Note: Descriptions are shown in the official language in which they were submitted.
-- 1 --
- DESC~IPTION
"NEW TET~AZINE ~ERIVATIVES"
This invention relates to ne~ tetrazine
derivatives, to processes for their preparation and to
pharmaceutical compositions containing them.
The compounas of the present invention are
the tetrazine derivatives of the general formula shown
in Figure I of the drawings assembled at the end of
the present speci~ication Lwherein Rl represents a
cycloalkyl group, or a straight- or branched-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.
bromine, iodine or, pre~erably, chlorine or fluorine)
atoms, straight- or branched-chain alkoxy, alkylthio,
alkylsulphinyl and alkylsulphonyl groups containing up
to 4 carbon atoms, and optionally substituted phenyl
groups, Al represents a nitrogen atom or a group
-CR3= wnerein R3 represents a hydrogen atom or a
substituent R4 wherein R4 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
halogen atoms, optionally substituted phenyl groups,
straight- or branched-chain alkoxy, alkylthio and
-- 2
alkylsulphonyl groups containing up to 3 car~on atoms,
or R~ represents a cycloal~yl, cyano, hyciroxy, nitro
or optionally substituted phenoxy group or a ~roup of
the formula -CoR5 (wherein R5 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 R4 represents a group of the formula
(O)nR , -So2NR7R8 or -CZ2NR7R8
(wherein n represents 0, 1 or 2, R~ represents a
straight- or branched-chain alkyl or alkenyl group,
containing up to 4 car~on atoms, which may carry an
optionally substituted phenyl substituent, a
cycloalkyl group or an optionally substituted phenyl
group, R7 and R8, which may be the same or
different, each represents a hydrogen atom or a
straigbt- 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 or an optionally substitutea phenyl
group or the group -NR7R8 represents a heterocyclic
group, and Z~ represents an oxygen or sulphur atom),
A2 represents a nitrogen atom or, when Al
represents a nitrogen atom, A2 represents a nitrogen
atom or a group -CR3= wherein R3 is as
hereinbefore defined, zl represents an oxygen or
3 ~2~ 3
sulphur atom, and R2 represents a group o~ the
formula -S(o)nR5~ -S02NR7R&, -CSNR7P~,
-CoNR7R9 or -CZ2NHN~2 wherein n, K6, K7,
R~ and z2 are as hereinbefore defined, and the
group -NR7R9 represents a heterocyclic group or
R7 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 phenyl group or, when Al
represents a nitrogen atom or a group -CR4= wherein
R4 is as hereinbefore defined and zl and A2 are
as hereinbefore defined or, when Al represents a
group -CH= and zl represents a sulphur atom and A2
is as herein~efore defined, R2 represents a group of
the formula -S(O)nR6, -So2NR7R8, -CZ2NR7R8
or CZ2NHN02 wherein n, R6, R7, R8 ana z2 are
as hereinbefore defined~ and when R2 and/or R3
represents a sulphamoyl or monosubstituted sulphamoyl
group and/or R3 represents a carboxy group, salts
thereof, more especially alkali metal, e.g. sodium,
salts. Whenever the context so permits reference in this
specification to the compounds o~ the ~eneral formula
shown in Figure I is meant to incluae reference to the
said salts. The salts are particularly useful as
intermediates.
q~
-- 4 --
Within the definition of the forrnula showrl in
Figure I the optional substituents on the phenyl and pherloxy
moieties may be selected frorn, for example, haloyen atorrls
and alkyl and alkoxy groups containing up to 4 carbon atoms,
and nitro groups. Cycloalkyl groups wit~lin 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 a 5-, 6- or 7-membered
heterocyclic ring 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 substitu-
ents each containing up to 4 carbon atoms, e.g. a piperidino
group or a 2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-,
or 3,5-dimethylpiperidino group, or a morpholino,
pyrrolidin-l-yl, perhydroazepin-1-yl, piperazin-l-yl, 4-
methylpiperazin-l-yl or 1,4-thiazin-4-yl group.
~y
- 4a -
Therefore, the invention relates to a process for
the preparation of tetrazine de~iva~ives of the ge~neral
formula:
~ N~
\~1 N ~ ~
zl ~R
Cwherein R1 represents a cycloalkyl group containing 3 to 8
carbon atoms, or a straight- or branched-chain alkyl,
alkenyl or alkylnyl group containing up to 6 carbon atoms,
each such alkyl, alkenyl or alkylnyl group being unsubsti-
tuted or substituted by from one to three substituents
selected from the group consisting of halogen atoms,
straight- or branched-chain alkoxy, alkylthio, alkylsulphi-
nyl and alkylsulphonyl groups containing up to 4 carbon
atoms, and phenyl groups(unsubstituted or substituted by one
or more substituents selected from the group consisting of
haloyen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group); Al represents a nitrogen atom or a group -CR
wherein R3 represents a hydrogen atom or a substituent R4
wherein R4 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 the group consisting of halogen atom, phenyl group,
phenyl group substituted by one or more substituents
selected from the group consisting of halogen atoms, alkyl
group containing up to 4 carbon atoms, alkoxy group
- 4b -
containing up to 4 carbon atoms and nitro group, straight-
or branched-chain alkoxy, alkylthio and alkylsulphonyl
groups containing up to 3 carbon atoms, or r~4 represents a
cycloalkyl group containing 3 to 8 carbon atoms, a cyano,
hydroxy, nitro, phenoxy group or phenoxy group substituted
by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group, or a group of the formula -CoR5 (wherein R
represents an alkyl or alkoxy group of up to 4 carbon atoms,
a hydroxy group, a phenyl group or a phenyl group substi-
tuted by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group~ or an alkanoylamino group containing up to
6 carbon atoms, or R4 represents a group of the formula
-S(O)nR6, -So2NR7R8 or -CZ2~R7R8 (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 a phenyl substituent(unsubstituted or substituted by
one or more substituents selected from the group consisting
of halogen atoms, alkyl group containing up to 4 carbon
atoms, alkoxy group containing up to 4 carbon atoms and
nitro group),a cycloalkyl group containing 3 to 8 carbon
atoms or a phenyl group(unsubstituted or substituted by one
or more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group~ R7 and R8, 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 a phenyl substituent (unsubstituted or
substituted by one or more substituents selected from the
group consisting of halogen atoms, alkyl group containing up
- 4c -
to 4 carbon atoms, alkoxy group containing up to 4 carbon
atoms and nitro group) or a cycloalkyl group containing 3 to
8 carbon atoms or a phenyl group (unsubstituted or substi-
tuted by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group) or the group -NR7R3 represents a 5,6 or 7
membered heterocyclic ring which may contain a further
heteroatom selected from the group consisting of nitrogen,
oxygen and sulfur, said heterocyclic ring being unsubsti-
tuted on substituted by one or two substituents selected
from the group consisting of straight- or branched- chain
alkyl substituents each containing up to 4 carbon atoms, and
Z represents an oxygen or sulphur atom)t A represents a
nitrogen atom or, when A1 represents a nitrogen atom, A
represents a nitrogen atom or a group -CR3= wherein R3 is as
hereinbefore defined, zl represents an oxygen or sulphur
atom; and R represents a group of the formula -S(o) R ,
-So2NR7R8, -CSNR7R8, -CoNR7R9 or -CZ NHN02, wherein n, R,
20 R7, R8 and z2 are as hereinbefore defined, and the group
-NR7R9 represents a 5,6 or 7 membered heterocyclic ring
which may contain a further heteroatom selected from the
group consisting of nitrogen, oxygen and sulfur, said
heterocyclic ring being unsubstituted or substituted by one
or two substituents selected from the group consisting of
straight- or branched-chain alkyl substituents each
containing up to 4 carbon atoms, or R7 iS as hereinbefore
defined and R9 represents a straight- or branched-chain
alkyl or alkenyl group containing up to 4 carbon atoms which
carries a phenyl substituent(unsubstituted or substituted
by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group) or a phenyl group(unsubstituted or substi-
- ~d -
tuted by one or more substi.tuerlts selected frorn th~ group
consisting of halogen atoms, alkyl group containirlg up to 4
carbon atoms, alkoxy group contai.nirlg up Lo ~ carboll atoms
and nitro group) or, when Al represerlts a nitro(3en a~oM or ~
group -CR4= wherein R4 is as hereinbefore defined and zl and
Z are as hereinbe~ore defined or, when A1 represents a
group -CH= and zl represents a sulphur atom and z2 is as
hereinbefore defined, R2 represents a group of the formula
-S(O)nR6, -So2NR7R8, -CZ2NR7R8 or CZ2NHNO2 wherein n, R6,
R ,R and Z are as hereinbefore defined~ and, when RZ
and/or R3 represents a sulphamoyl or monosubstituted
sulphamoyl group and/or R3 represents a carboxy group;
pharmaceutically acceptable salts thereof; excluding the
derivatives of formula (I) in which Al represents a group
-CR3= wherein R3 represents a hydrogen atom, A2 represents a
nitrogen atom and either Rl represents a straight- or
branched-alkyl, alkenyl or alkynyl group containing up to 6
carbon atoms, each such alkyl, alkenyl or alkynyl group
being unsubstituted or substituted by from 1 to 3 substi-
tuents selected from the group consisting of halogen atoms,
straight-or branched-alkoxy, alkylthio, alkylsulfinyl and
alkylsulfonyl groups containing up to 4 carbon atoms and
phenyl group(unsubstituted or substituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group),or Rl
represents a cycloalkyl group containing 3 to 8 carbon atoms
and R2 represents a carbamoyl group which is substituted on
the nitrogen atom i) by two groups selected from the group
consisting of phenyl group, phenyl group substituted b~ one
or more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group, phenylalkyl group and phenylalkyl group substituted
~, ~
~ ~r~
- 4e -
by one or more substituents selected frorn the group
consisting of halogen atoms, alkyl group contairliny up to 4
carbon atoms, alkoxy group containing up to ~ carbon atorns
and nitro group; or ii) a phenyl group substituted by one or
more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group, or a phenylalkyl group substituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon a~oms, alkoxy
group containing up to 4 carbon atoms and nitro group, or
iii) a phenyl group (unsubstitu-ted or substituted by one or
more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group) or a phenylalkyl group substituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group, and a
straight- or branched- alkyl group containing up to 4 carbon
atoms; which comprises:
(A) in the case of a tetrazine derivative of general formu~a
(I) wherein R2 is other than a sulphamoyl, monophenylcarba-
moyl, monophenylcarbamoyl substituted on the phenyl moiety
by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group, monophenylthiocarbamoyl, monophenylthio-
carbamoyl substituted on the phenyl moiety by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group,
nitrocarbamoyl or nitrothiocarbamoyl group, and Rl, A1, A2
and zl are as hereinbefore defined, reacting a compound of
the general formula:
.i
~ .
~A~N~
~ (ILL)
Rl/2 N2~3
(wherein Al and A2 are as hereinbefore defined and R
represents a group within the abovementioned definition of
R in relation to general formula (I) other than a
sulphamoyl, monophenylcarbamoyl, monophenylcarbamoyl
substituted on the phenyl moiety by one or more substituents
selected from the group consisting of halogen atoms, alkyl
group containing up to 4 carbon atoms, alkoxy group
containing up to 4 carbon atoms and nitro group,
monophenylthiocarbamoyl, monophenylthiocarbamoyl substituted
on the phenyl moiety by one or more substituents selected
from the group consisting of halogen atoms, alkyl group
containing up to 4 carbon atoms, alkoxy group containing up
to 4 carbon atoms and nitro group, nitrocarbamoyl or
nitrothiocarbamoyl group, with a compound of the general
formula:
R NCZ (IV)
wherein Rl and zl are as hereinbefore defined, or
(B) in the case of a tetrazine derivative of general formula
(I) wherein R2 represents a monophenylcarbamoyl, a
monophenylcarbamoyl substituted on the phenyl moiety by one
or more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group, a monophenylthiocarbamoyl, a monophenylthiocarbamoyl
substituted on the phenyl moiety by one or more substituents
selected from the group consisting of halogen atoms, alkyl
~5~
'I g
group containing up to 4 carborl atoms, alkoxy group
containing up to 4 carbon atoms and nitro g~oup, and R], ~ ,
A2 and zl are as hereinbefore defined in relatiorl to that
formula, the debenzylation of a cornpound of the general
formula: SO NR7R13 CZ NR R
~ N~ l
Z
(wherein R7 is as hereinbefore defined, R13 represents
benzyl group or a benzyl group sustituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group, and
z2 is as hereinbefore defined) by the application or
adaptation of methods known ~ se for the replacement of a
benzyl group or a benzyl group substituted on the phenyl-
moiety by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group, by a hydrogen atom, or
(C) in the case of a tetrazine derivative of general formula
(I) wherein Rl, Al, A2 and zl are as hereinbefore defined in
relation to that formula and R2 represents a group of the
formula -CZ2NHNO2, z2 being as hereinbefore defined, the
nitration of a corresponding compound of the general
formula:
J~I
- 4h --
CZ N112
~) ~ 7
~ R (VA)
(wherein Z , R , A , A and zl are as hereinhefore defined
in relation to general formula (I)), to convert the grouping
-CZ NH2 to -CZ2NHNO2, or,
(D) in the case of a tetrazine derivative of general formula
(I) wherein R1, Al, A2 and R2 are as hereinbefore defined in
relation to that formula and zl represents a sulphur atom,
reacting a compound of the general formula:
RlS
A2 ~ ~ (VI)
(wherein R1, A1 and R2 are as hereinbefore defined in
relation to general formula (I), and R15 represents a group
of the formula -S(O) R6, -So2NR7R8, -CZ2NR7R8 or -CZ2NHNO
R6, R , R , n and Z being as hereinbefore defined in
relation to general formula (I)) with phosphorus penta-
sulphide to convert the
\C~ moiety to ~C/ , or
O ls~
(E) in the case of a tetrazine derivative of general formula
(I) wherein R1, A1, A2 and zl are as hereinbefore defined in
relation to that formula and R2 represents a group of the
formula -CSNR7R8 wherein R7 and R8 are as hereinbefore
defined in relation to general formula (I), reacting a
corresponding compound of the general formula:
~r
CONR R~
N
2 ~ I ~V~IA)
Rl
(wherein R1, A1, A2, zl, R7 and R8 are as hereinbefore
defined in relation to general formula (I)J with phosphorus
pentasulphide to convert the grouping -CoNR7R8 to -CSNR R ,
and
optionally, when the tetrazine product obtained is a
compound of general formula I wherein R2 and/or R3 represent
a sulphamoyl or mono-substituted sulphamoyl group and/or R3
represents a carboxy group, converting by a method known
per _ the product into a pharmaceutically acceptable salt
(preferably an alkali metal salt).
Advantageously, for the preparation of a
tetrazine derivative of general formula (I)
wherein R is other than a sulphamoyl, monophenylcarbamoyl,
monophenylcarbamoyl substituted on the phenyl moiety by one
or more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group, monophenylthiocarbamoyl, monophenylthiocarbamoyl
substituted on the phenyl moiety by one or more substituents
selected from the group consisting of halogen atoms, alkyl.
group containing up to 4 carbon atoms, alkoxy group
containing up to 4 carbon atoms and nitro group,
nitrocarbamoyl or nitrothiocarbamoyl group, and Rl, A , A2
and zl are as defined hereinbefore,which comprises reac-ting a
compound of the general Eorrnll:l.a:
~2 ~ (III)
R 2
wherein Al and A2 are as defined hereinbefore and R
represents a group within the above-mentioned definition of
R , with a compound of the general formula:
R NCZ1 (IV)
wherein Rl and zl are as hereinbefore defined, to obtain the
desired compound.
~ dvantageously, for the preparation of a tetrazine
derivative of general formula (I) as defined hereinbefore,
wherein R represents a monophenylcarbamoyl, a monophenyl-
carbamoyl substituted on the phenyl moiety by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group, a
monophenylthiocarbamoyl or a monophenylthiocarbamoyl
substituted on the phenyl moiety by one or more substituents
selected from the group consisting of halogen atoms, alkyl
group containing up to ~ carbon atoms, alkoxy group
containing up to 4 carbon atoms and nitro group, and R1, A1,
A2 and zl are as defined hereinbefore in relation to that
formula, which comprises the debenzylation of a cornpound of
the general formula:
~q~
4 k
S02NR R ('~ NR R
~ ~ R ~ ~`~ 1
(wherein R7 is as de~ined hereinbefore, R13 represen-ts a benzyl
group or a benzyl group substituted on the phenyl moiety by
one or more substituents selected frorn the group consisting
of halogen atoms, alkyl group containing up to 4 carbon
atoms, alkoxy group containing up to 4 carbon atoms and
nitro group, and z2 is as defined hereinbefore by the
application or adaptation of methods known per se for the
replacement of a benzyl group or a benzyl group substituted
on the phenyl moiety by one or more substituents selected
from the group consisting of halogen atoms, alkyl group
containing up to 4 carbon atoms, alkoxy group containing up
to 4 carbon atoms and nitro group, by a hydrogen atom, to
obtain the desired compound.
Advantageously,~or the preparation of a tetrazine
derivative of general formula (I) as defined hereinbefore,
wherein R1, A1, A2 and zl are as hereinbefore defined
hereinbefore in relation to that formula and RZ represents a
group of the formula -CZ2NHNO2, ZZ being as defined hereinbefore
which comprises the nitration of a corresponding compound
of the general formula:
~Z N~2 (VA)
~f I
\\ l N~
.~
`~`~1< ,.
(wherein z2, Rl, Al, AZ ~nd zl aI~ as defir~ed hereinbefore in
relatio~ to general forrnul.a (I)), ~o convert ~lle groupirl-J
-CZ N112 to CZ NHNO2.
Advantageously, for the preparation of a tetrazine
derivative of general formula (I) as defined hereinbefore,
wherein R , Al, A2 and R2 are as defined hereinbefore in
relation to that formula and zl represents a sulphur atom,
which comprises reacting a compound of the general formula:
R15
~ ~ 1 (VI)
wherein Rl, Al and RZ are as defined hereinbefore, and Rl5
represents a group of the formula -S(O) R6, -SO2NR7R8,
-CZ NR R or -CZ2NHNO2, R6, R7, R8, n and Z being as
defined hereinbefore, with phosphorus pentasulphide to convert
\_/ . \/
the ~ molety to ~ .
O S
Advantageously, for the préparation of a tetrazine
derivative of general formula (I) as defined hereinbefore
wherein Rl, Al, A2 and zl are as defined
hereinbefore in relation to that formula and R2 represents a
group of the for~ula -CSNR7R3 wherein R7 and R8 are as
defined hereinbefore in relation to general formula (I), which
comprises reacting a corresponding compound of the general
formula:
- ~rn -
coN~c71~3
~N
~2 1 1 (VIIA)
~\A~N~N\
wherein Rl, Al, A , zl, Rl an-l R8 are as defined hereinbéfore,
with phosphorus pentasulphide to convert th~ grouping
-CoNR7R~ to -CSNR7R .
PreferabLy the process according to the invention may
further comprise converting the resuLting product of
formula ~I) wherein R2 and/or R3 represent a sulphamoyl or
mono-su~stituted sulphamoyl group and/or R3 represents a
carboxyl group, by a method known per se into a pharmaceu-
tically acceptable salt thereof.
Preferably, the cycloalkyl group referred to in
formula I is cyclohexyl.
Advantageously, the invention relates
to a process for the preparation of 3-(N-benzyl-
carbamoyl)-3-(2-chloroethyl)-C3H~-i.midazo-cS,l-d3-l,2,3,5-
tetrazin-4-one, which comprises reacting 8-rN-benzyl-N-(4-
methoxybenzyl) carbamoyl~-3-(2-chLoroethyl)-L3H~--imidazo
CS,l-d~-l,2,3,5-tetrazin-4-one with anisole to ~orm the
desired compound
~'
i
b ~
- 4n -
Advantageously, the invention relates to a
process for the preparation of 8~carbarnoyl-3-
(2-chloroethyl)-6-methyl-C311]-imi.(l.lzo- ~'j,],_dJ-].,2,.3,5-tetra-
zin-4-one, which comprises rcacting 5-diazo-2-rrtethyl-
S imidazole-4-carboxamide with 2-chloroethyl isocyanate to
form the desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-(N,N'-dimethylsulphamoyl)-r3~ -imidazo-[S,l-~ -
1,2,3,5-tetrazin-4-one, which comprises reacting 5-diazo-
imidazole-4-(N,N-dimethylsulphonamide) with 2-chloroethyl
isocyanate to form the desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-(N-methylsulphamoyl)-~3~ -imidazo- Ls,1-d]-1,2,3,5-
tetrazin-4-one, which comprises reacting 5-diazoimidazole-4-
tN-methylsulphonamide) with 2-chloroethyl isocyanate to form
the desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-methylsulphonyl-C3~ -imidazo-C5,1~d~-1,2,3,5-tetra-
zin-4-one, which comprises reacting 5-diazo-4-methylsulpho-
nylimidazole ~ith 2-chloroethyl isocyanate to form the
desired compound.
2S Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-methylsulphonyl-[3~ -imidazo-[5,1-d~-l,Z,3,5-tetra-
zin-4-one, which comprises reacting 5-diazo-4-methylsulpho-
nylimidazole with 2-chloroethyl isocyanate to form the
desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-methyl-8-
methylsulphonyl-C3H~-imidazo-LS,l-d~-l,Z,3,5-tetrazin-4-one,
which comprises reacting 5-diazo-4-methylsulphonylimidazole
with methyl isocyanate to form the desired compound.
.5~
- 90 -
Advantageously, the inv~ntion re:Lates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-[N-(~-methoxybenzyl)-s~llpharnoyl~ t3l~ imidazo-
[5,1-d~-1,2,3,5-tetrazin-4-one, whic~l comprises reacting 5-
diazoimidazole-4-cN-(4-methoxybenzyl)sulphonamide~ 2-chloro-
ethyl isocyanate to form the desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl3-8-sulphamoyl-[3~ -imidazo-L5,1-d~-1,2,3,5-tetrazin-4-
one, whieh eomprises reacting 3-(2-chloroethyl)-8-L~-(4-
methoxybenzyl)sulphamoyl~-C3~ -imidazoC5,1-d~-1,2,3,5-tetra-
zin-4-one with anisole to form the desired compound.
Advantageously, the invention relates
to a proeess for the preparation of 8-carbamoyl-3-
(2-ehloroethyl-~3~ -pyrazolo-C5,1-d~-1,2,3,5-tetrazin-4-one,
whieh eomprises reaeting 3-diazopyrazole-4-earboxamide with
2-ehloroethyl isoeyanate to form the desired eompound.
Advantageously, the invention relates
to a proeess for the preparation of 3-(2-ehloro-
ethyl)-8-piperidinocarbonyl-r3~ -imidazo-[5,1-d¦-1,2,3,5-
tetrazin-4-one, whieh eomprises reaeting 4-diazo-5-piperi-
dinocarbonylimidazole with 2-chloroethyl isocyanate to form
the desired compound.
Advantageously, the invention relates
to a proeess for the preparation af 6-butyl-8- ' -
earbamoyl-3-(2-ehloroethyl)-L3H~-imidazo-[5,1-d~-1,2,3,5-
tetrazin-4-one, whieh eomprises reacting 2-butyl-5-
diazoimidazole-4-earboxamide with 2-ehloroethyl isoeyanate
to form the desired eompound.
Advantageously, the invention relates
to a proeess for the preparation of 8-earbamoyl-3-
(2-ehloroethyl)-6-propyl-~3~ -imidazo-C5,1-d~-1,2,3,5-tetra-
zin-4-one, whieh eomprises reacting 5-diazo-2-propyl-
imidazole-4-carboxamide with 2-chloroethyl isocyanate to
form the desired compound.
t~
~ 4P -
Advan-tageously, the invention relates
to a process for the preparation o~ 8-carbamoyl-3-
(2-chloroethyl)-6-ethy~ 3ll~-imida~o--l5,l-d~-],2,3,5-~et~a-
zin-4-one, which comp~ises re.lc~ g 5-~1;azo--Z-ethylirrli-
dazole-4-carboxamide with 2-chLoroetl~yl isocyanate to form
the desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-6-methyl-8-sulphamoyl-[3H~-imidazo-~5~l-d~ 2~3~s-
tetrazin-4-one, which comprises reacting 3-(2-chloroethyl)-
8-(4-methoxybenzyl)sulphamoyl-6-methyl-r3H3-imidazo~5,1-dJ-
1,2,3,5-tetrazin-4-one with anisole to form the desired
compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-dimethylsulphamoyl-6-methyl-C3~ imidazo-C5,1-d~-
1,2,3,5-tetrazin-4-one, which comprises reacting 5-diazo-4-
dimethylsulphamoyl-2-methylimidazole with 2-chloroethyl
isocyanate to form the desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-6-methyl-8-methylsulphonyl- r3 - 3 -imidazo-~5,1-d~-
1,2,3,5-tetrazin-4-one, which comprises reacting 5-diazo-2-
methyl-4-methylsulphonylimidazole with 2-chloroethyl iso-
cyanate to form the desired compound.
Advantageously, the invention relates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-(dimethylcarbamoyl)-r3H~-pyrazolo-C5,1-d~-1,2,3,S-
tetrazin-4-one, which comprises reacting 3-diazopyrazole-4-
(N,N-dimethylcarboxamide) hydrochloride with 2-chloroethyl
isocyanate and 1,8-diazobicyclol5,4,0~undec-7-ene to form
the desired compound.
Advantageously, the inventiGrl relates
to a process for the preparation of 3-(2-chloro-
ethyl)-8-(N-nitrocarbamoyl)-[3H~-imidazo-cs~]-dJ -l,2,3,5-
- 4q -
tetrazin-4-one, which cornprises reactirlg a mixture of
concentrated sulphuric acid an~ ~3-carbarrloyl-3-(2-
chloroethyl)-~3~l~-irnidazor5,1--d~-1,2,3,5-tetrazirl-4-orle with
eoncentrated nitric acid to form the desired compound.
More partieularly, the inventi.on also relates
to tetrazine derivatives of the general formula:
~2
A ~ N~N (I~
\~1 N ~ ~
Cwherein Rl represents a cycloalkyl group containing 3 to 8
earbon atoms, or a straight- or branehed-chain alkyl,
alkenyl or alkylnyl group containing up to 6 carbon atoms,
eaeh such alkyl, alkenyl or alkylnyl group being unsubsti-
tuted or substituted by from one to three substituents
seleeted from the group eonsisting of halogen atoms,
straight- or branehed-ehain alkoxy, alkylthio, alkylsulphi-
nyl and alkylsulphonyl groups eontaining up to 4 earbon
atoms, and phenyl groups(unsubstituted or substituted by one
or more substituents selected from the group eonsisting of
halogen atoms, alkyl group eontaining up to 4 earbon atoms,
alkoxy group eontaining up to 4 carbon atoms and nitro
group); A1 represents a nitrogen atom or a group -CR
wherein R3 represents a hydrogen atom or a substituent R4
wherein R represents a halogen atom, or a straight- or
branched ehain alkyl or alkenyl group, eontaining up to 6
carbon atoms, which may carry up to 3 substituents selected
from the group consisting of halogen atom, phenyl group,
phenyl group substituted by one or more substituents
selected from the group consisting of halogen atoms, alkyl
group containing up to 4 carbon atoms, alkoxy group
3~2
- 4r -
containing up to 4 carbon atorns and nitro group, straight-
or branched-chain alkoxy, alkylthio ancl a].kylsulphonyl
groups containing up to 3 carbon a~oms, or l~4 represents a
cycloalkyl group containi.ng 3 to 8 carbon atorns, a cyano,
hydroxy, nitro, phenoxy group or phenoxy group substituted
by one or more substituents selected from the yroup
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group, or a group of the formula -CoR5 (wherein R5
represents an alkyl or alkoxy group of up to 4 carbon atoms,
a hydroxy group, a phenyl group or a phenyl group substi-
tuted by one or more substituents selected from the group
eonsisting of halogen atoms, alkyl group containing up to 4
earbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group~ or an alkanoylamino group eontaining up to
6 earbon atoms, or R4 represents a group of the formula
-S(O)nR6, -So2NR7R8 or -CZ2NR7R8 (wherein n represents 0, l
or 2, R6 represents a straight- or branehed-ehain alkyl or
alkenyl group, containing up to 4 carbon atoms, whieh may
earry a phenyl substituent(unsubstituted or substituted by
one or more substituents seleeted from the group eonsisting
of halogen atoms, alkyl group eontaining up to 4 carbon
atoms, alkoxy group eontaining up to 4 earbon atoms and
nitro group~, a cycloalkyl group eontaining 3 to 8 carbon
atoms or a phenyl group(unsubstituted or substituted by one
or more substituents seleeted from the group eonsisting of
halogen atoms, alkyl group eontaining up to 4 carbon atoms,
alkoxy group eontaining up to 4 carbon atoms and nitro
group) R7 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 a phenyl substituent (unsubstituted or
substituted by one or more substituents selected from the
group consisting of halogen atoms, alkyl group contalning up
- 4s -
to 4 carbon atoms, alkoxy group containing up to 4 carbon
atoms and nitro group) or a cyc:LoaLkyl grotlp contairling 3 to
8 carbon atoms or a phenyl group(unsubstituted or substi-
tuted by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atorns
and nitro group) or the group -NR7R8 represents a S,6 or 7
membered heteroeyclic ring which may contain a further
heteroatom selected from the group consisting of nitrogen,
oxygen and sulfur, said heterocyclic ring being unsubsti-
tuted on substituted by one or two substituents selected
from the group eonsisting of straight- or branched- chain
alkyl substituents each eontaining up to 4 carbon atoms, and
z2 represents an oxygen or sulphur atom); A2 represents a
nitrogen atom or, when Al represents a nitrogen atom, A
represents a nitrogen atom or a group -CR3= wherein R3 is as
hereinbefore defined, zl represents an oxygen or sulphur
atom; and R2 represents a group of the formula -S(O)nR6,
-So2NR7R8~ -CSNR7R8, -CoNR7R9 or -CZ2NHNO2, wherein n, R6,
R , R8 and Z are as hereinbefore defined, and the group
-NR7R9 represents a 5,6 or 7 membered heterocyclic ring
whieh may eontain a ~urther heteroatom seleeted from the
group consisting of nitrogen, oxygen and sulfur, said
heterocyelie ring being unsubstituted on substituted by one
or two substituents selected from the group consisting of
straight- or branched-chain alkyl substituents eaeh
containing up to 4 carbon atoms, or R7 is as hereinbefore
defined and R represents a straight- or branched-chain
alkyl or alkenyl group containing up to 4 earbon atoms whieh
earries and phenyl substituent(unsubstituted or sub~stituted
by one or more substituents selected from the group
consisting of halogen atoms, alkyl group containing up to 4
carbon atoms, alkoxy group containing up to 4 carbon atoms
and nitro group) or a phenyl group(unsubstituted or substi-
~5~
- 4t -
tuted by one or more substituer,ts selected from the group
consisting of halogen atoms, alkyl group contai.nirlg up to 4
carbon atoms, alkoxy group contailliflg up to 4 carbon atorns
and nitro group~ or, when A1 represents a nitrogen atom or a
group -CR4= wherein R4 is as hereinbefore defined and zl and
z2 are as hereinbefore defined or, when A1 represents a
group -CH= and zl represents a sulphur atom and z2 is as
hereinbe~ore defined, R2 represents a group of the formula
-S(O)nR , -SO~NR R , -CZ2NR7R8 or CZ2NHNO2 wherein n, R6,
R,.R . and Z are as hereinbefore defined~ and, when R
and/or R represents a sulphamoyl or monosubstituted
sulphamoyl group and/or R3 represents a carboxy group;
pharmaceutically acceptable salts thereof; excluding the
derivatives of formula (I) in which A1 represents a group
-CR3= wherein R3 represents a hydrogen atom, A2 represents a
nitrogen atom and either Rl represents a straight- or
branched-alkyl, alkenyl or alkynyl group containing up to 6
carbon atoms, each such alkyl, alkenyl or alkynyl group
being unsubstituted or substituted by from 1 to 3 substi-
tuents selected ~rom the group consisting of halogen atoms,straight-or branched-alkoxy, alkylthio, alkylsulfinyl and
alkylsulfonyl groups containing up to 4 carbon atoms and
phenyl group(unsubstituted or substituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group),or Rl
represents a cycloalkyl group containing 3 to 8 carbon atoms
and R2 represents a carbamoyl group which is substituted on
the nitrogen atom i) by two groups selected from the group
consisting of phenyl group, phenyl group substituted by one
or more substituents selected ~rom the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group, phenylalkyl group and phenylalkyl group substituted
. ~
~z~
- ~u -
by one or more substituents selected from the yroup
consisting of halogen atoms, alkyl group corltairlirl~ up to ~
carbon atoms, alkoxy group containirlg up to 4 carbon atomS
and nitrogroup~ or ii) a phenyl group substituted by one or
more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group, or a phenylalkyl group substituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group, or
iii) a phenyl group(unsubstituted or substituted by one or
more substituents selected from the group consisting of
halogen atoms, alkyl group containing up to 4 carbon atoms,
alkoxy group containing up to 4 carbon atoms and nitro
group) or a phenylalkyl group substituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group, and a
straight- or branched- alkyl group containing up to 4 carbon
atoms.
Advantageously, the invention relates
to tetrazine derivatives of formula (I)
wherein Rl is as defined hereinbefore~R2 represents a car-
bamoyl group unsubstituted or substituted on the nitrogenatom by one or two groups selected from straight- and
branched-chain alkyl and alkenyl groups, containing up to 4
carbon atoms, and cycloalkyl groups containing 3 to 8 carbon
atoms, Al represents a group -CR4= whe-rein R4 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, phenyl group and
phenyl groups substituted by one or more substituents
selected from the group consisting of halogen atoms, alkyl
- ~v -
group containing up to 4 carbon atoms, alkoxy group
containing up to 4 carbon atoms and nitro group, or R
represents a cycloalkyl group contai.ning 3 to 8 carbon
atoms, A2 represents a nitrogen atorn, and zl represents an
oxygen atom.
Advantageously, ~he invention relates
to tetrazine derivatives of formula (I)
wherein Rl is as defined hereinbefore, R2 represents a group
of the formula -S(O) R6 or -So2NR7R8, wherein n represents
0, 1 or 2, R6 represents a straight- or branched-chain alkyl
or alkenyl group, containing up to 4 carbon atoms, which may
carry a phenyl substituent(unsubstituted or substituted by
one or more substituents selected from the group consisting
of halogen atoms, alkyl group containing up to 4 carbon
atoms, alkoxy group containing up to 4 carbon atoms and
nitro group~, a cycloalkyl group containing 3 to 8 carbon
atoms, or a phenyl group (unsubstituted or substituted by
one or more substituents selected from the group consisting
of halogen atoms, alkyl group containing up to 4 carbon
atoms, alkoxy group containing up to 4 carbon atoms and
nitro group), R7 and R8, which may be the same or different,
each represents a hydrogen atom or a straight- or branched-
chain alk~l or alkenyl group, containing up to 4 carbon
atoms, which may carry a phenyl substituent (unsubstituted
or substituted by one or more substituents selected from the
group consisting of halogen atoms, alkyl group containing up
to 4 carbon atoms, alkoxy group containing up to 4 carbon
atoms and nitro group), or a cycloalkyl group containing 3
to 8 carbon atoms, or a phenyl group (unsubstituted or
substituted by one or more substituents selected from the
group consisting of halogen atoms, alkyl group containing up
to 4 carbon atoms, alkoxy group containing up to ~ carbon
atoms and nitro group), Al represents the group =CH-, A
represents a nitrogen atom, and zl represents an oxygen
- 4w -
atom.
~ dvantageously, the inverlt:iorl reLates
to tetrazine derivati.ves of forrnula (I)
wherein Rl is as defined hereinbefore,R2 represents a group
of the formula -S(O) ~6, -So2NR7R8 or -CZ2NR7R8 (wherein n
represents 0, 1 or 2, R6 represents a straight- or branched-
chain alkyl or alkenyl group, containing up to 4 carbon
atoms, which may carry a phenyl substituent(unsubstituted or
substituted by one or more substituents selected from the
group consisting of halogen atoms, alkyl group containing up
to 4 carbon atoms, alkoxy group containing up to 4 carbon
atoms and nitro group),a cycloalkyl group containing 3 to 8
carbon atoms, or a phenyl group (unsubstituted or
substituted by one or more substituents selected from the
group consisting of halogen atoms, alkyl group containing up
to 4 carbon atoms, alkoxy group containing up to 4 carbon
atoms and nitro group)), R7 and R8, 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 a phenyl substituent
(unsubstituted or substituted by one or more substituents
selected ~rom the group consisting of halogen atoms, alkyl
group containing up to 4 carbon atoms, alkoxy group
containing up to 4 carbon atoms and nitro group), or a
cycloalkyl group containing 3 to 8 carbon atoms or a phenyl
group (unsubstituted or substituted by one or more
substituents selected from the group consisting of halogen
atoms, alkyl group containing up to 4 carbon atoms, alkoxy
group containing up to 4 carbon atoms and nitro group),
represents a nitrogen atom, A2 represents a group -CR =,
wherein R3 represents a hydrogen atom or a substituent R4 as
defined hereinberofe,and zl represents an oxygen or sulphur
atom.:
- ~x -
Advantageously, the inventiorl re:Lates to aforesaid
tetrazine derivative.s o~ forrnuLa (I) in whiGh the cyGloalkyl
group referred to is cyclohexyl.
Advantageously, the invention relates to aforesaid
5 tetrazine derivatives of formula (I), which have one or more
of the following features:
(i) R represents a methyl or 2-haloethyl group
(preferably the 2-chloroethyl group);
(ii) R represents a group of the formula -SOR ,
-SO2R6, -So2NR7R3, -CoNR7R8 or -CONHNO2, wherein
R , R7 and R8 are as defined hereinbefore
(iii) one of A and A2 represents a nitrogen atom and
the other represents a group -CR3= wherein R3 is
as defined hereinbefore
(iv) R3 represents a substituent R4 wherein R4 represents
an alkyl group containing up to 6 carbon atoms-
(v) A2 represents a nitrogen atom;
(vi) zl represents an oxygen atom; and/or
(vii) Z represents an oxygen atom.
Preferably, R represents a group -SOR , -SO2R ,
-So2NR7R8, -CoNR7R8 or -CONHNO2 wherein R6 represents an
alkyl group containing up to 4 carbon atoms, R7 represents a
hydrogen atom or an alkyl group containing up to 4 carbon
atoms, and R8 represents a hydrogen atom, an alkyl group
containing up to 4 carbon atoms, a benzyl group or a benzyl
group substitu~ed by an alkoxy group containing up to 4
carbon atom.
Preferably, R3 represents a butyl, propyl, ethyl
or methyl group.
Advantageously, the invention relates to aforesaid
tetrazine derivatives of formula (I) which have one or more
of the following features:
(i) Rl represents a methyl or 2-haloethyl group;
(ii) R2 represents a group of the formula -SOR ,
5~i~
- 4y
-SO2R6, -SO NR7R~, -CoN~7RB or -corl~lNo~ wherein
R , R and R~ are as defirle~ hereirlbefore;
(iii) one of A1 and A2 represents a ni.trogen atorn an~
the other represents a group -CR3= wherein R3 is
as defined hereinbefore;
(iv) R represents a methyl group;
(v) A represents a nitrogen atom;
(vi) zl represents an oxygen atom; and/or
(vii) Z represents an oxygen atom.
Advantageously, the invention relates to aforesaid
tetrazine derivatives of formula (I) which have one or more
of the following features:
~i) Rl represents the 2-chloroethyl group;
(ii) R2 represents a group of the formula SOR6, -SO2R
-So2NR7R8, -CoNR7R8 or -CONHNO2, wherein R6, R7
and R8 are as defined hereinbefore;
(iii) one of Al and A2 represents a nitrogen atom and
the other represents a group -CR3= wherein R3 is
as defined hereinbefore;
(iv) R3 represents a methyl group;
(v) A represents a nitrogen atom;
(vi) zl represents an oxygen atom; and/or
(vii) z2 represents an oxygen atom.
The invention also relates to pharmaceutical
composition, characterized in that it comprises in
association with a pharmaceutically acceptable carrier, at
least one of tetrazine derivatives described hereinbefore.
The specification of British Patent Application
No. 2104522 describes compounds of the general formula shown
in Figure II of the drawings wherein Rl represents a
hydrogen atom, a cycloalkyl group or a straight- or
branched-chain
. _ .
-- 5
alkyl, alkenyl or alkynyl group containing up to 6
carbon atoms, each such alkyl, alkenyl or alkynyl
group being unsub.stituted or substituted by trom one
to three substituents selected from halogen atoms,
straight- or branched-chain alkoxy, alkylthio, alkyl-
sulphinyl and alkylsulphonyl groups containing up to 4
carbon atoms, and optionally substituted phenyl
groups, and Rll represents a carbamoyl group which
may carry on the nitrogen atom one or two groups
selected from straight- and branchea-chain alkyl and
alkenyl groups, each containing up to 4 carbon atoms,
and cycloalkyl groups.
The said tetrazine derivatives of tne formula
shown in Figure II possess valuable antineoplastic
activi~y, for example against carcinomas, melanomas,
sarcomas, lymphomas and leukaemias, and tbey 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, Eor
- 6 -
example as described later in this specification.
Particularly important clas6es of compounds
of the formula shown in Figure I include those which
exhibit one or more of the following features:-
(i) Rl represents a methyl or, more
especially, a 2-haloethyl group, in particular a
2-chloroetnyl group;
(ii) R2 represents a group of the formula
--SO~6,-S02R6, -So2NR7R&, -CoNR7R8 or -CON~N~2,
especially those wherein R6 represents an alkyl,
e.g. methyl, group and those wherein R7 represents a
hydrogen atom or an alkyl, e.g. methyl, group and R8
represents a hydrogen atom or an alkyl, e.g. methyl,
group or a benzyl group optionally substituted by an
alkoxy group, e.g. a 4-methoxybenzyl group;
(iii) one of Al and A2 represent a
nitrogen atom and the other represents a group -CR3=;
(iv) R3 represents a group R4 wherein
R4 represents an alkyl, e.g. butyl, propyl, ethyl
or, more particularly, methyl, group;
(v) A2 represents a nitrogen atom;
(vi) zl represents an oxygen atom; and/or
(vii) z2 represents an oxygen atom.
Important individual compounds of the general
formula shown in Figure I include the following:-
-- 7
&-(N-benzyl N-phenylcarbamoyl)-3-methyl-~3H]-
imi~azoL5~l-d~ 2~3~s-tetrazin-4-one~ A,
8-LN-benzyl-N-(4-methoxy~enzyl)carbamoylJ-3-
(2-chloroethyl)~-L3H]-imidazoL5~l-dJ-L~2~3~5-
tetrazin-4-one, B,
&-(N-benzylcarbamoyl)-3-(2-chloroethyl)-L3HJ-
imidazoL5,1-d]-1,2,3,5-tetrazin-4-one, C,
3-(2-chloroethyl)-8-LN-(4-metnoxybenzyl)-N-
phenylcarbamoyl~-L3H]-imidazoL5,1-d]-1,2,3,5-
10 tetrazin-4-one, D,
3-(2-chloroethyl)-8-(N phenylcarbamoyl)-L3H]-
imidazol5,1-d]-1,2,3,5-tetrazin-4-one, ~,
8-(N-benzyl-N-phenylcarbamoyl)-3-(2-chloroethyl)-
L3HI-imidazoL5,1-d~-1,2,3,5-tetrazin-4-one, F,
3-(2-chloroethyl)-8-(N-methyl-N-phenylcarbamoyl)-
L3H]-imidazoL5,1-d]-1,2,3,5-tetrazin-4-one, G,
&-car~amoyl-3-(2-chloroethyl)-6-methyl-L3H]-
imidazoL5,1-d]-1,2,3,5-tetrazin-4-one, H,
3-(2-chloroethyl)-8-(N,N-dimethylsulphamoyl)-
l3H~-imidazoL5,1-d]-1,2,3,5-tetrazin-4-one, I,
3-(2-chloroethyl)-8-(N-methylsulphamoyl)-
L3H]-imidazoL5~l-d]-l~2~3~5-tetrazin-4-one~ J,
3-(2-chloroethyl)-8-methylsulphonyl-[3H]-
imidazo-[5,1-d]-1,2,3,5-tetrazin-4-one, K,
3-methyl-8-methyls~lphonyl-L3H]-imidazo[5,1-d]-
1,2,3,5-tetrazin-4-one, L,
5~
,
-- 8 --
3-(2-chloroethyl)-&- LN- (4-methoxybenzyl)-
sulphamoyl~-L3HJ-imidazoL5,1-cl]-1,2,3,5-
tetrazin-4-one, M,
3-(2-chloroethyl)-8-sulphamoyl-L3H~-
imidazoL5,1-d~-1,2,3,5-tetrazin-4-one, N,
8-carbamoyl-3-t2-chloroethyl)-L3H~-pyrazoloL5,1-d~-
1,2,3,5-tetrazin-4-one, 0,
8-carbamoyl-3-methyl-[3H¦-pyrazoloL5,1-d~-1,2,3,5-
tetrazin-4-one, P,
3-(2-chloroethyl)-8-piperidinocarbonyl-L3H]-
imidazoL5,1-d]-1,2,3,5-tetrazin-4-one, Q,
6-butyl-8-carbamoyl-3-(2-chloroethyl)-L3H~-
imidazo[5,1-d]-1,2,3,5-tetrazin-4-one, R,
8-carbamoyl-3-(2-chloroethyl)-6-cyclohexyl-L3H~-
imidazo[5,1-d]-1,2,3,5-tetrazin-4-one, S,
8-carbamoyl-3-(2-chloroethyl)-6-phenethyl-[3H]-
imidazo[5,1-d]-1,2,3,5-tetrazin-4-one, T,
6-benzyl-8-carbamoyl-3-(2-chloroethyl)-L3H]-
imidazo[5,1-d]-1,2,3,5-tetrazin-4-one, U,
&-carbamoyl-3-(2-chloroethyl)-6-isopropyl-L3H~-
imidazo[5,1-a]-1,2,3,5-tetrazin-4-one, V,
8-carbamoyl-3-(2-chloroethyl)-6-propyl-[3H~-
imidazo[5,1-dJ-1,2,3,5-tetrazin-4-one, ~,
8-carbamoyl-3-(2-chloroethyl)-6-ethyl-[3H]-
imidazo[5,1-d~-1,2,3,5-tetrazin-~-one, X,
~7 ~f~ 7
-- 4
3-(2-chloroethyl)-&-(4-metnoxybenzyl)sulphamoyl-
6-methyl-L3H]-imidazoL5Jl-d~-lt2~3l5-tetrazin-~-oneJ Y,
3-(2-chloroethyl)-6-methyl-8-sulphamoyl~L3~1]-
imidazoL5,1-d]-1,2,3,5-tetrazin-4-one, Z,
3-(2-chloroethyl)-8-dimethylsulphamoyl-6~methyl-
L3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one, AA,
3-(2-chloroethyl)-6-methyl-8-methylsulphonyl-
L3HJ-imidazo~5Jl-d~ 2~3~5-tetrazin-4-one~ BB,
3-(2-chloroethyl)-8-(dimethylcarbamoyl~-[3H]-
pyrazoloL5,1-d]-1,2,3,5-tetrazin-4-one, CC,
an~ 3-(2-chloroethyl)-8-(N-nitrocarbamoyl)-
~3H]-imidazoL5,1-d~-l,2,3,5-tetrazin-4-one, DD,
3-methyl-8-methylsulpbonyl-[3HJ-pyrazolo~5~l-d3-
1,2,3,5-tetrazin-4-one, EE,
3-(2-chloroethyl)-8-methylsulphonyl-L3H]-pyrazolo-
[5,1-d]-1,2,3,5-tetrazin-4-one, FF,
3-(2-chloroethyl)-6-methyl-~-methylsulphinyl-
[3H]-imidazo[5,1-dJ-1,2,3,5-tetrazin-4-one, GG,
3-(2-chloroethyl)-&-ethylsulphonyl-6-methyl-
[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one, HH,
and 3-(2-chloroethyl)-6-methyl-8-propylsulphonyl-
3H]-imidazo[57l-d]-l~2~3~5-tetrazin-4-one. II.
The letters A to II are allocated to the
compounds for easy reference later in the
speci~ication.
'~ r~
- 10 -
-Compounds o~ particular irnportance include
compounds C, K, L, ~, 0, Q, R, ~, X and DD, more
especially compounds I, J, N and BB, and most
especial-ly compounds H, Z, AA and CC.
The new tetrazine derivatives of the general
formula shown in Figure I have proved particularly
active in mice at daily doses between 0.2 and 320mg/kg
animal body weigh~, administered intraperitoneally,
against TLX5(S) lymphoma according to the procedure of
&escher et al., Biochem. Pharmacol. (1~81), 30, &9
and ADJ/PC6A and M5076 (reticulum cell sarcoma).
Against leukaemia L1210, grafted intra-
peritoneally, intracerebrally and intravenously, and
P3&8, according to the proceaure described in "Methods
of Development of New Anticancer Drugs" (NCI Monograph
45, March 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.
Inhibition of both primary tumour and metastasis was
obtained against the Lewis lung carcinoma by similar
dosage regimes. Against the B16 melanoma and C3&
tumour in mice (NCI Monograph 45, op. cit.) the
compounds were active intraperitoneally at doses of
between 6.25 and 40 mg/kg animal body weight. Against
colon carcinoma C26 in mice, grafted subcutaneously,
the compounds were active orally at doses o~ between 2
and 40mg/kg animal Dody weight.
The compounds of the general formula shown in
- Figure I may be prepared by the application or
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 R2 is other than a sulphamoyl,
mono(optionally substituted phenyl)carbamoyl,
mono(optionally substituted phenyl)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
Al and A2 are as hereinbefore defined and R12
represents a group within the above definition of R2
other than a sulphamoyl, mono(optionally substituted
phenyl)carbamoyl, mono(optionally substituted phenyl)-
thiocarbamoyl, nitrocarbamoyl or nitrothiocarbamoyl
group] ~ith a compound of the general formula:-
R1NCZl IV
wherein Kl and zl 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
acetate, acetonitrile, N-methylpyrrolidin-2-one or
hexamethylphosphoramide, at a temperature between 0
and 120C. 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 forrnula shown in Figure
I wherein R2 represents a sulfamoyl, monosubstituted
sulfamoyl, carbamoyl, monosubstituted carbamoyl, thiocarba-
moyl, monosubstituted thiocarbamoyl group, R , A , A and Z
being as hereinbefore defined, are prepared from
corresponding compounds, within the general formula shown in
Figure I, wherein R2 represents a group of the formula
-S2NR R or-CZ NR R (wherein R13 re~resents an optionally
substituted benzyl group and z2 and R7 are as hereinbefore de-
fined) by the application or adaptation of methods known per se for
the replacement of optionally substituted benzyl groupsbyhydrogen 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 dimethylformamide); or when R13 represents a substituted
benzyl group in which the substituent or at least one of the
substituents carried by the benzyl group is an al~oxy (e.g.
methoxy) group in the o- or _-position, preferably by
reaction with trif1uoroace
i' '
~ r
- 13 -
presence of anisole, and usually at or near room
temperature.
Accordin~ to a further feature of the present
invention, compounds of the general formula shown in
Figure I wherein R2 represents a group of the
formula -CZ2NHNO2 (z2, Rl, Al, A2 and zl
being as hereinbefore defined) are prepared by the
nitration of compounds of the general formula shown in
Figure V of the drawings wherein R14 represents a
group of the formula -CZ2NH2 (z2, Rl, Al,
A2 and zl being as hereinbefore defined). The
reaction may be carried out near or below room
temperature, preferably between 0 and 10C, in the
presence of a nitrating mixture such as a mixture of
concentrated sulphuric acid and concentrated nitric
acid.
According to a further feature of the present
invention, compounds of the formula shown in Figure I
wherein Rl, Al, A2, and R2 are as hereinbefore
defined and zl represents a sulphur atom are prepared
from compounds of the general formula shown in Figure
VI of the drawin~s (wherein Rl, Al and R2 are as
hereinbefore defined) and R15 represents a group of
the formula -S(O)nR6, -So2NR7R&, -CZ2NR7R8 or -CZ2NHN02,
R6, R7, R~, n and z2 being as hereinbefore defined) by
- 14
the action of 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
lutidine, and preferably at an elevated temperature,
for example between 50 and 120C.
According to a further feature of the present
invention, compounds of formula I wherein Rl, Al,
A2 and zl are as hereinbefore de~ined and R2
represents a group of the formula -CSNR7R8 are
prepared from compounds of the formula shown in Figure
VII of the drawings wherein Rl, Al, A2 and Z1
are as hereinbefore defined and Rl6 represents a
group of the formula -CoNR7R8 (R7 and K~ being
as hereinbefore defined) by reaction with phosphorus
pentasulphide under conditions similar to those
described hereinbefore for the reaction of phosphorus
pentasulphide with compounds of the formula shown in
Figure VI.
The aforementioned salts of certain compounds
of the formula showo 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
hydroxide, carbonate or, preferably, bicarbonate, in
an aqueous or aqueous-organic medium, followed by
~ 5 ~7
- 15 -
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
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.
(1961), 26, 2396, and Cheng et al., J. Pharm. Sci.
(196&), 57, 10447 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
1~ used or described in the literature.
~L'~
- 16 -
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
Sodiu~ nitrite (0.44g) was dissolved in aqueous
acetic acid (2M; lOml) at 0C and the solution was
stirred at 0C and treated with finely ground 5-amino-
imidazole-4-N-benzyl-N-phenylcarboxamide hydrochloride
(0.7g; prepared as described in Reference Example 1)
in small portions. After 10 minutes the resulting
gummy solid was extracted with eth~l 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-benzyl-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-benzyl-N-
phenylcarbamoyl)-3-methyl-L3H]-imidazo[5,1-d]-1,2,3,5-
tetrazin-4-one (0.22g), in the form of a white,
crystalline solid, m.p. 168-170C (with decomposition)
- 17 -
LElemental analysis~ 62~6;H~4~41;N~22~3V/o; calculated:
C,63.32;H,4.47;N,23.32%; I.R. (K~r disc): 3100, 1735,
1620cm~l; N~IR (in DMSO-d6):- singlets at 3.75,
5.10 and 8.55ppm, multiplet at 7.0-7.4ppm; m/e 360
S (~+) ] -
EXAMPLE 2
Com~und ~
Sodium nitrite (3.7g) was dissolved in aqueousacetic acid (2M; 35ml) at 0C and the solution was
10 stirred at 0C 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 (lOml),
dropwise. A reddish gum separated which was extracted
15 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 .esulting solution of 5-diazoimidazole-4-
20 N-benzyl-N-(4-methoxybenzyl)carboxamide was treated
with 2-chloroethyl 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
25 pressure column chromatographyJ eluting with ethyl
acetate, to give crude 8-[N-benzyl-N-(4-methoxybenzyl)-
carbamoyl]-3-(2-chloroethyl)-L3~]-imidazoL5,1-d]-
1,2,3,5-tetrazin-4-one (1.5g) in the form of a brown
oil.
EXAMPLE 3
Compound C
8-LN-Benzyl-N-(4-methoxybenzyl)carbamoyl]-3-(2-
chloroethyl)-L3H]-imidazoL5,1-d]-1,2,3,5-tetrazin-4-one
(1.5g; crude material prepared as described in
Example 2) and anisole (0.5ml) were dissolved together
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
medium pressure column chromatography, eluting with a
mixture (2:1 v/v) of ethyl acetate and petroleum ether
(b.p. 60-80C), to give 8-(N-benzylcarbamoyl)-3-(2-
chloroethyl)-L3H]-imidazoL5,1-d]-1,2,3,5-tetrazin-4-one
(0.34g), in the form of a colourless solid, m.p.
153-155C (recrystallised from diethyl ether).
LElemental analysis: C~49~5;H~3~92;N~24~4;Cl~10~4~/o;
calculated: C~50~53;H~3~94;N~25~26;C1~10~65~/o; I.R.
(KBr disc) 3370, 3150, 1755 and 1660cm~l; NMR (in
D~SO-d6): singlets at 7.3 and 8.9ppm, doublet at
4.4ppm and triplets at 4.0, 4.6 and 9.05ppm].
- L~ -
EXAMPLE 4
Compound_D
Sodium nitrlte (0.61g) was dissolved in water
(lOml) and the solution was stirred at 0C and treated
with a solution of crude 5-aminoimidazole-4-~-(4-
methoxybenzyl)-N-phenylcarboxamide (2.5g; prepared as
described in Reference Example 3) in hydrochloric acid
(2M; 9ml) and l,~-dimethoxyethane (15ml), dropwise.
AEter 20 minutes the solution was extracted with ethyl
acetate (3 x 50ml) and the combined extracts were
dried over magnesium sulphate and evaporated, to give
5-diazoimidazole-4-N-(4-methoxybenzyl)-N-phenyl-
carbo;amide (2.8g), in the form of an orange oil.
This oil was dissolved in ethyl acetate (40ml) and
treated with 2-chloroethyl 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, to
give 3-(2-chloroethyl)-8-[N-(4-methoxybenzyl)-N-
phenylcarbamoyl]-L3H]-imidazoL5,1-d]-1,2,3,5-
tetrazin-4-one (1.5g) in the form of a glass, m.p.
55C [NMR (in D~SO-d6):- singlets at 3.6, 5.0 and
8.5ppm, triplets centred at 3.9 and 4.5ppm, multiplet
at 6.6-7.2ppm; I.R. (KBr disc) 1740 and 1640cm 1].
~ ~5
- 2~ -
EXAMPLE 5
Compound E
3-(2-Chloroethyl)-8- LN- (~-methoxybenzyl)-M-
phenylcarbamoyl~-[3H]-imidazo~5~l-d~ 2~3~5-
tetrazin-4-one (l.Og; prepared as described in
Example 4) and anisole (0.2ml) were dissolved together
in trifluoroacetic acid (lOml) and the solution was
allowed to stand at room temperature for 1~ hours.
The mixture was then evaporated to dryness and the
residue was triturated with diethyl ether, to give
3-(2-chloroethyl)-8-(N-phenylcarbamoyl)-L3H~-imidazo-
[5,1-d]-1,2,3,5-tetrazin-4-one (0.43g), in the form of
a tan solid, m.p. 166C (with decomposition) (after
recrystallisation from ethyl acetate) LElemental
L5 analysis: C,48.4jH,3.22jN,26.0~/o; calculated:
C~48~99jH~3~48;N~26~37~/o; I.R. (KBr disc): 3390, 1735
and 1680 cm 1, NMR (in DMSO-d6):- 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].
EXA~PLE 6
Compound F
Sodium nitrite (2.&g) was dissolved in aqueous
acetic acid (2M; 84ml) and the solution was stirred at
0C and treated with finely ground 5-aminoimidazole-
4-N-benzyl-N-phenylcarboxamide hydrochloride (2.8g;
prepared as described in Reference Example 1) in small
portions. After 10 minutes the resul~ing gummy-solid
was extracted with ethyl aceta~e (3 x 80ml) 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 of 5-diazoimidazole-4-N-
benzyl-N-phenylcarboxamide was trea~ed with
2-chLoroethyl isocyanate (9ml) and the mixture was
allowed to stand in the dark at room temperature for 4
lG 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-phenylcarbamoyl)-3-(2-chloroethyl)-
[3H]-imidazoL5,1-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;Cl,8.5V/o; calculated: C,58.75;H,4.15;N,20.56;
Cl,8.67%; I.R. (KBr disc): 1740 and 1640cm~l; NMR
(in DMSO-d6):- 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 0C 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
- 22 -
(2M; 40ml), dropwise. After 10 minutes the resulting
mixture was extracted with ethyl acetate (4 x lOOml),
and the combined extracts were filtered, and dried
over magnesium sulphate.
The resulting solution of 5-diazoimidazole-4-
N-methyl-N-phenylcarboxamide was treated with
2-chloroethyl isocyanate (llml) 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
recrys~allised from a mixture of petroleum ether
(b.p. 60-80C~ and ethyl acetate and then from a
mixture of ethyl acetate and diisopropyl ether, to
give 3-(2-chloroethyl)-8-(N-methyl-N-phenyl-
carbamoyl)-[3H]-imidazo-[5,1-d~-1,2,3,5-tetrazin-4-one
(0.8g), in the form of a colourless solid, m.p.
130-132 [Elemental analysis C,50.4jH,3.91;N,24.9;
Cl,10.6a/o; calculated: C,50.53;H,3.94;N,25.26;
Cl,10.65V/o; I.R. (KBr disc): 1750 ana 1640cm~l; NMR
(in DMS0-d6):- singlets at 3.4, 7.2 and 8.65ppm,
triplets centred at 3.~5 and 4.6ppm].
- 23 -
EXAMPLE 8 -~
Compound H
A stirred suspension of S-diazo-2-methylimidazole-
4-carboxamide (1.54g; prepared as described in
Reference Example 5) in ethyl acetate (45ml) was
treated with 2-chloroethyl isocyanate (6.33g) 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
off, washed with diethyl ether and dried in vacuo at
ambient temperature, to give 8-carbamoyl-3-(2-chloro-
ethyl)-6-methyl [3H]~imidazoL5,1-d]-1,2,3,5-tetrazin-4-
one (2.00g), m.p. 170C (with decomposition)
LElemental analysis: C,37.0;H,3.49;N,32.8;C1,13.3~/o;
calculated: C,37.44;H,3.54;N,32.75;C1,13.82%].
EXA~lPLE
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 in vacuo at below 40C to
about 15ml volume and diluted with dry diethyl ether.
The resulting solid was filtered off, to give
3-(2-chloroethyl)-8-(N,N-dimethylsulphamoyl)-[3H]-
~2
- ~4 -
imidazoL5,1-dJ-1,2,3,5-tetrazin-4-one (0.68g), in ~he
form of greyish needles, m.p. 15S-156C. LElemental
analysis: C~30~4;H~3~35;N,26~8;C1~ 8~o; calculated:
C,31.3;H,3.62;N,27.4;Cl,11.6%; I.R. 1755cm~l; NMR
(in DMSO-d6): singlets at 2.80, 8.9Gppm, triplets at
3.99, 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-ehloroethyl isocyanate (3ml) and the mixture was
stirred in a stoppered flask in the dark for 48
hours. The mixture was then evaporated in vacuo at
below 35C to approximately half its volume, an~ was
diluted with diethyl ether. The resulting solid was
filtered off and washed with diethyl ether, to give
3-(2-chloroethyl)-8-(N-methylsulphamoyl)-[3H]-imidazo-
L 5,1-dJ-1,2,3,5-tetrazin-4-one (0.32g), in the form of
shining buff plates, m.p. 147-148C LElemental
analysis: C~28.5;H~2.~0;N~28~7~/o; calculated:
C,28.7;H,3.08;N,28.7%; I.R. 1745cm~l; NMR (in
DMso-d6) doublet at 2.58ppm, triplets at 3.98,
4.61ppm, quartet at 7.~4ppm, singlet at &.84ppm].
s~
- ~5 -
EXAMPLE 11
Compound K
A solution of 5-diazo-4-methylsulphonyli~idazole
(0.65g; prepared as described in Reference Example 8)
in dry ethyl acetate (50ml) was treated with
2-chloroethyl isocyanate (3ml) and the mixture was
stirred at room temperature in the dark for 48 hours.
The mixture was then evaporated in vacuo and the oily
residue was triturated with petroleum ether (b.p.
60-80C). The resulting solid was filtered off and
subjected to medium pressure chromatography, eluting
with ethyl acetate, and the white solia product was
triturated with petroleum ether and filtered off, to
give 3-(2-chloroethyl)-&-methylsulphonyl-L3H~-imidazo-
L5,1-d]-1,2,3,5-tetrazin-4-one (0.72g), m.p.
154-155C. LElemental analysis: C,30.3jH,2.85;N,25.0;
Cl~ 5~/o; calculated: C,30.28;H,2.90;N,25.22;
Cl~ 55~/o]~
EXA~PLE 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
temperature in the dark for 3 days. A further
quantity of methyl isocyanate (3.5ml) was added and
s~
26 -
the mixture was warmed at 40C ~or 2 days and then was
left to stand at room temperature for 3 days. The~
mixture was then evaporated in vacuo to a volume o~
between lO and 15ml, and was subjected to medium
S pressure chromatography, eluting with ethyl acetate,
to givP 3-methyl-8-methylsulphonyl-[3H]-imidazo-
[5,1-d]-1,2,3,5-tetrazin-4-one (0.17g), in the form of
a white crystalline solid, m.p. 185-186C (with
decomposition). LElemental analysis: C,31.2;H,2.89;
N~30~3V/o; calculated: C,31.44;H,3.08;N,30.56%].
EXAMPLE 13
Compound M
A solution of 5-diazoimidazol~-4-~N-(4-methoxy-
benzyl)sulphonamide] (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 4~ 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 70C/lOmmHg for 1 hour, to give 3-(2-chloro-
ethyl)-8-~N-(4-methoxybenzyl)sulphamoyl]-L3H]-imidazo-
[5,1-d]-1,2,3,5-tetrazin-4-one (0.2g), m.p. 155-156C
3~ h~
- 27 -
(with decomposition) L~;~.R. 1745cm~1; Elemental
analysis: C~41~9;H~3~72;N~20~5~/o; calculated: C,42.16;
H,3.79;N,21.07%].
EXAMPLE 14
Compound N
3-(2-Chloroethyl)-8-LN-(4-methoxybenzyl)sulphamoyl]-
[3H]-imidazo-[5,1-d] 1,2,3,5-tetrazin-4-one (O.lg;
prepared as described in Example 13) was dissolved in
trifluoroacetic acid (l.Oml) and anisole (3 drops) and
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
petroleum ether (b.p. 60-80C) and ethyl acetate (1:1
v/v) as eluent, to give 3-(2-chloroethyl)-8-
sulphamoyl-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one
(50mg), in the form of a white solid, m.p. 183C (with
decomposition) LI.R. 1750cm~l; NMR (in DMSO-d6):
singlets at 8.8, 7.8ppm, triplets at 4.58, 3.95ppm].
EXAMPLE 15
Compound O
A stirred suspension of 3-diazopyrazole-4-
carboxamide (5.9g; prcpared as described by Cheng et
al., op. cit.) in ethyl acetate (150ml) was treated
with 2-chloroethyl isocyanate (24ml) and stirred at
- 28 -
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
cream solid (8.36g), m.p. 173-174C (with decompos-
ition).
A solution of a sample of the said mixtu~e (l.Og)
in dimethyl sulphoxide (20ml) was heated at 60C
overnight. Tbe solution was then evaporated to
dryness (at below 60C 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
solution was treated with deactivated silica gel (3g
containing 20% 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
recrystallising the product from acetonitrile, to give
8-carbamoyl-3-(2-chloroethyl)-L3H]-pyrazolol5,1-d]-
1,2,3,5~tetrazin-4-one (0.25g), in the form of
colourless needles, m.p. 203-204C ~with
decomposition) LElemental analysis: C,34.8;H,2.92;
N,34.7;C1,14.6~/o; calculated: C,34.65;H,2.91;N,34.64;
Cl,14.61%].
M~
- 2~ -
EXAMPL~ 1
Compound P
A stirred suspension of 3-diazopyrazole-4-
carboxamide (1.6g; prepared as described by
Cheng et al., opu 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
mixture in the form of a cream solid (2.24g), m.p.
179-L81C (with decomposition).
A solution of a sample of this solid (l.Og) in
dimethyl sulphoxide (lOml) was treated with
deactivated silica gel (8g; containing 20% water)
and the mixture was evaporated to dryness (at
60C/O.lmmHg). 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-carbamoyl-3-methyl-
[3H]-pyrazolo[S,l-d]-1,2,3,5-tetrazin-4-one (41mg), in
the form of a colourless solid, m.p. 170C (with
decomposition). [NMR (in DMSO-d6): singlets at
3.95, 7.45, 7.55, 8.50ppm; I.R. (KBr disc): 3400,
3160, 1750 and 1680cm~l~.
- 30 -
EXAMPLE 17
Compound~Q
A solution of sodium nitrite (0.79g) in water
(6ml) was treated with a solution oE crude
4-amino-5-piperidinocarbonylimidazole hydrocbloride
(2.lg; prepared as described in Reference Example 10)
in aqueous acetic acid (lM;17ml), dropwise with
stirring, at 5-10C 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 30C/O.lmmHg. The residue was dried
in a desiccator over phosphorus pen~oxide 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-piperidinocarbonyl-
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
30C/O.lmmHg and the residue was subjected twice to
medium pressure chromatography on silica gel, eluting
with a mixture of ethyl acetate and acetonitrile
(88:12 v/v). The appropriate fractions were combined
and evaporated and the residue was tri~urated with
petroleum ether (b.p. 40-60C), to give 3-(2-chloro-
- 31 -
ethyl)-8-piperidinocarbonyl-L3H]-imi~azoL5,1-d~-1,2,3,5-
tetrazin-4-one (1.46g), in the form of light purple
crystals, m.p. 92-94C LElemental analysis: C,45.3;
H,4.98;N,26.1%; calculated: C,46.4;H,4.87;N,27.1%;
N~ (in D~lSO-d6): singlet at 8.7ppm, triplets at 4.6
and 4.0ppm, multiplets at 3.2-3.4 and 1.5-1.8ppm; I.R.
(KBr disc): 1750, 1630cm~l].
EXAMPLE 18
Co~pound R
A stirred solution of sodium nitrite (1.61g) in
water (5ml) was cooled and maintained at 5-10C and
treated dropwise with a solution of 5-amino-2-
butylimidazole-4-carboxamide hydrochloride (1.61g;
prepared as described in West German Patent
Specification No. 2358509j in hydrochloric acid (lM;
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-butyl-5-diazoimidazole-
4-carboxamide (0.47g), in the form of a yellow solid,
m.p. 109-111C (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
isocyanate (1.5ml) and left to stand in the dark for
24 hours. The resulting fawn solid was filtered off
- 32 -
and recrystallised from a mixture of ethyl acetate and
acetonitrile, to give 6-butyl-&-carbamoyl-3-(2-chloro-
ethyl)-[3H]-imidazo~5,1-d~-1,2,3,5-tetrazin-4-one
(0.49g), in the form of colourless crystals, m.p.
165-167C (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;Cl~ 9~/o~
EXAMPLE 19
Compound S
A stirred solution of sodium nitrite (0.44g) in
water (3.7ml) was cooled and maintained at 5-10C and
treated dropwise with a solution of 5-amino-2-
cyclohexylimidazole-4-carboxamide hydrochloride (l.lg;
prepared as described in West German Patent
Specification No. 2358509) in aqueous acetic acid (2~;
28ml) during 5 minutes. The resulting orange
precipitate was filtered off and dried in a desiccator
over phosphorus pen~oxide for 1 hour, to give crude
2-cyclohexyl-5-diazoimidazole-4-carboxamide (0.86g),
in the form of an orange solid, pure enough for use in
the next stage.
A solution of the crude 2-cyclohexyl-5-dLazo-
imidazole-4-carboxamide (0.86g; prepared as described
above) in ethyL acetate (17ml) was treated with
2-chloroethyl isocyanate (2.Oml) and left to stand in
the dark for 24 hours. The resul~ing solid was
- 33 -
filtered off and recrystallised from ethyl acetate, to
give 8-carbamoyl-3-(2-chloroethyl)-6-cyclohexyl-[3H]-
imidazoL5,1-d~ 1,2,3,5-tetrazin-4-one (0.23g), in the
form of colourless crystals, m.p. 245-248C (with
decomposition) [Elemental analysis: C,47.6;H,5.16i
N,25.6;Cl,10.8%; calculated: C,48.1;H,5.28;N,25.9;
Cl,10.5V/o].
EXAMPLE 20
Compound T
A stirred solution of sodium nitrite (0.58g) in
water (4.7ml) was cooled and maintained at 5-10C 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 (2~; 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
hours. The resulting solid was filtered off and
recrystallised twice from ethyl acetate, to give
~'5
- 34
8-carbamoyl-3-(2-chloroethyl)-6-phenethyl-L3H]-
imidazo[5,1-d]-1,2,3,5-t:etrazin-4~one (0.44g), in the
form of colourless crystals, m.p. 17~-1&1C (with
decomposition) [Elemental analysis: C,51.8;H,4.1g;
N~24~2;Cl~10~2%; calculated: C,52.0;H,4.36;N,24.2;
Cl,10.2%].
~XAMPLE 21
Compound U
A solution of 2-benzyl-5-diazoimidazole-4-
10 carboxamide (2.4g; prepared as described in Reference
Example 12) in dry ethyl acetate (150ml) was treated
with 2-chloroethyl isocyanate (lOml) and the reaction
mixture was left to stand at room temperature in the
dark for 20 hours. The reaction mixture was then
15 evaporated to dryness and the residue was triturated
witb petroleum ether (b.p. 60-80C; 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
20 1,3-bis(2-chloroethyl)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 an~
25 recrystallised from ethyl acetate, to give 6-benzyl-
8-carbamoyl-3-(2-chloroethyl)-L3H~-imidazo[5,1-d]-
- 35 -
1,2,3,5-tetrazin-4-one (0.7g), m.p. 161-163C (with
decomposition) LElemental analyais: C,$0.4;~l,3.96;
N,25.4;Cl,10.8V/o; calculated: C,50.53;H,3.g4;N,25.26;
Cl,10.66U/o; I.R. 1740cm 1].
EXAMPLE 22
Comp~und 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
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.
60-80C), to give 8-carbamoyl-3-(2-chloroethyl)-6-
isopropyl-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4~one
(0.2g), m.p. 189-190C (with decomposition) [Elemental
analysis: C,42.0;H,4.64;N,29.5%; calculated: C,42.19;
H,4.60;N,29.5%; I.R. 1740cm~lJ.
EXA~lPLE 23
Compound W
A solution of sodium nitrite (0.7g) in water (6ml)
was added to a solution of 5-amino-2-propylimida~ole-
4-carboxamide (1.37g; prepared as described in West
German Patent Specification No 2358509) in aqueous
acetic acid (2M; 22ml) at 0-5C, dropwise, during 5
minutes. The resulting precipitate was filtered off
S~
- 3~ -
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-chloro-
ethyl isocyanate (1.6ml) and stirred in the dark for
24 hours. The resulting precipitate was filtered off
and washed with ethyl acetate, to give 8-carbamoyl-3-
(2-chloroethyl)-6-propyl-[3H]-imidazo~5,1-d~-1,2,3,5-
tetrazin-4-one (0.48g), in the form of a buff solid,
m.p. 145-148C (with decomposition) [Elemental
analysis: C,41.1;H,4.4;N,28.5V/o; calculated: C,42.2;
H,4.60;N,29. 5'/0; NMR (in DMS0-d6): singlet at 7.7ppm;
triplets at 4.6, 4.0, 3.2 and l.Oppm, multiplet at
1.8ppm; I.R. (KBr disc): 1750, 1695cm 1].
EXAMPLE 24
Compound X
A stirred solution of 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 West German Patent Specification No
2358509) in aqueous acetic acid (2M; 14ml) at 0-3C,
dropwise, during 5 minutes. The resulting precipitate
was filtered off and dried in a desiccator over
~z~
phosphorus pentoxide for 1 hour, to give 5-diazo-2-
ethylimidazole-4-carboxamide (0.62g), in the form of a
yellow solid, m.p. 139C ~with decomposition), pure
enough for use in the next stage.
A solution of crude 5-diazo-2-ethylimidazole-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-carbamoyl-3-(2-chloroethyl)-6-ethyl-L3H]-imidazo-
[5,1-d]-1,2,3,5-tetrazin-4-one (0.59g), in the form of
pale grey crystals, m.p. 172-174C (with decomposition)
[Elemental analysis: C,39.7;H,3.98;N,31.0;Cl,13.1%;
calculated: C,39.9;H,4.10;N,31.0;Cl,13.1].
EXAMPLE 25
Compound Y
Dry ethyl acetate (lOOml) was treated with 5-diazo-
4-(4-methoxybenzyl)sulphamoyl-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 -
reactioo mixture was tnen evaporated to dryness and
the residue was triturated with petroleum ether
(b.p. 60-80C; 3 x 25ml) to remove excess 2-chloro-
ethyl isocyanate. The remaining residue was then
triturated with dichloromethane (2 x 50ml) 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
with ethyl acetate, to give 3-(2-chloroethyl)-8-
(4-methoxybenzyl)sulphamoyl-6-methyl-L3H]-imidazo-
~S,l-d]-1,2,3,5-tetrazin-4-one (1.5g), m.p. 159-160C
(with decomposition) [I.R. 1760cm~l~.
EXAMPLE 26
Compound Z
A solution of 3-(2-chloroethyl)-8-(4-methoxy-
benzyl)sulphamoyl-6-methyl-[3H]-imidazo[5,1-d~-1,2,
3,5,-tetrazin-4-one (1.5g; prepared as described in
Example 25) in trifluoroacetic acid (lOml) and anisole
(10 drops) was left to stand at room ~emperature
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
3-(2-chloroethyl)-6-methyl-8-sulphamoyl-[3H~-imidazo-
[5,1-d]-1,2,3,5-tetrazin-4-one (0.55g), m.p. 199-200C
~,~d"~
~ - 3~ -
(with decomposition) [Elemental analysis: C,29.1;
H~3~02;N~28~8;C1~12~1;S~10~6%; calculated: C,28.12;
H~3~10;N~28~71;Cl~12~11;S~10~95~/o; I.R. 1760,
3310cm~l~ .
EXAMPLE 27
Compound AA
A solution of 5-diazo-4-dimethylsulphamoyl-2-
methylimidazole (1.8g; prepared as described in
Reference Example 15) in dry ethyl acetate (lOOml) was
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-chloroethy' isocyanate (4ml) and
left to stand at room temperature for a further period
of 6 days. The reaction mixture was then evaporated
in vacuo and the residue was triturated with petroleum
ether (b.p. 60-80C; 2 x 25ml). The remaining solid
was dissolved in ethyl acetate and subjected to medium
pressure chromatograpny on silica gel, eluting with
ethyl acetate. The appropriate fractions were
combined, evaporated to dryness, and triturated with
petroleum ether (b.p. 60-80C), to give 3-(2-chloro-
ethyl)-8-dimethylsulphamoyl-6-methyl-[3H]-imldazo
[5,1-d~-1,2,3,5-tetrazin-4-one (2.17g), m.p. 137-138C
[Elemental analysis: C,33.8;H,3.91;N,25.8;Cl,11.2;
- ~o -
S~9~7%; calculated: C,33.7;H,4.0g;N,26.20;C1,11.05;
Sl 10~0%~ ~
EXAMPLE 28
Compound BB
A solution of 5-diazo-2-methyl-4-methylsulphonyl-
imidazole (0.4g; prepared as described in Reference
Example 16) 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. 60-80C; 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 wit~ ethyl acetate, to give
3-(2-chloroethyl)-6-methyl-8-methylsulphonyl-L3H]-
imidazo[5,1-d]-1,2,3,5-tetrazin-4-one (0.22g), m.p.
149-150C [Elemental analysis: C,33.0;H,3.35;N,23.8;
Cl,12.7%;S,10.7%; calculated: C,32.94;H,3.46;N,24.01;
Cl,12.15;S,10.99V/o; I.R. 1745cm~l].
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 dichloro-
methane (50ml) was treated with 2-chloroethyl
~2~ rj~r7~i~
isocyanate (2.5ml) and the stirred suspension was then
treated with 1,~-diazobicycloL5,4,0]undec-7-ene (0.7g).
The resulting solution was stirred at room ~emperature
in the dark overnigh~. The dichloromethane was
evaporated off and the resulting gum was tritura~ed
with petroleum ether (b.p. 60-&0C). The insoluble
residue was subjected to medium pressure
chromatography, eluting with ethyl acetate. The
appropriate fractions were combined, evaporated to
dryness and the residue was recrystallised from ethyl
acetate, to give 3-(2-chloroethyl)-8-(dimethylcarbam-
oyl)-[3H]-pyrazoloL5,1-d~-1,2,3,5-tetrazin-4-one
(0.38g) in the form of colourless crystals, m.p.
116-118C (with decomposi~ion) [Elemental analysis:
C,35.7;H,3.96;N,30.9;C1,13.1%; calculated: C,3g.93;
H,4.10;N,31.05;C1,13.1V/o; I.R. (KBr disc): 1770,
1630cm~l; NMR (in acetone-d6): singlets at 3.25
and &.40ppm, triplets at 4.25ppm and 4.95ppm].
EXAMPLE 30
Compound DD
Stirred concentrated sulphuric acid (2.5ml) was
treated with 8-carbamoyl-3-(2-chloroethyl)-L3H]-
imidazoL571-d~-1,2,3,5-tetrazin-4-one (0.24g; prepared
as described in British Patent Specification No.
2104522). The mixture was cooled to 0C and treated
~ 42 -
dropwise with concentrated nitric acid (d = 1~42; lml).
The solution was maintained at 4C for 1 hour and then
was poured on to ice. The precipitated solid was
collected, washed with water, and recrystallised from
aqueous acetone, to give 3-(2-chloroethyl)-8-(N-nitro-
carbamoyl) [3H]-imidazoL5,1-d]-1,2,3,5-tetrazin-4-one
~0.2~g) in the form of colourless crystals, m.p.
160 161C (with decomposition) LElemental analysis:
C,28.6;H,1.89,Cl,12.0;N,33.6%; calculated: C,29.23;
H,2.10;Cl,12.33;N,34.09%; I.R. (KBr disc): 3200, 1750,
1720 and 1620 cm~l; NMR (DMS0-d6) triplets at
4.05ppm (J = 6Hz) and 4.70ppm (J = 6Hz), singlet at
9.05~pm, broad singlet at 8.25ppm; m/e 287/289 (M+)].
EXAMPLE 31
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 diaæo compounds as
intermediates (prepared by the application or
adaptation of methods described in the following
Reference Examples), there were prepared:-
3-methyl-8-methylsulphonyl-l3H]-pyrazolo[5,1-d]-
1,2,3,5-tetrazin-4-one, in the form of a colourless
solid, m.p. 182-184C;
3-(2-chloroethyl)-8-methylsulphonyl-[3H]-pyrazolo-
[5,1-d]-1,2,3,5-tetrazin-4-one, in the form of a
- 43 -
colourless solid, m.p. 166-171C ;
3-(2-chloroethyl)-6-methyl-8-methylsulphinyl-
L3H]-imidazoL5,1-d~-1,2,3,5-tetraziD_4_one, in the
form of a yellow solid, m.p. 118-120C;
3~(2-chloroethyl)-8-ethylsulphonyl-6-methyl-
[3H]-imidazoL5,1-d]-1,2,3,5-tetrazin-4-one, m.p.
146-147C; and
3-(2-chloroethyl)-6-methyl~8-propylsulphonyl-
[3H]-imidazo[5,1-d~-1,2,3,5-tetrazin-4-one, in the
form of a white crystalline solid, m.p. 85-86C.
~L~
- 44
REFER~NCE ~XAMPL~ 1
(i) An intimate mixture o~ 5 nitroimidazole-
4-carboxylic acid (2.0 ~) and phosphorus pentachloride
(~.67 g) was stirred and heated in an oil bath at
120C for 1 hour. The resul~ing yellow slurry was
evaporated at 60C/O.lmmHg for 30 minutes, to give
l,6-dinitro-5h,10H-diimidazoL1,5-a:1',5'-d]pyrazine-
5,10-dione (1.90 g) in the form of a yellow solid,
m.p. 24~-251C (with decomposition). LI.R. (KBr disc):
1750 cm~l; m/e 278 (~+)].
LWindaus, Ber., 1923, 56, 6&4 and Gireva,
Chem. Abs., 59, 1622e, using the same method, describe
their products as "5-nitroimidazole-4-carbonyl
chloride"].
(ii) A mixture of 1,6-dinitro-5H,lOH-diimidazo-
Ll,5-a:1',5'-dlpyrazine-5,10-dione (5.&g), N-benzyl-
aniline (15g) and tetrahydrofuran (250ml) was heatea
at reflux for 6 hours. The tetrahydrofuran was
evaporated off in vacuo and the residual gum was
partitioned between dilute hydrochloric acid
(2N;l litre) and ethyl acetate (1 litre). Insoluble
N-benzylaniline 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), and
~ 45 ~
then with water, dried over magnesium sulphate, and
evaporated to dryness to ~ive an orange gUM. The gum
was triturated twice with boiling diethyl ether, to
give a colourless solid, which was crystallised from
isopropanol, to give 5-nitroimidazole-4-N-benzyl-
N-phenylcarboxamide (4.0g), in the form of colourless
flakes, m.p. 237-240C LElemental analysis:
C,62.3;H,4.28;N,17.3~/o; calculated: C,63.35;H;4.38;
N, 17~38%; I.R. (KBr disc): 1665c~ 1~.
(iii3 A solution of 5-nitroimidazole-4-N-benzyl-
N-phenylcarboxamide (4.0g) in dry ethanol (450ml) was
hydrogenated at 26C and 3 atmospheres pressure, using
a Raney nickel catalyst. When hydrogen absorption was
complete (after 4 hours 50 minutes), the mixture was
filtered, treated with concentrated hydrochloric acid
(3.6ml) and evaporated to dryness below 40C.
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. 190-193C (with decomposition) LNMR (in
DMS0-d6): singlets at 5.05, 7.1-7.2 and 8.4ppm; I.R.
(KBr disc): 1640cm~l; m/e 292 (~+)J.
- 46 -
REFERENCE EXAMPLE 2
(i) A mixture of N-benzyl-N-~4-methoxybenzyl)amine
[21.9g; Annalen, (1931), 490, 185J, 1,6-dinitro-SH,lOH-
diimidazo[5,1-a:1',5'-d~pyrazine-5,10-dione (6.7g;
prepared as described in Reference Example 1)) and dry
tetrahydrofuran (200ml) was heated at reflux for 18
hours. The tetrahydrofuran was evaporated off in
vacuo and the residual oily solid was partitioned
between dilute hydroehloric acid (2N, 500ml) and ethyl
acetate (5~0ml). 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-methoxybenzyl)carboxamide (2.9g) in
the form of a tan solid, m.p. 167-170C [after
crystallisation from a mixture of petroleum ether
(b.p. 60-80C) and isopropanol] [Elemental analysis:
C,61.3;H,4.93;N,15.3%; calculated: C,62.29;
H,4.95; N,15.25Vlo; I.R. (KBr disc): 3100-2&00, 1640,
1510, 1450 and 1370 cm 1. N~R (in DMSO-d6 at
120C): singlets at 3.76, 4.5, 4.6, 7.3 and 7.8ppm,
~ 47 -
doublets centred at 6~5 and 7.Zppm (The NMR
spectrum at room temperature is complicated because of
doubling of signals caused by hinaered rotation about
the bond linking the amide carbonyl group to the amide
nitrogen atom).
(ii) A solution of 5-nitroimidazole-4-N benzyl-N-
(4-methoxybenzyl)carboxamide (2.2g) in dry ethanol
(200ml) was hydrogenated at room temperature and 3
atmospheres pressure using a Raney nickel catalyst.
When hydrogen absorption was complete (after 2 hours
48 minutes), the mixture was filtered, treated with
hydrogen chloride gas, and evaporated to dryness below
40C. Trituration with a mixture of isopropanol and
diethyl ether gave 5-aminoimidazole-4-N-benzyl-N-(4-
methoxybenzyl)carboxamide hydrochloride (2.2g), in theform of a gummy solid, which decomposed above 70C
[I.R. (KBr disc): 3400-2800, 1640cm~l; NMR (in
methanol-d4): singlets at 3.7, 4.4, 4.5, 7.2 and
8.3ppm, doublets centred at 6.7 and 6.9ppm (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,10H-diimidazo-
[1,5-a:1',5'-d]pyrazine-5,10-dione (5.5g; prepared as
described in Reference Example l),N-(4-methoxybenzyl)-
aniline [14.5g; Zechmeister et al, Ber., (1530), 63B,
~ 48
2883] and tetrahydrofuran (250ml) was heated at reflux
for 12 hours. The tetrahydrofuran was then evaporated
off in vacuo and the residual dark oil was partitioned
between dilute hydrochloric acid (2M; lOOOml) and
ethyl acetate (lOOOml). 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-nitroimidazole-4-N-(4-methoxybenzyl)-N-phenyl-
carboxamide (3.1~g), in the form of a peach-coloured
solid, m.p. 212-215C (after recrystallisation from
isopropanol). [Elemental anaylsis: C,60.4;H,4.41;
N~16~0%; calculated: C,61.37;H,4.58;N,15.91%; N~R (in
DMSO-d6): singlets at 3.7, 5.0 and 7.7ppm, multiplet
at 6.7-7.3ppm; I.R. (KBr disc) 1660cm 1].
(ii) A solution of 5-nitroimidazole-4-N-(4-
methoxybenzyl)-N-phenylcarboxamide (2.lg) in dry
ethanol (200ml) was hydrogenated at 25C 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-aminoimidazole-4-N-(4-methoxybenzyl)-N-phenyl-
carboxamide (1.9g), in the form of a gum.
- ~9 -
lA portion of this gum was characterised as its
picrate:- 5-aminoimidazole-4-N-(4-methoxybenzyl~-N-
phenylcarboxamide (0.15g) 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-
methoxybenzyl)-N-phenylcarboxamide picrate (0.07g), in
the form of a yellow solid, m.p. 20ioC (with
decomposi~ion) [Elemental analysis: C,49.1;H,3.64;
N,l6-5%;c~4H2lN7o9 2H20 requires: C,49.1;H,4.29;
N,16.69%3~ .
REFERENCE EXAI~PLE 4
(i) A mixture of 1,6-dinitro-5H,lOH-diimidazo-
[1,5-a:1',5'-d]pyrazine-5,10-dione (8.08g; 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
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-nitroimidazole-4-N-methyl-N-phenylcarboxamide
(4.68g), in the form of a white solid, m.p. lg3C
LElemental analysis: C,52.5;H,3.95;N,22.2%;
calculated: C,53.66;H,4.09;N,22.76V/o; I.R. 1660cm~l~.
- 50 -
(ii) A-solution of 5-nitroimidazole-4-N~methyl-
N-phenylcarboxamide (l.Og) in dry ethanol (llOml) wa~
hydrogenated at 23C and 3 atmospheres pressure, using
a Raney nickel catalyst. When hydrogen absorption was
complete (after 1 hour 39 minutes), the mixture was
filtered and treated with dry hydrogen chloride gas.
The solution was then evaporated to dryness, to give
5-aminoimidazole-4-N-methyl-N-phenylcarboxamide
hydrochloride (0.9g), in the form of an off-white
solid, m.p. 100C (with decomposition).
{ This compound was characterised as its picrate:-
A solution of 5-aminoimidazole-4-N~methyl-N-phenyl-
carboxamide hydrochloride (0.25g) in water (2ml) was
treated with a solution of picric acid (0.25g) in
1,2-dimethoxyethane (2ml). The precipitate was
filtered off and washed with 1,2-dimethoxyethane, to
give 5-aminoimidazole~4-N-methyl-N-phenylcarboxamide
picrate (0.12g), in the form of a yellow solid, m.p.
237-238C (with decomposition) [Elemental analysis:
C,45.3;H,3.26;N,21.8%; calculated: C,45.85;H,3.39;
N,22.02%; I.R. (KBr disc): 1640cm 1]~.
- 51 -
REFERENCE EXA~lPL~ S
A stirred solution of sodium nitrite (l.Og) in
water (8ml) was cooled to 0C and treated with a
solution of 4-amino-2-methylimidazole~5-carboxamide
hydrochloride (2.0g; prepared as described in West
German Patent Specification No. 2358505) in aqueous
acetic acid (2N; 24ml), maintaining the temperature at
between -2C and 0C. When the addition was compLete
the resulting yellow solid was filtered off and dried
in vacuo over phosphorus pentoxide, to give 5-diazo-2-
methylimidazole-4-carboxamide (1.26g), m.p. 175C
(explodes).
REFERENCE EXAMPLE 6
(i) A stirred aqueous solution of
dimethylamine (30% 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
by the method of Fisher et al, Can. J. Chem., 39,
501), in portions. The mixture was stirred for a
further 20 minutes ana was then evaporated in vacuo at
below 40C to reduce the volume by half. The mixture
was then made strongLy acidic by treatment with
concentrated hydrochloric acid and the resulting pale
yellow solid was filtered off and recrystallised from
dimethylformamide, to give 5-nitroimidazole-4-(N,N-
dimethylsulphonamide) (2.73g), in the form of brownish
52
plates, m.p. 282-283C (with decomposition) ~Elemental
analysis: C,27.3;H,3.65;N,25.4;S,14~2V/o; calculated:
C~27~3;~3~66;N~25~4;S~14~6J/o]~
(ii) A solution of 5-nitroimidazole-4-(N,N-
5 dimethylsulphonamide) (l.Og) in dry ethanol (lOOml)
was hydrogenated at 24C 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
10 slightly acidic. The mixture was then evapora~ed in
vacuo at below 30C. 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-dimethylsulphonamide)
hydrochloride (0.8g) in the form of pinkish-buff
needles, m.p. 188-189C (with decomposition)
LElemental analysis: C,26.1;H,4.80;N,23.6;Cl,15.g;
S~l3.9%;C5HloN402S:HCl requires C,26.5;H,4.85;
N~24~7;Cl~15~6;S~14~15//o~
(iii) A stirred solution of sodium nitrite
(0.31g) in water (5ml), cooled in an ice-bath, was
treated dropwise with a solution oi: 5-aminoimidazole-
4-(N,N-dimethylsulphonamide) hydrochloride (0.7g) in
dilute hydrochloric acid (2N;3.1ml). The resulting
~ 53
solid was filtered off an~ washed with ice-ccld water,
to give 5-diazoimidazole-4-(N,N-dimethylsulphonamide)
(0.3&g~, m.p. 10~C (with decompositon). ~I.R. 21&0,
2210cm~l] .
A further portion (0.21g) of slightly less
pure product was obtained by extraction of the aqueous
liquors at 0C with ethyl acetate, drying the extract
over magnesium sulphate and evaporation in 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., ~ cit.), in portions.
The mixture was stirred for a further 15 minutes and
was then evaporated in vacuo at below 40C 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. 260-263C (with
decomposition) LElemental analysis: C~23~1;H~2~87;
N~27~4;S~15~4~/o; calculated: C~23.3;H~2.~3jN~27.2;
S,15.55%].
~2~r~t;~
- 54 -
(ii) A solution of 5-nitroimidazole-4-(N-methyl-
sulphonamide) (l.Og) in dry ethanol (lOOml) was
hydrogenated at 24C and 3 atmospheres using a Raney
nickel catalyst. The mixture was then filtered and
immediately diluted with diethyl ether (200ml) and
~reated with dry hydrogen chloride gas until it was
slightLy acidic. The mixture was then evaporated in
vacuo at below 30C. The residual solid was dissolved :
in a minimum volume of hot ethanol and the solution
was treated with charcoal, ~iltered and diluted with
diethyl ether. The resulting solid was filtered off,
to give 5-aminoimidazole-4-(N methylsulphonamide)
hydrochloride (0.63g), m.p. 178-180C (with
decomposition) LElemental analysis: C,22.3;H,4.13;
N,25.5;Cl,16.9%;C4H&N402S:HCl requires
C~22~6;H~4~26;N~26~35;Cl~16~7V/o~ ~
(iii) A stirred solution of sodium nitrite
(0.285g) in water (4ml), cooled in an ice-bath, was
treated d~opwise with a solution of 5-aminoimidazole-
4-(N-methylsulphonamide) hydrochloride (0.55g) in
dilute hydrochloric acid (2N; 2.8ml). The resul~ing
solid was filtered off and washed with ice-cold water,
to give 5-diazoimidazole-4-(N-methylsulphonamide)
(0.36g), m.p. 150C (with decomposition). LElemental
analysis: C,25.2;~,2.47;N,37.0U/o; calculated: C,25.7;
H,2.69;N,37.4~/o; I.R. 2210cm 1].
$ 2~
A further portion (0.07g) of product was
obtained by extraction of the aqueous liquors at 0C
with ethyl acetate, drying the extract over magnesium
sulphate and evaporation in vacuo.
REFERENCE EXAMPLE 8
A solution of sodium nitrite (0.5g) in
water (5ml), maintained at 0C, was treated dropwise
with a solution of 5-amino-4-methylsulphonylimidazole
hydrochloride ~l.Og; prepared as described by Bennett
et al, J.A.C.S., 7~(3~, 2188-2151! (1557)] in dilute
hydrochloric acid (2N; 5ml). The solution was stirred
for a further 15 minutes and was then extractea with
ethyl acetate (5 x 20ml). The combined extracts were
dried over sodium sulphate and evaporated in vacuo to
leave a yellow oil that crystallised on standing, to
give 5-diazo-4-methylsulphonylimidazole (0.74g), m.p.
12~-130C [I.R. 2125cm lJ.
REFERENCE EXAMPLE 5
(i) A stirred solution of p-methoxybenzylamine
(lOg) in water (30ml) was treated with 5-nitro-
imidazole-4-sulphonyl 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., ~
cit.). The mixture soon set solid, whereupon it was
treated with isopropanol (20ml) and triturated, and
allowed to stand overnight. The resulting solid was
- 56 -
filtered off, washed with ice-cold wa~er, and ~hen it
was suspended in water (L50ml) and treated carefully
with dilute hydrochloric acid (2N) until the
suspension just attained pH2. The resulting yellow
solid was filtered off and washed with a little
ice-cold water to give 5-nitroimidazole-4- LN- (4
methoxybenzyl)sulphonamide~ (7.42g), m.p. 269-270C
(with decomposition).
(ii) A solution of 5-nitroimidazole-4-LN-(4-
methoxybenzyl)sulphonamide] (l.Og) in dry ethanol(lOOml) was hydrogenated for 6 hours at 3 atmosphees
using a Raney nickel catalyst (50%). 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 diethyl ether. The solid was
filtered off and washed with diethyl ether, to give
5-aminoimidaæole-4- LN- (4-methoxybenzyl)sulphonamide]
(0.25g), m.p. 154-155C.
(iii) A solution of sodium nitrite (0.14g) in
water (5ml) was treated dropwise with a solution of
5-aminoimidazole-4- LN- (4-methoxybenzyl)sulphonamide]
(0.5g) in dilute hydrochloric acid (2N; lOml),
maintaining the temperature at 0C. The mixture was
stirred at 0C for a further 15 minutes and then the
solid was filtered off, washed with water and dried
- 57 -
over phosphorus pentoxide, to give 5-diazoiimidazole-4-
LN-(4-methoxybenzyl)sulphonamide (0.3g), m.p.
144-146C (with decomposition) ~I.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-dione (4.59g;
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; ~2ml). 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-piperidinocarbonyl-
imidazole (2~72g), in the form of a yellow solid, m.p.149-150C. LElemental analysis: C,48.2;H,5.33;N,25.1~/o;
calculated: C,48.2;H,5.39;N,25.0%].
(ii) A solution of 4-nitro-5-piperidinocarbonyl-
imidazole (2.68g; prepared as described above) in
methanol (27ml) and dimethylformamide (27ml) was
treated with platinum oxide (0.27g) and the shaken
mixture was hyarogenated at room temperature and
atmospheric pressure. When hydrogen uptake was
complete, the mixture was fil~ered and the filtrate
was evaporateà in vacuo. The residue was dissolved in
dilute hydrochloric acid (2N; 50ml), the solution was
filtered and tne filtrate was evaporated in vacuo.
The resulting residue was washed witn acetone, to give
4-amino-5-piperi~inocar~onylimidazole nydrochloride
(2.1g), in thé form of a pale green solid, m.p.
175-177C, pure enough for use in the next stage.
REFERENCE EXAMPLE 11
(i) A stirred solution of 2-cyanoethylbenzene
(5.0g) and benzyl mercaptan (&.Og) in dly dioxan
(~Omlj was treated with hydrogen chloride gas until
saturated (3 hours), an~ left to stand at room
temperature for 5 days. The mixture was then treated
witb diethyl ether and the resulting precipitate was
filtered off and washed with diethyl ether, to give
S-benzyl 3-phenylpropionothioimidate hydrochloride
(9.7g), in the form of a colourless solid, m.p.
15&-160C, pure enough for use in the next stage.
(ii) A solution of ~-amino-.~-cyanoacetamide
(3.3g) in ethanol (20ml) was treate~ with crude
S-benzyl-3-phenylpropionothioimidate hydrochloride
(9.7g; prepared as described above) and the mixture
was heated at reflux for 15 minutes. The mixture was
: /
- 5~ -
cooled and the resulting solid was filtéred o~f and
recrystallised from methanol, to give 5-amino-2-
phenethylimidazole-4-carboxamide hydrochloride (2.3g),
in the form of colourless crystals, m.p. 270-274C
LElemental analysis: C,53.8;H,5.55;N,21. l~/o;
C12H14N40:HCl requlres: C~54.0;H~5.67;N~21.0~/o].
REFERENCE EXA~PLE 12
A solution of sodium nitrite (0.5g) in water
(15ml~ maintained at 0-5C was treatea dropwise with a
solution of 5-amino-2-benzyl-4-carbamoylimidazole
(1.26g; prepared as described in West German Patent
Specification No 2358509~ in dilute hydrochloric acid
(2N;15ml). The mixture was stirred at 0C for a
further period of 30 minutes and the resulting pale
yellow solid was filtered o~, washed with water and
dried in a desiccator over phosphorus pentoxide, to
give 2-benzyl-5-diazoimidazole-4-carboxamide (O.&g),
m.p. 121-122C (with decomposition) LI.R. 2180cm~l~.
REFERENCE EXAMPLE 13
(i) A solution of isobutyronitrile (6.9g) and
benzyl mercaptan (20ml) in dry dioxan (lOOml) was
treated with dry hydrogen chloride gas for 3 hours at
0-10C. 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
was then poured onto diethyl ether (1 litre) and the
- 6~ -
resulting ~hite precipitate was filtered off and washea
with diethyl ether, to give S-benzyl isobutylthi
imidate hydrochloride (20.3g), mOp. 165-16~C
[Elemental analysis: C,57.1;H,7.0;N,5.9;Cl,15.7;
S~13.5/o;C11~15NS:HCl requires: C,57.5;H,7.02;
N~6.l;cl~l5.43;sJl3.~6vlo] .
(ii) A solution of~-amino-c~-cyanoacetamide
(5.0g) and S-benzyl isobutylthioimidate hydrochlvride
(11.5g; prepared as described above) in ary
2-ethoxyethanol (150ml) was heated at reflux for 30
minutes. The solvent was evaporated. The resulting
dark oil was triturated with a mixture o~ chloroform
and methanol (4:1 v/~; lOOml) and the insoluble
material was filtered OLf and discarded. The filtrate
was subJectea 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-isopropylimidazole-4-
carboxamide hydrochloride (4.44g) in the form of a
gummy solid, pure enough for use in the next stage.
(iii) A solution o~ sodium nitrite (0.5g) in
water (5ml) maintained at 0C 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
~ Z,~ 3~
, '
_ 61
mixture was then stirred for a further period of S
minutes at 0C anc1 then was extracted with ethyl
acetate (3 x 2Gml). The combined extracts were dried
-over magnesium sulphate, concentrated ln vacuo to a
volume of 20ml, and subjectea to medium pressure
chromatography on siLica gel, eluting with ethyl
acetate. The appropriate fractions (iaenti~ied 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. 120C (with decomposition) LI.R.
2170cm~l].
REF~RENCE EXA~L~ 14
-
(i) A cooled, stirred solution of 2-methyl-
5-nitroimidazole (127g) in aqueous sodium hydroxide
solution (52 w/v; 1500ml) was treated with bromine
(160g), maintaining the temperature at 15-~0C. The
mixture was stirred at room temperature for 5.5 hours
and the solid which had precipitated was redissolved
by treatment of the mixture with aqueous sodium
hydroxide solution (2N). Traces of insoluble material
were filtered off and the filtrate was acidified to
pHl ~y treatment witn concentrated hydrochloric acid.
The resulting white solid was filtered off,
recrystallised from ethanol and dried in a desiccator
over phosphorus pentoxide, to give 4-bromo-2-methyl-5-
- 62 -
~ nitroimidazole (151g), in the forrrl of a white
crystalline solid, m.p. 267-26~C.
(ii) A stirred solution o~ 4-bromo-2-methyl-5
- nitroimidazole (20.6gms; prepared as described above)
in aqueous ammonia solution (5N; 180ml) was warmed at
45C and treated with a steady stream of hydrogen
sulphide gas for 40 minutes. A yellow crystalline
solid was slowly ~ormed. Yhe mixture was coolea in
ice and the solid was filtered o~, washed with
ice-water, and dried in a desiccator over phosphorus
pentoxide, to give 4-mercapto-2-methyl-S-nitroimidazole
ammonium salt (14.6g), darkens without melting below
300C LElemental analysis: C,27.2;H,4.41;N,31.6;
S,l~.2/o;c4H4o2N3s:NH4 requires: C,27.27;
H,4.58;N,31.8;S,1&.2V/o~.
(iii) An ice-cooled, vigorously stirred solution
of 4-mercapto-2-metnyl-5-nitroimidazole ammonium salt
(3.51g; prepared as described above) in dilute
hydrochloric acid (lN; 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 0C and then the solid was filtered off, washed
with water and dried in a desiccator over phosphorus
pentoxide, to give 4-chlorosulphonyl-2-methyl-5-
nitroimidazole (3.0g); m.p. 160-162C (with
decomposition) LElemental analysis: C,2U.&;~,1.73;
- 6~5 ~
N~18~3;C1~15~7;S~14~6~/o; calculated: C,21.25;H,1.7~;
N~18~63;Cl~15~72;S~14~21V/o~ ~
(iv) A cooled solution o~ 4-methoxybenzylamine
(5.48g) in dry absolute ethanol (20ml~ was treated
with 4-chlorosulphonyl-2-methyl-5-nitroimidazole
(2.25g; prepared as described above) and the mixture
was stirred at room temperature for 3 hours. The
yellow soli~ which precipitated was filtered off,
washed with ethanol and discarded as 4-methoxybenzyl-
amine hydrochloride. The combined filtrate and
washings were evaporated to dryness and the resulting
residue was suspended in wa~er (50ml), acidified to
pHl 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-
benzylsulphamoyl)-2-methyl-5-nitroimidazole (2.77g),
in the form of an o~f-white solid, m.p. 167-170C
Lelemental analysis C~44~2;H~4~32;N~17~2;S~9~5V/o;
calculated: C,44.17;H,4.32;N,17.17;S,5.83%].
(v) A solution of 4-(4-methoxybenzyl-
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 and washed with dry ethanol (lOml) and
the combined filtrate and washings were acidified to
- 64 -
pHl by treatme~t with concentrated hydrochloric acid
and evaporated to dryness. The resulting residue was
triturated with diethyl ether, to give 5-amino-4-
(4-methoxybenzylsulphamoyl)-2-methylimidazole
hydrochloride (3.25g); m.p. 183-185C.
(vi) A solution of sodium nitrite (0.3g) in
water (5ml) maintained at 0-5C was treated dropwise
with a solution of 5 amino-4-(4-methoxybenzyl-
sulphamoyl)-2-methylimidazole hydrochloride (l.Og;
prepared as described above) in dilute hydrochloric
acid (2N; lOml). The mixture was stirred for a
further period of 5 minutes at 0-5C 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-methoxybenzylsulphamoyl)-2-methyl-
imidazole (0.75g), m.p. 140C ~with decomposition)
[I.R. 2200cm~l~.
REFERENCE EXAMPLE 15
(i) An ethanolic solution of dimethylamine
(33U/o w/v; lOml) 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 pHl by treatment with concentrated
hydrochloric acid and the resulting white solid was
filtered off and washed wit~ cold water, to give
~ ~5
- 65 -
4-dimethylsulphamoyl-2-methyl-5-nitroimidazole ~ g),
m.p. 240-241C lElemental analysis: C,30.5;H,4.24;
N~23~8;S~13~8~/o; calculated: C,30.77;H,4.3;N,23.~2;
S,13.69~/o; NM~ (in D~SO-d6): 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 pHl by treatment with
concentrated hydrochloric acid and evaporated to
dryness. The resulting orange residue was triturated
with diethyl ether, to give 5-amino-4-dimethyl-
sulphamoyl-2-methylimidazole (8.9g), m.p. 215-217C
(with decomposition).
~ iii) A solution of sodium nitrite (l.Og) in
water (15ml) was maintained at 0C and treated
dropwise with a solution of 5-amino-4-dimethyl-
sulphamoyl-2-methylimidazole (2.4g) in dilute
hydrochloric acid (2N; 30ml), and stirred for a
further period of 10 minutes at 0C. 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. 60-80C), to give 5-diazo-4-dimethyl-
~ 5
- 66
- sulpnamoyl-2-methylimidazole (l.~g), ~I.p. 85-~7UC
(with decompositon) LI.~, 21&0cm~l~.
R~FEX~NCE ~XAMPLE 16
(i) A solution of 4-mercapto-2-methyl-5-nitro-
imidazole ammonium salt (10.5g; prepared as described
in Reference Example 14) in methanolic sodium
met~oxide solution Lprepared by carefuily dissolving
sodium (2.3g) in dry methanol (250ml)~ was treated
with methyl iodide (10.7g) and heated at reflux for 2
hours. The mixture was then evaporated to dryness and
the residue was suspended in aqueous sodium hydroxide
solution (2N; lOOml). The suspension was filtered and
tne fil~rate was acidified to pHl by treatment with
concentrated hydrochloric acia, to give 2-methyl-4-
methylthio-5-nitroimidazole (9.Og), in the rorm of a
yellow solid, m.p. 236-237C (with decomposition)
[Elemental analysis: C,34.7;H,4.04;N,24.3jS,18.5V/o;
calculated: C~34.67;H~4.07;N,24.26;S~L8.51J/o]~
(ii) A solution o~ 2-methyl-~-methylthio-5-
nitroimidazole (3.46g; prepared as described above) in
glacial acetic acid (35ml) was heated at 60C and
treated dropwise with aqueous hydrogen peroxide
solution (30% w/v; 35ml). The mixture was then heated
at 100C for 15 minutes, coolea to room temperature
and treated with suf~icient sodium sulphite to destroy
the excess of hydrogen peroxide (detected by testing a
sample with starch and potassium iodide). The mixture
v
- 67 -
was then subjected to continous liquid-liquid
extraction with ethyl aceta~e for 20 hours. The
extract was evaporated and the remaining white solid
was triturated with petroleum ether (b.p. ~0-&0C) and
filtered off, to give 2-methyl-4-methylsulphonyl-5-
nitroimidazole (3.6g), m.p. 222-224C Lelemental
analysis: C,29.8;H,3.28;N,20.6;S,15.7V/o; calculated:
C~25~27;H~3~44;N~20~48;S~15~63~/o]~
(iii) A solution of 2 methyl-4-methyl-
sulphonyl-5-nitroimidazole (4.9g; prepared as
described above) in dry ethanol (400ml) was
hydrogenated at 3.5 atmospheres pressure over a Raney
nickel catalyst for 30 minutes. The catalyst ws
filtered off and the filtrate was acidified to pH 1 ~y
treatment with concentrated hydrochloric acid and
evaporated to dryness and the resulting residue was
triturated with diethyl ether containing a trace of
ethanol to give a purple solid which was filtered off
and washed with diethyl ether, to give 5-amino-2-
methyl-4-methylsulphonylimidazole hydrochlori~e
(4.1g), m.p. above 300C ~Elemental analysis: C,27.3;
H,4.51;N,l9.9;C1,17.9;S,13.7V/o; calculated: C,28.37;
H,4.76;N,19.8;Cl,16.75;S,15.15%].
(iv) A solution of sodium nitrite (0.25g) in
water (5ml), maintained at 0C, was treatea dropwise
with a solution of 5-amino-2-methyl-4-methylsulphonyl-
~d~
- 63 -
imidazole hydrochloride (0.53g; prepare~ as aescribed
above). The mixture was stirred Eor a furtner period
of 15 minutes at 0C and was ex~racted with ethyl
acetate (5 x 15ml). The comDined extracts were dried
over magnesium sulphate and evaporated to dryness.
The resulting oil was ~riturated with petroleum ether
(b.p. 60-80C) to give 5-diazo-2-methyl-4-methyl-
sulphonylimidazole (0.4g), m.p. 1~0C (with
decomposition) LI.R. 21&5cm~l].
REFERENCE EXAMPLE 17
(i) A mixture of ~-cyano-N,N-dimethylacetamide
(~.2g; prepared as described by Bowman et al., J. Chem
Soc., 1954, 1171), acetic anhydride (21ml) and
triethyl orthoformate (21ml) was heated at 160-170C
in a flask fitted with a McIntyre 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 with
ethanol (lOml) and concentrated in vacuo again. The
residue was distilled at 160-170C/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 of
an off-white, oily solid, pure enough for use in the
next stage.
~ ,3
_ 69
(ii) A solution ot crude 2-cyano-3-ethoxy-N,~I-
dimethylpropenamide (5.3g; prepared as describe~
above) in dry ethanol (SOml) was treated dropwise with
hydrazine hydrate (1.58g). After the addition was
complete the mixture was heated at re~lux 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 and
methanol (17:3 v/v) and the appropriate fractions were
combined and evaporated to dryness. The resulting
residue was dissolved in hot isopropanol (5ml) and
treated with concentratea hydrochloric acid (4ml) and
the resulting crystalline precipitate was collected,
to give 3-aminopyrazole-4-(N,N-dimethylcarboxamide)
hydrochloride (1.3~g), in the form of colourless
crystals, m.p. 195C. LElemental analysis: C,37.8;
H~5~82;N~29~0;C1~18~3~/o; calculated: C,37.8;H,5.82;
N,29.39;Cl,1&.6%; I.R. (K~r disc): 3500, 3400, 3000-
2200, 1655cm~l; NMR (in DMSO-d6): singlets at 3.0
and 8.lppm 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-dimethylcarboxamide) hydro-
chloride (1.3~g; prepared as described above). The
stirred mixture was cooled to 0C and treated with
amyl nitrite (2.55g), dropwise during 15 minutes,
_ 70
maintaining the temperature at 0C. The resulting
solution was left to stand at 2-4C for 1 hour an~ was
then poured into diethyl ether (800al1). The resulting
solid was collected and washed with diethyl etner, to
give 3-diazopyrazole-4-(N~N-dimethylcarboxamide)
hydrochloride (0.92g), in the form of colourless
crystals, m.p. 150C (explodes). LElementaL analysis:
C,35.3;H,3.79jN,34.3%;C6H70N5Cl;HCl requires:
C~35~74;H~4~00;N~34~74~/o; I.R. (KBr disc): 3000-2100,
2280, 1630cm~l~.
The present invention includes within its scope
pharmaceutical compositions which compriset as active
ingredient, at least one compound of the general
formula shown in Figure I, together with 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.
~ethods of presentation o~ pharmaceutically active
compounds are well known in the art and 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 for 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
- 72 _
substances other than inert diluents, e.g. lubricating
agents, such as magnesium stearate. Liqui~
compositions for oral administration include
pharmaceutically~acceptable emulsions, solutions,
suspensions, syrups and elixirs containing inert
diluents commonly used in the art, such as water and
liquid paraffin. Besides inert diluents such
compositions may also comprise adjuvants, such as
wetting and suspending agents, e.g. polyvinyl-
pyrrolidone, and sweetening, flavouring, perfuming andpreserving 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 ~ 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 compounds.
Preparations according to the invention for
parenteral administr~tion incLude sterile aqueous or
non-aqueous solutions, suspensions, or emulsions.
Examples of non-aqueous solvents or suspending media
are polyethylene glycol, dimethyl sulphoxide,
vegetable oils such as olive oil, and injectable
- 7~ -
organic esters such as ethyl oleate. These
compositions may also include adjuvants such as
preserving, wetting, emulsifying and dispersing
agents. They may be sterilised, for example, by
filtration through a bacteria-re~aining filter, by
incorporation of sterilising agents in the
compositions, or by irradiation. They may also be
manufactured 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 of the invention may be varied, it being
necessary that it should 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 0.025% 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 0.1% by weight of active substance. The dose
employed depends upon the desired therapeutic effect,
the route of administration and the duration of the
treatment.
74 -
The tetrazine derivatives of general formula I ar~
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 presen~
invention.
COMPO~SITION EXAMPLE 1
A solution suitable for parenteral administration
was prepared from the following ingredients:-
8-(N-benzyl-N-phenylcarbamoyl)-3-methyl-[3H]-
imidazol5,1-d]-1,2,3,5-tetrazin-4-one 1.0 g
dimethyl sulphoxide 10 ml
by dissolving the 8-(N-benzyl-N-phenylcarbamoyl)-3-
methyl-[3H]-imidazoL5,1-d]-1,2,3,5-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-benzyl-N-phenylcarbamoyl)-3-methyl-[3H]-imidazo-
L5,1-d]-1,2,3,5-tetrazin-4-one.
Similar ampoules containing solutions suitable for
parenteral administration may be prepared by
proceeding in a similar manner but replacing the
3~ b~
- 75 -
8-(N-benzyl-N-phenylcarbamoyl-3-methyl-~3H]-imidazo-
[5,1-d~-1,2,3,5-tetrazin-4-one by another col-npound of
the general formula shown in Eigure I.
COMPOSITLON ~XAMPLE 2
A solution suitable for parenteral administration
was prepared from the following ingredients:-
3-(2-chloroethyl)-8-(N-methylsulphamoyl)-L3H3-
imiàazo[5,1-d~-1,2,3,5-tetrazin-4-one 1.0 g
dimethyl sulphoxide 10 ml
10 arachis oil 90 ml
by dissolving the 3-(2-chloroethyl)-8-(N-methyl-
sulpbamoyl)-~3~j-imidazoL5,1-dj-1,2,3,5-tetrazin-4-one
in the dimethyl sulphoxide and adding the arachis
oil. The resulting solution was divided, under
aseptic conditions, into ampoules at an amount of
10 ml per ampoule. The ampoules were sealed, to give
10 ampoules each containing 100 mg of 3-(~-chloro-
ethyl)-8-(N-methylsulphamoyl)-L3H]-imidazoL5,1-d]-
1,2,3,5-tetrazin-4-one.
Similar ampoules containing solutions suitable for
parenteral administration may be prepared by
proceeding in a similar manner but replacing the
3-(2-chloroethyl)-8-(N-methylsulphamoyl)-[3H]-imiaazo-
L5,1-d~-1,2,3,5-tetrazin-4-one by another compound of
the general formula shown in Figure I.
7~ ~
COMPOSITION EXAM~LE 3
Capsules suitable for oral administration were
preparea by placing 3-(2-chloroethyl)-8-(N-methyl-
sulphamoyl)-[3H]-imidazoL5,1-d]-1,2,3,5-tetrazin-4-one
into gelatin shelLs of number 2 size at a rate of
10 m8 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 shells.
s~
--i 77 _
R2 ~1 1
~N ;~
zl \~ N ~ N~
FIG. I FIG. II
R12 ~2~ /~\~
FIG. III FIG. V
R15 R16
~ R A~Z\N\Rl
FIG. VI FIG. VII
