Note: Descriptions are shown in the official language in which they were submitted.
11'~57~1
4-104 29/1+2/~/2/~
CA
Process for the manufacture of novel oxothia compounds
The invention relates to a process for the manuf~cture of
oxothia compounds, especially of 2-oxo-2,3-dihyd~.o-benzo
[b]thiophen compounds ofOthe formula
~ \ /C - NH - Rl
R/ ~-/ \S/ (I)
in which Rl is thienyl and R is hydrogen or in which Rl is
pyridyl, thienyl, thiazolyl or isoxazolyl unsubstituted or
substituted by lower alkyl and R denotes halogen with
an atomic number of not more than 35, and of their salts
with bases.
The above 2-oxo-2,3-dihydro-benzo[b]thiophen compounds
can also exist in the tautomeric form, i.e. in the form of
~-hydroxy-benzo[b]thlophen compounds.
In this speclfication the term "lower" used to qualify
organic radlcals and compounds denotes that these contain
not more than 7 and preferably not more than 4 carbon
atoms.
Lower alkyl is, for example, methyl, ethyl, n-propyl, iso-
propyl, n-butyl or tert.-butyl,
-
~57~
-- 2
Pyridyl is for example 2-, 3- or 4-pyridyl, thienyl is for
example 2-thienyl, thiazolyl is for example 2-thiazolyl,
isoxa~olyl is for example 3-isoxazolyl.
Lower alkoxy is, for exsmple, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy or isobutoxy.
Halogen ls in particular halogen with an atomic
number of not more than ~9, i.e. fluorine, chlorin~ or
bromine.
Salts of compounds of the ~ormula I are especi-
ally pharmsceutically usable salts with bases, in parti-
cular metal salts or ~mmonium salts. Metal salts are
in particular metal salts derived from metals of groups
Ia, Ib, IIa and IIb of the periodic table of the elements,
such as alkali metal salt~ or alkaline earth metal salts,
for example sodium salts, potassium salts, magnesium
salts, caloium salts, zinc salt~ or copper salts.
Ammonium sAlts are in particular salts with secondary or
ter~lary organic bases, for example with morpholine,
~hiomorpholine, piperid$ne, pyrrolidine, dimethyl- or
diethyl-amine or triethyla~ine, but, lesq importantly,
also salts wlth ammonia. The formation of ~alts wlth
~ompounds of the f~rmula I probably takes place ~rom
the tautomerlc 2-hydroxy-~enzo[b]thiophen form.
~ he novel compounds have ~aluable pharmacologi-
cal pro~erties. Perlpheral analgesic actions are in
the ~orefront o~ the ~pectru~ of aotion and these can be
demon-strated both in mice in the phenyl-p-ben20qulnone
wri~hing test and in rots in the acetic acid writhing
test, ~nelogously to the method described by Krupp et al.,
Schweiz. med. Wsch., volume 105, page 646 (1~753, in
dose~ o~ ebout 1 to about 109 mg/kg administered per
orally. In addi~ion, they have anti-inflammatory
actions whlch can be demon~trated, for example, ln the
kaolin oedema test on rats, an~logously to the method
11~57~;~
-- 3 --
described by Menassé and Krupp, Toxicol, Appl. Pharmacol.
volume 29 page ~89 (1974) ln doses of about 30 mg/kg to
about lOQ mg/kg administered perorally. In vitro,
in doses of 0.1-50 ~g/ml, these compounds alsoinhibit
the prostaglandin syntbetase system to a markedly ~reat
extent (method: Whlte and Glassmsn, Prostaglsndins,
vol. 7, No. 2, page 123 (1974. Furthermore the~ h ve
uricosuric actions, which can be demonstrated, for example,
in the phenol red excretion test, analogously to the
method described by Swingle et al., Arch. int. Ph~ccdyn.,
volume 189, page 129 (1971), in doses of about 100 mg/kg
administered perorally. The compounds are therefore
used as perlpheral analgesics, for example for the treat-
ment of conditions of pain of very diverse orig1n, or as
antiphlogistic agents, for exsmple for the tre~tment o~
arthritic inflammations, or to influence traumatic
inflamm~tory and oncotic conditions, and also as urico-
suric agents, for example for the treatment of gout.
m e novel compounds also ha~e antithrombotic
actlons, which can be demonstrated in rab~its in the
experimental pulmonary embolism snalogousiy to the method
descrlbed by Silver et al., Science, ~olume lB3, page
1085 (1974), in doses o~ about 3 mg/kg to about 30 mg/kg
admlnistered perorally. m ey can there~ore also be
used as thrombolytlc ~gentsn
The invention relates in particular to a process for the
manufacture of N-(2-Thiazolyl3-6-chloro-2-oxo-2,3-dihydro-
benzo[b]thiophen-3-carboxamide, W-[3-(5-Methylisoxazolyl)]-
6-chloro-2-oxo-2,3-dihydro-benzo[b]thiophen-3-carboxamide,
N-t2-Pyridyl~-6-chloro-2,3-dihydro-2-oxo-benzo[b]thiophen-
3-carboxamide and N- (2-Thienyl)-2-oxo-2,3-dihydro-benzo[b]
thiophen-3-carboxamide and to their salts with bases.
- 4 - i~ S7~
The compounds of the present invention can be
prepared in a manner known per se. Thus, they are obtained,
for example, by introducing a group of the formula
-CO-NH-Rl IIa) into a compound of the formula
\
~ Y l = o
either by reacting of a compound of the formula IL with a
compound of the formula
O = C - N\ 1 (III),
R2
Ro
wherein Ro represents an etherified or an esterified
hydroxyl group or a substituted or unsubstituted amino
group and R2 i9 hydrogen, or in which Ro and R2 together
form a bond, or by reacting of a compound of the formula
II with a compound of the formula Ro~CO~Ro (IV), in which
Ro and Ro represent an etherified or esterified hydroxyl
group and subsequently treating a compound of thç formula
R S ~IIa),
which is obtainable as intermediate, with an amine of the
formula H2N~Rl (V).
The 2-oxo-2,3-dihydro-benzo[b]thiophen starting
material of the formula II can also exist in the tauto-
meric form, i.e. in the form of the 2-hydroxy-benzo[b]-
_ 5 ~ 5761
thiophen compoun~.
m e group of the formula Ia can be introduceddirect or step-wise. Thus, this group can be intro-
duced direct by reaction with a compound of the formula
O - C N (III)
R~ R2
in which Ro ls an etherifled or an esterified hydroxyl
group or a ~ubstituted or unsubstltuted amlno group and
R2 is hydrogen, or in which Ro and R2 together form a
bond.
An ether~fied ~ydroxyl group Ro $s pre~erably
hydroxy etheri~ied by a substitut~d or unsubstituted
hydrocarbon radlcal, such as lower alkyl, for example
methyl or ethyl. or halogeno-lower alkyl, for example
2,2,2-trichloroethyl, and in particular by sub~tituted or
uns~bstituted phenyl, such as phenyl containing lower
alkyl, lower alkoxy, halogen ~nd/or nitro, and ls, lor
example, lower a:Lkoxy, such as methoxy or ethoxy, halo-
geno-lower alkoxy, ~or example 2,~,2-trichloroethoxy,
or phenoxy, whilst an esterlfied hydroxyl group is prefer-
ably esterified by a strong mineral acid and is, in
partlcular, halogen, especially chlorine. A sub-
stituted ~mino group contains, ~s substituents~
one substituted or unsubstituted hydrocarbon radicals,
such as lower alkyl and/or phenyl, which can be sub-
stituted , for example as indicated above, and is,
for example9 lower alkylamLno, such as methylamino or
ethylamino, di-lower alkylamino, such as dimethylamino or
diethylamino, or phenylamlno and preferably diphenylamino,
in which the phenyl rad~cal can be substituted, for
example by lower alkyl~ such as methyl, lower alkoxy,
for example methoxy, halogen, for example ~luorlne,
chlorine or bromlne, and/or nltro. A monosubstituted
~l
- 6 ~ 5~1
amino grou~ Ro can, however, also represent the radical
of the formula -NH-Rl.
m e above reaction ls customarlly carried out in
the presence of a basic agent, such as of a correspondil~g
inorganic or organic agent. Suitable inorganic bases
are, in partlcular, salt-forming agents, especially
alkali metal salt-forming agents, such as alkali metal
hydrides or alkali metal amides, and also alkali metal-
organic compounds, such as corresponding lower alkanol~es,
and also corresponding lower alkyl compounds or phenyl
compounds, for example ~odium methylate, sodlum ethylate,
potassium tert,butylate, n-butyl-lithium or phenyl-lithium.
Suitable organic bases are ~n particular amines, such as
tertiary smlnes, preferably tri-lower alkylamines, for
example triethylamine, heterocyclic tertiary b~s ~eiary
of the pyridine type, for example pyridine, or quaternary
ba-qes, such as tetra-lower alkyl-zmmonium hydroxides or
trl lower alkyl-phenyl-lower alkyl-Pmmonium hydroxides.
I~ the presence of the ba~e, the start~ng material of the
formula II reacts in the anionic form, l.e. in the ~orm
of a salt, with the starting material of the formula III.
The latter arecarba~lc ecid ester~, carb~mic acid
halides, ureas and lsocyanates which correspond to the
formula III, as well as the corresponding sulfur oompounds.
m e r~actlon is carried out in the pre ence or
absence of ~ solvent or dlluent Rnd, if necessary, wlth
coolln~ or h~ating~ ~or example ln a temperature range of
~bout -10C to about ~120C, in a closed ves~el ~nd/or ln
an lnert ga~ ~t~osphere, for example a nitrogen atmos-
phere.
m e step-wise introduction of a group of the
formula Ia into a starting material o~ the formula II can
~e carried out by reacting a compound of the formula II
with a compound of the ~ormula Rb-C~=0)-Ra (IV) in
which Ra and Rb lndependently of one another are an
etherified or esterifled hydroxyl group, and trestlng a
compound Or the formula
_ 7 - O ~ ~ ~576
~-\ /C-Ro (IIa)
/ l = o
which is obtainable as an intermediate, with an amine of the
formula H2N-Rl (V).
Etherlfied or esterified hydroxyl groups Ro ~nd
Rb have, ~or example, the mea ~ s defined above for th
correspondlng radlcal Ro ~nd ~re, ior example, lower
alkoxy, such as mcthoxy or ethoxy, end al~o substitute,i
or un~ubstltuted phenoxy, or halogen, for example chlorine.
Sultable compounds o~ the formula IV are, ior example,
di-lower alkyl csrbonate6~ for exRm~le diethyl carbonate
or dlphenyl carbonate, phosgene or lower alXyl halogeno-
tormat~s, ~or oxemple ~sobutyl chloro~ormate, as well as
the corre~pondlng sulfur compounds. ~he roact~o~ o~
the st~rtlng materlal of the for~ula IIa with ~ compound
o~ the formula IV i3 usually carried out ln ~he presence
o~ a b~so, uch as on~ Or those ment~oned above, ior
~x~mple in the pre~ence o~ an ~lk~li metal hydrlde or of
a trl-lower ~lkyla~ine. Usually, an lntermediat~
of the formula IIe is not lsolated but is reacted.direct
with the amlne o~ the ~ormul~ V.
The above process step3 are carrled out in the
~bsenco or prosonco Or ~ ~olvont or ~iluent ~nd, 1~
nQces~ary, wlt~ coollng or he~tlng, for example in 8
t~perature rAn4e o~ ~bout -10~ to about ~120C, in a
closed ve3sel and/or i~ an lnert gas atmosphere, for
~xemple a nitrogen atmosphere.
T~.e starting materials are known or can be pre-
pared in a manner k~own per se.
Startin~ materials of the ~ormula II can be
obtained~ for exQmple, by reac~n~ an enamine deriv~d from
a cyclohexanone, which ls unsub~tltuted or ~ub6tituted
as ind$cated for Ph, with a cyanoacet~te, acylhting ~he
..~.
1 ~ ~ 5~6 ~
amino group o~ the resulting 2-amino-4,5,6,7-tetrahydro-
benzothlophen-3-carboxylate, dehydrogenating the reactlon
product with ~ul~ur and treating the resulting 2-acyl-
amino-benzothiophen-3-carboxy1ate wlth sodium hydroxide
solution, or by convertlng a corresponding benzothiophen
wlth butyl-l~thium into the 2-llthium compound ~nd oxi-
dising the latter with hydrogen peroxide. A proc--ss
which is particularly suitable for the preparation G f
halogen-substituted compounds of the formula II com~rises
converting a corresponding benzothiophen-2-carboxyl~te
with hydrazlne to the acid hydr~z~de, reacting the iatter
with ~ltrous acid to give the azide, rearranging thi8 to
the lsocyanate, converting the isocyanate by alcoholysis
to the urethsne, hydrolyslng the latter to the carbamic
ac~d, decarboxylating thi8 acid and hydrolyslng the r~sul-
tlng 2-lminobenzothlophen.
Compounds of the formulQ III can be prepared, for
example, by reacting compounds of the formulae
Ro~C (=O) -Ro (IVI and H2N-Rl (v).
The novel compounds can also be obtained when a
compound of the formula 1l
,~c ~CH-C-NH--Rl
y~ C = o (Vl)
R/ ~-~ \ R
SH o
in which Ro is an etherified or esterified hydroxyl group
or a substituted or unsubstituted amino group, or a salt
thereof, is cycllsqd.
A salt of the starting material Or the fonnula VI
1~, for example, an allcall metal salt.
A group Ro can be, ~or example, as de~ined above
and is, fos~ example, lower 91koxy, such as methoxy or
ethoxy, h~logeno-lower alkoxy, rOr example 2,2,2-tri-
chloroethoxy, substituted or un~ubstituted phenoxy, or
_ 9 _ ~ ~ 2 S7~ ~
halogen, for example chlorine, or also lower alkylamlno,
for example methylamino, dl-lower alkylamino, for example
dimethylamino or diethylamino, phenylamino or diphenyl
amino,or also the group of the formula -N~-Rl.
m e abo~e cycl~sation reactlon can be carried out
in a manner known per se, if necessary in the presence of
a condenslng agent, usually a basic condenslng agent,such~s
a salt-forming agent, for example an alkalimetal salt-formil~
agent,lnteraliaincludingln the presence of an alkali metal ~Rr
alkanolate, for ex~mple sodium methylate, sodium ethylate,
or potasslum tert.-butylate. m e reaction ls carried
out in the absence or presence of a solvent or diluent,
if necessary wlth cooling or warming, for example in the
temperature r~nge o~ about 0C to ab~ut 150C, in a closed
vessel and/or in ~n inert gas atmosphere, for example a
~itrogen atmosphere.
The st~rtlng materials of tbe formul~ YI can be
prepared in a manner known per se, for example by intro-
ducing a group of the formula -Co-NH-Rl into the
mFhylene moiety of the benzyl group of a compound of the
formula ~ -S-Ph-CH2- ~ (VII),in which ~ ls the radical
o~ the ~ormula -C~ H-Rl ~Ia) or the radlcal of the
formula -C(~0)-Ro and ~ i8 hydrogen or pre~erably a
mercapto protective group, ~uch ~s hydrogenolytically
detachable ~-phenyl-lower alkyl, for example benzyl,
by roactl~ e co~pour~d o~ ~e ~ormulH VII wlth a sultable
der~vatl~e o~ carbo~ic or ~hlocerbonic acid, such a~ 2
corre~po~dln~ ostor, for oxnmplo a dl-lower ~lkyl cerbon~,
such es dlethyl carbonate, or diphenyl carbonate, a
dihalide, for example phosgene or thiophosgene~ a halogen-
ated ester, for example a lower alkyl halogenoformRte,
urea or thlourea, and also ~socyanate or isothiooyan2te,
ususlly ln the presence o~ a basic agent, such a~ of an
alkall ~etal hydride, alkall metal ~mide or alkall metal
lower alkanol~te, or Or ~n organic ba~e, for example
triethylamino. A ~ercapto protecti~e grcup cRn then
- lo - ~ 7 ~ ~
be detached 1~ the customary manner, for example by treat-
ment with c~talytically activated hydrogen, and the mer-
capto group can thus be set free.
m e novel compounds o~ the present inventlon can
also be obtained by, ln a compound of the formula
--i-C-NH-R (VTII)
in whlch R2 is ~ substituted or unsubstituted imlno group
convertible to the oxo group by hydrolysis, hydrolyslng
Rz to oxo.
In ~ substituted lmino group Rz, a substltuent is,
~or example, a sub~tltuted or unsubstltuted hydrocarbon
radlcal, BUCh A8 lower alkyl. for example methyl or ethyl,
or phenyl, or an acyl group d~rlved from a carboxylic
ecid or B half-e~ter of carbonlc acid~ for example lower
alka~oyl, such a~ acetyl, or be~zoyl, or iow~r aIkDxy-
carbonyl, ~uoh aa me~hoxycarbonyl or e~hoxycarbonyl.
~ he starting materi~l of the formula VIII, whlch
can ~180 exist in the tautomerlc form of a corresponding
2-~H-Rz~-benzorb]thiophen compound, ln which the group
-Rz-H 18 an umlno ~roup whlch ean bo ~onosubst~tuted, 18
converted to the desired co~pouad of the formula I by
hydrolysls, p~eforably by tro~tment wlth water in the
presence o~ a basic or acid agert, such as an lnorganlc
base, for example an alkali metal hydroxide, or a mineral
acid, for example hydrochloric acld or sul~urlc acid.
The reaction i8 carried out in the presence or
absence of a ~olYent or diluent, and if nece~sary wlth
cooling or heating, for ex2~ple ln a temperature range
of about -1~C to about ~120C, ~n a clo.ced vessel ~nd/or
ln an in~rt 8as atmospher~, for example ~ ~ltrogen
.~
2576
atmos~here~
~ he startlng materi 1 of the fo~mula VIlI can
be prepared ln a manner known per se, by! for example,
re~ctlng a compound of the formul~
R/ ~ / \S/ Rz H ( IX )
ln which Rz ls preferably an unsubstituted lmino group
and the group -Rz H ~s therefore in particular a primary
am~no group, w$th, ~or example, phosgene or a l~wer alkyl
chloro~ormate, and ~re~ting a compound of the formula
o
( X )
whlch is thus o~ta~nable, i~ de~ired after introducing a
substltu~nt into a ~ydrogRn-csnt~i~lng iml~o group Rz,
~or example by treatment with e lower alkyl halide in th~
pre~ence o~ fl reagent which rorms an alkali metal com-
pound, wit~ ~ ~mine c~ t~0 ~orr~ula R~ Ræ (V~ ~nd,
lr de~lred, ln a Dt6rting materl~l o~ ~he formul~ VIII
ln w~o~ Rz i~ an unAub~tltut~d ~lno ~roup, or 1n ~
tautomer thereoî ln whlch -Rz-H ls an unsubstituted amino
group, substituting this lmino or amino group, for
example by lower alkylatlon or acylation9 the latter
belng efiectedy for example, by trea~ment wlth a suitable
symmetrical, mixed or lnner aslhydride of a cQrboxylic
ac id .
The lnvention ~lso relates to those embodiments
o~ the process ln which ~ compou~d obt~lnable a~ an lnter-
~25761
/~
~~ 13--
mediate at any process stage is used as the starting
material and the missing process steps are carried out,
or in which a starting material is formed under the
reaction conditions or is used in the form of a deriva-
tive thereof, if desired in the form of a salt.
~ he starting materials used i~ the process of the
present invention are preferably those which result in
the compounds described above as being particularly
valuable.
The present invention also relates to pharma- -
ceutical preparations which contain compounds of the
formula I and to the use of th~se compounds, preferably
in the form of pharmaceutical preparations. ~he
pha~maceutical preparations according to the invention
are those which are intended for enteral, such as oral,
rectal or parenteral administration or for topical or
local application to warm-blooded animals and which con-
tain the pharmacological active Lngredient on its own or
together with a pharmaceutically usable carrier. ~he
dosage of the active Lngredient depends on the species
of warm-blooded animal, the age and the indiuidual condi-
tion and also on the mode of a~ministration.
me novel phar Aceutical preparations contain
from about lq~to about 95% and preferably from about 20~o
to about 90% of the active ingredient. Pharmaceutical
preparations according to the invention are, for example,
those in the form of elixirs, aerosols or sprays or in
the form of dosage units, such as sugar-coated tablets,
tablets, capsules, suppositories or ampoules.
me pharmaceutical preparations of the present
invention are prepared in a manner known per se, for
example by means of conventional mixing, granulating,
sugar-coating, dissolving or lyophilising methods.
Preparations for oral administration can be
obtained, for example, by combining the active ingredient
with solid carriers, granulating a resulting mixture o~
11~57~
desired and processing the mixture or granules, after
adding suitable adjuncts if desired or necessary, to
tablets or sugar-coated tablet cores. Suitable
carriers are in particular fillers, such as sugars, for
example lactose, sucrose, mannitol or sorbitol, cellulose
preparations and/or calcium phosphates, for example
tricalcium phosphate or calcium hydrogen phosphate, and
also binders, such as starch pastes, using, for example,
maize starch, corn starch, rice starch or potato starch,
gelatin, tragacanth, methylcellulose, hydroxypropyl-
methylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidDne, and/or, if desired, disintegrators,
such as the abo~e starches, and also carboxymethyl-starch,
crosslinked polyvinylpyrrolidone, agar or alginic acid
or a salt thereof~ such as sodium alginate. Adjuncts
are in particular glidants and lubricants, for example
silicic acid, talc, stearic acid or salts thereof, such
as magnesium stearate or calcium stearate, and/or poly-
ethylene glycol. Sugar-coated tablet cores are pro-
vided with suitable coatings which can be resistant to
gastric juices, using, inter alia, concentrate~sugar solu-
tions which may contain gum arabic, talc, polyvinyl-
pyrrolidor.e, polyethylene glycol and/or titanium dioxide,
shellack solutions in suitable organic solvents or solvent
m xtures or~ for the preparation of coatings resistant
to gastric juices, solutions of suitable cellulose pre-
parations, such as acetylcellulose phthalate or hydroxy-
propylmethylcellulose phthalate. Dyes or pigments can
be added to the tablets or sugar-coated tablet coatings
for axample to identify or indicate different doses of
active ingredient.
Further pharmaceutical preparations for oral
administration are dry-filled capsules made of gelatin,
and also soft, sealed capsules made of gelatin and a
plasticiser, such as glycerin or sorbitol~ m e dry-
filled capsules can contain the active ingredient in the
57
1'~
form of granules, for example in admixture with fillers,
such as lactose, binders, such as starches, and/or lubri-
cants, such as talc or magnesium stearate, and, if desired,
stabilisers. In soft capsules, the active ingredient
is preferably dissolved or suspended in suitable liquids,
such as fatty oils, paraf~in oil or liquid polyethylene
glycols, to which stabilisers can also be added.
Phar~aceutical preparations suitable for rectal
administration are, for example, suppositories, which
consist of a combination of the active ingredient with
a suppository base. Examples of suitable suppository
bases are natural or synthetic triglycerides, paraffin
hydrocarbons, polyethylene glycols or higher aIkanols.
Gelatin rectal capsules, which consist of a combination
of the active i~gredient with a base material9 are also
suitable; suitable base materials are, for example,
liquid triglycerides, polyethylene glycols or paraffin
hydrocarbons.
Preparations suitable for parenteral administration
are in particular aqueous solutions of an active ingre-
dient in water-soluble form, for example of a water-
solub~e salt, and also suspensions of the active ingr~ient,
such as corresponding oily injection suspensions, for
which suitable lipophilic solvents or vehicles, such as
fatty oils7 for example sesame oil, or synthetic fatty
acid esters, for example ethyl oleate or triglycerides,
are used, or aqueous injection suspensions which contain
substances which increase the viscosity, for example
sodium carboxymethylcellulose, sorb'tol and/or dextran,
and can also contain stabilisers.
Pharmaceutical preparations for topical and local
use are, for example, lotions and creams, which contain a
liquid or semi-solid oil-in-water or water-in-oil emulsion,
and ointments (which preferably contain a preservative),
for the treatment of the skin, eyedrops, which contain ~he
active compound in aqueous or oily solution, and eye
l~Lk.,~76SL
1~
ointments, which are preferably prepared in sterile form,
for the treatment of the yes, powders, aerosols and
sprays (similar to those described above for the treat-
ment of the respiratory passages) and coarse powders,
which are administered by rapid inhalation through the
nostrils, and nose drops, which contain the active com-
pound in aqueous or oily solution, for the treatment of
the nose, or lozenges, which contain the active compound
in a base which is generally formed from sugar and gum
arabic or tragacanth and to which flavourings can be
added, and also pastilles, which contain the active ingre-
dient in an inert base, for example of gelatin and gly-
cerin or sugar and gum arabic, for the local treatment
of the mouth.
The invention also includes the use o~ the novel
compounds as pharmacologically active substances, especi-
ally as anti-inflammatory agents, analgesics, uricosuric
age~ts, anti-allergic agents and/or thrombolytic agents,
preferably in the form o~ pharmaceutical preparations.
The daily dose, which in particular is dependent on the
condition of the organism to be treated and/or on the
indication, is from about 300 mg to about 1 g for a warm-
blooded animal weighing about 70 kg.
The following examples illustrate the invention
described above; however, they are not intended to
restrict the scope of the invention in any way. Tempera-
tures are in degrees centigrade.
Exam~le 1
De-oiled sodium hydride, obtained by de-oiling
0.82 g of a 50% suspension in mineral oil, W2S added at
10 to a suspension of 3 g of 6-chloro-2,3-dihydro-2-oxo-
benzo[b]thiophen and 3.85 g of phenyl N-(2-thiazolyl)-
carbamate in 3~ ml of hexamethylphosphoric acid triamide.
After a few minutes, the cooling ba~h is removed and
the mixture is stirred for a further 2 hours at room
temperature. me reaction mixture is poured into a
~1257~;~
1(,
mixture of 1 litre of ice-water and 20 ml of concentrated
hydrochloric acid, the precipitate is filtered off with
suction and washed successively with ice-water, diethyl
ether and hexane and taken up in 50 ml of acetone, the
acetone solution is heated under reflux, allowed to cool,
diluted with 100 ml of diethyl ether and cooled for some
time in an ice bathand the precipitate is again filtered
off with suction. N-(2-Thiazolyl)-6-chloro-2-oxo-2,3-
dihydro-benzo[b]thiophen-3-carboxamide with a mel~ing
point of 276-289 is obtained.
Example 2
De-oiled sodium hydride, obtained by de-oiling
0.82 g of a 5G% suspension in mineral oil~ was added at
10 to a suspension of 3 g of 6-chloro=2,3-dihydro-2-
oxo-benzo[b]thiophen and 3.75 g of phenyl N-[3-(5-methyl-
isoxazolyl)]-carbamate in 30 ml of hexamethylphosphoric
acid triamide. After a few minutes the cooling bath is
removed and the mixture is stirred for a further 2 hours
at room temperature. The reaction mixture is poured
into a mixture of 1 litre of ice-water and 20 ml of
concentrated hydrochloric acid and the precipitate is
filtered off with SUCtiOil and washed successi~ely with
ice-water, diethyl ether and hexane and taken up in
50 ml of acetone9 the acetone solution is heated under
reflux, allowed to cool, diluted with 100 ml of diethyl
ether and cooled for some time in an ice bath and the
precipitate is again filtered off with suction.
N-[3-(5-Methylisoxazolyl)]-6-chloro-2-oxo-2,3-dihydro-
ben2o[b]thiophen-3-carboxamide with a melting point of
22G-222 is obtained.
Exam~le_3
De-oiled sodium hydride, obtained by de-oiling
0.82 g of a 50% suspension in mineral oil, was added at
10 to a suspension of 3 g of 6-chloro-2,3-dihydro-2-
oxo-benzo[b]thiophen and 3.75 g of phenyl N-(2-pyridyl)-
carbam2te in 30 ml of hex~ethylphosphoric acid triamide.
_ _ _ . _ _ _ _ . _,,, _,, _ _ , . . . . . . . .
I 1 112576~
After a few minutes the cooling bath is removed and the
mixture is stirred for a further 2 hours at room tempera-
ture. The reaction mixture is poured into a mixture
of 1 litre of ice-water and ~0 ml of concentrated hydro-
chloric acid, the precipitate is filtered off with
suction and suspended in 50 ml of water, 15 ml of N sodium
hydroxide solution are added, the mixture is stirred for
4 hours and the precipitate is filtered off with suction,
washed with water and subjected to suction until dry.
The crude product can be purified by dissolving in ace- -
tone, treating the solution with active charcoal and
concentrating the filtrate, whereupon crystallisation
takes place. N-(2-Pyridyl)-6-chloro-2,3-dihydro-2-
oxo-benzo~b]thiophen-3-carboxamide is obtained in the
form of the sodium salt with a melting point of above
3ooo~
Example 4
A solution of 7.5 g of 2,3-dihydro-2-oxo-benzo[b]-
thiophen in 50 ml of hexamethylphosphoric acid triamide
is added dropwise, with cooling, to a suspension of 2.4 g
of a 50% sodium hydride/mineral oil dispersion in 100 ml
of hexamethylphosphoric acid triamide, the temperature
being kept below 15 during the addition. After
stirring for half an hour at room temperature, 52 g o~
phenyl N-(2-thienyl)-carbamate, dissolved in 50 ml of
hexamethylphosphoric acid triamide, are added dropwise,
with external cooling. m e reaction mixture is stir-
red for a further 16 hours at room temperature and is
poured into a mixture of 200 ml o~ 2N hydrochloric acid
and 1000 ml of ice-water. An oil separates out and
this crystallises a~ter about 2 hours. The crystal-
line product, which contains solvent, is dissolved in 2N
sodium hydroxide solution and the solution is washed
four times with ethyl acetate. The organic phase is
washed with water, the aqueous phases are combined and
acidi~ied to a pH of 1 and the crude product is filtered
257~
; . `
off with suction and recrystallised from tetrahydrofuran~
ether. N-(2-~hienyl)-2-oxo-2,3-dihydro-3-benzo[b]-
thiophen-carboxamide with a melting point of 142-144
(decomposition) is obtained.
Exam~le 5
0.8 g of N-(2-thienyl)-2-acetamino-benzo[b]thio-
phen-3-carboxamide is suspended in 5 ml of ethanol,
2.5 ml of water and 2.5 ml of concentrated hydrochloric
acid and the suspension is refluxed for 7 1/2 hours.
The reaction m~xture is left to stand overnight at room
temperature and the methanol is stripped off under
reduced pressure. me evaporation residue is tak~n
up i~ water, filtered off with suction and washed with
water. The residue is taken up i~ dilute sodium
hydroxide solution and insoluble material is filtered
off, the aqueous phase is acidified and the N-(2-thienyl)-
2-o~o-2,3-dihydro-3-benzo[b]thiophen-carboxamide with a
melting point of 142-144 (decomposition), which has
precipitated, is filter~ off.
The starting material can be prepared as follows:
3 g of magnesium curlings and 30 ml of anhydrous
-tetrahydrofuran are initially introduced into a sulfon-
ation flask and 13.5 g of ethyl bromide are added in
order to prepare ethyl-magnesium bromide. After the
magnesium has dissolved, 6.1 g of 2-aminothiophen, dis-
solved in 60 ml of absolute tetrahydrofuran, are added
dropwise and the mixture is stirred for one hour at room
temperature and then refluxed for a further 15 m;nute
8 g of ... 2-acetamido-benzo[b]thiophen-3-carboxylate,
dissolved in 100 ml of absolute tetrahydrofuran, are then
added dropwise at room temperature. ~he mixture is
then refluxed for 15 minutes and stirred for a further
15 minutes at room temperature, the reaction solution is
evaporated in vacuo, dilute hydrochloric acid is added
to the evaporation residue and the mixture is extracted
twice with chloroform. ~he chlorofor_ extracts are
1257~
combined, dried over sodium sulfate and evaporated to
dryness in vacuo. Crude N-(2-thienyl)-2-acetamino-
benzo~b]thiophen-3-carboxamide is obtained and this can
be used without further purification.
Exam~le 6
11.4 g of o-mercapto-phenylmalonic acid N-(2-
thienyl)-amide in 50 ml of dimethylformamide ard l ml of
concentrated hydrochloric acid are heated at 100 for
2 hours. ~he mixture is allowed to cool, lO0 ml of
water are added and the precipitate is filtered off with
suction and taken up in 100 ml of diethyl ether. N-
(2- mienyl)-2-oxo-2,3-benzo[b]thiophen-carboxamide with
a melting point of 142-144 (decomposition) is obtained
from the org~nic phases after washing, first with N sodium
hydroxide solution and then with water, drying over
sodium sulfate and evaporating, subjecting the residue to
chromatography and crystallising the product from ether.
The starting material can, for example, be pre-
pared as follows:
A vigorous stream of air is passed through a
solution of 9.4 g of o-mercaptophenylacetic acid in 56 ml
of N sodium hydroxide solution for 8 hours,with stirring.
me reaction mixture is evaporated to dryness in a rotary
evaporator. Twice 50 ml of toluene are added to the
residue, the mixture beirg evaporated to dryness after
each addition. The residue is then dried at 50 under
a high vacuum for 90 minutes and suspended in 180 ml of
dimethylformamide, and 7 g of dimethyl sulfate are added
to the suspension in the course of 3 minutes, with
stirring. The reaction mixture is heated at 110 for
1 hour, with stirring, and is then cooled and poured onto
ice. ~he suspension formed is extracted with ethyl
acetate and the organic phases are combined and washed
with water, dried over sodium sulfate and evaporated.
The residue (18 g) is dissolved in 200 m~ of dimethylfor-
m~mide and this solution is added dropwise to a suspensior
S~
of 4.8 g of 50% sodium hydride in 200 ml of dimethyl-
~ormamide. The mixture is stirred, with gentle warm-
ing, until the evolution of hydrogen has ceased. A
solution of 15 g of 2-thienyl isocyanate in lOO ml of
dimethylformamide is then added dropwise slowly at 0.
The solution is stirred for a further 24 hours at room
temperature and ice and dilute hydrochloric acid are
then added. ~he product which then separates out
is extracted with ethyl acetate and the extract is
washed with water, dried over sodium sulfate and evapor-
ated. o,o'-Bis-~a-methoxycarbonyl-N-(2-thienyl)-car-
bamylmethyl]-diphenyl disulfide is obtained and this can
be employed without purification.
20.0 g of crude o,o'-bis-[a-methoxycarbonyl-N-
(2-thienyl)-carbamylmethyl]-diphenyl disulfide are sus-
pended in 300 ml of ethanol and 7 g of sodium borohydride
are added in portions, with~stirring. ~he mixture is
stirred at room temperature for 4 hours and evaporated,
water is added to the residue and the mixture is acidified
with hydrochloric acid until it just gives an acid reac-
tion to congo red and extracted with ethyl acetate.
On evaporation, crude o-mercapto-phenylmalonic acid
N-(2-thienyl)-amide is obtained and this can be cyclised
without further purification.
EXamPle 7
Tablets containing 0.1 g of N-(2-thienyl)-2-oxo-
2,3-dihydro-3-benzo[b]thiophen-carbox~mide are prepared
as follows:
Com~osition (for lOOO tablets):
N-(2-Thienyl)-2-oxo-2,3-dihydro-3-
benzo~b]thiophen-carboxamide lOO.OO g
Lactose 50.00 g
Corn starch 73.00 g
Colloidal silica -13.00 g
Magnesium stearate 2.00 g
Talc 12.00 g
Water q.s.
761
_ ~ _
me N-(2-thienyl)-2-oxo-2,3-dihydro-3-benzo~b]thio-
phen-carboxamide is mixed with a portion of the corn starch
and with the lactose and the colloidal silica and ~he
mixture is forced through a sieve. A further portion
of the corn starch is mixed to a paste with five times
the amount of water on a water bath and the above powder
mixture is kneaded with this paste until a slightly plas-
tic mass has formed. The plastic mass is forced
through a sieve of about 3 mm mesh width and dried and
the dry granules are again forced through a sieve.
The rPm~inder of the corn starch, the talc and the mag-
nesium stearate are then mixed in and the resulti~g
mixture is compressed to tablets weighing 0.25 g.
Tablets which each contain 0.1 g of N-(2-pyridyl)-
6-chloro-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide,
N-[3-(5-methylisoxazolyl)}6-chloro-2-oxo-2,3-dihydro-3-
benzo[b]thiophen-carboxamide or N-(2-thiazolyl)-6-chloro-
2-oxo-2,3-dihydro-3-benzo[b~thiophen-carbox~mide, or the
sodium, zinc or morpholine salt thereof, can be prepared
in an analogous m~nner.
