DE3832848A1 - Benzothiophene-2-carboxamide-S,S-dioxides - Google Patents

Abstract

The invention relates to novel benzothiophene-2-carboxamide-S,S-dioxides of the general formula <IMAGE> in which R<1> to R<8> and Ar have the meaning indicated in the description, and their use in the control of diseases, in particular of mycoses.

Description

The invention relates to new benzothiophene-2-carboxamide-S, S-dioxide, Process for their preparation and their Use in fighting diseases, in particular Mycoses.

It is known that certain pyridones such as the compound 6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one or their addition product with ethanolamine have good antifungal activity (cf. e.g. B. Arzneimittel-Forsch, 23, 670-674 [1973]; Chemotherapy 24, 68-76 [1978]).

The effectiveness of these previously known compounds is however, not completely satisfactory in all indications.

There were new benzothiophene-2-carboxamide-S, S-dioxide of the general formula I,  

in which
R 1 represents hydroxy, mercapto, cyano, halogen, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, imidazolyl or triazolyl,
R² represents hydrogen or alkyl,
R³ represents hydrogen or alkyl,
R⁴ represents alkyl,
R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen, hydroxy, cyano, nitro, halogen, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoximinoalkyl, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl and
Ar represents optionally substituted aryl,
found.

The compounds of formula (I) can be dependent on the type of substituents R³ and R⁴ optionally as optical isomers or mixtures of isomers different Composition. Both the pure Isomers as well as the mixtures of isomers are the subject the invention.

Compounds of the general formula (I) in which R¹ Imidazolyl or triazolyl means can with acids form the corresponding salts. These salts are also Subject of the invention, especially those with physiologically acceptable acids, such as Hydrochloric acid, phosphoric acid or citric acid.

It was also found that the new benzothiophene-2-carboxamide-S, S-dioxide of the general formula (I),

in which
R 1 represents hydroxy, mercapto, cyano, halogen, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, imidazolyl or triazolyl,
R² represents hydrogen or alkyl,
R³ represents hydrogen or alkyl,
R⁴ represents alkyl,
R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen, hydroxy, cyano, nitro, halogen, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoximinoalkyl, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl and
Ar represents optionally substituted aryl,
get when one

• (a) 3-chlorobenzothiophene-2-carboxamides of the formula (II), in which
  R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and Ar have the meaning given above,
  with an oxidizing agent, if appropriate in the presence of a diluent and if appropriate in the presence of a reaction auxiliary, and
• (b) optionally then the 3-chlorobenzothiophene-2-carboxamide-S, S-dioxide of the formula (Ia) obtainable in this way in which
  R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and Ar have the meaning given above,
  with compounds of the formula (III), R ^1-1 -M (III) in which
  R ^1-1 for hydroxy, mercapto, cyano, for halogen with the exception of chlorine, for alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl,
  Haloalkylsulfonyl, represents imidazolyl or triazolyl and
  M represents hydrogen or an alkali metal cation,

optionally in the presence of a diluent and optionally in the presence of a Reaction auxiliary implemented.

Finally it was found that the new benzothiophene-2-carboxamide-S, S-dioxide of the general formula (I) good antimicrobial, especially good antifungal properties have.

Surprisingly, the benzothiophene-2-carboxamide S, S-dioxide according to the invention the general formula (I) a significantly better antifungal activity than the pyridones known from the prior art, such as for example the compound 6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one or their addition connection with Ethanolamine, which are the most effective compounds are from the prior art.

The benzothiophene-2-carboxamide-S, S-dioxide according to the invention are generally defined by the formula (I). Compounds of the formula (I) in which
R¹ for hydroxy, mercapto, cyano, fluorine, chlorine, bromine, iodine, for each straight-chain or branched alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each having 1 to 4 carbon atoms, for each straight-chain or branched haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl each having 1 up to 4 carbon atoms and 1 to 9 identical or different halogen atoms or for 1-imidazolyl or 1-triazolyl,
R² represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,
R³ represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,
R⁴ represents straight-chain or branched alkyl having 1 to 4 carbon atoms,
R⁵, R⁶, R⁷ and R⁸ independently of one another each for hydrogen, hydroxyl, cyano, nitro, fluorine, chlorine, bromine, iodine, for straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each having 1 to 4 carbon atoms, for straight-chain or branched alkoximinoalkyl each having 1 to 4 carbon atoms in the individual alkyl parts or for straight-chain or branched haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl each having 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms and
Ar stands for optionally mono- or polysubstituted or differently substituted aryl with 6 to 10 carbon atoms, the following being suitable as substituents: halogen, cyano, nitro, in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, each with 1 to 4 carbon atoms , each straight-chain or branched haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl each having 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, each straight-chain or branched alkoxycarbonyl or alkoximinoalkyl each having 1 to 4 carbon atoms in the individual alkyl parts and optionally simply or Phenyl, phenoxy, benzyl or benzyloxy substituted several times, identically or differently by halogen and / or straight-chain or branched alkyl having 1 to 4 carbon atoms.

Compounds of the formula (I) in which
R¹ for hydroxy, fluorine, chlorine, bromine, iodine, cyano, methoxy, ethoxy, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, for 1-imidazolyl or 1- (1,2,4) -triazolyl stands,
R² represents hydrogen, methyl or ethyl,
R³ represents hydrogen, methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl,
R⁴ represents methyl or ethyl,
R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, cyano, nitro, methyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, methoximinomethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl
Ar represents phenyl which is monosubstituted to trisubstituted by identical or different substituents, the following being suitable as substituents: fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, trifluoromethoxy, Trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, methoximinomethyl, ethoximinomethyl, methoximinoethyl, ethoximinoethyl or optionally phenyl, phenoxy, benzoxy or benzyl substituted by fluorine, chlorine, bromine, methyl and / or ethyl; and also represents a -naphthyl or β -napthyl.

In particular, except for the manufacturing examples mentioned compounds the following benzothiophene-2-carboxamide-S, S-dioxide the general formula (I) called:

For example, one uses N- (1-phenylethyl) -3-chlorobenzothiophene-2-carboxamide as starting compound and Hydrogen peroxide as an oxidizing agent, can be the course of the reaction of the process (a) according to the invention represented by the following formula:

If, for example, N- (1-phenylethyl) -3-chlorobenzothiophene-2-carboxamide-S, S-dioxide is used and sodium iodide as starting compounds, the course of the reaction can be of the inventive method (b) by the represent the following formula:

To carry out the method according to the invention (a) 3-Chlorobenzothiophene-2-carboxamides required as starting materials are general by the formula (II) Are defined. In this formula (II) R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and Ar preferably for those radicals which already in connection with the description of the invention Substances of formula (I) as preferred for these substituents were called.

The 3-chlorobenzothiophene-2-carboxamides of the formula (II) are not yet known and are also the subject of Invention.

They are obtained by using 3-chlorobenzothiophene-2-carboxylic acid chlorides of the formula (IV),

in which
R⁵, R⁶, R⁷ and R⁸ have the meaning given above,
with aralkylamines of the formula (V),

in which
R², R³, R⁴ and Ar have the meaning given above,
optionally in the presence of a diluent such as toluene and optionally in the presence of a reaction auxiliary such as potassium carbonate or triethylamine at temperatures between -20 ° C and + 120 ° C (see, for example, BZ Chem. 17, 133-134 [1977]).

3-chlorobenzothiophene-2-carboxylic acid chlorides of the formula (IV) are known or obtainable in analogy to known ones Process (see e.g. Bull. Soc. Chim. France 11, 4575-4580 [1968]; J. Heterocycl. Chem. 8, 711-714 [1971]).

Aralkylamines of the formula (V) are generally known Organic Chemistry Compounds.

To carry out the method according to the invention (b) 3-Chlorobenzothiophene-2-carboxamide-S, S-dioxide required as starting materials are represented by the formula (Ia) generally defined. In this formula (Ia), R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and Ar preferably for those Leftovers already related to the Description of the substances of the formula (I) according to the invention were mentioned as preferred for these substituents.

The 3-chlorobenzothiophene-2-carboxamide-S, S-dioxide of Formula (Ia) are compounds according to the invention and  obtainable with the aid of the method according to the invention (a).

Formula (III) provides a general definition of the compounds required as starting materials for carrying out process (b) according to the invention. In this formula (III), R ^1-1 preferably represents those radicals which have already been mentioned in connection with the description of the substances of the formula (I) according to the invention as being preferred for the substituent R1, with the exception of a chlorine radical.

M preferably represents hydrogen or a Sodium or potassium cation.

The compounds of formula (III) are general known compounds of organic chemistry.

As an oxidizing agent for performing the invention Process (a) are usually all for Sulfur Oxidations usable oxidizing agents in question. Hydrogen peroxide is preferably used or organic peracids, such as peracetic acid, 4-nitroperbenzoic acid or 3-chloroperbenzoic acid or also inorganic oxidizing agents, such as periodic acid, Potassium permanganate or chromic acid.

As a diluent for carrying out the invention Process (a) come depending on the one used Oxidizing agents inorganic or organic  Solvent in question. Alcohols are preferably used, such as methanol or ethanol or mixtures thereof Water as well as pure water; Acids such as Acetic acid, acetic anhydride or propionic acid or dipolar aprotic Solvents such as acetonitrile, acetone, Ethyl acetate or dimethylformamide as well optionally halogenated hydrocarbons, such as Petrol, benzene, toluene, hexane, cyclohexane, petroleum ether, Dichloromethane, dichloroethane, chloroform, carbon tetrachloride or chlorobenzene.

Process (a) according to the invention can, if appropriate carried out in the presence of a reaction auxiliary will. As such, all commonly used come organic and inorganic acid binders in Question. Alkaline earth metal or is preferably used Alkali metal hydroxides, acetates or carbonates, such as for example calcium hydroxide, sodium hydroxide, Sodium acetate or sodium carbonate.

Process (a) according to the invention can, if appropriate carried out in the presence of a suitable catalyst will. As such, everyone usually comes for such Sulfur oxidation usable catalysts in question. Heavy metal catalysts are preferably used; may be mentioned as an example in this context Ammonium molybdate.

The reaction temperatures can be carried out process (a) according to the invention in a larger one  Range can be varied. Generally one works at Temperatures between -30 ° C and + 100 ° C, preferably at temperatures between 0 ° C and 80 ° C.

To carry out process (a) according to the invention is set per mole of 3-chlorobenzothiophene-2-carboxamide of the formula (II) in general 2.0 to 10.0 mol, preferably 2.0 to 5.0 moles of oxidizing agent and optionally 1.0 to 1.5 mol, preferably 1.0 to 1.3 Mole of reaction auxiliary. The implementation of the reaction, workup and isolation the reaction products are carried out according to generally customary methods Methods.

As a diluent for carrying out the invention Process (b) are inert organic solvents in question. These include in particular aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, such as Petrol, benzene, toluene, xylene, chlorobenzene, petroleum ether, Hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, Ethers, such as diethyl ether, dioxane, Tetrahydrofuran or ethylene glycol dimethyl or diethyl ether, Ketones, such as acetone or butanone, nitriles, such as acetonitrile or propionitrile, amides such as dimethylformamide, Dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide, Esters, such as ethyl acetate, sulfoxides, such as dimethyl sulfoxide or alcohols, such as methanol, ethanol, Propanol or butanol.  

It is also possible when using reactants of the formula (III) in liquid form, this in a corresponding excess at the same time as a diluent to use.

Process (b) according to the invention is, if appropriate in the presence of a suitable reaction auxiliary carried out. As such, everyone usually comes usable inorganic and organic bases in Question. Alkali metal hydrides are preferably used, hydroxides, amides, alcoholates, carbonates or bicarbonates, such as sodium hydride, sodium amide, Sodium hydroxide, sodium methylate, sodium ethylate, Potassium t-butoxide, sodium carbonate or sodium hydrogen carbonate or also tertiary amines, such as Triethylamine, N, N-dimethylaniline, pyridine, N, N-dimethylaminopyridine, Diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicycloundecene (DBU).

The reaction temperatures can be carried out process (b) according to the invention in a larger one Range can be varied. Generally one works at Temperatures between 0 ° C and 130 ° C, preferably at Temperatures between 30 ° C and 100 ° C.

To carry out process (b) according to the invention is set per mole of 3-chlorobenzothiophene-2-carboxamide-S, S-dioxide of the formula (Ia) in general 1.0 to 10.0 mol, preferably 1.0 to 3.0 mol of compound of the formula (III) and optionally 1.0 to 2.0 moles, preferably 1.0 to 1.2 moles of reaction aids.  

The implementation of the reaction, workup and isolation the reaction products are carried out according to generally customary methods Methods.

Compounds of formula (I) in which R¹ is alkylsulfinyl, Alkylsulfonyl, haloalkylsulfinyl or Haloalkylsulfonyl is obtained from the corresponding Alkylthio or haloalkylthio compounds by oxidation analogous to the implementation of the Method (a) according to the invention.

The compounds of the formula (I) according to the invention exhibit good antimicrobial, especially good antifungal Effects on. They have a very broad one antifungal activity spectrum, especially against Dermatophytes and shoots as well as biphasic fungi, e.g. B. against Candida species, such as Candida albicans, Epidermophyton species, such as Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophytonmentagrophytes, Microsporon species, such as Microsporon felineum and Torulopsis species, such as Torulopsis glabrata. The list of these microorganisms represents in no way limit the number of germs that can be controlled represents, but is only explanatory.

Examples of indications in human medicine include:
Dermatomycoses and system mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, Microsporonarten as well as Epidermophyton floccosum, sprouts and biphasic fungi as well as molds.

For example, the following can be listed as an indication area in veterinary medicine:
All dermatomycoses and systemic mycoses, especially those caused by the pathogens mentioned above.

The present invention includes pharmaceutical preparations which in addition to non-toxic, inert pharmaceutical suitable carriers one or more of the invention Contain active ingredients or those from one or consist of several active substances according to the invention.

Pharmaceuticals also belong to the present invention Preparations in dosage units. This means that the preparations in the form of individual parts, e.g. B. tablets, Dragees, capsules, pills, suppositories and ampoules are present whose active ingredient content is a fraction or a multiple of a single dose. The Dosage units can e.g. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A Single dose preferably contains the amount of active ingredient which is administered in one application and which is usually a whole, a half or a third or a quarter of a daily dose.  

Among non-toxic, inert pharmaceutically suitable Carriers are solid, semi-solid or liquid diluents, Fillers or formulation aids to understand every kind.

The preferred pharmaceutical preparations are tablets, Coated tablets, capsules, pills, granules, suppositories, Solutions, suspensions and emulsions, pastes, Called ointments, gels, creams, lotions, powders or sprays.

Tablets, coated tablets, capsules, pills and granules can the active ingredient or ingredients in addition to the usual carriers contain, such as (a) fillers and extenders, e.g. B. strengths, Milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, Gelatin, polyvinylpyrrolidone, (c) humectant, e.g. B. glycerin, (d) disintegrant z. B. agar, Calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, e.g. B. kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stearate and solid Polyethylene glycols or mixtures of (a) to (i) listed substances.

The tablets, dragees, capsules, pills and granules can with the usual optionally opacifiers  containing coatings and sleeves and be composed so that it the active ingredient (s) only or preferably in a certain part of the intestinal tract, if necessary delayed delivery, whereby as Embedding compounds e.g. B. polymer substances and waxes are used can be.

The active ingredient (s) can optionally be combined with a or more of the above-mentioned carriers also in microencapsulated form.

Suppositories can in addition to the active ingredient (s) usual water-soluble or water-insoluble carriers included, e.g. B. polyethylene glycols, fats, e.g. B. Cocoa fat and higher esters (e.g. C₁₄ alcohol with C₁₆ fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels can next to the or the active substances contain the usual carriers, e.g. B. animal and vegetable fats, waxes, paraffins, Starch, tragacanth, cellulose derivatives, polyethylene glycols, Silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays can be used in addition to the active ingredient (s) contain the usual carriers, e.g. B. milk sugar, Talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances, sprays can also use the usual blowing agents such. B. chlorofluorocarbons contain.  

Solutions and emulsions can be added to the active ingredient (s) the usual carriers such as solvents, Solution retarders and emulsifiers, e.g. B. water, ethyl alcohol, Isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, Dimethylformamide, oils, especially cottonseed oil, Peanut oil, corn oil, olive oil, castor oil and Sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, Polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and can be used for parenteral administration Emulsions also in sterile and blood isotonic form are available.

In addition to the active ingredient or suspensions, the usual carriers, such as liquid diluents, e.g. B. water, ethyl alcohol, propyl alcohol, suspending agent, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Aluminum metahydroxide, bentonite, agar and Contain tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants, Preservatives as well as odor and taste improving Additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. contain saccharin.

The therapeutically active compounds should be in the pharmaceutical preparations mentioned above preferably  in a concentration of about 0.1 to 99.5, preferably from 0.5 to 95% by weight of the total mixture is present be.

The pharmaceutical preparations listed above in addition to the active compounds according to the invention can also contain active pharmaceutical ingredients.

The manufacture of the pharmaceutical listed above Preparations are carried out in the usual way according to known Methods, e.g. B. by mixing the active ingredient (s) with the carrier or carriers.

The use also belongs to the present invention of the active compounds according to the invention, and of pharmaceutical Preparations containing one or more of the invention Contain active ingredients in human and veterinary medicine for the prevention, improvement and / or healing of diseases listed above.

The active ingredients or the pharmaceutical preparations can be local, oral, parenteral, intraperitoneal and / or rectally, preferably parenterally, especially intravenously be applied.

In general, it has been in both human and proven to be beneficial in veterinary medicine or the active substances according to the invention in total amounts from about 2.5 to about 200, preferably from 5 to 150  mg / kg body weight per 24 hours, optionally in form several single doses to achieve the desired results to administer.

In oral applications, the inventive Active ingredients in total amounts from about 2.5 to about 200, preferably from 5 to 150 mg / kg body weight per 24 Hours and with parenteral administration in total from about 2.5 to about 50, preferably from 1 to 25 mg / kg Body weight administered every 24 hours.

However, it may be necessary from the dosages mentioned deviate depending on the Type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and the application of the drug and the Period or interval within which the administration he follows. So in some cases it may be sufficient be with less than the above amount of active ingredient get along, while in other cases the above Active substance amount must be exceeded. The definition the optimal dosage required in each case and The type of application of the active ingredients can be determined by any specialist easy to do due to his expertise.

Manufacturing examples Example 1 (Method a)

3.5 g (0.011 mol) of 3-chloro-N- (1-phenylethyl) benzo [b] thiophene-2-carboxamide and 3.23 g (0.033 mol) of hydrogen peroxide (35 percent aqueous solution) are in 20 ml of glacial acetic acid at 50 ° C for 8 hours, cooled, diluted with 200 ml of water, precipitate suction filtered, washed with water and in vacuo at 50 ° C. dried.

2.9 g (76% of theory) of 3-chloro-N- (1-phenylethyl) -benzo [b] thiophene-2-carboxamide-S, S-dioxide are obtained melting point 128 ° C.  

Example 2 (Method b)

To 15 g (0.0431 mol) of 3-chloro-N- (1-phenylethyl) -benzo [b] -thiophene-2-carboxamide-S, S-dioxide in 100 ml of dimethylformamide 5.87 g (0.087 mol) of imidazole are added, and 10 are stirred Hours at 50 ° C, then added 500 ml of water, extracted with dichloromethane, the organic phase washes with Water, dry over sodium sulfate and remove that Solvent in a vacuum.

11 g (68% of theory) of 3- (1-imidazolyl) -N- (1-phenylethyl) -benzo [b] thiophene-2-carboxamide-S, S - dioxide are obtained from melting point 171 ° C-172 ° C.  

In a corresponding manner and in accordance with the general information on the preparation, the following benzothiophene-2-carboxamide-S, S-dioxide of the general formula (I):

Preparation of the starting compounds Example II-1

To 4.9 g (0.173 mol) of 3-chlorobenzo [b] thiophene-2-carboxylic acid chloride (see, e.g., J. Heterocycl. Chem. 8, 711-714 [1971]) in 50 ml of toluene are added at room temperature 4.2 g (0.0346 mol) of 1-phenylethylamine while stirring one hour at room temperature, then gives 100 ml dilute hydrochloric acid and 100 ml of petroleum ether, sucks , dissolves the residue in ethyl acetate, washes with aqueous sodium hydrogen carbonate solution and water, dries over sodium sulfate and removes that Solvent in a vacuum.

3.7 g (68% of theory) of 3-chloro-N- (1-phenylethyl) benzo [b] thiophene-2-carboxamide are obtained from the melting point 112 ° C.  

Examples of use

In the following application examples, the one below listed compound as reference substance used:

6-Cyclohexyl-1-hydroxy-4-methylpyridin-2-one addition compound with ethanolamine
(known from Arzneimittel-Forsch. 23, 670-674 [1973]).

Example A In vitro antifungal activity Experiment description

The in vitro tests were average with germoculars 5 × 10³ germs / ml substrate carried out. As Kimmig medium was used as the nutrient medium.

The incubation temperature was 28 ° C, the incubation period was 24 to 96 hours for yeasts and 96 hours in dermatophytes and molds.

In this test, for example, show the invention Compounds according to Preparation Examples 1, 6 and 7 a significantly better antifungal activity compared to the state of the art.  

Table A

In vitro antifungal activity

MFK *) - values in µg / ml nutrient medium

Example B / formulations

Claims (15)

1. benzothiophene-2-carboxamide-S, S-dioxide of the general formula (I), in which
R 1 represents hydroxy, mercapto, cyano, halogen, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, imidazolyl or triazolyl,
R² represents hydrogen or alkyl,
R³ represents hydrogen or alkyl,
R⁴ represents alkyl,
R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen, hydroxy, cyano, nitro, halogen, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoximinoalkyl, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl and
Ar represents optionally substituted aryl. 2. Benzothiophene-2-carboxamide-S, S-dioxide according to claim 1, in which
R¹ for hydroxy, mercapto, cyano, fluorine, chlorine, bromine, iodine, for each straight-chain or branched alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each having 1 to 4 carbon atoms, for each straight-chain or branched haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl each having 1 up to 4 carbon atoms and 1 to 9 identical or different halogen atoms or for 1-imidazolyl or 1-triazolyl,
R² represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,
R³ represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,
R⁴ represents straight-chain or branched alkyl having 1 to 4 carbon atoms,
R⁵, R⁶, R⁷ and R⁸ independently of one another each for hydrogen, hydroxyl, cyano, nitro, fluorine, chlorine, bromine, iodine, for straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each having 1 to 4 carbon atoms, for straight-chain or branched alkoximinoalkyl each having 1 to 4 carbon atoms in the individual alkyl parts or for straight-chain or branched haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl each having 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms and
Ar stands for optionally mono- or polysubstituted or differently substituted aryl with 6 to 10 carbon atoms, the following being suitable as substituents: halogen, cyano, nitro, in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, each with 1 to 4 carbon atoms , each straight-chain or branched haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl each having 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, each straight-chain or branched alkoxycarbonyl or alkoximinoalkyl each having 1 to 4 carbon atoms in the individual alkyl parts and optionally simply or Phenyl, phenoxy, benzyl or benzyloxy substituted several times, identically or differently by halogen and / or straight-chain or branched alkyl having 1 to 4 carbon atoms. 3. benzothiophene-2-carboxamide-S, S-dioxide according to claim 1, in which
R¹ for hydroxy, fluorine, chlorine, bromine, iodine, cyano, methoxy, ethoxy, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, for 1-imidazolyl or 1- (1,2,4) -triazolyl stands,
R² represents hydrogen, methyl or ethyl,
R³ represents hydrogen, methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl,
R⁴ represents methyl or ethyl,
R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, cyano, nitro, methyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, methoximinomethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl
Ar represents phenyl which is monosubstituted to trisubstituted by identical or different substituents, the following being suitable as substituents: fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, trifluoromethoxy, Trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, methoximinomethyl, ethoximinomethyl, methoximinoethyl, ethoximinoethyl or optionally phenyl, phenoxy, benzoxy or benzyl substituted by fluorine, chlorine, bromine, methyl and / or ethyl; and also represents α- naphthyl or β- naphthyl. 4. 3-chloro-N- (1-phenylethyl) benzo [b] thiophene-2-carboxamide-S, S-dioxide. 5. 3-chloro-N-2- (2-phenylpropyl) benzo [b] thiophene-2-carboxamide-S, S-dioxide. 6. 3-Chloro-N-1- (1- (4-chlorophenylethyl) benzo [b] thiophene-2-carboxamide S, -S dioxide. 7. 3-Chloro-N-1- (1- (4-chlorophenylethyl) benzo [b] thiophene-2-carboxamide S, -S dioxide. 8. Benzothiophene-2-carboxamide-S, S-dioxide according to claims 1 to 6 for fighting diseases. 9. benzothiophene-2-carboxamide-S, S-dioxide according to claims 1 to 6 for combating mycoses. 10. Medicament containing benzothiophene-2-carboxamide-S, S-dioxide according to claims 1 to 6. 11. Antifungal agents containing benzothiophene-2-carboxamide-S, S-dioxide according to claims 1 to 6. 12. Use of benzothiophene-2-carboxamide-S, S-dioxides according to claims 1 to 6 in the fight of diseases. 13. Use of benzothiophene-2-carboxamide-S, S-dioxides according to claims 1 to 6 in the fight of mycoses.   14. Use of benzothiophene-2-carboxamide-S, S-dioxides according to claims 1 to 6 in the manufacture of drugs. 15. Use of benzothiophene-2-carboxamide-S, S-dioxides according to claims 1 to 6 in the manufacture of drugs to combat Mycoses.