PL198965B1 - New 5-substituted derivatives of 1h-pyrazolo[4,3-e][1,2,4] triazine system - Google Patents

Abstract

New 5-substituted derivatives of the 1H-pyrazolo[4,3-e][1,2,4]triazine system of the general formula 1, wherein R is a hydroxyl, alkoxy, amino, aminoalkyl, aminophenyl, aminobenzyl, hydrazide, thiophenyl and malonate group, R1 is a phenyl or methyl group, and R2 is a methyl group

Description

Description of the invention

The present invention relates to new 5-substituted derivatives of the 1H-pyrazolo [4,3-e] [1,2,4] triazine system.

All compounds described by the general formula 1 are new, not described in the literature and can be used in the pharmaceutical industry as agents with antibacterial and antifungal properties. antiviral and antitumor agents or in agriculture as new insecticides or herbicides. In the scientific literature: Smirnov. V.V .: Kiprianova, E.A .: Garagulya. A.D .: Esipov. S.E .; Dovjenko, S.A. FEMS Microbiology Lett. 1997, 153, 357, the biological activity of naturally occurring derivatives of the 1H-pyrazolo [4,3-e] [1,2,4] triazine system is described.

The new compounds have the general formula 1 in which R is hydroxy, alkoxy. amino, aminoalkyl, aminophenyl, aminobenzyl, hydrazide, thiophenyl and malonate. R ¹ is phenyl or methyl and R ² is methyl.

The synthesis of the 5-substituted 1H-pyrazolo [4,3-e] [1,2,4] triazine derivatives of the general formula I consists in the fact that the known 5-methylsulfanyl derivatives of the 1H-pyrazolo [4,3-e] system [1,2,4] triazines of general formula 2, in which R ¹ and R ² are as defined above, are subjected to oxidation with potassium manganate (VII) under two-phase catalysis to give 5-methylsulfonyl-1H-pyrazolo [4], respectively , 3-e] [1,2,4] triazines of general formula 3, wherein R ¹ and R ² are as defined above. Compounds of the general formula 3, when isolated in a known manner, easily undergo nucleophilic substitution reactions to give new 5-substituted 1H-pyrazolo [4,3-e] [1,2,4] triazine derivatives of the general formula 1.

Preparation of 5-methylsulfonyl-1H-pyrazolo [4,3-e] [1,2,4] triazines of general formula 3 is shown in Example 1 for the synthesis of 1-phenyl-3-methyl-5-methylsulfonyl-1H-pyrazolo [ 4,3-e] [1,2,4] triazines. On the other hand, the preparation of the 5-amino derivatives of the 1H-pyrazolo [4,3-e] [1,2,4] triazine system of the general formula 1 is given in Example 2 concerning the synthesis of 5-anilimim-1-phenyl-3-methyl-1H- pyrazolo [4,3-e] [1,2,4] triazine, residual derivative in example 3.

P r z k ł a d 1

Synthesis of 1-phenyl-3-methyl-5-methylsulfonyl-1H-pyrazolo [4,3-e] [1,2,4] triazine

To a solution of 257 mg (1 mmol) of 1-phenyl-3-methyl-5-methylsulfanyl-1H-pyrazolo [4,3-e] [1,2,4] triazine in 20 ml of benzene is added: potassium manganate (VII) (474 mg, 3 mmol), water (30 mL), tetrabutylammonium bromide (64 mg, 0.2 mmol), and acetic acid (1.5 mL). The mixture is stirred at room temperature until the starting sulfide has completely disappeared (TLC control). After completion of the reaction, excess KMnO4 was decomposed with saturated sodium metabisulfite solution (Na2S2O5). Then, the benzene phase is separated and the aqueous layer is extracted with benzene (3 x 15 ml). The combined benzene extracts are dried over anhydrous MgSO4. After evaporating off the solvent, the product is purified by column chromatography using chloroform as eluent.

Melting point 141 ° C;

¹ H-NMR (CDCl3) δ: 2.87 (s, 3 H), 3.60 (s, 3H), 7.40-7.49 (m, 1H), 7.56-7.67 (m , 2H), 8.33-8.39 (m, 2H); IR (KBr) cm ^-1 : 1600, 1350, 1120, 820, 780, 700;

GC-MS (m / z,%): 289 (22) [M ⁺ ], 141 (50), 104 (40), 77 (100);

Analysis for C12H11N5O2S: Calculated C, 49.82; H, 3.80; N, 24.22.

Measured: C, 49.82; H, 3.82; N, 24.14.

In an analogous manner there was prepared 1,3-dimethyl-5-methylsulfonyl-1H-pyrazolo [4,3-e] [1,2,4] triazine, m.p. 171 ° C.

PL 198 965 B1

93% yield.

¹ H-NMR (CDCl 3) δ: 2.77 (s, 3H), 3.57 (s, 3H), 4.39 (s, 3H);

IR (KBr) cm ^-1 : 2920, 1330, 1120;

GC-MS (m / z,%): 227 (8) [M ⁺ ], 199 (32), 120 (21), 95 (51), 79 (94), 67 (28), 52 (100);

Analysis for C17H13N5S: Calculated C, 37.00;

Measured C, 37.10;

H, 3.96; H, 3.85;

N, 30.83. N, 30.76.

P r z k ł a d 2

Synthesis of 5-anilino-1-phenyl-3-methyl-1H-pyrazolo [4,3-e] [1,2,4] triazine 289 mg (1 mmol) of 1-phenyl are placed in 2 ml of anhydrous, freshly distilled aniline -3-methyl-5-methylsulfonyl-1H-pyrazolo [4,3-e] [1,2,4] triazine. The reaction is carried out at the reflux temperature of the amine under an argon atmosphere. After 17 hours of reaction, the amine was distilled off and the residue was purified on a SiO2 column using a 50: 1 chloroform-acetone system. The product was isolated in 89% yield.

Melting point 264 ° C;

¹ H-NMR (CDCl3) δ: 2.72 (s, 3H), 6.65 (s, 1H, NH), 7.18-7.25 (m, 1H), 7,34-7,49 ( m, 3H), 7.50-7.61 (m, 2H), 7.68-7.81 (m, 2H), 8.12-8.25 (m, 2H);

IR (KBr) cm ^-1 : 3280, 2980, 1610, 1500, 1130, 770, 690;

GC-MS (m / z,%): 302 (46) [M ⁺ ], 273 (23), 232 (9), 197 (18), 104 (48), 77 (100);

Analysis for C17H14N6: Calculated C, 67.54; H, 4.63; N, 27.81.

Measured: C, 67.55; H, 4.71; N, 27.78.

P r z k ł a d 3

Synthesis of 1-phenyl-5-methoxy-3-methyl-1H-pyrazolo [4,3-e] [1,2,4] triazine

25 mg (1.1 mmol) of metallic sodium are added to 10 ml of anhydrous methyl alcohol.

After completion of the reaction of the alcohol with sodium, 289 mg (1 mmol) of 1-phenyl-3-methyl-5-methylsulfonyl-1H-pyrazolo [4,3-e] [1,2,4] triazine are added and the resulting mixture is heated to boil under argon. The reaction time is determined by TLC. The solvent is then evaporated and the residue is purified by column chromatography using chloroform as an eluent.

Melting point 121-122 ° C;

¹ H-NMR (CDCl3) δ: 2.70 (s, 3H), 4.27 (s, 3H), 7.29-7.38 (m, 1H), 7.50-7.60 (m, 2H), 8.31-8.38 (m, 2H);

IR (KBr) cm ^-1 : 1600, 1510, 1120, 1030.780;

GC-MS (m / z.%): 241 (45) [M ⁺ ], 213 (14), 129 (48), 104 (25), 95 (25), 77 (100);

Analysis for C12H11N5O: calculated Measured:

C, 59.75; H, 4.56; N, 29.04.

C, 59.59; H, 4.55; N, 28.96.

PL 198 965 B1

The compounds of general formula 1 presented in Table 1 are obtained in a similar way

T a b e l a 1

Relationship no R R ¹ R ¹ R ² Melting point [° C] 1a OH Ph CH3 235-237 1b OCH3 CH3 CH3 110 1c OCH3 Ph CH3 120 1d OCH2CH3 Ph CH3 103 1e OCH2CH2CHCH Ph CH3 134 1f OCH2CH2CH2CHCH Ph CH3 100 1g ^NC y ^ Ph CH3 208 1h S-Ph Ph CH3 141 1i CH (COOC2H5) 2 Ph CH3 140 1j NH2 Ph CH3 241 1k NH-CH2-Ph Ph CH3 173 1l NH-C4H9 Ph CH3 152 1 NH2-NH2 Ph CH3 190-193

Patent claim

Claims (1)

New 5-substituted 1H-pyrazolo [4,3-e] [1,2,4] triazine derivatives of general formula I, in which R is hydroxy, alkoxy, amino, aminoalkyl, aminophenyl, aminobenzyl, hydrazide, thiophenyl and malonate, R ¹ is phenyl or methyl and R ² is methyl.