CA1095518A - Pyrano-as-triazines - Google Patents
Pyrano-as-triazinesInfo
- Publication number
- CA1095518A CA1095518A CA299,081A CA299081A CA1095518A CA 1095518 A CA1095518 A CA 1095518A CA 299081 A CA299081 A CA 299081A CA 1095518 A CA1095518 A CA 1095518A
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- trifluoromethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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Abstract
CANADA
IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS
Abstract of the Disclosure This disclosure describes novel compounds of the formula wherein R1 and R2 each independently represent hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbon atoms, straight chain alkoxy of 1 to 4 carbon atoms, amino, nitro or trifluoromethyl, and X represents or
IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS
Abstract of the Disclosure This disclosure describes novel compounds of the formula wherein R1 and R2 each independently represent hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbon atoms, straight chain alkoxy of 1 to 4 carbon atoms, amino, nitro or trifluoromethyl, and X represents or
Description
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 . . -~9~
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 . . -~9~
- 2 - 600-67~1 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
with a compound of formula III
Rl ~ ~ C(OR3)3 III
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
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
with a compound of formula III
Rl ~ ~ C(OR3)3 III
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
- 3 - 600 6781 b) producing a compound of formula Iaa, 3C ~ ~ 1 Iaa 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 9~
- 4 - 600-6781 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 S5~L~
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 S5~L~
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:
3 ~ ~ N284 C8 ~OH
I
¦ IV (II) .. ~ .
;~95S~L~
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:
3 ~ ~ N284 C8 ~OH
I
¦ IV (II) .. ~ .
;~95S~L~
- 6 - 600-6781 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 . .
, .
~9~
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 . .
, .
~9~
- 7 - ~00-6781 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.
, ~ . , :;1 09S5i&3
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.
, ~ . , :;1 09S5i&3
- 8 - 600-67~1 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:
1095~18
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:
1095~18
- 9 - 600-6781 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
[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~
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.
.
~S~l~
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.
.
~S~l~
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
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 _ .
Claims (6)
1. A process for the production of a compound of formula I, (I) in which x signifies or and R1 and R2, which may be the same or different, each signifies hydrogen, fluorine, 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 R1 and R2 is nitro, the other is other than nitro or trifluoromethyl, and (ii) when one of R1 and R2 is t-butyl or trifluoromethyl, the other is other than trifluoromethyl on an adjacent carbon atom or t-butyl on an adjacent carbon atom, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) producing a compound of formula Ia, Ia in which R1 and R2 are as defined above, by reacting the compound of formula II, II
with a compound of formula III
III
in which R1 and R2 are as defined above, and R3 is methyl or ethyl, in an inert organic solvent and under an inert atmosphere or b) producing a compound of formula Iaa, Iaa in which R1 signifies hydrogen, fluorine, 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, Iab in which R1 is as defined above, in an inert organic solvent, or c) producing a compound of formula Ib, Ib in which R1 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 and where necessary converting the resulting compound of the formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
with a compound of formula III
III
in which R1 and R2 are as defined above, and R3 is methyl or ethyl, in an inert organic solvent and under an inert atmosphere or b) producing a compound of formula Iaa, Iaa in which R1 signifies hydrogen, fluorine, 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, Iab in which R1 is as defined above, in an inert organic solvent, or c) producing a compound of formula Ib, Ib in which R1 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 and where necessary converting the resulting compound of the formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
2. A compound of formula I, stated in Claim 1, or a pharmaceutically acceptable salt thereof, whenever prepared by a process according to Claim 1.
3. A process according to Claim 1 wherein R1 is m-CF3, R2 is hydrogen, and X is .
4. 3-(m-trifluoromethylphenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide of the formula or a pharmaceutically acceptable salt thereof, whenever prepared by a process as claimed in Claim 3 or by an obvious chemical equivalent thereof.
5. A process according to Claim 1, wherein R1 is m-NO2, R2 is hydrogen and X is .
6. 3-(m-nitrophenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-c]-as-triazine of the formula or a pharmaceutically acceptable salt thereof, whenever prepared by a process as claimed in Claim 5 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US77907177A | 1977-03-18 | 1977-03-18 | |
| US779,071 | 1977-03-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095518A true CA1095518A (en) | 1981-02-10 |
Family
ID=25115233
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA299,081A Expired CA1095518A (en) | 1977-03-18 | 1978-03-16 | Pyrano-as-triazines |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS53116400A (en) |
| AT (1) | AT366688B (en) |
| AU (1) | AU519623B2 (en) |
| BE (1) | BE864987A (en) |
| CA (1) | CA1095518A (en) |
| DE (1) | DE2810224A1 (en) |
| DK (1) | DK104978A (en) |
| ES (1) | ES467999A1 (en) |
| FI (1) | FI62837C (en) |
| FR (1) | FR2383947A1 (en) |
| GB (1) | GB1597924A (en) |
| IE (1) | IE46679B1 (en) |
| IL (1) | IL54295A (en) |
| IT (1) | IT7848478A0 (en) |
| NL (1) | NL7802746A (en) |
| NZ (1) | NZ186713A (en) |
| PT (1) | PT67791A (en) |
| SE (1) | SE7802773L (en) |
| ZA (1) | ZA781587B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4233469A (en) * | 1979-02-13 | 1980-11-11 | Steppe Theodore W | Conduit bushing |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH617435A5 (en) * | 1974-05-01 | 1980-05-30 | Sandoz Ag | Process for the preparation of novel 5,5,7,7-tetramethylfuro-[3,4e]as-triazine-4-oxides and their use |
-
1978
- 1978-03-09 DK DK104978A patent/DK104978A/en not_active Application Discontinuation
- 1978-03-09 FI FI780758A patent/FI62837C/en not_active IP Right Cessation
- 1978-03-09 DE DE19782810224 patent/DE2810224A1/en not_active Withdrawn
- 1978-03-10 SE SE7802773A patent/SE7802773L/en unknown
- 1978-03-14 NL NL7802746A patent/NL7802746A/en not_active Application Discontinuation
- 1978-03-15 GB GB10254/78A patent/GB1597924A/en not_active Expired
- 1978-03-16 IL IL54295A patent/IL54295A/en unknown
- 1978-03-16 JP JP2936378A patent/JPS53116400A/en active Pending
- 1978-03-16 AU AU34224/78A patent/AU519623B2/en not_active Expired
- 1978-03-16 IE IE540/78A patent/IE46679B1/en unknown
- 1978-03-16 CA CA299,081A patent/CA1095518A/en not_active Expired
- 1978-03-16 NZ NZ186713A patent/NZ186713A/en unknown
- 1978-03-16 BE BE186013A patent/BE864987A/en not_active IP Right Cessation
- 1978-03-17 PT PT67791A patent/PT67791A/en unknown
- 1978-03-17 ES ES467999A patent/ES467999A1/en not_active Expired
- 1978-03-17 FR FR7807768A patent/FR2383947A1/en active Granted
- 1978-03-17 IT IT7848478A patent/IT7848478A0/en unknown
- 1978-03-17 AT AT0189678A patent/AT366688B/en not_active IP Right Cessation
- 1978-03-17 ZA ZA00781587A patent/ZA781587B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2810224A1 (en) | 1978-09-28 |
| FI62837B (en) | 1982-11-30 |
| FI780758A (en) | 1978-09-19 |
| AU519623B2 (en) | 1981-12-17 |
| PT67791A (en) | 1978-04-01 |
| BE864987A (en) | 1978-09-18 |
| FI62837C (en) | 1983-03-10 |
| IL54295A (en) | 1981-02-27 |
| JPS53116400A (en) | 1978-10-11 |
| AU3422478A (en) | 1979-09-20 |
| ZA781587B (en) | 1979-10-31 |
| SE7802773L (en) | 1978-09-19 |
| NL7802746A (en) | 1978-09-20 |
| FR2383947B1 (en) | 1981-07-03 |
| DK104978A (en) | 1978-09-19 |
| ATA189678A (en) | 1981-09-15 |
| FR2383947A1 (en) | 1978-10-13 |
| GB1597924A (en) | 1981-09-16 |
| IL54295A0 (en) | 1978-06-15 |
| IE46679B1 (en) | 1983-08-24 |
| ES467999A1 (en) | 1979-09-01 |
| IT7848478A0 (en) | 1978-03-17 |
| NZ186713A (en) | 1980-09-12 |
| IE780540L (en) | 1978-09-18 |
| AT366688B (en) | 1982-04-26 |
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