Note: Descriptions are shown in the official language in which they were submitted.
~ r~3 4
-- 1
The present invention concerns the manufacture
of new 1,3,4,14b-tetrahydro-2H,lOH-pyraæino~1,2-a]pyrrolo
~2,1-c][1,4]benzodiazepines of the general formula I
C. _ N ~ R5
,L/
N / (I)
/ ~ R
/
n 2n R2
wherein each of Rl, R3 and R~ is hydrogen or lower alkyl;
R2 is hydrogen, lower or higher alkyl, lower aLkenyl, lower
alkynyl, or ~3 to 7 ring-membered cycloalkyl, hydroxy,
carboxy, lower carbalkoxy, carbamoyl, HPh, lower alkanoyl
or HPhC0)-lower alkyl; Ph is 1,2-phenylene, unsubstituted
or substituted by up to two members selected from lower
alkyl, lower alkoxy, halogeno and ~rifluormethyl; CnH2n is
lower alkylene separating both nitrogen ato~s by 2 or 3
carbon atoms and R5 is hydrogen, lower alkyl, lower carb-
alkoxy or hydroxy-lower alkyl; the lower alkoxycarbonyl,
lower or higher alkanoyl, adamantoyl, carbamoyl, or HPhC0-
derivatives; the 2-~-oxide, 2-lower al~yl or 2-HPh-lower
alkyl quaternaries of a compound in which R2 is different
from hydrogen; and acid addition salts thereof,
especially pharmaceutically acceptable acid additions
salts thereof.
~ lower alkyl group Rlg R2, R3, R4~ Rs a~d/or
such present in substituted 1, 2-phenylene Ph, or phenyl
HPh-groùp, is above all methyl, but also ethyl, n- or
i- (propyl, butyl, pentyl, hexyl or heptyl~, e.g. 2-methyl-
propyl or 3-me~hylbutyl. A higher alkyl group R2 is, for
example, n- (octyl, decyl, dodecyl, hexadecyl o~ octadecyl) .
, i
'
- 2 -
A lower alkenyl or lower alkynyl group R2 is pre-
ferably such containing the multiple bond separated fro~
the nitrogen atom by at least two carbon atoms~ such as
allyl, 2- or 3-butenyl or 3-methyl-2-bu~enyl~ propargyl,
~- or 3-butynyl.
A 3 to 7 ring-membered cycloalkyl-lower alkylgroup
R2 is preferably ~cyclopropyl, cyclobutyl or cyclopentyl)-
methyl or -ethyl.
A lower (hydroxy, carboxy, carbalkoxy, carbamoyl,
or lower alkanoyl)-alkyl group R2 is preferably such,
wherein said heteroatoms (O or N) are separated from the
ring-nitrogen atom by at least 2 carbon atoms, such as
2-(hydroxy, carboxy, carbomethoxy, carbethoxy, carbamoyl,
acetyl or propionyl)-ethyl or -propyl, 3-hydroxy-propyl or
(carboxy, carbomethoxy, carbethoxy, carbamoyl or acetyl)--
methyl.
A 1,2-phenylene radical Ph, or the (phenyl or
benzoyl, i.e. HPh or HPhCO)-lower alkyl group R2, is pre-
ferably unsubstituted or monosubstitu~ed in the benzene
ring by said substituents, for example ~ethyl or ethyl;
methoxy, ethoxy or i-propoxy; fluoro, chloro, bromo or
trifluoromethyl.
A lower alkylene group CnH2n is especially ethylene,
but also l,2- or 1,3-propylene or 1,2-, 1,3- or 2,3-butylene.
A lower carbalkoxy or hydroxy-lower alkyl group
R5 is preferably carbomethoxy or carbethoxy or hydroxy-
methyl graup.
.
- 3 -
Said acyl derivatives of the compounds o
formula I are preferably derived from those wherein R2
is hydrogen, but also from those wherein R2 and/or R5
being hydroxy-lower-alkyl, i.e. either amides or esters,
derived, for example, from said lower or higher aliphatic
acids, e.g. acetic, propionic, butyric, pivalic, decanoic,
palmitic, or adamantylcarboxylic acid; carbamic or
carbonic acid; benzoic, toluic, anisic or halobenzoic
acids.
Said N-oxides, lower alkyl or phenyl-lower alkyl
quaternaries of the compounds of Formula I are derived
fro~ those wherein R2 is di~ferent from hydrogen, and
wherein only the 2-nitrogen atom is functionaliz2d. The
anions of said quaternaries and acid addition salts are
preferably those of pharmaceutically acceptable acids,
e.g. those listed below. Those compounds of Formula I,
which contain carboxy within R2 also ~orm salts with
bases, e.g. ammonia, mono-, di- or tri-lower alkylamines;
lower alkyleneamines, morpholine, piperazine, pyridine or
lower alkyl-derivatives of said cyclic bases; alkali metal
or alkaline earth metal hydroxides.
The term "lower", referred to above or herein-
after in connection with organic radicals or compounds
respectively defines such with up to 7, preferably up to
4, and advantageously those with one or two ~arbon atoms.
The term "higher" defines analogous radicals with 8 to 20 3
preferably 8 to 16 carbon atoms.
,,
.. . . .
4 --
The compounds of the invention exhibit valuable
pharmacological properties, primarily antidepressant, but
also analgesic, antihistaminic and antiserotonergic activity.
It is demonstrable in animal tests using advantageously
mammals, e.g. mice, rats, guinea pigs or monkeys, as test
obiects. Said compounds can be applied to them enterally
or parenterally, advantageously orally, or subcutaneously,
intravenously or intraperi~oneally, for example, within
gelatin capsules or in the form of starchy su~pensions or
aqueous solutions respectively. The applied dosage may
range between about 0.01 and 100 mg/kg/day, preferably
between about 0.05 and 5 mg/kg/day, ad~antageou ly between
about 0.1 and 0.5 mg/kg/day. Said antidepressant proper-
ties can be shown in mice by antagonism to clonidine anal-
. ', , '
, ~
' ' ' ' , ' ' ' ' ' ` '
`~ ~ ' ',,' ':'
~ ,: ' ' ', ! ~ ' '
:,,:
' '~ . ,, ' :',,
, ,
.,~ .''.',
~ 3-`~Y3~
' ~ 5 -
;
gesia. In this test system, the compounds of the invention
are administered orally or intraperitoneally as aqueous
solutions to groups of at least 10 male mice and 30 minutes
thereafter 0.1 mg/kg of clonidine is intubated to them
; orally. 20 minutes later, they are injected with 3.75 mg/
kg of phenyl-p-benzoquinone intraperitoneally and the
number of mice that writhe is counted 5-15 minutes after
injection. Any animal not writhing is considered a reactor
and the ED50 for the experimental drug and clonidine combi-
nation is determined by the Berkson Logit method from the
number of reactors.
Said analgesic effects are similarly shown accord
ing to the phenyl-p-benzoquinone writhing test. According
to it, graups of at least lO male mice receive the com-
pounds of the invention orally or intraperitoneally and
50 minutes thereafter 3.75 mg/kg of phenyl-p-benæoquinone
intraperitoneally. Again, the number of mice that writhe
is counted 5-15 minutes after the last injection and the
ED50 for no-writhers is determined by the Berkson Logit
method.
Finally, said antihistaminic properties can be
shown in vitro according to Chasin et al, J. Neurochem.
22, 1031 (1974). Homogenates from a cell-free preparation
of guinea pig cerebral cortex are preincubated with H-
adenine to form endogenous 3H-~adenosine-triphosphate. The
homogenates are then incubated with 50 micromolar hista-
mine to activate H-cyclic adenosine-monophosphate synthe-
sis in the absence or presence of the test compound at a
concentration between 0.01 and 100 micromols. When said
compound is active, it inhibits the histamine activation
of adenylate cyclase.
- ~ ~
, :, . . .
, ~
, . . . .
- 6 - ~ ~3~
Accordingly7 the compounds of the invention are
useful anti~epressant, analgesic and antihistaminic agents,
for example, in the treatment or management of mental de-
pression, migraine a~d/or allergic conditions. They are
also useful intermediates in ~he preparation of other
valuable products, especially of pharmacologically active
compositions.
Par~icularly useful for said purposes are com-
pounds of Formula I, in which each of Rl, R3 and R4 is
hydrogen; R2 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, hydroxy-lower alkyl, 3 to 7 ring-membered cyclo-
alkyl-lower alkyl; Ph is 1,2-phenylene, (lower alkyl)-1,2-
phenylene, (lower alkoxy)-l r 2-phenylene, (halogeno)-1,2-
phenylene or (trifluoromethyl)-1,2-phenylene; n is the
integer 2 or 3 and R5 is hydrogen, lower alkyl or hydroxy-
lower alkyl; the lower alkanoyl, adamantoyl, carbamoyl,
or HPhCO-derivatives; 2-N-oxides; 2-lower alkyl or 2-HPh-
lower alkyl quaternaries; or pharmaceutically acceptable
acid addition salts thereof.
Outstanding compounds of the invention are those
of the general Formula II
R, r ~ (II)
R6
wherein ~6 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, hydroxy-lower alkyl or 3 to 7 ring-m~mbered cyclo-
C` ~.~5
' ' ` . ~ ' , ~ .. .
,, . : "' '' '' "', ' "
' ., ' ' , " ' ~ " ' '` '
:: ' ' :,
, ~ ~, ". . .;,
: ' '' '
, ' ' ' ` ' ' ~ ' ' :
alkyl~lower alkyl and R7 is hydrogen, halogeno or tri-
fluoromethyl, or a therapeutically acceptable aci~ addition
salt thereof,
The compounds of the invention are prepared
according to methods known per se by reducing a compound
of formula III
R3 R4
\ / R5
C - N ~
(III)
N (
~Y
X N - R2
wherein X is lower alkylene, mono- or dioxo-lower alkylene
separating both nitrogen atoms by 2 or 3 carbon atoms and
wherein oxo is attached to the carbon atoms adjacent to
the nitrogen atoms, and Y is oxo, two hydrogens or hydrogen
and lower alkyl; provided that at least one oxo group is
present in X or Y, and the other symbols have the meanings
given above, and
a) if a compound is required in which R2 is lower alkyl,
higher alkyl, lower alkenyl, lower alkynyl, cycloalkyl-
lower alkyl, HPh-lower alkyl or carbalkoxy-lower alkyl,
introducing such a radical into a product of the formula I,
in which R2 is hydrogen, and,
b) if a compound is xequired in which R2 is carboxy-
lower alkyl, hydrolysing a compound of the formula I, in
which R2 is carbalkoxy-lower alkyl, and,
~: - '';,, . ~ ';
: . ,: ~
. : . , " ~,, ,, . - . ~ - :
.: : .. i ~.. ,:, - ." : :. :
:. :: ~ .... ;
.~ .: ,..
- ~ : :
; ' ~
. . ~
3~
- 7a -
c) if a compound is required in which R2 is carbamoyl-
lower alkyl, converting into such a group a carbalkoxy-
lower alkyl radical R2 of a product, and,
d) if a compound is required in which R2 is lower alkanoyl-
lower alkyl or HPhCO lower alkyl, introducing such a radi-
cal into a product in which R2 is hydrogen, and
e) if a _ompound is required in which R2 is hydroxy-lower
alkyi, reducing to such a radical a carbalkoxy-lower alkyl
group present as R2 in a product, and,
f) if a compound is required in which R2 is lower alkoxy
-carbonyl, converting into such a radical a lower alkyl,
lower alkenyl or CH2-HPh group present as R2 in a product, and
g) if a compound is required in which R2 is lower alkyl,
reducing a product in which R2 is lower alkenyl or lower
alkynyl, and
h) if a compound is required in whlch an acyl radical
named above is present in the position 2, acylating a
product in which R2 is hydrogen, and,
i) if a compound is required in which R2 is hydrogen,
hydrolyzing a product which has an acyl radical named above
at the nitrogen atom in the position 2, and,
j) if a compound is required in which the substituent
in the position 2 is a (lower alkanoyloxy or a higher
al~anoyloxy)-lower alkyl group, esterifying a produc~
which contains one hydroxy-lower alkyl group in said posi-
tion, and,
R~
~k
! . '
' ' '' ' ' '~ ' . ~ ~ ' "' ' " " ' '
'
'''
" ," ~,
r?~
- 7b -
k) if a compound is required in which R2 repres~nts a
hydroxy-lower alkyl group, hydrolyzing a product containing
an esterified hydroxy-lower alkyl group as R2, and,
1) if a quaternary compound is required, i~troduci~g a
lower alkyl or HPh lower alkyl group into the position 2
of a product which is substltuted in said position, and,
m) if a 2-N-oxid is required, N-oxidizing a product which
is substituted in position 2, and, if required, converting
a resulting free compound into an acid addition salt or a
resulting salt into the free compound or into another salt
named above, and, if required, resolving a mixture of iso-
mers or racemates obtained lnto the slngle isomers or
racemates, and, if required, resolving a racemate obtained
into the optical antipodes.
The reduction of said lactams III is advantageous-
ly carried out with simple hydrides or complex light metal
hydrides, such as boranes or al~ne; or preferably alkali
metal alumini~mhydrides or alkali metai lower alkoxy-hydri-
des, e.g. lithium aluminium hydride, sodium tri-t-butoxy
, " ,: , ,,: ~
,;' ;, ' - ',. ' ~, ," ,;, ,: . .
. ~ - . . : .... , . :, . .
- , ~ , .
.. ~ ,. ,., . ~ .
- .-~ ~: -...... : :, ... .
:, ~ .
.. .: ., , ~ :
. .
,
.. . , :, ~ .. . .. . .
.
r~ll3~
-- 8
aluminiumhydride or sodium bis-(2-methoxy-e~hoxy)-aluminium-
hydride.
The starting materials can be prepared according
to methods described for known analogs thereof and those
illustrated by the examples herein.
Th~ starting material can be prepared by reacting
corresponding compounds of Formula III, wherein X repre-
sents two hydrogen atoms, each of which is attached to a
different nitrogen atom, with reactive derivatives of
corresponding glycols 9 glycolic acids or dicarboxylic
acids, such as lower alkyl esters, halides or anhydrides
thereof, or reactive esters oX said glycols or glycolic
acid deriva~ives, for example with hydrohalic acids or
aromatic sulonic acids, e.g. 1,2-dibromethane or -propane,
ethyl bromoacetate or -propionate, ethyl tosyloxyacetate;
d~ethyl oxalate or malonate, ethyL oxalyl chloride, oxalyl
dichloxide or malonic anhydride. Said precursors cor-
responding to the Formula III, in which X represents two
hydrogen atoms, each of which is attached to a different
nitrogen atom, can be prepared analogous to Il Farmaco,
Ed, ScO 24, Fasc. 3, page 276, or as illustrated by the
examples herein.
The compounds of the invention so obtained can
be converted, if desired or necessary, into other com-
pounds of Formula I according to known methods. Thus,
for example, those with R2 being hydrogen or alkali
metal, e.g. sodium salts thereof, can be reacted with
reactive esters of unsubstituted or correspondingly sub-
stituted aliphatic or araliphatic alcohols such as metha-
nol, ethanol, allyl alcohol, propargyl alcohol or benzyl
~ ~=r~.
:
- . . .. .
: . .: ~ : :,. :
,,
: j' -:
9 ~ 3~
alcohol respectively, e.g. such estarified by a strong in-
organic or organic acid, above all hydrohalic acids,
e.g. hydrochloric, hydrobromic or hydriodic acid; sulfuric
or an aromatic sul~onic acid, e.g. p-toluene or m-bromo-
benzene sulfonic acid, in order to obtain the corresponding
N-substituted compounds or quaternaries respectively, de-
penâing on the molar amount of the alkylating agent employed.
Conversely, resulting N-alkylated co~ounds can be conver-
ted into N-unsubstituted compounds, e.g. by catalytic
hydrogenolysis of N-benzyl compounds, or reaction of N-lower
alkyl, N-lower al~enyl or N-(CH2-HPh) derivatives with
lower alkyl haloformates, e.~. ethyl chloroformate, to
yield said N-acyl derivatives which, in tu~rn, may be hydro-
lyzed to said N-unsubstituted compounds, i.e. those with
R2 = H, for example with aqueous bases, such as alkali metal
hydroxides. Other acyl derivatives, either amides or esters,
can be obtained from compounds of formula I with R2 being
hydrogen or R2 and/or R5 being hydroxy-lower alkyl, and
corresponding reactive acid derivatives, e.g. halides,
simple or activated esters, such as alkyl or cyanoalkyl
esters, anhydrides or cyanates. Resulting esters may be
hydrolyzed as shown for said N acyl derivatives, and
unsaturated compounds, such as those with R2 being lower
alkenyl, alkynyl or cycloalkenyl, may be hydrogenated with
catalytically activated hydrogen as shown above. Resultlng
esters may also be reacted with ammonia, to obtain the
amide-(carbamoyl)-compounds or reduced with complex light
metal hydrides, such as lithiumaluminiumhydride to the
corresponding alcohols.
Resulting compounds of formula I with R3 and/or
R4 being hydrogen, can be converted to the corresponding
lower alkyl derivatives by metallation with reactive
~ ..
"
,
: ' . ~ . . .
- : :
:
- 10
organo~etallic agents, such as n-but~llithium or lithiu~
diisopropylamide, followed by additlon of said reactive
esters of lower alkanols Compounds I with R$ being hydro-
gen, can also be converted to corresponding 12-acyl deriva-
tives, e g. by acylation with said derivatives of HO~X-OH,
in which X has the meaning given above, (analogous to the
preparation of a starting material III), or a trihaloace-
tyl halide, followed by treatment with an alkali metal
lower alkoxide. Resulting 12-(carbalkoxy or hydroxymethyl)-
derivatives may be hydrolyzed as shown above and/or
reduced to either 12-(methyl, hydroxymethyl or 2-hydroxy-
ethyl)-compounds with said simple or complex light metal
hydrides.
Resulting ter~iary nitrogen compounds with R2 dif-
ferent from hydrogen, can be converted into the ~-oxides,
for example with hydrogen peroxide or organic peracids,
such as lower per~lkanoic or perbenzoic acids, e.g. per-
acetic or m-chloro-perbenzoic acid, advantageously at
temperatures at or below room temperature with the latter,
or up to 100 with diluted hydrogen peroxide in the pre-
sence of lower alkanoic acids, e.g. acetic acid. Care
should be taken, especially with said peracids, in order
to prevent overoxidation at overly long reaction times.
Finally, the compounds of the invention are either
obtained in the free, basic form, or as a salt thereof.
Any resulting base can be converted into a corresponding
acid addition salt, preferably with the use of a therapeu-
tically useful acid or anion exchange preparation, or re-
sulting salts can be converted into the corresponding free
bases, for exa~ple, with ~he use of a stronger base, such
as a metal hydroxide or ammonium hydroxide, basic salt or
cation exchange, e.g. an alkali metal hydroxide or carbo-
,r~
.~
~ ~ ~ 3~ 3 ~
nate. Said acid addition salts are such of therapeuticallyacceptable inorganic acids, for example hydrohalic, e.g~
hydrochloric or hydrobromic acid; sulfuric, phosphoric,
nitric or perchloric acid; but preferably organic acids
such of aliphatic or aromatic carboxylic or sulfonic acids,
e.g. formic, acetic, propionic, succinic, glycollic, lactic,
malic, tartarie, citric, maleic, fumaric, hydroxymaleic,
pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthrani-
lic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic,
nicotinic; methanesulfonic, ethanesulfonic, hydroxye~hane-
sulfonic, ethylenesulfonic, halogen-benzenesulfonic, tolue-
nesulfonic, naphthalenesulfonic, sulfanilic or cyclohexyl-
sulfamic acid; or ascorbic acid. These or other salts, for
example, the picrates, 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.
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 pos-
sible or appropriate under the circumstances.
In case mixtures o~ geometrical or optical isomers
of the above compounds, e.g. I to III, are obtaîned5 these
can be separated into the sin~le isomers by methods in
themselves known, e.g. by fractional distillation, crystal-
lization and/or chromatography. Racemlc products can like-
wise be resolved lnto the antipodes, for example, by sepa-
ration of diastereomeric salts thereof~ e.g. by the frac-
tional crystallization of d- or ~-tartrates.
,
12 -
The above-men~ioned reactions are carried out
according to standard methods, 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 obtain-
able at any stage of the process is used as s~arting mate-
rial and any remaining steps are carried out, or the pro-
cess 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 com-
pounds indicated above as being especially valuable~ e.g.
those of Formula II.
The pharmacologically active compounds of the in-
vention are useful in the manufacture of pharmaceutical
compositions containing an effective amount thereof in
conjunction or admixture with excipients suitable for
either enteral or parenteral application. Preferred are
tablets and gelatin capsules comprising the active ingre-
dient together with diluents, e.g. lactose, dextrose,
sucrose, mannitol, sorbitol, celluloseg and/or glycine,
and lubricants, e.g. silica, talcum, stearic acid, its
magnesium or calcium salt and/or polyethyleneglycol; for
... . . .. ~. ,,, . ; .. , , ... ..... ,~,, ... .. , . ~
~,.. . :
, . . .
.. , . ;~ , ,
. ~ . .. . . . . .
: ; ; .,,, , :
- 13 -
tablets also binders, e.g. magnesium aluminium silicate,
starch paste9 gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose and/or polyvinylpyrrolidone, if
desired, disintegarants, e.g. starches, agar, alginic acid
or its sodium salt, enzymes of the binders or effervescent
mixtures and/or adsorbents, colorants, flavors and sweete-
ners. Injectable compositions are preferably aqueous iso-
tonic solutions or suspensions, and suppositories are
advantageously fatty emulsions or suspensions. They may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution pro-
moters, salts for regulating the osmotic pressure and/or
buffers. They may also contain other therapeutically valu-
able substances. Said pharmaceutical compositions are pre-
pared according to conventional mixing, granul~ting or
coating methods respectively and contain about 0.1 to 75%,
preferably about 1 to 50% of the active ingredient.
The following examples illustrating the invention
are not to be construed as being limitations thereon. Tem-
peratures are given in degrees Centigrade, and all parts
wherever given are parts of weight. If not specified, all
evaporations are carried out under reduced pressure, e.g.
between about 15 and 100 mmHg.
~- , ,, ,; : . .
: : , ~, ::.,
: ~ , - . - - , .
: . .:.
. . . .
- 14 -
Example 1
To the suspension of 12.8 g of 2-methyl-3,4-dioxo-
1~3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo~2,1-c]
[1~4]benzodiazepine in 460 ml of tetrahydrofuran, 200 ml
of l-molar diborane in tetrahydrofuran are added while
stirring and cooling with ice. The mixture is reflu~ed
for one hour, again cooled and combined with 25 ml of
acetic acid. It is evaporated, the residue taken up in
50 ml of 30% aqueous sodium hydroxide and the mixture
extracted with methylene chloride. The extract is dried,
evaporated, the residue dissolved in diethyl ether, the
solution filtered and the filtrate evaporated, to yield
the 2-methyl-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]
pyrrolo[2,1-c][1,4]benzodiazepine.
~ .7 g thereof are dissolved in the minimum amount
of isopropanol and the solution acidified with a concentra-
ted solution of 4.45 g of maleic acid in isopropanol. The
precipitate formed is collec~ed and recrystallized from
methanol-diethyl ether, to yield the corresponding mono-
-maleate melting at 176-178.
One may also reduce 2.35 g of said dioxo-starting
material in 50 ml of methylene chloride with 20 ml of
l-molar alane in triethylamine, whereupon the mixtwre is
evaporated. The residue is triturated with ethyl acetate-
diethyl ether, chromatographed on 70 g of silica gel and
eluted with methanol-chloroform (1:9). The eluate is eva-
porated and the residue salified as shown above, to yield
a somewhat purer maleate melting at 180-182.
The starting material is prepared as follows: The
mixture o 54 g of N-potassium phthalimide, 50 g of
: : ~: ... .
: . , " .; ~ :
; ,: :
.
;, -
3~i~ ~ L~
- 15 -
o-nitro~enzyl chloride and 120 ml of dimethylformamide is
r~fluxed for 3 hours and poured into 900 ml of ice-water
while stirring. After 30 minutes, it is filtered, and the
residue washed with water, to yield the N-o nitrobenzyl-
-phthalimide melting at 190-209.
The mixture of 70 g thereof, 14.6 g of hydra~ine
hydrate and 600 ml of ethanol is refluxed for 4 hours and
combined with 50 ml of concentrated hydrochloric acid.
After 30 minutes, it is cooled to room temperature, fil-
tered and the residue washed with water. The filtrate is
concentrated, the aqueous concentrate filtered and the
filtrate basified with 3N aqueous sodium hydroxide. It is
~xtracted with diethyl ether~ the extract dried and evapo-
rated, to yield the o-nitrobenzylamine
To the solution of 7.6 g thereof in 25 ml glacial
acetic acid, 6.6 g of 2,5-dimethoxy-tetrahydrofuran are
added and the mixture is refluxed for one hour. It is eva-
porated, the residue poured into ice water and the mixture
extracted with ethyl acetate. The extract is washed with
saturated aqueous sodium bicarbonate, dried and evaporated.
The residue is taken up in diethyl ether, the solution
decolorized with charcoal, filtered and evaporated, to
yield the l~(o-nitrobenzyl) pyrrole,
Through the mixture of 13 42 g thereo, 140 ml of
diethyl ether and 6.85 ml of chloroacetonitrile, hydrogen
chloride is bubbled while stirring and cooling in an ice-
-salt bath. The saturated mixture is stirred at room
temperature overnight, filtered and the residue suspended
in 100 ml of water. It is extracted 3 times with 100 ml
of ethyl acetate, the combined ex~racts are warmed on the
steam bath wihile stirring until all is dissolved, the
, ,,
.
, . . . . .
. .
- : . : . ;. .: ,
-. . : ": ; :
.: . ,: .
,. :. . :: .
.: : , : , .,
., . :
- 16 -
solution is dried and evaporated, to yield the l-o-nitro~
benzyl-2-chloroacetylpyrrole.
To the so:Lution of 16.2 g thereof in 450 ml of
e~hanol, 14.10 g of N-methyl-benzylamine are added and
the mixture is refluxed for 3 hours. It is evaporated, the
residue taken up in methylene chloride, the solution
washed with saturated aqueous sodium carbonate~dried,
filtered and evaporated The residue is triturated with
diethyl ether, to yield the l-(o-nitrobenzyl)-2-(N-methyl-
N-benzylaminoacetyl)-pyrrole.
The solution of 3 g thereof in 30 ml of glacial
acetic acid is hydrogenated over 100 mg of platinum oxide
at 2.7 atm and room temperature until the theoretical
amount of hydrogen has been absorbed. It is fi~ered, and
the filtrate evaporated, the residue taken up in methylene
chloride-diethyl ether and the solution washed with satura-
ted aqueous sodium bicarbonate. It is dried, evaporated~
the residue chromatographed on 30 g of silica gel and
eluted with methanol-chloroform (1:9), to yield the ll-(N-
methyl-N-benzylamino-methyl)-10,11-dihydro-5H-pyrrolo
t2,1-c][1,4]benzodiazepine melting at 147-149
The solution of 500 mg thereof in 35 ml of ethanol
and 5 ml of glacial acetic acid is hydrogenated over 250 mg
of 5% palladium on charcoal at 2.7 atm and 40~ for 7 hours.
The mixture is filtered, the filtrate evaporated and the
residue taken up in methylene chloride. The solution is
washed with saturated aqueous sodium carbonate~ the aqueous
phase extracted with methylene chloride and the combined
organic solutions dried and evaporated, to yield the
ll-(N-methylamino-methyl) 10,11-dihydro-5H-pyrrolo~2,1-c]
[1,4]benzodiazepine.
.. .... .. ... ,.. ~ . , ,, . _,
. .:
., , ~ , : , r
' .', ~' ' '~ .
. . , ' ' ,, '
17 -
The mixture of 300 mg thereof and 232 mg of diethyl
oxala~e is slowly heated to 140~ during 45 minutes and to
180 during 15 minutes, at which temperature it is main-
tained for 30 minutes. It is cooled, diluted with benzene,
chromatographed on silica gel ~nd eluted with methanol-
chloroform (1:9), to yield the 2-methyl-3,4-dioxo-1,3,4,
14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]
benzodiazepine melting at 178-179.
Example 2
To the suspension of 315 mg of 7-chloro-2-methyl-
3,4~dioxo-1,3,4,14b-tetrahydro-2H,lOH-pyrazinoLl,2-a]pyr-
rolo[2,1-c][1,4]benzodiazepine in 20 ml of tetrahydrofuran,
6 ml of l-molar diborane in tetrahydrofuran are added while
stirring and cooling with ice. The mixture is refluxed for
2 hours, again cooled and combined with 1 ml of 6N hydro-
chloric acid. It is evaporated, the residue taken up in
5 ml of 30% aqueous sodium hydroxide and the mixture extr-
acted with methylene chloride. The extract is dried, eva-
porated, the residue dissolved in diethyl e~her, and the
solution combined with 97 mg of maleic acid in the minimum
amount of acetone. The precipitate formed is collected to
yield the 7-chloro-2-methy~ 3~4~l4b-tetrahydro-2H~loH
-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine mono-
-maleate melting at 200-202.
The starting material is prepared as follows: The
mixture of 9.4 g of N-potassium phthalimide, 31.35 g of
p-chloro-o-nitrobenzyl chloride and 75 ml of dimethylforma-
mide is refluxed for 3 hours and poured into 180 ml of ice
water while stirring. After 30 minutes, it is filtered and
the residue washed with water, to yield the N-p-chloro-o-
.
, . . . .. .
. . . .. .
-: : :,
-: : . ::: :,
- 18 -
-nitrobenzyl-phthalimide melting at 190-194.
The mixture of 29,6 g thereof, 5.5 g of hydrazine
hydrate and 300 ml of ethanol is refluxed for 4 hours and
~ombined with 21 ml of concentrated hydrochloric acid.
After 30 minutes, it is cooled to room temperature, fil-
tered and the residue washed with water. The filtrate is
concentrated, the aqueous concentrate filtered and the
filtrate basified with 3N aqueous sodium hydroxide. It is
extracted with diethyl ether, the extract dried and evapo-
rated, to yield the p-chloro-o-nitrobenzylamine.
To the solution of 42.8 g thereof în 400 ml of
glacial acetic acid 30,4 g of 2,5-dimethoxy-tetrahydro-
furan are added and the mixture is refluxed for one hour.
It is evaporated, the residue poured into ice water and
the mixture extracted with ethyl acetate. The extract is
washed with saturated aqueous sodium bicarbonate, drièd
and evaporated. The residue is taken up in diethyl ether,
the solution decoloriæed with charcoal, filtered and evapo-
rated, to yield the l-(p-chloro-o-nitrobenzyl)-pyrrole.
Through the mixture of 4.26 g thereof, 20 ml of
diethyl ether and 1.46 g of chloroacetonitrile, hydrogen
~hloride is bubbled while stirring and cooling in an ice -
-salt bath. The saturated mixture is stirred at room tempera-
ture overnight, filtered and the residue suspended in 50 ml
of water. It is extracted 3 times with 50 ml of ethyl ace-
tate. The extract is dried and evaporated, to yield the
l-(p-chloro-o-nitrobenzyl)-2-chloroacetyl-pyrrole.
To the suspension of 56.5 g thereof in 960 ml of
ethanol, 21.8 g of N-methyl-benzylamine and 18.2 g of tri-
ethylamine are added and the mixture is refluxed for 6 hours.
., ,, , : ,
;::
~ ~ ~3
- 19 -
It is evaporated, the residue taken up in chloroform, the
solution washed with saturated aqueous sodium carbonate,
dried, filtered and evaporated. The residuP is dissolved
in diethyl ether, the solution filtered, the filtrate eva-
porated and the residue triturated with methanol, to yield
the l-(p-chloro-o-nitrobenæyl)-2~(N-methyl-N-ben~ylamino-
acetyl)~pyrrole melting at 90 93.
To the solution of 1.0 g thereof in 30 ml of ben-
zene 0.545 g of ethyl chloroformate are added and the
mixture is reflu~ed ~or 4 hours. It is diluted with di-
ethyl ether, washed with N hydrochloric acid and saturated
aqueous sodium chloride, dried and evaporated, to yield
the l~(p-chloro~o-nitrobenzyl)-2-(N-methyl-N-carbethoxy-
amino-acetyl)-pyrrole.
To the solution of 1.43 g thereof in 20 ml of tetra-
hydrofuran 15 ml of titanium trichloride are added drop-
wise and the mixture is stirre~ overnight at room tempera-
ture. It is made basic with 60 ml of 10% aqueous ammonia,
filtered and the residue washed with methylene chloride.
The organic phase is separated, washed with saturated
aqueous sodium chloride, dried and evaporated, to yield
the 8-chloro-11-(~-methyl-N-carbethoxyaminomethyl-5H-pyr-
rolo[2,1-c][1,4]benzodiazepine.
To the solution of 430 mg thereof in 10 ml of etha-
nol, 760 mg of sodium borohydride are added and the mix-
ture is stirred at room temperature overnight. It is
acidified with 6N hydrochloric acid, diluted with methy-
lene chloride, washed with water and saturated aqueous
sodium chloride, dried and evaporated. The residue is
chromatographed on silica gel and eluted with ethyl
acetate-methylene chloride (1:19~, to yield the 8-chloro-
:; ,:
, . : . ~ . .
. . . "
: . . , - ::. . . i .. :
., .-: . ;:, . ~ ,
.
.:
3~
- 20 -
-ll-(N-methyl-N-carbethoxyamino methyl)-10,11-dihydro-
-5H-pyrrolo[2,1-c3[1~4]benzodiazepine.
The mixture of 200 mg thereof, 10 ml of ethanol and
3 ml of 20~/o aqueous sodium hydroxide is refluxed for 3 days
and evaporated The residue is taken up in watera the mix-
ture extracted with methylene chloride, the extract dried
and evaporated, to yield the 8-chloro-11-(N-methylamino
met~ l)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.
The mixture of 960 mg thereof, and 600 mg of diethyl
oxalate is slowly heated to 140 during 45 minutes and to
180 during 15 minutes, at which temperature it is main-
tained for 30 minutes. It is cooled, evaporated, the resi-
due washed with diethyl ether and triturated with ethyl
acetate, to yield the 7-chloro-2~methyl-3,4-dioxo-1,3,4,
14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][194
benzodiazepine melting at 203U.
Example 3
To the solution o 1.9 g of 2-methyl-1,3,4,14b-
-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzo-
diazepine in 50 ml ofbenze~,2.14 g of ethyl chloroformate
are added and the mixture is refluxed for 3 days. It is
diluted with diethyl ether, washed with N hydrochloric
acid and with both saturated aqueous sodium chloride and
sodium bicarbonate, dried and evaporated, to yield the
2-carbethoxy-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]
pyrrolo[2,1-c][1,4]benzodiazepine showing in the NMR-spec-
trum peaks at 8.55(t), 6.60(m), 5.65(q) and 3.90(d) ppm,
and in the mass-spectrum a molecular ion of 311.
, . , . ,:, ~. ,
: . ....
- 21 -
Examp 1 e 4
The mixture of 930 mg of 2-carbethoxy~1,3,4,14b-
tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo~2,1-c]~1,4]benzo-
diazepine, 40 ml of ethanol and 20 ml of 20% aqueous potas-
sium hydr~xide is refluxed for 2 days. After cooling, it
is diluted with ethyl acetate, washed with wa~er, dried
and evaporated. The residue is taken up in diethyl ether
and the s~lution combined with 0.55 g of maleic acid in
the minimum amount of acetone. The pre~ipitate formed is
collected and washed with diethyl ether, to yield the
1,3,4,1~b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c]
[1~4]benzodiazepine maleate melting at 173-175.
Analogously, the 7-chloro-1,3,4,14b-tetrahydro-2H,
lOH-pyrazino[1,2-a]pyrrolo~2,1-c][1,4~benzodiazepine maleate
is obtained (by hydrolysis with 20% aqueous sodium hydro-
xide) melting at 184-186.
Example 5
To the solution of 4.8 g of 1~3,4,14b-tetrahydro-
2H,lOH-pyrazino[1,2-a]pyrrolo~2,1-cl~1,4]benzodiazepine in
20 ml of dimethyl formamide and 2.44 g of triethylamine,
2.91 g of allyl bromide are added dropwise while stirring.
Ater one hour, the mixture is`diluted with diethyl ether,
washed with water and saturated aqueous sodium chloride
and the aqueous phase is once more extracted with diethyl
ether. The combined organic solutions are washed with satu-
rated aqueous sodium bicarbona~e, dried, evaporated and the
residue triturated with diethyl ether, to yield ~he 2-allyl-
1,3,4,14b-te~rahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1 c]
.
.:.. , ;, :- .
;' ` '~ ; " ~
~ ~ ~ 3
- 22 -
[1,4~benzodiazepine melting at 130~132.
.
In the analogous manner, the a) 2-(3-methyl-2-buten-
yl)-; b) 2-propargyl-; c) 2-cyclopropylmethyl-; d) 2-carbo-
methoxymethyl and e) 2-phenethyl-1,3,4,14b-tetrahydro-
2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c]~1,4Jbenzodiazepines
are prepared from equivalent-amounts of the corresponding
bromides. Said compounds of the invention a) to d) are
converted into the acid addition salts listed below, as
shown in Examples 1 and 2 herein, and crystallized from
the various solven~s as indicated. Said salts melt as
follows: a) maleate 152-153 (isopropanol); b) fumarate
138-140 (ethanol); c) maleate 189-190 (isopropanol);
d) maleate 162-164 (isopropanol-diethyl ether) and the
free base e) melts at 132-134 (isopropanol).
Example 6
.
The mixture of 1.5 g of 2-carbomethoxymethyl-1,3,4,
14b~tetrahydro-2H,lOH-pyrazino~1,2-a]pyrroloL2,1-c~1,4]
benzodiazepine and 10 ml of N aqueous sodium hydroxide is
refluxed for 45 minutes until homogeneousO The solution is
allowed to cool to room temperature and the precipitate
formed is collected and washed with diethyl ether to yield
the sodium salt of the 2-carboxymethyl-1,3,4,14b-tetrahydro-
2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c~[194]benzodiazepine
melting at 249-250.
F.xample 7
Through the solution of 300 mg of 2-carbomethoxy
methyl-1,3,4,14b-tetrahydro~2H,lOH-pyrazino~1,2-a]pyrrolo
- ~ " . ~
- .
.
. i
: , :
- 23 -
~2,1-c][1,4]benzodiazepine in 5 ml of methanol, ammonia
is bubbled for 2 hours while cooling to about -70U. The
mixture is stirred overnight at room temperature, where-
upon it is again saturated with ammonia and allowed to
stand at room temperature for 2 days. It is evaporated
and the residue triturated with diethyl ether, to yield
the 2-carbamoylmethyl-1,3,3,14b-tetrahydro-2H,lOH-pyrazino
[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at
198-200.
Example 8
To the solution of 78G mg of 2-carbomethoxymethyl-
1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c]
l1,4]benzodiazepine in 20 ml of tetrahydrofuran, 150 mg of
lithium aluminium hydride are added and the mixture is
stirred for 2 days at room temperature. It is combined
with 0.15 ml o water) 0.15 ml of 15% aqueous sodium hydro-
xide and 0.15 ml of water in this order, filtered and the
filtrate evaporated, to yield the 2-(2-hydroxyethyl)-1,3,4
14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4~
benzodiazepine, which is converted into its mono-fumarate
melting at 187-189 with decomposition.
Example 9
To the mixture of 100 mg of 1,3,4,14b-tetrahydro-
2H~lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine,
1 ml of N hydrochloric acid ~nd 10 ml of wat~r, the solu-
tion of 54.5 mg of sodium cyanate in 2 ml of water is
added while stirring followed by 2 ml of tetrahydrofuran.
.
- . , . , - , , .; . " .
. . . ,
,~ " .
.- . :
, . . . .
: . . ,
, ~ .
-- 26 -
Examp 1 e 13
.
The mixture of 500 mg of 2-methyl-1,3,4,14b-tetra-
hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiaze-
pine, 10 ml of methylene chloride and 0.5 ml of methyl
iodide is stirred at room tempera~ure for one hour. It is
filtered and the residue washed with methylene chloride,
to yield the 2,2-dimethyl-1,3,4,14b-tetrahydro-2H,lOH-
pyrazino[l,2-a]pyrrolo[2,1-c][1,4]benzodiazepinium iodide
melting at 258-260 with decomposition.
.
Example 14
To the solution of 300 mg of 2-methyl-1,3,4,14b-
-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzo-
diazepine in 10 ml of methylene chloride, 290 mg of m-chloro-
perbenzoic acid in 10 ml of methylene chloride are added
and the mixture is stirred at room temperature for 5 hours.
It is shaken with 5 ml of 10% aqueous sodium sulfite, washed
with saturated aqueous sodium bicarbonate, dried and evapo-
rated to yield the 2-methyl-1,3,4,14b-tetrahydro-2H,lOH-
pyrazino[l,2-a]pyrrolo~2,1-c][1,4~bPnzodiazepine-2-N-oxide
melting at 143-145.
Example 15
To the solution of 140 mg of 2-methyl-1,4-dioxo-
-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c]
[1,4]benzodiazepine in 5 ml of tetrahydrofuran, 2 ml of
l-molar diborane in tetrahydrofuran are added while stirring
and cooling in ice. The mixture is a]lowed to stlr at room
. ..-.
. : , :, .. . . .
,, ., ~ , . ..
- , ,, ,
,,
- 2~ -
After stirring overnight- at room temperature, it is extrac-
ted with methylene chloride, the extract washed with sa~ura-
ted aqueous sodium carbonate, dried and evaporated, to
yield the 2-carbamoyl-1,3,4,14b-tetrahydro-2H,lOH-pyrazino
[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 175-
177.
Example lO
The solution of 1.16 g of 2-allyl-1,3,4,14b-tetra-
hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiaze-
pine in 25 ml of ethanol is hydrogenated over 40 mg of
platinum oxide for 2.5 hours at room temperature and
atmospheric pressure. It is filtered, the filtrate ~vapora-
ted, the residue taken up in isopropanol and the solution
acidified with maleic acid, to yield the 2-n-propyl-1,3,4,
14b-~etrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4
benzodiazepine maleate melting at 157-159.
Analogously, the 2- (3-methyl-butyl)-1,3,4,14b-tetra-
hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiaze-
pine maleate is prepared, melting at 146-147. Both of
said compounds can also be obtained according to the method r
of Example 1.
. .
Example 11
To the solution of 50û mg of 1,3,4,14b-tetrahydro-
2X,lOH-pyrazino[1~2-a]pyrrolo[2,1-c][1,4]benzodiazepine
in 7.5 ml of dimethylormamide and 350 mg of triethylamine,
470 mg of a-bromo-p-chloroacetophenone are added and the
. .
.
, " . ~ ,, .
,, , ~ .... .,. ,,
- . :- : : ;
: : .,- ~ . : :
~ 3~-s~
- 25 -
mixture is stirred at room temperature for 2 hours. It is
diluted with 60 ml of diethyl ether9 washed with water,
dried and evaporated. The residue is taken up in 15 ml of
chloroform and the solution again evaporated, to yield the
2-(p-chlorobenzoylmethyl)-1,3,4,14b-tetrahydro-2H,lOH-
pyrazino[l,2-a~pyrrolo[2,1-c][1,4]benzodiazepine melting
at 71-74.
Example 12
According to the method illustrated by Examples 1
and 2S the 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetra-
hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiaze-
pine is reduced with diborane, to yield the 2,12-dimethyl-
-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c]
[1,4]benzodiazepine, which is converted into its monomaleate ``
meltin~ at 173-175
The starting material is prepared as follows:
The mixture of 170 mg of phosphorus oxychloride and
100 ml of dimethylformamide is stirred at room temperature
for 30 minutes, whereupon the solution of 281 mg of 2-methyl-
3,4-dioxo-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1~2-a]pyrrolo
[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is
added dropwise. After 30 minutes, the mixture is refluxed
for another 30 minutes and coo~led to room temperature. It
is combinPd with 1.5 g of sodium acetate in 15 ml of water,
stirred for 30 ~inutes and the organic layer separated. It
is washed with water, 5% aqueous sodium bicarbonate, dried,
evaporated and the residue triturated with diethyl ether,
to yield the 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetra-
hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c~1,4]benzodiaze-
pine melting at 300-302~.
"
, , ., : .
w`~
- 27 -
temperature overnight and is then refluxed for 4 hours.
~fter cooling to room temperature it is combined with
0.5 ml of glacial acetic acid, evaporated and the residue
basified with 3N aqueous sodium hydroxide. The mixture is
extracted with methylene chloride, the extract dried,
evaporated and the residue dissolved in diethyl ether. The
solution is filtered and the filtrate evaporated to yield
the 2-methyl-l~3~4~l4b-tetrahydro-2H~loH-pyrazino[l~2-a]
pyrrolo[2,1-c][1,4]benzodiazepine, which is identical with
that obtained according to Example l; its monomaleate
melts at 176-178.
The starting ma~erial is prepared as follows: To
the stirred solution of 16 g of oxalyl chloride in 150 ml
of diethyl ether, cooled to -50~ by means of a solid
carbon-dioxide-acetone bath, the solution of 7.36 g of
pyrrole in 30 ml of diethyl ether îs added at such a rate
that the internal temperature of the mixture is maintained
at -50. The stirring is contin~ed for 1 hour after comple-
tion of the addition and the mixture is poured slowly into
the solution of 27.5 g of sarcosine ethyl ester in 150 ml
of diethyl ether. The resulting precipitate is collected,
extracted thoroughly with methylene chloride and the
extract evaporated to yield the N-(2~pyrrylglyoxyl)-sarco-
sine ethyl ester melting at 114.
To the solution of 5.5 g thereof in 30 ml of di-
methyl formamide is added 1.07 g of a 50V/~ sodium hydride
suspension in mineral oil and 20 ml of dimethyl formamide.
The mixture is heated to 60-70 for 1 hour, cooled to room
temperature and combined with the solution o 5 g of
o-nitrobenzyl bromide in 20 ml of dimethyl form~mide. The
mixture is stirred at 45-50 for 1 hour, cooled to room
temperature, diluted with water and extracted with ethyl
~ . "''-'.. ' ~ " "
- 28 -
acetate. The extract is dried, evaporated and the residue
~riturated with diethyl ether to yield the N~ o-nitro-
benzyl-2-pyrrylglyoxyl)-sarcosine ethyl ester melting at
105-108.
The solution of 3 g thereof in 30 ml of ethyl ace-
tate is hydrogenated over 100 mg of platinum oxide at
3 atm. until 3 mole equivalents of hydrogen are absorbed.
The mixture is combined with 1,5 ml of glacial acetic acid
and the uptake of hydrogen is finalized a~ 3 atm, and at
40. I~ is filtered, the filtrate evaporated, the residue
taken up in methylene chloride and purified by column
chromatography on silica gel using 10% methanol-methylene
chloride as eluant, to yield the N- (1,2-dihydro-SH-pyrrolo
[2~1-c][1,4]benzodiazepin-2-yl-carbonyl)-sarcosine ethyl
ester melting at 147-148.
To the suspension of 100 mg thereof in 10 ml of
toluene are added 20 mg of sodium methoxide and the m~ture is
refluxed for 1 hour. It is cooled, filtered and evaporated
to yield the 2-methyl-1,4-dioxo-1,3,4,14b-tetrahydro 2H,
lOH-pyraæino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine
melting at 165-167.
Example 16
-
To the hot solution of 10 g of 2-methyl-1,3,4,14b
-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,43benzo-
diazepine (Example 1) in 300 ml of isopropanol is added
the hot solution of 3 g oE d-tartaric acid in 50 ml of iso-
propanol The mixture is allowed to cool overnight to
room temperature and the solids are collected by filtra-
tion. These are recrystallized from aqueous ethanol until
~ ' ` ': ' ;
- . ; .
`' .:: ...... ` ~ '
- 29 -
.
the optical rotation of the liberated free base is constant
(3 times), i,e., [~]25 = ~ 344.26 (c-l in methanol).
It is converted into the monomaleate melting at 190-191
with decomposition.
Similar use of Q-tartaric acid yields the correspond-
ing antipode of the free base with ~a]25 = -358.89~, the
monomaleate of which melts at 188-189 with decomposition.
Example 17
To the solution of 800 mg of 2-methyl-5 oxo-1,2,3,
4,5,15b-hexahydro-llH-[1,4]diazepino[1,2-a]pyrrolo[2,1-c]
[1,4]benzodiazepine in 50 ml of tetrahydrofuran, 6.2 ml of
l-molar diborane in tetrahydrofuran are added. The mixture
is refluxed for 2 hours, cooled and stirred overnight at
room temperature. It is combined wi~h 2 ml of glacial
acetic acid, evaporated and the residue basified with 3N
aqueous sodium hydroxide. The resulting mixture is extracted
with methylene chloride, the extract dried, evaporated and
the residue dissolved in the minium amount of methylene
chloride. The solution is chromatographed on silica gel
and eluted with 10% methanol-methylene chloride to yield
the 2-methyl-1,2,3,4,5,15b-hexahydro-llH-[1s4]diazepino
~1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine of Formula I
with Rl=R3=R4=R5=H, R2= methyl, Ph = 1,2-phenylene and
n = 3. It is converted into the monofumarate melting at
174-175.
The starting material is prepared as follows: The
solution of 1.5 g of ll-(N-methylaminomethyl)-10,11-dihydro-
-5H-pyrrolo[2,1-c][1,4]benzodiazepine (Example 1) in 7.5
ml of methyl acrylate is stirred at room temperature for
... .. . . . . .. . ..... . . ... . . .. . . ..
. .
: ~:: , , -, ,
.... ..
- - .:: , , ,, . ,
.. ..
'~
- 30 -
24 hours and the excess reagent is evaporated to yield the
N-methyl-N-(1,2-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiaze-
pine-~-yl-methylene)-~-alanine methyl ester as an oil,
which is chromatographed on silica gel and eluted with
2% methanol-methylene chloride.
The solution of 1 g thereof in 20 ml of tetrahydro-
furan is added to the stirred solution of 475 mg of 2,2,6,
6-tetramethylpiperidine (freshly distilled from calcium
hydride) in 10 ml of tetrahydrofuran, followed by 1.37 ml -~
of 2.45 molar n-butyl lithium in hexane at -75. The mix-
ture is stirred at this temperature for 30 minutes and
then allowed to warm gradually to 0~. It is diluted with
acetic acid-water (2:1), evaporated, the residue dissolved
in methylene chloride, chromatographed on silica gel and
eluted with 5% methanol-methylene chloride to yield the
2-methyl-5-oxo-1,2,3,4,5,15b-hexahydro-llH-[1,4]diazepino
[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 156-
158.
Example 18
To the solution of 2.5 g of 2-methyl-1,3,4,14b-tetra-
hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2jl-c][1,4]benzodiaze-
pine (Example 1) in 25 ml of tetrahydrofuran are added
4.5 ml of 2 45 molar n-butyl lithium in hexane at room
temperature while stirring under nitrogen. The pale yellow
solution rapidly becomes cherry-red and the temperature
rises about 7. The mixture is stirred for an additional
45 minutes, whereupon it is treated with methyl iodide
until the color of the solution is discharged. After stir-
ring for a further 30 minutes the mixture is poured into
100 ml of water, and the product is extracted with diethyl
,.
.
, ~
:
3~
.
- 31 -
ether The extract is washed successively with water and
saturated aqueous sodium chloride solution, evaporated
and the residual oil chromatographed on silica gel, using
2% methanol-methylene chloride as eluent, to yield the
2,10-dimethyl-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1~2-a]
pyrrolo[2,1-c~[1,4]benzodiazepine which is converted to
its mono maleate melting at 157. The identical product
is also obtained according to the methods of Examples 1
and 15 by selecting o-nitro-a-methylbenzyl chloride or
bromide respectively~
Example 19
- To the stirred solution of 1.3 g of 1,3,4,14b-tetra-
; hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2~1~c][1,4]benzodiaze-
pine (Example 4) and 550 mg of triethylamine in 15 ml of
tetrahydrofuran are added 765 mg of benzoyl chloride. After
allowing the mixture to stir at room temperature overnight
it is evaporated and the residue taken up in 100 ml of
water. The mixture is extracted with diethyl ether, the
extract washed successively with water and saturated aqueous
sodium chloride solution, dried and evaporated, to yield
the 2-benzoyl-1,3,4,14b~tetrahydro-2H,lOH-pyrazino[1,2-a]
pyrrclo[2,1-c][1,4]benzodia~epine melting at 137-139 ater
recrystallization from isopropanol.
Example 20
To the solution of 2.5 g of 2-(2-hydroxyethyl)-
1,3,4,14b-tetrahydro-2H~lOH-pyrazino[1,2-a]pyrrolo[2,1-c]
[1,4]benzodiazepine (Example 8) and 935 mg of triethyl-
amine in 72 ml of tetrahydrofuran are added 720 mg oE
,, , .".,: -: .,........................ .. :
~ ' ., i .,: :, ' ~,: ' ,' ! . . '
~ 3
- 32 -
acetyl chloride. The mixture is stirred at room tempera-
ture for 2 hours, evapora~ed and the residue extracted
with methylene chloride. The extract is washed successive-
ly with water and saturated aqueous sodium chloride solu-
tion, dried, filtered and evapora~ed to yield the 2-(2-
-acetoxyethyl)-l~3~4~l4b-tetrahydro-2H~loH-pyrazino[l~2-a]
pyrrolo[2,1-c][1~4]benzodiazepine, which is converted to
its mono-fumarate melting at 156-158 with decomposition.
Analogously, the free bases of the 2-[2-(n-hexa-
noyloxy, n-decanoyloxy, n-hexadecanoyloxy and l-adamantyl-
carbonyloxy)-ethyl]-1,3,4,14b- tetrahydro-2H,lOH-pyrazino
~1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine are prepared~
melting at 56-58, 59-61, 71-73 and 47-50 respectively.
Example 21
348 g of 2-methyl~3,4-dioxo-1,3,4,14b-tetrahydro-
2H,lOH-pyrazino[1,2-a]pyrrolo~2,1-c][1,4]benzodiazepine
are added portionwise over 1 hour to 4~500 ml of tetrahydro-
furan and 7,410 ml of l molar diborane in tetrahydrofuran
while cooling with ice to 18 and stirring under nitrogen.
The mixture is refluxed for 24 hours, again cooled to 5
and combined with 1,200 ml of glacial acetic acid followed
by 900 ml of water. The solution is refluxed for 24 hours,
evaporated and the residue taken up in 10,500 ml of metha-
nol. The solution is again refluxed for 2 hours, evaporated,
the residue dissolved in 3,000 ml of water and the pH of
the solution adjusted to 14 with 1,200 ml of 10% aqueous
sodium hydroxide. The mixture is extracted with diethyl
ether, the extract dried, filtered and evaporated to yield
the 2-methyl-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]
pyrrolo[2,1-c][1,4]benzodiazepine melting at 98-100.
. - . ...
.
-. : , ,. . , . - ,
.
. . ~ ,
. ~ . , ~ i,
3~p~
- 33 -
-
307 g thereof are dissolved in 1,280 ml of absolute
ethanol while refluxing, the solution is filtered, the fil-
trate cooled to 28U and combined with the 140.5 g of maleic
acid in 294 ml of ethanol. The precipitate formed is col-
lected, washed with cold ethanol and recrystallized from
ethanol again to yield the corresponding mono-maleate melt-
ing at 183-185; it is somewhat purer than that obtained
according to Example 1.
The starting material is prepared as follows: The
mixture o~ 3,078 g of o-nitrobenzylamine and 2~670 g of
2,5-dimethoxytetrahydrofuran is added rapidly to 10,000 ml
of glacial acetic acid at 86 while stirring under nitrogen.
The mixture is stirred at 95 for 1.25 hours, cooled to Z5
. . .
and combined with 30,000 ml of water. It is extracted with
ethyl acetate, the extract is washed with 10% aqueous sodium
hydroxide and 10% aqueous sodium chloride, filtered and eva-
porated to yield the l-(o-nitrobenzyl)-pyrrole.
Through the mixture of 3,468 g thereof, 8,500 ml of
tetrahydrofuran and 1,290 g of chloroacetonitrile, hydrogen
chloride is bubbled for 3 hours while stirring and cooling
to 5-35. The saturated suspension is stirred another hour
at 17, filtered, the residue suspended in 1,000 ml o tetra-
hydrofuran and filtered again, to yield the l-o-nitrobenzyl-
2-(1-imino-2-chloroethyl)-pyrrole hydrochloride, melting at
21O-212 with d~composition.
The suspension of 3,469 g thereof in 3,500 ml of
water is stirred for one hour at 80, thereafter cooled to
25 and filtered. The residue is washed with water~ dried
and 6,000 g thereof dissolved in 60,000 ml o~ ethanol while
refluxing under nitrogen. The solution is filtered hot,
concentrated by distilling 36,000 ml ethanol off, and
'
, :, ", ,.
,;, ;,; ",.; - , ,:
_ 3~ _
allowed to cool to 25 overnight. The resulting suspension
is filtered and the residue dried to yield the l-o~nitro-
benzyl-2-chloroacetylpyrrole melting at 112-114.
.
The suspension of 5,112 g thereof, 26,400 ml of
~oluene, 2,445 g o N-methylbenzylamine and 27040 g of tri-
ethylamine is stirred under nitrogen a~ 93 for 6 hours
and at room tempera~ure overnight. It is combined with
20,000 ml of water, the aqueous phase separated, the orga-
nic phase washed with 10% aqueous sodium chloride and eva-
porated. The residue is dissolved in 20,000 ml of hot etha-
nol, the solution concentrated by distilling off 2,000 ml
of ethanol, and allowed to stir overnight at room tempera-
ture. The crystals formed are filtered off, washed with
ethanol and dried to yield the l-(o-nitrobenzyl)~2-(N-
methyl-N-benæylaminoacetyl)-pyrrole melting at 103-105.
The solution of 300 g thereof in 3,000 ml of ethyl
acetate and 250 ml of glacial acetic acid is hydrogenated
over 30 g of platinum oxide at atmospheric pressure and
room temperature until the theoretical amount of hydrogen
has been absorbed. It is filtered, the residue washed with
ethyl acetate and the filtrate evaporated. The residue is
taken up in methylene chloride, the solution washed with
2.5 N aqueous sodium hydroxide and saturated aqueous sodium
chloride, dried and evaporated, The residue is triturated
with diethyl ether to yield the ll-(N~methyl-N-benzylamino-
methyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
melting at 151-152.
To the solution of 142.5 g thereof in 2,000 ml of
~oluene and 45 g of triethylamine, 61 g of ethyl oxalyl
chloride in 850 ml of toluene are added during 90 minutes
while stirring at 10-20~. A~ter 4 hours the mixture ls
.
.
. ~ :,. . -,:. . .
- . . ,.. .: , .. -.. , . .. :
, : ", . . .,:,. ., :
-, . : : ~ ~
. ~ /.... , ;~ :, . . . ..
~3~3
- 35 -
poured into 750 ml of water, the whole stirred for 20 minu-
tes and the organic layer separated. It is washed with
saturated aqueous sodium bicarbonate and sodium chloride
each, dried, evaporated and the residue recrystalliæed
from methanol, to yield the 10-ethyloxalyl-11-(N-methyl-
N-benzylaminomethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
ben~odiazepine melting at 99-101. (Utilization of greater
amounts o~ ethyl oxalyl chloride result in the formation
o~ the corresponding 3,10-bis-ethyloxalyl-compound melting
at 115-116, which is less soluble in isopropanol than the
former, and can be collected from concentrated solutions
thereof by filtration.)
The solution of 6.9 g of said 10-ethyloxalyl-compound
in 100 ml of ethanol and 27 ml of glacial acetic acid is
hydrogenated over 1.65 g of 5% palladium on charcoal at
2.7 atm and 40 for about one hour. The mixture is fil-
tered and the filtrate evaporated to yield the 2-methyl-
3,4-dioxo-1,3~4,14b-tetrahydro~2H,lOH-pyrazino[1,2-a]pyr-
rolo~2,1-c][1,4]benzodiazepine melting at 178-179.
Hydrogenating said 3,10-bis ethyloxalyl-compound
analogously, the ethyl (2-methyl-3,4-dioxo-1,3,4,14b-
tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzo-
diazepin-12-yl)-glycolate is obtained.
Example 22
Reducing 200 mg of the ethyl (2-methyl-3,4-dioxo-
1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]
benzodiazepin-12-yl)-glycolate o Example 21 with diborane
according to Examples 1 or 2, the 2-methyl-12-(2-hydroxy-
~ . ' , , , ", . ! ,, ,~. " . .. ..
,. ' : ' ' , '' ' '' - '`'.,'~ . : .;
:, ",: '
~' " , , ,, , .~' , ` -;
- 36 -
ethyl)-1,3~4,14b tetrahydro-2H,lOH-pyrazino[1,2-a]pyrrolo
[2,1-c][1,4]benzodiazepine mono-maleate melting at 153-156
is obtained.
Example 23
To the solution of 5 g of 2-methyl-1,3,4,14b-te~ra-
hydro-2H,lOH-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiaze-
pine and 2 g of triethylamine in 50 ml of toluene are added
3.6 g of trichloroacetyl chloride. The mixture is stirred
for 1 hour and then combined with 30 ml of water and 50 ml
of methylene chloride. The organic phase is washed with
water, dried and evaporated to yield the 2-methyl-12-tri-
chloroacetyl-1,3,4,14b-tetrahydro-2H,lOH-pyrazino[1,2-a]
pyrrolo[2,1-c][1,4]benzodiazepine.
5.4 g thereof are added ~o the solu~ion of 100 mg
of sodium in 75 ml of ethanol and the mixture is stirred
at room temperature overnight. The precipitate formed is
filtered of, washed with water and dried, to yield ~he
2-methyl-12-carbethoxy-1,3,4,14b-tetrahydro-2H,lOH-pyra-
zino[l,2-a]pyrrolo[2,1-c]~1,4]benzodiazepine melting at
12~-130, its monofumarate-monohydrate melts at 147-150
with decomposition.
Example 24
According to the methods illustrated by the previous
examples (advantageously Examples 1 and 21), the ollowing
compounds of Formula II are obtained from equivalent amounts
of the corresponding starting materials:
., . ..... . :; - . . ~: :~ . :
37 -
_____
No R6 ~ R7 ¦ Salt ~p. C
. d composition
_ . . , ............. . . ,. _ .
1 H 9-CH3 ! maleate 185~187
2 CH3 ~-CH3 maleate 172-174
. 3CH2=CH-CH2 9-CH3 maleate 159-161
4 H 8 CH3 maleate 1~9-171
CH3 8-CH3 maleate 162-164
6 CH3 7-F maleate 179-181
7 H 7-C~3 maleate 172-174
8 CH3 7-CF3 maleate 189-191
g(CH2)3-OH H fumarate 201-203
10~CH2)2-cO-cH3 ¦ H u~arate 155-157
11(CH2)11 CH3 H fumarate 144-148
_ ,
Example 25
Preparation of lO,O00 tablets each containing 5 mg
o the active ingredient
Formula:
2-methyl-1,3,4s14b-tetrahydro-2H,lOH- SO g
pyrazino[l,2-a]pyrrolo[2,1-c]~1,4]
benzodiazepine monomaleate
Lactose 1,157 g
Corn starch 75 g
Polyethylene glycol 6,ooo 75 g
Talcum powder 75 g
Magnesium stearate 18 g
Purified water q.s.
'.
, . . ,. , , .. ~ , ~ ,. .
~ 38 -
Procedure:
All the powders are passed through a screen with
openings of 0.6 mm. Then the drug substance, lactose, talcum,
magnesium stearate and half of the starch are mixed in a
suitable mixer. The other half of the starch is suspended
in 40 ml of water and the suspension added to the boiling
solution of the polyethylene glycol in 150 ml of water.
The paste formed is added to the powders which are granu-
lated, if necessary, with an additional amount of water.
The granulate is dried overnight at 35, broken on a screen
with 1.2 mm openings and compressed int~ tablets using
concave punches with 6.4 mm diameter, uppers bisected.
Example 26
Preparation of 10,000 capsules each containing 10 mg
of the active ingredient:
Formula-
2-methyl-1,3,4,14b-tetrahydro-2H,lOH- 100 g
pyrazino~l,2-a]pyrrolo[2,1-c][1,4]
benzodiazepine monomaleate
Lactose l,B00 g
Talcum powder 100 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 homogenous. No. 3 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 previous examples.
~ ,: .:, ;,.:. ",.. .. .. .
