NZ189537A - Cup selection apparatus for vending machine - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 89537 / 18953 7 jtlfl ^ ^ gjfi @ iii^ »{£ k u "&sd i |^|l 19 NZ. PATENT OFF!Cc NEW ZEALAND £ s1FEBiS79 PATENTS ACT, 1953 - F "v.-BE28V '.» .'.

No.: Date: COMPLETE SPECIFICATION PYRANO/4,3-e/-as-TRIAZINES, THEIR PRODUCTION AND TRANQUILLIZER/SLEEP INDUCER USE M/We, SANDOZ LTD., 35 Lichtstrasse, 4002 Basle / Switzerland, a Swiss Body Corporate hereby declare the invention for which 2l / we pray that a patent may be granted to fit®/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - _ 1 _ (followed by page la) - la - 1895 000 C701/D • PYRAMO [4,3-0] "■aa-TIlIABINEG» TIIEIR PRODUCTION AMB TRAHQUILLIGER/OLEDP INDUCER-PSE- This invention relates to 5,8-dihydro-6,6,8-trimethyl 5,8-ethano-6H-pyrano[4,3-e]-as-tria2ines and their 4-oxides Wore particularly, this invention provides compounds of formula I, h3c (I) 4-Ri in which X signifies or i and R^ and , 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 trifluoromethy1, provided that (i) and (ii) when one of R^ and R£ is nitro, the other is other than nitro or trifluoromethy1, when one of R^ and R£ is t-butyl or trifluoromethy1, the other is other than trifluoromethy1 on an adjacent carbon atom or t-butyl on 1 00 0 07P'l/D 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 la, la in which and R2 are as defined above, by reacting the compound of formula II, "—NH.

NOH II with a compound of formula III Vy_ 0,0*3,3 R.

III in which R^ and R^ are as defined above, and R^ is methyl or ethyl, in an inert organic solvent and under an inert atmosphere 189537 000 G701/D b) producing a compound of formula laa, h3c laa NO. in which 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, ch.5 lab in which Rj^ is as defined above, in an inert organic solvent, or c) producing a compound of formula lb, H3 lb - 4 I &,9 5 3 7 in which R^ and R£ are as defined above, by reacting a compound of formula la, 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 10 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 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 20 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 25 methylene chloride or chloroform, preferably methylene chloride. The reaction temperature is suitably from -80° 1 8953 0 00 C7 0.1/B to +70°C, preferably -35° to +35°C and the reaction time may, for example, vary from 19 to 9 6 hours, more usually 60 to 75 hours.

In process c), the noble metal catalyst is suitably 5 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 ususally from 10 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. 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 20 following reaction scheme: The resulting compounds of formula I may be isolated ch CH IV (II) G00-G7Q1/D 1 8953 7 6 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 5 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 10 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) . 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. 9_4, 7-11 (1948) ; 2) in the Cebus monkey using chronically implanted elec-20 trodes. 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 25 through Thursday. Gross behaviour is monitored via The compounds of formula I possess pharmacological 189537 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 5 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-10 tically 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 15 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.r 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 V?ilkins, 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 ? 1 8953 7 600 C781/D ) 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 10 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 15 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 25 in the form of pharmaceutically acceptable acid addition 1 8953 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, hydro-bromic and sulphuric acid, and organic acids, such as 5 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 10 racemic compounds. The latter are disclosed in earlier filings, as represented for example by^BQS—2-, 010 ,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 compar-15 ison with the corresponding racemates.

The following Examples illustrate the invention: 189537 - 10 - COO 0 701/D EXAMPLE 1: 8R,5S-3-(m-trifluoromethylphenyl)-5,8-dihydro-6,6,8-trimethy1-5,8-ethano-6H-pyrano[4,3-e] -as-triazine-4-oxide. [process a)] (i) 1R, 4S-1^3^3-trimethYl~2-oxo-bicYclo_[2 , 2_, 2 ]_-octane-5 6-one To a mechanically mixed solution of 180 ml of (-)-cc- o. S- terpineol ([a]!? = -100.1°) in 180 ml of glacial acetic 0-P- 20 nCtrCte, ^ acid and 205 ml of n-b u t y 3^1 i t h i urn, cooled to -10°C, is 'added, over a period exceeding 45 minutes, a mixture of 10 conc. 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 E^O and filtered in a glass funnel and the precipitate is washed thoroughly 15 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-cx-terpineol is dispersed in 300 ml of glacial acetic acid in a 2 1 Erlemeyer 20 flask, and then heated on a steam bath for 1.5 hours with occasional stirring. 600 ml of H^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 25 filtrate is extracted 3 x with 150-200 ml of diethylether 1 8953 7 600-6781/B. and, after drying over MgSO^, the combined extracts are • stripped to provide additional quantities of the resulting 1R, 4S-2-oxocineoleoxime. 100 g of this product are dissolved in 1600 ml 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 H2SO^ with vigorous shaking. The resulting mixture is allowed to stand at room temperature overnight and the 10 aqueous layer is removed and the diethyl ether layer washed twice with 10% NaHCO^ (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 yv 2 1 of distillate is collected. The resulting solid is 15 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. ^20 = ~68.1°. (ii) 3JR, 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 HC1 gas in 250 ml of diethyl ether is added, dropwise, 25 ml of ethyl 25 nitrite and, after the temperature has stabilised, the mix- 189537 - 12 - GOO G701/D ture is allowed to stand for 24 hours at room temperature, then washed with NaHCO^ and dried over MgSO^. After evaporation of the diethyl ether, the oil is triturated with a minimum of diethyl ether and the solid is removed by 5 filtration and air dried. The filtrate is evaporated and the residue is crystallised from I^O to yield the heading compound. (iii ) lRi.^S-2.^3^3-trimethy 1-2-oxabi c^clo [ 2Z2 ^2 ]_oc tan-S^-dione-S-oxime-e-h^drazone (compound 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 80°C for 1 hour. After evaporation of the solvent, the residue 15 is recrystallised from ether to give 1R,4S-1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone; (iv) 8R/.5S-3- jm- trif luoromethy lE^en^l)." § ~ trimethy1-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide A solution of 6.3 g (0.01 mol) 1R,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-trifluoromethy1)-benzoate and methyl(m-trifluoromethy1)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 1 8953 600 G701/Tj ■ hours at a bath temperature of 120°C during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. The residue is purified by Kiegelrohr distillation followed by prep-5 arative TLC. The material solidifies after vacuum drying at 60°C, 1 Torr for 72 hours to obtain the heading compound, m.p. 91-93°C; fa^20 = + 72-5° [ethanol].

EXAMPLE 2: 8R,5S-3-(m-Trifluoromethylphenyl)-5,8-dihydro-6,6,8-trimethy1-5,8-ethano-6H-pyrano[4,3-e]-as-trlazine [process c)] To a solution of 2.1 g (0.006 mol) 8R,5S-(m-trifluoromethylphenyl)-5,8-dihydro-6,6,8-trimethy1-5,8-ethanol-6H-pyrano[4,3-e]-as-triazine-4-oxide and 1.50 g (0.018 mole) cyclohexene in 30 ml absolute ethanol there 15 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-(m-trifluoromethyl-..' phenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano 20 [4,3-e]-as-triazine; m.p. 66-70°C; ^a^20 = Ethanol] 189537 - 14 ~ COO G70J/B.

Claims (1)

1. WHAT WE CLAIM IS: 1. A process for the production of a compound of formula I, r % i j) i R,. (I) in which X signifies or t and R^ and R£, 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 trifluoromethy1, provided that (i) and (ii) when one of and R^ is nitro, the other is other than nitro or trifluoromethyl, when one of R^ and R^ is t-butyl or trifluoromethyl, the other is other than trifluoromethyl on an adjacent carbon atom or t-butyl on an adjacent carbon atom^ - 15 - J 1 8953 7 600-6781/D ■ characterised by a) producing a compound of formula la, U3C la in which and R2 are as defined above, by reacting the compound of formula II, 5J0H with a compound of formula III, R 'Y3- 0(0*3,3 R. II III in which R^ 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 laa, »3C ~y laa NO. - 16 - 1 8953 600-6 7'8'1/B- in which signifies hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbon atoms, straight chain alkoxy of 1 to 4 carbon atoms, or amino, 5 by nitrating a compound of formula lab, lab in which R| is as defined above, in an inert organic solvent, or c) producing a compound of formula lb, ch. Ib in which R^ and R^ are as defined above, 10 by reacting a compound of formula la, stated above, with cyclohexene in the presence of a noble metal catalyst, in an inert organic solvent and under an inert atmosphere. - 17 - 1 8953 000 G701/D 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, 5 whenever produced by a process as claimed in Claim 1 or 2. 6. A compound as claimed in Claim 5, in which the 10 nitro or trifluoromethyl group is located in the meta position. 7. A compound of formula I, stated in Claim 1, in which X is N-»0, is m-trifluoromethyl and R2 is hydrogen . 15 8. A compound of formula I, stated in Claim 1, in which X is N, R^ is m-trifluoromethyl and R2 is hydrogen. 8, in the form of an acid addition salt. 10. A pharmaceutical composition comprising a 20 compound as claimed in any one of Claims 3 to 8, in free base or pharmacologically acceptable acid addition salt form, in association wth a pharmacologically acceptable diluent or carrier. 4. A compound of formula I, stated in Claim 1. S. 5. A compound as claimed in Claim^ 3 or 4, in which ^ R^ is a nitro or trifluoromethyl group, and R2 is hydrogen. 9. A compound as claimed in any one of Claims 3 to QATED this 29 DAY Of <j"u..Ly t9 §/ 370 O/MO/IID