FR2531958A1 - 1,2,3,5-Tetrazine-4-one or 4-thione derivs. - Google Patents

Abstract

Cpds. of formula (I) and their salts are new. In (I) R1 is cycloalkyl or opt. branched alkyl, alkenyl or alkinyl with upto 6C and opt.substd. by 1-3 substits. chosen from halogen or opt. branched 1-4C alkyloxy, alhylthio, alkylsulphonyl or alkylsulphinyl or opt. substd. Ph; Al is N or -CR3=; R3 is H or R4; R4 is halogen or opt. branched alkyl or alkenyl with up to 6C and opt. 1-3 substits or R4 is cycloalkyl, CN, OH, NO2, PhO (opt. substd), -COR5, upto 6C alkanoylamino, -S(O)nR6, -SO2NR7R8 or CZ2NR7R8; R5 is 1-4C alkyl or alkyloxy, OH or opt. substd. Ph; n is 0, 1 or 2; R6 is opt. branched 1-4C alkyl or alkenyl (opt. carrying an opt. substd. Ph substis), cycloalkyl or opt substd. Ph; R7 and R8 are each H, opt. brached upto 4C alkyl or alkenyl (opt. carrying an opt. substd. Ph substit), cycloalkyl or opt. substd. Ph, or -NR7R8 is a hetero-cyclic gp; Z2 is O or S; A2 is N or if A1 is N, A2 is N or -CR3-; R2 is -S(O)nR6, -SO2NR7R8, -CSNR7R8, -CONR7R8 or -CZ2NHNo2; or if A1 is N or -CR4= or if A1 is -CH0 and Z1 is S, R2 can be -S(O)nR6, -SO2NR7R8, -CZ2NR7R8 or -CZ2NHNO2; -NR7R9 is a heterocyclic gp or R7 is as before and R9 is opt. branched upto 4C alkyl or alkenyl (opt. carrying an opt. substd. Ph substit . (I) are anticancer agents, found to be effective against various tumours (primary tumours, metastoses, Lewis lung carcinomas, B16 melanome, C38 tumour, rectal carcinomas) in rice.

Description

 The present invention relates to novel tetrazine derivatives, processes for their preparation and pharmaceutical compositions containing them.

dans laquelle R1 représente un radical cycloalcoyle ou un radical alcoyle1 alcényle ou alcynyle en chaîne droite ou ramifiée contenant jusqu 6 atomes de carbone, chaque radical alcoyle, alcényle et alcynyle étant non substitué ou substitué par un à trois substituants choisis parmi les atomes d'halogène (tel que le brome, l'iode ou de préférence le chlore ou le fluor),les radicauxalcoylosy, alcoylthio, alcoylsulfinyle et alcoylsulfonyle en chaîne droite ou ramifiée contenant jusqu'à 4 atomes de carbone-et les radicauxphényle éventuellement substitué
A1 représente un atome d'azoe ou un radical - CR3 = dans lequel R3 représente un atome d'hydrogène ou un substituant R4 dans lequel R4 représente un atome d'halogène, ou un radical alcoyle ou alcényle en chaîne droite ou ramifié-e contenant jusqu'à 6 atomes de carbone, qui peut porter jusqu'à 3 substituants choisis parmi les atomes d'halogène, des radicaux phényle éventuelement subst::.tués, alcoyloxy, alcoylthio et alcoylsulfonyle contenant jusqu'à 3 atomes de carbone ou bien R4 représente un radical cycloalcoyle, cyano, hydroxy, nitro ou phénoxy éventuellement substitué,ou un radical de formule -COR5 (dans laquelle Rg représente un radical alcoyle ou alcoyloxy contenant jusqu'à 4 atomes de carbone, un radical hydro.::y ou un radical phényle éventuellement substitué) ou bien un radical alcanoylamino contenant jusqu 6 atomes de carbone, ou bien R4 représente un radical de formules
S(O)nR6,-SO2NR7R8 ou -CZ2NR7R8 (dans lesquelles n représente les chiffres 0, 1 ou 2, R6 représente un radical alcoyle ou alcényle en chaîne droite ou ramifiée contenant jusqu'a' 4 atomes de carbone ( qui peut porter un substituant phényle éventuellement substitué)) un radical cycloalcoyle ou un radical phényle éventuellement substitué, R, et R8 qui peuvent être identiques ou différents, représentent chacun un atome c'hydrogène ou un radical alcoyle ou alcényle en chaîne droite ou ramifiée, contenant jusqu'a' 4 atomes de carbone (qui peut porter un substituant phényle éventuellement substitué), ou ou un radical cycloalcoyle ou un radical phényle éventuellement substitué ou bien le radical -NR7R8 représente un radical hétérocyclique, et Z2 représente un atome d'oxygène ou de soufre),
A2 représente un atome d'azote ou bien, lorsque A1 représente un atome d'azote, A2 représente un atome d'azote ou un radical -CR3::
dans lequel R3 est défini comme ci-dessus, Z1 représente un atome d'oxygène ou de soufre, et R2 représente un radical de formules
- S(O)nR6, - SO2NR7R8, - CSNR7R8, -CONR7R9 ou -CZ2NHNO2 dans lesquelles n, R6, R7, R8 et Z2 sont définis comme précédemment et le radical -NR7R9 représente un radical hétérocyclique ou R7 est défini comme précédemment et R9 représente un radical alcoyle ou alcényle en chaîne droite ou ramifiée contenant jusqu'à i atomes de carbone (qui porte un substituant phényle éventuellement substitué} ou bien un radical phényle éventuellement substitué, ou, lorsque A1 représente un atome d'azote ou un radical -CR4 = dans lequel R4 est défini comme précédemment et
Z1 et A2 sont définis comme précédemment ou quand A1 représente un radical -CH= et Z1 représente un atome de soufre et A2 est défini comme précédemment, R2 représente un radical de formules
-S(O)n R, -S02NR7R81 -CZ2NR7R8 ou CZ2NHN0-2 dans lesquelles n, R6, R7, R8 et Z2 sont définis comme précédemmenti et, quand R2 et/ou R3 représente un radical sulfanoyle ou sulfamoyle mono substitué et/ou R3 représente un radical carboxy, leurs sels, plus spécialement leurs sels de métaux alcalins tel que les sels de sodium.The compounds of the present invention are tetrazine derivatives of the general formula

in which R 1 represents a cycloalkyl radical or a straight or branched chain alkyl or alkenyl or alkynyl radical containing up to 6 carbon atoms, each alkyl, alkenyl and alkynyl radical being unsubstituted or substituted by one to three substituents chosen from halogen atoms; (such as bromine, iodine or preferably chlorine or fluorine), straight-chain or branched-chain alkyl, alkylthio, alkylsulphinyl and alkylsulfonyl radicals containing up to 4 carbon atoms and optionally substituted phenyl radicals
A1 represents an azo atom or a radical - CR3 = in which R3 represents a hydrogen atom or a substituent R4 in which R4 represents a halogen atom, or a straight or branched-chain alkyl or alkenyl radical containing up to 6 carbon atoms, which can carry up to 3 substituents selected from halogen atoms, optionally substituted phenyl radicals, alkyloxy, alkylthio and alkylsulfonyl radicals containing up to 3 carbon atoms or R4 represents an optionally substituted cycloalkyl, cyano, hydroxy, nitro or phenoxy radical, or a radical of the formula -COR5 (in which Rg represents an alkyl or alkyloxy radical containing up to 4 carbon atoms, a hydro: y radical or a optionally substituted phenyl radical) or an alkanoylamino radical containing up to 6 carbon atoms, or R4 represents a radical of formulas
S (O) nR6, -SO2NR7R8 or -CZ2NR7R8 (wherein n represents the numbers 0, 1 or 2, R6 represents a straight or branched chain alkyl or alkenyl radical containing up to 4 carbon atoms (which may carry a optionally substituted phenyl substituent)) a cycloalkyl radical or an optionally substituted phenyl radical, R, and R8, which may be the same or different, each represents a hydrogen atom or an alkyl or alkenyl radical in a straight or branched chain, containing up to 4 carbon atoms (which may carry an optionally substituted phenyl substituent), or a cycloalkyl radical or an optionally substituted phenyl radical, or the -NR7R8 radical represents a heterocyclic radical, and Z2 represents an oxygen or sulfur atom) ,
A2 represents a nitrogen atom or, when A1 represents a nitrogen atom, A2 represents a nitrogen atom or a radical -CR3 ::
in which R 3 is defined as above, Z 1 represents an oxygen or sulfur atom, and R 2 represents a radical of formulas
- S (O) nR6, - SO2NR7R8, - CSNR7R8, -CONR7R9 or -CZ2NHNO2 in which n, R6, R7, R8 and Z2 are defined as above and the radical -NR7R9 represents a heterocyclic radical or R7 is defined as above and R9 represents a straight or branched chain alkyl or alkenyl radical containing up to 1 carbon atoms (which bears an optionally substituted phenyl substituent) or an optionally substituted phenyl radical, or, when A1 represents a nitrogen atom or a radical - CR4 = in which R4 is defined as above and
Z1 and A2 are defined as above or when A1 represents a radical -CH = and Z1 represents a sulfur atom and A2 is defined as above, R2 represents a radical of formulas
-S (O) n R, -SO2NR7R81 -CZ2NR7R8 or CZ2NHNO-2 wherein n, R6, R7, R8 and Z2 are defined as precedence and, when R2 and / or R3 represents a substituted sulfanoyl or sulfamoyl radical and / or R3 represents a carboxy radical, their salts, especially their alkali metal salts such as sodium salts.

 Whenever the context permits, when reference is made to the compounds of general formula (I), it is understood that reference is also made to salts. Salts are particularly useful as intermediates.

 In the definitions of the general formula (I), the optional substituents on the phenyl and phenoxy portions may be chosen from, for example, halogen atoms and alkyl and alkyloxy radicals containing up to 4 carbon atoms and nitro radicals. The cycloalkyl radicals in the definition of the general formula (I) contain 3 to 8 (preferably 6) carbon atoms. By heterocyclic radical is meant in the definition of the general formula (I) a 5, 6 or 7-membered heterocycle. which may optionally contain another heteroatom such as nitrogen, oxygen or sulfur and which may carry one or two straight or branched chain alkyl substituents each containing up to 4 carbon atoms, such as a piperidino radical, methyl-2, methyl-3, methyl-4, 2,4-dimethyl or dimethyl 395 piperidino or morpholino, pyrrolidinyl-1, perilydroazepinyl-1, piperazinyl-1, methyl-4 piperazinyl-1 or thiazin-1 , 4 yl4.

 Descriptions of British Patent Application 2,104,522 and equivalent applications in other countries claiming priority of the original UK Patent Application No. 8125791 such as US410656 disclose compounds of general formula (II) in US Pat. R10 represents a hydrogen atom, a cycloalkyl radical or a straight or branched chain alkyl, alkenyl or alkynyl radical containing up to 6 carbon atoms, each alkyl, alkenyl or alkynyl radical being unsubstituted or substituted with 1 to 3 carbon atoms; substituents selected from halogen atoms, unradical alkyloxy, alkyl and - thio, alkylsulphinyl / straight or branched challengers containing up to 4 carbon atoms, and optionally substituted phenyl radicals, and R represents a carbamoyl radical which may carry nitrogen atom one or two radicals selected from straight and branched chain alkyl and alkenyl radicals containing each of up to 4 carbon atoms and cycloalkyl radicals.

présentent une activité antinéoplastique remarquable, par exemple contre les carcinomes , mélanomes, sarcomes, lymphomes et leucémies; ils possèdent également une activité immunomodulatrice remarquable et sont utiles dans le traitement des greffes d'organes et greffes de peau et dans le traitement des maladies immunologiques.Derivatives of tetrazine of general formula

exhibit remarkable antineoplastic activity, for example against carcinomas, melanomas, sarcomas, lymphomas and leukemias; they also possess remarkable immunomodulatory activity and are useful in the treatment of organ transplants and skin grafts and in the treatment of immunological diseases.

 The compounds of the general formula (I) of the present invention have similar properties with, in some respects, an improvement.

 The tetrazine derivatives of general formula (II) are useful as intermediates in the preparation of some of the compounds of general formula (I) according to the present invention, for example as described later in the present description.

Particularly important are classes of compounds of the general formula (I) which comprise in their formula one or more of the following characteristics:
i) R1 represents a methyl radical or, more especially, a halogenoethyl radical, in particular a 2-chloromethyl radical,
ii) R2 represents a radical of general formula
-SOR6, -SO2R6, -50 2NR7R8, -CONR7R8 or -CONHN02 especially those in which R6 represents an alkyl radical such as methyl and csux in which R represents a hydrogen atom or an alkyl radical such as methyl, and R8 represents a hydrogen atom or an alkyl radical such as methyl or a benzyl radical optionally substituted with an alkyloxy radical, such as a 4-methoxy benzyl radical; iii) R3 represents a radical R4 in which represents a methyl radical alkyl such as butyl, propyl, ethyl or more particularly /
iv) one of the symbols A1 and A2 represents a nitrogen atom and the other represents a radical -CR3 =,
v) A2 represents a nitrogen atom,
vi) Z1 represents an oxygen atom and / or
vii) Z2 represents an oxygen atom.

The individual compounds of general formula (I) which are important include the following (N-benzyl N-phenylcarbamoyl) -8-methyl-3H-2-imidazo [5,1-d] tetrazine-1,2,3,5-one- 4 A,
N-benzyl N-methoxy-4-benzyl) carbamoyl] -8- (2-chloroethyl) -3 [3H] imidazo [5,1-d] tetrazine-1,2,3,5 o, e-4B, (N-Benzylcarbamoyl) -8 (2-chloroethyl) -3 [3H] imidazo [5,1-d] tetrazin-1,2,3,5-one-4C, (2-chloroethyl) -3- [N-Methoxy-4-benzyl] -N-phenylcarbamoyl] -8 [3H] imidazo [5,1-d] tetrazine-1,2,3,5-one-4D, (2-chloroethyl) -3 (N- phenylcarbamoyl) -8 [3H] imidazo [5,1-d] -tetrazine-1,2,3,5-one-4E,
(N-benzyl N-phenylcarbamoyl) -8 (2-chloroethyl) -3
[3H] -imidazo [5,1-d] -tetrazin-1,2,3,5-one 4-F, (2-chloroethyl) -3- (N-methyl-N-phenylcarbamoyl) -8
[3H] -imidazo [5,1-d] -tetrazine-1,2,3,5-one-4G,
carbamoyl-8 (2-chloroethyl) -3-methyl-6 [3H]
imidazo [5,1-d] 1,2,3,5-tetrazol-4 H, (2-chloroethyl) -3- (N, N-dimethylsulphamoyl) -8 [3H] imidazo [5.1 1,2,3,5-tetrazol-4-one-4 (2-chloroethyl) -3- (N-methylsulphamoyl) -8
[3H] -imidazo [5,1-d] tetrazine 1,2,3,5-a-4J, (2-chloroethyl) -3-methylsulfonyl-8 [3H]
imidazo [5,1-d] -tetrazine-1,2,3,5-one-4 K,
methyl-3-methylsulfonyl-8 [3H] imidazo [5,1-d]
tetrazin-1,2,3,5-one (4-chloroethyl) -3-CN-methoxy-4-benzyl) sulfa
avg] -8 [3H] -imidazo [5,1-d] tetrazine
1,2,3,5 one-4 M, (2-chloro-ethyl) -3 (sulfamoyl-8) [3H] -imidazo [5,1-d] -tetrazine-1,2,3,5-one-4 NOT,
carbamoyl-8 (2-chloroethyl) -3 [3H] -pyrazolo [5,1-d]
tetrazine-1,2,3,5 one-4 O,
8-carbamoyl methyl-3- [3H] -pyrazolo [5,1-d]
tetrazine-1,2,3,5 one-4 P,
(2-chloroethyl) -3-piperidinocarbonyl-8 [3H]
imidazop5,1-d2-tetrazine-1,2,3,5 one-4 Q,
carbamoyl-8-butyl-6 (2-chloroethyl) -3 [3H] imidazo
[5,1-d] 1,2,3,5-tetrazolone-4R,
carbamoyl-8 (2-chloroethyl) -3-cyclohexyl-6 [3H] -
imidazo [5,1-d] 1,2,3,5-tetrazolone-4 S,
carbamoyl-8 (2-chloroethyl) -3-phenethyl-3H] -
imidazo [5,1-d] 1,2,3,5-tetrazolone-4 T,
benzyl-6-carbamoyl-8 (2-chloroethyl) -3 [3H] imidazo
[5,1-d] 1,2,3,5-Tetrazin-1-carbamoyl-8 (2-chloroethyl) -3-isopropyl-6 [3H] -imidazo [5,1-d] 1,2-tetrazine , 3,5-one-4 V, carbamoyl-8 (2-chloro-ethyl) -3-propyl-6 [3H] -imidazo [5,1-d] 1,2,3,5-tetrazol-4-one carbamoyl 3- (2-chloroethyl) -3-ethyl-6- [3 H] imidazo [5,1-d] tetrazine-1,2,3,5-one-4
3- (2-chloroethyl) -3- (4-methoxybenzyl) -8-sulfamoyl-6-methyl-3H] imidazo [5,1-d] tetrazine-1,2,3,5-one-4-y,
3- (6-chloroethyl) -3-methyl-8-sulfamoyl [3H] -imidazo [5,1-d] tetrazin-1,2,3,5-one-4 Z, (2-chloroethyl) -3-dimethylsulfamoyl- 8-methyl-imidazo [5,1-d] 1,2,3,5-tetrazol-4-one AA,
(2-chloroethyl) -3-methyl-8-methylsulfonyl-8H-imidazo [5,1-d] tetrazine-1,2,3,5-one-4-B-BB,
(2-chloroethyl) -3-dimethylcarbamoyl-8 [3H] -pyrazolo [5,1-d] tetrazine-1,2,3,5-one CC,
(2-chloroethyl) -3- (N-nitrocarbamoyl) -8 gH7-imidazo [5,1-d] tetrazin-1,2,3,5-one-4-DD, 3-methyl-8-methylsulfonyl-3H7-pyrazoloCl 5 1,2,3,5-tetrazinone-4-EE,
(2-chloroethyl) -3-methylsulfonyl [3H] -pyrazolo [5,1-d] tetrazine-1,2,395 one-4 FF,
2-chloroethyl) -3-methyl-8-methylsulphinyl [3H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-GG,
2-chloro-2-ethyl-8-ethylsulfonyl-6-methyl-3H-imidazo [5,1-d] 1,2,3,5-tetrazol-1-one HH, and
(2-chloroethyl) -3-methyl-8-propylsulfonyl-53H7 imidazo [5,1-d] 1,2,3,5-tetrazolone-4.II
The letters A to II have been assigned to the compounds for ease of reference later in the description
Particularly important compounds include compounds C, K, L, M0, Q, R, W, X and DD, more especially
compounds I, J, N and BB and in a very particular way the
H, Z, AA and CC compounds
The new tetrazine derivatives of the general formula
(I) showed a particular activity in the mouse at doses
daily doses of between 0.2 and 320 mg / kg per kg of body weight
animal rel. by intraperitoneal administration, against the
TlX5 (S) phoma according to the technique of GESCHER et al., Biochem.

Pharmacol. 30, 89 (1981) and ADJ / PC6A and M5076 sacomas (sar
reticulocellular comes).

Against leukemia L 1210 grafted intraperitoneally, intracerebrally and intravenously and against leukemia
P 388 in the technique described in trMethods of Development of New Annerancer Drugs "(NCI Monographs No. 45, March 1977 pages -147-149,
National Cancer Institute, Bethesda, USA) the compounds are
are shown to be active both intraperitoneally and orally
at doses of between 1 and 320 mg per kg of animal body weight
Inhibition of both the primary tumor and metastases was obtained in Lewis lung cancer, with
similar doses.

Against melanoma B 16 and tumor C 38 in mice
(NCI Monograph No. 45 already cited), the compounds were shown
active intraperitoneally at doses of between
and 40 mg per kg body weight of animal.

Against colon carcinoma C 26 in the mouse subcutaneously grafted, the compounds were active orally at doses of between 2 and 40 mg per ke body weight animal,
The compounds of the general formula (:) can be prepared by application or adaptation of methods known per se.

dans laquelle A1 et A2 sont définis comme précédemment et Rg2 représente un radical entrant dans la définition de R2 ci-dessus autre que celle représentant un radical sulfamoyle, carbamoyle qui porte un substituant phényle éventuellement substitué ou thiocarbamoyle qui porte un substituant phényle éventuellement substitué et autre qu'un radical nitrocarbamoyle ou nitrothiocarbamoyle, avec un composé de formule générale
R1NCZ1 (1v) dans laquelle R1 et Z1 sont définis comme précédemment.According to a feature of the present invention,
compounds of the general formula (I) in which R is different from
sulfamoyl radical, carbamoyl which bears a phenyl substituent
substituted or thiocarbamoyl which has a substituent
phenyl which is substituted and different from a nitro carbamoyl or nitrothiocarbamoyl radical may be prepared by the action of a compound of the general formula

wherein A1 and A2 are defined as above and Rg2 represents a radical falling within the definition of R2 above other than that representing a sulfamoyl, carbamoyl radical which bears an optionally substituted phenyl substituent or thiocarbamoyl which bears an optionally substituted phenyl substituent and the like. a nitrocarbamoyl or nitrothiocarbamoyl radical with a compound of the general formula
R1NCZ1 (1v) in which R1 and Z1 are defined as above.

The reaction can be carried out in the absence or presence of an anhydrous organic solvent, for example a chlorinated alkane such as dichloromethane, or ethyl acetate, acetonitrile, N-methylpyrrolidone-2 or hexamethylphosphoramide, at a temperature between 0 and 1200C. The reaction can be continued for a period of 30 days, it is preferable to operate in the absence of light.
According to another characteristic of the invention, the compounds of general formula (I) in which R 2 represents a carbamoyl radical which bears an optionally substituted phenyl substituent or thiocarbamoyl which bears a substituted phenyl substituent and R 1, A 1, A 2 and Z 1 are defined as above, can be prepared from the corresponding compounds of general formula (I) in which R2 represents a radical of general formula :: -CZ2NR12R13 (v)
wherein R12 represents a phenyl radical optionally subs
R13 represents an optionally substituted benzyl radical
and Z2 is defined as above, by application or adaptation of methods known per se to replace a benzyl radical
replaced by a hydrogen atom.

As suitable reaction conditions, it is possible to
for example, catalytic hydrogenation (in the presence of a
catalyst such as palladium on black and in a solvent such as
ethyl acetate or dimethylformamide); or when R13
represents a substituted benzyl radical in which the substituent
or at least one substituent borne by the benzyl radical is a radi
cal alkyloxy (such as methoxy) in ortho or para position, by action
trifluoroacetic acid, preferably in the presence of anisole
ambient temperature or at a temperature close to it.

dans laquelle R14 représente un radical de formule Z2 NH2 dans laquelle Z2, R1, A1, A2 et z1 sont définis comme précédemment.According to another characteristic of the invention, the
compounds of the general formula (I) in which R2 represents a
dical of general formula
-CZ2NHNO2
in which Z1, R1, A1, A2 and Z1 are defined as above
can be prepared by nitration of the compounds of general formula

in which R14 represents a radical of formula Z2 NH2 in which Z2, R1, A1, A2 and z1 are defined as above.

 The reaction may be carried out in the vicinity of room temperature or below, preferably between 0 and 10 ° C, in the presence of a nitrating mixture such as a concentrated mixture of sulfuric and nitric acids.

dans laquelle N et R2 sont définis comme précédemment et R
15 représente un radical de formule - S(O) R. - SO NR R. -CZ NR R ou -CZ NHNO-.According to another characteristic of the invention, the compounds of general formula (I) in which R1, A1, A2 and R2 are defined as above and Z represents a sulfur atom can be prepared from compounds of general formula

in which N and R2 are defined as above and R
15 represents a radical of formula - S (O) R 1 - SO NR R -C Z NR R or -CZ NHNO-.

 (R6, R7, R8, n and Z2 being defined as above) by the action of phosphorus pentasulfide.

 The reaction may be carried out in an organic solvent, for example an aromatic solvent such as benzene, toluene or xylene, or in pyridine or a derivative thereof such as lutidine, preferably at elevated temperature, for example between 50.degree. and 120 C.

dans laquelle R1,A1,A2 et Z1 sont définis comme précédemment et R16 représente un radical de formule générale CONR7R8 dans laquelle R7 et R8 sont définis comme précédemment, par action du pentasulfure de-phosphore dans des conditions analogues à celles décrites ci-dessus pour la réaction du pentasulfure de phosphore avec les composés de formule générale (VI).According to another characteristic of the invention, the compounds of general formula (I) in laauelle R1, A1, A2, and are defined as above and R2 represents a radical that general formula: -CSNR7R8 may be prepared from compounds of formula General

in which R1, A1, A2 and Z1 are defined as above and R16 represents a radical of general formula CONR7R8 in which R7 and R8 are defined as above, by the action of pentasulfide dephosphorus under conditions similar to those described above for the reaction of phosphorus pentasulfide with the compounds of general formula (VI).

 The aforementioned salts of certain compounds of general formula (I) can be prepared by application or adaptation of methods known per se, for example by the action of the basic compound of general formula (I) with a hydroxide, a carbonate or preferably a alkali metal bicarbonate, in an aqueous or hydro-organic medium, followed by the isolation of the salt by known methods.

 When a mixture of products is obtained in one or other of the abovementioned processes, the products can be separated by application or adaptation of methods known per se, such as chromatography.

 The compounds of general formula (III) can be prepared by application or adaptation of methods known per se, for example the methods described by SHEALY et al J Org. Chem.

26, 2396- (1961) and CHENG et al., J. Pharm. Scion 57, 1044 (1968) and the methods described hereinafter in the reference examples
By the term known methods per se as used in the present description are methods already used or discussed in the literature.

 The following examples illustrate the preparation of the compounds of the general formula (I) according to the present invention and the reference examples illustrate the preparation of the intermediates.

EXAMPLE 1
Compound A 0.44 g of sodium nitrite was dissolved in 10 cm 3 of a 2M aqueous acetic acid solution at 0 ° C. The solution is stirred at 0 ° C. and treated with small protons at a time with 0.7 g of 5-amino-N-benzyl N-phenyl imidazolecarboxamide-4 hydrochloride (prepared as in Reference Example 1).

After 10 minutes the gummy solid obtained is extracted
with 2 times 20 cm3 of ethyl acetate. Organic extracts are
pooled and washed with water and dried over magnesium sulfate.

The obtained solution of diazo-5 N-benzyl N-phenyl
imidazolecarboxamide-4 is treated with 5 cm3 of isocyanate
methylated and the mixture is stirred at room temperature for
24 hours in the dark. The solution is then concentrated
low volume and the residue is subjected to chromatography on
medium pressure column eluting with ethyl acetate
0.22.9 of (N-benzyl N-phenylcarbamoyl) -8-methyl-3H7 is thus obtained.
imidazo [5,1-d] 1,2,3,5-tetrazolone-4, in the form of a solid
white crystalline melting at 168-1700C - (with decomposition)
Elemental analysis
Calc'd: C = 63.32; H = 4.47; N = 23.32
Found%: C = 62.6; H, 4.41; N = 22.3
IR spectrum (KBr tablet): 3100, 1735, 1620 cm
NMR spectrum (in DMSO-d6): singlet at 3.75; 5.10 and 8.55 ppm
multiplet at 7.0-7.4 ppm.

Mass spectrum: m / e = 360 (M +)
EXAMPLE 2
Compound B
Sodium nitrite (3.7%) was dissolved in 35 cm3 of a
2M aqueous acetic acid solution at 00C. The -solution is agitated
at 0 ° C. and treated dropwise with a solution of 2.2 g of
5-amino-N-benzyl N- (4-methoxybenzyl) imidazolecarbo hydrochloride
xamide-4 (prepared as in Reference Example 2) in 10 cm3 of
1,2-dimethoxy ethane. - The reddish gum that separates is extracted
with 2 times 20 cm3 of ethyl acetate. Organic extracts are
pooled and washed with water and saturated aqueous solution of
sodium chloride and then dried over sodium sulphate.

 The resulting solution of diazo-5 N-benzyl N- (4-methoxybenzyl) imidazolecarboxamide-4 is treated with 2 cm3 of 2-chloroethyl isocyanate and the mixture is left at room temperature for 24 hours in the dark. The solution is then concentrated to a small volume and the residue is subjected to medium pressure column chromatography eluting with ethyl acetate. 1.5 g of N-benzyl N- (4-methoxybenzyl) carbamoyl-8 (2-chloroethyl) -3H-imidazo [5,1-d] 1,2,315-tetrazine-4-one under nitrogen are thus obtained. form of a brown oil.

EXAMPLE 3
Compound C In 20 cm3 of trifluoroacetic acid, 1.5 g of N-benzyl N- (4-methoxybenzyl) carbamoyl2-8 (2-chloroethyl) -3 [3H] imidazo [5.1-d] were dissolved in ] 1,2,3,5-tetrazolone-4 (crude product prepared as described in Example 2) and 0.5 cm3 of anisole, then left to stand the mixture for 18 hours at room temperature. The reaction mixture is then concentrated to dryness and the residue is subjected to medium pressure column chromatography eluting with a mixture of ethyl acetate and petroleum ether (PE: 60-800 ° C) (2-1%). volumes).

 0.34 g of (N-benzylcarbamoyl) -8 (2-chloroethyl) -3H7-imidazo5,1-dietetrazin-1,2,3,5-one-4 are thus obtained in the form of a colorless solid. melting at 153-155 ° C. (after recrystallization, in ethyl ether).

Elemental analysis Calcd.%: C = 50.53; HH = 3.94; N = 25.26; C1 = 10.65
Found%: C = 49.9; H = 3.92; N = 24.4; Cl = 10.4
IR spectrum (KBr tablet): 3370, 3150, 1755 and 1660 cm
NMR spectrum (in DMSO-d6): singlet at 7.3 and 8.9 ppi; doublet at 4.4 ppm and triplets at 4.0; 4.6 and 9.05 ppm.

EXAMPLE. 4
Compound D 0.61 9 sodium nitrite is dissolved in 10 cm3 of water.

The solution is stirred at 00C. and treated drop to
dropwise with a solution of 2.5 g of 5-amino-N- (4-methoxybenzyl)
N-phenyl imidazolecarboxamide-4 (prepared as described in Example 1)
reference 3) in 9 cm 3 of 2M chlorhy-2-bric acid and 15 cm 3 of
1,2-dimethoxy ethane. After 20 minutes, the solution is extracted
with 3 times 50 cm3 of ethyl acetate and organic extracts
are combined and dried over magnesium sulfate. The solution is
filtered and the solvent evaporated. 2.8 g of diazo-5 are thus obtained
N- (4-methoxybenzyl) N-phenylimidazolecarboxamide-4, in the form
an orange oil.

This oil is dissolved in 40 cm3 of ethyl acetate
and treated with 8 cm3 of 2-chloroethyl isocyanate. The mixture
is allowed to rest for 5 days in the dark. The solution is
concentrated at low volume and the resulting residue is subjected to
medium pressure column chromatography eluting at
ethyl acetate. 1.5 g of (2-chloroethyl) -3 [N- (4-methoxy-benzyl) -N-phenylcarbamoyl] -8 [3H] imidazo [5,1-d] 1,2,3-tetrazine are thus obtained. , 5 one-4, in the form of a glass melting at 550C.

NMR spectrum (in DMSO-d6): singlet at 3.6; 5.0 and 8.5 ppm; triplets centered at 3.9 and 4.5 ppm; multiplet at 6.6-7.2 ppm.

IR spectrum (KBr tablet): 1740 and 1640 cm -1.

EXAMPLE 5
Compound E In 10 cm3 of trifluoroacetic acid, dissolve 1 g
(2-chloroethyl) -3 [N- (4-methoxybenzyl) -N-phenylcarbamoyl] -8H-imidazo [5,1-di] tetrazin-1,2,3,5-a-4-one (prepared as described in US Pat. Example 4) and 0.2 cc of anisole, and then allow the mixture to stand for 18 hours at room temperature. The reaction mixture is
then concertrated to dryness and the residue is triturated with ether
ethyl. 0.43 g of (2-chloroethyl) -3-phenyl are thus obtained.
carbamoyl-8 [3H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-one, in the form of
of a beige-brown solid, melting at 166 ° C (with decomposition) (after
recrystallization from ethyl acetate).

Elemental Analysis Calculated: C = 48.99; H = 3.48; N = 26.37 Found%: C = 48.4; H = 3.22; N = 26.0
IR spectrum: (KBr tablet): 3390, 1735 and 1680 cm
NMR spectrum (in DMSO-d6): singlet at 8.9 and 10.3 ppm; doublet centered at 7.8 ppm; triplets centered at 4.0 and 4.6 ppm; multiplet at 7.0-7.9 ppm.

EXAMPLE 6
Compound -F 2.8.9 of sodium nitrite is dissolved in 84 cm3 of a 2M aqueous acetic acid solution. The solution is stirred at 0 ° C. and treated in small portions with 2.8 g of finely pultrrated 5-amino-N-benzyl N-phenylimidazolecarboxamide hydrochloride prepared as described in Reference Example 1). After 10 minutes, the gummy solid obtained is extracted with 3 times 30 cm3 of ethyl acetate and the organic extracts are combined and washed with water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.

 The resulting solution of diazo-5-N-benzyl N-phenylimidazolecarboxamide-4 is treated with 9 cm3 of chloroethylethyl isocyanate and the mixture is allowed to stand for 4 days in the dark. The solution is then concentrated to a small volume and the residue is subjected to medium pressure column chromatography eluting with 11 ethyl acetate. 1 g of (N-benzyl N-phenylcarbamoyl) -8 (2-chloroethyl) -3 [3H] imidazo [5,1-d] 1,2,3,5-tetrazolone-4 are thus obtained. shape of a glass.

.4nalysis
Calc'd: C = 58.75; H, 4.19; N = 10.56 Cl = 8.67 Found%: C; 59.3; HH = 4.57; N, 9.9; Cl = 8.5
IR spectrum (tablet -KBr): 1740 and 1640 cm
NMR spectrum (in DMSO-d6): singlets at 5.2; 7.1; 7.3 and 8.6-ppm triplets centered at 4.0 and 4.6 ppm.

EXAMPLE 7
Compound GA a solution of 11 g of sodium nitrite in 50 cm3 of water cooled with OOC, is added dropwise a solution of 49% of 5-amino-N-methyl-N-phenylimidazolecarboxamide-4 hydrochloride (prepared as described in Reference Example 4) in 40 cm 2M aqueous acetic acid solution. After 10 minutes, the result mixture is extracted with 4 times 100 cm3 of ethyl acetate and the organic extracts are combined, filtered and dried over magnesium sulfate.

 The resulting solution of diazo-N-methyl-N-phenyl imidazolecarboxamide-4 is treated with 11 cm3 of 2-chloroethylisocyanate and the mixture is allowed to stand overnight in the dark.

The solution is then concentrated to a small volume and the residue is subjected to low pressure column chromatography, eluting with ethyl acetate to give 5.75 of a product which is triturated with water. isopropyl ether and then with methylene chloride. The insoluble residue is recrystallized from a mixture of petroleum ether (PE 60-800 ° C) and ethyl acetate. Finally, 0.8 g of (2-chloroethyl) -3 (N-methyl-N-phenylcarbamoyl) -8H-imidazo [5,1-d] 1,2,3,5-tetrazol-4-one, in the form of dichloromethane, are obtained. a colorless solid melting at 130-1320C.

Elemental analysis: Calculated%: C = 50.53; H, 3.94; NN = 25.26; Cl = 10.65
Found%: C = 50.4; H, 3.91; NN = 24.9; Cl = 10.6
IR spectrum (KBr tablet): 1750 and 1640 cm
NMR spectrum (in DMSO-d6): 3,4-singlet; 7.2 and 8.65 ppm triplets centered at 3.95 and 4.6 ppm.

EXAMPLE 8
Compound H To a suspension of 1.54 g of 5-diazo-2-methyl-4-imidazolecarboxamide (prepared as described in Reference Example 5) in 45 cm3 of ethyl acetate, 6.33 g of dichloromethane were added with stirring. 2-chloroethyl isocyanate and stirred at room temperature for 5 days in the dark.

 The mixture is then diluted with ethyl ether and the resulting solid is filtered off, washed with ethyl ether and dried under vacuum at room temperature. There is thus obtained 2 g of carbamoyl-8 (2-chloroethyl) -3-methyl-3H-imidazo [5.1-d] tetrazine-1, 2,3,5-one-4, melting at 170 ° C. (with decomposition).

Elemental analysis:
Calculated%: C = 37.44; H, 3.54; N, 32.75; Cl = 13.82
Found%: C = 37.0; H = 3.49; N = 32.8; Cl = 13.3
EXAMPLE 9
Compound IA a solution of 0.53 g of 5-diazol N, N-dimethylimidazolesulfonamide-4 (prepared as described in Reference Example 6) in 40 cm 3 of ethyl acetate added 3 cm 3 of chloro isocyanate -2-ethyl and stirred the mixture for 48 hours in the darkness. The reaction mixture is then evaporated under vacuum at a temperature below 400C to a volume of about 15 cm3 and then diluted with ethyl ether. The solid obtained is separated by filtration. 0.68 g of (2-chloroethyl) are thereby obtained
N, N-dimethylsulfamoyl) -8 [3H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-one as greyish needles melting at 155-1560C.

Elemental analysis
Calculated%: C = 31.3; H, 3.62; N = 27.4; Cl = 11.6
Found%: C = 30.4; H, 3.35; N = 26.8; Cl = 11.8
IR spectrum: 1755 cm
NMR spectrum (in DMSO-d6): singletes 2.80 and 8.90 ppm; triplets at 3.99 and 4.62 ppm.

EXAMPLE 10
To a suspension of 0.7 g of 5-diazo-N-methyl imidazolesulfonamide-4 (prepared as described in Reference Example 7) in 40 cm 3 of ethyl acetate was added 3 cm 3 of isocyanate. chlorine 2 ethyl and stirred the mixture in a sealed vial for 48 hours in the dark.

 The reaction mixture is then concentrated to about half of its volume under vacuum at a temperature below 350C, and then diluted with ethyl ether. The solid obtained is separated by filtration and washed with ethyl ether. 0.32 g of (2-chloroethyl) -3 (N-methylsulfamoyl) -8 [3H] imidazo [5,1-d] tetrazin-1,2,3,5-one-4 are thus obtained in the form of shiny beige sequins melting at 147 -1480C.

Elemental analysis:
Calculated%: C = 28.7; H = 3, -8; N = 28.7
Found%: C = 28.5; H = 2.90; NN = 28.7
IR spectrum: 1745 cm
FN spectrum (in DMSO-d6): doublet at 2.58 ppm; triplets at 3.98 and 4.61 ppm; quartet at 7.94 ppm; singlet at 8.84 ppm.

EXAMPLE 11
Compound KA, a solution of 0.65 g of 5-diazo-4-methylsulphonylimidazole (prepared as described in Reference Example 8) in 50 cm3 of anhydrous ethyl acetate, was added 3 cm3 of chlorinated isocyanate. 2 ethyl and stirred the mixture at room temperature for 48 hours in the dark. The mixture is then evaporated under vacuum and the oily residue is triturated with petroleum ether (PE 60800C). The solid obtained is separated by filtration and subjected to medium pressure chromatography, eluting with ethyl acetate. The solid white product obtained is triturated with petroleum ether and separated by filtration. There is thus obtained (2- (2-chloroethyl) -3-methylsulfonyl] [3H] imidazo [5,1-d] tetrazine1,2,3,5-one-4 (0.72 g), m.p. 154-550 ° C.

Elementary analysis:
Calcd.%: C = 30.28; H = 2.90; N = 25.22; Cl = 11.55
Found: C = 30.3, H =. 2.85; N = 25.0; Cl = 11.5
EXAMPLE 12
A solution of 0.65 g of 5-diazo-4-methylsulphonyl imidazole (prepared as described in Reference Example 8) in 60 cm 3 of ethyl acetate was added. 3.5 cm 3 of isocyanate were added. methylated and kept the mixture at room temperature for 3 days in the dark.

 A new quantity of 3.5 cm 3 of methyl isocyanate is then added and the mixture is heated at 400 ° C. for 2 days and then allowed to stand at room temperature for 3 days.

The mixture is then concentrated in vacuo to a volume of 10 to 15 cm 3 and chromatographed under medium pressure eluting with ethyl acetate. 0.17 g of methyl 3-methylsulfonyl-8H-imidazo [5], 1-dl 1,2,3,5-tetrazol-4-one are thus obtained in the form of a white crystalline solid, mp 185 ° -186 ° C. (with decomposition).

Elemental Analyzed
Calc'd: C = 31.44; H, 3.08; N = 30.56
Found%: C = 31.2; H = 2.89; N = 30.3
EXAMPLE 13
Compound MA a solution of 0.39 of 5-diazo N- (4-methoxy-benzyl) imidazolesulfonamide-4 (prepared as described in Reference Example 9) in 25 cm3 of anhydrous ethyl acetate. 5 g of 2-chloroethylisocyanate and the mixture is stirred at ambient temperature for
dark 48 hours. The solution / obtained is filtered and concentrated to dryness. The brown solid obtained is triturated with petroleum ether, separated by filtration and purified by medium pressure chromatography eluting with ethyl acetate. A white solid is obtained which is triturated with petroleum ether. filtered off and dried under reduced pressure (10 mm Hg) at 700 ° C for 1 hour.

If 0.2 g of (2-chloroethyl) -3 [N- (4-methoxybenzyl) sulfamoyl] -8 [3H] imidazo [5,1-d] tetrazine-1,2,3 is obtained, 5 one-4 melting at 155-156 C- (with decomposition ~).

IR spectrum: 1745 cm
Elemental analysis:
Calc'd: C = 42.16; H, 3.79; N = 21.07
Found%: C = 41.9; H = 3.72; N = 20.5
EXAMPLE 14
Compound N 0.1 g of (2-chloro-ethyl) -3-N-methoxy-4-benzyl) sulfamoyl-7- [3 H] imidazo [5,1-d] tetrazine-1,2,3,5-one 4 (prepared as described in Example 13) in 1 cc of trifluoroacetic acid and 3 drops of anisole and the solution is allowed to stand at room temperature for two hours. The mixture is then concentrated to dryness under vacuum and the residue is triturated with ethyl ether. The yellow solid obtained is subjected to medium pressure chromatography and eluting with a mixture of petroleum ether (PE 6o-800C) and ethyl acetate (1/1 by volume). This gives 50 mg of ( 2-chloroethyl) -3-sulfamoyl-8 [3H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-one in the form of a white solid melting at 183 ° C (with decomposition).

IR spectrum: 1750 cm
NMR spectrum (in DXSO-d6): singlet at 8.8 and 7.8 ppm; triplets at 4.58 and 3.95 ppm.

EXAMPLE 15
Compound OA a suspension of 5.9 g of diazo-3-pyrazolecarbooxamide-4 (prepared as described by CHENG et al., Supra) in 150 cm 3 of ethyl acetate> 24 cm 3 are added with stirring 2-chloroethyl isocyanate and maintained at room temperature with stirring for 7 days in the dark. The reaction mixture is diluted with ethyl ether and the resulting solid is filtered off and washed with ether. ethyl. There is thus obtained 8.36 g of a mixture in the form of a cream solid melts at 173-1740C (with decomposition).

 A 1 g sample of said mixture is dissolved in 20 cm3 of dimethylsulfoxide and heated overnight at 60 ° C. The solution is concentrated to dryness (at a temperature below 600 ° C. at a pressure of less than 0.1 mm of mercury) and The residue is triturated with a mixture of dichloromethane and ethyl ether. The solid obtained is collected and dissolved in approximately 50 cm3 of acetonitrile.

 The solution thus obtained is treated with 3 g of deactivated silica gel containing 20 ml of water and the mixture is evaporated to dryness. The residue is loaded onto a column of silica gel and subjected to medium pressure chromatography eluting with ethyl acetate. After recrystallization of the product obtained in acetonitrile, 0.25 g of carbamoyl-8 (2-chloroethyl) -3 [3 H] -pyrazolo [5,1-d] 1,2,3,5-tetrazine are obtained. -4, in the form of colorless needles melting at 203-2040C (with decomposition).

Elemental analysis
Calculated%: C = 34.65; H = 2.91; N, 34.64; Cl = i4.61
Found%: C = 34.8; HH = 2.92; N = 34.7; Cl = 14.6
EXAMPLE 16
Compound PA a suspension of 1.6 g of 3-diazophyrazolecarboxamide (prepared as described by CHENG et al., Supra) in 49 cm 3 of dichloromethane and 2.5 cm 3 of N-methylpyrrolidone-2 are added with stirring 6 cm3 of methyl isocyanate, then stirred for 7 days in the dark. The mixture is then diluted with ethyl ether and the solid formed is filtered off. There is thus obtained 2.24 g of a mixture in the form of a cream solid melting at 179-1810C (with decomposition).

 A sample of 1 g of this solid is dissolved in 10 cm3 of dimethylsulfoxide and treated with 8 g of deactivated silica gel containing 20% of water and the mixture is evaporated to dryness under reduced pressure (0.1 mm Hg) to 600C. The residue is loaded onto a column of silica gel and subjected to medium pressure chromatography eluting with ethyl acetate. The product obtained is triturated with a small amount of a saturated aqueous solution of sodium bicarbonate and separated rapidly by filtration. There is thus obtained 41 mg of 8-carbamoyl-3-methyl-3H-pyrazolol-5,1-d-1,2,3,5-tetrazol-4-one, in the form of a colorless solid melting at 1700C (with decomposition).

NMR spectrum (in DMSO-d6): singlet at 3.95; 7.45; 7.55 and 8.50 ppm.

IR spectrum (KBr tablet): 3400, 3160, 1750 and 1680 cm
EXAMPLE 17
Compound QA solution of 0.79% sodium nitrite in 6 cm3 of water was added dropwise with stirring a solution of 2.1 g of crude 4-amino-5-piperidinocarbonylimidazole hydrochloride (prepared as described in Reference Example 10) in 17 cm 3 of an aqueous acetic acid solution. Casting is carried out in 5 minutes at a temperature between 5 and 10 C. The solution is extracted with 4 times 45 cm 3 of ethyl acetate ; the extracts are combined and dried over magnesium sulphate and evaporated under reduced pressure (0.1 mm Hg) at 300 ° C. The residue is dried in a desiccator over phosphorus pentoxide for 45 minutes. 1.73 g of 4-diazopiperidinocarbonyl-5-imidazole are thus obtained in the form of red crystals of sufficient purity to be used as such in the next step.

 A solution of 1.73 g of crude diazo-4-piperidinocarbonyl-5-imidazole (prepared as described above) in 53 cm 3 of dry ethyl acetate is treated with 5.9 cm 3 of 2-chloroethyl isocyanate. and the mixture is stirred for 2 days in the dark. The solution is then evaporated under reduced pressure (0.1 mm Hg) at 300 ° C. and the residue is subjected twice to silica gel chromatography under medium pressure, in vacuo. eluent with a mixture of ethyl acetate and acetonitrile (88/12 by volume). The appropriate fractions are combined and evaporated and the residue is triturated with petroleum ether (mp = 40-600 ° C.). 1.46 g of (3-chloroethyl) -3-piperidinocarbonyl [3H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-one are thus obtained in the form of pale purple crystals with 92-94 C.

Elemental analysis:
Calculated%: C = 46.4; HH = 4.87; N = 27.1 Found%: C = 45.3; HH = 4.98; N = 26.1
NMR spectrum in DMSO-d6): singlet at 8.7 ppm; triplets at 4.6 and 4.0 ppm; multiplets at 3.2-3.4 and 1.5-1.8 pp.

IR spectrum (KBr tablet): 1750, 1630 cm
EXAMPLE 18
Compound R A stirred solution of 1.61 g of sodium nitrite in 5 cm 3 of water is cooled and maintained at a temperature of between 5 and 10 ° C. and a solution of 1.61 ml is added dropwise in the course of 5 minutes. g of 5-amino-2-butylimidazolecarboxamide-4 hydrochloride (prepared as described in German Patent Application No. 2,358,509) in 17.7 cm3 of 1N hydrochloric acid. A yellow precipitate is obtained which is filtered off and dried to phosphorus pentoxide. 0.47 g of butyl-2-diazo-5-imidazolecarboxamide-4 are thus obtained in the form of a yellow solid melting at 109 ° -110 ° C. (with decomposition), which is sufficiently pure to be used as it is in the next step. .

 A solution of 0.47 g of crude butyl-2-diazo-5-imidazolecarboxamide-4 (prepared as described above) in 14 cm3 of ethyl acetate is treated with 1.5 cm3 of chloroethylethyl isocyanate and left behind. at rest for 24 hours in the dark. The tan solid obtained is separated by filtration and recrystallized from a mixture of ethyl acetate and acetonitrile. 0.49 g of butyl-6-carbamoyl-8 (2-chloroethyl) -3g3H7-imidazo [5,1-d] tetrazin-1,2,3,5-one-4 are thus obtained in the form of colorless crystals. melting at 165-1670C (with decomposition).

Elemental analysis
Calculate%: C = 44.2; H, 5.06; N = 28.1; Cl = 11.9
Found 50: C = 43.9; H, 4.90; N = 27.9; Cl = 12.0 EXAMPLE, 19
The mixture is cooled and maintained at a temperature of between 5 and 10 ° C., a stirred solution of 0.44 g of sodium nitrite in 3.7 cm 3 of water and a solutin is added dropwise over a period of 5 minutes. of 1 g of 5-amino-cyclohexyl-2-imidazolecarboxamide-4 hydrochloride (prepared as described in German Patent Application No. 2,358,509) in 28 cm3 of a 2M acetic acid solution.

 The orange precipitate obtained is separated by filtration and dried in desiccator over phosphorus pentoxide for 1 hour.

There is thus obtained 0.86 g of 2-cyclohexyl-5-diazoimidazolecarboxamide4, in the form of an orange solid, sufficiently pure to be used as it is in the next step.

 A solution of 0.86 g of crude 2-cyclohexyl-5-imidazolecarboxamide-diazo-5 (prepared as described above) in 17 cm3 of ethyl acetate is treated with 2 cm3 of 2-chloroethyl isocyanate and left behind. at rest for 24 hours in the dark. The solid obtained is separated by filtration and recrystallized from ethyl acetate. 0.23 g of carbamoyl-8 (2-chloroethyl) -3-cyclohexyl-6 [3 H] imidazo [5,1-d] tetrazin-1,2,3,5-one-4 are thus obtained in the form of colorless crystals melting at 245-2480C (with decomposition).

Elemental analysis:
Calculated%; C = 48.1; H, 5.28; N = 25.9; Cl- = 10.9
Found%: C = 47.6; HH = 5.16; N = 25.6; C1 = 10.8
EXAMPLE 20
Compound T A stirred solution of 0.58 g of sodium nitrite in 4.7 cm 3 of water is cooled and maintained at a temperature of between 5 and 100 ° C. and a solution of 1.8 g is added dropwise over a period of 5 minutes. of 5-amino-phenethyl-4-imidazolecarboxamide hydrochloride (prepared as described in Reference Example 11) in 18 cm3 of a 2M aqueous acetic acid solution. The yellow precipitate obtained is separated by filtration and dried in a desiccator on phosphorus pentoxide for 1 hour. There is thus obtained 2 g of crude phenethyl-2-imidazolecarboxamide-4 diazo5, in the form of a yellow solid, sufficiently pure to be used as such in the next step.

 A suspension of 29% crude 2-diazo-2-phenylimidazolecarboxamide (prepared as described above) in 29 cm3 of ethyl acetate is treated with 3.4 cm3 of ethyl chloro-2 isocyanate and stirred for 2 hours. 24 hours in the dark. The solid obtained is separated by filtration and recrystallized twice in ethyl acetate.

 0.44 g of 2-carbamoyl-8 (2-chloroethyl) -phenethyl-6 [3H] -imidazo [5,1-d] 1,2,3,5-tetrazolone-4 are thus obtained in the form of colorless crystals1 melting at 179 ° -181 ° C decomposition).

Elemental analysis:
Calc'd: C = 52.0: H = 4.36. N = 24.2: Cl = 10.2 Found%: C = 51 8 H = 4.19 N = 24.2 2 Cl = 10.2
EXAMPLE 21
Compound UA a solution of 2.4 g of 2-benzyl-5-imidazolecarboxamide-diazo-5 (prepared as described in Example 12) in 150 cm3 of anhydrous ethyl acetate is added 10 cm3 of chloro-2 isocyanate and the reaction mixture is allowed to stand for 20 hours at room temperature and in the dark. The reaction mixture is then evaporated to dryness and the residue is triturated with twice 30 cm3 of ether. of oil (PE = 60-80 ° C) to remove the excess of 2-chloroethyl isocyanate. The residue remaining is then triturated with 2 times 50 cm 3 of dichloromethane to extract the desired product of bis (2-chloroethyl) ) -1.3 urea which is the insoluble by-product that forms during the reaction. The chloromethylenic extracts are combined and evaporated to dryness and the residue is subjected to chromatography on silica gel under medium pressure, eluting with ethyl acetate. The appropriate fractions are combined, evaporated and the product recrystallized from ethyl acetate. 0.7 g of 6-benzyl-8-carbamoyl (2-chloroethyl) -3 [3H] -imidazo [5,1-d] 1,2,3,5-tetrazol-1-one, m.p. 161-163 C (with decomposition).

Elemental analysis:
Calculated%: C = 50.53; H, 3.94; N = 25.26 * Cl = 10.66 Found: C = 50.4: H = 3.96; NN = 25.4; Cl = 10.8
IR spectrum: 1740 cm
EXAMPLE 22
Compound VA a solution of 1.2 g of 5-diazo-2-isopropylimidazolecarboxamide-4 (prepared as described in Reference Example 13) in 75 cm3 of ethyl acetate anhydride added 5 cm3 of 2-chloroethyl isocyanate and leave the mixture at room temperature for 5 days in the dark. The crystallized solid obtained is separated by filtration and washed with petroleum ether (mp = 60-80 ° C.).

0.2 g of carbamoyl-8 (2-chloroethyl) -3-isopropyl-6 [3H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-one, which melts at 189.degree. -1900C (with decomposition).

Elemental analysis
Calculated C = 42.19; H, 4.60; = 29.5
Found%: C = 42.0; H, 4.64; N = 29.5
IR spectrum: 1740 cm
EXAMPLE 23
Compound WA a solution of 1.37 g of 5-aminopropyl-2-imidazolecarboxamide-4 (prepared as described in the German patent application
No. 2,358,509) in 22 cm 3 of a 2M aqueous acetic acid solution, a solution of 0.7 g of sodium nitrite in 6 cm 3 of sodium hydroxide solution is added dropwise at a temperature of between 0 and 50 ° C. in the course of 5 minutes. 'water. The precipitate obtained is separated by filtration and dried in desiccator on phosphorus pentoxide. 0.56% of 5-diazopropyl-4-imidazolecarboxamide is thus obtained in the form of a yellow solid, sufficiently pure to be used as it is in the next step.

 A solution of 0.56 g of 5-diazo-2-propylimidazole carboxalside-4 (prepared as described above) in 14 cm3 of anhydrous ethyl acetate is treated with 1.6 cm3 of chlorobenzene isocyanate. 2 ethyl and stirred for 24 hours in the dark. The precipitate obtained is separated by filtration and washed with ethyl acetate. 0.48 g of carbamoyl-8 (2-chloroethyl) -3-propyl [3H] are thus obtained.

imidazo [5,1-d] 1,2,3,5-tetrazolone-4, in the form of a beige solid melting at 145-148 ° C (with decomposition)
Elemental Analysis Calculated%: C = 42.2; H = 4X60; N = 29.5
Found%: C = 41.1; H = 4.4: N = 28.5
Spectrum R> LN (in DMSO-d6): singlet at 7.7 ppm; triplets at 4.6 4.0; 3.2 and 1.0 ppm; multiplet at 1.8 ppm.

IR spectrum (KBr tablet): 1750, 1695 cm
EXAMPLE 24 Compound XA stirred solution of 0.8 g of 5-amino-2-ethylimidazolecarboxamide-4 (prepared as described in German Patent Application No. 2,358,509) in 14 cm3 of an aqueous acetic acid solution 2M, a solution of 0.44 g of sodium nitrite in 3.8 cm3 of water is added dropwise over a period of 5 minutes at a temperature of between 0 ° and 30 ° C. The precipitate obtained is separated by filtration and dried in a desiccator over phosphorus pentoxide for 1 hour. 0.62 g of 5-diazo-2-ethyl-4-imidazolecarboxamide are thus obtained in the form of a yellow solid, melting at 139 ° C. (with decomposition), sufficiently pure to be used as it is in the next step.

 A solution of 0.62 g of crude diazo-5-ethyl-2-imidazolecarboxamide-4 (prepared as described above) in 22 cm3 of anhydrous ethyl acetate is treated with 2.4 cm 3 of chloro-2 isocyanate. ethyl and stirred for 24 hours in the dark. The precipitate obtained is separated by filtration and washed with ethyl acetate.

0.59 g of 2-carbamoyl-8 (2-chloroethyl) -3-ethyl-3H-imidazo5,1-d-1,2,3,5-tetrazol-4-one are thus obtained in the form of gray crystals melting at 172-176 C (with decomposition)
Elemental analysis:
Calculated%:: C = 39.9. H, 4.10; N = 31.0. Cl = 13.1
Proof 0A: C = 39.7 g H = 3.98; N = 31.0 g Cl = 13.1
EXAMPLE 25 Compound Y To a solution of 2.45 g of diazo-5 (4-methoxy-benzyl) -4-sulfamoyl-2-methylimidazole (prepared as described in Reference Example 14) in 100 cm3 of ethyl acetate anhydrous, 3 cm3 of 2-chloroethyl isocyanate and stirred the mixture at room temperature for 56 hours in the dark.

The mixture is then treated again with 3 cm 3 of 2-chloroethyl isocyanate and stirred at ambient temperature for a further 24 hours in the dark. The reaction mixture is then evaporated to dryness and the residue is triturated with 3 times 25 cm 3 of dichloromethane. petroleum ether (MW = 60-800 ° C) to remove the excess of 2-chloroethyl isocyanate The remaining residue is then triturated with 2 times 50 cm 3 of dichloromethane to extract the desired product from bis (2-chloroethyl) ) -1.3 urea which is the insoluble by-product that forms during the reaction. The chloromethylenic extracts are combined, evaporated to dryness and the residue obtained is chromatographed on silica gel under medium pressure, eluting with ethyl acetate. 1.5 g of (2-chloroethyl) (methoxy) are thus obtained. 4-benzyl) 8-sulfamoyl-6-methyl [3H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-one melting at 159-1600C (with decomposition)
IR spectrum: 1760 cm
EXAMPLE 26
Compound Z In 10 cm3 of trifluoroacetic acid, 1.5 9 of (2-chloro-ethyl) -3 (4-methoxy-benzyl) -8-sulfamoyl-methyl-3H] -imidazo [5,1-d] tetrazine are dissolved -1.2.3.5 one-4 (prepared as described in Example 25) and 10 drops of anisole, and then let the mixture stand overnight at room temperature. The reaction mixture is concentrated under vacuum and the residue The light brown solid is separated by filtration and recrystallized from acetone to give 0.55 g of (2-chloro-ethyl) -3-methyl-6-sulfamoyl [3 H] imidazo [ 5.1-d] 1,2,3,5-tetrazolone-4, melting at 199-200 ° C (with decomposition)
Elemental analysis:
Calculated%: C = 28.72; H, 3.10; N, 28.71; Cl = 12.11; S = 10.95
Found%: C = 29.1; H = 3.02; N = 28.8; Cl = 12.1; S = 10.6
IR spectrum; 1760, 3310 cm
EXAMPLE 27
Compound AA To a solution of 1.8 g of 4-diazg-4-dimethylsulfamoyl-2-imidazole (prepared as described in Reference Example 15) in 100 cm 3 of ethyl acetate added 4 cm 3 of chloro isocyanate The reaction mixture is then treated again with 4 cm3 of 2-chloroethyl isocyanate and left standing at room temperature for a further 6 days. The reaction mixture is then concentrated under vacuum and the residue is triturated with 2 times 25 cm3 of petroleum ether (MW = 60-800 ° C.). The remaining solid is dissolved in ethyl acetate and chromatographed on silica gel under medium pressure eluting with methyl acetate. The appropriate fractions are combined, evaporated to dryness and the residue is triturated with petroleum ether (mp = 60-80 ° C.). 2.17 g of (3- (2-chloroethyl) -3-dimethylsulfamoylmethyl-6 [3H] -imidazo [5,1-d] tetrazin-1,2,3,5-one-4, melting at 137 are thus obtained. -1380C.

Elemental analysis:
Calculated $:: C = 33.7; H, 4.09; N, 26.20; Cl = 11.05; S = 10.0
Found%: C = 33.8; H, 3.91; H = 25.8; Cl = 11.2; S = 9.7
EXAMPLE 28
Compound BB To a solution of 0.4 g of 5-diazo-2-methyl-4-methylsulfonylimidazole prepared as described in Reference Example 16) in 30 cm3 of anhydrous ethyl acetate is added 2 cm3 of isocyanate 2-chloroethyl and left the reaction mixture at room temperature for 4 days in the dark. The mixture is then evaporated to dryness and the residue is triturated with 2 times 25 cm3 of petroleum ether (PE = 60-80 ° C.) to remove the excess of 2-chloroethyl isocyanate. The remaining residue is dissolved in the ether. ethyl acetate and chromatographed on silica gel under medium pressure, eluting with ethyl acetate to give 0.22 g of (2-chloroethyl) -3-methyl-8-methylsulfonyl [3H] imidazo [5,1-d] 1,2,5-tetrazinone 4-one melting at 149-150C.

Elemental analysis
Calculated%: C = 32.94; H = 3.46; N = 24.01; Cl = 12.15; S = 10.99
Found%: C = 33; H, 3.35; N = 23.8; Cl = 12.7; S = 10.7
IR spectrum: 1745 cm
EXAMPLE 29
Compound CC - Has a suspension of 0.92 g of diazo-3 hydrochloride
N, N-dimethyl pyrazolecarboxamide-4 (prepared as described in the example
dry reference 17) in 50 cm3 of dichloromethane / 2.5 cm3 of 2-chloroethyl isocyanate and stirred the suspension. 0.7 g of 1,8-dicyclo [bicyclo [5.4.0] undecene-7 is added. The solution obtained is stirred overnight at ambient temperature in the dark. The dichloromethane is removed by evaporation and the gum obtained is triturated with water. petroleum ether (MW = 60-80 ° C.). The insoluble residue is chromatographed under medium pressure, eluting with ethyl acetate. The appropriate fractions are combined and evaporated to dryness and the residue is recrystallized from ethyl acetate. 0.38 g of (2-chloroethyl) -3-dimethylcarbamoyl-8H3-pyrazolo-5,1-dgtetrazine-1,2,3,5-one-4 are thus obtained in the form of colorless crystals, m.p. 116-1180C (with decomposition).

Elemental analysis
Calculated 0 / o: C = 39.93; H, 4.10; N = 31.05; Cl = 13.1
Found: C, 39.7; H = 3.96; N = 30.9; Cl = 13.1
IR spectrum (KBr tablet): 1770, 1630 cm
NMR spectrum (in acetone-d6): singlet at 3.25 and 8.40 ppm triplets at 4.25 and 4.95 ppm.

EXAMPLE 30
Compound DD To 2.5 cm3 of concentrated sulfuric acid was added 0.24 g of 8-carbamoyl (2-chloroethyl) -3 [3 H] imidazo [5,1-d] 1,2-tetrazine. 5-one (prepared as described in Belgian Patent No. 894,175)
The mixture is cooled to 0 ° C. and treated dropwise with 1 cm3 of concentrated nitric acid (d = 1.42). The solution is kept at 40 ° C. for 1 hour and then thrown into ice. The solid which precipitates is collected, washed with water and recrystallized from aqueous acetone.

0.28 g of (2-chloroethyl) -N-nitrocarbamoyl-8H7-imidazo5,1-Q7 1,2,3,5-tetrazol-4-one are thus obtained in the form of colorless crystals, m.p. at 160-1610C (with decomposition).

Elemental analysis:
Calculated%: C = 29.23; H, 2.10; N. = 34.09; Cl = 12.33
Found%: C = 28.6; H, 1.89; N = 3316; Cl = 12.0
IR spectrum (KBr tablet): 3200, 1750, 1720 and 1620 cm
NMR spectrum (in DMSO-d6): triplets at 4.05 ppm (J = 6 Hz) and 4.70 (J = 6 Hz); singlet at 9.05 ppm; singlet broad at 8.25 ppm.

Mass spectrum: m / e = 287/289 (M +)
EXAMPLE 31 Compounds EE, FF, GG, HH and II
By operating in a manner analogous to those described in Examples 1, 2, 4, 6, 6 to 13, 15 to 25 and 27 to 29 but using as raw materials the appropriate diazo compounds (prepared by application or adaptation of the methods described in the examples of following reference), were prepared - 3-methyl-8-methylsulfonyl [3H] -pyrazolo [5,1-d] 1,2-tetrazine,
3.5 one-4, in the form of a colorless solid melting at 182-1840C, - (2-chloroethyl) -3-methylsulfonyl-7H7-pyrazolo5,1-dj tetra
zine-1,2,3,5 one-4, in the form of a colorless solid melting at 166
1710C, 2- (2-chloroethyl) methyl-6-methyl-8-sulfinyl-3H-imidazo [5,1-d]
tetrazine-1,213,5 one-4, in the form of a yellow solid, melting at 118-1200C1-la (2-chloroethyl) -3-ethylsulfonyl-6-methyl-3H] -imidazo [5,1-d]
1,2,3,5-tetrazine one-4, melting at 146-147 ° C, and 3- (2-chloroethyl) methyl-6-propylsulfonyl-r3H / imidazo
/ 5,1-dg tetrazin-1,2,3,5-one-4, in the form of a crystalline solid
white melting at 85-860C.

REFERENCE EXAMPLE 1
i) - An intimate mixture of 2 g of nitro-5 acid is heated in an oil bath at 120 ° C. with stirring for one hour
4-imidazolecarboxylic acid and 2.67 g of phosphorus pentachloride.

The yellow suspension obtained is evaporated to dryness under reduced pressure (0.1 mm of nercury) at 600 ° C. for 30 minutes. 1.90 g of 1,6-dinitro [5H], [10H] -diimidazo [1,5-a: 1 ', 5'-d] pyrazinedione-5,10 are thus obtained in the form of a yellow solid melting at 249-251 C (with decomposition).

IR spectrum: (KBr tablet): 1750 cm -1
Mass spectrum: m / e = 278 (M +)
WINDAUS, Ber. 56, 684 (1923) and GIREVA, Chem. Abstr. 59, 1622e, using the same method, described the product they had obtained as nitro-5-imidazolecarbonyl-4-chloride.

 ii) A mixture of 5.8 g of 1,6-dinitro [5 H], [1-H] -diimidazo [1,5-a: 1 ', 5'-d] pyrazinedione-2 was refluxed for 6 hours. 5.10, 15 g of N-benzylaniline and 250 cm3 of tetrahydrofuran.

The tetrahydrofuran is removed by evaporation under vacuum and the gum obtained is taken up in 1 liter of 1N hydrochloric acid and 1 liter of ethyl acetate. The insoluble N-benzylaniline hydrochloride is removed by filtration and the ethyl acetate layer is decanted. The aqueous phase is extracted twice more with ethyl acetate and the organic phases are combined and washed with 2N hydrochloric acid, then with water, dried over magnesium sulphate and concentrated to dryness. thus an orange gum which is triturated with boiling ether to give a colorless solid which is recrystallized from isopropanol. There is thus obtained 4 g of 5-nitro-N-benzyl N-pbenylimidazolecarboxamide-4, in the form of colorless scales, melting at 237-240 C.

Elemental analysis
Calculated%: C = 63.35; H, 4.38; N = 17.38 Found 7: C, 62.3; H = 4.28: N = 17.3
IR spectrum (KBr tablet): 1665 cm -1
iii) A solution of 4 g of 5-nitro-N-benzyl N-phenylimidazolecarboxamide-4 in 450 cm3 of anhydrous ethane is hydrogenated at 260 ° C. under a pressure of 3 atmospheres, in the presence of Raney nickel as catalyst. When the absorption of hydrogen is complete (after 4 hours 50 minutes), the mixture is filtered, treated with 3.6 cm3 of concentrated hydrochloric acid and evaporated to dryness at a temperature below 40 C. After trituration of the residue with of ethyl ether, 3.82 g of 5-amino-N-benzyl N-phenylimidazolecarboxamide-4 hydrochloride are obtained in the form of a pale yellow solid melting at 190-19 ° C. (with decomposition).

Spectrum RClN (in DNSO-d): singlet at 5.05; 7.1-7.2
6 and 8.4 ppm.

IR spectrum (KBr tablet): 1640 cm -1
Mass spectrum: m / e = 292 (M +) REFERENCE EXAMPLE 2
i) A mixture of 21.9 g of N-benzyl N- (4-methoxyphenyl) amine (prepared according to
Annalen 490, 189 - (1931), 6.7 g of 1,6-dinitro-5R, 10H-diimidazo [5,1-a: 1 ', 5'd] pyrazinedione-5,10 and 200 cm3 of tetrahydrofuran. The tetrahydrofuran is then removed by evaporation under vacuum and the remaining oily solid is taken up in 500 cm 3 of 2N hydrochloric acid and 500 cm 3 of ethyl acetate.

The insoluble N-benzyl N- (4-methoxybenzyl) amine hydrochloride is removed by filtration and the ethyl acetate layer is decanted.
The aqueous phase is extracted twice more with ethyl acetate and the organic extracts are combined, washed successively with 2N hydrochloric acid, with water and with a saturated aqueous solution of sodium chloride and then dried over sodium sulfate. and evaporated to dryness. The remaining strand is subjected to medium pressure column chromatography eluting with ethyl acetate.

2.9 g of 5-nitro-N-benzyl N- (4-methoxybenzyl) imidazolecarboxamide-4 are thus obtained in the form of a beige-brown solid,
at 167-170 ° C (after recrystallization from a mixture of
oil (MW = 60-80 C) and isopropanol).

Elemental analysis
Calculated x: C = 62.29; H = 4.95; N = 15.29
Found 7: C = 61.3; H, 4.93; N = 15.3
IR spectrum (KBr tablet): 3100-2800, 1640, 1510, 1450
and 1370 cm-1
NMR spectrum (in DMSO-d6 at 1200C): .sulphers at 3.76 4.5; 4.6; 7.3 and 7.8 ppm; doublets centered at 6.85 and 7.2 ppm.

 (The NMR spectrum at room temperature is complicated by the doubling of the signals caused by the restricted rotation around the valence bond linking the carbonyl radical of the amide to the nitrogen atom of the amide).

ii) A solution of 2.2 g of 5-nitro-N-benzyl N- (4-methoxybenzyl) imidazolecarboxamide-4 in 200 cm3 of anhydrous ethanol is hydrogenated at room temperature under a pressure of 3 atmospheres, in the presence of nickel. of Raney as a catalyst. When the hydrogen absorption is complete (after 2 hours 48 minutes), the mixture is filtered, treated with a stream of dry gaseous hydrochloric acid and evaporated to dryness at a temperature below 40 C. After tritura
in a mixture of isopropanol and ethyl ether,
2.2 g of 5-amino-N-benzyl N- (4-methoxybenzyl) hydrochloride
imidazolecarboxamide-4, in the form of a gummy solid which is decomposed above 700C.

IR spectrum (KBr tablet): 3400-2800, 1640 cm
NMR spectrum (in d4-meghanol): singlet at 3.7; 4.4;
4.5; 7.2 and 8.3 ppm; doublets centered at 6.7 and 6.9 ppm (signals
widened to catse of the restricted rotation around-the link
of valence linking the carbonyl radical of the amide to the nitrogen atom
amide).

REFERENCE EXAMPLE 3
i) A mixture of 5.5 g of 1,6-dinitro-5H, 10H-diimidazo [1,5-a: 1 ', 5'-d] pyrazine-5,10-dione is refluxed for 12 hours. 14.5 g of N- (4-methoxybenzyl) aniline prepared according to Zechheimer et al., Ber. 63 B, 2883 (1930)] and 250 cm3 of tetrahydrofuran. The tetrahydrofuran is then removed by evaporation under vacuum and the residual dark oil is taken up in 1 liter of 2N hydrochloric acid and 1 liter of ethyl acetate. The organic layer is decanted, washed with water, dried over magnesium sulphate and evaporated to dryness. The remaining solid is triturated with ethyl ether. Thus, 3.18 g of 5-nitro-N- (4-methoxybenzyl) -N-phenylimidazolecarboxamide-4 is obtained in the form of a peach-colored solid, m.p. -2150C (after recrystallization from 1-isopropanol).

Elemental analysis:
Calculated%: C, 61.37; H, 4.58; N = 15.91
Found%: C = 60.4; H, 4.41; N = 16.0
NMR spectrum (in DMSO-d6): singlet at 3.7; 5.0 and 7.7 ppm; multiplet at 6.7-7.3 ppm
IR spectrum (KBr tablet): 1660 cm
ii) A solution of 2.1 g of 5-nitro-N- (4-methoxybenzy)!
N-Phenyl imidazolecarboxamide-4 in 200 cm3 of anhydrous ethanol is hydrogenated at 250C under a pressure of 3 atmospheres, in the presence. of Raney nickel as a catalyst. When the absorption of hydrogen is complete (after 5 hours), the mixture is filtered and evaporated to dryness. The residue is triturated with ethyl ether. There is thus obtained 1.9 g of 5-amino-N- (4-methoxybenzyl) -N-phenylimidazolecarboxamide-4, in gum form.

 This gum can be characterized as a picrate.

For this, 0.15 g of 5-amino-N- (4-methoxybenzyl) N-phe-nylimidazolecarboxamide-4 are dissolved in 3 cm3 of 1,2-dimethoxyethane and the solution obtained is treated with a solution of 0.25 g of picric acid in 5 cm3 of 1,2-dimethoxyethane. The crystals obtained are separated by filtration and washed with ethyl ether. 0.07 g of 5-amino-N- (4-methoxy benayl) picrate is thus obtained.
N-phenyl imidazolecarboxamide-4, in the form of a yellow solid, melting at 2070C (with decomposition).

Elemental analysis
Calculated: C = 49.1; H, 4.29; N = 16.69
Found%: C = 49.1; H, 3.64; N = 16.5
REFERENCE EXAMPLE 4
i) A mixture of 8.08 g of 1,6-dinitro-5H, 10H-diimidazo, 5-a: 1-5'-dl pyrazinedione-5,10, 12.44 g is heated under reflux for 24 hours. N-methyl aniline and 400 cm3 of tetrahydrofuran. The tetrahydrofuran is removed by evaporation under vacuum and the dark residual solid is taken up with boiling ethyl ether. The remaining undissolved solid is subjected to medium pressure column chromatography, eluting with a mixture of ethyl acetate and methanol (1-1 in volumes). Thus 4.68 g of 5-nitro-N methyl N-phenyl imidazolecarboxamide-4, in the form of a white solid melting at 193 ° C.

Elemental analysis
Calculated%: C = 53.66; H, 4.09; N = 22.76
Found: C = 52.5; H = 3.95; N = 22.2
-1
IR spectrum: 1660 cm
ii) A solution of 1 g of 5-nitro-N-methyl-N-phenylimidazolecarboxamide in 110 cm3 of anhydrous ethanol is hydrogenated at 230 ° C. under a pressure of 3 atmospheres in the presence of Raney nickel as catalyst. When the hydrogen uptake is complete (after 1 hour 39 minutes), the mixture is filtered and treated with a stream of dry gaseous hydrochloric acid. The solution is then evaporated to dryness. There is thus obtained 0.9 g of 5-amino-N-methyl-N-phenylimidaolecarboxamide hydrochloride, in the form of an off-white solid, melting at 100 ° C. (with decomposition).

 This compound can be characterized as a picrate.

For this purpose, 0.25 g of 5-amino-N-methylhydrochloride is dissolved.
N-phenylimidazolecarboxamide-4 in 2 cm3 of water and the solution is treated with a solution of 0.25 g of picric acid in 2 cm3 of 1,2-dimethoxyethane. The precipitate is filtered off and washed with dimethoxt-1,2 ethane. There is thus obtained 0.12 g of 5-amino-N-methyl-N-phenylimidazolecarboxamide-4-picrate. in the form of a
yellow solid, melting at 237-238 C (with decomposition).

Elemental analysis:
Calculated%: C = 45.85; H, 3.39; N = 22.08
Found%: C = 45.3; H = 3.26; N = 21.8
IR spectrum (KBr tablet): 1640 cm1.

REFERENCE EXAMPLE 5
To a solution of 1 g of sodium nitrite in 8 cm3 of water cooled to 0 ° C. with stirring, a solution of 2 g of 4-amino-2-methylimidazolecarboxamide-5-hydrochloride (prepared as described in the application) is added. German Patent No. 2,358,509) in 24 cm3 of a 2N aqueous acetic acid solution while maintaining the temperature between -2 and OOC. When the addition is complete, the yellow solid obtained is separated by filtration and dried under vacuum over phosphorus pentoxide. There is thus obtained 1.26 g of 5-diazo-2-methyl-4-imidazolecarboxamide melting at 175 ° C (with explesion).

REFERENCE EXAMPLE 6
(i) To an ice bath solution of 35 cm3 of dimethylamine in water (30 wt.%), 4.15 g of 5-nitroimidazolesulfonyl chloride are added in small portions at a time and with stirring. - (wet product, freshly prepared from 3.33 g of ammonium salt of 5-nitro-4-mercaptoimidazole by the method of Fischer et al Can J. Chem., 9, 501). The mixture is stirred for a further 20 minutes then the mixture is concentrated to half its volume under vacuum at a temperature below 40 ° C. The mixture is then strongly acidified by treatment with concentrated hydrochloric acid and the pale yellow solid obtained. is filtered off and recrystallized from dimethylformamide to give 2) 73 g of 5-nitro-N, N-dimethylsulfamoyl) -4-imidazole as brownish flakes melting at 282-283 ° C (with decomposition).

Elemental analysis:
Calculated%: C = 27.3; H = 3.66; N = 25> 4 S = 14.6
Found%: C = 27.3; H, 3.65; N = 25.4; S = 14.2
ii) A solution of 1 g of 4-nitro-N, N-dimethylsulfamoyl-4-imidazole in 100 cm3 of anhydrous ethanol is hydrogenated at 24 ° C. under a pressure of 3 atmospheres in the presence of Raney nickel as catalyst. The mixture is then filtered and diluted immediately with 200 cm3 of ether and treated with a current of hydrochloric gas until a slightly acidic medium is obtained.The mixture is then concentrated under vacuum at a temperature below 30 C. The solid remaining is dissolved in 20 cm3 of boiling anhydrous ethanol and the solution is treated with decolorizing charcoal, filtered and evaporated to a volume of 15 cm3, taken up with 60 cm3 of ethyl ether and left crystallized. The solid obtained is separated by filtration.

0.8 g of 5-amino-N, N-dimethylimidazolesulfonamide-4 hydrochloride are thus obtained in the form of pinkish beige needles melting at 188 ° -189 ° C. (with decomposition).

Elemental analysis:
Calculated%: C = 26.5; H = 4.85; N = 24.7; Cl = 15.6; S = 14.15
Found X: C = 26.1; H, 4.80; N = 23.6; C1 = 15.9
S = 13.9
iii) To an ice-cold solution of 0.31 g of sodium nitrite in 5 cm 3 of water, a solution of 0.7 g of 5-amino-5-chlorohydrate is added dropwise with stirring.
N, N-dimethylimidazolesulfonamide-4 in 3.1 cm3 of 2N hydrochloric acid. The solid obtained is separated by filtration and washed with ice water. 0.38 g of 5-diazo-N, N-dimethylimidazolesulfonamide-4, which melts at 10 ° C. (with decomposition), are thus obtained.

IR spectrum: 2180 and 2210 cm-1
A second batch of 0.21 g of slightly less pure product is obtained by extracting the mother liquors at 0 ° C. with ethyl acetate, drying the extracts with magnesium sulphate and evaporation under vacuum.

REFERENCE EXAMPLE 7
(i) To 35 cm3 of a 25% (w / w) aqueous solution of methylamine cooled in an ice bath is added with stirring in small portions at a time, 4.15 g of 5-nitroimidazolesulfonyl-4-chloride product Wet prepared from 3.33 g of ammonium salt of 4-mercapto-5-nitroimidazole according to the method of Fischer et al. (cit.) The reaction mixture is stirred for a further 15 minutes and then concentrated in vacuo at less than 40 ° C until half. of the initial volume. The mixture is then strongly acidified with concentrated hydrochloric acid and the remaining solid is separated by filtration and recrystallized from water. This gives 2.07 g of
N-methyl-5-nitroimidazolesulfonamide-4 as pale yellow lamellae melting at 260-263 ° C (with decomposition).

Elemental analysis:
Calc'd: C = 23.3; H, 2.93; N = 27.2; S = 15.55
Found%: C = 23.1; H = 2.87; N, 27.4; S = 15.4
ii) A solution of 1 g of N-methyl-5-nitroimidazolesulfonamide-4 in 100 cm3 of anhydrous ethanol is hydrogenated at 240 ° C. under a pressure of 3 atmospheres in the presence of Raney nickel as catalyst. The mixture is then filtered and diluted immediately with 200 cm3 of ethyl ether and treated with a current of hydrochloric gas until the medium is slightly acidic. The reaction mixture is then concentrated to dryness under vacuum at 300 ° C.

The solid residue is dissolved in the minimum volume of boiling ethanol; the solution is treated with decolourising charcoal, filtered and diluted with ethyl ether. The solid obtained is separated by filtration. 0.63 g of 5-amino-hydrochloride are thus obtained.
N-methyl imidazolesulfonamide-4 melting at 178-180 ° C (with decomposition).

Elemental analysis:
Calculated "C = 22.6, H = 4.26, N = 26.35, C1 = 16.7
Found%: C = 22.3; H, 4.13; N = 25,; C1 = 16.9
iii) To a solution of 0.285 g of sodium nitrite in 4 cm3 of water cooled in an ice bath, a solution of 0.55 g of 5-amino-5-chlorohydrate is added dropwise with stirring.
N-methyl imidazolesulfonamide-4 in 2.8 cm3 of 2N hydrochloric acid. The solid obtained is separated by filtration and washed with ice water. 0.36 g of diazo-5-N-methyl imidazolesulfonamide-4, mp 150 ° C. (with decomposition) is thus obtained.

-1
IR spectrum: .2210 cm
Elemental analysis:
Calculated%: C = 25.7; H, 2.69; N = 37.4
Found%: C = 25.2; H = 2.47; N = 37.06
A second batch of 0.07 g of product is obtained by extracting the mother liquors at 0 ° C. with ethyl acetate, drying the extracts over magnesium sulphate and evaporation under vacuum.

REFERENCE EXAMPLE 8
To a solution of 0.5 g of sodium nitrite in 5 cm3 of water cooled to 0 ° C., a solution of 1 g of 5-amino-4-methylsulfonylimidazole hydrochloride prepared as described above is added dropwise with stirring. by BENNETT and roll., J. Am.

Chem. Soc. 79 (3), 2188-2191 (1957)] in 5 cm3 of 2N hydrochloric acid. The solution is stirred for a further 15 minutes and extracted with 5 times 20 cm3 of ethyl acetate. The extracts are combined, dried over sodium sulfate and concentrated in vacuo to leave a yellow oil which crystallizes on standing. 0.74 g of 4-diazo-4-methylsulphonylimidazole, m.p. 128-130 ° C., are thus obtained.

-1
IR spectrum: 2125 cm
REFERENCE EXAMPLE 9
(i) To a solution of 10 g of 4-methoxybenzylamine in 30 cm3 of water is added with stirring 6.8 g of nitro-5-imidazolesulfonyl-4 product wet freshly prepared from 6 g of sodium salt. ammonium of 4-mercapto-5-nitroimidazole according to the method of Fischer et al. (cit.) The mixture does not show signs of solidification; it is taken up with 20 cm3 of isoprópanol, triturated and left to rest one night. The solid obtained is separated by filtration, washed with ice water and then suspended in 150 cm3 of water and treated with caution with a 2N hydrochloric acid solution to pH 2. The yellow solid obtained is separated. by filtration and washed with ice-cold water. 7.42 g of 4-N- (4-methoxybenzyl) -5-nitroimidazolesulfonamide-4, m.p. 269-270 ° C (with decomposition) are thus obtained.

 ii) A solution of 1 g of N- (4-methoxybenzyl) nitro-5-imidazolesulfonamide-4 in 100 cm3 of dry ethanol is hydrogenated for 6 hours under a pressure of 3 atmospheres in the presence of 50% Raney nickel. as a catalyst. The catalyst is rapidly separated by filtration on diatomaceous earth and the filtrate is immediately taken up with 20 cm3 of hydrochloric acid. The mixture is concentrated to dryness and the resulting residue is triturated with ethyl ether. The solid obtained is separated by filtration and washed with ethyl ether.

There is thus obtained 0.25 g of 5-amino-N- (4-methoxybenzyl) imidazolesulfonamide-4 melting at 154-1550C.

 iii) To a solution of 0.14 g of sodium nitrite in 5 cm3 of water is added dropwise a solution of 0.5 g of 5-amino-N- (4-methoxybenzyl) imidazolesulfonamide-4 in 10 cm3 of 2N hydrochloric acid, keeping the temperature at 0 ° C. The mixture is stirred for a further 15 minutes at 0 ° C. and the solid formed is separated by filtration, washed with water and dried over phosphorus pentoxide. There is thus obtained 0.3 g of diazo-5 N- (4-methoxybenzyl) imidazolesulfonamide-4 melting at 144-1460C (with decomposition).

IR spectrum: 2180 cm-1
REFERENCE EXAMPLE 10
(i) To a solution of 6.4 cm3 of piperidine in anhydrous tetrahydrofuran (92 cc) was added 4.59 g of 1,6-dinitro-5H, 10H-diimidazo [1,5-a: 1 ', 5'- d] pyrazinedione-5.1 (prepared as described in Reference Example 1) and stir at room temperature for 1 hour. The mixture is then concentrated to dryness and the residue is dissolved in 92 cm3 of 2N hydrochloric acid. The solution is extracted with 3 times 200 cm3 of ethyl acetate, the organic extracts are combined and dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel under medium pressure, eluting with a mixture of chloroform and methanol (9-1 by volume). The appropriate fractions are combined and evaporated; the residue is washed with ethyl ether and then with ethyl acetate. 2.72 g of 4-nitro-5-piperidinocarbonylimidazole are thus obtained in the form of a yellow solid melting at 149-150 ° C.

Elemental analysis:
Calculated%: C = 48.2; H, 5.39; N = 25.0
Found x: C = 48.2; H, 5.33; N = 25.1
(ii) A solution of 2.68 g of 4-nitro-5-piperidinocarbonyl imidazole (prepared as described above) in 27 cm 3 of methanol and 27 cm 3 of dimethylformamide is treated with 0.27 g of platinum oxide and mixture is hydrogenated under stirring. at room temperature and at atmospheric pressure. When the absorption of hydrogen is complete, the mixture is filtered and the filtrate is evaporated under vacuum. The residue is dissolved in 50 cm3 of 2N hydrochloric acid, the solution is filtered and the filtrate is evaporated to dryness in vacuo. The residue obtained is washed with acetone. 2.1 g of 4-amino-5-piperidinocarbonylimidazole hydrochloride are thus obtained in the form of a pale green solid, melting at 175 ° -177 ° C., sufficiently pure to be used. as is in the next step.

REFERENCE EXAMPLE
i) In a stirred solution of 5 g of 2-cyanoethylbenzene and 8 g of benzyl mercaptan in 90 cm3 of anhydrous dioxane, a stream of gaseous hydrochloric acid is passed over for 3 hours and the mixture is allowed to stand at room temperature for 5 hours. The mixture is then taken up in ethyl ether and the precipitate formed is filtered off and washed with ethyl ether. There is thus obtained 9.7 g of S-benzyl phenyl-3 propionothioimidate hydrochloride, in the form of a colorless solid melting at 158-1600C, sufficiently pure to be used as such in the next step.

 ii) A solution of 3.3 g of α-amino-α-cyanoacetamide in 20 cm 3 of ethanol is treated with 9.7 g of S-benzyl phenyl-3-propionothioimidate hydrochloride (prepared as described above) and the mixture is refluxed for 15 minutes. The mixture is then cooled and the solid formed is filtered off and recrystallized from methanol. 2.3 g of 5-amino-2-phenethylimidazolecarboxamide hydrochloride are thus obtained in the form of colorless crystals, m.p. 270-2740C.

Elemental analysis
Calculated%: C = 54.0; H, 5.67; N = 21.0
Found%: C = 53.8; H, 5.55; N = 21.1
REFERENCE EXAMPLE 12
To a solution of 0.5 g of sodium nitrite in 15 cm3 of water maintained at 0-5 ° C, a solution of 1.26 g of 5-amino-2-benzylimidazolecarboxamide-4 (prepared as as described in German Patent Application No. 2,358,509) in 15 cc of 2N hydrochloric acid. The mixture is stirred at 0.degree. C. for a further 30 minutes and the pale yellow solid formed is filtered off, washed with water and dried in a desiccator over phosphorus pentoxide. 0.8 g of 2-benzyl-5-diazo-4-imidazolecarboxamide, melting at 121-12 ° C. (with decomposition) are thus obtained.

-l
IR spectrum: 2180 cm
REFERENCE EXAMPLE 13
i) In a stirred solution of 6.9 g of isobutyronitrile and 20 cm3 of benzyl mercaptan in 100 cm3 of anhydrous dioxan, a stream of gaseous hydrochloric acid is passed for 3 hours at a temperature between 0 and 10 C. Allowed to warm to room temperature and the device is closed and allowed to stand for 14 days at room temperature. The mixture is then poured onto 1 liter of ethyl ether and the white precipitate formed is separated by filtration and washed with ethyl ether. There is thus obtained 20.3 g of S-benzyl isobutylthioimidate hydrochloride, melting at 165-1670C.

Elemental analysis:
Calculated%: C = 57.5; H = 7.02; N = 6.1; Cl = 15.43
S = 13.96
Found%: C = 57.1; H = 7.0; N = 5.9; C1 = 15.7;
S = 13.9
ii) A solution of 5 g of? -amino-cyanoacetamide and 11.5 g of S-benzyl isobutylthioimidate hydrochloride (prepared as described above) in 150 cm3 of anhydrous 2-ethoxy-ethanol is heated to reflux. during 30 minutes. The solvent is evaporated.

The remaining black oil is triturated with 100 cm3 of a mixture of chloroform and methanol (4-1 by volume); the insoluble material is separated by filtration and removed. The filtrate is chromatographed on silica gel under medium pressure, eluting with a mixture of chloroform and methanol (4-1 by volume). The appropriate fractions (identified by ninhydrin sputtering on a sample, giving an intense yellow-brown colpration) are combined and evaporated. 4.44 g of 5-amino-2-isopropyl-4-imidazolecarboxamide hydrochloride are thus obtained in the form of a gummy solid, which is sufficiently pure to be used as it is in the next step.

 iii) To a solution of 0.5 g of sodium nitrite in 5 cm3 of water maintained at 0 ° C., a solution of 1.1 g of 5-amino-2-isopropyl-4-imidazolecarboxamide hydrochloride is added dropwise. (prepared as described above) in 20 cm3 of a 2M aqueous acetic acid solution. The mixture is stirred for a further 5 minutes at 0 ° C. and is then extracted with 3 times 20 cm 3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated in vacuo to a volume of 20 cm3 and chromatographed on silica gel eluting with ethyl acetate.

Suitable fractions (identified by sputtering of naphthol-2 on a sample to give a dark red color) are combined and evaporated to dryness. 0.43 g of diazo-5-isopropyl-2-imidazolecarboxamide-4 are thus obtained, melting at 120 ° C. (with decomposition).

-l
IR spectrum: 2170 cm
REFERENCE EXAMPLE 14
i) A cooled and stirred solution of 127 g of 2-methyl-5-nitroimidazole in 1500 cm3 of a 5% aqueous solution of sodium hydroxide (w / v) is treated with 160 g of brone, maintaining the temperature between 15 and C. The reaction mixture is stirred at room temperature for 5 1/2 hours and the solid which has precipitated is redissolved by adding again 2N sodium hydroxide to the reaction mixture. The traces of insoluble product are separated by filtration and the filtrate is acidified to pH 1 with concentrated hydrochloric acid. The white solid obtained is separated by filtration, recrystallized from ethanol and dried in a desiccator over phosphorus pentoxide. 151 g of 4-bromo-2-methyl-5-nitroimidazole, in the form of a crystalline crystalline solid, are then obtained. at 267-268C.

 ii) A stirred solution of 20.6 g of 4-bromo-2-methyl-5-nitroimidazole (prepared as described above) is heated in 45 ° C. in 180 cm 3 of 5N ammonia and then a continuous stream of hydrogen sulfide for 40 minutes. A yellow crystalline solid is slowly formed. The mixture is cooled in ice and the solid is filtered off, washed with iced water and dried in a desiccator over phosphorus pentoxide. There is thus obtained 14.6 g of 4-mercapto-2-methyl-5-nitroimidazole in the form of ammonium salt which darkens without melting above 300 C.

Elemental analysis
Calculated%: C = 27.27; H, 4.58; N = 31.8; S = 18.2
Found%: C = 27.2; H, 4.41; N, 31.6; S = 18.2
iii) In an ice-cooled and vigorously stirred solution of 3.51 g of ammonium salt of 4-mercapto-2-methyl-5-nitroimidazole (prepared as described above) in 120 cm3 of 1N hydrochloric acid, a current of chlorine is passed until a white solid is formed. The mixture is then stirred for a further 30 minutes at 0 ° C. and the solid is filtered off, washed with water and dried in a desiccator over phosphorus pentoxide. There is thus obtained 3 g of 4-chlorosulfonyl-2-methyl-5-nitroimidazole, melting at 160-162 ° C (with decomposition).

Elemental analysis:
Calculated%: C = 21.29; H, 1.79; N, 18.63; C1 = 15.72;
S = 14.21
Found%: C = 20.8; H, 1.73; N = 18.3; C1 = 15.7; S = 14.6
iv) To a cooled solution of 5.48 g of 4-methoxybenzylamine in 20 cm3 of absolute absolute ethanol, 2.25 g of 4-chlorosulfonyl-2-methyl-5-nitroimidazole (prepared as described above) is added. and the mixture is stirred at room temperature for 3 hours. The yellow solid which precipitates is separated by filtration, washed with ethanol and removed: it is 4-methoxy benzylamine hydrochloride. The filtrate and the washing liquors are combined and evaporated to dryness. The residue obtained is suspended in 50 cm 3 of water, acidified to pH 1 with concentrated hydrochloric acid and the mixture is extracted with 3 times 20 cm 3 of water. 'ethyl acetate.

The organic extracts are combined and dried over magnesium sulphate and evaporated to dryness. 2.77 g of 4- (4-methoxybenzyl) -4-sulfamoyl-2-methyl-5-nitroimidazole are thus obtained in the form of an off-white solid, melting at 167-170 ° C.

Elemental analysis
Calculated%: C = 44.17; H, 4.32; N, 17.17; S = 9.83
Found%: C = 44.2; H, 4.32; N, 1712; S = 9.5
v) A solution of 4.5 g of 4-(4-methoxybenzyl) -4-sulfamoyl-2-methyl-5-nitroimidazole (prepared as described above) in 120-cm3 of anhydrous ethanol is hydrogenated under a pressure of 3 atmospheres. on Raney nickel catalyst for 30 minutes.

The catalyst is filtered and washed with 10 cm3 of anhydrous ethanol.

The filtrate and the washings are combined and acidified to pH 1 with concentrated hydrochloric acid and the solvent is removed by evaporation. The residue obtained is triturated with ethyl ether. 3.25 g of 5-amino-4- (4-methoxybenzyl) -4-sulfamoyl-methyl-2-imidazole hydrochloride are thus obtained, melting at 183 ° -185 ° C.

 vi) To a solution of 0.3 g of sodium nitrite in 5 cm3 of water maintained between 0 and 50 ° C., a solution of 1 g of 5-amino-4- (4-methoxybenzyl) sulfamoyl hydrochloride is added dropwise. 4-methyl-2-imidazole (prepared as described above) in 10 cm3 of 2N hydrochloric acid. The mixture is stirred for a further 5 minutes at 0.degree. C. to 50.degree. C. and the orange solid obtained is filtered off, washed with water and dried in a desiccator over phosphorus pentoxide. 0.75 g of 5-diazo-4-methoxybenzyl-4-sulfamoylmethyl-2-imidazole are thus obtained, melting at 140 ° C. (with decomposition).

IR spectrum: 2200 cm-1
REFERENCE EXAMPLE 15
(i) To 10 cc of a cooled and stirred dimethyl dimethylamine solution of 33% (w / v) was added in small portions at a time 2.25 g of 4-chlorosulfonyl-2-methyl-5-nitroimidazole (prepared as described in Reference Example 14) and stir room temperature for another 45 minutes. The solution is acidified to pH 1 with concentrated hydrochloric acid. The white solid obtained is separated by filtration and washed with cold water. There is thus obtained 1.9 g of 4-dimethylsulfamoyl-2-methyl-5-nitroimidazole mp 240-2410C.

Elemental analysis:
Calculated%: C = 30.77; H, 4.3; N = 23.92; S = 13.69
Found Z: C = 30.5; H, 4.24; N = 23.8; S = 13.8
NMR spectrum (in DMSO-d6): singlet at 2.3 and 2.8 ppm.

 ii) A solution of 12 g of 4-dimethylsulfamoyl-2-methyl-5-nitroimidazole (prepared as described above) in 300 cm3 of anhydrous ethanol is hydrogenated at a pressure of 3.5 atmospheres on a Raney nickel catalyst for time. The catalyst is filtered off and the filtrate is acidified to pH 1 with concentrated hydrochloric acid and evaporated to dryness.

The orange residue is triturated with ethyl ether. There is thus obtained 8.9 g of 5-amino-4-dimethylsulfamoyl-2-methylimidazole, melting at 215-2170C (with decomposition).
iii) To a solution of 1 g of sodium nitrite in 15 cm3 of water maintained at 0 ° C., a solution of 2.4 g of 5-amino-4-dimethylsulfamoyl-2-methylimidazole in 30 cm3 is added dropwise. 2N hydrochloric acid and stirred the mixture during the encode
10 minutes at -00C. The mixture is extracted with 5 times 30 cm 3 of ethyl acetate; the organic extracts are combined and dried over magnesium sulphate, evaporated to dryness and the residue is triturated with petroleum ether (PE = 60-80 ° C.) to give 1.8 g of 5-diazo-dimethylsulfamoyl. 4-methylimidazole melting at 85-87 ° C (with decomposition).

-1
IR spectrum: 2180 cm. REFERENCE EXAMPLE 16
i) A solution of 10.5 g of ammonium salt of 4-mercapto-2-methyl-5-nitroimidazole (prepared as described in Reference Example 14) in a methanolic solution of sodium methoxide (prepared by dissolving with Precaution 2.3 g of sodium in 250 cm3 of anhydrous methanol) is treated with 10.7 g of methyl iodide and the solution is refluxed for 2 hours. The mixture is then concentrated to dryness and the residue is suspended in 100 cm3 of a 2N aqueous sodium hydroxide solution. The suspension is filtered and the filtrate is acidified to pH 1 with concentrated hydrochloric acid. 9 g of 2-methyl-4-methylthio-5-nitroimidazole are thus obtained in the form of a yellow solid melting at 236-237 ° C. (with decomposition).

Elemental analysis
Calculated%: C = 34.67; H, 4.07; N. = 24.26; S = 18.51
Found%: C = 34.7; H, 4.04; N = 24.3; S = 18.5
ii) A solution of 3.46 g of 2-methyl-4-methylthio-5-nitroimidazole (prepared as described above) in a solution of 35 cm3 of glacial acetic acid is heated to 600 ° C. and 35 cm3 of toluene are added dropwise. an aqueous hydrogen peroxide solution at 30% (w / v).

The mixture is then heated at 1 ° C. for 15 minutes, cooled to room temperature and treated with sulfite. of sufficient sodium to destroy excess hydrogen peroxide (detected by the starch and potassium iodide test). The mixture is then subjected to liquid-liquid extraction continuously for 20 hours with ethyl acetate. The extract is concentrated to dryness and the remaining white solid is triturated with petroleum ether (bp = 60-80 ° C) and separated by filtration. There is thus obtained 3.5 g of 2-methyl-4-methylsulphonyl-5-nitroimidazole, melting at 222-224 C.

Elemental analysis:
Calculated%: C = 29.27; H, 3.44; N = 20.48; S = 15.63
Found%: C = 29.8; H = 3.28; N = 20.6; S = 15.7
iii) A solution of 4.9 g of 2-methyl-4-methylsulphonyl-5-nitroimidazole (prepared as described above) in 400 cm3 of anhydrous ethanol is hydrogenated under a pressure of 3.5 atmospheres on a nickel catalyst. Raney for 30 minutes. The catalyst is filtered off and the filtrate is acidified to pH 1 with concentrated hydrochloric acid and evaporated to dryness.

The residue is triturated with ethyl ether containing a trace of ethanol to give a purple solid which is filtered off and washed with ethyl ether. There is thus obtained 4.1 g of 5-amino-methyl-4-methylsulfonylimidazole hydrochloride, melting above 3000C.

Elemental analysis;
Calcd. 20: C = 28.37; H, 4.76; N = 19.8; C1 = 16.75; S = 15.15
Found%: C = 27.3; H, 4.51; N = 19.9; Cl = 17.9; S = 13.7
iv) To a solution of 0> 25 g of sodium nitrite in 5 cm3 of water maintained at 0 ° C., a solution of 0.53 g of 5-amino-methyl-2-methylsulfonylhydrochloride is added dropwise. 4 imidazole (prepared as described above). The mixture is stirred for a further 15 minutes at 0 ° C. and is extracted with 5 times 15 cm 3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate and evaporated to dryness. The remaining oil is triturated with petroleum ether (PE @ 60-800C). 0.4 g of 5-diazo-2-methyl-4-methylsulphinylimidazole are thus obtained, melting at 100 ° C. (with decomposition).

IR spectrum: 2185 cm -1
REFERENCE EXAMPLE 17
i) A mixture of 8.2 g of a-cyano is heated at 160-170 ° C. in a flask fitted with a McIntyre head for 90 minutes.
N, N-dimethylacetamide prepared as described by BOWMAN et al.

J. Chem. Soc. (1954), 1171], 21 cm3 of acetic anhydride and 21 cm3 of ethyl orthoformate. 26 cm3 of ethyl acetate are thus collected and distilled. The reaction mixture is concentrated in vacuo. A dark oil is obtained which is taken up in 10 cm3 of éthaiol and concentrated again under vacuum. The residue is distilled at 160-170 ° C. under a pressure of 0.5 mm of mercury and then the distillate is chromatographed on silica gel under medium pressure. There is thus obtained 5.3 g of 2-cyano-3-ethoxy-N, N-dimethyl propenamide, in the form of an off-white oily solid, sufficiently pure to be used as it is in the next phase.

 ii) To a solution of 5.3 g of crude 3-cyano-3-ethoxy-N, N-dimethyl propenamide (prepared as described above) in 50 cm3 of anhydrous ethanol, 1.58 g of dichloromethane were added dropwise. hydrazine hydrate. After the end of the addition, the mixture is refluxed for 6 hours and then evaporated to dryness. The residue is chromatographed on silica gel, eluting with a mixture of chloroform and methanol (17-3 by volume) and the appropriate fractions are combined and evaporated to dryness. The residue obtained is dissolved in 5 cm3 of isopropanol, treated with 4 cm3 of concentrated hydrochloric acid and the crystalline precipitate obtained is collected. 1.39 g of 3-amino-N, N-dimethyl pyrazolecarboxamide-4 hydrochloride are obtained in the form of painless crystals melting at 195.degree. C.

Elemental analysis Calculated%: C = 37.8 -; H, 5.82; N, 29.39; Cl = 18.6
Found%: C = 37.8; H, 5.82; N = 29.0; Cl = 18.3
IR spectrum (KBr tablet): 3500, 3400, 3000-2200, 1655 cm -1
NMR spectrum (in DEiSO-d6): singlet at 3.0 and 8.1 ppm and singlet at 1.2 ppm.

 iii) 70 cm3 of a solution of anhydrous methanol-methanol saturated with gaseous hydrochloric acid are treated with 1.39 g of 3-amino-N-N-dimethyl pyrazolecarboxamide-4 hydrochloride (prepared as above). the mixture is stirred and cooled to 0 ° C. and then 2.55 g of amyl nitrite are added dropwise over 15 minutes while maintaining the temperature at 0 ° C. The solution obtained is left standing for 1 hour at a temperature of between 2 and 40 ° C. and is then discarded in 800 cm 3 of ether. The solid obtained is collected and washed with ethyl ether. 0.92 g of 3-diazo-N, N-dimethyl pyrazolecarboxamide-4 are thus obtained in the form of colorless crystals melting at 150 ° C. (with explosion).

Elemental analysis:
Calculated%: C = 35.74; H = 4.00; N = 34.74
Found x: C = 35.3; H, 3.79; N = 34.3
-1
IR spectrum (KBr tablet): 3000-2100, 2280, -1630 cm.

 The present invention also relates to pharmaceutical compositions which contain, as an active ingredient, at least one product of general formula (I) with a pharmaceutical diluent or coating. In clinical products of general formula (I) are normally administered orally rectally, vaginally or parenterally, for example intravenous or intraperitoneal.

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

 Among the solid compositions for oral administration include tablets, pills, dispersible powders and granules.

 In these solid compositions are found one or more active products in admixture 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 as magnesium stearate.

 Among the liquid compositions for oral administration, mention may be made of emulsions, solutions, pharmaceutically acceptable suspensions, syrups and elixirs containing common inert diluents such as water and liquid petrolatum. In addition to the inert diluents, these compositions may also contain adjuvants such as wetting agents, suspending agents (for example polyvinylpyrrolidone), sweetening agents, flavoring agents, perfumes and preserving agents.

 Among the compositions for oral administration there may also be mentioned capsules of absorbable material such as gelatin which contain one or more active products with or without the addition of diluents or other excipients.

 Among the compositions for vaginal administration there may be mentioned pessaries formulated in the usual manner and containing one or more active products.

 Among the compositions for rectal administration there may be mentioned suppositories formulated in the usual manner and containing at least one active product.

 Compositions according to the invention for parenteral administration comprising aqueous or nonaqueous sterile solutions, suspensions or emulsions. As for example non-aqueous solvents or vesicles include: propylene glycol,) olyethylglycols, dimethylsulfoxide, vegetable oils (eg olive oil) or injectable organic esters (eg ethyl oleate).

 These compositions may 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 as sterile solid compositions which will be dissolved or dispersed, at the time of their use, in water or any other sterile injectable medium.

 The proporticn of active product in the compositions according to the invention may vary; insofar as it makes it possible to obtain an appropriate dosage for the desired therapeutic effect.

Naturally, several unit doses can be administered simultaneously. In general, the injection-administrable compositions contain at least 0.025% by weight of active material, and the oral compositions contain at least 0.1% by weight. The dose used 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 carcinomas, melanomas, sarcomas, lymphomas and leukemias, at doses generally between 0.1 and 200 (and preferably between 1 and 20) mg. / kg per day.

 The following examples illustrate compositions according to the invention.

EXAMPLE OF COMPOSITION 1
A solution suitable for parenteral administration is prepared from the following ingredients - (N-benzyl N-phenylcarbamoyl) -8 methyl-3
[3H] -imidazo [5,1-d] 1,2,3,5-tetrazinone-4 .......... 1.0 g -dimethylsulfoxide .......... ......................... 10 cm3 by dissolving (N-benzyl N-phenylcarbamoyl) -8 methyl-3 g3H7-imidazo5 → 1-d 1,2,3,5-tetrazinone-4 in dimethylsulfoxide.

The solution obtained is aseptically distributed in 10 ampoules at a rate of 1.1 cm 3 per ampoule. The ampoules, each containing 100 mg of (N-benzyl N-phenylcarbamoyl) -8-methyl-3 [3 H] imidazo [5,1-d] 1,2,3,5-tetrazol-4-one, are sealed.

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

EXAMPLE OF COMPOSITION 2
A solution suitable for parenteral administration is prepared from the following ingredients - (2-chloroethyl) -3-N-methylsulfamoyl-8
[3H] -imidazo [5,1-d] 1,2,3,5-tetrazinone-4 ......... 1.0 g - dimethylsulfoxide. ~ 10 cm3 - peanut oil .................................. 90 cm3 by dissolving the (chlorinated 2 ethyl) -3-N-methylsulfamoyl-8βE-imidazoC5,1-dy-1,2,3,5-tetrazol-4-one in dimethylsulfoxide and adding peanut oil. The solution obtained is aseptically distributed in 10 ampoules at a rate of 10 cm 3 per ampoule. The ampoules, each containing 100 mg of (2-chloroethyl) -3-N-methylsulfamoyl-8H-imidazot-5,1-dl-1,2,3,5-tetrazolone, are sealed.

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

EXAMPLE OF COMPOSITION 3
Capsules suitable for oral administration are prepared by depositing (2-chloroethyl) -N-methylsulfamoyl-8H-imidazol5,1-dg 1,2,9-tetrazol-4-one dan; 2 mg gelatin capsules at a rate of 10 mg per capsule.

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

Claims (6)

R E V E N D I C A T I O N S 1 - New derivative of tetrazine, characterized in that it meets the general formula

 In which R 1 represents a cycloalkyl radical or a straight or branched chain alkyl, alkenyl or alkynyl radical containing up to 6 carbon atoms, each alkyl, alkenyl and alkynyl radical being unsubstituted or substituted by one to three substituents chosen from the atoms halogen, the straight or branched chain alkyloxy, alkylthio, alkylsulfinyl and alkylsulfonyl radicals containing up to 4 carbon atoms and the optionally substituted phenyl radicals, A1 represents a nitrogen atom or a radical - CR3 = in which R3 represents a hydrogen atom or a substituent R4 in which R4 represents a halogen atom or a straight or branched chain alkyl or alkenyl radical containing up to 6 carbon atoms; carbon, which can carry up to 3 substituents chosen from halogen atoms, optionally substituted phenyl radicals, alkyloxy, alkylthio and alkylsulphonyl radicals containing up to 3 carbon atoms, or R 1 represents a cycloalkyl, cyano, hydroxy or nitro radical; or optionally substituted phenoxy, or a radical of the formula -COR5 (wherein R5 represents an alkyl or alkyloxy radical containing up to 4 carbon atoms, a hydroxy radical or an optionally substituted phenyl radical) or an alkanoylamino radical containing up to 6 carbon atoms, or R4 represents a radical of formulas :: - S (O) nRg, - SO2NR7R8 or - CZ2NR7R8 (in which n represents the numbers 0.1 or 2, R6 represents a straight or branched chain alkyl or alkenyl radical containing up to 4 carbon atoms (which may carry an optionally substituted phenyl substituent), a cycloalkyl radical or an optionally substituted phenyl radical, R7 and R8, which may be the same or different, each represents a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing up to 4 carbon atoms (which may carry an optionally substituted phenyl substituent), or a cycloalkyl radical; or an optionally substituted phenyl radical or the radical -NR R represents a heterocyclic radical, and Z2 represents an oxygen or sulfur atom), A2 represents a nitrogen atom or, when A1 represents a nitrogen atom, A2 represents a nitrogen atom or a radi-cal -CR3 = in which R3 is defined as above, Z1 represents an atom of oxygen or sulfur, and R2 represents a radical of the formulas -S (O) nR6, -50 2NR7R8, -CSNR7R8, -CONR7R9 or -CZ2NHNO2 in which n, R6, R7, R8 and Z2 are defined as above and the radical - NR7R9 represents a heterocyclic radical or R7 is defined as above and R9 represents a straight or branched chain alkyl or alkenyl radical containing up to 4 carbon atoms (which bears an optionally substituted phenyl substituent), or an optionally substituted phenyl radical, or when A1 represents a nitrogen atom or a radical -CR4 = in which R4 is defined as above and Z1 and A2 are defined as above or when A1 represents a radical -CH and Z represents a sulfur atom and A2 is defined as before , R2 ;; - is a radical of formulas  S (O) nR6, SO2NR7R8, -CZ NR7R8 or -CZ2NHNO2 wherein n, R6, R7, R8 and Z2 are defined as above] and, when R2 and / or R3 represents a sulfamoyl or sulfamoyl mono-substituted radical and / or R3 represents a carboxyl radical, their salts, it being understood that in the above definitions, the optional substituents on the phenyl and phenoxy portions may be chosen from halogen atoms and alkyl and alkyloxy radicals containing up to 4 carbon atoms and nitro radicals, that the cycloalkyl radicals contain 3 to 8 carbon atoms, that heterocyclic radical is understood to mean a 5-, 6- or 7-membered heterocycle which may optionally contain another heteroatom such as nitrogen, oxygen or sulfur and which may carry one or two straight or branched chain alkyl substituents each containing up to 4 carbon atoms. 2 - Process for the preparation of a product according to claim 1 in the formula of which R2 is different from a sulfamoyl radical,  carbamoyl which bears an optionally substituted phenyl or thiocarbamoyl substituent which bears an optionally substituted phenyl substituent and is different from a nitrocarbamoyl or nitrothiocarbamoyl radical, characterized in that a compound of general formula is reacted

 in which A1 and A2 are defined as in claim i and R12 represents a radical falling within the definition of R2 other than that representing a sulphamoyl, carbamoyl radical which bears an optionally substituted phenyl substituent or thiocarbamoyl bears to it an optionally substituted phenyl substituent and other than a nitrocarbamoyl or nitrothiocarbamoyl radical, with a compound of formula general: R1NCZ1 (IV) in which R1 and Z1 are defined-as in revendiation 1, then isolates: the product and optionally converts it to a salt when R2 represents a monosulphosulphosulfonyl radical and / or R3 represents a sulfamoyl or sulfamoyl radical; monosubstituted or represents a carboxy radical. 3 - Process for the preparation of a product according to claim 1 in the formula of which R2 represents a carbamoyl radical which bears an optionally substituted phenyl or thiocarbamoyl substituent which bears an optionally substituted phenyl substituent and R1, Al, A2 and Z1 are defined as in claim 1, characterized in that debenzyl is a compound of the general formula

 in which R 12 represents an optionally substituted phenyl radical, R 13 represents an optionally substituted benzyl radical and Z 2 is defined as in claim 1, by application or adaptation of methods known per se to replace a benzyl radical optionally substituted with an atom. hydrogen, and then isolating the product and optionally converting it to a salt when R represents a sulfamoyl or monosubstituted sulfamoyl radical or a carboxy radical. 4 - Process for the preparation of a product according to claim 1 in, the formula of which R1, A1, A2 and Z1 are defined as in claim 1 and R2 represents a radical of general formula: - CZ NHNO  In which Z2 is defined as in claim 1, characterized in that stol. nitre a compound of general formula

 in which R14 represents a radical of formula  - CZ2NH2 wherein Z2, R1, A1, A2 and Z1 are defined as in claim 1 and then isolates the product and optionally is converted into a salt  when R3 represents a sulfamoyl or monosubstituted sulfamoyl radical or a carboxy radical. 5 - Process for the preparation of a product according to claim 1 in the formula of which R1, A1, A2 and R2 are defined as in claim 1 and Z1 represents a sulfur atom, characterized in that one transforms a compound of general formula

 in which R1, A1 and R2 are as defined in claim 1 and R15 represents a radical of formula: - S (O) nR6, - SO2NR7R8, - CZ2NR7R8 or - CZ2NHNO2, R, R, R, n and Z2 being defined as in claim 1 by  phosphorus pentasulfide is optionally reacted, and the product is isolated and / or converted to a salt when R2 and / or R3 is a radical. sulfamoyl or monosubstituted sulfamoyl and / or R represents a carboxy radical. 36. Process for the preparation of a product according to claim 1, in which R 1, Al 2, Al 2 and Z 1 are as defined in claim 1 and R 2 represents a radical of general formula  - CSNR7R8 in which R7 and R8 are defined as in claim 1, characterized in that one transforms a compound of general formula

 in which R1, A1, A2 and Z1 are defined as in claim I and R represents a radical of general formula 16  - CONR7R8 wherein R7 and R8 are defined as in claim 1 by optionally phosphorus pentasulfide action and then isolates the product and / or transforms it into a salt when R3 represents a monounsubstituted sulfamoyl or sulfamoyl radical or a carboxy radical. 7 - pharmaceutical composition, characterized in that comprises as active ingredient, at least one tetrazine derivative according to claim 1, in combination with one or more pharmaceutically acceptable adjuvants or coatings.