FI73434B - PROFESSIONAL FRAMSTATION OF AV / 3H / -IMIDAZO- / 5,1-D / -1,2,3,5-TETRAZIN-4-ONDERIVAT MED THERAPEUTIC NETWORK. - Google Patents

Description

1 73434

This invention relates to a process for the preparation of a therapeutically active β-imidazo [5,1-47-1] 2,3,5-tetrazin-4-one derivative. To prepare a 3,5-tetrazin-4-one derivative of the formula:

/ R

CO — N 3

L V

/ W '' N | 0 wherein R is a straight or branched alkyl or alkenyl group containing up to 6 carbon atoms, a straight or branched alkyl group containing up to 6 carbon atoms and substituted by 1-3 halogen atoms (i.e. bromine, iodine or preferably chlorine or fluorine) ) or a straight or branched alkoxy group containing: up to 4 carbon atoms (e.g. nitro), or R is a benzyl or methoxybenzyl group or a cycloalkyl group, 2. 3

containing 3 to 8, preferably 6 carbon atoms, R and R

are the same or different and are each hydrogen or a straight or branched alkyl group containing up to 4 carbon-2 to 3 atoms, or R is hydrogen and R is an allyl group.

When the symbol R1 represents an alkyl group substituted by two or three halogen atoms, the above-mentioned halogen atoms may be the same or different.

Preferred tetrazine derivatives of the formula I are those in which R 1 is a straight-chain or branched alkyl group having 1 to 6 carbon atoms and optionally substituted by one or two halogen atoms (preferably chlorine, fluorine or bromine) or an alkoxy group having 1 to 4 carbon atoms. 2,73434 atoms (preferably with nitroxy), or a benzyl or methoxybenzyl group, or R is an alkenyl group having 2 to 6 carbon atoms (preferably allyl) or a cyclohexyl group.

Particularly preferred tetrazine derivatives a are those compounds of the formula I in which R is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and in particular an alkyl group having 1 to 3 carbon atoms which is unsubstituted or substituted by halogen, in particular chlorine or fluorine. More particularly R is a methyl or 2-halogen alkyl group, e.g. a 2-fluoroethyl group or preferably a 2-chloroethyl group.

2 3

Preferably R and R are both hydrogen or one is hydrogen and the other is methyl or allyl.

According to the present invention, compounds of general formula I are prepared by reacting a compound of general formula: 1 v ?;

Rx c © 11

N-CO N

Il 3 wherein R and R are as defined above, to react with an isocyanate of general formula:

RXNC0 III

where R is as defined above. The reaction may be carried out in the presence of an anhydrous organic solvent, e.g. a chlorinated alkane, e.g. dichloromethane, or ethyl acetate, acetonitrile, N-methylpyrrolid-2-one or, preferably, hexamethylphosphoramide, or at a temperature of 0 to 700 ° C. , eg ambient heat in space. The reaction can be continued for up to 30 days. The reaction mixture should preferably be protected or protected.

3,73434

Compounds of formula II may be prepared using or applying methods known per se, for example those described by Shealy Y.F., Struck R.F., Hoium L.B. and Montgomery J.A., J. Org. Chem. (1961), 26, 2396.

Compounds of general formula III may be prepared using or applying methods known per se.

The term "methods known per se" means methods previously used in this specification or described in the literature.

The novel tetrazine derivatives11a of the general formula Ia have valuable antitumor activity, for example against cancer, nuclear cell tumor, sarcoma, lymphoma and leukemia. They have been shown to be particularly active in mice at daily doses of 0.5 to 16 mg / kg body weight, administered intraperitoneally, against TLX5 (S) lymphoma according to the method described by Gescher et al. have reported in Biochem. Pharmacol. (1981), 30, 89, and against ADJ / PC6A and M5076 (reticulated cell sarcoma). Intraperitoneally, intracerebrally and intracranially transplanted leukemia Li210 and P388, in the article "Methods of Development of New Anticancer Drugs" (NCI Monograph 45, March 1977, pages 147-149, National Cancer Institute, Bethesda, USA), according to the method described, the compounds were active both intraperitoneally and orally at doses of 2.5-10 mg / kg body weight of the animal. Prevention against both primary tumors and branch colonies was obtained against Lewis lung carcinoma at similar dose levels. Against B16 nuclear cell tumor and C38 tumor in mice (MCI Monograph 45, op cit.), The compounds were active at intraperitoneal doses of 6.25-25 mg / kg animal body weight.

Tetrazine derivatives 11a also have valuable immunomodulatory activity and are useful in the treatment of organ and skin grafts and in the treatment of immunological diseases.

73434 Important individual compounds of general formula I are the following: 8-carbamoyl-3-methyl- [3H] -imidazo [5,d] -1,2,3,5-tetrazin-4-one A, 8- carbamovyl-3-n-propyl- [3H] -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one B, 8-carbamoyl-3- (2-chloroethyl) - [3H N-imidazo [5,1-d] -1,2,3,5-tetrazin-4-one C, 3- (2-chloroethyl) -8-methylcarbamoyl- [3H7-imidazo] [5,1d] -1,2, 3,5-Tetrazin-4-one D, 8-carbamoyl-3- (3-chloropropyl) - [3H7-imidazo-5,11] -1,2,3,5-tetrazin-4-one E, 8-carbamoyl-3- (2,3-dichloropropyl) - [3H] imidazo [5,1] -1,2,3,5-tetrazin-4-one F, 3-allyl-8-carbamoyl- "3H7-imidazo [5,1-d7-1,2,3,5-tetrazin-4-one G, 3- (2-chloroethyl) -8-dimethylcarbamoyl] -3H7-imidazo [5,1d] 1H-2,3,5-tetrazin-4-one H, 3- (2-bromoethyl) -8-carbamoyl- [3H7] imidazo-5,11d-1,2,3,5-tetrazine -4-one-1,3-benzyl-8-carbamoyl- (3H) -imidazo [s, 1,1-d] -1,2,3,5-tetrazin-4-one] -8-carbamoyl-3- (2-methoxyethyl) - (3H) -imidazo [5,1d] -1,2,3,5-tetrazine -4-one K, 8-carbamoyl-3-cyclohexyl- [3H] -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one L,

and 8-carbamoyl-3- (p-methoxybenzyl) -3H-imidazo [5,1-d] -1,2,3,5-tetrazin-4-one M

Of particular importance are compounds A and D and in particular C.

The letters A to M are given for the compounds to make them easier to refer to later in the description.

~ \ 5 73434

Pharmacological Experiments and Their Results A. Activity of the Compounds of the Invention Against TLX5 Lymphoid Tumor Implanted in Mice

Table I

Compound Optimal dose mg / kg Survival Mean time given 3 days, compare survival ★ control time after implantation, day _________ after __________ in animals__ A 160 157% 16.0 I 160 137% 16.2 C 40 All 5 treated mice were alive 60 days after implantation D 40 All 5 treated mice were alive 60 days after implantation H 40 All 5 treated mice were alive 60 days after implantation * Mice , who were alive after 60 days, survived and were not monitored further.

73434 B. Activity of Compound C of the Invention Against Various Tumors Implanted in Mice

Table II

Tumor type Dose, Survival mg kcj time of administration, number of days days L1210 ^ 40 1 60 20 5 60 10 5 60 25 9 60 12.5 9 60 P388 (2) 40 1 60 20 1 60 20 5 60 10 5 60 7 , 5 5 60 * Mice that survived after 60 days survived and were not monitored further.

5 (1) 10 L-1210 cells were implanted intraperitoneally into BDF 2 mice on day 0. Mice were treated on day 1 with Compound C dissolved in 10% dimethyl sulfoxide in peanut oil solution (0.1 mL) by intraperitoneal administration, and then as shown in Table II.

6 (2) 10 P388 cells were implanted intraperitoneally into BDF 2 mice on day 0. The mice were then treated with Compound C as described in (1).

The following examples describe the preparation of the compounds of formula I of the present invention.

n 73434

Example 1 Compound A

4- [5] -Diazoimidazole- [4] -carboxamide (500 mg) was suspended in methyl isocyanate (3.0 ml) and stirred in the dark at room temperature for 21 days. The reaction mixture was then diluted with anhydrous diethyl ether and filtered. The residue was washed rapidly with anhydrous methanol, then with anhydrous diethyl ether, and air-dried in the dark at room temperature to give 8-carbamoyl-3-methyl-3H-imidazo [5,11] -1,2,3,5 -tetrazin-4-one, in the form of a light brown microcrystalline solid (198 mg), m.p. 210 ° C (swells and darkens at 160-210 ° C).

Elemental analysis: found C 36.8; H 3.10, N 44.3%; C, HCN, 0?

- __ b b b Z

requires: C, 37.1; H 3.09; N 43.3%.

Example 2 Compound B

4/5-N-diazoimidazole-5/4-carboxamide (300 mg) was suspended in anhydrous dichloromethane (10 ml) and treated with excess n-propyl isocyanate. The reaction mixture was then stirred in the dark at room temperature for 30 days. The reaction mixture was then filtered and the residue was washed rapidly with anhydrous diethyl ether and dried in air at dark room temperature to give 8-carbamoyl-3-n-propyl- (3H) -imidazo [5,1d] -1,2,3,5-tetrazole. 4-one (102 mg), in the form of a pale red powder, m.p. 167 ° C (effervescent). Elemental analysis: found C 43.4; H 4.57; N 38.0%; C 8 H 10 N 6 O 2 requires: C, 43.2; H 4.53; N 37.8% 7-

Example 3 Compound C

4-N-diazoimidazole-57 4-N-carboxamide (300 mg) was suspended in anhydrous dichloromethane (10 ml) and 2-chloroethyl isocyanate (1.0 ml) was added. The reaction mixture was then stirred in the dark at room temperature for 30 days. The resulting cream suspension was filtered and the residue was washed rapidly with anhydrous diethyl ether 8,73434 and air dried in the dark to give 8-carbamoyl-3- (2-chloroethyl) - [3H] -imidazo [5,d] -1 , 2,3,5-tetrazin-4-one (483 mg), in the form of a cream powder, m.p. 158 ° C (decomposes violently). Elemental analysis: found C 34.7; H 3.01; M 34.9%; C 7 H 7 ClN 6 O 2 requires: C, 34.7; H 2.91; N 34.7% 7-

By repeating the above procedure, 8-carbamoyl-3- (2-chloroethyl) -βH7-imidazo [5,11] -1,2,3,5-tetrazin-4-one in another polymorphic form has also been obtained, m.p. . 164-165 ° C (decomposes).

Example 4 Compound A

A suspension of 4- [5-diazoimidazole-57 4-carboxamide (1.37 g) in ethyl acetate (20 ml) was treated with methyl isocyanate (7.0 g) and stirred in a sealed vessel in the dark at room temperature for 3 weeks. The resulting solid was removed by filtration and washed with diethyl ether to give 8-carbamoyl-3-methyl- (3H) -imidazo [5,1d] -1,2,3,5-tetrazin-4-one (1.9 g) as a cream in solid form, m.p. 212 ° C (bubbling).

This material was recrystallized from three different solvent systems to give three different products, each with a slightly different infrared spectrum. These three products were probably all polymorphic forms of 8-carbamoyl-3-methyl- (3H) -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one.

(i) Colorless needles were obtained from a 3: 1 v / v mixture of acetone and water, vma] <: S 3410, 3205, 1758, 1730 and 1678 cm m.p. 212 ° C (bubbling).

(ii) White microcrystals were obtained from a 1: 3 v / v mixture of acetone and water, vmaj <s 3430, 3200, 1740 and 1675 cm m.p. 210 ° C (effervescent).

Il: 9 73434 (iii) The granular solid was obtained from hot water, v.

, max 3450, 3380, 3200, 1742, 1688 and 1640 cm -1, mp 215 ° C (effervescent) (darkens from 200 ° C upwards).

Example 5 Compound B

A suspension of 4/5-diazoimidazole-5/4-carboxamide (1.37 g) in acetonitrile (20 ml) was treated with n-propyl isocyanate (6.5 g) and stirred in a sealed vessel in the dark at room temperature. 3 weeks. The resulting pink solid was removed by filtration, washed with diethyl ether and recrystallized from a mixture of water and acetone (1: 4 v / v) to give 8-carbamoyl-3-n-propyl- [3H] -imidazo-[5,1d] - 1,2,3,5-tetrazin-4-one (1.6 g), m.p. 170-172 ° C (effervescent). Concentration of the recrystallization mother liquor gave an additional 0.2 g of the same product.

Example 6 Compound C

A suspension of 4/5 N-diazoimidazole-5-7-carboxamide (1.0 g) in ethyl acetate (30 ml) was treated with 2-chloroethyl isocyanate (3.3 ml) and the mixture was stirred in the dark at ambient temperature. days. The reaction mixture was then diluted with diethyl ether and the resulting solid was removed by filtration to give 8-carbamoyl-3- (2-chloroethyl) - [3H] -imidazo [5,11] -1,2,3,5-tetrazole. -4-one (1.6 g) as a colorless solid, m.p. 164-165 ° C (decomposes). Elemental analysis: found C 34.5; H 2.88; N 34.5; Cl 14.6%; C 18 H 18 N 2 O requires C 34.65; H 2.91; N 34.65; Cl 14.6,% J.

Example 7 Compound C

A suspension of 4 / 5T-diazoimidazole-5/4-carboxyamide (5.0 g) in a mixture of dichloromethane (158 ml) and N-methylpyrrolidin-2-one (8.3 ml) was treated with 2-chloroethyl -isocyanate · (16.7 ml) and the mixture was stirred in the dark at room temperature for 73 days. The reaction mixture was then diluted with anhydrous diethyl ether, and the resulting solid was removed by filtration and washed with diethyl ether to give 8-carbamoyl-3- (2-chloroethyl) - [3H] -imidazo [5,d] -1,2,3,5 -tetrazin-4-one (6.3 g), as a purple solid, m.p. 164-165 ° C (decomposes). / Elemental analysis: found C 34.7; H 2.95; N 34.5; Cl 14.4%; C7HgClN6O2 requires: C, 34.65; H 2.91; N 34.65; Cl 14.4% 7-

Example 8 Compound C

A suspension of 4- (5-diazomidazole-5H-carboxyamide) (145 g) in ethyl acetate (2175 ml) was treated with 2-chloroethyl isocyanate (478.5 ml) and stirred at 30 ° C. protected from light for 2 days. The mixture was then filtered to give 8-carbamoyl-3- (2-chloroethyl) - [3H7] imidazo [5,11] -1,2,3,5-tetrazin-4-one (250 g), in the form of peach-colored solids, m.p. 166 ° C.

Example 9 Compound A

A stirred suspension of N-diazoimidazole-5-carboxamide (2.2 g) in a mixture of dichloromethane (70 ml) and N-methylpyrrolid-2-one (3.5 ml) was treated with methyl isocyanate. (7.0 ml) and stirred at room temperature for 4 days. The mixture was diluted with diethyl ether and the resulting solid was removed by filtration to give 8-carbamoyl-3-methyl- [3H] -imidazo [5,1d] -1,2,3,5-tetrazin-4-one (2.38 g). , in the form of a light purple solid, m.p. 202-203 ° C (decomposes). Elemental analysis: found C 36.8; N 43.1%; C 9 H 9 N 9 O 2 requires: C, 37.11; H 3.14; N 43.3% 7.

The polymorphic form of 8-carbamoyl-3-methyl- (3H) -imidazo [5,1d] -1,2,3,5-tetrazin-4-one was obtained by dissolving it in acetonitrile, filtering, concentrating the filtrate to dryness and triturating. residue with diethyl ether. This 11,73434 substance was in the form of an orange solid, m.p. about 200 ° C (decomposes). Elemental analysis: C 37.4; H 3.26; N 43.5%. Its NMR spectrum in dimethyl sulfoxide was identical to that of the light purple solid mentioned above, but there were some differences in its infrared spectrum (KBr plate).

Example 10 Compound D

A stirred solution of sodium nitrite (0.64 g) in water (4.6 ml) was cooled to 5-10 ° C and treated dropwise at this temperature with a solution of 5-amino-4-methylcarbamoylimidazole (1.00 g). in aqueous acetic acid (1M; 14.3 mL) for 5 min. Stirring was continued at 5-10 ° C for 5 min. The dark red solution was then extracted with ethyl acetate (4 x 35 mL) and the combined extracts were dried over magnesium sulfate. The resulting solution contained crude 4/5-diazo-5/4-methylcarbamoyl-imidazole, which was unstable and was used immediately in the next step without further purification.

A solution of 4/5-diazo-5/4-methylcarbamoylimidazole in ethyl acetate prepared as above was treated with 2-chloroethyl isocyanate (4.3 ml) and allowed to stand in the dark for one day. The solution was then evaporated at 40 ° C / 10 mm Hg and the residue triturated with petroleum ether (b.p. 40-60 ° C) to give an orange gum (4.23 g). This gum was treated with ethyl acetate (50 ml) and filtered, the filtrate evaporated at 40 ° C / 1 mm mm Hg to give an orange gum (2.94 g). This gum was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate and acetonitrile (4: 1 v / v) to give 3- (2-chloroethyl) -8-methylcarbamoyl- [3H7] imidazo [5,1d] -1, 2,3,5-tetrazin-4-one (0.81 g), as a purple solid, m.p. 120-122 ° C (decomposes). Elemental analysis: found 734 34 12 C 37.3; H 3.58; N 31.9%; C 9 H 9 ClN 2 Cl 2 requires: C, 37.4; H 3.53; N 32.7% 7 ·

Example 11 Compound E

A suspension of 4/5-diazoimidazole-5-7-carboxamide (1.0 g) in ethyl acetate (50 ml; dried over anhydrous potassium carbonate) was treated with 3-chloropropyl isocyanate (4.86 g) and the mixture was stirred at ambient temperature. at 3 days. The reaction mixture was then diluted with anhydrous diethyl ether, and the resulting solid was removed by filtration and washed with anhydrous diethyl ether to give 8-carbamoyl-3- (3-chloropropyl) - [3H7] imidazo [5,11] -1,2,3,5-tetrazole. -4-one (1.05 g) in the form of a pink solid, m.p. 153-154 ° C (decomposes). Elemental analysis: found C 37.1; N 32.7; Cl 13.8%; C 9 H 9 ClN 6 O 2 requires: C, 37.4; H 3.53; N 32.8; Cl 13.8% /.

Example 12 Compound F

By proceeding in the same manner as described in Example 11 above, but substituting an appropriate amount of 2,3-dichloropropyl isocyanate for the starting 3-chloropropyl isocyanate, 8-carbamoyl-3- (2,3-dichloropropyl) was prepared. (3H) -imidazo [5,1] -1,2,3,5-tetrazin-4-one in the form of an off-white solid, m.p. 153-155 ° C (decomposes). Elemental analysis: found C 32.7; H 2.51; N 28.7;

Cl 24.1%; C 8 H 9 Cl 2 N 6 O 2 requires: C, 33.0; H 2.77; N 28.9;

Cl 24.4% 7.

Example 13 Compound G

The stirred allyl isocyanate (4.5 ml, redistilled immediately before use) was treated with 4 H -diazoimidazole-5 H -carboxamide (1-0 g) followed by hexamethylphosphoramide (20 ml). The mixture was stirred at room temperature and in the dark for 18 hours and then diluted with anhydrous diethyl ether and filtered. The resulting colorless solid was washed with anhydrous diethyl ether to give 3-allyl-8-carbamoyl-3H7-imidazo [5,1-d] -1,2,3,5-tetrazin-4-one (1.6 g), - In the form of an insoluble solid, m.p. 149-150 C. ly -1 max (KBr plate): 1730, 1675 cm; NMR in DMSO-d: singlets δ at 8.75, 7.67 and 7.60 δ; double triplet at 6.02 5 (J = 5.5, 8, 10 Hz), double doublet at 5.35 6 (J = 1.5, 8 Hz) and 5.20 <S (J = 1.5, 10 Hz) and a doublet at 4.88 <5 (J = 5.5) 7 ·

Example 14 Compound H

A solution of 4T-5-diazo-5/4-dimethylcarbamoylimidazole (1.59 g) in dry diethyl acetate (57 ml) was treated with 2-chloroethyl isocyanate (6.36 g) and stirred at room temperature in the dark for 24 hours. The solution was then evaporated in vacuo at 35 ° C, finally at 0.1 mm Hg to remove excess 2-chloroethyl isocyanate. The remaining liquid was purified by medium pressure column chromatography on silica gel, eluting with a mixture of ethyl acetate and acetonitrile (4: 1 v / v) to give 3- (2-chloroethyl) -8-dimethylcarbamoyl-73H7-imidazo [5,1]. -d7-1,2,3,5-tetrazin-4-one (0.82 g), as colorless crystals, m.p. 114-116 C.

Elemental analysis: obtained C 39, -; H 3.95; N 30.8%; C H CIN O requires: C, 39.9; H 4.10; N 31.0% 7 9 11 6 2 The starting 4/57-diazo-5/4-dimethylcarbamoylimidazole was prepared as follows: (i) 5-nitroimidazole-4-carboxylic acid (2.0 g) and phosphorus pentachloride ( 2.67 g) of the homogeneous mixture was stirred and heated in an oil bath at 120 ° C for 1 hour. Received o.

the yellow slurry was evaporated at 60 ° C / 0.1 mm Hg 30 mm to give 1,6-dinitro-5H, 10H-diimidazo [1,5-a: 1 ', 5'-d7-pyrazine-5, 10-dione (1.90 g) in the form of a yellow solid in the form of 14 734 34 O x r, m.p. 249-251 C (decomposes), / y (KBr plate) 1750 -1. , +, - 7 max cm; m / e 278 (M) _ /.

The same method was used by Windaus, Ber., 1923, 56, 684 and Gireva, Chem. Abs. 5 * 9, 1622e, disclose "5-nitroimidazole-4-carbamoyl chloride".

(ii) An aqueous solution of dimethylamine (25% w / v; 60 ml) was cooled to 0-5 ° C and treated portionwise and with stirring with 1,6-dinitro-5H, 10H-diimidazo [1,5-a: 1 ' With 5'-dj-pyrazine-5,10-dione (6.0 g) in this temperature range. The resulting dark purple solution was stirred for 2 hours.

o.

The solution was evaporated at 50 ° C / 10 mm Hg and then acidified by treatment with concentrated hydrochloric acid to give an orange solution. This solution was extracted with ethyl acetate (7 x 200 ml) and the combined extracts dried over magnesium sulphate and evaporated to give a yellow solid (6.6 g). This solid was triturated with toluene (50 ml) and then recrystallized from ethyl acetate to give 5/4-nitro-4 / 5γ-dimethylcarbamoylimidazole (2.53 g) as yellow crystals, m.p. 193-195 ° C. Elemental analysis: found C 38.9; H 4.23; N 30.4%; C H N O requires: C 39.1; H 4.38; N 30.4% 7.

6 8 4 3 (iii) A solution of 5/4-nitro-4/57-dimethylcarbamoylimidazole (1.62 g) in dry dimethylformamide (32 ml) was treated with platinum oxide (0.32 g) and shaken under a nitrogen atmosphere. at atmospheric pressure and room temperature. After 3 hours, water absorption was complete (710 mL). The mixture was treated with charcoal and filtered through diatomaceous earth. The dark brown filtrate was evaporated at 50 ° C / 0.1 mm Hg and the resulting residue was triturated with diethyl ether to give crude 5/47-amino-4/57-dimethylcarbamoylimidazole (1.75 g) as a dark brown crystalline solid or -1. in the form of, m.p. 179-181 C / v (KBr plate) 1595 cm; max

II

15,734 34 NMR in DMSO-d: singlets at 3.2 and 7.0 6_J, where 6 was still impurity colloidal platinum and used in the next step without further purification.

(iv) A stirred aqueous solution o (5.7 ml) of sodium nitrite (0.79 g) was cooled to 5-10 ° C. 3a was treated dropwise at this temperature range with a solution of 5/4-7-amino-4,5-dimethylcarbamoylimidazole. (1.75 g) in aqueous acetic acid (1M; 17.6 ml) over 5 min. The resulting solution was extracted with ethyl acetate (4 x 40 mL), the combined extracts o.

dried over magnesium sulphate 3a and evaporated at 30 ° C / 10 mm Hg to give 4-5-diazo-5/47-dimethylcarbamoylimidazole (1.59 g), as orange crystals, mp 101-103 ° C (decomposes) . Elemental analysis: found C 42.6; H 4.17; N 41.4%; C H N 0 requires: C, 43.6; 6 7 5 H 4.27; N 42.4% J.

Example 15 Compound I

A stirred suspension of 4-5-diazoimidazole-5-7-carboxamide (1.0 g) in hexamethylphosphoramide (4 ml) was treated with 2-bromoethyl isocyanate (4.5 ml) and the mixture was stirred in the dark at room temperature for 2 days.

The reaction mixture was then diluted with anhydrous diethyl ether, and the resulting solid was removed by filtration and washed with anhydrous diethyl ether to give 3- (2-bromoethyl) -8-carbamoyl- [3H] -imidazo [5,1d] -1,2,3,5- tetrazin-4-one (1.17 g), as a colorless solid, m.p. 156-157 ° C (dec.). Elemental analysis: found C 29.5; N 2.36; N 29.1; Br 27.3%; C 7 H 7 BrN 6 O 2 requires: C, 29.3; H 2.46; N 29.3; Br 27.8% 7.

16

Example 16 7 ύ 4 3 4

Compound J

By proceeding in the same manner as described above in Example 15, but substituting an appropriate amount of benzyl isocyanate for the starting 2-bromomethyl isocyanate, 3-benzyl-8-carbamoyl- [3H7-imidazo- [5,11] -1, 2,3,5-tetrazin-4-one (0.83 g), in the form of a tan solid, m.p. 176-177 ° C (decomposes). Elemental analysis: found C 53.6; H 3.66; N 31.0%; C, -. H-, nN, 0 „afor- _ 12 1U Ό 2 requires: C 53.3; H 3.73; N 31.1%.

Example 17 Yhcisre K

A suspension of 4- [5-diazoimidazole-57 4-carboxyamycia (0.3 g) in acetonitrile (5 ml) was treated with 2-methoxyethyl isosvanate (0.5 g) and the mixture was stirred at 45-47 °. In C in the dark for 24 hours. The resulting solid was removed by filtration and washed with diethyl ether to give crude 8-carbamoyl-3- (2-methoxyethyl) - [3H] -imidazo [5,1-c] -1,2,3,5-tetrazin-4-one (0.45 g), m.p. 145-147 ° C (decomposes).

The product was purified by recrystallization from aqueous acetone to give pink bows or aqueous dimethyl sulfoxide to give colorless needles, m.p. 164-165 ° C (decomposes). Elemental analysis: C 40.4; H 4.20; N 35.2%; C 9 H 11 N 2 O requires: C, 40.34; H 4.20; K 35.2% 7.

Example 18 Compound L

A suspension of 4- [5-7-diazoimidazole-5- [4-7-carboxamide ”(0.30 g) in acetonitrile (10 ml) was treated with cyclohexyl isocyanate (1.0 g) and the mixture was stirred at 60 ° C. The resulting solid was removed by filtration and washed with aqueous ethanol and 0.880 ammonia (100: 0.5 v / v; 20 mL) for 1 minute to give 8-carbamoyl-3-cyclohexyl- [3H7-imidazo] / 5.1d-1,2,3,5-tetrazin-4-one (0.015 g), m.p.

196 ° C (effervescent).

1 7 7 3 4 3 4

Example 19 Compound J

A suspension of 4/5-diazoimidazole-5H-4-carboxyamide (0.4 g) in acetonitrile (10 ml) was treated with benzyl isocyanate (0.6 g) and the mixture was stirred at 60 ° C: in the dark overnight. The reaction mixture was then cooled and filtered to give 3-benzyl-8-carbamoyl- (3H) -imidazo [5,1d] -1,2,3,5-tetrazin-4-one (0.75 g) as a pink solid. in solid form, m.p. 187-188 ° C (effervescent).

Example 20 Compound M

A suspension of 4- (5-N) -diazimidazole -5 / 4-carboxyamide (0.1 g) and p-methoxybenzyl isocyanate (0.4 g) in acetonitrile (5 ml) was stirred at 60 ° C. in the dark for 4 hours. The resulting pink solid was removed by filtration and washed several times with cold diethyl ether to give 8-carbamoyl-3- (p-methoxybenzyl) - [3H] -imidazo [5,1d] -1,2,3,5-tetrazin-4- onia (0.23 g), m.p. 180-182 ° C (effervescent).

Example 21

Following the same procedure as in the previous examples, 8- (N-allylcarbamoyl) -3- (2-chloroethyl) - [3H] -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one was prepared IR 1760 cm NMR (in DMSO-d 6): multiplets 3.96, 5.06 and 5.84 ppm: triplets 4.60 and 6.2 ppm: singlet 8.78 ppm7, 5-amino-4-allylcarbamoylimidazole Via 5-diazo-4-allylcarbamoyl-imidazole. 5-Amino-4-allylcarbamoylimidazole was prepared from 5-nitro-4-allylcarbamoylimidazole (m.p. 218-220 ° C) by reduction with titanium chloride.

Claims (3)

A process for the preparation of a therapeutically useful (3H7-imidazo [5,1-d7-1] 2,3,5-tetrazin-4-one derivative of the general formula: R2 / CO-N - 3 K / VNNN, Wherein R is a straight or branched alkyl or alkenyl group containing up to 6 carbon atoms, a straight or branched alkyl group containing up to 6 carbon atoms and substituted by 1 to 3 halogen atoms or a straight or branched alkoxy group, containing up to 4 carbon atoms, or R 1 is a benzyl or methoxybenzyl group or a cycloalkyl group containing 3 to 8 carbon atoms, R and R are the same or different and are each hydrogen or a straight or branched 2 alkyl group containing up to 4 carbon atoms; carbon atom, or R 3 is hydrogen and R is an allyl group, characterized in that the compound of general formula: 11 R 1. / - \ / N-CO N- Θ 3 'R 2 3 wherein R and R are as defined above, is reacted with an isocyanate having the general formula: R 1 NCO III wherein R 2 is as defined above. 19 73434 Process for the preparation of 8-carbamoyl-3-methyl- [3H7] imidazo [5,1-d7-1,2,3,5-tetrazin-4-one according to Claim 1, characterized in that the compound of general formula II wherein R and R are each hydrogen are reacted with an isocyanate of general formula III wherein R is methyl. Process for the preparation of 8-carbamoyl-3- (2-chloroethyl) [3H] n-imidazo [5,1-d] -1,2,3,5-tetrazin-4-one according to Claim 1, characterized in that that 2. 3 A compound of general formula II wherein R and R are each hydrogen is reacted with an isocyanate of general formula III wherein R is 2-chloroethyl. 1. A preferred form of a compound comprising 3-H7-imidazo / 5,11-d7-1,2,3,5-tetrazin-4-one derivative having the following formula: 2 R y CO-N .. 3 <4S VN. / NYV o color R betkylar en rakkedjig eller grenad alkyl- eller alkenylgrupp med upp account 6 kolatomer, en rakkedjig eller grenad alkylgrupp med upp account 6 kolatomer substituent med 1-3 halogenatom eller med en rakkedjig eller grenad alkoxy group med upp account 4 kolatomer eller betecnar en benzyl-eller methoxybenz ^ lgrupp eller en cycloalkylgrupp med 3-8 kolatomer, R och R är lika eller olika och vardera betecknar väte eller en rakkedjig eller grenad alkylgrupp med upp 2 3 account 4 kolatomer, eller R betecknar väte och R en al -lylgrupp, kännetecknat av att en förening med den allmänna formuleln: