Note: Descriptions are shown in the official language in which they were submitted.
1077475
~`; .
i ,
...
.`~ This invention relates to a process for the preparation of .
substituted 6-aryl-4H-s-triazolo-[3,4-c]-thieno-[2,3-e]-1,4-diasepines and
.~ to intermediates useful in the preparation of such compounds.
According to one feature of the present invention there are
provided co.mpounds of general formula II,
R ~ N C ~ (II)
R4
'.
wherein either Rl and R2, which may be the same or different, each represents
a hydrogen or halogen atom or an aIkyl group containing 1 or 2 carbon atoms
or, together with the two carbon atoms to which they are attached, they re-
present an unsubstituted 5- or 6-membered carboxylic ring; and R4 and R5,
which may be the same or different, each represents a hydrogen, fluorine,
chlorine or bromine atom; and pharmaceutically acceptable addition salts
thereof. : -
According to another feature of this invention there is provided
~- a process for the preparation of a compound of general formula II, ..
R ~ \ (II)
5 ~ 4
.1 wherein either Rl and R2, which may be the same or different, each represents
a hydrogen or halogen atom or an alkyl group containing 1 or 2 carbon ato~s
:, .
.~ or, together with the two carbon atoms to.which they are attached, they
' 20 represent an unsubstituted 5- or 6-membered carboxylic ring; and R4 and R5,
- -
.. ..
.; , , .
,i`
` `:
1077475
`.. ~;.
:~; which may be the same or different, each represents a hydrogen, fluorine,
: ; chlorine or bromine atom; and pharmaceutically acceptable acid addition
;~ salts thereof selected from the following:
A. Cyclisation of a compound of formula Ia,
~ ? . . .
~ S H
s~ Rl ~ N - CO - CH - X (Ia)
. R2 CH - OH
R5 ~ R4
,~,,.", l~
'.'"'`,
.~ (wherein Rl, R2, R4 and R5 are as defined above and X represents a chlorine
: or bromine atom or a hydroxy group) and
.:~ B. for the preparation of compounds of general formula II as defined
. .
above wherein Rl and/or R2 represents a chlorine or bromine atom: -
Halogenation of a compound of formula II as defined above wherein :
the said Rl and/or R2 represents a hydrogen atom.
us, the compounds of general formula II are prepared, for
example, by cyclising a compound of formula Ia, :
!r ¢
.'~'`,i '. .
.,,, ~ :
' :.; ,' , ~
. :
¢;. .
,'; :
~`,' -'..
. . .
:
~ - 2a -
!
, ,1
1077475
.. . .
. ~ .
.~-` , .
.... .
.
. ~ ,................................................................... .
. , .
; H
v, 1 ~ N - CO - CH2 - X (Ia)
R2 ICH - OH
R5 ~ ~4
,.,j . ~' -
~f' ~ .
wherein R1J R2, R4 and R5 are as hereinbefore defined and X represents
a chlorine or bromine atom or a hydroxy group).
When, in the compound of formula IaJ X represents a halogen
atom, the cyclisation is conveniently effected with an alkali metal
alcoholate or sodium hydride, preferably with sodium isopropylate or
sodlum tert.butylate. Preferred solvents for the cyclisation include,
~4 for example, alcohols, tetrahydrofuran, dioxan, dimethylformamide or
inert solvents such as benzene and its homologues. Preferred reaction
temperatures are from 0C to the boiling point of the reaction mixture
depending upon the particular starting materials employed.
When, in the compound of formula Ia, X represents a hydroxy
group then the cyclisation may be effected in the presence of conven-
tional dehydrating agents such as, for example, thionyl chloride,
sulfuric acid, polyphosphoric acid or dicyclohexylcarbodimide.
"
-
~'''-. '' ' :~
~j 3 ~
~ :
".~.
.:~
,. .
r ~
~ '
.
.~ i , . . . . .
' ' ' ' ' . . : ,
.
` 1077475
`. ,.;
.; Compounds of general formula Ia wherein X represents a
:
hydroxy group may, if desired, be obtained by reaction of a compound
. of formula Ia',
:~ .
, ....
~` N - CO - CH - W
: R2 CIH - OH (Ia~
.:'' 1
... R5 ~ / ~ R4
~JJ
. . .
...... .
, .,~,
~ (wherein Rl, R2, R4 and R5 are as hereinbefore defined and W represents
, . . .
an acyloxy group) with a strong alkali.
Compounds of general formula Ia wherein Rl is other than a
hydrogen atom and X represents a chlorine or bromine atom may, for
~; example, be obtained by reaction of a compound of formula Ia",
;;,~.
",~, .
~ ` 10 Rl~ ~N - CO - CHz - NHz ~ ~ ~
~.:, . . .
,; R2~ \ CH - OH (Ia~ ;
~,
s:~ R5 y ~ R4 :
., .
wherein R2, R4 and R5 are as hereinbefore defined and Rl is as here-
inbefore defined other than a hydrogen atom) with concentrated hydro-
:~i chloric or hydrobromic acid solution in the presence of nitrous acid.
i Such a reaction is not desirably effected with
, ..................................................................... .. . .
- 4 -
'' :
"~' .
'.~
: . ,, , - - . , . , - - - . -
:` 1077475
.-,.-:
~ . ..
~,;.
a compound of formula Ia" wherein Rl represents a hydrogen atom due
. , .
.;`: to the simultaneous addition under the reaction conditions employed,
'.~'.':
: of a nitroso group in this position.
, ......................................................................... .
.- The compounds of general formula Ia wherein X represents a
~. chlorine or bromine atom and the compounds of general formula Ia'
'~t'`' and Ia" may all be obtained, if desired, by reduction of a compound
of formula I,
~s
~S' Rl~N - CO - Cll - Z
R2 C = O ~I)
~/ R5~ R4
(wherein Rl, R2, R4 and R5 are as hereinbefore defined and Z repre-
sents a chlorine or bromine atom or an amino or acyloxy group). The
reduction may, for example, be effected by means of sodium borohydride
;.i in dimethylformamide or dimethylacetamide at low temperatures, pre-
. ferably of from 0 to 10C. It will be appreciated that in certain
solvents, such as those described above, this reduction of the carbonyl
~; group to a carbinol group proceeds with little simultaneous reductive :
cleavage of the group X or hydrolytic cleavage of the radical - C0 -
CH2 - X. However, in some solvents, for example lower alcohols, the
cleavage reactions will exceed the carbinol
.; - 5 -
,
,i., rA~.7
, ..................................... .
~ --,
7747~
",
., `
:`
;; ~
.:
'''!
,"
formation reaction, hence leading to lower yields of the
desired carbinol.
` We have surprisingly found that 2-aminobenzoyl-
; thiophenes are not themselves easily reduced as are the cor-
~ ,.
-;. responding 2-aminobenzophenones (see e.g. German Offenlegungs-
Schrift 15 45 639) thus necessitating a detour via a function-
al derivative thereof before reduction of the keto group to
a carbinol can take place.
~, The carbinols of general formula Ia are, unlike the
s 10 corresponding keto compounds of general formula I which are
.~:i - .
sensitive to hydrolysis, extremely stable under alkaline con-
ditions which accounts for the high yields obtained when the
~ above reduction is effected with compounds such as sodium
,~ ,.,
~, borohydride. ~`
,"~ :
When Rl and/or R2 represent substituents other than ~ ~`
a hydrogen atom then these substituents may be introduced at
~-, various stages during the processes described above. Thus
,; ," ,.
- when Rl and/or R2 represent lower alkyl groups or together
~i' with the two carbon atoms to which they are attached repre-
,
sent a 5- or 6-membered ring then they are advantageously
already present before formation of the thiophene ring. How-
ever, when Rl and/or R2 represent halogen atoms then they may
be introduced either into a compound of formula I or into the
" :
,
.
.;. ~ .
. , .
:
;
i` ~ -
: . . :
.~ .: , -
! `'~ '
:::
!.'. ' 1077475
~`.
- ,.,
..;
~:` compound of formula II itself by halogenation of the corres-
`~ ponding compound wherein the said groups Rl and/or R2 repre-
~", ~
~,~r sent hydrogen atoms. In either case the halogenation may,
'f~'~,'! for example, be effected by means of the appropriate halogen,
sulfuryl halide or halosuccinimide, preferably in the pre-
sence of carbon tetrachloride, chloroform, methylene chloride,
dioxan, tetrahydrofuran, dimethylformamide or a hydrocarbon
as solvent. The halogenation is also preferably effected in
.$ 1 the presence of a tertiary organic base e.g. pyridine. Pre- -
, 10 ferred temperatures for the halogenation are from ambient
~I temperature to the boiling point of the reac`tion mixture
depending on the reagents used. As will be appreciated,
either one or two halogan atoms may be introduced depending
on the reaction conditions and the quantities of the reagents
employed. Appropriate methods for either mono- or di-
halogenation are well known in the art. Thus, in order to
introduce a single halogen atom, the reactants are preferably
employed in equimolar quantities.
The compounds of general formula I are known from
the literature and may be obtained according to the method
described in "Monatsheften der Chemie" Vol. 104,~p. 704
~1973).
The compounds of general formula II are useful
intermediates in the production of therapeutically active sub-
stituted thieno-[2,3-e]-triazolo-[3,4-c]-1,4-diazepines as
ic ~l .
" ~ .
. ~ :
~ "~ :
~ _ 7 _
. .
,....
,.; - :
, . , -
`:`:
1077475
, `;
, ......................................................................... .
.....
. . .
, . . ~
.". ",;,
.:: described in detail hereinafter. The following is a
, .
summary of a reaction sequence whereby such compounds
.~ may be obtained from compounds of formula II.
. .
, . ~
~ "
; .,
~'' .
~;t.S
;' ? :: ,
."~'."~' ., ,
~`.`'' ' '
~'1'; ' . .
~; ,.'.;, . . .
,:"~
'`i'~'r :. .
.~",
~, d
:~,1 `~
, . ..................................................................... .
:.. ',,~ ,.
'';' :'
C' ~'
.1 '',. .
",; ~, . ,
"',,~:''
~, ....
,5..
;':,1,
.,'," ~1 :
~,''",' ' '
"i"'~l . .
.'.'','-,` ' ''
. ! ~ .
. ~ .
. .
`,~:, "
. ~ A
' '~. . .
.,1, .
~,.,.'
' ,.~ .'
:i.. - ~ 8 -
........ .
.,.,~ .
- . . : : . . : . - . ,
: 1077475
i~? '
~,,
~'
H
R~ N-CO-CH2-Z
r ~ ~
~CH ~-- ,~ N \
i, I
5 ~ 4~ro~ R~ c ~ ~
R5 ~ R4
VI I
s ~ _ 9 _
:
.` ~ : - - .
1077~7
`.~,
.,
. The compounds of general formula II may, for ex-
. ample, be reacted with phosphorus pentasulfide to give a
compound of formula IIIa
,. .
O .~ i, ..
... .
~!t~ SH
,,,~ ~ / :
S N
, Rl ~ CH - (IIIa)
.~ 10 R5 ~ R4 ~; .
:, i . ::
. ,
. :
herein Rl, R2, R4 and R5 are as hereinbefore defined),
. - this compound being a tautomeric equilibrium with the cor-.. , -:
~..................... responding thione compound of formula IIIa '. :
,, !. . .
SH H
R2 ~ 0~ R2 ~ N
R5 _ ~ R4 ~ 5
, ~
`` ' tIIIa) (IIIa ')
The reaction is preferably effected in the pre-
~....................... sence of a sol~ent such as dimethylformamide, diglyme or
Jr!~` tetrahydrofuran and preferably in the presence of an alkali
~; metal bicarbonate, pyridine or mixtures thereof. Preferred
; 3Q react~on temperatures are from ambient temperature up to the
boiling point of the reaction mixture.
.
t', - 1 0
C~ ''
~; .
" ':
... . .
~`` ` 1~77475
The compounds of general formula IIIa may them-
selves be converted, if desired, into compounds of general
formula IIId,
¦ X3
R ~ CH -
R5_~--R4
(IIId)
(wherein Rl, R2, R4 and R5 are as hereinbefore defined and
X3 represents a lower thioalkyl group) by forming a salt
~ of the compound of formula IIIa by reaction with sodium
-~`i methylate or sodamide in the presence of a solvent and
subsequent reaction of the salt thus formed with an ap-
,!,~, propriate alkylating agent e.g. an alkyl halide, prefer-
ably the iodide.
The compounds of general formula II may if de-
sired, al~ernatively be reacted with an appropriate tri-
~'1 alkyloxonium-fluoroborate to give a compound of formula
IIIb
(rllb)
~ R5 ~ - R4
~,, :'
~1
~ ' .
i.~ -- 11 --
.::
' ., '':
~'
~.
-'''~',
',': :,` -, ' . :
774'7~;
,~ :
..,
wherein Rl, R2, R4 and R5 are as hereinbefore defined and Xl repre-
~'- sents a lower alkoxy group). The trialkyloxoniumfluoroborate, ob-
., .
` tained, for example, according to the process described by H. Meerwein
~; et al in J. pr. Chem. (2), 147, 257 (1937) and 154, 83 (1939) from a
borotrifluoride etherate and epichlorohydrin, is desirably prepared
in situ.
Preferably the reaction is effected in the presence of an -~
, ether or halogenated hydrocarbon, e.g. carbon tetrachloride, as solvent
and preferably at temperatures of from 0C to the boiling point of the
` 10 reaction mixture.
Alternatively compounds of general formula II may, if desired,~.
be reacted with an appropriate acidic inorganic chloride or bromide,
~ preferably phosphorus pentachloride or pentabromide, to give a compound
- of formula IIIc -
,
" ~1 S ~-X2
Rl ~ ~ N =C
L'~' R ~ / CH2 (IIIc)
R5 - ~ ~ 4
:.~i,,;,
. ;s ~ .
- (wherein Rl, R2, R4 and R5 are as hereinbefore defined and X2 represents
~ a chlorine or bromine atom). Such a reaction is preferably effected
,. ...................................................................... .
` in the presence of an anhydrous organic solvent such
., . ~ .
;.',''' ', '.
- 12 -
.
.. ~ ,
" ~; ' '
.' ~'
1077475
... .
~*~ as, for example dioxan or tetrahydrofuran and preferably at temperatures
, ~ :
of from -50 to 50C.
The compounds of general formulae IIIa-d may collectively be
denoted by the general formula III,
C ~ N =
CH - 0
~ , .
~, 5 ~ R4
~; (wherein Rl, R2, R4 and R5 are as hereinbefore defined and X represents
.. si a chlorine or bromine atom or a lower alkoxy, thio or lower alkylthio group). -
The compounds of general formula III may, for example, be reacted :-
with a compound of formula lV,
R3' - C0 - NH - NH2
(wherein R3' represents a hydrogen atom, a straight or branched chain alkyl
or w-hydroxyaIkyl group containing from 1 to 3 carbon atoms, a cycloalkyl
group containing from 3 to 6 carbon atoms tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothiopyranyl, pyridyl, N-methyl-dihydropyridyl, piperidyl, N-methyl-
'.7:.~' piperidyl, pyrrolidyl, thienyl or tetrahydrothienyl to ~orm a compound of
:":
~ formula V,
~`'
.,.* ,j
. .
~ .
.~
,,~",
:
.
.
13 -
:, .. .
~ ',
.
7747~
.~
.~ , .
., .
: ,~ N\
R3 ~ / N
S /N ~ (V) -
R~ H2
2 CH 0
'~, 1
R5 ~ / ~ R4
^., ~ :
(wherein Rl, R2, R4 and R5 are as hereinbefore defined and R3 represents a
hydrogen atom, a straight and branched chain alkyl or ~-hydroxyalkyl group
, ~ ,
containing from 1 to 3 carbon atoms, a cycloalkyl group containing from 3 to
6 carbon atoms tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl,
pyridyl, N-methyl-dihydropyridyl, piperidyl, N-methylpiperidyl, pyrrolidyl,
,~." ,
~: thienyl or tetrahydrothienyl.
~- The reaction is preferably effected at temperatures of from 100
. . .
to 250C and may be carried out either in the presence or in the absence of
a solvent, suitable solvents including, for example, methanol, ethanol, dioxan,
,.,~ ;~ ,
; chloroforn, tetrahydrofuran, benzene, toluene, xylene or mixtures thereof.
e reaction mayalso, if desired, be carried out in the presence of an acid
catalyst e.g. hydrochloric, sulfuric, phosphoric, polyphosphoric, acetic,
: ,
.; propionic, benzenesulfonic or toluenesulfonic acid.
,.. .
,.:
:~ ,
`' :
,.... .
, ,.
... .
, ~,
. ~ .
.' ,
.,
,'~:,
.
- 14 -
- ;_ , . .
: . . .
- ,-, - : - : :
. .:
77475
~'`' '
e intermediate product formed during the reaction, having the
formula:
/ NH - NH - COR'
>
R2 CH -
i,~.; : ~
is not isolated.
When the above campounds of general formula V are prepared from
a compound of formula III in which X represents a chlorine or bromine atom,
then the compound of formula III is preferably prepared in situ.
e above compounds of general formula V wherein R3 represents
a hydrogen atom, a straight or branched chain aIkyl or ~-hydroxy,~lkyl group
contains from 1 to 3 carbon atoms, a cycloalkyl group containing from 3 to
6 carbon atoms tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl,
pyridyl, N-methyl-dihydropyridyl, piperidyl, N-methyIpiperidyl, pyrrolidyl,
thienyl or tetrahydrothienyl may, if desired, be converted by chlorination
or bromination into further compounds of general formula V wherein R3 re-
presents a chlorine or bromine atom. The chlorination or bramination is
preferably effected in the presence of a solvent such as carbon tetrachloride,
chloroform, methylene chloride, dioxan, tetrahydrofuran, dimethylformamide
~:,
f~
.:
'-::,
,~ .:.` '
:.~
. . .
''''' '
,. ,.~
"-.',
, .
; n~ - 15 _
. ..
, ~ ~ . , .
: `
.- -~ 10774~7S
i . ,.~ .
~ or a hydrocarbon and preferably at temperatures of from
; ambient temperature to the boiling point of the reaction
...:
:~. mixkure. Chlorination or bromination may, for example, be
carried out by means of chlorine or bromine or by means of
N-chloro- or N-bromo-succinimide and is desirably effected
-~ in the presence of a tertiary organic base.
me compounds of general formula V (wherein R3
represents a chlorine or bromine atom or represents a hydro-
." ~ .
gen atom, straight or branched chain alkyl or ~-hydroxyalkyl
,:
~ 10 gFoup containing from l to 3 carbon atoms, a cycloalkyl
, . . .
~ group containing from 3 to 6 carbon atoms tetrahydrofuranyl,
,,,;,,.
tetrahydropyranyl, tetrahydrothiopyranyl, pyridyl, N-methyl-
dihydropyridyl, piperidyl, N-methylpiperidyl, pyrrolidyl,
thienyl or tetrahydrothienyl are themselves novel compounds
~,:
; and constitute a further feature of the present invention.
According to a still further feature of the
present invention there are provided compounds of general
formula VI,
,A . I . ,
i~;~ ,;,.
i~;.,'~ .
~ .
~'~
~, '
~'',
.j ' '
.~.,~ . .
', '
i'.. ;' ' ,
i':''
i.'.',
-~ ID - 16 -
: ~ -., , . , . ~ ,
.. ,: . : , . ~ ,, .
,, . , - - , , ~, :. -
"'.' . . , : , , -' ': ' , ~.: - :
;.` 1~77~7~
.. . .
~ .
,............................ .
.,
,. . .
:,:
~ . .
... .
.,.,~,
~ N
,.~ ~ \
,............................ R3 - C 7
~.~ N C
: ~ 1 ~ / H2 (VI)
. ~ R2 ÇH N
I H
~: R5 ~ R4
~ '
,,~. .
(wherein Rl, R2, R3, R4 and R5 are as hereinbefore defined).
,~ The compounds of general formula VI are novel
~l compounds also useful as intermediates in the preparation -
!:- j 20 of substituted 6-aryl- 4H-s-triazolo-[3,4-c]-thieno-[2,3-e]-
1,4-diazepines. They may, for example, be prepared by
':~ reaction o a compound of formula VI',
'..;~
:
;S~ ..J
x~
'
~'
,.;:.. i .
",.,q,
i"", ~ .
. . .
.
.'' ;:
:- ~ 17 -
~;
i ~ -
.
;
~``. 1077475 -
Hz-Hal2 (Vl ' ~
~'~ R2 ICH-Hall -
R5 ~3 14
'
(wherein Rl, R2, R3, R4 and R5 are as hereinbefore defined
and Hall and Hal2, which may be the same or different, each ~-
represents a chlorine or bromine atom) with ammonia or an ammonia
~,,
precursor such as, for example, urotropine.
~;, The reaction is preferably effected in the presence of
~, a solvent such as liquid ammonia, Q lower alcohol, e.g.
methanol or ethanol, ethyl acetate, dioxan, tetrahydrofuran
~, or an inert hydrocarbon e.g. benzene or a homologue thereof.
10 Preferred reaction temperatures are from 0C to the boiling
point of the reaction mixture. It is particularly preferred
~, that the reaction is effected in an autoclave.
,; The compound of formula VI' may itself be obtained,
;,-~ if desired, by reaction of a compound of formula V',
~.;,~,
~. .
:,,s~
~' :
,, ~
,
:
.~
,......................................................................... .
c: ~.` - 18 -
;. !
,. . ~. . ,
, ` . , .
r~
` 10774
~. '
,
;`, ~ N \
R3 ~ //N
~ ~ CH2
i~:'i'. ~ ~
R2 fH - Y (V')
R4
~:'
'~ (wherein Rl, R2, R3, R4 and R5 are as hereinbefore defined
and Y represents a chlorine or brominè atom or a hydroxy group) with
a phosphorus or sulfur chloride or bromide e.g. thionyl chloride or
bromide or phosphorus trichloride or tribromide. The reaction is
preferably effected at temperatures of from 0 to 40C, most preferably
about 20C. As will be appreciated, if, in the compound of formula V'
Y represents a hydroxy group, then, on reaction with the phosphorus
or sulfur chloride or bromide, a compound of formula VI' wherein
Hall and Hal2 are identical will be obtained.
The compound of formula V' may, for example, be obtained
from a compound of formula V as hereinbefore defined. Thus,
when it is desired to obtain a compound of formula V' wherein
Y represents a chlorine or bromine atom, the compound of formula V
is treated with concentrated hydrochloric or hydrobromic acid,
preferably by allowing the two reagents to stand together for from
~; several minutes up to several hours at ambient temperature. When it
~,1 . .
'
~, '
,'`. ~W - 19-
. . ,
;,, , ,, . . , : : -
,;, .. , , . , . ~ ,. .
r
` ` 10774~75
is desired to obtain a compound of formula V' where Y
represents a hydroxy group then preferably the compound
of formula V is heated in a concentrated acid solution.
~;;` In either case the compound of formula V' is preferably
'~ isolated from the reaction mixture by extraction with a
... .
~i solYent immiscible with water, preferably a chlorinated
:,.
....
~; hydrocarbon e.g. chloroform or methylene chloride.
The compounds of general formula VI may, if
;: .
~ desired, be directly converted into compounds of general
,. .~
formula VII,
~'
~,) R3 ~ / N
R2~ H2 (Vll)
R5 \ ~ 4
~ 20
,1 ~wherein Rl, R2, R3, R4 and R5 are as hereinbefore de-
~,' ined) by dehydrogenation. Suitable dehydrogenating
~ agents include, for example, the halogen or reagents
,~' containing chromium or manganese in a high oxidation
r'l stat~
:.l, ':
;~ When the dehydrogenation is effected by means
~ of a halogen then the dehydrogenation is preferably ef- -
;~ fected in the presence of a chlorinated hydrocarbon e.g. ~-
: - .
,:.
20 -
(, : -
~,' , ~ .
''~ .
:'
- ' - ' ' ' '- ~ ' . '.'- ' ' ~ ' : ' :
` ~077475
.~, ~` ; -
.,,':,,: .:
chloroform or methylene chloride, as solvent. Advantage-
~; ously the dehydrogeneration will be carried out in the
presence of a tertiary organic base e.g. pyridine, the
said base serving as a binding agent for the hydrogen
halide formed during the dehydrogenation. If, in the
compound of formula VT R3 represents a hydrogen atom,
~;, . .
`;~ then it will be appreciated that the use of excess
~/, r
halogen in the dehydrogenation may lead to some replace-
ment of the said hydrogen atom by the halogen. If it is
desired to obtain a compound of formula VII wherein R3 re-
presents a chlorine or bromine atom from a compound of
formula VI wherein R3 represents a hydrogen atom then the
dehydrogenation should be effected with an excess of
chlorin~ or bromine.
The dehydrogenation of the compound of formula
VI may also be effected, if desired, using a reagent con-
talning chromium or manganese in a high oxidation state
e.g. Mn with a valence of 7 or Cr with a valence of 6.
~' Suitable reagents include, for example, chromates, dichro-
~i 20 mates and permanganates. In this case the dehydrogenation
is preferably effected m solvents such as acetone, tetra-
~, hydrofuran or dioxan, and preferably at temperatures of
~ from 0C to the boiling point of the reaction mixture.
~
'",.
,. ....
..;,
.~,; .1
~
.
,~,,
:s~'
` ~
~ - 21 -
.~, ~ -
;`,` 1077475
~`
me compounds of general formula VII may, if
;-.,.
~ ~ desired, be converted into their pharmaceutically acceptable
~ .:
acid addition salts by reaction with an appropriate acid such
as, for example, sulfuric, phosphoric, nikric, succinic,
cyclohexylsulfaminic, citric, tartaric, ascorbic, maleic,
formic, salicyclic, methanesulfonic, toluenesulfonic or a
hydrohalic acid.
ii me co~pounds of general formula VII have previously
: been described in Canadian Patent Applications Nos. 220,982 and
315,113 as well as in German Offenlegungsschrift No. 2,229,845.
By various pharmacological test methods these conpounds, together
,; .
with their pharmaceutically acceptable acid addition salts, have
`~ been shown to possess anxiolytic,tensiolytic, muscle relaxant,
: antiaggressive and anticonvulsive activity, particularly in
a dosage of from 0.1 to 3 mg/kg, whilst having a low toxicity.
ey also have the ability to considerably increase the up-
~, take of food in warm-blooded animals.
~, mus, according to a yet still further feature ofthe present invention we provide pharmaceutical compositions
;~ 20 comprising, as active ingredient, a compound of formula VII
"~,
as hereinbefore defined prepared by a process according to the
- present invention, or a pharmaceutically acceptable acid
` ::
.'' ' ~ ~
~, :
..
:- :
':
,
.:
22 ~
.
-
: ` -
~;~.'f`'` 11)77475
.` j~
;, . .
1 5., .
addition salt thereof, in association with a pharmaceuti-
cal carrier or excipient.
`?
."~
~'
~ ,
,' '
: ~
~ .
,.
,~.
,, , ~ ,
!,. - 23 -
!;- .
~; 1. . .
: 107747S
,`:.
J. The following non-limiting examples serve to illustrate the present invent-
` ion:
` Example 1
8-Bromo-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[3,4-c]-thieno-[2,3-e]-1,
4-diazepine
'`.
a,~) 314 g (1 mol) of 2-chloroacetylamino-3-(o-chlorobenzoyl)-thiophene
are dissolved in 500 ml of dimethylformamide and the solution obtained is
-` mixed at 0C while stirring vigorously for one hour with 36 g of pulverised
~ sodium borohydride. The resultant mixture is subsequently poured into 2 ltr.
,., :
. 10 of ice-water, whereupon a smeary precipitate forms. The aqueous phase is
decanted off and the grease is washed 2 or 3 times with water and then taken
'~"- up in methylene chloride. After drying of the methylene chloride phase and -
" evaporation, 300 g of an oil are obtained, which solidifies gradually and is
then recrystallized from methanol-ether.
294 g (93.1% of theory) of 2-chloroacetylamino-3-[(o-chlorophenyl)-
hydroxymethyl~-thiophene of m.p. 118 - 120C are obtained.
This oil may be used directly in the cyclisation reaction.
~) 253 g (0.8 mol) of 2-chloroacetylamino-3-[(o-chlorophenyl)-
hydroxymethyl]-thiophene, dissolved in 200 ml of isopropanol, are added to a
boiling solution of 52 g (2.25 mol) of sodium in 1.8 ltr. of isopropanol.
The resultant mixture is refluxed for 5 minutes. Subsequently, the brownish
suspension thus formed is poured into 1.5 ltr. of ice-water and the solution
obtained is acidified with concentrated hydrochloric acid. A precipitate is
formed which is filtered off with suction and washed with water. The moist
`; residue is then dissolved in 2 ltr. of methylene chloride, dried with
magnesium sulfate, evaporated and the residue is recrystallized from methanol.
.
242 g (87% of theory) of 5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-
oxazepin-l-one of m.p. 175 - 176C are obtained.
; b) 27.9 g (0.1 mol) of 5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-
oxazepin-l-one are dissolved in 300 ml of chloroform and 8.5 ml of pyridine.
A solution of 5.5 ml of bromine in 50 ml of chloroform is added thereto over
a period of 10 to 15 minutes at room temperature. Decoloration takes place
:
-~ - 24 -
; .
., ~ .
.. , , . , , ~ ~':,. . :' - .
107747S
..:.
~; immediately. The title compound precipitates and is filtered off with
. suction and washed with ether.
.
i~ Yield of 7-bromo-5-(o-chlorophenyl)-thieno-r2,3-e]-4,1-oxazepinone:
t~i;
30 g (83% of theory) of m.p. 178 - 180C (decomp.).
c,~) 35.8 g (O.l mol) of 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-
oxazepinone are heated with 350 ml of diglyme, 24 g of P2S5 and 19 g of
NaHCO3 for 30 minutes at 60C. The mixture thus obtained is subsequently
poured into approx. 1 ltr. of ice-water, whereupon a crystalline product
precipitates out. The precipitate is filtered off with suction, washed with
water and dried.
37 g = 99% of theory of 7-bromo-5-(o-chlorophenyl)-thieno~2,3-~
;~ 4,1-oxazepine-2-thione are obtained.
M.p. from 200C (decomp.).
) 37.5 g (0.1 mol) of 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]-4,1-
!;.
~, oxazepine-2-thione are dissolved in 370 ml of tetrahydrofuran and the solution ~-
obtained is mixed with 10 ml of hydrazine hydrate. After 5 minutes at room
temperature reaction is complete and the solution is subsequently evaporated.
'J' The residue is taken up in methylene chloride and the resultant solution is
r .j
~, washed several times with water. The methylene chloride phase is then
~;- 20 separated and evaporated. The residue is taken up in 200 ml of ethanol
?'i; and mixed with 50 ml of o-triethyl acetate. The mixture obtained is refluxed
, after 30 minutes and then evaporated in vacuo. The residue is crystallized
with ether.
Yield of 8-bromo-6-(o-chlorophenyl)-1-methyl-thieno-[2,3-e]-
triazolo-[3,4-c~-4,1-oxazepine: 34.5 g = 87% of theory of m.p. 146 - 148C.
d,~) 39.6 g (0.1 mol) of 8-bromo-6-(o-chlorophenyl)-1-methyl-thieno-
[2,3-e]-triazolo-[3,4-c]-4,1-oxazepine of m.p. 146 - 148C are suspended in
.~ 250 ml of conc. hydrobromic acid. As soon as a clear solution has formed
~.:
-~ ~after lS to 20 minutes), it is diluted with 300 ml of ice-water and the
- 30 resultant solution is shaken with methylene chloride. The methylene
i' chloride phase is separated, dried and evaporated. The residue is crystal-
:; lized with ether. 52 g of 3-methyl-4-[3-(_-chlorophenyl-bromomethyl)-5-
- 25 -
; -- 1077475
.``'
bromo-thienyl-(2)~-5-hydroxy-methyl-1,2,4,-triazole hydrobromide (94% of
theory) of m.p. 200C (decomp.) are obtained.
~) 27.9 g (0.05 mol) of the hydrobromide obtained above are stirred
.,, - .
;~ with 100 ml of thionyl chloride for 30 minutes at room temperature. Excess
. .
- thionyl chloride is then distilled off in vacuo and the residue is taken up
~: in methylene chloride. The solution obtained is washed with ice-water and
i ' . '~ r" then a dilute ammonia solution. The dried methylene chloride phase is
. ~..................................................................... . .
subsequently evaporated and the residue is triturated with ether.
.~.:
Yleld: 24.2 g of 3~ethyl-4-~3-(o-chlorophenyl]-bromomethyl)-5-
~; 10 bromo-thienyl (2)]-5-chloromethyl-1,2,4-triazole of m.p. 167-169C.
~) 12.4 g of the compound obtained in the previous stage are dissolved
~. , .
in 270 ml of methanol and 100 ml of liquid ammonia are added thereto. The
solution thus formed is heated for 30 minutes at 100C in an autoclave and ~
then evaporated. The residue is taken up in methylene chloride and the ~-
solution obtained is washed with water, dried and evaporated. The residue is
recrystallized from methanol. Yield of 8-bromo-6-(o-chlorophenyl)-1-methyl-
thieno-[2,3-e]-triazolo-~3,4-c]-5j6-dihydro-1,4-diazepine: 9.0 g = 91% of
theory of m.p. 160 - 162C.
e) 39.5 g (0.1 mol) of 8-bromo-6-~o-chlorophenyl)-1-methyl-4H-s-
~'~'r~ 20 triazolo-~3,4-c~-thieno-[2,3-e]-5,6-dihydro-1,4-diazepine of m.p. 162C
~;i
are dissolved in 500 ml of methylene chloride and 15 ml of pyridine. The
, solution obtained is mixed, within 10 minutes while stirring at room tempera-
;~ ture, with 10 ml of bromine in 50 ml of methylene chloride. The solution,
.
which decolours immediately, is stirred for 30 minutes and then extracted
several times with water. The organic phase is dried and evaporated and the
~, residue is recrystallized from ethanol.
Yield: 32 g = 81% of theory of m.p. 208 - 210C.
il Very good yields are also obtained if the dehydrogenation is ef-
fected with potassium permanganate, as described hereinafter in Example 3.
: . .................................................................... .
' 30 Example 2
` 8-Bromo-6-~Q-chlorophenyl)-1-[tetrahydropyranyl-(4)]-4H-s-triazolo-[3,4-c]-
'`-'' thieno-12,3-e]-1,4-diazepine : ~.
, 3.75 g (0.01 mol) of the 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]
,....................................................................... .
- 26 -
' ~ ' '
i -- lQ77475
~.`
... .
~; -4,1-oxazepine-2-thione lobtained in accordance with Example 1 c, ~) are re-
fluxed with 100 ml of dioxan and 1.5 g of tetrahydropyrano-4-carbonic acid
hydrazide for 30 min. The mixture obtained is then processed further as in
Example 1 c, ~).
Yield of 8-bromo-6-(o-chlorophenyl)-1-[tetrahydropyranyl-(4)]-
thieno-~2,3-e~-triazolo-r3,4-c]-4,1-oxazepine: 2.7 g (58% of theory) of m.p.
182 - 184~C. -
Analogously to the processes described in Examples 1 d) and 1 e);
~ the title compound is obtained via 8-bromo-6-(o-chlorophenyl)-1-[tetrahydro-
,~ 10 pyranyl-~4)]-thieno-[2,3-e]-triazolo-[3,4-c]-5,6-dihydro-1,4-diazepine of m.p.
~1 174 - 175C.
;.,' Yield: 98% of theory; m.p. 157 - 158C.
Example 3
8-Bromo-6 (o-chlorophenyl~-l-cyclohexyl-4H-s-triazolo-[3~4-c]-thieno-[2~3-e]
1,4-diazepine
4.65 g ~0.01 mol) of 8-bromo-6-(_-chlorophenyl)-1-cyclohexyl-4H-s-
~i~ triazolo-l3,4-c]-thieno-~2,3-e]-5,6-dihydro-1,4-diazepine of m.p. 192C
'~ ~obtained from 7-bromo-5-~o-chlorophenyl)-thieno-[2,3-e]-4,1-oxazepine-2-
thione (Example 1 c,~), m.p. 200C via 8-bromo-6-(o-chlorophenyl)-1-
cyclohexyl-thieno-[2,3-e~-triazolo-[3,4-c]-4,1-oxazepine (see Example 1 c,~),
m.p. 172 - 174C according to the process described in Example 1 d,~ ]
are dissolved in 100 ml of acetone distilled via KMnO4. While boiling the
solution thus obtained there are added thereto with stirring, first 3 g of
.".
sodium dichromate in 15 ml of water and then 2 ml of 20% sulfuric acid.
Boiling is continued for 30 minutes and then the solvent is distilled off.
The residue is diluted with some water and the solution obtained is made
ammoniacal and then extracted with methylene chloride. After washing and
drying the organic phase is evaporated to leave a crude product, which is
recrystallized from ethanol.
3Q Yield: 4,1 g = 88% of theory of m.p. 190 - 192C.
Instead of sodium dichromate, potassium permanagnate may be used
,~
- 27
.. ~ - .
`?
`-` 10774~5
. . .
!' ~
~for the dehydrogenation. In this case the procedure is as follows:
;.,
4.65 g (0.01 mol) of 8-bromo-6-(o-chlorophenyl)-l-cyclohexyl-4H-s-
triazolo-I3,4-c~-thieno-r2,3-e]-5,6-dihydro-1,4-diazepine are dissolved in a
mixture of 50 ml of acetone and 50 ml of methylene chloride. 1.4 g of finely
diyided K~nO4 are added thereto in one portion and the solution obtained is
stirred for 6 hours at room temperature. Manganese dioxide separates out.
The solution is filtered with suction over kieselguhr and the light-yellow
filtrate thus obtained is evaporated. The residue is triturated with ether.
4 g = 86% of theory of the title compound of m.p. 190 - 192C are
obtained.
Example 4
1,8-Dibromo-6-(o-chlorophenyl)-4H-s-triazolo-r3,4-c]-thieno-[2,3-e]-1,4-
diazepine
3.8 g ~0.01 mol) of 8-bromo-6-(_-chlorophenyl)-4H-s-triazolo-
I3,4-c]-thieno-r2,3-e]-5,6-dihydro-1,4-diazepine of m.p. 178C [obtained
from 7-bromo-5-(Q-chlorophenyl)-thieno-r2,3-e]-4,1-oxazepin-2-thione via 8-
bromo-6-~o-chlorophenyl)-thieno-[2,3-e]-triazolo-[3,4-c]-4,1-oxazepine (m.p.
182C) analogously to Example l d, a)-~] are dissolved in 50 ml of methylene
chloride and l ml of pyridine. Over a period of lO minutes are added thereto
1.5 ml of bromine in 15 ml of methylene chloride. The mixture thus obtained
is then refluxed for 30 minutes, washed with water, dried and evaporated.
The resultant concentrate is applied on a SiO2 column and eluted with -
methylene chloride containing 2% methanol.
:c' ;: :
.~ The first main fraction contains 4.2 g of the title compound of
:,
m.p. 209 - 210C = 92% of theory.
Analogously to the procedure described above the following products
were obtained ~ia the named intermediates:
. ,,
~'' .
:
''', ''
'
.~.
:
.', - '.
;
28
, _ _
. .
. ~ ,: . . , . ~ . : . .
, .. : . . . .. . .
:. , ' ,. , . .: - :- ''
:
~077475
, . .
,` ,
,.~., ~
H
O~ 0 N 0~ ~ OIn O
O N N ~~ N N_I N--I N N
~7 ~ i~ I I II I I ~ I I I I I
.~" . ~ 1/~ ~ ~00 0 ~ NCO ~ ~
~l~~ 4 h NONO N--I N ~ N--I G~ N NO
~.,.',~.,. ~ ~
_ ,.,
i ~ l
~ ~.
t~ N N O N N n 00 00
~) ~D ~ ~00N N ~~) I~Il~
. ~ ~ ~1 ~ I N ~ I N_I
33~ .. ~ I I o o a~ o o ~ `D ~
~,r.P~ ~ r~t~'l00 N _I~D G~1~U)r~ O t~
',~~ ~3 ~ IH N ~1 ~ I N H
.~:, :':
j~ .'
~ h . ~ .
~' .~
D ~ c~ 0 'J ~ I~
~:; ~ I I Io I I I I Iooa> I
:'i. .~1 t~ ~ O5~ 0 N Ncr~ . .
~ ~ ~ N1~ CO ~ ~ ~1
~q ''
~ f~ ~
~, ~ ~_ ~ ~ ' .
.,~ ~ ~ ~ OO ~ O O O O O O O
~r'r;~C~ ~ ~ Nu~ .tlooco oooOoooo oo
., D ~ ~r N~1_I N r-l_I
Ul00 ~ 0000 00000000 Ot~
.', ~ ~ ~ N ~~ ~ ~I~ I~t~1~ ~ t~
. ~3 ~3 ~ N~1~ I
,."S,,
'~. '
~ ~ ~ X X X ~ X X ~ ~i
.
`.,'' ,,
j.~i ~ ~ ~ .:
i~.i
~ :'''
~ ~ ~~ ~ ~ ~ O O
~, ~ ~ ~ ~, a S t~ N h
~;~,.",' :C . -
N t~
~1 ~ ~ Xi~ S ~ X ~T~ ~ S S Ci X
_ l
:~ h _ h ~ , h h h h -~i h h .
,., ~ . .
,.,,,~,~
2 g
i::
:- .
.',' ~ : ' ' . . . . .
~ .. . . .
