FR2511679A1 - NEW IMIDAZOTETRAZINONES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Abstract

[3H]-Imidazo[5,1-d]-1,2,3,5-tetrazin-4-one derivatives of the formula: in which R<1> denotes hydrogen or an alkyl, alkenyl or alkynyl group having up to 6 carbon atoms, each such group being unsubstituted or substituted by one to three substituents selected from halogen atoms, alkoxy, alkylthio, alkylsulphinyl and alkylsulphonyl groups having up to 4 carbon atoms and optionally substituted phenyl groups, or R<1> denotes a cycloalkyl group having 3 to 8 carbon atoms, and R<2> denotes a carbamoyl group, optionally N-substituted by one or two groups selected from alkyl and alkenyl groups having up to 4 carbon atoms and cycloalkyl groups having 3 to 8 carbon atoms, are novel therapeutically useful compounds having antineoplastic and immunomodulatory activity.

Description

The present invention relates to novel 3HS imidazo f5, -dJ tetrazine-1,2,3,5 ones-4, their preparation and medicaments which contain them.

dans laquelle
R représente un atome d'hydrogène ou un radical alcoyle, alcényle ou alcynyle, contenant au maximum 6 atomes de carbone en chaine droite ou ramifiée, non substituée ou portant 1 à 3 substituants choisis parmi les atomes d'halogène, c'est-à-dire brome, iode ou de préférence chlore ou fluor, les radicaux alcoxy, alcoylthio, alcoylsulfinyle et alcoylsulfonyle contenant au maximum 4 atomes de carbone en chaine droite ou ramifiée et les radicaux phényle éventuel- lement substitués, ou r représente un radical cycloalcoyle-contenant 3 à 8 atomes de carbone, par exemple cyclohexyle, et R2 représente un radical carbamoyle qui peut porter sur l'atome d'azote un ou deux radicaux choisis parmi les radicaux alcoyles et alcényles contenant au maximum 4 atomes de carbone en. chaîne droite ou ramifiée et les
groupes cycloalcoyle, par exemple méthylcarbamoyle ou diméthylcarbamoyle.The compounds according to the invention correspond to the -general formula

in which
R represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical containing a maximum of 6 carbon atoms in a straight or branched chain, unsubstituted or carrying 1 to 3 substituents chosen from halogen atoms, that is to say - say bromine, iodine or preferably chlorine or fluorine, the alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl radicals containing at most 4 carbon atoms in a straight or branched chain and the optionally substituted phenyl radicals, or r represents a cycloalkyl-containing radical 3 to 8 carbon atoms, for example cyclohexyl, and R2 represents a carbamoyl radical which may bear on the nitrogen atom one or two radicals chosen from alkyl and alkenyl radicals containing at most 4 carbon atoms. straight or branched chain and
cycloalkyl groups, for example methylcarbamoyl or dimethylcarbamoyl.

When R1 represents an alkyl, alkenyl or alkynyl radical substituted by 2 or 3 halogen atoms, these atoms can be identical or different.

When the symbol R represents an alkyl, alkenyl or alkynyl radical substituted by one, two or three optionally substituted phenyl groups, said optional substituents can be chosen from, for example, alkoxy or alkyl groups
containing -1 to 4 carbon atoms (for example methoxy or methyl) and nitro, and the symbol R can represent for example a -benzyl group or p. methoxybenzyl. The cycloalkyl groups falling within the definition of the symbols R1 and R2 contain 3 to 8 carbon atoms, preferably 6.

The preferred tetrazine derivatives of general formula I are those for which the symbol R1 represents an alkyl radical of 1 to 6 carbon atoms in a straight or branched chain optionally substituted by one or two halogen atoms (preferably chlorine, fluorine or bromine) or by an alkoxy radical containing t at 4 carbon atoms (preferably methoxy) or by a phenyl radical (optionally substituted by one or two alkoxy radicals containing t at 4 carbon atoms1 preferably methoxy) or the symbol R1 represents a alkenyl radical containing 2 to 6 carbon atoms (preferably allyl) or a cyclohexyl radical.

Preferably R represents an alkyl radical containing t to 6 carbon atoms in a straight or branched chain, and more especially t to 3 carbon atoms, unsubstituted or substituted by a halogen atom, preferably chlorine or fluorine. More especially R represents a methyl or halo-2alkyl radical, for example fluor2ethyl or preferably chloro-2ethyl.

Preferably, the symbol R2 represents a carbamoyl, monoalkylcarbamoyl or monoalkenylcarbamoyl radical, for example methylcarbamoyl.

The present invention also relates to the salts of the products of general formula (I) in which R represents a hydrogen atom and R is defined as above, more especially the alkali metal salts such as the sodium salts. In what follows, and when the context permits, the mere reference to the products of general formula (I) also implies their salts. These salts are particularly useful as intermediates.

According to one aspect of the invention, the products of formula (I) in which R is defined as above and R is other than hydrogen, can be prepared by the action of a product of general formula.

(in which R has the-df - corresponding inition) on an isocyanate of general formula
R NCO (III) in which R represents an alkyl, alkenyl or alkynyl radical optionally carrying 1 to 3 hydrochloric substituents among halogen atoms, the alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl radicals and the optionally substituted pheuyl radicals or represents a cycloicoyl radical , as defined above for R.

The reaction can be carried out in the absence or in the presence of an anhydrous organic solvent, for example a haloalkane (such as dichloromethane), ethyl acetate, acetonitrile, N-methylpyrrolidone or preferably hexamethylphosphorotriamide. , at a temperature of 0 to -700C, for example at room temperature
(about 200C). The reaction may continue for a period of time
up to 30 days. Preferably the reaction mixture
must be protected from light.

(dans laquelle R2 à la définition correspondante) ou un de ses sels alcalins, par exemple le sel de sodium, sur un produit de formule générale :
R X (V) dans laquelle R est défini comme ci-dessus et X représente le reste acide d'un ester réactif, par exemple un atome d'halogène tel que le chlore, ou un reste d'ester sulfurique ou sulfonique tel qu'un radical méthoxysulfonyloxy, méthanesulfonyloxy/ou p. toluènesulfonyloxy.According to another aspect of the invention, the products of general formula (I), (in which R2 is defined as above, and R is other than hydrogen, can further be prepared by the action of a product included in formula general (I) I, of general formula

(in which R2 has the corresponding definition) or one of its alkali metal salts, for example the sodium salt, on a product of general formula:
RX (V) in which R is defined as above and X represents the acid residue of a reactive ester, for example a halogen atom such as chlorine, or a residue of a sulfuric or sulphonic ester such as a methoxysulfonyloxy, methanesulfonyloxy / or p. toluenesulfonyloxy.

When, in the compound of general formula (V), R3 represents a
haloalkyl, radical / haloalkenyl or haloalkynyl the acid residue of a reactive ester represented by X will be chosen from those known to us not less reactive than the halogen atom substituting R3. When, in the compound of general formula (V) IX X represents a halogen atom, the compound of general formula IV is preferably used in the form of an alkali metal salt and when, in the compound of general formula (V), X represents a halogen atom and R3 represents a halocalcoyl, haloalkenyl or haloalkynyl radical in which the halogen atom is the same as that represented by X, an excess of dihalogenated compound of general formula (V) is preferably used.

The reaction of the compound of formula (IV) or its alkali salt with a product of general formula (V) can be carried out in a suitable anhydrous inert organic solvent, for example dichloromethane, acetonitrile, N-methylpyrrolidone-2 or mixtures of such solvents, at a temperature of 0 to 120 C and, when the product of formula (IV) is used, in the presence of an acid scavenger such as an alkali metal carbonate or bicarbonate, for example sodium or potassium .

(dans laquelle R est défini comme ci-dessus et R5 représente un radical protecteur tel que benzyle ou p. méthoxybenzyle) par une méthode connue en soi.According to another aspect of the invention, the products of general formula (IV), (that is to say the products of general formula (I) in which R represents a hydrogen atom and R is defined as above -before) or their alkali metal salts can be prepared by reacting a product of general formula (II) with a product of general formula:
R4 NCO (VI) in which R4 represents an alkali metal atom, for example sodium, or a protective radical such as a benzyl radical or p. methoxybenzyl, followed, when R4 represents a protective radical, by removing this protective radical from the compound obtained intermediate of general formula:

(in which R is defined as above and R5 represents a protective radical such as benzyl or p. methoxybenzyl) by a method known per se.

The reaction of the compound of general formula (II) with the compound of general formula (VI) in which R4 represents a protective radical can be carried out as described above for the reaction of (II) on (III).

The reaction of (II) on a compound of general formula (VI) in which r4 represents an alkali metal atom can be carried out in a suitable inert organic solvent, for example ethanol, acetonitrile or N-methylpyrrolidone, optionally in the presence of a acid, at a temperature of 0 to 120 C. The radical
R5 of the product of general formula (VII) can be removed by a method known per se to give the product of formula (IV).

The compounds of general formula (II) can be prepared by application or adaptation of methods known per se, for example the methods described by SHEALY YF, STRUCK RF, HOLUH L,
B. and MONTGOMERY JA, J. Org. Chem. (1961), 26, 2396.

The compounds of formulas (III), (V) and (VI) can be prepared by known methods or by analogy with such methods. By “methods known per se” is meant any method already used or described in the literature.

The new compounds of general formula (I) have an interesting anticancer activity, for example against oarcinomas, melanomas, sarcomas, lymphomas and leukemias. They have been shown to be particularly active in mice, at daily doses of 0.5 to 16 mg / kg ip, against TLX5 (S) lymphoma according to the method of GESCHER et al., Biochem. Pharmacol. (5981), 30, 89, and ADJ / PC 6A and M 5076 (reticulosarcoma). Against L 1210 leukemia grafted intraperitoneally, intracerebrally and intravenously, and P 388, according to the method described in "Methods of Development of
New Anticancer Drugs "(NCI Monograph 45, March 1977, pages -147-149,
National Cancer Institute, Bethesda, United States) the products were found to be active at doses of between 2.5 and 10 mg / kg ip and po.With the same dosage, inhibition of the primary tumor and metastases of the lung carcinoma
Lexis. Against B 16 melanoma and C 38 mouse tumor (NCI Monograph 45 above), the products were found to be active at doses of between 6.25 and 25 mg / kg ip

The products according to the invention also have an interesting immunomodulatory activity and therefore they are useful on the occasion of organ or skin transplants and for the treatment of immunological disorders.

Among the products of formula (I), mention may be made of
A - 8-carbamoyl-3-methyl [3H] -imidazo [5,1-d] tetrazine-1,2,3,5 -one-4
B - 8-carbamoyl-3-n-propyl [3H] -imidazo [5,1-d] tetrazine-1,2,3,5
one-4
C - carbamoyl-8 (2-chloroethyl) -3 [3H] -imidazo [5,1-d] tetrazine
1,2,3,5 one-4
D - Cchloro-2ethyl) -3 methylcarbamoyl-8 3H2-imidazo Ç5, t-dJ
tetrazine-1,2,3,5 one-4. ;;
E - carbamoyl-8 (3-chloro propyl) -3 3HJ-imidazo [5,1-d] tetrazine
1,2,3,5 one-4
F - carbamoyl-8 (2,3-dichloropropyl) -3 [3H] -imidazo [5,1-d]
tetrazine-1,2,3,5 one-4
G - allyl-3carbamoyl-8 [3H] -imidazo [5,1-d] tetrazine-1,2,3,5 one-4
H - (2-chloroethyl) -3 dimethylcarbamoyl-8 f3HJ-imidazo [5,1-d]
tetrazine-1,2,3,5 one-4
I - (2-bromo-ethyl) -3-carbamoyl-8 [3H] = imidazo [5,1-d] tetrazine
1,2,3,5 one-4
J - 3-benzyl-8-carbamoyl i3Hj-imidazo [5,1-d] tetrazine-1,2,3,5 one-4
K - carbamoyl-8 (2-methoxyethyl) -3 [3H] -imidazo [5,1-d] tetrazine
i, 2,3,5 one-4
L - carbamoyl-8 cyclohexyl-3 f3Hj-imidazo g5,1-dg tetrazine-1,2,3,5 one-4
M - carbamoyl-8 (p. Methoxybenzyl) -3 [3H] -imidazo [5,1-d] tetrazine
1,2,3,5 one-4.

N - N-allylcarbamoyl-8 (2-chloroethyl) -3 [3H] imidazo [5,1-d]
tetrazine-1,2,3,5 one-4
The products A, D and more especially C are of particular importance.

The letters A to N assigned to the products will make it possible to refer to them more easily in the remainder of the description.

The examples below illustrate the preparation of products of general formula (I) according to the invention, and the reference examples illustrate the preparation of intermediates.

EXAMPLE 1
PRODUCT A
500 mg of diazo-405j-imidazole carboxamide-5 [4] were suspended in 3.0 cm3 of methyl isocyanate and stirred in the dark at room temperature for 21 days. The reaction mixture is then diluted with anhydrous diethyl ether and filtered. The residue is then washed rapidly with anhydrous methanol and then with ethyl ether and dried in air, in the dark, at room temperature. 198 mg of 8-carbamoyl-3-methyl [3H] -imidazo [5,1-d] tetrazine-1,2,3,5 one-4 are obtained in the form of a light brown microcrystalline solid, Mp @ 210 C ( with effervescence and browning Se 100 at 210 ° C).

Elemental analysis: C% H% N%
Calculated (for C6H6N602) 37.1 3.09 43.3
Found 36.8 3.10 44.2 EXAMPLE 2
PRODUCT B
300 mg of diazo-4 252-imidazole carboxamide-5 [4] are suspended ion in 10 cm3 of anhydrous dichloromethane and an excess of isocyanate of n. propyl. The reaction mixture is stirred in the dark at room temperature for 30 days.

The mixture is then filtered, the residue quickly washed with anhydrous ethyl ether and air dried in the dark at room temperature. 102 mg of 8-carbamoyl-3-propyl [3H] -imidazo 5,1- d] tetrazine-1,2,3,5 one-4 are obtained in the form of a pale pink powder, Mp = 1670C (effervescence).

Elemental analysis: C% H% N%
Calculated (for C8H1oN602) 43.2 4.53 37.8
Found 43.4 4.57 38.0
EXAMPLE 3
PRODUCT C
300 mg of 4-diazo [5] -imidazole carboxamide-5 [4] are suspended in 10 cm3 of anhydrous dichloromethane and 1.0 cm3 of 2-chloroethyl isocyanate is added. The mixture is stirred in the dark at room temperature for 30 days. The cream-colored suspension thus obtained is filtered, the residue washed quickly with anhydrous ethyl ether and air-dried in the dark. 483 mg of carbamoyl-8 (2-chloro-ethyl) -3 are obtained
[3H] -imidazo 5,1-dg tetrazine-1,2,3,5 one-4 as a cream-colored powder, Mp = 1580C (with vivid decomposition).

Elemental analysis C% H% N%
Calculated (for C7H7ClN6O2) 34.7 2.91 34.7
Found 34.7 3.01 34.9
Repeating this operation also gave product C in another polymorphic form, M = 164-1650C (dec).

EXAMPLE 4
PRODUCT A
Is suspended 1.37 g of diazo-4 [5] -imidazole carboxamide-5 [4] in 20 cm3 of methyl acetate with 7.0 g of methyl isocyanate and stirred in a closed cup in darkness for 3 weeks at room temperature. The solid obtained is separated on a filter and washed with ether. 1.9 g of 8-carbamoyl-3-methyl f3Hj-imidazo [5,1-d] tetrazine-1,2,3,5 one-4 are obtained in the form of a cream-colored solid, F = 2120C (effervescence ).

This product was recrystallized in 3 different solvent systems, and three distinct products were obtained, differing slightly in their IR spectra. These three products are probably all polymorphs of product A (i) from the acetone / water mixture 3/1 (vol) we obtain colorless needles, # max 3410, 3205, 1758, 1730 and 1678 cm, F = 2120C ( effervescence).

(ii) from the acetone / water mixture 1/3 (vol) white microcrystals are obtained, # max 3430, 3200, 1740 and 1675 cm, F = 210 C (effervescence).

(iii) from hot water a granular solid is obtained, # max 3450, 3380, 3200, 1742, 1688 and 1640 cm, F = 2150C (effervescence) (blackening from 2000C).

EXAMPLE 5
PRODUCT B
A suspension of 1.37 g of diazo-4f5) '- imidazole carboxamide-5 [4] in 20 cm3 of acetonitrile is treated with 6.5 g of isocyanate of n. propyl and stirred in a closed vessel in the dark for 3 weeks at room temperature.

the pink solid obtained is separated on a filter, washed with ether and recrystallized from a water / acetone mixture 1/4 (vol). 1.6 g of 8-carbamoyl are obtained. 3-propyl f3Hj-imidazo 5,1-da tetrazine-1, 2,3,5 one-4, F = 170-1720C (effervescence).

By concentrating the same recrystallization liquor, another 0.2 g of the same product is recovered.

EXAMPLE 6
PRODUCT C
A suspension of 1.0 g of diazo-4 [5] -imidazole carboxamide-5 [4] in 30 cm3 of ethyl acetate is treated with 3.3 cm3 of 2-chloroethyl isocyanate, and stirred in the dark for 6 days at room temperature. Diluted with ether and the solid isolated by filtration. 1.6 g of carbamoyl-8 (chloro2 ethyl) -3 3H2-imidazole [5,1-d] tetrazine-1,2,3,5 one are obtained. -4 as a colorless solid, M = 164-165 (dec.)
Elemental analysis C% H% N% Cl%
Calculated for C7H7ClN6O2 34.65 2.91 34.65 14.61
Found 34.5 2.88 34.5 14.6 EXAMPLE 7
PRODUCT C
A suspension of 5.0 g of 4-diazo [5] imidazole carboxamide-5042 in a mixture of 158 cm3 of dichloromethane and 8.3 cm3 of N-methylpyrrolidone is treated with 6.7 cm3 of 2-chloro isocyanate
ethyl, and the mixture was stirred in the dark for 14 days at room temperature. The mixture is then diluted with anhydrous ether, the solid is isolated by filtration and washed with ether. 6.3 g of 8-carbamoyl-2-Chloroethyl) -3 [3H] -imidazo [5.1 -d] tetrazine1,2,3,5 one-4 in the form of a solid of purple hue, M = 164-1650C (dec.)
Elemental analysis C% H% N% Cl%
Calculated for C7H7ClN602 34.65 2.91 34.65 14.61
Found 34.7 2.95 34.5 14.4
EXAMPLE 8
PRODUCT C
A suspension of 145 g of diazo-4 [5] -imidazole carboxamide-5E4J in 2175 cm3 of ethyl acetate is treated with 478.5 cm3 of 2-chloroethyl isocyanate and stirred at 300C to protected from light for 2 days. 250 g of carbamoyl-8 (2-chloroethyl) -3 [3H] -imidazo [5,1-d] tetrazine-1,2,3,5 one-4 are obtained in the form of a colored solid. peach, F = 166 C.

EXAMPLE 9
PRODUCT A
A stirred suspension of 2.2 g of 4-diazo [5] imidazole carboxamide-5 [4] in a mixture of 70 cm3 of dichloromethane and 3.5 cm3 of N-methylpyrrolidone is treated with 7.0 cm3 of isocyanate of methyl and stirred for 4 weeks at room temperature.

Diluted with ethyl ether and the solid is separated on a filter.
2.28 g of 8-carbamoyl-3-methyl [3H] -imidazo [5,1-3] tetrazine-1,2,3,5 one-4 are obtained in the form of a pale purple solid, Mp = 2022030C (dec. ).

Elemental analysis C% H% N
Calculated for C6H6N602 37.11 3.14 43.3
Found 36.8 2.94 43,
A polymorphic form of 8-carbamoyl methyl3 3H2-imidazo [5,1-d] tetrazine-1,2,3,5 one-4 is obtained by dissolution in acetonitrile, filtration, concentration to dryness and trituration of the residue in ether. The product is in the form of an orange-colored solid, F close to 2000C (dec.).

Elemental analysis: C = 37.4% H ~ 3926% N = 43.5%
Its NMR spectrum (DMSO-D6) is identical to that of the pale purple product, but its IR spectrum (KBr tablet) shows some differences.

ZXAMPLE 10 -
PRODUCT D
Cooled to 5-100C a stirred solution of 0.64 g of sodium nitrite in 4.6 cm3 of water and added dropwise at this temperature, over 5 minutes, a solution of 1.00 g of amino -5 methylcarbamoyl-4imiazole in 14.3 cm3 of aqueous solution of 1M acetic acid. Stirred further at 5-10 C for 5 minutes. The dark red solution is extracted with 4 times 35 cm3 of ethyl acetate and the combined extracts are dried over magnesium sulfate. The solution contains crude diazo-4 [5] methylcarbamoyl / iJ-imidazole, which is unstable and is used immediately in the next step without further purification.

This solution is treated with 4.3 cm3 of 2-chloroethyl isocyanate and left in the dark for 1 day. The solvent is evaporated off under reduced pressure (10 mm Hg; 1.33 KPa) at 400C and the residue triturated with petroleum ether (Bp 40-600C).

4.23 g of an orange gum are obtained. This gum is treated with 50 cm3 of ethyl acetate, filtered and the solvent evaporated (10 mm Hg; 1.33 KPa) at 400C. 2.94 g of an orange gum is obtained, which is purified on silica gel in a column at medium pressure, eluting with a 4/3 ethyl acetate / acetonitrile mixture. (flight).

0.81 g of 2-Chloroethyl) -3 methylcarbamoyl-8 [3H] -imidazo 5.1-d; 1,2,3,5 one-4 tetrazine as a purple solid, Mp = 120-1220C (dec.).

Elemental analysis C% H%
Calculated for C8H9ClN6O2 37.4 3.53 32.7
Found 3713 3.58 31.9
EXAMPLE 11
PRODUCT E
To a suspension of 1.0 g of diazo-4f5J-imidazole carboxamide-5 [4] in 50 cm3 of ethyl acetate (dried over anhydrous potassium carbonate) is added 4.86 g of 3-chloro isocyanate propyl and stirred at room temperature for 3 days.

It is diluted with anhydrous ether, the solid is filtered off and washed thoroughly with anhydrous ether.

1.05 g of carbamoyl-8 (3-chloropropyl) -3 [3H] -imidazo [5,1-d] tetrazine-1,2,3,5 one-4 is obtained in the form of a pink solid, Mp 153-154 C (dec).

Elemental analysis C% H% N% Cl '%
Calculated for C8H9ClN6O2 37.4 3.53 32.8 t3.8
Found 37.1 3.42 32.7 13.8
EXAMPLE 12
PRODUCT F
By operating as in Example 11 but replacing the 3-chloropropyl isocyanate with the appropriate amount of 2,3-dichloro-propyl isocyanate, 8-carbamoyl (dichloro2,3 propyl) -3 f3Hj- is obtained. imidazo [5,1-d] tetrazine-1,2,3,5 one-4 as an off-white solid, mp = a53-1550C (dec.).

Elemental analysis C% H%% N% C1%
Calculated for C8H8C12N602 33.0 2.77 28.9 24.4
Found 32.7 2.51 28.7 24.1
EXAMPLE 13
PRODUCT G
1.0 g of 4-diazo [5] imidazole carboxamide-5 [4] then 20 cm3 of hexamethylphosphorotriamide are added to 4.5 cm3 of allyl isocyanate (redistilled just before use) with stirring.

Stir at room temperature in the dark for 18 hours, then dilute with ethyl ether and filter. The colorless solid is washed with anhydrous ether and 1.6 g of allyl-3-carbamoyl-8 [3H] -imidazo [5,1-d] tetrazine1,2,3,5 one-4 is obtained in the form of d 'a colorless solid, F = 149-1500C, # max (compressed
KBr): 1730 and 1675 cm-1 NMR (DMSO-d6): singlets at 8.75, 7.67 and 7.60 #; double double triplet at 6.026 (J = 5.5, 8 and 10Hz), double doublet at 5.35 (J = 1.5 and 8 Hz) and 5.20 # (J = 1.5 and 10 Hz) and doublet a 4.88 # (J 5.5).

EXAMPLE 14
PRODUCT H
To a solution of 1.59 g of 4-diazo [5] dimethylcarbamoyl-5 [4] imidazole (prepared according to the example of reference) in 57 cm3 of anhydrous ethyl acetate is added 6.36 g of chloro isocyanate -2 ethyl and stirred in the dark at room temperature for 24 hours. The excess of 2-chloroethyl isocyanate is removed by evaporation under vacuum at 350C ending under 0.1 mm
Hg (13 Pa). The residual liquid is purified by chromatography on silica gel in a medium pressure column, eluting with an ethyl acetate / acetonitrile mixture (4/1 by volume). 0.82 g of (2-chloroethyl) -3 is obtained. 8-dimethylcarbamoyl [3H] -imidazo [5,1-3] tetrazine-1,2,3,5 one-4 as colorless crystals, F 114-116 C
Elemental analysis C% H% N%
Calculated for C9H11ClN6O2 59.9 4, w 31.0
Found 39.7 3.95 30.8
EXAMPLE 15 -
PRODUCT I
To a stirred suspension of 1.0 g of 4-diazo [5] imidazole carboxamide-5 [4] in 4 cm3 of hexamethylphosphorotriamide is added 4.5 cm3 of 2-bromo-ethyl isocyanate and stirred in the dark. for 2 days at room temperature. The reaction mixture is diluted with ethyl ether, the solid is filtered off and washed with ethyl ether. 1.17 g of (2-bromo-ethyl) -3 carbamoyl-8 [3H] are obtained. -imidazo 5,1-dZ tetrazine-1,2,3,5 one-4 in the form of a colorless solid, - F = 156157 C (dec.).

Elemental analysis C% H 9Ó N% Br%
Calculated for C7H7BrN6O2 29.3 2.46 29.3
Found 29.5 2.36 29.1 27.3
EXAMPLE 16
PRODUCT J
By operating as described in Example 15 but replacing the 2-bromo-ethyl isocyanate with the appropriate amount of benzyl isocyanate, 0.83 g of 3-benzyl carbamoyl is prepared.
[3] -imidzo f5,1-d7 tetrazine-1,2,3,5 one-4 as a buff solid, M = 176-1770C (dec.).

Elemental analysis C% H% N%
Calculated for C12H10N6O2 53.3 3.73 31.1
Found 53.6 3.66 31.0
EXAMPLE 17
PRODUCT K
To a suspension of 0.3 g of 4-diazo [5] -imidazole carboxamide-5 [4] in 5 cm3 of acetonitrile, 0.5 g of 2-methoxyethyl isocyanate is added and the mixture is stirred in the dark. for 24 hours between 45 and 470C. The solid obtained is separated by filtration and washed with ethyl ether. 0.45 g of carbamoyl-8 (2-methoxyethyl) -3 [3H] -imidazo [5,1-d] tetrazine-1, 2,3,5 one-4, F = 145-1470C (dec .).

The product is purified by recrystallization in aqueous acetone (tufts of pink crystals are obtained) or in dimethyl sulfoxide (Con obtains colorless needles),
Mp = 164-165 C, (dec.).

Elemental analysis C% H% N%
Calculated for C8H oN603 40.34 4.20 35.2
Found 40.4 4.20 35.2
EXAMPLE 18
PRODUCT L
To a suspension of 0.30 9 of diazo-4 [5] -imidazole-carboxamide-5 [4] in 50 cm3 of acetonitrile, 1.0 g of cyclohexyl isocyanate is added and the mixture is stirred in the dark for 3 turns 2 60 C,
The solid obtained is separated by filtration and washed with 20 cm3 of a mixture (100 / Q, 5 V / V) of ethanol and ammonia (d = 0.88) for one minute. 0.015 g of 8-carbamoyl-cyclohexyl-3 [3H] -imidazo [5,1-d] tetrazine-1,2,3,5 one-4, Mp = 196 C (effervescence) is obtained.

EXAMPLE 19
PRODUCT J
To a suspension of 0.4 g of 4-diazo [5] imidazolecarboxamide-5 [4] in 10 cm3 of acetonitrile, 0.6 g of benzyl isocyanate is added and the mixture is stirred in the dark overnight at 60 C. After cooling and filtration, 0.75 g of benzyl-3 carbamoyl-8 f3ii7-imidazo [5,1-d] tetrazine-1,2,3,5 one-4 is obtained in the form of a pale pink solid, M = 187-1880C (effervescence).

EXAMPLE 20
PRODUCT M
A suspension of 0.1 g of 4-diazo [5] imidazole carboxamide-5 [4] and 0.4 g of p. methoxybenzyl in 5 cm3 of acetonitrile is stirred at 600C in the dark for 4 hours.

The pale pink solid obtained is separated by filtration and washed several times with ethyl ether. 0.23 g of (p. Methoxybenzyl) -3 carbamoyl-8 [3H] -imidazo [5,1-d] tetrazine-1,2, 3,5 one-4, F = 180-1820C (effervescence) is obtained. .

EXAMPLE 21
PRODUCT N
By operating as described above but starting from
N-allyl diazo-4 [53 imidazolecarboxamide-5 [4], one obtains the
N-allylcarbamoyl-8 (2-chloroethyl) -) [3E] imidazo [5,1-d] tetrazine-1,2,3,5 one-4, the physicochemical characteristics of which are as follows) max 1750 cm-1; NMR (DMSO-d6): multiplets at 3.96, 5.06 and 5.84 #, triplets at 4.60 and 6.2 # and singlet at 8.78
N-allyl diazo-4 [5] imidazolecarboxamide-5 [4] can be obtained by diazotizing N-allyl amino-4 [53 imidazolecarboxamide-5 [4].

N-allyl amino-4 [5] imidazolecarboxamide-5 [4] can be obtained by reduction with titanium chloride of
N-allyl nitro-4E5] imidazolecarboxamide-5 [4] melting at 218-2200C.

REFERENCE EXAMPLE 1
(a) Stirred for 1 hour while heating in a bath
oil (120 C) an intimate mixture of 2.0 g of 5-nitro-imidazole acid
carboxylic-4 and 2.67 g of phosphorus pentachloride. The
yellow slurry obtained is concentrated under vacuum (0.1 mmHg; 13 Pa)
at 60 C for 30 minutes. 1.90 g of dinitro-t, 6-5H, 10H- are obtained.
diimidazo 1,5-a: 1 ', 5'-d] pyrazinedione-5,10 as a
yellow solid, mp = 249-251 C (dec.); # max 1750 cm-1 (KBr tablet)
m / e 278 (M +).

Using the same method, WINDAUX, Ber., 1923, 56,
684 and GIREVA, Chem. Abs. 59, 1622nd describe their products as
5-nitroimidazolecarbonyl-4 "chloride.

(b) Cooled 60 cm3 of aqueous solution of dimethyl
25% amine (W / V) between 0 and 5 C and added in portions, in
stirring, 6.0 g of dinitro-1,6-5H, 10H-diimidazo 1,5-a: i ', 5'-dj
pyrazinedione-5,10 while maintaining the temperature in this range.

The solution obtained, dark purple, is stirred for 2 hours. We
evaporates at 50 C under 10 mmHg (a, 3 kPa) and aczdifies with acid
hydrochloric acid concentrate. We obtain an orange solution, which we
extracted with 7 times 200 cm3 of ethyl acetate. The collected extracts
are dried over magnesium sulfate and evaporated. We obtain 6.6 g
a yellow solid. This solid is triturated with 50 cm3 of toluene,
recrystallized from ethyl acetate and obtained 2.53 g of 5-nitro
[4] 4-dimethylcarbamoyl [5] imidazole in the form of yellow crystals,
F = 193-195 C.

Elemental analysis C% H% N%
Calculated for C6H8N403 39.1 4.38 30.4
Found 38.9 4.23 30.4
(c) To a solution of 1.62 g of nitro-5042 dimethyl
4-carbamoyl [5] imidazole in 32 cm3 of anhydrous dimethylformamide
0.32 g of platinum oxide is added and the mixture is stirred under hydrogen at
atmospheric pressure and ambient temperature. After 3 hours
hydrogen absorption is complete (710 cm3). We treat the
dark mixture and filtered through diatomaceous earth. The filtrate
brown-black is evaporated at 500C under 0.1 mmHg (13 Pa) and triturated
the residue with ethyl ether. 1.75 9 of 5-amino is obtained.
[4] 4-dimethylcargamoyl [5] imidazole as a solid cris
tall black-brown, F = 179-181 C [9 max 1595 cm (KBr tablet)
NMR (DMSO d6): singlets at 3.2 and 7.0 #] which is still contaminated
by colloidal platinum and which can be used without further purification
fication for the next step.

(d) A stirred solution of 0.79 g of sodium nitrite in 5.7 cm3 of water is cooled to 5 to 10 ° C. and a solution of sodium nitrite is added dropwise over 5 minutes at the same temperature range. 1.75 g of 5-amino [4] dimethylcarbamoyl4f5i imidazole in 17.6 cm3 of 1M aqueous acetic acid. The solution obtained is extracted with 4 times 40 cm3 of ethyl acetate, the combined extracts are dried over magnesium sulfate, evaporated at 300 ° C. under 10 mmHg (1.33 kPa) and 1.59 g of diazo-4e52 dimethylcarbamoyl is obtained. -5 [4] imidazole as orange crystals, Mp = 101-103 C (dec.).

Elemental analysis c% H% N%
Calculated for C6H7N5O 43.6 4.27 42.4
Found 42.6 4.17 41.4
The present invention also relates to pharmaceutical compositions which contain, as active ingredient, at least one product of general formula (I) with a pharmaceutical diluent or coating. In the clinic, the products of general formula (I) are normally administered orally, rectally, vaginally or parenterally, for example intravenously or intraperitoneally.

The modes of presentation of pharmaceutically active products are well known and the physician or pharmacist is able to choose an appropriate vehicle depending on factors such as the desired effect, size, age, sex and condition. general patient or the properties of the active product. The compositions may also contain, according to usual practice, ingredients such as solid or liquid diluents, wetting agents, preservatives, perfumes, colorants and the like.

Among the solid compositions for oral administration, mention may be made of tablets, pills, dispersible powders, and granules.

In these solid compositions there is one or more active products mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid or lactose. These compositions may also contain additives other than inert diluents, for example lubricants such
than magnesium stearate.

Among the liquid compositions for oral administration, mention may be made of emulsions, solutions, drug suspensions.
tically acceptable syrups and elixirs containing diluents
Inerts of common use such as water and petrolatum oil. In addition to inert diluents, these compositions may also contain
adjuvants such as wetting agents, suspending agents (e.g. poly
vinylpyrrolidonev, sweeteners, flavorings, fragrances and preservatives.

Among the compositions for oral administration are
may also cite capsules made of absorbable material such as
gelatin which contains one or more active products with or
without the addition of diluents or other excipients.

Among the compositions for vaginal administration are
can cite the pessaries formulated in the usual and con
holding one or more active products.

Among the compositions for rectal administration, mention may be made of suppositories formulated in the usual manner and containing at least one active product.

Compositions according to the invention for parenteral administration comprising sterile aqueous or non-aqueous solutions, suspensions or emulsions. As examples of non-aqueous solvents or vehicles, mention may be made of: propylene glycol, polyethylene glycols, dimethyl sulfoxide, vegetable oils (for example olive oil) or injectable organic esters (for example ethyl oleate).

These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants.

They can be sterilized for example by aseptic filtration, addition of sterilizing agents or irradiation.

They can also be prepared in the form of sterile solid compositions which will be dissolved or dispersed, at the time of their use, in batting or any other sterile injectable medium.

The proportion of active product in the compositions according to the invention can vary, insofar as it makes it possible to obtain a dosage suitable for the desired therapeutic effect.

Of course, several unit doses can be administered simultaneously. In general, compositions for administration by injection contain at least 0.025% by weight of active material, and compositions for the oral route contain at least 0.1%. The dose employed depends on the desired effect, the route of administration and the duration of treatment.

The compounds of general formula (I) are useful in the treatment of malignant neoplasms such as carsinomas, melanomas, sarcomas, lymphomas and leukemias, at doses generally between 0.1 and 200 (and preferably between let 20) mg / kg per day.

The following examples illustrate compositions according to the invention.

COMPOSITION EXAMPLE 1
A solution suitable for parenteral administration is prepared from the following ingredients
Carbamoyl-8 (2-chloroethyl) -3 3H2-imidazo [5,1-d] tetrazine-1,2,3,5 one-4 1.0 g Dimethyl sulphoxide 10 cm3
Peanut oil 90 cm3 by dissolving carbamoyl-8 (2-chloroethyl) -3 [3H] -imidazo [5,1-d] tetrazine-1,2,3,5 one-4 in dimethylsulfoxide and adding oil. The solution obtained is distributed aseptically into 10 ampoules, at a rate of 10 cm3 per ampoule. The ampoules, which each contain 100 mg of carbamoyl-8 (2-chloroethyl) -3 [3H] imidazo: 5.1-d; tetrazine-1,2,3,5 one-4.

Similar ampoules suitable for parenteral administration can be prepared by working in the same manner starting from another compound of general formula (I).

COMPOSITION EXAMPLE 2
Capsules suitable for oral administration are prepared by depositing carbamoyl-8 (2-chloroethyl) -3 C3H-imidazo [5,1-d] tetrazine-1,2,3,5 one-4 in capsules. 2-gauge gelatin at 10 mg per capsule.

Similar capsules can be prepared using another product of general formula (I) or other capsules of suitable size.

Claims (7)

R E V E N D I C A T I O N S 1 - New derivative of [3H] imidazo [5,1-d] tetrazine-1,2,3,5 one-4, characterized in that it corresponds to the general formula: in which

represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical containing a maximum of 6 carbon atoms in a straight or branched chain, unsubstituted or carrying 1 to 3 substituents chosen from halogen atoms, alkoxy, alkylthio radicals, alkylsulfinyl and alkylsulfonyl containing a maximum of 4 carbon atoms in a straight or branched chain and the optionally substituted phenyl radicals, or R represents a cycloalkyl radical containing 3 to 8 carbon atoms, and R represents a carbamoyl radical which may bear on the atom d 'nitrogen one or two radicals chosen from alkyl and alkenyl radicals containing a maximum of 4 carbon atoms in a straight or branched chain and cycloalkyl groups containing 3 to 8 carbon atoms and, when R represents a hydrogen atom, their salts of alkali metals. 2 - Process for the preparation of a product according to claim 1 in the formula of which R and R2 are defined as in claim 1 except for R to represent a hydrogen atom, characterized in that one makes react a compound of general formula

in which R is defined as in claim 1 on an isocyanate of the general formula: R3NCO in which R3 represents an alkyl, alkenyl or alkynyl radical containing at most 6-unsubstituted carbon atoms or carrying 1 to 3 substituents chosen from halogen atoms, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl radicals containing at most 4 atoms of carbon, and the optionally substituted benyl radicals, or else R3 represents a cycoalkyl radical containing 3 to 8 carbon atoms. 3 - PROC6 for the preparation of a product according to claim 1 in the formula of which R and R are defined as in claim 1 except for R1 to represent a hydrogen atom, characterized in that one makes react a compound of general formula

wherein R is defined as in claim 1, or an alkali metal salt thereof, on a compound of the general formula R3X wherein P.3 is defined as in claim 2 and X represents an acid residue of a reactive ester. 4 - The method of claim 3 wherein X represents a halogen atom or a methoxysulfonyloxy, methanesulfonyloxy or p. toluenesulfonyloxy. 5 - Process for the preparation of a product according to claim 1 in the formula of which R represents eun hydrogen atom and R is defined as in claim 1, or an alkali salt of this product, characterized in that one reacts a compound of the general formula

on a compound of general formula: R4NCO in which R4 represents an alkali metal atom or a protective group, followed, when R4 represents a protective group, by replacing the latter with a hydrogen atom in the intermediate compound of general formula:

in which R is defined as in claim 1 and R5 represents said protecting group, by methods known per se. 6 - Process according to claim 5 characterized in that the protective group is chosen from the benzyl and p radicals. methosybenzyl. 7 - Pharmaceutical composition characterized in that it contains, as active ingredient, at least one product according to claim 1, in combination with a carrier or a pharmaceutically acceptable coating.