IE48044B1 - Pyrano (4,3-e)-as-triazines,their production and tranquillizer/sleep inducer use - Google Patents

Abstract

The invention provides compounds of formula I, indicated for use as sleep-inducers and minor tranquillisers, pharmaceutical compositions containing them and processes for their production, where X is 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, the other is other than trifluoromethyl on an adjacent carbon atom or t-butyl on an adjacent carbon atom.

Description

This invention relates to 5,8-dihydro-6,6,8-trimethyl5,8-ethano-6H-pyrano^,3-e] -as-triazines and their 4-oxides.

More particularly, this invention provides compounds of formula I, in which X signifies or and R-j and Rg, 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 trifluoromethy!, provided that (i) when one of R-j and Rg is nitro, the other is other than nitro or trifluoromethyl, and (ii) when one of R1 and Rg is j;-buty1 or trif 1 uoromethyl, 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, (la) % in which R] and Rg are as defined above, by reacting the compound of formula II, with a compound of formula III C(OR,) 3'3 (ΙΠ) 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. b) producing a compound of formula Iaa, (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 lab in which R^‘ is as defined above, in an inert organic solvent, or c) producing a compound of formula lb, in which 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 200°C, preferably 130° to 150°C, 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, 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 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°C to +70°C, preferably -35° 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, preferably, palladium, either neat or on a support, such as charcoal. The process is then conveniently effected at a temperature of from 20° to 200°C, preferably 70° 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 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: The reaction is suitably effected at a temperature of from 0° to 150°C, preferably 75° 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 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 materials, for example as hereinafter described in the Examples or as described by Bandaralli et al., Gazz. Chim. Itali. 105, 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 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 tlie 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 -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 1 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-sulfainoylazepine; ) by scoring for loss of righting reflex according to the method of Reed-Muench [American Journal 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 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, (I960)].

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 process 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.

It will be appreciated that the compounds of the invention are optically active isomers having the 8R, 5S configurations. Such isomers may also be produced by separation in conventional manner from the corresponding racemic compounds. The latter are disclosed in earlier filings, as represented for example by DOS 2,810,224. It has been found that in general the 8R, 5S isomers of the invention, in particular that of Example 1 hereinafter, have a considerably improved therapeutic ratio in comparison with the corresponding racemates.

The following Examples illustrate the invention: ΕΧΛΚη,Γ. 1: 8R, 5S-3- (m-triflugromethylpheny 1) -5,8-dihydro6,6 , S-trimethyl-5, S-ethano-gn-pyrano Γ4,3-e]as-triazine-4-oxide. [process a)] (i) IR, 43-1^3,3itrimethyl-2-oxapbicycloTlf.Jj.^poctane6-one To a mechanically mixed solution of 180 ml of (-)-ccterpineol ([nJ^Q = --1·00··1·0) in Ιθθ π>1 glacial acetic acid and 205 ml of n-butyl nitrite cooled to -10°C, is added, over a period exceeding 45 minutes, a mixture of cone. HC1 (75 ml) and glacial acetic acid (75 ml), while maintaining the temperature below 0°C. After standing for 2 1/2 hours at room temperature without stirring, the resulting mass is triturated with f^O and filtered in a glass funnel and the precipitate is washed thoroughly with cold water. After air drying overnight, the precipitate 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-a-terpineol is dispersed in 300 ml of glacial acetic acid in a 2 1 Erlemeyer flask, and then heated on a steam bath for 1.5 hours with occasional stirring. 600 ml of t^O is added to the resulting liquid and the mixture is allowed to stand at room temperature overnight. The precipitate is removed by filtration, washed once with cold water and air dried. The filtrate is extracted 3 x with 150-200 ml of diethylether and, after drying over MgSO^, the combined extracts are stripped to provide additional quantities of the resulting IR,4S-2-oxocineoleoxime. 100 g of this product are dissolved in 1600 nil of 5 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 H^SO^ with vigorous shaking. The resulting mixture is allowed to stand at room temperature overnight and tbe aqueous layer is removed and the diethyl ether layer washed twice with 10% NaHCOg (500 ml). After evaporation of the diethyl ether, 100 ml of cone, ammonium hydroxide is added slowly with ice cooling and the mixture is distilled until zw 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 MgSO^ and evaporated. The combined semi-solids are vacuum dried at room temperature to obtain the heading compound. [α]2θ = (ii) lR,4S-l,3,3-trimethyl~2-oxabieyclo[2,2,2]octane-5,6dione-5-oxime To an ice-cooled solution prepared by adding 50 g of the product of preceding step to a solution of 5g of HCI gas in 250 ml of diethyl ether is added, dropwise, 25 ml of ethyl nitrite and, after the temperature has stabilised, the mix13 ture is allowed to stand for 24 hours at room temperature, then vzashed with NaliCO., and dried over MgS04. After evaporation 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 UgO to yield the heading compound. (iii) 1β£432ΐ£3Δ3-ΐΓΪΐΓ£ΐΐ2^1-22θχη^Ϊ£γσ1ο_[2Λ2£2)_οοΐ3η25Λ6^ΐ2Π2ΐ5-22ίπ12ΐ523ϊ322ζ222_^22ϊ,Ε2225_2ί_£2252χ2_ΐϊ1 A mixture of 1.97 g (0.01 mol) l,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dicne-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 80°C for 1 hour. After evaporation of the solvent, the residue is recrystallised from ether to give lR,4S-l,3,3-triinethyl2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone. (iv) §R,5S23-{m;trifluoromethylghenyl)25,.8-dihydro-6£6£8ί·2ίϊ223χί;ΐ5ι§ΐ223 2D2"55lBf 22221 li2I2ll22l£EiS2i-§" 4foxide A solution of 6.3 g (0.01 mol) 1R,4S-1,3,3-trimethyl2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone and 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 o a Dean-Stark trap filled with 5A molecular sieves, for 48 hours at a bath temperature of 120nC during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. The residue is purified by Kiegeirohr distillation followed by preparative TLC. The material solidifies after vacuum drying at 60°C, 1 Torr for 72 hours to obtain the heading compound, m.p. 91-93oCj [Η^θ ~ + 7Ζ·2β (ethanol).

EXAMPLE 2: 8P,5S-3-(m-frifluoromethylphenyl)-5,S-dlhyd.ro6,6,8-trimethy1-5,S-ethano-6H-pyrar!O(4,3-e1-astriazine [process c)] To a solution of 2.1 g (0.006 mol) 8R,5S-(mtrif1uoromethylphenyl)-5,8-dihydro-6,6,8-trimethyl-5,8ethanol-6E-pyrano[4,3-e)-as-triazine-4-oxide and 1.E0 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 1C hours. The catalyst is then removed by filtration and the filtrate evaporated to give 8R,5S-3-(m-trifluororriethylphenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-GiI-pyrano [4,3-e]-as-triazine; m.p. 66-70°C,· [αΐ^θ =-3,3° (ethanol). 1. A process for the production of a compound of formula I, 480 44

Claims (10)

1. in which X signifies \„/ or \,Z 5 40 and R ; and Rg, 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 Rj and Rg is nitro, the other is other 10 than nitro or trif1uoromethyl, and (ii) when one of Rj and Rg 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, with a compound of formula III, (III) R c(or 3 ) 3 in which R-j and R 2 are as defined above, and R 3 is methyl or ethyl, in an inert organic solvent and under an inert atmosphere, b) producing a compound of formula Iaa, in which Rj' 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 lab, in which Rj' is as defined above in an inert organic solvent, or 10 in which Rj and Rg are as defined above, by reacting a compound of formula la, stated above, with cyclohexene in the presence of a noble metaT catalyst, in an inert organic solvent and under an inert atmosphere.

2. Λ 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, vzhenever 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 R^ is a nitro or trifluoromethyl group, and R.g 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 X, stated in Claim 1, in which X is tf-,0, is m-trifluoromethyl and Rg is hydrogen .

8. A compound of formula I, stated in Claim 1, in which X is K, is m-trifluoromethyl and Rg it. nydrogen.

9. A compound as claimed in any one of Claims 3 to 8, in the form of an acid addition salt.

10. A pharmaceutical composition comprising a compound as claimed in any one of Claims 3 to 8, in free base or pharmacologically acceptable acid addition salt form, in association with a pharmacologically acceptable diluent or carrier.