CA1070302A - Substituted benzodiazepin-10-ones and method of use - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
9-Aminoalkyl-4,9-dihydro-10H-thieno[3,4-b] [1,5] ben-zodiazepin-10-ones and 10-Substituted amino-4,9-dihydro-4H--thieno[3,4-b]-[1,5]benzodiazepines having neuroleptic and analgesic activity.

Description

25,618 : ' ~
This invention is concerned with compounds of the formula:

Rz 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- .

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 '''~

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

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 ~

wherein R is hydrogen and Rl, R2 and R3 are as herein above defined, with a compound of the formula:

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 -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:

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 /
10R R O ~

~C~S ~;, 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 ~

H S

25 R ~ N-C ~ (CH30)2502 R~ ! S-CH3 R2~ ~ R

C~ '\

H O O
R2 ,,f~N-C ~ 3 3 O-S~ CH
Rl , " 3 ~ N=C~(~
R 2 t l~s \/

Rl ~R7 R2~--~=NC,~S

.. . . , , . . ,`., . ... , ` .... ...

`~ 1070302 Cli 3 R ~ 7 =~ N-C~, Cll Rl~ ~ R7 R 2~ )~\S

R3 ~ .
~ .

H O
R~

R3 ~-P

~=C/~

H O
R ' "
-C ~ TiC14 ~W ~ --,, . , ., , ; , , ,, , ,~, ~ "".. .. .,. , .. , .. " ., "" ,, .,.,,, ,", , ;,. ", .,:",. .. ., " , .
.. -:- `` - . : : ..... : :: . .. -. . .

R~N--C~

.

H O
R
N-~ PC15 ~ ;

, . ;
Rl ,Cl R2~ ,~,J~ N~\ ' 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-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.

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 ~
, 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 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.

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 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 , ` ` 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 .; .

.~ ~

--``` 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 ~:

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 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 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.
:' , 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 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:

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``` 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:
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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 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 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:

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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:

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~s s ~s JJO a) ~so ~ ~s ~.co ~so 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-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.

~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.

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-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]-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]-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 ` 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-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 ~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-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 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 ~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-~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 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-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.

:

Claims (16)

THE EMBODDMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRrVILEGE IS CLAIMED ARE DE rNED AS FOLLOWS:

1. A method of preparing a compound of the formula:

(I) wherein R1 and R2 are hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen, nitro, trifluoromethyl, methylthio, methylsulfonyl or hydroxy; R3 is hydrogen or C1-4 alkyl; R7 is , or -?(CH2)nN(R5)2, wherein R4 is hydrogen, C1-4 alkyl, 2-hydroxyethyl, phenyl or phenyl C1-4 alkyl, n is 2 or 3, and R5 is C1-4 alkyl, and pharmaceutically acceptable acid addition salts thereof, characterized by (a) reacting a compound of the formula:

where n R1, R2 and R3 are as defined above, with an amine of the formula , or H-?(CH2)n-N(R5)2 wherein R4 is hydrogen, C1-4 alkyl, 2-hydroxyethyl, phenyl, or phenyl C1-4 alkyl, n is 2 or 3, and R5 is C1-4 alkyl, at a temperature from 100°C to 250°C under acid conditions;
(b) reacting at a temperature from 100° C to 250°C a compound of the formula wherein R is hydrogen and R1, R2 and R3 are as defined above with an amine of the formula:

, or H2N(CH2)nN(R5)2 wherein R4, R5 and n are as defined above;
(c) reacting a compound of the formula wherein R is hydrogen and R1, R2 and R3 are as defined above with a compound of the formula:

wherein x is C1-4 alkyl, phenyl or substituted phenyl followed by reaction with an amine of the formula:
, or H2N(CH2)nN(R5)2, wherein R4 and R5 and n are as defined above;
(d) reacting a compound of the formula:

wherein R is hydrogen and R1, R2 and R3 are as herein above defined, with a compound of the formula:

wherein R7 is an amine of the formula:

, or H2N-(CH2)nN(R5)2 wherein R4, R5 and n are defined above;

(e) reacting a compound of the formula wherein R is hydrogen and R1, R2 and R3 are as herein above defined, with a compound of the formula:

followed by reaction with an amine of the formula:

, or H2N(CH2)nN(R5)2 wherein R4, R5 and n are as defined above;
(f) reacting a compound of the formula:

wherein R is hydrogen and R1, R2 and R3 are as herein above defined, with a compound of the formula:

wherein R7 is an amine of the formula:

, or H2N-(CH2)nN(R5)2, wherein R4, R5 defined above;
(g) reacting a compound of the formula:

wherein R is hydrogen and R1, R2 and R3 are as herein above defined with phosphorus pentachloride followed by reaction with an amine of the formula:

, or H2N-(CH2)nN(R5)2 wherein R4, R5 and n are as defined above;
(h) reacting a compound of the formula wherein R is hydrogen and R1, 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:

, or H2N(CH2)nN(R5)2 wherein R4, R5 and n are as defined above at a temperature from 100°C to 250°C in the presence of a solvent;
and (i) reacting a compound of the formula wherein R is hydrogen and R1, 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 20°C. followed by reaction with an amine of the formula: , or H2N-(CH2)nN(R5)2 wherein R4, R5 and n are as defined above in the presence of a weak acid at a temperature from 100°C to 250°C;
and recovering the product therefrom and where required preparing a pharmaceutically acceptable acid addition salt thereof.

2. A compound of formula (I) as defined in claim 1, whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.

3. A process according to claim 1, wherein 10-(1-piperazinyl)-4H-thieno [3,4-b][1,5]benzodiazepine is prepared by reacting 10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine with piperazine.

4. 10-(1-piperazinyl)-4H-thieno [3,4-b][1,5]benzodiazepine and pharm-aceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 3, or by an obvious chemical equivalent thereof.

5. A process according to claim 1 wherein 10-(4-methyl-1-piperazinyl)-4H-thieno [3,4-b][1,5]benzodiazepine is prepared by reacting l0-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine with N-methyl-piperazine.

6. 10-(4-methyl-1-piperazinyl)-4H-thieno[3,4 b][1,5]benzodiazepine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 5, or by an obvious chemical equivalent thereof.

7. A process according to claim 1 wherein 4-methyl-10-(4-methyl-1-piper-azinyl)-4H-thieno[3,4-b]-[1,5]benzodiazepine is prepared by reacting 4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine with N-methylpiper-azine.

8. 4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b]-[1,5]benzodia-zepine and pharmaceutically acceptable acid addition salts thereof, when-ever prepared by a process according to claim 7, or by an obvious chemical equivalent thereof.

9. A process according to claim 1, wherein 7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b]-[1,5]benzodiazepine is prepared by reacting 7-chloro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine with N-methyl-piperazine.

10. 7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b]-[1,5]benzodia-zepine, and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 9, or by an obvious chemical equivalent thereof.

11. A process according to claim I wherein 6-chloro-10-(4-methyl-1-pipera-zinyl)-4H-thieno[3,4-b]-[1,5]benzodiazepine is prepared by reacting 6-chloro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine with N-methylpiperazine.

12. 6-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b]-[1,5]
benzodiazepine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 11, or by an obvious chemical equivalent thereof.

13. A process according to claim 1, wherein 7-chloro-4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[3,4-b][1,5]benzodiazepine is prepared by reacting 7-chloro-4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine with N-methylpiperazine.

14. 7-chloro-4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[3,4-b]
[1,5]benzodiazepine, and pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 13 of by an obvious chemical equivalent thereof.

15. A process according to claim 1 wherein 10-piperidino-4H-thieno[3,4-b]
[1,5]benzodiazepine is prepared by a reacting 10-(methylthio)-4H-thieno [3,4-b][1,5]benzodiazepine with pipiderine.

16. 10-piperidino-4H-thieno[3,4-b][1,5]benzodiazepine, and pharmaceut-ically acceptable acid addition salts thereof, whenever prepared by a process according to claim 15, or by an obvious chemical equivalent thereof.