CA1125761A - Process for the manufacture of novel oxothia compounds - Google Patents

Abstract

Abstract of the Disclosure 2-Oxo-2,3-dihydro-benzo[b]thiophen compounds of the formula

Description

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~

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~;~

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), 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 .~

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 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.

_ ~ _ 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.

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of an oxothia compound of the formula (I) in which R1 is thienyl and R is hydrogen or in which R1 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, or of a salt there-of with a base, characterised in that a group of the formula -CO-NH-R1 (Ia) is introduced into a compound of the formula (II) either by reacting of a compound of the formula II with a compound of the formula (III), wherein Ro represents an etherified or an esterified hy-droxyl group or a substituted or unsubstituted amino group and R2 is hydrogen, or in which Ro and R? together form a bond, or by reacting of a compound of the formula II
with a compound of the formula R?-CO-R? (IV), in which R? and R? represent an etherified or esterified hydroxyl group and subsequently treating a compound of the formula (IIa) which is obtainable as intermediate, with an amine of the formula H2N-R1 (V)or in that a compound of the formula (VI) in which R0 is an etherified or an esterified hydroxyl group or a substituted or unsubstituted amino group, or a salt thereof is cyclised, or, in that in a compound of the formula (VIII) in which Rz is a substituted or unsubstituted imino group, Rz is hydrolysed to oxo, and, if desired, a resulting free compound is converted into a salt or a resulting salt is converted into the free compound or into another salt.

2. A process according to claim 1 characterised in that compounds of the formulae II and III, II and IV, VI or VIII are selected as starting materials so as to produce N-(2-Thiazolyl)-6-chloro-2-oxo-2,3-dihydro-benzo[b]thio-phen-3-carboxamide or a pharmaceutically usable salt thereof.

3. A process according to claim 1 characterised in that compounds of the formulae II and III, II and III, VI or VIII are selected as starting materials so as to produce N-[3-(5-Methylisoxazolyl)]-6-chloro-2-oxo-2,3-dihydro-benzo[b]thiophen-3-carboxamide or a pharmaceutically usable salt thereof.

4. A process according to claim 1 characterised in that compounds of the formulae II and III, II and III, VI or VIII are selected as starting materials so as to produce N-(2-Pyridyl)-6-chloro-2-oxo-2,3-dihydro-benzo[b]thio-phen-3-carboxamid or a pharmaceutically usable salt thereof.

5. A process according to claim 1 characterised in that compounds of the formulae II and III, II and III, VI or VIII are selected as starting materials so as to produce N-(2-Thienyl)-2-oxo-2,3-dihydro-benzo[b]thiophen-3-carboxamide or a pharmaceutically usable salt thereof.

6. An oxothia compound of the formula (I) wherein R1 is thienyl and R is hydrogen or in which R1 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 their pharma-ceutically usable salts whenever prepared by the process as claimed in claim 1 or by any process which is an obvious equivalent thereof.

FO 7.4 DH/rn*