DE2642877A1 - SUBSTITUTED 2-NITRO-3-PHENYLBENZOFURANE COMPOUNDS - Google Patents

Description

"Substituted 2-nitro-3-phenylbenzofuran compounds"

The invention relates to a group of 2-nitro-3-phenylbenzofuran compounds, those on the phenyl ring by a carboxyl or acetic acid group or on the benzene ring by a carboxyl group are substituted and their esters, amides, acid halides and pharmaceutically acceptable salts.

It is known that 3-phenylbenzofuranylalkanoic and alkenoic acids and certain derivatives thereof have anti-inflammatory effects (e.g. US Pat. Nos. 3,682,976 and 3,862,134). Certain monosubstituted 2-H itrobenzofurans are known as antibacterial agents (eg J ¹ R-PS 2 081 585 and publications by Rene Royer et al.). However, compounds with the structural features of the compounds according to the invention are not known.

The invention relates to a group of compounds of the formula:

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in the either

Q
(1) A is an -ÖOH group, B is a hydrogen atom, X is a fluorine or chlorine atom or a lower alkyl or lower alkoxy group, Y is a fluorine or chlorine atom or a methyl or methoxy group and m and η independently of one another either 0, 1 or 2 and their esters amides, acid halides and pharmaceutically acceptable salts or salts

0 (2) A is a hydrogen atom, B is the group -ÖOH, and X is a Fluorine or chlorine atom or a lower alkyl or lower alkoxy group, T a fluorine or chlorine atom or a methyl or methoxy group and m and η each independently represent 0, 1 or 2 and their pharmaceutically acceptable salts or

(3) A is a hydrogen atom, B is the group -CH ₂ COH, X is a halogen atom, a lower alkyl, lower alkoxy or trifluoromethyl group, T is a halogen atom or a methyl or methoxy group and m and η independently. are each 0, 1 or 2, depending on one another, and their esters and pharmaceutically acceptable salts.

The invention thus relates to benzofuran compounds which in the 2-position by a nitro group and in the 3-position are substituted by a phenyl ring and in which one of the rings of the benzofuran structure by a Carboxyl group or an acetic acid group is substituted

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vind certain derivatives of these compounds. The free Acids are usually white or yellowish to brown crystalline or amorphous substances when purified are. They are essentially insoluble and more soluble in water or aliphatic hydrocarbons lower alcohols, halogenated solvents, benzene, Dimethylformamide, among others; the esters and amides are generally somewhat more soluble in organic solvents. The alkali salts have considerable solubility in water and in lower alcohols.

All compounds according to the invention are effective against bacteria and some also against other microorganisms, such as fungi and protozoa, when applied in vitro and topically. They can therefore be used for disinfection and sterilization, e.g., of medical and dental instruments as components of Disinfectant solutions. The compounds are particularly useful as antibacterial agents. Generally own the compounds also have in vivo activity in animals. The free acids are due to them in general higher antimicrobial efficacy in vitro preferred. For areas of application where water solubility is important salts are commonly used.

A preferred subgroup of compounds of group (1) (ai% round their high antimicrobial activity) are the compounds in which Y and X are hydrogen atoms and the compounds in which the 4-position of the benzofuran structure through Hydrogen is substituted (unsubstituted). The preferred compounds have antimicrobial activity in vitro and in vivo and are effective when administered orally and result in detectable anti-microbial effects effective blood levels in mammals. Some of them are effective at concentrations less than 1.0 / Ug / ml

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against streptococci. The "most preferred compounds (which have a broad spectrum of activity against Microbes and good therapeutic ratios LD ^ iED, ^ own) are:

2-l! Ίitro-3-phenyl-7-benzofuranoarboxylic acid, 2-nitro-3-phenyl-6-benzofurancarboxylic acid and 2-nitro-3-phenyl-5-benzofurancarboxylic acid.

A preferred subgroup of compounds of group (2) (due to their high antimicrobial activity) are the compounds in which X and Y are hydrogen atoms and the compounds which are unsubstituted * in the 4-position of the benzofuran structure. The preferred compounds have antimicrobial activity in vitro and in vivo and are effective when administered orally and give detectable levels of antimicrobial blood in mammals. Some of these connections are sinä. effective in concentrations of less than 1.0 / Ug / ml against streptococci. The particularly preferred compounds (which have a broad antimicrobial spectrum and good therapeutic ratios LD _n -QiED ₁ -Q) are 3- (2-nitro-3-benzofuranyl) benzoic acid and 4- (2-nitro-3-benzofuranyl) benzoic acid.

The preferred compound of group (3) (which has a broad antimicrobial spectrum and a good therapeutic ratio LD ₁ -Q: ED ₁ -Q) is 4- (2-nitro-3-benzofuranyl) phenyl setic acid.

Alkali, alkaline earth, aluminum, iron and other metal and amine salts are often the. corresponding acid forms of the compounds are equivalent and offer advantages in terms of solubility, absorption, resistance, ( inter alia; the salts are of particular interest for topical application, e.g. in eye and skin products. the *) (unsubstituted by hydrogen)

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Alkali salts (e.g. the sodium and potassium salts) preferred. The esters, amides and acid halides are also suitable for modifying the solubility, Resistance, absorption and other properties of the compounds under the conditions of use. Examples of esters are ethyl, diethylaminoethyl, 2-hydroxyethyl, glyceryl and methoxymethyl esters.

Among the other important subgroups of the invention Compounds of group (1), which are given by specific examples, include the lower alkyl esters, Hydroxyalkyl esters and N, N ~ dialkylaminoalkyl esters, amides, e.g. dialkylaminoalkylamides, quaternary ammonium alkylamides, Bis (2-hydroxyethyl) amide, glycinamides, carboxyphenylamides and heterocyclic amides, suIfoäthylamide, Sulfamoylphenylamides, 5-tetrazolylamides.

The free acids of the compounds according to the invention can be prepared in various ways, starting from of known starting materials:

A. Direct nitration of the 2-position of a compound the formula:

B. Specific halogenation of the 2-position of a compound of Formula II to form an intermediate the formula:

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- «er • 40

in

(III)

where Q is a bromine or iodine atom, and then selective replacement of the 2-halogen atom by one Nitro group or

C. Acid hydrolysis of a corresponding compound of the formula:

■ NO,

(IV)

in which A ^{1 is} a cyano, carboxyl ester group or a hydrogen atom and B ^{1 is} a cyano, carboxyl ester, acetic acid ester, gyanomethyl group or a hydrogen atom.

The direct nitration (method A) can be carried out with fuming nitric acid in acetic acid or acetic anhydride or with dinitrogen tetroxide in an inert solvent such as dichloromethane. To a To avoid aromatic nitration, moderate temperatures of 0 to 30 ° C are generally used.

The halogenation of stage B can be a bromination or

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Be iodination. The bromination can be carried out using bromine water, N-bromosuccinimide or, preferably, bromine in a suitable solvent such as dichloromethane or acetic acid. The bromination is carried out under mild conditions, for example 0 to 30 ^° C., in order to avoid aromatic bromination. The bromine compound can be isolated or used without further isolation. Isolation can be carried out by extraction, precipitation by adding a solvent such as water, evaporation of the volatile reaction components, etc .; the iodination is carried out, for example, with molecular iodine in the presence of yellow mercury (II) oxide in an inert solvent such as benzene. In general, these reactions are carried out at about 25 to 125 ° C., for example at the reflux temperature of the solvent.

In the final stage of process B, the 2-halogen substituent can be replaced by selective nitrating agents, such as strong nitric acid solution, for example 70% aqueous nitric acid, dinitrogen tetroxide in, for example, acetic acid or dichloromethane or a mixture of sodium nitrate and a strong acid. When 70% nitric acid is used as the nitrating agent for the 2-halogen derivatives, about 2 to 3 moles of sodium nitrite and nitric acid are preferably used per mole of benzofuran. Approximately 4 to 20 ml of acetic acid per gram of 2-halobenzofuran derivative is used, depending on the solubility. It is desirable to keep the 2-halobenzofuran derivative in solution and the amount of acetic acid used and the reaction temperature are adjusted to achieve this. The reaction temperature is about 25 to 100 ° 0, and preferably about 60 to 80 ⁰ C when the halogen atom is bromine.

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It has been shown that a mixture of sodium nitrite, sulfuric acid and acetic acid also successfully leads to nitration of the 2-halobenzofuran derivatives in the 2-position. The 2-halobenzofuran derivative is dissolved in acetic acid to keep it in solution (up to 20 ml per g) and concentrated sulfuric acid is added in an amount of 2 to 10 ml per g of benzofuran. Sodium nitrite is then added to the solution. 2 to 5 moles of nitrite per mole of benzofuran derivative are used. The reaction temperature is about 20 to 100 ⁰ C and preferably about 55 ° G · The sodium nitrate can in this reaction with other nitrites such as potassium nitrite, be replaced.

A combination of nitrogen tetroxide in an inert solvent in the presence of an alkene is the preferred nitrating agent according to Method B, with acetic acid and dichloromethane being the preferred solvents. For example, 2 to 5 liters of acetic acid are generally used per mole of benzofuran or halobenzofuran. At least 1 mole of nitrogen tetroxide per mole of benzofuran is used. The exact amount will depend on the rate of reaction desired, volatility and other physical losses, and the strength of the competing reaction with the added olefin. An alkene is preferably used in a 2-bromobenzofuran intermediate in order _{to eliminate the elements of BrNO 2} and to largely reduce the bromination as a side reaction. Cyclohexene is suitable for this purpose. Equimolar amounts of alkene and nitrogen tetroxide are preferably used. The olefin is chosen to be less reactive with NpO. is than benzofuran, but more reactive towards BrNOp than benzofuran. An acidic olefin, for example 3-cyclohexenecarboxylic acid, is advantageous if the nitrated product is neutral. The temperature of these reactions is generally from about 0 to 80 ⁰ C, preferably 20 to 45 ° C for the bromine exchange and

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about 0 to 25 C for iodine exchange and direct nitration. If 2-iodobenzofuran are used, the olefin is not required (since the iodine is generally not reactive with the benzofuran under the reaction conditions) and only half a mole of ^N 2 ° 4 is theoretically required.

The 2-nitro-3-phenylbenzofliranoic acid esters used in Method C. are produced by nitration of the corresponding 2-halo-3-phenylbenzofuranic acid esters. These esters, preferably the lower alkyl esters, can easily be hydrolyzed by conventional acid hydrolysis. (The term "lower" in the context of this description means groups with 1 to 4 carbon atoms,)

The 2-Mtro-3- (cyanomethylphenylbenzofurans used for process C) are produced (a) from new 2-nitro-3- (bromomethylphenyl) benzofurans by replacing the bromine with a gyanide group in inert solvents such as ketones, alcohols and Ν, Ν dimethylformamide, generally at the reflux temperature of the solvent, or at about 100 ⁰ C, or (b) by replacing the halogen of 2-bromo-3- (cyanomethylphenyl- and -cyanophenyl) benzofurans by the above method and in the conditions indicated above The hydrolysis of 2-nitro-3- (cyanomethylphenyl and cyanophenyl) benzofurans is achieved under acidic conditions, for example in aqueous sulfuric acid at 60 to 175.degree.

The hydrolysis of the 2-halo-3- (cyanomethylphenyl and cyanophenyl) benzofurans with formation of the intermediates for process B is carried out under strongly acidic or basic conditions, e.g. in aqueous sulfuric acid at 60 to 175 ° C or in aqueous alcoholic alkali Reflux temp eratur.

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The 2-nitro-3-phenylbenzofurancarboxylic acid esters of group (1) are produced either by nitration the corresponding 2-halogen compounds or by esterification of 2-nitro-3-phenylbenzofuran cartonic acid derivatives, such as acyl halides with alcohols or acid salts with alkyl halides. The amides are made from the acid halide and the corresponding amine or by aminolysis of an ester. Quaternary aminoalkylamides and esters are made by alkylating the corresponding aminoalkylamides or esters. The acid halides the S-nitro-jj-phenylbenzofurancarboxylic acids can can be easily prepared by reacting the acid with thionyl chloride, generally in a non-reactive manner Solvents such as dichloromethane or benzene.

The 3-i ⁾ henylbenzofurancarboxylic acid intermediates of group (1) are prepared from chloro- or bromo-3-phenylbenzofurans by replacing the halogen with cyanide and subsequent hydrolysis of the cyano group to give the carboxylic acid group e.

Chloro- and bromo-3-phenylbenzofurans are known and generally described in U.S. Patent 3,862,134. you will be produced e.g. by reacting a-bromoacetophenone and substituted oc-bromoacetophenones with halogenated Phenols and subsequent cyclization, e.g. in polyphosphoric acid. For the synthesis sequence according to the invention, halogen atoms are - unless specifically stated otherwise - chlorine, bromine or iodine atoms.

The reaction of the halogen of the chloro- or bromo-3-phenylbenzofurans with cyanide is generally in a basic organic solvent such as pyridine or quinoline carried out. The preferred cyanide is copper-I cyanide.

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Elevated temperatures of 100 to 25O ⁰ C be used in order to achieve satisfactory reaction rates, even though the temperature employed should not be so high that the benzofuran ring is decomposed.

The hydrolysis of the cyano group can take place under alkaline or acidic conditions. The extent of hydrolysis to the desired product can easily be determined as the product is an acid and has significantly different solubility properties than the starting material ·.

The making of compounds where X or X means a chlorine atom, makes it necessary that that by the halogen atom to be replaced by the cyano group is more reactive than chlorine, i.e. a bromine atom or that an alternative Synthesis route is chosen.

The intermediates of the formula:

in which X is a fluorine or chlorine atom or a lower alkyl or lower alkoxy group and m and η are independent each other 0, 1 or 2, Y a fluorine or chlorine atom or a methyl or methoxy group and Q a hydrogen, Mean bromine or iodine atom or the esters, amides, acid halides or pharmaceutically acceptable salts thereof Connections are new.

The (3-benzofuranyl) benzoic acid intermediates of the compounds

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Group (2) fertilizers are made from (chlorine or Brom-2-phenyl) "benzofurans by replacing the halogen by a cyanide group and subsequent hydrolysis of the cyano group to the carboxylic acid group. The (chlorine or Bromo-3-phenyl) benzofurans are produced e.g. by Implementation of chlorine or bromine-oc-bromoacetophenonen with optionally substituted phenols and subsequent cyclization, e.g. in polyphosphoric acid. The description of the reaction conditions for the replacement of the halogen atoms by cyanide groups and the corresponding hydrolysis of the cyanide, as described above in connection with the preparation of the as Intermediate acids of the compounds of group (1) are indicated, can also be used here will.

The compounds of the formula occurring as an intermediate product:

HOOC - K) JX _n

in which X is a fluorine or chlorine atom or a lower alkyl or lower alkoxy group, X is a fluorine or chlorine atom or a methyl or methoxy group, m and η independently from each other 0, 1 or 2 and Q is hydrogen, bromine or Mean iodine atom are also new. In this formula and throughout the description, if m. And / or η 0 mean that the positions indicated in the ring are unsubstituted.

The (2-nitro-3-benzofuranyl) phenylacetic acid esters of the group

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(3) are produced either by nitration of the appropriate 2-halogen compounds or by esterification of (2-ITitro-3-benzofuranyl) phenylacetic acid derivatives, such as the acyl halides with alcohols or acid salts with alkyl halides. The salts of (2-Kitro-3-benzofuranyl) phenylacetic acids are produced by reacting the corresponding acids with an organic one or inorganic base in a suitable solvent. The acid halides of (2-nitro-3- "benzofuranylphenylacetic acid can be easily prepared by reacting the acids with thionyl chloride generally in one non-reacting solvents, such as dichloromethane or Benzene.

The (3-benzofuranyl) phenylacetic acids and their esters, which are used as intermediates in the preparation of the inventive Connections applied are also new connections. They are made from known starting substances by a synthetic method given below:

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Il

AlCl ₃

CH ₃ CCl

O = CCH-

CHp COpCHpCHo

CHpCOpCHpOHq

+ Br,

O = CCH ₂ Br

X.

H ₂ CO H

The StTUfe (1) is a Friedel-Crafts reaction of an ethylphenyl acetate with acetyl chloride using aluminum chloride as a catalyst. Typical solvents that are inert to the reaction conditions, such as dichloroethane. are applied. Substituted phenylacetic acids and their esters and methods of synthesis are known.

- i ^e ° step (2) is the formation of an oc-Bromacetophenonderivats, and the bromination proceeds easily in the expected manner in an inert solvent such as dichloromethane from.

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In step (3) , equimolar amounts of known phenols and optionally substituted ethyl-a-bromoacetophenyl acetates, which are prepared according to step (2), or an excess of phenol are reacted in the presence of a base. Generally the base is a weak inorganic base such as an alkali carbonate. A solvent such as glycol dimethyl ether, tetrahydrofuran, benzene, ethanol, pyridine, etc. is used and an inert atmosphere is used. The reaction is carried out at a temperature from about 50 ° G to the reflux temperature. The product is isolated by conventional methods such as extraction or chromatography.

In step (4-) the products of step (3) are cyclized by heating in polyphosphoric acid. The resulting benzofurans are new and can easily be separated and isolated by diluting the reaction mixture with water and filtration or extraction.

In some cases the acid intermediate can be used for the the following synthesis steps are preferably used.

Step (5) shows the hydrolysis of the ester to the acid. This is generally achieved under conventional acidic or basic hydrolysis conditions.

The (2-nitro-3-benzofuranyl) alkancyanides used as intermediates for the preparation of compounds according to the invention are also new. They are made from known starting substances by the following reaction sequence:

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NBS

CCH ₂ B

(c)

Br _c

CH ₂ Br

(e)

CH ₂ CN

Steps (a) and (b) are analogous to steps (3) and (4) as indicated above and are described as above carried out. The starting substances are known.

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Step (c) is the bromination of the furan ring with the aid of bromine water or preferably bromine in a suitable solvent such as dichloromethane, carbon tetrachloride or acetic acid.

Step (d) requires bromination of the methyl group with N-bromosuccinimide with the aid of free radicals (under freeradical conditions) in a manner known per se.

Step (e) is the conversion of the bromomethyl group with the alkali cyanide to form a gyanomethyl group. The 2-bromo substituent can either be converted to the cyanomethyl derivative or before or after hydrolysis of the cyano group to the acid group by a nitro group be replaced.

The intermediates of the formula:

in which X is a halogen atom, a lower alkyl, lower alkoxy or trifluoromethyl group, Y is a halogen atom or a methyl or methoxy group and m and η independently of each other 0, 1 or 2 and Q is a hydrogen, bromine or iodine atom, or their esters or pharmaceutical compatible salts are also new.

The salts of the free acids of the compounds according to the invention can easily be prepared by reacting the Acid with a base and evaporation to dryness. The base used to prepare the salts can be organic, e.g.

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Sodium methoxide or an amine or inorganic. You can also use other salts that are not pharmaceutical are compatible, successful for the synthesis of the compounds in the form of the free acid or other compatible Salts' or other suitable intermediates, such as the ester, can be used. The free acids can also be made from the corresponding esters are prepared by processes known per se.

The antimicrobial activity of the compounds of the invention is determined by using a modification of the Original agar plate diffusion method according to Vincent and Vincent (see e.g. Vincent, J.G. and Vincent, Helen W., Proc. Soc. Exptl. Biol. Med. 55: 162-164, 1944 and Davis, B.D., and Mingioli, E.S., J.Bac, 66: 129-136, 1953) · With the help of this test it has been shown that the compounds according to the invention have a broad spectrum of activity against both gram-positive and gram-negative Own bacteria. The procedure gives information about the amount of a compound that is required to achieve complete, partial, or no inhibition of microbial growth on agar plates reach. The microbial growth on each plate is read visually and the minimum inhibitory concentration written down.

The microorganisms used were: Staphylococcus aureus, Bacillus subtilus, Pseudomonas aeruginosa, Escherichi coli, Streptococcus sp. (Strains isolated from dental caries in rats or hamsters at the National Institute of Dental Health and grown on Pi ¹ X or APT agar), Asperigillus niger, Candida albicans, Mima polymorpha, Herellea vaginicola, Klebsiella pneumoniae and Streptococcus fecaelis.

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These strains are selected so that they are representative of various bacteria and fungal groups and a "broad spectrum of activity can be predicted based on activity against these strains. All of the compounds according to the invention have an antimicrobial activity against one or more of the above-mentioned microorganisms. The compounds retain their high levels Activity against the microorganisms in the absence or in the presence of 10 % horse serum.

The in vivo antimicrobial effect is determined against infections caused by Streptococcus pyogenes C-203 and Staphylococcus aureus (Smith) or other types of bacteria. The type used is determined by that in vitro antimicrobial spectrum of the compound. Groups of 5 or 10 mice weighing 18 to 22 g were made infected intraperitoneally with the test culture. Treatment consisted of three oral doses 1, 6 and 24 hours after the infection. All mice were observed for extended periods, e.g., two weeks, and deaths were observed daily Intervals noted. Control groups consisted of an infected, untreated group and another infected group Groups that received different doses of the calibration standard.

The acute oral toxicity of the compounds according to the invention is generally moderate to low compared to with the effective oral dose and they have a good to excellent therapeutic ratio.

The compounds of the invention can be prepared by placing them in conventional pharmaceutical carriers, the can be organic or inorganic and which are suitable for oral or intraperitoneal administration, incorporates. For in vitro or topical application, the most popular

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. tv.

quemsten simple aqueous solutions or suspensions applied. For this purpose, concentrations on the order of 100 ppm up to about 5 % c are suitable and the preparation is applied by immersing the object to be treated therein or by applying the solution or suspension to the infected area. The amount of the compound which is used, for example, for the oral treatment of a microbial infection, is chosen so that it is effective but not toxic. The amount to be administered to a person or an animal and the type of administration to combat infection depend on the type of organism, sex, weight, physical condition of the patient, the location of the infection and many other factors. The assessment of the corresponding amount is, however, within the scope of the expert knowledge. The amount used is usually less than 100 mg per kg and dose. For oral treatment, the compounds are usually administered in the form of one or the other pharmaceutical preparation, such as capsules, tablets, emulsions, suppositories, etc.; Excipients, fillers, coating materials, etc. are used in the manufacture of tablets or capsules, as is customary.

It is often advantageous to combine the compounds of the invention with other antimicrobial agents such as Coccidiostats, anthelmintics, antifungal agents, antibiotics, steroids or other antibacterial agents to combine or to combine several of the compounds according to the invention in one agent.

Certain of the compounds of the invention are also effective against other parasites, such as through activity in laboratory tests against the protozoa Trichomonas sp. could be shown. In terms of extraordinary good antimicrobial activity of the compounds according to the invention

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genes are also expected to be good growth accelerators for different species of animals and birds.

The invention is illustrated by the following non-limiting ones Examples explained in more detail. Although the majority of the examples refer to the free acids, it goes without saying that other compounds according to the invention can also be prepared. The melting points are not corrected and the pressure is given in mm Hg.

Example 1

123 g (0.45 mol) of 5-bromo-3-phenylbenzofuran, 50.3 g (0.562 mol) of copper-I-cyanide and 30 ml of pyridine were heated to 150-175 ° C., then in 108 g anhydrous iron III chloride, 67 ml conc. Poured hydrochloric acid and 300 ml of water. The mixture was heated without boiling for 1 hour and the solid was then collected and washed with 6N hydrochloric acid and water. The product was stirred in 3 l of benzene for 1 hour, the benzene solution was filtered and the piltrate was washed with 6N hydrochloric acid, water, 10% strength sodium hydroxide solution and saturated sodium chloride solution and dried over magnesium sulfate. Evaporation gave the product, 5-cyano-3-phenylbenzofuran _; as a tan solid, Ip. Ί07 to 116 ° C.

Using the procedure of Example 1, the following intermediate was prepared: 7-Oyano-3-phenylbenzofuran.

Example 2

Using the method according to Example 1, starting from 6-chloro-3-phenylbenzofuran, 6-cyano-3-phenylbenzofuran was obtained.

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Example 5

90 g (0.411 mol) of 5-cyano-3-phenylbenzofuran, 90 g of 85% strength potassium hydroxide and 900 ml of 95% strength aqueous ethanol were heated to reflux temperature for 16 h. The solvent was evaporated and the residue was diluted with water and diethyl ether. The aqueous layer was separated and poured into cold dilute hydrochloric acid. A solid precipitated out and was filtered off, washed with water and dissolved in diethyl ether. The ether solution was washed with water and saturated sodium chloride solution and dried over magnesium sulfate. Evaporation gave a solid which was recrystallized from aqueous ethanol and a benzene-hexane mixture. Light-tan needles 205 was obtained from 3-phenyl-5-benzofurancarboxylic acid, mp. 209 to ⁰ O.

Using the procedure of Example 3 the following compound was prepared: 3-phenyl-7-benzofurancarboxylic acid, mp 215-216 ⁰ C..

Example 4

54.7 g of 6-cyano-3-phenylbenzofuran, 200 ml of acetic acid and 100 ml of hydrochloric acid were heated to reflux temperature for 20 hours. 100 ml of hydrochloric acid were added and the mixture was refluxed for a further 27 hours. The mixture was added to water and extracted with diethyl ether. The ether layer was washed with dilute sodium hydroxide solution extracted. The alkaline aqueous solution was acidified with 6N hydrochloric acid and the precipitate was collected and recrystallized from aqueous ethanol. 3-Phenyl-6-benzofurancarboxylic acid, melting point 160 ° to 170 ° C., was obtained.

Example 5

89 grams (0.374 moles) of 3-phenyl-5-benzofurancarboxylic acid, 59.8 grams

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(0.374 mol) of bromine and 2 l of dichloromethane were heated to reflux temperature, filtered and the piltrate was heated to reflux temperature and 41 g (0.256 mol) of bromine in 20 ml of dichloromethane were added over the course of 4 h. The mixture was cooled to give a solid product 2-bromo-3-phenyl-5-benzofurancarboxylic acid, mp ^265-0.

example

Using the procedure of Example 5, 3-phenyl-7-benzofurancarboxylic acid was converted to 2-Bromo-3-phenyl-7-benzofurancarboxylic acid, Ip. 241 to

Example 2.

20 g (0.063 mol) of 2-bromo-3-phenyl-5-benzofurancarboxylic acid and 1.25 l of acetic acid were heated to 55 ° C. with stirring. To this end, 7 g (0.094 mol) of cyclohexene were added 7 and then 8.7 g (0.094 mol) of dinitrogen tetroxide in 25 ml of acetic acid are added dropwise. After 5 liters the mixture was poured into cold water and the solid was recrystallized from aqueous ethanol and a benzene-ethanol mixture. 2-Nitro-3-phenyl-5-benzofurancarboxylic acid, melting point 271 ° to 273 ° C., was obtained.

Example 8

2.2 g (0.007 mol) of 2-bromo-3-phenyl-7-benzofurancarboxylic acid and 50 ml of acetic acid were heated on the steam bath for 45 minutes and then 2 ml of nitric acid were added and then 0.96 g (0.0139 mol) of sodium nitrite, the mixture being stirred at 80 to 90 ^° C. for about 45 minutes. The mixture was poured into water and the solid

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substance recrystallized from ethanol. 2-Nitro-3-phenyl-7-benzofurancarboxylic acid was obtained, mp 271 bis 272 ° G.

example

2 s 3 - phenyl-6-benzofurancarboxylic acid in 100 ml dichloromethane and 20 drops of acetic acid were treated with 3.0 g of nitrous tetroxide. The mixture was stirred for 70 hours and then evaporated. The residue was treated with cold 5% sodium hydroxide solution until solution occurred. The solution was acidified with 6N hydrochloric acid and the yellow solid collected and recrystallized from ethanol. 2-nitro-3-phenyl-6-benzofurancarboxylic acid was obtained, Mp. 244 to 247 ° C.

Example 1O_

28.3 g (0.10 mol) of 2-kitro-3-phenyl-7-benzofurancarboxylic acid and 100 ml of thionyl chloride in 100 ml of benzene were refluxed for 1.5 Ii and then evaporated. To give 2-Witro-3-phenyl-7-benzofurancarboxylchlorid, mp. 146 to 149 ⁰ C.

Example 1J_

5.1 g (0.05 mol) of N, N-dimethylamino-3-aminopropane in 100 ml of benzene became a solution of 2-nitro-3-phenyl-7-benzofurancarboxyl chloride in 100 ml of benzene added, stirred for 3½ hours, cooled in an ice bath and filtered. The filtrate was washed three times with water, twice with saturated sodium chloride solution, once with saturated Sodium bicarbonate solution and twice with saturated Sodium chloride solution, then dried, with active

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• us.

charcoal decolorized and filtered. Evaporation gave an oil which was triturated with petroleum ether, a precipitate being formed. When twice recrystallization from a cyclohexane-benzene mixture to obtain N, N-dimethylaminopropyl-2-nitro-3-phenyl ~ 7 ~ -benzofuranearboxamid, I ¹ P. 85 to 88 ⁰ C..

Following the procedure of Example 11, 2-nitro-3-phenyl-7-benzofuran carboxyl chloride was obtained reacted with various amines to give the following product

TABLE I.

At- F?

game product (in ⁰ C)

12 N, N-bis (2-hydroxyethyl) ~ 2-nitro-3-phenyl-7-benzofurancarboxamide 159-161

13 N, N-bis (N ', N'-dimethylaminoethyl) -2-nitro-3-phenyl-7-benzofuran

carboxamide 151-153

14 2-nitro-3-phenyl-7-benzofuran-

carb.oxamid 267-269

15 N- (5-0? Etrazolyl) -2-nitro-3-phenyl-7-benzofurancarboxamide 300

16 ethyl N- (2-nitro-3-ptienyl-7-benzofuranyl felycinate 178-180

17 4- (2-Nitro-3-phenyl-7-benzofuranylcarboxamidobenzoic acid 308-311

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»30.

Cont'd, to TABLE I.

At- £ p

game product ^ ^{111 0} ^

18 sodium-2-nitro-3-pliene; 7l-7-be: azo-

furanylcarboxamidoethanesulfonate y 325

19 4- (2-Nitro-3-phenyl-7-benzofurancarboxamido) benzenesulfonamide 280-281.5

(Decomp.)

20 1- (2-Witro-3-phenyl-7-benzofuranoyl) -4-methylpiperazine 229-231

21 2-Nitro-3-phenyl-7-benzofuranyl-240-245 penicillin Na salt (decomp.)

22 Ethyl 4- (2-nitro-3-piienyl-7-benzofurancarboxamide ^ benzoate 168-171

Example 2j5

The compound of Example 21 was dissolved in methanol and stirred for Ϊ h with cold sodium methylate. Diethyl ether was then added and the precipitate was filtered off. The product was 2-nitro-3-phenyl-7-carboxamidopenicilloic acid monomethyl ester monosodium salt hydrate, ffp. 191 to 196 ⁰ C (dec.).

Example 24

Ethyl N- (2-nitro-3-phenyl-7-benzofuranoyl) glycinate was

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by stirring in ethanolic sodium hydroxide solution
hydrolyzed. N- (2-nitro-3-phenyl-7-benzofuranoyl) glycine, melting point 123 to 126 ° C., was obtained.

Example 2 £

14.2 g (0.05 mol) of 2-nitro-3-phenyl-7-benzofurancarboxylic acid, 8.6 g (0.05 mol) of N, If-diethylamino-2-chloroethane hydrochloride, 10.1 g (0.1 Mol) triethylamine and 75 ml of N ₁ N-dimethylformamide were ^{heated to 90 to 100 °} C. for 16 h, cooled in an ice bath and filtered. The filtrate was
dissolved in diethyl ether, washed three times with water and twice with saturated sodium chloride solution and dried. The solution was evaporated, whereby one
N, N = diethylaminoethyl 2-nitro-3-phenyl-7-benzofurancarboxylate was obtained as an oil. This oil was dissolved in diethyl ether and treated with 25 ml of 4N hydrochloric acid in isopropanol, resulting in a product that gradually and
after solidified and was recrystallized twice from ethanol. N, N-diethylaminoethyl-2-nitro-3-phenyl-7-tert-enzofuran carboxylate hydrochloride, melting point 194.5 ° to 195 ° C., was obtained as a pale yellow solid.

Example 26_

Following the procedure of Example 25, N, N-dimethylamino-3-chloropropane hydrochloride was reacted with
2-Nitro-3-phenyl-7-benzofurancarboxylic acid with formation of N, N-dimethylaminopropyl ^ -nitro ^ -phenyl ^ -benzofurancarboxylate, m.p. 65.5 "to 67.5 ° C as a yellow
Solid.

Example 2 £

4.0 g (0.0011 mol) N, N-dimethylaminopropyl-2-nitro-3-

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phenyl 7-benzofurancarboxylate in 10 ml of ethanol was treated with 0.4 g of methyl iodide and the solution was stirred for 30 minutes. Diethyl ether was then added to the solution and a precipitate formed which was separated and recrystallized from methanol. It was (2-nitro-3-phenyl ~ 7-benzofuranylcarboxypropyl) -trimethylammoniumgodid, mp. 24-6 ⁰ C (dec.).

Example 28

Following the procedure of Example 27, N, N-dimethylaminopropyl-2-nitro-3-phenyl-7-benzofurancarboxamide was reacted with methyl iodide to give (2-nitro-3-phenyl-7-benzofuranylcarboxamidopropyl-trimethylammonium iodide, pp. 178.5-181 ⁰ G (dec.).

Example 2 £

Level a

40.5 g (0.43 mol) of phenol, 100 g (0.428 mol) of 4-chloroc-bromoacetophenone, 100 g (0.725 mol) of potassium carbonate and 500 ml of glycol dimethyl ether were refluxed for 6 h, evaporated, and the residue with water and diethyl ether thinned and the layers separated. The ether layer was washed with water and saturated sodium chloride solution and dried over magnesium sulfate and evaporated to give a dark oil which solidified and was recrystallized from ethanol. It was 4-chloro-oc-phenoxyacetophenone, mp. 81 to 86 ⁰ C.

Level B.

350 g polyphosphoric acid and 51.3 g (0.208 mol) 4-chloro

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α, -phenoxyacetophenon were heated to 80 ⁰ C and held at this temperature 1 h. The mixture was poured into cold water, the product collected, washed with water and dissolved in diethyl ether. The ether solution was washed with cold dilute sodium hydroxide solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. A dark oil of 3- (4-chlorophenyl) benzofuran resulted which solidified.

Level G

Following the procedure of Example 1, 3- (4-chlorophenyl) benzofuran was obtained converted to 3- (4-cyanophenyl) benzofuran.

Level D

Following the procedure of Example 3 3- (4-cyanophenyl) benzofuran was converted to 4- (3-Benzofuranylbenzoesäure, mp. 222-225 ⁰ C.

Level E.

Following the procedure of Example 5 4- (3-Benzofuranylbenzoesäure was converted to 4- (2-bromo-3-benzofuranyl) benzoic acid, mp. 218-220 ⁰ C.

Level F

Following the procedure of Example 7, mp 4- (2-bromo-3-benzofuranyl) benzoic acid was converted to 4- (2-nitro-3-benzofuranylbenzoesäure. 274-278 ⁰ C.

Example ^ 50

Following the procedure of Example 29 starting in step A.

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of 3-chloro-a-bromoacetophenone and phenol and work up to stage D was obtained as the product of stage D 3- (3-benzofuranylbenzoic acid, ip. 188 to 191 ^° C.

The product of Step E was 3- (2-bromo-3-benzofuranyl) benzoic acid, raw melting point 212-220 ⁰ G.

The product of Step F was 3- (2-nitro-3-benzofuranyl) benzoic acid, mp. 233-243 ⁰ C.

Example 3_1_

Level a

To 5 l of dichloroethane and 798 g (6.0 mol) of aluminum chloride were at 37 to 40 ° C 492.6 g (3.0 mol) of ethylphenyl acetate and 471 g (6.0 mol) of acetyl chloride added within 3 h. The reaction mixture was stirred at 45 ° C. for a further 20 h, in an ice-vasser mixture poured the organic layer separated, dried over magnesium sulfate and evaporated, an oil remaining. The oil was in vacuo distilled. Individual fractions boiling between 100 and 130 ° G at 0.1 mm Hg were collected. The fractions which crystallized were recrystallized from petroleum ether. A solid was obtained of ethyl (4-acetyl) phenyl acetate, m.p. 56 bis

Level B.

To 14.7 g (0.07 mol) of ethyl (4-acetyl) phenyl acetate in 150 ml of dichloromethane were 11.4 g (0.071 mol) of bromine in 25 ml of dichloromethane were added within 1.5 k. The GE

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mix was made with a 5% solution of sodium acetate washed in water, dried over magnesium sulfate and evaporated. An orange oil was obtained from Ethyl / ~ 4- (oc- "bromo) acetyl 7-phenyl acetate.

Level C

20.2 g (0.071 mol) ethyl / ~ 4- (α-bromo) acetyl_7phenyl acetate, 9.4 g (0.10 mol) of phenol, 20.0 g (0.145 mol) of potassium carbonate and 150 ml of benzene were refluxed for one day heated. The mixture was filtered, the filtrate with water, cold sodium hydroxide solution and again Washed water and saturated sodium chloride solution, dried over magnesium sulfate and given a dark oil evaporated =, It was ethyl- / ~ 4- (a-phenoxy) -acetyl_7pnenylacetat.

Level D

Polyphosphoric acid (350 g) was heated to 50 ° C. and stirred while 17.0 g (0.057 mol) of ethyl (4-ot-phenoxyacetyl) phenyl acetate were admitted. After heating and stirring for about 2 hours, the mixture became in poured cold water. An oil separated out and was taken up in diethyl ether. The ethereal solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and given a dark Evaporated oil. The product was purified by chromatography on a silica gel column eluting with chloroform-hexane mixture cleaned. The first fraction was a pale yellow oil containing the desired product ethyl 4- (3-benzo.furanyl) phenyl acetate was.

Level E.

6.4 g (0.023 mol) of ethyl 4- (3-benzofuranyl) phenyl acetate,

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64 ml of 90% aqueous ethanol and 19.2 g of sodium hydroxide in water was refluxed for about 3 η. The mixture was evaporated with water and diethyl ether, the aqueous layer separated and poured into dilute hydrochloric acid. The solid became collected, washed with water and dissolved in diethyl ether. The ether solution was saturated with water and Sodium chloride solution and washed over sodium sulfate solution dried. The ethereal solution was evaporated, leaving an oily orange solid of 4- (3-Benzofuranylphenylacetic acid was obtained.

step Έ

Following the procedure of Example 5, 4- (3-benzofuranyl) phenylacetic acid was obtained brominated to give a yellow oil of 4- (2-bromo-3-benzofuranyl-phenylacetic acid.

Level G

To 6.7 g (0.020 mol) of 4- (2-bromo-3-benzofuranyl) phenylacetic acid, 2.5 g (0.030 mol) of cyclohexene in 150 ml of acetic acid became 2.8 g (0.030 mol) of dinitrogen tetroxide given in 20 ml of acetic acid. After 6 hours the mixture was poured into cold water. It was different a yellow gummy product that dissolves in diethyl ether has been resolved. The ether solution was washed four times with water and then six times with 100 ml of cold 0.5 η sodium hydroxide solution extracted. The alkaline extracts were heated to evaporate residual ether and then in poured cold dilute hydrochloric acid. The yellow product was filtered off and dissolved in dichloromethane. The dichloromethane solution was washed with water and saturated sodium chloride solution and over magnesium sulfate

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dried. The organic solution was then evaporated. 4- (2-Mitro-3-benzofuranyi,) phenylacetic acid was obtained, which was recrystallized from aqueous ethanol, a benzene-hexane mixture and then isopropyl alcohol, yellow crystals being formed, melting point 175 to 178 ^° C.

PATENT CLAIMS:

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Claims (1)

PATENT CLAIMS (1) A is -COH- group, B is hydrogen, X is Fluorine or chlorine atom or a lower alkyl or lower alkoxy group, Y a fluorine or chlorine atom or a methyl or methoxy group and m and η are either O, 1 or 2 independently of one another and their esters, amides, acid halides and. pharmaceutically acceptable salts or O
; i (2) A is a hydrogen atom, B is the group -CÖH, and X is a i'luoro or chlorine atom or a lower alkyl or lower alkoxy group, X a I'luoro or chlorine atom or a methyl or methoxy group and m and η independently of one another each denote O, Λ or 2 and their pharmaceutically acceptable salts or 709815/1183 il A is a hydrogen atom, B is the group -GH ₂ GOH, Σ is a halogen atom, a lower alkyl, lower alkoxy or trifluoromethyl group, X is a halogen atom or a methyl or methoxy group and m and η are each independently 0, 1 or 2 and their esters and pharmaceutically acceptable salts. .2 Compounds of the formula (I), characterized in that they are in the form of the free acid. 3 compounds according to claim 1 or 2, characterized in that A is the group -GOH,
B is a hydrogen atom and m = 0. 4- compounds according to claim 1 or 2, characterized in that A is the group Il
-COH, B is a hydrogen atom and m = 1. 5. Compounds according to claim 1 or 2, characterized in that A is a hydrogen atom and B the group 0 -COH
and m = 0. 6 compounds according to claim 1 or 2, characterized in that A is a hydrogen atom, B group 0 Il -COH
and m = 1. 709815/1183 7 2-nitro-3-phenyl-5-benzofurancarboxylic acid. 8 2-nitro-3-phenyl-6-benzofurancarboxylic acid. 9 2-Nitro-3-phenyl-7- benzofurancarboxylic acid. 10 4- (2-nitro-3-benzofuranyl) benzoic acid. 11 3- (2-Nitro-3-benzofuranyl) benzoic acid. 12 compounds according to claim 1 or 2, characterized in that X is a hydrogen atom is. 13 4- (2-nitro-3-benzofuranyl-phenylacetic acid. 14, a method for producing the compounds according to claim 1, characterized in that one either (A) the 2-position of a compound of the formula: A-fOO ^Yra . LQ B nitrided directly; or (B) the 2-position of a compound of formula (II) to form an intermediate of formula: (III) 709815/1 183 in which Q is a bromine or iodine atom, halogenated directly and then the 2-halogen atom through a nitro group replaced or (G) a corresponding compound of the formula: : B ¹ in which A ^{1 is} a cyano, a carboxylic acid ester group or a hydrogen atom and B ^{1 is} a cyano, a carboxylic acid ester, a cyanomethyl, an acetic acid ester group or a hydrogen atom which is subjected to acid hydrolysis. 15 Use of the compounds according to claims 1 to 13 as antimicrobial agents. 709815/1183