DE4128871A1 - BENZO (B) THIOPHENE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS - Google Patents

Abstract

New benzo[b]thiophene derivates have formula (I), in which R<1> and R<2> are identical or different and stand for a lower alkyl residue; X stands for hydrogen and Y for a group -Z-(CH2)nCO-R<3>, wherein Z stands for a valency bond, a sulphur atom or a group NOH; R<3> stands for a hydroxyl group, a lower alkoxy group, a group (a) or a group (b), or, when Z stands for a group NOH, for a lower alkyl residue; n is an integer from 0 to 4 or X and Y represent together a residue =CH-CO-R<3>, wherein R<3> has the above-mentioned meaning. Also disclosed are the physiologically acceptable salts of these derivates, a process for producing the same and medicaments containing these derivates for treating allergic diseases, as well as inflammatory bronchospasmodic and bronchoconstrictive reactions.

Description

The present invention relates to Benzo [b] thiophene derivatives, process for their preparation and Medicines that contain these compounds.

The invention relates to benzo [b] thiophene derivatives of the general Formula I.

in which

R¹ and R², identical or different, are a lower alkyl radical,
X is hydrogen and Y is a group -Z- (CH₂) _n CO-R³,
wherein
Z is a valence bond, a sulfur atom or a group NOH,
R³ is a hydroxy group, a lower alkoxy group, a group

or a group

or, when Z represents a NOH group, a lower alkyl radical and
n is an integer from 0 to 4 or
X and Y together represent a radical = CH-CO-R³, where R³ has the meaning given above,

mean and their physiologically tolerable salts.

The new compounds of general formula I have valuable le pharmacological properties, in particular they can the antigen-related contraction of lung tissue strips hem men. They are therefore suitable for the treatment of allergic people and inflammation-related, bronchospastic and bronchoconstrictor reactions.

The alkyl radicals in the alkyl and alkoxy groups mentioned ent hold 1-6 carbon atoms and can be straight-chain or branched. Preferred alkyl radicals are the methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and 3- Pentyl group. Preferred alkoxy radicals are methoxy, ethoxy or propoxy residue.

In addition to the compounds mentioned in the examples, Gegen stood the invention in particular all substances, each possible combination of the substi mentioned in the examples exhibit tuenten.

The process according to the invention for the preparation of the compounds Formula I is characterized in that in itself known way either

• a) if X is hydrogen, a compound of the general formula II, in which R ¹ and R ^{2 have} the abovementioned meaning and A represents a reactive radical, with a compound of the general formula IIIHZ (CH₂) _n COR³ (III) in which Z, n and R ^{3 have} the abovementioned meaning, or
• b) if X is hydrogen and Z is a bond, a compound of general formula IV in which R ¹ , R ² , n and A have the abovementioned meaning, with a compound of the general formula VB-CH₂-COR³ (V), in which R ^{3 has} the abovementioned meaning and B is hydrogen or a radical which activates the CH ₂ group represents, with subsequent elimination of the radical B or,
• c) in the event that X and Y together represent the radical = CH-COR ³ , a compound of general formula VI in which R ¹ and R ^{2 have} the meaning given above, with a compound of the general formula V with subsequent elimination of the radical B or
• d) in the event that X is hydrogen, Z is a NOH group and n = O mean a compound of the general formula VI with hydroxylamine or a derivative thereof below ender reduction of the aldoxime function and implementation with a compound of the general formula VII D-CO-R³ (VII),

in which R ^{3 has} the meaning given above and D represents a reactive radical, is reacted and then, if desired, one of the radicals R ¹ , R ² , R ^{3 is converted} into another radical given by the definition or a double bond representing X and Y is reduced to a single bond and, if desired, converting the compound of formula I obtained into a salt by reaction with physiologically acceptable bases.

The reactive radicals A are chlorine, bromine, mesyloxy or tosyloxy in question. Reactive residues D are a carboxylic acid function four groups such as halogen atoms such as chlorine and Bromine, alkoxy and aryloxy groups, alkanoyloxy and aroyloxy residues or the azide residue.

As a CH ₂ group activating radicals B, for example the carboxy group or its esters, the cyano group, the nitro group, trisubstituted phosphonium radicals or phosphonic acid ester groups can be used.

A radical R ¹ or R ^{2 is converted} into another radical defined by the claim, for example by ether cleavage with a protonic acid or Lewis acid such as hydrogen bromide, hydrogen chloride, hydrogen iodide, aluminum trichloride, boron tribromide and subsequent alkylation with the desired alkyl halide or alkyl sulfate.

A hydroxyl group representing R ³ can, if desired, be replaced by an alkoxy group or substituted amino group via a reactive derivative such as a halide, imidazolide or anhydride; an alkoxy group representing R ³ can be converted into the hydroxyl group by acidic or basic hydrolysis, and into the amino group by aminolysis.

A double bond representing X and Y is reduced appropriately with catalytically excited hydrogen.

The implementation of compounds of formulas II and III or IV and V or VI and V is expediently carried out in neutral or basic medium, for example in water or a lower one Alcohol such as methanol, ethanol or 2-propanol in the presence an alkali hydroxide or alkali alcoholate or in aprotic Solvents such as acetone, butanone or dimethylformamide in Presence of an acid binding agent such as potassium carbonate or Calcium carbonate at temperatures between 0 ° C and the boiling point point of the reaction mixture.

Insofar as B stands for trisubstituted phosphonium radicals also the Wittig agents obtainable by reaction with bases isolated and in a neutral medium with compounds of the formula VI are implemented, the remainder of B being the same as for phosphon split off acid esters in the course of the reaction. In the case, that B represents a carboxyl group or a derivative thereof, The separation is expediently carried out by thermal decarboxy after saponification if necessary.

The reduction of one from a compound of formula VI Aldoxime obtained with hydroxylamine is advantageously carried out with a selective reducing agents such as sodium cyanoborohydride in new tral or slightly acidic environment. Implementation with Verbin of formula VII can be added without adding a base Isolation of the intermediate take place, given one if necessary, esterification of the hydroxyl group takes place simultaneously can be reversed by mild saponification.

The starting compounds II to VII are known from the literature Substances or can in analogy to Ver drive are manufactured.

In particular come as pharmacologically acceptable salts Alkali, alkaline earth and ammonium salts in question.

The salts are obtained in the usual manner, for. B. by Neutralisa tion of the compounds of formula I with the corresponding Alkalis.

The compounds of general formula I in a known manner with suitable pharmaceutical carrier substances, aroma, taste and  Dyes mixed and for example as tablets or Dragees shaped or with the addition of appropriate auxiliaries in water or oil, such as B. olive oil, suspended or dissolved.

The substances of the general formula I can be in liquid or solid form can be administered orally and parenterally. As Injection medium preferably water is used, which is the usual stabilization for injection solutions contains medium, solubilizer and / or buffer. Such Additives are e.g. B. tartrate or borate buffer, ethanol, Dimethyl sulfoxide, complexing agent (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of Sorbitan hydrides.

Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, high molecular weight Polymers (such as polyethylene glycols).

Preparations suitable for oral administration can if desired, contain flavoring and sweetening agents. For the External use, the substances I can also be used in the form of powders and ointments. you will be to this z. B. with powdered, physiologically compatible Diluents or common ointment bases mixed.

The dose administered depends on age, health and the Weight of the recipient, the extent of the disease, the type simultaneous further treatment, if necessary lungs, the frequency of treatment and the type of desired effect. Usually the daily is Dose of the active compound 0.1 to 50 mg / kg body weight. Usually 0.5 to 40 and preferably 1.0 to 20 mg / kg / day effective in one or more applications per day, to get the results you want.

In addition to the substances mentioned in the examples are in the sense the present invention the following compounds prefers:

1. 5,6-diethoxy-benzo [b] thiophene-2-yl acetic acid
2. 5,6-Dimethoxy-benzo [b] thiophene-2-yl acetic acid
3. N-hydroxy-N-methyl- (5,6-diethoxy-benzo [b] thiophene-2-yl) acetic acid amide
4. N- (2H-tetrazol-5-yl) -5,6-diethoxy-benzo [b] thiophene-2-yl acetic acid amide
5. (5,6-Diethoxy-benzo [b] thiophene-2-yl) butyric acid

example 1 3-6-Diethoxy-benzo [b] thiophene-2-yl) propenoic acid ethyl ester

A mixture of 16.3 g (65 mmol) 5,6-diethoxy-ben zo [b] thiophene-2-aldehyde, 22.6 g (65 mmol) ethoxycarbonyl methylene triphenylphosphorane and 230 ml of ethanol for 4 h Heated to reflux. The mixture is concentrated and chromatographed on pebble gel (eluent isohexane / ethyl acetate 1: 1). One isolates 16.2 g of the title compound (78% of theory), mp. 86-87 ° C.

The 5,6-diethoxy-benzo (b) thiophene used as the starting material 2-aldehyde can be obtained as follows:

• a) To a suspension of 11.1 g of lithium aluminum hydride in 100 ml of tetrahydrofuran (THF) is added dropwise to a solution of 20 g (75 mmol) 5,6-diethoxy-benzo [b] thiophene-2-carboxylic acid in 200 ml of THF, heated to reflux for 6 h, decomposed with cook saline solution, extracted with ether, washes the extract with Sodium hydroxide solution, dries, concentrates and triturates with isohexane. 16.7 g of 5,6-diethoxy-benzo [b] thiophene-2 remain methanol (88% of theory), melting point 62-64 ° C.
• b) A mixture of 22.0 g (87 mmol) of the above ver bond, 75 g of manganese dioxide and 350 ml of toluene for 3 h Heated to reflux, filtered after cooling and the Concentrated filtrate. After rubbing with Ligro in 18.3 g of 5,6-diethoxy-benzo [b] thiophene-2-aldehyde (84% i.e.) of mp. 93-94 ° C.

Example 2 Ethyl 3- (5,6-diethoxy-benzo [b] thiophene-2-yl) propionate

A mixture of 20.5 g (64 mmol) of compound of Example 1, 200 ml ethanol, 200 ml THF and 1 g 10 percent. Palladium carbon will hydrogenated at room temperature and 1 bar hydrogen pressure. To Theoretical amount is filtered, concentrated and triturated with ligroin. 17.6 g of the title compound (85 % of theory) of melting point 55-57 ° C.

Example 3 3- (5,6-DiethoxY-benzo [b] thiophene-2-yl) propionic acid

A mixture of 3.2 g (10 mmol) of compound from Example 2, 100 ml of ethanol and 100 ml of 2N sodium hydroxide solution are refluxed for 2 h heated, then concentrated, taken up in water and with Ether washed. The mixture is isolated from the aqueous phase Acidify 2.4 g of the title compound (82% of theory) with a melting point of 161- 163 ° C.

Example 4

The following is obtained in an analogous manner to that described in Example 3 the compound of Example 1 in 89% yield 3- (5,6-Diethoxy-benzo [b] thiophen-2-yl) propenoic acid of mp. 224-225 ° C.

Example 5 3- (5,6-Diethoxy-benzo [b] thiophene-2-yl-methylthio) propionic acid

2.4 is added to a solution of 1.3 g of sodium in 60 ml of ethanol ml of 3-mercapto-propionic acid, stirred for 10 min, mixed with 8.8 g (28 mmol) 2-bromomethyl-5,6-diethoxy-benzo [b] thiophene, warmed 2 h to reflux, concentrated, take up in water, wash with ether and acidifies the aqueous phase. 4.2 g of title ver binding (44% of theory) of melting point 108-110 ° C.

The 2-bromomethyl-5,6-diethoxy benzo (b) thiophene used as starting material can be obtained as follows:
A solution of 1.8 ml of phosphorus tribromide in 60 ml of ether is added dropwise to a solution of 15 g (59 mmol) of 5,6-diethoxy benzo [b] thiophene-2-methanol in 390 ml of ether. After stirring for 6 h, the mixture is decanted off, the ethereal solution is washed neutral, dried and concentrated. There remain 17.7 g of title compound (95% of theory) as an amorphous crude product.

Example 6 5- (5,6-Diethoxy-benzo [b] thiophene-2-yl) valeric acid sodium

A solution of 0.46 g sodium in 75 ml ethanol is added with 3.1 ml of diethyl malonate and 7.3 g (21 mmol) 3- (5,6-Diethoxy-benzo [b] thiophen-2-yl) propyl bromide, warmed for 4 h to reflux, concentrated, mixed with water, extracted with Ether and constricts. 7.2 g of 3- (5,6-diethoxy benzo [b] thiophene-2-yl) propyl malonic acid diethyl ester (81% i.e.) as a crude oil. To do this, add 20 ml of 5 percent. Caustic soda, heated to reflux for 6 h, allowed to cool, washed with ether, acidifies the aqueous phase, extracted with ether, dries the extract and concentrates. After rubbing with ligroin you get 4.3 g of the title compound (73% of theory), mp. 123-125 ° C.

The 3- (5,6-diethoxy benzo [b] thiophene-2-yl) propyl bromide can be obtained as follows will:

• a) In an analogous manner to that described in Example 1 under a) is obtained from 3- (5,6-diethoxy-benzo [b] thiophene-2- yl) propionic acid in 94% yield the 3- (5,6-diethoxy benzo [b] thiophene-2-yl) propanol as an oily crude product.
• b) To a solution of 8.2 g (29 mmol) of the above ver binding in 240 ml dichloromethane and 0.5 ml N, N-dimethyl formamide, a solution of 0.8 g is added dropwise Phosphorus tribromide in 25 ml dichloromethane, stirred for 4 h, washes neutral, dries the organic phase, concentrates and chromatographed on silica gel (eluent Isohexane / ethyl acetate 1: 1). 7.3 g of title compound are obtained dung (73% of theory) of mp. 79-81 ° C.

Example 7 N-hydroxy-N-methyl-3- (5,6-diethoxy-benzo [b] thiophene-2- yl) propionic acid amide

To a mixture of 4.9 g (17 mmol) of the compound of the example 3 and 60 ml of THF are added 5.4 g of N, N'-carbonyldiimidazole, stirred 30 min, adds a solution of 1.5 g of N-methyl-hydroxylamine in 25 ml of THF, stirred for 2 h, concentrated, takes the residue in dichlor methane, washes with sodium hydrogen carbonate solution and extra with 1 N sodium hydroxide solution. After acidifying the extract and Trituration with ligroin gives 2.1 g of the title compound (38% i.e.) m.p. 174-176 ° C.

Example 8

The following is obtained in an analogous manner to that described in Example 7:

Example 9 N-HYDroxy-N-methyl-3- (5,6-diethoxy-benzo [b] thiophene-2 yl) valeric acid amide

To a mixture of 3.2 g (9.3 mmol) of the compound of the example 6, 65 ml of dichloromethane and 0.8 ml of N, N-dimethylformamide drips 2.4 ml of oxalyl chloride at 0 ° C., stirring is continued for 40 min and dripping  this mixture then in a solution of 2.2 g of N-methyl hydroxylamine, 20 ml triethylamine and 65 ml THF. After 90 min Stirring at room temperature is mixed with dichloromethane, washes with water, concentrated, takes up in ethyl acetate, extra with sodium carbonate solution and acidifies the aqueous phase. To Drying the precipitate leaves 1.8 g of the title compound (55% of theory) of mp. 123-124 ° C.

Example 10 N- (1H-tetrazoyl-5-yl) -3- (5,6-diethoxy-benzo [b] thiophene-2- yl) propionic acid amide

To a solution of 2.94 g (10 mmol) of the compound of Example 3 in 30 ml of N, N-dimethylformamide there are 1.8 g of N, N'-carbonyldi imidazole, heated at 100 ° C for 1 h, adds 0.95 g of 5-amino-1H-tetra zol, stir for 3 h at 100 ° C, concentrate, take up in water and acidifies. The precipitate is taken up in soda solution with Washed ether and precipitated again by acidification. To Recrystallization from ethanol gives 1.7 g of the title compound (47% of theory) of mp. 246-248 ° C.

Example 11

In an analogous manner to that described in Example 10, N is obtained (1H-tetrazoyl-5-yl) -3- (5,6-diethoxy-benzo [b] thiophene-2- yl) valeric acid amide in 59% yield from mp. 244-245 ° C. the connection of example 6.

Example 12 N- (5,6-diethoxy-benzo [b] thiophene-2-methyl) -N-hydroxy-acetamide

A mixture of 10.4 g (40 mmol) 5,6-diethoxy-2- oximinomethyl-benzo [b] thiophene, 80 ml methanol, 120 ml THF and 2.6 g of sodium cyanoborohydride is adjusted to pH 3 and 1 h stirred at room temperature. Then 55 ml of triethylamine are added and 19 ml of acetic anhydride, stir for 1 h, concentrate, take in Water, extracted with ethyl acetate, washed with sodium hydrogen carbonate solution, dries and concentrates. After Chromato graph on silica gel (eluent isohexane / ethyl acetate 1: 1) 0.9 g of N- (5,6-diethoxy-benzo [b] thiophene-2-methyl) -N- acetoxy-acetamide. 25 ml of 2-propanol and one are added  Solution of 0.6 g of lithium hydroxide in 1 ml of water, stirred for 1 h Room temperature, mixed with water, washed with ether, acidified the aqueous phase, extracted with ethyl acetate and concentrated Extract a. after rubbing with ether, 0.6 g is obtained Title compound (5% of theory) of melting point 101-103 ° C.

The 5,6-diethoxy-2-oximinomethyl used as the starting material benzo [b] thiophene can be obtained as follows:

A mixture of 12.5 g (50 mmol) 5,6-diethoxy benzo [b] thiophene-2-aldehyde, 70 ml of ethanol, 4.9 g of sodium acetate and 5.2 g of hydroxylamine hydrochloride is heated to 60 ° C with 2 ml of water are added and the mixture is stirred for 1 h. You narrow it down, take it Residue in water, extracted with dichloromethane, dried and constricts. There remain 9.9 g of the title compound (75% of theory) from mp. 194-196 ° C.

Example 13 Ethyl 3- (5,6-dimethoxy-benzo [b] thiophene-2-yl) propenate

In an analogous manner to that described in Example 1, the Title compound of mp 137-139 ° C in 92% yield from 5.6- Dimethoxy-benzo [b] thiophene-2-aldehyde.

Example 14 Ethyl 3- (5,6-dimethoxy-benzo [b] thiophen-2-yl) propionate

In an analogous manner to that described in Example 2, the Title compound of mp. 75-76 ° C in 74% yield from the Connection of example 13.

Example 15 3- (5,6-Dimethoxy-benzo [b] thiophen-2-yl) propenoic acid

In an analogous manner to that described in Example 3, the Title compound of mp. 210-211 ° C in 62% yield from the Connection of example 13.  

Example 16 3- (5,6-Dimethoxy-benzo [b] thiophene-2-yl) propionic acid

In an analogous manner to that described in Example 3, the Title compound of mp 158-160 ° C in 85% yield from the Connection of example 14.

Example 17 N-hydroxy-N-methyl-3- (5,6-dimethoxy-benzo [b] thiophene-2- yl) propionic acid amide

In a manner analogous to that described in Example 7, the Title compound of mp 123-125 ° C in 54% yield from the Connection of example 16.

Example 18 N- (1H-tetrazol-5-yl) -3- (5,6-dimethoxy-benzo [b] thiophene-2- yl) propionic acid amide

In an analogous manner to that described in Example 10, the Title compound of mp. 258-260 ° C in 69% yield from the Connection of example 16.

Example 19 3- (5,6-Dimethoxy-benzo [b] thiophene-2-yl-methylthio) propionic acid

In an analogous manner as described in Example 5, the Title compound of mp 84-86 ° C in 37% yield from 2- Chloromethyl-5,6-dimethoxy-benzo [b] thiophene.

Example 20 N-Hydrrox-y-N-methyl-3- (5,6-dimethoxy-benzo [b] thiophene-2-yl- methylthio) propionic acid amide

In an analogous manner to that described in Example 9, the Title compound as an oily product in 49% yield from the Connection of example 19.

Claims (6)

1. Benzo [b] thiophene derivatives of the formula I. in which
R¹ and R², identical or different, are a lower alkyl radical,
X is hydrogen and Y is a group -Z- (CH₂) _n CO-R³,
wherein
Z is a valence bond, a sulfur atom or a group NOH,
R³ is a hydroxy group, a lower alkoxy group, a group or a group or, when Z represents a NOH group, a lower alkyl radical and
n is an integer from 0 to 4 or
X and Y together represent a radical = CH-CO-R³, where R³ has the meaning given above,
mean, and their physiologically tolerable salts. 2. Process for the preparation of benzo [b] thiophene derivatives of the formula I. in which
R¹ and R², identical or different, are a lower alkyl radical,
X is hydrogen and Y is a group -Z- (CH₂) _n CO-R³,
wherein
Z is a valence bond, a sulfur atom or a group NOH,
R³ is a hydroxy group, a lower alkoxy group, a group or a group or, when Z represents a NOH group, a lower alkyl radical and
n is an integer from 0 to 4 or
X and Y together represent a radical = CH-CO-R³, where R³ has the meaning given above,
mean, and their physiologically tolerable salts, characterized in that in a manner known per se

• a) in the event that X is hydrogen, a Ver compound of the general formula II in which R ¹ and R ^{2 have} the abovementioned meaning and A represents a reactive radical, with a compound of the general formula IIIHZ (CH₂) _n COR³ (III], in which Z, n and R ^{3 have} the abovementioned meaning, or
• b) if X is hydrogen and Z is a bond, a compound of general formula IV in which R ¹ , R ² , n and A have the abovementioned meaning, with a compound of the general formula VB-CH₂-COR³ (V), in which R ^{3 has} the abovementioned meaning and B is hydrogen or an activating the CH ₂ group Represents the residue, with subsequent elimination of the residue B, or,
• c) in the event that X and Y together represent the radical = CH-COR ³ , a compound of the general formula VI wherein R ¹ and R ^{2 have} the meaning given above, with a compound of the general formula V with subsequent elimination of the radical B or
• d) in the event that X is hydrogen, Z is a NOH group and n = 0, a compound of the general formula VI with hydroxylamine or a derivative thereof with subsequent reduction of the aldoxime function and reaction with a compound of the general formula VII D-CO -R³ (VII) implements,

and then, if desired, one of the radicals R ¹ , R ² , R ^{3 is converted} into another radical as defined or a double bond for X and Y is reduced to a single bond and the compound of the formula I obtained is, if desired, by reaction with physiologically acceptable bases converted into a salt. 3. Medicament containing at least one compound according to Claim 1 in addition to conventional carriers and auxiliaries.   4. Use of compounds according to claim 1 for treatment lung allergic diseases. 5. Use of compounds according to claim 1 for treatment inflammation-related, bronchospastic and bronchoconstrictor reactions.