DK154343B - ANALOGY PROCEDURE FOR THE PREPARATION OF N-SUBSTITUTED 1,2,4-TRIAZOLES - Google Patents

Description

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DK 154343 B

The invention relates to an analogous process for the preparation of N-substituted 1,2,4-triazoles of the general formula:

Ri ^ N ^ N

Il \ or i \ -Ri (0 NV n- /

I I

G G

wherein R represents carbamoyl or thiocarbamoyl and G represents either an o-alkoxyalkyl of the formula: O - R "((II) Έ 'where R' and R" represent aliphatic groups having 1-4 C atoms or also together with the O atom forms a tetrahydrofuran-2-yl or a tetrahydropyran-2-yl ring.

Various U.S. patent applications disclose that certain 3-substituted 1- (β-ϋ-ribofuranosyl) -1,2,4-triazoles, especially the 3-carbamoyl, 3-thiocarbamoyl, and 3-guanyl substituted, possess potent antiviral activity. . These applications disclose the preparation of precursors for the bioactive 1,2,4-triazole nucleosides (and corresponding cyclic and non-cyclic phosphorylated analogs) by processes involving either reaction of trimethyl-silylated 1,2,4-triazoles with O-acyl-haio sugars or acid-catalyzed fusion of the respective 3-substituted 1,2,4-triazole with tetra-O-acyl sugar. Aminolysis of the resulting 1- (P * D-ribofuranosyl) -3-alkoxycarbonyl 1,2,4-triazoles yields the bioactive 3-carbomoyl derivative, while similarly formed 3-cyano-1- (p-15-D-ribofuranosyl) -1,2,4-triazoles can be converted to corresponding 3-thiocarbamoyl and 3-guanyl derivatives by reaction with hydrogen sulfide and ammonia, respectively.

In the United States patent applications, the discovery of antiviral activity of the known compounds 3-carbamoyl-1,2,4-triazole and 3-thiocarbamoyl-1,2,4-thiazole is disclosed and preparation of the corresponding Ι-β-D-riboside by reaction of the former with the enzyme nucleoside phosphorylase. However, these bioactive bases 20 are only slightly soluble. It has now been discovered that the solubility and lipophilicity of the bioactive bases could be increased, under which a new class N-substituted 1,2,4-triazole analog of the antiviral ribosides is prepared which, unlike the latter, is readily subjected to hydrolytic so-called cleavage under in vivo conditions to give the 3-substituted 1,2,4-triazole base in situ. Although no theory is desired, it is believed that the base is then enzymatically converted to corresponding 1- (β-D-ribofuranosyl) -1,2,4-triazole nucleosides and / or nucleotides as a result of the formation of an active metabolite. The invention relates to an analogous process for preparing novel compounds of the formulas

R1 ^ N ^ N

II 'V or I' Vri (O

NV

I ·

G G

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DK 154343 B

where R, and G have the above meanings.

G of the above formulas is thus chosen so that the bond GN is activated for hydrolysis to a degree sufficient to give at least 50% conversion to 3-R1-1,2,4-triazole in about 1 hour at 37 ° C in simulated gastric juice. (a pH 1.3 solution consisting of 2.0g NaC1.7.0 ml of concentrated 5 HCl and water to 1000 ml of solution), as determined by ultraviolet spectroscope). Particularly for the group G are groups in which an electronegative atom such as nitrogen or oxygen is alpha to the carbon atom which is directly linked to the nitrogen of the triazole ring. For the former, see the N-carbamoyl-1,2,4-triazoles according to H. Becker and V. Eisenschmidt, Journal f. Parkt. Chemie 315,640 (1973) and German Offenlegungsschrift No. 2,147,794. As to the latter, see e.g. 1,2,4-triazol-10 N-yl carboxylic acid esters from "The Chemistry of 1,2,4-triazoles", K.T. Potts, Chem. Review 61, 87 (1961).

The analogous process of the invention is characterized in that under anhydrous conditions an acid-catalyzed addition reaction of a) 1,2,4-triazoles of the general formula is carried out:

R2V * N

y> i

H

Wherein R 2 represents carbamoyl or thiocarbamoyl, and α, β-unsaturated ethers corresponding to the α-alkoxy ethers or the cc cyclic ethers of formula (I), or b) between 1,2,4-triazoles of the general formula (III) wherein R 2 is alkoxycarbonyl having 1-4 C atoms in the alkyl moiety and said α, β-unsaturated ethers corresponding to the α-alkoxyalkyl ethers or α-cyclic ethers of formula (III), after which the intermediate is treated with ammonia and 20 isolates the compound of formula (I), or c) between 1,2,4-triazoles of the general formula (III) wherein R 2 is cyano and said α, β-unsaturated ethers corresponding to α-alkoxyalkyl ethers or α -cyclic ethers of formula (II), after which the intermediate is treated with hydrogen sulfide and the compound of formula (I) is isolated.

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Example 1:

A mixture of methyl 1,2,4-triazole-3-carboxylate (12.7g, 0.10 mol), 2,3-dihydropyran (16ml), bis- (p-nitrophenylphosphate (0.1 ) and anhydrous dimethylformamide (100 ml) were heated to 75-80 ° for 3 hours. Additional 2,3-dihydropyran (8 ml) was added and heating to 75-80 ° continued for 3 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (150ml). The ethyl acetate solution was washed with aqueous sodium bicarbonate (two 25ml portions) and water. The solution was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The crude product, methyl-1- (d, 1-Tetrahydropyran-2-yl) -1,2,4-triazole-3-carboxylate is treated for 20 hours at 25 ° with methanol saturated with anhydrous ammonia, the solvent is removed in vacuo and the product is crystallized from ethanol to give 14 0 g (71%) Recrystallization from ethanol gave 11.7 g (60%) of pure 1- (d, 1-tetrahydropyran-2-yl) -1,2,4-triazole-3-carboxamide, m.p. 158 ° NMR [DMSO-d 6) 58.82 (S.1H-5).

DK 154343B

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Analysis. Calcd for CeH12N4O2: C, 48.97; H, 6.17; N, 28.56. Found: C, 48.95; H, 6.22; N

28.42.

Example 2: Methyl 1,2,4-triazole-3-carboxylate (6.35g, 0.050 mol) was suspended in 75 ml of anhydrous dimethyl formamide and bis (p-nitrophenylphosphate) (100 mg) was added. Then, 2,3-dihydrofuran (7, and, 0.10 mol) was added dropwise at room temperature with stirring. The mixture was heated in a steel pressure bomb to 75 ° for 3.5 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate and with water and dried over magnesium sulfate (some of the product was dissolved in water and it was necessary to extract the aqueous solution with ethyl acetate). The organic solution was filtered and evaporated to dryness to give 9.1g of syrup. This syrup (9, Og) was dissolved in methanol (150 ml) pre-saturated with ammonia at 0 ° and the solution was kept at room temperature overnight. The solvent was removed and the solid residue was evaporated several times with ethanol. The product was crystallized from ethanol to give 6.8 g (75%) of 1- (d, 1-tetrahydrofuran-2-yl) -1,2,4-triazole-3-carboxamide. Recrystallization from ethanol gave 5.5 g (60%) of pure material, m.p. 171-173 °. NMR (DMSO-d 6) δ 8.78 (S, 1, H-5).

Analysis. Calcd for C 7 H 10 N 4 O 2: C 46.15, H 5.52, N 30.76. Found: C 45.95, H 5.51, N

30.64.

Examples 3 and 4

A mixture of methyl 1,2,4-triazole-3-carboxylate (25.4 g, 0.20 mol), dimethylformamide (200 ml), bis (p-nitrophenyl) phosphate (0.20 g) and ethyl vinyl ether (80 ml) was stirred in a stoppered bottle, at 25 ° for 120 hours. The solvent was removed in vacuo and ethyl acetate (300 ml) was added to the residue.

A small amount of insoluble material was removed by filtration and the filtrate was evaporated to a syrup.

The crude product was treated at 25 ° for 24 hours with methanol saturated with anhydrous ammonia (300 ml). The solvent was removed in vacuo and the addition of ethanol (100 ml) to the residue gave a crystalline product (12.0 g). Recrystallization from ethanol gave 10.0 g (27%) of pure 1- (1-ethoxyethyl) -1,2,4-triazole-3-carboxamide, m.p. 163-166 °.

NMR (DMSO-d 6) δ 1.11 (t, 3, J = 7Hz, CH 3 -CH 2 -), 1.70 (d, 3, J = 6Hz, CH 3), 3.44 (m, 2, CH 3 CH2-), 5.80 (q, 1, J = 6Hz, CH), 7.65 and 7.85 (2, S, 2, NH 2) 8.90 (s, 1, H-5).

Analysis. Calcd for C 7 H 12 N 4 O 2: C 45.64, H 6.57, N 30.42. Found: C, 45.48; H, 6.61; N

30.54.

The filtrate from the crystallization of the above product was evaporated to dryness and the residue was extracted with hot ether (250 ml). The ether solution was filtered and the filtrate was evaporated to a small volume. The addition of cyclohexane gave a crystalline product 16.3 g (44%). Recrystallization from ether cyclohexane gave pure 1- (1-ethoxyethyl) -1,2,4-triazole-5-carboxamide, m.p. 87-89 °.

NMR (DMSO-d 6) δ 1.08 (t, 3, J = Hz, CH 3 -CH 2 -), 1.65 (d, 3, J = 6Hz, CH 3 -), 3.35 (m, 2.01 Δ -01β -), 6.76 (q, 1, J = 6Hz, CH), 8.05 and 8.25 (2 S, 2, NH 2), 8.20 (s, 1. H-3) .

Analysis. Calcd for C 7 H 12 N 4 O 2: C 45.64, H 6.57, N 30.42. Found: C 45.46, H 6.47, N

30.62.

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DK 154343 B

Example 5

A solution of 3-cyano-1,2,4-triazole (4.70 g, 0.050 mol), 2,3-dihydropyran (5.0 ml) and bis (p-nitrophenyl) phosphate (0.10 g) ) in ethyl acetate (100 ml) was refluxed for 1.5 hours. The solution was cooled and washed with aqueous sodium bicarbonate (two 25 ml portions) and water. The ethyl acetate solution was dried over magnesium sulfate, filtered and evaporated to dryness. Purification of the crude product by chromatography on a silica gel column with chloroform as eluent gave pure 3-cyano-1- (d, 1-tetrahydropyran-2-yl) -1,2,4-triazole (6.74 g, 76%) like an oil. This product was characterized by the nmr spectrum (CDCl3, δ 8.43, DMSOde, δ 9.17) and by conversion to 1- (d, 1-tetrahydropyran-2-yl) -1,2,4-triazole 3-thiocarboxamide as described below.

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Example 6

1- (d, 1-Tetrahydropyran-2-yl) -1,2,4-triazole-3-thiocarboxamide.

\

Method 1.

A solution of 3-cyano-1- (dr1-tetrahydropyran-2-yl) -1,2,4-triazole (1.78 g, 0.010 mol) and triethylamine (5.0 ml) in ethanol (50 ml) was stirred at room temperature while hydrogen sulfide gas was bubbled into the solution for 2 hours. The solvent was removed under reduced pressure and the product crystallized from ethanol to give the thiocarboxamide (2.10 g, 99%) with m.p. 157-159 °.

Method 2.

A mixture of 1,2,4-triazole-3-thiocarboxamide (1.28 g, 0.010 mol), 2,3-dihydropyran (5.0 ml), bis (p-nitrophenyl) phosphate (50 ml) and dimethylformamide (50 ml) was stirred at room temperature for 48 hours. The resulting solution was evaporated to dryness and the residue was treated with ethyl acetate (30 ml). The product was collected by filtration to give 1.80 g (85% thiocarboxamide. Recrystallization from ethanol gave 1.40 g of pure product, mp 157-159 °.

Analysis. Calcd for C 8 H 12 N 4 O 5: C 45.26, H 5.70, N 26.40, S 15.11.

Found: C 45.19, H 5.80, N 26.46, S 15.23.

Compounds of the invention are tested for in vivo activity against influenza Aa (Japan 305) induced death in Swiss male mice. (18 = 2 µg) the rogue results are compared with those obtained with compounds known to be active (1- $ - D-ribofuranosyl) -1,2,4-triazole-3-carboxamide and 3-carbamoyl-1,2,4-triazole) and with analogous compounds which are resistant to hydrolysis in simulated gastric fluid. The mice were intranasally inoculated with virus and treated with the compound tested by oral administration twice daily for 9 days starting 2 hours before and 4 hours after grafting. The infected mice were observed for 21 days: The results of the test are presented in Table I. All of the compounds tested were orally non-toxic at the doses used.

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DK 154343 B

TABLE I

Effects of compounds on influenza A2 (Japan 305). Induced death in mice.

Through- Through- Over average cut

Infection life - survival - survival.

Medication exceeded the expiry period

Virus dose live life time rise.

Name of compound dose mg / kg / day total p * (days) pb - Salt control 2LD «10ml / - 1/40 - 7.7 - Salt control LD«, -do- 3/20 - 8.2 1. l- (PD -ribofuranosyl) -1, 4- -do- 75 6/10 <0.05 9.3> 0.05 triazole-3-carboxamide 2. -do- 2LDjo 75 6/10 0.00008 9.3 0, 05 37.5 1/10> 0.3 7.2 3. 3-Carbamoyl-1,2,4- -do- 300 5/10 0.0006 10.2 <0.05 triazole 150 4/10 0.004 9.3 > 0.05 4. 1- (d, 1-Tetrahydropylan 3.2LDjo 300 3/9> 0.3 9.3 <0.05 2 · yl) -U, 4-triazole-150 2/9> 0, 3 7.6 3-carboxamide 75 2/10> 0.3 8.5> 0.05 37.5 1/10 - 5.6> 0.05 5. 1- (d, 1-tetrahydrofuran-LDgo 300 7/10 <0.01 10.3> 0.05 2-yl) -1,2,4-triazole-150/10 - 8,7-3-carboxamide 75/10 - 8,4 - 37,5 0/9 - 6.9 6. 1- (1-Ethoxyethyl-1,2,4-2LD) 300 7/10 0.000009 9 Triazole-5-carboxamide 150 6/10 0.00008 8.8> 0.05 75 5 / 0.0006 8.8> 0.05 37.5 1/10> 0.3 7.4 7. 1- (1-Ethoxyethyl) -1,2,4- -do- 300 6/10 0.00008 9, 3> 0.05 triazole-3-carboxamide 150 3/10 0.021 8.3> 0.05 75 1/10> 0.03 7.8> 0.05 37.5 0.10 - 7.1 8. Κβ-D -ribofuranosyl) -1,2,4- -do- 300 6/10> 0.3 8.0> 0.05 triaz ol-5-carboxamide 150 2/10 0.092 7.4 - 75 3/10 0.021 6.8 37.5 1/10> 03 7.3 9. H2'-deoxy-pD-ribofuran- -do- 300 0/10 - 8.3> 0.05 osyl) -13,4-triazole-3- 150 O / 10 - 8.3> 0.05 carboxamide 75 2/9 0.078 8.7> 0.05 373 O / 10 - 6, 9 10.1-methyl-13,4-triazole-3- -do- 300 1/10> 0.3 7.1 carboxamide 150 1/10> 0.3 7.2 - 75 1/10> 0.3 7, 1 37.5 1/10> 0.3 8.2> 0.05 a - Probability (chi square analysis), b - Probability (t test), c - Surviving animals are assumed dead on day 21.

DK 154343 B

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Various of the compounds tested in the above manner were studied from a hydrolysis standpoint in stimulated gastric fluid at 37 ° C to 1,2,4-triazole-3-carboxamide as determined by thin layer chromatography and infrared spectra. % hydrolysis was determined by ultraviolet spectroscope. The resulting data are presented in Table II.

TABLE I »% hydrolysis in simulated gastric fluid 5 20 40 60 2 4 6 24

Compound no. mine. mine. mine. hours hours hours hours 1 00000000 4 10 44 69 85 96 97 98 100 6 100 7 11 44 71 81 98 100 8 000000 10 60 9 0 0 0 2 10 28 50 100 10 00000000 5 Considering in its entirety, the previous experiments emphasize the apparent significance of the susceptibility activity to hydrolysis-giving base, which is again believed to be ribolysed as a result of the formation of the active metabolite.

Thus, each of the active compounds 4.6 and 7 was readily hydrolyzed to base in simulated gastric fluid and each was found to be active in vivo. Compounds 8.9 and 10 were neither readily hydrolyzed nor significantly active. Obviously, the compounds (1,2) are active despite the resistance to hydrolysis. If this inherently active compound cleavage exists, the formation of base need not occur prior to delivery of active metabolite to the source of infection.

The compounds of the invention can be administered as mentioned in U.S. Patent No. 3,976,545.

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Claims (1)

-7- EN 154343 B Analogous process for the preparation of N-substituted 1,2,4-triazoles of the general formula: R 1 NMI or Γ "VR 1 (I) in GG where R 1 represents carbamoyl or thiocarbamoyl and wherein G represents either a α-alkoxyalkyl of the formula: O - RH _ ((II) No. 5 wherein R 'and RM represent aliphatic groups having 1-4 C atoms or also together with the O atom forms a tetrahydrofuran-2-yl or a tetrahydropyran A 2-yl ring, characterized in that, under anhydrous conditions, an acid-catalyzed addition reaction is carried out between: a) 1,2,4-triazoles of the general formula: r2v ^ ny> H where R2 represents carbamoyl or thiocarbamoyl, and a, β-unsaturated ethers corresponding to the α-alkoxy-10 ethers or α-cyclic ethers of formula (II) and isolating the compound of formula (I), or b) between 1,2,4-triazoles of the general formula (III) ) wherein R 2 is alkoxycarbonyl having 1 -4 Catoms in the alkyl moiety and said α, β-unsaturated ethers corresponding to α-alkoxyalkyl ethers or the α-cyclic therein of formula (III), then treating the intermediate with ammonia and isolating the compound of formula (I), or c) between 1,2,4-triazoles of the general formula (III) where R2 is cyano, and said α, β-unsaturated ethers of formula (II), after which the intermediate is treated with hydrogen sulfide and the compound of formula (I) isolated. 20