Note: Descriptions are shown in the official language in which they were submitted.
600-6422/C
31
Thi.s invention relates to 2,5-substituted thiadia--
zoles.
The invention provides cornpcunds of formula I,
Rl ~ N-N
R2 Z~S~NH2
in which Rl is hydrogen, fluorine, chlorine or
trifluoromethyl,
R2 is hydrogen, fluorine or chlorin~,
and Z is 13
2tn ' HtCH2t(n-
~- 13
or tCH~ ~ C~-,
~ in which R3 is an alkyl sroup having
from 1 to 4 carbon atoms,
n is 112,3 or 4
.: and m is 1,2 or ~,
pro~ided that laj when R~ is trifluoromethyl, the two
. trifluoromethyl groups are not attached
lS to ad~acent carbon atoms, and
i
~ 2 - 600-6422/~
3~L
(b) when Rl is trifluoromethyl, R2 is
hydrogen.
The invention also provides a process for the
production of compounds of formula I, characterised by
subjecting a compound of formula II t
z~ ~NH/ ~C~ 2 II
in which Rl, ~2' Z and the proviso are as defined
above,
to strong Lewis acid c~nditions.
: The strong Le~7is acid conditions may
be provided by employing a medium comprisins a strong
mineral acid, for example phosphoric, hydrochloric or
sulphuric acids, or a phosphorus halide or o~yhalide, for
~xample phosphorus tribromide. Suitable reaction times vary,
for example from 0.5 to 20 hours, preferably from 2 to 6
hours~and temperatures of from 40 to 100C, preferably
: from 50 to 65C may suitably be employed.
The reactions may be carried out in the absence
of a solvent, or in the presence of an inert solvent,
,
- 3 - ~00-6~22/C
3~
preferably an inert aromatic solvent, for example b~nzene,
toluene, xylene or chlorobenzene.
The compounds of formula I may be isolated and
purified using conventional techniques. Where required,
free base forms of the compounds may be converted into acid
addition salt forms in con~entional manner, and vice versa.
The compounds of formula II may be obtained by
reacting a compound of formula III,
~ 3 III
in which Rl, R2, Z and the proviso are as defined
above,
and X is chlorine or bromine,
with thiosemicarbazide of formula IV,
NH2-NH-~-NH2 - IV
The process is suitably carried out in an inert
solvent, suitably a dialkylformamide, for example dimethyl-
formamide. A convenient reaction temperature is from 0 to
80C, preferably from 15 to 50C. A suitable reaction
t~me is from 1 to 24 hours, preferably from 2 to 6 hours.
31
The compounds of formula II may be isolated and
purified using conventional techniques. Alternatively, by
carrying out the above process under strong Le~is acid con-
ditions, the compound of formula II may undergo ring
closure ln situ to give the compo~nd of formula I.
The compounds of formula III are known or
may be obtained in kno~m manner from available starting
materials.
The compounds of formula I , possess pharmacolo-
gical activity. In par.icular, they pocsess sedative-
hypnotic and minor tranquilizer activity as indicated by
1) their ability to produce docility in behaviour tests in
mice given 25 to 200 mg/kg OL animal body ~eight, i.p.
of the test compound accordir.g to the 30-~Jord adjective
check sheet system basically as described by Ir~in, S.
(Gordon Research Conference, Medicinal Chemistry, 1959~ and
Chen (Symposium on Sedative and Hypnotic Drugs, Williams
and l~lilkins, 1954): 2) by their ability to antagonize
clonic convulsions and death in mice aiven 50 to 250 mg/kg
i.p. of the test substance prior to administration of 50 mg/kg
i.p. of N-sulfamoylazepine; 3) by the hexobarbital
reinduction method of Winter, (J. Pharmacol and Exp.
Therapc, 94, 7-11 1946) in ~hich th~ reinduction of
ancsthesia after recovery from hexobarbital induced
i
~,~
- 5 - 600-6422/C
~05~(~31
anesthesia is used to determine sedative-hypnotic activity
in mice given 70 mg/kg of animal body weight, i.p. of
hexobarbital followed immediately after the mice regain
their righting reflexes by 25 to 200 mg/kg of animal body
weight, i.p. of the test compound; 4) as indicated in
Cebus monkeys using chronically implanted electrcdes.
Brain readings are obtained via a ten or sixteen channel
elec~ncephalograph. For the recording sessions, the
monkeys are restrained by neck and waist plates in chairs
in full side observation cages at the same time every night
for thirteen and one half hours from Monday to Thursday.
Gross behaviour is monitored via closed circuit television
and video tape recordings. The compounds of formula (I)
are administered p.o. at a dosage of from about 1.8 to
about 30 mg/kg immediately on placing the monkey in the
observation cages with at least seven days intervening
between drug administration~. Physiological saline is
administered via a similar route and at the same times on
all control runs. Control data are collected at least
three days per ~eek and accumulated to give control data
for fifteen sessions per monkey. Data from each session
are statistically compared via computer analysis ~ith the
previous 5-15 control sessions for the particular ani~al,
w1th part cu1ar emphasls given to the fo11owing phases of
,
- 6 ~ 600-6422/C
31
the sleep-wakefulness cycle: resting awake, light sleep,
deep sleep, paradoxical (R~M) sleep, "pseudo-" paradoxical
sleep, latency to onset of deep sleep, and latency to onset
of first epoch of paradoxical sleep; and 5) as indicated
in the cat given typically 5 to 30 mg/kg of animal body
weight of the active material and tested in sleep studies
using chronic cortical and subcortical electrode placements,
with eye movement measured via electro-oculogram. Brain
readings are obtained via Gross Model 6 electroencephalo-
graphs, and the gross behaviour of the animal is monitored ~;
vla closed circult television and video tape recordings.
The compounds of formula I are accordingly
;~ indicated for use as minor tranquillisers and sedative-
hypnotic agents.
lS An indicated suitable daily dosage for both uses
is from 75 to 1500 milligrams. FQr minor tranquilliser use
the dosage is preferably administere in divided doses of
from 18 to 750 milligrams two to four times daily, or in
retard form. For sedative-hypnotic use the dosage is
preferably administered in a single dose at bedtime.
-T~e compounds may be used in free base form or
in the form of pharmaceutically acceptable acid addition
,.. . .
. ~ .
~ 7 - ~00-6~22/C
3~
salts, which salt forms have the same order of activity as
the free base orms. Suitable acids for salt formation in-
clude inorganic acids, for example hydrochloric acid, and
organic acids, for example succinic acid.
For such usage, the compounds of formula I may
be admixed with conventional pharmaceutically acceptable
diluents or carriers, and, optionally, other excipients,
and administered in such forms as tablets or capsules.
- A preferred group of compounds of formula I are
those in which Rl and R2 are hydrogen, the CF3 group is
in the meta-position, and Z is tCH2~ where n= 1,2,3 or 4.
n
A particularly preferred compound is 2-amino-5-(3-t~ifluoro-
methylbenzyl)-1,3,4-thiadiazole.
The iollowing Examples i.lustrate the in.ention:-
, .
- .. . . .
~()50(~3~ 600-6 ~22~c
)
EXAMPLE 1
1-(3'-Trifluoromethylphenylacetyl)-thiosemicarbazide (II)
A mixture of 60.0 g (0.3 mole) of 3-trifluorome-
thylphenylacetic acid and 80 ml of thionyl chloride in the
S presence of 10 drops of dimethylformamide is heated on a
water bath for 3 hours. The e~cess thionyl chloride is
evaporated ur.der reduced pressure, and any rem2ining traces
of thionyl chloride are removed by addition of dry benzene
followed by evaporation. To the resultins acid chloride
dissolved in 100 ml of absolute di~.ethylfor~a~ide is added
with cooling 29.3 g (0.32 mole~ of thiosemica~bazide. The
mixture is maintained at room temperature overnight and the
excess solvent is removed under reduced pressure. On
addition of lce ~tater to the residue, a solid is precipi-
tated ~Ihich is then recrystallized from acetone/hexane to
give 1-(3'-trifluoromethylphenylacetyl)-thiosemicarbazide,
m.p. 197 - 199C.
EX~SPLE ? ~Compounds of formula II)
Follo~ing the procedure of Example 1 and using
appropriate starting materials in approximately equivalent
amounts, the fol1ow~ng compounds may be obtained:-
.. , ~' ' .
.. . .
~5~33l
a) 1-(4'-trifluoromethylrhenylacetyl.) thiosemicarbazide~
b) 1-(3',5'-di(trifluoromethyl)phenylacetyl)~thiosemi~
car~azide,
c) 1-(5'-chloro-3'~trifluoromethylphenylacetyl~-thio-
se~icarbazide,
d) 1-(2',5'-dlchloro-3'-trifluoromethylphenylacetyl)-
~hiose~icarbazide,
. .
e) 1-(3-/3'-trifluoromethylphenyl7-propionyl)-thiosemi-
carbazide,
: . f) 1-(4-/3'-trifluoromethylphenyl7-butyryl) ~thiosemi-
carbazide,
g) 1-(5-/3'-trifluoromethylphenyl7 pentanoyl)-thiosemi~arbazide
h) 1-(2-/3'-trifluoromethylphenyl7-propionyl)-thiosemi-
carbazide,
i) 1-(3-/3'-trifluoromethylphenyl7-butyryl)-thiosemicarbazide,
(4-/3'-trifluoromethylphenyl7-pentanoyl)-thiosemi-
carbazide, or
~ k) 1-(2-methyl-3~/3'-trifluoromethylphenyl7-propionyl)-
: thiosemicarbazide.
: EX~PLE 3 2-Amino-5-~3-trifluoromethylbenzyl)-1,3,4-thia
_
diazole (I)
I
A mixture of 32.0 g ~0.115 mole) of 1-~3'-trifluoro-
methylphenylacetyl)-thiosemicarbazide and 48.0 g of phosphorus
tribromide is heated in a waterbath to a temperatur~ of 60-
65C and mai~tained at that temperature for 4 hours. The
resulting mixture is cooled and poured into a 50% weight/volume
., .
~ ' ~1
~ 10 - 600-6422/C
3~
-
solution of sodium hydroxide in ice water. The resulting
product is extracted with methylene chloride, washed with
water and dried over anhydrous potassium carbonate. The
solvent is evaporated and the residue recrystallized from
methanol and water to give 2-amino-5-(3-trifluoromethyl-
~enzyl)-1,3,4-thiadiazole, m.p. 174-176C.
EXA~PLE 4 (Compounds of formula I)
Follo~ling the procedure of Example 3 and using
. in place of 3'-trifluoromethylphenylacetyl-3-thiosemi-
carbazide, an approximately equivalent amount of the
comPounds of Example 2 a)to k), the follo~ing compounds may
be obtained:-
a) 2-amino-5-(4-trifluoromethylbenzyl)-1,3,4-thiadiazole,
m.p. 194 - 195C.
b) 2-amino-5-(3,5-di[trifluoromethyl]benzyl)-1,3,4-thia-
diazole,
c) 2-amino-5-(5-chloro-3-trifluoromethylbenzyl)-1,3,4-
thiadiazole,
d) 2-amino-5-(2,5-dichloro-3-trifluoromethylbenzyl)-
1,3,4-thiadiazole,
e) 2-amino-5-(3-trifluoromethylphenethyl)-1,3,4-
thiadiazole, m.p. 151-152C,
f) 2-amino-5-(3-trifluorcmethylphenylpropyl)-1,3,4-thia-
diazole, m.p. 161-162C,
.
,~
~ 600-6422/C
~J g) 2-amino-5-(4-[3-trifluoromethylphenyl]butyl)-1,3,4-
thiadiazole, m.p. 135 - 137C.,
h) 2-amino-5~ [3-trifluoromethylphenyl3-ethyl) 1,3,4-
thiadiazole, m.p. 163 - 164.5C.,
i) 2-amino-5-(2-[3-trifluoromethylphenyl3-propyl)-1,3,4-
thiadiazole, m.p. 138 - 140C.,
j) 2-amino-5-(3-[3-trifluororethylphenyl]-butyl)-1, 3, A -
thiadiazole, or
- k) 2-amino-5~ methyl-2-r3-trifluoromethylphenyl]-ethyl)-
1,3,4-thiadiazole, m.p, 131-133C.
A~
.. . .. .
~ . .
