Note: Descriptions are shown in the official language in which they were submitted.
1049009
The present invention relates to diazepine derivatives. More par-
ticularly, the invention is concerned with thienotriazolodiazepine deriva-
tives and a process for the manufacture thereof
The thienotriazolodiazepine derivatives provided by the present
invention are compounds of the general formula
~ 8 \
R4-----C~5 ~
~1 ~ 4 5 / 2 (I)
1 R2
wherein R1 represents a halogen atom, R2 represents a phenyl, o-trifluoro- -
methylphenyl, o-halophenyl, o,o'-dihalophenyl or o-nitrophenyl group or a
pyridyl or thienyl group and R4 represents a hydrogen atom or an aIkyl group
or a group of the formula -alkyl-Z in which Z represents the grouping -N(R5)
(R6) wherein R5 and R6 each independently represent a hydrogen atom or an
alkyl group and pharmaceutically acceptable acid addition salts thereof.
As used in this description the term ~alkyl~ alone or in com_
bination such as in hydroxyalkyl, denotes a straight-chain or branched-
chain hydrocarbon group containg 1-4 carbon atoms such as, for example,
methyl, ethyl, propyl, isopropyl, tertbutyl and the like. The term "hal-
ogen" denotes bromine~ chlorine~ fluorine~ and iodine.
A preferred class of thienotriazolodiazepine derivatives provided
by this invention comprises those in which R1 represents a halogen atom, es-
` 20 pecially a chlorine atom, R2 preferably represents an o-halophenyl, o,o'-
dihalophenyl or 2-pyridyl group. When R2 represents an o-halophenyl group,
.,; '
: -1-
~049009
the o-fluorophenyl and o-chlorophenyl groups are preferred. When R2
represents an o,o'-dihalophenyl group, the two halogen atoms are preferably
identical and are especially fluorine atoms. R4 preferably represents an
alkyl or aminoalkyl group, particularly a methyl group.
As will be evident from the foregoing, especially preferred thieno-
triazolodiazepine derivatives provided by this invention are those in which
Rl represents a chlorine atom, R2 represents an o-chlorophenyl or o-fluoro-
phenyl group and R4 represents a methyl group.
A particularly preferred compound of formula I is 2-chloro-4-(o-
chlorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine.
Other examples of compounds of formula I are:
2-chloro-4-(o-chlorophenyl~-9-methyl-6H-thieno[3,2-f]-s-triazolo-
~4,3-a~[1,4]diazepine-5-oxide,
2-chloro-9-methyl-4-(2-pyridyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a]-
~1,4]diazepine,
2-chloro-9-methyl-4-(o-nitrophenyl)-4H-thieno[3,2-f]-s-triazolol4,
s 3-a]~1,4]diazepine,
2-chloro-9-methyl-4-phenyl-6H-thieno~3,2-f]-s-triazolo~4,3-a]~1,4]-
diazepine,
2-chloro-4-(o-fluorophenyl)-9-methyl-6H-thieno~3,2-f]-s-triazolo-
[4,3-a]~1,4]diazepine,
2-chloro-4-(o,o'-difluorophenyl)-9-methyl-6H-thienol3,2-f]-s-tria-
zolo[4,3-a][1,4]diazepine,
9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno~3,2-f]-s-tria-
zolo[4,3-a]~1,4]diazepine,
2-chloro-4-(o-chlorophenyl)-9-dimethylaminomethyl-6H-thienor3,2-f]-
s-triazolo~4,3-a][1,4]diazepine,
2-chloro-9-methyl-4-(o-trifluoromethylphenyl)-6H-thieno13,2-f]-s-
~` triazolo[4,3-a]~1,4]diazepine.
According to the process provided by this invention, the thienotria-
~ .
';
, ':
10491~9
zolodiazepine derivatives aforesaid, i.e. the compounds of formula I and
their pharmaceutically acceptable acid addition salts, are manufactured by
a process which comprises:
a) cyclising a compound of the general formula
R - C - NH
4 //
O NH
S~/N=c\
CH2 (II)
C = N
R
wherein Rl, R2 and R4 have the significance given earlier, or
b) cyclising a compound of the general formula
N \
R -C N
Rl S \N - C ~III)
~( CH2
f=o NH2
R2
wherein Rl, R2 and R4 have the significance given earlier, or
c) halogenating a compound of the formula
.
R4 C N
, ¦ ~N
N - C IA
C = N
R2
30 ~herein R2 and R4 have the significance given earlier, or
' - 3 -
:
,. .
:
. : '
1049(~09
d) for the manufacture of a compound of formula I in which R4 is a
group of the formula -alkyl-Z in which Z has the significance given earlier,
reacting a corresponding compound which carries a group of the formula -alkyl-
A in place of R4 with a compound of the general formula BR; in which formulae
one of the symbols A and B represent the grouping -NH-R5 in which R5 has the
significance given earlier and the other symbol represents a leaving atom or
group and R represents an alkyl group, provided that, when the symbol B
represents the grouping -NH-R5, R can also represent a hydrogen atom and
wherein steps a) to d) may be followed by the step of
e) converting a compound of formula I obtained into a pharmaceutically
acceptable acid addition salt.
According to embodiment a) of the present process, compounds of
formula I can be manufactured by cyclising a corresponding compound of
formula II.
S The cyclisation of a compound of formula II is carried out accord-
ing to methods known per se; for example, by heating a compound of formula
II. The temperature at which the cyclisation is carried out is not critical,
but it depends, however, on the starting material and the conditions used.
The cyclisstion can be carried out at a temperature of between about room
temperature and 300C. The cyclisation can be carried out in the absence of,
or, preferably, in the presence of, an inert organic solvent. If the cyclisa-
tion is carried out in the presence of an inert organic solvent, the preferred
temperature range lies between about 60C and 180C, preferably at the reflux
' temperature of the cyclisation mixture. If, on the other hand, the cyclisa-
tion is carried out in the absence of a solvent, the preferred temperature
range lies between about 200C and 260C. Suitable inert organic solvents
are, for example, hydrocarbons such as toluene, xylene and the like, halogen-
ated hydrocarbons such as chlorobenzene and the like, ethers such as tetra-
hydrofuran, dioxane, diethyleneglycol dimethyl ether, diethyleneglycol diethyl
ether and the like, amides such as hexamethylphosphoric acid triamide, dimethyl-
- 4 -
.' ~
~, '~''~ ,
.
:
:~. ` , - - ~ ' .'
... . . . .
1049~
formamide and the like, dimethyl sulphoxide and, especially, alkanols such
as methanol, ethanol, l-propanol, 2-propanol, l-butanol, 2-butanol, cyclo-
hexanol and the like. The cyclisation time depends, of course, on the tem-
perature used and the fact whether a solvent is present and lies between a
few minutes and 48 hours. In the absence of a solvent the reaction is pre-
ferably effected in a few minutes. In the presence of a solvent the time
lies preferably between 1 and 24 hours.
The compounds of formula II need not, and can not in all cases, be
used in an isolated form since they frequently spontaneously cyclise under
the conditions used for their preparation.
According to embodiment b) of the present process, compounds of
formula I are manufactured by cyclising a compound of formula III.
The cyclisation of a compound of formula III is also carried out
according to methods known per se. For example, this cyclisation can be
carried out by warming a compound of formula III in an organic medium; in
many cases the presence of an acid is desirable in order to obtain satisfac-
tory ~ields. Thus, the cyclisation can be carried out, for example, by
heating a compound of formula III to boiling under reflux for several hours
; in a solution of an aliphatic carboxylic acid such as formic acid or acetic
acid in an alkanol such as ethanol or n-propanol, or for a relatively short
time (ca 5 minutes to 0.5 hour) in an aliphatic carboxylic acid such as
acetic acid, isobutyric acid or pivalic acid.
The compounds of the formula III need not, and can not in all cases,
be used in an isolated form since they frequently spontaneously cyclise under
the conditions used for their preparation.
~ According to embodiment c) of the present process, compounds of
ormula I can be manufactured by halogenating a compound of formula IA.
The halogenation is carried out according to one of the halogenation
methods con~entional in thiophene chemistry; for example, using elementary
chlorine, bromine or iodine, sulphuryl chloride etc, the conditions being
- 5 -
~ . .
'':
1049~09
primarily governed by the nature of the halogenating agent used. Chlorina-
tion can be carried out using elementary chlorine, for example in chloro-
form/pyridine or nitrobenzene, expediently at room temperature. Bromination
can be carried out using elementary bromine, for example in chloroform, at an
elevated temperature, for example at the boili~g temperature at reflux.
Iodination using elementary iodine can, for example, be carried out in chloro-
form and in the presence of mercuric oxide at room temperature. Chlorination
using sulphuryl chloride can, for example, be carried out in chloroform or
glacial acetic acid at room temperature or at an elevated temperature, for
example at the reflux temperature.
According to embodiment d) of the present process, compounds of
formula I in which R4 represents a group of the formula -alkyl-Z in which Z
has the significance given earlier are manufactured by reacting a correspond-
ing compound which carries a group of the formula -alkyl-A in place of R4
with a compound of the formula BR. One of the symbols A and B represents
the grouping -NH-R5 in which R5 has the significance given earlier and the
other symbol represents a leaving atom or group, preferably a halogen atom
~especiallr a chlorine atom) or a reactive ester group te.g. a methanesul-
phonic acid ester group). R represents an alkyl group or, when B represents
the grouping -NH-R5, R can also represent a hydrogen atom.
Where B represents the grouping -NH-R5 and R represents an alkyl
group or has anr of the additional meanings mentioned earlier, the reaction
consists in the formation of aminoalkrl-substituted compounds. This aspect
; of the process can be carried out in accordance with methods known per se.
For example, a compound of formula I in which R4 represents a hydroxyalkyl
group can be converted into the methanesulphonic acid ester and this ester
can be reacted with an amine of the general formula HNR5R6 in which R5 and
R6 have the significance given earlier. The reaction is carried out in a
manner known per se, preferably in the presence of a suitable inert organic
3~ solvent such as dimethylformamide or an alcohol such as methanol or ethanol
- 6 -
.
' ~ '
1049~Q9
at a temperature between 0C and 100C, preferably at 0-5C.
Compounds of formula I can be converted into pharmaceutically
acceptable acid addition salts by treatment with inorganic or organic acids.
Example of acids which form pharmaceutically acceptable salts are hydro-
chloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid,
tartaric acid, citric acid, maleic acid, ascorbic acid, formic acid, acetic
acid, succinic acid, methanesulphonic acid, benzenesulphonic acid, p-toluene-
sulphonic acid etc.
The starting materials of formula II can be prepared from the
corresponding thienodiazepine derivatives of the general formula
,., I O
Rl ~ N - C /CH2 (IV)
C = N
R2 ' .
~herein Rl and R2 have the significance given earlier.
In a first step, a thienodiazepine derivative of formula IV is
reacted with a sulphide such as phosphorus pentasulphide to give a thione of
the general formula
Rl S N - C~
\~3( CH2 ~V)
~ = N
R2
wherein Rl and R2 have the significance given earlier. In this reaction,
the sulphide is preferably used in excess. The reaction is advantageously
carried out in an inert organic solvent such as pyridine, xylene and the like
at a temperature of from about 40C up to the reflux temperature of the
~ reaction mixture, preferably at the reflux temperature. Pyridine is a preferred
; 30 solvent for this reaction.
-- 7 --
,:
~'
~0~9OQ~
A thione of formula V is then reacted with an organic acid hydra-
zide of the general formula
H2N- NH- C0 -R (VI)
wherein R4 has the significance given earlier, to give a compound of formula
II. The reaction of a thione of formula V with an acid hydrazide of formula
VI is carried out in an inert organic solvent, preferably an alkanol such as
methanol, ethanol, 1- or 2-propanol, 1- or 2-butanol and the like at a temper-
ature between about 60C and 120C, preferably at the reflux temperature of
the reaction mixture. In a preferred procedure, the acid hydrazide is used
in a 2- to S-fold excess over the theoretically required amount. The reaction
time depends on the reaction temperature and lies between a few minutes and
48 hours, preferably between about 1 and 24 hours. The thus-obtained crude
product consists mainly of the desired compound of formula II and of the
already cyclised compound of formula I. This mixture can be separated on the
basis of the different solubility of these compounds in organic solvents such
as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate and
the like. After separation in the manner described hereinbefore, the compound
of formula II can be converted into the compound of formula I. According to
a simpler method, the mixture of compounds of formulae I and II can be con-
verted into a uniform compound of formula I by heating in the manner described
earlier. The reaction of a thione of formula V with an acid hydrazide of
~ formula VI is preferably carried out while conducting an inert gas, prefer-
- ably nitrogen, through the reaction mixture so that the hydrogen sulphide
; formed is continuously removed.
The acid hydrazides of formula VI are known compounds or can be
readily prepared in an analogous manner to the known compounds, for example
by heating an ester of the formula R4-COO-alkyl to reflux with hydrazine
hydrate ~e.g. in methanol).
3Q The thienodiazepine derivatives of formula IV are also known
d~,'''`
... . .
. .
~49~Q9
compounds or can be readily prepared in an analogous manner to the known
compounds. Thus, they can be prepared, for example, from 2-amino-3-benzoyl-
thiophene by reaction with an ~-halocarboxylic acid halide such as chloro-
scetyl chloride, treatment of the resulting compound with ammonia and subse-
quent cyclisation. Where thienodiazepine derivatives of formula IV are
desired in which Rl and/or R3 represents other than a hydrogen atom and R2
represents other than a phenyl group, then, depending on the desired substitu-
ents, the reaction can be carried out using appropriately substituted amino-
aroyl-thiophene derivatives and/or substituents can be introduced at one of
the subsequent stages according to generally known methods and/or substituents
can be converted into other substituents.
Starting materials of formula II can also be prepared from compounds
of the general formula
NH - NH2
Rl~S\~N=C/
CH2 (VII)
C = N
R2
wherein Rl and R2 have the significance given earlier, by reaction with a
carboxylic acid of the general formula R4-COOH, wherein R4 has the signifi-
cance given eariler, or with a reactive derivative thereof. Suitable reactive
derivatives of the foregoing carboxylic acids are, for example, the esters,
anh~drides, halides, amides, iminoethers, amidines and orthoesters, the
orthoesters being especially preferred. Examples of such orthoesters are
o~hoacetic acid trimethyl ester, orthoacetic acid triethyl ester, orthoformic
' acid triethyl ester, orthopropionic acid triethyl ester, orthobutyric acid
triethyl ester and the like.
The reaction of a compound of formula VII with a carboxylic acid or
a reactive derivative thereof is preferably carried out in the presence of an
inert organic solvent and an acid catalyst such as a hydrohalic acid ~e.g.
_ g _
~.tl'.' .
.,
1049~9
hydrochloric acid), p-toluenesulphonic acid and the like. Suitable solvents
are alkanols such as methanol, ethanol and the like, ethers such as tetra-
hydrofuran, diethyl ether and the like, dimethyl sulphoxide, dimethylform-
amide and the like. The temperature is not critical, but the reaction is
preferably carried out at an elevated temperature, that is to say a tempera-
ture between about 30C and the reflux temperature of the reaction mixture,
preferably at the reflux temperature.
Again, starting materials of formula II can be prepared from com-
pounds of the general formula
NH - alkyl
Rl ~ N = C / (VIII)
f=N
R2
~herein Rl and R2 have the significance given earlier, by reaction with an
acid hydrazide of formula VI. The reaction is carried out in an inert organic
solvent such as an alkanol (e.g. ethanol, propanol, butanol and the like),
dimethylformamide, an ether (e.g. diglyme and methoxyethanol) or the like in
the presence of a strong base such as an amine (e.g. a tertiary amine such
as triethylamine, methylpiperidine and the like) at an elevated temperature,
preferably at the reflux temperature of the reaction mixture.
Compounds of formula VIII can be readily prepared from corresponding
thienodiazepine derivatives of formula IV by treatment with an alkylamine in
the presence of a Lewis acid such as titanium tetrachloride.
The compounds of formula VII can be prepared from the corresponding
compounds of formula VIII by reaction in a manner known per se with nitrous
acid to give a corresponding N-nitroso compound. By reaction of such an N-
nitroso compound with hydrazine there is obtained a desired compound of
formula VII. The compounds of formula VII can also be prepared by treating a
` 3Q compound of formula V with hydrazine.
- lQ _
,
- .
~490~9
The appropriately 2-unsubstituted thienotriazolodiazepine deriva-
tives required as starting materials for embodiment c) of the present process
can be obtained in analogy to embodiments a) of the present invention.
The compounds of formula I and their pharmaceutically acceptable
acid addition salts are valuable medicaments and can be used, for example,
as anticonvulsants, sedatives, muscle-relaxants, tranquillizers and anxioly-
tics. Thus, for example, 2-chloro-4-~o-chlorophenyl)-9-methyl-6H-thieno~3,2-
f~-s-triazolo~4,3-a][1,4]diazepine exhibits an HD50 of 0 5 mg/kg p.o. in the
rotating rod test ~mouse), an ED50 of 1.0 mg/kg p.o. in the chimney test
~mouse) and an APR2 0 of 0.03-0.1 mg/kg p.o. in the antipentetrazole test
~mouse). These tests were carried out according to generally known standard
methods.
The compounds of formula I and their pharmaceutically acceptable
acid addition salts can be made up into pharmaceutical preparations ~e.g.
tablets, dragées, suppositories, capsules, solutions, suspensions, emulsions
etc) according to generally known procedures. Apart from the usual pharmaceu-
tically inert carrier materials such as, for example, lactose, starch, talc,
magnesium stearate, water, vegetable oils, polyalkyleneglycols and the like,
these preparations can also contain preservatives, stabilisers, wetting agents,
emulsifiers, salts for varying the osmotic pressure, buffers or other thera^
peutically~valuable materials. If necessary, the pharmaceutical preparations
can be sterilised or can be subjected to other operations usual in the phar-
maceutical industry. It will therefore be appreciated that the invention
includes within its scope a pharmaceutical preparation containing a compound
of formula I or a pharmaceutically acceptable acid addition salt thereof in
association with a compatible pharmaceutical carrier material.
A suitable pharmaceutical dosage unit can contain about 1 to 50 mg
of a compound provided by the present invention. Suitable daily doses for
oral administration to mammals lie in the range of from about 0.1 mg/kg to
about 30 mg/kg and, in the case of parenteral administration to mammals, a
. . -. :
-:
1049009
suitable daily dose amounts to about 0.1 mg/kg to about 10 mg/kg. These
doses are, however, given merely by way of example and the specific dosage
should be adjusted in each case to the individual requirements.
The following Examples illustrate the process provided by the
present invention.
Example 1
2.5 g of 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-
thieno[2,3-e]-1,4-diazepine are heated under reduced pressure (water-jet
vacuum) for 5-7 minutes in an oil bath ~250C) until gas evolution is no
longer observed. The resulting product is finely triturated in a mortar and
boiled out several times with a total of 400 ml of ethyl acetate. After
removal of the solvent, the resulting crude product is recrystallised from
ethanol containing active carbon to give 2-chloro-4-(o-chlorophenyl)-9-methyl-
6H-thienol3,2-f]-s-triazolo~4,3-a][1,4]diazepine in the form of cream-coloured
crystals of melting point 205-206C.
The starting material can be prepared as follows:
~, 3.1 g ~0.01 mol) of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro~2H-
thieno~2,3-e]-1,4-diazepin-2-one are heated to reflux for 30 minutes with
2.45 g of phosphorus pentasulphide in 100 ml of absolute pyridine, dry nitro-
gen being conducted through the solution. The solution is separated on a
35 cm long column ~p 3.5 cm) filled with 100 g of Kieselgel [(0.05 to 0.2 mm)
tMerck)]. The separation is followed by thin-layer chromatography (eluant:
benzene/ethanol 9:2). When impurity, which runs substantially slower, appears
the elution is stopped. The solvent is removed under a vacuum, whereby 7-
chloro-5~(o-chlorophenyl)-1,3-dihydro-2H-thieno~2,3-e]-1,4-diazepine-2-thione
^ immediately crystallizes out in the form of yellow crystals of melting point
223-225C. This thione is not further purified prior to use in the next
step.
3.3 g (0.01 mol) of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-
thieno~2,3-e~-1,4-diazepine-2-thione are heated to reflux for 30 minutes
- 12 _
~ .
'' ''
- : .
. . ~ , :
1049009
under a nitrogen atmosphere with 2.5 g of acetic acid hydrazide and 150 ml of
n-butanol. The solvent is removed under a vacuum, the residue treated with
200 ml of ethyl acetate and shaken out three times with 200 ml of water each
time. The precipitated starting material is filtered under a vacuum and
combined with the ethyl acetate phase. After concentration of the solution
to 50 ml, the product is left to crystallize. Thereupon, the product is
filtered under a vacuum and again recrystallized from ethyl acetate containing
active carbon to give 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-
thieno[2,3-e]-1,4-diazepine in the form of orange crystals of melting point
211-213~C.
Example 2
0.2 g of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno~2,3-e]-
1,4-diazepine-2-~hione are heated to reflux for 5 hours under a nitrogen
atmosphere with 0.2 g of acetic acid hydrazide in 30 ml of n-butanol. After
evaporation of the solvent, the product is taken up in methylene chloride and
extracted several times with l-N hydrochloric acid, the organic phase being
treated portionwise with ether such that it comes to the surface in the
separating funnel. After neutralisation of the aqueous phase with sodium
bicarbonate, the mixture is extracted with methylene chloride, the solvent
evaporatet after drying over sodium sulphate and the residue made into a
paste with ethyl acetate. The resulting crystals are recrystallized from
eth~l acetate containing active carbon to give colourless crystals of 2-chloro-
9-methyl-4-~o-nitrophenyl)-6H-thieno~3,2-f]-s-triazolo~4,3-a][1,4]diazepine
of melting point 210-212C.
The starting material can be prepared as follows:
1 g (0.00327 mol) of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-
thieno~2,3-e]-1,4-diazepin-2-one are heated to reflux with 0.8 g of phosphorus
pentasulphide in 30 ml of absolute pyridine, nitrogen being conducted through
the solution. The mixture is separated on a column (0 3 cm) filled with 50 g
of Kieselgel 1(.05 to 0.2 mm) CMerck)~ (the product travelling on the front
- 13 -
A~ .
'.
1049009
and the impurities travelling only slowly). After concentration of the
pyridine solution under a vacuum, the residue is treated with methylene
chloride and brought to crystallization. After completion of the crystalli-
zation in a refrigerator, the mixture is filtered under a vacuum and washed
with a small amount of ice-cold methylene chloride. Recrystallization from
absolute methanol yields 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno-
[2,3-e]-1,4-diazepine-2-thione in the form of yellow crystals of melting
point 213-215C.
Example 3
3.0 g of 7-chloro-1,3-dihydro-5-(o-trifluoromethylphenyl)-2H-thieno-
~2,3-e]-1,4-diazepin-2-one are dissolved in 50 ml of diethyleneglycol dimethyl
ether at 80C, treated with 4.2 g of phosphorus pentasulphide and 3 g of
finely triturated sodium bicarbonate and warmed for 15 minutes at 80-85C.
The mixture is then evaporated under a vacuum and taken up in 60 ml of butanol.
3 g of acetyl hydrazine are added and the mixture is heated under reflux for
90 minutes. The butanol is evaporated under a vacuum, the residue taken up
in methylene chloride, the organic phase shaken out several times with water,
dried and evaporated. The oily residue is brought to crystallization with
ether. There is obtained 2-chloro-9-methyl-4-(o-trifluoromethylphenyl)-6H-
thieno~3,2-f]-s-triazolo[4,3-a]l1,4]diazepine which, after recrystallization
from eth~l acetate, has a melting point of 193-195C.
Example 4
6.8 g of 2-~2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-
thienoI2,3-e]-1,4-diazepine a~e boiled under reflux for 9 hours in 300 ml of
absolute xylene. After cooling, the precipitated impurities are filtered off
under a vacuum. The solvent i5 then evaporated under reduced pressure and
the product recrystallized from ethyl acetate containing active carbon.
~, There is obtained 2-chloro-4-~o-fluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-
triazoloI4,3-s]Il,4~diazepine of melting point 187-189C.
The starting material is prepared as follows:
.' .
- 14 -
`
~'
- ,: : .
~ . ; ' ' ' . ' ' . . '' ;: . . ' ~ : . ~
:~ , . : . , . . ;
1049~09
10 g 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-
diazepin-2-one are dissolved in 150 ml of diethyleneglycol dimethyl ether at
55C and stirred with a mixture of 15 g of finely triturated phosphorus
pentasulphide and 10 g of sodium bicarbonate for 40 minutes. The solvent is
distilled off and the residue digested with water, filtered under a vacuum
and dried. The 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-
diazepine-2-thione thus-obtained is boiled in 200 ml of methanol with 15 g .
of acetyl hydrazine for 30 minutes. On cooling, 2-(2-acetylhydrazino)-7-
chloro-5-(o-fluorophenyl)-3H-thienol2,3-e]-1,4-diazepine precipitates. The
methanol is distilled off and the residue partitioned between methylene
chloride and water. In so doing, additional product precipitates. The
solvent is evaporated under reduced pressure and additional product is obtain-
ed from the residue by digestion with methanol. The 2-(2-acetylhydrazino)-
7-chloro-5-~o-fluorophenyl)-3H-thienol2,3-e]-1,4-diazepine thus-obtained has
a melting point of 207-209C.
Example 5
2.2 g of 2-(2-acetylhydrazino)-7-chloro-5-(2-pyridyl)-3H-thieno-
~2,3-e~-1,4-diazepine are boiled under reflux for 2 hours in 120 ml of
absolute xylene. The solution is then cooled and the precipitated impurities
are filtered off. The solvent is evaporated under reduced pressure and there
i5 obtained 2-chloro-9-methyl-4-(2-pyridyl)-6H-thieno~3,2-f]-s-triazolol4,3-a]-
4]diazepine in the form of a crystalline product which, after recrystalli-
zation from ethyl acetate, melts at 174-176C.
The starting material is prepared as follows:
14.6 g of cyanomethyl-2-pyridyl-ketone and 7.6 g of bismercapto-
` acetaldehyde are dissolved or suspended in 60 ml of absolute dioxane and
treated with 5 ml of triethylamine with stirring. After a period of 1.5
hours at room temperature, the mixture is poured into ea 500 ml of water and
extracted ~ith meth~lene chloride. The methylene chloride phase is shaken
out twice with l-N sodium hydroxide, dried over sodium sulphate with the
- 15 -
''`'`~ ~
: . :
1049~09
addition of active carbon and evaporated. There is obtained 2-amino-3-
thienyl-2'-pyridyl-ketone which, after recrystallization from benzene, yields
yellow crystals of melting point 122-124C.
65 g of 2-amino-3-thienyl-2'-pyridyl-ketone are dissolved in 500
ml of dry dioxane and 80 g of potassium csrbonate are suspended in the
solution which is then treated with 80 g of chloroacetyl chloride. After the
exothermic reaction has died down, the mixture is stirred for a further 2
hours at room temperature and then poured into a solution of 50 g of potas-
sium carbonate in 2 litres of water. The precipitate which separates is
filtered under a vacuum, washed with water and taken up in methylene chloride.
After drying over sodium sulphate containing active carbon, the solvent is
distilled off under a vacuum, the residue digested with a small amount of
methanol and filtered under a vacuum. There is obtained 2-chloroacetylamino-
3-thienyl-2'-pyridyl-ketone which, after crystallization from methanol,
yields yellow needles of melting point 130-132C.
76 g of 2-chloroacetylamino-3-thienyl-2'-pyridyl-ketone are dissolv-
ed in 1 litre of acetone and, after the addition of 45 g of sodium iodide,
stirred for 15 hours at room temperature. The acetone solution is then evapor-
ated to dryness under a vacuum and the residue partitionet between ca 300 ml
of methylene chloride and water, the organic phase covered with ca 1.5 litres
of concentrated ammonia and stirred for 48 hours without mixture of the phases.
After completion of the reaction, the phases are separated, the organic phase
evaporated to dryness and the residue taken up in methylene chloride. This
solution is thoroughly extracted with 0.1-N hytrochloric acid, the aqueous
,~,
extracts neutralised with potassium carbonate and the separated solid -
material filtered under a vacuum and dried. After crystallization from
ethanol, there is obtained 2-aminoacetylamino-3-thienyl-2'-pyrityl-ketone in
the form of yellow crystals of melting point 259-262C.
A solution of 32.4 g of 2-aminoacetylamino-3-thienyl-2'-pyridyl-
ketone in 350 ml of acetic acid is heated under reflux for 15 minutes. The
solvent is then distilled off under a vacuum, the residue digested with a
- 16 -
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.
1049~09
small amount of methylene chloride and the solid material filtered under a
vacuum. After crystallization from ethanol, there is obtained 1,3-dihydro-
5-(2'-pyridyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one in the form of colourless
crystals of melting point 263-266C (decomposition).
9.8 g of 1,3-dihydro-5-(2'-pyridyl)-2H-thieno[2,3-e]-1,4-diazepin~
-2-one are dissolved in 350 ml of acetic acid and treated dropwise at room
temperature with stirring with a solution of 8.0 g of sulphuryl chloride in
20 ml of acetic acid. After completion of the addition, the mixture is
stirred for a further 15 hours. The separated yellow solid material is
filtered under a vacuum, dissolved in water and the solution neutralised
with sodium bicarbonate. The yellow-green solid material which separates is
filtered under a vacuum, washed with water and dried. After crystallization
from ethanol, there is obtained 7-chloro-1,3-dihydro-5-(2-pyridyl)-2H-thieno-
~2,3-e]-1,4-diazepin-2-one in the form of yellowish-green crystals of melting
point 250-252C (decomposition).
3.5 g of 7-chloro-1,3-dihydro-5-(2-pyridyl)-2H-thieno[2,3-e]-1,4-
diazepin-2-one are dissolved in 200 ml of diethyleneglycol dimethyl ether at
65C and stirred for 30 minutes with 5 g of finely triturated phosphorus
pentasulphide. The solvent is then distilled off and the residue taken up
in methy~lene chloride and shaken out three times uith water. The organic
phase is dried and evaporated. The 7-chloro-1,3-dihydro-5-(2-pyridyl)-2H-
thieno[2,3-e]~1,4]diazepine-2-thione is dissolved in 200 ml of methanol and
boiled for 30 minutes with 6 g of acetyl hydrazine. The solvent is distilled
off and the residue taken up in methylene chloride and shaken three times
with water. The methylene chloride is distilled off and the crystalline
residue digested with methanol. After crystallization from methanol, there
is obtained 2-(2-acetylhydrazino)-7-chloro-5-(2-pyridyl)-3H-thieno[2,3-e]-1,4-
diazepine of melting point 193-195C.
Example 6
3Q 0.35 g of 2-(2-acetylhydrazino)-7-chloro-5-(2,6-difluorophenyl)-3H-
,
1049009
thienoL2,3-e]-1,4-diazepine are distributed on a metal plate in as thin as
possible a layer and maintained at 270C for 1 minute in a sand bath. The
melt is taken up in methylene chloride and shaken three times with 0.1-N
hydrochloric acid in order to remove the starting material. The methylene
chloride is distilled off and the product recrystallized from ethyl acetate
containing active carbon. There is obtained 2-chloro-4-(2,6-difluorophenyl)-
9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a]Il,4]diazepine of melting point
` 185-l87C.
The starting material is prepared as follows:
0.06 g of 7-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-2H-thieno-
~2,3-e]-1,4-diazepin-2-one are introduced into 25 ml of diethyleneglycol
dimethyl ether and warmed to 85C. 0.85 g of finely triturated phosphorus
pentasulphide are added to the solution which is then stirred for 35 minutes
at 85C. The solvent is then evaporated under reduced pressure, the residue
taken up in 80 ml of methylene chloride and shaken three times with water.
The organic phase is evaporated, the crude 7-chloro-5-~2,6-difluorophenyl)-
1,3-dihydro-2H-thienol2,3-e]-1,4-diazepine-2-thione taken up in 20 ml of
methanol and boiled under reflux for 40 minutes with 1 g of acetyl hydrazine.
The product which precipitates in crystalline form is filtered off under a
vacuum and rinsed with methanol. In order to obtain further product, the
mother liquor is evaporated, the residue taken up in methylene chloride and
shaken out three times with 0.1-N hydrochloric acid. The hydrochloric acid
phase is neutralised with sodium bicarbonate and shaken out with methylene
chloride. The organic phase is dried and evaporated under reduced pressure.
The 2-(2-acetylhydrazino)-7-chloro-5-(2,6-difluorophenyl)-3H-thienoI2,3-e]-1,
4-diazepine thus-obtained melts at 257-260C after crystallization from
methanol.
Example 7
` Unpurified 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-
1,4-diazepine-2-thione, obtained from 5 g (0.0155 mol) of 7-chloro-1,3-dihydro-
..
- 18 -
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; . . .
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1049009
5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one, is dissolved in 500 ml
of methylene chloride and boiled under reflux for 15 hours with stirring
with 15 g of sodium bicarbonate and 7 g of acetic hydrazide dimethylammonium
chloride After filtration of the solid material, the solution is washed
twice with 200 ml of water each time and dried over sodium sulphate. After
evaporation of the solvent, the residue is triturated with ethyl acetate,
whereupon 7-chloro-2-(2-dimethylglycylhydrazino)-5-(o-nitrophenyl)-3H-thieno-
[2,3-e]~1,4]diazepine precipitates in crystalline form. The product obtained
is boiled under reflux in 300 ml of dry butanol for 24 hours and, after
evaporation of the solvent, triturated with ethyl acetate. After recrystal-
lization from ethanol, there is obtained 2-chloro-9-dimethylaminomethyl-4-
(o-nitrophenyl)-6H-thieno[3,2-f]-s-triazolo~4,3-a][1,4]diazepine as a colour-
less product of melting point 234-236C.
Example 8
0.75 g of 2-chloro-4-(o-chlorophenyl)-6H-thienol3,2-f]-s-triazolo-
' ~4,3-a]~1,4]diazepine-9-methanol are dissolved in 25 ml of absolute chloroform
and there are added thereto 0.7 g of triethylamine and 0.6 g of methanesulpho-
; chloride. The mixture is stirred for 2.5 hours at 25C, then washed twice
with water and twice with saturated sodium chloride solution, dried over
sodium sulphate and evaporated. The resulting oily methanesulphonic acid
ester of 2-chloro-4-~o-chlorophenyl)-6H-thieno~3,2-f]-s-triazolol4,3-a~1,4~-
diazepine-9-methanol is dissolved in 10 ml of dimethylformamide and the
solution added dropwise at 0-5C to a solution of 1 ml of liquid ammonia in
5 ml of dimethylformamide. The mixture is stirred for 2 hours at room temper-
ature and then partitioned between saturated sodium chloride solution and
meth~lene chloride. The organic phase is dried and evaporated and the residue
recrystallized from ethanol. There is obtained 9-aminomethyl-2-chloro-4-(o-
chlorophenyl)-6H-thieno~3,2-f]-s-triazolol4,3-a]~1,4]diazepine of melting
point 190-192C.
3Q The following Examples illustrate pharmaceutical preparations con-
-- 19 --
.~ ~ .
~049009
taining the thienotriazolodiazepine derivatives provided by this invention:
Example A
Manufacture of suppositoriesper suppository
2-Chloro-4-(o-chlorophenyl)-9-
-methyl-6H-thieno[3,2-f]-s-
-triazolo[4,3-a][1,4]diazepine0.010 g
Cocoa butter ~melting point
36-37C) 1.245 g
Carnauba wax 0.045 g
Suppository weight: 1.3 g
The cocoa butter and carnauba wax are melted in a glass or steel
vessel, thoroughly mixed and cooled to 45C. Finely powdered 2-chloro-4-
(o-chlorophenyl)-9-methyl-6H-thieno~3,2-f]-s-triazolo~4,3-a][1,4]diazepine
- is then added and the mixture stirred until it is completely dispersed. The
mixture is poured into suppository moulds of suitable size, allowed to cool,
the suppositories then removed from the moulds and packed individually in
wax paper or metal foil.
Example B
Manufacture of capsules per capsule
; 20
2-Chloro-4-(o-chlorophenyl)-9- -
-methyl-6H-thienoI3,2-f]-s-
-triazoloI4,3-a]Il,4]diazepine10 mg
Lactose 165 mg
Maize starch 30 mg
Talc 5 mg
Total capsule content 210 mg
,' :', ~ ,
1 The 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thienol3,2-f]-s-tria-
zolol4,3-a~l1,4]diazepine, lactose and maize starch are first mixed in a
mixer and then in a comminuting machine. The mixture is returned to the mixer,
:.
- 20 -
.
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,~ : , - :
~049009
the talc added and thoroughly mixed. The mixture is mechanically filled into
hard gelatine capsules.
Example C
Manufacture of an injection solution per ml
2-Chloro-4-(o-chlorophenyl)-9-
-methyl-6H-thieno[3,2-f]-s-
-triazolo[4,3-a][1,4]diazepine5.0 mg
Propyleneglycol 0.4 ml
Benzyl alcohol (benzaldehyde-free)0.015 ml
Ethanol (95%) 0.10 ml
Sodium benzoate 48.8 mg
Benzoic acid 1.2 mg
Water for injection q.s. ad 1.0 ml
,
For the manufacture of 10,000 ml of an injection solution, 50 g of
2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno~3,2-f]-s-triazolo[4,3-s]~1,4]-
diazepine are dissolved in 150 ml of benzyl alcohol and there are added
thereto 4000 ml of propyleneglycol and 1000 ml of ethanol. 12 g of benzoic
acid are then dissolved in the foregoing mixture and a solution of 488 g of
sotium benzoate in 300 ml of water (for injection) is added. The solution
obtained is made up to a volume of 10,000 ml by the addition of water ~for
injection), filtered and filled into ampoules of a suitable size; the remain-
ing volume of the ampoules is filled with nitrogen, the ampoules are heat-
sealed and sterilised for 30 minutes in an autoclave at 0.7 atmospheres.
. ~ .
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