+ l-(l-Phenylpropyl-3~
-methyl-3-~2-hydroxy-
ethyl)-thiocarbamide 30 + 3.8
+ 1-(4-Fluorobenzyl)-3-,
-allyl-thiocarbamide 30 ~ 3.8
.
" :
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: : .~
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~ .
:; :
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:
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-20- ~