Note: Descriptions are shown in the official language in which they were submitted.
4-14458/CGC 1043/+
Trisazolor2.3-clrl,31benzodiazepines
The invention concerns 5-diazacycloalkyl-1,2,4-tr:iazolo[2,3-c]-
[1,3]benzodiazepines of formula I
I/
R o j \ N
3 \ / \ \
o -R (I)
1 11 1 11 1
o NUN
I/\ /
R4 l- N= o 3- -
\/ \
N N-R2
CnH2n
wherein Al is hydrogen, lower alkylthio, amino, (azalea, moo- or
Delaware allcyl)-amino, lower alkoxy, acyloxy, lower alkyd, lower
alkanoyl, hydroxy, halogen, trifluoromethyl, cyan, car boxy, lower
alkoxycarbonyl, carbamoyl, moo- or Delaware alkyl-carbamoyl,
hydroxy-lower alkyd or Delaware alkylamino-lower alkyd;
C Ho is lower alkaline separating both nitrogen atoms by 2 or 3
carbon atoms; R2 is hydrogen, lower alkyd, lower alkenyl, lower
alkynyl, lower alkanoyl, aryl-lower alkyd, lower alkoxycarbonyl,
phenol lower alkoxycarbonyl or (hydroxy, lower alkanoyloxy, airlocks
or lower alkoxy)-lower alkyd having at least two carbon atoms;
R3 and R4 independently represent hydrogen, lower alkyd, lower
alkoxy, lower alkylthio, halogen, trifluoromethyl, hydroxy, lower
alkanoyloxy, sulfamoyl, moo- or do lower alkylsulfamoyl; and R5 and
R6 represent hydrogen or lower alkyd; the N-oxides; and salts,
- 2
especially pharmaceutically acceptable salts thereof, process for
their manufacture, pharmaceutical preparations containing these
compounds and their therapeutic application.
The general definitions used herein have the meanings within the
scope of the present invention as described below.
The term "lower" referred to above and hereinafter in connection
with organic radicals or compounds respectively defines e.g. such
alkyd, alkenyl or alkynyl radicals with up to and including 7,
preferably up and including 4 and advantageously one or two carbon
atoms.
Halogen is preferably flyer or sheller, but may also be broom or
idea.
A lower alkyd group or such present in said alkoxy, alkylthio or
other alkylated groups, is above all methyl, but also ethyl, n- or
i-(propyl, bottle, ponytail, Huxley or hotly), e.g. 2-methylpropyl or
3-methylbutyl.
Lower alkenyl is preferably ally.
Lower alkynyl is preferably propargyl.
Aryl-lower alkyd is preferably bouncily, 1-, 2- or 3-phenylpropyl,
l-or 2-phenylethyl, said radicals being optionally substituted on
the phenol ring preferably by e.g. halogen, lower alkoxy or lower
alkyd.
A lower alkoxy group preferably contains 1 to 4 carbon atoms and
represents for example ethics, propoxy, isopropoxy or advantageously
methoxy.
A lower alkylthio group preferably contains 1 to lo carbon atoms and
represents for example ethylthio, propylthio or advantageously
methylthio.
I
-- 3 --
The term "azalea" represents for example lower alkanoyl, lower
alkoxycarbonyl carbamoyl, sulfamoyl, moo- or Delaware alkyd-
(carbamoyl or sulfamoyl), halosulfonyl or phenylloweralkoxy-
carbonyl.
Lower alkanoyl is preferably acutely or propionyl.
Lower alkanoyloxy is preferably acetyloxy or propionyloxy.
A lower alkoxycarbonyl, moo- or diloweralkyl-(carbamoyl or
sulfamoyl) group is preferably methoxycarbonyl or ethoxycarbonyl,
moo- or dimethyl(carbamoyl or sulfamoyl).
A phenylloweralkoxycarbonyl group represents preferably phenol-
methoxy carbonyl or phenylethoxycarbonyl.
A lower alkaline group CnH2 is especially ethylene; but also 1,2-or
1,3-propylene, 1,2-, 1,3- or battalion; thus forming with both
adjacent nitrogen atoms a piperazinyl or homopiperazinyl moiety.
A lower hydroxyalkyl group is preferably 2-hydroxy-(ethyl or
propel), 3-hydroxy-(propyl or bottle) or 4-hydroxybutyl.
A lower alkanoyloxy-lower alkyd group represents preferably lower
alkanoyloxy-(ethyl, pupil or bottle), e.g. 2-acetyloxy- or
2-propionyloxy-(ethyl, propel or bottle), 3-acetyloxy- or propane-
yloxy-(propyl or bottle), 4-acetyloxy- or 4-propionyloxybutyl.
A lower alkyloxy-lower alkyd group represents preferably lower
alkyloxy-(ethyl, propel or bottle), e.g. 2-methoxy- or ethoxy-(ethyl,
propel or bottle), 3-methoxy- or 3-ethoxy-(propyl or bottle),
4-methoxy- or ~-ethoxybutyl.
An aryloxy-lower alkyd group represents preferably phenyloxy-(ethyl,
propel or bottle), said radicals being optionally substituted on the
phenol ring preferably by e.g. halogen, lower alkoxy or lower alkyd.
I
Although Oxides of compounds of formula I may represent such
functionalized at one or more of any of the depicted ring nitrogen
atoms in formula I, said N-oxides of the compounds of formula I are
preferably derived from those wherein R2 is lower alkyd, aryl-lower
alkyd, or (hydroxy, lower alkanoyloxy, airlocks or lower alkoxy)-
lower alkyd having at least 2 carbon atoms in the lower alkyd group
and wherein only the nitrogen atom bearing said R2 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 hydraulic, e.g.
hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric
acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g.
formic, acetic, prop ionic, succinic, glycolic, lactic, mafia,
tartaric, citric, malefic, fumaric, hydroxymaleic, pyruvic, phenol-
acetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic,
salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic,
ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogen,
benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic
or cyclohexylsulfamic acid; or ascorbic acid.
Certain compounds of formula I, e.g. those with Al being car boxy
also form salts with bases, preferably with such bases, which yield
pharmaceutically acceptable salts, for example ammonium salts, moo-
dip or troweler alkyd amine, lower alkyleneamines, morpholine,
piperazine, piperazine, piper dine or lower alkyd derivatives of said
cyclic bases; alkali or alkaline earth metal salts.
The compounds of the invention exhibit valuable pharmacological
properties, psychoactive, e.g. neuroleptic, as well as anti allergic,
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
entirely or parenterally, advantageously orally, or subcutaneously,
~2~L5~
-- 5 --
intravenously or intraperitoneally, for example, within gelatin
capsules or in the form or starchy suspensions or aqueous solution
respectively. The applied dosage may range between about 0.1 and 50
mg/kg/day, preferably between about 0.3 and 30 mg/kg/day,
advantageously between about 1 and 20 mg/kg/day.
Said neuroleptic properties can be demonstrated in adult rats or
squirrel monkeys, which are trained to press a lever to avoid the
onset of an electric foot shock. Each lever press postpones the
shock for 30 seconds. Whenever 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
Nanette (rats) and up to 4-hour experimental session. Said
compounds evaluated for neuroleptic activity, 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 marked increase in shocks
taken by the animal. Both the avoidance responses and failures
(shocks received) are recorded separately for evaluation.
Finally, said antihistiaminic properties can be shown Lo vitro,
e.g., according to Chasing et at., J. Neurochem. 22, 1031 (1974).
Vehicles from a cell free preparation of guinea pig cerebral cortex
are preincubated with 3H-adenine to form endogenous H--adenosine
triphosphate. me vehicles are then incubated with 50 micro molar
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 micro molar. When said compound is active, it
inhibits the histamine activation of adenylate Seychelles. The ISSUE
represents the concentration at which histamine activation is
inhibited by 50 %.
- 6 - I
Accordingly, the compounds of the invention are useful neuroleptic
and antihistiaminic 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 of other
valuable products, especially of pharmacologically active compost-
lions.
Preferred embodiments of this invention relate to compounds of the
formula I wherein Al is hydrogen, lower alkyd, halogen, troweler-
methyl, lower alkoxy or lower alkylthio; n represents the integer 2
to 4; R2 is hydrogen, lower alkyd, lower alkoxycarbonyl or hydroxy-
lower alkyd of 2 to 4 carbon atoms; R3 represents hydrogen, lower
alkyd, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; R4
represents hydrogen; and R5 and R6 represent hydrogen or lower
alkyd; the N-oxides; and salts, especially pharmaceutically
acceptable salts thereof.
Highly preferred are compounds of the formula I wherein Al is
hydrogen, methyl, ethyl, methylthio, sheller, methoxy or trifler-
methyl; n represents the integer 2 or 3; R2 is hydrogen, alkyd ox 1
to 3 carbon atoms, alkoxycarbonyl of 1 to 3 carbon atoms in the
alkoxy portion, hydroxyethyl or hydroxypropyl; R3 represents
hydrogen, methyl, methoxy, methylthio, sheller or trifluoromethyl; R4
represents hydrogen; R5 and R6 represent hydrogen or methyl; the
N-oxides; and salts especially pharmaceutically acceptable salts
thereof.
~2~5~
-- 7 --
Especially preferred are the compounds of the formula II
OH N
2\ // \
R
R3~
; N - N (II)
o No
\/ \
N N-R
\ /
CnH2n
wherein Al represents hydrogen, halogen, trifluoromethyl, lower
alkylmercapto, lower alkoxy or lower alkyd; R2 represents hydrogen,
lower alkyd or hydroxy-lower alkyd wherein the hydroxy group is
separated from the nitrogen atom by at least 2 carbon atoms; R3
represents hydrogen, lower alkyd, lower alkoxy, lower alkylthio,
halogen or trifluoromethyl; C Ho represents ethylene or propylene;
the N-oxides; and salts, especially pharmaceutically acceptable
salts thereof.
Further preferred are compounds of formula II wherein Al represents
hydrogen, halogen, lower alkylthio, lower alkoxy or lower alkyd; R2
represents hydrogen, lower alkyd or hydroxy-lower alkyd wherein the
hydroxy group is separated from the nitrogen atom by 2 or 3 carbon
atoms; R3 represents hydrogen, lower alkyd, halogen or trifler-
methyl; and C Ho represents ethylene; and salts, especially
pharmaceutically acceptable salts thereof.
Of particular interest are compounds of formula II wherein Al
represents hydrogen, methyl, ethyl, sheller, methylthio or methoxy;
R2 represents hydrogen, methyl, ethyl, propel, 2-hydroxyethyl or
3-hydroxypropyl; R3 is hydrogen, methyl, methoxy, flyer, sheller or
trifluoromethyl; and CnH2n represents ethylene and salts, especially
pharmaceutically acceptable acid addition salts thereof.
I
Indicative of the anti psychotic utility of the compounds of this
invention, e.g. the compound of example l, namely methyl-
methyl-l-piperazinyl)-llH-l,2,4-triazolo[2,3-c~[1,,3~benzodiazepine
Malta, disrupts avoidance behavior, e.g. decreases avoidance
responses in rats and monkeys at an oral dose of about 1.0 mg/kg or
lower.
furthermore, the compound of example l, an illustrative example of
this invention, is essentially free of extra pyramidal side effects,
e.g. dyskinesias and dustiness in the monkey at effective anti-
psychotic doses.
Illustrative of the antihistaminic activity, 2-methyl-5-(4-methyl-1-
piperazinyl)-llH-1,2,4-triazolo[2,3-c][1,3]benzodiiazepine Malta,
the compound of example 1, inhibits histamine activation of
adenylate Seychelles, with an ISSUE of about 3 x 10 7 M.
The compounds of the invention are prepared according to methods
known per so, advantageously by
a) condensing a compound of the formula III
o
R3 \ / \ yin / 1 (III)
o O
l 11 1 11
9 o LO
I/\ /
R40 No
wherein X is a group detachable together with hydrogen or an alkali
metal and the remaining symbols have meaning as defined for for--
mute If with a compound of formula IV
~L2~5~
o
(IVY
CnH2n
or an alkali metal derivative thereof wherein R2 has meaning as
defined for formula l; and, if desired converting 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 Marquette
group, also an optionally functionally modified reactive hydroxy
group, the Senate, thiocyanato or the nitroamino group.
An etherified Marquette group is especially a Marquette group ether-
fled by an optionally substituted hydrocarbon, particularly one of
aliphatic character. It is especially lower alkylthio, for example
methylthio, ethylthio or butylthio, or phenyl-lower-alkylthio, for
example ben~ylthio, or phenylthio. A 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 bromide or lower alkylsulfon-
yolks, for example methanesulfonyloxy. An etherified hydroxy group
is for example lower alkoxy such as methoxy or ethics.
Said condensation is advantageously carried out with an excess of
the compound IV, or with equivalent amounts of said metal derive-
lives prepared in situ therefrom, preferably when X in formula III
is halogen, lower alkylthio or Cynthia, advantageously and
depending on the nature of said X, at temperatures between about 0
and 150, and preferably in an appropriate solvent e.g. a lower
alkanol such as Amy alcohol, dimethylformamide, hexamethylphos-
formed or Tulane. Said condensation of a compound of formula III
with a compound of formula IV may also e carried out in the presence
of an acid, e.g., a hydraulic acid such as hydrochloride acid.
- 10-
The novel 11l1--1,2,4-triazolo~2,3-c][1,3]benzodiazepine starting
materials of formula III, are prepared according to ring closure
procedures known per so. Advantageously by condensing compounds of
formula V
\ /
R3 I / ; // \ /R1
O D O I (V)
l 11 1 11
O it N - N
/ \ H
R4~ NH2
wherein Al and R3-R6 have meaning as previously defined for come
pounds of formula I, with reactive carbonic acid derivatives such as
phosgene, thiophosgene, l,l'-carbonyldiimidazole, cyanogen bromide
or phenol chloroform ate.
Compounds of formula III wherein X is hydroxy can be converted to
compounds wherein X is sulfihydryl by conventional sulfurating
agents, such as phosphorus pentasulfide.
Compounds of formula III, e.g. wherein X is hydroxy or sulfhydryl,
can be further derivatized to compounds of formula III above wherein
X has the meaning given above, according to methods known per so or
analogous to the procedures illustrated by the examples herein.
Starting materials of formula V are preferably prepared by reduction
of the corresponding variously substituted 5-(o-nitrobenzyl)-1,2,4-
triazoles, which are in turn preferably prepared by condensation of
the correspondingly substituted o-nitrobenzylnitriles and lower
alkyd amino ethers derived therefrom, with the hydrazides of the
formula Rl-CONHNH2 wherein Al has the meaning as defined above for
compounds of formula I; by known methods illustrated in the examples
herein.
A further process for the preparation of the compounds of general
formula I consists in
b) cyclizing a compound of formula VI
R R N
5\ / 6 R\
R - C OR
I\/ 1 11 1
o o N - N (VI)
l if H
.. . .----
I/\ / \
R o N~l-G--N N-R
4 Al \ / 2
Z C Ho
wherein Z is oxygen, sulfur, or NH, and the other symbols have the
above-given meaning, under dehydrating, dehydrosulfurating or
delamination 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 and advantageously in an inert solvent, such as asset-
nitrite and Tulane, with reagents such as phosphorous halides
and/or oxyhaLides e.g. phosphorous pentachloride or phosphorous
oxychloride, or cyanogen halides e.g. cyanogen bromide, with or
without crown ether catalysts, such as 18-crown-6-ether, and with or
without basic catalysts such as triethylamine or potassium
carbonate.
m e starting materials of formula VI can be obtained from precursors
of formula III or tautomers thereof, wherein X is hydroxy, trio 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 ethylene chloride or
Tulane at temperatures bitterly 0 and 150, advantageously between
- 12 - ~5Q~
10 and 50. The rung opening reaction is preferably carried out at
low temperature to minimize side reactions when Rl-R~ represent
reactive functional groups.
Alternatively, starting materials of formula Al, wherein R2 is lower
alkanoyl, lower alkoxycarbonyl or phenyl-lower-alkoxcarbonyl, are
prepared by condensing a compound of formula V above with a compound
of formula VII
YIN N-R (VII)
CnH2n
wherein Y' represents halocarbonyl, halothiocarbonyl or cyan,
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 R2 has the meaning given
for formula IV or advantageously e.g. the N-trimethylsilyl derive-
live thereof, with e.g. phosgene, thiophosgene or cyanogen bromide
in an inert solvent such as ethyl ether, ethylene chloride or
dimethoxyethane at temperatures of about -70 to t50 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 R2 being hydrogen or alkali metal, e.g., sodium
or lithium salts thereof, can be reacted with substituted or
unsubstituted oxiranes, such as ethylene oxide, or reactive esters
of unsubstituted or correspondingly substituted aliphatic or
araliphatic alcohols such as methanol, ethanol, nethoxyethanol,
phenoxyethanol, ally alcohol, propargyl alcohol, e.g. such ester-
I
- 13 -
fled by a strong inorganic or organic acid, above all hydraulic
acids, e.g. hydrochloric, hydrobromic or hydriodic acid; sulfuric or
an aromatic sulfonic acid, e.g. Tulane or m-bromobenzene-
sulfonic acid, in order to obtain the corresponding N-substituted
compounds. Alkali metal intermediates of the compounds of formula I
wherein R2 is hydrogen and of the compounds of formula IV are
obtained by mutilation 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 hydrides
Unsaturated compounds, such as those with R2 being lower alkenyl,
lower alkynyl may be hydrogenated with catalytically activated
hydrogen to obtain compounds wherein R2 is the corresponding lower
alkyd. Conversely, resulting N-alkylated compounds can be converted
into N-substituted compounds, e.g. by catalytic hydrogenolysis of
N-benzyl compounds, or reaction of N-lower alkyd derivatives with
lower alkyd haloformates, e.g. ethyl chloroform ate, to yield Nuzzle
derivatives which, in turn, may be hydrolyzed to said unsubstituted
compounds, those with R2 = H, for example with aqueous bases, such
as alkali metal hydroxides, e.g. aqueous sodium hydroxide solution.
Compounds of formula I wherein R2 is hydroxy-lower alkyd can also be
prepared by first reacting corresponding compounds of formula I,
wherein R2 represents hydrogen with reactive derivatives of
corresponding glycols, glycolic acids or dicarboxylic acids, such as
lower alkyd esters, halides or androids thereof, or reactive
esters of said glycols or glycolic acid derivatives, for example
with hydraulic or aromatic sulfonic acids, 1,2-dibromoethane or
-propane, ethyl bromoacetate or -preappoint, ethyl tosyloxyacetate,
deathly oxalate or malonate or ethyl oxalyl chloride. The inter-
mediates so obtained are either hydrolyzed or reduced with simple or
complex light metal hydrides such as lithium aluminum hydrides
alone or with diborane to compounds of formula I wherein R2 is
hydroxyalkyl.
- 14 -
Compounds of formula I wherein R2 is lower alkyd, e.g. methyl can be
prepared by reacting the corresponding compounds of formula I
wherein R2 represents hydrogen with lower alkyd or phenol lower
alkyd haloformates, such as ethyl chloroform ate, to obtain compounds
of formula I wherein R2 is lower alkoxycarbonyl or lower phenol-
alkyloxycarbonyl, and reducing said azalea derivatives with simple or
complex light metal hydrides such as lithium aluminum hydrides
sodium bis-(2-methoxy-ethoxy)-aluminium hydrides or sodium tryout-
butoxy-aluminium hydrides
N-acylated derivatives of formula I wherein R2 is lower alkanoyl can
preferably be obtained from compounds of formula I with R2 being
hydrogen and corresponding reactive carboxylic acid derivatives,
e.g., halides, simple or activated esters, such as alkyd or cyan-
alkyd esters androids or isocyanates. These in turn can be reduced
as above to the compounds of formula I wherein R2 is lower alkyd.
Compounds of formula I wherein R2 is hydroxy-lower alkyd may be
assaulted as above to the compounds wherein R2 is lower alkanoyloxy-
lower alkyd.
Compounds of formula I with Al being hydrogen, may be converted to
the corresponding compounds with Al being halogen or azalea, e.g. by
halogenation, preferably with chlorine in acetic acid or by azalea-
lion under Friedel-Crafts conditions with e.g. a lower allcanoyl
halide, a lower alkyd haloform ate or a trihaloacetyl halide option-
ally followed by treatment with an alkali metal lower alkoxide,
hydroxide or aside. Any resulting carboxylic acid derivatives may
then be hydrolyzed in known fashion, preferably under alkaline
conditions and/or amidized with ammonia, moo- or Delaware alkyd-
amine; the resulting primary carboxamides may in turn be dehydrated
to the corresponding nitrites according to conventional methods.
Compounds of the formula I in which Al represents car boxy, can be
prepared, for example, by hydrolysis of compounds wherein R
represents cyan, lower alkoxycarbonyl or carbamoyl.
- 15 -
Tertiary amine in which R2 differs from hydrogen and is e.g. lower
alkyd, aureole lower alkyd, can be converted into the N-oxides, for
example with hydrogen peroxide or organic persuades, such as lower
peralkanoic or perbenzoic acids, e.g. parasitic or m-chloroper-
benzoic acid, advantageously at temperatures at or below room
temperature with the latter, or up to 100 with hydrogen peroxide in
the presence of lower alkanoic acids, e.g. acetic acid.
In any of the above processes, any interfering reactive functional
group, e.g. hydroxy, amino, car boxy in any of the starting materials
or intermediates may be temporarily protected by methods well-known
to the art.
Finally, the compounds of the invention are either obtained in the
free form, or as a salt thereof. any resulting base can be converted
into a corresponding acid addition salt, preferably with the use of
acids which yield a pharmaceutically acceptable salt, or with an
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 salt are preferably such of
pharmaceutically acceptable inorganic or organic acids described
previously.
Compounds of formula I with Al being car boxy can be converted into
the corresponding metal or ammonium salts by e.g. treatment with the
alkaline or alkaline earth metal hydroxides or carbonates, ammonia
or the amine listed previously.
These or other salts, for example, the pirates, can also be used
for purification of the bases obtained; the bases are converted into
salts, the salts are separated and the bases are liberated from the
salts.
- 16 -
In view of the close relationship 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 free-
tonal distillation, crystallization and/or chromatography. Rhizomic
products can likewise be resolved into the antipodes, for example,
by separation of diastereomeric salts thereof, e.g. by the free-
tonal crystallization of the salts formed with e.g. d- or
l-tartaric acid, mandelic acid, cinchonidine and dehydroabietyl-
amine.
m e above-mentioned reactions are carried out according to standard
methods, in the presence or absence of delineates, preferably such as
are inert to the reagents and are solvents thereof, of catalysts,
condensing or said other agents respectively and/or inert atom-
spheres, at low temperatures, room temperature or elevated tempera-
lures, preferably at the boiling point of the solvents used, at
atmospheric or super atmospheric pressure.
The invention further includes any variant of the present process,
in wick 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 come
pounds, indicated above as being especially valuable, e.g. those of
formula II.
- 17 -
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 excipients
suitable for either entirely or parenteral application. Preferred are
tablets and gelatin capsules comprising the active ingredient
together with a) delineates, e.g. lactose, dextrose, sucrose,
minutely, sorbitol, cellulose and/or Gleason, b) lubricants, e.g.
silica, talcum, Starkey acid, its magnesium or calcium salt and/or
polyethyleneglycol, for tablets also c) binders, e.g. magnesium
aluminum silicate, starch paste, gelatin, tragacanth, methyl-
cellulose, sodium carboxymethylcellulose and/or polyvinylpyr-
rolidone, if desired, d) disintegrants, e.g. starches, ajar, alginic
acid or its sodium salt, or effervescent mixtures and/or e) absorb
bunts, colorants, flavors and sweeteners. Injectable composition are
preferably aqueous isotonic solutions or suspensions, and suppose-
tories are advantageously prepared from fatty emulsions or suspend
sons. Said compositions may be sterilized and/or contain adjutants,
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 prepared 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. A unit dosage for a mammal of about 50 to 70 kg
weight may contain between about 10 and 100 my of the active
ingredient.
The following examples are intended to illustrate the invention and
are not to be construed as being limitations thereon. Temperatures
are given in degrees Centigrade, and all parts wherever given are
parts ho weight. If not mentioned otherwise, all evaporations are
performed under reduced pressure, preferably between about 15 and
100 mm HUG. Proportions wherever given for liquids are in parts by
volume.
- 18 -
Example 1: A mixture of 6.94 g of 1-{o-[5-methyl-3-(1,2,4-triazol-
yl)methyl~-phenylcarbamoyl}-4-methylpiperazine, 52 ml of phosphorus
oxychloride and 4.65 g of phosphorus pentachloride is stirred at
room temperature for 5 hours and evaporated to dryness. The residue
is suspended in 125 ml of ethylene chloride, the mixture is cooled
to 0 and 15.5 ml of triethylamine is added drops. ale mixture is
stirred at room temperature for 30 minutes and washed with cold
water. The aqueous layer is in turn washed with ethylene chloride
and the combined organic layers are washed with water, dried over
magnesium sulfate, decolonized with charcoal and evaporated. rho
residue is chromatographed with 50 g ox silica gel using ethylene
chloride methanol-ammonium hydroxide (450:50:1) as fluent to give as
the less polar component 2-methyl-5-(4-methyl-1-piperazinyl)-llH-
1,2,4-triazolo[2,3-c][1,3]benzodiazepine.
A solution of2-methl-5-(4-methyl-1-piperazinyl)-llH-1,2,4-triazzoo-
[2,3-c~[1,3~benzodiazepine in isopropanol is treated with a solution
of an equimolar quantity of malefic acid in isopropanol to give
2-methyl-5-(4-methyl-1-piperazinyl)-llH-1,2,4-triaazolo[2,3-c~[1,3]-
-benzodiazepine monomaleate, mop. 206-208, representing a salt of
the compound of formula I wherein Al and R2 SHEA, R3-R6 = H and
CnH2n = CH2CH2.
rho starting material is prepared as follows:
Absolute ethanol (2,250 ml) and 1,500 g (9.25 moles) of o-nitro-
phenylacetonitrile is 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 and dried (5 mm Hg/40) to give ethyl
2-(o-nitrophenyl)-acetimidate hydrochloride, mop. 122-123 (doe).
- 19 -
To a solution of 4.1 g of ethyl 2-(o-nitrophenyl)-acetimidate
hydrochloride in 40 ml of ethanol is added at room temperature and
over a period of 10 minute, a solution of Sydney ethoxide prepared
by dissolving 0.38 g of sodium in 40 ml of ethanol. The mixture is
stirred for 10 minutes and filtered. Acetylhydrazide (1.29 g) is
added to the filtrate, the mixture is stirred at room temperature
for 2 hours, the solids are filtered off and washed with ethanol to
give N-acetyl-o-nitrophenylacetamidrazone, mop. 195-197.
A mixture of 1.29 g of N-acetyl-o-nitrophenylacetamidrazone and
20 ml of ethanol is reflexed for 60 hours and evaporated to dryness.
The oily residue is crystallized from ether to give 5-methyl-3-o-
nitrobenzyl)-1,2,4-triazole, mop. 119-123.
A mixture of 1.67 g of 5-methyl-3-(o-nitrobenzyl)-1,2,4-triazole,
42 my of 10 % palladium on charcoal and 15 ml of ethanol is hydra-
jointed at 3 atmospheres pressure for 4 hours, filtered, recolor-
iced, evaporated to a small volume and diluted with ether to give
3-(o-aminobenzyl)-5-methyl-1,2,4-triazole, mop. 143-145.
A mixture of 12.87 g of 3-(_-aminobenzyl)-5-methyl-1,2,4-triazole,
11.21 g of l,l'-carbonyldiimidazole and 470 ml of ethylene chloride
is stirred at room temperature for 5 days and filtered. The lit-
trades are washed with water, dried over magnesium sulfate, recolor-
iced, evaporated. The residue is recrystallized from tetrahdrofuran
to give2-methyl-llH-1,2,4-triazolo~2,3-c~[1,3]benzodiazeppine-5-
(one, mop. 245-247, the intermediate of formula III wherein X =
3 6 H, Al = SHEA and CnH2n = CH2CH2
mixture of 7.23 g of methyl triazolo[2,3-c]~1,3]-
benzodiazepine-5(6H)-one, 5.45 g of N-methylpiperazine and 76 ml of
ethylene chloride is reflexed for 48 hours and evaporated to
dryness. The residue is chromatographed with silica gel using
ethylene chloride-methanol-ammonium hydroxide (150:50:1) as fluent
to give1-[o-[5-methyl-3-(1,2,4-triazolyl)methyl]-phenylcaarbamoyl]-
- 20 - I
4-methylpiperazine as a foamy material; mass spectrum: M ye = 314;
the intermediate of formula VI wherein C Ho OH OH , R and R
SHEA, R3-R6 = H, and Z = 0.
Example 2: Prepared similarly according to the process of example 1
are the following compounds of formula I wherein C Hen is ethylene,
R2 is methyl and R4-R6 are hydrogen.
Compound Al R3 Salt m p
2 3 H Malta 196-l99
2 H H Malta 202-204
3 H clue Malta 215-217
4 Of H Malta 216-218
SHEA H Malta 209-212
6 COOCH2CH3 H
Intermediates of formula VI wherein CnH2n is ethylene, R2 is methyl,
R4 to R6 are hydrogen and Z is ox, for compounds 1 to 6 of for-
mute I:
Intermediate Al R3 mop. Remarks
l/a OH SHEA H 153-159
2/a H H 205-208
3/a H Of 182-186
4/a Of H 190-195 C1 pane to
triazolylmethyl
group
5/a SKYE H 177-180
6/a COOCH2CH3 H
5(~4~
- 21 -
Intermediates of formula III wherein X represents OH and R to R
are hydrogen, for compounds 1 to 6 of formula I:
Intermediate I R3 mop.
l/b CH2CH3 H 165-178
2/b H H 133-136
3/b H 8-C1 252-254
4/b Of H
5/b SHEA H 250-252
6/b 2 3 216-220
Intermediates or compound 1:
a) N-propionyl-o-nitrophenylacetamidrazone, mop. 184.5-186.5 .
b) 5-ethyl-3-(o-nitrobenzyl)-1,2,4-triaæole, mop. 100-103.
c) 5-ethyl-3-(o-aminobenzyl3-1,2,4-triazole, mop. 148.5-151.5.
Intermediates for compound 2:
a) N-formyl-o-nitrophenylacetamidrazone, mop. 149-151, starting
with formylhydrazide.
b) 3-(o-nitrobenzyl)-1,2,4-triazole, mop. 123-125.
c) To a solution of 9.64 g of 3-(o-nitrobenzyl)-1,2,4-triazole in
150 ml of tetrahydrofurane, 220 ml of 1.3M aqueous solution of
titanium trichloride is added and the mixture is stirred at room
temperature for 24 hours. The mixture is cooled in an ice-water
bath and concentrated ammonium hydroxide is added drops to
bring the pi of the solution to 8; the solution is diluted
further with water and extracted 4 times with ethylene chloride.
The combined extracts are decolonized with charcoal, dried over
magnesium sulfate, evaporated to a small volume and diluted with
ether to give 3-(o-aminobenzyl)-1,2,4-triazole, mop. 134-136.
so
- 22 -
Intermediates for compound 3
a) N-formyl-p-chloro-o-nitrophenylacetamidrazone, mop. 173-175
doe.
b) 3-(p-chloro-o-nitrobenzyl)-1,2,4-triazole, mop. 180-185.
c) 3-(p-chloro-o-aminobenzyl)-1,2,4-triazole, mop. 149-152.
Intermediates for compound 4
a) To a solution of 2.36 g of ethyl o-nitrophenylacetimidate in
23 ml of ethanol is added drops at 0 a solution of sodium
ethoxide prepared by dissolving 0.22 g of sodium in 11 ml of
ethanol. me mixture is stirred for 30 minutes, filtered and to
the filtrate us added 1 g of ethyl hydrazinocarbonate. The
mixture is stirred at room temperature for 60 hours, evaporated
to a small volume and filtered to give N-ethoxycarbonyl-o-nitro-
phenyl-acetamidrazone, mop. 183-185.
b) A mixture of 1 of N-ethoxycarbonyl-o-nitrophenylacetamidraæone
and 10 ml of Amy alcohol is reflexed overnight, cooled and
filtered to give 5-hydroxy-3-(o-nitrobenzyl)-1,2,4-triazole, mop.
210~212.5.
c) A mixture of 1 g of 5-hdroxy-3-(o-nitrobenzyl)-1,2,4-triazole,
10 ml of phosphorus oxychloride and 1.89 g of phosphorus pent-
chloride is stirred at 70 for 11 hours, then at room temperature
over the weekend and evaporated to dryness. me residue is
dissolved in water, the solution is gasified with 10 % aqueous
potassium carbonate and extracted 3 times with ethyl acetate. The
combined extracts are dried over magnesium sulfate, decolonized
with charcoal and evaporated to dryness. m e residue is cremate-
graphed with 50 g of silica gel using ethylene chloride-ethyl
acetate (1:1) as fluent to give 5-chloro-3-(o-nitrobenzyl)-1,2,4-
triazole, mop. 160-163.
~2:~L5~
- 23 -
d) To a solution of 6.27 g of 5-chloro-3-(o-nitrobenzyl)-1,2,4-
triazole in 146 ml of tetrahydrofuran is added to 0 with
stirring 146 ml of 20 % Allis solution of titanium trichloride.
The mixture is stirred at room temperature overnight gasified
with concentrated ammonium hydroxide and extracted 3 times with
ethylene chloride. The combined extracts are dried, evaporated
and the residue is crystallized from ether to give omen-
benzyl)-5-chloro-1,2,4-triaæole, mop. 162-165 .
e) A mixture of 0.35 g of 3-(o-aminobenzyl)-5-chloro-1,2,4-triazole,
9 ml of ethylene chloride and 0.284 g of l,l'-carbonyldiimid-
azalea is stirred at room temperature overnight. The mixture is
evaporated to a small volume and diluted with ether to give
1-{o-~5-chloro-3-~1,2,4-triazolyl)methyl]-phenylcaarbamoyl}-imid-
azalea, mop. 165-167.
f) A mixture of 0.324 g of 1-{o-~5-chloro-3-(1,2,4-triazolyl)-
methyl]-phenylcarbamoyl}-imidazole, 3 ml of ethylene chloride
and 0.11 g of N-methylpiperazine is stirred at room temperature
overnight. The mixture is washed with water, dried over magnesium
sulfate and evaporated to give 1- ~-[5-chloro-3-(1,2,4-triazol-
yl)methyl~-phenylcarbamoyl]-4-methylpiperazine, mop. 190-195
(intermediate 4/a).
Intermediates for compound 5:
a) To a solution of 4.1 g of ethyl 2-(o-nitrophenyl)acetimidate in
40 ml of ethanol a solution of sodium ethoxide (prepared by
dissolving 0.38 g of sodium in 40 ml of ethanol) is added
drops at 0. After stirring at room temperature for 30 mint
vies, the solids are filtered off, the filtrate is evaporated to
a volume of approximately 10 ml and diluted with 20 ml of
dim ethyl sulfoxide. To the resulting solution 1.52 g of trio-
semicarbazide is added and the mixture it stirred at room
temperature for 2 days. ale solvent is evaporated in vacua, the
residue is treated with water and ethyl acetate, the aqueous
layer is extracted once more with ethyl acetate and the combined
- 24 - I
organic extracts are washed with water, dried over magnesium
sulfate, evaporated to a small volume and diluted with ether to
giveN-(aminothiocarbonyl)-o-nitrophenylacetamid}azone,, mop.
172-174.
b) A mixture of 1 g of N-(aminothiocarbonyl)-o-nitrophenylacet-
amidrazone and lo ml of Amy alcohol is reflexed for 6 hours,
evaporated to a small volume and diluted with ether to give
5-mercapto-3-(o-nitrobenzyl)-1,2,4~triazole, mop. 239-241.
c) To a suspension of 0.61 g of sodium hydrides in 50 ml of twitter-
hydrofuran, 5 g of mercapto-3-(o-nitrobenzyl)-1,2,4-triazole is
added in portions with stirring at room temperature over a period
of 30 minutes. The mixture is stirred for 2 hours, 1.51 ml of
methyl iodide is added at once, the mixture is stirred overnight
at room temperature and evaporated to dryness in vacua. The
residue is treated with water and ethylene chloride, the aqueous
layer is extracted once more with ethylene chloride, the come
brined organic extracts are dried over magnesium sulfate, ova-
prorated to a small volume and diluted with ether to give Matthew-
ylmercapto-3-(o-nitrobenzyl)-1,2,4-triazolo, mop. 120-132.
d) row a solution of 2 g of 5-methylmercapto-3-(o-nitrobenzyl)-
1,2,4-triazole in 45 ml of tetrahydrofuran is added 44 ml of 20 %
aqueous titanium trichloride drops at 0. The mixture is
stirred at room temperature overnight, diluted with water, cooled
to 0, gasified with ammonium hydroxide and extracted three times
with ethylene chloride. The organic extracts are dried and
evaporated and the residue is crystallized from Tulane to give
3-(o-aminobenzyl)-5-methylmercapto-1,2,4-triazole,, mop. 99-102.
e) A mixture of 7 g of 3-(o-aminobenzyl)-5-methylmercapto-1,2,4_
triazole, 5.26 g of l,l'-carbonyldiimida701e and 179 ml of
ethylene chloride is heated at reflex overnight. Most of the
solvent is removed in vacua, the solids are filtered and washed
- 25
with small amount of ethylene chloride to give 2-methylmercapto-
llH-1,2,4-triazolo~2,3-c][1,3]benzodiazepine-5(6H)one,
mop. 250-252 (intermediate 5/b).
Intermediates for compound 6:
. . _ _
a) To a solution of 1.86 g of ethyl-2-(o-nitrophenyl)acetimidate in
19 ml of ethanol a solution of sodium ethoxide (prepared by
dissolving 0.17 g of sodium in 8.7 ml of ethanol) is added
drops at 0. After stirring the mixture for 30 minutes, the
solids are filtered off, 1 g of ethyl oxalyl hydrazide is added
and the mixture is stirred at room temperature for 48 hours. m e
product is filtered off and washed with ethanol to give N-carbo-
ethoxy-carbonyl-o-nitrophenylacetamidrazone, mop. 136-138.
b) A mixture of 23.97 g of N-carboethoxycarbonyl-o-nitrophenyl-acet-
amidrazone and 240 ml of ethanol is reflexed overnight, filtered
and evaporated. The residue is chromatographed with silica gel
using ethylene chloride-methanol-ammonium hydroxide (300:50:1)
as fluent to give 5-ethoxycarbonyl-3-(o-nitrobenzyl)-1,2,4-
triazole, mop. 135-140.
c) A mixture of 1 g of 5-ethoxycarbonyl-3-(o-nitrobenzyl)-1,2,4-
trizole, 10 ml of ethanol and 25 my of platinum oxide is hydra-
jointed at 3 atmospheres pressure for 2 hours, filtered and
evaporated to give 3-(o-aminobenzyl)-5-ethoxycarbonyl-1,2,4-
triazole.
d) A mixture of 13.96 g of 3~(o-aminobenzyl)-5-ethoxycarbonyl-
i,2,4-triazole, 4]0 ml of ethylene chloride and 9.19 g of
l,l'-carbonyldimidazole is stirred at room temperature for 2 days
and filtered. m e filtrate is washed with water, dried over
magnesium sulfate, decolonized with charcoal, evaporated to a
small volume and diluted with ether. The product is filtered off
and recrystallized from tetrahydrofuran to give 2-ethoxycarbonyl-
llH-1,2,4-triazolo[2,3-c][1,3~benzodiazepine-5-(6HHun, mop.
216-220 (intermediate 6/b).
~2;3LS~
Example 3: To a solution of 6.25 g of 2-methyl-5-cyanothio-llH-
1,2,4 triazolo~2,3-c~[1,3]benzodiazpeine in 7.3 ml of hexamethyl-
phosphoramide is added drops, at 0, 4.94 g of N-methylpiperazine
over a period of 5 minutes. m e mixture is stirred at room tempera-
lure for 4 hours, poured into water and extracted with ethyl
acetate. m e organic extracts are washed with water, dried o'er
magnesium sulfate and evaporated to dryness to give 2-methyl-5-
(4-methyl-1-piperazinyl)-llH)-1,2,4-triazoloC2,3-cc~[1,3~benzo-
diazepinel mop. 185-187. This material is treated with an equip
valet amount of malefic acid to give 2-methyl-5-(4-methyl-1-piper-
azinyl)-llH-1,2,4-triazolo[2,3-c][1,3]benzodiazepiire monomaleate of
example 1.
me starting material is prepared as follows:
To a solution of 5.41 g of thiophosgene in 30 ml of ethylene
chloride is added drops at 0 a solution of 7.5 g of 5-methyl-
3-(o-aminobenzyl)-1,2,4-triazole and 8.07 g of triethylamine in
285 ml of ethylene chloride over a period of 45 minutes. The mixture
is stirred at room temperature overnight, washed first with 10 %
aqueous potassium bicarbonate, then with water, dried over magnesium
sulfate, decolonized with charcoal and evaporated to dryness to give
5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazolee; IT 2080 cm 1
To a suspension of 0.91 g of sodium hydrides in 27 ml of toreador
Furman is added drops a solution of 8.74 g of knotholes-
thiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a
period of 20 minutes. The mixture is stirred at room temperature for
2 hours. To the resulting suspension a solution of 4.02 g of
cyanogen bromide in 35 ml of tetrahydrofuran is added drops at 0
over a period of 15 minutes. m e mixture is stirred at 0 for
1.5 hours, poured into water and extracted three times with ethyl
acetate. m e organic extracts are dried over magnesium sulfate,
decolonized with charcoal and evaporated to give Molly cyan-
thio-llH-1,2,4-triazolo[2,3-c][1,3]benzodiazepine;; IT 2150 cm
I
- 27 -
Example 4: To a solution of 1.0 g of 2-methyl-5-(4-ethoxycarbonyl-1-
piperazinyl)-llH-1,2,4-triazolo[2,3-c][1,3~benzodiiazepine in 10 ml
of dry tetrahydrofuran, 500 my of lithium aluminum hydrides are
added at once and the mixture is reflexed under nitrogen for
24 hours. The mixture is cooled to 0, the excess of the lithium
aluminum hydrides is destroyed with ethyl acetate, the mixture is
then poured into water and extracted with ethyl acetate. me
extracts are dried and evaporated to give after purification
2-methyl-5-(4-methyl-1-piperazinyl)-llH-1,2,4-triaazolo[2,3-c][1,3J-
benzodiazepine of example 1.
The starting material is prepared e.g. according to the procedure of
example 3 by condensing 2-methyl-5-cyanothio-llH-1,2,4-triazolo-
C2,3-c][1,3]benzodiazepine with N-carboethoxypiperazine.
Example 5: To a solution of 200 my of 2~methyl-5-(4-benzyloxy-
carbonyl-l-piperazinyl)-llH-1,2,4-triazolo[2,3-cJ~~1,3]benzodiazepin
in 0.6 ml of acetic acid are added 0.70 ml of a ON solution of
hydrobromic acid in acetic acid. m e mixture is heated at 100 for 2
hours and stirred at room temperature overnight. Workup yields
2-methyl-5-(4H-l-piperazinyl)-lH-1,2,4-triazoloC2,,3-c][1,3]benzo-
diazepine.
The starting material is prepared similarly to starting material of
example 4 by replacing l-ethoxycarbonylpiperazine with the equiva-
lent amount of l-benzyloxycarbonylpiperazine.
Example 6: A mixture of 300 my of 5-(4H-l-piperazinyl)-llH-1,2,4-
triazolo[2,3-c~C1,3]benzodiazepine, 0.5 g of potassium carbonate,
1 mole equivalent of methyl iodide and 2 ml of acetone is stirred at
room temperature overnight and evaporated. Water is added to the
residue. and the mixture is extracted with ethylene chloride. The
extracts are dried over magnesium sulfate, evaporated, and the
residue is purified to give 2-methyl-5-(4-methyl-1-piperazinyl)-
llH-1,2,4-triazolo[2,3-c][1,3Jbenzodiazepine of example 1.
- 2
Example 7: To solution of 5 g of 2-methyl-5-(4-methyl-1-piper~zin~
yl)-llH-1,2,4-triazolo~2,3-~[1,3]benzodiazepine in 50 ml of
elan chloride is sodded in portion 375 g of m~chloroperbenzoi~
acid with stirring at 0-. me mixture is then stirred at root
temperature overnight end evaporated to dryness. The foamy residue
it passed through 100 g of kmberliee~ IRA-400 ion exchange resin
us water as fluent. Evaporation of the fluent give 2-methyl-5-
(4-methyl-4-oxido-1-piperazinyl)-llH-1,2,4-triazollucks
benzodiazepine.
Example 8_ m e following compound are prepared according to the
method illustrated by the previous examples and are obtained from
equivalent mounts of the correspondingly substituted starting
materials.
a)2-methyl-5-(4-benzyl-1-piperazinyl)-llH-1,2,4-triaazolo~2,3-c~-
C1,3]benzodiazepine;
b) 2-methyl-5-(4-allyl 1-piperazinyl)-llH-1,2,4-triazolo~2,3-c~-
[1,3]benzodiazepine;
c)2-methyl-5-(4-methyl-1-homopiperazinyl)-llH-1,2,4--triazolo-
[2~3-c]~l~3]ben2odiazepine;
d) 2,8-dimethyl 5-(4-methyl-1-piper~zinyl~-llH-1,2,4-triazolo-
~2,3-c]~1,3~benzodiazepine;
e)8-fluoro-2-methyl-5-(4-methyl-1-piperazinyl)-llH-11,2,4-triazolo-
[2l3-c]cll3]benzodiazepine;
$)~-methoxy-2-methyl-5-(4-methyl-1-piperazinyl)-llH--1,2,4-triazolo-
I 3 3~benzodiazepine~
g)2-methyl-5-(4-hydroxyethyl-1-piperazinyl)-llH-1,2,,4-triazolo-
[2~3-c][ll3]benzodiazepine.
- 29 - I
Example 9: Molly alcohol (5100 ml) and 918.35 g of N-methylpiperazine
are charged into a 12 lithe 3-necked reaction flask fitted with
Dean-Stark adapter. The solution is stirred under nitrogen atom-
sphere and 989 ml of lo ethanolic hydrogen chloride solution are
added rapidly. me reaction mixture is heated to reflex and the
distillate is collected in the Dean-Stark adapter. When the tempera-
lure of the reaction mixture reaches 131, the Dean-Stark adapter is
removed and an additional 918.35 g of N-methylpiperazine followed by
1112.6 g of2-methyl-5-methylthio-llH-1,2,4-triazolo[213-c]C1,,3]-
benzodiazepine are added. m e mixture is heated to reflex under
nitrogen atmosphere for 20 hours. Amy alcohol is then removed under
reduced pressure at a water bath temperature of 80. The viscous
residual oil it dissolved in 10,000 ml of ethylene chloride, washed
with 3 x 4,000 ml of ON sodium hydroxide and 6 x 4,000 ml of water.
m e ethylene chloride solution is then extracted with 3 x 2,000 ml
of ON hydrochloric acid. The aqueous solution is washed with
2 x 2,000 ml of ethylene chloride, decolonized With charcoal and
filtered. The aqueous filtrate is adjusted to pi 9-10 with 1,500 ml
of concentrated ammonium hydroxide solution. The separated oil is
extracted with 3 x 4,000 ml of ethylene chloride, the extracts are
dried over 1000 g of sodium sulfate and the solvent is removed to
give2-methyl-5-(4-methyl-1-piperazinyl)-llH-1,2,4-triaazolo~2,3-c~-
~1,3]benzodiazepine of Example 1. Treatment with an equimolar
amount of malefic acid in isopropanol yields 2-methyl-5-(4-methyl-1-
piperazinyl)-llll-1,2,4-triazolo[2,3-c]~1,3]benzoddepone moo-
Malta of Example 1, mop. 206-208.
The starting material is prepared as follows:
To a suspension of 0.91 g of sodium hydrides in 27 ml of tetrahydro-
Furman is added drops a solution of 8.74 g of methyls-
thiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a
period of 20 minutes. The mixture is stirred at room temperature for
2 hours. To the resulting suspension is added a solution of 5.4 g of
methyl iodide in 35 ml of tetrahydrofuran drops at 0 over a
period of 15 minutes. The mixture is stirred at room temperature for
- 30 -
1 hour, poured into water and extracted three times with ethylene
chloride. The organic extracts are dried over magnesium sulfate,
decolonized with charcoal and evaporated to give 2-methyl-5-methyl-
thio-llH-1,2,4-triazolo[2,3-c][1,3]benzodiazepine..
2-Methyl5-methylthio-llH-1,2,4-triazolo[2,3-c][1,3]benzodiiazepine
is also prepared as follows:
A suspension of 8 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-
triazole in 100 ml of Tulane is reflexed overnight and cooled to
room temperature to give 2-methyl-llH-1,2,4-triazolo[2,3-c~1,3]-
benzodiazepine-5(6H)-thione. Treatment with methyl iodide as
described above yields 2-methyl-5-methylthio-llH-1,2,4-triazolo-
~2,3-c][1,3]benzodiazepine.
Example 10 Preparation of 10,000 tablets each containing 25 my of
the active ingredient:
Formula-
2-Methyl-5-(4-methyl-1-piperazinyl)-llH-1,2,4-
triazolo[2,3-c][1,3]benzodiazepine monomaleate 250.00 g
Lactose 957.00 g
Corn Starch 75.00 g
Polyethylene glycol 6,000 75.00 g
Talcum powder 75.00 g
Magnesium Stewart 18.00 g
Purified water us
Procedure. All the powders are passed through a screen with openings
of 0.6 mm. Then the drug substance, lactose, talcum, magnesium
Stewart and half of the starch are mixed in a suitable mixer. The
other half of the starch is suspended in 40 ml of water. The paste
formed is added to the powders which are granulated, if necessary,
with an additional amount of water. The granulate is dried overnight
at 35C, broken on a screen with 1.2 mm openings and compressed into
tablets using concave punches with 6.4 mm diameter, uppers bisected.
- 31
Example 11: Preparation of 10,000 capsules each containing 10 my of
the active ingredient:
Formula:
__
2-Methyl-5-(4-methyl-1 piperazinyl)-llH-1,2,4-
triazolo[2,3-c][1,3]benzodiazepine monomaleate 100.0 g
Lactose 1,800.0 g
Talcum powder 100.0 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 and
mixed first with the talcum then with the lactose until homogeneous.
No. 3 capsules are filled with 200 my, using a capsule filling
machine.
analogously tablets or capsules are prepared from the remanning
compounds of the invention, e.g. those illustrated by the other
examples herein.
