NZ205272A - Tetrazine derivatives and pharmaceutical compositions - Google Patents

Tetrazine derivatives and pharmaceutical compositions

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Publication number
NZ205272A
NZ205272A NZ205272A NZ20527283A NZ205272A NZ 205272 A NZ205272 A NZ 205272A NZ 205272 A NZ205272 A NZ 205272A NZ 20527283 A NZ20527283 A NZ 20527283A NZ 205272 A NZ205272 A NZ 205272A
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NZ
New Zealand
Prior art keywords
group
tetrazin
chloroethyl
imidazo
carbon atoms
Prior art date
Application number
NZ205272A
Inventor
G U Baig
M F G Stevens
C G Newton
B L Pedgrift
C Smith
C G Straw
R J A Walsh
P J Warren
Original Assignee
May & Baker Ltd
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Filing date
Publication date
Priority claimed from GB838306904A external-priority patent/GB8306904D0/en
Application filed by May & Baker Ltd filed Critical May & Baker Ltd
Publication of NZ205272A publication Critical patent/NZ205272A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

New Zealand Paient Spedficaiion for Paient Number £05272 *272 Priority Date(s): n-& t2 n.t-t* .'Mfi(¥:■.}.
Complete Specification Filed: Class: Publication Date: P.O. Journal, No: ... .E.5.DEC JSS6 i'p.Xv. ms«*6S NEW ZEALAND N/36783 THE PATENTS ACT 1953 PATENTS FORM NO- 5 COMPLETE SPECIFICATION "NEW TETRAZINE DERIVATIVES" WE, MAY & BAKER LIMITED, a British Company of r^Mio 7 xs, Dagenham, EssexEngland, hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: -1- (followed by page la) - ice- 205272 "'DESCRIPTION "NEW TETRAZ IME DCni VATi^ES*' This invention relates to new tetrazine derivatives, to processes tor their preparation ana to 5 pharmaceutical compositions containing them.
The compounds of the present invention are the tetrazine derivatives of the general formula shown in Figure 1 of the drawings assembled at the end of the present specification [wherein R^ represents a 10 cycloalkyl group, or a straight- or brancned-chain alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, each such alkyl, alkenyl or alkynyl group being unsubstituted or substituted by from one to three substituents selected from halogen (i.e. 15 bromine, iodine or, preterably, cnlorine or fluorine) atoms, straight- or branched-chain alkoxy, aikylthio, alkylsulphinyl and alkyIsulphony1 groups containing up to 4 caroon atoms, and optionally substituted phenyl groups, A^" represents a nitrogen atom or a group 20 -CR = wnerein R represents a hydrogen atom or a substituent wherein R^ represents a halogen atom, or a straight- or branched-chain alkyl or alkenyl group, containing up to 6 carbon atoms, which may carry up to 3 substituents selected from 25 halogen atoms, optionally substituted phenyl groups, straight- or oranched-chain alkoxy, aikylthio and 2 - 2 0 5 2 7 alkyIsulphony1 groups containing up to 3 carbon atoms, or represents a cycloalKyl, cyano, hydroxy, nitro or optionally substituted phenoxy group or a group of the formula -COR^ (wherein R-3 represents an alkyl or alkoxy group of up to 4 carbon atoms, or a hydroxy group, or an optionally substituted phenyl group) or an alkanoylamino group containing up to 6 carbon atoms, or represents a group of the formula -S(0)nR6, -S02NR7Ra or -CZ2NR7Rti (wherein n represents 0, 1 or 2, R^ represents a straight- or branched-chain alkyl or alkenyl group, containing up to 4 carDon atoms, wnich may carry an optionally substituted phenyl substituent, a cycloalkyl group or an optionally substituted phenyl 7 h group, R and R , which may be the same or different, each represents a hydrogen atom or a straight- or branched-chain alkyl or alkenyl group, containing up to 4 carbon atoms, which may carry an optionally substituted phenyl substituent, or a 20 cycloalkyl group or an optionally substituted phenyl group or the group -NR'r*5 represents a heterocyclic 2 group, and Z represents an oxygen or sulphur atom), 2 l A represents a nitrogen atom or, when A ? represents i nitrogen atom, A represents a nitrogen 25 atom or a group -CR^= wnerein is as hereinbefore defined, Z^ represents an oxygen or 205272 o sulphur atom, and R* represents a group of the formula -S(0)nR6, -S02NR7Ra, -CSNR7R6, -C0NR7R^ or -CZ^NHN02 wherein n, R^, R7, 8 2 R and Z are as hereinbefore defined, and the 7 9 group -NR'R represents a heterocyclic group or 7 9 R is as hereinbefore defined ana R represents a straight- or branched-chain alkyl or alkenyl group containing up to 4 carbon atoms which carries an optionally substituted phenyl substituent, or an optionally substituted phenyl group or, when A^" represents a nitrogen atom or a group -CR^= wnerein R^ is as hereinbefore defined and l)- and A^ are as hereinbefore defined or, wnen A^" represents a group -CH35 and represents a sulphur atom and A^ 2 is as hereinbefore defined, R represents a group of the formula -S(0)nR6, -S02InR7R8, -CZ2NR7R& or CZ^NhNC^ wherein n, , R7, R^1 ana 1?~ are as hereinbefore defined] and when R^ represents a sulphamoyl or monosubstituted sulphamoyl group and/or represents a sulphamoyl, monosubstituted sulphamoyl or carboxy group, salts thereof, more especially alkali metal, e. sodium, salts. Whenever the context so permits reference in this specification to the compounds of the general formula shown in Figure I is meant to include reference to the said salts. The salts particularly useful as intermediates.
/'•V f-10(^1986 , c 205272 Within the definition of the formula shown in Figure I the optional substituents on the phenyl and phenoxy moieties may be selected from, for example, halogen atoms and alkyl and alkoxy groups containing up to 4 carbon 5 atoms, and nitro groups. Cycloalkyl groups within the definition of the formula shown in Figure I contain 3 to 8, preferably 6, carbon atoms. A heterocyclic group within the definition of the formula shown in Figure I is preferably a 5-, 6- or 7-membered heterocyclic ring 10 containing the nitrogen atom which may optionally contain a further heteroatom, i.e. nitrogen, oxygen or sulphur, and which may carry one or two straight- or branched-chain alkyl substituents each containing up to 4 carbon atoms, e.g. a piperidino group or a 2-metnyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, or 3,5-dimethy 1-piperidino group, or a morpholino, pyrrolidin-l-yl, perhydroazepin-l-yl, piperazin-l-yl, 4-methyl-piperazin-l-yl or l,4-thiazin-4-yl g roup.
The specification of New Zealand Patent 20 specification No. 201668 describes compounds of the general formula shown in Figure II of the drawings wherein represents a hydrogen atom, a cycloalkyl group or a straight- or branched-chain 2052 alkyl, alkenyl or alkynyl group containing up co 6 carbon atoms, each such alkyl, alkenyl or alkynyl group being unsubstituted or substituted by from one to three suostituents selected trom halogen atoms, straight- or branched-chain alkoxy, aikylthio, alkyl-sulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms, and optionally substituted phenyl groups, and represents a carbamoyl group which may carry on the nitrogen atom one or two groups selected from straight- and branched-chain alkyl and alkenyl groups, eacn containing up to 4 carbon atoms, and cycloalkyl groups.
The said tetrazine derivatives of the formula shown in Figure II possess valuable antineoplastic activity, for example against carcinomas, melanomas, sarcomas, lymphomas and leukaemias, and they also possess valuable immunomodulatory activity and are of use in the treatment of organ grafts and skin grafts and in the treatment of immunological diseases.
The compounds of the formula shown in Figure I of the present invention possess similar properties with, in certain aspects, an improvement.
The said tetrazine derivatives of the formula shown in Figure II are useful as intermediates in the preparation of some of the compounds of the formula shown in Figure I of the present invention, for ■ '■■■■■■■* --*— „«-*«**»*!•£ - 6 - 2 0 w- 2 / 2 example as described later in this specification.
Particularly important classes of compounds of Che formula shown in Figure I include those which exhibit one or more of the following features:- (i) R^ represents a methyl or, more especially, a 2-haloethyl group, in parCicular a 2-chloroetny1 group; (ii) R2 represents a group of Che formula -S0Rb,-S02R6, -S02NR7R°, -CONR7R& or -C0NHN02, especially Chose wherein Rb represents an alkyl, e.g. methyl, group and those wherein R; represents a hydrogen atom or an alkyl, e.g. methyl, group and R*5 represents a hydrogen atom or an alkyl, e.g. methyl, group or a benzyl group optionally substituced by an alkoxy group, e.g. a 4-methoxybenzyl group; (iii) one of A-*- and A^ represent a "5 nitrogen atom and the other represents a group -CRJ=; (iv) R^ represencs a group R^ wherein R^ represencs an alkyl, e.g. butyl, propyl, ethyl or, more particularly, methyl, group; (v) A represents a nitrogen atom; (vi) Z^~ represents an oxygen atom; and/or (vii) Z represents an oxygen atom.
Important individual compounds of the general formula shown in Figure I include the following:- 6-(N-benzyl-N-phenylcarbamoy1)-3-methyl-[3H J -imidazo[ 5,1—clJ-1,2,3, 5- tet razin-4-one , 8-[N-benzy1-N-(4-methoxybenzyl)carbamoyl J-3-(2-chloroethy1)-l3H]-imidazot5,l-dj-l,2,3,5-te traz in-4-one, 6-(N-benzylcarbamoy1)-3-(2-chloroethy1)- I 3H]-imidazol5,l-d]-l,2,3, 5-tetrazin-4-one, 3-(2-chloroethy1)-8-[N-(4-metnoxybenzy1)-N-phenylcarbamoy1 J-[3H]-imidazol5,l-d]-l,2,3,5-tetraz in-4-one, 3-(2-chloroethy1)-8-(N-phenylcarbamoy1)-I3H]-imidazo[5,l-dj-l,2,3,5-tetrazin-4-one, 8-(N-benzyx-N-phenylcarbamoyl)-3-(2-chloroethyl) 13HJ-imidazo[5,l-dj-l,2,3,5-tetrazin-4-one, 3-(2-chloroethyl)- 8-(N-methy 1-N-phenylcarbamoy1) l3H]-imidazol5,l-d]-l,2,3,5-tetraz in-4-one, 8-car baaioy 1-3 - (2-chloroethy 1) -6-methy 1- [ 3H j-imidazol5,l-d]-l,2,3,5-tetrazin-4-one, 3-(2-chloroethyl)-8-(N,N-dimethylsulphamoy1)-l3HJ-imidazoL5,l-d]-l,2,3> 5-tetraz in-4-one, 3-(2-chloroethyl)- 8-(N-methylsulphamoy1)-[3H]-imidazoL5fl-dJ-l,2,3,5-tetraz in-4-one, 3-(2-chloroethyl)-8-methyIsulphony1-I3H]-imidazo-(.5,l-d]-lI2,3,5-tetrazin-4-one, 3-methy 1-8-methyIsulphony1-[3HJ-imidazol5,1-d]-1,2,3 , 5-tetrazin-4-one, r 205272 3-(2-chloroethyl)-8-(N-(4-methoxybenzyl)-sulphamoylj-13HJ-imida2o[5,1-d J —1,2,3,5— tetrazin-4-one, M, 3- (2-chloroethy1)-a-sulphamoyl-13H J -5 imidazo[5,i-dJ-1,2,3,5-tetrazin-4-one, N, 8-carbamoy1-3-(2-chloroecnyl)- 13HJ-pyrazolol5,1-d J-1,2,3,5-tetrazin-4-one, 0, 8-carbamoy1-3-methy 1-[3H]-pyrazolol5,1—dj —1,2,3,5 — tetrazin-4-one, P, 3-(2-chloroethyl)-8-piper id inocarbony1-[3H]- imidazot5,l-d]-l,2,3,5-tetrazin-4-one, Q, 6-butyl-8-carbamoyl-3-(2-chloroethyl)-L3HJ-imidazo[5,1-d]-l,2,3,5-tetrazin-4-one, R, 8-carbamoy1-3-(2-chloroethy1)-6-cyclohexy1-[3H]-15 imidazo[5,i-d]-1,2,3,5-tetrazin-4-one, S, 8-carbamoy1-3-(2-ch lor oe thy l)-o-phenethyl-|. 3H ]-imidazo[5,l-d]-l,2,3,5-tetraz in-4-one, T, b-benzy1-b-carbamoy1-3-(2-chloroethy1)- I3H]-imiaazo(.5,l-d]-l,2,3,5-tetrazin-4-one, U, 8-carbamoy1-3-(2-chloroethy1)-6-isopropyl-I3HJ - imidazo[5,l-a]-l,2,3,5-tetrazin-4-one, V, o-carbamoy1-3-(2-chloroethy1)-o-propyl-[3HJ -imidazo[5,l-dJ-l,2,3,5-tetraz in-4-one, W, 8-carbamoy1-3-(2-chloroethyl)-6-ethyl-[3Hj-25 imidazo[5,1-d]-1,2,3,5-tetrazin-4-one , X, 205272 - i - 3-(2-chloroethyl)-8-(4-metnoxybenzyl)su Lphamoy 1-6-mecny 1-I 3H ] -imidazol5,L-dJ — 1,2,3,5-tetraz in-4-one, Y, 3-(2-chloroethy 1)-6-me thy 1-8-sulphamoy1-I3HJ -imiaazo[5,l-d]-l,2.3,5-cetrazin-4-one, Z, 3-(2-chloroethyl)-8-d imethy Isulphamoy1-6-methy 1-l3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, AA, 3-(2-chloroethy1)-6-me thy 1-8-methyIsulphony1-l3H]-imiddzo[5,l-d]-L,2,3,5-tetraz in-4-one, BB, 3-(2-chloroetnyl)-8-(dimethyIcar bamoy1) -[3H J -pyrazolol5,l-dJ-l,2,3,5-tetraz in-4-one, CC, and 3-(2-chloroethyl)-8-(N-n i t rocarbamoy1)-1.3Hj-imidazol5,l-dJ-l,2,3,5-tetraz in-4-one, DD, 3-me thy 1-8-methy Isu1 phony 1-[3Hj-pyrazolo[5,1-d j-1,2,3,5-tetrazin-4-one, EE, 3-(2-chloroethyl)-d-methylsulphonyl-l.3H]-pyrazolo-[5,l-d]-l,2,3,5-tetrazin-4-one, FF, 3-(2-chloroethyl)-6-methyl-8-methylsulphinyl-L3H]-imidazo[5,l-dJ-l,213,5-tetrazin-4-one, GG, 3-(2-chloroethyl)-o-ethyIsulphony1-6-me thy 1-[3Hj-imidazo(5,l-dJ-l,2,3,5-tetrazin-4-one, HH, and 3-(2-chloroethy 1)-6-methy1-8-propyIsulphony1-|.3Hj-imidazo[5,l-dJ-l,2,3,5-tetrazin-4-one. II.
The letters A to II are allocated to the compounds for easy reference later in the spec i £ ica t ion.
T £ n r o h 10CT 1986 .:.s- - 2052 7 Compounds or particular importance include compounds C, K, L, M, 0, Q, R, W, X and DD, more especially compounds I, J, N and BB, and most especially compounds H, Z, AA and CC. 5 The new tetrazine derivatives ol the general formula shown in Figure I have proved particularly active in mice at daily doses between 0.2 and 320mg/kg animal body weight, administered intraperitoneally, against TLX5(S) lymphoma according to the procedure of 10 Gescher jet al. , Biocnem. Pharmacol. (1981), 30, 89, and ADJ/PC6A and M5076 (reticulum cell sarcoma). Against leukaemia LI210, grafted intraper i toneally , intracerebrally and intravenously, and P388, according to the procedure described in "Methods 15 of Development of New Anticancer Drugs" (NCI Monograph 45, Marcn 1977, pages 147-14^, National Cancer Institute, Bethesda, United States), the compounds were active both intraperitoneally and orally at doses of between 1 and 320mg/kg animal body weight. 20 Inhibition of both primary tumour and metastasis was obtained against the Lewis lung carcinoma by similar dosage regimes. Against the B16 melanoma and C38 tumour in mice (NCI Monograph 45, 0£. cit.) the compounds were active intraperitoneally at doses of 25 between 6.25 and 40 mg/kg animal body weight. Against colon carcinoma C2^ in mice, grafted subcutaneously, n 11 - 2052 7? the compounds were active orally at doses ot between 2 and 40mg/kg animal Dody weight.
The compounds of tne general formula shown in Figure I may be prepared by the application or 5 adaptation of methods known per se.
According to a feature of the present invention, the compounds of the general formula shown in Figure I wherein is other than a sulphamoyl, mono(optionally substituted phenyl)carbamoyl, 10 mono(optionally substituted ptienyl) thiocarbamoyl, nitrocarbamoyl or nitrothiocarbamoyl group are prepared by the reaction of a compound of the general formula shown in Figure III of the drawings [wherein 1 7 1 9 AA and A are as hereinbefore defined and R o represents a group within the above definition of R other than a sulphamoyl, mono(optionally substituted phenyl)carbamoyl, mono(optionally substituted phenyl)-thiocarbamoy1, nitrocarbamoy1 or nitrothiocarbamoyl group] with a compound ot the general formula:-20 R1NCZ1 IV wherein R"*" and Z^ are as hereinbefore defined. The reaction may be effected in the absence or presence of an anhydrous organic solvent, for example a chlorinated alkane, e.g. dichloromethane, or ethyl 25 acetate, acetonitrile, N-methylpyrrolidin-2-one or hexamethylphosphoramide, at a temperature between 0° 205272 and 120°C. The reaction may be continued for up to 30 days. Light should preferably be excluded from the reaction mixture.
According to a further feature of the present invention, compounds of the general formula shown in Figure 2 I wherein R represents a sulphamoyl, monosubstituted sulphamoyl, carbamoyl, monosubstituted carbamoyl thiocarbamoyl or monosubstituted thiocarbamoyl group, R^, 12 1 A , A and Z being as hereinbefore defined, are prepared from corresponding compounds, within the general formula 2 shown in Figure I, wherein R represents a group of the formula -SO^NR^R^ or -CZ^NR^R*^ (wherein represents an 2 7 optionally substituted benzyl group and Z and R are as hereinbefore defined) by the application or adaptation methods known per se for the replacement of optionally substituted benzyl groups by hydrogen atoms. Suitable reaction conditions include, for example, catalytic hydrogenation (using a catalyst such as palladium on charcoal and in a solvent such as ethyl acetate or 13 dimethylformamide); or when R represents a substituted benzyl group in which the substituent or at least one of the substituents carried by the benzyl group is an alkoxy (e.g. methoxy) group in the o- or p-position, preferably by reaction with trif1uoroacetic acid, preferably in the , - K r A ~ ':-'- //■V 'z 4l)n2T4 105272 presence of anisole, and usually at or near room temperature.
According to a furtner feature ot the present invention, compounds of the general formula shown in 5 Figure I wherein represents a group of the formula -CZ2NHN02 (Z2, R1, A1, A2 and Z^ being as hereinbefore defined) are prepared by the nitration of compounds of the general formula shown in Figure V of tne drawings wherein R^ represents a 10 group of the formula -CZ2NH2 (Z2, R*", A^", A2 and Z^ being as hereinbefore defined). The reaction may be carried out near or below room temperature, preferably between 0° and 10°2, in the presence or a nitrating mixture such as a mixture of 15 concentrated sulphuric acid and concentrated nitric ac id.
According to a further feature of the present invention, compounds ot the formula shown in Figure I 1 1 o 0 wherein R , A , A , and R are as hereinbefore defined and Z^ represents a sulphur atom are prepared from compounds ot the general formula shown in Figure 11 2 VI of the drawings (wnerein R , A and A are as hereinbefore defined) and R^ represents a group of the formula -S(0)nR6, -S02NR7R&, -CZ2NR7R8 or -CZ2NHN02, fi 7 f\ """ n R , R , R , n and Z being as hereinbefore defined) by ( - 10CT 1986 14 2 0 ,c ?. 7 2 r the action ot phosphorus pentasulphide. The reaction may be carried out in an organic solvent, for example an aromatic solvent such as benzene, toluene or xylene, or in pyridine or a derivative such as 5 lutidine, and preterably at an elevated temperature, for example between 50° and 120°C.
According to a turther feature of the present invention, compounds ot formula I wherein R^, , 7 1 9 k1- and Z are as hereinDetore detined and R represents a group of the formula -CSNR^R^ are prepared from compounds of the formula shown in Figure VII of the drawings wherein R*-, A^, A^ and Z^ are as hereinbefore defined and R*-^ repvesents a group of the formula -C0NR7R^ (R7 and R® being as hereinbefore defined) by reaction with phosphorus pentasulphide under conditions similar to those described hereinbefore for the reaction of phosphorus pentasulphide with compounds ot the formula shown in Figure VI.
The aforementioned salts of certain compounds — of the formula shown in Figure I are prepared by the application or adaptation of methods known per se, for example by reaction of the parent compound of the formula shown in Figure I with an alkali metal -J hydroxide, carbonate or, preterably, bicarbonate, in an aqueous or aqueous-organic medium, followed by ; ' w ■ - ... - .- 2 0 5 7 7?, isolation of the salt by methods known per se.
When a mixture of products is obtained in any of the abovementioned processes they may be separated by the application or adaptation of methods known per 5 se, e.g. chromatography.
Compounds of the general formula shown in Figure III may be prepared by the application or adaptation of methods known per se, for example methods described by Shealy et al., J. Org. Chem. 10 (1961), 26_, 2396, and Cheng e£ al ■ , J. Pharm. Sci. (196t>), 52, 1044, and methods described hereinafter in the Reference Examples.
By the term 'methods known per se' as used in the present specification is meant methods heretofore 15 used or described in the literature. 2 0 527 The following Examples illustrate the preparation of compounds of general formula I according to the present invention, and the Reference Examples illustrate the preparation of intermediates.
EXAMPLE 1 Compound A Sodium nitrite (0.44g) was dissolved in aqueous acetic acid (2M; 10ml) at 0°C and the solution was stirred at 0°C and treated with finely ground 5-amino-imidazole-4-N-benzy1-N-phenylcarboxamide hydrochlor ide (0.7g; prepared as described in Reference Example 1) in small portions. After 10 minutes the resulting gummy solid was extracted with ethyl acetate (2 x 20ml). The combined ethyl acetate extracts were washed with water and dried over magnesium sulphate.
The resulting solution of 5-diazoimidazole-4-N-benzy1-N-phenylcarboxamide was treated with methyl isocyanate (5ml) and the mixture was stirred at room temperature in the dark for 24 hours. The solution was then evaporated to low volume and the residue was subjected to medium pressure column chromatography, eluting with ethyl acetate, to give 8-(N-benzy1-N-pheny lcar bamoy 1) -3-methyl-I3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one (0.22g), in the form of a white, crystalline solid, m.p. 168-170°C (with decomposition) 2052 [Elemental analysis: C,62.6;H,4.41;N,22.3%; calculated C,63.32;H,4.47;N,23.32%; l.R. (KBr disc): 3100, 1735, lt>20cm~^; NMR (in DMSC-d^):- singlets at 3.75, .10 and 8.55ppm, multiplet at 7.0-7.4ppm; m/e 360 (M+) ] .
EXAMPLE 2 Compound B Sodium nitrite (3.7g) was dissolved in aqueous acetic acid (2M; 35ml) at 0°C and the solution was stirred at 0°C and treated with a solution of 5-amino-imidazole-4-N-benzyl-N-(4-methoxybenzyl)carboxamide hydrochloride (2.2g; prepared as described in Reference Example 2) in 1,2-dimethoxyethane (10ml), dropwise. A reddish gum separated which was extracted with ethyl acetate (2 x 20 ml). The combined ethyl acetate extracts were washed with water and with saturated aqueous sodium chloride solution, and dried over sodium sulphate.
The resulting solution of 5-diazoimidazole-4-N-benzyl-N-(4-methoxybenzyl)carboxamide was treated with 2-chloroethy1 isocyanate (2ml) and the mixture was allowed to stand at room temperature in the dark for 24 hours. The solution was then evaporated to low volume and the residue was subjected to medium pressure column chromatography, eluting with etnyl acetate, to give crude 8-[N-benzyl-N-(4-methoxybenzy1)- ZQ 5 2 7 n carbamoyl]-3-(2-chloroethyl)-[3H]-imidazol5,l*d]-1,2,3,5-tetrazin-4-one (1.5g) in the form of a brown oil.
EXAMPLE 3 Compound C 8-[N-Benzyl-N-(4-methoxybenzy1)carbamoy1J -3 —(2 — chloroethy1)-[3H]-imidazol5,l-d]-l,2,3,5-tetrazin-4-one (1.5g; crude material prepared as described in Example 2) and anisole (0.5ml) were dissolved together 10 in trifluoroacetic acid (20ml) and allowed to stand at room temperature for 18 hours. The mixture was then evaporated to dryness and the residue was subjected to mecium pressure column chromatography, eluting with a mixture (2:1 v/v) of ethyl acetate and petroleum ether 15 (b.p. 60°-80°C), to give 8-(N-benzylcarbamoy1)-3-(2- chloroethy1)-[3H]-imidazoL5,l-d]-l,2,3,5-tetrazin-4-one (Q.34g), in the form of a colourless solid, m.p. 153-155°C (recrystallised from diethyl ether). [Elemental analysis: C,49.9;H,3.92;N,24.4;CI,10. 20 calculated: C , 50 . 53 ; h , 3 . 94; N , 25 .26 ; C1,10 . 657„; l.R. (KBr disc) 3370, 3150, 1755 ana 1660cm-^; NMR (in DMSO-d^): singlets at 7.3 and 8.9ppm, doublet at 4.4ppm and triplets at 4.0, 4.6 and 9.05ppm]. - 19 - ' EXAMPLE 4 Compound D Sodium nitrite (G.blg) was dissolved in water (10ml) and the solution was stirred at 0°C and treated 5 with a solution of crude 5-aminoimidazole-4-N-(4- methoxybenzy1)-N-phenyIcarboxamide (2.5g; prepared as described in Reference Example 3) in hydrochloric acid (2M; 9ml) and 1,2-dimethoxyethane (15ml), dropwise. After 20 minutes the solution was extracted with ethyl 10 acetate (3 x 50ml) and the combined extracts were dried over magnesium sulphate and evaporated, to give 5-d iazoimidazole-4-N-(4-methoxybenzyl)-N-pheny1-carboxamide (2.8g), in the form of an orange oil.
This oil was dissolved in ethyl acetate (40ml) and 15 treated with 2-chloroethyi isocyanate (8ml). The mixture was allowed to stand in the dark for 5 days. The solution was evaporated to low volume and the resulting residue was subjected to medium pressure column chromatography, eluting with ethyl acetate, Co 20 give 3-(2-chloroethy1)-8-[N-(4-methoxybenzy1)-N-phenylcarbamoy1J -[3H]-imidazo[5,1-dJ-l,2,3,5-tetrazin-4-one (1.5g) in the form of a glass, m.p. 55°C [NMR (in DMS0-d^):- singlets at 3.6, 5.0 and 8.5ppm, triplets centred at 3.9 and 4.ippm, multiplet 25 at 6.6-7.2ppm; I.R. (KBr disc) 1740 and 1640cm~^"].
EsSr-" 2 C " ? " "* Example 4) and anisole (0.2ml) were dissolved together in trifluoroacetic acid (10ml) and the solution was allowed to stand at room temperature for 16 hours. The mixture was then evaporated to dryness and the 10 residue was triturated with diethyl ether, to give 3- (2-chloroethy1)-8-(N-phenylcarbamoy1) — [3H J — imidazo-[5 ,1-d ]-l,2,3,5-tetrazin-4-one (0.43g), in the form of a tan solid, m.p. 16b°C (with decomposition) (after recrystallisation from ethyl acetate) [Elemental analysis: C , 48 .4; H , 3 . 22; N , 26 . O/'o; calculated: C, 48 . 99; H, 3 . 4 ti; N , 26 .3 7; I.R. (KBr disc): 3390, 1735 Compound F Sodium nitrite (2.8g) was dissolved in aqueous acetic acid (2M; 84ml) and the solution was stirred at 0°C and treated with finely ground 5-aminoimidazole-25 4-N-benzyl-N-phenyIcarboxamide hydrochloride (2.8g; prepared as described in Reference Example 1) in small and 1660 cm"^; NMR (in DMSO-d^):- singlets at 8.9 and 10.3ppm, doublet centred at 7.8ppm, triplets centred at 4.0 and 4.6ppm, multiplet at 7.0-7.9ppm].
EXAMPLE 6 2 052 portions. Afters 10 minutes the resulting gummy solid was extracted with etnyl acetate (3*x 30ml) and the combined extracts were washed with water, and then with saturated aqueous sodium chloride solution, and then dried over magnesium sulphate.
The resulting solution ot 5-diazoimidazole-4-N-benzyl-N-phenylcarboxamide was treated with 2-chloroethy1 isocyanate (9ml) and the mixture was allowed to stand in the dark at room temperature for 4 days. The solution was then evaporated to low volume and the residue was subjected to medium pressure column chromatography, eluting with ethyl acetate, to give 8-(N-benzyl-N-phenylcar bamoy1)-3-(2-chloroethy 1)-[3HJ-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one (l.Og), in the form of a glass [Elemental analysis: C,59.3;H,4.57 N, 19 . 9; CI, 8. 57c; calculated: C , 58 . 7 5; H, 4.19; N , 20 . 56; Cl,8 .6770; I.R. (KBr disc): 1740 and 1640cm" ^; NMR (in DMSO-d^):- singlets at 5.2, 7.1, 7.3 and 8.6ppm, triplets centred at 4.0 and 4.6ppm].
EXAMPLE 7 Compound G A solution of sodium nitrite (llg) in water (50ml) was cooled to 0°C and treated with a solution of 5-aminoimidazole-4-N-methyl-N-phenylcarboxamide hydrochloride (4.0g; prepared as described in Reference Example 4) in aqueous acetic acid solution 2 0 - ? (2M; 40ml), dropwise. After 10 minutes the resulting mixture was extracted with ethyl acetate (4 x 100ml), and the combined extracts were filtered, and dried over magnesium sulphate.
The resulting solution of 5-diazoimidazole-4-N-methy1-N-phenyIcarboxamide was treated with 2-chloroethy1 isocyanate (11ml) and the mixture was allowed to stand in the dark at room temperature overnight. The solution was then evaporated to low volume and the residue was subjected to medium pressure column chromatography, eluting with ethyl acetate, to give a solid (5.75g). This solid was triturated with diisopropyl ether, and then with dichloromethane. The insoluble residue was recrystaHised from a mixture of petroleum ether (b.p. 60°-80°C) and ethyl acetate and then from a mixture of ethyl acetate and diisopropyl ether, to give 3-(2-chloroethyl)-8-(N-me thy 1-N-pheny1-carbamoy1)-13H]-imidazo-[5,l-dJ-l,2,3,5-tetrazin-4-one (O.bg), in the form of a colourless solid, m.p. 130-132° [Elemental anaLysis C,50.4;H,3 .91;N,24.9; Cl.10.67o; calculated: C , 50. 53 ; H, 3 . 94 ; N , 25 . 2t>; C1.10.65X; I.R. (KBr disc): 1750 ana 1640cm~^; NMR (in DMSO-d^):- singlets at 3.4, 7.2 and 8.65ppm, triplets centrea at 3.95 and 4.6ppm].
I - 23 - 2 0 52 EXAMPLE 8 Compound H A stirred suspension of 5-diazo-2-methylimidazole-4-carboxamide (1.54g; prepared as described in 5 Reference Example 5) in ethyl acetate (45ml) was treated with 2-chloroethy1 isocyanate (b.33g) and the mixture was stirred at ambient temperature for 5 days in the dark. The mixture was then diluted with diethyl ether and the resulting solid was filtered — 10 off, washed with diethyl ether and dried in vacuo at ambient temperature, to give 8-carbamoy1-3-(2-chloroethy l)-6-me thy l-[3Hj-imidazol5,l-dj-l,2,3,5- tetrazin-4-one (2.00g), m.p. 170°C (with decomposition) [Elemental analysis: C,37.0;H,3.49;N,32.8;Cl,13.3%; calculated: C,37.44;H,3 . 54;N,32.75;Cl,13.82%].
EXAMPLE 9 Compound I A solution of 5-diazoimidazole-4-(N,N-dimethyl-sulphonamide) (0.55g; prepared as described in Reference Example 6) in dry ethyl acetate (40ml) was ^ treated with 2-chloroethyl isocyanate (3ml) and the mixture was stirred in the dark for 48 hours. The mixture was then evaporated _rn vacuo at below 40°C to about 15ml volume and diluted with dry diethyl ether.
O1 The resulting solid was filtered off, to give 3-(2-chloroethyl)-8-(N,N-dimethylsulphamoy1)-[3H]- 2052 imidazol5,1-dJ-1,2,3,5-tetrazin-4-one (0.68g), in the form of greyish needles, m.p. 155-156°C. [Elemental analysis: C, 30 . 4;H, 3 . 3 5 ; N , 26 . 8;CI, 11. 6 V, calculated: C,31.3;H.3.62;N,27.4;C1,11.6%; l.R. 1755cm~L; NMR (in DMSO-d^); singlets at 2.80, 8.90ppm, triplets at 3.59, 4.62ppm].
EXAMPLE 10 Compound J A suspension of 5-diazoimidazole-4-(N-methyl-sulphonamide) (0.7g; prepared as described in Reference Example 7) in ethyl acetate (40ml) was treated with 2-chloroethyl isocyanate (3ml) and the mixture was stirred in a stoppered flask in the dark for 4a hours. Tne mixture was then evaporated _in vacuo at below 35°C to approximately half its volume, and was diluted with diethyl etner. Tne resulting solid was filtered oft and washed with diethyl ether, to give 3-(2-chloroethyl)-8-(N-methylsulphamoy1)-[3H]-imidazo-[5,1-dj- 1,2,3,5-tetrazin-4-one (0.32g), in the form of shining buff plates, m.p. 147-148°C [Elemental analy s i s : C, 28 . 5; H, 2 . 90; N , 28 . 77<>; calculated : C,28.7;H,3.08;N,28.770; l.R. 1745cm-1; NMR (in DMSO-dg): doublet at 2.58ppm, triplets at 3.98, 4.61ppm, quartet at 7.94ppm, singlet at 8.84ppm], r- • 5 2 0 52 EXAMPLE II Compound K A solution of 5-diazo-4-methyLsulphonylimidazole (0.65g; prepared as described in Reference Example &) 5 in dry ethyl acetate (50ml) was treated with 2-chloroethyl isocyanate (3ml) and the mixture was stirred at room temperature in the dark for 46 hours. The mixture was then evaporated jjri vacuo and the oily residue was triturated with petroleum ether (b.p. 10 60-80°C). The resulting solid was filtered off and subjected to medium pressure chromatography, eluting with ethyl acetate, and the white solid product was triturated with petroleum ether and filtered off, to give 3-(2-chloroethyl)-&-methylsulphony1-[3H]-imidazo-15 [5,1-d]-1,2,3,5-tetrazin-4-one (0.72g), m.p. 154-155°C. [Elemental analysis: C,30.3;H,2.85;N,25.0; CI,11.5%; calculated: C,30.26;H,2.90;N,25.22; CI,11.55%].
EXAMPLE 12 Compound L A solution of 5-diazo-4-methylsulphonylimidazole (0.65g; prepared as described in Reference Example 8) in dry ethyl acetate (60ml) was treated with methyl isocyanate (3.5ml) and was left to stand at room 25 temperature in the dark for 3 days. A further quantity of methyl isocyanate (3.5ml) was added and ^ the mixture was warmed at 40°C for 2 days ana then was left to stand at room temperature for 3 days. The mixture was then evaporated jun vacuo to a volume of between 10 and 15ml, and was subjected to medium pressure chromatography, eluting with ethyl acetate, to give 3-methy1-b-methyIsulphonyl-[3H]-imidazo-[5,1-d]-1,2,3,5-tetrazin-4-one (0.17g), in the form of a white crystalline solia, m.p. 185-166°C (with decomposition). [Elemental analysis: C,31.2;H,2.89; N, 30.37c; calculated: C, 31.44 ; H , 3 . 08; N , 30 . 56% ] .
EXAMPLE 13 Compound M A solution of 5-uiazoimidazoLe-4-[N-(4-methoxy-benzyl)sulphonamideJ (0.3g; prepared as described in Reference Example 9) in dry ethyl acetate (25ml) was treated with 2-chloroethyl isocyanate (1.5g) and the mixture was stirred at room temperature for 4a hours. The resulting dark solution was filtered and evaporated to dryness. The resulting brown solid was triturated with petroleum ether, filtered off and subjected to medium pressure chromatography, eluting with ethyl acetate, to give a white solid that was triturated with petroleum ether, fiLtered off and dried at 70°C/10mmHg for 1 hour, to give 3-(2-chloro-ethyl)-8-[N-(4-methoxybenzyl)sulphamoyl]-L3H]-imidazo-[5,1-d]-l,2,3,5-tetrazin-4-one (0.2g), m.p. 155-156°C 27 - 2 o r" (with decomposition) [l.R. 1745cm"1; Elemental analysis: C , 41. 9; H, 3 . 72; N , 20.570; calculated: C,42.16; H,3.79;N,21.07%].
EXAMPLE 14 Compound N 3-(2-Chloroethyl)-e-[N-(4-methoxybenzyl)s ulphamoy1] [3H]-imiaazo-[5,1-d]- 1,2,3,5-tetrazin-4-one (O.lg; prepared as described in Example 13) was dissolved in trifluoroacetic acid (1.0ml) and anisole (3 drops) and ^ 10 the solution was allowed to stand at room temperature for two hours. The mixture was then evaporated in vacuo and the residue was triturated with diethyl ether, to give a yellow solid, which was subjected to medium pressure chromatography, using a mixture of 15 petroleum ether (b.p. 60-80°C) and ethyl acetate (1:1 v/v) as eluent, to give 3-(2-chloroethyl)-8-sulphamoy1-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one (50mg), in the form of a white solid, m.p. 183°C (with decomposition) [l.R. 1750cm"1; NMR (in DMSO-d^) 20 singlets at 8.8, 7.8ppm, triplets at 4.58, 3.95ppm], EXAMPLE 15 Compound 0 A stirred suspension of 3-diazopyrazole-4-carboxamide (5.9g; prepared as described by Cheng e_t 25 al., op. c i t .) in ethyl acetate (150ml) was treated with 2-chloroethyl isocyanate (24ml) and stirred at - 28 y ambient temperature for 7 days in the dark. The mixture was diluted with diethyl ether and the resulting solid was filtered off and washed with diethyl ether, to give a mixture in the form of a 5 cream solid (8.36g), m.p. 173-174°C (with decomposition) .
A solution of a sample of the said mixture (l.Og) in dimethyl sulphoxide (20ml) was heated at 60°C overnight. The solution was then evaporated to 10 dryness (at below 60°C and at pressures down to O.lmmHg) and the residue was triturated with a mixture of dichloromethane and diethyl ether. The resulting solid was collected and dissolved in boiling acetonitrile (approximately 50ml). The resulting 15 solution was treated with deactivated silica gel (3g containing 207o water) and the mixture was evaporated to dryness. The residue was loaded onto a column of silica gel and subjected to medium pressure chromatography, eluting with ethyl acetate, and 20 recrystallising the product from acetonitrile, to give 8-carbamoy1-3-(2-chloroethyl)-[3H]-pyrazolo[5,l-d]-1,2,3,5-tetrazin-4-one (0.25g), in the form of colourless needles, m.p. 203-204°C (with decomposition) [Elemental analysis: C,34.8;H,2.92; 25 N , 34 . 7; CI, 14 . 6%; calculated: C,34.65;H,2.91;N,34.64; CI,14.61%J. 52 7 2 EXAMPLE 16 Compound P A stirred suspension of 3-diazopyrazole-4-carboxamide (1.6g; prepared as described by 5 Cheng e£ a 1., op. cit.) in dichloromethane (49ml) and N-methylpyrrolid-2-one (2.5ml) was treated with methyl isocyanate (6ml) and stirred in the dark for 7 days. The mixture was then diluted with diethyl ether and the resulting solid was filtered off, to give a 10 mixture in the form of a cream solid (2.24g), m.p. 179-181°C (with decomposition).
A solution of a sample of this solid (l.Og) in dimethyl sulphoxide (10ml) was treated witn deactivated silica gel (8g; containing 207o water) 15 ana the mixture was evaporated to dryness (at 60°C/0.ImmHg). The residue was loaded onto the top of a column of silica gel and subjected to medium pressure chromatography, eluting with ethyl acetate. The product was triturated with a small amount of 20 saturated aqueous sodium bicarbonate solution and quickly filtered, to give 8-carbamoy1-3-methyl-[3H]-pyrazolo[5,1-d]-1,2,3,5-tetrazin-4-one (41mg), in the form of a colourless solid, m.p. 170°C (with decomposition). [NMR (in DMSO-d^): singlets at 25 3.95, 7.45, 7.55, 8.50ppm; l.R. (KBr disc): 3400, 3160, 1750 and 1680cm"1J. 2 0:27 EXAMPLE 17 Compound Q A solution of sodium nitrite (0.79g) in water (6ml) was treated with a solution of crude 4-amino-5-piperid inocarbonylimidazole hydrochior ide (2.1g; prepared as described in Reference Example 10) in aqueous acetic acid (lM;17ml), dropwise with stirring, at 5-10°C during 5 minutes. The solution was extracted with ethyl acetate (4 x 45ml) and the combined extracts were dried over magnesium sulphate and evaporated at 3Ci°C/0 . ImmHg . The residue was dried in a desiccator over phosphorus pentoxide for 45 minutes, to give 4-diazo-5-piperidinocarbonylimidazole (1.73g) in the form of red crystals, pure enough for use in the next stage.
A solution of crude 4-diazo-5-piperidinocarbony1-imidazole (1.73g; prepared as described above) in dry ethyl acetate (53ml) was treated with 2-chloroethyl isocyanate (5.9ml) and the mixture was stirred in the dark for 2 days. The solution was then evaporated at 30°C/0. ImmHg and the residue was subjected twice to medium pressure chromatography on silica gel, eluting with a mixture of ethyl acetate and acetonitrile (68:12 v/v), The appropriate fractions were combined and evaporated and the residue was triturated with petroleum ether (b.p. 40-60°C), to give 3-(2-chloro- 205272 ethy 1)-6-piper id inocarbonyI-l3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one (1.46g), in the form of light purple crystals, m.p. 92-94°C [Elemental analysis: C,45.3; H,4.98;N,26.1%; calculated: C,46.4;H,4.87;N,27.11; 5 NMR (in DHSO-d^); singlet at 8.7ppm, triplets at 4.6 and 4.0ppm, multiplets at 3.2-3.4 and 1.5-l.Sppm; l.R.
^ (KBr disc): 1750, 1630cm"1!.
EXAMPLE 18 Compound R A stirred solution of sodium nitrite (1.61g) in water (5ml) was cooled and maintained at 5-10°C and treated dropwise with a solution of 5-amino-2-butylimidazole-4-carboxamide hydrochloride (1.61g; prepared as described in U.K. Patent 15 Specification No. 1421787 in hydrochloric acid (1M; 17.7ml) during 5 minutes to give a yellow precipitate, which was filtered off and dried in a desiccator over phosphorus pentoxide, to give 2-buty1-5-diazoimidazole-4-carboxamide (0.47g), in the form of a yellow solid, 20 m.p. 109-111°C (with decomposition), pure enough for use in the next stage.
A solution of crude 2-butyl-5-diazoimidazole-4-carboxamide (0.47g; prepared as described above) in ethyl acetate (14ml) was treated with 2-chloroethyl 25 isocyanate (1.5ml) and left to stand in the dark for 24 hours. The resulting fawn solid was filtered o.fi^ o I'jM v> 20527t and recryscallised from a mixture of ethyl acetate and acetonitrile, to give 6-butyl-6-carbamoyl-3-(2-chloroethy 1)-[3H)-imidazoI 5,1-d]-1,2,3,5-tetrazin-4-one (0.49g), in the form of colourless crystals, m.p. 5 165-167°C (with decomposition) (Elemental analysis: C,43.9;H,4.90;N,27.9;C1,12.0%; calculated: C,44.2; H, 5 .06 -, N , 28 . 1; C1,11. 9% ] .
EXAMPLE 19 Compound S A stirred solution of sodium nitrite (G.44g) in water (3.7ml) was cooled and maintained at 5-10°C and treated dropwise witn a solution of 5-amino-2-cyclohexylimidazole-4-carboxamide hydrochloride (l.lg; prepared as described in U.K. Patent 15 Specification No. 1421787 in aqueous acetic acid (2M; 28ml) during 5 minutes. The resulting orange precipitate was filtered off and dried in a desiccator over phosphorus pentoxide for 1 hour, to give crude 2-cyclohexyl-5-diazoimidazole-4-carboxamide (0.86g), 20 in the form of an orange solid, pure enough for use in the next stage.
A solution of the crude 2-cyclohexyl-5-diazo-imidazole-4-carboxamide (0.86g; prepared as described above) in ethyl acetate (17ml) was treated with 25 2-chloroethyl isocyanate (2.0ml) and left to stand in the dark for 24 hours. The resulting solid was • - 33 - 20Z272 filtered off and recrystal1ised from ethyl acetate, to give 8-carbamoy1-3-(2-chloroethy1)-6-cyclohexy1-[3H ]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one (0.23g), in the form of colourless crystals, m.p. 245-248°C (with 5 decomposition) [Elemental analysis: C,47.6;H,5.16; N , 25 . 6; Cl, 10 . 870; calculated: C,46.1;H,5.28;N,25.9; CI,10.9%].
EXAMPLE 20 Compound T A stirred solution of sodium nitrite (0.58g) in i water (4.7ml) was cooled and maintained at 5-10°C and treated dropwise with a solution of 5-amino-2- phenethylimidazole-4-carboxamide hydrochloride (1.8g; prepared as described in Reference Example 11) in aqueous acetic acid (2M; 18ml) during 5 minutes. The resulting yellow precipitate was filtered off and dried in a desiccator over phosphorus pentoxide for 1 hour, to give crude 5-diazo-2-phenethylimidazole-4- carboxamide (2.0g), in the form of a yellow solid, pure enough for use in the next stage.
A suspension of crude 5-diazo-2-phenethylimidazole- 4-carboxamide (2.0g; prepared as described above) in ethyl acetate (29ml) was treated with 2-chloroethyl ^ , isocyanate (3.4ml) and stirrea in the dark for 24 MP hours. The resulting solid was filtered off and recrystallised twice from ethyl acetate, to give 2i- f.
U w Z. 8-carbamoy1-3-(2-chloroethyl)-6-phenethy 1-[3H]-imidazo[5,1-dj-1,2,3,5-tetrazin-4-one (0.44g), in the form of colourless crystals, m.p. 179-181°C (with decomposition) [Elemental analysis: C,51.8;H,4.19; N,24.2;CI,10.2%; calculated: C , 52 . 0;H,4.36;N,24.2; CI,10.2%].
EXAMPLE 21 Compound U A solution of 2-benzy1-5-diazoimidazole-4-carboxamide (2.4g; prepared as described in Reference Example 12) in dry ethyl acetate (150ml) was treated with 2-chloroethyl isocyanate (10ml) and the reaction mixture was left to stand at room temperature in the dark for 20 hours. The reaction mixture was then evaporated to dryness and the residue was triturated with petroleum ether (b.p. 60-80°C; 2 x 30ml) to remove excess 2-chloroethyl isocyanate. The remaining residue was then triturated with dichloromethane (2 x 50ml) to extract the desired product from insoluble 1,3-bis(2-chloroethy1)urea byproduct. The combined dichloromethane extracts were evaporated to dryness and subjected to medium pressure chromatography on silica gel, eluting with ethyl acetate. The appropriate fractions were combined, evaporated and recrystallised from ethyl acetate, to give 6-benzyl-8-carbamoy1-3-(2-chloroethyl)-[3H]-imidazo[5,1-d]- 205272 - 35 -* 1, 2,3,5-tetrazin-4-one (0.7g), m.p. 161-163°C (with decomposition) [Elemental analysis: C,50.4;H,3.56; N,25.4;CI,10.8%; calculated: C.50.53;H,3.94;N,25.26; CI,10.66%; l.R. 1740cm"1j.
EXAMPLE 22 Compound V A solution of 5-diazo-2-isopropylimidazole-4-carboxamide (1.2g; prepared as described in Reference Example 13) in dry ethyl acetate (75ml) was treated ^ 10 with 2-chloroethyl isocyanate (5ml) and the mixture was left to stand in the dark at room temperature for 5 days. The resulting crystalline solid was filtered off and was washed with petroleum ether (b.p. 60-a0°C), to give 8-carbamoy1-3-(2-chloroethyl)-6-15 isopropy1-[3H]-imidazo[5,1-d]-1.2,3,5-tetrazin-4-one (0.2g), m.p. 189-190°C (with decomposition) [Elemental analysis: C ,42 .0; H , 4 . 6A ; N , 29 . 570; calculated: C.42.19; H, A.60;N,29.5%; l.R. 1740cm_1J.
EXAMPLE 23 Compound U A solution of sodium nitrite (0.7g) in water (6ml) was added to a solution of 5-amino-2-propylimidazole-4-carboxamide (1.37g; prepared as described in U.K. Patent Specification No. 14 21787 in aqueous c acetic acid (2M; 22ml) at 0-5°C, dropwise, during 5 minutes. The resulting precipitate was filtered off , r -- " c> ' ' * V - V n <20.->272~ 10S27Z - 3b - and dried in a desiccator over phosphorus pentoxide, to give 5-diazo-2-propylimidazole-4-carboxamide (0.56g), in the form of a yellow solid, pure enough for use in the next stage. a solution of crude 5-diazo-2-propylimidazole-4- carboxamide (0.56g; prepared as described above) in dry ethyl acetate (14ml) was treated with 2-chloroethyl isocyanate (1.6ml) and stirred in the dark for 24 hours. The resulting precipitate was filtered off 10 and washed with ethyl acetate, to give 8-carbamoyl-3-(2-chloroethyl)-6-propyl-[3H]-imidazo[5,l-d)-l,2,3,5-tetrazin-4-one (0.48g), in the form of a buff solid, m.p. 145-148'C (with decomposition) [Elemental analysis: C , 41.1; H, 4 .4 ; N , 28. 57„; calculated: C,42.2; 15 H,4 .60;N,29.5%; NMR (in DMSO-d^): singlet at 7.7ppm; triplets at 4.6, 4.0, 3.2 and l.Oppm, multiplet at 1.8ppm; l.R. (KBr disc): 1750, 1695cm"*"]. example 24 Compound X a stirred solution ot sodium nitrite (0.44g) in water (3.8ml) was added to a solution of 5-amino-2-ethylimidazole-4-carboxamide (0.80g; prepared as described in U.K. Patent Specification No. 1421787 in aqueous acetic acid (2M; 14ml) at 0-3°C, 25 dropwise, during 5 minutes. The resulting precipitate was filtered off and dried in a desiccator over """ ° -t OCT 1986 phosphorus pentoxide for 1 hour, to give 5-diazo-2-ethy1imidazole-4-carboxamide (0.62g), in the form of a yellow solid, en.p. 139°C (with decomposition), pure enough for use in the next stage.
A solution of crude 5-diazo-2-ethy1imidazole-4-carboxamide (0.62g; prepared as described above) in dry ethyl acetate (22ml) was treated with 2-chloroethyl isocyanate (2.4ml) and stirred in the dark for 24 hours. The resulting precipitate was filtered off and washed with ethyl acetate, to give 8-carbamoy1-3-(2-chloroethy1)-6-ethyl-l3H]-imidazo-[5,1-dj-1,2,3,5-tetrazin-4-one (0.59g), in the form of pale grey crystals, m.p. 172-174°C (with decomposition) [Elemental analysis: C,39.7;H,3.98;N,31.0;CI,13.1%; calculated: C,39.9;H,4.10;N,31.G;C1,13.1].
EXAMPLE 25 Compound Y Dry ethyl acetate (100ml) was treated with 5-diazo-4-(4-methoxybenzy1)sulphamoy1-2-methylimidazole (2.45g; prepared as described in Reference Example 14), followed by 2-chloroethyl isocyanate (3ml) and the reaction mixture was stirred in the dark at room temperature for 56 hours. The mixture was then treated with a further quantity of 2-chloroethyl isocyanate (3ml) and stirred in the dark at room temperature for a further period of 24 hours. The - 38 2 > 2 reaction mixture was tnen evaporated to dryness and the residue was triturated with petroleum ether (b.p. 6G-8G°C; 3 x 25ml) to remove excess 2-chloroethyl isocyanate. The remaining residue was then 5 triturated with dichloromethane (2 x 5Gml) to extract the desired product from insoluble 1,3-bis(2-chloro-ethyl)urea byproduct. The combined dichloromethane extracts were evaporated to dryness and subjected to medium pressure chromatography on silica gel, eluting /-v 10. with ethyl acetate, to give 3-(2-ch loroethy1)-8- (4-methoxybenzy1)sulphamoyl-6-methy 1-I3H]-imidazo-[5,1-d]-1,2,3,5-tetrazin-4-one (1.5g), m.p. 159-160°C (with decomposition) [l.R. 176Gcm~1J.
EXAMPLE 26 Compound Z A solution of 3-(2-chloroethy1)-8-(4-methoxy-benzy1)sulphamoy1-6-methy 1-I3H]-imidazo[5,1-d J-1,2, 3 , 5,-tetrazin-4-one (1.5g; prepared as described in Example 25) in trifluoroacetic acid (10ml) and anisole 20 (10 drops) was left to stand at room temperature overnight. The reaction mixture was evaporated in vacuo and the residue was triturated with diethyl ether. The resulting pale brown solid was filtered off and recrystallised from acetone, to give 25 3-(2-chloroethyl)-6-methy 1-8-sulphamoyl-[3H]-imidazo-[5,1-d]- 1,2,3,5-tetrazin-4-one (0.55g), m.p. 199-200°C Tstsm, ? t • '2. i - 35 - ^ w w / (with decomposition) [Elemental analysis: C.29.1; H,3.02;N.28.8;C1,12.1;S,L0.6%; calculated: C.28.72; H,3.10;N,26.71;C1,12.11;S,10.95%; l.R. 1760, 3310cm"1].
EXAMPLE 2 7 Compound AA A solution of 5-diazo-4-dimetnylsulphamoyl-2-methylimidazole (1.8g; prepared as described in Reference Example 15) in dry ethyl acetate (100ml) was 10 treated with 2-chloroethyl isocyanate (4ml) and the mixture was left to stand for 2 days at room temperature. The mixture was then treated with a further quantity of 2-chloroethyl isocyanate (4ml) and left to stand at room temperature for a further period 15 of 6 days. The reaction mixture was then evaporated in vacuo and the residue was triturated with petroleum ether (b.p. 60-b0°C; 2 x 25ml). The remaining solid was dissolved in ethyl acetate and subjected to medium pressure chromatograpny on silica gel, eluting with 20 ethyl acetate. The appropriate fractions were combined, evaporated to dryness, and triturated with petroleum ether (b.p. 60-80°C), to give 3-(2-chloro-ethy1)-8-dimethylsulphamoy1-6-methyl-[3H]-imidazo- ' [5,1-d]-1,2,3,5-tetrazin-4-one (2.l7g), m.p. 137-138°C v > [Elemental analysis: C,33.8;H,3.91;N,25.8;Cl,11.2; s,9.7%; calculated: C,33.7;H,4.09;N,26.20;Cl,11.05; s,10.0*j.
EXAMPLE 28 Compound BB A solution of 5-diazo-2-methyl-4-methylsulphonyl-imidazole (0.4g; prepared as described in Reference Example lb) in dry ethyl acetate (30ml) was treated with 2-chloroethyl isocyanate (2ml) and left to stand at room temperature, in the dark, for 4 days. The mixture was then evaporated to dryness and the residue was triturated with petroleum ether (b.p. 60-80°C; 2 x 25ml) to remove excess 2-chloroethyl isocyanate. The remaining residue was dissolved in ethyl acetate and subjected to medium pressure chromatography on silica gel, eluting with ethyl acetate, to give 3-(2-chloroethy1)-6-methyl-8-methylsulphony1-[3H]-imidazo[5,l-dj-1,2,3,5-tetrazin-4-one (0.22g), m.p. 149-150°C (Elemental analysis: C,33.0;H,3.35;N,23.8; C1,12.7%;S,10.7%; calculated: C,32.94;H,3.46;N,24.01; Cl,12.15;S,10.957o; l.R. 1745cm-1].
EXAMPLE 29 Compound CC A suspension of 3-diazopyrazole-4-(N,N-dimethyl-carboxamide) hydrochloride (0.92g; prepared as described in Reference Example 17) in dry dichloromethane (50ml) was treated with 2-chloroethyl 20o2Z3^ 2o52?Z • isocyanate (2.5ml) ana the stirred suspension was then treated with 1,3-diazoDicyclo[5,4,0]undec-7-ene (0.7g). Tne resulting solution was stirred at room temperature in the dark overnight. The dichloromethane was 5 evaporated off and the resulting gum was triturated —v with petroleum ether (b.p. b(J-60°C) . The insoluble residue was subjected to medium pressure chromatography, eluting with ethyl acetate. The appropriate fractions were combined, evaporated to 10 dryness and the residue was recrystallised from ethyl acetate, to give 3-(2-chloroethyl)-ti-(dimethylcarbam-oyl)-l3H]-pyrazoLo[5,l-d|-l,2,3, 5-tetraz in-4-one (0.38g) in the form of colourless crystals, m.p. 116-116°C (with decomposition) [Elemental analysis: 15 C,3S.7;H,3.96;N,30.9;C1,13.U; calculated: C.35. 93; H , 4 . 10 ; N , 3 1. 05 ; C1,13 .170; l.R. (KBr disc): 1770, 1630cm"1; NMR (in acetone-d&): singlets at 3.25 and b.40ppm, triplets at 4.25ppm and 4.95ppm].
EXAMPLE 30 ^ 20 Compound DP Stirred concentrated sulphuric acid (2.5ml) was treated with 8-carbamoyl-3-(2-chloroethy1)-[3H]-imidazol5,1-dJ-1,2,3,5-tetrazin-4-one (0.24g; prepared as described in New Zealand Patent Specification No. 25 2016S8). The mixture was cooled to 0°C and treated \ OCT 1986 . # - 42 - 2 f , dropwise with concentrated nitric acid (d = 1.42; 1ml). The solution was maintained at 4°C for 1 hour and then was poured on to ice. The precipitated solid was collected, washed with water, and recrystallised from 5 aqueous acetone, to give 3-(2-chloroethyl)-6-(N-nitro-carbamoy1)-13HJ -imidazoL 5,l-d]-l,2,3,5-tetrazin-4-one (0.2bg) in the form ot colourless crystals, m.p. 160-161°C (with decomposition) [Elemental analysis: C,28.6;H,1.89;C1,12.0;N,33.6%; calculated: C,29.23; 10 H,2.10;Cl,12.33;N,34.097c; l.R. (KBr disc): 3200, 1750, 1720 and 1620 cm-1; NMR (DMSO-d^): triplets at 4.05ppm (J = 6Hz) and 4.70ppm (J = 6Hz), singlet at 9.05ppm, broad singlet at 8.25ppm; m/e 267/289 (M+)].
EXAMPLE 31 15 Compounds EE, FF, GG, HH and II By proceeding in a manner similar to that described in Examples 1, 2, 4, 6 to 13, 15 to 25 and 27 to 29 and using the appropriate diazo compounds as intermediates (prepared by the application or 20 adaptation of methods described in the following Reference Examples), there were prepared:- 3-methy1-tt-methylsulphony1-[3H]-pyrazolo[5,1-d]-1,2,3,5-tetrazin-4-one, in the form of a colourless solid, m.p. 182-184°C; 25 3-(2-chloroethy1)-8-methylsulphony1-[3H]-pyrazolo- [5,1-d ] -1,2,3,5-tetrazin-4-one, in the form of a 2 , < colourless solid, m.p. 166-171°C ; 3-(2-chloroethyl)-6-methy 1-8-methy Isulphinyl-13H]-imidazo[5,1-dJ-1,2,3,5-tetrazin-4-one, in trie form of a yellow solid, m.p. 118-120°C; 3-(2-chloroethyl)-8-ethylsulphony1-6-methy1-[3H]-imidazo[5,l-dJ-l,2,3,5-tetraz in-4-one, m.p. 146- 147 °C; and 3-(2-chloroetny1)-6-methy 1-8-propylsulphony1-[3H]-imidazoL5,1-dJ - 1,2,3,5-tetrazin-4-one, in the form of a white crystalline solid, m.p. 85-86°C. - 44 REFERENCE EXAMPLE 1 205272 (i) An intimate mixture of 5-nitroimidazole-4-carboxylic acid (2.0 g) and phosphorus pentachioride (<£.67 g) was stirred and neated in an oil bath at 5 120°C for 1 hour. The resulting yellow slurry was ^ evaporated at 60°C/0.ImmHg for 30 minutes, to give I,6-dinitro-5h,lGH-di imidazo[l,5-a:l',5'-a]pyrazine-5,10-dione (1.50 g) in the form of a yellow solid, m.p. 249-25i°C (with decomposition). II.R. (KBr disc): ^ 10 1750 cm-1; m/e 276 (M+) J .
[Windaus, Ber. , 1523, 5ji, 664 and Gireva, Chem. Abs., 59, 1622e, using the same method, describe their products as "5-nitroimidazole-4-carbonyl chlor ide"J . (ii) A mixture ot 1, 6-dinitto-5H,IGH-aiimidazo- II,5-a:1',51-a Jpyrazine-5, 10-dione (5.bg), N-benzyl-aniline (15g) and tetrahydroturan (250ml) was heatea at reflux for b hours. The tetrahydrofuran was evaporated off ^_n vacuo and the residual gum was partitioned between dilute hydrochloric acid (2N;1 litre) and ethyl acetate (1 litre). Insoluble N-benzylani1ine hydrochloride was removed by filtration, and tne ethyl acetate layer was separated. The aqueous phase was extracted twice more 25 with ethyl acetate and the comDined organic phases were washed with dilute hydrochloric acid (2N) , and - 45 " V. 4u. / Chen with water, dried over magnesium sulphate, and evaporated to dryness to give an orange gum. The gum was triturated twice with Doiling diethyl ether, to give a colourless solid, which was crystallised from isopropanol, to give 5-nitroimidazole-4-N-benzyl-N-phenyIcarboxamide (4.0g), in the £orm of colourless flakes, m.p. 237-240°C lElemental analysis: C,62.3;H,4.28;N,17.3%; calculated: C , 63.35;H;4.38; N, 17.36%; l.R. (KBr disc): l665cin-i"l. (iii) A solution of 5-nitroimidazole-4-N-benzy1-N-phenylcarDoxamide (4.0g) in dry etnanol (450ml) was hydrogenated at 26°C and 3 atmospheres pressure, using a Raney nickel catalyst. When hydrogen absorption was complete (after 4 hours 50 minutes), the mixture was filtered, treated witn concentrated hydrochloric acid (3.t>ml) and evaporated to dryness below 40°C. Trituration of the residue with diethyl ether gave 5-aminoimidazole-4-N-benzyl-N-phenylcarboxamide hydrochloride (3.82g), in the form of a pale yellow solid, m.p. 190-193°C (with decomposition) (.NMR (in DMSO-d^): singlets at 5.05, 7.1-7.2 and 8.4ppm; l.R. (KBr disc): 1640cm""1; m/e 292 (M+) ].
U" P0 c ■- J-. u REFERENCE EXAMPLE 2 (i) A mixture of N-benzyl-N-(4-metnoxybenzyl)amine [21.5g; Annalen, (1931), 490, 189J, 1,6-dinitro-5H,10H-diimiaazo[5,1-a:i',5'-dJpyrazine-5,10-dione (6.7g; prepared as described in Reference Example L)) and dry tetrahydroturan (200ml) was heated at reflux for 18 hours. The tetrahydrofuran was evaporated off in vacuo and the residual oily solid was partitioned between dilute hydrochloric acid (2N, 500ml) and ethyl acetate (500ml). Insoluble N-benzyl-N-(4-methoxy-benzyl)amine hydrochloride was removed by filtration, and the ethyl acetate layer was separated. The aqueous phase was extracted twice more with ethyl acetate and the combined organic phases were washed with dilute hydrochloric acid (2N), then with water, and then with saturated aqueous sodium chloride solution, and then it was dried over sodium sulphate and evaporated to dryness. The residual gum was subjected to medium pressure column chromatography, eluting with ethyl acetate, to give 5-nitroimidazole-4-N-benzyl-N-(4-methoxybenzy1)carboxamide (2.9g) in the form of a tan solid, m.p. 167-170°C [after crystallisation from a mixture of petroleum ether (b.p. 60-80°C) and isopropanol] [Elemental analysis: C,61.3;H,4.93;N,15.3%; calculated: C,62.29; H.4.95; N,15.297c; l.R. (KBr disc): 3100-2800, 1640, 1510, 1450 ano 1370 cm-''". NMR (in DMSO-d^ at 120°C): singlets at 3.76, 4.5, 4.6, 7.3 and 7.8ppm, 2 0 ~ Z , doublets centred at 6-85 and 7.2ppm. (The NMR spectrum at room temperature is complicated because of doubling of signals caused by hindered rotation about the bond linking the amide carbonyl group to the amide nitrogen atom). (ii) A solution ot 5-nitroimidazole-4-N-benzyl-N-(4-methoxybenzy1)carboxamide (2.2g) in dry ethanol (200ml) was hydrogenateo at room temperature and 3 atmospheres pressure using a Raney nickel catalyst. When hydrogen absorption was complete (after 2 hours 46 minutes), the mixture was filtered, treated with hydrogen chloride gas, and evaporated to dryness below 40°C. Trituration with a mixture of isopropanol and diethyl ether gave 5-aminoimidazole-4-N-benzyl-N-(4-methoxybenzyl)carboxamide hydrochloride (2.2g), in the form of a gummy solid, which decomposed above 70°C [l.R. (KBr disc): 34U0-2800, 1640cm"1; NMR (in methanol-d^): singlets at 3.7, 4.4, 4.5, 7.2 and 8.3ppm, doublets centred at 6.7 and 6.5ppm (signals broadened because of hindered rotation about the bond linking the amide carbonyl group to the amide nitrogen atom).
REFERENCE EXAMPLE 3 (i) A mixture of 1,6-dinitro-5H,lOH-diimidazo-[1,5-a:1',51-dJpyrazine-5,10-dione (5.5g; prepared as described in Reference Example 1),N-(4-methoxybenzy1)-aniline [14.5g; Zechmeister al, Ber., (1930), 63B, 'w s^- «lLm 2683] and tetrahydrofuran (250ml) was heated at reflux for 12 hours. The tetrahydrofuran was then evaporated off vacuo and the residual dark oil was partitioned between dilute hydrochloric acid (2M; 1000ml) and ethyl acetate (1000ml). The organic layer was separated, washed with water, dried over magnesium sulphate and evaporated to dryness. The resulting solid was triturated with diethyl ether, to give 5-ni troimidazole-4-N-(4-methoxybenzy1)-N-pheny1-carboxamide (3.log), in the form of a peach-coloured solid, m.p. 212-215°C (after recrystallisation from isopropanol). [Elemental anaylsis: C,60 .4;H,4.41; N,16.0%; calculated: C,61.37;H,4.58;N,15.51%; NMR (in DMSO-d^): singlets at 3.7, 5.0 and 7.7ppm, multiplet at 6.7-7.3ppm; l.R. (KBr disc) 1660cm"1]. (ii) A solution of 5-nitroimidazole-4-N-(4-methoxybenzy1)-N-phenyIcarboxamide (2.1g) in dry ethanol (200ml) was hydrogenated at 25°C and 3 atmospheres pressure, using a Raney nickel catalyst. When hydrogen absorption was complete (after 5 hours), the mixture was filtered, and evaporated to dryness. The residue was triturated with diethyl ether, to give 5-aminoinudazole-4-N-(4-methoxybenzy1)-N-pheny1-carboxamide (1.9g), in the form of a gum. 2 j^A portion of this gum was characterised as its picrate:- 5-aminoimidazole-4-N-(4-methoxybenzyl)-N-phenylcarboxamide (0.l5g) was dissolved in dry 1,2-dimethoxyethane (3ml) and treated with a solution 5 of picric acid (0.25g) in 1,2-dimethoxyethane (5ml).
^ The resulting crystals were filtered off and washed with diethyl ether, to give 5-aminoimidazole-4-N-(4-methoxybenzy1)-N-phenyIcarDoxamiae picrate (0.07g), in the form of a yellow solid, m.p. 207°C (with 10 decomposition) [Elemental analysis: C , 49.1; H, 3 .64; N , 16 . 57o; C2^H2]_NyO^ : 2H2O requires: C , 49 .1; H, 4 .29; N.16.69%]} .
REFERENCE EXAMPLE 4 (i) A mixture of 1,6-dinitro-5H,lOH-diimidazo-15 [1,5-a:1',51-dJpyrazine-5,10-dione (6.06g; prepared as described in Reference Example 1), N-methyl-aniline (12.44g) and tetrahydrofuran (400ml) was heated at reflux for 24 hours. The tetrahydrofuran was then evaporated off _in vacuo and the residual dark 20 solid was treated with boiling diethyl ether. The remaining, undissolved solid was subjected to medium presure column chromatography, eluting with a mixture of ethyl acetate and methanol (1:1 v/v), to give 5-ni troimidazole-4-N-methyl-N-phenylcar boxamide 25 (4.68g), in the form of a white solid, m.p. 193°C [Elemental analysis: C, 52 . 5; H, 3 . 95 ; N , 22 . 2?0; calculated: C,53.66;H,4.09;N,22.76%; l.R. 1660cm-1].
L O (ii) A solution of 5-nitroimidazole-4-N-methyl-N-phenyIcarboxamide (l.Og) in dry ethanol (110ml) was hydrogenated at 23°C and 3 atmospheres pressure, using a Raney nickel catalyst. When hydrogen absorption was 5 complete (after 1 hour 39 minutes), the mixture was x-v. filtered and treated with dry hydrogen chloride gas.
The solution was then evaporated to dryness, to give 5-aminoimidazole-4-N-methyl-N-phenyIcarboxamide hydrochloride (0.5g), in the form of an off-white 10 solid, m.p. 100°C (with decomposition).
|~This compound was characterised as its picrate:-A solution of 5-aminoimidazole-4-N-methy1-N-pheny1-carboxamice hydrochloride (0.25g) in water (2ml) was treated with a solution of picric acid (0.25g) in 15 1,2-dimethoxyethane (2ml). The precipitate was filtered off and washed with 1,2-dimethoxyethane, to give 5-aminoimidazole-4-N-methy1-N-phenylcarboxamide picrate (0.12g), in the form of a yellow solid, m.p. 237-238°C (with decomposition) [Elemental analysis: 20 C,45.3;H,3.26;N,21.8%; calculated: C,45.85;H,3.39; N.22.02%; l.R. (KBr disc): 1640cm"1]J . c '• / v.. ^ .-^272 lo^ziz REFERENCE EXAMPLE 5 A stirred solution of sodium nitrite (l.Og) in water (8ml) was cooled to 0°C and treated with a solution of 4-amino-2-methylimidazole-5-carboxamide 5 hydrochloride (2.0g; prepared as described in U.K. Patent Specification No. 1421787) in aqueous tiT acetic acid (2N; 24ml), maintaining the temperature at between -2°C and 0°C. When the addition was complete the resulting yellow solid was filtered off and dried 10 j_n vacuo over phosphorus pentoxide, to give 5-diazo-2-methylimidazole-4-carboxamide (1.26g), m.p. 175°C (explodes).
REFERENCE EXAMPLE 6 (i) A stirred aqueous solution of dimethylamine (30% w/w; 35ml), cooled in a cola water bath, was treated with 5-nitroimidazole-4-sulphonyI chloride (4.15g of damp material, freshly prepared from 3.33g of 5-nitroimidazole-4-thiol ammonium salt by the method of Fisher jat al, Can. J. Chem., 35, 501), in portions. The mixture was stirred for a further 20 minutes ana was tnen evaporated _in vacuo at below 40°C to reduce the volume by half. The mixture was then made strongly acidic by treatment with concentrated hydrochloric acid and the resulting pale 25 yellow solid was filtered off and recrystallised from dimethyl formamide , to give 5-nitroimidazole-4-(N,N-dimethylsulphonamiae) (2.73g), in the form of brownish V cv i - f OCT 1986171 fall I plates, m.p. 282-283°C (with decomposition) [Elemental analysis: C,27.3;H,3.65;N,25.4;S,14.2%\ calculaCed: C,2 7.3;H,3.66;N,25.4;S,14.6%]. (ii) A solution of 5-nitroimidazole-4-(N,N-5 dimethylsulphonamide) (l.Og) in dry echanol (100ml) was hydrogenaced aC 24°C and 3 aCmospheres using a Raney nickel cacalyst. The mixture was then filtered and immediately diluted with diethyl ether (200ml) and treated with ary hydrogen chloride gas until it was 10 slightly acidic. The mixture was then evaporated in vacuo at below 30°C. The residual solid was dissolved in hot dry ethanol (20ml) and the solution was treated with charcoal, filtered, evaporated to 15ml volume, treated with dry diethyl ether (60ml) and allowed to 15 crystallise. The resulting solid was filtered off, to give 5-aminoimidazole-4-(N,N-dimethyIsulphonamide) hydrochloride (O.bg) in the form ot pinkish-buff needles, m.p. lb8-l»9°C (with decomposition) [Elemental analysis: C,2b.1;H,4.80;N,23.6;Cl,15.9; 20 S,13.9X;C5HL0N4O2S:HC1 requires C , 26.5;H,4.85; N,24.7;C1,15.6;S,14. 1570] . (iii) A stirred solution of sodium nitrite (0.31g) in water (5ml), cooled in an ice-bath, was treated aropwise with a solution ot 5-aminoimidazole- 4-(N,N-dimethylsulphonamide) hydrochloride (0.7g) in dilute hydrochloric acid (2N;3.lml). The resulting - 53 2C 2 7 solid was filtered off and washed with ice-cold water, to give 5-diazoimidazole-4-(N,N-dimethylsulphonamide) (0.38g), m.p. 109°C (with decompositon). [l.R. 2180, 2210cm"1].
A further portion (0.21g) of slightly less pure product was obtained by extraction of the aqueous liquors at 0°C with ethyl acetate, drying the extract over magnesium sulphate and evaporation ui vacuo REFERENCE EXAMPLE 7 (i) A stirred aqueous solution of methylamine (25% w/w; 35ml), cooled in a cold water-bath, was treated with 5-nitroimidazole-4-sulphonyl chloride (4.15g of damp material, freshly prepared from 3.33g of 5-nitroimidazole-4-thiol ammonium salt according to the method of Fisher et^ al.. , op. c it.) , in portions. The mixture was stirred for a further 15 minutes and was then evaporated ji_n vacuo at below 40°C to reduce the volume by half. The mixture was then made strongly acidic by treatment witn concentrated hydrochloric acid and the resulting solid was filtered off and recrystallised from water, to give 5-nitro-imidazole-4-(N-methylsulphonamide) (2.07g), in the form of pale yellow blades, m.p. 260-263°C (with decomposition) [Elemental analysis: C,23.1;H,2.87; N, 27. 4;S, 15.47=; calculated: C, 23 . 3 ; H, 2. 93; N , 27 . 2 ; S, 15. 557c]. 2, G «u (ii) A solution of 5-nitroimidazole-4-(N-methyl-sulphonamide) (l.Og) in dry ethanol (100ml) was hydrogenated at 24°C and 3 atmospheres using a Raney nickel catalyst. The mixture was then filtered and immediately diluted with diethyl ether (200ml) and treated with dry hydrogen chloride gas until it was slightly acidic. The mixture was then evaporated in vacuo at below 30°C. The residual solid was dissolved in a minimum volume of not ethanol and the solution was treated with charcoal, filtered and diluted with diethyl ether. The resulting solid was filtered off, to give 5-aminoimidazole-4-(iN-methylsulphonamide) hydrochloride (0.b3g), m.p. 178-160°C (with decomposition) [Elemental analysis: C,22.3;H,4.13; N,25.5;C1,16.5%;C^HyN^02S:HC1 requires C,22.6;H,4.26;N,26.35;C1,16.7%J. (iii) A stirred solution of sodium nitrite (0.285g) in water (4ml), cooled in an ice-bath, was treated dropwise with a solution of 5-aminoimidazole-4-(N-methylsulphonamide) hydrochloride (0.55g) in dilute hydrochloric acid (2N; 2.8ml). The resulting solid was filtered off and washed with ice-cold water, to give 5-diazoimidazole-4-(N-methylsulphonamide) (0.36g), m.p. 150°C (with decomposition). [Elemental analysis: C,25.2;H,2.47;N,37.07o; calculated: C, 25 . 7; H, 2 . 6 9; N , 3 7 .47o; l.R. 2210cm"1]. 2 1 ' k <w A— # A further portion (Q.07g) ot product was obtained by extraction of the aqueous liquors at 0°C with ethyl acetate, drying the extract over magnesium sulphate and evaporation jjn vacuo.
REFERENCE EXAMPLE 6 A solution of sodium nitrite (0.5g) in water (5ml), maintained at 0°C, was treated dropwise with a solution of 5-amino-4-methylsuiphonylimidazole hydrochloride [l.Og; prepared as described by Bennett et al, J.A.C.S., 75(3), 2188-2151, (1557)] in dilute hydrochloric acid (2N; 5ml). The solution was stirred for a further 15 minutes and was then extracted with ethyl acetate (5 x 20ml). The combined extracts were dried over sodium sulphate ana evaporated _iri vacuo to leave a yellow oil that crystallised on standing, to give 5-diazo-4-methylsulphony1 imidazole (0.74g), m.p. 12a-130°C [l.R. 2125cm-1 J.
REFERENCE EXAMPLE 5 (i) A stirred solution of £-methoxybenzylamine (lOg) in water (30ml) was treated with 5-nitro-imidazole-4-sulphony1 chloride (6.8g of damp material, freshly prepared from 6.0g of 5-nitroimidazole-4-thiol ammonium salt by the method of Fisher _et_ al., op. c i t.) . The mixture soon set solid, whereupon it was treated with isopropanol (20ml) and triturated, and allowed to stand overnight. The resulting solid was 2 0 : 2 filtered off, washed with ice-cold water, arid then it was suspended in water (150ml) and treated carefully with dilute hydrochloric acid (2N) until the suspension just attained pH2. The resulting yellow solid was filtered off and washed witn a little ice-cold water to give 5-nitroimidazole-4-[N-(4-methoxybenzy1)sulphonamide] (7.42g), m.p. 265-270°C (with decomposition). (ii) A solution of 5-nitroimidazole-4-[N-(4-methoxybenzyl)sulphonamideJ (l.Og) in dry ethanol (100ml) was hydrogenated for o hours at 3 atmosphees using a Raney nickel catalyst (507o). The catalyst was quickly filtered off with the aid of diatomaceous earth and the filtrate was immediately treated with concentrated hydrochloric acid (20ml). The mixture was evaporated to dryness and the resulting residue was triturated with dietnyl etner. Tne solid was filtered oft and washed with diethyl ether, to give 5-aminoimidazole-4-[N-(4-methoxybenzyl)sulphonamide j (0.25g), m.p. 154-155°C. (iii) A solution of sodium nitrite (0.14g) in water (5ml) was treated dropwise with a solution of 5-aminoimidazole-4-1N-(4-methoxybenzyl)sulphonamide] (0.5g) in dilute hydrochloric acid (2N; 10ml), maintaining the temperature at 0°C. The mixture was stirred at 0°C for a further 15 minutes and then the solid was filtered off, washed with water and dried 2 C A. v.- w <«. over phosphorus pentoxide, to give 5-diazoiimidazole-4-[t4-(4-methoxybenzy 1) sulphonamide (0.3g), m.p. 144-146°C (with decomposition) [l.R. 2180cm"1].
REFERENCE EXAMPLE 10 (i) A solution of piperidine (6.4ml) in dry tetrahydrofuran (92ml) was treated with 1,6-dinitro-diimidazo[l,5-a:1',5'-d]pyrazine-5,10-d ione (4.55g; prepared as described in Reference Example 1) and stirred at room temperature for 1 hour. The mixture was then evaporated and the residue was dissolved in dilute hydrochloric acid (2N; 92ml). The solution was extracted with ethyl acetate (3 x 200ml) and the combined extracts were dried over magnesium sulphate and evaporated. The residue was subjected to medium pressure chromatography on silica gel, eluting with a mixture of chloroform and methanol (9:1 v/v). The appropriate fractions were combined and evaporated and the residue was washed with diethyl ether, followed by ethyl acetate, to give 4-nitro-5-piperidinocarbony1-imidazole (2.72g), in the form of a yellow solid, m.p. 149-150°C. [Elemental analysis: C , 48 .2 ; H, 5 .33 ; N , 25 .1/i; calculated: C,4&.2;H,5.39;N,25.0%]. (ii) A solution of 4-nitro-5-piperidinocarDony1-imidazole (2.68g; prepared as described above) in methanol (27ml) and dimethyIformamide (27ml) was treated with platinum oxide (0.27g) and the shaken mixture was hydrogenated at room temperature and atmospheric pressure. When hydrogen uptake was complete, the mixture was filtered and the filtrate was evaporated vn vacuo. The residue was dissolved in dilute hydrochloric acid (2N; 50ml), the solution was filtered and tne filtrate was evaporated j_n vacuo. The resulting residue was washed with acetone, to give 4-amino-5-piperidinocarDonylimidazole nydrochloride (2.1g), in the form ot a pale green solid, m.p. 175-177°c, pure enough tor use in the next stage.
REFERENCE EXAMPLE 11 (i) A stirred solution of 2-cyanoethylbenzene (5.0g) and benzyl mercaptan (6.0g) in dry dioxan (50ml) was treated with hydrogen chloride gas until saturated (3 hours), and left to stand at room temperature for 5 days. The mixture was then treated with diethyl ether and the resulting precipitate was filtered off ana washed with diethyl ether, to give -benzyl 3-phenylpropionothioimidate hydrochloride (9.7g), in the form of a colourless solid, m.p. 156-160°C, pure enough for use in the next stage. (ii) A solution of x-amino-x-cyanoacetamide (3.3g) in ethanol (20tnl) was treated with crude S-benzy1-3-phenylpropionothioimidate hydrochloride (5.7g; prepared as described above) and the mixture was neated at reflux for 15 minutes. The mixture was .->2?2^ "" 205272 cooled and the resulting solid \ias filtered off and recrystallised from methanol, to give 5-amino-2-phenethylimidazole-4-carboxamiae hydrochloride (2.3g), in the rorm of colourless crystals, m.p. 270-274°C 5 (Elemental analysis: C , 53 . 6; H, 5 . 5 5 ; N , 21.1%; : HCl requires: C, 5 A . 0 ; H , 5 .6 7 ; N , 21.07» ] .
REFERENCE EXAMPLE 12 A solution of sodium nitrite (u.5g) in water (15ml) maintained at 0-5°C was treated dropwise with a — 10 solution of 5-amino-2-benzyl-4-carbamoylimidazole (1.26g; prepared as described in U.K. Patent Specification No 1421787) in dilute hydrochloric acid (2N;15ml). The mixture was stirred at 0°C for a further period of 30 minutes and the resulting pale 15 yellow solid was filtered ott, washed with water and dried in a desiccator over pnosphorus pentoxide, to give 2-benzyl-5-diazoimidazole-4-carboxamide (0.8g), m.p. 121-122°C (with decomposition) (l.R. 21b0cm~1].
REFERENCE EXAMPLE 13 20 (i) A solution of isobutyronitrile (6.9g) ana benzyl mercaptan (2Gml) in dry dioxan (100ml) was treated with dry hydrogen chloride gas for 3 hours at 0-10°C. The mixture was then allowed to warm to room ' temprature and the vessel was closed and allowed to stand at room temperature for 14 days. The mixture Pi t was then poured onto diethyl ether (1 litre) and thje£> h $ !;Z °i; \ - 10CT 1986r 60 - resulting white precipitate was filtered oft and washed with diethyl ether, to give S-benzyl isobutylthio-imidate hydrochloride (20.3g) , m.p. 165-lbb°C [Elemental analysis: C,57.1;H,7.0;N,5.9;Cl,15.7; S , 13 . 5%; Cj^H^NS :HC 1 requires: C , 5 7 . 5 ; H, 7 .02; N,6.1;C1, 15.43 ; S , i3 . 96%] . © (ii) A solution of ^<-amino-;x-cyanoacetamide (5.0g) ana S-benzyl isobutyIthioimidate hydrochloride (11.5g; prepared as described above) in dry 2-ethoxyethanol (150ml) was heated at retlux tor 30 minutes. The solvent was evaporated. The resulting dark oil was triturated with a mixture ot chloroform and methanol (4:i v/v; 100ml) ana the insoluble material was filtered orf and discarded. Tne filtrate was subjected to medium pressure chromatography on silica gel, eluting with a mixture of chloroform ana methanol (4:1 v/v). The appropriate fractions (identified with ninhydin spray on a sample, which gave an intense yellowish brown colour) were combined and evaporated, to give 5-amino-2-isopropy1imidazole-4- C~\ carboxamide hydrochloride (4.44g) in the form of a gummy solid, pure enough for use in the next stage. (iii) A solution ot sodium nitrite (G.5g) in water (5ml) maintained at 0°C was treated dropwise with a solution of crude 5-amino-2-isopropylimidazole-4-carboxamide hydrochloride (l.lg; prepared as descriDed above) in aqueous acetic acid (2N; 20ml). The _ 61 20Z2 mixture was then stirred for a turther period of 5 minutes ac 0°C and then was extracted with ethyl acetate (3 x 20ml). The combined extracts were dried over magnesium sulphate, concentrated in vacuo to a volume of 20ml, and subjected to medium pressure chromatography on silica gel, eluting with ethyl acetate. The appropriate tractions (identified with 2-naphthol spray on a sample, which gave a deep red colour) were combined ana evaporated to dryness, to give 5-diazo-2-isopropylimidazole-4-carboxamide (0.43g), m.p. 120°C (with decomposition) [l.R. 2170cm"i].
REFERENCE EXAMPLE 14 (i) A cooled, stirred solution ot 2-methyl- -nitroimidazole (127g) in aqueous sodium hydroxide solution (57o w/v; 1500ml) was treated witn bromine (I60g), maintaining the temperature at i5-20°C. The mixture was stirred at room temperature for 5.5 hours and the solid which had precipitated was redissolved by treatment ot the mixture with aqueous sodium nydroxide solution (2tt). Traces of insoluble material were filtered oft and the filtrate was acidified to pHi by treatment witn concentrated hydrochloric acid. The resulting white solid was filtered ott, recrystallised from ethanol and dried in a desiccator over phosphorus pentoxide, to give 4-bromo-2-methy1-5- 2 72 nitroimidazole (151g), in Che form oi a whice crystalline solid, m.p. 2b7-2bb°C. (ii) A sCirred soluCion ol 4-bromo-2-meChy1-5-nicroimidazole (20.bgms; prepared as described above) in aqueous ammonia soluCion (5N; 180ml) was warmed at 45°<J and creacea wich a sceaay scream of hydrogen sulphiae gas tor 4U minuCes. A yellow cryscalline solid was slowly tormed. The mixCure was coolea in ice and Che solid was tilcered ott, washed with ice-waCer, and dried in a desiccator over phosphorus pencoxide, to give 4-mercapto-2-methyl-5-nitroimidazole ammonium sale (14.6g), darkens wichout melcing below 300°C [.Elemental analysis: C,27.2;H,4.41;N,31.6; S , lb. TU\C^H^02N.jS : Nh^ requires: C.27 .27; 15 H,4.58;N,31.8;S,lb.2%]. (iii) An ice-cooled, vigorously scirred soluCion of 4-mercapto-2-metny1-5-nitroimidazole ammonium salt (3.51g; prepared as described above) in dilute hydrochloric acid (IN; 120ml) was treated with chlorine gas until a white solid had been formed. The mixture was stirred for a further period of 30 minutes at 0°C and then the solid was filtered off, washed with water and dried in a desiccaCor over phosphorus ^ pencoxide, Co give A-chlorosulphonyl-2-methyl-5- O nicroimidazole (3.0g); m.p. 160-lo2°C (wiCh decomposiCion) [Elemencal analysis: C,2u.8;H,1.73; N,18.3;Cl,15.7;S,14.b%; calculated: C,21.25;H,1.7S; N,18.63;Cl,15.72;S,14.21%]. (iv) A coolea solution ot 4-methoxybenzylamine (5.48g) in dry absolute ethanol (20ml) was treated with 4-chlorosu1 phony 1-2-methy1-5-nitroimidazole (2.25g; prepared as described above) and the mixture was stirred at room temperature tor 3 hours. The yellow solid which precipitated was filtered off, washed with ethanol and discarded as 4-methoxybenzy1-amine hydrochloride. The combined filtrate and washings were evaporated to dryness and the resulting residue was suspended in water (50ml), acidified to pHi by treatment with concentrated hydrochloric acid, and extracted with ethyl acetate (3 x 20ml). The combined extracts were dried over magnesium sulphate and evaporated to dryness, to give 4-(4-metnoxy-benzylsulphamoy1)-2-methyl-5-ni troimidazole (2 . 7 7g), in the form of an otf-white solid, m.p. 167-170°C [elemental analysis C,44.2;H,4.32;N,17.2;S,9.5%; calculated: C,44.17;H,4.32;N,17.17;S,9.83%]. (v) A solution of 4-(4-methoxybenzy1-sulphamoyl)-2-methyl-5-nitroimidazole (4.5g; prepared as described above) in dry ethanol (120ml) was hydrogenated at 3 atmospheres pressure over a Raney nickel catalyst for 30 minutes. The catalyst was filtered off ana washed with dry ethanol (10ml) and the combined filtrate and washings were acidified to - 64 - o r Z. , pHi by treatment with concentrated hydrochloric acid and evaporated to dryness. The resulting residue was triturated with diethyl ether, to give 5-amino-4-(4-methoxybenzyIsulphamoy1)-2-methylimidazole hydrochloride (3.25g); m.p. 183-185°C. (vi) A solution of sodium nitrite (0.3g) in water (5ml) maintained at 0-5°C was treated dropwise with a solution of 5-amino-4-(4-methoxybenzy1-sulphamoyl)-2-methylimidazole hydrochloride (l.Og; prepared as described above) in dilute hydrochloric acid (2ls; 10ml). The mixture was stirred for a further period of 5 minutes at 0-5°C and the resulting orange solid was filtered off, washed with water and dried in a desiccator over phosphorus pentoxide, to give 5-diazo-4-(4-methoxybenzylsulphamoy1)-2-methy1-imidazole (0.75g), m.p. 140°C (with decomposition) (l.R. 2200cm" 1J.
REFERENCE EXAMPLE 15 (i) An ethanolic solution of dimethylamine (337o w/v; 10ml) was cooled and stirred and treated portionwise with 4-chlorosulphonyl-2-methyl-5-nitro-imidazole (2.25g; prepared as described in Reference Example 14) and stirred at room temperature for a further period of 45 minutes. The solution was acidified to pHi by treatment with concentrated hydrochloric acid and the resulting white solid was filtered off and washed with cold water, to give 2 C - 2 4-dimethylsulphamoyl-2-methyl-5-nitroimidazole (1.5g), m.p. 240-241°C [Elemental analysis: C,30.5;H,4.24; N,23.8;S,13.6%; calculated: C,30. 77;H,4.3;N,23 . 52; 5,13.69%; NMR (in DMSO-d^); singlets at 2.30 and 2.80ppm]. (ii) A solution of 4-dimethylsulphamoyl-2-methyl-5-nitroimidazole (12g; prepared as described above) in dry ethanol (300ml) was hydrogenated at 3.5 atmospheres pressure over a Raney nickel catalyst for 1 hour. The catalyst was filtered off and the filtrate was acidified to pHi by treatment with concentrated hydrochloric acid and evaporated to dryness. The resulting orange residue was triturated with diethyl ether, to give 5-amino-4-dimethy1-sulphamoy1-2-methylimidazole (8.5g), m.p. 215-217°C (with decomposition). (iii) A solution of soaium nitrite (l.Og) in water (15ml) was maintained at 0°C and treated dropwise with a solution ot 5-amino-4-dimetnyl-sulphamoyl-2-methylimidazole (2.4g) in dilute hydrochloric acid (2N; 30ml), and stirred for a further period of 10 minutes at G°C. The mixture was extracted with ethyl acetate (5 x 30ml) and the combined extracts were dried over magnesium sulphate, evaporated to dryness and triturated with petroleum ether (b.p. 60-80°C), to give 5-diazo-4-dimethyl- sulpnamoy1-2-methylimidazole (l.og), m.p. 65-87°C (with decompositon) [l.R. 2180cm~*].
REFERENCE EXAMPLE 16 (i) A solution of 4-mercapto-2-methy1-5-nitro-imidazole ammonium salt (10.5g; prepared as described in Reference Example 14) in methanolic sodium methoxide solution [prepared by carefully dissolving sodium (2.3g) in dry methanol (250ml)J was treated with methyl iodide (10.7g) and heated at reflux tor 2 hours. The mixture was then evaporated to dryness and the residue was suspended in aqueous sodium hydroxide solution (2N; IGUml). The suspension was filtered and tne filtrate was acidified to pHi by treatment with concentrated hydrochloric acid, to give 2-methyl-4-methylthio-5-nitroimidazole (9.0g), in tne form of a yellow solid, m.p. 236-237°C (with decomposition) [Elemental analysis: C , 34 . 7 ; H , 4 .04; N , 24 . 3 ; S , 18 . 5%.; calculated: C, 34.67;H,4.07;N,24.26;S,L6 . 51% ]. (ii) A solution ot 2-methyl-4-methylthio-5- nitroimidazole (3.46g; prepared as described above) in glacial acetic acid (35ml) was heated at b0°C and treated dropwise with aqueous hydrogen peroxide solution (30% w/v; 35ml). The mixture was then heated at 100°C for 15 minutes, cooled to room temperature and treated with sufticient sodium sulphite to destroy the excess of hydrogen peroxide (detected by testing a sample with starch and potassium iodide). The mixture W w JL was then subjected to continous 1iquid-1 iquia extraction with ethyl acetate for 20 hours. The extract was evaporated and the remaining wnite solid was triturated with petroleum ether (b.p. 60-80°C) and filtered off, to give 2-methyl-4-methylsulphonyl-5-nitroimidazole (3.6g), m.p. 222-224°C (elemental analysis: C,29.8;H,3.28;N,20.6;S,15.7X; calculated: C,29.27;H,3.44;N,2G.46;S, 15.63%]. (iii) A solution of 2-methy1-4-methyl-sulphony1-5-nitroimidazole (4.9g; prepared as described above) in dry ethanol (400ml) was hydrogenated at 3.5 atmospneres pressure over a Raney nickel catalyst for 30 minutes. The catalyst was filtered off and the riltrate was acidilied to pH 1 by treatment with concentrated nydrochloric acid ana evaporated to dryness and the resulting residue was triturated with diethyl ether containing a trace of ethanol to give a purple solia which was filtered off and washed with diethyl ether, to give 5-amino-2-methy1-4-methylsulphonylimidazole hydrochlor iae (4.1g), m.p. above 300°C [Elemental analysis: C,27.3; H,4.51;N,19.9;C1,17.9;S,13.770; calculated: C,28.37; H,4.76;N,19.8;Cl,16.75;S,15.157o]. (iv) A solution of sodium nitrite (0.25g) in water (5ml), maintained at 0°C, was treatea dropwise with a solution of 5-amino-2-methy1-4-methylsulphony1- 2 0 _ imidazole hydrochloride (0.53g; prepared as aescribed above). The mixture was stirred for a furtner period of 15 minutes at 0°C and was extracted with ethyl acetate (5 x 15ml). The conjoined extracts were dried over magnesium sulphate and evaporated to dryness. The resulting oil was triturated with petroleum ether (d.p. 60-80°C) to give 5-diazo-2-methy1-4-methyl-sulphonylimidazole (0.4g), m.p. 100°C (with decomposition) [l.R. 2105cm"1"].
REFERENCE EXAMPLE 17 (i) A mixture of o<-cyano-N,N-dimethylacetamide (6.2g; prepared as described by Bowman £t aJL. , J. Chem Soc., 1554, 1171), acetic anhydride (21ml) and triethyl orthotormate (21ml) was heated at 160-170°C in a flask fitted witn a Mclntyre head for 90 minutes, during which time 26ml of ethyl acetate distillate was collected. The reaction mixture was concentrated in vacuo to give a dark oil, which was treated witn ethanol (10ml) and concentrated ni vacuo again. The residue was distilled at 160-170°C/0.5mmHg and then subjected to medium pressure chromatography on silica gel, eluting with ethyl acetate, to give 2-cyano-3-ethoxy-N,N-dimethylpropenamide (5.3g) in the form ot an off-white, oily solid, pure enough for use in the next stage. - 69 ' - 205272 (ii) A solution of crude^2-cyano-3-ethoxy-N,N-dimethylpropenamide (5.3g; prepared as describea above) in dry ethanol (50ml) was treated dropwise with hydrazine hydrate (1.53g). Alter the addition was complete the mixture was heated at reflux for 6 hours and then was evaporated to dryness. The residue was substituted to medium pressure chromatography on silica gel, eluting with a mixture of chloroform ana methanol (17:3 v/v) and the appropriate fractions were combined and evaporated to dryness. The resulting residue was dissolved in not isopropanol (5ml) and treated with concentrated hydrochloric acid (4ml) and the resulting crystalline precipitate was collected, to give 3-aminopyrazole-4-(N,N-dimethylcarboxamide) hydrochloride (1.39g), in the form of colourless crystals, m.p. 195°C. [Elemental analysis: C.37.8; h,5.82;n,29.U;Cl,lb.3%; calculated: C,37.6;H,5.82; N,29.39;C1, lts.6%; l.R. (KBr disc): 3500, 3400, 3000-2200, 1655cm"1; NMR (in DMSO-d^): singlets at 3.0 and 8.1ppm and broad singlet at 7.2ppmj. (iii) A saturated solution of dry hydrogen chloride in dry methanol (70ml) was treated with 3-aminopyrazole-4 - (N , N-d imethy lcar'boxamide) hydro-chloride (1.39g; prepared as described above). The stirred mixture was cooled to 0°C and treated with amyl nitrite (2.55g), dropwise during 15 minutes, i 70 2C5272 maintaining the temperature at 0°C. Trie resulting solution was left to stand at 2-4°C for 1* hour ana was then pourea into diethyl ether (bOGml). The resulting solid was colLectea and washed with diethyl etner, to 5 give 3-diazopyrazole-4-(N,N-dimethylcarboxamide) hydrochloride (0.52g), in the form of colourless crystals, m.p. 150°C (exploaes). [Elemental analysis: C,35.3;H,3.79;N,34.37<.;C^H-70N^C1;HC1 requires: C,35.74;H,4.00;N,34.74%; l.R. (KBr disc): 3000-2100, © 22S0, 1630cm"1). o - 71 29527 The present invention incLudes within its scope pharmaceutical compositions which comprise, as active ingredient, at least one compound of the general formula shown in Figure I, together witn a pharmaceutical carrier or coating. In clinical practice the compounds of the general formula shown in Figure I will normally be administered orally, rectally, parenterally, for example intraperitoneally or intravenously, e.g. by infusion, or vaginally.
Methods of presentation of pharmaceutical^ active compounds are well known in the art ana a suitable vehicle may be determined by the physician or pharmacist, depending upon such factors as the effect sought, the size, age, sex and condition of the patient and on the properties of the active compound. The compositions may also contain, as is usual in the art, such materials as solid or liquid diluents, wetting agents, preservatives, flavouring and colouring agents and the like.
Solid compositions tor oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid compositions one or more of the active compounds is, or are, admixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, or lactose. The compositions may also comprise, as is normal practice, additional 205272 substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups ana elixirs containing inert diluents commonly used in the art, such as water ana liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting and suspending agents, e.g. polyvinylpyrrolidone, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing one or more of the active substances with or without the addition of diluents or excipients.
Solid compositions for vaginal administration include pessaries formulated in manner known per se and containing one or more of the active compounds.
Solid compositions for rectal administration include suppositories formulated in manner known per se and containing one or more of the active compounas.
Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples ot non-aqueous solvents or suspending media are polyethylene glycol, dimethyl sulphoxide, vegetable oils such as olive oil, and injectable ._ organic esters such as ethyl oleate. These compositions may also include adjuvants such as preserving, wetting, emulsifying ana dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, or by irradiation. They may also be manufacturea in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
The percentage of active ingredient in the compositions ot the invention may be varied, it being necessary that it snoula constitute a proportion such that a suitable dosage for the therapeutic effect desired shall be obtained. Obviously several unit dosage forms may be administered at about the same time. In general, the preparations should normally contain at least 0.0257„ by weight of active substance when rquired for administration by injection, including administration by infusion; for oral administration the preparation will normally contain at least 0. L% by weight ot active substance. The dos employea depends upon the desired therapeutic effect, the route of administration ana the duration of the treatment. 205272 The tetrazine derivatives of general formula I are useful in the treatment of malignant neoplasms, for example carcinomas, melanomas, sarcomas, lymphomas and leukaemias, at doses which are generally between 0.1 and 200, preferably between 1 and 20, mg/kg body weight per day.
The following Composition Examples illustrate pharmaceutical compositions according to the present invention.
COMPOSITION EXAMPLE 1 A solution suitable for parenteral administration was prepared from the following ingredients:-6-(N-benzy1-N-phenylcar bamoy1)-3-me thy 1-[ 3H ] -imidazol5,1-d]- 1,2,3,5-tetrazin-4-one 1.0 g dimethyl sulphoxide 10 ml by dissolving the 6-(N-benzyl-^-pnenylcarbamoyl)-3-methyl-[3H ] -imidazo[5,l-d]-l,2,3,5-tetrazin-4-one in the dimethyl sulphoxide. The resulting solution was divided, under aseptic conditions, into ampoules at an amount of 1.1 ml per ampoule. The ampoules were sealed, to give 10 ampoules each containing 100 mg of 8-(N-benzy1-N-phenylcar bamoy1)- 3-methyl-[3H]-imidazo-{.5,1—d] —1,2,3, 5-tetraz in-4-one .
Similar ampoules containing solutions suitable for parenteral administration may be prepared by proceeding in a similar manner but replacing the 20527 2 8-(N-benzy1-N-phenylcarbamoy1-3-methy 1-[3HJ-imidazo-• [5,1-d]-1,2,3,5-tetrazin-4-one by another compound of the general formula shown in Figure I.
COMPOSITION EXAMPLE 2 5 A solution suitable for parenteral administration was prepared from the following ingredients:-w 3-(2-chloroethyl)-8-(N-methylsulphamoy1)-[3Hj- imiaazo (. 5 , 1-a ] - 1, 2 , 3 , 5-tetraz in-4-one 1.0 g dimethyl sulphoxide 10 ml aracnis oil 90 ml by dissolving the 3-(2-chloroethyl)-8-(N-methy1-sulphamoy1)-|.3HJ-imidazol5,l-dj-i,2,3,5-tetraz in-4-one in the dimethyl sulphoxide and adding the arachis oil. The resulting solution was divided, under 15 aseptic conditions, into ampoules at an amount of ml per ampoule. The ampoules were sealed, to give 10 ampoules each containing 100 mg ot 3-(2-chloro-ethyl)-8-(N-methylsulphamoy1)-[3H]-imidazoL5,1—d]-1,2,3,5-tetrazin-4-one.
Similar ampoules containing solutions suitable for v-" parenteral administration may be prepared by proceeding in a similar manner but replacing the 3-(2-chloroethyl)-8-(N-methylsulphamoy1) — [3H J — imiaazo-l5,1-d]-1,2,3,5-tetrazin-4-one by another compound of 25 the general formula shown in Figure I.
M9H&U 2 c „ COMPOSITION EXAMPLE 3 Capsules suitable for oral administration were preparea by placing 3-(2-chloroethy 1)-8-(N-methyl-sulphamoy1)-[3H]-imidazo[5,l-d]-l,2,3,5-tetraz in-4-one into gelatin shells of number 2 size at a rate of 10 mg per capsule.
Similar capsules may be prepared by using another compound of the general formula shown in Figure I or any other conveniently sized capsule snells. - \ % n . - 2052 72 o PIG. I FIG. II /A V-< r12 n2® fig. ill 'O'" ,15 ,16 n; *n Sk V V 0 n y\, II i R Z fig. vi fig. vii 3£y 20o272 205272 < • - o

Claims (5)

WHAT WE CLAIM IS:-
1. Tetrazine derivatives of the general formula: R2 * f"*7 z R1 ^herein R^ represents a cycloalkyl group containing 3 to 8 carbon atoms, or a straight- or branched-chain alkyl, 5 alkenyl or alkynyl group containing up to 6 carbon atoms, each such alkyl, alkenyl or alkynyl group being unsubstituted or substituted by from one to three substituents selected from halogen atoms, straight- or branched-chain alkoxy, aikylthio, alkylsulphinyl and alkylsulphonyl groups 10 containing up to k carbon atoms, and optionally substituted phenyl groups, A^" represents a nitrogen atom or a group -CR^= wherein represents a hydrogen atom or a substituent k k R wherein R represents a halogen atom, or a straight- or branched-chain alkyl or alkenyl group, containing up to 6 15 carbon atoms, which may carry up to 3 substituents selected from halogen atoms, optionally substituted phenyl groups, straight- or branched-chain alkoxy, aikylthio and alkyl- 4 sulphonyl groups containing up to 3 carbon atoms, or R • ' is f«i ' n . represents a cycloalkyl group containing 3 to 8 carbon -atoms, c ' ' * si' h '■ jjZ 1 "" ? ] f986 - 79 - a cyano, hydroxy, nitro or optionally substituted phenoxy 5 5 group, or a group of the formula -COR (wherein R represents an alkyl or alkoxy group of up to 4 carbon atoms, a hydroxy group, or an optionally substituted phenyl group) or an 5 alkanoylamino group containing up to 6 carbon atoms, or *4 6 7 8 R represents a group of the formula -S(0)nR , -SC>2NR R 2 7 8 6 or -CZ NR R (wherein n represents 0, 1 or 2, R represents a straight- or branched-chain alkyl or alkenyl group, containing up to 4 carbon atoms, which may carry an 10 optionally substituted phenyl substituent, a cycloalkyl group containing 3 to 8 carbon atoms or an optionally 7 8 substituted phenyl group, R and R , which may be the same or different, each represents a hydrogen atom or a straight- or branched-chain alkyl or alkenyl group, 15 containing up to h carbon atoms, which may carry an optionally substituted phenyl substituent or a cycloalkyl group containing 3 to 8 carbon atoms or an optionally 7 8 substituted phenyl group or the group -NR R represents a 2 heterocyclic group, and Z represents an oxygen or sulphur 2 1 20 atom), A represents a nitrogen atom or, when A represents 2 a nitrogen atom, A represents a nitrogen atom or a group 3 3 1 -CR = wherein R is as hereinbefore defined, Z represents 2 an oxygen or sulphur atom, and R represents a group of the formula -S(0) R6, -SO.,NR7R8, -CSNR7R8, -CONR7R9 or n 2. 2 ~~ 6 7 8 2 25 -CZ NHNC>2< wherein n, R , R , R and Z are as hereinbefore 7 9 defined, and the group -NR R represents a heterocyclic 2l)r>272 ' 1 205272 - 80 - 7 . 9 group, or R is as hereinbefore defined and R represents a straight- or branched-chain alkyl or alkenyl group containing up to 4 carbon atoms which carries an optionally substituted phenyl substituent, or an optionally substituted 5 phenyl group or, when A^" represents a nitrogen atom or a ^ ^ 1 group -CR = wherein R is as hereinbefore defined and 2 and A2 are as hereinbefore defined or, when A^" represents 1 2 a group -CH= and Z represents a sulphur atom and A is 2 as hereinbefore defined, R represents a group of the 10 formula -S(0)nR6, -SC>2NR7R8, -CZ2NR7R8 or CZ2NHNC>2 wherein 6 7 8™" 2 n, R , R , R and Z are as hereinbefore defined] and, 2 when R represents a sulphamoyl or monosubstituted ■3 sulphamoyl group and/or R represents a sulphamoyl, monosubstituted sulphamoyl or carboxy group, salts thereof. 15 2. Tetrazine derivatives according to claim 1 1 2 wherein R is as defined in claim 1, R represents a carbamoyl group optionally substituted on the nitrogen atom by one or two groups selected from straight- and branched-chain alkyl and alkenyl groups, containing up to 20 ^ carbon atoms, and cycloalkyl groups containing 3 to 8 1 4.4 carbon atoms, A represents a group -CR = wherein R represents a straight- or branched-chain alkyl or alkenyl group containing up to 6 carbon atoms, which may carry up to 3 substituents selected from halogen atoms and 25 optionally substituted phenyl groups, or R represents a 2 cycloalkyl group containing 3 to 8 carbon atoms, A ' represents a nitrogen atom, and Z^~ represents an oxygen'■atom. v' f**10CTI986
2 C 527 2 - 81 -
3.Tfetrazine derivatives according to claim 1, 1 2 wherein R is as defined in claim 1, R represents a group of the formula -SCOl^R^ or -SC^NR^R®, wherein n represents 0, 1 or 2, R^ represents a straight- or 5 branched-chain alkyl or alkenyl group, containing up to k carbon atoms, which may carry an optionally substituted phenyl substituent, a cycloalkyl group containing 3 to 8 carbon atoms or an optionally 7 8 substituted phenyl group, R and R , which may be the 10 same or different, each represents a hydrogen atom or a straight- or branched-chain alkyl or alkenyl group, containing up to 4 carbon atoms, which may carry an optionally substituted phenyl substituent, or a cycloalkyl group containing 3 to 8 carbon atoms, or an optionally 15 substituted phenyl group, represents the group =CH-, 2 1 A represents a nitrogen atom, and Z represents an oxygen atom.
4. Tetrazine derivatives according to claim 1 1 2 wherein R is as defined in claim 1, R represents a group 20 of the formula -S(0)nR^, -SC^NR^R8 or -CZ2NR7R8 (wherein n represents 0, 1 or 2, R represents a straight- or branched-chain alkyl or alkenyl group, containing up to k carbon atoms, which may carry an optionally substituted phenyl substituent, a cycloalkyl group containing 3 to 8 25 carbon atoms, or an optionally substituted phenyl group, 7 8 R and R , which may be the same or different, each 2l)r>272 2o51?2 - 82 - represents a hydrogen atom or a straight- or branched-chain alkyl or alkenyl group, containing up to k carbon atoms, which may carry an optionally substituted phenyl substituent, or a cycloalkyl group containing 3 to 8 5 carbon atoms, or an optionally substituted phenyl group), 1 2 A represents a nitrogen atom, A represents a group 3 3 -CR =, wherein R represents a hydrogen atom or a 4 1 substituent R as defined in claim 1, and Z represents an oxygen or sulphur atom. 10 5. Tetrazine derivatives according to claim 1 1 2 wherein R is as defined in claim 1, R represents a carbamoyl group which carries on the nitrogen atom (i) two groups selected from optionally substituted phenyl groups and optionally substituted phenylalkyl groups; 15 or (ii) one optionally substituted phenyl or optionally substituted phenylalkyl group; or (iii) one optionally substituted phenyl or optionally substituted phenylalkyl group and a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, A^" represents the 2 1 20 group =CH-, A represents a nitrogen atom, and Z represents an oxygen atom.
6. Tetrazine derivatives according to any one of claims 1 to 5 in which the optional substituents on phenyl and phenoxy groups are selected from halogen atoms, 25 alkyl and alkoxy groups containing up to k carbon atoms, and the nitro group. ^ ^ v. lf-1 OCT 1986 20D2?2^1 " 2o52-?2 83
7. Tetrazine derivatives according to any one of claims 1 to 6 in which the cycloalkyl group referred to is cyclohexyl.
8. Tetrazine derivatives according to claim 1 5 in which the heterocyclic group referred to is a 5-, 6- or 7-membered heterocyclic group containing the nitrogen atom which may optionally carry a further hetero atom selected from nitrogen, oxygen and sulphur, and which may carry one or two straight- or branched-10 chain alkyl substituents each containing up to 4 carbon atoms.
9. Tetrazine derivatives according to claim 1 which have one or more of the following features: (i) R"*" represents a methyl or 2-haloethyl group; 15 2 6 (ii) R represents a group of the formula -SOR , -S02R6, -S02NR7R8, -CONR7R8 or -C0NHN02, 6 7 8 wherein R , R and R are as defined in claim 1; 1 2 (iii) one of A and A represents a nitrogen atom and the other represents a group -CR^= wherein R^ is as defined in claim 1; 20 3 4 4 (iv) R represents a substituent R wherein R represents an alkyl group containing up to 25 6 carbon atoms; 2 (v) A represents a nitrogen atom; (vi) 7?~ represents an oxygen atom; and/or 2 (vii) Z represents an oxygen atom. s i '^-T0CT!986^ o . 2 o r i / - 84 -
10. Tetrazine derivatives according to claim 9 wherein R* represents the 2-chloroethyl group.
11. Tetrazine derivatives according to claim 9 wherein R2 represents a group -SOR6, -S02R6, -S02NR7R8, 7 8 6 5 -CONR R or -C0NHN02 wherein R represents an alkyl group containing up to 4 carbon atoms, R7 represents a hydrogen atom or an alkyl group containing up to 4 carbon g atoms, and R represents a hydrogen atom, an alkyl group containing up to 4 carbon atoms, or a benzyl group 10 optionally substituted by an alkoxy group.
12. Tetrazine derivatives according to claim 9 or 11 in which the alkyl group is methyl.
13. 8-Carbamoyl-3-(2-chloroethyl)-6-methyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. 15 14. 3-(2-Chloroethyl)-6-methyl-8-sulphamoyl-[3H]- imidazo[5,l-d]-l,2,3,5-tetrazin-4-one.
15. 3- ( 2-Chloroethyl) -8-dimethylsulphainoyl-6-methyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one.
16. 3-(2-Chloroethyl)-8-(dimethylcarbamoyl)-[3h]-20 pyrazolo[5,l-d]-l,2,3,5-tetrazin-4-one.
17. 3-(2-Chloroethyl)-8-(N,N-dimethylsulphamoyl)-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one.
18. 3-(2-Chloroethyl)-8-(N-methylsulphamoyl)-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. 25 19. 3-(2-Chloroethyl)-8-sulphamoyl-[3H]-imidazo le5 ,l-d]-l,2,3,5-tetrazin-4-one. - 85 -
20. 3-(2-Chloroethyl)-6-methyl-8-methylsulphonyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. 21- 8-(N-Benzylcarbamoyl)-3-(2-chloroethyl)-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. 5 22. 3-(2-Chloroethyl)-8-methylsulphonyl-[3H]- imidazo-[5,l-d]-l,2,3,5-tetrazin-4-one.
23. 3-Methyl-8-methylsulphonyl-[3H]-imidazo-[5,l-d]-l,2,3,5-tetrazin-4-one. 2b. 3-(2-Chloroethyl)-8-[N-(4-methoxybenzyl)-10 sulphamoyl]-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one.
25. 8-Carbainoyl-3 -( 2-chloroethyl )-[3H]-pyrazolo-[5,l-d]-l,2,3,5-tetrazin-4-one.
26. 3-(2-Chloroethyl)-8-piperidinocarbonyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. 15 27. 6-Butyl-8-carbamoyl-3-(2-chloroethyl)-[3h]~ imidazo[5,l-d]-l,2,3,5-tetrazin-4-one.
28. 8-Carbamoyl-3-(2-chloroethyl)-6-propyl-[ 3H]-irnidazo[ 5 , l-d]-l, 2 , 3 ,5-tetrazin-4-one.
29. 8-Carbamoyl-3-(2-chloroethyl)-6-ethyl-[3H]-20 imidazo[5,1- d]-l,2,3,5-tetrazin-4-one.
30. 3-(2-Chloroethyl)-8-(N-nitrocarbamoyl)-[3h]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one. - 86 -
31. 8-(N-Benzyl-n-phenylcarbamoyl)-3-methyl-[3H]~ imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 8-[n-benzy1-n-(4-methoxybenzyl)carbamoyl]-3-(2-chloroethyl)-[3h]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 3-(2-chloroethyl )-5 8-[n-(4-methoxybenzy1)-n-phenylcarbamoyl]-[3H]-imidazo-[5,l-d]-l,2,3,5-tetrazin-4-one, 3-(2-chloroethyl)-8-(N-phenylcarbamoyl)-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 8-(n-benzyl-n-phenylcarbamoyl)-3-(2-chloroethyl)-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 3-(2-chloro-10 ethyl)-8-(N-methyl-n-phenylcarbamoyl)-[3H]-imidazo-[5,l-d]-l,2,3,5-tetrazin-4-one, 8-carbamoyl-3-methyl-[3H]-pyrazolo[5,1-d]-1,2,3,5-tetrazin-4-one, 8-carbamoyl-3-(2-chloroethyl)-6-cyclohexyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 8-carbamoyl-3-(2-chloroethyl)-6-phenethyl-15 [3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 6-benzyl-8-carbamoyl-3-(2-chloroethyl)~[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 8-carbamoyl-3-(2-chloroethyl)-6-isopropyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 3-(2-chloroethyl )-8-(4-methoxybenzy1)sulphamoyl-6-methyl-[3H]-20 imidazo[5,l-d]-l,2,3,5-tetrazin-4-one, 3-methyl-8-methyl-sulphonyl-[3H]-pyrazolo[5,l-d]-l,2,3,5-tetrazin-4-one, 3-(2-chloroethyl)-8-methylsulphonyl-[3H]-pyrazolo-[5,l-d]-l,2,3,5-tetrazin-4-one, 3-(2-chloroethyl)-6-methyl-8-methylsulphinyl-[3H]-imidazo[5,l-d]-l,2,3,5-tetrazin-4-25 one, 3-(2-chloroethyl)-8-ethylsulphonyl-6-methyl-[3H]- imidazo[5,l-d]-l,2,3,5-tetrazin-4-one and 3-(2-chloroethyl)-6-methyl-8-propylsulphonyl-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one. I , \ . - . - 20*272 - 87 -
32. A process for the preparation of tetrazine derivatives of the general formula depictad in—claim 1, wherein R is other than a sulphamoyl, mono(optionally substituted phenyl)carbamoyl or mono(optionally substituted 5 phenyl)thiocarbamoyl, nitrocarbamoyl or nitrothiocarbamoyl group,which comprises reacting a compound of the general formula: 12 12 (wherein A and A are as defined in claim 1, and R 2 10 represents a group within the definition of R in claim 1 other than a sulphamoyl, mono(optionally substituted phenyl)carbamoyl or mono(optionally substituted phenyl)-thiocarbamoyl, nitrocarbamoyl or nitrothiocarbamoyl group) with a compound of the general formula: 15 R^CZ1 wherein R^" and Z^" are as defined in claim 1.
33. A process for the preparation of a tetrazine derivative of the gsneral formula depicted in claim 1 wherein R represents a sulphamoyl, monosubstituted 20 sulphamoyl, carbamoyl, monosubstituted carbamoyl, thiocarbamoyl or monosubstituted thiocarbamoyl group, 112 1 and R , A , A and Z are as defined in claim 1, which comprises the debenzylation of a compound of the generS&'i fcrt f Cj.. formula: 'v **rv - I - 88 - 20*272
3. os 2.92 R17 /WN^ V ' 1 v.ky»xr1 z1 (wherein R^"7 represents a group -S02N7R^ or CZ2NR7R13 wherein, R"*"3 represents an optionally 2 7 substituted benzyl group and Z and R 5 are as defined in claim 1) by the application or adaptation of methods known per se for the replacement of optionally substituted benzyl groups by hydrogen atoms.
34. A process for the preparation of a tetrazine derivative of the general formula depicted in claim 1 112 1 10 wherein R , A , A and Z are as defined in claim 1 and 2 2 2 R represents a group of the formula -CZ NHNC>2, Z being as defined in claim 1, which comprises the nitration of a corresponding compound of the general formula: 15 (wherein Z2, R^", A^", A2 and Z^" are as defined in claim 1) 2 2 to convert the grouping -CZ NH2 to -CZ NHN02. ..-cvC/V fc N A j-Ov £'V t\ {J 2 °l> \ T OCT 1986 * , 205272 t - 89 -
35. A process for the preparation of a tetrazine derivative of the general formula depicted in claim 1, 112 2 wherein R , A , A and R are as defined in claim 1 and represents a sulphur atom, which comprises reacting 5 a compound of the general formula: .15 11 2 (wherein R , A and A are as defined in claim 1, and 15 6 R represents a group of the formula -S(0)nR , -S02NR7R8, -CZ2NR7R8 or -CZ2NHN02, R6, R7, R8. n and 10 Z2 being as defined in claim 1) with phosphorus pentasulphide to convert the moiety to^ C ii ii 0 S
36. A process for the preparation of a tetrazine derivative of the general formula depicted in claim 1, 112 1 wherein R , A , A and Z are as defined in claim 1 and 2 7 8 15 R represents a group of the formula -CSNR R wherein 7 8 R and R are as defined in claim 1, which comprises reacting a corresponding compound of the general formula: CONR7R8 ; ENTX -1 OCT 1986 . < C p \ ' \ to 20n27^ - 205^2 • O - 90 - 112 17 8 (wherein R , A , A , Z , R and R are as defined in claim 1) with phosphorus pentasulphide to convert the 7 8 7 8 grouping -CONR R to -CSNR R .
37. A process according to any of claims 32 5 to 36 wherein the tetrazine product obtained is a compound of the general formula depicted in claim 1 wherein R represents a sulphamoyl or mono-substituted sulphamoyl group and/or R^ represents a sulphamoyl, monosubstituted sulphamoyl or carboxy group, 10 and the product is converted by a method known per se into a salt.
38. Pharmaceutical compositions which comprise, as active ingredient, at least one tetrazine derivative as claimed in any one of claims 1 to 31 in association 15 with a pharmaceutical carrier or coating.
39. Pharmaceutical compositions according to claim 38 siibstantially as hereinbefore described with especial reference to Composition Example 1, 2 or 3.
40. Tetrazine derivatives of the general formula 12 12 1 20 depicted in claim 1, wherein R , R , A , A and Z are as defined in claim 1, for use in the treatment of malignant neoplasms such as carcinomas, melanomas, sarcomas, lymphomas and leukaemias. .■"-S ~.\:Z£D TK!3 j DAY CF Ocfe-(j^.19 §£ a. j i son r-ta AGui'JT
S FOH THE A^FLIQMlfS 0> // ijN 'Z- 10CT 1986 h ^ ^ ,-o;' V.^C £ I \i ^
NZ205272A 1982-08-17 1983-08-15 Tetrazine derivatives and pharmaceutical compositions NZ205272A (en)

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DK (1) DK374983A (en)
ES (1) ES8502441A1 (en)
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GR (1) GR78688B (en)
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IE (1) IE55849B1 (en)
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OA07174A (en) * 1981-08-24 1984-04-30 May & Baker Ltd New imidazotetrazionones, their preparation and medicines containing them.

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AU575782B2 (en) 1988-08-11
HU189321B (en) 1986-06-30
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FR2531958A1 (en) 1984-02-24
DK374983D0 (en) 1983-08-16
IT8322566A0 (en) 1983-08-16
CA1254563A (en) 1989-05-23
SE455198B (en) 1988-06-27
IL69500A (en) 1989-01-31
GR78688B (en) 1984-09-27
FR2531958B1 (en) 1986-10-31
FI832927A0 (en) 1983-08-15
FI832927A (en) 1984-02-18
FI80273C (en) 1990-05-10
NL8302863A (en) 1984-03-16
ES8502441A1 (en) 1985-01-01
DK374983A (en) 1984-02-18
IT1194375B (en) 1988-09-22
DE3329505A1 (en) 1984-02-23
AU1796883A (en) 1984-02-23
IE55849B1 (en) 1991-01-30
SE8304415L (en) 1984-02-18
BE897548A (en) 1984-02-17
SE8304415D0 (en) 1983-08-15
FI80273B (en) 1990-01-31
IE831913L (en) 1984-02-17
LU84969A1 (en) 1984-03-23

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