Note: Descriptions are shown in the official language in which they were submitted.
This invention relates to a novel class of compounds
having useful central nervous system (hereinafter abbreviated to
'CNS') activity and/or which are useful as intermediate in pre-
paring such active compounds. The invention also includes processes
for preparing the novel compounds of the invention. Furthermore,
-the invention includes wi-thin its scope pharmaceutical compositions
containing the active compounds and methods of treating animals,
including humans, comprising administering thereto an effective
dose of the compound or compounds or of pharmaceutical compositions
comprising the active compound or compounds. More particularly,
the invention is concerned with the hitherto unknown thienoIl,5]-
benzodiazepine ring system depicted belo~:
8 9 10
6 ~ 4 ~ 2
where the symbol :
2Q signifies a thiophene ring.
In recent times, there has been intense activity in the
area o~ pharmaceutical chemistry relating to tricyclic and benzo-
diazepine systems. A large number of patents have issued of which
United Kingdom Patents Nos. 980,853; 1,291,684; 1,380,242;
1,380,243; 1,380,244 and United States Patents Nos. 2,893,992;
3,102,116; 3,109,843; 3,~36,815; 3,474,099; 3,654,286; 3,749,786
and 3,842,082 represent only a very small proportion.
According to the present invention there is provided a
novel thieno[l,53benzodiazepine of formula (I):
~I N / 3
or a pharmaceutically acceptable acid addition sa~t thereof,
wherein Rl and R2 independently represent hydrogen, Cl 4 alkyl, C~ 4 alkenyl,
. C3 6 cycloalkyl~ halogen~ Cl 4 haloalkyl9 nitro~ amino, C2 4 acylamino,
.~ hydroxyl9 Cl 4 alkoxy, Cl 4 alkylthio or a group of formula -502N(R4)2 or
LO So2R4, where R4 is Cl_4 alkyl;
where ` -
wherein R6 is hydrogen, phenyl optionally substituted by halogen or Cl 4 ~ :
loalkyl~ C1_4 alkyl~ C3_6 cycloalkyl C2_4 alkenyl, Cl 4 alkanoyl~ ben~yl,
Cl 4 carbalkoxy or -(CH2)nOX, where n is 2 or 3 and where X is hydrogen or : :
~ an ester radical; or ;
(B) R is a group of fonmula :
¦ -NH-(CH2)D-Z ¦ I
i vhere n is 2 or 3 and ~ is . .
~ ~ 3
D where R is as above defined,
~ ~ _ 3 D
(ii) ~N ~
(ii~) -N O
(iv) -N ~ -~
R " '
, ~ :
where R~' and R ~ ~ are independently hydrogen or Cl_4 alkyl, or
~nd wherein the group
; represents a thiopher.e ring optionally substitu~ed by one or two groups
selected from Cl 8 alkyl, C ~ 4 alkenyl, Cl 4 haloal~yl, C2 4 alkanoyl,
nitro, halogen, and phenyl optionally substituted by one or more groups
~; selected fr-~; halogenz trifluoromethyl, methyl, metho~y or nitro, fused
to the diazepine nucleus.
Prefer~ly~ in the compounds of for¢.ula (I) and their r.cld addltion
~: si~"lt5~ Rl and R2 independer,tly represent hydrogen~ Cl 4 alkyl7 I.. logen;
Cl ~ haloc,.lkyl, nitrot amino~ Cl 4 alkoxy~ Cl 4 alkylthio or a group of ~:
fonmuela -S02N(R )2 w~.ere R4 is Cl 4 alkyl;
; (A~ ~ is a group of form~.la :
-N N R6
~herein R6 is hydrogen, phenyl optionally substituted by halogen, Cl 4 alkyl,
- ¦ Cl 4 carb~koxy or -(CH2)nOH where n is 2 or 3; o~
: . ~ (B) R5 is a group of formula :
where n is 2 or 3 and Z is
where R is as deiined i = ediately ~bove,
( ii ) -N~
~ ' A
: . . (iii) -N 0
`, 20 o~
(iv) <R "
where R~ a~d R~ are independently hydrogen or Cl 4 alkyl~
~' Those skilled in the srt will appreciate that the novel thieno[l35]benzo-
¦ dlazep~nes of the ~n~entîon can exist in three forms which can be
¦ represented by the following structures :
~ 11 . _ 5 _
_ ~ (DII)
~5 ~ V)
: 20 In the above structural formulae, for ease of LepreSentatiOnl the
thiophene ring is shown as unsubstituted but it is to be understood that
: the thiophene ring may be substituted,for instance, by one or two groups
: selected from Cl 8 alkyl, typically Cl_6 alkyl~ C2_4 alkenyl~ Cl_~ haloal y ,
C2 4 alkanoyl, nltro, halogen and optionally substituted phenyl. In add~tlon,
~; 25 in the structures of formulae (II) and (IV)7 the thiophene ring may be fused
to a G3 8 cycloalkyl ring.
` ~referred compounds fallin~ within the scope of compounds defined in
.. any of forntulae ~I) to (IV) above are those having one or ~oTe of the
~ ~ 30~ ~ ollowins char.c eris~ice :
~:~ ~ .
~,~ , : ' ~ .
~ !1 -- 6 ~ ~ r~
~ ' ', ' ' . . ' ' . ' ' ' . . ' ' ' ' . '
~07 56t3 7
(~) Rl is a 6 or 7-halo substituent, such as chlorille or 1uorine;
(B) Rl is a 7 halo substituent such as chlorine or fluorine ~hen R
(C) Rl is a 7-Eluoro substituent ~hen R2 is hydrogen;
(D) R2 is hydrogen;
(E) R or R i9 trifluoromethyl;
(F) Rl is a 6- or 7-trifluoromethyl substituent wllen R2 is hydrogen;
(G) Rl or R is methylthio or methoxy;
(H) Rl and R both represen~ halogen atoms, for example fLuorine;-
(I) R5 is a group of formula :
where R6 is hydrogen, Cl 4 alkyl, benzyli or (CH2)ll0X;
(J) R5 is a group of formuLa :
15 . A
~'`, . ,, /
~K) the compound o~ formula ~I) has the structure (II);
(L) the thiophene ring is substituted by a Cl ~ allcyl group; such as ethyl;
(M) the thiophene ring is unsubstituted,
(N) the thiophene ring is substituted by an electron withdrawing group
such as halogen~ nitro~ trifluoromethyl or C2_4 alkanoyl.
A presently most preferred class of compounds is that having features
(A) to (E~ (J) and (L).
,~ 25 One particularly active compound falling within this class which may be
mentioned is 2-ethyl-7-fluoro-lO-(4'-methyl-l'-piperazinyl)-4H-thiello~93-b~-
~l~S~benzodia~epine, both in the form of its free base and pharma~eutically
~ I acceptable saIts thereof.
i ~ The term "Cl ~ alkyl" as used herein means a stralght or branchad chain
, alkyl group containing from 1 to 4 carbon atoms, l.e. m thyl, ethyl, _ -
propyl, n-butyl, s-butyl, isobutyl~ and n-butyl. The term "Cl_4 haloalkyl"
means the aforesaid alkyl groups substituted by one or more halogen atoms,
7 _ ~7
j~' ' , ' ' ', . ' ' "~' ,.'' .' '' "' '' ' , ' ' ' ~ ,
';, , . .' ' ' ' : . ~
e.g. trifluoromethyl. The terms "Cl ~ alkoxy" and "Cl 4 alkyLthio" refer
to the aforementioned alkyl groups attacl-ed through all oxygen or suLphur
atom respectively to the benzene or thiophene ringO
The term"C2 4 alkenyl" refers to groups such as viny~ allyl and butenyl.
The term "amino" as used herein indicates a group of formula NH2 and
also substituted amino groups such as mono-Cl 4 alkylamino and di-Cl 4
alkylamino groups. The term C2 4 acylamino means an amino group substituted
by a C2 ~ acyl group such as acetylO The term "Cl 4 alkanoyl~' refers to
groups such as formyl or acetyl. ;`
''C3 8 cycloallcyl" means a saturated ring having Erom 3 to 8 carbon atoms
in the ring such as cyclopropyl~ cyclobutyl, cyclopentyl, cyclohexyl9 or
cyclooctyl. The term "optionally substituted phenyl" as used herein means a
phenyl group unsubstl~uted or substituted by one or more gro~lps such as
halogen~ trifluoromethyl, methyl~ methoxy or nitro. I-
Examples which may be given of the compounds of the ln~rention are -
benzodiazepine ~ '
2-ethyl-7-nitro-10-~4'-methyl~ piperazinyl)-4H-~hieno[2,3-b][1~5~benzodiaze- jpine ¦
~2 9 3-b]~1,5~be~zodiazepine I~
,, 2-pentyl-7-fluoro-10-(4~-methyl-1-piperazinyl)-4H-thienoC2~3-~[1~5~benzo- ',
- 8 -
epine ~ .
1~2~dimethyl-7-chloro-10-(4'-methyl-1' plperazinyl)-4H-l:hienoC2,3-b~[1~53benzo- ,~.
: 20 . 2-vinyl-7-fluoro-10-(4t methyl-1'-plperazinyl)-4H-thieno[2~3-b~[1~5~benzo-
7-chloro-2-ethyl~10-(4'-methy~ piperazinyl)-4H-thieno[3,2-b3El~s3beLlzodiaze ¦p~ne ,
: ~: pine
~-ethyL-7-trif luoromethyl-lOA- (4 ' -methyl-1 ' -piperazinyl )-4H thieno[3 ~ 2-b~ C1~ 5 j
7-amino-2 eth~ l.0-~4'~met}lyl-L'-piperazillyl)-4~ thieno~3,2 b~[l75]benzodiaze-
; 6~7-difluoro-2-ethyl-10-~4'-me~hyl-1'-piperazinyl)-4H-thieno[3~2-b~[1~5~benzo- :~
. 7-fluoro-10-(4'-methyl l'-plperazinyl)-4H-~hieno[3~2~b~[1~5]benzodiazepine
2~d~nethyl-7-chloro-10-(4'-methyl~ piperazinyl)-4H-thieno[3~2 b~[l~5]benzo-
:~ 2-ethyl-7-fluoro-10-~4l-(2-hydroxyethyl)-l-pipera7.inyl~-4H-thieno~2,3-b~ 53
,'. ~' 10-
. . -
~ 756~37 -~
¦ 2-ethyl-7-fluoro~lo~ -piperazinyl)-4H-thie~o[293-b~l95~ben2odi2zepine
: 10 2-ethyl-7-chloro 10-[3'-(4-hydroxyethyl-1-piperazinyl)propyl~amino-4H~thieno-
. 3-methyl-7-chloro-10-(4'-methyl~ piperazinyl)-4H-thieno[3~4-b][1,5~benzodiaze-
7-methyl~mino 10-(4'-methyl-l'-piperazinyl)-4H-thieno[293-b~ 5~be~30diaze-
. i I pine
., I . 6~fluoro-10-(41-methyl-l'-piperazi~yl)-4H-thieno[3~4-b~rl,5~ben2odiaze-
~ 10756~ '
As indicated above, the novel thieno[l,S~enzodiazepines of the invention
are useful both in their free base and acid addition salt forms. The acid
addition salts are preferably the pharmaceutically acceptable, non-toxic
addition salts with suitable acids, such as those with lnorganic aclds~ for
.~ , example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids,
or with organic acids, such as organic carboxylic acids, for example, gl3rcollic 7
~;~ maleic, hydroxymaleic, fumaric,malic, tartaric, citric, salicylic, o-acetoxy-
.. benzoic, n~cotinic or isonicotinic: acid, or organic sulphonic acids for exampl
. ~ methane sulphonic~ ethane sulphonlc, 2-hydroxyethane sulphonic, toluene-~-
sulphonic, or naphthalene-2-sulphonic acid Apart from pharmaceutically
~ 25 acceptable acid addition salts, other salts are also included within the
.~. scope o acid addition salts such as~ for example, those with picric or
~j~ . oxalic acidj they may serve as inter~ediates in the purification of the
compounds or in the preparation of other, for example, pharmaceutically
. acceptable, acid addition salts, or are useful for identification~ character-
~¦ ization cr puri i ation oi the bases.
~` - 12 -
~.,' ' : .
According ~o a second aspect of the invention there is provided a method
of preparing a compound of Eormula(I)whicll comprises ;
. (a) reacting an amine of formula R H with a compound of formula (V)~
where Rl9 R2 and R5 are as defined above and wherein
; 15 represents an optionally substituted fused thiophene ring as before, and
wherein Q represents a radical capable of belng spllt off with the hydrogen
atom of the amine R5H, followed, if desired, in the case where R5 is
I ~ ~
~ ¦ - N R-R6
and R6 is Cl 4 carbalkoxy by hydrolysis to the amine in which R6 is hydrogen;
: (b) reacting a compound of formula (VI) :
~ 13 ~
r r ~ -
with an alkylating agent of formula R X, whe~e R is as above defined with the
exception of hydrogen and phenyl, and where X is a reactive at~m, and where
desire~, forming a pharmaceutically acceptable acid addition salt of said
compound of formu~a I.
j It should be no~ed that both processes (a~ and (b) aboYe a~e "analogS~
¦Processes" of a reaetion type previously described in the literature (see,
~for example, United Kingdom Patent Specification No. 1,216,523 for the
reacti~n (a) and almost any standard treatise in the art for
re~erences to alkylation). Thus~ once the nature of the starting materials
nd final prod~cts is understood, those skllled in the art will appreciate
the identity of suitable Q and X radicals, as well as appropriate reaction
However~ it may be mentioned that the radical Q may be hydroxyl or thiol9
an alkoxr or alkylthio group containing 1 to 4 carbon atoms~ e.g. the methoxy
or methylthio group, an aryloxy, aralkylthio or arylthio group which may be
activated as a lea~ing group by substituents thereon conveniently in the aryl
moiety thereof, e.g. the p-nitrobenzylthio group, an alkyl- or arylsulpheno ~ ~
gro~p, preferably acti~ated as a leaving group by substituents on ~he ~ulphur ~:
tom and the hydrocarbon moiety thereof, e.g. a tosyl group, a halogen atom,
onveniently a chlo.ine atom~ an amgno group or a mono- or dialkyl-substituted
~mino group~ the or each slkyl substituent thereof containing 1 to 4 carbon
P~eferably~ Q is hydroxyl~ thiol~ Cl ~ alkoxy, Cl 4 alkylthio, halogen
N 2 -
Most preferably, Q is hydroxyl or thiol, w~en the intermediates of formula
~ ~V~ exist predGminantly in their amide and t~ oamide forms:
:~ R 1l
~ ¦ ~ H - C \ or / NH - C \
.'` ~ .
he~ Q is hydroxyl9 a~d thus the compound of formula (V~ ls an amide~
¦reaction (a) can be accomplished in the presence of titanium tetrachloride~
This last named rePgent has the ability to react with the amine of formula
R5~ to fonm 8 metal amine complex. Other metal chlorides ~UC~ as those
, - : , . .. ~ , . .
j ``` ~7~687 11
. l I
of zi~conium, haf~ium or ~anadium also possess this propertyc The reaction
is preferably carried ~ut in the presence of an acid binding agent such as
a tert~ary amine, ox example, triethylamine~
Alternatively, the reactlon can be carried out using excess of the amine o
formula R5H to act as acid-binding agent~
Any suitable organic solYent such as toluene or chlorobenzene can be
used although it has been found that the use of anisole is particularly
desirable at least as a co-solvent, in view of its abllity to fonm 8 soluble
complex ~ith TiC14.
If desired~ elevated temperatures (up to 140~C) can be used to expedite
the reaction. A prefesred temperature range for carrying out the reaction
lies in the range 50 to 100C.
The am~nesof formula ~V)~ i~e. where Q is NH2, can be slmilarly condensed
with the amine of formula R5H, although the yield ~rom this reaction may be
rather low. In fact, it is generally preferable to convert the amidlne lnto
the corresponding amide by alkaline hydrolysis snd use the thus formed amide
for the condensation react~on.
Th$oamides o~ fonmula (V), Q is SH~ can be prepared by treating 8 solution
of the corresponding amide in an anhydrous basic solvent such as dry pyridine
wlth phosphorug pen~asulphide. S~milarly~ the amides may be converted to
iminothioethers, iminoethers or iminohalides, or other deri~atives containing
ACtiVe Q rsdicals as spec~ied above, by treatment ~ith co~ventlonal reagents
such as, for example, an iminochloride, or phosphorus pentachloride.
; Such derivatives derived from the amides tend to be more reactive towards
the amine R H and can usually be reacted with that entity without the
necessity for the presence of TiCl4.
Compounds of formula (VI) can be alkylated by dissolving the amine in a
¦¦ suitable inert polar solrent such as ethanol, adding the alkylating agent to
the solution thus formed and refluxing in the presence of base ~ ca~ be any
s~table reactl~e atom such as chlorine, bromi~e or iodine or a reactive
g~oup such as tos~l or mesylr
~ - 15 -
Compounds of or~1ula (I) in which R represents :
-N ~ ~1
are preferahly prepared by hydrolysis of the correspondlng Cl 4 carbalkoxy
Electrophilic substitution reactions on the aroma~ic nucleus can, if
desired, be carried out on compounds of fG~mula (I) or (V) in conventional
manner to produce derivatives bearing electron-withdrawing groups on the
thiophene ring. For instance, acetylation oE an amide of formula (V~ can
be effected using acetyl chloride/SnCl4. This amide may also be halogenated
using, for example, N-chlorosuccinimide to give the corresponding chlorinated ¦
derivative Products of formula (I) in which Rl or R2 are NH2 may be acylated
or alkylated in conventional manner to form the corresponding N-acyl and
N-alkylamino derivatives N-Hydroxyalkylpiperazines7 i.e.R6 is -(CH2)nOH,
can be esterified using acid chlorides of fatty acids to give ~orresponding
esters~ such as decanoates or enanthates.
The compounds of formula (I) produced by the foregoing process may be
isolated ~ se or may be converted to their corresponding acid addition
salts using conventional methods.
The amides of formula (V) can be formed by a novel process which involves
the intramolecular ring-closure o an amino ester of formala (VII):
1 ~ ~ (VII)
where R9 is Cl 4 alkyl, e.g. ethyl, and ~l~ R2 and
30 ~ ~ [~
1; ~ . l r~ ' ' 3~r~
.. ~ . ~ ~ . . . . .. .
are as defined pre~iously~ This reactioIl can be accomplished using dimsyl
¦ sodium in a s~litable solvent~ preferably dimethyl sulphoxide.
; Alteruatively~ ,mides of formula (V) can be produced by intramolecular
ring-closure oE amino acid of f~rm~la (VIII):
~ 3 ~VIII)
using dicyclohexylcarbodiimide (D.C.C.) with a suitable solvent such as
tetrahydrofuran~ The amino acids can be obtained from the esters by
basic hydrolysis using, e.g~ NaOH/EtOH.
As mentioned previously, a convenient way of preparing ~mides of formula
(V) il~volres the following reaction :
~ > (IX)
2S ~ O
I The hydrolysis may be carried out using alkaline hydrolytic conditions~ !
, ~ for exQmple~ K2C03/H20,~EtOH.
One con~enient method of preparing amidines of formula (IX) is illustrated
,',, '~ , :
~ ~- - 17
;,'' ' ' '
~ R~ 75
~ ~ ~ R2C0
~¦ Rl~H a _ ~
~ ~ Rl NR2
~ ~ ~ ' p
Alternativel~, amidines in the ~3,4-b~ system may be prepared by the following
reaction sequence: Xl 1 Xi
L5 ~ ~ ~ heat
.~ ~ I Chloranil/xylene
2N ~ H /LdC ~ ,~
* ~ X2 R2 H 2
( I~ 5 -
¦ where X and X indicate optio~lal. s~lbstituents on the thiophene ringO As t
can be seen; ~he ahoYe reaction involves an 1'arornatisation'lleaction using
¦ chloranil and xyLene.
Alternatively9 the a~ove condeDsation reaction may be effected uslr,~
o-phenylened:;amines in pLace of the nitroanilinès~
The es~ers of formula (VII) are novel compounds which can be prepared
by condensation of a thiophene compound of formula :
wheru~ is as above def in~ ~ f ] uoro~ni troben~ene .,- formula:
in the presence of an n-butyl lithium derivative, or in the presence
of a base such as sodium hydride9 sodium amide, triethylamine~ or
K~C03 in dimethyl sulphoxide,to form a nitro ester of
formula: . .
~ - 19 ~
~ , , ,, . ,, ~ ,
which can then be reduced to the amino es~er of Eorm~ a (VII) catalytical~y~
for instclnce using hydlogen over palladium on charcoal~or chemically us:ing 1,
Zn/NH4Cl~ al~lonium pol~sulphide or Fe/HC10
For example, 4H-~hieno~2,3-b~[1,5~benzodiazepin-10-ones can be prepared by the
following illustrative reaction scheme :
C2~t Xl Rl 2 CO Et XL
~ ~ S ~ x2 ~ 2 R ~ \ N2 / ~ 5 ~ x2
/ ~10% PdC
. ~ ,
Other thienoC1~5~benzodiazepin-lO ones can be similarly prepared ¦ ~
vi.~ the asin ster route outlined above. I ¦
3D ~ ~
- 20- .
` ~ ~075687
The thiophene starting materials used in the processes of the invention
are either kno~l compounds~ see~ror example, Chem Berichte9 99~ 94-lC0,~l966)¦
and J. Chem. Soc., 68 2232 (1946)
I or can be prepared by conventional techniques from k~ow~ compounds. The
S o-fluoro nitrobenzene i~termediates are either c`ommercially a~ailable or can
be simply preparedfrom~commercially available substances.
It will be understood the scope of the invention extends not only
to an o~erall process for preparing the novel compounds of the in~ention as
described hereinbefore but ~lso to the individual synthetic steps as herein
descr~bed, and combinations of two or more of such synthetic steps. Further,
the intermediates of formula (V)~ (YII), (VIII), (rx) and (X) are all novel
compounds and are provided in further aspects of the invention.
As stated previously, the compounds of the inventio~ have useful central
nervous system activity. This activity has been demonstrated in extensive
testing in animal models using well-established procedures, such as the
production of catalepsy~ block of conditioned avoidance respo~se and reversal
of amphetamine-induced stereotyped behaviour in ratsO Specifically, the
compounds of formula (I) a~d acid additio~ salts thereof~ ara potent centrally
acting compounds with neuroleptic, sedative or relaxant or anti-emetic
properties~ These properties7 coupled with their high therapeutic index~
re~der them uQeful in the treatment of mild anxie~y states and certain kinds
of psychotic conditions such as schizophrenia and acute mania
The compounds of this invention are effective over a wide dossge range,
the actual dose admlnistered being dependent on such factors as the partictlar
compound being used, the condition being treated and the type and size of
msmmal being treated~ However~ the dosage required ~7ill normally fall within ¦
the range of 0.1 to 20 mg./Kg. per day~ for example in the treatment of adult ¦
huma~s dosages of from 0.1 to 10 mg./Kg. may be used.
The compouDds and salts of the present inYention will normally be
administered orally or by injection and~ for this purpose, said compounds
a~d salts will usually be u~lllsed in the form of a pharmaceutical composition.
Such composltions are prepared in a manner well known in the pharmace~tical
~: ~ .,. .
~ l ~' .
art and normally comprise at least one active compound or pharmaceutically-
acceptable salt of the invention associated ~ith a pharmaceutically-accep~able
carrler therefor. In making the cGmpositions of the present in~ention~ the
active ingredient will usually be mixed with a carrier, or dlluted Dy a
carrier, or enclosed within a carrier which may be in the fonm of a capsule,
sachet, paper or other container. WhPn the carrier serves as a diluent~ it may
be a solid~ semi-solid or liquid material which acts as a vehicle~ excipient
li or medium for the active ingredient. Some examples of suitable carrie;s are
lactose, dextrose, sucrose~ sorbitol, mannitol, starches, gum acacia~ calcillm
phosphate~ alginates~ tragacanth, ge~atin~ syrup, methy1 cellulose, methyl-
and propyl-hydroxyben~oate, talc, magnesium stearate or mineral oil. The
compositions of the invention may, as is well-known in the art, be formulated
so as .o provide quick, sustained or delayed release of ~he qc~ve ingredient
after adminis~ration to the patient.
Depending on the route of administration, the foregoing compositions
may be formulated as tablets~ capsules or suspensions for oral use and
ir~ection solutions for parenteral use. Prefersbly the composition3 are
fo~mulated in a dosage unit form, eacb dosage containing fro~ 1 to 200 mg.
more usually 5 to lO0 mg~ of the active in~redient.
The following preparation and Examples will further illustrate the
~nvention. In cases where melting polnts are not given,support for the
structure o fil1al (title)products was usually obtained by thin-layer
chromatography and/or spectral data.
.'';1 , ~ ; . -
,' ~ , ` `~~ 1-
:. 30 1~ ~
'' , . I
~ -Z2 - I
th~ carbox eth l-~-eth ~ethv]meth lsuL hide
~_ = Y
Ethyl pen~ enoate (L2.6 g, O.L moL) J. Or~. _hem. 12~ l38-154~
was added dropwise to a solution of rnethyl ~hioglycolate (].OL6 g, 0.1 mol) a~dS piperidine (Ool ml) which were ~tirred together in a three-necked 100 ml
flask equipped with a dropping funnel, theTmometer and condense~. ~`he
temperature o~ the reaction was kept between 40 - 50C~ piperidine (006 ml~
being added in OsO5 ml amounts over a period of 45 minutes~ Af~er the addition
of pentenoate9 the reaction was maintained at 50C for 10 ~inutes. The
reaction mixture was then cooled, ~7ashed with water, dried over MgSO~;
filtered and the filter pad washed wlth ether. The com~ined filtrate was
evaporated to dry~ess and the title compound obtained as a yellow liquid.
. . .
(a) ~ _t ~ _
Ethyl 2-amino-5-ethyl-thiophene-3-carbo~ylate (Ber~ 99, 94-lOO) (40 gs
0~2 mol) in dry tetrahydrofuran (150 ml) ~as stirred under nitrogen and
cooled to -40C. n-Butyl lithium (125 ml of 10.2% w/v solution in hexane,
0.2 mol) was added keeping the temperature below -30C. The mixture was then
s~irred at -30C for a further 15 minutes. This solution was blo~ by
nitrogen through an inverted "U" tube lnto a solution of o-fluoro-nitrobenzene
(28 g~ 0.2 mol) in dry ~etrahydrofuran (100 ml) maintained at 15-30C. The
mixture was stirred overnight. The resulting ink-blue solution was poured
~` into three volumes of ice water, extracted with ether (3 x 500 ml)3 washed
with water `(2 x SOO ml)~ dried and then evaporated to dryness. The deep red
oil was dissolved in ethanol (200 ml) and chilled overnight. Crystals of the
title compound were filtered off and dried in vacuo at 50C.
Recrystallisation from ethanol gave pure product having a m.p. of 66-68CO
The title compound was similarly prepared but using 295~di~1uoro-nitroben-
jzene in place of tlle o-fluorollitrobenzerle used in ExaMple l(a) above~ m.pO
90C (a~ter reeL~ ilisa~ioll from ethanol)~
~na~.CalC~ ~o~ C15~115FN2~S C: 53~24; l-l: 4045; N~ 8.28~ F: 5.61
Found C: 53.45; H: 4.75; N: 8.15~ F~ 5.71;
Similarly, using the procedure described in Example l(a)9 the following
compounds were prepared. ~n each case, the nitrobenzene used in place of the
o-nitrobenzene of Example l(a) is given, as is the melting point of the title
compound1 together with recrystallisation solvent - indicated ln parenthesis.
~c)_ _ ~__
2,4,6-Tri1uoro-nitrobenzene, m.p. 74-75C (EtOH)o
2~4-Difluoro-nitrobenzene~ m.p. 87-88C (EtOH)~
(e) ~ O
' 5-Chloro-2-fluoro-nitrobenzene~ m~p. 75-76.5 C (EtOH).
(~) ~ 2~ di r
2~4-Dinitro-fluorobenzene, 148C (~tOH).
. . '
The title compound was similarly prepared using the process of Exarnp~ l(a)
but usi~g as starting materials 2~5-difluoro-nitrobenzene ~nd ethyl 2-amino-
¦l495~6~7-tetrahydrobenzo[b~thiophene-3-carboxylate~ m.pO 140~142C (EtOH).
~ ` .
~ - ~4 -
(h) Ethyl 2- ~ 5-difluoro-2-nitroanilin~ LL ~LI~L~h~ te
2 9 4,5-Tri~LIloro~nitrobellzene, m.p~ 105C (EtOH)o
(i) ~ 2-nitroanilino)-thio~hene-2-carboxylate
The ~itle compound was prepared ~sing the process of Example l(a) but
with 2-fluoro-nitrobenzene and methyl 3 aminothiophene-2-carboxylate (U~Ko
Patent No. 837,086) as starting materials, m.p. 184C, (toluelle/MeOH, 2
(;) Methyl 3-(4 Eluoro-2-nitroanilino?-thiophene~ 2_ate
The title compound was prepared using the process of Example I(a) but with
2,5-difluoronitrobenzene and methyl 3-aminothiophene-2-carboxylate as starting
materials~ m.p. 172-175C (benzene).
¦ Similarly Irepared were :
(k) Ethyl 5-i-propyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate
(1) Ethyl 5-n-hexyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate
. . .
o-Fluoronitrobenzene (56.4 gg 0.4 mol) and ethyl 2-amino-5-ethylthiophene
;~ 3-carboxylate (lO0 g, 0.5 mol) were dlssolved in dry dimethylsulphoxide (320
ml). The stirred solution, under nitrogen, was heated in an oil bath. When
the internal temperature reached 60C, potassium carbonate ~55 g~ 0.4 mol)
was added and the mixture stirred at 100C until GLC indicated that all the
': ~ .
- 25 -
¦o fluoronitrobellze~le had been consulQed (6~5 hours) Tlle mixture ~Jas then
poured onto ice-water~ acidified with concerltrate~l hydrochloric acid and
extracted ~ith met~ylene chloride. The com~ined extrac~s ~ere washed wi~h
water~ dried (MgS04) and the solvent evaporated to give a red semi~solid whlch
was recrystallised from ethanol to give the title product as a soli~ (mOp~
The following compounds were similarly prepared using the process oE
E~ample 2(a). In each case, the melting point of the title compound, the
recrystallisation solvent - indicated in parentheses - and the starting
materials (when different from those oE Example 2~a) ) are given~
5-Chloro-2-fluoro-nitrobenzene, m.p. 75 76C (EtOH).
(c) ~ ~ in r
294-Dinltro-Eluorobenzene~ m.p. 146-148C (EtOH).
~ 4-Fluoro-3-nitrobenzotrifluoride, m.pO ln2C (EtOH).
~e) Eth~l 5-et
3-Fluoro-4-nitrotoluene~ m.p. 55-57C (EtOH).
(f) ~ (4 ~ ~ _ oe~ sy__te
5-Difluoromethyl-2-fluoro-nitrobenzeneg m.p. 88-90 C ~EtOH).
~.,, ~g) ~ ~
5-N~N-Dimethylsulphonamido-2~Eluoro-nitrobenzene and methyl 2-amino-5-
ethyl-thiophen~- -carboxylate~ m.p. 166-163C ~EtOh).
- 26 -
'; ' ' ' ' , " ', ~ ' , ' ' ' . '
(h) Me~hvl 5-etll~l 2-(4 ~ ~
2-Fluoro-5 methoxy nitrobenzene and rnethyl 2~amino-5 ethyl-thiophelle-
3-carbox~late, m~p. 125-127 C (Et~H)~
(i) ~ ~ n~ ~ hen
295 Difluoro-nitrobenzene and e~hyl 2-amino-thiophene-3 carboxylate~
m.p. 125C (EtOHj.
~.' (j)~_~=~!~ .
4~Fluo-so 3-nitro~-~hioanisole and ethyl 2-amino-5-ethyl-thiophene-3-
(k) Et ~ _ ~
Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and 3-clloro-2-fluoro-
nitrobenzene7 m.p. 67-70C (EtOH).
Ethyl 2-amino-5~e~hylthiophene-3-carboxylate and 2-fluoro-3-trîfluoro~
methylnitrobenzene~ m.p. 72-73C (EtOH)o
5-ChLoro-2-fluoro-nitrobenzene and methyl 3-amino thiophene-2-carboxylate,
m~pl 207-208C (~tOAcjHexane).
(Il) ~ ~
Methyl 2-amino-5-methyl thiophene-3-carboxylate and 2,5-difluoro-
nitrobenzane, m.p. 149-151C (EtOH).
(o) Ethyl_2-(4- r
Ethyl 2-amino-5-ethyl-thiophene-3-carboxyLate and 5-bromo-2-fluoro~
nltrobenzene~ m.p. 76-78 C (EtOH)~
'~ . I ~
(p) ~I~UQrO-~2-nitr~an:L1.Ltlo~ thiO~ ne~3~carboxy~e
MethyL 2-amino~S-~ enyl-tlliophene-3-carboxylate and 295-difluoro-
nitrobenzene, m.pO 150C (C~I~C12~.
(q) 5-Ethyl~ 2-ritroanilino)- hio~ene-3~car xy~ cid
Ethyl 5-ethyl~2-(2-llitroanilino)-thiophene-3-carboxylate (6.0 g)
dissolved in ethanol (100 ml) and water (50 m]) and heated to 60C with
stirring. Sodium hydroxide (5N~50 ml) was then added and the temperature
malntained for 16 hours. The reaction mixture was cooled and diluted with
water (500 ml), and solid title product filtered of~ m.pO 189-191C ~E~O~c).
(r) ~-r hV 4- o ~
The title compound was similarly prepared from ethyl 5~ethyl-2-~4-
fluoro-2 nitroanilino)-thiophene-3-carboxylate but uslng a reaction temperature
o~ 25C~ m~p. 198-200 C (EtOAc).
(s) Methyl 5 Ethyl-3-(4-fluoro-2 nitroanilin~-thiophene-2-~arboxylate
~ AMP~ 3
3-Carboxymethyl-4 aminothiophene hydrochloride J.A.C.S. 68, 2232 (194G~
(48.5 g, 0~25 mol) was dissolved in a minimum of water and shaken in the
presence of saturated sodium bicarbonate solution and ether. The ether
extract was drled with MgSO4, filtered and e~ap~rated to an oil~ dissolved
in dimethylfol~amide (DMF)9 2-methoxyethanol~ or dimethylsulphoxide (DMSO)
(anhydrous), preferably the latter (100 ml~. To this stirred solution at
100C~ under nitrogen~ ~as added 2~5-di~luoronitrobenzene (40 g~ 0~25 mol)
and triethyla~ine (35 ml), the reaction was kept at ~hese conditions for
¦ an hour (under reflux~ and more triethylamine (35 ml) added. The reactlon
¦ was then heated, with stirring under nitrogen for a further 40 hours.
; ~ The chilled mixture was poured into saturated brine ~1~ litres) with
stirring~ in the presence of ethyl acetate~ the two phase mix~ure was filtered
, . .
- 28 -
~ . . .
~he organic phase was run off, washed with brine, dried with MgSO4,
filtered and evaporated to a brown gum. This gum was dissolved in
a minimum of ethyl acetate and vacuum-filtered through a pad of
"Florisil" (trade mark) contained in a sintered funnel, the pad was
washed with ethyl acetate until all the product had been removed,
the filtrates bulked, evaporated to an oil, dissolved in cold eth-
anol (250 ml) and left at 0C for 24 hours. The red-orange crys-
talline product occasionally contained traces of brown tar, but
it was found that this could be removed by adding a little ethyl
acetate and triturating. The crystals so obtained were filtered,
washed with ethanol, 40-60C petrol, and then dried under vacuo
to give the title compound as a solid product, m~p. 164C.
(b) Methyl 3-(2-nitro-4-trifluoromethylanilino)-thiophene-4-car-
The title compound was similarly prepared using the
process described in Example 3(a) above, m.p. 175C (EtOH).
g,0.02 mol) and 2,5-difluoronitrobenzene (3.2 g, 0.02 mol) in dry
DMSO (20 ml) was stirred and heated on an oil bath. When the in-
ternal temperature reached 60C, potassium carbonate (2.76 g,0.02
mol) was added and the mixture then stirred at 100C for 5 hours.
The reaction mixture was poured onto ice-water, acidified and ex-
tracted with methylene chloride. The combined extracts were washed
with water, dried (MgSQ4) and the solvent removed in vacuo, m.p. `
137-139 C (EtOAc~.
Similarly the following compounds were prepared using
- 29 -
-- ! ~7s687
(f) 5 Eth 1-2- 4-meth lthio-2-nitroanilino~-thio hene-3-nitrile
(38.1 g, 0.25 mol) and 4-chloro-2-nitroaniline (51.8 g, 0.28 mol) were
dissol~ed in ref1uxing toluene (~ 200 ml) in a three-necked flask (500 ml)
fitted with a Dean and Stark apparatus. A few drops of boron trifluoride
etherate were added and the re~ction was left to reflux for 4 hours, the
water formed being tapped of~. i
The reaction mlxture was left So cool whexeupon a brown solid precipitated
and was filtered of$. The so}id was recrystallised from absolute ethanol
using activated charcoal as a decolouriser, and the orange crystalline solid
which ~as obtained was filtered, washed with ethanol and then dried at 50C
under Yac~um. The dried solid so obtained was the title compound which had
a melting point of 154-155C.
The title compound was obtained using a similar procedure to that outlined
in Example 4(a) abo~e~ m.p. 141-142C (EtOH).
., (c) ~=~
3~4-ChloTo-2-nitroa~llino)-2~5-dihydrGthiophene-4-~itrile ~14~09 g,
0.05 mol) dissol~ed i~ xyle~e ~150 ml) was added ts a solution of chloranil
~1203 g~ 0.05 mol) i~ hot xylene (100 ml). The mixture was allowed to reflux
~ 30 _
Eor two hours. After coollng~ the x~lene was evaporated ofE under vacuum
~to lea~e a red-browll solid wh;ch was trit~1rated with methanol to givè a
brick red solidO The solid was recrys~allised from hot methanol to give red
crystals which were filtered oEf, washed with me~hanol and dried at 50C
under vacuum. The dried product so obtained was the title compound, mOpo
was similarly prepared~ m.p. 167-169C (MeOH)~
(c~ ~ oro-2-nitroanilino)-2-e~h~ io~hene-3-nit~ile
(a) Ethyl 2-(2-aminoanilino)-5-ethyl-thiophene-3-carboxylate
,Ethyl 5-ethyl-2-(2-nitroanilino)~~I;ophene-3-carboxylate (20.7 g) in
ethanol (150 ml) was catalytically reduced over lOZ palladium on charcoal
(2,0 g) at 60 p.s.i. The catalyst was removed by filtration and the solvent
removed by distillation in vacuo. The title product so obta-ined had a meltillgpoint of 50-52C (hexane),
The following compounds were similarly prepareds
(b) ~ a
m,p. 82-84C (hexane).
(c~ Et~ 2~(2-a~ ___fluor ~ l-th ophene-3-carbo~y~
m,p, 106C (EtOH~.
m~p, 100-101C (EtOH).
m,pO 119-121 C (EtOH).
., . I
; - 31 - I
l ~f~ Ftby] ,3-~2 ~i~dialT~ a ~ 5 eth~-t~ Dhene-3-carl)ox~rldte,m~p.152 5C
(g) Eth~(~3^amir30 4-t,rifluoro~ thyl,.~n lo~,-5-~,~ hi,o~le,~3~ r~-~o.~"'J clt-~
(h) E_~2~1 2 (2 ~ tll~hene-3-carhox~late
(i) ~,L_ difll10romethyl itroa ~o
(j) Methyl 2-(2~_m -4-N~N-dimethyls~e___aTnidoa ~ C_~
(1) Ethyl 2-(2-a ~ ~ n~o ~ -
~n) ~ i~b2~a:~b~ ' ~ e~y~ hene-3-carb y~
The title compound was prepared by the reduction of meth~L 3-~2-
,: (P) ~
The title compound was similarly p~epared by the reduction of methyl 3-
(r) M~h~2-(_amino l~-flu~5 metll~ e_-cLtr~
m7p~ 116 11gC~ '
(s~ Ethyl 5-~-propyl-2-(4-1uoro-2-amilloanilino)-thiophene-3-carboxrlate
~ ~ _.
(t) Ethyl 5-n-hexyl-2 (4-fluoro~2-aminoan~ o)~thiophene-3-carboxylate
(v) ~ etllyl ~ oanilino)-thio hene-3-carbox late
(w) 2-(2-Aminoanilino~-5-ethyl-thiophene-3-carbox~lic ac d
5-Ethyl-2-(2-nitroanilino)-thiophene-3-carboxylic acid (8.0 g, 00027 mol)
in ethanol (150 ml) was catalytically reduced over 10% palladium on charcoal
(900 mg) at 60 p.s.i. The catalyst was removed by filtration and the solvent
removed by distillation in vacuo to give the title compound.
(x) ~ y_____t~l_____ a
Ethyl 2-(2,4-dinitroanilino)-5-ethyl-thiophene~3 carboxylate (0.5 g) in
6N ammonia (25 ml) ~nd ethanol (10 ml) was stirred at reflux temperature and
hydrogen sulphide gas passed in over a period oi 2 hours. The reaction
mixture was cooled to room temperature and the title compound obtained as
a yellow precipitate filtered off, washed with water, and dried in vacuo,
mOp 174-176C (EtOAc).
E AMPLE 8
~: ~ I .
Ethyl 2 (4-bromo-2-nitroanilino)-5-ethyl-thiophene-3~carboxylate (0.4 g~ ¦
0.001 mol) was added to powdered zinc (0.4 g) and ammonium chloride ~0~4 g)
in water (10 ml) and stirred at 50C for 24 hours. The reaction mixture was
filtered and the recovered solid washed successively with ~a~er and ethyl
acetate~ The organic phase was separated9 washed with water~ dried (M~SO~
_ 33 -
, . ~ ,. . .~ '
,' ' ' , ' ~, '- . '. ' '' .' ', . .
~ and evaporate~l irl _a~!o ~o give tlle title compo-~nd.
¦ EX~PLl~' 9
(a) ~ 3 ~ Il~ ~ 2~ d o~ene 4-c~ c~te
3-Carbo~yme'~hyltetrahydrothiophen-4~one t48.06 g~ 0~3 m) and o-phenylene-
diamine (3204 Ol 0.3 m) were dissolved in boilin~ e~hanol (500 mL)y to wl~ h
a few drops of acetic acid had been addedO The solution was then heated
under re~luY~3 in a nitrogen atmosphere for four hours and left 'LO cool.
The crystallLne material so obtained was fil~ered offg washed wlth ethanol
and dried under vacuum. The product was recrystallised from absolu~e athanol
using activated charcoal as a decolouriser~ a yellow solution being obtained
from which white needles crystallised out. The wl~ite crystaLlirle solid was
filtered off~ washed with ethanol and dried under vacullm to give the ~i~le
product~ m.p. 101C.
. . I
(b) Methyl 3-(2-ami ~ thio~h e-3-carbox~
The title compound, m.p. 162C, was obtained by a process similar to that
of Example 9(a~.
~ EXAMP'LE 10
~a) 3~(2-Am noani _n ~ ~ ~
Methyl 3-(2-aminoanilino)-2~5-dihydrothlophene-4-carboxylate (25.03 g,
0.1 mol) and ch'loranil (24.6 g~ 0.1 mol) were refluxed together in xylene
(900 ml) for two hours. The soLvellt was then Pvaporated off, under vacuum
to leave a dark brown solid ~ich was triturated with ethyl acetate to give
a light brown solid, wllich was filtered, washed with ethyl acetate and dried
under vacuum to give the title product~ melting point 120-122C.
S-imilarly prepared was :-
(b) _t~y~ (2-a n
~ _ 34 _
~ 75687 -`
M th 1 3 2-aminoanilino~-thio hene-4-carbo late
Methyl 3-(2-aminoanilino)-275-dihydrothiophene 4-carboxylate (2.5 g,
0.001 mol) was added to a flask containing palladium on charcoal catalyst
(5%, 200 mg) in cyclohexene (or norbor~adie~e or norbornylene) (50 ml)
and the reaction was heated at reflux with stirring for 4 hours, the reaction
belng followed by t~loc~
The reaction mlxtùre was then cooled, the solvent e~aporated o~f under
vacuum to leave a dark brown oil which was column chromatographed using a
"Florisil" column and chloroform to give the title prod~ct as an orange
solid, m.p. 120-122C.
(a) 3-(2-Amino- ~t_fluorometh~1anilino)-245-dihydro- thioehene-4-nitrile
4-Trifluoromethyl-o-phenylenediamine (24 g~ 0.136 mol) and 3-keto~4-nitril~ _
2~5-dihydrothiophene (17.3 g, 0.136 mol) were dissol~ed in 200 ml of warm
ethanol, acetic acid (3 ml) was added and the solution heated under reflux
for 24 hours~ the~ left to cool. The title product was thus obtained as a
white solid which was filtered off and combined with solld obtained from
evaporating the filtrate to small bulk, and cooling~ m.p. 189C.
Similarly prepared were :-
3-Keto-4-cyanotetrah~drothiophene ~80 g, 0.629 mol) and o-phenylenediamine
(68 g, 0.629 mol) were dissol~ed by heating in 1.5 litres of industrial
methylated spirit. To the solution, glacial acetic acid (3 ml) was added,
the 501ution then belng heated under reflux with mechanical stirring for 24
hours. The solutio~ was then chilled and filtered to gi~e the title product
as a solid~ ~pO 163C-
*Trademark for a highly selective adsorben~ of a hard, whi~e granular
or powdered magnesium-silica gel.
~,J~ ,, ' ' !'
3-(4-Chloro-2-rlitroan:i.lino)-thiophcne-4-nltrile (17~18 g~ OnOG mol) was
hydrogenated in ethanol (300 ml) and ethyl acetate (100 ml) using a palladium/
charcoal catalyst (3.5 gg ~0%~ in a Parr hydro~enator to give 3-(4~Chloro~2-
aminoanilino)-thiophene-4-nitrile. After two hours9 the reaction was complete
the catalyst was filtered off and ~he solution was evaporated to dryness
The light bro~n solid obtained was redissolved in absolute ethanol ~100
ml) in a three~necked flask (500 ml). Concentrated hydrochloric acid (12 ml)
was added dropwise carefully to the stirred solution. The alcoholic solu~ion
was then allowed to reflux for approximately 24 hours. Sodium hydroxide
solution (10%, 60 ml) was then added dropwise to the cooled solution un~il
the solution was slightly basic. During additiorl, a precipitate of the
title compound was formed, which was filtered off to give a pale yellow/
brown solid, whlch was washed with wa~er and dried a~ 50C under vacuum9 m,p~
Similarly prepared were ;-
(~ m.p. 195~7C.
; (d) 10-Amino-2-e uoro-4I~-th ~ ~
~f~ ~ zod
30 ~ 36
(g) 10-Amir.o 2-eth~rl 7~tr;fluorotnetl~ thiello ~ -h~ benzodia_~lne
(h) lo-Amino-l~ethy1 7-fluoro-4l-l-thieno[3,4 b~[l,5¦benzodLazepine
I EXAMPLU 14
(a) 10-~mino~ y~thien ~ ~- ~ lL51ben~od~ p~
3-(2-Aminoanilino)-2,5-dihydrothiophene-4-nitrile (84.5 g, 0~3~ rnol)
was suspended by mechanicQl stirring in hot industrial methylated spirit
(1.5 litres). Concentrated hydrochloric acid (57 ml~ 0~66 mol) was added
dropwise, the solution was stirred at refLux temperature or 1 hour then
chilled~ and the solid so obta-Lned iltered9 washed with a little industrial
methyla~ed spirit, petrol (40-60C) and dried at 50C under vacuum. The
title compound so obtained had a meltin~ point of 292C (decomp~)0
(b) 10-Amino~ DY9}~ 5Y ~ L~5 ~ ze~
The hydrochlorlde oE (a) above (54.5 g) was suspended in 1 litre of
chloroform with mechanical stirring and 500 ml. of 10% w/w sodium hydroxide
was added in one portion~ The suspension was stirred ~or two hours whereupon
the title compound was obtained as a white solid. This was filtered off,
, washed with water~ ethanol, ether and dried under vacuum to gi~e the free
base~ m.p. 240-250C (decomp.)
(c) ~ o-4~l-2~5-dihydro ~ o~
Methyl 3-~2 aminoanilino)-2~5-dihydrothiophene-4-carboxylate (0.5 g~
0.002 mol) in dry DMS0 (2 ml) W3S added to a solution of 50% w/w sodium
hydride~oil suspension (300 mg~ in dry DMS0 at 90C under nitrogen. When
effer~escence had ceased, the solution was stirred for two hours and poured
onto 300 ml~ of ice/brine. The solution was then extracted into ethyl
acetate, the extract dried with magnesium sulphate9 filtered and evaporated
to small bulk. Ether was added to the suspension and this was filtered.
The filtrate was evaporated to dryness and triturated with chloroform to
yield the title compound as a yellow solid~ m.p ~10C ~decomposition).
: ~ ~ ' .
_ 37 _
(a) 10~ lno~4ll ~ 5 dih ~ thieLIol3 4 l ~ 5 ~enzodia
3~Cyanotetrahydrothlop11en-4-one (80 g~ 0.629 mol) and o-phenyletledlatnine
1 (68 g~ 0.629 mol) were dissolved in 1 5 litres of ind~lstrial met11yLated
spirit by hea~ing under reflux with stirring, acetic acid (3 ml) was then t
added and the mixture heated under reflux with stirring for 5 hour~. To
the cooled solu1ion there was carefully added concentrated hydrochloric
acid (92 ml, 1.08 mol) with stirringO The solL1tion was then heated under
reflux for one hour and to the chilled, stirred solution of hydrochloride
there was added 10% w/w sodium hydroxide (500 ml) dropwise, keeping the temp-
erature below 40C~ The solution was then stirred for one hour, the solid
filtered off,~ashed wit11 water~ ethanol, acetone9 ether~ dried under vacuum.
The dried productS which was the title compound, had an m.p. of 230-240C
~decompO ) . ~'
(b) lO-Amino-4H-thieno ~ 4-~ ~ b~ i ~
lO-Amino-4H-2~5-dihydrothieno[394-b~[l~5~benzodiazepine (43 g~ 0.198 mol)
was suspended with Mechanical stirring in boiling xylene (l litre)0 To this
was added chloranil (49 g)~ t}-e suspension being stirred at reflux temp-
erature for 2-6 hours and then left to stand o~ernight at room temperaturs.
The suspension was then filtered, and the solid washed with xylene until the
washings were colourless. It was then dried on a ~ilter ~mnel. The dried
black solid thus obtained was suspended in hot uater (200 ml) and SM
hydrochloric acid (36 ml) was added to fo1m a red solution which was boiled
for lO minutes~ ¦
The solution was then ~iltered and residual tar extracted with another
36 ml of 5M ~Cl in water (200 ml) and refiltered. The collected hot filtrates¦
were added dropwise to an ice-cooled solutlon of sodium hydroxlde (14~4 g~ ¦
0~36 mol) in water (lO0 ml) at such a rate that the temperature of 40C ~s not
exceeded. The solution was stirred for l hour~ filtered~ the aolid being
washed with water and dried ~mder vacuum at 50C~ The dried ~itle compound
. . ,. .
~ 38 - i ~
. . ~'
~L~756l37 1 ~
thus obtallled had a melting point of 140C (decomp~ ~;
(a) 10-Amino-6-trifluorom~ H-2~A__di~ydrothlen_[39~bl ~ 51benzod~
3-(2-Amino-5-trifluoromethylani11no)-4~cyano-2~5-dihydrothiophene (10~5 g,
0~0368 rnol) was dissolved in industrial methylated spirit (100 ml) by heating,
and to this stirred solu~ion, a solution oL concentrated hydrochloric acid
(3.2 ml9 0~0368 mol) was carefully added. The red solution so formed ~as
heated under reflux for 1 hour. To the chilled~ stirred solution, a solution
of sodium h~droxide (106 g) in water (10 ml) was added dropwise9 the ~emp-
erature being kept below 40C. The buff amidine thus formed was filtered
ofE~ washed with water3 ethanol~ 40-60C petrol~ and then dried at 50C under
vacuum. The filtrate was diluted with an excess of water and the solid so
produced was flltered off and dried and lncluded with the other solidO
The title compound thus produced had a melting point of 200-210C (decompO).
Similarly prepared was :-
The product of Examples 16~a) and 16(b) were "aromatised" to
(a) 10-Amino-6-trifluoromethyl-4H-thieno[3,4-b~1,5~benzodiazepine, m.p.178C
(b) 10-Am~no-6-chloro-4H~thieno[3,4-b][1~5~benzodiazepine~ using the
process of Example 15(b).
~ ~ ! ~
~ AMPIE 18
(a) 9~10~D~hydro~?. etllvl ~ " ~ benzodiazepin -10-one
Sodium ~ethyl sulphinyl carbanlon was generated by stirring sodium
hydride (7.2 ~ 0.15 mol) in dry dimethylsulphoxide (100 ml) at 70C until
gas evolution ceased~ Ethyl 2-(2-aminoanilLno) 5-ethyl-~hiophelle-3-
carboxylate (14.5 g, 0.05 mol) in dry dlmethylsuLphoxide (50 ml) was added
and stirred for 15 minutes. The mixture was poured onto ice water (600 ml)
and stirred for fifteen minutesO The solid was filtered off, washed well
with water~ dried~ washed with carbon tetrachloride and dried in vacuo at
60C~ The dried product ~hich was the title co~pound had a rnelting point
of 218-220C (CHC13).
(b) 2-Ethyl-7-fluoro-9~10-di ~ enæodiazepin -10-
The title compound~ m.p. 210-212C~ ~as similarly prepared from cthyl
2-(2-amino-4-fluoroanilino)-5-ethyl-thiophene-3-carboxylate. The title
compound ~as recrystallised from ethanol.
The following compounds were also similarly prepared nsing the proce~s of
Example 18(a). In each case, the starting thiophene material, melting point
of title product, and recrystallisation solvent are indicated,
(c) 6~8-Difluoro-9,10-dihydro-2-ethyl-41-l-thieno~2,3-b~1,5~benzod-iazepin ~
m.p. 230-232C (CHC13).
, . ~ ~__
m,p, 255-~57` EtOAc),
, . .'
(e) ~ thyl~4~l-thieno[2,3-b~[1~5~benzodiazep~n -lO-one
Ethyl 2-~2-ainino-4-cllloroanilLno)-5-ethyl~hiophene 3-carboxylat:e9
m.p. 216-218C (EtO~c).
S (f) 7-Amino-9710-dihydro-2-ethyl-4H-thieno[2,3-bl[175~benzodiazepin-~lO~one
Ethyl 2-~2~4-diaminoanilino)-5-ethyl-thiophene-3 ca~boxyla~e~ m~p. 230 C
(decompO ) (CHC13/MeOII).
2-(2-Amino-5-methylanilino)-5-ethyl-thiophene-3-carboxylate m.p. 205-207C
b~n~ L~ 2:~
lS Methyl 2-(2-amino-4-N,N-dimethylsulphonamidoanilino)-5-ethyl thiophene~
3-carboxylate, m~p~ 258-260C (EtOAc).
Ethyl 2-(2-amino-4 nitroanilino)-5~ethyl-thiophene-3 carboxylate~
m,p. 264-266C (EtOAc)~
(j) 991 ~ e
Ethyl 2-(2-amino-4-fluoroanillno)-thiophene-3-carboxylate, m.p. 235-
240C (CCl~/hexane)~ ~
(k) 9 Fl u-6~ I,293,4,11712-hexahydrob z ~ _
Ethyl 2-(2-amino-4 fluoroanilino)495,6~7-tetrahydrobenæo~b~thiophene 3-
(l? ~ ~
_ 41 _ '
.. . . .
Ethyl 2-(2~amillo-4~tri~].uoromethyl~li.11rlo)-5-etllyl thiopherle^3-cclrboxylate!.
(m) 9~10-DihydT ~ ne
Ethyl 2~(2-amino~4-mcthoxyanilino)-5-ethy3 thiopllene-3 carboxylate.
~ ___ ~_
Ethyl 2-(2-amino-4~methylthioanilino)-S ethyl-thiophene-3-carboxyla;e~
(p) 9,10-Dihydro-7-~luoro-2-phenyl-4H-tllleno[2,3-b~[1,5~benzodiazepin~10 one
._____ ____ __ ~_____~_
m.p~ 250-252C (dec.) (EtOAc)~
(q) 9,10 D:ihydro-7-fluoro-2-rnethyl-4H-thieno[2,3-b~1,5~benzodiaæepin~10wone
m.p. 250-25~ C (EtOAc).
_ ._ ________ .
Methyl 3-(2~aminoanillno)-thiophene-2-carboxylate, m.p. 226C (CC14)~
(s) 9~10-D-Lhydro-7-fluoro-4H thieno[3~2-b~ S~benzodiazepln-10-one
Methyl 3-(2-amino-4-fluoroanilino)-thiophene-2-carboxylategm p~ 225-230C
Methyl 3~(2-amino-4-chloroanilino)-tlliopherle~2-carboxylate9 m~p. 255-256C
¦ (u) 9~lO-Dillydro-41~ hlenoL37~ [l55~beflzodiazepin~lo-one
m,pO 233-~3 'JC C .
(v) 9,10-D;hyd-ro 7-fluoro-4H-thieno[3~4-bj¦1,5lbenzodiazepi~10-o1le
MeLting point 238C (decomposltion)~
(w) 6,7-Dichloro-9,1~dih~ iH-thiello[3~4-b~ 5~benzodiazepi~ o-one
Melting point 284-287C.
(x) 2 i-Propyl-7-fluoro-9~10-dihydro-4H-tlliello[293-b~[1~5~]'benzodiazepin-iO-one
(y) 2-n-Hexyl-7-fluoro-9910-dihydro 4H-th-ieno~2,3-b~[1~5~b&nzodiaYepin lO-one
(aa) 1-'~ thVL 1-7-fluoro-9,10-dihydro-4H-thienor253-b~[1~5~benzodiaze-
. ~ ~.
. , ~ _ . _ . ~ . ~
~0 (cc) 2-Ethyl-9910-d;hydro-4II-thieno[273~b~[1,5~benzodiazepin~-lO-one
5-Ethyl~2-(2-aminoanilino)~thiophene-3-carboxylic acid was dissolved in
tetrahydrofuran (distilled from lithium aluminiurn hydride) (200 ml) and solid
dicyclohexyLcarbodiîmide (5.7 g7 0.027 mol) added. The mixture was stirred
under a nitrogen atrnosphere for 16 hours a-.ld the solution thus formed filtered
and evaporated ~o dryness. The residue was boiled with carbon tetrachloride
and allowed to crystallise to yield the title compound~ m.p~ 218-220C (CHC13)
I0-AmiDo- - h10ro-4H-thieno[3~4-b][1~5]benzodiazepine ~4 g~ 0.I5 mol)
- J~3 _
. . I
. . I'
, , : . : : : ..
was di~so3vld in the ~linimum of ~ater (100 rnl) to which WRS added potasslllm
! carbona~e ~13~0 g) in w~ter ~20 ml)~ Absoll~te ethanol (40 ml) w~s then
¦ added t:o redi~solve ~he amidine and the reaction mixture gently refluxed
l for 17 hourq, during the las~ houl of ~hich9 the e~hanol was slowly distilled
The reaction mixture was then allowed ~o cool~ and concentrated hydrochlor
ic acid added dropwise to the solution~ in the presence of ethyl acet~te,
until the solution was slightly acidicu The aqueous phase ~as extracted with ~
: ethyl acetate, dried over MgS04 and the bulked extracts e~raporated to dryness ¦
under vacuum, the title produc~ being ob~ained as a light brown solid. The
solid was triturated with ether, Eiltered and dried at 50C under vacuum to
¦ give a yellow solid; m.p. 212-213C.
Using the hydrolytic procedure of Example 19(a) the following other
amides were obtained :-
(b) 9~10~Dihydro-4H-thieno~3~4-b~ 5~benzodiazepin~10-one
Melting point 234C (decomp~).
(c~ 9~10-Dihydro-7-methylthio~4H-thieno~3,4-b~ n,~d.-~pln-10
(d) 9,10-Dihydr . ,~ ~ 3 ~ .one9
(e) 9~10-Dihydro-2-ethyl-7-fluoro-4H-thieno~2,3-b~ 5~benzodia~epin-10-one
. , _ _ _ ______
I (f) 9tlO Dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b~[175~benzodiazepin 10-one
.~: _ ~
(g) 9,10-Dihydro-2-ethyl-7-methylthio-4H-~thieno[2,3-b~[1,5~benzodiazepin-10- 1
- ~4 -
. . I
10 . ~
Ev~ PLE 20
9,10-Dihydro-4H-2,5-dihydrothieno[3~4-b~C1~5]benzodiazepin-lO-one (0.33 g)
was stirred in cyclohexene (~orbornadiene or norbornylene) ~t reflux
temperatures in the presence of a palladium o~ charcoal catalyst (Ool g~
5%~, the reaction being followed by t.l.c. measurements.
The r~actlon mixture was then cooled~ the solvent evaporated off
under ~acuum to lea~e a dark brown solid which was column chrom~tographed
.~ using a "FIorisil" column and 5% methanol in chloroform to give the title
compound as a pale yellow solid~ m.p. 230-232C.
(100 mg) was suspended in methylene chloride (5 ml) and triethylamine ~0,1 ml)¦.
Acetic a~hydride (10.1 ml) was added and the reaction mixture stirred for
18 hours. The prec~pitate was filtered off, washed with water, dried in
~ ~ R at 60 o give tht ~l~Le CR ound as a solid, m.p.264C.
~ ~ '
3-(~hlolo '3~ d-it~ydrt~-4~ ienoc394--bl~l75lb~rlzod:iaxcpin~lo~nne
4ll-ThieQo[3,4~b~C1~5~benzodiclzepi~ O~one ~4~32 g, 0.02 moL) in ho~
dichlcromethane was reacted with stirring9 with N-chLorosucc;nimide
(3.0 g~ 0~025 mol) ln the presence of a trace of benzoyl peroxide~ After
refluxing for 1 hour the hot solutlon was filtered~ The blue residue was
washed witll three quantities of hot e~hyl alcohol which were combined and
bulked with thedi~loromethane filtrate and evaporated to a brown solid~
Soxhlet extraction with benzene and subsequent washing with K2C03 solution~
drying and evaporatlon yielded the ti~le compound as a buff solid
To a stirred solution of 9,10-dihydro-2-ethyl-7-1uoro-4H thieno~2~3~b~
[1,5~benzodiazepine (00 26 g, 0.001 mol) in acetyl chloride (3 ml) was added
with stirring stannic chloride (2 drops)~ The reaction was diluted with
ben~ene (5 ml) and stirred for 18 hours at room temperature. The reaction
mixture was diluted with water and extracted into chloroform, the
chloro~orm extracts were ~ashed with water5 dried (MgS04~ and evaporated
ln vacuo to glve the title product as a solid~ m.p. 215~218C (MeOH/hexane).
(20 gg 0.076 mol~ was added to a stirred solution of phosphoru: pentasulphide
~17 g7 0.076 mol) in dry pyrid~ne (400 ml). The solution was stlrred at
- 46 -
, I ~.
. ', ` , ' . ~ ' ` `
~ 10756B7 - I
. gentle reflux for 1,5 hours, poured onto ice-water9 stirred for 1 hour,
filtered, washed with cold water and dried~ Recrystallisation from EtOH
¦ /water gave the title compound as bron7.e plates m.p. 203-206C.
~b) 9~10-Dihydro-2-ethyl-4H-thieno~2,3-b~[1,5~benzodia epin-10-thione
The title compound was similarly prepar.ed using the process of
~xample 24(a) with 9~10-dihydro-2-ethyl-4~--thieno[293-b~[1,5]benzodiazepin-
10-one as starting material, m.p. 233-235 C (EtOH-H20~.
Similarly prepared were :-
(c) 9,10-Dihydro-2 ethyl-7-nitro-4H-thieno[2,3-b][1,53benzodiazepin-10-
, . _ _ _ _ __ _ ___
(d) ~ ,
Other amides of Example 18 were similarly con~erted i~to their thioamide
derivatives using the procedure of Example 24(a). In each case~ the
identi~ication a~d confirmation of the ~inal product was e~ected by means
of t.l.c. and microanalytical evidence.
.` . .
1 . EXAKPLE 25
. (a) 2-Ethyl-6-fluoro-10-(4-methyl-l-piperazinyl)~4H-thieno[2,3~b~[1,5~ber.7.o-
: one ~0~5 g), phosphorus oxychloride (4 ml) and N~N-dir~ethylaniline (0.15 ml)
were ref}uxed for 3 hours. The reaction mixture was e~aporated in vacuo
and the residue evaporated twice more with xyle~e. The crude imlno chloride
_ ~7 -
. " '.
~ a~ ~,ssolved in absolute dioxan (1 ml) and N-methyl piperazine (3 ml)
¦¦ added. ~he reaction was refluxed for 4 hours and then evaporated to dryncss
¦I in ~acuo. The residue was partitioned bet~een aqueous al~nonia and ether
and the ether phase extracted with N,HCl. The product was precipitated by
the addition o~ 0 ~8 ammonia and extracted into ether, washed with water,
dried (MgS04) and evaporated in vacuo, m.p. 175-177C (EtOAc~hexane)O
Similarly prepared was:-
(b) 2-Ethyl-7-fluoro-10~ piperazinyl)-4H-thieno[2,3-b~[1~5~enzodiazepine,
m.p. 138-140C (CC14/hexane)
. , _ j ~
9~10-Dihydro-2-ethyl-4H-thieno~2~3-b~[1~5]benzodia2epin -10-one (2.4 g, I
0.01 mol) was suspended in N~methyl pipera~ine (10 ml). Titanium tetrachloride
(1~2 ml~ 0.011 mol) in dry anisole ~5 ml) was added and the mixture stirred
and heated at 120 C for 2 hours. The reaction ~ixture was poure~ into ice-w~ter and ¦
sha~en until a greyish white precipitate ~ormed. The suspension was ex~ractcd
with methylene chloride until no more yellow colour was removed. The coI~bined
extracts were washed with water, dried (~IgS04) and evaporated in vacuo to
y~eld the title compound as a yellow solid. Thîs solid was triturated w~th
ether, filtered, and recrystallised from hexane, m.p. 195-197C.
The free base was then converted to its maleate salt~ m.p. 186-188C
(b) 2-Ethyl-7-rluoro-10~ methyl~l-piperazinyl~-4H-~hi~ Z,3-b][l,~]~
. ~ ..
diazepine ¦ ~
~ _ .. .
The title compound~ m.p. 161-163C (hexane)~ was prepared using a !
il procedure similar to that of Example 26(a) from 9,lO-dihydro-2-ethyl-7- ¦
¦¦ fluoro-4H~thieno~273-b~ 5~benzodiazepin-10-one.
~ 48 ~
Anal~Calc, for C]8H21FN4S C; 62~76; tl: 6.14; N: 16~26; F: 5,51
Found C: 62~99; H: 5087; N: 16~06; F: 5,67t
The free base was con~Terted to its maleate salt, m~p. 125-127C
Anal.Calc~ for C22H~5FN404S C: 57.37; H: 5.47; N: 12.16; F: 4~12; ~:
S: 6.96% t
Found C: 57,53; H: 5.54; N: 11s99; F: ~s.16;
~'~ ' l
The ~ollowing benzodiazepines were similarly prepared uslng the process
of Example 26(a). The material given beneath the title is the amide
~ intermediate9 the melting point is that o~ the title product and the
`, 15 recrystallisation solvent is indlcated in parentheses.
~1' . .
d (C) 2-Ethyl-6-1uoro-10-(4~methyl-1 piperazinyl)-4H-thieno[2,3~b~,rl~5~benæo-
' :~ ~
-I 20 m.p. 206-208C (hexane)~ maleate salt, m.p. 125-127C tEt0H/Et20).
~d) 6~8-Difluoro-2-ethyl-10--(4-methyl-l-piperazinyl)-~sH-thieno[293-b~[l"S~ben- . ~
6t8-Difluoro-9~10 dihydro-2-ethyl-4sH-thieno~r2~3-b~ 5~benzodiazepi;l~ .
l0-one~ m.p. 243-246 C (CC14/hexa~e); maleate salt~ m.pO L22-4~ (EtOH/Et)0)~
m.p. 235-240 C maleate saLt, m.p, Ll9-i2L C (Et0H/Et20),
. " .
, ~ _
'' : - .; ' , . ' . ' ~ ' ~ ' ' . '
(f~ 2-Et]~yf-6~rnet}lyl-10~(4-~nethyl-1-plperaz;nyl) 4H-thîenoC2~3-b]jl,5~benzQ-
The title compound was simila~ly prepared using 9,10-dihy-lro~2-ethyl-
6 methyl-4H-thieno[2~3-b~[175~benzodiazepirl-10-one, m.p~ 177-179C (CH2~17
(g) 7-N~N-Dime~hvl~--lph~ ~ Id~ h/~' 10- (4-met =
thieno[2~3-blf[1~5~benzodiazepine I f
zodiazepin-lO~one, m.p. 225-227C (EtOAc/hexane).
(h) 7-Fluoro-10w(4 methyl-l-piperazinyl)-4H-thieno[273 b~rl~5~benzodi~qzepine
9~10-Dihydro-7-fluoro-4H thieno[2,3 b~[l~5~benzodiazepin-10-one~ mOpo
228-230C (CH2C12/hexane). f
(i) 9-Fluoro~12 (~-methyl-1-piperazinyl)-6H-1,2,3~4-tetrahydrobenzothleno
:, . ~ pi~
12-one, m.p. 196-199 C (CH2C12/hexane) f
~.p. 160-165 dec.~ (EtO~c/hexane).
,~: ; ~
The free base of the chloride identified above was prep~red usin~ 7-
fluoro-7. methyl-9~10-dihydro-4H~thieno~2~3-bf[1~51fbenzodiazepin-10-oneO ;f 30 This was then converted to the dihydrochloride~ m.p. 235-240C ~dec.)
. ' ~
- 50 -
'" ' ~
' ~, . , . . ~ ' ~ '.
' ' '. . ' , ~
~1) 7-Trifluororllethyl-2-ethyl 10 (4-metll5~1~'1-pi.perazlllyl)~41-l~thieno~
C2 9 3- b~ ~:I., 5 Jbellzodiazepine
I _~~_.;~,~ ~ .
' 7-Tri~luorometl1yl-2 ethyl-~3710~di'hydro~41-l--thienoC2,3-b¦C1,5~benzodi,lze
I pin -10-one~
9,10-Di~.ydro 4H-thieno[3,2-b~C195~benzocliaz~pin-lO-one, m.p. 202~-
(n) 7-Fluoro 10-(4-methyl-1-piperazinyl) 4~l-thienoC3~2-b~C195~benzodiazepine
7-Fluoro 9510~dihydro-4H-thieno[392-b¦[1~5lbenzodiazepin-10-one, m.pL
(o) 7-Chloro-10-(4-methyl-1 piperazinyl) ~4H-thieno[392-'b~¦ 195~benzodiazepine
7-Chloro 9~10-dihydro-41-l-thienoC3~2-b~[l,5~benzodiaYepin-10-one, m.p~
7-Chloro 9~10~dihydro-4H-thierlo[3,4-b~[l,5~benzodiazepin-10-one, m~p.
(q) 7-Methylthio-10~4-methyl-l-piperazi.nyl)--4H..thienoC374-b~c195~bellzodiazepin e
: (r) 10-(4-Metllyl.-l-piperazinyl)-~-trifluoromethyl--4H-thieno[3,4~b~[1,~5~benzo~l
~_ _ _ _ _ _ _ I
m.p. 202C ~CC14/petrol 40-60C)~
j (s) 3-Chloro-10-~4~methyl-1-piperazinyl)-4H~thieno~3~4-b~[1~5~benzodiazepine
I (u) 7~Fluoro~10-~4 methyl l~piperazinyl)~4--!-thieno~3~4-b~[l,S~bell~odiazepine
m.p. 190.5 - 19105C~
(v) 6,7-Dichloro-]0-(4-methyl-l~piperazinyl)-4ll-thieno~3~4-b~ s~b-n
(w) 2-i-Propyl-7~fLuoro-10~(4-methyl-1 piperaz~nyl)-4H-thieno[273-b~C1~5~-
(x) 2-n-Hexyl-7-fluoro-10-(4-methyl l-piperazinyl)-4H-thieno[293-b~C1,5Jberl-
~ . . .
(y) l-Methyl-7-fl ~ y ~ 3
,, (Z)~ ~ .
~ 20 ~ ]~
benzodiazepine, m.p. 172C (CC14/hexane).
, ~, (cc) 2-Ethyl-7-fluoro-10-(4~methyl-l-piperazinyl)-4H-thieno[352-b ¦~1,5 ~benzo
.1 _ .
The processes of ~xample 26 ~ould be repeated by usin~ the thioamldes
, produced by the process of Example 2~ in place of the am;des~ with production
l~ of the benzodiazepines specified in Examples 26(~) ~o (cc).
~ 52 -
', ' . '.
10 (~-Methyl~l pil~crazlnvl~-4Is thle~Lo~3~4~b~ 51bellzodiayepine 5
4H-2,5~Dihydrolhieno[394~b~1,5]benzodLazepin~-10-one (10 g) in dry anisol~
(5 ml) was hcated with stirring in the preseLIce of titanium tetraohloricIe
(0,04 ml~ and N methylpiperazine to 120Co rrhe reaction ~as quenched
after 1~ hours~ shaken with ethyl acetate~ which was run off, evaporated
to dryness at 70C under reduced pressure~ The solid was column chromato-
graphed down a "Florisil", 5% methanol in chloroform~ column, The collected
fractions, when evaporated to dryness~ yielded the title compound as a
yellow solid7 m~p. 200-201C
10-Amino 41I-~2~5-dihydro-thieno[3~4-b][1~5~benæodia~epine (2.17 g) in
anisole~ and N-metIlylpiperazine (10 ml) were stirred at room temperature
lS in a 100 mlr round-bottomed flask. The complex derived from titanium
tetrachloride (2~6 ml) in anisole tl5 ml) was added slowly to the stirred
mi~ure. After complete addition, the reaction mixture was stirred under
nitrogen and heated to 120C. The reaction was followed by t~loc~ whioh
witnessed formation of the aromatised starting material before condensation ¦
with the N-methylpiperazine. The mixture was heated overnight at 120Co~
cooled, and poured into water. The aqueous mixture was made basic with dilute
sodium hydroxide solution, and shaken with chloroEormO The organic extract
was washed with water~ dried ~nd evaporated to an oil under vacuum~ Column
chromatography of the oil on a silicic acid column with 5% methanol in
chloroEorm gave fractions containing the title compound
, EXI~iPLE 30
10-~mino-4H-thieno[3~4-b~[195~benzodiazepine (215 mg) in anisole (1 ml)
was treated with N~metIIylpiperazine (2.5 ml) at room ~emperature undex
nitro~en. Titanium tetracbloride (0,12 ml) in anisole ~1 ml) was added
_ 53 _
; ' ' . ' `
to the stirr~d mixture at- room temperature~ The mi~ture7 under nitrogen9
was heated to llOC ~nd stirred overnightO
The resultin~ mix~ure was cooled, poured Lnto wa-ter, made basic witll
dilute sodium hydroxide solution; and shaken wi~h chloroform~ The orgaIIic
solvent was extracted, washed wlth water, dried and evaporated to an oil
under vacuum~ The required product was isolated via column chromalo~raphy
using a silicic acid column with 5% methanol in chloroEorm to give the title
product as a pale yellow solid9 m.p. 200-201C.
Similarly, the benzodiazepines specified in Examples 26(a) to ~cc)were
prepared from'the corresponding 10-amino derivatives, although in many cases
yields were extremely poor.
~ ~ .
A suspension of 9~10-dihydro-2~ethyl-7~fluoro-4H-thienoC2~3-b~[1~5~benzo-
d'iazepin-10-one (2.6 g~ 0.01 mol) in a mixture of anisole (5 ml)~ toluene (10
ml) and ethyl-N-piperazino-carboxylate (9.6 g, 0.06 mol) was ~reated wlth a
1 20 solution o~ titanium tetrachloride (1.2 mll 0.011 mol) in dry anisole (5 ml)
and toluene (10 ml). The mixture was refluxed for 3 hours and poured into
i ice-water (200 ml). The aqueous material was extracted with methylene chlorid~
was'hed with water~ dried tMgS04) and evaporated to a gum (5 g). Trituration
with ether gave the title product as a yellow solid, m~p. 168~171C (CH2C12/
hexane)~ maleate salt, m.p. 149-151C (EtOH/Et20).
~¦~ ~ Similarly prepared were -
¦ (b) 10-(4-Carboethoxy-l-piperazinyl)-2~ethyl-4H-thieno[2D3~b]C1,5]benæodiaze-
m.p. 169C (CH2C12/CC14/n-hexane).
,,~. ,. .
~ ~ _ 54 _ I
, , .
' ' ,'. ~. " " '' ' .' ' . ' ' ' . ' '. ', " ' . ' ' '' ' ' .
' ' ' ' ' .
I ~07$687 l l
¦ (c) 10~(4-Carboel~l~o~;:y~ pi.perazi.llyl)-7-c.lllo~o-.~-ethyl-4H-1:hietlo[2~-b~C1,5l~
m.p~ 15~5 lSSC (l~`~OAc~hexane).
The title compound was similarly prepared ~Ising 7-chloro-9,10-dihydro-2-
ethyl-4H-thieno[293-b~[1,5~benzodia2epin-10-one; m~p. 155-158 C (EtOAc/hexane)
(d) lO-(4-Carboethoxy-l-piperazinyl) 2-ethyl~6-fluoro-4H thierlo[293-b~cla5~-
m~p. 176 178 C (EtOAc~hexane).
m.p. 166C (CHC13)~
~ ' '
(f) 10-~4-Carboethoxy-l-piperazinyl)-7-fllloro-4H thieno[3,2-b~[1,5~benzodiaze-
m.p. 162-164C (EtOAc).
m p. 186-187C.
(h) 10-(4-Carboetboxy-1 piperazinyl)-7-fluoro-4H~thieno[3,4-b~C1~5~benzo-
m,p. 197-199 C.
(i~ 10-(4-Carboxyethyl-l-piperazinyl)-6~7-dichloro-4H-thieno[3,4 b~[l,5~-
1 ~ ~ , . ___ _ _ ___~
3/~ m.p. 213-214C.
3~ (j) 10-(4-Carboxyethyl l-piperazinyl)-7-chloro-4~l-thieno[3~4 b~[l~5~benzo-
~ ~ 30
~ ~.p. ~95-196C. S5~
~ ~ :
- 1 ~(~75687
(a~ 2-l~ yl~7~~ 0~ (l peraz nyl)-411-tHietlo[2,3-b~[1,5~bellzodi_ epi~e
10~(4 cclrboetho~ plperazinyl)-2 el:hyl-7~ o.ro 4H tllieno~2.~3-b¦Cl,S~
benzodiazepine (1.0 g), and potassi~lm hyd~v~ide pellets (6.0 g) in 96%
etllanol (50 ml) were refluxed for 16 hours. The res~lting suspension was
evaporated to dryness and partitioned between w~ter and chlorofor~ The
chloroform layer was l~ashed with water~ dried (MgS04) and evaporated to git~e
the title product as a yellow solid9 mOp. 133-140C (CCl~/hexane)
The following benzodiazepines were similarly prepared :
(b) 2-~thyl-10-(1 piperazinyl)~4H-thieno[293-b~[1,5~benzodiazepine
m.p. 170-171C (EtOAc/hexana)O
___ . ____ _ ______
m.p. 203-206C (EtOAc)o
", . '
i 20 (e) 7-Fluoro-10-(1-piperazinyl)-4H--thieno[3~2-b~ 5~benzodiazepine
: m.pO 165-167C (CC14)
m p. 213-214C,
: - 56 -
' . ,~,~
' ' " ' ' ~. ' ' ' ' " " ' ~ ' ''. . ' ' ' ' ' " . ' ' ' ' '
' " ' ' ''' ' ~ ~ ' ' ' " ' '' ~ " '
(i) 7-c~ o~o~ uzi-n~rl~-4ll-t~ rlol39~-blrl~5~benz~dl.1z~pille
m.p. l,8-l.7~ C`O
(a) ].0 (4 ~ Chlorobenzyl-l piperaz.lnyl)~2-ethy: 7-fl~G'~'41~ Cl~5
2-Ethyl-7-fluoro-10~ piperazinyl)-4H-thieno[2s3 b~l95~benæodiazepille
(1.0 g~ 0.003 mol)~ p-chlorobenzyl chloride (0.38 ml) 0.0033 mol) and
triethylamille (loO ~nl) in 90~/0 ethanol (25 ml) was refluxed for 16 hoursO
The reaction mixture was evaporated to dryness and partitioned between
~ater and methyle~le chlorideO The organi.c ex~racts were washed ~ith water~
dried (MgSO~) and evaporated in vacuo to yield the title product as a solid,
. melting point 166-168C when recrystalliled ~rom Cl-l2Cl~/he~:ana.
: The followin~ compounds were similarly prepared I_
i m.p. 79-80C~
Howe~er, in this reaction benzyl bromide was as the alkylating agentO
m.p. 198-200 C (EtOAc).
m,p. 180-182C (CHC13)~
(e) 10 (4-Benzyl-l-piperazinyl)-4H-thieno[3,4-b~ 5~benzodiazepine
: m.p. 221-222,5C.
(f~ 2-Ethyl-7-fluoro-1 clopropyl-1-piperaæinyl)-4H~thieno[2,3-b]~l~5~-
- 57 -
~.. ' . .
¦ EXA~IPLE 34
~ ~. I
(a) 2-Ethyl~7-fluoro-10-C4-(2-Ilydroxye~Ilyl~ piperazillyl~-4l-I-thieno[2~3-bJ
(1.6S g~ 00005 mol) and ethylene bromohydrin (1.25 g9 0.01 mol) in 90%
ethanol (150 ml) and triethylaMine (2.02 g, 0.02 mol) were refluxed ~mder
a nitrogen at~osphere for 16 hours. The reaction mixture was evaporated to
; dryness~ partitioned between water and methylene chloride9 the methylene
chloride ex~ract washed with water, dried (MgSO~) and evaporated to dryness
IO to yield the title compound as a solid, nI.p. 173-175C (CH2C12/hexane)~
Similarly prepared were :-
m~p. 205-210C (CHC1
i (c) 2-Ethyl-7~fluorow10-[4-(3-hydroxypropyl)-1-piperazinyl~ 4H thiello~ l
m.p. 145--148C ~CH2C12/hexane~
m.p. 175-176C (~tOAc/hexane).
,, ., ,
i (e) lo-C4 ~3-Hydroxypropyl)-l-piperazinyl~-4H-thienor3,2-b~Cl~5~benzodiazepine
i 25 _ _ _
m.p. 172-173 C (EtOAc~he~ane)O
3D ~.p. 138-140C (CHC13~.
~,: : . , .
,: ~ . . .
,~ ~ ~ ~
(g) 10-[4-t3 11ydroxsrpxopyl)-l-piperl~lrlyl~41-l~tllieno[3~4-b~C1~5~benY,odia~.er)ine
F AMPLE 35
(a) 2-E~thyl-7-f]uoro~10-~3-N(4 mcthyl-l-plpeA~æ~inyl~propylamlno~ H-tllieno-
. . ~
(2 g, 0.0072 mol)~ 1-(3-aminopropyl)-4-phenylpipcrazine (1.3 ml?,trietllylaTnine
(8 ml), and dry dimethylformamide (10 ml) were hea~ed ~mder nitrogen at
65 C until the reaction was complete by t~l~co (Et20) (20 hours)7 lhe
mixture was poured onto excess molar maleic acid solution9 washed t~ice ~ith
ether and basified with 0.88 ammonia solutloll, extracting with ethylacetate.
The combined extracts were washed with water~ dried (MgS0~) and the solvent
evaporated to give the title product as a yellow semi solid which was
crystallised from ethyl acetate/n-hexane, m.p~ 1~1C.
The following compounds were similarly prepared :-
l m.p. 193-195C (isopropanol/n-hexane)~
(c) 2-Ethyl-7-fluoro-10-(3-N-morpholinopropylaTnin~ 4 .t~i-n~[2,3-l~]ll "~b~n
z azepine dimaleate
m~p. 182-186C (isopropanol/n-hexane).
- (d) 2-Ethyl-7~fluoro-10-(Z i-1r~y~tt~ o) ~H-thieno[2s3~
'I ~ I
m.p. 196-198C (ethanol/ethyl acetate/n-hexane)~ I
(e) 10-(2-N~N-Dimethylaminoethylamino)-2-ethyl-7-fluoro-~E~ thieno[2,3 b~l,5~-
_ ~ ~ ~ ~ ~_~
:' . .
mOp. 183-184C (ethanol/ethyl acetate/n-hexane).
_ 59 _
(f) 2-Ethyl 7~ oco~ (3~hydroxypropylclm3no)--4~ LIlienol2~3~bl[1~5lbenz~d:ia~e~
m.pO 174~175 C (ethanol/ethyl acetatefn-hexalle).
(g) 2-~.thyl-7 fluoro-10-(2-N-piperidinoethylamino)-4H-thieno[2?3-b~1,5
m.p. 184 185C (ethanol/ethyl acetate/n-hexane)0
(h) 2-Ethyl-7-fluoro-10-(2-N-morpholinoethylamino)-4H-thieno[2~3~h~ 5~benzo--
1 0 . ~
~ ine fumarate
m.p. 189 203 C (ethanol/ethyl acetate/~-hexane)0
(i) 2 Ethyl-7-fluoro-10-(4-methyl-l-piperazinyl)-4EI-thieno[2,3-b~[195~benzo-
m,p. 153-155C (ethylacetate/n-hexane).
(j) 2-Ethyl-7-Eluoro-10-(4-pllenyl-1-piperaziny1)-~1 thieno[2~3-b~[l,S~benzo-
, ~ e
m.pl 154-156C (CH2C12/hexane)~ ;
. ~_, _____
m~p. (di HCl salt) 265-270 C (EtOH~Et20).
(1) ~ ]
~ benzodiazez_ne ~
.p~ (HCl salt) 250-260C.
mOp. (HCl salt) 184-187C,
- 60 - ~ ~.
(Il) 10-(2-N-p.iperidi.rloetllylam:ino)~411- t:hieno~3~ b~L1~5~benzodiazepille
m.pO 182 1~3C.
(a) 10-~4~ Decanoyloxypropy].) I-piper.a~inyl~ 4H-thieno[372-b~195~benzo-
_ ,..__,. .
To a solution Gf 10-C4-~3-hydrox~propyl)-l-piperazinyl~-4H thieno-
[3,2-b~C1,5~benzodiazepine (1.71 g$ 00005 mol) in dry benzene (40 ml)
was added decanoyl chloride tl~42 g, 000075 mol) i.n benzene (10 ml) dropw:ise
with stirring and the solution heated at 75C unt.il the reaction had gone to
completion by TI.C, The reaction mi~ture on washing gave the ~itle compound.
Similarly9 llsing the process of Example 36(a) other hydroxyallcyL
derivatives of Example 34 were esterified to give the corresponding decanoate
and enanthate esters.
" . I .
The following Examples illustrate pharmaceutical form~11a~ions con~aining
the ackive compounds of the inventionO The active ingredient used was 2-
,. ethyl-7-fluoro-10-t4-methyl-1-piperazinyl)-4H thieno[2~3-b~[l~S~benzodiazepine~
however, it will be appreciated tha~ this compound may be replaced by other
active solid compounds of the invention.
: Tablets each containing 10 mg of active ingredient were made up
as follows :-
- 5~. -
~' . ' . ,
Active ;ngrecliellt 10 mg
Potato Starch~5 mg
Lactose 35 mg
Polyvinylpyrrolidone 4 mg
(as 10% solution in
Sodium starch glycolate 4r5 mg
Magnesium S~earate 0.5 mg
Talc 1 mg
Total 100 mg
-~ , 10
The active ingredient, starch and lactose were passed through a No. 44
mesh B.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone
was mixed with the resultant powders which were then passed through a No. 12
mesh B~S~ sieve. The granules so produced were dried at 50~60C and passed
through a No. 16 mesh B.S/ sieve. The sodium skarch glycolate, magnesium
stearate and taLc7 previously passed through a No~ 60 mesh B~So sieve~ were
~hen added to the granules which~ after mixing~ were compressed on a tablet
machine to yield tablets each weighing 100 mg~
.' ~ .
Capsules each containing 20 mg of medicament were made as follows -
Active ingredient20 mg
~5 Starch 89 mg
; ~ Lactose 89 mg
Magnesium Stearate 2 mg
Total 200 mg
` 30 The active ingredient, lactose, starch and magnesium stearate were
I 62 -
:' ~ .
passed through a ~o.~ ~14 m~sh B.S~ sieve and filLed illtO hard gela~in capsulesin 200 mg quantit:ies~
Suppositories each containing 25 mg of active ingredient were made as
Medicament 25 mg
Saturated fatty acid
glycerides to2~00 mg
,~ 10 .
: The active ingredient was passed through a NoO 60 mesh B.S. sieve and
suspended in the saturated fatty acid glycerides previously mel~ed using
the minimum lleat necessary. The mixture was then poured into a suppository
. mould of nominal 2 g capacity and allowed to cool,
Suspensions each con-tai~ing 5 mg of medicament per 5 ml dose were made
as follows :-
Medicament 5 mg
. cell.ulose 5050 mg
.~ Syrup 1.25 ml
~enzoic Acid solution 0.10 ml
. . Flavour q.s.
Chloroform water to 5 ml
'': . I
The medicament was passed through a ~o. 44 mesh BoS~ sie~é and mixed with
,~ 30 the sodium carbo~ymeth~lcellulose 50 and syrup to form a smooth paste~ The
benzoic acid solu~ion, flavour and colour were diluted with some of the
- 63 -
. . . .
chlorol~or.m ~.~7~ter ancl addecl~ wlth constallt stirring. Suffic:tent c~llorof3Ym
1 I water W615 t~er! ~:dded to produce the required volllm~d.
~ 64 ~