Note: Descriptions are shown in the official language in which they were submitted.
Case 600-6781
~s~si~
IMPROVl~MENTS IN OR RELATI~G TO Ol-~GANIC COMPOUNDS
This invention relates to 5,8-dihydro-6,6,8-trimethyl-
5,8-ethano-6H-pyrano r4 ~ 3-e]-as-triazines and their 4-oxides.
- More particularly, this invention provides compounds
of formula I,
~3
H3C ~ X ~ (I~
C~3 ~ Rl
R2 :' :" ' '' ' ' ''-
in ~hich X signifies ~ N ~ or ~N~
and Rl and R2, which may be the same or
different, each signifies hydrogen,
fluorine, chlorine, alkyl of l to 4
carbon atoms, straight chain alkoxy of
l to 4 carbon atoms, aminor nitro or
trifluoromethyl,
provided that (i) when one of Rl and R2 is nitrol the :
other is other than nitro or
lS trifluoromethyl,
and (ii) when one of Rl and R2 is t-butyl
: or trifluoromethyl, the other is
other than trifluoromethyl on an
adjacent carbon atom or t-butyl on
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an adjacent carbon atom.
The invention also provides processes for the
production of compounds of formula I, characterised by
a) producing a compound of formula Ia,
~2
. . - . -
5in which Rl and R2 are as defined above,
by reactiny the compound of formula II,
0 ~ r~_~ 2 II
CH3
with a compound of formula III
Rl
~ ~ C(OR3)3 III
R2
in which Rl and R2 are as defined above,
. and R3 is methyl or ethyl,
in an inert organic solvent and under an inert atmosphere ,
.
1~99~8
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b) producing a compound of formula Iaa,
3C ~ ~ 1 Iaa
N02
in which Rl signifies hydrogen, fluorlne, chlorine,
alkyl of 1 to 4 carbon atoms, straight
chain alkoxy of 1 to 4 carbon atoms,
or amino,
by nitrating a compound of formula Iab,
3 ~ I ~ , Iab
in which Rl us as defined above,
in an inert organic solvent,
or c) producing a compound of formula Ib,
H3C I ~ , ~ Ib
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in which Rl and R2 are as defined above,
by reacting a compound of formula Ia, stated above, with
cyclohexene in the presence of a noble metal catalyst, in
an inert organic solvent and under an inert atmosphere.
Process a) is suitably effected at a temperature
of from 70 to 200C, preferably 130 to 150C, and the
reaction time may, for example, vary from 12 to 36 hours,
more typically 15 to 20 hours. Suitable solvents include
aromatic hydrocarbons, such as benzene or toluene, and
lower alkanols, such as methanol or ethanol. Alternat-
ively and preferably, an excess of the compound of formula
III may he employed to provide a reaction medium. The
inert atmosphere may, for example, be helium, argon or,
preferably, nitrogen.
Process b) is a conventional aromatic nitration
process which may be effected using conventional nitron-
ium ion-forming reagents, including a mixture of sulphuric
and nitric acid, a mixture of trifluoromethanesulphonic
acid and fuming nitric acid, or a mixture of hydrogen
fluoride and dinitrogen peroxide in nitromethane at -20~C
saturated with boron trifluoride. The preferred reagent
is a mixture of trifluoromethanesulphonic acid and
fuming nitric acid, preferably in a molar ratio of 2:1.
Suitable solvents include aromatic hydrocarbons, such as
methylene chloride or chloroform, preferably methylene
chloride. The reaction temperature is suitably from -80
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5 - 600-6781
to +70C, preferably -35 to ~35C and the reaction
time may, for example, vary from 19 to 96 hours, more
usually 60 to 75 hours.
In process c), the noble metal catalyst is suitably
platinum, rhodium or, preferably, palladium, either neat
or on a support, such as charcoal. The process is then
conveniently effected at a temperature of from 20 to
200C, preferably 70 to 110C and the reaction time may
vary, for example from 5 to 72 hours, more ususally from
15 to 30 hours. Suitable solvents include lower alkanols,
such as methanol or ethanol, preferably the latter.
Process c) is effected under an inert atmosphere such as
helium, argon or, preferably, nitrogen.
The resulting compounds of formula I may be isolated
and purified using conventional techniques. Where required,
free base forms thereof may be converted into acid addition
salt forms in conventional manner and vice versa.
The compound of formula II may be prepared by treatiny
the compound of formula IV with hydrazine according to the
following reaction scheme:
CH3 CH3
3 ~ ~ N284 C8 ~OH
CH3 3
I
¦ IV (II)
.. ~ .
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The reaction is suitably effected at a temperature
of from 0 to 150C, preferably 75 to 85C, in an inert
organic solvent, for example a lower alkanol, preferably
ethanol, and under an inert atmosphere. The reaction time
S may vary from 1 to 18 hours, more usually 2 to 8 hours.
The compounds of formulae III and IV are either
known or may be produced in conventional manner from
available materials.
The compounds of formula I possess phannacological
activity. In particular, they possess sleep-inducing
and minor tranquillising activity, as indicated
- 1) by the hexobarbital reinduction method of Winter,
J. Pharmacol. and Exp. Therap. 94, 7-11 (1948); 2) in
the Cebus monkey using chronically implanted elect-
rodes. Brain readings are obtained via a ten or sixteen
channel electroencephalograph. 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, Monday
through Thursday. Gross behavior is monitored via
closed circuit television and video tape recordings.
The compound of formula I is administered p.o. immedi-
ately 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 time on all control
. .
, .
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runs. Control data are collected at least three days
per wec]c and accumulated to yive control data for fif-
teen sessions per monkey. Data from each session are
statistically compared via computer analysis to the
previous 5-15 control sessions for the particular animal,
with particular emphasis being given to the following
phases of the sleep-wakefulness cycle: resting awake, light
sleep, deep sleep, paradoxical (P~EM) sleep, "pseudo-"
paradoxical sleep, latency to onset of deep sleep, and
latency to onset of first epoch of paradoxical sleep;
3) by their ability to produce docility in behaviour
tests in mice given 25 to 200 mg/kg of animal body
weight, i.p., of the test compound according to the 30-
word adjective check sheet system basically as deserihed
by Irwin S. (Gordon Research Conferenee, Medieinal
Chemistry, 1959) and Chen (Symposium on Sedative and
Hypnotie drugs, Willians and Wilkins, 1954);
4) by their ability to antagonize chronic convulsions
and death in miee given 20-250 mg/kg i.p. of the test
eompound ~0 minutes prior to administration of 50 mg/kg
i.p. of N-sulfamoylazepine;
5) by scoring for loss of righting reflex aeeording to
the method of Reed-Muench [American Journal of Hygiene
27, 493-497, (1938)], in whieh mice are administered
12.5 mg/kg, i.p. of Thioridazine, immediately after
whieh the test eompound is administered at dosages of 5
to 100 mg/kg in a volume of 0.1 ml/10 g body weight.
,
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Sixty minutes after dosing, the mice are scored for loss
of righting reflex, and
6) by their ability to reduce conflicts as defined in
the Geller Conflict Test [Irving Geller, Psychopharma-
cologia, I, 42-492, (1960)].
The compounds are therefore indicated for use as
sleep inducers and minor tranquillisers. For sleep
inducing usage, an indicated suitable daily dosage is
from 1 to 300 mg, suitably given as a single dosage
at bedtime. For minor tranquillisin~ usage, an indicated
suitable daily dosage is from 5 to 500 mg, suitably
administered in divided dosages of from 1.25 to 250 mg,
two to four times daily or in retard form.
The compounds may be admixed with conventional
pharmaceutically acceptable diluents or carriers and,
optionally, other excipients, and administered in such
forms as tablets or capsules.
The compounds may be employed in free base form
or in the form of pharmaceutically acceptable acid
addition salts, which salt forms possess the same order
of activity as the free base forms. Suitable acids for
salt formation include mineral acids, such as hydrochloric,
hydrobromic and sulphuric acid, and organic acids, such as
succinic, benzoic and maleic acid.
The preferred compounds of formula I are those
in which Rl is NO2 or CF3, preferably in the m-position,
and R2 is hydrogen.
The following Examples illustrate the invention:
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EX~MPLE 1: 3-Ph~enyl-5,8-dihy~ro-6,6,8-trimethy~--5!8-
ethano-6H- rano[4 3 e-]-as'-tri'azine-4-oxide.
[process a)] -
(i~ 1,3,3-Trimethyl-2-oxabicyclo[2,2,2~octan-5,6-dione-
___ _________ __________ ___._______________________
5-oxime-6-hydrazone (com~ound of formula II)
A mixture of 1.97 g (0.01 mole~ 1,3,3-trimethyl-
2-oxabicyclo~2,2,2]octan-5,6-dione-5~oxime and 0.35 ml
(0.011 mole) anhydrous hydrazine (98~) in 25 ml
absolute ethanol is refluxed under nitrogen at a bath
temperature of 80C for 1 hour. After evaporation of
the solvent, the residue is recrystallized from ether
to give 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-
5,6-dione-5-oxime-6-hydrazone; m.p. 138 to 142C.
(ii) 3-Phenyl-5L8-dihydro-6L6 8-trimethyl-5,8-ethano-
_._ ____ _ __ _ __ __ __ _ _ _L____ ____ _ ___ ____ __ __
6H-~yrano[4,3-el-as-triazine-4-oxide (com~ound of
formula Ia)
___________,
A solution of 2.11 g (0.01 mole) 1.3.3-trimethyl-
2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone
in 10 ml trimethylorthobenzoate is refluxed under
nitrogen for 18 hours at a bath temperature of 140C
during which time all distillate is removed. The
resulting mixture is cooled and evaporated to dryness
in vacuo. After filtering the residue,dissolved in ~-
- 2% methanol-chloroform,through silica gel, and
evaporation of the filtrate the resulting solid is
.
.
~09~;S18
- 10 - 600-6781
triturated with ether,giving 3-phenyl-5,8-dihydro-
6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-
triazine-4-oxide; m.p. 186.5 to 189C.
EXA~lPLE 2- 3-(m-nitrophenyl)-5,8-dih~dro-6,6,8-trimethyl-
5,8-ethano-6H-p~yrano[4!-3--e]-as-triazine-4-oxide.
[process b)]
To a mixture of 0.2 ml (0.005 mole) fuming nitric
acid and 1.5 g (0.01 mole) trifluoromethanesulfonic acid in
15 ml anhydrous methylene chloride maintained at a tempera-
ture of -30C there is added dropwise a solution of 0.60 g
(0.002 mole) 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-
6H-pyrano[4,3-e]-as-triazine-4-oxide in 15 ml methylene
chloride, maintaining the temperature at -30C throughout
the addition. The resulting mixture is stirred at ambient
temperature for 72 hours, then poured onto ice and
neutralized with solid sodium bicarbonate. The oryanic layer
is removed, washed with saturated brine solution, dried over
magnesium sulfate and evaporated. Trituration of the resul-
ting residue with ether gives 3-~m-nitrophenyl)-5,8-dihydro-
6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-
oxide~monohydrate; m.p. 150C (decomposes).
EXAMPLE 3: 3-Phen~1-5,8-dihydro-6,6,8-trimethyl- ~ ethano-
. . _
6H-pyrano[4,3-e]-as-triaz~ine [process c)]
To a solution of 1.80 y (0.006 mole) 3-phenyl-5,8-
dihydro-6,6,8-trimethyl~5,8-ethano-6H-pyrano[4,3-e]-as-
~o?s5~
11 - 600-67~31
triazine-4-oxide and 1.50 g (0.018 mole) cyclohexene in
30 ml absolute ethanol there is added 60 mg 10~ palladium
on charcoal. The resulting mixture is refluxed under a
nitrogen atmosphere for 18 hours. The catalyst is then
removed by filtration and the filtrate evaporated to give
3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6IJ-pyrano
[4,3-e]-as-triazine; m.p. 180 to 189C.
Further compounds of formula I, in which X, Rl and
R2 have the significances indicated in the following
table,may be prepared in manner analogous to the indicated
Example(s) using appropriate starting materials in
approximately equivalent amounts.
.
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12 - 600 6781
.. _ _ I __ .. _ ._ ~ _ . ,
Ex. ~nalogy to Process X Rl R2 m-p- C
No. Ex. No.
.. .. _ ~ ._. .. _ ...
4 1 a N~ O p-Cl H
1 a ~ p-F H 157-158
6 1 a l~ p-CH3 H 177-178
7 1 a ~l p-OCH3 H 148-149
8 1 a ., m-CF3 H 157.5-158.5
9 1 a ~ p-NH2 H . - - .
10 1 a - P-N02 H
11 1 a ~ m-N02 H
12 1 a ~ m-Cl H 180
13 1 a ~ m-OCH3 p-OCH3
14 2 b ~ m-N02p-CH3
15 2 b ~ m-N02p-OCH3133-135
16 3 c N p-C1 H
17 3 e ~ p-F H
18 3 c ~ p-CH3 H
19 3 c ~ p-OCH3 H
20 3 e ~ m-CF3 H235-250 (dec.)
21 3 e ~ p-NH2 H
22.3 e - P-N02 H
23 3 e ~ m-N02 H300 (dec.)
24 3 c ~ m-Cl H
25 3 c ~ m-OCH3 p-OCH3
. _ ~ . L _
.
