FI57416B - REFERENCE FOR TREATMENT OF THERAPEUTIC ANALYTICAL PRODUCTS 5,5,7,7-TETRAMETHYLFURO (3,4-E) -AS-TRIAZINER - Google Patents

Description

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Patents and registers are registered in the United States of America.

Patent- and ragiaterstyralsan 'Ai »6ktn udagd odi utijkiiftm publtc« nd 30.0U.80

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12.08.7U USA (US) U65759, U96578 (Tl) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Gregory Benjamin Bennett, Mendham, Nev Jersey, USA (US) (7U) 0y Roister Ab (5U) Method for the preparation of new therapeutically useful 5,5,7,7-tetramethyl-furo [3, U-e7-triacylsines - Förfarande för framställ-Ning av therapeutisktvvvabbara nya 5,5,7,7 ^ tetramethylfuro / '3 U-e7-as-triaziner

The invention relates to a process for the preparation of new therapeutically useful 5,5,7,7-tetramethylfuro / 3, U-e7-as-triazines of general formula I

CH- CH,> Vw.

CH3 CH3 (S) n R2 wherein R1 and R2 are the same or different and are hydrogen, fluorine, chlorine, alkyl having 1 to U carbon atoms, straight-chain alkoxy containing 1 to U carbon atoms, amino, nitro or trifluoromethyl, one of the substituents R1 or being nitro, trifluoromethyl or tert-butyl, the other may be hydrogen, fluorine, chlorine, alkyl having 1 to U carbon atoms or straight-chain alkoxy having 1 to U carbon atoms, and n is 0 or 1.

5741 6

The compounds of formula I can be converted into acid addition salts and vice versa.

The process according to the invention is characterized in that the 2,2,5,5-tetramethyl-3,1 + (2H, 5H) -furanedione-3-hydrazone-1 + oxime of the formula II

CH CH ~ X '"' 1 CH3 CH3

is reacted in an inert atmosphere with an orthobenzoic acid ester of general formula III

V

<ry-c (qr3) 3 hi wherein R1 and R2 are as defined above and R3 is methyl or ethyl to give compounds of formula I wherein n is 1, optionally preparing compounds of formula I wherein Rg is nitro in the meta position, and R 1 is hydrogen, fluorine, chlorine, alkyl of 1-1 + carbon atoms, but not tert-butyl if R 1 is on a carbon atom adjacent to the nitro group, or straight-chain alkoxy of 1-1 + carbon atoms, and n is 1, nitrating a compound of formula I obtained above wherein Rg is hydrogen and n is 1, or, if desired, preparing compounds of formula I where n = 0, reducing in an inert atmosphere a compound of formula I wherein n = 1.

The reaction of a compound of formula II with a compound of formula III may conveniently be carried out at 70 to 200 ° C, preferably at 130 to 150 ° C, the reaction time being, for example, 12 to 36 hours, in particular 15 to 20 hours. The reaction is conveniently carried out in an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene or toluene, or a lower alcohol such as methanol or ethanol. Instead of inert organic solvents, an excess of a compound of formula III can be used as the reaction medium. The inert atmosphere may be e.g. helium, argon or preferably nitrogen.

The additional nitration can be performed as described below: 3 5741 6

A compound of formula I wherein R 1 is hydrogen may be nitrated in a manner known per se using conventional nitronium ion generating reagents, e.g. a mixture of sulfuric acid and nitric acid, a mixture of trifluoromethanesulphonic acid and fuming nitric acid, or a mixture of hydrogen fluoride and nitrous oxide in nitromethane (-20 ° C). ). However, the preferred nitrating agent is a mixture of trifluoromethanesulfonic acid and fuming nitric acid, preferably in a molar ratio of 2: 1.

The nitration is conveniently carried out in an inert organic solvent. Suitable solvents are aromatic hydrocarbons, such as methylene chloride or chloroform, preferably methylene chloride.

The reaction temperature is suitably -θθ to + 70 ° C, preferably -35 to + 35 ° C, and the reaction time may be, for example, 19 to 76 hours, especially 60 to 75 hours.

If it is desired to prepare compounds of formula I in which n is 0, reduction of the N-oxide group is carried out, e.g. with a compound of formula IV.

pz3 IV

wherein Z is chlorine, bromine or an alkoxy group having 1-U carbon atoms. Suitable solvents for this reaction include, for example, aromatic hydrocarbons such as benzene or toluene, or preferably an excess of a compound of formula IV. A suitable reaction temperature is 100 to 210 ° C, preferably 11 to 180 ° C, and the reaction time may be, for example, 12 to 36 hours, especially 15 to 20 hours. Instead of the above-mentioned compounds of the formula IV, cyclohexene can be used in the presence of a catalyst, in particular in the presence of a noble metal catalyst such as platinum, rhodium or preferably palladium, these noble metals being used either neat or on a support, e.g. carbon support. The reaction is conveniently carried out at 20 to 200 ° C, preferably at 70 to 110 ° C, and the reaction time may be, for example, 5 to 72 hours, especially 15 to 30 hours. Suitable solvents are lower alkanols, such as methanol or ethanol, preferably the latter.

The inert atmosphere used in this method is e.g. helium, argon or preferably nitrogen.

The compounds of the formula I obtained according to the above methods can be isolated and purified in a manner known per se.

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The compounds of formula I have a very advantageous pharmacodynamic effect. In particular, the compounds of the formula I have a sleep-inducing and slightly sedative effect, which has been demonstrated, for example, by the experiments described in "Winter; J. Pharm. And Exp. Therap. 9 **, 7-H (190), S Irwin (Gordon Research Conference, Medicinal Chemistry, 1959) Chen (Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins, 195 * 0 »Reed-Muench; ^ American Journal of Hygiene 27, ** 93 - * + 97, (1938) 7 and I, Geller; / Psychopharmacologia, I, h2-k92 (1960) 7 ·

The following table summarizes the test results obtained with the compounds of the invention as well as the LDj.q. toxicity.

The compound of Example No. 1 2 * + 9 11 Lö

LDC_ 1 * 00 325 UOO UOO UOO 26U

50 ED50 Experiment 1 * 63.1 72.0 167 112 - 68 2 76.5 21.9 150 80.0 171 0.9 3 70.0 0.7 - 77.8 160 0.0 1+ - 1 +8.0 150 150 169 68.8

Experiment No. 1. Hexobarbital reinduction (Winter) 2. Adaptability test (irvin, Chen) (sedative properties) 3. "" "(muscle relaxant properties) O Absence of performance reflex (Reed-Muench).

The compounds of formula I can be used for sleep management and as mild sedatives. The dose of the sleeping pill is 35 ~ 750 mg given as a single dose before going to bed. When the compounds of the formula I are used as mild sedatives, their daily dose is 75 to 1000 mg, suitably administered in sub-doses of 18 to 500 mg twice a day or in retard form.

The compounds of formula I are administered in the form of tablets or capsules of suitiram.

5,57416

The compounds of formula I may be administered as the free bases or as their pharmaceutically acceptable acid addition salts, the effect of the salts being of the same order of magnitude as that of the bases. Suitable acids for salt formation include, in particular, mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acids such as succinic acid, benzoic acid and maleic acid.

Preferred compounds of formula I are those in which R 1 is a nitro group in the meta position, and in particular those in which R 8 is hydrogen.

Example 1: 5,7-Dihydro-5,5,7,7-tetramethyl-3-phenyl-furo- [3,4-? 7-as-triazine-4-oxide

A mixture of 6.84 g of 2,2-5,5-tetramethyl-3,4- (2H, 5H) -furanedione-3-hydrazone-4-oxime and 15 ml of triethylorthobenthoate is heated at 140 ° C. under nitrogen for 18 hours. To C boiling at bath temperature. The resulting solution is further heated for 8 hours at bath temperature, whereupon the volatile components are distilled off. The remaining mixture is cooled to 25 ° C and 100 ml of ether are added. The precipitate formed is filtered off and the filtrate is evaporated to dryness in vacuo at 100 ° C. The residue obtained is dissolved in ether and hydrogen chloride gas is bubbled through the solution until saturation. In this case, 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro [3,4-e] az-4-triazine-4-oxide precipitates in the form of its hydrochloride, m.p. 154-156 ° C.

Example 2; 5,7-Dihydro-5,5,7,7-tetramethyl-3 '(m-nitrophenyl) -furo [3,4-b] az-triazine-4-oxide

A mixture of 6.84 g of 2,2,5,5-tetramethyl-3 '4- (2H, 5H) -furanedione-3-hydrazone-4-oxime and 16.14 g of m-nitrotriethylorthobenzoate is heated under nitrogen for 24 minutes. to 140 ° C at bath temperature. Finally, the mixture is cooled to 25 ° C and 250 ml of ether are added. The precipitate formed is filtered off and the filtrate is evaporated in vacuo at 100 ° C. The residue is recrystallized from methylene chloride / hexane to give 5, T-dihydro-5,5,7,7 'tetramethyl-3- (m-nitro-phenyl) furo [3,4-e] -az-triazine-4- an oxide having a m.p. is 202-204 ° C.

Example 3: 5,7-Dihydro-5,5,7,7-tetramethyl-3- (m-nitrophenyl) -furo [3,4-c] aa-triazine-4-oxide

A mixture of 0.2 ml of fuming nitric acid and 1.5 g of trifluoromethanesulfonic acid in 15 ml of anhydrous methylene chloride is stirred for 1 hour at 25 ° C and finally added dropwise to a solution of 0.542 g of 5,7-dihydro-5 , 5,7,7 'tetramethyl-3-phenylfuro [3,4-e] -az-triazine-4-oxide in 15 ml of anhydrous methylene chloride at -30 ° C. The resulting heterogeneous mixture is stirred at 6,57416 at 25 ° C for 72 hours, then shaken on ice and neutralized with solid sodium bicarbonate. The organic layer is removed and the aqueous layer is extracted several times with methylene chloride. The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally evaporated. This gives a white residue which is recrystallized from methylene chloride / hexane. The resulting 5,7 "dihydro-5,5,7,7-tetramethyl-3 '(nitrophenyl) -furo [3,1-a] α-triathine U-oxide melts at 202-20 ° C.

Example U: 5,7-Dihydro-5,5,7,7-tert-methyl-3-phenylfuro- [3> -az-1-azine

A mixture of 5'-2-dihydro-5,5,7,7-tetramethyl-3-phenylfuro (3,1 *%) - as-triazine-U-oxide and 70 ml of triethyl phosphite is heated boiling in a nitrogen atmosphere for 18 hours at 180 ° C bath temperature. The solvent is then removed in vacuo and the residue is recrystallized from aqueous ethanol. The obtained 5,7-dihydro-5,7,7,7-tetramethyl-3-phenylfuro [3,3-b] az-triazine is obtained at 90-91 ° C.

Example 5: 5,7-Dihydro-β, β, 7,7-tetramethyl-3-phenylfuro- [3] U- [7-α] -triazine To a solution of 0.271 g of 5,7-dihydro-5,5,7,7 "tetramethyl-3- phenyl-furo-N, N-α-triazine-U-oxide and 0.2 .mu.g of cyclohexene in U ml of absolute ethanol are added 10 mg of 10 .mu.l of palladium-carbon catalyst and the resulting mixture is heated under boiling under a nitrogen atmosphere for 18 hours. Finally, it is filtered off from the catalyst and the filtrate is evaporated to dryness, and the residue is recrystallized from ether / hexane to give 5 * 7-dihydro-5 → 5> 7-7-tetramethyl-3-phenyl-furo [3,4-a] triacaine, m.p. ° C.

Other compounds of formula I wherein X 1 and R 2 have the meanings given in the following combination may be obtained using the methods of the above examples and using the appropriate starting compounds in approximately equivalent amounts.

τ 57416

Example Correspondingly, n R 2 is Salt-Melting point as in the preform ^ o ^ ^ in the sign 6 1 1 £ -Cl H - 133-13 ^ ° 7 2 1 E ~ CH 3 "- 120-122 ° 8 2 - 165-167 ° 9 2 1 m-CF3 "- lU7-li + 8 ° 10 2.3 1 £ -NO2" - 2l + 0-2l + 2 ° 11 2 1 m-Cl H - 81-85 ° 12 11 1 -F "HCl 129-131 ° 13 U, 5 0 £ -CH 3" - 90-92 ° 1U "0 £ -CH 3 O" - 118-119 ° 15 "0 m-CF 3" - 73-75 ° 16 "0E -NH2" - 9 ^ -95.5 ° 17 "0 3-Cl 5-Cl - 129-131 ° 18" 0 m-NO 2 H - 11 + 9-152 ° 19 1 1 mF H - kp . lU0-150 ° (0.5 mm)

Claims (1)

0. II CH 3 CH 3 is reacted in an inert atmosphere with an orthobenzoic acid ester of general formula III wherein R 1 and R 2 are as defined above and R 3 is methyl or ethyl to give compounds of formula I wherein n is 1, wherein it is desired to prepare compounds of formula I wherein R 2 is nitro in the meta position and R 1 is hydrogen, fluorine, chlorine, alkyl of 1-1 + carbon atoms, but not tert-butyl if R 1 is adjacent to the nitro group carbon atom, or 9 57416 n is 1, nitrate a compound of formula I obtained above wherein Rg is hydrogen and n is 1, or, if desired, prepare compounds of formula I in which n = 0, reducing in an inert atmosphere a compound of formula I in which n = 1.