GB1597924A

GB1597924A - Pyranotriazidines processes for their production and their use as pharmaceuticals

Info

Publication number: GB1597924A
Application number: GB10254/78A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1977-03-18
Filing date: 1978-03-15
Publication date: 1981-09-16
Also published as: IE780540L; ES467999A1; ATA189678A; FI780758A; CA1095518A; FI62837C; NL7802746A; IT7848478A0; SE7802773L; IL54295A0; FR2383947B1; AT366688B; JPS53116400A; AU3422478A; ZA781587B; NZ186713A; FR2383947A1; DK104978A; FI62837B; DE2810224A1

Description

(54) PYRANOTRIAZINES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE AS PHARMACEUTICALS (71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to 5,8 - dihydro - 6,6,8 - trimethyl - 5,8 - ethano - 6Hpyrano[4,3-e] - as triazines and their 4 - oxides.

More particularly, this invention provides compounds of formula I, in which X signifies

and R1 and R2, which may 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 trifluoro- methyl, 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.

The invention also provides processes for the production of compounds of formula I, characterised by a) producing a compound of formula Ia,

in which R1 and R2 are as defined above, by reacting the compound of formula II,

with a compound of formula III

in which R1 and R2 are as defined above, and R, is methyl or ethyl, in an inert organic solvent and under an inert atmosphere, b) producing a compound of formula 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,

in which R,' is as defined above, in an inert organic solvent, or c) producing a compound of formula IbJ m;

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.

Process a) is suitably effected at a temperature of from 700 to 2000 C, preferably 1300 to 1500C, 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. Altematively 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, preferably, nitrogen.

Process b) is a conventional aromatic nitration 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 --20"C saturated with boron trifluoride. The preferred reagent is a mixture of trifluoro methanesulphonic acid and fuming nitric acid, preferably in a molar ratio of 2:1.

Suitable solvents include aromatic hydrocarbons, such as methylene chloride or chloro form, preferably methylene chloride. The reaction temperature is suitably from - 800 to +700C, preferably 350 to +35 C 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, prefer ably, palladium, either neat or on a support, such as charcoal. The process is then conveniently effected at a temperature of from 20 to 2000 C, preferably 700 to 110 C 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 con ventional techniques. Where required, free base forms thereof may be converted into acid addition salt forms in conventional manner and vice verso.

The compound of formula II may be prepared by treating the compound of formula IV with hydrazine according to the following reaction scheme:

The reaction is suitably effected at a temperature of from 0 to 1500C, preferably 750 to 85"C, 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 formulae III and IV are either known or may be produced in conventional manner from available materials.

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 electrodes. 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 behaviour is monitored via closed circuit television and video tape recordings. The compound of formula I is administered p.o. 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 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 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 (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 behaviour tests in mice given 25 to 200 mg/kg of animal body weight, i.p., of the test compound according to the 30word adjective check sheet system basically as described by Irwin S. (Gordon Research Conference, Medicinal Chemistry, 1959) and Chen (Symposium on Sedative and Hypnotic drugs, Willians and Wilkins, 1954); 4) by their ability to antagonize chronic convulsions and death in mice given 20-250 mg/kg i.p. of the test compound 60 minutes prior to administration of 50 mg/kg i.p. of N-sulfamoylazepine.

5) by scoring for loss of righting reflex according to the method of Reed Muench [American Joumal of Hygiene 27, 493-497, (1938)], 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 my/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, 1, 421-492, (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 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 R1 is NO2 or CF2, preferably in the m-position, and R2 is hydrogen.

The following Examples illustrate the invention: EXAMPLE 1.

3 - Phenyl - 5,8 - dihydro - 6,6,8 - trimethyl - 5,8 - ethano - 6H - pyrano [4,3-e] - as - triazine - 4 - oxide [process a)] (i) 1,3,3 - Trimethyl - 2 - oxabicyclo[2,2,2]octan - 5,6 - dione - 5 - oxime - 6 hydrazone (compound 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 80"C 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 1420 C.

(ii) --3 -- Phenyl - 5,8 - dihydro - 6,6,8 - trimethyl - 5,'8 - ethano - 6H - pyrano [4,3-e] - as - triazine - 4 - oxide (compound 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 140"C 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 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. 186.50 to 1890C.

EXAMPLE 2.

3 - (m - nitrophenyl) 5,8 - dihydro - 6,6,8 - trimethyl - 5,8 - ethano - 6H - pyrano [4,3-e] - as - triazine - 4 - oxide rprocess 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 temperature of - 300C 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 -300C 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 organic layer is removed, washed with saturated brine solution, dried over magnesium sulfate and evaporated. Trituration of the resulting residue with ether gives 3 - (m - nitrophenyl) - 5,8 - dihydro - 6,6,8 - trimethyl - 5,8 - ethano - 6H pyrano[4,3e] - as - triazine - 4 - oxide - monohydrate; m.p. 150"C (decomposes).

EXAMPLE 3.

3 - Phenyl - 5,8 - dihydro - 6,6,8 - trimethyl - 5,8 - ethano - 6H - pyrano[4,3-e] - as - triazine [process c)] To a solution of 1.80 g (0.006 mole) 3 - phenyl - 5,8 - dihydro - 6,6,8 - trimethyl - 5,8 - ethano - 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 3phenyl - 5,8 - dihydro - 6,6,8 - trimethyl - 5,8 - ethano - 6H - pyrano[4,3-e] - astriazine; m.p. 1800 to 1890C.

Further compounds of formula I, in which X, R1 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.

Ex. Analogy to No. Ex. No. Process X R1 R2 m.p. C 4 1 a N # O p-CI H 5 1 a " p-F H 157-158 6 1 a ,. p-CH3 H 177-178 7 1 a " 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-NO2 H 11 1 a , | m-NO2 H 12 1 a ,. m-C1 H 1800 13 1 a " m-OCH p-OCH3 14 2 b " m-NO2 p-CH3 15 2 b " m-NO2 p-OCH3 133-135 16 3 c N p-Cl H 17 | 3 c " p-F H 18 3 c " p-CH3 H 19 3 c " p-OCH3 H 20 3 c " m-CF3 H 235-250 (dec.) 21 3 c " p-NH2 H 22 3 c " p-NO2 H 23 3 c " m-NO2 H 3000 (dec.) 24 3 c " m-Cl H 25 3 c " m-OCH p-OCH3

Claims

WHAT WE CLAIM IS:1. A process for the production of a compound of formula I, in which X signifies

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, characterised by a) producing a compound of formula Ia,

in which R1 and R2 are as defined above, by reacting the compound of formula II,

with a compound of Formula 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, b) producing a compound of formula Iaa,

in which R,' 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,

in which R1, is as defined above, in an inert organic solvent, or c) producing a compound of formula Ib,

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.
2. A process for the production of a compound of formula I, stated in Claim 1, substantially as described in any one of the Examples.
3. A compound of formula I, stated in Claim 1, whenever produced by a process as claimed in Claim 1 or 2.
4. A compound of formula I, stated in Claim 1.
5. A compound as claimed in Claims 3 or 4, in which R1 is a nitro or trifluoromethyl group, and R2 is hydrogen.
6. A compound as claimed in Claim 5, in which the nitro or trifluoromethyl group is located in the meta position.
7. A compound of formula I, stated in Claim 1, in which X is NeO, Rl is hydrogen and R2 is hydrogen.
8. A compound of formula I, stated in Claim 1, in which X is NoO, R1 is p-chloro and R2 is hydrogen.
9. A compound of formula I, stated in Claim 1, in which X is N # O, Rl is p-fluoro and R2 is hydrogen.
10. A compound of formula I, stated in Claim 1, in which X is N # O, Rl is p-methyl and R2 is hydrogen.
11. A compound of formula I, stated in Claim 1, in which X is N # O, R, is p-methoxy and R2 is hydrogen.
12. A compound of formula I, stated in Claim 1, in which X is N # O, Rl is m-trifluoromethyl and R2 is hydrogen.
13. A compound of formula I, stated in Claim 1, in which X is NoO, R1 is p-amino and R2 is hydrogen.
14. A compound of formula I, stated in Claim 1, in which X is N X O, R1 is p-nitro and R2 is hydrogen.
15. A compound of formula I, stated in Claim 1, in which X is N # O, R1 is m-nitro and R2 is hydrogen.
16. A compound of formula I, stated in Claim 1, in which X is NeO, Rl is m-chloro and R2 is hydrogen.
17. A compound of formula I, stated in Claim 1, in which X is N # O, R, is m-methoxy and R2 is p-methoxy.
18. A compound of formula I, stated in Claim 1, in which X is N # O, R1 is m-nitro and R2 is p-methyl.
19. A compound of formula I, stated in Claim 1, in which X is N # O, R1 is m-nitro and R2 is p-methoxy.
20. A compound of formula I, stated in Claim 1, in which X is N, R1 is hydrogen and R2 is hydrogen.
21. A compound of formula I, stated in Claim 1, in which X is N, R1 is p-chloro and R2 is hydrogen.
22. A compound of formula I, stated in Claim 1, in which X is N, Rl is p-fluoro and R2 is hydrogen.
23. A compound of formula I, stated in Claim 1, in which X is N, R1 is p-methyl and R2 is hydrogen.
24. A compound of formula I, stated in Claim 1, in which X is N, Rl is p-methoxy and R2 is hydrogen.
25. A compound of formula I, stated in Claim 1, in which X is N, R1 is mtrifluoromethyl and R2 is hydrogen.
26. A compound of formula I, stated in Claim 1, in which X is N, R1 is p-amino and R2 is hydrogen.
27. A compound of formula I, stated in Claim 1, in which X is N, Rl is p-nitro and R2 is hydrogen.
28. A compound of formula I, stated in Claim 1, in which X is N, R1 is m-nitro and R2 is hydrogen.
29. A compound of formula I, stated in Claim 1, in which X is N, R1 is m-chloro and R is hydrogen.
30. A compound of formula I, stated in Claim 1, in which X is N, R1 is mmethoxy and R2 is p-methoxy.
31. A compound as claimed in any one of Claims 3-30, in the form of an acid addition salt.
32. A pharmaceutical composition comprising a compound as claimed in any one of Claims 3-30, in free base or pharmacologically acceptable acid addtiion salt form, in association with a pharmacologically acceptable diluent or carrier.