Note: Descriptions are shown in the official language in which they were submitted.
`' 1~014Zl
PYRANO[4,3~e]-as-TRIAZINES, THEIR PRODUCTION AND
TRANQUILLISER/SLEEP-INDUCER USE
This invention relates to 5,8-dihydro-6,6,8-
trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazines and their
4-oxides.
More particularly, this invention provides compounds
of formula I,
CH3
¦(R)
H3C ~ (I)
CH3(S) ~ 1
R2
in which X signifies - N ~ or \ N
and Rl and R2, which may be the same or
different, each signifies hydrogen,
f luorine, chlorine, alkyl of 1 to 4
carbon atoms, straight chain alkoxy of
1 to 4 carbon atoms, amino, nitro or
trifluoromethyl,
provided that (i) when one of Rl and R2 iS nitro, the
other is other than nitro or
trifluoromethyl,
and (ii) whPn 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
--1--
llO~9~Zl
-- 2 --
an adjacent carbon atom, or a pharma-
ceutically acceptable acid addition salt
thereof.
The invention also provides processes for the
production of compounds of formula I, characterised by
a) producing a compound of formula Ia,
CH3
33C ~ ~N ~ R1 Ia
in which Rl and R2 are as defined above, or the
8R, 5S isomer thereof, by reacting the compound of
formula II,
CH3
~ ~ NH
H3C ~ NOH ~ II
CH3
or the 8R, 5S isomer thereof, with a compound of
formula III,
1 ~ C(OR3)3 III
R2
in which Rl and R2 are as defined above,
;~.,~
1~01421
-- 3 --
and R3 is methyl or ethyl,
in an inert organic solvent and under an inert atmosphere,
or
(b) producing a compound of formula Iaa,
C13
H3 ~ ~ ~ ,// ~3 Iaa
N02
in which Rl signifies hydrogen, fluorine, chlorine,
alkyl of 1 to 4 carbon atoms, straight chain
alkoxy of 1 to 4 carbon atoms, or amino,
or the 8R, 5S isomer thereof, by nitrating a compound of
formula Iab,
C13
O ~ ~N
crr3 N ~ / ~ Iab
in which Rl is as defined above, or the 8R, 5S
isomer thereof, in an inert organic solvent,
or c) producing a compound of formula Ib,
-
11014Zl
-- 4 --
0~/ ~N
CH3 N J~} R2 Ib
Rl
in which Rl and R2 are as defined above, or the
8R, 5S isomer thereof, by reacting a compound of formula
Ia, stated above, or the 8R, 5S isomer thereof, with
cyclohexene in the presence of a noble metal catalyst, in
an inert organic solvent and under an inert atmosphere;
and, if required, separating the desired 8R, 5S isomer
from a racemic mixture thus obtained, and, where neces-
sary, converting the resulting compound of formula I thus
obtained into a pharmaceutically acceptable acid addition
salt thereof~
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. Alternatively
and preferably, an excess of the compound of formula III
may be employed to provide a reaction medium. The inert
atmosphere may, for example, be helium, argon or, pre-
ferably, nitrogen.
Process b) is a conventional aromatic nitration
, '
' 11014Z~
- 4a -
process which may be effected using conventional nitronium
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 -20C 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
.
.... .
1101421
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 usually 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
treating the compound of formula IV with hydrazine according
to the following reaction scheme:
T3 CH3
~ ~ + N2H4 ~ ~
H3C ~ OH C1,
IV (II)
.~
`` :110~421
The reaction is suitably effected at a temp~rature
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
may vary from 1 to 18 hours, more usually 2 to 8 hours.
The compounds of formula III are either known or
- may be produced in conventional manner from available
materials.
The compound of formula IV is either known or may
be produced in conventional manner from available mater-
ials, for example as hereinafter described in the Examples
or as described by Bandaralli et al., Gazz. Chim. Itali.
05, 1317 (1975).
The compounds of formula I possess pharmacological
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 elec-
trodes. Brain readings are obtained via a ten or sixteenchannel 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 behaviour is monitored via
~1014Z~
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
runs. Control data are collected at least three days
per week and accumulated to give control data for fifteen
sessions per monkey. Data from each session are statis-
tically compared via computer analysis to the previous5-15 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 (REM) 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 behavior
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 described by
Irwin S. (Gordon Research Conference, Medicinal Chemistry,
1959) and Chen (Symposium on Sedative and Hypnotic drugs,
Williams and Wilkins, 1954);
4) by their ability to antagonise chronic convulsions
and death in mice given 45 to 250 mg/kg i.p. of N-sulfam-
oylazepine;
`--` 11014Zl
5) by scoring for loss of righting reflex according to the
method of Reed-Muench ~American Journal of Hygiene 27,
493-497, tl938)], in which mice are administered 12.5
mg/kg, i.p. of Thioridazine, immediately after which the
test compound is administered at dosages of 5 to 100 mg/kg
in a volume of 0.1 ml/10 g body weight. 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, Psychopharmacologia,
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 tranquillising usage, an indicated suitable daily
dosage is from 5 to 500 mg, suitably administered in div-
ided 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
.~
014ZI
salts, which salt forms possess the same order of activ-
ity as the free base forms. Suitable acids for salt
formation include mineral acids such as hydrochloric, hydro-
bromic and sulphuric acid, and organic acids, such as
succinic, benzoic and maleic acid.
This invention is related to copending Canadian
application Serial No. 299,081, filed March 16, 1978 which
describes the corresponding racemic compounds. The com-
pounds of this invention, which are optically active isomers
having the 8R, 5S configurations, have a considerably im-
proved therapeutic ratio in comparison with the correspond-
ing racemates. This is particularly so with the isomers
of Example 1 hereinafter.
The isomers of this invention may also be produced by
separation in a conventional manner from the corresponding
racemic compounds.
The following Examples illustrate the invention:
.
:
al~z~
EXAMPLE 1: 8R,5S-3-(m-trifluoromethylphenyl)-5,8-dihydro-
6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-
as-triazine-4-oxlde. [process a)]
(i) lRL_S-lL3~3-trimethyl-2-oxo-bicyclo[2L2,21-octane-
6-one
To a mechanically mixed solution of 180 ml of (-)-
~-terpineol ([a]20 = -100.1) in 180 ml of glacial acetic
acid and 205 ml of n-butylnitrile, cooled to -10C, is
added, over a period exceeding 45 minutes, a mixture of
conc. HCl (75 ml) and glacial acetic acid (75 ml), while
maintaining the temperature below 0C. After standing for
2 1/2 hours ~t room temperature without stirring, the
resulting mass is triturated with H2O and filtered in a
glass funnel and the precipitate is washed thoroughly
with cold water. After air drying overnight, the precip-
itate is vacuum dried at room temperature for 6-12 hours.
An intimate mixture of 75 g of sodium acetate and
150 g of the resulting chloro-oximino-~-terpineol is dis-
persed in 300 ml of glacial acetic acid in a 2 1 Erlemeyer
flask, and then heated on a steam bath for 1.5 hours wi.th
occasional stirring. 600 ml of H2O is added to the res-
ulting liquid and the mixture is allowed to stand at room
temperature overnight. The precipitate is removed by fil-
tration, washed once with cold water and air dried. The
filtrate is extracted 3 x with 150-200 ml of diethyl ether
-- 10 --
0~4Zl
and, after drying over MgSO4, the combined extracts are
stripped to provide additional quantities of the resulting
lR,4S-2-oxocineoleoxime.
100 g of this product are dissolved in 1600 ml of
diethyl ether, placed in a 4 1 separatory funnel, together
with 80 g of sodium nitrite dissolved in 500 ml of water.
To this mixture is added, portionwise, 500 ml of 2N H2SO4
with vigorous shaking. The resulting mixture is
allowed to stand at room temperature overnight and the
aqueous layer is removed and the deithyl ether layer washed
twice with 10% NaHCO3 (500 ml~. After evaporation of the
diethyl ether, 100 ml of conc. ammonium hydroxide is added
slowly with ice cooling and the mixture is distilled until
2 1 of distillate is collected. The resulting solid is
removed by filtration and air dried. The filtrate is
extracted 2 x with 250 ml of diethyl ether and the extracts
dried over MgSO4 and evaporated. The combined semi solids
are vacuum dried at room temperature to obtain the heading
compound. [~]20 = -68.1.
(ii) lR,4S-1,3,3-trimethyl-2-oxabicyclo[2,2,2]octane-5,6-
dione-5-oxime
To an ice-cooled solution prepared by adding 50 g of the
product of preceding step to a solution of 5g of HCl gas in
250 ml of diethyl ether is added, dropwise, 25 ml of ethyl
nitrite and, after the temperature has stabilised, the mix-
-" ~1014~
ture is allowed to stand for 24 hours at room temperature,
then washed with NaHCO3 and dried over MgSO4. After evap-
oration of the diethyl ether, the oil is triturated with
a minimum of diethyl ether and the solid is removed by
filtration and air dried. The filtrate is evaporated and
the residue is crystallised from H2O to yield the heading
compound.
tiii) lRL4S-1,3L3-trimethyl-2-oxabicyclo[2L2L21octan-5L6-
dione~5-oxime-6-hydrazone (com~ound of formula II)
A mixture of 1.97 g (0.01 mol) 1,3,3-trimethyl-2-oxa-
bicyclo[2,2,2]octan-5,6-dione-5-oxime and 0.35 ml (0.011
mol) 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 recrystallised from ether to give lR,4S-1,3,3-trimethyl-
2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone.
(iv) 8RL5S-3-(m-trifluoromethyl~henyl)-5 L 8-dihydro-6L6L8-
trimethyl-5L8-ethano-6H-E~yrano[4L3-el-as-triazine-
4-oxide
_ _ _ _ _ _ _
A solution of 6.3 g (0.01 mol) lR,4S-1,3,3-trimethyl-
2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone and
20 g of a 1:1 mixture of trimethylortho(m-trifluoromethyl)-
benzoate and methyl (m-trifluoromethyl) benzoate in 100 ml of
toluene is refluxed under nitrogen in a flask equipped with
a Dean-Stark trap filled with 5A molecular sieves, for 48
- 12 -
.
1~014Zl
hours at a bath temperature of 120C during which time
all distillate is removed. The resulting mixture is cool-
ed and evaporated to dryness in vacuo. The residue is
purified by Kiegelrohr distillation followed by prep-
arative TLC. The material solidifies after vac-
uum drying at 60C, 1 Torr for 72 hours to obtain the
heading compound, m.p. 91-93C; [~]20 = + 72.5 [ethanol].
EXAMP~E 2: 8R,5S-3-(m-Trifluoromethylphenyl)-5,8-dihydro-
6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-
triazine [process c~]
To a solution of 2.1 g (0.006 mol) 8R,5S-(_-
trifluoromethylphenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-
ethanol-6H-pyrano[4,3-e]-as-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 8R,5S-3-(_~trifluoromethyl-
phenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano
[4,3-e]-as-triazine; m.p. 66-70C, [~]20 = ~3 5 [ethanol].
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