FI62837C - FREQUENCY REQUIREMENT FOR THERAPEUTIC THERAPEUTIC PYRANO (4,3-E) -AS-TRIAZINER AND DERASE 4-OXIDER - Google Patents

Description

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Mj (11) UTLÄCCNINGSSKRIFT 0 ^ 00 / C MÄ: i Un l ti uySnnelly 10 03 1933 Patent aoJdelnt ^ ^ (51) Kv.Ha / Inta3 C 07 D 491/08 FINLAND — FINLAND (21) ΜΜΜΜΜΝί.ΝηΜβΜ ^ Τδογ ^ δ (22) Hukumltptlvl — AmMmlnp ^ 09-03-78 * (23) AlkupUvt — GHtlfhMfdai 09-03.78 (41) Tullut iulklMkal - ftlMt offumMf 19.09.78

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Patent, oeh registrantyrclaan v 'AmMcu uttagd ocfc ucMkrlftM pubikwnd 30.11.82 ¢) 2) (33) (31) Pn * 4 ** tjr utuellwu · - «« gird priorHtc 18.03.77 USA (US) 779071 (71) Sandoz AG , Basel, Switzerland-Switzerland (CH) (72) Gregory Benjamin Bennett, Mendham, UJ, USA (US) (7 ^) Oy Kolster Ab (54) Method for the development of new therapeutically useful pyranoA, 3-e7-as-triazines and The present invention relates to a process for the preparation of novel therapeutically useful pyrano / 4,3-e-7-as-triazines of the following formula: The present invention relates to a process for the preparation of new therapeutically useful pyrano / 4,3-e-7-as-triazines of the formula CH3 "3c-A ^ n4 CH-, - | -R1 <O)" R2 in which n is 0 or 1, 2 62837 Rj represents a hydrogen, fluorine or chlorine atom, or an alkyl group having 1 to 4 carbon atoms, or a straight-chain alkoxy group having 1 to 4 carbon atoms, or an amino, nitro or trifluoromethyl group, and R 2 represents a hydrogen, fluorine or chlorine atom or an alkyl group having 1 to 4 carbon atoms, or a protecting group an alkoxy group having 1 to 4 carbon atoms of the ra chains, or an amino group, wherein when there is a trifluoromethyl or tert-butyl group, R 2 may further be a trifluoromethyl group in the meta-tha position relative to R 1, or when R 1 is a trifluoromethyl or tert-butyl group, R2 in the sense of tert-butyl can only be in the meta or para position relative to R1.

The process of the invention is characterized in that a compound of formula II ch3 CH3 is reacted with a compound of formula III R2 wherein and R2 are as defined above and R1 is methyl or ethyl, in an inert organic solvent and in an inert atmosphere to give a compound of formula I wherein n is 1, after which the resulting compound is optionally reacted with cyclohexene in the presence of a noble metal catalyst in an inert organic solvent and an inert atmosphere to give a compound of formula I wherein n is f), or in case R 2 is a hydrogen atom and R 1 is a hydrogen, fluorine or chlorine atom, or an alkyl group having 1 to 4 carbon atoms or a straight-chain alkoxy group having 1 to 4 carbon atoms, or an amino group, the compound is nitrated in an inert organic solvent to prepare a compound in which R 1 is a nitro group.

The process is suitably carried out at a temperature in the range of 70 to 200 ° C, preferably in the range of 130 to 150 ° C, and the reaction time may vary, for example, 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 a compound of formula III may be used to produce the reaction medium. The inert atmosphere may be, for example, helium, argon or, preferably, nitrogen.

The noble metal catalyst is suitably platinum or rhodium, or preferably palladium either unmixed or with a support such as carbon. The reduction is preferably carried out at a temperature between 20 and 200 ° C, preferably between 70 and 110 ° C, and the reaction time may vary, for example between 5 and 72 hours, most usually between 15 and 30 hours. Suitable solvents include lower alkanols such as methanol or ethanol, preferably the latter. The reduction is performed in an inert atmosphere such as helium, argon or nitrogen.

Nitration uses standard nitronium ion-forming reagents, including a mixture of sulfuric and nitric acid, a mixture of trifluoromethanesulfonic acid and fuming nitric acid, a mixture of hydrogen fluoride and nitrous oxide in nitromethane at -20 ° C saturated with boron trifluoride. The preferred reagent is a mixture of trifluoromethanesulfonic 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 to + 70 ° C, preferably from -35 to + 35 ° C, and the reaction time may vary, for example, from 19 to 96 hours, most usually from 60 to 75 hours.

The resulting compounds of formula I can be isolated and purified using standard procedures. If necessary, their free base forms can be converted into acid addition salt forms in a manner known per se.

A compound of formula II can be prepared by treating a compound of formula IV with hydrazine according to the following reaction scheme: 4 62 837 CH3 CH3

i> J * ** - * J) T

V / M ^ ilOH H3C y ^ l / \ nK

CH3 ch3 ™ h (IV) (II)

The reaction is suitably carried out at a temperature between 0 and 150 ° C, preferably between 75 and 85 ° C, in an inert organic solvent, for example a lower alkanol, preferably ethanol, and in an inert atmosphere. The reaction time may vary from 1 to 18 hours, most often from 2 to 8 hours.

The compounds of formulas III and IV are either known or can be produced in the customary manner from available substances.

The compounds of formula I have pharmacological activity. In particular, they have a sleep-inducing and mild sedative effect.

Pharmacological experiments and their results 1) Winter's hexobarbital re-induction method. The method is described in J. Pharmacol, and Exp. Therap.

94, 7-11 (1948).

2) Experiment with Cebus monkeys using continuously implanted electrodes.

Brain curves were obtained using 10- or 16-channel electroencephalography. The monkeys were fastened with neck and waist plates to chairs in full-size observation cages, at the same time each night, for 13.5 hours, Monday through Thursday. Overall behavior was monitored by internal television and video recordings. The compound of formula I was administered orally and monkeys (5-15 monkeys / experimental group) were placed in observation cages. Experimental animals in the control group were given physiological saline. Comparative data were collected at least 3 days per week. Data from each subtest were statistically compared by computer analytics to previous comparative experiments, with particular emphasis on the following layers of the sleep-valve state cycle: resting, light sleep, deep sleep, para- sleep, latency at the onset of deep sleep, and latency at the first turning point of paradoxical sleep.

3. "^ O-word adjective ^ test

The method has been described by Irwin S. (Gordon Research Conference, Medicinal Chemistry, 1959) and Chen (Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins, 1954). In this experiment, experimental animals (mice) were administered 25 to 200 mg / kg of test compound intraperitoneally.

4. N-sulfamoylazepine test for anticonvulsant activity of compounds

Experimental animals (mice) were administered test compound 20-250 mg / kg intraperitoneally 60 minutes before N-sulfamoylazepine (50 mg / kg i.p.).

5. Absence of an extension reflex

The experiment was performed according to the method of Reed-Muench (American Journal of Hygiene 27, 493-497, (1938)). Experimental animals (mice) were first administered 12.5 mg / kg intraperitoneally of thioridazine, followed immediately by 5-100 mg / kg of test compound. After one hour, mice were sorted based on the absence of extension reflex.

6. Geller's experiment

The method is described in Psychopharmacology, I, 421-492, (1960).

The results of these experiments are shown in the following table: ΕΡ ~ * β (mg / kg)

Example No. Experiment No. 1 2 3 4 5 6 1,100 - 71.4 81.2 2 9.8 - 3.8 25.0 18.8 3 91.7 - 90.0 75.0 7 8.2 1.9 8.0 20.4 5.7 15.0 6 62837

The compounds are proposed for use as sleep inducers and as mild sedatives. A suitable daily dose for sleep-induced use is 1 to 300 mg, suitably administered as a single dose at bedtime. When used as a mild sedative, a suitable daily dose is in the range of 5 to 500 mg, suitably administered in divided doses of 1.25 to 250 mg two to four times daily or in delayed form.

The compounds may be mixed with conventional pharmaceutically acceptable diluents or carriers and, optionally, other excipients and administered in such forms as tablets or capsules.

The compounds may be used in free base form or in the form of pharmaceutically acceptable acid addition salts, which salt classes have the same activity as the free base forms. Suitable acids for salt formation include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid and organic acids such as succinic, benzoic and maleic acids.

Preferred compounds of formula I are those having NO 2 or CF 2, preferably in the m-position, and R 2 is a hydrogen atom.

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] -az-triazine-4-oxide Preparation of starting material 1.3, 3-Trimethyl-2-oxabicyclo / 2,2,27-octane-5,6-dione-5-oxime-6-hydrazone (Compound of Formula II)

A mixture of 1.97 g (0.01 mol) of 1,3,3-trimethyloxabicyclo / 2.2.2-7 octane-5,6-dione-5-oxime and 0.35 ml (0.011 mol) of anhydrous hydrazine (98%) in 25 ml of anhydrous ethanol, was refluxed under nitrogen at 80 ° C for 1 hour. After evaporation of the solvent, the residue was recrystallized from ether to give 1,3,3-trimethyl-2-oxabicyclo [2.2.2] octane-5,6-dione-5-oxime-6-hydrate-Son; mp. 138-142 ° C.

3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano / 4,3-e7as-triazine-4-oxide

A solution containing 2.11 g (0.01 mol) of 1,3,3-trimethyl-7 6? 8 3 7 2-Oxabicyclo / 2,2,27-octane-5,6-dione-5-oxime-6-hydrazone in 10 ml of trimethyl orthobenzoate was refluxed under nitrogen for 18 hours at 140 ° C, during which time all the distillate was removed. The resulting mixture was cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel and evaporating the filtrate, the solid obtained was triturated with ether to give 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H- pyrano / 4,3-e7-as-triazine-4-oxide; mp. 186.5-189 ° C.

Example 2 3- (m-Nitrophenyl) -5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano / 4,3-e7-as-triazine-4-oxide

To a mixture of 0.2 ml (0.005 mol) of fuming nitric acid and 1.5 g (0.01 mol) of trifluoromethanesulfonic acid in 15 ml of anhydrous methylene chloride at -30 ° C was added dropwise a solution containing 0, 60 g (0.002 moles) of 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e] -triazine-4-oxide per ml of methylene chloride, keeping the temperature at -30 ° C during the addition. The resulting mixture was stirred at ambient temperature for 72 hours, then poured onto ice and neutralized with solid sodium bicarbonate. The organic layer was removed, washed with brine, dried over magnesium sulfate and evaporated.

The resulting residue was triturated with ether to give 3- (m-nitrophenyl) -5,8-dihydro-6,6,8-trimethyl-5,8-ethanol-6H-pyrano / 4,3-e-7-as-triazine. 4-oxide monohydrate; mp. 150 ° C (decomposed).

Example 3 3-Phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e] az-triazine

To a solution of 1.80 g (0.006 moles) of 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e] -triaria -cine-4-oxide and 1.50 (0.018 mol) of cyclohexene in 30 ml of anhydrous ethanol, 60 mg of 10% palladium-on-carbon were added, and the resulting mixture was refluxed under nitrogen for 18 hours. to give 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [1,3-e] -7-triazine;

180-189 ° C.

8 62857

In an analogous manner, the following compounds of formula I were prepared in which n, R 1 and L have the meanings given in the following table:

Compound Method _ D, oP | π * 2 mp · \ L] n: on: o 4 1 1 pF H 157 - 158 ° 5 1 1 P "CH 3 h 177-178 ° 6 1 1 p-OCH 3 H 148 - 149 ° 7 1 1 m_CF 3 H 157 , 5-158.5 ° 8 1 1 p-NO 2 H 226 - 227.5 ° 9 1 1 m-Cl H 180 ° 10 2 1 m-NO 2 p-OCH 3 133 - 135 ° 11 3 0 m ~ CF 3 H 235 "250 ° (dec.) 12 3 0 m-NH» H (light wax; no clear color) 13 3 0 m-NP2 H 300 ° (dec.)

Claims (5)

9 Claims: 6 2 S ό 7 A process for the preparation of novel therapeutically useful pyrano- {4,3-e7-as-triazines of the formula ch3 (I) c <3; hr, <n> 2 'n where 2 is 0 or 1, represents a hydrogen, fluorine or chlorine atom, or an alkyl group having 1 to 4 carbon atoms, or a straight-chain alkoxy group having 1 to 4 carbon atoms, or an amino, nitro - or a trifluoromethyl group, and R 2 represents a hydrogen, fluorine or chlorine atom or an alkyl group having 1 to 4 carbon atoms or a straight-chain alkoxy group having 1 to 4 carbon atoms, or an amino group, wherein R 1 is trifluoromethyl or tert. -butyl group, R 2 may further be a trifluoromethyl group in the meta or para position relative to R 1, or when R 1 is a trifluoromethyl or tert-butyl group, R 2 in the sense of tert-butyl may be only meta or para in a position relative to the ree, characterized in that the compound of the formula II CH3 -3 / nnoh CH3 is reacted with the compound of the formula III -C (OR3> 3 (III) 10 62 837 in which R1 and have the same meaning as above, and R1 is a methyl or ethyl group, in an inert organic solvent and in an inert atmosphere to give a compound of formula I wherein n is 1, after which the resulting compound is optionally reacted with cyclohexene in the presence of a noble metal catalyst in an inert organic solvent and an inert atmosphere to give a compound of formula I wherein n is 0, ..... or in the case where R 2 is a hydrogen atom and R 1 is a hydrogen, fluorine or chlorine atom, or an alkyl group having 1 to 4 carbon atoms or a straight-chain alkoxy group having 1 to 4 carbon atoms, or an amino group, the compound is nitrated in an inert organic solvent to prepare a compound wherein R1 is a nitro group. Process according to Claim 1 3- (m-trifluoromethylphenyl) -5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano-ε-4,3-e-triazine For the preparation of 4-oxide, characterized in that a compound of formula III is used as starting material, in which n is 1, R1 is an m-trifluoromethyl group and R2 is a hydrogen atom. Process according to claim 1 3- (m-nitrophenyl) -5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano-4,3-e] -az-triazine For the preparation of -4-oxide, characterized in that the starting material used is a starting material of the formula III in which n is 0, is an m-nitro group and R2 is a hydrogen atom. 11 Patent: 6 2 8 7 * 7 A process for the preparation of a therapeutically active pyran / 4,3-e.7-as-triazine with the formula ix! I "3 i <° k R2 is 0 or 1, betecnar en väte-, fluor- or a chlorine atom, or an alkyl group having 1 to 4 colatomers or an alkoxy group having 1 to 4 cholatomers, an amino group, a nitro or a trifluoromethyl group, and an R2 alkyl group, a fluorine or a chlorine atom or an alkyl group 1-4 cholatomers or substituted alkoxy groups with 1-4 cholaters, or amino groups, colors R1 are trifluoromethyl or tert-butyl groups, R2 is a trifluoromethyl group having the same content as the para-paring group R1, or R In the case of trifluoromethyl or tert-butyl groups, R2 is a tert-butyl group in which the tert-butyl group is substituted with a metal or para-starch account R II CH3 NH2 J Sf omsättes med en förening med formuleln III „Ά = / (III) R2 color R ^ och R2 har den ovan angivna betydelsen, och R ^ är en methyl- eller e n ethyl group, i inert organic organic solution