Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
iQ~345~1
The present invention relates to imidazolobenzodia-
zepines and, more particularly, to certain pharmaceutically
active 1,2-dihydro 6-phenyl lH, 4H-imidazo-~1,2a~ ~1,4~ benzo-
diazepin-l-ones that may be of use in human or veterinary me-
dicine, as well as to a process for-their preparation.
The 1,2-dihydro 6-phenyl lH, 4H-imidazo fl,2a~ fl, ~
benzodiazepin-l-ones with which the invention is concerned are
represented by the ge~eral formula :
/ R4 --
;C \ R5
N (I)
}1,1~'\~
~ R2
wherein:
Rl represents a hydrogen atom, a halogen atom, a nitro
radical or a trifluoromethyl radical;
R2, which may be at any appropriate position in the
phenyl ring, represents a hydrogen atom or a halogen atom;
R3 represents a hydrogen atom or a methyl radical; and
R4 and R5, which are the same of different, each re-
presents a hydrogen atom, an alkyl radical containing from 1 to5 carbon atoms, a hydroxyalkyl radical containing from 1 to 5
carbon atoms, an aminoalkyl or alkylaminoalkyl radical ~the
LD~
` 1073454
alkyl moieties each containing from 1 to 5 carbon atoms), a
phenyl radical or a cycloalkyl radical containing from 3 to 8
carbon atoms, or R4 and R5 represent together with the
nitrogen atom to which they are bound a heterocyclic radical
selected from the group consisting of pyrrolidinyl, piperidino,
morpholino, thiomorpholino, piperazin-l-yl, 4-alkyl-piperazin-
l-yl, 4-hydroxyalkyl-piperazin-1-yl, 4-phenyl-piperazin-l-yl,
4-(l'-phenyl-5'-imidazolyl-4'-one) piperazin-l-yl and R6-
piperazin-l-yl radicals, in which R6represents a cycloalkyl-
-alkyl radical containing from 3 to 8 carbon atoms, an
alkenyl radical containing from 2 to 5 carbon atoms or a ~-
4-dialkylphosphinyl alkyl radical, the alkyl moieties containing
from 1 to 5 carbon atoms. Pharmaceutically acceptable acid
addition salts of these derivatives are also within the scope
of the present invention.
~ Where Rl represents a halogen atom, it may convenient-
ly be a fluorine, chlorine or bromine atom, but is preferably
a chlorine atom.
Where R represents a halogen atom, it too may con-
- 20 veniently be a fluorine, chlorine or bromine atom, but is pre-
ferably a fluorine or chlorine atom. Furthermore, the halogen
atom R2 is preferably in the ortho-position.
R3 is most preferably a hydrogen atom.
Where either of R4 and R5 represents an alkyl radical,
it may conveniently be a methyl, ethyl, propyl, isopropyl, butyl,
t-butyl or pentyl radical, but is preferably a methyl, ethyl,
n-propyl, n-butyl or t-butyl radical.
Where either of R4 and R5 represents a hydroxyalkyl
radical, the alkyl moiety may conveniently be a methyl, ethyl,
propyl, butyl or pentyl radical, but is preferably an ethyl
radical.
Where either of R4 and R5 represents an aminoalkyl
-2-
.
1073~5~
or alkylaminoalkyl radical (which latter term includes both
monoalkyl- and dialkylaminoalkyl), each of the alkyl moieties
may conveniently be a methyl, ethyl, propyl or butyl radical, but
is preferably a methyl or ethyl radical. Preferably R4 and/orR5
represent an aminomethyl, aminoethyl, dimethylaminoethyl or die-
thylaminoethyl radical, but may also represent an aminopropyl,
aminobutyl, methylaminomethyl, methylaminoethyl or dimethyl-
aminopropyl radical.
- . . ~ .............. ........ .
:: - -' : - ': .......... , : . ,,,~
. .. , -; . . : . :
0734 ~
Where either of R4 and R5 represents a cycloalkyl
radical, it is conveniently one containing from 3 to 8 carbon
atoms, and is preferably a cyclohexyl radical.
R4 and R5 may be the same - they each may be, for
example, a methyl group - or different, and when they are
different one of them is preferably hydrogen.
Where R4 and R5, together with the conjoining nitrogen
atom, form a heterocyclic grouping, this grouping is saturated,
may be substituted or unsubstituted, and may optionally contain
a second heteroatom. Typical examples of unsubstituted hetero-
cyclic groupings are pyrrolidinyl,piper~ino, m~holin~ thiom~rpholino
and pipe~azin-l-yl. Preferred substituents for such heterocyclic
groupings are alkyl radicals containing from 1 to 5 carbon atoms,
such as methyl~ ethyl and propyl; hydroxyalkyl radicals con-
taining from 1 to 5 carbon atoms, such as hydroxyethyl; dialkyl-
phosphinylalkyl radicals, each alkyl moiety of which contains
from 1 to 5 carbon atoms, such as methyl; cycloalkylalkyl radicals
containing from 3 to 6 carbon atoms in the cycloalkyl moie$y and
from 1 to 5 carbon atoms in the alkyl moiety, such as cyclo-
propylmethyl; alkenyl radicals containing from 2 to 5 carbon -
atoms, such as allyl; aryl radicals, such as phenyl; and nitrogen
heterocyclic radicals, such as l-phenyl-5-imidazolyl-4-one.
~ypical examples of substituted heterocyclic groupings are the
4-a1kyl-piperazin-1-yls and especially 4-methyl , 4-ethyl- and
4-propyl-piperazin-1-yl; the 4-hydroxyalkyl-piperazin-1-yls and
especially 4-hydroxyethyl-piperazin-1-yl; the 4-dialkylphosphinyl-
alkyl-piperazin-l-yls and especially 4-dimethylphosphinylmethyl-
piperazin-l-yl; the 4-cycloalkylalkyl-piperazin-1-yls and
especially 4-cyclopropylmethyl-piperazin-1-yl; 4-alkenyl-
piperazin-l-yls and especially 4-allyl-piperazin-1-yl; 4-phenyl-
piperazin-l-yl; and 4-(1'-phenyl-5'-imidazoyl-4'-one)-piperidin-
l-yl .
- 3 -
~0~3454
Within the broad area encompassed by general formula I,
the following smaller groups of compounds are preferred :
a) the imidazolobenzodiazepine~ of general formula I wherein
either R4 and R5, which may be the same or different, each
represents a hydrogen atom, an alkyl radical containing from
1 to 5 carbon atoms, a hydroxyethyl radical, a dimethyl- or
diethylaminoethyl radical, a phenyl radical, or a cyclohexyl
radical, or R4 and R5 together with the nitrogen atom form a
pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-
l-yl, 4-alkyl-piperazin-1-yl, 4-hydroxyalkyl-piperazin-1-yl,
4-phenyl-piperazin-1-yl or 4-(1~-phenyl-5~-imidazolyl-4'-one)
piperidin-l-yl radical;
b) the imidazolobenzodiazepines of general formula I wherein
Rl represents a chlorine atom or a nitro radical, R2 represents
a hydrogen atom, a chlorine atom or a fluorine atom, R3 represents
a hydrogen atom, and either R4 and R5, which may be the same or
different, each represents a hydrogen atom, a straight aIkyl
radical containing from 1 to 5 carbon atoms~ a hydroxyethyl
radical, a phenyl radical, or a cyclohexyl radical, or R4 and -
R5 together with the nitrogen atom form a piperidino, morpholino,
piperazin-l-yl, 4-alkyl-piperazin-1-yl or 4-hydroxyethyl-
piperazin-l-yl radical;
c) the imidazolobenzodiazepines of general formula I wherein
Rl represents a chlorine atom or a nitro radical, R2 represents
a hydrogen, chlorine or fluorine atom, R3 represents a hydrogen
atom, and either R4 represents a hydrogen atom and R5 represents
a methyl, ethyl, propyl or butyl radical, or R4 and R5 together
with the nitrogen atom form a piperazin-l-yl, 4-methyl-
piperazin-l-yl, 4-ethyl-piperazin-1-yl, 4-propyl-piperazin-1-yl
or 4-hydroxyethyl-piperazin-1-yl radical;
d~ the imidazolobenzodiazepines of general formula I wherein
Rl represents a chlorine atom or a nitro radical, R2 represents
~ 4 ~
. , ' : ' ~ .
`` ` iO~34S4
a hydrogen, chlorine or fluorine atom, R3 represents a hydrogen
atom, and R4 and R5 together with the nitrogen atom form a
4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl or 4-propyl-
piperazin-l-yl radical;
e) the imidazolobenzodiazepines of general formula I wherein
Rl represents a hydrogen atom, a chlorine atom or a nitro radical,
R represents a hydrogen atom, a chlorine atom or a fluorine
atom, R3 represents a hydrogen atom and R4 and R5 together with
the nitrogen atom form a 4-dialkylphosphinylalkyl-piperazin-1-yl
radical; and
f) the ;midazolobenzodiazepines of general formula I wherein
Rl represents a hydrogen atom, a chlorine atom or a nitro radical,
R2 represents a hydrogen atom or a chlorine atom, R3 represents
a hydrogen atom and R4 and R5 together with the nitrogen atom
form a 4-dimethylphosphinylmethyl-piperazin-1-yl radical.
The imidazolobenzodiazepines ~ may be in the form of
pharmaceutically acceptable acid addition salts, and these may
be salts with mineral or organic acids. Typical mineral acids ~ --
are hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric and
phosphoric acids, while typical organic acids are acetic, form c,
benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic~
glyoxylic, aspartic, alkanesulphonic and arylsulphonic acids.
Preferred acid addition salts are the tartrates and alkane-
sulphonates, and the methanesulphonates are especially preferred.
~ here are further preferred groups of compounds of
formula I in the form of pharmaceutically acceptable acid
addition salts. ~hese are as follows:-
g) acid addition salts of the imidazolobenzodiazepines of
general formula I wherein Rl represents a hydrogen atom, a
chlorine atom or a nitro radical, R2 represents a hydrogen atom9
a chlorine atom or a fluorine atom, R3 represents a hydrogen
atom and R4 and R5 together with the nitrogen atom form a
0~345~
4-alkyl-piperazin-1-yl radical; and
h) the tartrates and alkanesulphonate~ (particularly methane-
sulphonates) of the imidazolobenzodiazepines of general formula I
wherein Rl represents a chlorine atom or a nitro radical, R2
represents a hydrogen atom or a chlorine atom~ R3 represents a
hydrogen atom and R4 and R5 together with the nitrogen atom
form a 4-methyl-piperazin-1-yl or a 4-ethyl-piperazin-1-yl
radical.
Specifically preferred imidazolobenzodiazepines of
general formula I and their pharmaceutically acceptable salts
are : .
8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo ~ ,2~ benzodiazepin-l-one;
8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzodiazepin-l-one
tartrate; -~
8-chloro-1,2-dihydro-2-(N-hydroxyethyl-piperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,y benzodiazepin-l-one;
8-chloro-1~2-dihydro-2-(~-methyl-piperazin-1-yl)
methylene-6-(o-chlorophenyl)-lH,4H~imidazo ~ ,2 ~ ~ ,~ benzo-
diazepin-l-one;
8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one tartrate;
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo ~ ,2-~ ~ ,~ benzodiazepin-
l-one;
8-chloro-1,2-dihydro-2-(n-butyl-amino)methylene-6-
phenyl-lH~4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one; .-
~o 8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-(o-~luorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one
- 6 -
.
073454
8-chloro-1,2-dihydro-2-(_-propylamino)methylene-6-
phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one;
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-(o-chlorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one
8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)
methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzo-
diazepin-l-one methanesulphonate;
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-(o-fluorophenyl)-~H,4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one;
8-chloro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl)
methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~1,~ benzodiazepin-
l-one;
8-chloro-1,2-dihydro-2-(N-propyl-piperazin-l-yl)
methylene-6-phenyl-lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-
l-one;
8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl)
methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzo-
diazepin-l-one;
8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)
methylene-6-(o-fluorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one;
8-nitro-1,2-dihydro-2-~N-ethyl-piperazin-l-yl)
methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one;
8-nitro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl)
methylene-6-(o-fluorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one;
8-chloro-1,2-dihydro-2-(ethyl~mino)methylene-6-phenyl-
lH,4H-imidazo ~ ,2 ~ ~ ,~ benzodiazepin-l-one;
8-chloro-1~2-dihydro-2-(~-dimethylphosphinylmethyl-
- 7 -
lOq3454
piperazin-l-yl)methylene-6-phenyl-IH,4H-imidazo ~ ,2~ ~ ,~
benzodiazepin-l-one;
8-chloro-1~2-dihydro-2-(N-dimethylphosphinylmethyl-
piperazin-l-yl)methylene-6-(o-chlorophenyl)-lH,4H-imidazo- ~ ,2
,~ benzodiazepin-l-one;
1,2-dihydro-2-(~-dimethylphosphinylmethyl-piperazin-1-
yl)methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-
l-one; and
8-nitro-1,2-dihydro-2-(~-dimethylphosphinylmethyl-
piperazin-1-yl)methylene-6-(o-chlorophenyl)-lH~4H-imidazo-
,2~ ~ ,~ benzodiazepin-l-one.
Of these specifically preferred compounds, 8-nitro-1,2-
dihydro-2-(~-methyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-
lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one methanesulphonate
has shown a particularly remarkable pharmacological activity.
The imidaz~olobenzodiazepines of general formula I may
conveniently be prepared starting from corresponding compounds
unsubstituted at the 2-position, and these in their turn can be
prepared from corresponding 2-alkoxycarbon~l- or 2-carboxy-
methyl~ino-benzodiazepinesO These processes are set out in
the Reaction Scheme shown in the accompanying drawings, and
will now be described. In this description, the Roman numerals
refer to the general formulae in the Reaction Scheme, and each
substituent group symbol is as first defined.
Thus~ the present invention also provides a process
for the preparation of compounds of the aforesaid general for-
mula I wherein :
Rl represents a hydrogen atom, a halogen atom, a
nitro radical or a trifluoromethyl radical;
R2, which may be at any appropriate position in the
phenyl ring, represents a hydrogen atom or a halogen atom;
R3 represents a hydrogen atom or a methyl radical; and
- 8 -
. . .
` ~
` 10'~345~
either R4 and R , which may be the same or different,
each represents a hydrogen atom, an alkyl radical containing
from l to 5 carbon atoms, a hydroxyalkyl radical containing from
1 to 5 carbon atoms, an aminoalkyl or alkylaminoalkyl radical
(the alkyl moieties each containing from 1 to 5 carbon atoms),
a phenyl radical or a cycloalkyl radical containing from 3 to 8
carbon atoms,
or R and R r.epresent together with the nitrogen atom
to which they aee bound a heterocyclic radical selected from
the group consisting of pyrrolidinyl, piperidino, morpholino,
thiomorpholino, piperazin-l-yl, 4-alkyl-piperazin-1-yl, 4-hydro-
xyalkyl-piperazin-l-yl, 4-phenyl-piperazin-1-yl, 4-(1'-phenyl-
5'-imidazolyl-4'-one) piperaz n-l-yl and R6-piperazin-1-yl
radicals, in which R6 represents a cycloalkyl-alkyl radical
containing from 3 to 8 carbon atoms, an alkenyl radical contain-
ing from 2 to 5 carbon atoms or a 4-dialkylphosphinyl alkyl
radical, the alkyl moieties containing from l to 5 carbon atoms;
and pharmaceutically acceptable acid addition salts thereof,
characterized in that a compound of formula:
~ ~ N
//
Bll~`~ (V)
R2
~30 in which Rl and R2 have the meaning already indicated is reacted,
- either with a dimethylformamide acetal of formula :
(AlK-0~2 = CH - N = (CH3)2 (VI)
g
. ~
10~3~15~
in which AlR represents a lower alkyl radical containing from
l to 5 carbon atoms to give the 8-R2-l,2-dihydro-2-(dimethyl-
amino)methylene-6-(R2-phenyl)-lH, 4H-imidazo ~l,2a~ ~l,4~ benzo-
diazepin-l-one of formula :
~. .. ..... . ... ...
~ i :;: . , . .. : ,
- . : . . . : . .
: : ,
iO73~S4
CH N / 3
~ ~ N 3
Rl ~ ~ (Ia)
~R2
in which Rl and R2 have the aforesaid meaning and that, if
desired, said compound of formula (Ia) is either salified or
transaminated by reaction with a suitable amine of formula ~
R4
H - N \ (YIII)
R5
wherein R4 and R5 have the meaning already indicated, except
that they do not both represent a methyl radical~ to give the
desired compound of formula :
R4
C \ R5
N
(Io~
~ R2
-- 10 --
, :
``` 10734S~
in which Rl, R2, R4 and R5 have the meaning already indicated,
except that R4 and R5 do not both represent a methyl radical~
which compound is salified if deæired,
- or~ ~aid compound of formula (V) is reacted, with a N-dimethyl-
acetamide of formula :
/ 3
0 = C - N . (VII)
\ CH~
to give the corresponding compound of formula :
/ CH3
H~C \ / N \
C~H~ .
N
(Ib)
Rl ~ = N
, .
~ ~2
in which Rl and R2 have the aforesaid meaning and that, if
desired, said compound of formula (Ib) is either salified or
transaminated by reaction with a suitable amine cf formula :
R4
H - N < (VIII)
R5
wherein R4 and R5 have the meaning already indicated, except
that they do not both represent a methyl radical, to give the
desired compound of formula :
-- 11 --
,. , , ~ .
`~ 10~3454
/ R4
3 \ / \
R5
N
~ Id)
[~ R2
in which Rl, R2, R4 and R5 have the meaning already indicated,
except that R4 and R5 do not both represent a methyl radical,
which compound is salified if desired.
~he reaction with the acetal VI is conveniently carried
out in an anhydrous organic solvent - for example, an arene `
such as benzene - and in the presence of a base (preferably a
nitrogenous base such as an amine like triethylamine).
~he reaction with the acetamide VII is conveniently
carried out in an anhydrous organic solvant - for example, a
chlorinated alkane such as methylenechloride - at a temperature
below room temperature (and preferably lower than 10C), and
in the presence of a condensation promotor - for example, a
halogenated derivative such as phosphorus oxychloride. `
~he reaction with the amine VIII is conveniently
carried out in an anhydrous organic solvant - for example, an
arene such as toluene - and at a high temperature, which is
preferably the boiling temperature of the reaction mixtureO
It will be understood that when it is desired to form a
compound I wherein R4 and R5 are both hydrogen the compound
VIII used in the transamination will be ammonia itself.
- - 12 -
- -- ~ : .............................. .
: , . ~ . ,
`` ` 10~34S4
The formed imidazolobenzodiazepines Ic or Id, may
if desired, be further reacted to ¢onvert them into d~fferent
compounds of general formula Ic or Id. In particular, com-
pounds wherein R4 and R5 together with the nitrogen atom re-
present a heterocycle may be further reacted 80 aB to introduce
sub~tituents onto the heterocyclic ring.
When it i8 desired to prepare a compound of formula
I in which Rl, R2 and R3 have the meaning already indicated
and R4 and R5 form together with the nitrogen atom a R6-
piperazin-l-yl radical, in which R6 repre~ent~ a oycloalkylalkyl
radical containing from 3 to 8 carbon atoms, an alkenyl radical
containing from 2 to 5 carbon atoms or a 4-dialkylphosphinyl ~ -
alkyl radical in which the alkyl moieties each contain~ from 1
to 5 carbon atom~, an appropriate compound of formula Ic or Id
wherein R4 and R5 form together with the nitrogen atom a
piperazin-l-yl radical i~ first prepared and i~ then reacted
- with an appropriate halo-R6, wherein the halo is an halogen
atom, to form the corresponding R6-piperazin-1-yl compound
of formula Ic or Id.
When it is desired to prepare a compound Ic or Id
wherein R4 and R5 form, with the ~itrogen atom, a 4-dialkyl- -
phosphinylalkyl-piperazin-l-yl radical in which the aIkyl
moietie~ each contains from 1 to 5 carbon atoms, one may first
prepare an appropriate compound Ic or Id wherein R4 and R5
form, with the nitrogen atomj a piperazin-l-yl radical and then
react this compound with an appropriate haloalkyl-dialkylphos-
phine oxide to form the corresponding 2-(n-dialkylphosphinyl-
alkyl-piperazin-l-yl) compound Ic or Id.
The preferred haloalkyl-dialkylphosphine oxides for
uæe in such a conversion are the chloroaIk~l- dialkylphosphine
oxide~, and the reaction is preferably carried out in an organic
solvent - for example, an arene such as toluene.
The imidazolobenzodiazepine starting material (V)
may be prepared from a compound of formula:
- 13 -
`~` . lOq3454
~ N
11 )
Rl ~ ~ N (II)
[~ R2
in which Rl and R2 have the meaning already indicated, by reac-
tion thereof with a compound of formula : ~ -
/ - CH2 (III)
R-0 ~H2
in which R represents a hydrogen atom or an alkyl radical
having from 1 to 5 carbon atoms, to give a compound of formula :
O ~- .
/ ~ I~H ~.
~ ~ (I~)
Rl / ~ N
~ R2
in which R, Rl and R2 have the aforesaid me~ning~ which is
reacted with a deshydrating agent or subjected to a pyrolysis
to give the desired compound of formula (v).
~he reaction of the compound of formula II with the
- 14 _
073454
compound of formula III is advantageously carried out in an
organic solvent, preferably an alcohol such as ethanol, and at
a high temperature, which is conveniently the boiling temperature
of the reaction mixture.
The dehydrating agent reacted with the acid IV is
conveniently a carbodiimide, such as dicyclohexylcarbodiimide,
and the reaction is advantageously performed in a chlorinated
alkane such as methylene chloride. The pyrolysis of the ester
IV is conveniently carried out in a high boiling point solvent
such as an arene like toluene. -;
~ he formed compounds Ia, Ib, Ic- and Id may be
salified by nor~al methods. In another aspect, this invention
provides processes for the preparation of acid addition salts
of compounds of general formula I, in which an appropriate com- -
pound Ia, Ib, Ic or Id is reacted, in substantially stoichio-
metric proportions,~with a suitable mineral or organic acid to
form the desired pharmaceutically acceptable acid addition
salt.
The salification reaction is conveniently effected in
an organic solvent or a mixture of organic solvents~ such as one
or more alkanols - for example, methanol or ethanol - and/or
one or more alkyl halides - for example, methylene chloride.
The imidazolobenzodiazepin-l-ones of formula I and
their acid addition salts possess very interesting pharmacological
properties. ~hey are endowed especially with remarkable sedative,
hypnotic, anxiolytic, tranquillising, anticonvulsive and
myorelaxant properties which may make the compounds of formula
I and their pharmaceutically acceptable acid addition salts
of use as medicaments in the treatment of states of agitation
or irritability, of aggression, of insomnia, of certain
psychosomatic syndromes, of certain character and behavioural
disorders, and of certain spasms or muscular contractions.
- 15 -
- .
~ -
`~ ioq3454
However, before any of the compounds of formula I and
their pharmaceutically acceptable acid addition salts may be
used in medicine, they should preferably be formed into phar-
maceutical compositions by association with suitable pharma-
ceutical vehicles.
~ he term "pharmaceutical" is used herein to exclude
any possibility that the nature of the vehicle, considered, of
course, in relation to the route by which the composition is
intended to be administered, could be harmful rather than
beneficial. The choice of a suitable mode of presentation,
- together with an appropriate vehicle~ is believed to be within
the competence of those accustomed to the preparation of phar-
maceutical formulations.
The compounds of formula I may be employed for the
preparation of pharmaceutical compositions containing one or
more imidazolobenzodiazepin-l-ones I, or pharmaceutically
acceptable acid addition salts thereof, in association wi-th a
suitable pharmaceutical vehicle.
~hese compositions may be administered orally,
transcutaneously or rectally, and in respect of these modes
the "pha~maceutical vehicle" is preferably~
a) the ingestible excipient of a tablet, coated tablet, sublin-
gual tablet or pill; the ingestible container of a capsule
or cachet; the ingestible pulverulent solid carrier of a `
powder; or the ingestible liquid medium of a syrup, solution,
suspension, or elixir;
b) a sterile injectable liquid solution or suspension medium;
or
c) a base material of low melting point capable of releasing
the active ingredient to perform its pharmacological func-
tion, which base material when appropriately shaped forms
a suppository~
- 16 -
.. . . .
- , . :; :' ,,,'
. ~ , - ,, ,
`` 1073454
The vehicle may, as appropriate, be a solid (such as
talc, gum arabic, lactose, starch, an animal or vegetable fat,
magnesium stearate, or cocoa butter), or it may be an aqueous
or non-aqueous liquid (such as an ànimal or vegetable oil, a
paraffin derivative, or a glycol). It may if desired incorporate
wetting~ dispersing or emulsifying agents, and preserving agents. -~^
~ 1st the modes of presentation just listed represent
those most likely to be employed, they do not necessarily exhaust
the possibilities.
The compounds of formula I and the pharmaceutically
acceptable acid addition salts thereof may preferably be
administered in the form of tablets, of injectable solutions or
suspensions dispensed in single-dose ampoules or multi-dose
phials, and of suppositories.
Whilst the dosages of the pharmacologically-active
ingredient will, to ~ certain degree, depend upon the route by
which the compositions are to be administered, nevertheless,
by way of general indication, it may be said the useful dose
ranges from l mg to 50 mg active ingredient per day:for an
adult~ a unit dose containing from 0.5 mg to 20 mg active
ingredientO
The 2-carboxymethylamino-7-Rl-5-(R2-phenyl)-3H-1,4-
benzodiazepines IV, and the corresponding 2-aIkoxycarbonyl-
methylamino-7-Rl-5-(R2-phenyl)-3H-1,4- benzodiazepines IV wherein
the alkyl group R is other than an ethyl group, are new compoundsO
The following ~xamples, ~ormulations and Test Results
are now given, though only by way of illustration, to show
details of various aspects of the invention.
- - 17 -
.. . .. ..... .. - :
073454
~XA~?IES
Example 1: 8-chloro-1,2-dihydro-2-(dimethylamino)methylene-
6-phenyl-lH,4H-imidazo-~ ,2~ ~ ,~ benzodiazepin-
l-one (Ia)
Stage A: 2-carbox~methvlamino-7-chloro-5-Phen~1-3H-1~4-
benzodiazepine (IV)
7-Chloro-1~3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-
thione II (3.5g), glycine III (5.5g) and sodium carbonate (5.5g)
were suspended in ethanol (lOOml) and water (30ml), and were
stirred and refluxed for 1 hour. The suspension was then poured -
; into water to give a clear solution~ and this was acidified to -; -
pH 4 with 2~ HCl, and extracted with CHC13. Some solid precipi-
tated from the extracts, and was filtered off. ---
~he organic layer was dried (on MgS04) and evaporated - ;
to give a gum which crystallized on trituration with methanol. - - -
This solid~ and the solid filtered off above, was crystallized
from a large amount of ethanol to give 2-carboxymethylamino-
7-chloro-5-phenyl-3H-1,4-benzodiazepine, 3.1g (77%).
m.p. = 215-220Co
Sta~e B: 8-chloro-1,2-dihydro-6-phenyl-lH,4H-imidazo ~1,2~ -
~ ,~ benzodiazepin-l-one (V)
2-Carboxymethylamino-7-chloro-5-phenyl-3H-1~4-benzo-
diazepine (IV) (2.5g) was suspended in dry CH2C12 (120ml), and
stirred, and dicyclohexylcarbodiimide (2.lg) was added. The
suspension was stirred at room temperature for 3 hours, then
filtered, and the filtrate was evaporated to give 8-chloro-
1,2-dihydro-6-phenyl-lH~4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-
l-one V in the form of a colourless oil, which was used as it
is in the following stage.
.. . . . . . . . .
.
073454
Stage C: 8-chloro-1,2-dihydro-2-(dimethylamino)methylene-
6-phenyl-lH.4H-imidazo /I.2a7 /I,~ benzodiazein-
l-one (Ia)
The 8-chloro-1,2-dihydro-6-phenyl-lH,4H-imidazo ~ ,2~
,~ benzodiazepin-l-one V obtained in stage B above was - `
dissolved in dry benzene, and dimethylformamide diethyl acetal
YI (1.5g) and triethylamine (lml) was added. ~he solution was
stirred at room temperature for 1.5 hours, then evaporated to
give a brown-yellow residue. Recrystallization from ethylacetate/
methanol gave pale yellow rods of 8-chloro-1~ 2-dihydro-2-(dime-
thylamino~methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzo-
diazepin-l-one I_, 2.7g (97%). m.p. = 264-5~.
Anal~sis: C20H17Cl N4 0 = 364-9
Calculated: C% 65.85 H% 4.66 N% 15.37 Cl% 9.74
Found: 65.87 4.67 15.37 9.79
I.R. Spectra (KBr diSC) :
.
C-0 at 1690 cm 1; C~N at 1621 cm
ExamPles 2 to 6
Using a similar method to that used in Example 1, the
` following compounds IV, V and I_ were prepared :
~xam~le ComPounds
2. Compound IV: 2-carboxymethylamino-7-nitro-5-phenyl-3H-
1,4-benzodiazepine.
Compound V: 8-nitro-1~2-dihydro-6-phenyl-lH~4H-
imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one
Compound Ia: 8-nitro-1,2-dihydro-2-(dimethylamino)
methylene-6-phenyl-lH,4H-imidazo ~ ,2
~ ,y benzodiazepin-l-one.
3. Compound IV: 2-carboxymethylamino-7-chloro-5-o-
chlorophenyl-3H-1,4-benzodiazepineO
Compound V: 8-chloro-1,2-dihydro-6-o-chlorophenyl-
lH~4H-imidazo ~ ,2 ~ ~ ,~ benzodiaze-
pine-l-one
-- 19 --
-
0~3454
~xample Compounds
3. Compound Ia: 8-chloro-1,2-dihydro-2-(dimethylamino)
methylene 6-o-chlorophenyl-lH,4H- -
imidazo ~ ,2~ ~ ,y benzodiazepin-l-
one.
4. Compound IV: 2-carboxymethylamino-7-nitro-5-o-chloro-
phenyl 3H-1~4-benzodiazepine.
Compound V: 8-nitro-1,2-dihydro-6-o-chlorophenyl-
lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-
l-oneO
Compound la: 8-nitro-1,2-dihydro-2-(dimethylamino) ~-
methylene 6-o-chlorophenyl-lH,4H-imidazo
~ ,2 ~ ~ ,~ benzodiazepin-l-one.
5. Compound IV: 2-carboxymethylamino-7-chloro-5-o-fluoro-
phenyl-3H-1,4-benzodiazepine.
Compound V~: 8-chloro-1,2-dihydro-6-o-fluorophenyl-
lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-
l-one.
Compound Ia: 8-chloro-1,2-dihydro-2-(dimethylamino)
methylene 6-o-fluorophenyl-lH,4H-imidazo
~ ,2~ ~ ~ benzodiazepin-l-one
6. Compound IV: 2-carboxymethylamino-7-nitro-5-o-fluoro-
phenyl 3H-1,4-benzodiazepine.
Compound V: 8-nitro-1~2-dihydro-6-o-fluorophenyl-lH, -
4H-imidazo ~ ,2~ ~ ,~ benzodiazepin--
l-one.
Compound Ia: 8-nitro-1~2-dihydro-2-(dimethylamino)
methylene 6-o-fluorophenyl-lH,4H-imidazo
,2~ ~ , ~ benzodiazepin-l-one.
- 20 -
``` 10~34S4
In each case the compound III was glycine, the com-
pound ~I was dimethylformamide ethyl acetal, the compound V was
used without further purification, and the crystallization
solvent for the compound Ia was methanol. The data for these
compounds (excluding the compounds Y) is summarized in Table I
below.
TA~IE 1
Example Compound IV ¦ amino
Crystalli-
Yield% Mop~Csation Rl R2 YieldYo MopoC
.. .
2 66 154-5 MeOH N02 H 43 227-8
3 75 136-9 MeOH-Et20 Cl o-Cl 53 288-90
4 83 158-61 Et20 P02 _-Cl 78 253-5
.
69 gum _ Cl o-F 63 257-60
_
6 44 I ~ Et20 ~02 o-P 80 228-31
Example 7: 8-chloro-2-/I'-(dimethylamino)et~ylidene~-1,2-
dihydro-6-Phenyl-lH.4H-imidazo/I,2a7~i~47benzodia- ~`
ze~in-l-one (Ib)
8-Chloro-1~2-dihydro-6-phenyl-lH,4H-imidazo~ ~2~7
~ ~47benzodiazepin-1-one V, prepared as described in Stage B of
Example 1, was dissolved in dry methylene chloride (200ml) with
dimethylacetamide VII (2.0g). The solution was cooled to 0C,
and phosphorus oxychloride (3.7g) was added dropwise over 5
minutes with good stirring. The solution was then stirred at
room temperature over 20 hours, and poured into saturated NaHC03
solution (500ml). The mixture was stirred until the evolution
f o02 ceased~ the org~n;c layer was removed, and the aqueous
layer was extracted with methylene chloride (2xlOOml). ~he
combined organic extracts were washed with saturated ~aHC03
;' ' ` ' ~ ' "' ' " ''" ` ` '' " ''' '
" ~0~3454
solution, and water, dried (on MgS04)~ and evaporated to give
a yellow solid. Recrystallization of this solid from chlorofo ~
ether gave 8-chloro-2-~ ~-(dimethylamino)ethyliden~ -1~2-dihydro-
6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ib, 203g
(40%). m.p. = 251-2C
Analysis: C21HlgC1 ~4 0 = 378-9
Calculated: C% 66058 H% 5002 N~o 14.79 Cl% 9038
~ound: 66.32 4091 14.77 9.02
I.R. Sectra (Kbr disc): ~ -
C=O at 1653 cm 1; C=N at 1610 cm 1
Example 8. 8-chloro-1.2-dih~dro-2-(~-meth~lPiperazin-l-Yl)
meth,ylene-6-Phenrl-lH,4H-imidazo/~i.2a7/~i,47 -
benzodiazePin-l-one (Ic), and its tartrate
A) 8-Chloro-1,2-dihydro-2-(dimethylamino)methylene-6-phenyl~
lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ia (obtained as in
Stage C of ~xample ~) (203g) and ~-methyl-piperazine (4.0g) were
stirred under reflux in dry toluene (50ml) for 24 hours.- On
cooling, crystals separated out, and were filtered off. Evapo-
ration of the solvent gave a pale yellow solid, and this was
treated with methanol, and filtered. The two sets of solids -
were combined and recrystalIized from methano ~ ethyl acetate to
give 8-chloro-1~2-dihydro-2-(N-methylpiperazin-l-yl)methylene-
6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one Ic 2.3g
(87%). m.p. = 255-6C.
Anal~sis C23H22C1 ~5= 419-9
Calculated: C% 65.80H% 5.24 ~% 16.69 Cl% 8.46
~ound: 65.64 5.27 16.63 8.56
_~R. Spectra (Kbr disc):
C=O at 1705 cm~l; C=~ at 1635 cm~l
B) ~he tartrate salt of 3-chloro-1,2-dihydro-2-(~-methyl-
piperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one Ic was prepared by adding a stoichiometric
- 22 -
.
10~3454
amount in methanol of tartaric acid to the 8-chloro-1~2-dihydro-
2-(N-methyl-piperazin-l-yl)methylene-6-phenyl-lH~4H-imidazo
,~ benzodiazepine-l-one Ico ~he formed crude salt was
recrystallized from methanol to give the desired product.
M.Pt. = 146-150C.
Analysis: C2 ~28ClN ~ 570.1
5 7
Calculated: C~O 56089H% 4092 N% 11.29 Cl~o 6023
~ound: 56044 4093 11.79 5-93
I.R. SPectra (Kbr disc):
OH at 3400 cm 1 and 2500 cm 1, C=O at 1730cm 1 and 1690cm 1;
C=N at 1630 cm 1.
Exam~les 9 to 46/32B
In these Examples, except where it is stated otherwise,
a method analogous to that used in the preparation of 8-chloro-
1,2-dihydro-2-(N-methylpiperazin-l-yl)methylene-6-phenyl-lH,4H-
imidazo~ ,2~ ~ ,~ be~nzodiazepin-l-one Ic in Example 8 was used
to prepare the foll~wing compounds I :
Example Com~ound I
9. 8-Chloro-1,2-dihydro-2-(morpholino)methylene-6-phenyl-
lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
10. 8-Chloro-1,2-dihydro-2-(N-hydroxyethyl-piperazin-l-yl)
methylene-6-phenyl-lH~4H-imidazo~ ,2~ ~ ,~ benzo-
diazepin-l-one.
11. 8-Chloro-1,2-dihydro-2-(~-phenyl-piperazin_l-yl)
methylene-6-phenyl-lH,4H~imidazo ~ ,2~ ~ ,~ benzodla-
zepin-l-one.
12. 8-Chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-(o-chlorophenyl)-IH,4H-imidazol~ ,2
~ ,~ benzodiazepin-l-one~
3 12B 8-Chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-(Q-chlorophenyl)-lH,4H-imidazo~ ,'2
benzodiazepin-l-one tartrate.
Method: analogou~ to Example 8B
- 23 -
3~54
~xample ComPound I
13O 8-Nitro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~benzodia-
zepin-1-one.
14. 8-Chloro-1,2-dihydro-2-(piperazin-1-yl)methylene-6-
phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
15. 8-Chloro-1,2-dihydro-2-(n-butyl-amino)methylene-6-
phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodiazepin-l-oneO ~-
16. 8-Chloro-1,2-dihydro-2-(amino)methylene-6-phenyl-
lH,4H-imidazo~ ,2~7 ~ ,9;7benzodiazepin-1-oneO
Method: -
8-Chloro-1,2-dihydro-2-(dimethyl~ino~ -
methylene-6-phenyl-lH,4H-imidazo~i~2,~ ~ ,~7benzodia-
zepin-l-one Ia (2.1g) was suspended in dry methanol
(lOOml)0 The suspension ~as stirred, cooled in dry-
ice/acetone bath~ and ammonia gas VIII was bubbled
through for 15 minutes. The suspension was then
warmed to room temperature, stirred for a further two
days, and the solvent was evaporated. The solia
residue was recrystallized from methanol/ethyl acetate
to give 8-chloro-1,2-dihydro-2-(amino)methylene-6-
phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodiazepin-l-one
Ic, l.9g (98%)o m.pO = 26~-7C.
~xamPle Compound I
17. 8-Chloro-1,2-dihydro-2-(piperidino)methylene-6-phenyl-
lH,4H-imidazo ~ ,2~ ~ ,~benzodiazepin-l-one.
18. 8-Chloro-1,2-dihydro-2-(thiomorpholino)methylene-6-
phenyl-lH,4H-imidazo~ ,2~ ~ ~ ~ benzodiazepin-l-one.
19. 8-Chloro-1~2-dihydro-2-(diethylaminoethylam no)
methylene-6-phenyl-lH,4H-imidazo ~ 92~ benzO_
diazepin-l-one.
- 24 -
.
`` 10~3454
20. 8-Chloro-1,2-dihydro-2-(N-methyl-N-(dimethylamino)
ethylamino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.
21. 8-Chloro-1,2-dihydro-2-(methylamino)methylene-6-phenyl-
lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
22. 8-Chloro-1,2-dihydro-2-(cyclohexylamino)methylene-6-
phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-oneO
23. 8-Chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)methy-
lene-6-(o-fluorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-oneO
24. 8-Chloro-1,2-dihydro-2-~ -(1'-phenyl-5'-imidazolyl- - --
4'-one)piperidin-1-y~ methylene-6-phenyl-lH,4H-
imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
25. 8-Chloro-1,2-dihydro-2-(phenyl~mino)methylene-6- -
phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
26. 8-Chloro-1~2-dihydro-2-~ ~(N-methyl-piperazino)ethyli-
den~ -6-phenyl-IH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-
l-one.
Method:
8-Chloro-2-~ '-(dimethylamino)ethyliden~ -
1~2-dihydro-6_phenyl-lH,4H-imidazo~ ,2~ ~ ,~benzo-
diazepin-l-one Ib (example 7) (2.3g) and ~-methyl- - -
piperazine VIII (15 ml) were stirred at 120C under
nitrogen for 9 hours. The cooled solution was poured
into water, ~aCl was added to complete precipitation,
and the brown precipitate was filtered off, dissolved
in CHC13, washed with water, dried (on MgS04), and
evaporated to give a dark red oil. The oil crystallized
on triturating with ether/methanol, and was recrys-
tallized from ethyl acetate to give 8-chloro-2-
~-N-methylpiperazin-l-yl~ethyliden~ -1,2-dihydro-
6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one
Id, l.Og (38%). m.p. = 193-5QC. ~ -
- 25
-; .. .. I .,.. ,. -
- -, - - ,, : :, , - - .
, . .... . ~ . .
0~3~45~
~xample Compound I
27. 8-Chloro-1~2-dihydro-2-(t-butylamino)methylene-6-phenyl-
lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-oneO
28. 8-Chloro-1,2-dihydro-2-(hydroxyethylamino)methylene-6-
phenyl-lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
29. 8-Chloro-1,2-dihydro-2-(n-propylamino)methylene-6-
phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-oneO
30. 8-Nitro-1,2-dihydro-2-(~-methyl-piperazin-1-yl)
methylene-6-(o-chlorophenyl)-lH~4H-imidazo~ ,2~ ~ ,~
benzodiazepin-1-one.
31. 8-~itro-1,2-dihydro-2-(~-methyl-piperazin-1-yl)
methylene-6-(o-fluorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~ `
benzodiazepin-l-one.
32. 8-Chloro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl)
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodiazepin-
. l-oneO ~-
32~ 8-Chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodia~
zepin-l-one tartrate.
Method: analogous to Example 8~
33. 8-Chloro-1,2-dihydro-2-(M-propyl-piperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiaze-
pin-l-one.
34. 8-Chloro-1,2-dihydro-2-~ -(_-butyl)-piperazin-l-y~
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiaze-
pin-l-one.
35. 8-Chloro-1,2-dihydro-2-@ -(isopropyl)-piperazin-l-y~
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodia-
zepin-l-oneO
Method:
8-Chloro-1,2-dihydro-2-(piperazin-1-yl)
methylene-6-phenyl-lH,4H-imidazo~ ~2~ ~ ,~ benzodiaze-
- - 26 -
0~3454
pin-l-one ( the compound of Example 14, obtained as in
~xample 8) (1.5g.), isopropyl iodide (205go) and
sodium carbonate (3~0g~) were stirred at 80C in
acetonitrile (25 ml) and methylene chloride (5ml.)
for 18 hours. The cooled solution was poured into
water and extracted with chloroform. The extracts
were washed with water~ dried (on MgS04), and
evaporated to give a pale yellow solid. Recrystalli-
zation of this solid from ethyl acetate gave 8-chloro-
1~2-dihydro-2-(N-isopropyl-piperazin-l-yl)methylene- -
6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one
Ic, 1.2g. (73%). M. pt. - 146-8C.
Example Compound I
36. 8-Chloro-1,2-dihydro-2-(N-allyl-piperazin-l-yl)
methylene-6-phenyl-lH~4H-imidazo ~ 92~ ~ ,~ benzodia-
zepin-l-on~e.
Method: analogous to Example 35~
37~ 8-Chloro-1,2-dihydro-2-(~-cyclopropylmethyl-piperazin-
l-yl)methylene-6-phenyl-lH~4H~imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.
Method: analogous to Example 35. -~
380 8-Chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl)
; methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,
benzodiazepin-l-one.
39~ 8-Chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl)
methylene-6-(o-fluorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.
40. 8-~itro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl)
methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
` benzodiazepin-l-oneO
41. 8-Nitro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl)
methylene-6-(o-fluorophenyl)-lH,4H-imidazo~ 7 2~ ~ ,~
- 27 _
, .. . . ..
`` lOq3454
benzodiazepin-l-one.
420 8-Chloro-1~2-dihydro-2-(ethylamino)methylene-6-phenyl-
lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
43. 8-Chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-
piperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2
~ ,~ benzodiazepin-l-one.
Method:
8-Chloro-1,2-dihydro-2-(piperazin-1-yl)
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodia-
zepin-l-one (the compound of Example 14, obtained as
in ~ample 8) (2.5g.), chloromethyldimethylphosphine
oxide (1.5g.) and sodium carbonate (5.0g.) were
stirred under reflux in toluene (80 ml) for 3 days.
~he cooled suspension was distributed between chloro-
form and water, and the chloroform extract was
separated~ dried (on MgS04)~ and evaporated to give
a pale yellow oil which crystallized with methanol;
~he solid (unrequired by-product) was filtered off,
and the filtrate was evaporated to give a pale orange
oil. ~his oil was dissolved in chloroform and
chromatographed on Kieselgel 60. Elution with
chloroform/methanol (5%) gave a pale yellow solid,
hich on recrystallization from methylene chloride/
ether gave 8-chloro-1,2-dihydro-2-(N-dimethylphosphinyl-
methyl-piperazin-l-yl)methylene-6-phenyl-lH,4H-
imidazo~ ,2~ ~ ,~ benzodiazepin-l-one. Ic (1.25 g.)
(41~). M.Pt. = 261-2C.
~xam~le Compound I
44. 8-Chloro-l,~-dihydro-2-(N-propyl-piperazin-l-yl)
methylene-6-o-chlorophenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.
- 28 -
.
.~; -, ... .
lOq3454
Example Compound I
45. 8-Chloro-1,2-dihydro-2-(ethyl~m~no)methylene-6-o-
chlorophenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-1-
oneO
46. 8-Chloro-1,2-dihydro-2-(n-propylamino)methylene-6-o-
chloro-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-
l-one.
- 29 -
10'73~5
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1073454
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10'73454
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- 34 --
-,.
- . .
10~345~
- ~xample 47: 8-chloro-1.2-dihydro-2-(N-dimeth~lPho~phinylmeth~l- piPerazin-l-yl)methylene-6-(o-chlorophen~ H~4H
imidazo/I,2a7/I,47benzodiazePin-l-one
8-Chloro-1~2-dihydro-2-(piperazin-1-yl)methylene-6-
(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ic
(obtained by a method analogous to that described in Example 8)
(850 mg)~ chloromethyl-dimethylphosphine oxide (1.0 g), sodium
iodide (1.0 g) and sodium carbonate (2.0 g) were stirred under
reflux in dry toluene (50 ml) for 24 hours. The cooled solution
was partitioned between chloroform and water, the chloroform
extract separated, dried on magnesium sulphate and evaporated to
give a gummy solid. This was chromatographed on silica eluting
with chloroform to give a solid which on crystallisation from
methano~ ethyl acetate/ether gave 8-chloro-1,2-dihydro-2-
(N-dimethylphosphinylmethyl-l-yl)methylene-6-(o-chlorophenyl)-
lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ic, mOp. ~ 231-4DC.
I.R. SPectra (KBr disc):
C=0 at 1700 cm 1; C=N at 1630 cm 1
ExamPle 48: 1~2-dih~dro-2-(N-dimethvlPhos~hin~lmeth~ iPerazin-
1-vl)meth~lene-6-phen~l-lH 4H-imidazo/~.2a7/~47
benzodiazepin-l-one ~ -
This compound was prepared, by a method analogous to
that used in Example 47, from 1,2-dihydro-2-(piperazin-1-yl)-
methylene-6-phenyl-lH,4H--imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one
Ic - ~vhich in turn was prepared by a method analogous to that
described in ~xample 8.
~he formed 1,2-dihydro-2-(N-dimethylphosphinylmethyl-
piperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one Ic melted at 245-7Co
I.R. Spectra (KBr disc)
C=0 at 1695 cm 1; C~N at 1630 cm 1
_ 35 _
10~3454
~xample 49: 8-nitro-1~?-dih,~dro-2-(N-dimethylphosphinylmethyl-
piPerazin-l-yl)methylene-6-(o-chlorophenyl)-lH,4H-
imidazo/i,2~/i,47benzodiazepin-1-one
~his compound was prepared, by a method analogous to
that used in Example 47, from 8-nitro-1,2-dihydro-2-(piperazin- -
l-yl)methylene-6-(o-chlorophenyl)-IH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one Ic - which in turn was prepared by a method
analogous to that described in Example 8.
~he formed 8-nitro-1,2-dihydro-2-(N-dimethylphosph;nyl- -
methyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-lH,4H_imidazo
,2 ~ ~ ,~ benzodiazepin-l-one Ic melted at 245-8C.
I.R. Spectra (KBr disc)
C=0 at 1700 cm 1; C=~ at 1642 cm 1
~xamPle 50: 8-nitro-1.2-dihydro-2-(N-meth~l-piPerazin-l-yl)- ;~s
meth~lene-6-(o-chlorophen~ lH,4H-imidazo/I,2a7
~1~47benzodiazePin-l-one methanesulphonate
Methanesulphonic acid (1.1 g) was added dropwise to
8-nitro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)methylene-6-
(o-chlorophenyl)-lH~4H-imidazo~ ~2~ ~ benzodiazepin-1-one
(obtained as in Example 30) (4.6 g) in dry methylene chloride
(100 ml) and methanol (5 ml). Dry ether was added slowly until
crystals formed on scratching and the solution was allowed to
crystallise, further ether being added to complete the crystal-
lisation. The pale yellow solid was filtered off, washed with
ether and recrystallised from methylene chloride-methanol either
to give 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)methylene-
6-~o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one
methanesulphonate (5.4 g), m.p. - 205-lO~C.
.
- 36 -
10~3~54
~OR~ TIONS
~ormulation 1: ~ablets
.
Tablets were prepared having the following constituents
per tablet:
8-chloro-1,2-dihydro-2-(N-methylpiperazine-l-yl)
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepine-l-oneOOOO.. O.O..O.O.OOO............. 5 mg
Excipient (qOs. for a tablet) up to...~..O..O.O 100 mg
The excipient was lactose, starch, talc and mag~esium
stearate.
~ormulation 2: Capsules
The ingredients for gelatin capsules were prepared to
have the following constituents per capsule:
8-chloro-1~2-dihydro-2-(N-methylpiperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodia-
zepine-l-o~e tartrate..... O.OO.O.O.. O.... O......... 5 mg
Excipient (q.s. for a gelatin capsule) up to... 100 mg
The excipient was talc, starch and magnesium stearate. --
Formulation 3-: Injectable ampoules
Injectable ampoules were prepared containing a solution
having the following constituents: ~ - -
8-chloro-1,2-dihydro-2-(N-methylpiperazin-l-yl)
methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~benzodia-
zepine-l-one tartrate............................. 10 mg
aqueous solvent--.O~---O-.--OO-O----O---Oq.s.v- 2 ml
~ormulation 4: Tablets
Tablets were prepared having the following constituents
per tablet:
8-chloro-1,2-dihydro-2-(N-methylpiperazin-l-yl)
methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~
~ ,~ benzodiazepine-l-oneO......................... 5 mg
Excipient (q.s. for a tablet) up to.............. 100 mg
~ 37 -
07 ~ 54
~ he excipient was lactose, starch, talc and magnesium
stearateO
Formulation 5: Tablets
Tablets were prepared having the following constituents
per tablet:
8-chloro-1,2-dihydro-2-(~-methylpiperazin-1-yl)
methylene-6-(o-fluorophenyl)-lH,4H-imddazo~ ,2 ~ ~ ,~
benzodiazepin-l-one--O-~------.O--O.-.O--.-OO~ 5 mg
Excipient (qOsO for a tablet) up to~OOOO.OO... 100 mg
~he excipient was lactose, starch, talc and magnesium
stearate.
Formulation 6: ~ablets
~ ablets were prepared having the following constituents
per tablet:
8-nitro-1,2-dihydro-2-(~-methylpiperazin-1-yl)
~ methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
; benzodiazepin-l-one.................................... 5 mg -~
Excipient (q.s. for a tablet) up to.................. 100 mg
~he excipient was lactose, starch, talc and magnesium
~20 stearateO
Formulation 7: ~ablets
-~ Tablets were prepared having the following constituents
per tablet:
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl)-
methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ .~
benzodiazepin-l-one methanesulphonate.................. 5 mg
Excipient (~.s. for a tablet) up to.................. 100 mg
~ he excipient was lactose, starch, talc and magnesium
stearateO
~ormulation 8: ~ablets
~ ablets were prepared having the following constituents
per tablet:
- ~8 -
iO~3~54
8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)
methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ~
benzodiazepin-l-one tartrate....................... 5 mg
Excipient (q.s. for a tablet) up toOO...... O.OO. 100 mg
The excipient was lactose, starch, talc and magnesium
stearate.
PHARMACO~OGICA~ AC~IVITY
1) Antiag~ressive activit~ in mice (AAM)
Groups of 20 randomly selected male mice (25-30g body
weight; Tuck T.O. strain) were given oral doses of either
vehicle alone (10 ml per kg distilled water) or vehicle plus
test compound. 30 minutes after dosing~ pairs of mice were
placed under an inverted 1 litre pyrex beaker on a metal grid.
~he grid was connected to a Palmer square wave stimulator, and
the feet of the mice were electrically stimulated wqth 90 volt
pulses of 5 milli-second duration at a frequency of 2 pulses per
second for a period of 2 minutes. ~his procedure provoked
fighting in the control mice (a fight being defined as a
frontal aggressive attack, usually biting, by either mouse on
the other one). ~he total number of fights in the control group
was calculated.
~he ~D50 of a test compound is that dose which causes -
a 50~0 reduction in the number of fights of the batch of mice
given that compound as compared with the control batch.
(~edeschi. R.E. et al (1959) JO PHARM. ~xptl. ~her. 125.28-34).
~he results are shown in ~able 3 belowO
2) Anticonvulsant test a~ainst maximal electroshock in mice-
~AEM~
Groups of ten mice were injected orally with the test
compound in a vehicle at various dose levels (a control group
receiving the vehicle alone). 30 minutes after dosing each group
~ 39 ~
. ~
0~3454
was then shocked via auricular electrodes using electroshock
apparatus (Ugo ~asile ECT apparatus for small mammals). The
shocks has a pulse width of 0.2 milliseconds, and a frequency
of 100 Hz, and each shock was given for 0.2 seconds at a
current of 55 milliamps.
The number of mice which underwent tonic extension of
their hind limbs was notedO ~he dose protecting 50% of the mice
(~ED50), as compared with the control group, was noted, and the r
results are shown in Table 3 below.
103) Anticonvulsant test against Pent~lenetetrazole in mice (AIM)
Groups of ten mice were injected orally with the test
compound in a vehicle at various dose levels, with a control
group receiving the vehicle alone. 30 minutes after dosing each
mouse received a sub-cutaneous 130 m~/kg pentylenetetrazole
challenge (pentylenetetrazole is a central nervous system
sti~ulant), and the mice were then individually housed in
observation boxes. The number of mice showing tonic convulsions
within 30 minutes of the pentylenetetrazole challenge was noted,
and the results for the tonic phase were expressed as a percentage
20reduction of the control levels. From a constructed dose response
curve, the doses protecting 50% of the mice (TED50) against
tonus were estimated, and are shown in Table 3 below.
4) ~nticonvulsant test a~ainst str~chnine in mice (A~)
Groups of ten mice received the test compound and
vehicle orally at various dose levels, with a control group
receiving the vehicle alone. 30 minutes after dosing, each
mouse received a sub-cutaneous lmg/kg strychnine challenge
(strychnine is a central nervous system stimulant), and the
mice were then housed individually in observation boxes. The
30number of mice exhibiting tonic convulsions within 15 minu~es
of the strychnine challenge was noted, and the results for the
tonic phase expressed as a percentage reduction of the control
- - 40 -
~73454
v~lue. ~rom a constructed dose response line~ the doses
protecting 50% of the mice (TED50) against tonus were esti-
- mated, and are shown in Table 3 below.
5) Potentiation of hexobarbital in mice (PHM)
A group of ten control mice received an ED20 dose of
hexobarbital intraperitoneally (150 m~/kg) (hexobarbital is a
sedative and hypnotic), followed by an oral dose of either a
vehicle alone or various oral doses of the vehicle and a test
compound. The number of mice which exhibited loss of the
righting reflex for 30 seconds half-an-hour after dosing was
noted, and a dose response curve was constructed; the dose of --
test compound which caused 50% of the mice in a group to lose
the righting reflex was estimated (ED50), and the results are -~
shown in ~able 3 below.
6) Potentiation of chlorprothixene in mice (P~)
Groups of ~ten randomly selected male C~P mice
(Carworth Europe)~ weighing 20-25g each, were given chlorprothi-
xene (12.5 mg/kg) intraperitoneally (chlorprothixene is a
tranquillizer and antipsychotic); this dose consistently caused
10~ of mice to lose their righting reflex 30 minutes after
dosing. At the same time the test groups of mice were given
- orally either vehicle alone (distilled water, 10 m~/kg)~ or a -
dose of vehicle plus test compound. Each mouse was then placed
individually in a small observation ch~mber, and tested for loss
of righting reflex 30 minutes after dosing.
The ED50 value of a test compound is the dose which
causes loss Qf the righting reflex in 50% of the number of mice
in a group which~ in the absence of oral treatment, would not
be expected to lose their righting re~lex. The re~ults are
shown in ~able 3 belowO
7) Rotatin~ drum test in mice (RDM)
Groups of ten mice were injected orally with vehicle
- 41 -
10734S4
plus the test compound at various dose levels~ with a control
group receiving the vehicle alone. 30 minutes after dosing~ -
each group of mice ~as placed on a 30 cm diameter rotating drum
revolving at 1 revolutio~ minuteO The mice were placed on the
drum against its direction of movement~ and the number of mice
falling off within a 2 minute test period was r.oted. ~rom the
results obtained a dose response line was constructed, and the
dose causing 50~0 of the mice to fall off the drum (ED50) was
estimatedO ~he results are shown in Table 3 below.
8) Mouse Acute ~oxicity Test (ATM)
Acute toxicity tests by oral and intraperitoneal routes
were conducted using groups of ten mice at various dose levels.
~he groups were assessed for mortality at 24 hours, and the
results are shown in ~able 3 below, given in ~ kg.
- 42 -
.. . .
i()~34S4
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-- 43 --
iO73
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iO73454
~ he results obtained show that the compounds of the
invention possessa very important activity on the central nervous
system as anticonvulsantj anti-anxiety and hypnotic æedatives,
~nd that they have a very low toxioity.
'~
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:
- 45 -
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,
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~EACTION SCHEME
H S C -- CH2R o NH
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R~
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(VII) / \ (VI)
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(Ib) / (Ia)
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R2 R2
( Id) ( Ic)
-- 46 --
