BE897548A - NOVEL TETRAZINE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

New tetrazine derivatives, their preparation and the pharmaceutical compositions containing them. New tetrazine derivative characterized in that it corresponds to the general formula (I), in which A1 represents a nitrogen atom or a radical - CR3 = A2 represents a nitrogen atom or, when A1 represents an atom nitrogen or else when A1 represents a nitrogen atom, A2 represents a nitrogen atom or a radical -CR3 = Z1 represents an oxygen or sulfur atom, and R2 represents a radical of formulas: -S (0 ) nR6, -S02Nr7R8, -CSNR7R8, -CONR7R9 or -CZ2NHN02 and which are useful against neoplasms and immunological diseases.

Description

       

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 for New tetrazine derivatives, their preparation and the pharmaceutical compositions containing them. English patent applications Nos. 8223583 and 8223580 of August 17, 1982, No. 8226169 of September 14, 1982 and No. 8306904 of March 14, 1983 in his favor.

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 EMI2.1
 



  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 tetrazine & e general formula:
 EMI2.2
 
 EMI2.3
 (in which RI represents a cycloalkyl radical or a straight or branched alkyl, alkenyl or alkynyl radical containing up to 6 carbon atoms, each alkyl, alkenyl and alkynyl radical being unsubstituted or substituted by one to three substituents chosen from halogen atoms (such as bromine, iodine or preferably chlorine or fluorine), radicals alkyloyioxy, alkylsulfinyl and alkylsulfinyl and alkylsulphonyl in straight or branched chain containing up to 4 carbon atoms and optionally substituted phenyl radicals represents a nitrogen atom or a raw radical = in leauel Ro represents a hydrogen atom or a substituent R4 in which R4 represents a halogen atom,

   or a straight or branched chain alkyl or alkenyl radical containing up to 6 carbon atoms, which may bear up to 3 substituents:; chosen from halogen atoms, optionally phenyl radicals. substituted, alkyloxy, alkylthio and alkylsulfonyl containing up to 3 carbon atoms or alternatively R represents an optionally substituted cycloalkyl, cyano, hydroxy, nitro or phenoxy radical. or a radical of formula-COR (in which R represents an alkyl or alkoxy radical containing up to 4 carbon atoms, a hydro:: y radical or an optionally substituted phenyl radical) or else an alkanoylamino radical containing up to 6 atoms of carbon, or else R4 represents a radical of formulas:

   

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 EMI3.1
 - S (0) nR6, -S02NR7Ra or -CZ2NR7Ra nb 27 "2/0 (in which n represents the digits 0, 1 or 2, R6 represents an alkyl or alkenyl radical in a straight or branched chain containing up to 4 atoms of carbon (which may carry a phenyl substituent optionally substituting a cycloalkotyl radical or an optionally substituted phenyl radical, R7 and Ra 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 4 carbon atoms (which may carry an optionally substituted phenyl substituent) or a cycloalkyl radical or an optionally substituted phenyl radical or else the radical-NR Rn represents a heterocyclic radical, and Z2 represents an oxygen or sulfur atom ),

   A2 represents a nitrogen atom or else, when Al represents a nitrogen atom, A2 represents a nitrogen atom or a radical -CR3 = in which R, is defined as above, represents an oxygen atom or of sulfur, and R2 represents a radical of formulas:
 EMI3.2
 - S (0) R ..- SO., NRRo, -CSNR7Ro, -COXRR ou-CZ NHO n '(9 2
 EMI3.3
 in which n, R6'R7'RS and Z2 are defined as above and the radical-NRR represents a heterocyclic radical or R7 is defined as previously and R9 represents an alkyl or alkenyl radical in a straight or branched chain containing up to 4 atoms carbon (which carries an optionally substituted phenyl substituent), or an optionally substituted phenyl radical, or,

   when represents a nitrogen atom or a radical -CR4 = in which R4 is defined as above and and A2 are defined as above or when Al represents a radical -CH = and Z1 represents a sulfur atom and A2 is defined as above) R represents a radical of formulas:

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 EMI4.1
 -S (OR, -SONRRg, -CZNR Rg or CZ2NHN02 in which n, and Z2 are defined as above. J and, when R2 and / or R3 represents a sulfamoyl radical or mono substituted sulfamoyl and / or R3 represents a carboy radical. their salts, more especially their alkali metal salts such as sodium salts Whenever the context allows, when reference is made to the compounds of general formula (1), it is understood that reference is also made with salts.

   The salts are particularly useful as intermediates.



  In the definitions of general formula (1), 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 (1) contain 3 8 (preferably 6) carbon atoms.

   In the definition of general formula (1), the term heterocyclic radical is intended to mean a 5: 6 or 7-membered heterocyclic group which may optionally contain another heteroatom such as nitrogen, oxygen or sulfur and which may carry one or two substituents straight or branched chain alkyl each containing up to 4 carbon atoms, such as a piperidino, methyl "2, methyl-3, methyl-4, dimethyl-2, 4 or dimethyl-3, 5 piperidino radical or a radical morpholino, pyrrolidinyl-1, perhydroazepinyl-1, pipera:: inyl-l. methyl-4 piperazinyl-1 or thi azin - 1, 4 yl- 4 ..



  The descriptions of l. i British patent application 2,104,522 e: applications; ; equivalent in the other countries which claim priority from the initial British patent application No. 81 25791 as from patent application U. S0410656 describe compounds of general formula (II) in which represents a hydrogen atom, a cycloalkyl radical or a alkyl radical,

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 EMI5.1
 alkenyl or alkynyl in straight or branched chain containing up to 6 carbon atoms, each alkyl, alkenyl or alkynyl radical being unsubstituted or substituted by 1 to 3 substituents chosen from halogen atoms, an alkyloxy radical, alkyl thio alkylsulfonyl, alkylsulfinylejen straight or branched chain containing up to 4 carbon atoms, and optionally substituted phenyl radicals,

   and R11 represents a carbamoyl radical which can bear, on the nitrogen atom, one or two radicals chosen from the straight and branched chain alkyl and alkenyl radicals each containing up to 4 carbon atoms and the cyclalkyl radicals.



  The tetrazine derivatives of general formula:
 EMI5.2
 
 EMI5.3
 have remarkable antineoplastic activity, for example against carcinomas, melanomas, sarcomas, lvmDhomes and leukemias: they also have remarkable immunomodulatory activity and are useful in the treatment of organ and skin grafts and in the treatment of immunological diseases. Compounds of general formula (1) of the present invention have similar properties with, in certain aspects, improvement.



  The tetrazine derivatives of general formula (II. Are useful as intermediates in the preparation of some of the compounds of general formula (1) according to the present invention, for example as described below in; the present description 0 Of particular importance are the classes of compounds of general formula (1) which include in their formula one or more of the following characteristics:

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 EMI6.1
 i) R1 represents a methyl radical or more especially a 2-haloethyl radical, in particular a 2-chloroethyl radical, ii) R2 represents a radical of general formula:

   -SOR, -SOR., - SO NRRg, -CONRRg or -COHNOspecially those in which R6 represents an alkyl radical such as methyl and those in which R represents a hydrogen atom or an alkyl radical such as methyl, and Rn represents a hydrogen atom or an alkyl radical such as methyl or a benzyl radical optionally substituted by an alkyllexy radical, such as a 4-methoxy-benzyl radical, iii) R3 represents a radical R in which R represents a methoxy alkyl radical such as bubble , propyl, ethyl or more particularly / iv) 11 one of the symbols A1 and A2 represents a nitrogen atom and the other represents a radical -CR3 = 'v) A2 represents a nitrogen atom, vs) 2 represents an atom oxygen and / or vii) represents an oxygen atom.



  The important individual compounds of general formula (I) include the following: (N-benzyl N-phenylcarbamoyl) -8 methyl-3 / 3H / imidazo / 5, Id} tét "azin-1,2,3,5 one-4 A, / N-benzyl K-methoxy-'t benzyl) carbamoyl / -8- (2-chloro-ethyl) -3.3H, 7-imidazo / 5, ld / tetrazine-1,2,3, S one-4 B, (N-benzylcarbamoyl) -8 (2-chloroethyl) -3 / 3H / imidazo / 5, 1-d / tetra ine-1, 2, 3, 5-one-4 C, (chloro- 2 ethyl) -3-,:

   N-4-methoxybenzyl) phenylcarbamoyl-8 / 3H / -imidazo / 5, 1-dy tetrazine-1,2,3, S-one-4 D, (2-chloroethyl) -3 (N-phenylcarbamoyl) - 8 3ji / imidazo / 5, lq / -tetrazine-1, 2, J, S-one-4 E,

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 EMI7.1
 (N-benzyl N-phenylcarbamoyl) -8 (2-chloro ethyl) -3 / 3H / -imidazc / '5, 1-d-tetrazine-1, 2, 3, 5 one-4 F, (2-chloro ethyl ) -3- (N-methyl N-phenylcarbamoyl) -8 / 3Himidazo / 5, ld / - tetrazine-1, 2, 3, 5 one-4 G, carbamoyl-8 (2-chloro-ethyl) -3-methyl- 6 / 3H / imidazo L5, 1-dJ tetrazine-1, 2, 3, 5 one-4 H, 0h101'o-2 ethyl) -3- (N, N-dimethylsulphamoyl) -8 L3H7-imidazo5, 1-dl -tét1'azine-1, 2, 3, 5 one-4 I, (2-chloro-ethyl) -3- (N-methylsul? hamcyl) -8 / 3-imidazo / 5, ld / tetrazine 1, 2,:

  , 5 one-4 J, (2-chloro ethyl) -3.-methylsul-fonyl-8 / 3H / imidazo 3, 1-d / -tetrazine-1, 2, 3, 5 one-4 K, methyl-3 -methylsulfonyl-8 / 31i7-imidazo / 5, l-d7tét1'azine-l, 2, 3, 5 one-4 L, (2-chloro-ethyl) -3-N-4-methoxy-benzyl) sulfamoyl / -8 / 3 / -imidazo 3, 1-d / tetrazine 1, 2, 3, 5 one-4 (2-chloro-ethyl) -3 (sulfamoyl-8) / 3ti / imidazo! '5, 1-1-tetrazine-1, 2, 3, 5 one-4K, carbamoyl-8 (2-chloro ethyl) -3 / 3H / -pyrazolo. 5''d / "tét1'azine-1, 2, 3, 5 one-4 0, carbamoyl-8 methyl-3 / 3H / -pyrazolo / 5, ld / tét1'ôzine-1, 2, 3, 5 one -4 P, (2-chloro-ethyl) -3 piperidinocar.

   bonyl-8 / 3H / imidazo / 5, ld / -tetrazine-1, 2, 3, 5 one-4 Q, carbamoyl-8 butyl-6 (2-chloro-ethyl) -3 / 31i / -imidazo- / '5 , 1-d / tetrazine-1, 2, 3, 5 one-4 R, carbamoyl-o (2-chloro-ethyl) -3 cyclohexyl-6/3 / imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4 S, carbamoyl-8 (2-chloro-ethyl) -3 phenethyl-6 / 3H / imidazo / 5, ld / tetrazine-1, 2, 3i5 one-4 T, 6-benzyl carbamoyl-8 (chloro- 2 ethyl) -3 / 3ij / -imidazo- / 5, ld / tetrazine-1, 2, 3, 5'me-4 V,

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 EMI8.1
 carbamoyl-8 (2-chloro ethyl) -3 isopropyl-6 / 3H / imidazo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 V, carbamoyl-8 (2-chloro ethyl) -3 propyl-6 / 3ii / -imidazo- / 5, ld / tetrazine-1, 2, 3, 5 one-4 W, carbamoyl-8 (2-chloroethyl) -J ethyl-6 LJH1-imidazo- / 5, ld / tetrazine-1, 2, 3, 5 one-4 X, (2-chloro-ethyl) -3 (4-methoxy benzyl) sulfamoyl-8 methyl-6/37-imidazo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 Y, (chloro-2 methyl)

  -3 methyl-6 sulfamoyl-8 / 3H / imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4 Z, 2-chloroethyl) -J dimethylsulfamoyl-8 methyl-6 LJH1imidazo / 5, 1- d / tetrazine-1, 2, 3, 5 one-4 AA, (2-chloro methyl) -3 methyl-6 methylsulfonyï-8/3 / imidazo / 5, ld / tetrazine-1, 2, 3, 5 one- 4 BB, (2-chloroethyl) -3 dimethylcarbamoyl-8 37-pyrazolo- / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 CC, (2-chloro ethyl) -3 (N- nitrocarbamoyl) -8 / 37imidazo / '5, ld / tetrazine-1, 2, J, 5 one- DD, 3-methyl-methylsulfonyl-8/37-pyrazolo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 EE, (chlor3-2 ethyl) -3 methylsulfonyï-8 / 3H / -pyrazolo- / 5, ld / tetrazine-1, 2, 3, 5 one-4 FF, (chloro-2 methyl) -3 6-methyl-methylsulfinyl-8 / JH Jimidaz3 / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 GG, (chlorD-2 ethyl) -3 ethyl-sulfonyl-8 methyl-6 / 3H / imidaz), ( 5, 1-d) tetrazine-1, 2, 3, 5 one-4 HH.

   and (chlor) -2 ethyl) -J methyl-6 propylsulfonyï-8/3 / L imidaz3, l-d / tetrazine-1, 2, 3, 5 one-4. II <, The letters A to II have been assigned to the compounds to facilitate later reference in the description.



  Compounds of particular importance

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 EMI9.1
 include compounds C, K, L, M, O, Q, R, W, X and DD, more particularly compounds I, J, N and BB and in a very particular way compounds H, Z, AA and CCo The new tetrazine derivatives of general formula (1) have shown a particular activity in mice at daily doses of between 0.2 and 320 mg / kg per kg of animal body weight by intraperitoneal administration, against TLX5 lymphoma (S) according to the technique of GESCHER et alo, Biochem.



  Pharmacol. 30, 89 (lu81) and sarcomas ADJ / PC6A and M5076 (reticulocellular sarcomas .. ires).



  Against intraperitoneal, intracerebral and intravenous grafted leukemia L 1210 and against leukemia P 388 in the technique described in "Methods of Development of New Anticancer Drugs" (monographs NC1 no 45, March 1977 pages 147-149, 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 animal body weight Inhibition of both primary tumor and metastases a was obtained in Lewis lung cancer, with similar doses, Against melanoma B 16 and tumor C 38 in mice (NCI monograph No. 45 already cited, the compounds have been shown to be active intraperitoneally there doses between 6,

   25 and 40 mg per kg of animal body weight Against colon carcinoma C 26 in mice, grafted subcutaneously, the compounds have been shown to be active orally at doses of between 2 and 40 mg per ke of animal body weight The compounds of general formula (1) 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 (1) in which R2 is different from a sulfamoyl radical, carbamoyl which carries an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted phenyl substituent and which is different from a radical nitro-

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 EMI10.1
 carbamoyl or nitrothiocarbamoyl can be prepared by the action of a compound of general formula:

   
 EMI10.2
 
 EMI10.3
 in which A. and -Ap are defined as above and Rio represents a radical falling within the definition of R2 above other than that representing a sulfamoyie, carbamoyie radical which carries a possible phenyl substituent. ment substituted or thiocarbamoyie which carries an optionally substituted phenyl substituent and other than a nitrocarbamoyl or nitrothiocarbamoyl radical, with a compound of general formula: / - r \ R in which Ri and Zl 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-methylpyrrolidone-2 or hexamethylphosphoramide, at a temperature between 0 and i20oC.

   The reaction can be continued up to a duration of 30 days. It is preferable to operate in the absence of lights. According to another characteristic of the invention, the compounds of general formula (1) in the present R2 represents a carbamoyl radical which carries an optionally substituted phenyl or thiocarbamoyl substituent which carries an optionally substituted phenyl substituent and R, A, A and are defined as above, can be prepared from the corresponding compounds of general formula (1) in which R represents a radical of general formula = -CZRR (V)

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 EMI11.1
 in which R12 represents an optionally substituted phenyl radical, R13 represents an optionally substituted benzyl radical and Z2 is defined as above,

   by application or adaptation of methods known per se to replace a benzyl radical 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 dimethylformamide); or, when R13 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, preferably in presence of anisol at ambient temperature or at a temperature close to this.



  According to another characteristic of the invention, the compounds of general formula (1) in which R2 represents a radical of general formula: -CZNHNO 2 2 in which and Z1 are defined as above i 1 1 1 can be prepared by nitration of the compounds of general formula:
 EMI11.2
 
 EMI11.3
 in which Ruz represents a radical of formula: - CZ in which Z, R., A., A and Z1 are defined as above.



  The reaction can be carried out at or near room temperature, preferably between 0 and 10 C.

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 EMI12.1
 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 (1) in which R, A, A and R are defined as above and Z represents a sulfur atom can be prepared from the compounds of general formula:
 EMI12.2
 
 EMI12.3
 in which R ,, A and R, are defined as above and R15 ll represents a radical of formula: - S (0) R .., -SO NR R .., -CZ NR R or -CZ NHN02 '(R, R-, Ri, n and Z being defined as above) by action of phosphoreo pentasulfide 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 (for example, between 50 and 120oC.



  According to another characteristic of the invention, the compounds of general formula (1) in which n ^, and are defined as above and Ro represented a radical of general formula:., -., Nn -, j 7 8 can be prepared from the compounds of general formula:
 EMI12.4
 

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 EMI13.1
 in which R1, A1, A2 and Zl are defined as above and R16 Y 1 lb represents a radical of general formula:

   - CONRJRn in which R and Ra are defined as above, by the action of phosphorus pentasulfide under conditions analogous to those described above for the reaction of phosphorus pentasulfide with the compounds of general formula (VI) c The previously mentioned salts of certain compounds of general formula (1) can be prepared by application or adaptation of methods known per se, for example by action of the basic compound of general formula (1) 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 processes 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 and ale Je Orgo Chemo 26, 2) 96 (1961) and CHENG et alto, j Pharm. Scio, 57, 1044 (1968) and the methods described below in the example references.



  The term “methods known per se” as used in the present description means the methods already used or known in the literature The following examples illustrate the preparation of the compounds of general formula (1) according to the present invention and the examples of reference illustrate the preparation of intermediaries.



  EXAMPLE 1 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

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 EMI14.1
 by shaking at 0 C and treated in small portions at a time / O,? 9 of 3-amino hydrochloride N-benzyl N-phenyl imidazolecarbaxamide-4 (prepared as in reference example 1) 0 After 10 minutes, the gummy solid obtained is extracted with twice 20 cm3 of ethyl acetate . The organic extracts are combined and washed with water and dried over magnesium sulfate. 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 temperature. room 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. 0.22 g of (N-benzyl N-phenylcarbamoyl) -8 methyl- is thus obtained. 3 13 imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4, in the form of a white crystalline solid melting at 168-1700C (with decomposition) 0 Elemental 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 NMR spectrum (in DHSO-d 6): singlets 2. 3.75; 5, 10 and 8.55 ppm multiplet at 7.0-7.4 ppm.



  Mass spectrum: crumb = 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 Ce The solution is stirred at OOC and treated dropwise dropwise with a solution of 2.2 g of 5-amino hydrochloride N-benzyl N- (4-methoxy benzyl) imidazolecarboamide-4 (prepared as in reference example 2) in 10 cm3 of dimethoxy-1, 2 ethanes The reddish gum which separates is extracted with 2 times 20 cm3 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.

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 EMI15.1
 



  The solution obtained from 5-diazo N-benzyl N- (4-methoxybenzyl) imidazolecarboxamide-4 is treated with 2 cm 3 of 2-chloro-ethyl isocyanate and the mixture is left at room temperature for 2 hours in the dark. 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- (4-methoxybenzyl) carbamoyl are thus obtained. -8 (2-chloroethyl) -3 / 3H / -imidazo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 in the form of a brown oil.



  EXAMPLE 3 - -------- years cm ac1de tr1 uoroacet1queon d1ssout 1, g of / N-benzyl N- (4-methoxy benzyl) carbamoyl} -8 (2-chloro methyl) -3 / 3H7- imidazo / 5, ld / 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: 60-800C) (2-1 year volumes).



  0.3 g of (N-benzylcarbamoyl) -8 (2-chloroethyl) -3 / 3 / -imidazo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 is thus obtained of a colorless solid melting at 153-1550C (after recrystallization from ethyl ether) 0 Elemental analysis: Calculated%: C = 50.53; H = 3.9; N = 25, 26; Cl = 10.65 Found Pc: C = 9.9; H = 3.92; N = 24, 4: Cl = 10, IR spectrum (KBr tablet): 3370, 3150, 1755 and 1660 cm-1 NMR spectrum (in DMSO-d6): singlets at 7, 3 and 8, 9 ppm; doublet at 4.4 ppm and triplets at 4.0; 4, 6 and 9, 0:; ppm.



  EXAMPLE 4 ---'----- 0.61 g of sodium nitrite is dissolved in 1 cm of water

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 EMI16.1
 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 reference example 3 ) in 9 cm3 of 2M hydrochloric acid and 15 cm3 of 1,2-dimethoxyethane. 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-methJxy-benzyl) N-phenyl imidazolecarboxamide-4 are thus obtained in the form of an orange h -ile.



  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 (chloro-2 methyl) -3 l - (4-methoxy-benzyl) N-phenylcarbamoyl / -8 / H / -imidazo / 5, ld / tetrazine-1, 2, 3, 5 are thus obtained. -4, in the form of a glass melting at 550C.



  NMR spectrum (in DMSO-d6): singlets at 3, 6; 5.0 and 8.5 ppm; triplets centered at 3, 9 and 4, 5 ppm; multiplet at 6, 6-7, 2 ppmo IR spectrum (KBr tablet): 1740 and 1640 cm -10 EXAMPLE 5 - -------- years 1 cm aCl e rl uoroace lque, 1 g of (chlro -2 ethyl) -3 / N- (4-methoxy benzyl) N-phenylcarbamoyl / '- 8/3! / -imidazo / 5, ld / betrazine-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 methyl ether.

   0.43 g of (2-chloroethyl N-phenylcarbamoyl-8 / 3H / -imidazo / 5, 1d / tetrazine-1, 2, 3, 5 one-4, is obtained in the form of a beige solid brown, melting at 1660C (with decomposition) (after re-crystallization in ethyl acetate).

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 EMI17.1
 



  Elementary analysis; Calculated%: C = 48.99; H = 3.4, 8: 8; N = 26, 37 Found%: C = 4: 8, 4; H = 3.22; N = 26.0 IR spectrum: (KBr tablet): 3390, 1735 and 1680 cm-1 RUN spectrum (in DHSO-d6): 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 - -------- n lSSOU, 9 of sodium nitrite in 84 cm3 of a 2M aqueous solution of acetic acid. 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 the minute, the gummy solid obtained is extracted with 3 times 30 cm3 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 of 5-diazo N-benzyl N-phenyl imidazolecarboxamide-4 is treated with 9 cm 3 of 2-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 of (-benzyl N-phenylcarbamoyl) -8 (2-chloroethyl) -3 / 3H / -imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4, is thus obtained. a glass.



  Elementary analysis; Calculated%: C = 58.75; H = 4.19; N = 20.56; CI = 8.67 Found%: C = 59.3; H = 4:, 57; N = 19.9; Cl = 8.5 IR spectrum (KBr tablet): 1740 and 1640 cm-1 NMR spectrum (in DMSO-d): singlets at 5.2; ?, 1; 7.3 and 8.6 ppm; triplets centered at 4.0 and 4.6 ppm.

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 EMI18.1
 



  EXAMPLE 7 ---'---- To a solution of 11 g of sodium nitrite in 50 cm3 of water cooled to 0 C, a solution of 4 g of 5N amino hydrochloride is added dropwise methyl N-phenyl imidazolecarboxamide-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 of 5-diazo N-methyl N-phenyl imidazolecarboxaide-4 is treated with 11 cm 3 of 2-chloro-ethyl isocyanate and the mixture is left to stand for 1 night in the dark.



  The solution is then concentrated to low volume and the residue is subjected to column SUF chromatography under low pressure, eluting with ethyl acetate. This gives 5.75 9 of a product which is triturated with l isopropyl oxide and then with methylene chloride. The insoluble residue is recrystallized from a mixture of petroleum ether (PE. 60-BoOC) and ethyl acetate. 0.8 g of (chloro-2 methyl) -3 (N-methyl N-phenylcarbamoyl) -8 / 3H / -imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4, is finally obtained. form of a colorless solid melting at 130-1320C.



  Elementary analysis: Calcula%: C = 50, 53; H = 3.94; N = 25, 26; Cl = 10.65 Found%: C = 50.4; H = 3.91; N = 24.9; Cl = 10.6 i IR spectrum (KBr tablet): 1750 and 1640 cm-1 NMR spectrum (in DMSO-d): singlets at 3.4, 7, 2 and 8, 65 ppr); Triplets centered at 3 , 95 and 4.6 ppm.



  EXAMPLE 8 Compos, H. 5 '.. 5'h 1 2 ..



  - ----- .. - Has a suspension1. on 1, 'i: g of diazo-5 methyl-2 imidazole-1 carboxEmide-4 (prepared as described in reference example 5) in 45 cm3 ethyl acetate, added with stirring 6, 33 g of 2-chloro-ethyl isocyanate and the mixture is stirred at room temperature for 5 days in the dark.

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 EMI19.1
 



  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. This gives 2 g of carbamoyl-8 (2-chloro-ethyl) -3 methyl-6 / 3H / -imidazo- / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 melting at 1700C (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; Cl = 13.3 EXAMPLE 9 --------- To a solution of 0.55 g of diazo-5 N, N-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 under vacuum at a temperature below 400c until reaching a volume of approximately 15 cm3 and then diluted with ethyl ether. The solid obtained is separated by filtration. 0.68 g of (2-chloro methyl) -3 (K, N-dimethylsulfamoyl) -8 / 3 / -imidazo / 5, l-d / tetrazine-1 is thus obtained. 2, 3, 5 one-4 in the form of greyish needles melting at 155-1560c.



  Elementary analysis: Calculated zo: C = 31, 3: H = 3.62: N; :: 27, 4; CI = 11.6 Found%: C = 30.4; H = 335 N = 26.8; Cl = 11.8 IR spectrum: 1755 RUN spectrum (in DHSO-d6): singlets at 2.80 and 8.890 ppm; triplets at 3.99 and 4.62 ppm.



  EXAMPLE 10 EXAMPLE 10 --------- a suspension e, 9 e lazo- 1 -me y lml azo esulfonamide-4 (prepared as described in reference example 7) in 40 cm3 of acetate ethyl, 3 cm 3 of 2-chloro-ethyl isocyanate are added and the mixture is stirred in a stoppered flask for 48 hours in the dark.

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 EMI20.1
 



  The reaction mixture is then concentrated to approximately half of its volume under vacuum at a temperature below 350C, then diluted with ethyl ether. The solid obtained is separated by filtration and washed with ethyl ether. 0.32 g of (2-chloroethyl) -3 (N-methylsulfamoyl) -8 / 3H / -imidazo / 5, ld / tetrasine-1, 2, 3, 5 one-4 are thus obtained in the form of beige flakes brilliant melting at l47-148 C.



  Elementary analysis: Calculated%: C = 28, 7; H = J, 0 8.; N = 28.7 Found%: C = 28.5; H = 2.90; N = 28.7 IR spectrum: 1745 cm RHN spectrum (in DMSO-d): doublet at 2.58 ppm: triplets at 3.98 and 4.61 ppm; 7.94 ppm quartet; singlet at 8.84 ppm.



  EXAMPLE 11 - -------- a so utlon of, 9 e dlazo-) methylsulfonylimidazole (prepared as described in reference example 8) in 50 cm3 of anhydrous ethyl acetate, 3 cm3 d are added 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 60-800c). 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 (2-chloroethyl) -3 methylsulfonyl-8 '3H7-imidazo / 5, 1-d / tetrszine- 1, 2, 3, 5 one-4 melting at 154-1550C are thus obtained.



  Elementary analysis: Calculated 6: C = 30, 28: H = 2.90; N = 22; Cl = 11.55 Found 6: C = 30.3: H = 2.85; N = 2: ', 0: Cl = 11, 5 EXAMPLE 12 --- P - To a solution of 0.65 g of 5-diazo-methylsulfonyl-4 imidazole (prepared as described in reference example 8) in

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 EMI21.1
 60 cm3 of ethyl acetate, 3.5 cm3 of methyl isocyanate are added and the mixture is left to stand at room temperature for 3 days in the dark.



  A further quantity of 3.5 cm 3 of methyl isocyanate is then added and the mixture is heated at 400 ° C. for 2 days and then 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-3-methylsulfonyl-8 / 3H / -imidazo5, 1-d / tetrazine-1, 2, 3, 5 one-4 is thus obtained in the form of a white crystalline solid melting at 185-1860C. (with decomposition) c Elementary analysis: Calculated%: C = 31, 44; H = 3.08: N = 30.56 Found%: C = 31.2: H = 2.89: N = 30.3 EXAMPLE 13 ---'----- To a solution of 0.5 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 isocyanate is added ethyl and stirred the mixture at 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 700C for 1 hour 9.



  0.2 g of (2-chloroethyl) -3 / K- (4-methoxy-benzyl) sulfamoyl / -8 / 3H / -imidazo / 5, 1-d tetrazine-1, 2, 3, 5 is thus obtained. -4 melting at 155-1560c (with decomposition).



  IR spectrum: 1745 cm Elemental analysis: Calculated%: C = 42, 16; H = 3.79; K = 21.07 Found%: C = 41.9; H = 3.72; N = 20.5

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 EMI22.1
 EXAMPLE 14 Compound N 0.1 g of (2-chloro-ethyl) -3 / N-4-methoxy-benzyl) sulfamoyl / -8 / 3H / -imidazo / f5, 1-d / tetrazine-1, 2 is dissolved. , 5 one-4 (prepared as described in Example 13) in 1 cm3 of trifluoroacetic acid and 3 drops of anisol 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 chromatography under medium pressure and eluting with a mixture of petroleum ether (PE 60-BoOc) and ethyl acetate (1/1 by volume).

   This gives 50 mg of (2-chloro-ethyl sulfamoyl-8; / 3H / -imidazo / 5, 1-d / 'tetrazine-1, 2, 3, 5 one-4 in the form of a white solid melting at lake (with decomposition).



  IR spectrum: 1750 cm NMR spectrum (in DHSO-d6): singlets at 8, 8 and 7, 8 ppm; triplets at 4.58 and 3.95 ppm.



  EXAMPLE 15 EXEHPLE 15 --------- To a suspension of 5.9 g of 3-diazo pyrazolecarboamide-4 (prepared as described by CHENG et al., Op. Cit.) In 150 cm3 of acetate d ethyl, 24 cm3 of 2-chloro-ethyl isocyanate is added with stirring and the mixture is kept at ambient temperature with stirring for 7 days in 11 days. 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 under forum are thus obtained. ne of a solid cream melting at l73-174 C (with decomposition).



  A sample of 1'J said mixture is dissolved in 20 cm3 of dimethyl sulfoxide and heated overnight at 60oc. The solution is concentrated to dryness (at a temperature below 600 ° C. under a pressure of less than 0.1 m 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.

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 EMI23.1
 



  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 ethyl acetate. After recrystallization of the product obtained from acetonitrile, 0.25 g of carbamoyl-8 (2-chloroethyl) -3 / '3H / -pyrazolo / 5, 1d /' tetrazine-1, 2, 3, 5 is obtained. -4, in the form of colorless needles melting at 203-20oC (with decomposition) 0 Elemental analysis: Calculated%: C = 3.65; H = 2.91; N = 34.64: Cl = 1.61 Found%: C = 3.8, H = 2.92; N = 3.7; Cl = 1.6 EXAMPLE l6 Compound P A. d 6 d d. 3.



  - -------- suspenSIon e 1, ge lazo- pyrazolecarboxamlde- 4 (prepared as described by CHENG et al., op. cit.) in 49 cm3 of dichloromethane and 2.5 cm3 of N-methylpyrrolidone- 2Jon added with stirring 6 cm3 of methyl isocyanate, then stirred for 7 days in the dark. The mixture is then diluted with ethyl ether and the solid formed is separated by filtration. 2.2 g of a mixture are thus obtained in the form of a solid cream melting at 179-1810C (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% water and the mixture is evaporated to dryness under reduced pressure (0.1 mm of mercury) at 60oc. The residue is loaded onto a column of silica gel and subjected to chromatography under medium pressure, eluting with ethyl acetate. L8 product: obtained is triturated with a small amount of a saturated aqueous solution of sodium bicarbonate and quickly separated by filtration. 1 mg of carbamoyl-8 methrl-3 131pyrazoLo / '5, l-d7 tetrazine-1, 2, 3, 5 one-4 is thus obtained in the form of a colorless solid melting at 1700C (with decomposition).



  NMR spectrum (in DMSO-d6): singlet at 3.95; 7.5; 7.55 and 8.50 ppm.



  IR spectrum (KBr tablet): 300, 3160, 1750 and 1680 cm-la

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 EMI24.1
 EXAMPLE 17 -------- To a solution of 0.79 g of sodium nitrite in 6 cm 3 of water) a solution of 2.1 g of amino hydrochloride is added dropwise with stirring 4 piperidinocarbonyl-5 imidazole crude (prepared as described in reference example 10) in 17 cm3 of an aqueous solution of acetic acid 1. The casting is carried out in 5 minutes at a temperature between 5 and 10oC. The solution is extracted with 4 times 45 cm3 of ethyl acetate; the extracts are combined and dried over magnesium sulphate and evaporated under reduced pressure (0.1 mm of mercury) at 30 C. The residue is dried in a desiccator over phosphorus pentoxide for 45 minutes.

   1.7) 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 1.7 g of 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) at 30 C and the residue is subjected twice to chromatography on silica gel under medium pressure, eluting with a mixture of ethyl acetate and d 'acetonitrile (E8 / 12 by volume). The suitable fractions are combined and evaporated and the residue is triturated with petroleum ether (EF = 40-600C). 1.469 of (chloro-2 ethyl) -3 piperidinocarbonyl-8 / J / -imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4 are thus obtained in the form of pale purple crystals melting at 92-940c.



  Elementary analysis: Calculated 9b: c. = 46.4; H = 4.87; N = 27, 1 Found%: (. = 45, 3; H = 4, 98; N = 26, 1 NMR spectrum (in DMSO-d ,.): singlet at 8.7 Ppm: triplets at 4.6 and 4, 0 ppm: multiplets at 3, 2-), 4 and 1, 5-1, 8 ppm.



  IR spectrum (KBr tablet): 1750, '.'. 630 cm

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 EMI25.1
 EXAMPLE 18 ---'----- A stirred solution of 1.61 9 of sodium nitrite in 5 cm3 of water is cooled and kept at a temperature between 5 and 100C and added dropwise. 5 minutes a solution of 1.61 g of 5-amino-2-butyl-hydrochloride imidazolecarboamide-4 (prepared as described in German patent application NO 2 358 509) in 17.7 cm 3 of hydrochloric acid IN. A yellow precipitate is obtained which is separated by filtration and dried in a desiccator over phosphorus pentoxide. 0.47 g of butyl-2-diazo-5 imidazolecarboxamide-4 is thus obtained, in the form of a yellow solid melting at 109-1110C (with decomposition), and which is sufficiently pure to be used as it is in the following stage. .



  A solution of 0.47 g of crude 2-butyl-5 diazo-imidazolecarboxamide-4 (prepared as described above) in 14 cm) of ethyl acetate is treated with 1.5 cm3 of chloro-2 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 L3imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4 is thus obtained in the form of colorless crystals melting at 165- 1670C (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 EXAMPLE 19 Compound S A stirred solution of C, 44 g of sodium nitrite in 3.7 cm3 of water is cooled and maintained at a temperature between 5 and 10 ° C. added dropwise over 5 minutes a solution of 1.1 g of 2-amino-2-cyclohexyl imidazolecarboxamide-4 hydrochloride (prepared as described in German patent application No 2 358 509) in 28 cm3 of a solution of 2M acetic acid.

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 EMI26.1
 



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



  0.86 9 of cyclohexyl-2 diazo-5 imidazolecarboxamide-4 is thus obtained in the form of an orange solid, sufficiently pure to be used as it is in the following stage.



  A solution of 0.86 9 of crude 2-cyclohexyl-5 diazo-imidazolecarboxamide-4 (prepared as described above) in 17 cm 3 of ethyl acetate is treated with 2 cm 3 of 2-chloro ethyl isocyanate and left at rest for 24 hours in the dark. The solid obtained is separated by filtration and recrystallized from ethyl acetate. 0.22 carbamoyl-8 (chloro-2 methyl) -3 cyclohexyl-6 / 3HZ-imidazo5, ld / tetrazine-1, 2, 3, 5 one-4 are thus obtained in the form of colorless crystals melting at 245 -2480c (with decomposition).



  Elementary analysis: 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 9 of sodium nitrite in 4.7 cm3 of water is cooled and maintained at a temperature between 5 and 100C. a solution of 1.89 5-amino-2-phenethyl-2-imidazolecarboxamide-4 hydrochloride (prepared as described in reference example 11) is added dropwise over 5 minutes in 13 cm3 of an aqueous solution of acetic acid 21'1. The yellow precipitate obtained is separated by filtration and dried in a desiccator over phosphorus pentoxide for 1 hour. 29 diazophene1 are thus obtained. : crude hyl-2 imidazolecarboxamide-4, in the form of a yellow solid, sufficiently pure to be used as it is in the following stage.



  A suspension of 2 9 of 5-diazo-2-phenethyl imidazolecarboxar. crude tide-4 (prepared as described above) in 29 cm3 of ethyl acetate is treated with 3.4 cm3 of 2-chloroethyl isocyanate and stirred for 24 hours in the dark. The solid obtained is separated by filtration and recrystallized twice from ethyl acetate.

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 EMI27.1
 



  This gives 0.4: 4: g of carbamoyl-8 (chloro-2 methyl) - 3 phenethyl-6 / 3H / -imidazo / 5, -l.-d. / Tetrazine-1, 2, 3, 5 one -4, in the form of colorless crystals, melting at 179-1810C (with decomposition).



  Elementary analysis: 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 --------- To a solution of 2.4 g of 2-benzyl-5-diazo imidazolecarboxamide-4 (prepared as described; reference example 12) in 150 cm3 of anhydrous ethyl acetate is added 10 cm3 of 2-chloro-ethyl isocyanate 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 (P.E = 60-800C) to remove the excess of 2-chloro-ethyl isocyanate.

   The remaining residue is then triturated with 2 times 50 cm3 of dichloromethane to extract the desired product from bis (2-chloro-methyl) -1, 3 urea which is the insoluble by-product which forms during the reaction. The chloromethylenic extracts are combined and evaporated to dryness and the residue is subjected to chromatography on silica gel under medium pressure, eluting with ethyl acetate. The suitable fractions are combined, evaporated and the product recrystallized from ethyl acetate. This gives 0.7 g of 6-benzyl-carbamoyl-8 (2-chloroethyl) -3 / 3 / imidazo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4, melting at 161- 1630C (with decomposition).



  Elementary analysis: Calculated%: C = 50, 53; H = 3.94; N = 25, 26: Cl = 10, 66 Found%: C = 50, 4; H = 3.96; N = 25, 4: Cl = 10, 8 IR spectrum: 1740 cm EXAMPLE 22 -------- To a solution of 1.2 g of 5-diazo-2-isopropyl-2 imidazolecarboxamide-4 (prepared as described in reference example 13) in

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 EMI28.1
 75 cm3 of anhydrous ethyl acetate) 5 cm3 of 2-chloro-ethyl isocyanate is added and the mixture is left to stand at room temperature for 5 days in the dark. The crystallized solid obtained is separated by filtration and washed with water. petroleum ether (PE = 6o-800C) o 0.29 carbamoyl-8 (2-chloro methyl) -3 isopropyl-6 / 3H / -imidazo / 5, 1-d / tetrazine-1 is thus obtained, 2, 3, 5 one-4, melting at 189-190oC (with decomposition).



  Elementary analysis: Calculated%: C = 2, 19; H = 4.60; N = 29.5 Found%: C = 2.0; H =, 6; N = 29.5 IR spectrum: 1740 cm EXAMPLE 23 - -------- a solu lon e 1, 9 amlnopropy - lml azo ecarboxamide-4 (prepared as described in the German patent application NO 2 358 509) in 22 cm3 of a 2M aqueous solution of acetic acid, a solution of 0.79 sodium nitrite in 6 cm3 of water is added dropwise at a temperature between 0 and 50C in 5 minutes. The precipitate obtained is separated by filtration and dried in a desiccator over phosphorus pentoxide. This gives 0.56 g of 5-diazo-propyl-2 imidazolecarboxamide-4, in the form of a yellow solid, sufficiently pure to be used as it is in the following step.



  A solution of 0.569 of 5-diazo-propyl-2 imidazolecarboxamide-4 (prepared as described above) in 1 cm3 of anhydrous ethyl acetate is treated with 1.6 cm3 of 2-chloro-ethyl isocyanate and stirred for 24 hours in the dark. The precipitate obtained is separated by filtration and washed with ethyl acetate. 0.43 g of carbamoyl-8 (2-chloroethyl) -3 propyl-6 / 3H / imidaz) L5, 1-d} tetrazine-1, 2, 3, 5 one-4 is thus obtained in the form of ln beige solid melting at l45-l48 C (with decomposition).



  Elementary analysis: Calculated 96: C = 2, 2; H = 4:, 60; N = 29.5 Found%: C = 1.1: H = 4.4; N = 28.5

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 EMI29.1
 RUN spectrum (in DMSO-d6): singlet at 7.7 ppm: triplets at 4.6; 4.0; 3.2 and 1.0 ppm; multiplet at 1.8 ppm.



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



  EXAMPLE 24 - -------- an agutated soluton, 9 amnoyethylimidazolecarboxamide-4 (prepared as described in German patent application No. 2,358,509) in 14 cm3 of a 2M aqueous solution of 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 30C. The precipitate obtained is separated by filtration and dried in a desiccator over phosphorus pentoxide for 1 hour. 0.69 9 of 5-diazo-2-ethyl-imidazolecarboamide-4 is thus obtained in the form of a yellow solid, melting at 1390C (with decomposition), sufficiently pure to be used as it is in the following stage.



  A solution of 0.62 9 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 precipitate obtained is separated by filtration and washed with ethyl acetate.



  This gives 0.59 9 of carbamcyl-8 (2-chloro-methyl) -3 ethyl-6 L3Hl-imidazoL5, 1-d} tetrazine-1, 2, 3, 5 one-4, in the form of gray crystals melting at 172-1760c (with decomposition)., Elementary analysis: Calculated%: C = 39, 9; H = 4.10: N = 31.0; Cl = 13.1 Found%: C = 39.7; H = 3.98; N = 31.0; CI 13, 1 EXAMPLE 25 ----------. a solution of 2.9 of diazo-5 (4-methoxy-benzyl) sulfamoyl-4-methyl-2-imidazole ((prepared as described in reference example 14) in 100 cm3 of anhydrous ethyl acetate, 3 cm3 of 2-chloro-ethyl isocyanate and the mixture is stirred at room temperature for 56 hours in the dark.

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 EMI30.1
 



  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 cm 3 of petroleum ether (P. Eo = 60-800c) to remove the excess of 2-chloroethyl isocyanate. The remaining residue is then triturated with 2 times 50 cm3 of dichloromethane to extract the desired product from bis (2-chloro-methyl) -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 (chloro-2 methyl) -3 (4-methoxy-benzyl) sulfamoyl-8 methyl-6/3 / -imidazo5, 1-d / tetrazine-1, 2, 3, 5 one-4 are thus obtained. melting at 159-160oc (with decomposition).



  IR spectrum: 1760 cm EXAMPLE 26 --------- In 10 cm3 of trifluoroacetic acid, 1.5 g of (2-chloro methyl) -3 (4-methoxy-benzyl) -sulfamoyl-8 methyl- are dissolved. 6 h / imidazo / 5, ld / tetrazine-1, 2, 3, 5 one-4 (prepared as described in exemon pie 25) and 10 drops of anisole, then / let the mixture stand 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 acetonec. This gives 0.55 g of (2-chloro-methyl) -3 methyl-6 sulfamoyl-8/3 / -imidazo / 5, 1-d / tetrazine- 1, 2, 3, 5 one-4, melting at 199-200oC (with decomposition).



  Elementary analysis: Calculated G: C = 28, 72; H = 3.10; N = 8, 71: Cl = 12, 11; S = 10.95 Found%: C = 29.1; H = 3.02; N = 8, 8: Cl = 12, 1; 5 = 10, 6 IR spectrum: 1760, 3310 cm.



  EXAMPLE 27 --------- To a solution of 1.9 d1azo-5 d1methylsulfamoylmethyl-2 imidazole (prepared as described in reference example 15)

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 EMI31.1
 in 100 cm3 of ethyl acetate, 4 cm3 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 is then concentrated in vacuo and the residue is triturated with 2 times 25 cm 3 of petroleum ether (P.E. = 60-800c). The remaining solid is dissolved in ethyl acetate and chromatographed on silica gel under medium pressure, eluting with ethyl acetate.

   The suitable fractions are combined to evaporate to dryness and the residue is triturated with petroleum ether (PE = 6o800c). 2.17 g of (chloro-2 methyl) -3 dimethylsulfamoyl-8 methyl-6 3.3H7imidazo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4 are thus obtained, melting at 137-1J80c.



  Elementary analysis: Calculated%: C = J3, 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 - --------- a so u on e, ge dazo- met yl- met y su 0nyl-4 jmidazole (prepared as described in the example 16) in 30 cm3 of 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 cm 3 of petroleum ether (PE = 6o-800c) to remove the excess of 2-chloro-ethyl isocyanate The remaining residue is dissolved in ethyl acetate and chromatographed on silica gel under medium pressure, eluting with ethyl acetate.

   0.22 g of (chloro-2 methyl) -3 methyl-6 methylsulfonyl-8 3H / -imidazo / 5, 1-d7 tetrazine-1, 3, 5 one-4 thus melting at 149-150oCo are obtained. : Calculated%: C = 32.9; H = 3.46; NOT ; 24.01: Cl = 12.15; S = 10.99 Found%: c = 33.0; H = 3.35; N = 23.8; Cl = 12.7; s = 10.7 IR spectrum: 1745 cm

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 EMI32.1
 EXAMPLE 29 ---'----- To a suspension of 0.92 g of dlazo-3 N hydrochloride, N-dimethyl pyrazolecarboxamide-4 (prepared as described in the dry example, reference 17) in 50 cm3 of dichloromethane / 2.5 cm 3 of 2-chloro-ethyl isocyanate are added and the suspension is stirred. 0.7 g of diazo-1.8 bicycio / 5o4 is added. 0 / undecene-7.

   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 .: 6o-800C). The insoluble residue 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-8/31 / -pyrazoloL5, 1-tetrazine-1, 2, 3, 5 one-4 are thus obtained in the form of colorless crystals, melting at 116 -118oC (with decomposition).



  Elementary analysis: Calculated%: C = 39, 93; H = 4.10; N = 31.05; Cl = 13.1 Found%: C = 39.7: H = 3.96; N = 30.9; Cl = 13.1 IR spectrum (KBr tablet): 1770, 1630 cm-1 NMR spectrum (in acetone-d '): singlets at 3.25 and 8.40 ppm; triplets at 4.25 and 4.95 ppm.



  EXAMPLE 30 Compound DD A 2 3 dl 0 dl, 0, 0 0 24 ---------- To 2, cm3 of concentrated sulunque acid, one adds, g of carbamoyl-8 (2-chloro-ethyl) -3 / 3H / -imidazo / 5, 1d / tetrazine-1, 2, 3, 5 one-4 (prepared as described in Belgian patent? 894 175).



  The mixture is cooled to 0 ° C. and treated dropwise with 1 cm 3 of concentrated nitric acid (d = 1.42). The solution is kept at 40C 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 (chloro-2 methyl) -3 N-nitrocarbamoyl-8/3 / -imidazo / 5, 1-d / 'ketrazine-1, 2, 3, 5 one-4, sub-form is thus obtained colorless crystals, melting at 160-1610C (with decomposition).

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 EMI33.1
 



  Elementary analysis: Calculated%: C = 29, 23: H = 2, 10; N = 3.09; 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-l NMR spectrum (in DMSO-d6): 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 ways analogous to those described in examples 1, 2,, 6 to 13, 15 to 25 and 27 to 29 but using as starting materials the appropriate diazo compounds (prepared by application or adaptation of the methods described in the following reference examples), were prepared:

   - 3-methyl-methyl-sulfonyl-8 '3H / -pyrazolo / 5, 1-d / tetrazine-1, 2, 3, 5 one-4, in the form of a colorless solid melting at 182-13oc, - (chloro -2 ethyl) -3 methylsulfonyl-8/37-pyrazolo / 5, ld / tetrazine-1, 2, 3, 5 one-4, in the form of a colorless solid melting at 166-1710C, - la (chloro-2 ethyl) -3 methyl-6methylsulfinyl-8 / 3jH / -imidazo / 5, ld / tetzine-1, 2, 3, 5 one-4, in the form of a yellow solid, melting at 118-120oC, - la (chloro -2 ethyl) -3 ethylsulfonyl-8 methyl-6 l3Hl-imidazo / S, lq / tetrazine-1, 2, 3, 5 one-4, melting at 146-147 C and - la (2-chloro ethyl) -J 6-methyl-propylsulfonyl-8 í3 / -imidaz0 / 5. 1-d / tetrazine-1, 2, 3, 5 one-4, in the form of a white crystalline solid melting at 85-860c.

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 EMI34.1
 



  REFERENCE EXAMPLE 1 i) An intimate mixture of 2 g of 5-nitro-imidazolecarboxylic-4 acid and 2.67 g of phosphorus pentachloride is heated in an oil bath at 1200 ° C. and with stirring for one hour.



  The yellow suspension obtained is evaporated to dryness under reduced pressure (0.1 mm of mercury) at 600C for 30 minutes. 1.90 g of dinitro-1, 6 / 5H7, / '10H7-diimidazo / l, 5-a: l', 5'-d7 pyrazinedione-5, 10 are thus obtained in the form of a yellow solid melting at 249-25loC (with decomposition).



  IR spectrum: (KBr tablet): 1750 cm-l Mass spectrum: crumb = 278 (M) WINDAS, Ber. 56, 684 (1923) and GIREVA, Chem. Abstr. , 1622e, using the same method, described the product they had obtained as 5-nitro-imidazolecarbonyl-4 chloride. ii) A mixture of 5.8 g of dinitro-1, 6 5HJ, / 10H7-diimidazoZ1, 5-a: l ', S'-pyrazindone-5, 10, 15 g of N is heated at reflux for 6 hours. -benzylaniline and 250 cm3 of tetrahydrofuran.



  The tetrahydrofuran is removed by evaporation under vacuum and the gum obtained is taken up in 1 liter of 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 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 colorless solid which is recrystallized from isopropanol. 4 g of nitro-5 N-benzyl N-phenylimidazolecarboxamide-4 are thus obtained, in the form of colorless scales, melting at 23 ° -240 ° C.



  Elementary analysis: Calculated X: C = 63, 35; H = 4.38; N = 17, 38 Found? : C = 62.3; H = 4.28; N = 17.3 IR spectrum (KBr tablet): 1665 cm'l

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 EMI35.1
 iii) A solution of 4 g of nitro-5 N-benzyl N-phenylimidazolecarboxamide-4 in 450 cm3 of anhydrous ethanol is hydrogenated at 260C under a pressure of 3 atmospheres, in the presence of nickel Raney as catalyst. When the absorption of hydrogen is complete (after 4 hours 50 minutes), the mixture is filtered, treated with 3.6 cm3 of concentrated hydrochloric acid and evaporated to dryness at a temperature below 40oC. After trituration of the residue with ethyl ether, 3.82 N-5-amino hydrochloride N-benzyl N-phenylimidazolecarboxamide-4 is obtained, in the form of a pale yellow solid melting at 190 -1930C (with decomposition).



  NHN spectrum (in DHSO-d6): singlets at 5.05; 7, 1-7, 2 b and 8, 4 ppm.



  IR spectrum (KBr tablet): 1640 cm-l Mass spectrum: crumb = 292 REFERENCE EXAMPLE 2 i) A mixture of 21.9 g of N-benzyl N- (4-methoxyphenyl) is refluxed for 18 hours amine (prepared according to Annalen 490, 189 (1931), 6,7 g of dinitro-1, 6 5H. 10Hdiimidazo5, la: l ', 5'-d7 pyrazinedione-5, 10 and 200 cm3 of tetrahydrofuran. The tetrahydrofuran is then eliminated 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 and the organic extracts are combined, washed successively with 2N hydrochloric acid, with water and with a saturated aqueous solution of sodium chloride and then dried. ; ur sodium sulfate and evaporated to dryness. The remaining gum is subjected to column chromatography under medium pressure, eluting with ethyl acetate. 2.9 g of nitro-S N-benzyl N- (4-methoxybenzyl) imidazolecarboxamide-4 are thus obtained, in the form a solid beige brown, melting

  <Desc / Clms Page number 36>

 
 EMI36.1
 at l67-l70oC (after recrystallization from a mixture of petroleum ether (P.E = 60-800C) and isopropanol).



  Elementary analysis: Calculated X: C = 62, 29; H = 4.95; N = 15.29 Found X: 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-d6 at 1200C): singlets at 3.76; 4, 5; 4, 6; 7.3 and 7.8 ppm; doublets centered at 6, 85 and 7.2 ppm.



  (The NMR spectrum at room temperature is complicated due to the splitting of the signals caused by the restricted rotation around the valence bond linking the carbonyl radical of the amide to the nitrogen atom of the amide). ii) A solution of 2.2 g of nitro-S N-benzyl N- (4-methoxy benzyl) imidazolecarboxamide-4 in 200 cm3 of anhydrous ethanol is hydrogenated at room temperature under a pressure of 3 atmospheres, in the presence of nickel of Raney as a catalyst. When the 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 400C.

   After trituration in a mixture of isopropanol and ethyl ether, 2.2 g of 5-amino hydrochloride N-benzyl N- (4-methoxy benzyl) imidazolecarboxamide-4 are obtained, in the form of a gummy solid which decomposes above 700C.



  IR spectrum (KBr tablet): 3400-2800, 1640 cm RXK spectrum (in methanol-d4): singlets at 3, 7; 4, 4; 4, 5; 7, 2 and 8, 3 ppir,; doublets centered at 6, 7 and 6, 9 ppm (signals widens; because of the restricted rotation around the valence bond binding the carbonyl radical of the amide to the nitrogen atom of the amide).

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 EMI37.1
 



  REFERENCE EXAMPLE 3 i) A mixture of 5.5 g of dinitro-1, 6 5H, 10H-diimidazog, 5-a: 1 ', 5'-d7pyrazinedone-5, 10, 14, is refluxed for 12 hours. 5 g of N- (4-methoxy benzyl) aniline prepared according to ZECHMEISTER et al, Ber. 63 B, 2883 and 250 cm3 of teterahydrofuran. The tetrahydrofuratin 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 2l2-2l50C (after recrystallization from isopropanol).



  Elementary analysis: Calculated X: C = 61, 37; H = 4.58; N = 15.91 Found X: C = 60.4; H = 4.41; N = 16.0 NMR spectrum (in DMSO-d6): singlets at 3.7; 5.0 and 7.7 ppm; multiplet at 6, 7-7, 3 ppm IR spectrum (KBr tablet): 1660 cm ii) A solution of 2.1 g of nitro-5 N- (4-methoxy benzyl) N-phenyl imidazolecarboxamide-4 in 200 cm3 d anhydrous ethanol is hydrogenated at 250C 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 imidazolecarboxamide-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 of 0.25 g of acid

  <Desc / Clms Page number 38>

 
 EMI38.1
 picrique in 5 cm3 of 1,2-dimethoxyethane. The crystals obtained are separated by filtration and washed with ethyl ether. 0.07 g of 5-amino picrate N- (4-methoxy-benzyl) N-phenyl imidazolecarboxamide-4 is thus obtained, in the form of a yellow solid, melting at 2070C (with decomposition).



  Elementary analysis: Calculated%: C = 49, 1; H = 4.29; N = 16.69 Found%: C = 49.1; H = 3.64; N = 16.5 REFERENCE EXAMPLE 4 i) A mixture of 8.08 g of dinitro-1, 6 5H, 10H-diimidazoll, 5-a: l ', 5'-d / pyrazindone is refluxed for 24 hours -5, 10, 12, 44 g of N-methyl aniline and 400 cm3 of tetrahydrofuran. The tetrahydrofuran is removed by evaporation under vacuum and the dark residual solid is taken up with boiling ethyl ether. The remaining undissolved solid is subjected to 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 imidazolecarboamide-4 are thus obtained, in the form of a white solid melting at 1930C.



  Elemental analysis: Calculated%: C = 53, 66; H = 4.09; N = 22.76 Found X: 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 230C under a pressure of 3 atmospheres in the presence of Raney nickel as a catalyst. When the absorption of hydrogen is complete (after 1 hour 39 minutes), the mixture is filtered and treated with a stream of dry gaseous hydrochloric acid. The solution is then evaporated to dryness. This gives 0.9 g of 5-amino-hydrochloride N-methyl N-phenyl imidazolecarboxamide-4, in the form of an off-white solid, melting at 1000C (with decomposition).

  <Desc / Clms Page number 39>

 
 EMI39.1
 



  This compound can be characterized as a picrate.



  To this end, 0.25 g of 5-amino-hydrochloride N-methyl N-phenyl imidazolecarboxamide-4 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 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 237-2380C (with decomposition).



  Elementary analysis: Calculated X: 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 2-amino-methylimidazolecarboxamide-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, melting at 1750C (with explosion), are thus obtained.



  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 nitro chloride are added in small portions at a time and with stirring. -5 imidazolesulfonyle-4 (wet product, freshly prepared from 3.33 g of ammonium salt of 5-nitro-mercapto-4 imidazole by the method of Fischer et al. Can. J. Chem. 21, 501). The mixture is stirred for a further 20 minutes then the mixture is concentrated to half its volume under vacuum at a temperature below 40oC. The mixture is then strongly acidified by

  <Desc / Clms Page number 40>

 
 EMI40.1
 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 N, N-dimethylsulfamoyl) -4 imidazole are thus obtained in the form of brownish flakes, melting at 282-2830C (with decomposition).



  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 nitro-5 N, N-dimethylsulfamoyl-4 imidazole in 100 cm3 of anhydrous ethanol is hydrogenated at 240C 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 under vacuum at a temperature below 30oC. 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.



  0.8 g of 5N amino hydrochloride, N-dimethyl imidazolesulfonamide-4 is thus obtained in the form of pinkish beige needles, melting at 188 -1890C (with decomposition).



  Elementary analysis: Calculated%: C = 26.5; H = 4.85; N = 24.7; Cl = 15.6; 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 amino hydrochloride is added dropwise with stirring -5 N, N-dimethyl imidazolesulfonamide-4 in 3, 1 cm3 of 2N hydrochloric acid. The solid obtained is separated by filtration and

  <Desc / Clms Page number 41>

 
 EMI41.1
 washed in ice water. 0.38 g of diazo-5 N is thus obtained. N-dimethyl imidazolesulfonamide-4 melting at 1090C (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 on magnesium sulphate and evaporation under vacuum.



  REFERENCE EXAMPLE 7 i) To 35 cm3 of a 25% aqueous solution of methylamine (weight to weight) cooled in an ice bath, the mixture is added with stirring in small portions at a time. 4. 15 g of nitro-5 imidazolesu1fonyle-4 chloride 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. L7. 0nitation the reaction mixture for another 15 minutes then concentrated in vacuo at a temperature below 400C until half the initial volume. The mixture is then strongly acidified with concentrated hydrochloric acid and the remaining solid is separated by filtration and recrystallized from water to obtain 2. 07 g of Nit-methyl nitro-5 imidazolesulfonamide-4 in the form of pale yellow strips melting at 260-2630C (with decomposition).



  Elementary analysis: Calculated%: C = 23, 3; H = 2.93; N = 27.2; S = 15. 55 Found X: C = 23, 1; H = 2.87; N = 27. 4; S = 15. 4 ii) A solution of 1 g of N-methyl 5-nitro-imidazolesulfonamide-4 in 100 cm3 of anhydrous ethanol is hydrogenated at 240 ° C. under a pressure of 3 atmospheres in the presence of Raney nickel as catalyst. The mixture is then filtered and immediately diluted with 200 cm3 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 ethanol

  <Desc / Clms Page number 42>

 
 EMI42.1
 boiling; 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-imidazo-sulfonamide-4 is thus obtained, melting at 178-180 c (with decomposition).



  Elementary analysis: 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 0.25 g of sodium nitrite in 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 imidazolesulfonamide-4, melting at 1500C (with decomposition), is thus obtained.



  IR spectrum: 2210 cm Elemental analysis: Calculated%: C = 25.7; H = 2.69; N = 37.4 Found%: C = 25.2; H = 2.47; N = 37.06 A second batch of 0.07 g of product is obtained by 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 cm3 of water cooled to 0 C, a solution of 1 g of 5-amino-4-methylsulfonyl-4 imidazole hydrochloride is added dropwise. prepared as described by BENNETT et al., J. Am.



  Chem. Soc. J7 (3), 2188-2191 (1957) J 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 on standing. 0.74 g of 4-diazo-methylsulfonyl-imidazole is thus obtained, melting at 128-230 ° C.



  IR spectrum: 2125 cm

  <Desc / Clms Page number 43>

 
 EMI43.1
 REFERENCE EXAMPLE 9 i) To a solution of 10 g of 4-methoxy-benzylamine in 30 cm 3 of water, 6.8 g of nitro-5 imidazolesulfonyl-4 chloride / wet product freshly prepared from 6 is added with stirring. g of ammonium salt of 4-mercapto-5 nitro-imidazole, 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-methoxy benzyl) 5-nitro-imidazolesulfonamide-4 are thus obtained, melting at 269-270oC (with decomposition). ii) A solution of 1 g of N- (4-methoxybenzyl) 5-nitro-imidazolesulfonamide-4 in 100 cm 3 of dry ethanol is hydrogenated for 6 hours under a pressure of 3 atmospheres in the presence of Raney nickel at 50% as catalyst. The catalyst is quickly separated by filtration on diatomaceous earth and the filtrate is immediately taken up with 20 cm3 of hydrochloric acid. The mixture is concentrated to dryness and the 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) imidazolesulfonamide-4 is thus obtained, melting at 154-1550C. iii) To a solution of 0.14 g of sodium nitrite in 5 cm 3 of water, a solution of 0.5 g of amino-5 N- (4-methoxy-benzyl) imidazolesulfonamide-4 is added dropwise 10 cm3 of 2N hydrochloric acid) while 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-S N- (4-methoxy-benzyl) imidazolesulfonamide-4, melting at 1444 ° -60 ° C., is thus obtained (with decomposition).



  IR spectrum: 2180 cm '

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 EMI44.1
 REFERENCE EXAMPLE 10 i) To a solution of 6.4 cm3 of piperidine in 92 cm3 of anhydrous tetrahydrofuran, 4.59 g of dinitro-1, 6-5H, OHdiimidazol, 5-a: l ', 5'- are added pyrazinedione-5, 10 (prepared as described in reference example 1) and left 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 4-nitro-piperidinocarbonyl-5 imidazole are thus obtained, in the form of a yellow solid melting at 1449-150oC.



  Elementary analysis: Calculated X: C = 48, 2; H = 5.39; N = 25.0 Found%: C = 48.2; H = 5.33; N = 25.1 ii) 0.27 g of 4-nitro-piperidinocarbonyl-5 imidazole (prepared as described above) in 27 cm3 of methanol and 27 cm3 of dimethylformamide is added with 0.27 g of oxide of platinum 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.

   2.1 g of 4-amino-piperidinocarbonyl-5 imidazole hydrochloride are thus obtained, in the form of a pale green solid, melting at 175 -1770C, sufficiently pure to be used as it is in the following step.

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 EMI45.1
 



  REFERENCE EXAMPLE 11 i) In a stirred solution of 5 g of 2-cyanoethylbenzene and 8 g of benzylmercaptan in 90 cm3 of anhydrous dioxane, a stream of gaseous hydrochloric acid is passed for 3 hours and the mixture is allowed to stand 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) are thus obtained (7 g of 3-phenyl propionothioimidate hydrochloride from S-benzyle) in the form of a colorless solid melting at 158-160oC, sufficiently pure to be used as it is in the following step. ii) A solution of 3.3 g of α-amino α-cyanoacetamide in 20 cm 3 of ethanol is treated with 9.7 g of 3-phenyl propionothioimidate hydrochloride of S-benzyl (prepared as described above) 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-imidazoecarboxamide-4 hydrochloride are thus obtained, in the form of colorless crystals, melting at 270-2740C.



  Elementary analysis: Calculated%: C = 54, 0; H = 5.67; N = 21.0 Found%: C = 53.8; H = 5.55; N = 21, 1 REFERENCE EXAMPLE 12 To a solution of 0.5 g of sodium nitrite in 15 cm3 of water maintained at 0-50C, a solution of 1.26 g of amino-5 is added dropwise 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 separated by filtration, washed with water and dried in an endessifier over phosphorus pentoxide. 0.8 g of 2-benzyl-5-diazo-imidazo1ecarboxamide-4 is thus obtained, melting at 121-1220C (with decomposition).



  IR spectrum: 2180 cm

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 EMI46.1
 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, a stream of hydrochloric acid is passed for 3 hours at a temperature between a and 100C. gaseous. 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, melting at 165-1670C.



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



  The remaining black oil is triturated with 100 cm 3 of a mixture of chloroform and methanol (4-1 by volume); the insoluble material 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.

  <Desc / Clms Page number 47>

 
 EMI47.1
 iii) To a solution of 0.5 g of sodium nitrite in 5 cm 3 of water maintained at 0 ° C., a solution of 1.1 g of 5-amino-2-isopropyl-2-imidazolecarboamide-4 hydrochloride is added dropwise (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 then is 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 appropriate 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 1200 ° C. (with decomposition).



  IR spectrum: 2170 cm REFERENCE EXAMPLE 14 i) A cooled and stirred solution of 127 g of 2-methyl-5-nitroimidazole in 1500 cm3 of an aqueous sodium hydroxide solution at 5 X (weight / volume) is treated with 160 g bromine keeping the temperature between 15 and 20oC. 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 over phosphorus pentoxide.

   151 g of 4-bromo-2-methyl-5-nitro-imidazole are thus obtained, in the form of a crystalline solid melting at 267-2680C. ii) A stirred solution of 20.6 dildo-4-bromo-2-methyl-5-nitroimidazole (prepared as described above) is heated to 4SoC

  <Desc / Clms Page number 48>

 
 EMI48.1
 in 180 cm3 of 5N ammonia then a continuous stream of hydrogen sulfide is passed through 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 300oC.



  Elementary analysis: Calculated%: C = 27) 27; H = 4) 58; N = 31) 8; S = 18.2 Found%: C = 27.2; H = 4.41; N = 31.6; S = 18, 2 iii) In an ice-cooled and vigorously stirred solution of 3.51 g of ammonium salt of 4-mercapto-2-methyl-5-nitroimidazole (prepared as described above) in 120 cm3 d hydrochloric acid IN, a current 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 160-1620C (with decomposition).



  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 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

  <Desc / Clms Page number 49>

 
 EMI49.1
 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 167-170oC.



  Elementary analysis: Calculated X: C = 44, 17; H = 4.32; N = 17, 17; S = 9.83 Found X: C = 44.2; H = 4.32; N = 17.2; S = 9.5 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 -1850C. vi) To a solution of 0.3 g of sodium nitrite in 5 cm 3 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 between 0 and 50C and the orange solid obtained is separated by filtration, washed with water and dried in a desiccator over phosphorus pentoxide.

   0.75 g of diazo-5 (4-methoxy-benzyl) sulfamoyl-4-methyl-2-imidazole is thus obtained, melting at 1400C (with decomposition).



  IR spectrum: 2200 cm

  <Desc / Clms Page number 50>

 
 EMI50.1
 REFERENCE EXAMPLE 15 i) To 10 cm 3 of an ethanolic solution of dimethylamine at 33% (weight / volume) cooled and stirred, 2.25 g of 4-chlorosulfonyl-2-methyl-5-nitro are added in small portions at a time imidazole (prepared as described in reference example 14) and stirred at room temperature for another 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 240-241oC.



  Elemental 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-d6): 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 using concentrated hydrochloric acid and evaporated to dryness.



  The orange residue is triturated with ethyl ether. 8.9 g of amino-5 dimethylsulfamoyl-4 methyl-2 imidazole are thus obtained, melting at 215-Zl70C (with decomposition). iii) To a solution of 1 g of sodium nitrite in 15 cm3 of water maintained at 0 ° C., a solution of 2.4 g of 5-amino-dimethylsulfamoyl-4 methyl-2-imidazole in 30 cm3 is added dropwise of 2N hydrochloric acid and the mixture is stirred for a further 10 minutes at 0 C. The mixture is extracted with 5 times 30 cm 3 of ethyl acetate; the organic extracts are combined and dried over magnesium sulfate, evaporated to dryness and the residue is triturated with petroleum ether (P.E. = 60-800C). 1.8 g of diazo-5 dimethylsulfamoyl-4 methyl-2 imidazole, melting at 85-870C, are thus obtained.

  <Desc / Clms Page number 51>

 
 EMI51.1
 (with decomposition).



  IR spectrum: 2180 cm.



  REFERENCE EXAMPLE 16 i) A solution of 10.5 g of ammonium salt of 4-mercapto-2-methyl-5-nitroimidazole (prepared as described in reference example 14) in a methanolic solution of sodium methylate ( prepared by carefully dissolving 2, 3 g of sodium in 250 cm 3 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 236-2370C (with decomposition).



  Elementary analysis: Calculated%: C = 34, 67; H = 4.07; N = 24, 26; S = 18.51 Found%: C = 34.7; H = 4.04; N = 24.3; S = 18.5 ii) A solution of 3.46 g of 2-methyl-4-methylthio-5-nitro-imidazole (prepared as described above) in 35 cm 3 of glacial acetic acid is heated to 600 ° C. and added dropwise. drop 35 cm3 of an aqueous solution of hydrogen peroxide at 30% (weight / volume).



  The mixture is then heated at 1000 ° C. for 15 minutes, cooled to room temperature and treated with sufficient sodium sulfite to destroy the excess hydrogen peroxide (detected by the starch and potassium iodide test) . 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 (P.E. = 60-800e) and separated by filtration. This gives 3.6 g of 2-methyl-4-methylsulfonyl-5-imidazole, melting at 222-2240 °.

  <Desc / Clms Page number 52>

 
 EMI52.1
 



  Elementary analysis: Calculated: C = 29, 27; H = 3.44; N = 2048; S = 15. 63 Found%: C = 29.8; H = 3.28; N = 20.6; S = 15.7 iii) A solution of 4.9 g of 2-methyl-4-methylsulfonyl-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-methylsulfonyl-4-imidazole hydrochloride are thus obtained, melting above 300 ° C.



  Elementary analysis: Calculated X: 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 iv) To a solution of 0.25 g of sodium nitrite in 5 cm3 of water maintained at 0 C, a solution of 0.53 g of 5-amino methyl hydrochloride is added dropwise -2-methylsulfonyl-4 imidazole (prepared as described above). The mixture is stirred for a further 15 minutes at 0 ° C. and is extracted with 5 times 15 cm 3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate and evaporated to dryness. The remaining oil is triturated with petroleum ether (P.E. = 60-800C). 0.4 g of 5-diazo-2-methyl-4-methylsulfonyl imidazole is thus obtained, melting at 1000 ° C. (with decomposition).



  IR spectrum: 2185 cm

  <Desc / Clms Page number 53>

 
 EMI53.1
 REFERENCE EXAMPLE 17 i) A mixture of 8.2 g of α-cyano N, N-dimethylacetamide prepared as described by BOWMAN et al. Is heated to 160-170 ° C. in a flask fitted with a Mcintyre head for 90 minutes.



  J. Chem. Soc. (1954), dz 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 160-170oC 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 of d are added dropwise hydrazine hydrate.

   After the end of the addition, the mixture is heated at reflux 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 isopropanol, treated with 4 cm3 of concentrated hydrochloric acid and the crystalline precipitate obtained is collected. 1.39 g of 3 N amino hydrochloride, N-dimethyl pyrazolecarboxamide-4 are thus obtained in the form of colorless crystals melting at 1950e.



  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 IR spectrum (KBr tablet): 3500, 3400, 3000-2200, 1655 cm-l NMR spectrum (in DMSO-d6): singlets at 3.0 and 8.1 ppm and wide singlet at 7.2 ppm .

  <Desc / Clms Page number 54>

 
 EMI54.1
 iii) 70 cm3 of an anhydrous methanol solution saturated with gaseous hydrochloric acid are treated with 1.39 g of 3 N amino hydrochloride, N-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 included between 2 and 40C 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 N, N-dimethyl pyrazolecarboxamide-4 is thus obtained in the form of colorless crystals melting at 1500C (with explosion) Elemental analysis: Calculated%: C = 35.74; H = 4.00; N = 34.74 Found%: C = 35.3; H = 3.79; N = 34.3 IR spectrum (KBr tablet): 3000-2100, 2280, 1630 cm The present invention also relates to pharmaceutical compositions which contain, as active ingredient, at least one product of general formula (1) with a diluent or a pharmaceutical coating. Clinically, the products of general formula (1) 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 based on factors such as the desired effect, size, age, sex and general condition. the 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.

  <Desc / Clms Page number 55>

 
 EMI55.1
 



  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 may also contain additives other than inert diluents, for example lubricants such
 EMI55.2
 as magnesium stearate.Among liquid compositions for oral administration include emulsions) solutions) pharmaceutically acceptable suspensions, syrups and elixirs containing inert diluents in common use such as water and petrolatum oil. In addition to the inert diluents, these compositions can also contain adjuvants such as wetting agents, suspending agents (for example polyvinylpvrrolidone), sweeteners, flavorings, perfumes and preservatives.



   Among the compositions for oral administration are
 EMI55.3
 may also cite the capsules made 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 are
 EMI55.4
 may include suppositories formulated in the usual way 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).

  <Desc / Clms Page number 56>

 



   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
 EMI56.1
 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 doses can be administered simultaneously
 EMI56.2
 unitary. In general, the compositions which can be administered by injection contain at least 0.025% by weight of active ingredient, and the compositions for the oral route contain at least 0.1 dz. The dose used depends on the desired effect, on the route of administration. and the duration of treatment.



   The compounds of general formula (1) are useful in the treatment of malignant neoplasms such as carcinomas, melanomas, sarcomas, lymphomas and leukemias, at doses generally included
 EMI56.3
 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:
 EMI56.4
 - (N-benzyl N-phenylcarbamoyl) -8 methyl-3 / '3H7-imidazo /' 5, 1-d7 tetrazine-1, 2, 3, 5 one-4 "" "" '"1.0 g - dimethylsulfoxide .............., ...................... 10 cm3 by dissolving the (N-benzyl N-phenylcarbamoyl) -8 methyl-3 3H7 * imidazo5, 1-d7 tetrazine-1, 2, 3, 5 one-4 in dimethyl sulfoxide.



  The solution obtained is aseptically distributed in 10 ampoules,

  <Desc / Clms Page number 57>

 
 EMI57.1
 at a rate of 1.1 cm3 per bulb. The ampoules which each contain 100 mg of (N-benzyl N-phenylcarbamoyD-8 methyl-3 H7-imidazoZ5, l-d7 tetrazine-1, 2, 3, S one-4 are sealed.



  Similar ampoules suitable for parenteral administration can be prepared by operating in the same manner from another compound of general formula (1).



  COMPOSITION EXAMPLE 2 A solution suitable for parenteral administration is prepared from the following ingredients: - (2-chloro-ethyl) -3 N-methylsulfamoyl-S / 31i7-imidazo5, 1-d7 tetrazine-1, 2, 3, S one-4 ........... 1.0 g - dimethyl sulfoxide. ................................... 10 cm3 - peanut oil ........ .............................. 90 cm3 by dissolving (2-chloro-ethyl) -3 N-methylsulfamoyl-8 / 3H7imidazo5 , l-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-imidazoZ5, l-d7 tetrazine-1, 2, 3, 5, one-4 are sealed.



  Similar ampoules suitable for parenteral administration can be prepared in the same manner but from another compound of general formula (1).



  COMPOSITION EXAMPLE 3 Capsules suitable for oral administration are prepared by depositing (2-chloro-ethyl) -3 N-methylsulfamoyl-8 3H7 "imidazo / 5, l-d7 tetrazine-1, 2, 3, 5 one -4 in size 2 gelatin capsules at a rate of 10 mg per capsule.



  Similar capsules can be prepared using another product of general formula (1) or other capsules of adequate size.


    

Claims (7)

 EMI58.1   R E V E N D I C A T I o N S CLAIMS 1 - New tetrazine derivative, characterized in that it corresponds to the general formula:  EMI58.2    EMI58.3  / in which represents a cycloalkyl radical or an alkyl, alkenyl or alkynyl radical in a straight or branched chain containing up to 6 carbon atoms, each alkyl, alkenyl and alkynyl radical being unsubstituted or substituted by one to three substituents chosen from the atoms of halogen, the alkyloxy, alkylthio, alkylsulfinyl and alkylsulphonyl radicals in straight or branched chain containing up to 4 carbon atoms and the phenyl radicals optionally substituted, represents a nitrogen atom or a radical-CR = in which R-represents an atom hydrogen or a substituent R, in which R <represents a halogen atom,  or a straight or branched chain alkyl or alkenyl radical containing up to 6 carbon atoms, which may bear up to 3 substituents chosen from halogen atoms, optionally substituted phenyl, alkyloxy, alkylthio and alkylsulfonyl radicals containing up to with 3 carbon atoms or alternatively R represents a cycloalkyl, cyano, hydroxy, nitro or phenoxy radical optionally substituted, or a radical of formula -COR5 (in which R5 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) R., - SONRR8 ou-CZ2NR7R8 n 6 27o 2 7 o  <Desc / Clms Page number 59>    EMI59.1  (in which n represents the digits 0, 1 or 2, R6 represents an alkyl or alkenyl radical in a straight or branched chain containing up to 4 carbon atoms (which may bear an optionally substituted phenyl substituent), a cycloalkyl radical or a radical optionally substituted phenyl, R7 and Rn which may be the same or different, each represent a hydrogen atom or an alkyl or alkenyl radical in a straight or branched chain, containing up to 4 carbon atoms (which may carry an optionally substituted phenyl substituent ), or a cycloalkyl radical or an optionally substituted phenyl radical or else the radical-NRRn represents a heterocyclic radical, and Z2 represents an oxygen or sulfur atom),  A2 represents a nitrogen atom or, when represents a 2 1 nitrogen atom, A2 represents a nitrogen atom or a radical-CRJ in which R is defined as above, Zl represents an oxygen atom or of sulfur, and R2 represents a radical of formulas: - S (0) nR6 '-S02NR7Ra'-CSNR7Ra'-CONR7R9 or -CZ2NHN02 no / o 7o 7'? 2 in which n, R6, R7, Ra and Z2 are defined as above and the radical "RQ represents a heterocyclic radical or R7 is defined as above and R9 represents an alkyl or alkenyl radical in a straight or branched chain containing up to 4 atoms of carbon (which carries an optionally substituted phenyl substituent), or else an optionally substituted phenyl radical, or, when represents a nitrogen atom or a —CR radical, = in which R,  is defined as above and Zl and A2 are defined as above or when represents a radical -CH = and represents a sulfur atom and A2 is defined as above, R2 represents a radical of formulas: - S (O), -SORg, - CZRg ou-CZNHNO in which n, R6, R7, Ra and Z2 are defined as above and, when R2 and / or Ru represents a sulfamoyl or sulfamoyl 2 mono-substituted radical and / or Ru represents a carboy radical, their salts being it is understood that in the preceding definitions, the optional substituents on the phenyl and phenoxy portions can be chosen from halogen atoms and alkyl radicals  <Desc / Clms Page number 60>    EMI60.1  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 5, 6 or 7-membered heterocycle which may optionally contain another heteroatom such as nitrogen, oxygen or sulfur and which may carry one or two alkyl substituents in a straight or branched chain each containing up to 4 carbon atoms. 2 - Process for the preparation of a product according to claim 1 in which formula R2 is different from a sulfamoyl radical, carbamoyl which carries an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted phenyl substituent and which is different from a radical nitrocarbamoyl or nitrothiocarbamoyl, characterized in that a compound of general formula is reacted:  EMI60.2    EMI60.3  in which and A2 are defined as in claim 1 and R12 represents a radical falling within the definition of R2 12 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 nitrocarbamoyie or nitrothiocarbamoyl radical, with a compound of general formula:  in which and are defined as in claim 1, then isolates the product and optionally transforms it into a salt when represents a mono-sub-substituted sulfamoyl radical and / or-R represents a sulfamoyl or monosubstituted sulfamoyl radical or represents a carboy radical. 3 - Process for the preparation of a product according to claim 1 in which formula R2 represents a carbamoyl radical which carries an optionally substituted phenyl substituent or thiocarbamoyl which carries an optionally substituted phenyl substituent  <Desc / Clms Page number 61>    EMI61.1  and R, A, A2 and Z are defined as in claim 1, characterized in that ondébenzyle a compound of general formula:    EMI61.2    EMI61.3  in which R12 represents an optionally substituted phenyl radical, R13 represents an optionally substituted benzyl radical and Z2 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 R represents a monosubstituted sulfamoyl or sulfamoyl radical or a carboy radical. 4 - Process for the preparation of a product according to claim 1 in the formula of which and Zl are defined as in claim 1 and R2 represents a radical of general formula: - CZ. NHNO 2 2 in which Z2 is defined as in claim 1, characterized in that a compound of general formula is nitrated:  EMI61.4    <Desc / Clms Page number 62>    EMI62.1  in which R14 represents a radical of formula: - CZ2NH2 2 2 in which and are defined as in claim 11 1 1 then isolates the product and optionally it is transformed into a salt when R3 represents a sulfamoyl or sulfamoyl monosubstituted radical or a carboy radical . 5 - Process for the preparation of a product according to claim 1 in the formula of which Rl, Al, A2 and R2 are defined as in claim 1 and Z represents a sulfur atom, characterized in that a compound is transformed of general formula:  EMI62.2    EMI62.3  in which Ri, Al and R2 are defined as in claim 1 il and Ri5 represents a radical of formula: - S (O) nR6 '- S02NR7RS'- CZ2NR7RS or - CZ2NHN02'  EMI62.4  R-, R-, RQ, n and Z2 being defined as in claim 1, optionally by action of phosphorus pentasulfide, then isolates the product and! the  EMI62.5  transforms into a salt when R2 and / or represents a sulfamoyie or sulfamoyie monosubstituted radical and / or represents a carboy radical. 6 - Process for the preparation of a product according to claim 1 in the formula of which and are defined as in the revenT. T. 1 dication 1 and R2 represents a radical of general formula: - CSNRRc 7 o  <Desc / Clms Page number 63>    EMI63.1  in which R7 and Rp are defined as in claim 1, characterized in that a compound of general formula is transformed:  EMI63.2    EMI63.3  in which R, A, A2 and are defined as in claim 1 and R16 represents a radical of general formula: - CONR7R8 7 o  EMI63.4  in which R and Rp are defined as in claim 1, optionally 7, action of phosphorus pentasulfide is carried out, then the product is isolated and the  EMI63.5  transforms into a salt when R represents a sulfamoyl or sulfamoyl monosubstituted radical or a carboy radical. 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.