LU84969A1 - NOVEL TETRAZINE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

'-v i *

The present invention relates to new tetrazine derivatives, their preparation methods and the pharmaceutical compositions containing them.

"The compounds of the present invention are derivatives of 2 tetrazine of general formula: $ (I>! Z 1 / in which R ^ represents a cycloalkyl radical or an alkyl, alkenyl or alkynyl radical in straight or branched chain containing up to with 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), the alkyloxy, alkylthio, alkylsulfinyl and alkylsulphonyl radicals in straight or branched chain containing up to 4 carbon atoms and the optionally substituted radLcauxphenyl represents a nitrogen atom or a radical - CR ^ = in which Rjj represents an atom hydrogen or a substituent R ^ in which R ^ represents a halogen atom, or an alkyl or alkenyl radical in a straight or branched chain containing up to 6 carbon atoms, which can bear up to 3 substituents chosen by mi halogen atoms, optionally substituted phenyl radicals.

.. * - "alkyloxy, alkylthio and alkylsulfonyl containing up to 3 carbon atoms or else R ^ represents a cycloalkyl, cyano,% hydroxy, nitro or phenoxy radical optionally substituted, or a radical of formula -COR ^ (in which R ^ represents an alkyl or alkoxy radical containing up to 4 carbon atoms, a hydroxy radical or a fully substituted phenyl radical) or else an alkanoylamino radical containing up to 6 carbon atoms, or else R ^ represents a radical formulas:

K

<c

X

2 ρ '"WW OR' CZ2NR7R8 (in which n represents the digits 0, 1 or 2, Rg represents an alkyl or alkenyl radical in a straight or branched chain containing up to 4 carbon atoms (which can bear a 5 (optionally substituted phenyl substituent), a cycloalkyl radical or an optionally substituted phenyl radical, R_ and Rg which may be identical or different, each represent a hydrogen atom or an alkyl or alkenyl radical in a straight or branched chain, containing up to with 4 carbon atoms (which may bear an optionally substituted phenyl substituent ^ or a cycloalkyl radical or an optionally substituted phenyl radical or else the radical -NR ^ Rg represents a heterocyclic radical, and represents an oxygen or sulfur atom) , A represents a nitrogen atom or, when A represents a

"X

Nitrogen atom, A ^ represents a nitrogen atom or a radical -CR ^ = in which R ^ is defined as above, Z ^ represents an oxygen or sulfur atom, and R represents a radical of ύ formulas: - S (O) ^ Rg, - SO ^ NR ^ Rg, - CSNR ^ Rg, -CONR ^ or -CZ2NHN02 20 in which n, Rg, R, _, Rg and Z2 are defined as above and the radical -NR ^ R ^ represents a heterocyclic radical or R „is defined as above and represents an alkyl or alkenyl radical in a straight or branched chain containing up to 4 carbon atoms (which carries an optionally substituted phenyl substituent), or else a optionally substituted * * ...... phenyl radical, or, 'when A ^ represents a nitrogen atom or a - -CR ^ = radical in which is defined as above and Z and A are defined as above or when A represents a J. d * J.

radical -CH = and Z represents a sulfur atom and A ,. is defined - x 30 as before, R2 represents a radical of formulas: 3 <\ * -3 (° 1 R6, -so2nr7r8, -cz2nr? r8 or cz2nh.mo2; in which n, Rg, R ^, Rg and Z2 are defined as above / and, when R and / or R represents a sulfamoyl radical Δ j * or mono substituted sulfamoyl and / or represents a carboxy radical, their salts, more 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 the salts. The salts are particularly useful as intermediates.

In the definitions of general formula (I), the optional substituents on the phenyl and phenoxy portions can 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. In the definition of general formula (I), the term heterocyclic radical is intended to mean a 5, 6 or 7-membered heterocycle which may eventually contain another heteroatom such as nitrogen, oxygen or sulfur and which can carry one or two alkyl substituents in a straight or branched chain each containing up to 4 carbon atoms, such as a piperidino, methyl-2, methyl-3, methyl-4, dim ethyl-2,4 or dimethyl- ^ radical 3,5 piperidino or a morpholino radical, pyrrolidinyl-1, perhydro-azepinyl-i, piperazinvl-1, methyl-4 piperazinyl-1 or thiazin-1,4 yl- - 4.

• · «- -

The descriptors of the British patent application * 2,104,522 and equivalent applications in other countries which claim priority from the initial British patent application No. 81 25791 such as patent application U, Sc410656 describe compounds of general formula (II) in which R ^ q represents a hydrogen atom, a cycloalkyl radical or an alkyl radical, / 1 4 <\ 1 c alkenyl or alkynyl in a straight or branched chain containing up to 6 carbon atoms, each alkyl radical , alkenyl or alkynyl being unsubstituted or substituted by 1 to 3 substituents i chosen from halogen atoms, an alkyloxy, alkyl- and alkylsulphonyl thio, alkylsulfinyl / straight or branched chain containing up to? 4 carbon atoms, and the phenyl radicals optionally substituted, and R represents a carbamoyl radical which can bear on the nitrogen atom one or two radicals chosen from the alkyl and alkenyl radicals in straight or branched chain each containing 10 up to to 4 carbon atoms and cycloalkyl radicals.

The tetrazine derivatives of general formula: ïju CII) K I | V‘Y \.

o Rl ° exhibit remarkable antineoplastic activity, for example against carcinomas, melanomas, sarcomas, lymphomas and leukemias; They also have remarkable immunomodulatory activity and are useful in the treatment of organ transplants and peav grafts and in the treatment of immunological diseases.

The compounds of general formula (I) of the present invention have similar properties with, in certain aspects, 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 imention, for example as described later in this description. Of particular importance are the classes of compounds of general formula (I) which include in their formula one or more of the following characteristics: / 5 X 1

AT

i) R represents a methyl radical or more especially a 2-halo ethyl radical, in particular a 2-chloro ethyl radical, ii) R ^ represents a radical of general formula: 5 -SO2R6, -SO ^ NR ^ Rg, -CONR ^ Rg or -CONHNOg, especially those in which Rg represents an alkyl radical such as methyl and those in which R_ represents a hydrogen atom or an alkyl radical such as methyl, and Rg represents a hydrogen atom or an alkyl radical such as methyl or a benzyl radical optionally substituted by an alkyl-xy radical, such as a 4-methoxy-benzyl radical, iii) R represents a radical R in which R represents a methyl, alkyl radical such as butyl, propyl, ethyl or more particularly / iv) one of the symbols A and A ^ represents a nitrogen atom 15 and the other represents a radical -CR =, v) A represents a nitrogen atom, vi) represents a atom d oxygen and / or vii) Z represents an oxygen atom.

The individual compounds of general formula (I) which are important include the following: (N-benzyl N-phenylcarbamoyl) -8 methyl-3 / 3H / - imidazo / 5,1-d / tetrazin-1,2,3, 5-cne-4 A, / N-benzyl N-4-methoxy-benzyl) carbamoyl / -8- ^ (2-chloro-ethyl) -3 / 3H / -imidazo / 5,1-d / 25 tetrazine-1,2 , 3,5 one-4 B, (N-benzylcarbamoyl) -8 (2-chloroethyl) -3 ./Oh/-. "-Î; --- - imidazo / dd, 1 ~ (/ tetrazme-1,2,3,5-one-4 C,; (2-chloro etl yl) -3- / N-methoxy-4 benzyl) N_- phenylcarbamoyl / -8 / 3 * i / -imidazo / 5,1-d / 30 tetrazine-1,2,3,5-one-4 D, (2-phloroethyl) -3 (N-phenylcarbamoyl) - 8 / 3H7-imidazo / 5, ld / -tetrazine-1,2,3,5-one-4 E, Ê ί ϊ 'i 6 (N-benzyl N-phenylcarbamoyl) -8 (2-chloro ethyl) -3 / 33 / -itnidazo / 5, ld / -tetrazine-1,2,3,5 one-4 F, (2-chloro ethyl) -3- (N-methyl N-phenylcarbamoyl) -8 / 3HAmi dazo / * 5 , 1-d / - tetrazine-1,2,3,5 one-4 G, 5 carbamoyl-8 (2-chloro ethyl) -3-methyl-6 / 3H / - * imidazo / 5,1-d / tetrazine -1,2,3,5 one-4 H, (2-chloro-ethyl) -3- (N, N-dimethylsulphamoyl) -8 / 3H / -imidazo / 5,1-d / -tetrazine-1,2, 3,5 one-4 I, (2-chloro ethyl) -3- (N-methylsulphamoyl) -8 10 / 3H / -imidazo / 5, ld.7 tetrazine 1,2,3,5 one-4 J, ( 2-chloroethyl) -3-methylsulonfonyl-8 / * 3h / - imidazo / 5,1-d / -tetrazine-1,2,3,5 one-4 K, methyl-3-methylsulfonyl-8/397 -imidazo / 5, l-d7-tetrazine-1,2,3,5 one-4 L, 15 (2-chloro ethyl) -3-ÎN-4-methoxy benzyl) sulfa-moyl / -8 / 3 | l / -imidazo / 5,1-d / tetrazi born-

1,2,3,5 one-4 M

(2-chloro-ethyl) -3 (sulfamoyl-8) / 3H7 ~ imidazo / 5, 1-d / "- tetrazine-1,2,3,5 one-4 N, 20 carbamoyl-8 (2-chloro ethyl) -3 / 3-H / ~ pyrazolo / 5,1-4 / - tetrazine-1,2,3,5 one-4 0, carbamoyl-8 methyl-3 / 5H / - pyrazolo / * 5, 1-d / - tetrazine-1,2,3,5 one-4 P, (2-chloro-ethyl) -3 piperidinocarbonyl-8 / 3H / -25 imidazo / 5, ld / -tetrazine-1,2,3,5 one-4 Q, carbamoyl-8 butyl-6 (2-chloro-ethyl) -3 / 3H / -imidazo- / 5,1-d / tetrazine-1,2,3,5 one-4 R, carbamoyl-8 (chloro-2 ethyl) -3 cyclohexy.1-6 / 3H / -imidazo / 5.1-d / tetrazine-1,2,3,5 one-4 S, 30 carbamoyl-8 (2-chloro-ethyl) -3 phenethyl -6 / 3H / - imidazo / 5,1-d / tetrazine-1,2,3 ", 5 one-4 T, benzyl-6 carbamoyl-8 (2-chloro-ethyl) -3 / 3N / ~ imidazo- / 5, 1-d / tetrazine-1,2,3,5 one-4 U, ff * X i 4 7 carbamoyl-8 (2-chloro-ethyl) -3 isopropyl-6 / 3H / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 y, carbamoyl-8 (2-chloro-ethyl) -3 propyl-6 / 3H7-imidazo- * / 5,1-d / tetrazine-1,2,3,5 one-4 5 carbamoyl-8 (2-chloro-ethyl) -3 ethyl-6 / 3H / -imidazo- / 5,1-d / tetrazine-1,2,3,5 one-4 χ, (2-chloro ethyl ) -3 (m 4-ethoxybenzyl) sulfamoyl-8 methyl-6 / 3H / - imidazo / * 5, 1-d / tetrazine-1,2,3,5 one-4 Y, 10 (2-chlorine-ethyl) -3 methyl-6 sulfamoyl-8 / 3H / - imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 Z, (2-chloro-ethyl) -3 dimethylsulfamoyl-8 methyl-6 / 3H / -imidazo / 5 , 1-d / tetrazine-1,2,3,5 one-4 AA, (2-chloro ethyl) -3 methyl-6 methylsulfonyl -8 / 3H / -15 imidazo / 5,1-d / tetrazine-1, 2,3,5 one-4 BB, (2-chloro-ethyl) -3 dimethylcarbamoyl-8 / 3H / -pyrazolo- / 5,1-d / tetrazine-1,2,3,5 one-4 CC, (chloro -2 ethyl) -3 (N-nitrocarbamoyl) -8 / 3H / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 DD, 20 methyl-3 methylsulfonyl-8 / 3H / - pyrazolo / 5,1-d / tetrazine-1,2,3,5 one-4 EE, (2-chloro-ethyl) -3 nethylsulfonyl-8 [yàj- pyrazolo- / 5,1-d / tetrazine-1,2 , 3,5 one-4 FF, (2-chloro ethyl) -3 6-rrethyl-methylsulfinyl-8 / 3H / -25 imidazo / 5,1-d / tetrezine-1,2,3,3 one-4 GG, (2-chloro-ethyl) -3 ethylsulfonyl - 8 methyl-6 / 3H / - imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 HH,. . - and (2-chloro-ethyl) -3 methyl-6 propylsulfonyl -8 / 3H / -30 imidazo / 5, 1-d / tetrazine-1,2,3,5 one-4c II ".

The letters A to II have been assigned to the compounds to facilitate later reference in the description.

Compounds of particular importance // t Î ί 8 include compounds C, K, L, M, 0, Q, R, W, X and DD, more particularly compounds I, J, N and BB and a very particular compounds H, Z, AA and CC <,, The new tetrazine derivatives of general formula 5 (I) showed a particular activity in mice at daily doses * between 0.2 and 320 mg / kg per kg of body weight of animal by intraperitoneal administration, against TLX5 (S) lymphoma according to the technique of GESCHER et al ”, Biochem. . Pharmacol. 30 ^ 89 (1981) and sarcomas ADJ / PC6A and M5076 (sar-10 reticulocellular horns).

Against leukemia L 1210 grafted intraperitoneally, intracerebrally and intravenously and against leukemia P 388 in the technique described in "Methods of Development of New Anticancer Drugs" (NCI monographs n ° 45, March 1977 pages l47 ~ l49, 15 National Cancer Institute, Bethesda, USA) the compounds have been shown to be active both intraperitoneally and orally at doses between 1 and 320 mg per kg of body weight dT animalc

Inhibition of both the primary tumor and metastases has been achieved in Lewis lung cancer, with similar doses o

Against melanoma B 16 and tumor C 38 in mice (NCI Monograph No. 45 already cited), the compounds have been shown to be active intraperitoneally at doses between 6.25 25 and 40 mg per kg of body weight d 'animalo

Against carcinoma C 26 of the colon in mice, grafted subcutaneously, the compounds have been shown to be active by the r route:. oral at doses of between 2 and 40 mg per ke of animal body weight “3C The compounds of general formula (II) can be prepared by application or adaptation of methods known per se.

According to a characteristic of the present invention, the compounds of general formula (I) in which R is different from a sulfamoyl radical, carbamoyl which carries an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted and different phenyl substituent of a nitro- 9 ί t "ί I 'V- carbamoyl or nitrothiocarbamoyl radical can be prepared by the action of a compound of general formula: A- / lX e

• A2 N

^ -I (III) R12 N „ô Δ

S

in which and are defined as above and represents a radical falling within the definition of R2 above other than that representing a sulfamoyl radical, carbamoyl which carries an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted phenyl substituent and the like than a nitrocarbamoyl or nitrothiocarbamoyl radical, with a compound of general formula: / T, r \ 1 ° R NCZ (IV) 1 1 in which R ^ and Z ^ are defined as above "

The reaction can be carried out in the absence or in the presence of an anhydrous organic solvent, for example a chlorinated alkane such as dichloromethane, or ethyl acetate, acetonitrile, N-methvlpyrrolidone-2 or 1 hexaraethylphosphoramide, at a temperature between 0 and 120 ° C. The reaction can be continued for up to 30 days "It is best to operate in the absence of light0

According to another characteristic of the invention, the compounds of general formula (I) in which Rp represents a carbamoyl radical which carries an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted phenyl substituent and R ^, A ^, Â0 and Z ^ are defined as above, can be prepared from the corresponding compounds of general formula (I) in which R ^ represents a radical of general formula: _cz ^ TR,, - 2 12 13 1 fi î 'i 10 in which represents an optionally substituted phenyl radical, R13 represents an optionally substituted benzyl radical and is defined as above, by application or adaptation of methods known per se to replace a benzyl radical optionally substituted by a hydrogen atom.

; As suitable reaction conditions, there may be mentioned, for example, catalytic hydrogenation (in the presence of a catalyst such as palladium on black and in a solvent such as ethyl acetate or diraethylformamide); or, when -, 10 represents a substituted benzyl radical in which the substituent or at least one substituent carried by the benzyl radical is an alkyloxy radical (such as methoxy) in the ortho or para position, by the action of trifluoroacetic acid, of preferably in the presence of anisole at room temperature or at a temperature close to it.

According to another characteristic of the invention, the compounds of general formula (I) in which Rg represents a radical of general formula: -CZ NHN0 „2 2 20 in which Z, R, A, A and Z are defined as above 1 1 X ώ 1 can be prepared by nitration of the compounds of general formula: ^ l4

X

"% Z1 - ..... in which R ^ represents a radical of formula:! -CZ2NH2 25 in which, R ^ and Z ^ are defined as above.

The reaction can be carried out near room temperature or below, preferably between 0 and 10 ° C, it \ *

L

• i 11 in the presence of a nitrating mixture such as a mixture of concentrated sulfuric and nitric acids.

According to another characteristic of the invention, the compounds of general formula (I) in which R ^ jA ^ jAg and are defined as above and Z represents a sulfur atom i 1 can be prepared from the compounds of general formula: R15 ip î H Ra (VI) o

in which, A ^ and are defined as above and R

represents a radical of formula: 10 - S (0) IL, -SO NR R, -CZ NR R or -CZ NHN0 „, nb '278 278 2 2, R,,, n and 2 ^ being defined as above) by action of phosphorus pentasulfide0

The reaction can be carried out in an organic solvent, for example an aromatic solvent such as benzene, toluene or xylene, or in pyridine or one of its derivatives such as lutidine, preferably at high temperature, by example between 50 and 120 ° C.

According to another characteristic of the invention, the

compounds of general formula (I) in which R „, A .., A0. and 2M

are defined as above and R2 represents a radical ce ·· - general formula: _ - CoiNiiTn Kg can be prepared from the compounds of general formula: * 20 ^ 16 <vn :) ^ Tsi N.

^ V \, zi û

V

12 * vi in which Ι ^, Α ^, Α ^ and are defined as above and R ^ g represents a radical of general formula: -CONR Rg in which R and Rg are defined as above, by action of phosphorus pentasulfide in conditions analogous to those described above for the reaction of phosphorus pentasulfide with the compounds of general formula (VI) "'Λ

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 action of the basic compound of general formula (I) with a hydroxide, a carbonate or preferably an 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 methods mentioned above, 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. Sci, 57 · 1044 (1968) and the methods described below in the example references “

By the term "methods known per se" as used in the present description is meant the methods already used or known in the literature.

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

EXAMPLE 1

30 Compound A

0.44 g of sodium nitrite is dissolved in 10 cm 3 of a 2M aqueous acetic acid solution at 0 ° C. The solution is ä

- V

13 by stirring at 0 ° C. and treated in small portions at a time / 0.7 g of 5-amino hydrochloride N-benzyl N-phenyl imidazolecarb <ixamide-4 (prepared as in reference example 1).

"

After 10 minutes, the gummy solid obtained is extracted with twice 20 cm 3 of ethyl acetate. The organic extracts are

Jr combined and washed with water and dried over magnesium sulphate

The solution obtained of 5-diazo N-benzyl N-phenyl imidazolecarboxamide-4 is treated with 5 cm 3 of methyl isocyanate and the mixture is stirred at room temperature for 10 24 hours in the dark. The solution is then concentrated to low volume and the residue is subjected to column chromatography under medium pressure, eluting with ethyl acetate. 0.22 g of (N-benzyl N-phenylcarbamoyl) -8 methyl-3 / 3H / imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 is thus obtained, in the form of a white crystalline solid melting at 168-170 ° C (with decomposition).

Elementary analysis:

Calculated%: 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 1 20 ′ NMR spectrum (in DMSO-dg): singlets at 3.75; 5, lû and 8.55 ppm multiplet at 7.0-7.4 ppm.

Mass spectrum: m / e = 360 (M +) EXAMPLE 2

Compound B

'3.7 g of sodium nitrite are dissolved in 35 cm3 of a 2M aqueous acetic acid solution at 0 ° C. The solution is stirred · "" “at 0 ° C. and treated dropwise with a solution of 2.2 g of 5-amino hydrochloride N-benzyl N- (4-methoxybenzyl) imidazolecarboxamide-4 (prepared as in the reference example 2) in 10 cm3 of 1,2-dimethoxyethane. The reddish gum which separates is extracted with 2 times 20 cm 3 of ethyl acetate. The organic extracts are combined and washed with water and with a saturated aqueous solution of sodium chloride and then dried over sodium sulfate.

l4 c.

ι '

The solution obtained from diazo-5 N-benzyl N- (4-methoxy benzyl) imidazolecarboxamiâe-4 is treated with 2 cm 3 of 2-chloro-ethyl isocyanate and the mixture is left at room temperature "for 24 hours in the dark" The solution is then concentrated to low volume and the residue is subjected to column chromatography under medium pressure, eluting with ethyl acetate. 1.5 g of / N-benzyl N- (methoxy- 4 benzyl) carbamoyl / -8 (2-chloro ethyl) -3 / 3H / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 in the form of a brown oil.

10 EXAMPLE 3

Daring corner C

--------- In 20 cm3 of trifluoroacetic acid ^ 1.5 g of / N-benzvl N- (4-methoxy benzyl) carbamoyl / -8 (2-chloroethyl) -3 / 3H are dissolved / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 (crude product prepared as described in Example 2) and 0.5 cm3 of anisole, then leave the mixture to stand for 18 hours at room temperature. The reaction mixture is then concentrated to dryness and the residue is subjected to column chromatography under medium pressure, eluting with a mixture of ethyl acetate and petroleum ether (PE: βΟ-δΟ'Ό) (2- 1 by volume).

20.34 g of (N-benzylcarbamoyl) -8 (2-chloroethyl -) - 3/3 ^ 7 -imidazo / 5) 1-dy7 tetrazine-1,2,3 is thus obtained. 5 one-4, in the form of a colorless solid melting at 153-155 ° C (after recrystallization in ethyl ether) o Elemental analysis 25 Calculated%: C = 50.53; H = 3.94; N = 25.26; Cl = 10.65

Found%: C = 49.9; H = 3.92; N = 24.4; Cl = 10.4 - -1

IR spectrum (KBr tablet): 3370, 31.50, 1755 and 1660 cm

NMR spectrum (in DMSO-dg): singlets at 7.3 and 8.9 pp i; doublet at 4.4 ppm and triplets at 4.0; 4.6 and 9.05 ppm.

3 ° EXAMPLE 4 --- S ----? 0.6l g of sodium nitrite is dissolved in 10 cm 3 of water o? * ί * 15

The solution is stirred at 0 ° C. and treated dropwise with a solution of 2.5 g of amino-5 N- (4-methoxy benzyl) N-phenyl imidazolecarboxamide-4 (prepared as described in the reference example 3) in 9 cm3 of 2M hydrochloric acid and 15 cm3 of 1,2-dimethoxy-1,2 ethane. After 20 minutes, the solution is extracted. with 3 times 50 cm3 of ethyl acetate and the organic extracts are combined and dried over magnesium sulfate. The solution is filtered and the solvent evaporated. 2.8 g of diazo-5 N- (4-methoxy benzyl) N-phenyl imidazolecarboxamide-4 are thus obtained, in the form - 10 of an orange oil

This oil is dissolved in 40 cm3 of ethyl acetate and treated with 8 cm3 of 2-chloro ethyl isocyanate. The mixture is left to stand for 5 days in the dark. The solution is concentrated at low volume and the residue obtained is subjected to column chromatography under medium pressure, eluting with ethyl acetate. 1.5 g of (2-chloroethyl) -3 / N- (4-methoxy-benzyl) N-phenylcarbamoyl / - 8 / 3ji / -imidazo / 5,1-d / tetrazine-1,2,3 are thus obtained , 5 one-4, in the form of a glass melting at 55 ° C. NMR spectrum (in DMSO-dg): 3 * 6 singlets; 5.0 and 8.5 ppm; 20 triplets centered at 3.9 and 4.5 ppm; multiplet at 6.6-7.2 ppm. • IR spectrum (KBr tablet): 1740 and 1640 cm ^ EXAMPLE 5

Compound E _ --------- In 10 cm3 of tnfluoroacetic acid, 1 g of (2-chloro-ethyl) -3 / N— (4-methoxy benzyl) N-phenylcarbamoyl / -8 25 / is dissolved 3H / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 (prepared as described in example 4) and 0.2 cm3 of anisole, then leave the mixture to stand for 13 hours at room temperature. The reaction mixture is then concentrated to dryness and the residue is triturated with ethyl ether. 0.43 g of (2-chloroethyl) -3 N-phenyl- 2o carbamoyl-8 / 3H / -imidazo / * 5.1-d / tetrazine-1,2,3,5 one-4 is thus obtained, in the form of a beige-brown solid, melting at 166 ° C. (with decomposition) (after recrystallization from ethyl acetate).

i * ί l6

Elementary analysis:

Calculated ° / o i 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 l680 cm-. 5 NMR spectrum (in DMSO-dg): singlets 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

2.8 g of sodiam nitrite are dissolved in 84 cm 3 of a 2M aqueous acetic acid solution. The solution is stirred at 0 ° C. and treated in small portions at a time with 2.8 g of 5-amino-hydrochloride N-benzyl N-phenyl imidazolecarboxamide-4 finely pulverized (prepared as described in reference example 1 ). After 10 minutes, the gummy solid obtained is extracted with 3 times 30 cm 3 of ethyl acetate and the organic extracts are combined and washed with water then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate ..

The solution obtained from 5-diazo N-benzyl N-phenyl imidazolecarboxamide-4 is treated with 9 cm 3 of 20-chloro-ethyl isocyanate and the mixture is left to stand for 4 days in the dark. The solution is then concentrated to low volume and the residue is subjected to column chromatography under medium pressure, eluting with ethyl acetate <= 1 g ce (N-benzyl N-phenylcarbamoyl) -8 (2-chloroethyl) is thus obtained -3 / 3H / -imidazo 25 / 5,1-d / tetrazine-1,2,3,5 one-4, in the form of a glass.

Elementary analysis; - '’Calculated%: C = 58.75; H = 4.19; N = i, 56; Cl = 8.67

Found ° / o: C = 59.3; H = 4.57; N = - 9.9; Cl = 8.5

IR spectrum (KBr tablet): 1740 and ΐ64θ cm- 30 NMR spectrum (in DMSO-dg): 5.2 singlets; 7.1; 7.3 and 8.6 ppm; triplets centered at 4.0 and 4.6 ppm.

V *

V

17 EXAMPLE 7

Compound G. ,,. , --------- To a solution of 11 g of sodium nitrite in 50 cm3. of water cooled to 0 ° C., a solution of 4 g of 5-amino hydrochloride N-methyl N-phenyl imidazolecarboxa- is added dropwise; 5 mide-4 (prepared as described in reference example 4) in 40 cm of 2M aqueous acetic acid solution. After 10 minutes, the resulting mixture is extracted with 4 times 100 cm3 of ethyl acetate and the organic extracts are combined, filtered and dried over magnesium sulfate.

The solution obtained from diazo-5 N-methyl N-phenyl imida-zolecarboxamide-4 is treated with 11 cm 3 of 2-chloro-ethyl isocyanate and the mixture is left to stand overnight in the dark. The solution is then concentrated at low volume and the residue is subjected to column chromatography under low pressure, eluting with ethyl acetate. Or thus 5.75 g of a product is obtained which is triturated with isopropyl ether and then with methylene chloride. The insoluble residue is recrystallized from a mixture of petroleum ether (PE. 60-80 ° C) and ethyl acetate. 0.8 g of (2-chloroethyl) -3 (N-methyl N-phenylcarbamoyl) -8 20 '/ 3H / -imidazo / 5.1-d / tetrazine-1,2,3,5 one is finally obtained -4, in the form of a colorless solid melting at 130-132 ° C.

Elementary analysis ί

Calculated%: C = 50.53; H = 3.94; N = 25.26; Cl = 10.65 Found ° / o: C = 50.4; H = 3.91; N = 24.9; Cl = 10.6 Λ 25 IR spectrum (KBr tablet): 1750 and 1640 cm-

NMR spectrum (in DMSO-dg): singlets at 3.4: 7.2 and 8.65 ppm; ... triples centered at 3.95 and 4.6 ppm.

EXAMPLE 8

6.33 g of a suspension of 1.54 g of 5-diazo-2-methyl-imidazole-30 carboxamide-4 (prepared as described in reference example 5) in 45 cm3 of ethyl acetate are added with stirring 2-chloro-ethyl isocyanate and stir the mixture at room temperature for 5 days in the dark.

V

i8 "'

The mixture is then diluted with ethyl ether and the solid obtained is separated by filtration, washed with ethyl ether and dried under vacuum at room temperature. We obtain . thus 2g of carbamoyl-8 (2-chloro-ethyl) -3 methyl-6 / 3H / -imidazo- 5 / 5.1-4 / tet razine-1,2,3,5 one-4 melting at 170 ° C (with decomposition ).

; Elementary analysis:

Calculated #: C = 37.44; H = 3.54; N = 32.75; Cl = 13.82 Found%: C = 37.0; H = 3.49; N = 32.8 5 Cl "13.3 EXAMPLE 9 y

Compound I. , J „10 --------- To a solution of 0.5 d> g of diazo-5 Ν, Ν-dimethyl imidazolesulfonamide-4 (prepared as described in reference example 6) in 40 cm3 of ethyl acetate, 3 cm3 of 2-chloro-ethyl isocyanate is added and the mixture is stirred for 48 hours in the dark. The reaction mixture is then evaporated in vacuo at a temperature below 40 ° C until reaching a volume of approximately 15 cm 3 and then diluted with ethyl ether. The solid obtained is separated by filtration. 0.68 g of (2-chloroethyl) ~ 3 (Ν, Ν-dimethylsuifamoyl) -8 / 3H / -imidazo / 5.1-d / tetrazine-1,2,3,5 one-4 is thus obtained form of greyish needles melting at 155-156 ° C.

20 Elementary analysis:

Calculated%: C = 31.3; H = 3.62; N * 27-4; Cl = 11.6 Found%: C = 30.4; H = 3.35; N = 26.8; CI = 11.8 IR spectrum: 1755 cm-1

NMR spectrum (in DMSO-dg): singuiets at 2.80 e-; 8.90 ppm; triplets 25 to 3.99 and 4.62 ppm.

EXAMPLE 10 --- £ — To a suspension of 0.7 g of 5-diazo-N-methyl imidazole-sulfonamide-4 (prepared as described in reference example 7) in 40 cm3 of ethyl acetate, add 3 cm3 of 2-chloroethyl isocyanate and stir the mixture in a stoppered flask for 48 hours in the dark.

ί 19%

Lg niθlange r * e3, c * fcxorineX GS "t Gnsuitg οοποβη-Ίη © a srivinon half its volume under vacuum at a temperature below 35 C, then diluted with ethyl ether. The solid obtained is separated by filtration and washed with ethyl ether to obtain 0.32 g 5 of (2-chloro-ethyl) -3 (N-methylsulfamoyl) -8 / 3H / -imidazo / 5,1-d / tetra-zine-1,2 , 3.5 one-4 in the form of shiny beige flakes, melting at 1447 ° C.

Elementary analysis:

Calculated%: C = 28.7; H = 3.08_; N = 28.7 10 Found%: C = 28.5; H = 2.90; N = 28.7 - -1 IR spectrum: 1745 cm

NMR spectrum (in DMSO-dg): doublet at 2.58 ppm; triples at 3.98 and 4.6l ppm; 7.94 ppm quartet; singlet at 8.84 ppm.

EXAMPLE 11 Compound K

15 --------- To a solution of 0.55 g of 5-diazo-4-methylsulfonyl imidazole (prepared as described in reference example 8) in 50 cm3 of anhydrous ethyl acetate, add 3 cm3 of 2-chloro-ethyl isocyanate and stir the mixture at room temperature for 48 hours in the dark. The mixture is then evaporated in vacuo and the oily residue is triturated with petroleum ether (PE 60-80 ° C). The solid obtained is separated by filtration and subjected to chromatography under medium pressure, eluting with ethyl acetate. The solid white product obtained is triturated with petroleum ether and separated by filtration. 0.72 g of 25 (2-chloroethyl) -3 methylsulfonyl-8 / 3H7-imiaazo / 5,1-d / tetrazine- 1,2,3,5 one-4, melting at 154-155 ° C., are thus obtained. .

Elementary analysis: _ * *

Calculations ° / o: 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 30 EXAMPLE 12

Compound L. . ... n rr. _ --------- To a solution of 0, t> 5 g of diazo-5-methylsulfonyl-4 imidazole (prepared as described in reference example 8) in 20 c * '60 cm3 of acetate of ethyl, 3.5 cm 3 of methyl isocyanate are added and the mixture is left to stand 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 40 ° C for 2 days and then left to stand at room temperature for 3 days.

The mixture is then concentrated under vacuum until a volume of 10 to 15 cm3 is obtained and chromatographed under medium pressure, eluting with ethyl acetate. 0.17 g of methyl ~ 10 3 methylsulfonyl-8 / 3H / -imidazo / 5, ld / tetrazine-1,2,3,5 one-4 is thus obtained in the form of a white crystalline solid melting at 185- iS6 ° C (with decomposition) o

Elementary analysis:

Calculated%: C = 31.44; H = 3.08; N = 30.56 15 Found%: C = 31.2; K = 2.89; N = 30.3 EXAMPLE 13

Compound Μ,,. , Λ „. „,, --------- To a solution of 0.3 g of diazo-5 N- (4-methoxy benzyl) imidazolesulfonamide-4 (prepared as described in reference example 9) in 25 cm3 of anhydrous ethyl acetate, 1.5 g of 2-chloro-ethyl isocyanate are added and the mixture is stirred. room 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 chromatography under medium pressure, eluting with ethyl acetate. A white solid is obtained which is triturated with petroleum ether, separated by filtration and dried under reduced pressure (10 mm of mercury) at 0 ° C for 1 hour.

Air is obtained if 0.2 g of (2-chloro ethyl) -3 / N- (4-methoxy benzyl) sulfamoyl / -8 ^ 3H / -imidazo / 5, ί-ûj tetrazine-1,2,3,5 one-4 melting at 155-156 ° C (with decomposition).

-1 50 IR spectrum: 1745 cm Elementary analysis:

Calculated%: C = 42.16; H = 3.79; N = 21.07 Found%: C = 41.9; H = 3.72; N = 20.5 EXAMPLE 14 21 • Compound N. .

--------- 0.1 g of (2-chloro ethyl) -3 / N-4-methoxy-benzyl) sulfamoyl / -8 / 3H / -îmidazo / 5, ld / tetrazine-1 is dissolved, 2,3,5 one-4 (prepared as described in Example 13) in 1 cm 3 of trifluoroacetic acid and 3 drops of anisole and the solution is left 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 60-80 ° C) and ethyl acetate (1/1 by volume). 50 mg of (2-chloroethyl) -3 sulfamoyl-8 / 3_H / -imidazo / 5, ld / tetrazine-1,2,3,5 one-4 are thus obtained in the form of a white solid melting at 183eC ( with decomposition).

IR spectrum: 1750 cm ^ 13 NMR spectrum (in DMSO-d ^): singlets at 8.8 and 7.8 ppm; triplets at 4.58 and 3.95 ppm.

EXAMPLE 15

Compound 0, ,, --------- To a suspension of 5.9 g of 3-diazo pyrazolecarbo-xamide-4 (prepared as described by CHENG et al., Op. Cit.) In 20,150 cm3 ethyl acetate, 24 cm3 of 2-chloro-ethyl iso cyanate is added with stirring and the mixture is kept at room temperature with stirring for 7 days in the dark. The reaction mixture is diluted with ethyl ether and the solid obtained is separated by filtration and washed with ethyl ether. 8.36 g of a mixture are thus obtained in the form of a creamy solid foundation at 173-174 ° C (with decomposition).

A sample of 1 3 of said mixture is dissolved in 20 cm3 of dimethylsulfoxide and heated laying overnight at 60 ° C. The solution is concentrated to dryness (at a temperature below 60 ° C under a pressure below 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.

ί.

22 * ι

The solution thus obtained is treated with 3 g of deactivated silica gel containing 20% water and the mixture is evaporated to dryness. The residue is loaded on a column of silica gel and subjected to chromatography under medium pressure, eluting with 5 ethyl acetate. After recrystallization of the product obtained; in acetonitrile, 0.25 g of carbamoyl-8 (2-chloroethyl) -3 / 3H / -pyrazolo / 5,1-d / tetrazine-1,2,3,5 one-4 is obtained, in the form colorless needles melting at 203-204 ° C (with decomposition) o Elemental analysis î -4 10 Calculated: C = 34.65; H = 2.91; N = 34.64; Cl = l4.6l

Found%: C = 34.8; H = 2.92; N = 34.7; Cl = i4.6 EXAMPLE l6

Compound P. ,, --------- To a suspension of l, og of 3-diazo pyrazolecarboxamide-4 (prepared as described by CHENG et al., Op. Cit.) In 49 cm3 of dichloromethane and 2.5 cm3 of N-methylpyrrolidone-2, 6 cm3 of methyl isocyanate are added with stirring, then the mixture is stirred for 7 days in the dark. The mixture is then diluted with ethyl ether and the solid formed is separated by filtration. 2.24 g of a mixture are thus obtained in the form of a cream solid, melting at 179-188 ° C (with decomposition).

A sample of 1 g of this solid is dissolved in 10 cm 3 of dimethyl sulfoxide and treated with 8 g of deactivated silica gel containing 20 ° / a of water and the mixture is evaporated to dryness under reduced pressure (0.1 mm of mercury ) at 60 ° C. The residue is loaded on 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 quickly separated by filtration. 4l mg of carbamoyl-8 methyl-3 / 3h / -30 pyrazolo / 5,1-d / tetrazine-1,2,3,5 one-4 are thus obtained, in the form of a colorless solid melting at 1 '70 ° C (with decomposition).

NMR spectrum (in DMSO-dg): singlet at 3.95; 7.45; 7.55 and 8.50 ppm. IR spectrum (KBr tablet): 3400, 3l60, 1750 and 1680 cm î 23 EXAMPLE 17 --------- To a solution of 0.79 g of sodium nitrite in 6 cm3 of water) is added dropwise and with stirring a solution of 2.1 g of 4-amino-piperidinocarbonyl-5 imidazole hydrochloride 5 (prepared as described in reference example 10) in 17 cm3 of an aqueous solution of acetic acid IM. The casting is carried out in 5 minutes at a temperature between 5 and 10 ° C. The solution is extracted with 4 times 45 cm3 of ethyl acetate; the extracts are combined and dried over magnesium sulfate and evaporated under reduced pressure (0.1 mm of mercury) at 30 ° C. The residue is dried in desiccator over phosphorus pentoxide for 45 minutes. 1.73 g of 4-diazo-piperidinocarbonyl-5 imidazole are thus obtained in the form of red crystals sufficiently pure to be used as they are in the following step.

A solution of 1.73 g of crude 4-diazo-piperidinocarbonyl-5 imidazole (prepared as described above) in 53 cm3 of dry ethyl acetate is treated with 5.9 cm3 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 of mercury) 20 at 3 ° C. and the residue is subjected twice to chromatography on silica gel under medium pressure, eluting with a mixture of acetate ethyl and acetonitrile (88/12 by volume). The suitable fractions are combined and evaporated and the residue is triturated with petroleum ether (PE = 40-60 ° C). 1.46 g of (chloro-25 2 ethyl) -3 piperidinocarbonyl-8 / 3H / -irnidazo / 5,1-d / tetrazine-1,2,3,5 one-4 are thus obtained, in the form of bad crystals. ; pale melting at 92 ~ 940C.

Elementary analysis

Calculated%: C = 46.4; H = 4.87; N = 27) 1 Found ° / ü: C = 45.3: H = 4.98; N = 26.130 NMR spectrum (in DMS0-dg): singlet at 8.7 ppm; triplets at 4.6 and 4.0 ppm; multiplets at 3.2-3.4 and 1.5-1.8 ppm.

IR spectrum (KBr tablet): 1750, 1630 cm ~ ^ EXAMPLE 18 \ 24 * «

Compose , .

--------- Cooled and maintained at a temperature between 5 and 10 ° C a stirred solution of 1.61 g of sodium nitrite "in 5 cm3 of water and added dropwise in 5 minutes a solution of 1.61 g of 5-amino-2-butyl hydrochloride imidazolecarbo-xamide-4 (prepared as described in the German patent application: No. 2 358 509) in 17.7 cm3 of IN hydrochloric acid. A yellow precipitate is obtained which is separated by filtration and dried in a desiccator = on phosphorus pentoxide. 0.47 g of 2-butyl-5 diazo-5 imidazolecarboxamide-4 is thus obtained, in the form of a yellow solid melting at 109-111 ° C (with decomposition), and which is sufficiently pure to be used as it is in l 'next step.

A solution of 0.47 g of crude 2-butyl-5 diazo-imidazolecarboxamide-4 (prepared as described above) in 14 cm3 of ethyl acetate is treated with 1.5 cm3 of 2-chloro isocyanate ethyl and left to stand for 24 hours in the dark. The tawny 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-chloro-ethyl) -3 / 3H / ~ 20 imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 is thus obtained colorless crystals melting at 165-167 ° C (with decomposition).

Elementary analysis:

Calculated%: C = 44.2; H = 5.06; N = 28.1; Cl = 11.9 Found%: C = 43.9; H = 4.90; N = 27.9; Cl = 12.0 "25 EXAMPLE 19

Compound S

A stirred solution of 0.44 g of sodium nitride in 3.7 cm 3 of water is cooled and maintained at a temperature of between 5 and 10 ° C. at a temperature of between 5 and 10 ° C. and added dropwise over 5 minutes. a solution of 1.1 g of 5-amino-2-cyclohexyl-imidazole-carboxemide-4 hydrochloride (prepared as described in German patent application No. 509) in 28 cm 3 of a 2M acetic acid solution.

\ 25

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

0.86 g of cyclohexyl-2-diazo-5 imidazolecarboxamide- is thus obtained. 4, in the form of an orange solid, sufficiently pure to be used 5 as is in the next step.

* A solution of 0.86 g of crude cyclohexyl-2 diazo-5 imidazole-carboxamide-4 (prepared as described above) in 17 cm3 of ethyl acetate is treated with 2 cm3 of chloro-2 isocyanate ethyl and left to stand for 24 hours in the dark. The solid "10 obtained is separated by filtration and recrystallized from ethyl acetate. This gives 0.23 g of carbamoyl-8 (2-chloroethyl) -3 cyclohexyl-6 / 3H / -imidazo / 5, ld / tetrazine-1,2,3,5 one-4, in the form of colorless crystals melting at 245-248 ° C (with decomposition).

Elementary analysis: 15 Calculated%: C = 48.1; H = 5.28; N = 25.9; Cl = 10.9 Found%: C = 47.6; H = 5.16; N = 25.6; Cl = 10.8 EXAMPLE 20 --------- A stirred solution of 0.58 g of sodium nitrite 20 in 4.7 cm3 of is cooled and kept at a temperature between 5 and 10 ° C. water and a solution of 1.8 g of 5-amino-2-phenethyl-2-imidazole-carboxamide-4 hydrochloride (prepared as described in reference example 11) is added dropwise over 5 minutes in 18 cm3 of a 2M aqueous acetic acid solution. The yellow precipitate obtained is separated by filtration and dried in a desiccator over phosphorus pentoxide for 1 hour. 2 g of 5-diazo-2-phenethyl-imidazolecarboxamide-4 are thus obtained, in the form of a solid - ----- yellow, sufficiently pure to be used as it is in the following stage.

The suspension of 2 g of crude 5-diazo-2-phenethyl-imidazole-30-carboxanide-4 (prepared as described above) in 29 cm 3 of ethyl acetate is treated with 3.4 cm 3 of 2-chloro isocyanate ethyl and stirred for 24 hours in the dark. The solid obtained is separated by filtration and recrystallized twice from ethyl acetate.

i "26"

0.44 g of carbamoyl-8 (2-chloro-ethvl) -3 phenethyl-6 / 3H / “imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 is thus obtained, in the form of colorless crystals, melting at 179-181 ° C (with decomposition). Elementary analysis: 5 Calculated%: C = 52.0; H = 4.36; N = 24.2; Cl = 10.2, Found%: C = 51.8; H = 4.19; N = 24.2; Cl = 10.2 EXAMPLE 21

Compound U,.

--------- To a solution of 2.4 g of 2-benzyl-5-diazo-imidazole- * carboxamide-4 (prepared as described in the example, reference 12) 10 in 150 cm3 of acetate d anhydrous ethyl, 10 cm 3 of 2-chloro-ethyl isocyanate are added and the reaction mixture is left 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 2 times 30 cm 3 of petroleum ether (m.p. = 60-80 ° C) to remove the excess of 2-chloro-ethyl isocyanate. The remaining residue is then triturated with 2 times 50 cm 3 of dichloromethane to extract the desired product from the bis (2-chloro-ethyl) -1.3 urea which is the insoluble by-product which forms during the reaction. The chloro-methylenic 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 suitable fractions are combined, evaporated and the product recrystallized from ethyl acetate. 0.7 g of 6-benzyl-carbamoyl-8 (2-chloroethyl) -3 / 3h / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 is thus obtained, melting at 16 l -163 ° C (with 25 decomposition).

Elementary analysis:, - Calculated%: C = 50.53; H = 3.94; N = 25.26; Cl = 10.66

Found%: C = 50.4; H = 3.96; N = £ 5.4; Cl = 10.8 _ Λ

IR spectrum: 1740 cm 30 EXAMPLE 22

Compound V.

--------- To a solution of 1.2 g of 5-diazo-2-isopropyl-imidazole-carboxamide-4 (prepared as described in reference example 13) in \ 27 "75 cm3 of acetate anhydrous ethyl> 5 cm 3 of 2-chloro-ethyl isocyanate is added and the mixture is left to stand at room temperature for 5 days in the dark. The crystalline solid obtained is separated by filtration and washed with petroleum ether ( PcE. = 60 - 80 ° C) <,

5 0.2 g of carbamoyl-8 (2-chloroethyl) -3 isopropyl-6 i / 3H / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 is thus obtained. at l89-l90 ° C

(with decomposition).

Elementary analysis:

Calculated ° / o: C = 42.19; H = 4.60; N = 29.5 10 Found ° / o: C = 42.0; H = 4.64; N = 29.5 IR spectrum: 1740 cm ^ EXAMPLE 23

Comuose W

--------- To a solution of 1.37 g of 5-amino-2-propyl imidazole-carboxamide-4 (prepared as described in German patent application 15 No. 2 358 509) in 22 cm3 of a 2M aqueous solution of acetic acid, a solution of 0.7 g of sodium nitrite in 6 cm3 of water is added dropwise at a temperature between 0 and 5 ° C over 5 minutes. The precipitate obtained is separated by filtration and dried in a desiccator over phosphorus pentoxide. 0.56 g 20 · of 5-diazo-propyl-2 imidazolecarboxamide-4 is thus obtained, in the form of a yellow solid, sufficiently pure to be used as it is in the following step.

A solution of 0.56 g of 5-diazo-propyl-2 imidazolecarboxamide-4 (prepared as described above) in 14 cm3 of anhydrous ethyl acetate is treated with 1.6 cm3 of 2-chloro isocyanate 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-6 / 3H / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 is thus obtained, in the form of a beige solid melting at 145-148 ° C (with decomposition).

Elementary analysis:

Calculated%: C = 42.2; H = 4.60; N = 29.5 Found%: C = 41, 1; H = 4.4; N = 28.5 \ 28

NMR spectrum (in DMSO-d ^): singlet at 7.7 ppm; triples at 4.6 5 4.0; 3.2 and 1.0 ppm; multiplet at 1.8 ppm.

IR spectrum (KBr tablet): 1750, 1695 cm "" 1.

EXAMPLE 24

Compound X. , • 5 A stirred solution of 0.8 g of 5-amino-2-ethyl-imidazolecarboxamide-4 (prepared as described in German patent application No. 2 358 509) in 14 cm3 of an aqueous acid solution 2M acetic acid, a solution of 0.44 g of sodium nitrite in 3.8 cm3 of water is added dropwise over 5 minutes at a temperature between 0 and 3 ° C. The precipitate obtained is separated by filtration and dried in a desiccator on phosphorus pentoxide for 1 hour. 0.62 g of diazo-5-ethyl 2-imidazolecarboxamide-4 is thus obtained, in the form of a yellow solid, melting at 1339 ° C. (with decomposition), sufficiently pure to be used as it is in the following step 15.

A solution of 0.62 g of crude 5-diazo-2-ethyl-imidazolecarboxamide-4 (prepared as described above) in 22 cm3 of anhydrous ethyl acetate is treated with 2.4 cm3 of 2-chloro isocyanate ethyl and stirred for 24 hours in the dark. The preci-20 pity obtained is separated by filtration and washed with ethyl acetate. 0.59 g of carbamoyl-8 (2-chloro-ethyl) -3 ethyl-6 / 3H / -imidazo / * 5 is thus obtained, 1-d / tetrazine-1,2,3,5 one-4, .so \ is gray crystals melting at 172-176 ° C (with decomposition) "

Elementary analysis: 25 Calculated%: C = 39, 9; H = 4.10; N = 31.0; Ci. = 13.1 found? O: C = 39.7; H = 3.98; N = 31.0; Cl = 13.1 EXAMPLE 25 -2 -? ----- To a solution of 2.45 g of diazo-5 (4-methoxy benzyl) sulfamoyl-4 methyl-2 imidazole, (prepared as described in example 30 of reference 14) in 100 cm3 of anhydrous ethyl acetate, 3 cm3 of 2-chloro-ethyl isocyanate are added and the mixture is stirred at room temperature for 56 hours in the dark.

29 J>

The mixture is then treated again with 3 cm 3 of 2-chloro-ethyl isocyanate and stirred at room 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 cm3 5 of petroleum ether (PE "= 60-80 ° C) to remove the excess 2-chloro-ethyl isocyanate" The remaining residue is then triturated with 2 times 50 cm3 of dichloromethane to extract the product desired bis (2-chloroethyl) -1.3 urea which is the insoluble by-product which is formed 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-chloro-ethyl) -3 (4-methoxy-benzyl) sulfamoyl-8-methyl-6 / 3H / -imidazo / 5,1-d / tetrazine-1,2,3,5 are thus obtained. -4 melting at l59_l60 ° C (with decomposition).

_ i

IR spectrum: 1760 cm 15 EXAMPLE 26

Compound Z _ Λ. ,. ,.

--------- In 10 cm3 of trifluoroacetic acid, 1.5 g of (2-chloro-ethyl) -3 (4-methoxy-benzyl) -sulfamoyl-8-methyl-6 / 3H / - imidazo / 1, 1-d / tetrazine-1,2,3,5 one-4 (prepared as described in Example 25) and 10 drops of anisole, then / let the mixture sit overnight at temperature ambient. The reaction mixture is concentrated in vacuo and the residue is triturated with ethyl ether. The pale brown solid is separated by filtration and recrystallized from acetone. This gives 0.55 g of (2-chloro-ethyl) -3-methyl-6-sulfamoyl-8 / 3H / -imidazo / 5,1-d / tetrazine -1,2,3,5 one-4, melting at 25 199-200 ° C (with decomposition).

Elementary analysis:

Calculated ° / o: 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 *.

30 EXAMPLE 27

Compound AA. ,. . n ---------- To a solution of 1.8 g of dxazo-5 dimethylsulfamoyl-4 methyl-2 imidazole (prepared as described in reference example 15) * * 30 in 100 cra3 d ' ethyl acetate, 4 cm 3 of 2-chloro-ethyl isocyanate is added and the reaction mixture is left to stand at room temperature for 2 days. The reaction mixture is then * treated again with 4 cm 3 of 2-chloro-ethyl isocyanate and left to stand at room temperature for a further 6 days. The reaction mixture 1 is then concentrated under vacuum and the residue is triturated with 2 times 25 cm 3 of petroleum ether (POE = 60-80 ° C). The remaining solid is dissolved in ethyl acetate and chromatographed on silica gel under medium pressure, eluting with ethyl acetate = 10. The suitable fractions are combined, evaporated to dryness and the residue is triturated with petroleum ether (PE = 60r * 80 ° C). 2.17 g of (2-chloroethyl) -3 dimethylsulfamoyl-8 methyl-6 / 3Ji / -imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 are thus obtained, melting at 137 -138 ° C.

Elementary analysis: 15 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 diazo-5 methyl-2 methylsulfonyl-4 imidazole (prepared as described in reference example l6) 20 in 30 cm3 d anhydrous ethyl acetate; 2 cm 3 of 2-chloro-ethyl isocyanate is added and the reaction mixture is left to stand 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 isocyanate * "25 of 2-chloro-ethyl The remaining residue is dissolved in ethyl acetate and chromatography on silica gel under medium pressure, i * eluting with ethyl acetate. Or. thus obtains 0.22 g of (2-chloro-ethyl) -3 methrl- 6 methylsulfonyl-8 / 3H / -imidazo / 5,1-d / tetrazine-1,2, * 3,5 one-4 melting at 149-150 ° Co 30 Elemental analysis:

Calculated? 0: C = 32.94; H = 3.46; N = 24.01; Cl = 12.15; S = 10.99 Found? 6: C = 33.0; H = 3.35; N = 23.8; Cl = 12.7 i S = 10.7

IR spectrum: 1745 cm "" 1.

V

31 he EXAMPLE 29

Compose_CC To a suspension of 0.92 g of diazo-3 Ν, Ν-dimethyl pyrazolecarboxamide-4 hydrochloride (prepared as described in example *, dry, reference 17) in 50 cm3 of dichloromethane / 2.5 is added cm3 ï 5 of 2-chloro-ethyl isocyanate and stir the suspension. 0.7 9 of diazo-1.8 bicyclo /5=4.0/ undecene-7 are added. · The solution obtained - is stirred overnight at room temperature in the dark "The dichloromethane is eliminated by evaporation and the gum obtained is - triturated with petroleum ether (PE = 60-80 ° C). The insoluble residue 10 is chromatographed under medium pressure, eluting with ethyl acetate. The suitable fractions are combined and evaporated to dryness and the residue is recrystallized from ethyl acetate. 0.38 g of (2-chloroethyl) -3 dimethylcarbamoyl-8 / 3H / -pyrazolo- / 5.1-d / tetrazine-1,2,3,5 one-4 is thus obtained, in the form of colorless crystals , Melting at 116-1618 ° C (with decomposition).

Elementary analysis:

Calculated%: C = 39.93; H = 4.10; N = 31.05; Cl = 13.1

Found 9fi: C = 39.7; H = 3.96; N = 30.9; Cl = 13.1

IR spectrum (KBr tablet): 1770, 1630 cm 1 20 NMR spectrum (in acetone-dg): singlets at 3.25 and 8.40 ppm; triplets at 4.25 and 4.95 ppm.

EXAMPLE 30 ---------- To 2.5 cm3 of concentrated sulfuric acid, 0.24 g of carbamoyl-8 (2-chloro-ethyl) -3 / 3 ^ 7 “imidazo / 5 is added, 1-d / tetrazine-1,2, 3,5 3,5 one-4 (prepared as described in Belgian patent N ° 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 4 ° 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) -3 N-nitrocarbamoy.l-8 / 3H7-imidazo / 5,1-d / tetrazine-1,2,3,5 one-4 is thus obtained, in the form colorless crystals, melting at 160-116 ° C (with decomposition).

* i 32>

Elementary analysis:

Calculated%: C = 29.23; H = 2.10; N = 34.09; Cl = 12.33

Found%: C = 28.6; H = 1.89; N = 33.6; Cl = 12.0

IR spectrum (KBr tablet): 3200, 1750, 1720 and 1620 cm-1 * 5 SP NMR spectrum (in DMSO-dg): triplets at 4.05 ppm (J = 6Hz) and 4.70 (J = 6Hz); singlet at 9.05 ppm; single singlet 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 that described in Examples 1, 2, 4, 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 ), were prepared: 15 - 3-methyl-methyl-sulfonyl-8 / jH / -pyrazolo / 5,1-d / tetrazine-1,2, 3,5 one-4, in the form of a colorless solid melting at 182-184 ° Cr - la (2-chloro-ethyl) -3 methylsulfonyl-8 / 3H / -pyrazolo / 5,1-d / tetrazine-1,2,3,5 one-4, in the form of a colorless solid melting at 166-171 ° C, 20 - la (2-chloro-ethyl) -3 methyl-6methyl suifinyl-8 / 3H / -imidazo / ~ 5,1-d / tetrazine-1,2,3,5 one -4, in the form of a yellow solid, melting at II8-120 ° Cf - la (2-chloro-ethyl) -3-ethyl-sulfonyl-8 methyl-6 / 3H / ~ imidazo / 5,1-d / tetrazine-1, 2,3,5 one-4, melting at 146 -147 ° C, and 25 - la (2-chloro-ethyl) -3 methyl-6 propylsulfonyl-8 / 3H / -imidazo / 5,1-d / tetrazine-1 , 2,3,5 one-4, in the form of a white crystalline solid melting at 85-86 ° C.

, 4 "" 33 REFERENCE EXAMPLE 1 i) An intimate mixture of 2 g of 5-nitro acid "imidazolecarboxylic-4 and 2.67 g is heated in an oil bath at 120 ° C. and with stirring for one hour. phosphorus pentachloride. 5 The yellow suspension obtained is evaporated to dryness under reduced pressure (0.1 mm of mercury) at 60 ° C for 30 minutes. This gives 1.90 g of dinitro-1,6 Z * 5Hj, / "lOHj-diimidazo / I j5-a: 1 ', 5' - 47 pyrazinedione-5,10, in the form of a melting yellow solid at 249-251 ° C (with decomposition).

10 IR spectrum: (KBr tablet): 1750 cm ”l

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 5-nitro-imidazole-15 carbonyl-4 chloride.

ii) A mixture of 5.8 g of dinitro-1,6 Z * 5H7, / 10Pj-diimidazoZTl, 5-a: 1 ', 5'-d7 pyrazinedione-5,10, 15 g is refluxed for 6 hours of N-benzylaniline and 250 cm3 of tetrahvdrofuran. The tetrahydrofuran is removed by evaporation in vacuo and the gum obtained is taken up in 1 liter of IN 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 25N 2N hydrochloric acid, then with water, dried over magnesium sulphate and concentrated to dryness. An orange gum is thus obtained which is triturated with boiling ether to give a solid. , - ... «· colorless which is recrystallized in 1 isopropanol. We get this. 4 g of nitro-5 N-benzyl N-pbénylimidazolecarboxamide-4, in the form of colorless scales, melting at 237-240 ° C.

Elementary analysis:

Calculated 1: C = 63.35; H = 4.38; K = 17.38

Found 7: C = 62.3; H = 4.28; N = 17.3

IR spectrum (KBr tablet): 1665 cm -1 34 iii) A solution of 4 g of 5-nitro-N-benzyl N-phenyl-imidazolecarboxamide-4 in 450 cm3 of anhydrous ethanol is hydrogenated at 26 ° C under a pressure of 3 atmospheres, in the presence of * Raney nickel as catalyst. When the absorption of hydrogen i 5 is complete (after 4 hours 50 minutes), the mixture is filtered, treated with 3.6 cm 3 of concentrated hydrochloric acid and evaporated to dryness at a temperature below 40 ° C. After trituration of the residue with ethyl ether, 3.82 g of 5-amino hydrochloride N-benzyl N-phenylimidazolecarboxamide-4 are obtained, in the form of a pale yellow solid, melting at 190-193 ° C ( with decomposition).

NMR spectrum (in DMSO-d ^): singlets at 5.05; 7.1-7.2 and 8.4 ppm.

IR spectrum (KBr tablet): 1640 cm 1

Mass spectrum: m / e = 292 (M +) 15 REFERENCE EXAMPLE 2 i) A mixture of 21.9 g of N-benzyl N- (4-methoxyphenyl) amine is refluxed for 18 hours (prepared according to Annalen 490, 189 (1931), 6.7 g of dinitro-1,6 5H, 10H-diimidazo ^ 5, la: 1 ', 5'-dJ pyrazinedione-5,10 and 200 cm3 of tetra-20 hydrofuran. is then removed by evaporation under vacuum and the remaining oily solid is taken up in 500 cm3 of 2N hydrochloric acid and 500 cm3 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 an aqueous solution saturated with sodium chloride and then dried over sulfate. of sodium and 'evaporated to dryness. The remaining gum is subjected to column chromatography under medium pressure, eluting with ethyl acetate.

2.9 g of nitro-5 N-benzyl N- (4-methoxy-benzyl) imidazolecarboxamide-4 are thus obtained in the form of a beige-brown solid, melting 4 * 35 ♦ at 167-170 ° C (after recrystallization in a mixture of petroleum ether (PE = 60-80 ° C) and isopropanol).

Elementary analysis:

Calculated%: C = 62.29; H = 4.95; N = 15.29 5 Found%: C = 61.3; H = 4.93; N = 15.3

IR spectrum (KBr tablet): 3100-2800, 1640, 1510, 1450 and 1370 cm ^

NMR spectrum (in DMSO-dg at 120 ° C): singlets at 3.76; 4.5; 4.6; 7.3 and 7.8 ppm; doublets centered at 6.85 and 7.2 ppm.

10 (The NMR spectrum at room temperature is complicated due to the splitting of the signals caused by the restricted rotation around the valence bond binding 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-methoxy-benzyl) imidazolecarboxamide-4 in 200 cm 3 of anhydrous ethanol is hydrogenated at room temperature under a pressure of 3 atmospheres, in the presence of Raney nickel as a catalyst. When the absorption of hydrogen 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 trituration in a mixture of isopropanol and ethyl ether, 2.2 g of 5-amino hydrochloride N-tenzyl N- (4-methoxy benzyl) imidazolecarboxamide-4 are obtained, in the form of a gummy solid which decomposes above 70 ° C.

25 IR spectrum (KBr tablet): 3400-2800, 1640 cm

NMR spectrum (in d-ethanol); singlets 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 the extent of the restricted rotation around the valence bond binding the carbon radical) (from the amide to the nitrogen atom 30 of the amide).

* 36 * REFERENCE EXAMPLE 3 i) A mixture of 5.5 g of dinitro-1,6 5h, 10H-diimidazoZl, 5-a: 1 ', 51-d7pyrazine-dione-5 is heated at reflux for 12 hours , 10, 14.5 g of N- (4-methoxybenzyl) aniline ^ prepared according to ZECHMEISTER et al, Ber. 63 B, 2883 (1930) J 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 sulfate and evaporated to dryness. The remaining solid is triturated with ethyl ether. 3.18 g of nitro-5 N- (4-methoxy-benzyl) N-phenylimidazolecarboxamide-4 are thus obtained, in the form of a peach-colored solid, melting at 212-215 ° C (after recrystallization from isopropanol) .

15 Elementary analysis:

Calculated%: C = 61.37; H = 4.58; N = 15.91 Found%: C = 60.4; H = 4.41; N = 16.0 NMR spectrum (in UMSO-d ^.): Singlets at 3.7; 5.0 and 7.7 ppm; multiplet at 6.7-7.3 ppm 20 IR spectrum (KBr tablet): 1660 cm ^ ii) A solution of 2.1 g of nitro-5 N- (4-methoxy benzyl) N-phenyl imidazolecarboxamide-4 in 200 cm3 of anhydrous ethanol is hydrogenated at 25 ° C under a pressure of 3 atmospheres, in the presence of = Raney nickel as 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. 1.9 g of amino-5 N- (4-methoxy benzyl) N-phenyl imidazole- • carboxamide-4 are thus obtained in the form of a gum.

This gum can be characterized as a picrate.

For this, 0.15 g of amino-5 N- (4-methoxy-benzyl) N-phenyl imidazolecarboxamide-4 is dissolved in 3 cm 3 of 1,2-dimethoxy-ethane and the solution obtained is treated with a solution 0.25 g of acid 37 -> * * picric in 5 cm3 of dimethoxy-1,2 ethane. The crystals obtained are separated by filtration and washed with ethyl ether. 0.07 g of 5-amino picrate N- (4-methoxy benzyl) N-phenyl imidazolecarboxamide-4 is thus obtained, in the form of a yellow solid, melting at 207 ° C (with decomposition).

Elementary analysis:

Calculated%: C = 49.1; H = 4.29; N = 16.69 Found%: C = 49.1; H = 3.64; N = 16.5 5 REFERENCE EXAMPLE 4 10 i) A mixture of 8.08 g of dinitro-1,6 5H, 10H-diimidazo / Ί., 5-a: 1 ', 5 is refluxed for 24 hours '-to] pyrazine-dione-5,10, 12.44 g of N-methyl aniline and 400 cm3 of tetrahydro-furan. The tetrahydrofuran is removed by evaporation in vacuo and the dark residual solid is taken up with boiling ethyl ether. The remaining undissolved solid is subjected to column chromatography under medium pressure, eluting with a mixture of ethyl acetate and methanol (1-1 by volume). 4.68 g of nitro-5 N-methyl N-phenyl imidazolecarboxamide-4 are thus obtained, in the form of a white solid, melting at 193 ° C.

20 Elementary analysis:

Calculated%: C - 53.66; H = 4.09; N = 22.76

Found%: C = 52.5; H = 3.95; N = 22.2

IR spectrum: 1660 cm ^ ii) A solution of 1 g of 5-nitro-N-methyl N-phenyl imidazolecarboxamide-4 in 110 cm3 of anhydrous ethanol is hydrogenated, „at 23 ° C. under a pressure of 3 atmospheres in the presence of Raney nickel as a catalyst. When the absorption of hydrogen is • finished (after 1 hour 39 minutes), the mixture is filtered and treated with a stream of dry gaseous hydrochloric acid. The solution 30 is then evaporated to dryness. 0.9 g of amino-5 N-methyl N-phenyl imidazolecarboxamide-4 hydrochloride is thus obtained, in the form of an off-white solid, melting at 100 ° C (with decomposition).

Ύ 38 * *

This compound can be characterized as a picrate.

To this end, 0.25 g of 5-amino-N-methyl N-phenyl imidazolecarboxamide-4 hydrochloride is dissolved in 2 cm 3 of water and the solution is treated with a solution of 0.25 g of acid. picrique in 2 cm3 i 5 of 1,2-dimethoxyethane. The precipitate is separated by filtration and washed with 1,2-dimethoxyethane. 0.12 g of 5-amino-picrate N-methyl N-phenyl imidazolecarboxamide-4 is thus obtained, in the form of a yellow solid, melting at 237-238 ° C (with decomposition).

^ Elementary analysis: 10 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 cm 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 hydrochloride is added ainino-4-methyl-2 imidazolecarboxamide-5 (prepared as described in German patent application No. 2 358 509) in 24 cm3 of an aqueous solution of 2N acetic acid while maintaining the temperature between -2 and 0 ° C. When the addition is complete, the yellow solid obtained is separated by filtration and dried under vacuum over phosphorus pentoxide. 1.26 g of 5-diazo-2-methyl-imidazolecarboxamide-4 are thus obtained, melting at 175 ° C. (with explosion).

REFERENCE EXAMPLE 6 i) To a solution cooled in an ice bath of 35 cm3 of dimethylamine in water (30% by weight), 4.15 g of chloride are added in small portions at a time and with stirring. nitro-5 imidazolesulfonyle-4 (wet product, freshly prepared from 3.33 g ammonium salt of nitro-5 mercapto-4 imidazole by the method of Fischer et al. Can. J. Chem. _39, 501 ). The mixture is stirred for a further 20 minutes and then the mixture is concentrated to half its volume in vacuo 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 separated by filtration and recrystallized from dimethylformamide. 2.73 g of nitro-5 Ν, Ν-dimethyl- * sulfamoyl) -4 imidazole are thus obtained in the form of brownish flakes, melting at 5 at 282-283 ° C (with decomposition).

i

Elementary 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 5 N-nitro, N-dimethylsulfamoyl-4 10 imidazole in 100 cm 3 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 immediately diluted with 200 cm3 of ether and treated with a stream of hydrochloric gas until a slightly acid medium is obtained. The mixture is then concentrated in vacuo at a temperature below 30 ° C. The remaining solid is dissolved in 20 cm3 of boiling anhydrous ethanol and the solution is treated with bleaching black, filtered and evaporated to a volume of 15 cm3, taken up with 60 cm3 of ethyl ether and left to crystallize. The solid obtained is separated by filtration. 20 0.8 g of 5-amino hydrochloride, Ν-dimethyl imidazolesulfonamide-4 are thus obtained in the form of pinkish beige needles, melting at 188-189 ° C (with decomposition).

Elementary analysis:

Calculated%: C = 26.5; H = 4.85; N = 24.7; Cl = 15.6; 25 S = 14.15

Found%: C = 26.1; H = 4.80; N = 23.6; Cl = 15.9; S = 13.9 iii) To a solution cooled in an ice bath of 0.31 g of sodium nitrite in 5 cm 3 of water, a solution of 0.7 g of hydrochloride d is added dropwise with stirring. '5-amino, Ν-dimethyl imidazolesulfonamide-4 in 3.1 cm3 of 2N hydrochloric acid. The solid obtained is separated by filtration and 4ο> »* washed with ice water. 0.38 g of diazo-5 N, N ~ dimethyl imidazolesulfonamide-4 is thus obtained, melting at 109 ° C. (with decomposition).

IR spectrum: 2180 and 2210 cm ^

A second batch of 0.21 g of slightly less pure product is obtained by extraction of the mother liquors at 0 ° C. with ethyl acetate, drying of the extracts over magnesium sulphate and evaporation under vacuum.

REFERENCE EXAMPLE 7 i) To 35 cm3 of a 25% aqueous methylamine solution 10 (weight to weight) cooled in an ice bath, 4.15 g of nitro chloride are added with stirring in small portions at a time. 5 imidazolesulfonyl-4 / wet product prepared from 3.33 g of ammonium salt of mercapto-4 nitro-5 imidazole according to the method of Fischer et al. (loc. cit.) 7. The reaction mixture is stirred for a further 15 minutes and then concentrated in vacuo at a temperature below 40 ° C. until half the initial volume is obtained. The mixture is then strongly acidified with concentrated hydrochloric acid and the remaining solid is separated by filtration and recrystallized from water. 2.07 g of 20 N-methyl 5-nitro-imidazolesulfonamide-4 are thus obtained in the form of pale yellow strips, melting at 260-263 ° C (with decomposition).

Elementary analysis:

Calculated%: 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 25 ii) A solution of 1 g of N-methyl 5-nitro-imidazole sulfonamide-4 in 100 cm3 of anhydrous ethanol is hydrogenated at 24 ° C under a pressure of 3 atmospheres in the presence of Raney nickel. as a catalyst. The mixture is then filtered and immediately diluted with 200 cm 3 of ethyl ether and treated with a stream of hydrochloric gas until the medium is slightly acidic. The reaction mixture is then concentrated to dryness under vacuum at 30 ° C.

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

*

Elementary analysis: 4 Calculated%: C = 22.6; H = 4.26; N = 26.35; Cl = 16.7

Found%: C = 22.3; H = 4.13; N = 25.5; Cl = 16.9 iii) To a solution of 0.285 g of sodium nitrite in 10 4 cm3 of water cooled in an ice bath, a solution of 0.55 g of amino hydrochloride is added dropwise with stirring. 5 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 imidazole-15 sulfonamide-4 is thus obtained, melting at 150 ° C. (with decomposition).

IR spectrum: 2210 cm ^

Elementary 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 extraction of the mother liquors at 0 ° C with ethyl acetate, drying of the extracts on magnesium sulphate and evaporation under vacuum.

REFERENCE EXAMPLE 8 To a solution of 0.5 g of sodium nitrite in 5 cm 3 of water cooled to 0 ° C., a solution of 1 g of 5-amino-methylsulfonyl hydrochloride is added dropwise with stirring. 4 · - j * imidazole / prepared as described by BENNETT et al., J. Am. Chem. Soc. 79. (3) "2188-2191 (1957) 7 in 5 cm3 of 2N hydrochloric acid. The solution is stirred for a further 15 minutes and extracted with 5 times 20 cm 3 of ethyl acetate. The extracts are combined, dried over sodium sulfate and concentrated in vacuo to leave a yellow oil which crystallizes at rest. 0.74 g of 5-diazo-4-methylsulfonyl imidazole is thus obtained, melting at 128-130 ° C. IR spectrum: 2125 cm ^ ♦ 42 * Λ REFERENCE EXAMPLE 9 i) To a solution of 10 g of tnethoxy-4 benzylamine in, 30 cm3 of water, 6.8 g of 5-nitro-imidazolesulfonyl chloride are added with stirring -4 / wet product freshly prepared from ^ 5 of 6 g of ammonium salt of 4-mercapto-5-nitroimidazole, according to the method of Fischer et al. (loc. cit.) 7 * The mixture does not take long to solidify; it is taken up with 20 cm3 of isopropanol, triturated and left to stand overnight. The solid obtained is separated by filtration, washed with ice water, then suspended in 150 cm3 of water and treated carefully with a 2N hydrochloric acid solution until pH 2. The yellow solid obtained is separated by filtration and washed with ice water. 7.42 g of N- (4-methoxybenzyl) 5-nitro-imidazolesulfonamide-4 are thus obtained, melting at 269-270 ° C (with decomposition).

Ii) A solution of 1 g of N- (4-methoxybenzyl) 5-nitro-imidazolesulfonamide-4 in 100 cm3 of dry ethanol is hydrogenated for 6 hours under a pressure of 3 atmospheres in the presence of Raney nickel at 50% as a catalyst. The catalyst is quickly removed 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 residue obtained is triturated with ethyl ether. The solid obtained is separated by filtration and washed with ethyl ether.

0.25 g of amino-5 N- (4-methoxybenzyl) imidazole-sulfonamide-4 is thus obtained, melting at 154-155 ° C.

Iii) To a solution of 0.14 g of sodium nitrite in 5 cm 3 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, maintaining 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. 0.3 g of diazo-5 N- (4-methoxy-benzyl) imidazolesulfonamide-4 is thus obtained, melting at 144-146 ° C (with decomposition).

IR spectrum: 2180 cm * * *

V

* 43 REFERENCE EXAMPLE '10 i) To a solution of 6.4 cm3 of piperidine in 92 cm3. anhydrous tetrahydrofuran, 4.59 g of dinitro-1.6-5H, 10H-diimidazo / 1.5-a: 11.5'-dj pyrazinedione-5.10 (prepared as described • 5 in the example) are added 1) and leave to 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 suitable fractions are combined and evaporated; the residue is washed with ethyl ether and then with ethyl acetate. 2.72 g of nitro-4 piperidino-15 carbonyl-5 imidazole are thus obtained, in the form of a yellow solid melting at 149-150 ° C.

Elementary analysis:

Calculated%: C = 48.2; H = 5.39; N = 25.0

Found%: C = 48.2; H = 5.33; N = 25.1 20 ii) A solution of 2.68 g of 4-nitro-5 piperidinocarbonyl-5 imidazole (prepared as described above) in 27 cm3 of methanol and 27 cm3 of dimethylformamide is added with 0.27 g of platinum oxide and the mixture is hydrogenated with stirring at room temperature and at atmospheric pressure. When the absorption of hydrogen is complete, the mixture is filtered and the filtrate is evaporated in vacuo. The residue is dissolved in 50 cm3 of 2N hydrochloric acid, the solution is filtered and the filtrate is evaporated to dryness under vacuum. The residue obtained is washed with acetone. We obtain

H

thus 2.1 g of 4-amino-piperidinocarbonyl-5 imidazole hydrochloride, in the form of a pale green solid, melting at 175-177 ° C., sufficiently pure to be used as it is in the following stage.

1 * »44 REFERENCE EXAMPLE 11 i) In a stirred solution of 5 g of 2-cyanoethylbenzene. and 8 g of benzylmercaptan in 90 cm 3 of anhydrous dioxane, a stream of gaseous hydrochloric acid is passed for 3 hours. 5 the mixture is left to stand at room temperature for 5 days. The mixture is then taken up in ethyl ether and the precipitate formed is separated by filtration and washed with ethyl ether. 9.7 g of S-benzyl 3-phenylpropionothioimidate hydrochloride are thus obtained, in the form of a colorless solid melting at 158-160 ° C., sufficiently pure to be used as it is in the following stage.

ii) A solution of 3.3 g of α-amino α-cyanoacetamide in 20 cm3 of ethanol is treated with 9.7 g of 3-phenyl propionothioimidate hydrochloride (prepared as described above) 15 and the mixture is heated at reflux for 15 minutes. The mixture is then cooled and the solid formed is separated by filtration and. recrystallized from methanol. 2.3 g of 5-amino-2-phenethyl imidazolecarboxamide-4 hydrochloride are thus obtained, in the form of colorless crystals, melting at 270-274 ° C.

20 Elementary analysis:

Calculated%: C = 54.0; H = 5.67; N = 21.0

Found%: C = 53.8; H "5.55; No. 21.1 REFERENCE EXAMPLE 12, To a solution of 0.5 g of sodium nitrite in 15 cm 3 of water maintained at 0-5 ° C., a solution of 1.26 g of d is added dropwise 5-amino-2-benzyl imidazolecarboxamide-4 (prepared as described in German patent application No. 2 358 509) in 15 cm3 of 2N hydrochloric acid. The mixture is stirred at 0 ° 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-imidazolecarboxamide-4 is thus obtained, melting at 121-122 ° C (with decomposition).

IR spectrum: 2180 cm 4 5 * »

V

REFERENCE EXAMPLE 13 i) In a stirred solution of 6.9 g of isobutyronitrile 'and 20 cm3 of benzylmercaptan in 100 cm3 of anhydrous dioxane, it is passed for 3 hours at a temperature between 0 and 5 10 ° C. a stream of gaseous hydrochloric acid. It is allowed to warm to room temperature and the device is closed and left to stand for 14 days at room temperature. The mixture is then thrown onto 1 liter of ethyl ether and the white precipitate formed is separated by filtration and washed with ethyl ether. 20.3 g of S-benzyl isobutylthioimidate hydrochloride are thus obtained 20.3 g, melting at 165-167 ° C.

Elementary analysis:

Calculated%: C = 57.5; H = 7.02; N = 6.1; Cl = 15.43; S = 13.96 15 Found%: C = 57.1; H = 7.0; N = 5.9; Cl - 15.7; S = 13.9 ii) A solution of 5 g of α-amino cx-cyanoacetamide and 11.5 g of S-benzyl isobutylthioimidate hydrochloride (prepared as described above) in 150 cm3 of 2-ethoxy anhydrous ethanol 20 is heated at reflux for 30 minutes. The solvent is evaporated. The remaining black oil is crushed with 100 cm3 of a mixture of chloroform and methanol (4-1 by volume); the insoluble matter is separated by filtration and eliminated. 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 spraying ninhydrin on a sample, which gives an intense yellow-brown coloration) are. combined and evaporated. 4.44 g of 5-amino-2-isopropyl-2-imidazolecarboxamide-4 hydrochloride are thus obtained, in the form of a gummy solid, sufficiently pure to be used as it is in the following step.

V

46 days * iii) To a solution of 0.5 g of sodium nitrite in 5 cm3 of water maintained at 0 ° C., a solution s of 1.1 g of 5-amino-isopropyl hydrochloride is added dropwise -2 imidazolecarbo-xamide-4 (prepared as described above) in 20 cm3 of a 2M aqueous solution of acetic acid. 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.

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

15 IR spectrum: 2170 cm REFERENCE EXAMPLE 14

6 —Tl II I- - I. I

i) A cooled and stirred solution of 127 g of 2-methyl-5-nitroimidazole in 1500 cm 3 of an aqueous 5% sodium hydroxide solution (weight / volume) is treated with 160 g of bromine while maintaining the temperature between 15 and 20 ° C. The reaction mixture is stirred at room temperature for 5 and a half hours and the solid which has precipitated is redissolved by again adding 2N sodium hydroxide to the reaction mixture. The traces of insoluble product are separated by filtration and the filtrate is acidified to pH 1 using concentrated hydrochloric acid. The white solid obtained is separated by; filtration, recrystallized from ethanol and dried in a desiccator on phosphorus pentoxide. 151 g of 4-bromo-2-methyl-5-nitro-imidazole are thus obtained in the form of a crystalline solid melting at 267-268 ° C.

Ii) A stirred solution of 20.6 g of 4-bromo-2-methyl-5-nitroimidazole (prepared as described above) is heated to 45 ° C. "" 47 in 180 cm 3 of 5N ammonia and then passed through a continuous stream of hydrogen sulfide for 40 minutes. A yellow crystalline solid forms slowly. The mixture is cooled in ice and the solid is separated by filtration, washed with ice water and dried in a desiccator over phosphorus pentoxide. 14.6 g of mercapto-4-methyl-2-nitro-5 imidazole are thus obtained in the form of an ammonium salt which darkens without melting above 300 ° C.

Elementary analysis:

Calculated%: C = 27.27; H = 4.58; N = 31.8; S = 18.2 10 Found%: C = 27.2; H = 4.41; N = 31.6; S = 18.2 iii) In an ice-cold 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 d hydrochloric acid IN, a stream of chlorine is passed through until a white solid is formed. The mixture is then stirred for a further 30 minutes at 0 ° C. and the solid is separated by filtration, washed with water and dried in a desiccator over phosphorus pentoxide. 3 g of 4-chlorosulfonyl-2-methyl-5-nitro-imidazole are thus obtained, melting at 160-162 ° C (with decomposition).

20 Elementary analysis:

Calculated%: C = 21.29; H = 1.79; N = 18.63; Cl = 15.72; S = 14.21

Found%: C = 20.8; H = 1.73; N = 18.3; Cl = 15.7; S = 14.6 25 iv) To a cooled solution of 5.48 g of 4-methoxy-benzylamine in 20 cm 3 of anhydrous absolute ethanol, 2.25 g of 4-chlorosulfonyl-2-methyl-5-nitroimidazole is added (prepared as described above) and the mixture is stirred at room temperature for 3 hours. The yellow solid which precipitates is separated by filtration, washed with ethanol and eliminated. 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 cm3

V

"*" 48 of water, acidified to pH 1 with concentrated hydrochloric acid and the mixture is extracted with 3 times 20 cm3 of ethyl acetate.

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

Elementary analysis

Calculated%: C = 44.17; H = 4.32; N = 17.17; S = 9.83 Found%: C = 44.2; H = 4.32; N = 17.2; S = 9.5 10 v) A solution of 4.5 g of (4-methoxy-benzyl) -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 cm 3 of anhydrous ethanol.

The filtrate and the washing liquors are combined and acidified to pH 1 using 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-methoxy-benzyl) 4-sulfamoyl-2-methyl-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 5 ° C., a solution of 1 g of 5-amino hydrochloride (4-methoxy-benzyl) is added dropwise ) 4-sulfamoyl-2-methylimidazole (prepared as described above) in 10 cm3 of 2N hydrochloric acid. The mixture is stirred for a further 5 minutes at 0 to 5 ° C and the orange solid obtained is Λ "" * separated by filtration, washed with 1 water and dried in a desiccator over phosphorus pentoxide. 0.75 g of diazo-5 * is thus obtained

(4-methoxybenzyl) 4-sulfamoyl-2-methyl-imidazole, melting at 140 ° C

30 (with decomposition).

IR spectrum: 2200 cm ^

V

49 ♦ REFERENCE EXAMPLE 15 i) At 10 cm3 of an ethanolic solution of dimethylamine at 33% (weight / volume) cooled and stirred, 2.25 g of 4-chlorosulfonyl-2-methyl-2-nitro are added in small portions at a time -5. 5 imidazole (prepared as described in reference example 14) and stirred at room temperature for a further 45 minutes. The solution is acidified to pH 1 using concentrated hydrochloric acid. The white solid obtained is separated by filtration and washed with cold water. 1.9 g of 4-dimethylsulfamoyl-2-methyl-5-nitro-imidazole are thus obtained, melting at 240-241 ° C.

Elementary analysis:

Calculated%: C = 30.77; H = 4.3; N = 23.92; S = 13.69

Found%: C = 30.5; H = 4.24; N = 23.8; S = 13.8

NMR spectrum (in DMSO-d ^): singlets 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 under a pressure of 3.5 atmospheres on a Raney nickel catalyst for 1 hour. 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. 8.9 g of 5-amino-4-dimethylsulfamoyl-2-methyl-imidazole are thus obtained, melting at 215-217 ° C (with decomposition), iii) To a solution of 1 g of sodium nitrite in 15 cm3 of water kept at 0 ° C., a solution of 2.4 g of 5-amino-dimethylsulfamoyl-2-methyl-2-imidazole in 30 cm 3 of 2N hydrochloric acid is added dropwise and the mixture is stirred for a further 10 minutes at 0 ° C. The mixture is extracted with 5 times 30 cm3 of acetate

ethyl; the organic extracts are combined and dried over magnesium sulfate, evaporated to dryness and the residue is triturated with petroleum ether (m.p. = 60-80 ° C). 1.8 g of 5-diazo-4-dimethylsulfamoyl-2-methyl-imidazole are thus obtained, melting at 85 ~ 87 ° C

-1 50

V

* * r (with decomposition).

IR spectrum: 2180 cm s REFERENCE EXAMPLE '16 i) A solution of 10.5 g of ammonium salt of 4-mercapto-5 methyl-2-nitro-5 imidazole (prepared as described in reference example 14) in a methanolic solution of sodium methylate (prepared by carefully dissolving 2.3 g of sodium in ~ 250 cm3 of anhydrous methanol) is treated with 10.7 g of methyl iodide and the solution is heated at reflux for 2 hours. The mixture is then concentrated to dryness and the residue is suspended in 100 cm 3 of a 2N aqueous sodium hydroxide solution. The suspension is filtered and the filtrate is acidified to pH 1 using concentrated hydrochloric acid. 9 g of 2-methyl-4-methylthio-5-nitro-imidazole are thus obtained in the form of a yellow solid, melting at 236-237 ° C (with decomposition).

Elementary analysis:

Calculated%: C "34.67; H = 4.07; N = 24.2 6; S = 18.51 Found%: C = 34.7; H = 4.04; N = 24.3; S = 18.5 ii) A solution of 3.46 g of methyl-2-methylthio-5-nitro-imidazole (prepared as described above) in 35 cm 3 of glacial acetic acid is heated to 60 ° C. add dropwise 35 cm3 of an aqueous solution of hydrogen peroxide at 30% (weight / volume). The mixture is then heated at 100 ° C for 15 minutes, cooled to room temperature and treated with sodium sulfite in an amount sufficient to destroy the excess hydrogen peroxide (detected by the starch and iodide test potassium). The mixture is then subjected to a 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 (m.p. = 60-80 ° C) and separated by filtration. 3.6 g of 2-methyl-4-methylsulfonyl-5-nitro-imidazole are thus obtained, melting at 222 ° -224 ° C.

51> ♦

Elementary 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-methylsul 4 onyl-5 5-nitroimidazole (prepared as described above) in 400 cm3 of anhydrous ethanol is hydrogenated under a pressure of 3 , 5 atmospheres on Raney nickel catalyst for 30 minutes. The catalyst is filtered off and the filtrate is acidified to pH 1 using 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 separated by filtration and washed with ethyl ether. 4.1 g of 5-amino-2-methyl-methyl-4-sulfonylimidazole hydrochloride are thus obtained, melting above 300 ° C.

15 Elementary analysis:

Calculated%: C = 28.37; H = 4.76; N = 19.8; Cl = 16.75; S "= 15.15

Found%: C = 27.3; H = 4.51; N = 19.9; Cl = 17.9; S = 13.7 20 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 amino hydrochloride is added dropwise 5-methyl-4-methylsulfonylimidazole (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 (m.p. = 60-80 ° C). 0.4 g of 5-diazo-2-methyl-4-methylsulfonyl-imidazole is thus obtained, melting at 100 ° C. (with decomposition).

30 IR spectrum: 2185 cm ^> Λ 52 * REFERENCE EXAMPLE17 i) A mixture of 8.2 g of a- is heated to 160-170 ° C in a flask fitted with a Mclntyre head for 90 minutes. cyano Ν, Ν-dimethylacetamide / prepared as described by BOVJMAN et al.

5 J. Chem. Soc. (1954), 1171.7, 21 cm3 of acetic anhydride and 21 cm3 of ethyl orthoformate. 26 cm3 of ethyl acetate are thus collected which have distilled. The reaction mixture is concentrated in vacuo. A dark oil is obtained which is taken up in 10 cm 3 of ethanol 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. 5.3 g of cyano-2-ethoxy-3 N, N-dimethyl propenamide are thus obtained, in the form of an off-white oily solid, sufficiently pure to be used as it is in the following phase.

Ii) To a solution of 5.3 g of 2-cyano-3-ethoxy-N, N-dimethyl propenamide (prepared as described above) in 50 cm3 of anhydrous ethanol, 1.58 g are 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 suitable fractions are combined and evaporated to dryness. The residue obtained is dissolved in 5 cm3 of isopro-panol, treated with 4 cm3 of concentrated hydrochloric acid and the crystalline precipitate obtained is collected. 1.39 g of 3-amino hydrochloride Ν, Ν-dimethyl pyrazolecarboxamide-4 are thus obtained in the form of colorless crystals melting at 195 ° C.

Elementary 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 30 IR spectrum (KBr tablet): 3500, 3400, 3000-2200, 1655 cm

NMR spectrum (in DMSO-d ^): singlets at 3.0 and 8.1 ppm and wide singlet at 7.2 ppm.

V

(Iii) 70 cm3 of an anhydrous methanol solution saturated with gaseous hydrochloric acid are treated with 1.39 g of 3-amino hydrochloride, Ν-dimethyl pyrazolecarboxamide-4 (prepared as above). The mixture is stirred and cooled to 0 ° C, 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 to stand for 1 hour at a temperature between 2 and 4 ° C and is then thrown into 800 cm3 of ether. The solid obtained is collected ~ and washed with ethyl ether. 0.92 g of diazo-3 10 Ν, Ν-dimethyl pyrazolecarboxamide-4 is thus obtained in the form of colorless crystals melting at 150 ° C (with explosion).

Elementary analysis:

Calculated%: C = 35.74; H = 4.00; N = 34.74

Found%: C = 35.3; H = 3.79; N = 34.3 15 IR spectrum (KBr tablet): 3000-2100, 2280, 1630 cm

The present invention also relates to pharmaceutical compositions 1 which contain, as active ingredient, at least one product of general formula (I) with a pharmaceutical diluent or coating. Clinically, the products of general formula (i) are normally administered by the oral, rectal, vaginal or parenteral route, for example intravenous or intraperitoneal.

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

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

jr * (.

V

54

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

Liquid compositions for oral administration include emulsions, solutions, pharmaceutically acceptable suspensions, syrups and elixirs containing inert diluents 10 in common use such as water and petroleum jelly. In addition to the inert diluents, these compositions can also contain adjuvants such as wetting agents, suspending agents (for example polyvinylpyrrolidone), sweeteners, flavorings, perfumes and preservatives.

Among the compositions for oral administration, mention may also be made of 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, mention may be made of pessaries formulated in the usual manner and containing one or more active products.

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

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

1 * 55

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

; They can be sterilized for example by aseptic filtration, addition of sterilizing agents or irradiation. They can also be prepared in the form of sterile solid compositions which will be dissolved or dispersed, at the time of their use, in water or any other sterile injectable medium.

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

Naturally, several unit doses can be administered simultaneously. In general, the compositions which can be administered by injection contain at least 0.025% by weight of active material, and the compositions for the oral route contain at least 0.1%. 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, in 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.

COMPOSITION EXAMPLE 1

A solution suitable for parenteral administration is prepared from the following ingredients: - (N-benzyl N-phenylcarbamoyl) -8 methyl-3 / "3H7-imidazo / 5,1-47 tetrazine-1,2,3, 5 one-4 ........... 1.0 g - dimethyl sulfoxide ............................. ........ 10 cm3 by dissolving (N-benzyl N-phenylcarbamoyl) -8 methyl-3 ZT3H7- 30 imidazo / 5,1-47 tetrazine-1,2,3,5 one-4 in the dimethyl sulfoxide.

The solution obtained is aseptically distributed in 10 ampoules,

AT

V * 56 Λ.

at a rate of 1.1 cm3 per bulb. The ampoules, which each contain 100 mg of (N-benzyl N-phenylcarbamoyl) -8 methyl-3 £ 3H7-imidazo £ 5, 1, “d7 tetrazine-1,2,3,5 one-4, are sealed.

Similar ampoules suitable for. 5 parenteral administration by operating in the same way from another compound of general formula (i).

COMPOSITION EXAMPLE 2

A solution suitable for parenteral administration is prepared from the following ingredients: 10 - (2-chloro-ethyl) -3 N-methylsulfamoyl-8 / 3I7-imidazoZ5, l ~ àj tetrazine-1,2,3,5 one- 4 ........... 1.0 g - dimethyl sulfoxide. ».................................. 10 cm3 - peanut oil ........ .............................. 90 cm3 by dissolving (2-chloro-ethyl) -3 N-methylsulfamoyl-8 £ 3h7 Imidazo £ 5,1-d7 tetrazine-1,2,3,5 one-4 in dimethyl sulfoxide and adding peanut oil. The solution obtained is aseptically distributed in 10 ampoules at a rate of 10 cm3 per ampoule. The ampoules which each contain 100 mg of (2-chloroethyl) -3 N-methylsulfamoyl-8 / 3H7-imidazo £ 5.1- ^ 7 tetrazine-1,2,3,5 one-4 are sealed.

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

- COMPOSITION EXAMPLE 3 Capsules suitable for oral administration * are prepared by depositing (2-chloro-ethyl) -3 N-methylsulfamoyl-8 Z "3H7_ imidazo / 5, 1-d7 tetrazine-1,2, 3.5 one-4 in 2-gauge gelatin capsules at 10 mg per capsule.

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

//

Claims (7)

1. H -s * rr χ ~ zi 5 in which R ^, A, Α ^ and Z1 are defined as in claim 1 and R 6 represents a radical of general formula: - CONR? Rg in which R and are defined as in claim 1, by '0 optionally acting on phosphorus pentasulfide, then isolating the product and transforming it into a salt when R 4 represents a sulfamoyl or monosubstituted sulfamoyl radical or a carboxy raclical. 1 Ci R 2 represents a radical falling within the definition of R2 other than that representing a sulfamoyl, carbamoyl radical which carries an optionally substituted phenyl substituent or thiocarba- hub which carries an optionally substituted phenyl substituent and other than a nitrocarbamoyl or nitrothiocarbamoyl radical , with a compound of general formula: R NCZ 11 - ü in which R ^ and Z ^ are defined as in claim 1, then * isolates the product and optionally transforms it into a salt when RA represents a monosubstituted sulfamoyl radical and / or R.sup.4 represents a sulfamoyl or monosubstituted sulfamoyl radical or represents a carboxy radical. 1. New tetrazine derivative, characterized in that it corresponds to the general formula: f2 - A2 j (I) X 1 / in which R represents a cycloalkyl radical or a straight chain alkyl, alkenyl or alkynyl radical or branched 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, alkyl radicals, alkyl thio, alkylsulfinyl and alkylsulphonyl in straight chain or branched 10 containing up to 4 carbon atoms and the optionally substituted phenyl radicals, A „represents a nitrogen atom or a radical - CR„ = 1 3 in which R ^ represents a hydrogen atom or a substituent R ^ in which R ^ _ represents a halogen atom, or an alkyl or alkenyl radical in a straight or branched chain containing up to 6 carbon atoms, which can bear up to 3 substituents chosen from halogen atoms, radicals phenyl vent uly substituted, alkyloxy, alkylthio and alkylsulfonyl containing up to 3 carbon atoms or R ^ _ represents a cycloalkyl, cyano, hydroxy, nitro or phenoxy radical optionally substituted, or a radical of formula -COR ^ (in which R ^ represents an alkyl or alkyloxy radical containing up to 4 carbon atoms, a hydroxy radical or an optionally substituted phenyl radical) or else an alkanoylamino radical containing up to 6 carbon atoms, or else R ^ represents a radical of formulas: - S (0) nR6, - S02NR? R8 or - CZ2NR? R8 // Λ · * * 58 (in which n represents the digits 0.1 or 2, R g 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 A 5, R 1 and R 6 which may be the same or different, each represent a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing up to 4 carbon atoms (which may have a substituent; optionally substituted phenyl), or a cycloalkyl radical or an optionally substituted phenyl radical or else the radical -NR_RQ 7 o represents a heterocyclic radical, and represents an oxygen or sulfur atom), A represents a nitrogen atom or else , when A represents a Ci 1 nitrogen atom, A represents a nitrogen atom or a radical -CR = ^ j 15 in which R ^ is defined as above, represents an oxygen or sulfur atom, and Rg represents a radical of formulas: -S (0) nRg, -S02NR7Rg, -CSNR ^ Rg, -CONR ^^ or -CZ2NHN02 in which n, RgjR ^ jRg and Z2 are defined as above and the radical -NR ^ R ^ represents a heterocyclic radical or R ^ is defined as above and R ^ represents an alkyl or alkenyl radical in a straight or branched chain containing up to 4 carbon atoms (which carries an optionally substituted phenyl substituent), or alternatively a phenyl radical substituted, or, when A ^ represents a nitrogen atom or a radical -CR ^ = in which R ^ is defined as above and Z ^ and Ag are defined as above - or when represents a radical -CH = and represents a sulfur atom and Ag is defined as above, Rg represents a radical * of formulas: ~ S (0) nR6, -S02NR? Rg, -CZ2NR? Rg or -CZ2NHN02 in which n, RgjR ^ jRg and Zg are defined as previously / and, when R and / or R_ represents a sulfamoyl radical or sulfamoyl & i mono-substituted and / or R ^ represents a carboxy radical, their salts, it being understood that in the preceding definitions, the optional substituents on the phenyl and phenoxy portions can be chosen from halogen atoms and alkyl radicals % 59 * and alkyloxy containing up to 4 carbon atoms and the nitro radicals, that the cycloalkyl radicals contain 3 to 8 carbon atoms, that by heterocyclic radical is meant a heterocycle; with 5, 6 or 7 members which may optionally contain another heteroatom such as nitrogen, oxygen or sulfur and which may carry one or two alkyl substituents in a straight or branched chain each containing up to 4 atoms carbon. 2 I - A <VII) 2. Process for the preparation of a product according to claim 1, in the formula in which R 4 is different from a sulfamoyl or carbamoyl radical which carries an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted and different phenyl substituent of a nitrocarbamoyl or nitrothiocarbamoyl radical, characterized in that a compound of general formula is reacted: Λ β AÊ N) \ (III): RÎ2 N2 <£> 15 in which A and A are defined as in claim 1 and 3. Process for the preparation of a product according to claim 1, in the formula in which R represents a carbamoyl radical which has an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted phenyl substituent // //, \ * 60 and R., A ,, A_ and ΖΛ are defined as in claim 1, carac-112 1 terized in that 11 a compound of general formula is debenzylated: »» CZ2 * ^ 2 R 13 * i in which R represents a radical optionally substituted phenyl 5, R 1 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 by a hydrogen atom, then isolates the product and optionally it is transformed into a salt when 10 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 R „, A. A0 and Z „are defined as in claim 112 1 and R ^ represents a radical of general formula: 15. CZ2NHN02 * X in which Z2 is defined as in claim 1, characterized • in that one nitre a compound of general formula: \ 4 Vv \ Z 1 / 1- i "* 61 in which R ^ represents a radical of formula: - CZ2NH2 in which Z2 '^ l ^ 2 Zl its ^ defined as in claim 1 then isolates the product and optionally it is transformed into a salt ~ 5 when R ^ represents a sulfamoyl or sulfamoyl monosubstituted radical or a carboxy radical. 5. Process for the preparation of a product according to claim 1 in the formula of which R jA ^ jAg and R2 are defined as in claim 1 and represents a sulfur atom, characterized in that a compound of general formula: VYN ", o in which R, A and R are defined as in claim 1 X a and R, _ represents a radical of formula: 15 - S (0) nRg, - S02NR? R8, - CZ2NR7R8 or" CZ2NHN02 '"" 15 R £ »r-7îRq5 n Z being defined as in claim 1 by 0' 0“ optionally on J action of phosphorus pentasulfide, then isolates the product and / the * transforms into a salt when R and / or R represents a "J sulfamoyl or monosubstituted sulfamoyl radical and / or R represents a carboxy radical. 6. Process for the preparation of a product according to claim 1 in the formula in which R „, A_, A„ and Z „are defined as in claim 112 1 dication 1 and R2 represents a radical of general formula: - csnr? r8 AJ% 62 ** ς> in which and Rg are defined as in claim 1, characterized in that a compound of general formula is transformed: R16 * 7. Pharmaceutical composition, characterized in that it comprises, as active principle, at least one tetrazine derivative according to claim 1, in combination with one or more pharmaceutically acceptable adjuvants or coatings. Drawings: ........ plates · - pages ûonî / 1 cover page T · ....... pages of description l .......... 6 Paass of claim ... ....... descriptive abstract * Luxembourg! q The representative: ^ ® AUGUST 1983 * Me Alain ^ uka ^ ina