Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
25,618
107030Z
: ' ~
This invention is concerned with compounds of
the formula:
R 7
Rz
R3
wherein Rl and R2 are hydrogen, lower alkyl, lower al~
koxy r halogen, nitro, tri f luoromethyl, methylthio,
methylsulfonyl and hydroxy; R3 is hydrogen or lower
alkyl; R7 is -N N-R4, -N ~ , or -N(CH2)nN(R5)~
wherein R4 is hydrogen, lower alkyl, 2-hydroxyethyl,
phenyl or phenylloweralkyl; n is 2 or 3 and R5 is lower
- 2 -
., ~ , , , . ~ --
` `` 107030Z
1 alkyl, and acid addition salts thereo.~. The term lower
as ~efined above is intended to lnclude thosc Wll~?l'e~
the hydrocarbon group contains from 1 to 4 car~on atoms.
~alogen is chlorine, bromine, fluorine or iodine.
The compounds of the present invention may be
prepared by the following reaction sequence and includes
a process for the conversion of a lactam to an amidine
. . in one or several stages by the introduction of a labile
leaving group followed by in situ or subsequent displace- ` '
~:10 ment with an amine. ~ .
~- H O ~.
..
~ ~ N C ~
R lt l l I s ~ . .
~ N ~ :
R2 .
X -
;: R3
~2 .:
. Rl /N R3
N=C
R 2~
3 :.
: 25 The leaving group X includes the following: =S; (halo-
gen) C1; -OR, where R = lower alkyl; -SR, where R = lower
alkyl; -O-S-R, where R = lower alkyl, phenyl or substi-
tuted phenyl; or -OZ where Z includes the elements Ti, -~:
Si, P, Zr or Al; in various stages of oxidation and sub- ~
30 stituted with lower alkyl, lower alkoxy, phenyl, ~substi- .
- 3 -
z
tuted phenylJ halogen or phenoxy. Accordingly, the present invention provides
a method of preparing a compound of the formula:
R .;.-,`
R~N =~
! R3
: ' :
wherein Rl and R2 are hydrogen, Cl 4 alkyl, Cl 4 alkoxy, halogen, nitro,
trifluoromethyl, methylthio, methylsulfonyl or hydroxy; R3 is hydrogen or
Cl 4 alkyl; R7 is -N N-R4, -N ~ or -N ~CH2)nN~R5)2~ wherein R4
is hydrogen, Cl 4 alkyl, 2-hydroxyethyl, phenyl or phenyl Cl 4 alkyl, n is
2 or 3, and R5 is Cl 4 alkyl, and pharmaceutically acceptable acid addition
. salts thereof, characterized by
(a) reacting a compound of the formula:
! SCH3
R ~ S
R3 ~.
,~ ` '
wherein Rl, R2 and R3 are as defined above, with an amine of the formula
H :~
H-N N-R4, H-N ~ or H-N (CH2)n-N~R5)2 wherein R4 is hydrogen, Cl 4
alkyl, 2-hydroxyethyl, phenyl, or phenyl Cl 4 alkyl, n is 2 or 3, and R5 .
is Cl 4 alkyl, at a temperature from 100C to 250C under acid conditions;
~b) reacting at a temperature from 100C to 250C a compound of
the formula R S
~ N
: R N '''~
2 R3
wherein R is hydrogen and Rl, R2 and R3 are as defined above with an amine
of the formula:
.. . . . .. .... .. . . . . . . . . . . . . . .
` 1070302
/~ ~
H-N N-R4, H-N ~ or ~l2N(cH2)nNcRs)2 wherein R4, R5 and n are as
defined above;
~c) reacting a compound of the formula
Rl N
~ -N
R2 3
wherein R is hydrogen and Rl, R2 and R3 are as defined above with a compound ;
of the formula: ~ `
O :: . -
Cl - S - x
1~ . ,
O ', ,~ '
wherein x is Cl 4 alkyl, phenyl or substituted phenyl followed by reaction
with an amine of the formula~
H-N ~ N~R4, H-N ~ or H2N~CH2)nN~R5)2, wherein R4 and R5 and n are as
defined above;
(d) reacting a compound of the formula~
R~ A~
wherein R is hydrogen and Rl, R2 and R3 are as herein above defined, with
a compound of the formula:
~ ~P ~ 7)2
wherein R7 is an amine of the formula:
H-N N-R4, H-N ~ or H2N-CCH2)nNCR5)2 wherein R4, R5 and n are defined
\ .
above,
10703~2 ;
(el reacting a compound o thq formula
Xs ~
R2 3
wherein R is hydrogen and Rl, R2 and R3 are as herein above defined, with
a compound of the formula:
1 3
followed by reaction with an amine of the formula:
-N N-R4, -N ~ or H2N(CH2)nN(R5)2 wherein R4, R5 and n are as defined
above
(f) reacting a compound of the formula:
R Q
R -N -
2 R3
wherein R is hydrogen and Rl, R2 and R3 are as herein above defined, with
: a compound of the formula: ::
, 3
CH3 - Si - R7
wherein R7 is an amine of the formula:
-N N-R4, -N ~ or H2N-(CH2)nN(R5)2~ wherein R4~ R5
defined above;
(g) reacting a compound of the formula:
R 0
3Q ~2 ~ ~
3 :
-4b- ~
,
~070302
wherein R is h~dragen and Rl, R2 and R3 are as.herein above de~ined, with
phosphorus pentachloride followed ~y.reaction with an amine of the formula:
~ ~ .
-N N-R4~ N ~ 2 ~ H2)nN~R5)2 wherein R4, R5 and n are as
defined above; : ~
(h) reacting a compound of the formula `.-
R 0 ~.
~ ~S
~ 2 R
! 3
....
wherein R is hydrogen and Rl, R2 and R3 are as defined above with a metal~
amine complex of a metal of group IVb of the Periodic Table and an amine of
the formula:
H-N~ N-R4, H-N ~ or H2N(CH2)nN(R5)2 wherein R4, R5 and n are as defined ~ ~
~ ~ .
; above at a temperature from 100C to 250C in the presence of a solvent;
and
.: (i) reacting a compound of the formula :
R 0 . .
; 20 3
.
wherein R is hydrogen and Rl, R2 and R3 are as herein above defined, with
; triethyloxonium fluoborate in a solvent such as methylene chloride at a
temperature of from 5 to 20C. followed by reaction with an amine of the : ;.
formula: -N N-R4, -N ~ or H2N-(CH2)nN(R5)2 wherein R4, R5
and n are as defîned above in the presence of a weak acid at a temperature .. !.;
from 100C to 250C;
and recovering the product therefrom and where required preparing
; 30 a.pharmaceutically accepta~le acid addition salt thereof.
~ ~ -4c- ~.
10~'0302
The present invention also provides compounds o forumla CI)
above, and pharmaceutically acceptable salts thereof, whenever prepared
by the above process, or by an obvious chemical equivalent thereof.
The starting materials may be prepared according to the following
reaction sequence:
CH3~ C R2
O R3
/
10R R O ~
~C~S ~;,
R2 R3 II
r
wh~rein R, Rl, R2 and R3 are as defined hereinabove.
An appropriately substituted 1, 3, 4, 9-tetrahydro-lOH-thieno ;
[3,4-b][1,5] benzodiazepin-10-one (I) wherein R3 is methyl is prepared by
the reaction of N-methyl-o-phenylenediamine and methyl tetrahydro-4-oxo-
3-thiophenecarboxylate atreflux temperature. The compound ~I) i5 then
fused with sulfur to produce the comparably substituted 4,9-dihydro-lOH-
thieno [3,4-b][1,5]-benzodiazepin-10-one (II).
The compounds of Examples 14-15 may be prepared by the above
procedure where ~I) has the R3 substituent altered to ethyl by employing
N-ethyl-o-phenylenediamine. The compound (I) is then reacted with N-
chlorosuccinimide in a suitable solvent to produce compound CII)
'. ~
-4d- ; -
l~, '
- 10~(~3Q2
1 where R3 is ethyl.
The compound (I) where Rl and R2 are chloro,
R3 is methyl is prepared by the reaction of rl-methyl- `~
-4,5-dichloro-o-phenylenediamine and methyl tetrahydro-
5 -4-oxo-3-thiophenecarboxylate at reflux temperature. -~
This co~pound (I) is converted to the comparably substi-
tuted compound (II) by reaction with N-chlorosuccinimide.
The appropriately substituted compound (I)
where R, Rl and R2 are hydrogen is prepared by the re-
action of methyl tetrahydro-4-oxo-3-thiophenecarboxylate
and o=phenylenediamine in a solvent such as for example,
toluene at reflux temperature. Compound (I) is convert-
ed to the comparably substituted compound (II) by treat-
ment with N-bromosuccinimide in dimethylformamide at am-
bient temperature.
Tne final -products are yrepared according to
the following reaction scheme:
H O
R~
~N ~
R3 N
H S
25 R ~ N-C ~ (CH30)2502
R3
R~ ! S-CH3
R2~ ~ R
3 R3-N-H
-- 5 --
1070302
C~ '\
R3
H O O
R2 ,,f~N-C ~ 3 3
R3
O-S~ CH
Rl , " 3
~ N=C~(~
R 2 t l~s
R3
R7
\/
Rl ~R7
R2~--~=NC,~S
R3
-- 6 --
.. . . , , . . ,`., . ... , ` .... ...
`~ 1070302
Cli 3
R ~ 7
=~ N-C~, Cll
R3
Rl~ ~ R7
R 2~ )~\S
R3 ~ .
~ .
H O
R~
R3 ~-P
~=C/~
R 3
H O
R ' "
-C ~ TiC14
~W ~ --
R3
,, . , ., , ; , , ,, , ,~, ~ "".. .. .,. , .. , .. " ., "" ,, .,.,,, ,", , ;,. ", .,:",. .. ., " , .
.. -:- `` - . : : ..... : :: . .. -. . .
1070302
R~N--C~
.
H O
R
N-~ PC15 ~ ;
, . ;
Rl ,Cl
R2~ ,~,J~ N~\ '
R 3 R2 3
H O
R . .,
20 ~ ~\ (C2H51 3O HF4
Rl ~OCH2 3
25 ~=C~
N 1 ,R7
R
` ` ~07030Z
1 This intermediate (I) is then converted to the corre-
spondingly substituted 10-(methylthio)-4H-thlello[3,~
[1,5]benzodiazepine (II) by reaction with methyl sulfate
and an alkaline base in methanol. The latter reaction
is carried out at from 40C. to 100C. for a period of
from about 1/2 hour to 10 hours. The intermediate (II)
is then converted to the corresponding 10-substituted ~`
amino-4,9-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine
(III) by reaction with the appropriate amine at reflux
temperature in acid. The temperature of the reaction
may vary from 100C. to 250C. depending upon the amine.
The reaction is heated from 10 to 120 hours.
Specific compounds included within the scope
of this invention are: 10-(4-Methyl-l-piperazinyl)-4H-
-thieno[3,4-b]~1,5]benzodiazepine; 7-Chloro-4-methyl-
-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzo-
diazepine; 6-Chloro-10-(4-methyl-1-piperazinyl)-4~-
-thieno[3,4-b][1,5]benzodiazepine; 7-Chloro-10-(4-methyl-
-l-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine;
4-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b]-
[1,5]benzodiazepine; 10-Piperidino-411-thieno[3,4-b]-
[1,5]benzodiazepine; 10-(1-Piperazinyl)-4H-thieno[3,4-b]-
[1,5]benzodiazepine; 10-[4-(2-Hydroxyethyl)-1-piper-
azinyl]-4H-thieno[3,4-b]El,5]benzodiazepine; 10-(4-
-Phenyl-l-piperazinyl)-4H-thieno[3,4-b][1,5]benzodi-
azepine; 10-(4-Benzyl-l-piperazinyl)-4H-thieno[3,4-b]-
[1,5]benzodiazepine; 7-Chloro-10-[4-(2-hydroxyethyl)-1-
-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine;
4-Methyl-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5]benzo-
diazepine; 10-[4-(2-Dimethylaminoethyl)-l-piperazinyl]-
.
~07030Z
1 -4H-thieno[3,4-b][l,5]benzodiazepine; 5-Fluoro-10-(4-
-methyl-l-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiaze-
pine; 6-Trifluoromethyl-10-(1-piperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine; 6-Fluoro-4-methyl-10-(4-
-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiaze-
pine; 7-Methoxy-10-(4-methyl-1-piperazinyl)-4H-thieno-
[2,4-b][1,5]benzodiazepine; 6,7-Dichloro-10-(4-methyl
-l-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine;
5-Methoxy-10-(1-piperazinyl)-4II-thieno[3,4-b][l,5]benzo-
diazepine; 6,7-Dimethyl-10-~4-(2-hydroxyethyl)-1-piper-
azinyl]-4H-thieno[3,4-b][1,5]benzodiazepine; 6,7-Dimeth-
oxy-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]-
benzodiazepine; 8-Chloro-10-(1-piperazinyl)-4H-thieno- :~
[3,4-b][1,5]benzodiazepine; 4-Ethyl-10-(4-methyl-1-
-piperazinyl)-4H-thleno[3,4-b][1,5]benzodiazepine;
7-Chloro-4-propyl-10-(4-methyl-1-piperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine; 7-Chloro-4-methyl-10-(1-
-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine;
7-Chloro-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5]benzo-
20 diazepine; 5-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine; 7-Hydroxy-10-(4-methyl-1-
-piperazinyl)-4H-thieno[3,4-b][1,53benzodiazepine;
6-Hydroxy-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b]-
[1,5]benzodiazepine; 10-[4-(3-Dimethylaminopropyl)-l-
-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine;
7-Methylsulfonyl-10-(4-methyl-1-piperazinyl)-4H-~hieno-
[3,4-b][1,5]benzodiazepine; 10-(1-Piperazinyl)-4-ethyl-
-4H-thieno[3,4-b][1,5]benzodiazepine; 4-Ethyl-10-[4-(2-
-hydroxyethyl)-l-piperazinyl]-4H-thieno[3,4-b][1,5]benzo-
diazepine; 7-Nitro-10-(4-methyl-1-piperazinyl)-4H-thieno-
-- 10 --
1070302
1 [3,4-b][1,5]benæodiazepine; and 6-Methylthio-10-(4-
methyl-l-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiaze-
pine.
The compounds of the present invention are ac-
tive analgesics when measured by the "writhing syndrome"
test for analgesic activity as described by Siegmund,
et al., Proc. Soc. Exp. Bio. and Med., 95, 729 (1957),
with modifications. This method is based upon the re-
duction of the number of writhes following the intra-
peritoneal injection of one mg./kg. of body weight ofphenyl p-quinone in male Swiss albino mice weighing
15-25 g. The syndrome is characterized by intermittent
contractions of the abdomen, twisting and turning of the
trunk, and extension of the hind legs beginning 3 to 5
minutes after injection of the phenyl _-quinone. The
test compounds are administered orally at the indicated
dose to groups of 2 mice each, 30 minutes before injec-
tion of the phenyl p-quinone. The total number of
writhes exhibited by each group of mice is recorded for
a 3 minute period commencing 15 minutes after injection
of the phenyl _-quinone. A compound is considered active
if it reduces the total number of writhes in 2 test mice
from a control value of approximately 30 per pair to a
value of 18 or less. Table I summarizes the results of
this test on representative compounds of this invention.
1070302
U~,
~.
h
~'~ ~ o ~ ~ ~
~I S~ ~ O ~ D
0~ . ~ .
Z .
_ ~
~ u~ In
O ~ U~ O ~ 1
a
_
a) . j
~ S'S I s~
Q O II O I a~ N
E~
1 ~ ~
I O
~) ~1 ID rl O ~I N .
~ N ~N ~ N
tC
~ ~ Q
IO a)~D ~L) (L) a) 5~
--- ~ NQ~ N ~ N~ U~
`
. ' . >1
1 ~ O--I O ~I O ~r
~N a) I N I NI N --Q
OId N~1 ~ r-i ~ I I
Ql ~ D ~ a) o ~r
E~ O~
OQ~ ~ ~ ~ ~ I
.) ~1 oa) 1~
Pl N~ '~3 ' J3 ' ~ O
~1 a~ ~ ~ a
Q ~ Q, ,~ ~ Q E~
o I o I I ~ a
_I . I ' I ' I ' I ~ O
a~--~ ~1 ~ o ~ ~ o ~ o
h ~ I ~
I .q ~ o o o ~a o o o--t)
O ~ a) ~ ~ a)
' o ~ y ~ ,PJ
_I ~~r1` ~ C) ~D ~ I` N ~
,
-- 12 --
1070302
1 The compounds of this invention are useful for
the relief of pain and inflammation in warm-blooded ani-
mals. To determine analgesic activity, a modification
of the method of Randall and Selitto [~rch. Int. Pharma-
codyn., 111, 409 (1957)] is used. This test measures
the pain threshold of rats whose paws are made sensitive
to pressure by the injection of 0.1 ml. of a 20% aqueous
suspension of brewers yeast into the plantar surface of
the left hind paw. Constantly increasing force (16
g/second) is applied to the swollen paw using an Anal-
gesy Meter, Ugo Basile. The pressure is cut off at 250
. of force when there is no response (sudden struggle
or vocalization). Control rats treated with starch
vehicle respond to a pressure of about 30 g. Pressure-
-pain thresholds are always recorded t~o hours after
administration of Brewers' yeast. Test compounds are
administered at the same time as the yeast, at an oral
dose of 200 mg./kg. Ratios of treated (T)/control(C)
reaction thresholds are calculated as estimates of anal-
gesic efficacy (degree of analgesia obtainable). Testcompounds are accepted as active when they produce a
100~ elevation of pain (T/C - 1.37). The results of this
test on representative compounds of the present invention
appear in Table II.
Table II
Compound Ratio TjC
10-(4-Methyl-l-piperazinyl)-4H- 1.57
thieno[3,4-b][1,5]benzodiazepine
7-Chloro-4-methyl-10-(4-methyl-1- 1.55
piperaæinyl)-4H-thieno[~,4-b]-
11,5]benzodiazepine diperchlorate
107030Z
1 The compounds of the present invention are
physiologically active on the central nervous system
and show high activity as anti~psychotic or neuroleptic
agents. A useful test for anti-psychotic activity con-
sists of measuring the reduction of spontaneous motor
activity in animals.
Groups of 4 rats are treated orally with the
test compound dissolved or suspended in starch vehicle
at a maximum tolerated dose. At the estimated time of
peak effect, the animals are placed singly into an Ani-
max Activity Counter and the activity of each rat is
recorded over a 5 minute period. The activity counts
are compared to historical or parallel control values to
determine significant increased or decreased locomotor
activyt.
The compound is considered an active depress-
ant if the counts are 50% or less of control values.
Median effective doses (MDD50) (doses which
decrease locomotor activity by 50%) are determined, in
groups of 6 rats, for those compounds deemed active, by
a method of least-squares [D.F. Finney, Statistical
Methods in Biological Assay, Second Edition, Hofner Pub-
lishing Co., New York, 456-457 (1964)]. The effective
dose that causes a 50~ reduction in motor activity
(MDD50), expressed in mg./kg. of body weight, of some
typical compounds of this invention is set forth in
Table III.
- 14 -
1~n030~
l Table III
.
,Co~p,o,und ' ,MDD50 (mg/Kg)
lO-(4-Methyl-l-piperazinyl)-4H- 6.l
thieno[3,4-b][l,5]benzodiazepine
6-Chloro-lO-(4-methyl-l-pipera- 7.7
ziny.l)-4H-thieno[3,4-b][l,5]benzo-
dla zepine
7-Chloro-lO-(4-methyl-l-pipera- 20.
zinyl)-4H-thieno[3,4-b][l,5]benzo-
diazepine diperchlorate
7-Chloro-4-methyl-lO-(4-methyl-l- 25
piperazinyl)-4H-thieno13,4-b]-
[l-,5]benzodiazepine diperchlorate
4-Methyl-lO-(4-methyl-l-pipera- 12
zinyl)-4H-thieno[3,4-b][1,5]benzo-
diazepine
The compounds of the present invention are
physiologically active on the central nervous system and
show high activity as anti-psychotic or neuroleptic
agents. A useful test for anti-psychotic activity con-
sists of measuring ptosis in animals.
Ptosis is defined as closure of the palpebral
; aperture (eyelid) greater than 70%. The compounds to
be tested were administered orally to groups of lO rats
each. Periodically after treatment the rats were gently
placed on the cage top and examined for 90 seconds for
signs of ptosis. This manipulation eliminates spontane-
ous ptosis. The rats were then dropped from a height of
about 18 inchds (exteroceptive stimulation) onto the cage
top for reversibility of ptosis. Reversible ptosis is
defined as less than 70% closure of the palpebral aper-
ture for longer than one minute after the exteroceptive
~ ~70302
1 stimulation and is indicative of neuroleptic activityof the drug administered. This test has been described
by Tedeschi, D. H., "Criteria for the Selection of
Pharmacological Test Procedures Useful in the Evaluation
of Neuroleptic Drugs", Proceedings of the VI International
Congress of the Collegium Internationale Neuropsycho-
pharmacologicum, pp. 145-153 (1968). The results of
this test on representative compounds of the present
invention appear in Table IV, wherein the dose (ED50)
estimated to create reversible ptosis in 50~ of the
animals is given.
Table IV
; ~ompo~nd ~ ED50 ~mg/Kg)
~ ..
10-(4-Methyl-l-piperazinyl)-4H- 13
thienol3,4-b3[1,5]benzodiazepine
7-Chloro-10-(4-methyl-1-pipera- 10
zinyl)-4H-thieno[3j4-b][1,5]benzo-
diazepine diperchlorate
6-Chloro-10-(4-methyl-1-pipera- 17
zinyl)-4H-thieno[3,4-b]l1,5]benzo-
diazepine
The compounds of the present invention exhibit
anti-psychotic activity when measured by the Discrete
Trial Conditioned Avoidance Test.
In this test the compounds are administered
orally to male Long-Evans rats in a universal starch
vehicle. The rats have been pre-conditioned to make a
70% avoidance response.
The rats are placed in individual cages and a
warning tone is sounded every 20 seconds. Each rat has
the opportunity to press a bar which, if done within 5
- 16 -
107030Z
1 seconds, prevents an electric shock through the gri~
floor of the cage and is termed an avoidance response. ~ !
Each rat is given 50 trisls and a score of
avoidance responses is kept. The drug is administered
at various dose levels. Drugs exhibiting anti-psychotic
activity are known to block this avoidance response.
- The effective median dose (ED50) which re-
ducês avoidance response by 50% as compared to controls
is estimated. The results sf such a test are recorded
in Table V.
Table V
. . .. , . .... .. . ___, .
. . . - . .
; ; Co~po~nd ED50 (mg/Kg)
10-(4-Methyl-1-piperazinyl)-4H- 7
thieno[3,4-b][1,5]benzodiazepine
4-Methyl-10-(4-methyl-1-pipera- 17
zinyl)-4H-thieno[3,4-b][1,5]benzO-
diazepine
Chlorpromazine 9
.. . .
The active components of this invention can
be used in compositions such as tablets; the principal
active ingredient is mixed with conventional tableting
ingredients such as corn starch, lactose, sucrose, sorb-
itol, talc, stearic acid, magnesium stearate, dicalciumphosphate, gums, or similar materials as non-toxic
pharmaceutically acceptable diluents or carriers. The
tablets or pills of the novel compositions can be lamin-
ated or otherwise compounded to provide a dosage form
affording the advantage of prolonged or delayed action
,
- 17 -
` ` 1070302
l or predetermined successive action of the enclosed
medication. For example, the tablet or pill can com-
- prise an inner dosage and an outer dosage component,
the latter being in the form of an envelope over the
former. The two componets can be separated by an en-
teric layer which serves to resist disintegration in
- the stomach and permits the inner component to pass
intact into the duodenum or to be delayed in release.
A variety of materials can be used for such enteric
layers or coatings, such materials including a number
of polymeric acids or mixtures of polymeric acids with
such materials as shellac, shellac and cetyl alcohol,
cellulose acetate and the like. A particularly advan-
tageous enteric coating comprises a styrene maleic acid
copolymer together with known materials contributing to
the enteric properties of the coating.
The liquid forms in which the novel composi-
tions of the present invention may be incorporated for
administration include suitably flavored emulsions with
edible oils, such asl cottonseed oil, sesame oil, coco-
nut oil, peanut oil, and the like, as well as elixirs
and similar pharmaceutical vehicles. Sterile suspensions
or solutions can be prepared for parenteral use. Iso-
tonic preparations containing suitable preservatives are
also desirable for injection use.
The term dosage form as described herein re-
fers to physically discrete units suitable as unitary
dosage for warm-blooded animal subjects, each unit con-
taining a predetermined quantity of active component
calculated to produce the desired therapeutic effect in
.; .
.~ ~
- 18 - --
--``` 107V302
l association with the required pharmaceutical diluellt,
carrier or vehicle. The dosage may vary from l mg. to
70 mg. per kg. of warm-blooded animal per day ~referably
in multiple doses. The daily dosage requirement may be
from 50 mg. to 2000 mg. The specification for the
novel dosage forms of this invention are indicated by
characteristics of the active component and the partic-
ular therapeutic effect to be achieved or the limitations
inherent in the art of compounding such an active com-
ponent for therapeutic use in warm-blooded animals as
disclosed in this specification. Examples of suitable
oral dosage forms in accordance with this invention are
tablets, capsules, pills, powder packets, granules,
wafers, cachets, teaspoonfuls, dropperfuls, ampules,
vials, segregated multiples of any of the foregoing and
other forms as herein described.
The following examples describe in detail the
preparation of compounds of the present invention.
Example l
Preparation of 1,3,4,9-Tetrahydro-4-methyl-lOH-thieno-
[3,4-b][1,5]benzodiazepin-lO-one
An aqueous solution of 1.2 g. of N-methyl-_-
-phenylenediamine is made alkaline with excess lN sodium
hydroxide solution and is extracted with toluene. To
the dried toluene extracts (100 ml.) is added 0.8 g. of
methyl tetrahydro-4-oxo-3-thiophenecarboxylate. The
solution is heated under reflux for 3 hours during which
50 ml. of distillate is collected in a Dean-Stark trap.
The toluene solution is concentrated to dryness and the
residue is recrystallized from ethyl acetate to give
~:
- 19 -
10~0302
1 yellow crystals, m.p. 196-198C.
Example 2
Preparation of 4,9-Dihydro-4-methyl-10ll-thiello[3,4-b]-
[1,5]benzodlazepine-10-one
A mixture of 0.5 g. of 1,3,4,9-tetrahydro-4-
-methyl-10~-thieno[3,4-b][1,5]benzodiazepin-10-one and
0.5 g. of sulfur is fused at 160C. + 5 for 1 hour. The
fusion mixture is slurried with chloroform and filtered.
The filtrate is chromatographed on silica gel with ben-
zene:methanol 9:1 to give a solid, which is recrystalli-
zed from methanol-water to give a tan solid, m.p. 224-
-225C. (dec.).
Example 3
Alternative Preparation of 4,9-Dihydro-4-methyl-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-one
To a suspension of 3.8 g. of 1,3,4,9-tetrahy-
dro-4-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one
in 15 ml. of dry pyridine is added, in portions, a total
of 2.18 g. of N-chlorosuccinimide. The resulting solu-
tion is heated on a steam bath for 15 minutes, cooledand diluted with water. The solid is collected and re-
crystallized from methanol, to give a tan solid, m.p.
224-225C. (dec.).
Example 4
Preparation of 4,9-Dihydro-4-methyl-9-[2-(4-phenyl-1-
-piperazinyl~e~ l]-lOH-thieno[3,4-b][1,5]benzodiazepin-
-10-one, dihydrochloride
A mixture of 0.13 g. of 55% sodium hydride-
-mineral oil dispersion and 0.5 g. of 4,9-dihydro-4-
-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one in 25
- 20 -
1ff7030Z
1 ml. of dry dimethylformamide is stirred at room temper-
ature for 0.5 hour. To the mixture is added 0.8 g. of
N-(2-bromoethyl)-N'-phenylpiperazine and stirring is
continued for 18 hours. The reaction mixture is cooled,
quenched with water and extracted with chloroform. The
dried chloroform extracts are concentrated to a brown
oil, which is purified by preparative thin layer chroma-
tography (tlc) on silica gel with 2:1 benzene:ethyl ace-
tate as eluent. The oily product is converted to the
dihydrochloride salt and recrystallized from ethanol-
-ether to give a white solid, m.p. 180-183C. (dec.).
Example 5
Preparation of 4-Ethyl-1,3,4,9-tetrahydro-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one
An aqueous suspension of 4.3 g. of N-ethyl-_-
-phenylenediamine hydrochloride is made alkaline with
excess sodium hydroxide solution and is extracted with
toluene. To the dried toluene extracts (200 ml.) is add-
ed 2.4 g. of methyl tetrahydro-4-oxo-3-thiophenecarboxyl-
ate. The solution is heated under reflux for 3 hours,
during which 100 ml. of distillate is collected in a
Dean-Stark trap. The toluene solution is concentrated
to dryness and the residue is recrystallized from ethyl
acetate go give yellow crystals, m.p. 195-197C.
Example 6
Preparation of 4,9-Dihydro-4-ethyl-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-one
To a suspension of 0.246 g. of 4-ethyl-1,3,4,9-
-tetrahydro-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one
in 2 ml. of dry pyridine is added in portions a total of
1070302
1 0.133 g. of N-chlorosuccinimide. The resulting solution
is heated on a steam bath for 15 minutes, cooled and
- diluted with water. The solid is collected and recrys-
tallized from methanol-water to give off-white crystals,
m.p. 201-202C.
Example 7
Preparation of 1,3,4,9-Tetrahydro-4,6,7-trimethyl-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-one
An aqueous suspension of 4.7 g. of N-methyl-
-4,5-dimethyl-o-phenylenediamine dihydrochloride is made
alkaline with sodium hydroxide solution and is extracted
with toluene. T o the dried toluene extracts (400 ml.)
is added 2.25 g. of methyl tetrahydro-4-oxo-3-thiophene-
carboxylate. The solution is heated under reflux for 3
hours, during which 250 ml. of distillate is collected
in a Dean-Stark trap. The solution is cooled and the
solid which separates is collected and recrystallized
from ethyl acetate to give yellow crystals, m.p. 250-
-252C. (dec.).
Example 8
Preparation of 4,9-Dihydro-4,6,7-trimethyl-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one
To a suspension of 0.40 g. of 1,3,4,9-tetra-
hydro-4,6,7-trimethyl-lOH-thieno[3,4-b][1,5]benzodiaze-
pin-10-one in 3 ml. of dry pyridine is added, in portions,
a total of 0.21 g. of N-chlorosuccinimide. The result-
ing solution is heated on a steam bath for 15 minutes,
cooled and diluted with water. The solid which separates
is collected and recrystallized from methanol to give
~ 30 yellow crystals, m.p. 260-262C.
:' ,
- 22 -
1070302
1 Example 9
Preparation of 6,7-Dichloro-1,3,4,9-tetrahydro-4-methyl-
-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one
.
- A solution of 2.7 g. of N-methyl-4,5-dichloro-
-o-phenylenediamine and 1.85 g. of r,lethyl tetrahydro-4-
-oxo-3-thiophenecarboxylate in 150 ml. of toluene is heat-
ed under reflux for 3 hours during which 100 ml. of dis-
tillate is collected in a Dean~Stark trap. The solution
is cooled and the solid which separates is recrystallized
from ethyl acetate to give yellow crystals, m.p. 281-
-283C.
Example 10
Preparation of 6,7-Dichloro-4,9-dihydro-4-methyl-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-one
To a suspension of 0.40 g. of 6,7-dichloro-
-1,3,4,9-tetrahydro-4-methyl-lOH-thieno[3,4-b][1,5]-
benzodiazepin-10-one in 2.7 ml. of dry pyridine is added,
in portions, a total of 0.18 g. of N-chlorosuccinimide.
The resulting solution is heated on a steam bath for 15
- 20 minut~s, cooled and diluted with water. The solid which
separates is collected and recrystallized from methanol-
-water to give off-white crystals, m.p. 270-272C. (dec.).
Example 11
Preparation of 1,3,4,9-Tetrahydro-lOH-thieno[3,4-b][1,5]-
benzodiazepin-10-one
A solution of 0.4 g. of methyl tetrahydro-4-
-oxo-3-thiophenecarboxylate and 0.27 g. of o-phenylene-
diamine in 35 ml. of toluene is heated under reflux for
2.5 hours during which 15 ml. of distillate is collected
in a ~ean-Stark trap. The solution is cooled and the
- 23 -
1070302
1 precipitate is collected. Recrystallization from di-
methylformamide-water gives a yellow solid, m.p. 216-
-218C.
In a similar fashion 4-fluoro-_-phenylenedi-
5 amine is condensed with methyl tetrahydro-4-oxo-3-thio- ;~
phenecarboxylate to give a mixture of 7-fluoro- and
6-fluoro-1,3,4,9-tetrahydro-lOH-thieno[3,4-b][1,5]benzo-
diazepin-10-one.
Employing the same general procedure the fol-
lowing starting materials produce their corresponding
mixture of products:
; 25 :
.~ .
~ 30
:
- - 24 -
- 1070302
o
O O ~-rl I
~ a) o
O O ` N ~1 5~ a)` N
h S~ I o
'1~ 1 0 ~1a) o `-~1
0 ~ ~O ~ l Ol O
Ola O rC N~ ~ 1 N
O~ O ` I~1
o ~ o a) ~
Q S~ o~ o~ rlO R
` ~ ~ ~I N
~7 N 1~ N,I Q ~ N~ N~: O~ ,4
0~D ~ ~ O~ O,5: Q I
X N X N ~ I N~ N~) ,~
O ~ O ~: ~ O O ~ I) U O
R 'C1 Q1~ ~ O QO QI ~1~:: a)
o ,~ o
~1 ~ ~ ~ I ~ O
~r ~ o o ~ 1 O~1 0
~ ~ O ~ I ~ ~ ~ ~~ ~
X ~ X ~ ~ ~ O ~I ~~ ~1~ ~ .,,*
O OO O ~1 ~ ~ S~ O O O
o~ o
o~~ O E~ a~ o
S rl
o l ~ ~ ~ O I
~ ~ ~I ~ ~ s
G~ ~ S ~ ~ I
s s ~ a~ ~: o l
g~ s ~ I o
~ s o
ol ol o
o l I s
ol ~ u,
X X ~ o I ~I
o o ~ ~ ~ o
s ~ ~ ~ o s~ s
h
Ei S 1
l ~
``` 1070302
1 Example_12
Preparation of 4,9-Dihydro-10~-thieno[3,4-b]l1,5]benzo-
diazepin-10-one
A solution of 1.1 g. of 1,3,4,9-tetrahydro-lOH-
-thieno[3,4-b~[1,5]benzodiazepin-10-one and 0.9 g. of
N-bromosuccinimide in 30 ml. of dimethylformamide is
stirred for 1 hour at room temperature, diluted with
200 ml. of water and cooled. The precipitate is collect-
ed and recrystallized from methanol-water to give tan
crystals, m.p. 218-220C. (dec.).
In a similar fashion the mixture of 7-fluoro-
and 6-fluoro-1,3,4,9-tetrahydro-lOH-thieno[3,4-b][1,5]-
benzodiazepin-10-one is treated with N-bromosuccinimide
to give 7-fluoro- and 6-fluoro-4,9-dihydro-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one.
Employing the same general procedure the fol-
lowing staiting materials produce their corresponding
mixture of¦products:
I~ ,
.
- 26 -
--` 107Q30~
o o o , ~,
, , o ~ .,, .:
s s ~-,, a) o I I a
,1 ~ o a~ ~
I ~ ` o
O O ~ ~ ~ O I O
~ ~a o I -~ O ~1 1
O O O O ~1 ~ ~ I
~; N I ~0 1 0~ ~ ~ . `
s O s a~ o Q~ a~O a) ~ ~ ~ N
O ~ O ,1 U) S O ~ O O ~ ~1 -~
O ~ O -rl ~~ OS O S N f: O
~rl ~ ~1 ~ I~ ~1CS~ -rl S O I Q
X P~X P~ ~ N ~7
O O O ~D ~ `O Q)
S N ~I N ~ l N I N
0 ~ 0 0~0 0 0 0 1
O I O ~ 0~1 0r l O
N ~ N ~ rlI N~ N
1 S ~a ~ ~ ~ r
~: Q ~ Q O I~ R Q I Q O ~
0 ~ 0 r~ ~ ~ ~ o I
Ln Ul O 00 1r~ 1 ~ ~1 0
h ~1~ 0 ~ S ~
X ~~ X ~ ~ OO ~ I ~ ~ ~ 1~1 rl
t~ ~ O ~ ~ O ~ ~ 0 ~1S
Q S~ R ~ 'OO QS~ Q S ~ S ~
~3 ` S ` ~ ~ S ~ O
1` 1 ~ 1`
o a~~ 0 1
o ~ O ~ ~ N
1 0 a~ o o o --1 o
a) o S I N
~ rl ~ ~) 0 0
I o ~ e ~ ~
o o x ~ ~ Q~ o o ~ ~ ~) ~ D S N
S ~ S N S~ 3 ~ N ~ I-J O
1) 0 0 0o a) ~u o ~ I 1 0 ~ ~ Q
O ~ ~ O I ~ ~1-1 ~ 0 ~ ~) S-l ~ ~) U')
~D I O~D I O ~ ~) N I I O ~ O ~ :~ N ~ a~ r l
m,1 ~ a) 0s ~
o I ~a o I ~ o~ a~ o I ~ 0 a) ç~
O I h Q O ` 51
0 1 ~10 1 ~ 1~ S I o ~ ~ 4-1 ~ I
O ~ O ~ O ~0 0 ~ ~ ~ O rl a.) Lr
~ ra N :~ N O ~ ~1 1 ~ N }~ I ~) I ~ U~ I
X ~1 0X ~1 0 ~O ~1 0 1 ~ ~ ~ ~ ~I ~ ~
O ~ rlO S~rl ~l I ~ ~ S-~l O ~ rl ~ ~ ~ ~ O G)
.C 0 ~~-~ 0 '~ 41 ~1 ~ O t~l ~a s-, I P, s ~r ~ S 1~
h O ~ ~1 0 ~1 ~ I S ~ O ~ O au IJ ~ I ~ O ~J O
0 ~ N ~ ~ N ~ S ~~1 ~) N rl ~ N ~1) ~ el~ Cl ~1 ~rl I
s ~ 0 ~ ~ ~ e ~I so
r~ I Q 1` I Q ~ ~ ~ In I R r` S ~ I~ I ~ [~ t~ I I
-- 27 --
10'703Q2
1 Example 13
Preparation of 4,9-Dihydro-9-methyl-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-one
To a stirred mixture of 0.84 g. of 4,9-dihydro-
-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one and 0.18 g.
of 55% sodium hydride-mineral oil dispersion in 25 ml.
- of dimethylformamide is added 0.3 ml. of methyl iodide.
The reaction mixture is stirred for 2.5 hours, cooled,
diluted with water and filtered. The solid product is
recrystallized from methanol-water to give pale yellow
crystals, m.p. 195-198C.
Example 14
Preparation of 4-Benzyl-4,9-dihydro-9-methyl-lOH-thieno-
[3,4-b][1,5~benzodiazepin-10-one
To a stirred solution of 0.18 g. of 57~ sodium
hydride-mineral oil dispersion in 25 ml. of dimethyl-
formamide is added 0.92 g. of 4,9-dihydro-9-methyl-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-one and 0.8 ml. of
benzyl bromide. The mixture is stirred at room temper-
ature for 3.5 hours, quenched by dropwise addition of
water, diluted with 200 ml. of water and extracted sev-
eral times with chloroform. The chloroform extracts
are dried over magnesium sulfate and concentrated under
reduced pressure to give an amber oil, which crystallizes
on trituration with methanol. Recrystallization from
aqueous methanol and then from ethyl acetate gives off-
-white crystals, m.p. 151.5-153C.
Example 15
Preparation of 6-Chloro-4,9-dihydro-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-one
- 28 -
107030Z
1 To a solution of 1.6 g. of a mixture of 7-
-chloro- and 6-chloro-1,3,4,9-tetrahydro-lOH-thieno-
[3,4-b][l,S]benzodiazepin-10-one (prepared by the con-
densation of 4-chloro-_-phenylenediamine with methyl
tetrahydro-4-oxo-3-thiophenecarboxylate in toluene at
reflux temperature) in 12 ml. of pyridine, is added,
portionwise, 0.85 g. of N-chlorosuccinimide. A 3 ml. ;.-~
portion of pyridine is added and the mixture is heated
on a steam bath for 15-20 minutes. The mixture is
cooled and diluted with water resulting in the forma-
tion of golden crystals which are collected by filtra-
tion. These are recrystallized from methanol yielding
0.39 g., m.p. 279-281C.
The filtrate from the water addition is pro-
cessed as described in Example 16.
Example 16
; Preparation of 7-Chloro-4,9-dihydro-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-one
The aqueous filtrate, prepared as described
in Example 15, is diluted further with water resulting
in the formation of a yellow solid. This solid is re-
crystallized from aqueous methanol yielding 0.4 g., m.p.
197-198C.
Example 17
Preparation of 7-Chloro-4,9-dihydro-4-methyl-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one
A 532 mg. portion of 7-chloro-1,3,4,9-tetra-
hydro-4-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one
(prepared by the reaction of 4-chloro-2-amino-N-methyl-
aniline and 3-keto-4-carbomethoxy tetrahydro thiophene
- 29 -
1070302
1 at reflux temperature in toluene) is suspended in 4 ml.
of pyridine. A 276 mg. portion of N-chlorosuccinimide
is added in portions while rinsing with 1 ml. of pyri-
dine. The mixture is heated on a steam bath for 15-20
5 minutes, cooled and diluted with water yielding a brown
solid which is recrystallized twice from methanol yield-
ing 0.25 g., m.p. 244-246C.
Example 18
Preparation of 4,9-Dihydro-lOH-thieno[3,4-b][1,5]-benzo- r
10 diazepine-10-thione
.
A mixture of 0.76 g. of 4,9-dihydro-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one and 1.0 g. of phosphorus
pentasulfide in 10 ml. of dry pyridine is stirred and
heated under reflux for 4 hours. The reaction mixture
15 is concentrated to dryness and the oily residue is stirred
for 18 hours with 25-30 ml. of lN sodium carbonate solu-
tion (pH 7-7.2). The solid thus obtained is collected,
washed with water and recrystallized from methanol to
give orange crystals, m.p. 210-212C.
In a similar fashion 7-fluoro-4,9-dihydro-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-one is treated with
phosphorus pentasulfide to give 7-fluoro-4,9-dihydro-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-thione.
Employing the same general procedure the fol-
lowing starting materials produce the listed products:
- 30 -
10'~0302
o
o ,~ I N ... 7"
,~ N 11 ~-- ~
I a~ ,-1 I Q
O ~ ` I
~1 ~r O
~ ~ I O
O O O '~
O ~ .~ O O
a~ o ~ ~1
rl rl O a~
~ O ~ .~ ~ ~ O
O O ~ ~ I O S ~
~1 a~ ~1 a) ~ ~o o ~ ~ 1 ~ o
O O O O ~ O I O~1 ~1 01
rl h rl ` ~10 -rl I~ rl ~ ~1 0
I ~ ~ Orl S ` IS~
~1 O ~i o~ Q,S o:~ oa~ o~1 ~ S o
~) N~ I~1 S~r I ~ N~ ~:
~ rl I IO rl W -l~ I
er Q, ~r Q, O ~~ Q~cn o~1 ~ ~1 ~ ` o
al I Ql h O~r al ` ~IS a) ~ O ~r ~1
~ N :~ N O N I N~ I ~ NU~ N
x la X 1~ o 1
O -1 0~ O~
o ~ o ~ o~ a~ ~ o~ ~ ~ a)
0 N ~ N .4 1~1~-1 Nrl N - 0 N 0 Il~ al N
t ~ / ~ \ ~ r ' r ~ ~
~ I I I
O ~ O ~ o
0 ~ I ~ 1 o l o
~ O O O I Q,~ O O O 0~ O
S S O ~I N rl 0 O 1:: N O N rl O
~ ~1 ~ ~1~ ~S ~1~1--IO ~ d S .~
0~,1 0-~ O m-,~ o o ~ o ~ rl
~I Q, ~ N O ~ N rl N O p~
O N O N 0~ a)I N-1 N ~ ID I 0 I N
`R O ~ .C Q l~ Q o (d
~ O ~ O ~1 ` ~0 ~ O I ` I ` ~0
rl N rl N:~--I .C N ~ N ~ ~_1 ~1 ~I S N
a~ ,4 a~ Q a~ Q I R ~ R I R O R I Q
X ~ X--~ ~ ~ O ~ I ~ ~ _1
o --- o ,~~1 o a)~ ~ o ~ ~ o ~ ~ o ~
5: Q h R 4~ O QS~ QS 1~ S Q
I ~ I ~1 0 o~ I~ I~ a~ o ~ o o ~ I
~ ~ ~ ~ ~ '~ ` f3So El ~: E3 `
- 31 -
13QZ
1 Example 19
Pre aration o~ 10-(Meth lthio)-4H-thieno[3,4-b][1,5]-
P Y
benzodiazepine
To a stirred suspension of 1.3 g. of 4,9-di-
hydro-lOH-thieno[3,4-b][1,5]benzodiazepin-10-thione in
15 ml. of dioxane is added simultaneously at ~ 40C.,
a solution of 1.9 g. of potassium hydroxide in 10 ml~
of methanol and 2.2 g. of methyl sulfate. After addi-
tion is complete, stirring is continued for 1.5 hours.
10 The mixture is diluted with methanol and filtered. The ~;
filtrate is concentrated to about 20 ml., diluted with
water and filtered. The sticky precipitate is dissolv-
ed in chloroform; the chloroform solution is dired and
concentrated to give a solid, which is recrystallized
from methanol-water to give deep yellow crystals, m.p.
- 128.5-130C.
In a similar manner 7-fluoro-4,9-dihydro-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-thione is reacted
with potassium hydroxide and methyl sulfate to give
7-fluoro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzo-
diazepine.
Employing the same general procedure the fol-
lowing starting materials produce the listed products:
- 32 -
~.070302
O r_ I N
Q ~ ~ Q a)
,_ ~ el~ I 0 ~1 I Q
R ~ ~r ~
O ~ ` I ~ ,1
O
Q ~
rl Q ~ ~ ~D Q
I Q ~ rl
~r I O
-- m
o o ~r ~ ~ m
O ~ rC ~r o
o
rl rl O ~ ~ I ~ a.
m o
m m ,~
~ 1 o ~I ~
~r m r~
o o a) _ I ~ ~
O _ ~ ~ O
,, ,1 o ~ ~ ~ ' a) '
s ~
~ s l ~ ~ ~
-- a1 .IJ N ~ N E3
O-rl 0~ O rl~-~1 1
I ~ O ~:10 ~ I ri ~ 1 0
o _I ~ o .C a~~ o ~
N ~ N O N I N ~1 0 ~ NUl N I O
X 1~ X ~ O (~ I ~:~I tl1 ~1 ~ ~ 1
O -rl O -rl~1 ~ S~ -rl 0 -~1~-~1 >1 a~ ~ ~1
)~ ~IQ 0~ ~ ~ S~ ~Q ~C
O ~ O ~ 1 0 ~ QJ~ O ~ r~
o~ N ~ N~ 10 ~I N ~I NO N a) u~ al N
D .4 1~ R u~ Q ~ D Q ~ ~ ,~ rO
C C iC
S O S O ~-1 O N a~ m NO N rl O
~ ~ ~ ,1 ~ N ~ I O ~ S ~
Om.~ 0.~ s~ Qm ~o ~ o ~aO s ~o m-~
~ O N m ~, ~ N,1 N O Q,
O N O N ~ ~ I aJ ,I N ~ I N
~ O Q I Id S Q~ ~ O ~
.5 ON '1 N ~ I ~S ~1 ~ ON a~ I ,1 S ON
S ~ ~~ ~ S ~
~ Sa~ , o 1
X ~-- X ~ 1 ~10--~ o I ~ ~1 ~ O ~ ~ O ~1
a) o ~ I s I ~ o ,~ o ~ ~ ~ o ~1 ~1 0 ~
j~ R ~ Q ~ O ~ S~ R ~:: S ~: S S~ ~ S S~ Q
~s s ~s JJO a) ~so ~ ~s ~.co ~so
-- 33 --
107030Z
1 Example 20 r
Preparation of 10-(4-Methyl-l-~iperazil~yl)-4ll-tl~iello-
[3,4-b][1,5]benzodiazepine
A solution of 1.0 g. of 10-(methylthio)-4H-
-thieno[3,4-b][1,5]benzodiazepine in 5 ml. of N-methyl-
piperazine is treated with 2-3 drops of glacial acetic -
acid and heated under reflux for 4 days. The solution
is concentrated to dryness and the residue is warmed
with dilute acetic acid. The acidic solution is filter-
10 ed, cooled and made alkaline with concentrated ammonium - -~
hydroxide. The precipitate is collected, washed with
water and recrystallized from acetone-petroleum ether
(30-60C.) to give yellow crystals, m.p. 197.5-199C.
In a similar manner 7-fluoro-10-(methylthio)-
-4H-thieno[3,4-b][1,5]benzodiazepine is reacted with
N-methylpiperazine to give 7-fluoro-10-(4-methyl-1-
-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine and
7-methoxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzo-
diazepine gives 7-methoxy-10-~4-methyl-1-piperazinyl)-
-4H-thieno[3,4-b][1,5]benzodiazepine.
Example 21
Preparation of 10-(1-Piperazinyl)-4H-thieno[3,4-b][1,5]-
benzodiazepine
A bomb charged with 2.5 g. of 10-(methylthio)-
-4H-thieno[3,4-b][1,5]benzodiazepine, 8.6 g. of piper-
azine, and three drops of acetic acid is placed in an
oil bath and heated at 155-160C. for 4 days. The
bomb is then cooled and the contents are dissolved in
2N acetic acid. The solution is filtered and the fil-
trate is made alkaline with ammonium hydroxide and ex-
- 34 -
1 tracted with chl~Q70rm. The extracts are dried, filt-
ered and evaporated to give a yellow solid. Recrystal-
lization from ethanol gives the product as light tan
crystals which melt at 228-231C. (dec.).
Example 22
Preparation of 10-(Piperidino)-4H-thieno[3,4-b][1,5]-
benzodiazepine
A solution of 0.7 g. of 10-(methylthio)-4H-
-thieno[3,4-b][1,5]benzodiazepine in 5 ml. of piperidine
- 10 is treated with a drop of glacial acetic acid and heated
under reflux for 4 days. Excess piperidine is removed
under reduced pressure and the oily residue is warmed
with dilute acetic acid and filtered. The filtrate is
cooled and made alkaline with concentrated ammonium hy-
droxide to give a yellow solid. Recrystallization fromacetone-petroleum ether (30-60C.) gives yellow crystals,
m.p. 157-159C.
Example 23
Preparation of 4,9-Dihydro-4-methyl-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-thione
A mixture of 0.4 g. of 4,9-dihydro-4-methyl-
-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one and 0.5 g.
of phosphorus pentasulfide in 5 ml. of dry pyridine is
stirred and heated under reflux for 4 hours. The reaa-
tion mixture is concentrated to dryness and the residueis stirred with 10 ml. of lN sodium carbonate solution
for 18 hours. The precipitate is collected, washed with
water and recrystallized from methanol to give gold crys-
tals, m.p. 203-204C.
10;'0302
,
1 Example ~4
Preparation of 4-Meth~l-10-(methylthio)-4ll-thiotlol3,4-b]-
[1,5]benzodiazepine
To a stirred suspension of 0.7 g. of 4,9-di-
- 5 hydro-4-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-
-thione in 10 ml. of dioxane is added dropwise and sim-
ultaneously at 30-40C., a solution of 0.95 g. of potas-
sium hydroxide in 10 ml. of methanol and 0.8 ml. of
methyl sulfate. After addition is complete, the mixture
is stirred for 3 hours, diluted with methanol and filt-
ered. The filtrate is concentrated to about 20 ml., di-
luted with water and extracted with chloroform. The
chloroform solution is concentrated to give a solid,
which is recrystallized from methanol-water to give
orange~crystals, m.p. 113-115C.
Example 25
Preparation of 4-Methyl-10-(4-methyl-1-piperazinyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
A solution of 1.2 g. of 4-methyl-10-(methyl-
thio) 4H-thieno[3,4-b][1,5]benzodiazepine in 6 ml. of
N-methylpiperazine is treated with 2-3 drops of glacial
acetic acid and heated under reflux for 4 days. The so-
lution is concentrated to dryness and the residue is
warmed with dilute acetic acid. The acidic solution is
filtered, cooled, and made alkaline with concentrated
ammonium hydroxide solution. The precipitate is collect-
ed, washed with water and dissolved in chloroform. The
chloroform solution is dried and concentrated to an oil,
which slowly crystallizes. Recrystallization from eth-
anol gives yellow crystals, m.p. 83-85C.
- 36 -
~L07C~302
1 Example 26
Preparation of a rnixture of 6-Chloro-1,3,4,9-tetrahydro-
-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one and 7-Chloro-
-1,3,4,9-tetrahydro-lOH-thieno[3,4-b][1,5]benzodiazepin-
-10-one
A solution of 0.4 g. of methyl tetrahydro-4-
-oxo-3-thiophenecarboxylate and 0.36 g. of 4-chloro-_-
-phenylenediamine in 20 ml. of toluene is heated under
reflux for 3 hours, cooled and filtered. The solid ob-
tained is recrystallized from dimethylformamide to givea yellow solid, m.p. 233-235C. (dec.).
Example 27
Preparation of 6-Chloro-4,9-dihydro-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-one and 7-Chloro-4,9-dihydro-lOH-
-thieno[3,4-b][l,5]benzodiazepin-10-one
To a suspension of 1.5 g. of the mixture of
6-chloro-1,3,4,9-tetrahydro-lOH-thieno[3,4-b][1,5]benzo-
diazepin-10-one and 7-chloro-1,3,4,9-tetrahydro-lOH-
-thieno[3,4-b][1,5]benzodiazepin-10-one (prepared as des-
cribed in Example 26) in 15 ml. of dry pyridine is added,in portions, 0.8 g. of N-chlorosuccinimide. The result-
ing solution is heated on a steam bath for 15-20 minutes,
cooled and diluted with water. The precipitate is col-
lected and recrystallized from methanol to give deep
gold crystals, m.p. 279-281C., which are pure 6-chloro-
-4,9-dihydro-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one.
The methanol filtrate is diluted with water to give a
yellow solid, m.p. 197-198C. which is pure 7-chloro-
-4,9-dihydro-lOH-thieno[3,4-b~[1,5]benzodiazepin-10-
-one.
- 37 -
1070302
1 Example 28
Preparation of 7-Chloro-4,9-dihydro-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-thione
A mixture of 0.88 g. of 7-chloro-4,9-dihy~ro-
-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one and 1.0 g.
of phosphorus pentasulfide in 10 ml. of dry pyridine is
stirred and heated under reflux for 4 hours. The mix-
ture is concentrated to dryness and the residue is
stirred in 20 ml. of lN sodium carbonate solution (pH
7-7.2) for 18 hours. The precipitate is collected,
washed with water and recrysta-lized from methanol-
-water to give a deep yellow sol~d, m.p. 197-198.5C. ;~
(dec.).
Example 29
Preparation of 7-Chloro-10-(methylthio)-4H-thieno[3,4-b]-
[1,5]benzodiazepine
To a stirred suspension of 0.8 g. of 7-chloro-
-4,9-dihydro-lOH-thieno[3,4-b][1,5]benzodiazepine-10-
-thione in 10 ml. of dioxane is added dropwise and sim-
ultaneously at 30-40C., a solution of 0.95 g. of po-
tassium hydroxi-e in 10 ml. of methanol and 0.3 g. of
methyl sulfate. After addition is complete, the reac-
tion mixture is stirred for 3 hours, diluted with meth-
anol and filtered. The filtrate is concentrated to 20
ml., diluted with water and extracted with chloroform.
The chloroform solution is concentrated under reduced
pressure to give a solid, which is recrystallized from
methanol-water to give yellow crystals, m.p. 111-113C.
Example 30
Preparation of 7-Chloro-10-(4-methyl-1-piperazinyl)-4H-
- 38 -
107()302
1 -thieno[3,4-b][1,5]benzodiazepine diperchlorate
A solution of 0.9 g. of 7-chloro-10-(methyl-
thio)-4H-thieno[3,4-b][1,5]benzodiazepine in 4.5 ml. of
N-methylpiperazine is treated with 2-3 drops of glacial
acetic acid and heated under reflux for 4 days. The so-
lution is concentrated to dryness and the residue is
warmed with dilute acetic acid. The acidic solution is
filtered, cooled and made alkaline with concentrated
ammonium hydroxide. The sticky precipitate is collected
and dissolved in chloroform. The dried chloroform so-
lution is concentr ated under reduced pressure to give
7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b]-
[1,5]benzodiazepine as an oil. An ethanolic solution of
the oil is treated with 70~ perchloric acid and diluted
with water. The precipitate is recrystallized from
methanol to give yellow crystals, m.p. 268-270C. (dec.).
Example 31
Preparation of 6-Chloro-4,9-dihydro-lOH-thieno[3,4-b]-
[1,5]benzodia~epine-10-thione
A mixture of 0.88 g. of 6-chloro-4,9-dihydro-
-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one and 1.0 g.
of phosphorus pentasulfide in ln ml. of dry pyridine
is stirred and heated under reflux for 4 hours. The re-
action mixture is concentrated to dryness and the resi-
due is stirred with 20 ml. of lN sodium carbonate solu-
tion (pH 7-7.2) for 18 hours. The precipitate is collect-
ed, washed with water and recrystallized from methanol
to give an orange solid, m.p. 235-237C. (dec.).
Example 32
Preparation of 6-Chloro-10-(methylthio)-4H-thieno[3,4-b]-
- 39 -
10~0302
1 [1,5]ben~odiazepine
To a stirred suspension of 0.7 ~. of 6-chloro-
-4,9-dihydro-lOH-thieno[3,4-b][1,5]benzodiazepin-10-
-thione in 10 ml. of dioxane is added dropwise and simul-
taneously at 30-40C., a solution of 0.95 g. of potas-
sium hydroxide in 10 ml. of methanol and 0.8 g. of methyl-
sulfate. After addition is complete, the mixture is
stirred for 3 hours, diluted with methanol and filtered.
The filtrate is concentrated to 20 ml. and diluted with
water. The precipitate is collected, washed with water
and recrystallized from methanol-water to give yellow ~;
crystals, m.p. 152-154C.
Example 33
Preparation of 6-Chloro-10-(4-methyl-1-piperazinyl)-4H-
lS -thieno[3,4-b][l,5]benzodiazepine
A solution of 0.7 g. of 6-chloro-10-(methyl-
thio)-4H-thieno[3,4-b][l,S]benzodiazepine in 3.5 ml. of -
N-methylpiperazine is treated with 1-2 drops of glacial
acetic acid and heated under reflux for 4 days. The so-
lution is concentrated to dryness and the residue is
warmed with dilute acetic acid. The acidic solution is
filtered, cooled, and made alkaline with concentrated
ammonium hydroxide. The precipitate is collected, wash-
ed with water and recrystallized from acetone-petroleum
ether (30-60C.) to give yellow crystals, m.p. 148-
-149C. (dec.).
Example 34
Preparation of a mixture of 7-Chloro-1,3,4,9-tetrahydro-
-4-methyl-lOH-thieno[3,4-b][l,5]benzodiazepin-10-one and
6-Chloro-1,3,4,9-tetrahydro-9-methyl-lOH-thieno[3,4-b]-
- 40 -
1(1~703C)2
: `
[1,5]benzodiazepln-10-one
A solution of 2.~ g. of methyl tetrallydro-4-
-oxo-3-thiophenecarboxylate and 4.0 g. of 5-chloro-2-
-methylaminoaniline in 200 ml. of toluene is heated un-
der reflux for 3 hours, during which 100 ml. of distil-
late is collected. The solution is cooled and the solid
is collected and recrystallized from ethylacetate to
give a yellow solid, m.p. 233-235C. (dec.).
Example 35
Preparation of 7-Chloro-4-methyl-4,9-dihydro-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one
To a suspension of 0.53 g. of the mixture of
7-chloro-4-methyl-1,3,4,9-tetrahydro-lOH-thieno[3,4-b]-
[1,5]benzodiazepin-10-one and 6-chloro-9-methyl-1,3,4,9-
-tetrahydro-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one
(prepared as described in Example 34) in 5 ml. of dry
pyridine is added, in portions, 0.27 g. of N-chlorosuc-
cinimide. The resulting solution is heated on a steam
bath for 15-20 minutes, cooled, diluted with water and
filtered. The solid is recrystallized from methanol to
give a yellow solid which consists of the single isomer
of the title, m.p. 244-246C. (dec.).
Example 36
Preparation of 7-Chloro-4-methyl-4,9-dihydro-lOH-thieno
~3,4-b][1,5]benzodiazepin-10-thione
A mixture of 0.5 g. of 7-chloro-4-methyl-4,9-
-dihydro-lOH~thieno[3,4-b][1,5]benzodiazepin-10-one and
0.5 g. of phosphorus pentasulfide in 5 ml. of dry pyri-
dine is stirred and heated under reflux for 4 hours. The
mixture is concentrated to dryness and is stirred with 10
- 41 -
` 1070302
1 ml. of lN sodium carbonate solution for 18 hours. The
precipitate is collected, washed wlth water and recrys-
tallized from methanol to give a yellow solid, m.p.
238-240C.
Example 37
Preparation of 7-Chloro-4-methyl-10-(methylthio)-4H-
-thieno[3,4-b][l,5]benzodiazepine
To a stirred suspension of 1.1 g. of 7-chloro-
-4-methyl-4,9-dihydro-lOH-thieno[3,4-b][1,5]benzodiaze-
pin-10-thione in 15 ml. of dioxane is added dropwise and
simultaneously at 30-40C., a solution of 1.3 g. of
potassium hydroxide in 15 ml. of methanol and 1.1 g. of
methyl sulfate. After addition is complete, the mixture !;
is stirred for 3 hours, diluted with methanol and filt-
ered. The filtrate is concentrated to 20 ml., diluted
with water and the precipitate is collected. Recrystal-
lization from methanol-2ater gives deep yellow crystals, - ;
m.p. 156-158C.
Example 38
Preparation of 7-Chloro-4-methyl-10-(4-methyl-1-piper-
.
azinyl)-4H-thieno[3,4-b][l,5]benzodiazepine diperchlorate
A solution of 0.7 g. of 7-chloro-4-methyl-10-
-(methylthio)-4H-thieno[3,4-b][l,S]benzodiazepine in 3.5
ml. of N-methylpiperazine is treated with 1-2 drops of
glacial acetic acid and heated under reflux for 4 days.
The solution is concentrated to dryness and the residue
is warmed with dilute acetic acid. The acidic solution
is filtered, cooled and made alkaline with concentrated
ammonium hydroxide. The sticky precipitate is collected
- 30 and dissolved in chloroform. The dried chloroform solu-
- 42 -
1~)70302
1 tion is concentrated under reduced pressure to ~ivc an
- oil. An ethanolic solution of the oil is treated with
70% perchloric acid and is diluted with water. The pre-
cipitate is collected and recrysta-lized from ethanol
to give a white solid, m.p. 212-215C. (dec.).
Example 39
Preparation of 7-Methylthio-10-[4-(2-hydroxyethyl)-1-
-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine
A solution of 7,10-bis(methylthio~-4H-thieno-
[3,4-b][1,5]benzodiazepine in excess of N-(2-hydroxy-
ethyl)-piperazine and glacial acetic acid is heated at
140-160C. for 2 days. The solution is poured into
water and the product is collected.
Example 40
Preparation of 6-Nitro-10-(4-benzyl-1-piperazinyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
; A solution of 6-nitro-10-(methylthio)-4H-thieno-
[3,4-b][1,5]benzodiazepine in excess N-benzylpiperazine
and glacial acetic acid is heated at 140-160C. for 2
days. The solution is poured into water and the product
is collected.
Example 41
Preparation of 7-Hydroxy-10-(4-phenyl-1-piperazinyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
A solution of 7-hydroxy-10-(methylthio)-4H-
-thieno[3,4-b][1,5]benzodiazepine in excess N-phenyl-
piperazine and glacial acetic acid is heated at 140-
-160C. for 2 days. The solution is poured into water
and the product is collected.
Example 42
- 43 -
~07030Z
1 Pre~aration of 7-Trifluoromethyl-10-[4-(2-dimethylamino-
ethyl)-l-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine
A solution of 7-trifluoromethyl-10-(methyl-
thio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess 2-di-
methylaminoethylamine and glacial acetic acid is heatedat 140-160C. for 2 days. The solution is poured into
water and the product is collected.
Example 43
Preparation of 6-Methylsulfonyl-10~ iperazinyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
A SQlution of 6-methylsulfonyl-10-(methylthio)-
-4H-thieno[3,4-b][1,5]benzodiazepine in excess piperazine
and glacial acetic acid is heated in a bomb at 150C.
for 2 days. The solution is poured into water and the
product is collected.
Example 44
Preparation of 6-Methaxy-10-(4-methyl-1-piperazinyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
A solution of 6-methoxy-10-(methylthio)-4H-
-thieno[3,4-b]~1,5]benzodiazepine in excess N-methyl-
piperazine and glacial acetic acid is heated at reflux
for 2 days. The solution is poured into water and the
product is collected.
Example 45
Preparation of 7-Methyl-10-(4-methyl-1-piperazinyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
A solution of 7-methyl-10-(methylthio)-4H-
-thieno[3,4-b][1,5]benzodiazepine in e cess N-methylpip-
erazine and glacial acetic acid is heated at reflux for
2 days. The solution is poured into water and the prod-
- 44 -
1070302
1 uct is collected.
Example 46
Preparation of 10-(4-Methyl-l-piperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine
A mixture of 2.32 gms. of 4,9-dihydro-lOH-
-thieno[3,4-b][1,5]benzodiazepine-10-thione, 23 ml. of
N-methylpiperazine, and 3 drops of glacial acetic acid
is refluxed with stirring for 18 hours. The reaction
is poured, while hot, into 400 ml. of stirred ice/water.
The product is extracted with methylene chloride, dried
over potassium carbonate and passed through magnesium
silicate. Recrystallization from hot ethanol gives
yellow crystals, m.p. 192-194C.
Example 47
Preparation of 10-(4-Methyl-l-piperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine
To a mixture of 2.16 grams of 4,9-dihydro-lOH- ~ -
-thieno[3,4-b][1,5]benzodiazepine-10-one and 1.06 grams
of sodium carbonate in 250 ml. of toluene is added in
small portions with stirring 1.90 gms. of p-toluene-
sulfonyl chloride. The reaction is heated at 60. for
1 hour and then 6 grams of N-methylpiperazine is added.
The reaction is heated at reflux for 8 hours and is then
cooled and extruded once with aqueous sodium carbonate
and then several times with lN hydrochloric acid. The
combined acid washings are made basic with lN sodium
hydroxide. The solid is removed by filtration, purified
by chromatography and recrystallized from hot ethanol
to give yellow crystals, m.p. 192-194C.
Example 48
1070302
1 Preparation of 10-(4-Methyl-l-piperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine
To a mixture of 2.16 gms. of 4,9-dihydro-lOH-
-thieno[3,4-b][1,5]benzodiazepine-10-one and 2.02 gms. of
triethylamine in 250 ml. of benzene is added dropwise
with stirring a solution of 1.08 gms. of trimethylchloro-
silane in 50 ml. of benzene. When addition is complete
the mixture is refluxed for 9 hours and then 6 grams of
N-methylpiperazine is added. The reaction is refluxed
an additional 8 hours, cooled, and extracted several
times with lN hydrochloric acid. The combined acid wash- `
ings are made basic with lN sodium hydroxide. The solid
is removed by filtration, purified by chromatography and
recrystallized from hot ethanol to give yellow crystals,
m.p. 192-194C.
Example 49
Preparation of 10-(4-Methyl-l-_iperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine
A mixture of 2.16 grams of 4,9-dihydro-lOH-
-thieno[3,4-b][l,5]benzodiazepine-10-one and 3.38 grams
of phenyl bis(4-methyl-1-piperazinyl)phosphinate in 250
ml. of diphenyl ether is heated at 235 for 1 hour. The
reaction is cooled and then extracted several times with
lN hydrochloric acid. The aqueous layer is separated
and basified. The solid is removed by filtration, puri-
fied by chromatography and recrystallized from hot eth-
anol to give yellow crystals, m.p. 192-194C.
Example 50
Preparation of 10-(4-Methyl-l-piperazinyl)-6-(trifluoro-
methyl)-4H-thieno[3,4-b][1,5]benzodiazepine
- 46 -
~0~0302
1 To a mechanically stirred mixture of 22 ml. of
toluene and 2.3 ml. of amide refluxing in a nitrogen
atmosphere is added by means of a syringe 1.2 ml. of
titanium tetrachloride. The resulting red-brown solu-
tion is treated (syringe) with 4.75 ml. of N-methylpiper-
azine followed by 2.6 ml. of toluene. The resulting
- yellow-brown slurry is treated, using a hot syringe, with
a solution prepared by heating 3.0 grams of 4,9-dihydro-
-6-(trifluoromethyl)-lOH-thieno[3,4-b][1,5]benzodiazepine-
-10-one, 2.4 ml. of N-methylpiperazine and 5 ml. of tol-
uene on a hot plate. After 2 hours at reflux the hot
mixture is treated with 2 g. of diatomaceous earth fol-
lowed by 3.3 ml. of isopropyl alcohol and 2.9 ml. of
concd. ammonium hydroxide and transferred with a stream
of water to a filter funnel. The filter cake is washed
thoroughly with toluene and the layers in the filtrate
are separated. The toluene layer is extracted with 10%
hyd rochloric acid and the aqueous extract is made basic
with concd. ammonium hydroxide to yield a light yellow
20 solid, m.p. 198-199C. ~ `
Example 51
Preparation of 10-(1-Piperazinyl)-l-trifluoromethyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
The procedure of Example 50 is repeated with
molar amounts of piperazine replacing N-methylpiperazine.
Thus a hot solution of 35 ml. of toluene containing 3.7
ml. of anisole and 1.9 ml. of titanium tetrachloride is
treated with 5.9 g. of anhydrous piperazine and 5 ml. of
toluene followed by a hot mixture of 2.9 g. of piperazine,
4.9 g. of 4,9-dihydro-6-(trifluoromethyl)-lOH-thieno-
- 47 -
~070302
1 [3,4-b][1,5]benzodiazepin-10-one and 7 ml. of toluene.
After 3 hours at reflux the mixture is treated with 4
grams of diatomaceous earth, 6.5 ml. of isopropyl alco-
hol and 5.8 ml. of concd. ammonium hydroxide, filtered
and extracted with toluene. The separated toluene
layer is extracted with 10% hydrochloric acid and the
aqueous layer is made basic with ammonium hydroxide to
precipitate a yellow product which, after crystalliza-
tion from a mixture of ether and hexane, melta at 184-
185C.
Example 52Preparation of 10-(4-Methyl-l-piperazinyl~-7-(trifluoro-
methyl)-4H-thieno[3,4-b][1,5]benzodiazepine
The procedure of Example 50 is repeated sub-
stituting 4,9-dihydro-7-(trifluoromethyl)-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one for the 6-(trifluoro-
methyl)isomer. Thus a hot mixture of 32 ml. of toluene,
3.3 ml. of anisole and 1.7 ml. of titanium tetrachlor-
ide is treated with 7.0 ml. of N-methylpiperazine and 3.8
ml. of toluene followed by a hot mixture of 4.3 grams
of 4,9-dihydro-7-(trifluoromethyl)-lOH-thieno[3,4-b][1,5]-
benzodiazepin-10-one, 3.5 ml. of N-methylpiperazine and
7.2 ml. of toluene. After 2 hours at reflux, the mix-
ture is treated with 2.7 grams of diatomaceous earth,
4.7 ml. of isopropyl alcohol and 4.2 ml. of concd. am-
monium hydroxide, filtered and extracted with toluene.
The toluene layer is separated and extracted with 10%
hydrochloric acid. Making the aqueous layer basic with
ammonium hydroxide gives a yellow solid, m.p. 133-135C.
which melts at 175-176~C. after recrystallization from
- 48 -
10~0302
1 ether and hexane.
Example 53
Preparation of 4-Methyl-10-(4-methyl-1-piperazinyl)-
-4H-thieno[3,4-b][1,5]benzodiazepine
To a mechanically stirred solution of 42 ml.
of dry toluene, 4.5 ml. of anisole and 2.3 ml. of titan-
ium tetrachloride is added 9.3 ml. of N-methylpiperazine
and 5 ml. of toluene while maintaining the temperature
between 30-55C. To this complex is added 4.5 gms. of
10 1,3,4,9-tetrahydro-lOH-thieno[3,4-b][1,5]benzodiazepin-
-10-one and 4.7 ml. of N-methylpiperazine, and the re- -
sulting solution is refluxed for 3 hours.
The reaction is cooled and 6.5 ml. of isopropyl
alcohol, 4 gms. filter aid and 5.8 gms. concentrated am-
monium hydroxide are added. The resulting solid is filt-
ered and washed extensively with toluene. The organic
layer is extracted with 3N hydrochloric acid and the
product precipitated, while cooling, with concentrated
ammonium hydroxide. The product is collected, dried,
dissolved in methylene chloride and passed through mag-
nesium silicate. Recrystallization from hot ethanol
gives yellow crystals, m.p. 64-67C.
Example 54
Preparation of 10-(4-Methyl~ perazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine
To a mechanically stirred mixture of 148 ml.
of dry toluene, 15.9 ml. of anisole and 8.13 ml. of ti-
tanium tetrachloride is added 32.9 ml. of N-methylpiper-
azine and 17.7 ml. of dry toluene while maintaining the
temperature between 30-55C. To this complex is added
: :10~0302
1 15.9 gms. of 1~3~4~9-tetrahydro-loH-thienol3~4-b][l~5
benzodiazepin-10-one and 16.6 ml. of N-methyl ~i~erazine,
and the resulting solution is refluxed for 6 1/2 hours.
The reaction is cooled and 23 ml. of isopropyl
alcohol, 14 gms. of filter aid and 21 ml. concentrated
ammonium hydroxide are added. The resulting solid is
filtered and washed extensively with toluene. The or-
ganic layer is extracted with 3N hydrochloric acid and
the product precipitated, while cooling, with concentrat-
ed ammonium hydroxide. The product is collected, dried,dissolved in methylene chloride and passed through mag-
nesium silicate. Recrystallization from hot ethanol
gives yellow crystals, m.p. 197-200C.
Example 55
Preparation of 4-Methyl-10-(4-methyl-1-piperazinyl)-4H-
-thieno[3,4-b][1,5]benzodiazepine
A solution of l.S g. of 10-ethoxy-4-methyl-4H-
-thieno[3,4-b][1,5]benzodiazepine fluoborate in 200 ml.
of methylene chloride is washed with two 50 ml. portions
of lN sodium carbonate solution. After drying and evap-
oration of the methylene chloride, the recovered yellow
oily base is treated with 4 ml. of N-methylpiperazine
and 0.225 gram of ammonium chloride and the mixture is
stirred and heated at reflux for 24 hours. The mixture
is concentrated on a steam bath under a stream of air.
The residue is dissolved in 2N acetic acid and filtered.
The cooled filtrate is made alkaline with concentrated ;
ammonium hydroxide. The precipitated product is filt-
ered, dissolved in chloroform, dried with magnesium
-30 sulfate, filtered, and the solution is evaporated to dry-
- 50 -
1~7Q30Z
1 ness. The product is recrystallized from ethanol to
give light yellow crystals, m.p. 83-85C.
Example 56
Preparation of 10-ethoxy-4-methyl-4H-thieno[3,4-b][1,5]-
benzodiazepine fluoborate
To a solution of 4.6 g. of 4,9-dihydro-4-methyl-
-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one in 500 ml.
of methylene chloride, cooled to +5C., there is added
during 1/2 hour, 8 g. of triethyloxonium fluoborate dis-
solved in 100 ml. of methylene chloride. The solutionis allowed to stand at 25 for 17 hours and concentrated
to about 100 ml. Addition of ether gives the product
as a crystalline salt which after recrystallization from
methylene chloride/ether gives light yellow crystals,
m.p. 175-177C. (dec.).
Example 57
Preparation of 10-(4-Methyl-l-piperazinyl)-4H-thieno-
[3,4-b][1,5]benzodiazepine
A mixture of 2.2 g. of 4,9-dihydro-lOH-thieno-
[3,4-b][1,5]benzodiazepin-10-one, 5.1 g. of 1-methyl-4-
-(trimethylsilyl)piperazine and 0.1 g. of _-toluenesul-
fonic acid is placed in a pressure vessel and heated at
190C. for 24 hours. The reaction mixture is dissolved
in chloroform and washed with water. The chloroform
solution is dried over magnesium sulfate and concentrated
under reduced pressure to give 2.0 g. of a brown glass.
Purification of this material gives yellow crystals,
m.p. 192-194C.
Example 58 .
Preparation of 10-(4-Methyl-l-piperazinyl)-4H-thieno-
... .
~ - 51 -
1~70302
1 [3,4-b][1,5]benzodiazepine
A mixture of 2.16 gms. of 4,9-dihydro-lOH-
-thieno[3,4-b][1,5]benzodiazepine-10-one and 2.28 gms.
of phosphorus pentachloride in 20 ml. of toluene is re-
fluxed with stirring for four hours. The solvent isremoved under reduced pressure and the residue is dis-
solved in 20 ml. of dimethylformamide and 3 gms. of
N-methylpiperazine. The reaction is heated 18 hours at
100, cooled and is then poured into water. The solid
is separated and recrystallized from hot ethanol to give
yellow crystals, m.p. 192-194C.
:
- 52 -
