CY1288A - Oxothia compounds processes for their preparation pharmaceutical preparations containing these compounds and their use as a medicinal active compound - Google Patents

Description

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GB 2 024 220 A

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SPECIFICATION

' Novel oxothia compounds, processes for their preparation, pharmaceutical preparations containing these compounds, and their use as a medicinal active compound

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The invention relates to oxothia compounds, especially 2-oxo-2,3-dihydro-benzo[b]thiophen compounds of the formula

II ' /"i

10 Ph CH — C —N

\ | Nv (I>

\ ^ C ~ 0

15

in which Ph is a substituted or unsubstituted 1,2-phenylene radical, X is oxygen or sulfur, R-i is a substituted or unsubstituted heteroary! radical bonded via a carbon atom and R2 is hydrogen, and their salts with bases and also to processes for their preparation and pharmaceutical preparations which contain compounds of the formula I or salts thereof and the use of such compounds.

20 The above 2-oxo-2,3-dihydro-benzo[b]thiophen compounds can also exist in the tautomeric form, i.e. in the form of 2-hydroxy-benzo[b]thiophen compounds.

In this specification the term "lower" used to qualify organic radicals and compounds denotes that these contain not more than 7 and preferably not more than 4 carbon atoms.

A substituted or unsubstituted hetero-aromatic radical bonded via a carbon atom is in particular a 25 monocyclic hetero-aromatic radical having 5 or 6 ring members, at least one ring member being a hetero-atom, for example a nitrogen, oxygen or sulfur atom.

Substituents of the abovementioned hetero-aromatic radicals Rn and also of the 1,2-phenylene radical Ph are, inter alia, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxyl, halogen, trifluoromethyl or nitro, and two adjacent carbon atoms, especially in a hetero-aromatic radical, can also be substituted by 30 1,3-butadien-1r4-ylene, which can be substituted, for example like an aromatic radical, i.e. with fusing of an aromatic radical and formation of a bicyclic, and especially a benzohetero-aromatic, radical.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert.-butyl, whilst lower alkenyl is, for example, allyl or methallyl and lower alkynyl is, for example, propargyl.

A hetero-aromatic radical containing a heteroatom is, inter alia, monocyclic monoaza-, monooxa- or 35 monothia-aryl, for example pyridyl, such as 2-, 3- or 4- pyridyl,furyl,such as 2-furyl, orthienyi, such as 2-thienyl. A corresponding radical cotaining two heteroatoms is, inter alia, 6-membered monocyclic diazaaryl, for example pyridazinyl, such as 3- or 4-pyridazinyl, pyrimidinyl, such as 2- or 4-pyrimidinyl, or pyrazinyl, such as 2-pyrazinyl, or 5-membered monocyclic oxazaaryl or thiazaaryl, such as oxazolyl, for example 2-oxazolyl, isoxazoiyl, for example 3-isoxazolyl, thiazolyl, for example 2-thiazolyl, or isothiazolyl, for 40 example 2-isothiazolyl. Corresponding hetero-aromatic radicals in which two adjacent ring carbon atoms are substituted by 1,3-butadien-1,4-ylene, i.e. benzohetero-aromatic radicals, are, inter alia, bicyclic ben-zoazaaryl, for example quinolinyl, such as 4-quinolinyl, or isoquinolinyl, or bicyclic benzoxazaaryl or benzothiazaaryl, for example benzoxazolyl, for example 2-benzoxazolyl, or benzthiazolyl, for example 2-benzthiazoiyl.

45 Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy.

Halogen is in particular halogen with an atomic number of not more than 39, i.e. fluorine, chlorine or bromine.

Salts of compounds of the formula I are especially pharmaceutically usable salts with bases, in particular metal salts or ammonium salts. Metal salts are in particular metal salts derived from metals of groups la, lb, 50 lla and lib of the periodic table of the elements, such as alkali metal salts or alkaline earth metal salts, for example sodium salts, potassium salts, magnesium salts, calcium salts, zinc salts or copper salts.

" Ammonium salts are in particular salts with secondary or tertiary organic bases, for example with morpholine, thiomorpholine, piperidine, pyrrolidine, dimethyl- or diethyl-amine ortriethylamine, but, less importantly, also salts with ammonia. The formation of salts with compounds of the formula I probably takes 55" place from the tautomeric 2-hydroxy-benzo[b]thiophen form.

The novel compounds have valuable pharmacological properties. Peripheral analgesic actions are in the forefront of the spectrum of action and these can be demonstrated both in mice in the phenyl-p-benzoquinone writhing test and in rats in the acetic acid writhing test, analogously to the method described by Krupp et al., Schweiz. med. Wsch., volume 105, page 646 (1975), in doses of about 1 to about 100 mg/kg 60 administered perorally. In addition, they have anti-inflammatory actions which can be demonstrated, for example, in the kaolin oedema test on rats, analogously to the method described by Menasse and Krupp, Toxicol, Appl. Pharmacol, volume 29 page389 (1974) in doses of about 30 mg/kg to about 100 mg/kg administered perorally. In vitro, in doses of 0.1-50 jjg/ml, these compounds also inhibit the prostaglandin synthetase system to a markedly great extent (method: White and Glassman, Prostaglandins, vol. 7, No. 2, 65 page 123 (1974)). Futhermore they have uricosuric actions, which can be demonstrated, for example, in the

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phenol red excretion test, analogously to the method described by Swingle et al.. Arch, int Pharmacodyn., volume 189, page 129 (1971), in doses of about 100 mg/kg administered perorally. The compounds are therefore used as peripheral analgesics, for example for the treatment of conditions of pain of very diverse origin, or as antiphlogistic agents, for example for the treatment of arthritic inflammations, or to influence 5 traumatic inflammatory and oncotic conditions, and also as uricosuric agents, for example forthe treatment 5 of gout.

The novel compounds also have antithrombotic actions, which can be demonstrated in rabbits in the experimental pulmonary embolism analogously to the method described by Silver et al. Science, volume 183, page 1085 (1974), in doses of about 3 mg/kg to about 30 mg/kg administered perorally. They can 10 therefore also be used as thrombolytic agents. 10

The invention relates in particularto compounds oftheformula l in which Ph is 1,2-phenylene which is • unsubstituted or substituted by lower alkyl, lower alkoxy, lower alkoxycarbonyl,carboxyl, halogen, trifluoromethyl and/or nitro, X is oxygen, R, is a 6-membered mono- or diazaaryl or 5-membered oxa-, thia-, oxaza-orthiaza-ary! radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, lower 15 alkoxycarbonyl, carboxyl, halogen, trifluoromethyl and/or nitro, especially corresponding pyridyl, pyrimi- 15 dinyl,furyl,thienyl, oxazolyl, isoxazolyl, thiazolyl orisothiazolyl, and R2 is hydrogen.

The invention relates in particularto compounds oftheformula I in which Ph is 1,2-phenylene which is unsubstituted or substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkoxycarbonyl, for example methoxycarbonyl, carboxyl, halogen with an atomic number of not more than 20 35, i.e. fluorine, chlorine or bromine, ortrifluoromethyi, X is oxygen, R-i is pyridyl, for example 2- or 4-pyridyl, 20 furyl, for example 2-furyl, thienyl, for example 2-thienyl, oxazolyl, for example 2-oxazolyl, isoxazolyl, for example 3-isoxazolyl, thiazolyl, for example 2-thiazolyl, or isothiazolyl, for example 3-isothiazolyl, which radicals are unsubstituted or substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkoxycarbonyl, for example methoxycarbonyl, carboxyl, halogen with an atomic number of 25 not more than 35, i.e. fluorine, chlorine or bromine, trifluoromethyl and/or nitro, and R2 is hydrogen. 25

The invention relates in particularto compounds ofthefomula I in which Ph is 1,2-phenylene, which can be substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, and/or halogen with an atomic number of not more than 35, for example fluorine or chlorine, such substituents being in particular in the 5-position and/or 6-position of the 2,3-dihydrobenzo[b]thiophen ring, X is oxygen, R, is pyridyl, for 30 example 2- or 4-pyridyl, furyl, for example 2-furyl, thienyl, for example 2-thienyl, oxazolyl, for example 30

2-oxazolyl, isoxazolyl, forb example 3-isoxazolyl, thiazolyl, for example 2-thiazolyl, or isothiazolyl, for example 3-isothiazolyl, which radicals can be substituted by lower alkyl, for example methyl, and R2 is hydrogen.

The compounds of the present invention can be prepared in a manner known per se. Thus, they are 35 obtained, for example, by introducing a group of the formula -C(=X)-N(R1)(R2) (la) into a compound of the 35 formula

Ph CH_

I 2

A

,C = 0

40 's ^ 40

The 2-oxo-2,3-dihydro-benzofb]thiophen starting material oftheformula II can also exist in the tautomeric form, i.e. in the form of the 2-hydroxy-benzo[b]-thiophen compound.

The group oftheformula la can be introduced direct or step-wise. Thus, this group can be introduced direct by reaction with a compound of the formula III

45 -R 45

/ 1

X » C N

^*2

50

*o

50

in which R0 is an etherified or an esterified hydroxyl group or a substituted or unsubstituted amino group * and R°2has the meaning defined forR2, or in which R0and R°2 together form a bond.

An etherified hydroxyl group R0 is preferably hydroxy etherified by a substituted or unsubstituted hydrocabon radical, such as lower alkyl, for example methyl or ethyl, or halogeno-lower alkyl, for example 55 2,2,2-trichloroethyl, and in particular by substituted or unsubstituted phenyl, such as phenyl containing 55 lower alkyl, lower alkoxy, halogen and/or nitro, and is, for example, lower alkoxy, such as methoxy or ethoxy, halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, or phenoxy, whilst an esterified hydroxyl group is preferably esterified by a strong mineral acid and is, in particular, halogen, especially chlorine. A substituted amino group contains, as substituents, one or preferably two substituted or unsubstituted 00 hydrocarbon radicals, such as loweralkyl and/or phenyl, which can be substituted, for example as indicated above, and is, for example, lower alkylamino, such as methylamino or ethylamino, di-loweralkylamino, such as dimethylamino or diethylamino, or phenylamino and preferably diphenylamino, in which the phenyl radical can be substituted, for example by lower alkyl, such as methyl, lower alkoxy, for example methoxy, halogen,for example fluorine, chlorine or bromine, and/or nitro. A disubstituted amino group R0 can, 65 however, also representthe radical of the formula -N(R1)(R2). 65

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The above reaction is customarily carried out in the presence of a basic agent, such as of a corresponding , inorganic or organic agent. Suitable inorganic bases are, in particular, 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 alkanolates, and also corresponding lower alkyl compounds or 5 phenyl compounds,for example sodium methylate, sodium ethylate, potassium tert-butylate, n-butyl- 5

lithium or phenyl-lithium. Suitable organic bases are in particular amines, such as teriary amines, preferably tri-lower alkylamines, for example triethylamine, heterocyclic teriary bases especially of the pyridine type, for example pyridine, or quaternary bases, such astetra-loweralkyl-ammonium hydroxides or tri-lower alkyl-phenyl-lower aikyl-ammonium hydroxides. In the presence of the base, the starting material of the 10 formula II reacts in the anionic form, i.e. in the form of a salt, with the starting material oftheformula 111. 10

The latter are carbamic acid esters, carbamic acid halides, ureas and rsocyanates which correspond to the formula 111, as well as the corresponding sulfur compounds.

The reaction is carried out in the presence or absence of a solvent or diluent and, if necessary, with cooling or heating, for example in a temperature range of about-10°C to about+120°C, in a closed vessel and/or in 15 an inert gas atmosphere, for example a nitrogen atmosphere. 15

The step-wise introduction of a group oftheformula la into a starting material of the formula II can be carried out by reacting a compound oftheformula II with a compound oftheformula Rq-C(=X)-Ro (IV) in which R® and R£ independently of one another are an etherified or esterified hydroxyl group, and treating a compound oftheformula.

20 X 20

I!

Ph CH — C — R

V

O

.C - 0

25 ° ' 25

which is obtainable as an intermediate, with an amine of the formula R-|-HN-R2 (V).

Etherified or esterified hydroxyl groups R„ and R£ have, for example, the meanings defined above for the corresponding radical R0 and are, for example, lower alkoxy, such as methoxy or ethoxy, and also substituted or unsubstituted phenoxy, or halogen, for example chlorine. Suitable compounds of the formula 30 fVare, for example, di-fower alkyl carbonates, for example diethyl carbonate ordiphenyl carbonate, 30

phosgene or lower alkyl halogeno-formates, for example isobuty! chloroformate, as well as the corresponding sulfur compounds. The reaction of the starting material oftheformula lla with a compound of the formula IV is usually carried out in the presence of a base, such as one of those mentioned above, for example in the presence of an alkali metal hydride or of a tri-lower alkylamine. Usually, an intermediate of 35 the formula lla is not isolated but is reacted direct with the amine of the formula V. 35

The above process steps are carried out in the absence or presence of a solvent or diluent and, if necessary, with cooling or heating, for example in a temperature range of about -10°C to about +120°C, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

The starting materials are known or can be prepared in a manner known per se.

40 Starting materials of the formula II can be obtained, for example, by reacting an enamine derived from a 40 cyclohexanone, which is unsubstituted or substituted as indicated forPh, with a cyanoacetate, acylating the amino group of the resulting 2-amino-4,5,6,7-tetrahydro-benzothiophen-3-carboxylate, dehydrogenating the reaction product with sulfur and treating the resulting 2-acylamino-benzothiophen-3-carboxylate with sodium hydroxide solution, or by converting a corresponding benzothiophen with butyl-lithium into the 45 2-lithium compound and oxidising the latter with hydrogen peroxide. A process which is particularly suitable 45 for the preparation of halogen-substituted compounds of the formula II comprises converting a corresponding benzothiophen-2-carboxylate with hydrazine to the acid hydrazide, reacting the latter with nitrous acid to give the azide, rearranging this to the isocyanate, converting the isocyanate by alcoholysisto the urethane, hydrolysing the latter to the carbamic acid, decarboxylating this acid and hydrolysing the 50 resulting 2-iminobenzothiophen. 50

Compounds oftheformula III can be prepared, for example, by reacting compounds of the formulae Ro-C(=X)-Rq (IV) and HNR,R2 (V).

The novel compounds can also be obtained when a compound of the formula

X _

55 |j // 1 55

Ph CH C N

\

(VI)

SH

r2

60 Ko 60

in which R-, is an etherified or esterified hydroxyi group or a substituted or unsubstituted amino group, or a salt thereof, is cyclised.

A salt of the starting material oftheformula VI is, for example, an alkali metal salt.

A group R0 can be, for example, as defined above and is, for example, lower alkoxy, such as methoxy or 65 ethoxy, halogeno-lower alkoxy, for example 2,2,2-tri-chloroethoxy, substituted or unsubstituted phenoxy, or 65

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halogen, for example chlorine, or also lower alkylamino, for example methylamino, di-lowera!kylamino,for example dimethylamino or diethylamino, phenylamino or diphenyl amino, or also the group oftheformula -N(Ri)(R2).

The above cyclisation reaction can be carried out in a manner known per se, if necessary in the presence of 5 a condensing agent, usually a basic condensing agent, such as a salt-forming agent, for example an alkali 5 metal salt-forming agent, inter alia including in the presence of an alkali metal lower alkanolate, for example sodium methylate, sodium ethylate, or potassium tert.-butylate. The reaction carried out in the absence or presence of a solvent or diluent, if necessary with cooling or warming, for example in temperature range of about 0°C to about 150°C, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen 10 atmophere. 10

The starting materials of the formula VI can be prepared in a manner known perse, for example by introducing a group of the formula C(=X)-N(Ri)(R2) into the methylene moiety of the benzyl group of a compound oftheformula Ry-S-Ph-CH2-Rx (VII), in which Rx is the radical of the formula-C(=X)-N(Ri)(R2)(la)

or the radical oftheformula -C(=0)-Ro and Ryis hydrogen or preferably a mercapto protective group, such as 15 hydrogenolytically detachable a-phenyl-lower alkyl, for example benzyl, by reacting a compound of the 15

formula VII with a suitable derivative of carbonic orthiocarbonic acid, such as a corresponding ester, for example a di-iower alky! carbonate, such as diethyl carbonate, or diphenyl carbonate, a dihalide, for example phosgene or thiophosgene, a halogenated ester, for example a lower alkyl halogenoformate, urea or thiourea, and also isocyanate or isothiocyanate, usually in the presence of a basic agent, such as of an alkali 20 metal hydride, alkali metal amide or alkali metal lower alkanolate, or of an organic base, for example 20

triethylamine. A mercapto protective group can then be detached in the customary manner, for example by treatment with catalytically activated hydrogen, and the mercapto group can thus be set free.

The novel compounds of the present invention can also be obtained by, in a compound of the formula

25 25

f

Ph CH C W

\ i-V **

30 S 30

in which Rz is a substituted or unsubstituted imino group convertible to the oxo group by hydrolysis,

hydrolysing Rzto oxo.

In a substituted imino group Rz, a substituent is, for example, a substituted or unsubstituted hydrocarbon 35 radical, such as lower alkyl, for example methyl or ethyl, or phenyl, or an acyl group derived from a 35

carboxylic acid or a half-ester of carbonic acid, for example lower alkanoyl, such as acetyl, or benzoyl, or lower alkoxy-carbonyl, such as methoxycarbonyl or ethoxycarbonyl.

The starting material oftheformula VIII, which can also exist in the tautomeric form of a corresponding 2-(H-Rz)-benzo[b]thiophen compound, in which the group -Rz-H is an amino group which can be 40 monosubstituted, is converted to the desired compound of the formula I by hydrolysis, preferably by 40

treatment with water in the presence of a basic or acid agent, such as an inorganic base, for example an alkali metal hydroxide, or a mineral acid, for example hydrochloric acid or sulfuric acid.

The reaction is carried out in the presence or absence of a solvent or diluent, and if necessary with cooling or heating, for example in a temperature range of about -10°C to about +120°C, in a closed vessel and/or in 45 an inert gas atmosphere, for example a nitrogen atmosphere. 45

The starting material of the formula VIII can be prepared in a manner known per se, by, for example,

reacting a compound of the formula

X

50 Ph — C — C OH 50

II ?

•c—R2—H

\

55 in which Rz is preferably an unsubstituted imino group and the group-Rz-H is therefore in particular a primary 55 amino group, with, for example, phosgene or a lower alkyl chloroformate, and treating a compound of the formula

Ph C 0

c» . J.O

\

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which is thus obtainable, if desired after introducing a substituent into a hydrogen-containing imino group Rz, for example by treatment with a lower alkyl halide in the presence of a reagent which forms an alkali metal compound, with an amine of the formula RrHN-Rz (V) and, if desired, in a starting material of the formula VIII in which Rz is an unsubstituted imino group, or in a tautomer thereof in which -Rz-H is an 5 unsubstituted amino group, substituting this imino or amino group, for example by lower alkylatiori or 5

acylation, the latter being effected, for example, by treatment with a suitable symmetrical, mixed or inner anhydride of a carboxyiic acid.

The invention also relates to those embodiments of the process in which a compound obtainable as an intermediate at any process stage is used as the starting material and the missing process steps are carried 10 °ut, or in which a starting material is formed under the reaction conditions or is used in the form of a 10

derivative thereof, if desired in the form of a salt.

The starting materials used in 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 pharmaceutical preparations which contain compounds of the 15 formula I and to the use of these compounds, preferably in the form of pharmaceutical preparations. The 15 pharmaceutical 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 contain the pharmacological active ingredient on its own or together with a pharmaceutically usable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, the age and the 20 individual condition and also on the mode of administration. 20

The novel pharmaceutical preparations contain from about 10% to about 95% and preferably from about 20% 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.

25 The pharmaceutical preparations of the present invention are prepared in a manner known per se, for 25

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 of 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 30 particularfillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations 30 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, methylceliuiose, hydroxypropyl-methylcelluiose, sodium carboxymethylcellulose and/ or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above starches, and also carboxy-35 methyl-starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium 35

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 polyethylene glycol. Sugar-coated tablet cores are provided with suitable coatings which can be resistant to gastric juices, using, inter alia,

concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol 40 and/or titanium dioxide, shellack solutions in suitable organic solvents or solvent mixtures or, for the 40

preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcelluiose phthalate. Dyes or pigments can be added to the tablets or sugar-coated tablet coatings for example to identify or indicate different doses of active ingredient.

Further pharmaceutical preparations for oral adminstration are dry-fiiled capsules made of gelatin, and 45 also soft, sealed capsules made of gelatin and a plasticiser, such as glycerin or sorbitol. The dry-filled 45

capsules can contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilisers. In soft sapsules, the active ingredient is preferably dissolved or suspended in suitable liquids,

such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers can also be added. 50 Pharmaceutical preparations suitable for rectal administration are, for example, suppositories, which 50

- 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 alkanols. Gelatin rectal capsules, which consist of a combination of the active ingredient with a base material, are also i suitable; suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin 55 hydrocarbons. 55

Preparations suitable for parenteral adminstration are in particular aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, for which suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or 60 triglycerides, are used, or aqueous injection suspensions which contain substances which increase the 60

viscosity, for example sodium carboxymethylcellulose, sorbitol 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 orsemi-solid oil-in-waterorwater-in-oil emulsion, and ointments (which preferably contain a 65 preservative), for the treatment of the skin, eyedrops, which contain the active compound in aqueous or oily 65

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solution, and eye ointments, which are preferably prepared in sterile form, forthe treatment of the eyes, powders, aerosols and sprays (similar to those described above forthe treatment of the respiratory passages) and coarse powders, which are administered by rapid inhalation through the nostrils, and nose drops, which contain the active compound in aqueous or oily solution, for the treatment of the nose, or 5 lozenges, which contain the active compound in a base which is generally formed from sugar and gum arabic ortragacanth and to which flavourings can be added, and also pastilles, which contain the active ingredient in an inert base, for example of gelatin and glycerin or sugar and gum arabic,for the local treatment of the mouth.

The invention also includes the use of the novel compounds as pharmacologically active substances, 10 especially as anti-inflammatory agents, analgesics, uricosuric agents, anti-allergic agents and/or thrombolytic agents, preferably in the form of 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 aboui 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 15 restrict the scope of the invention in any way. Temperatures are in degrees centigrade.

Example 1

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 3g of 6-chloro-2,3-dihydro-2-oxo-benzo[b]thiophen and 3.85 g of phenyl N-(2-thiazolyl}-20 carbamate in 30 ml of hexamethylphosphoric acid triamide. After a few minutes, the cooling balh is removed and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is pou -ed into a mixture of 1 litre of ice-water and 20 ml of concentrated hydrochloric acid, the precipitate is filtes ed 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 25 for some time in an ice bath and the precipitate is again filtered off with suction. N-(2-Thiazolyl}-5-chloro-2-oxo-2,3-dihydro-benzo[b]thiophen-3-carboxamide with a melting point of 276-289° is obtained.

Example 2

De-oiled sodium hydride, obtained by de-oiling 0.82 g of a 50% suspension in mineral oil, was added at 105 30 t.o a suspension of 3 g of 6-chloro-2,3-dihydro-2-oxo-benzo[b]thiophen and 3.75 g of phenyl N-U -(5-methylisoxazolyl)]-carbamate in 30 ml of hexamethylphosphoric acid triamide. After a few mini tes the cooling bath is removed and the mixture is stirred for a further 2 hours at room temperature. Th 3 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 suction and washed successively with ice-water, diethyl ether and hexane and 35 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 sometime in an ice bath and the precipitate is again filtered off with suction. N-[3-(5-Methylisoxazolyl)]-6-chloro-2-oxo-2,3-dihydrobenzo[bjthiophen-3-carboxamide with a melting point of 220-222° is obtained.

40 Example 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)-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 45 mixture of 1 litre of ice-water and 30 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 for4 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 acetone, treating the solution with active charcoal and concentrating thefiltrate, whereupon crystallisation takes place. N-(2-Pyridyl)-6-chloro-2,3-50 dihydro-2-oxo-benzo[b]thiophen-3-carboxamide is obtained in the form of the sodium salt with a melting point of above 300°.

Example 4

Asolution of7.5 g of 2,3-dihydro-2-oxo-benzo[b]-thiophen in 50 ml of hexamethylphosphoric acid triamide 55 is added dropwise, with cooling, to a suspension of 1.4 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 of phenyl N-(2-thienyl)-carbamate, dissolved in 50 ml of hexamethylphosphoric acid triamide, are added dropwise, with external cooling. The reaction mixture is stirred for a further 16 hours at room temperature and is poured into a mixture of 200 ml of 2N ydrochloric 60 acid and 1000 ml of ice-water. An oil separates out and this crystallises after about 2 hours. The crystalline 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 acidified to a pH of 1 and the crude product is filtered off with suction and recrystallised fro n tetrahydrofuran/ether. N-(2-Thienyi)-2-oxo-2,3-dihydro-3-benzo[b]-thiophen-carboxamide with a melting 65 point of 142-144° (decomposition) is obtained.

: <GB 2024220A l_>

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20

25

30

35

40

45

50

5§

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65

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GB 2 024 220 A

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Example 5

0.8 g of N-(2-thienyl)-2-acetamino-benzo[b]thiophen-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 mixture is left to stand overnight at room temperature and the methanol is stripped off under ® reduced pressure. The evaporation residue is taken up in water, filtered off with suction and washed with 5

water. The residue is taken up in dilute sodium hydroxide solution and insoluble material is filtered off, the aqueous phase is acidified and the N-{2-thienyi)-2-oxo-dihydro-3-benzo[b]thiophen-carboxamine with a melting point of 142-144° (decomposition), which has precipitated, is filtered 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 10

sulfonationfiaskand 13.5 g of ethyl bromide are added in orderto prepare ethyl-magnesium bromide. After the magnesium has dissolved, 6.1 g of 2-aminothiophen, dissolved 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 minutes. 8 g of... 2-acetamido-benzo[b]thiophen-3-carboxylate, dissolved in 100 ml of absolute 15 tetrahydrofuran, are then added dropwise at room temperature. The mixture is then refluxed for 15 minutes 15 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. The chloroform extracts are 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 20 purification. 20

Example 6

11.4 g of o-mercapto-phenylmalonic acid N-(2-thienyl)-amide in 50 ml of dimethylformamide and 1 ml of concentrated hydrochloric acid are heated at 100° for 2 hours. The mixture is allowed to cool, 100 ml of water 25 are added and the precipitate is filtered off with suction and taken up in 100 ml of diethyl ether. 25

N-(2-Thienyl)-2-oxo-2,3-benzo[b]thiophen-carboxamide with a melting point of 142-144° (decomposition) is obtained from the organic 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 prepared as follows: 30

A vigorous stream of air is passed through a solution of 9.4 g of o-mercaptophenylaceticacid in 56 ml of N sodium hydroxide solution for 8 hours, with stirring. The reaction mixture is evaporated to dryness in a rotary evaporator. Twice 50 ml of toluene are added to the residue, the mixture being evaporated to dryness after each addition. The residue is then dried at 50° under a high vacuum for 90 minutes and suspended in 35 180 m! of dimethylformamide, and 7 g of dimethyl sulfate are added to the suspension in the course of 3 35 minutes, with stirring. The reaction mixture is heated at 110° for 1 hour, with stirring, and is then cooled and poured onto ice. The 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 ml of dimethylformamide and this solution is added dropwise to a suspension of 4.8 g of 50% sodium hydride in 200 ml of dimethylformamide. The mixture is stirred, with gentle warming, until the evolution of hydrogen 40 has ceased. A solution of 15 g of 2-thienyl isocyanate in 100 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. The product which then separates out is extracted with ethyl acetate and the extract is washed with water, dried over sodium sulfate and evaporated. o,o'-Bis-[a-methoxycarbonyl-N-(2-thienyl)-carbamylmethyi]-diphenyl disulfide is obtained and this can be employed without purification. 45

20.0 g of crude o,o'-bis-[a-methoxycarbonyl-N-(2-thienyl)-carbamy!methyl3-diphenyl disulfide are suspended in 300 ml of ethanol and 7 g of sodium borohydride are added in portions, with stirring. The 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 reaction to congo red and extracted with ethyl acetate. On evaporation, crude o-mercapto-phenylmalonic acid N-(2-thienyl)-amide is obtained and this can 50 * be cyclised without further purification.

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Example 7

Tablets containing 0.1 g of N-(2-thienyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide are prepared as follows:

Composition (for 1000 tablets):

N-(2-Thienyl)-2-oxo-2,3-dihydro-3-

benzo[b]thiophen-carboxamide

Lactose

10

Corn starch Colloidal silica 15 Magnesium stearate Talc

Water

25

30

100.00 g 50.00 g 73.00 g 13.00g 2.00 g 12.00 g q.s.

20

The N-{2-thienyl)-2-oxo-2,3-dihydro-3-benzo[b}thiophen-carboxamide is mixed with a portion of the corn starch and with the lactose and the colloidal silica and the mixture isforced through a sieve. A further portion of the com stach 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 plastic 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 remainder of the corn starch, the talc and the magnesium stearate are then mixed in and the resulting 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, M-[3-(5-methylisoxazolyl)]-6-chloro-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide or N-(2-thiazo!yl)-6-chloro-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide, or the sodium, zinc or morpho-line salt thereof, can be prepared in an analogous manner.

Claims (19)

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15

20

35 1. An oxothia compound oftheformula

X

II

CH — C

40

/"Rl

J

(i)

25

30

35

40

C = 0

45

50

in which Ph is a substituted or unsubstituted 1,2-phenylene radical, X is oxygen or sulfur, Ri is a substituted or unsubstituted heteroaryl radical bonded via a carbon atom and R2 is hydrogen or a substituted or unsubstituted hydrocarbon radical of aliphatic character, or a saltthereof with a base.

2. Acompound oftheformula I accordingto claim 1, in which Ph is 1,2-phenylene which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or nitro, X is oxygen, Rn is mono- or di-azaary! with 6 ring members or oxa-, thia-, oxaza- or thiaza-aryl with 5 ring members, which radicals can be substituted by lower alkyl, lower alkoxy, halogen, tri-fluoromethyl and/or nitro, and R2 is hydrogen, or a pharmaceutically usable salt thereof with a base.

3. Acompound oftheformula I according to claim 1, in which Ph is 1,2-phenylene which is unsubstituted or substituted by lower aikyl, lower alkoxy, halogen with an atomic number of not more than 35 or trifluoromethyl, X is oxygen, Rt is pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, which

55 radicals can be substituted by lower alkyl, lower alkoxy, halogen with an £tomic number of not more than 35, trifluoromethyl and/or nitro, and R2 is hydrogen, or a pharmaceutically usable salt thereof with a base.

4. Acompound oftheformula I according to claim 1, in which Ph is 1,2-phenylene, which can be substituted in the 4- and/or 5-position by lower alkyl, lower alkoxy or halogen with an atomic number of not more than 35, X is oxygen, Rt is pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, which

60 radicals can be substituted by lower alkyl, lower alkoxy and/or halogen with an atomic number of not more than 35, and R2 is hydrogen, or a pharmaceutically usable saltthereof with a base.

5. N-(2-Thienyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide or a pharmaceutically usable salt thereof with a base.

6. N-(2-Pyridyl)-6-chloro-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide or a pharmaceutically us-

65 able salt thereof with a base.

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GB 2 024 220 A

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7. N-(2-Thiazolyl)-6-chloro-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide or a pharmaceutically usable saltthereof with a base.

8. IM-[3-{5-Methylisoxazolyl)]-6-chloro-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide or a pharmaceutically usable saltthereof with a base.

5 9. A pharmaceutical preparation containing one of the compounds claimed in claims 1 to 8. 5

10. A process forthe preparation of an oxothia compound of the formula ii '/-Rl

10 \h f . C (i) 10

1 R

75 in which Ph is a substituted or unsubstituted 1,2-phenylene radical, X is oxygen or sulfur, R-, is a substituted or unsubstitued heteroaryl radical bonded via a carbon atom and R2 is hydrogen or a substituted or unsubstituted hydrocarbon radical of aliphatic character, or a salt thereof with a base, which comprises introducing a group oftheformula -C(=X)-N(Ri)(R2) (la) into a compound of the formula

20 Ph CH2

\

I

orcyclising a compound oftheformula

25

X

Ph CH C N

20

25

\

C » 0 R.

30 SH

'2

30

R

in which R, is an etherified or an esterified hydroxyl group or a substituted or unsubstituted amino group, or a salt thereof, or, in a compound of the formula

35 X R 35

I! / 1

Ph — CH — C — N

C ■ R V

\

40

40

in which Rz is a substituted or unsubstituted imino group which is convertible to the oxo group by hydrolysis, hydrolysing Rz to oxo, and, if desired, converting a resulting free compound into a sait or converting a resulting salt into the free compound or into another salt.

11. A process according to claim 10, wherein the radical of the formula la is introduced into a starting 45 material oftheformula II by reacting a compound of the formula II with a compound of the formula

X - C N

50 ! \

50

R

*2

in which R0 is an etherified or esterified hydroxyl group or a substituted or unsubstituted amino group end , Rf has the meaning defined for R2, or in which Rc and R£ together form a bond.

55

12. A process according to claim 11, wherein the compound of the formula III which is employed is a carbamate, a carbamic acid halide or an isocyanate or a corresponding sulfurcompound.

13. A process according to claim 10, wherein the radical of the formula la is introduced into a starting material oftheformula II by reacting a compound oftheformula II with a compound of the formula Ro-C(:X)-Rp (IV), in which R® and R£ independently of one another are an etherified or esterified hydroxyl 60 group, and treating a compound oftheformula 60

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Ph CH — C — Ra

V

{lla)

10

15

which is obtainable as an intermediate, with an amine of the formula Ri-HN-R2 (V).

14. A process according to any one of claims lOto 13, wherein a compound obtainable as an iq intermediate at any process stage is used as the starting material and the missing process steps are carried out, or a starting material is formed under the reaction conditions.

15. The process described in Examples 1 to 4.

16. The process described in Examples 5 and 6.

17. The compounds obtainable by the process of claims 10 to 16. 15

18. The compounds obtainable by the process of Examples 1 to 6.

19. The use of a compound claimed in claims 1 to 8 as a medicament or for the preparation of a medicament by a non-chemical route.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.

: <GB 2024220A l_>