Note: Descriptions are shown in the official language in which they were submitted.
-- 1 --
4-13694/CGC 961/~
IMIDAZOBENZODI~Z~PINES
The invention concerns 5-diazacycloalkyl-imidazo~1,2-c]~1,3]benzo-
diazepines of formula I
6\ / 7
\i / \ .~ \.-R (I)
n ~
wherein each of the symbols Rl and R2 is hydrogen, lower alkyl, lower
alkanoyl, halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl,
sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); C H2
is lower alkylene separating both nitrogen atoms by 2 or 3 carbon
atoms; R3 is hydr~)gen~ lower alkyl, lower alkenyl, lower alkynyl,
lower alkanoyl, aryl lower alkyl, lower alkoxycarbonyl, phenyl lower
alkoxycarbonyl or (hydroxy, lower alkanoyloxy, aryloxy or lower
alkoxy) lower alkyl having at least two carbon atoms; R4 and R5 in-
dependently represent hydrogen, lower alkyl, lower alkoxy, lower ~^``i
alkylthio, halogen, trifluoromethyl, hydroxy, lower alkanoyloxy,
sulfamoyl, mono- or .li-lower alkylsulfamoyl; and R6 and R7 represent
h~7drogen or lower alkyl; tle N-oxides, lower alkyl quaternary
derivatives, and salts, especially pharmaceutically acceptable salts
i:hereof, process for their manufacture, pharmaceutical preparations
containing these compounds and their therapeutic application.
l'he term ~lower~ referred to above and hereinafter in connec~ion with
organic radicals or compounds respectively deEines e.g. such alkyl,
alkenyl und aLkynyl radicals with up to and including 7, preferably
#
-- 2 --
up and including 4 and advantageously one or two carbon atoms.
Halogen is preferably fluoro or chloro, but may also be bromo or
iodo.
A lower alkyl group or sucll present in said alkoxy, alkylthio or
other alkylated groups, is above all methyl, but also ethyl, n- or
i-(propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or
3-methylbutyl, lower alkenyl is preferably allyl and lower alkynyl
is preferably propargyl.
Aryl lower alkyl is preferably benzyl, 1-, 2~ or 3-phenylpropyl9
1- or 2-phenylethyl, said radicals being optionally substituted on
the phenyl ring preferably by e.g. halogen, lower alkoxy or lower
alkyl.
A lower alkoxy group preEerably contains 1 to 4 carbon atoms and
represents for example ethoxy, propoxy, isopropoxy or advantageously
methoxy.
A lower alkylthio group preferably contains 1 to 4 carbon atoms and
represents for example ethylthio, propylthio or advantageously
methylthio.
The term "acyl" represents for example lower alkanoyl, lower alkoxy
carbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl (carbamoyl
or sulfamoyl), halosulfonyl5 phenyl lower alkoxycarbonyl and the
like,
I.owe~ allcalloyl is preferably acetyl or propionyl. Lower alkanoyloxy
is preferably ace~yloxy or propionyloxy.
A lower alkoxycarbonyl, mono- or di-lower alkyl (carbamoyl or
sulfamoyl) group is preferably methoxycarbonyl or ethoxycarbonyl;
mono- or dimethyl(carbamoyl or sulfamoyl).
A phenyl lower alkoxycarbonyl group represents preferably
phenylmethoxycarbonyl or phenylethoxycarbonyl.
A lower alkylene group C H2 is especially ethylene; but also 1,2-
or 1,3-propylene, 1,2-, 1,3- or 2,3-butylene; thus forming with both
adjacent nitrogen atoms a piperaæinyl or homopiperazinyl moiety.
A lower hydroxyalkyl group is preferably 2-hydroxy-(ethyl or propyl),
3-hydroxy-(propyl or butyl) or 4-hydroxybutyl.
A lower alkanoyloxy lower alkyl group represents preferably lower
alkanoyloxy (ethyl, propyl or butyl), e.g. 2-acetyloxy- or 2-propion-
yloxy (ethyl, propyl or butyl) 7 3-acetyloxy- or 3-propionyloxy-
(propyl or butyl), 4-acetyloxy- or 4-propionyloxybutyl and the like.
A lower alkyloxy lower alkyl group represents preferably lower
alkyloxy-(ethyl, propyl or butyl), e.g. 2-methoxy- or ethoxy-
(ethyl, propyl or butyl), 3-methoxy- or 3-ethoxy-(propyl or butyl),
4-methoxy- or 4-ethoxybutyl and the like.
An aryloxy lower alkyl group represents preferably phenyloxy-
(ethyl, propyl or butyl), said radicals being optionally substi-
tuted on the phenyl ring preferably by e.g. halogen, lower alkoxy
or lower alkyl.
Lower alkyl quaternary salts of compouncls of formula I are pre-
Eerably, e,g. methyl, ethyl or propyl quaternary salts derived from
reactive es~ers of lower alkcmols having preEerably from l ~o 4
carbon a~oms, e.g. methanol, ethanol or propanol. The anions of said
quaternary salts are preferably those corresponding to pharma-
4 --
ceutically acceptable acids such as halide, e.g. bromide or iodide;sulfate; or lower alkylsulfonate, e.g. methylsulfonate.
Although N-oxides or lower alkyl quaternary salts of compounds of
formula I may represent such functionalized at one or more of any
of the depicted ring nitrogen atoms ;n formula I9 said N-oxides,
lower alkyl quaternary salts of the compounds of formula I are pre~
ferably derived from those wherein R3 is lower alkyl, aryl lower
alkyl, or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy)
lower alkyl having at least 2 carbon atoms in the lower alkyl group
and wherein only the nitrogen atom 'bearing said R3 substituent is
thus functionalized.
Said compounds of Formula I form acid addition salts, which are
preferably such of pharmaceutically acceptable inorganic or organic
acids, such as strong mineral acids, for example hydrohalic9 e.g.
hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric
acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g.
formic,acetic, propionic, succinic, glycolic, lactic, malic,
tartaric, citric, maleic, fumaric, hydroxymaleic, pyruvic, phenyl-
acetic, benzoic, 4-aminobenzoic, anthrani'lic, 4-hydroxybenzoic,
salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic,
ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogeno
benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic
or cyclohexylsulfamic acid; or ascorbic acid.
Compounds oE formula I with RL and/or R2 being carboxy also form salts
with 'lases, preferably with such bases which yield pharmaceutically
acceptable salts, for example, ammonium salts, mono, dl- or tri-lower
alkyl amines, lower alkylene amines, morpholine, piperazine, piperidine,
or lower a]kyl deriva~:ives of said cyclic bases, alkali or alkaline
earth metal salts.
-- 5 --
The compounds of the invention exhibit valuable pharmacological
properties, psychoactive, e.g. neuroleptic, as well as antiallergic,
e.g. antihistaminic effects. Such are demonstrable in animal tests
using advantageously mammals, e.g. mice, rats, guinea pigs or monkeys,
as test objects. Said compounds can be applied to them enterally
or parenterally, advantageously orally, or subcutaneously, intra-
venously or intraperitoneally, for example, within gelatin capsules or
in the form of starchy suspensions or aqueous solutions respec-
tively.
The applied dosage may range between about 0.1 and 100 mg/kg/day,
preferably between about 0.5 and 50 mg/kg/day, advantageously between
about 1 and 30 mg/kg/day.
Said neuroleptic properties can be demonstrated in adult rats or
squirrel monkeys, which were trained to press a lever to avoid the
onset of an electric foot shock. Each lever press postpones the
shock for 30 seconds. I~henever the animal fails to press the lever
once within said period, brief (0.5 sec.) shocks are delivered at
15 second intervals until the animal again presses the lever.
Under control conditions the animals press the lever at a moderately
steady rate and seldom receive more than five or six shocks during
a 25-minute (rats) and up to 4-hour experimental session. Said
compounds are administered to the animals 30, 90, 210 minutes prior
to the experimental session and block the learned conditioned
avoidance behavior, manifested by a decrease in avoidance responding
with a marlced increase in shocks taken by the animal. Both the
avoidance responses and Eailures (shocks receivecl) are recorded
separa~ely for evaluation.
Finally, said antihistaminic properties can be shown in vitro, e.g.,
according to Chasin et al., J. Neurochem. 22, 1031 (1974). Vesicles
Erom a cell free preparation of guinea pig cerebal cortex are
preincubated with H-adenine to Eorm endogenous H-adenosine
~'~8~
triphosphate. The vesicles are then incubated with 50 micromolar
histamine to activate H-cyclic adenosine monophosphate synthesis
in the absence or presence of the test compound at a concentration
between 0.01 and 100 micromolar. When said compound is active, it
inhibits the histamine activation of adenylate cyclase. The IC50
represents the concentration at which histamine activation is in-
hibited by 50%.
Accordingly, the compounds of the invention are useful neuroleptic
and antihistaminic agents, for example, in the treatment or
management of psychotic manifestations, e.g., aggression, agitation,
schizophrenia, and/or allergic conditions in mammals, including man.
They are also useful intermediates in the preparation oE other
valuable products, especially of pharmacologically active
compositions.
Preferred embodiments of this invention relate to compounds of
formula I wherein each of Rl and R2 is hydrogen, lower alkyl, cyano,
carboxy, lower alkoxycarbonyl or carbamoyl; n represents the integer
2 to 4; R3 is hydrogen, lower alkyl~ lower alkoxycarbonyl, or hydroxy
lower alkyl of 2 to 4 carbon atoms; R4 represents hydrogen, lower
alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl;
R5 represents hydrogen; and R6 and R7 represent hydrogen or lower
alkyl; the N-oxides; lower alkyl quaternary salts; or salts,
especially pharmaceutically acceptable salts thereof.
~lighly preEerred are compounds of formula I wherein each of Rl and
R2 is hyclrogen, methyl, ethyl, cyano, carboxy, alkoxycarbonyl
Oe 1 to 3 carbon atoms in the alkoxy portion or carbamoyl; n re-
presents the integer 2 or 3; R3 is hydrogen, alkyl of 1 to 3 carbon
atoms, alkoxycarbonyl of 1 to 3 carbon atoms in the alkoxy portion,
hydroxyethyl or hyclroxypropyl; R4 represents hydrogen, methyl,
methoxy, methylthio, chloro or trifluoromethyl; R5 represents hydro-
gen; R6 and R7 represent hydrogen or methyl; the N-oxides; methyl
~L8~
-- 7 --
quaternary salts; and salts, especially pharmaceutically acceptable
salts thereof.
Especially useful are compounds of formula II
R (II)
N\ ~ 3
CnH2n
wherein Rl and R2 independently represent hydrogen or lower alkyl;
R3 represents hydrogen, lower alkyl or hydroxy lower alkyl wherein
the hydroxy group is separated from the nitrogen atom by at least
2 carbon atoms; R4 represents hydrogen, lower alkyl, lower alkoxy,
lower alkylthio, halogen or trifluoromethyl; C H2 represents
ethylene or propylene; the N-oxides; and salts, especially pharma-
ceutically acceptable salts thereof.
Of particular interest are compounds of formula II wherein Rl and R2
independently represent hydrogen or methyl; R3 represents hydrogen,
methyl, ethyl, propyl, 2-hydroxyethyl or 3-hydroxypropyl; R4 is
hydrogen, methyl, methoxy, fluoro,chloro or trifluormethyl; C ~12
represents ethylene or propylene; the N-oxides and salts, especially
pharmaceutically acceptable salts thereof.
Further preferred are compounds of formula II wherein Rl and R2
independeTltly represent hydro~en or methy:l; R3 represents hydrogen,
methyl, ethyl, propyl or 2-hydroxyethyl; R~ is hydrogen, methyl,
~luoro, c.hloro or trifllloromethyl and C H2 is ethylene, and salts,
especially pharmaceutically acceptable salts thereof.
~L8~
-- 8 ~
Indicative of the antipsychotic utility of the compounds of this
invention, e.g., the compound of example 1, namely 5-(4-methyl-1-
piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine disrupts
avoidance behavior, e.g. decreases avoidance responses in rats and
monkeys at an oral dose of 30 mg/kg or lower.
Illustrative of the antihistaminic activity, 5-(4-methyl-1- ~
piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine, the compound of
example 1, inhibits histamine activation of adenylate cyclase,
with an IC50 of about 1 x 10 ~.
Furthermore, 5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]-
benzodiazepine, the compound of example 1, an illustrative
example of this invention, is essPntially free of extrapyramidal
side effects, e.g. dyskinesias and dystonias in the monkey (dyskinetic
movements and dystonic postures) and shows only minimal ~-adrenergic
blocking activity in vitro.
The compounds of, the invention are prepared according to methods
known per se, advantageous]y by
a) condensing a compound of formula III
6\ / 7
\ / \.~ \~/ 1 (III)
~ =u ~ \R
20 Whereirl X iY a group detachable together with hydrogen or an alkali
metal and the remaining symbols have meaning as deEined Eor
formula I; with a compound o~ formula IV
_ 9 _
HN\ ~ -R3 (IV)
Cn 2n
or an alkali metal derivative thereof wherein R3 has meaning as
defined for formula I; and, if desired, convertitlg any resulting
compound of formula I into another compound of the invention.
A group detachable together with hydrogen or an alkali metal atom
is for example in particular a free or preferably etherified
mercapto group, also an optionally functionally modified reactive
hydroxy group, the cyanato, thiocyanato or the nitroamino group. An
etherified mercapto group is especially a mercapto group etherified
by an optionally substituted hydrocarbon, particularly one of ali-
phatic character. It is especially lower alkylthio, for example
methylthio, ethylthio or butylthio, or phenyl-lower-alkylthio,
for example phenylthio or benzylthio. An optionally functionally
modified reactive hydroxy group is a free hydroxy group or, for
example, a corresponding esterified hydroxy group. This is for
example halogen, such as chlorine or bromine, or lower alkylsulfonyl-
oxy, for example methanesulfonyloxy. An etherified hydroxy group is
for example a lower alkoxy group, such as methoxy or ethoxy.
Said condensation is advantageously carried out with an excess of
the compound IV, or with equivalent amounts of said metal deri-
vcltives prepared in situ therefrom, preferably when X in Eortnula III
is halogeno, lower alkylthio or thiocyanato, advantageously and
depending on the nature oE said X, at temperatures between about 0
and 150, flnd preeerably in an appropriate solvent e.g. a lower
alkanol such as amyl alcohol7 dimethylformamide, hexamethylphosphor-
amide or toluene. Said condensation of a compound of formula III
with a compound oE formula IV may also be carried out in thc pre-
sence of an acid, e.g., a hydrohalic acid such as hydrochloric acid.
., :
- 10 -
The novel llH-imidazo[1,2-c][1,3]benzocliazepine starting materials
of formula III are prepared according to ring closure methods known
per se. Advantageously by condensing compounds of formula V
R 6\./ 7
~ \./ \.~ \./ 1 (V)
R~ ~ H2 H R2
wherein Rl, R2, R~-R7 have meaning as previously defined for
Eormula I with reactive carbonic acid derivatives such as phosgene~
thiophosgene, l,l~-carbonyldiimidazole, cyanogen bromide or
phenyl chloroformate.
Compounds of formula III wherein X is hydroxy can be converted to
compounds wherein X is sulfhydryl by conventional sulfurating agents,
such as phorphorus pentasulfide.
These compounds of formula III can be further derivatized to com-
pounds of formula III above wherein X has the meaning given above,
analogous to the procedures illustrated by the examples herein.
Starting materials of formula V are preferably prepared by reduction
of the corresponding variously substituted 2-(o-nitrobenzyl)imidazoles,
which are in turn preferably prepared from the correspondingly
substituted o-nitrobenzylnitriles and 2-aminoacetals (or ketals) 9
e.g. aminoacetald~tlyde dimethyl acetal, by known methods illu-
~0 s~rated in the examples herein.
Eurther process Eor the preparation of the compounds of generalEormula I consists in
b) cyclizing a compound of formula VI
~ \ ~ IN- 3 Rl (VI)
Rs ~ C~ R3
wherein Z is oxygen, sulfur, or NH, and the other symbols have the
above-given meaning, under dehydrating, dehydrosulfurating or
deamination conditions, and if desired converting any resulting
compound into another compound of the invention.
Said cyclization is preferably carried out at temperatures between
0 and 120, with a reagent such as a phosphorus halide, for example,
phosphorus pentachloride and/or phosphorus oxychloride or a
10 cyanogen halide, with or without a crown ether catalysator, for
example 8-crown-6-ether, with or without basic catalysts such as
triethylamine or potassium carbonate, advantageously in an inert
solvent, such as acetonitrile or tolueneO
The starting materials of Fo~nula VI ~an be
obtained according to methods known per se. For example they can
be prepared from percursors of Formula III or tautomers thereof,
wherein X is hydroxy, thio or amino by condensing them with compounds
of Formula IV in the presence or absence of other bases, e.g. those
listed above, preferably in an inert solvent, such as methylene
chloride or toluene at temperatures between 0 and 150 advantageously
between 10 and 50. The ring opening reaction is preEerably
carried out at low temperature to minimiæe side reactions when R
and R2 represent reactive functional groups.
~lternately, starting materials of formula VI, wherein R3 is lower
alk~moyl, lower alkoxycarbonyL or phenyl lower alkoxycarbonyl, are
prepared by condensing a cornpound of formula V above with a compound
of formula VII
Yl-N\ \N ~ R (VII)
CnH2n
wherein Y' represents halocarbonyl, halothiocarbonyl or cyano,
preferably in an inert solvent, at temperatures between about 0 and
150, with or without basic catalysts such as triethylamine or
potassium carbonate.
Starting materials of formula VII are preferably obtained by
reacting compounds of formula IV wherein R3 has the meaning given
for formula VII, or advantageously e.g. the N-trimethylsilyl
derivative thereof, with phosgene, thiophosgene or cyanogen bromide
in an inert solvent such as ethyl ether, methylene chloride or
dimethoxyethane at temperatures of about -70 to -~50 with or
without basic catalysts such as triethylamine or potassium carbonate.
The compounds of the invention so obtained can be converted into
other compounds of Formula I according to known methods. Thus, for
example, those with R3 being hydrogen or alkali metal, e.g., sodium
or lithium salts thereof, can be reacted with substituted or un-
substituted oxiranes, such as ethylene oxide, or reactive esters
of unsubstituted or correspondingly substituted aliphatic or arali~
phatic alcohols such as methanol, ethanol, methoxyethanol, phenoxy-
ethanol, allyl alcohol, propargyl alcohol, e.g. such esteriEied by
a strong inorganic or organic acicl, above all hydrohalic acids~ e.g.
hydrochloric, hydrobromic or hydriodic acid; sulfuric or an aromatic
sulfonic acid, e.g. p-toluene or m-bromobenzene sulfonic acid, in
order to obtain the corresponding N-substituted compounds or
quaternaries respectively, depending on the molar amount of the
alkylating agent employed. Intermediates of formula I wherein R3 i9
- 13 -
alkali metal or alkali metal derivatives of compounds of formula IV are
obtained by metallation with reactive organometallic agents such as
lithium diisopropylamide, with alkali metal alkoxides such as sodium
methoxide, or alkali metal hydrides such as sodium or potassium hydride.
Unsaturated compounds, such as those with R3 being lower alkenyl,
lower alkynyl may be hydrogenated with catalytically activated
hydrogen to obtain compounds wherein R3 is the corresponding lower
alkyl. Conversely, resulting N-alkylated compounds can be converted
into N-unsubstituted compounds, e.g. by catalytic hydrogenolysis of
N-benzyl compounds, or reaction of N-lower alkyl derivatives with
lower alkyl haloformates, e.g. ethyl chloroformate, to yield N-acy:L
derivatives which, in turn, may be hydrolyzed to said unsubstituted
compounds, those with R3 = H, for example with aqueous bases,
such as alkali metal hydroxides, e.g. aqueous sodium hydroxide
solutionO
Compounds of formula I wherein R3 is hydroxy lower alkyl can also
be prepared by first reacting corresponding compounds of Formula I,
wherein R3 represents hydrogen, with reactive derivatives of corres-
ponding glycols, glycolic acids or dicarboxylic acids, such as
lower alkyl esters, halides or anhydrides thereof, or reactive
esters of said glycols or glycolic acid derivatives, for example
with hydrohalic or aromatic sulfonic acids, 1,2-dibromoethane or
-propane, ethyl bromoacetate or -propionate, ethyl tosyloxyacetate;
diethyl oxalate or malonate or ethyl oxalyl chloride. The inter-
mediates so obtained are either hydrolyzed or reduced with simpleor complex light metal hydrides such as lithium alumlnium hydride,
alone or with diborane to compounds of Eormula I wherein R3 is
hydroxyalkyl.
Compounds of formula I wherein R3 is lower alkyl, e.g. methyl carl be
prepared by reacting the corresponding compounds Oe Eormula I wherein
R3 represents hydrogen with lower alkyl or phenyl lower alkyl halo-
formates, such as ethyl chloroformate, to obtain compounds of for-
mula I wherein R3 is lower alkoxycarbonyl or lower phenylalkyloxy-
carbonyl, and reducing said acyl derivatives with simple or complex
light metal hydrides such as lithium aluminium hydride~ sodium tri~
t-butoxy or sodium bis-(2-methoxyethoxy) aluminium 'hydride.
N-acylated derivatives of formula I wherein R3 is lower alkanoyl can
preferably be obtained from compounds of Formula I with R3 being
hydrogen and corresponding reactive carboxylic acid derivatives,
e.g.~ halides, simple or activated esters, such as alkyl or cyano-
alkyl esters, anhydrides or isocyanates. ~hese in turn can be re-
duced as above to the compounds of formula I wherein R3 is lower
alkyl. Compounds of formula I wherein R3 is hydroxy lower alkyl may
be acylated as above to the compounds wherein R3 is lower alkanoyloxy
lower alkyl.
Compounds of Formula I with Rl and/or R2 being hydrogen~ may be
converted to the corresponding compounds with Rl and/or R2 being
halogen or acyl, e.g. by halogenation, preferably with chlorine in
acetic acid or under Friedel Crafts conditions ~y'acylation
with a trihaloacetyl halide or a halosulfonic acid optionally
followed by treatment with an alkali metal lower alkoxide, hydroxide
or amide. Any resulting carboxylic or sulfonic acid derivatives may
then be hydrolyzed in known fashion, preferably under alkaline
conditions and/or amidi~ed with ammonia, mono- or di-lower alkyl~
amines; the resulting primary carbo~amides may in turn be dehydrated
to th~ corresponding ni~riles according to conventional methods.
Compounds o~ ~he Eormula I in which Rl and/or R2 represents carboxy,
can be preparecl, ior example, by hydro'lysis of compounds wherein R
cmd/or R2 represen~s cyano, lower alkoxycarbonyl or carbamoyl.
- 15 ~
Tertiary amines in which R3 differs from hydrogen and is e.g. lower
alkyl or aryl lower alkyl, can be converted into the N-oxides, for
example with hydrogen peroxide or organic peracids, such as lower
peralkanoic or perbenzoic acids, e.g. peracetic or m-chloroperbenzoic
acid, advantageously at temperatures at or below room temperature
with the latter, or up to 100 with hydrogen peroxide in the pre-
sence of lower alkanoic acids, e.g. acetic acid. If only a mono
N-oxide is desired, care should be taken in order to prevent further
oxidation.
Finally, the compounds of the invention are either obtained in the
free form, or as a salt thereof. Any resulting base can be conver-
ted into a corresponding acid addition salt, preferably with the use
of acids which yield a pharmaceutically acceptable salt or with anion
exchange preparation, or any resulting salt can be converted into
]~ the corresponding free base, for example, with the use of a stronger
base, such as a metal or ammonium hydroxide or a basic salt, e.g.
an alkali metal hydroxide or carbonate, or a cation exchange
preparation. Said acid addition salts are preferably such of
pharmaceutically acceptable inorganic or organic acids described
previously.
Compounds of formula I with Rl and/or R2 being carboxy can be con-
verted into the corresponding metal or ammonium salts by e.g.
treatment with the alkaline or alkaline earth metal hydroxides or
carbonates, ammonia or the amines listed previously.
These or other salts, for exmaple, the picrates, can also be used
for purif;ca~ion of the bases obtained; the bases are conver~ed into
salts, the sal~s are separated and the bases are liberated from ~he
salts.
- 16 -
In view of the close relatiollship between the free compounds and the
compounds in the form of their salts, whenever a compound is referred
to in this context, a corresponding salt is also intended, provided
such is possible or appropriate under the circumstances.
In case mixtures of geometrical or optical isomers of the above
compounds, e.g. I to VII are obtained, these can be separated into
the single isomers by methods in themselves known, e.g. by fractional
distillation, crystallization and/or chromatography. Racemic products
can likewise be resolved into the antipodes, for example, by se-
paration of diastereomeric salts thereof, e.g. by the fractionalcrystallization of the salts formed with d- or l-tartaric acid.
The above-mentioned reactions are carried out according to standard
methods9 in the presence or absence of diluents, preferably such
as are inert to the reagents and are solvents thereof, of catalysts,
condensing or said other agents respectively and/or inert atmospheres,
at low temperatures, room temperature or elevated temperatures,
preferably at the boiling point of the solvents used, at atmospheric
or superatmospheric pressure.
The invention further includes any variant of the present process,
in which an intermediate product obtainable at any stage thereof
is used as starting material and the remaining steps are carried out,
or the process is discontinued at any stage thereof, or in which
the starting materials are formed under the reaction conditions, or
in which the reaction components are used in the form of their
salts or optically pure antipodes. Mainly those starting materials
should be used in said reactions, that lead to the formation of
those compounds, indicated above as being especially valuable, e.g.
those of Formula II.
The pharmacologically active compounds of the invention are useful
in the manufacture of pharmaceutical compositions comprising an
effective amount thereof in conjunction or admixture with exci-
pients suitable for either enteral or parenteral application.
Preferred are tablets and gelatin capsules comprising the active
ingredient together with a) diluents, e.g. lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose and/or glycine, b) lubricants,
e.g. silica, talcum, stearic acid, its magnesium or calcium salt
and/or polyethyleneglycol, for tablets also c) binders, e.g.
magnesium aluminium silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and/or polyvinyl-
pyrrolidone, if desired, d) disintegrants, e.g. starches, agar,
alginic acid or its sodium salt, or effervescent mixtures and/or
e) absorbents, colorants9 flavors and sweeteners. Injectable compo-
sitions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions
or suspensions. Said compositions may be sterilized and/or contain
adjuvants, such as preserving, stabilizing, wetting or emulsifying
agents, solution promoters, salts for regulating the osmotic
pressure and/or buffers. In addition, they may also contain other
therapeutically valuable substances. Said compositions are pre-
pared according to conventional mixing, granulating or coating
methods, respectively, and contain about 0.1 to 75%~ preferably
about 1 to 50%, of the active ingredient. ~ unit dosage for a
mammal of about 50 to 70 kg weight may contain between about 25
and 200 mg of the active ingredient~
The following Examples a) to e) are intended to illustrate ~ome
typical forms of application, but in no way do they represent the
only embodiments thereof. SpeciEic demonstrations are given in the
~xamples.
0~
a) 100.0 g of active substance are mixed with 610.0 g of lactose
and 442.0 g of potato starch; the mixture is then moistened with an
alcoholic solution of 8 g of gelatine, and is granulated through a
sieve. The granulate is dried, and 60.0 g of talcum, 10.0 g of
S magneisum stearate and 20.0 g of colloidal silicon dioxide are
mixed in; and the mixture is subsequently pressed to form 10,000
tablets~ each weighing 125 mg and each containing 10 mg of active
substance. The tablets can, if desired, be provided with grooves for
a more precise adjustment of the dosage amount.
b) A grallulate is prepared from 100.0 g of active substance, 379 g
of lactose and the alcoholic solution of 6.0 g of gelatine; after
drying, the granulate is mixed with 10.0 g of colloidal silicon
dioxide, 40.0 g of talcum, 60.0 g of potato starch and 5.0 g of
magnesium stearate, and the mixture is pressed out to form 10,000
dragée cores. These are subsequently coated with a concentrated
syrup prepared from 533.5 g of crystallised saccharose, 20.0 g of
shellac, 75.0 g of gum arabic, 250.0 g of talcum, 20.0 g of
colloidal silicon dioxide and 1.5 g of colouring agent, and finally
dried. The dragees obtained each weigh 150 mg and each contain 10 mg
of active substance.
c) 10.0 g of active substance and 1990 g of finely ground supposi
tory foundation substance (for example cocoa butter) are
thoroughly mixed and then melted. The melt is maintained homogeneous
by fitirring whilst 1000 2.0 g suppositories each containing 25 mg
oE active substance are being poured.
d) To prepare a syrup having a content oE active substance of 0.25%,
there are disso~Lved in 3 litres of distilled water, 1.5 litres of
glycerin, 42 g oE p-hydroxybenzoic ac-id methyl ester, 18 g of
p-hydroxybenæoic acid-n-propyl ester ancl, with slight warming,
19 -
25.0 g of active substance; to this solution are then added 4 litres
of 70% sorbitol solution, 1000 g of crystallised saccharose, 350 g
of glucose and an aroma substance, for example 250 g of "Orange Peel
Soluble Fluid", Eli Lilly and Co., Indianapolis, or 5 g of
natural lemon aroma and 5 g of "half and half" essence, both from
Haarmann and Reimer, Holzminden, Germany; the solution obtained is
filtered, and the filtrate is subsequently made up with distilled
water to 10 litres.
e) To prepare a drip solution containing 1.5% of active substance,
150.0 g of active substance and 30 g of sodium cyclamate are
dissolved in a mixture of 4 litres of ethanol (96%) and 1 litre of
propylene glycol. A mixture of 3.5 litres of 70% sorbitol solution
and 1 litre of water is prepared separately and is then added to the
above solution of active substance An aroma substance, for example
5 g of cough-sweet aroma or 30 g of grapefruit essence, both from
Haarmann and Reimerg Holzminden, Germany, is added; the whole is
well mixed, filtered, and made up with distilled water to 10 litres.
The following examples are intended to illustrate the invention
and are not to be construed as being limitations thereon. Tempera-
tures are given in degrees Centigrade, and all parts wherever givenare parts by weight. If not mentioned otherwise, all evaporations
are performed under reducecl pressure, preferably between about 15
and 100 mm Hg.
~xample 1: ~myl alcohol (5100 ml) and 913.35 g (9.17 moles) of N-nlethyl-
.. . . ~.
piperaæine are charged into a 12 Liter 3-necked reaction Elask fitted
with a Dean-Stark adapter. The solution is stirred under nitrogen
atmosphere ancl 989 ~1 of lON ethanolic hydrogen chloride solution are
20 -
added rapidly. The reaction mixture is heated to reflux and the
distillate is collected in the Dean-Stark adapter. When the tempera-
ture of the reaction mixture reaches 131 the Dean-Stark adapter is
removed and an additional 918.35 g ~9.17 moles) of N-methylpiperazine
followed by 1045.0 g (4.56 moles) of 5-methylthio-llH-imidazo[1,2-c]-
[1,3]benzodiazepine are added. The mixture is heated at reflux under
nitrogen atmosphere for 20 hours. Amyl alcohol is then removed under
reduced pressure at a water bath temperature of 80. The viscous
residual oil is dissolved in 10,000 ml of dichloromethane, washed
with 3 x 4,000 ml of 4N sodium hydroxide and 6 x 4,000 ml of water.
The dichloromethane solution is then extracted with 3 x 2,000 ml of
6N hydrochloric acid. The aqueous solution is back washed with
2 x 2,000 ml of dichloromethane, treated with 100 g of activated
carbon and filtered. The clear filtrate is adjusted to pH 9-10 with
1,500 ml of ammonium hydroxide solution ~29%). The oil which separates
is extracted with 3 x 4,000 ml of dichloromethane, the extracts are
dried over 1,000 g of sodium sulfate and the solvent removed at
reduced pressure with a water bath temperature of 60. An oil is
obtained which rapidly solidifies and after drying further (5 mm
Hg/40) yields crude product, m.p. 113-120. The crude product is
dissolved in 8,000 ml of hot ~60-70~) isopropanol. The solutiGn is
decolorized with 200 g of activated carbon and filtered. To this
solution is added a solution of 760.7 g (8.28 moles) of maleic acid
in 2,500 ml of warm (30) isopropanol and the maleate salt begins to
precipitate. The suspension is stirred overnight at ambient tempera--
ture to complete crystallization and the solid is collected by
fil~ration. The product is washed with 3 x 500 ml of cold iso-
propanol and dried (0.5 mm/50). This i8 recrystallized from
ethanol, the resulting product is washed first with ethanol and then
with ether and then dried to give 5-(4-methyl-1-piperazinyl)-llh-
imidazo[l,2-c~[1,3]benzodiazeplne monomaleate, m.p. 204-205
(decomposition).
- 21 -
A solution of 2,246 g of the above maleate salt in 9000 ml of water
is treated with 100 g of activated carbon and filtered. The aqueous
solution is adjusted to pH 9 with 1000 ml of 29% ammonium hydroxide
and the free base separated as an oil. The oil is extracted with
5 3 x 2000 ml of dichloromethane, the extract is dried over sodium
sulfate, filtered and the solvent is removed under reduced pressure
at a water bath temperature of 40. The solid obtained is recrystal-
lized from 14,130 ml of heptane. The light yellow solid is collected
and washed with 2 x 500 ml of heptane and dried (0.01 mm/50) to
10 give 5-(4-methyl-1-pipera~inyl)-llH-imidazo[1,2-c][1,3]benzodiazepine,
m.p. 123-4.
The starting material is prepared as follows: Absolute ethanol
(24,000 ml) and 3,240 g (60.0 moles) of sodium methoxide are charged
into a 70 litre reaction flask. The solution is stirred under
15 nitrogen while a solution of 8228.4 g (60.0 moles) of o-nitrotoluene
and 8768.4 g (60.0 moles) of diethyl oxalate is added all at once.
The resulting solution is heated at reflux ~or 25 minutes, cooled
to 60 with an ice-bath and 18,000 ml of water are cautiously
added. Heat is then applied and the mixture is held at the reflux
20 temperature for 1 hour. Most of the ethanol is then removed. The
turbid solution is cooled at 50 and a solution of 4,140 g (59.6
moles) of hydroxylamine hydrochloride in 6,000 ml of water is added
all at once.The temperature is maintained at 50, the pH is
adjusted to 7.0 with 6,000 ml of 10 N sodium hydroxide solution
25 and the reaction mixture stirred overnight at ambient temperature~
The suspension is cooled to 10 and the pH is ad~justed to 1.0 wlth
6,000 ml of 12 N hydrochlorid acid. The stirring is contin~led over-
night at 10 to complete the liberation of the Eree acid. The solid
is collected, washed wi~h 6 x 4,000 ml of water, air dried overnight
and suspellded in 20,000 ml of toluene. The suspension is stirred
for 1 hour under nitrogen atmosphere. The product is collected,
washed with 4 x 2,000 ml of toluene followed by 4 x 2,000 ml of
- 22 -
petroleum ether and dried (5 mm llg/60) to give 2-nitrophenylpyruvic
acid oxime, m.p. 158-60 (decomposition).
Water (50,000 ml), 2,940 ml of glacial acetic acid and (22.22 moles)
of 2-nitrophenylpyruvic acid oxime are charged into a 70 litre
reactor. The stirred suspension is heated over two hours under
nitrogen atmosphere to 90 and this temperature is maintained for
2 hours. The dark solution is allowed to cool slowly and is stirred
overnight at ambient temperature. The suspension is extracted with
5 x 4,000 ml of methylene chloride, washed with 3 x 3,000 ml of
water, dried over magneisum sulfate and filtered. The filtrate is
treated with activated carbon, filtered and the solvent is removed
under reduced pressure. The solid residue is recrystallized from
1,000 ml of isopropanol to give 2-nitrophenylacetonitrile, m.p.
~2-84~
Absolute ethanol (2,250 ml) and 1,500 g (9.25 moles) of o-nitro-
phenylacetonitrile are charged into a 22 liter flask. The suspension
is cooled to 5-10 and hydrogen chloride is bubbled into the mixture
for 2.5 hours. The reaction mixture is stirred at 10 under nitrogen
atmosphere overnight. It is then diluted with 16,000 ml of ether
and stirred for 1 hour; the solid is collected by filtration, washed
with 4 x 1,000 ml of ether, dried (5 mm Hg/40), to give ethyl
2-(2-nitrophenyl)acetimidate hydrochloride, m.p. 122-123 (de-
composition).
Ethanol (2,200 ml) and 5,15~ g (8.81 moLes) oE ethyl 2-(2~nitro-
phenyl)acetimida~e hydrochloride are charged into a 22 liter Elask.
The suspension is stirrecl under nitrogen ac room temperature and
1022.9 g (9.73 moles) of aminoacetaldehyde dimethylacetal are
added all at once. The mixtllre is stirred for 1 hour and 1,693 ml
- 23 -
of 12N hydrochloric acid are added all at cnce to cause a gentle
exotherm reaction (to 40). Heat is then applied and the temperature
is maintained at 70-80 for 30 minutes. The solution is cooled to
20 (ice-water bath) and diluted with 2,700 ml of lON sodium hydroxide
solution to precipitate the product. The suspension is stirred at
10 for 1 hour under nitrogen atmosphere, the solid collected by
filtration and washed with 3 x 2,000 ml of water to give 2-(2-n;tro-
benzyl)-imidazole, m.p. 155-157.
50% Aqueous ethanol (5,672 ml) and 2,890 g (1~.22 moles) of 2-(2-
nitrobenzyl)-imidazole are charged into a 22 liter flask. The sus-
pension is stirred under nitrogen atmosphere and 2,400 g (42.97 moles)
of iron powder (100 mesh) are added all at once. The mixture is then
warmed to 70 and a solution of 1~7 ml of 12N hydrochloric acid in
8.3 ml absolute ethanol are added. ~ vigorous exotherm reaction
lS results and a strong reflux occurrs that persists for 1.5 hoursO
When the exotherm reaction subsides, a mixture of 290 ml of 12N HCl
and 1400 ml of absolute ethanol are added over 30 minutes. Heat is
applied and the mixture is refluxed for 2 hours, diluted with 6,500 ml
of absolute ethanol and adjusted to pH 8-9 with 700 ml of lON sodium
hydroxide. The suspension is stirred for 1 hour and filtered. The
cake is washed with 1,000 ml of absolute ethanol, the filtrates are
combined and the solvent is removed. The remaining solid is then
suspended in 10,000 ml of water, stirred under nitrogen atmosphere
for two hours, collected, washed with 2,000 ml of water, and dried to
yield 2-(2-aminobenzyl)-imidazole, m.p. 153-155o
Di.chloromethane (42,000 ml) and 5,120 g (50,65 moles) of triethyL-
amine are charged into a 70 litre Elask. The solution is stirred under
nitrogen atmosphere and 4,370 g (25.23 moles) of 2-(2-aminobenzyl)-
imidazole are aclded. The suspension is cooled to 0-5 and 3,~21 g
(29.75 moles) of 85% thiophosgene in carbon tetrachloride are added
over 3 hours, during which time the reaction temperature rises slowly
- 2~ -
to 15D. The suspension is then stirred at 10 for 4 hours and at
ambient temperature overnight. The precipitated product is collectedg
washed with 2 x 3000 ml of dichloromethane and 5 x 4000 ml of water,
and dried (5 mm llg/60) to give llH-imidazo[1,2-c][1,3]benzodiazepine-
5(6H)-thione, m.p. 182-183.
Absolute ethanol (20,000 ml) is charged into a 70 litre flask and
stirred under nitrogen atmosphere; 517,62 g (9.58 moles) of sodium
methoxide are added. ~fter stirring for 30 minutes there is complete
solution and 2,063 g (~.58 moles) of llH-imidazo[1,2-c]El,3]benzo-
diazepine-5(6H)-thione are added. There is complete solution after
stirring at room temperature for 1 hour. The solution is then cooled
to 1, and 1.360 g (9.58 moles) of methyl iodide are added over 30
minutes. The reaction mixture is stirred at 5 for 4 hours and
at ambient temperature overnight. The turbid solution is then cooled
to 5 and diluted with 50,000 ml of water. The resulting suspension is
stirred for 4 hours at 5. The solid is collected, and dried (5 mm
Hg/60) to give 5-methylthio-llH-imidazo[1,2-c][1,3]benzodiazepine,
m.p. 87-88.
Similarly prepared from 4-chloro~2-nitrophenyl-acetonitrile is
8-chloro-llH-imidazorl,2-c]El,3]benzodiazepine-5(6H)-thione, m.p.
200-201 and 8-chloro-5-methylthio-llH-imidazo[1,2-c][1,3]benzo-
diazepine hydrochloride, m.p. 255-257.
The following starting materials are similarly prepared Erom the
correspondingly su~stituted 2-nitrophenylacetonitriles:
a) 8-methyl-5-methyl~hio-llH-imidQzoEl,2-c]~1,3]-benæQdiazepine;
~) 8-Eluoro-5-methylthio-llH-imidazoEl,2-c][1,3]-benzodiazepine;
c) 8-methoxy-5-methylthio~ 1-;midazQEl,2-c][1,3]benzodiQzepine.
~:~L8`~
- 25 -
~xample 2: To a suspension of 2.46 g of 1-[2-(2-imidazolylmethyl)-
phenylcarbamoyl]-4-methylhomopiperazine in l9.4 ml of phosphorus
oxychloride is added at once 1.66 g of phosphorous pentachloride
and the mixture is stirred at room temperature for 4 hours. The
mixture is evaporated to dryness, the residue is suspended in 45.2 ml
of methylene chloride, the suspension is cooled to 0 and 21.4 ml of
triethylamine are added dropwise with stirring over a period of
15 minutes. The mixture is allowed to warm up to room temperature,
stirred for 1.5 hours and poured into 10% aqueous potassium carbonate.
The methylene chloride layer is separated, the aqueous layer is
washed with methylene chloride and the combined methylene chloride
extracts are dried over magnesium sulfate, decolorized with charcoal
and evaporated to dryness. The residue is purified by column chromato-
graphy with 50 g of silica gel, using methylene chloride-methanol-
conc. ammonium hydroxide (300:50:1) as eluent to give 5-(4-methyl-1-
homopiperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine as an oil.
This free base is dissolved in acetone and treated with maleic acid
to give 5-(4-methyl-1-homopiperazinyl)-llH-imidazo[1,2-c][1,3]benzo-
diazepine monomaleate, m.p. 160-163.
5-(4-Methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]-benzodiazepine
monomaleate of example 1 is similarly prepared from 1-[2-(2-imidazolyl-
methyl)phenylcarbamoyl]-4-methyl-piperazine.
The starting materials are prepared as follows:
A solution of 32.4 g of phenyl chloroformate in 100 ml of aceto-
nitrile is added dropwise under nitrogen while stirring to a mixture
oE 34.6 g oE 2-(2-aminobenzyl)-imidazole ancl 71 g of triethylamine in
600 ml of acetonitrile A~ room temperature. After addition is com-
ulete, the reac~ion mixture is heated under reflux for 12 hours,
and allowed to cool to room temperature. Water (150 ml) is added,
the mixture is stirred at roo-m temperature for 0.5 hour and cooted
to 5. The resulting precipitate is filtered off, washed first twice
with 50 ml of water, then 3 times with 33 ml of cold acetone and
- 26 -
dried to give llH-imidazo[1,2-c][1,3]benzodiazepin-5(6H)-one,
m.p. 255-257.
Alternately, 0.75 g of l,l'-carbonyldiimidazole is added at once to
a suspension of 0.79 g of 2-(2-aminobenzyl)-imidazole in 38 ml of
methylene chloride and the mixture is stirred at room temperature
overnight. The resulting precipitate is collected and recrystallized
from methylene chloride to give the crude llH-imidazo[1,2-c][1,3]
benzodiazepin-5(6H)-one, m.p. 238-240.
In analogous fashion, or by using phosgene as the reagent for
cyclization, the following intermediates are obtained.
a) 2,3-dimethyl-11l1-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one;
b) 8-chloro-llH-imidazo[1,2-c][1,3]benzodiazepin-5(6H)-one;
c) 8-methyl-llH-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one;
d) 8-methoxy-llH-imidazo[1,2-c][1,3]benzodiazepine-5 (6H)-one.
To a suspension of 0.76 g of llH-imidazo[1,2-c][1,3]benzodiazepin-5-
(6H)-one in 9 ml oE methylene chloride is added at once 0.41 g
of N-methylhomopiperazine and the mixture is stirred at room
temperature for 2~ hours. The reaction mixture is filtered and
the filtrate is evaporated to dryness. Recrystallization of the
residue from methylene chloride-ether gives 1-[2-(2-imidazolyl-
methyl)-phenylcarbamoyl]-4-methylhomopiperazine, melting at 139-1~3.
Similarly prepared from ~-methylpiperazine is 1-[2-(2-imidazolyl
metllyl)-phellylcRrbamoyl~ methylpiperazine, rn.p. 172-17~.
'rhe follo~ing compounds are prepared ac.cording to the above proce-
dures:
a) '1-[2-(~,S~dimethyl-2-imidazoly'l.methyl)-pllenylcarbamoy'L]-~-me~hyl-
piperaæine; and
b) l-[2-(2-imidazolylmethyl) 5-chlorophenylcarbamoyl]-~ methyl-
piperazine.
- 27 -
Example 3: A solution of 2.~i g of 5-cyanomercapto-llH-imidazo~1,2-c]-
-
[1,3]benzodiazepine in 5 ml of hexamethylphosphoramide is cooled to
~5 and 2.1 g of N-methylpiperazine is added dropwise with efficient
mechanical stirring and under nitrogen, over a period of 5 minutes.
Stirring is continued for 10 minutes at -5 and another 10 minutes
after removal of the cooling bath. The mixture is diluted with 100 ml
of ethyl acetate and the solution washed twice with brine, dried over
magnesium sulfate, and evaporated to dryness. To the residue, a
solution of 1.2 g of maleic acid in 3 ml acetone is added and the
mixture is diluted with ether. The crude product crystallized, m.p.
183-186, and is recrystallized to give the 5-(4-methyl-1-piperaziny~-
llH-imidaæo[1,2-c][1,3]benzodiazepine monomaleate of example lo
It melts at 204-205 (decomposition)~
The starting material is prepared as follows:
l$ Sodium hydride (50~ in mineral oil9 1.44 g,) is washed with dry
ether and suspended in 100 ml of dry tetrahydrofuran7 6c45 g of
llH-imidazo[l~c]~1,3]benzodiazepine-5(6H)-thione is added in por-
tions to the suspension of sodium hydride, with stirring and under
nitrogen7 over a period of 2 minutes. The mixture is stirred at
room temperature for 1.5 hours. The white suspension, which was
formed by the end of this time, is cooled to 0 and 3.5 g of
cyanogen bromide dissolved in 10 ml of dry tetrahydrofuran is added
dropwiese. The mixture is stirred at room temperature for 0.5 hour
and evaporated under reduced pressure at 45. The residue is
dissolved in methylene chloride, the solution is washed with water,
dried over ma~lesi-lm sulfate, decolorized with charcoal, and
evclporated to a small volume. 5-Cyanomercapto-llll-imidazo[1,2-c]-
~1,3]benzodiazepine~ m.p. 111-113, crystallized on dilution with
ether.
- 28 -
Example 4: To a solution oE 8.9 g of 1-~2-(2-imidazolylmethyl)-
phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine in 70 ml of aceto-
nitrile, cooled to 0, is added 2.4 g of solid potassium carbonate
while stirring, followed by dropwise addition of a solution of 2.5 g
of cyanogen bromide in 10 ml of acetonitrile; the mixture is allowed
to warm up to room temperature overnight. The solids are filtered
off, washed with ethyl acetate, and the filtrate is evaporated to
dryness. The residue is dissolved in methylene chloride, the solution
is washed with water, dried over magnesium sulfate, decolorized with
charcoal and evaporated to dryness. The residue is chromatographed
with 250 g of silica gel using ethyl acetate-methanol (9:1) as eluant
to give 5-(4-ethoxycarbonyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]-
benzodiazepine, m.p. 137-139.
The starting material is prepared as follows- A solution of 20 g
of l-ethoxycarbonylpiperazine in 400 ml dry tetrahydrofuran is
cooled to -65 and 6105 ml of 2.1M solution of n-butyllithium in
hexane is added dropwise over a period of 15 minutes. The mixture is
stirred for 15 minutes and a solution of 16.44 ml of chlorotrimethyl-
silane in 68 ml of tetrahydrofuran is added dropwise over a period
of 15 minutes. The mixture is then allowed to warm up to room tem-
perature overnight and evaporated to dryness. Ethyl ether is added,
the solids are filtered off9 the filtrate is evaporated to dryness
and the residue is distilled to give l-ethoxycarbonyl-4-trimethyl-
silylpiperazine, b.p. 102-107/0.1 mm Hg.
To a solution of 4.66 ml of 85% thiophosgene in 200 ml of ethyl
ether, cooled ~o -/6~ is aclded7 while stirring and under nitrogen,
a solu~-on of 7 g of 1-ethoxycarbonyl-4-trimethylsilylpiper~æine in
35 ml of ethyl ether over a period oE 20 minutes. The mixture i9
allowed to warm up to room temperature overnight. The suspension is
~a~8~
- 29 -
filtered and the filtrate is evaporated to dryness. The residue is
crystallized from methylene chloride-hexane to give ~-ethoxycarbonyl-
l-piperazinyl-thiocarbonyl chloride, m.p. 107~111.
To a suspension of 3.8 g of 2-(2-aminobenzyl)-imidazole in 38 ml of
tetrahydrofuran and 3.23 ml of triethylamine is added dropwise a
solution of 5.5 g 4-ethoxycarbonyl-1-piperazinyl-thiocarbony]
chloride in 10 ml of methylene chloride at room temperature. The
mixture is stirred for 1 week and the suspension filtered. The
filtrate is washed with first 10% aqueous potassium carbonate, then
with water, dried and evaporated to dryness to give amorphous 1-~2~
(2-imidazolylmethyl)-phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine,
characterized by NMR.
Example 5: According to the methods illustrated by the previous
.
examples, the following compounds of formula I, especially II wherein
Rl and R2 represent hydrogen, and C H2 represents 1,2-ethylen were
obtained from equivalent amounts of the corresponding starting
materials.
No. R3 R4 Salt m.p.
1 CH2CH20H H __ 143-4
20 2 CH2CH20H Cl HCl 225 (decompo-
sitlon)
3 CH3 Cl 2HC1 226-8 tdec.)
4 CH3 H 2HC1 ~250 (dec.)
CH3 H HCl 217-220.
Example 6: The mixture oE 315 mg of 1-~2-(2 imidazolylmethyl)phenyl-
thiocarhamoyl~-4-metllylpiperazineJ 3.3 ml of dimethylformamide,
276 mg of potassium carbonate, 116 mg of cyanogen bromide and 50 mg
of 8-crown-6 ether is stirred at room temperature under nitrogen
for 3 hours. It is diluted with ethyl acetate~ washed with saturated
- 30 -
aqueous sodium chloride, dried and evaporated. The residue is dis-
solved in acetone, the solution treated with 116 mg of maleic acid
and diluted with diethyl ether, to yield 5-(4-methyl-1-piperazinyl)-
llH-imidazo[1,2-c][1,3]benzodiazepine monomaleate. The product is
identical with that of Example 1.
The starting material is prepared as follows:
The mixture of 2.1 g of llH-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-
thione, 23 ml of methylene chloride and 1.0 g of l-methylpiperazine
is stirred at room temperature for 15 hours. The crystalline product
formed is filtered off and washed with methylene chlorideS to yield
1-[2-(2-imidazolylmethyl)-phenylthiocarbamoyl]-4-methylpiperazine~
Example 7: A mixture of 9.5 g of 5-methylthio-llH-imidazo[1,2-c~[1,3]-
-
benzodiazepine hydrochloride, 3.~2 g of piperazine, and 350 ml of
amyl alcohol is refluxed with stirring and under nitrogen for
20 hours. The solvent is evaporated under vacuum, the residue is
triturated with methylene chloride, washed with 2N sodium hydroxide
solution, dried over magnesium sulfate, and evaporated to dryness.
The residue is dissolved in 10 ml of methanol and treated with 2N
ethereal hydrochloric acid solution to give 5-(4H-l-piperazinyl)-llH-
imidazo[l~2-c][1,3]benzodiazepine dihydrochloride.
Examples 8: To a solution of 0.2 g of 5-(4-carboethoxy-1-piperazinyl-
llH-imidazo[1,2-c][1,3]benzodiazepine in 2 ml of dry tetrahydrofuran,
100 mg of lithium aluminium hydride are added at once and the
mixture is ref]uxed under nitrogen for ~8 hours. The mixtllre is cooled
to room temperature, stirred with 0.2 ml of 30% aqueous sodium
hydroxide, and filtered. The fi.ltrates are evaporated to dryness
and the product is purified to give 5-(4~methyl-1-piperazinyl]-
llH-imidazo[1,2 c][1,3]benzodiazepine, which is identical wi~h the
procluct of example 1. It melts at 123-124.
~8~
- 31 -
Example 9: To a solution of 82 mg of 5-~4-methyl-1-piperazinyl)-llH-
imidazo[l,2-c][1,3]benzodiazepine in 1 ml of methylene chloride, 74 mg
of m-chloroperbenzoic acid are added at 0. The mixture is stirred at
0 overnight; this is diluted with 1 ml of ether, one equivalent of
5 ethereal hydrochloric acid solution is added and the resulting
precipitate is collected. Recrystallization gives 5-(4-methyl-4-oxi-lo-
l-piperazinyl-llH-imidazo[1,2-c][1,3]benzodiazepine hydrochloride.
Example 10: To a solution of 100 mg of 5-(4-benzyloxycarbonyl-1-
piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine in 0.3 ml of
10 acetic acid are added 0.35 ml of a 2N solution of hydrobromic acid in
acetic acid. The mixture is heated at 100 for 1 hour and stirred at
room temperature overnight. Ether is added, and the 5-~4H-l-piperazin-
yl)-llH-imidazol192-c][1,3]benzodiazepine hydrobromide precipitatesO
The starting material is prepared similarly to starting material of
15 exm~ple 4 by replacing l-ethoxycarbonylpiperazine with the equivalent
amount of l-benzyloxycarbonylpiperazineO
Example 11: A mixture of 265 mg of 5-~4H-l-piperazinyl)-llH-imidazo-
-
[1,2-c][1,3]benzodiazepine 0.5 g of potassium carbonate, 0.142 g of
methyl iodide and 2 ml of acetone is stirred at room temperature over-
20 night and evaporated. Water is added to the residue, and the mixtureis extracted with methylene chloride. The extracts are dried over
magnesium sulfate, evaporated, and the residue is purified to give
5-(4-methyl-l-piperazinyl)-llH-imidazo[192-c][1,3]benzodiazepineO
~xample L2: The following compounds of formula I (R -R =~1) are
n______ _ 5 7
25 prepared according to the methods illustrated by the previous examples
and are obtained from equivalent amounts oP the corresponding substi-
tuted starting materials.
- 32 -
No. Rl R2 R3 R4 n 2n
1 CH3 H CH3 H (CH2)2
2 CH3 CH3 C113 H (CH2)2
3 H H C~13 8-CF3 (CH2)2
5 4 ll H CH3 8-F (CH2)2
H H CH3 8-OCH3 (CH2)2
6 H H CH3 8~0H (CH2)2
7 H H CH30CH2CH2 H (CH2)2
3 H H CH3COOCH2CH2 H (CH2)2
10 9 H H CH3 8-CH3 (CH2)2
Examples 13: Preparation of 10,000 tablets each containing 25 mg of
the active ingredient:
Formula:
5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]-
15 benzodiazepine 250.00 g
Lactose 957 0O g
Corn Starch 75.00 g
Polyethylene glycol 6,000 75 00 g
Talcum powder 75.00 g
20 Magnesium stearate 18.00 g
Purified water q.s.
Procedure: All the powders are passes through a screen with openings
. _
of 0 6 mm. Then the drug substance, lactose, talcum, magnesium
stearate and half o~ the starch are mixed in a suitable mixer. Tile
other half of the starch is suspended in 40 ml of water and the sus-
pension added to the boi-Ling solution of polyethylene glycol in 150 ml
water. The paste formed is added to the powders which are granlllated,
if necessary, with an additional amount of water. The granulate is
dried overnight at 35, broken on Q screen with 1.2 mm openings and
compressed into tablets using concave punches with 6.4 mm diameter,
uppers bisected.
_ 33 -
Example 14: Preparation of lO,000 capsules each containing 50 mg of
the active ingredient:
Eormula:
5-(4-methyl-1-piperazinyl)-llH-imidazo[1,2-c][1,3]- 500.0 g
5 benzodiazepine monomaleate
Lactose 1,400.0 g
Talcum powder lOOoG g
Procedure: All the powders are passed through a screen with openings
of 0.6 mm. Then the drug substance is placed in a suitable mixer
10 and mixed first with the talcum, then with the lactose until
homogenous. No. 34 capsules are filled with 200 mg, using a capsule
filling machine,
Analogously tablets or capsules are prepared from the remaining
compounds of the invention, e.g. those illustrated by the other
15 examples herein.
Example 15: A mixture of 10 g of 1-[2-(4-methyl-2-imidazolylmethyl)-
phenylcarbamoyl]-4-methylpipera~ine, 86 ml of phosphorous oxychloride
and 7.24 g of phosphorous pentachloride is stirred at room temperature
for 4 hours and evaporated to dryness. The residue is suspended in
20 186 ml of methylene chloride and 55.2 ml of triethylamine is added
dropwise at 0 over a period of 15 minutes. The mixture is stirred at
room temperature overnight, poured into cold water, basified with
10% aqueous potassium carbonate and extracted with methylene chloricle.
Tlle methylene chloride extracts are re-extracted with 2N aqueous
25 hydrochloric acid. The acidic extracts are basified with 2N aqueous
sndium hydroxide and extracted three times with methylene chloride.
The organic extracts are clried over magnesium sulfate~ decolorized
with charcoal and evaporated to dryness. The residue is chromato-
~80~
- 34 -
graphed from 180 g of silica gel using methylene chloride-methanol-
ammonium hydroxide (300:50:1) as eluant to give a foamy material
which is dissolved in acetone and treated with an equivalent amount
of maleic acid to give on dilution with ether the 2-methyl-5-~4-methyl-
1-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine mono-maleate,
m.p. 195-197.
The starting material is prepared as follows: A solution of ethanolic
sodium ethoxide, prepared by desolving 4.48 g of sodium metal in 112 ml
of absolute ethanol, is added dropwise to a suspension of 47.84 g of
ethyl 2-(2-nitrophenyl)-acetimidate hydrochloride in 224 ml of ethanol
and the mixture is stirred at room temperature for one hourc The sodium
chloride formed is filtered, 22.82 g of the ethylene ketal of l-amino-
2-propane is added to the filtrates and the mixture is stirred at
room temperature overnight. The insoluble material is filtered off
and the filtrates are evaporated to dryness. The residue is dissolved
in 470 ml of concentrated hydrochlorid acid and the solution is re-
fluxed for 1 hour. The mixture is washed once with ether, basified
with 2N sodium hydroxide and extracted three times with ethyl acetate.
The extracts are dried over magnesium sulfate, decolorized with
charcoal and evaporated. The residue is crystallized from methylene
chloride-ether to give 4-methyl-2~(2-nitrobenzyl)-imidazole, m.p.
125-128.
A mixture of 23044 g of 4-methyl-2-(2-nitrobenzyl)-imidazole, 2.34 g
of 10% pallaclium on charcoal and 234 ml of ethanol is hydrogenated
at ~2 psi (3 atmospheres) at room temperature for 4 hours. The
catalyst is f;ltered ancl the filtrates are evaporated to dryness
to give 4-methyl-2-t2-aminobenzyl)-imidadole showing signals in the
NMR spectrum at ~ 2.09, 3.78, 6,08.
A mixture of 18.61 of ~-methyl-2-(2 aminobenzyl)-imidazole, 16.12 g
of l,l~-carbonyldiimidaæole and 375 ml of methylene chloride is
stirred at room temperature overnight. The mathylene chloride is
evaporated to a small volume, the mixture is cooled to 0 and the solids are
filtered and washed with ether to give ~-methyl-llH-imidazo[1,2 c]~l,3]benzodi-
azepine-5(6H)-one, m.p. 23~.5-236.5.
A mixture of 16 g of 2-methyl-llH-imidazo[1,2-c][1,3]benzodiazepine-5-
(6H)-one, 9.58 g of N-methylpiperazine and 160 ml of methylene chloride is
stirred at room temperature overnight. The mixture is decolorized with charcoal
and evaporated to dryness. The residue is crystallized from methanol-ether to
give l-[2-(4-methyl-2-imidazolylmethyl)-phenylcarbamoyl]-4-methylpiperazine, m.p.
]77-179.
Example 16: To a solution of 5 g of 5-~4-methyl-1-piperazinyl)-llH-
imidazo[l,2-c][1,3]benzodiazepine in 50 ml of methylene chloride is added in
portions 3.75 g of m-chloroperbenzoic acid with stirring at 0. The mixture is
then stirred at room temperature overnight and evaporated to dryness. The foamy
residue is passed through 100 g of Amberlite IRA-400* ion exchange resin using
water as eluent. Evaporation of the eluent gives 5-(4-methyl-4-oxido-1-pipera--
zinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine as foamy material having Rf = 0.173
on silica gel plates using methylene chloride-methanol-ammonium hydroxide
(150:50:1) as eluent, which is identicaL with product obtained in Example 9.
Example 17: A mixture of 8.67 g of 5-methylthio-11~ idazo[1,2-c~-
~1~3]benzodiazepine,-3.38 g of piperazine and 326 ml of amyl alcohol is refluxed
under nitrogen for 6 days and evaporated to dryness under reduced pressure.
The residue is dissolved in methylene chloride and the solution is washed
succossively with 10% aclueous potassium carbonate and brine, driocl over magnesium
sul~ate~ decolorized with charcoal cmd evaporated. T1le residue is chromatographed
with 300 g o~ silica gel using methylene chloride-methanol-ammonium hydroxicle
(150:50:1~ as eluent to give S-~ L-piperazinyl)-ll~l-imidazo[1,2-c][1,3]benzncli-
azepine as an oil. The oil is trcatccl with 2.74 g o~ maleic acid in acetone to
give 5-(~ll-1-piperazinyl)-ll~l-imidazo[1,2-c~-
*Trade Mark
-35-
O~
- 36 -
[1,3]benzodiazepine bis-maleate, m.p. 171.5-173.5.
Example 18: A mixture of 0.2 g of 5-(4-ethoxycarbonyl-1-piperazinyl)-
. ... . , . _ _
llH-imidazo[1,2-c]~1,`3]-benzodiazepine, 10 ml of tetrahydrofuran and
50 mg of lithium aluminium hydride is refluxed overnight with
5 stirring. The mixture i9 cooled to 0, and the excess of the lithium
aluminium hydride is destroyed with ethyl acetate, and the mixture s
then poured into cold water and extracted with ethyl acetate. The
extracts are dried and evaporated to give after purification 5-(4-
methyl-l-piperazinyl)-llH-imidazo[1,2-c][1,3]benzodiazepine of
10 example lo
Example 19o A mixture of 0.1 g of 5-(4H-l-piperazinyl)-llH-imidazo
~ .
~192-c][1,3]benzodiazepine, 0.058 g of methyl iodide, 0016 g of
potassium carbonate and 1 ml of dimethylformamide is stirred at
room temperature overnight. The mixture is poured into water and
15 extracted three times with ethyl acetate. The extracts are washed
with brine, dried and evaporated to give 5-(4-methyl~l-piperazinyl)-
llH-imidazo[1,2-c][1,3]benzodiazepine of example 1.
Sidman aroidance data in the rat
-
In teh test-procedure described above a selection of the new compounds
20 gives the following data
. . . _. .
Compound of Dose n Number of Avoidance Failures
mg/kg (difference from vehicle)
example ~ _ _ __ __
p.o. 30 min 90 min 210 min
. . _, I ~ .. __ . ..
1 10 6 ~31 ~13 +14
1 30 6 ~44 +49 -~40
255/2 30 3 ~22 +1~ + 8
S/3 10 3 ~ +14 _
~ _ _
n ~ number oE rats
A decrease in the avoidance response is indica~ive of neuroleptic
activity and is characterized by an increase in the number of avoidance
30 failures.
