CH644863A5 - AETHANOPYRANO- (4,3-E) -AS-TRIAZINE, THEIR PRODUCTION AND THE RELEASING AND SLEEPING INGREDIENTS CONTAINED THEREOF. - Google Patents

Description

The invention relates to 5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e] -as-triazines and their 4-oxides. The invention relates to compounds of the formula

30 I,

(I)

in the X N or N

45 I

o represents and

Ri hydrogen, fluorine, chlorine, (C1-C4) alkyl, straight-chain (Ci-C4) alkoxy, NH2, NO2 or CF3 and 50 R.2 hydrogen, fluorine, chlorine, (Ci-C4) alkyl, straight-chain (Ci-C4 ) Mean alkoxy or NH2 and if Ri is CF3 or t-butyl, R2 is additionally CF3, but as t-butyl or CFh can only be in the meta or para position to Ri,

55 and their acid addition salts.

The invention additionally relates to a process for the preparation of compounds of the formula I in which X represents N — O or their acid addition salts, characterized in that a compound of the formula

60 CH.

NH.

II

NOH

3rd

644863

with a compound of formula III

in an inert organic solvent and an inert atmosphere to a compound of formula I, wherein X is

N

l

O

stands, is reacted, wherein in formulas II and III Ri and R2 have the meanings mentioned above and R3 stands for methyl or ethyl and optionally the compound of formula I thus obtained is converted into an acid addition salt or vice versa.

Another object of the invention is a process for the preparation of compounds of formula I according to claim 1, in which X = N or acid addition salts thereof, characterized in that a compound of formula I, in which XN ^ O means in the presence of a noble metal catalyst in an inert organic solvent and in an inert atmosphere with cyclo-hexane, and optionally the compound of formula I thus obtained is converted into an acid addition salt or vice versa.

Another object of the invention is a process for the preparation of compounds of formula I according to claim 1, in which XN- * 0, R2 is hydrogen, fluorine, chlorine, (Ci-4) alkyl, straight-chain (Ci-4) alkoxy or NH2 and Ri represents NO2 in the meta position to the hetero ring or of acid addition salts thereof, characterized in that a corresponding compound of the formula I in which Ri is hydrogen is nitrated in an inert organic solvent, and optionally the compound of the formula I thus obtained is converted into an acid addition salt is transferred or vice versa.

The process is advantageously carried out at temperatures from 70 to 200 ° C., preferably from 130 to 150 ° C., and then takes about 12 to 36, preferably 15 to 20, hours. Suitable solvents are hydrocarbons, such as benzene or toluene, and lower alkanols, such as methanol or ethanol. However, a reaction medium from an excess of compound III is preferred. The inert atmosphere is e.g. Helium or argon and is preferably nitrogen.

Post-nitriding is conventional for aromatic compounds and is accomplished using conventional nitronium ion-forming reagents, e.g. a mixture of sulfuric acid and nitric acid, a mixture of trifluoromethanesulfonic acid and smoking nitric acid or a mixture of hydrogen fluoride and dinitrogen peroxide in nitromethane, which was saturated with boron trifluoride at -20 ° C. The preferred reagent is a mixture of trifluoromethanesulfonic acid and fuming nitric acid, especially when it is present in a 2: 1 mol-is ratio. Suitable solvents are aromatic hydrocarbons such as benzene or toluene or halogenated hydrocarbons such as CHCh or preferably CH2Cl2.

The reaction is advantageously carried out at temperatures between 20 -80 ° and + 70 ° C, preferably between -35 ° and + 35 ° C and takes e.g. 19 to 96, preferably 60 to 75 hours.

When converting from

25 N

i

O

in -N = the noble metal catalyst is advantageously Pt, Rh or 30 preferably Pd and is optionally on a support, such as activated carbon. The process is advantageously carried out at 20-200 ° C, preferably at 70 to 110 ° C, and takes 5 to 75 or rather 15 to 30 hours. Suitable solvents are the "lower alkanols, such as methanol 35 or preferably ethanol. This process is carried out in an inert atmosphere such as helium, argon or preferably nitrogen.

The products of the formula I can be isolated and purified by known methods. If desired, the free bases can be converted into their acid addition salts in a known manner or the reverse reaction can be carried out.

The compound of formula II can be prepared by a compound of formula IV according to the following scheme

40

45

+ K2H4

is reacted with hydrazine. The reaction is advantageously carried out at temperatures between 0 and 150 ° C, preferably between 75 and 85 ° C in an inert organic solvent, e.g. a low alkanol, preferably ethanol, in an inert atmosphere and takes about 1 to 18 or rather 2 to 8 hours.

The compounds of the formulas III and IV are either known or can be prepared from available starting materials by known methods. Thus, the compounds IV can be prepared as mentioned in the exemplary embodiments or as described by Bandaralli C.S. Gazz. Chim. Italy. 105, 1317 (1975).

The compounds of formula I are pharmacologically active. They have a sleep-inducing and slightly calming effect, demonstrable

60

1) Using the hexobarbital reinduction method from Winter, J. Pharmacol. and Exp. Therap. 94.7-11 (1948);

2) in Cebus monkeys, to which electrodes are constantly planted. Brain waves are with a ten- or sixteen-

65-channel electroencephalographs registered. For registration, the monkeys are held at the neck and waist in chairs that are in observation cages and every night during the same time by

644863

4th

Checked Monday to Thursday for 13 hours. The behavior is registered optically. Special interest is devoted to the different phases of waking and sleeping;

3) by causing obedience in mice in behavioral experiments, which is assessed according to a control system with 30 adjectives, which is fundamentally by Irwin S. (Gordon Research Conference, Médicinal Chemistry, 1959) and Chen (Symposium on Sedative and Hypnotic Drugs, Willians and Wilkins , 1954);

4) by their ability to antagonize clonic convulsions and death in mice given N-sulfamoyla-zepin;

5) by registering the loss of reflex to straighten up in mice given thioridazine [Method by Reed-Muench, American Journal of Hygiene 27,493-497, (1938)];

6) by their ability to reduce conflicts, measured according to the Geller conflict test [Irving Geller, Psychophar-macologia, 1,42-492, (I960)].

The compounds are therefore used as sleep-inducing agents and as light sedatives. The daily dose to be administered to induce sleep is expediently 1 to 300 mg, advantageously administered as a single dose at bedtime. For use as a light sedative, the daily dose is advantageously 5 to 500 mg and is conveniently administered in portions of 1.25 to 250 mg, 2 to 4 times a day or in the form of a sustained release.

The compounds can be administered in the form of tablets or capsules with the customary pharmacologically acceptable diluents or carriers and, if appropriate, other additives.

The compounds are administered in free form or in the form of pharmacologically acceptable acid addition salts. The salt forms are of the same order of magnitude as the free forms. Suitable acids for salt formation are mineral acids, such as hydrochloric acid and hydrobromic acid and sulfuric acid, and organic acids, such as succinic acid, benzoic acid and maleic acid.

The preferred compounds of formula I are those in which R 1 is NO 2 or CF 3, preferably in the meta position, and R 2 is hydrogen.

The compounds according to the invention are optically active and therefore occur as isomeric compounds with 8R, SS configurations. Such isomers can be separated in a known manner by the corresponding racemic mixtures. The mixtures are described in previous patent applications, e.g. DOS 2 810 224.

It was found that the 8R, 5S isomers according to the invention, in particular those of Example 1, generally have a considerably more favorable therapeutic behavior than the corresponding racemates.

example 1

8R, 5S-3- (m-trifluoromethylphenyl) -5,8-dihydro-6,6,8-tri-methyl-5,8-ethane-6H-pyrano [4,3-e] -as-triazine-4 -oxide [process a)]

(i) IR, 4S-l, 3,3-trimethyl-2-oxobicyclo [2,2,2] octan-6-one

A mixture of 75 ml of concentrated hydrochloric acid and 75 ml of glacial acetic acid is added in 45 minutes while the temperature is kept below 0 ° C., with stirring, to a solution of 180 ml (-) - a-terpineol ([a ] P0 = -100.1 °) in 180 ml of glacial acetic acid and 205 ml of n-butyllithium. The resulting mixture is in 2Vi hours at room temperature

Let it rest and then pull it out with water and filter it on a glass filter. The precipitate is washed thoroughly with cold water, dried overnight and further dried in vacuo for 6 to 12 hours at room temperature.

150 g of the chloro-oximino-a-terpineol formed is mixed well with 75 g of sodium acetate and dispersed in 300 ml of glacial acetic acid in a 21 Erlen-meyer bottle and heated on a steam bath with occasional stirring for 1.5 hours, after which 600 ml of water are added and the mixture is left overnight at room temperature. The precipitate formed is filtered off and washed once with cold water and air-dried. The filtrate is washed three times with 150 to 200 ml of diethyl ether, the extracts are combined and dried over MgSO4, after which a remaining amount of the IR, 4S-2-oxocineol oxime is obtained.

100 g of this product is dissolved in 1600 ml of diethyl ether, placed in a separatory funnel and dissolved in 500 ml of water together with 80 g of sodium nitrite. With vigorous stirring, 500 ml of 2N H2SO4 are added to the mixture, after which it is left to stand at room temperature overnight, the aqueous layer is removed and the diethyl ether layer is washed twice with 10% NaHCOa (500 ml). The diethyl ether is evaporated. While cooling with ice, 100 ml of concentrated ammonium hydroxide is slowly added. The resulting mixture is distilled until about 21 distillate has accumulated. The residue is removed by filtration and air dried. The filtrate is extracted twice with 250 ml of diethyl ether and the extracts are dried over MgSO4. The diethyl ether is evaporated. The semi-solid residues are combined, dried in vacuo at room temperature and give the title compound [a] ^ = -68.1 °.

(ii) IR, 4S-1,3,3-trimethyl-2-oxabicyclo [2,2,2] octane-5,6-dione-5-oxime

25 ml of ethyl nitrite is added dropwise to an ice-cooled solution, which is prepared by adding 50 g of the title compound mentioned under 1) to a solution of 5 g of HCl gas in 250 ml of diethyl ether.

After the temperature has set, the mixture is left to stand at room temperature for 24 hours, washed with NaHC03 and dried over MgS04. After the diethyl ether has evaporated, the remaining oil is extracted with very little diethyl ether. The solid residue is filtered off and air-dried. The filtrate is evaporated. The residue is crystallized from water and provides the title compound.

(iii) IR, 4S-1,3,3-trimethyl-2-oxabicyclo [2,2,2] octane-5,6-dione-5-oxime-6-hydrazone (compound of formula II)

A mixture of 1.97 g (0.01 mole) l, 3,3-trimethyl-2-oxa-bicyclo [2.2.2] octane-5,6-dione-5-oxime and 0.35 ml ( 0.011 mol) of anhydrous hydrazine (98%) in 25 ml of absolute ethanol is boiled in a nitrogen atmosphere under reflux for 1 hour while the bath temperature is 80 ° C. After evaporation of the solvent, the residue is recrystallized from ether and gives the title compound under (iii).

(iv) 8R, 5S-3- (m-trifluoromethylphenyl) -5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e] -as-triazine 4-oxide

A solution of 6.3 g (0.01 ml) 1 R, 4S-l, 3,3-trimethyl-2-oxabicyclo [2,2,2] octane-5,6-dione-5-oxime-6- hydrazone and 20 gs

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5 644863

a 1: 1 mixture of trimethyl ortho (m-trifluoromethyl) - Example 2

benzoate and methyl (m-trifluoromethyl) benzoate in 100 ml of 8R, 5S-3- (m-trifluoromethylphenyl) -5,8-dihydro-6,6,8-tri-

Toluene is refluxed in a nitrogen atmosphere in methyl-5,8-ethano-6H-pyrano [4,3-e] as-triazine [process c)]

boiled in a bottle, which is filled with a Dean Stark separator, 60 mg of 10% palladium-containing charcoal, provided with a 5À molecular sieve. The reflux solution of 2.1 g (0.006 mol) of 8R, 5S- (m-trifluoromethyl-

takes 48 hours and is at a bath temperature of phenyl) -5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-

120 ° C executed. All distillate is removed. The pyrano [4,3-e] -as-triazine-4-oxide obtained and 1.50 g (0.018 mol)

The mixture is cooled and evaporated to dryness in vacuo. Cyclohexene added in 30 ml of absolute ethanol. That get

The residue is distilled according to the Kiegelten mixture, is tube in a nitrogen atmosphere for 18 hours and then boiled under reflux by thin-layer chromatography. The catalyst is

nends. The material solidifies after 72 hours of drying in the trier and the filtrate is evaporated and provides vacuum at 60 ° C, 1 Torr and provides the title compound of the title compound with mp. 66-70 ° C, [ct] ° 0 = -3, 5 °

Mp 91-93 ° C; [<x] 2D0 = +72.5 (ethanol). [Ethanol],

B

Claims (9)

644863 2nd PATENT CLAIMS 1. Compounds of formula I, (I) R in which X represents N or N and O Ri is hydrogen, fluorine, chlorine, (C1-C4) alkyl, straight-chain (C1-C4) alkoxy, NH2, NO2 or CF3 and R2 is hydrogen, fluorine, chlorine, (C1-C4) alkyl, straight-chain (Ci-Gt) alkoxy or Mean NH2 and if Ri is CF> or t-butyl, R2 is additionally CF3, but as t-butyl or CF3 can only be in the meta or para position to Ri, or their acid addition salts. 2. A compound according to claim 1, wherein Ri is NO2 or CF3 and R2 is hydrogen. 3. A compound according to claim 2, wherein NO2 or CF3 take the meta position. 4. A compound according to claim 1, wherein X is N-O, Ri m-CFs and R2 are hydrogen. 5. A compound according to claim 1, wherein X N, Ri m-CF3 and R2 are hydrogen. 6. Medicament, an active ingredient according to any one of claims 1-5 in free form or in the form of a pharmacologically acceptable acid addition salt and a pharmacologically acceptable diluent or a pharmacologically acceptable carrier. 7. A process for the preparation of compounds of the formula I according to claim 1 in which XN-O is or acid addition salts thereof, characterized in that a compound of the formula II 20th ^ NH. NOH with a compound of formula III "VS-C <OR,> II C (OR3, III in an inert organic solvent and in an inert atmosphere to a compound of formula I, wherein X for N 1 O stands, is implemented, in the formulas II and III Ri and R2 have the meanings mentioned in claim 1 and R3 is methyl or ethyl and, if appropriate, the compound of the formula I thus obtained is converted into an acid addition salt or vice versa. 8. A process for the preparation of compounds of the formula I according to claim 1 in which X = N or acid addition salts thereof, characterized in that a compound of the formula I in which XN — O means in the presence of a noble metal catalyst in an inert organic solvent and is reacted with cyclohexane in an inert atmosphere and, if appropriate, the compound of the formula I thus obtained is converted into an acid addition salt or vice versa. 9. A process for the preparation of compounds of the formula I according to claim 1, in which XN ^ O, R2 are hydrogen, fluorine, chlorine, (Ci-4) alkyl, straight-chain (C1-4) alkoxy or NH2 and Ri is NO2 in meta- Represents position to the hetero ring or of acid addition salts thereof, characterized in that a corresponding compound of the formula I in which R 1 is hydrogen is nitrated in an inert organic solvent and, if appropriate, the compound of the formula I thus obtained is converted into an acid addition salt or vice versa. 25th