CA1053673A - Pharmacologically active benzoyl benzofurans and benzothiophenes - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A compound is disclosed of the formula:

or a pharmaceutically acceptable acid addition salt thereof, in which:
R1 is phenyl, halophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, di-lower alkylphenyl, tri-lower alkylphenyl, lower alkoxyphenyl, di-lower alkoxyphenyl, tri-lower alkoxyphenyl, lower alkyl-di-lower alkoxyphenyl or lower alkoxy-di-lower alkylphenyl;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, nitro or trifluoromethyl;

R3 is ;

R4 is hydrogen, methyl, ethyl or propyl and R5 is methyl, ethyl or propyl or R4 and R5 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, N-(lower alkyl)piperazine, morpholine or perhydroazepien ring;
R6 is hydrogen or hydroxy;
m is 0 or 1 when R6 is hydrogen and 1 when R6 is hydroxy;
n is 0 or 1; and Z is oxygen or sulfur.
These compounds have been found to have pharmacological activity, in particular, coronary vasodilator activity useful for the treatment of anginapectoris.

Description

1 This invention relates tc new benzoyl benzofurans which have useful pharmacological activity~
More specifically~ these compGunds have cGronary vasodilator activity and are u~eful in the treatment of angina pectorisO
In add~tion~ t:hese compounds ma.y be usefuL as hypotensive agentsO Also included in this lnvention are intermediates for the preparation of the benzoyl benzofursnsO
The benzoyl benzofurans of this invention are represented by the followi.ng structural formula 1 0 ~-Rl R2~ ~CH2)nR3 lS or a pharmaceutically acceptabl.e acid addition salt thereof, in which:
Rl is phenyl, halophenyl 9 dihalophenyl 9 trihalophenyl9 lower alkylphenylv di-lower alkylphenyl, tri-lower alkylphenyl~ lower alkoxyphenyl9 di-lower ?.0 alkoxyphenyl, tri-lower alkG~yphenylg lower alkyl-di-lower aLkoxyphenyl or lower alkoxy-d~-lower alkylphenylO
R2 iS kydrOgen9 ha109 lower ~lkyl~ lower alkoxy9 nitro cr trifluoromethyl,

2~ R3 is ~ O CH2 ~ (~H2)m N\

R4 is hydrogen, methyl9 ethyl or propyl and R5 is methyl~ ethyl or propyl or R4 and R5 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidineq N-(lower alkyl)pipera2ine, morpholine or perhydroa~epine ring, 1 R6 is hydrogen or hydroxy 3 m is 0 or 1 when R6 is hydrogen and 1 when R6 i 8 hydroxy, and n is 0 or lo As used herein~ the terms "lower alkyl" and "lower alkoxy'l denote groups havi~g from one to fcur carbcn atoms, "halo" refers to f luQro a chloro and bromoO
Advantageous compounds of this invent~on are represented by Formula I in which R4 is hydrogen, methyl, ethyl or propyl9 R5 is methyl, ethyl or propyl and Rl, R2, R3, R6, m and n are defined a~ aboveO
Most advsntageous are the compounds of formula I

in which -~Rl is in the 3-position of the benzofuran nucleus, Rl is dihalophenyl, ~rihalophenyl, di-lower alkylphenyl, tri-lower alkylphenyl, di-lower alkoxyphenyl, tri-lower al~oxyphenyl~ lcwer alkyl-di-lower alkoxyphenyl or lower alkoxy-dl-lower alkylphenyl, R2 is hydrogen9 halo or lower alkyl; -(CH2)nR3 is in the 2-position of the benzofuran nucleus; R3 is 0-cH2-cH-(cH~)m-N

or / R4 2S ___ " ~CH2~ ~-(CH2)m-N
~ R6 \R5 R4 and R5 are methyl9 ethyl, propyl or together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, N-(lower alkyl)piperazine9 morpholine or perhydroazepine ring, R6 is hydrogen and m and n are 0 or lo Preferred compounds of this inventicn are ~3~

1 represented by formula I in which ~-Rl is ln the 3~positio~
of the benzofuran nucleus; Rl is halophenyl 9 395-dihalophenyl~

3,5-di-lower alkyl.phenyl, 3,495-trl-lower ~l.kylphenyL, 3,5 di-lower alkoxyphenyl or 3,5-di lower alkyl~4-lower alkoxy-phenyl, R2 ls hydrogen or halo~ (CH2)nR3 ~ in the ~-position of the benzofuran nucleus, R3 is ~ o-cH~-lH~(cH2)m-N

or ,R4 ~CH2~CH-(CH2) -N
~ R6 R5 R4 and R5 are methyl9 ethyl, propyl or together with the nitrogen atom to which they are attached form a pyrrolidlneS
piperidine, N-(lower alkyl)piperazine~ morpholine or perhydroazepine ring, R6 is hydrogen and m and n are O or lo Most preferred compounds are represented by ?.0 formula I in which -e-Rl is in the 3-position of the benzofuran nucleus; Rl is chlorophenyl, 3~5-dimethylphenyl~ 3,4,5-trimethylphenyl, 3,5-dimethoxyphenyl or 3~5-dimethyl~4~
methoxyphenyl; R2 is hydrogen or chloro; -(CH2)nR3 is in the 2-pcsiti.on of the benzofursn nucleus~ n ~s 0; R3 is ~O-CH2-1H;~(CH2)m-N~

R4 and R5 are ethyl or together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring, R6 is hydrogen and m is 0.

~ -4-1()53673 Especially preferred are the eompounds of fcrmula I

in which -~Rl is in the 3-position of th~ benzofuran nucleus, Rl is chlorophenyl, 3,5-dimethylphenyl9 3~4~5 trimethylphenyl~
3,5-dimethoxyphenyl or 3~5~dimethyl 4-metho~phenyl, R2 ~s hydrogen or chloro; -(CH2)nR3 is in the 2=position of the benzofuran nucleus, n is 0, R3 is ~ 0-CH2 CH-(CH2)m-N

R4 and R5 are ethyl, R6 is hydrogen and m is 00 Particularly preferred are those compounds of this invention which, in addition to having coronary vasodilator activity, also inhibit or attenuate the chronotropic effect of isoproterenol-induced tachycardiag fcr example 2-[4'~(2-diethylaminoethoxy)phenyl]-3-(3'~5^-d~methylbenzoyl)benzofuran, 2-14'-(2-diethylaminoethoxy)phenyl]-3-(3'94',5'~trimethyl-benzoyl)benzofuran, 5-chloro-2-[4'-(2-diethylaminoethoxy)-?.~ phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran9 3-(3',5'-dimethyl-benzoyl)-2-[~-'-(2-N-pyrrolidinoethoxy)phenyl]benzofuran, 3-(3',5'-dim~thylbenzoyl)-2-[4'-(2-N-piperidinoethoxy)phenyl~-benzofuran ard 2-(4'-chlorobenzcyl)-3-[4'-(2-hydroxy-3-isopropylamiropropoxy)phenyl]benzofuranO
Sone of the compounds of this invention may exist as optical i~omers due to an ssymmetric carbon atom in the aminoalkoxy ~ide chainO All of the isomers9 including sepa-rated isomers and mixtures thereof, are inc~uded within the scope of ~his inventionO
The compounds of formula I in which -e-Rl is in the 3-position, -(CH2)nR3 is in the 2-position and R6 is hydro~en are prepared as shown in the following schemeo R2 ~ 3--(CH2)n~oCH3 Il Demethyla tlon R2~3_ (( H2)n~OH

III \

X- ( CN2) p-~/ \ `N- (CN2) -Y

R2~ ~5/ (CH2)pX \~

RlC-Cl ~ R2~(CH2)n~(CH2)pN

~O

R2 ~(CH2~n~0 (CH2)pX R~ Cl S ¦ R4R5NN

L~ R2~ (CH2)n_~(CH2)p 3~) 1 in which the terms Rl9 R2, R4~ R5 and n are defined as above9 p is 2 or 3D X iS ha1o9 preferably chloro or bromo and Y is halo~ preferabl.y chloro~ or a leavi.ng group such as tosyl cr mesylO
Accordi.ng to the above procedure~ a methoxyphenyl or methoxybenzyl benzofuran of formula II is demethylated by known methods9 for example by use of pyridine hydrochloride or boron tribromide, to the corresponding hydroxyphenyl or hydroxybenzyl benzofuran of formula lIIo Reaction of III
with a substituted aminoalkyl halide or tosylate of the formula R4R5N-tCH2)p-Y in the presence of a base such as potassium carbonate, sodium methoxide or sodium hydride in a solvent such as acetonea methanol, toluene, 3-pentanone or dimethylsulfoxide followed by acylation of the product aminoalkoxyphenyl or aminoalkoxybenzyl benzofuran (IV) or the corresponding salt9 preferably a hydrochloride salt, with an acid chloride of the formula Rl~-Cl by standard procedures~ for example in the presence of stannic chloride or aluminum chlor~de in a solvent such as methylene chloride, ?.0 nitrobenzene or carbon disulfide at a temperature from about 0C0 to ambient temperature (caO 25C~) gives compounds of formula I where R6 is hydrogenO
These benzoyl benzofurans are also prepared as shown in Scheme 1 from the intermediate of formula III
2~ by reaction of III with a dihaloalkane, X-(CH2)p~X, preferably dibromo or dichloro~ in the presence of a base such as potassium carbonate in a solvent such as acetone or 3-pentanone, preferably at the reflux temperature, followed by acyla~ion as previously described of the haloalkoxyphenyl or haloalkoxybenzyl benzofuran (V) thus formed to give a haloalkoxyphenyl- or benzyl-3-benzcyl benzofuran (VI). Treatment of VI with an amine of the formula R4R5NH where R4 and R5 are defined as above in a solvent such as refluxing ethanol, gives the corresponding compounds of formula Io Also included within this invention are the compounds of formula IV shown in Scheme 1~ In addition LO
being useful as intermediates in the preparation of compounds of formula I, these aminoalkoxyphen~l and benæyl ~ benzofurans, such as the compound where the side chaln 15 ~n the 2-position of the benzofuran nucleus, R2 is hydrogen, R4 and R5 sre ethyl, n i9 0 and p is 2, also have corona~y vasodilator activity.
In addition, when Rl does not contain an alkoxy ~5 group(s), the corresponding compounds of formula I are prepared as shown below:

O O
II Rl e Cl~ R2 ~ ~ C-Rl' ~ OCH3 VII
Demethylation .~, O
R2 ~ C-Rl' ~ OH

I R4~
3(~ ~ RS~ ( 2 p where R2, R4, R5, p, n and Y are defined as above and Rl' is phenyl, halophenyl, dihalophenyl, trihalophenyl, lower alkyl-phenyl, di-lower alkylphenyl or tri-lower alkylphenyl.
Thus, a methoxyphenyl or methoxybenzyl benzofuran of formula II is acylated as previously described ~o give the methoxypnenyl- or methoxybenzyl-benzoyl benzofuran VII. De-methylation of VII followed by reaction with a substituted aminoalkyl halide, tosylate or mesylate as described above gives the corresponding compounds of this invention.
The corresponding compounds of formula I where R6 is hydroxy are prepared according to Scheme 3:

2 ~ C-Rl ~H

VII

R2 ~ ~ CH2-CH-CH2 ~ ~ R4R5NH

R2 ~ CH2)n ~ CH2_~H_cH2_N

The terms Rl, R2, R4, R5 and n are defined as above.
As shown in the above procedure, a hydroxyphenyl benzofuranyl ketone of formula VIII is converted to the epoxy intermediate IX which is then opened by reaction with an appropriàte amine (R4R5NH). The epoxy intermediates lOS3~73 1 of formula IX are prepared by reactlon of a compound of formula VILI with an epihalohydrin such as epich1Orohydrln or epibromohydrin in the presence of a base such as sodlum hydroxide or potassium carbonate ln a solvent such as water~
ethanol or acetoneO
The ring opening of the epoxy intermediates of formula IX is preferably carried out in A minimum amount of a solvent such as ethanol or with excess amine as solvent ln a pressure bomb at from about 25 to about 125Co ~
preferably at 100C., for from one to about six hours, preferably from three to four hour~.
The benzofuran products of formula I are isolated and purified as such by standard techniques inciuding solvent extraction, crystallization and chromatographic methods or as the corresponding acid addition salts which are also objects of this invention~ The salts are formed with orga~ic and inorganic acids according to methods known to the artO Thus, a solution of the amine in ether or an alcohol such as methanol or ethanol is treated with a so1ution of an organic or inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or in an aqueous immiscible solvent, such as ether, with the desired salt separating directly. Exemplary of ~uch organic sa1ts are those with maleic, fumaric, benzoic~ ascorbic, pamolc, succinic, hexamic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic~
3( itaconic, glycolic, p-aminobenzoic, glutamic, benzen~
sulfonic and theophylline acetic acids as well as with the 8-halotheophyllines, for example, 8-bromotheophylline. Exem-plary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
Of COurSQ, these salts may also be prepared by the classical method of doubl~ decomposition of appropriate salts which is well known to the art. The salts may be purified by the stan-dard methods described above.
The substituted benzofuranyl ketone starting materials of Scheme 3 (VIII) are prepared by standard methods for the synthesis of benzofurans. For example, an acid chloride of the formula Rl-C-Cl is used to acylate a methoxyphenyl or methoxybenzyl substituted benzofuran nucleus by known proce-dures, for example in the presence of stannic chloride or aluminum chloride in a solvent such as methylene chloride, carbon disulfide or nftrobenzene. The resulting methoxyphenyl or methoxybenzyl benzofuranyl ketone is then demethylated by known methods, for example by use of pyridine hydrochloride or boron tribromide.
The methoxyphenyl or methoxybenzyl substituted benzo-furan nuclei used as starting materials in 6chemes 1 and 2 (II) and in the preparation of the compounds of formula VIII
are either known to the art or are prepared by one of the general methods for the synthesis of benzofurans described by Buu-Hoi et al., J. Chem. Soc. 3693 (1955), 625 (1957), 2593 (1957) and 173 (1964); Tanaka, J. Amer. Chem. Soc. 73:
872 tl951); Bisagni et al., J. Chem. Soc. 3688 (1955); Grinev et al., Zhur. Obshchei Khim. 27:1087 (1957); Castro et al., J. Orq. Chem. 28:3313 (1963), 31:4071 (1966); Rodd, Chemistry of Carbon Compounds Vol. IV-A, 168-191; Mustafa, The Chemistry of Heterocyclic Compounds Vol. 29, ~enzofurans and French Patent 1,537,206 10536~3 1 Representative methods for preparing these starting material~ are exemplified hereinafterO
Alternatively, the methoxybenzyl substituted benzofuran starting materials (II) are prepared by add~tion of a phenyl magnesium halide to a cyanobenzofuran followed by hydrolysis and reduction of the product with a reducing agent such as hydrazine hydrate.
When Rl contains an alkoxy group(s) andtor R2 is alkoxy, the corresponding compound3 of formula I in which is in the 3-position and R6 is hydrogen are preferably prepared as shown in Scheme 4 in which the terms Rl, R29 R4, R5, n and p are a8 defined above:

Cl~(CH2)p-0 ~ R2 (CH2)n-CCH2-Br + HO

Ba Qe ~ R2{~L~-cH2-l~-(cH2) ~0-(CH2)p-XI

? S R2~L (CH2)n~~ (CH2)p-Cl XII ¦ 1) Acylation ~ ) R4 5NH

3() Thus, reaction of a substituted phenol with a bromomethyl chloroalkoxyphenyl or benzyl ketone of formula X
in the presence of a base such as potassium carbonate in a solvent such as acetone gives the corresponding compound of formula XI. Cyclization of XI, for example with polyphos-phoric acid, produces benzofuran XII which, upon acylation followed by reaction of the product with an amine (R4R5NH) as previously described, gives the corresponding compounds of formula I.
The bromomethyl chloroalkoxyphenyl or benzyl ketones of formula X are either known to the art or are prepared by reaction of the corresponding bromomethyl hydroxyphenyl or benzyl ketone with a chloroalkyl halide of the formula Cl-(CH2)p-X. The bromomethyl hydroxyphenyl or benzyl ketones are obtaimed from hydroxyphenylacetyl or hydroxybenzoyl ha-lides, preferably chlorides, according to known procedures such as reaction of a hydroxyphenylacetyl or hydroxybenzoyl chloride with diazomethane and hydrogen bromide.
The acid chloride acylating agents, ~l-C-Cl, are either known to the art or are prepared by standard methods, for example by treatment of the corresponding benzoic acid with thionyl chloride or phosphorus pentachloride.
The coronary vasodilator activity and hypotensive effects of the compounds of this invention are demonstrat~d in dogs by an increase in coronary blood flow with concomi-tant decrease of mean arterial blood pressure upon intrave-nous administration of doses of from about 0.32 to about 5.0 mg./kg. These parameters are measured as follows:
Adult mongrel dogs (13-16 kg.) are pretreated with 2 mg./kg. s.c. of morphine sulfate followed in one hour by intravenous administration of 1-1.5 ml./kg. of an aqueous solution containing 1.5~ chloralose and 20% urethane. Sup-plemental doses of morph~ne and chloralose-urethane are given to maintain an adequate and uniform depth of anesthesia.
A caro~id artery is catheterized and connected to a Sanborn pressure transducer to measure arterial blood pressure. A femoral vein is also catheterized for adminis-tering a solution of the test compound or its salt and sup-plemental anesthesia. A left thoractomy is made at the fourth or fifth intercostal space, the lung is displaced, the peri-cardium is opened and the left circumflex coronary artery is isolated for measurement of coronary blood flow, a "snare"
being placed around the artery distally to obtain zero flow.
Coronary blood flow is measured with a Statham electromagnetic flowmeter and Flo-Probe (MDS).
In addition, the particularly preferr~d compounds of formula I, namely 2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran, 2-t4'-~2-diethylaminoeth-oxy)phenyl]-3-(3',4',5'-trimethylbenzoyl)benzofuran, 5-chloro-2-[4'-(2-diethylaminoethoxy)phenyl]-3-~3',5'-dimethylbenzoyl)-benzofuran, 3-(3',5'-dimethylbenzoyl)-2-r4'-(2-N-pyrrolidino-ethoxy)phenyl]benzofuran, 3-(3',5'-dimethylbenzoyl)-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran and 2-(4'-chloroben-zoyl)-3-t4'-(2-hydroxy-3-isopropylaminopropoxy)phenyl]benzo-furan also inhibit or attenuate the chronotropic effect of isoproterenol-induced tachycardia upon administration to dogs at doses of from about 1.25 to about 10.~ mg./kg. i.v. Abad et al [Acta Pharmacol. et Toxicol. 25:85 (1967)] have corre-lated the inhibition of isoproterenol-induced tachycardia to utility as an anti-anginal agent.

~ -13-The pharmacologically active compounds of this in-vention may be administered orally or parenterally in an amount to produce the desired activity.
Preferably the compounds are admimistered in con-ventional dosage unit forms prepared by combining an appro-priate dose of the compound with standard pharmaceutical carriers. The dosage units will contain the active ingredient in an amount of from about 100 mg. to about 600 mg., prefer-ably 150 mg. to 300 mg. per dosage unit.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pec-tin, acacia, magnesium stearate, stearic acid and the like.
Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be em-ployed. Thus, if a solid carrier is used the preparation canbe tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granula~mng, and compressing when necessary or variously mix-~ -13a-ing and dissolving the ingredients as appropriate to the desired composition.
The method of producing coronary vasodilator ac-tivity in accordance with this invention comprises adminis-S tering internally to an animal an effective amount of acompound of this invention. The compound will preferably be administered in a dosage unit form as described above orally or parenterally, the oral route being preferred. Advanta-geously equal doses will be administered one or two times daily with the daily dosage regimen being from about 200 mg.
to about 1200 mg., preferably from about 300 mg. to about 600 mg. When the method described above is carxied out, coronary vasodilator activity is produced.
One skilled in the art will recognize that in deter-mining the amounts of the compound needed to produce the de-sired pharmacological effect without toxic side effects, the activity of the compound as well as the size of the host ani-mal must be considered.
The following examples illustrate the invention but are not to be construed as limiting the scope thereof.

-13b-lOS3673 Temperatures are in degrees Centigrade unless otherwise stated.
When formed, acid addition salts may be converted to the corresponding free amines by treating a solution of the salt in a solvent such as water, a chloroform-water or a benzene-water mixture with a base such as 10~ aqueous so-dium hydrox~de, sodium carbonate or sodium bicarbonate until basic followed by extra~tion of the amine into benzene or chloroform. Salts other than hydrochlorides may be converted to the corresponding hydrochloric acid salts by passing a solution of the salt in methanol or ethanol through an Amber-lite IRA-401 chloride ion exchange column.

2-[4'-(3-Diethylaminopropoxy)phenyl]-3-(~'-methylbenzoyl)-benzofuran To a cooled (0) mixture of 4.07 g. (0.018 mol.)of 2-~-methoxyphenylbenzofuran and 4.17 g. (0.027 mol.) of p-toluic acid ahloride in 100 ml. of methylene chloride was added dropwise 11.25 g. (0.043 mol.) of stannic chloride.
The reaction mixture was stirred for 1.5 hours at 0, then for 0.5 hour at 25. The mixture was poured into water and stirred vigorously, the layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated to give 2-p-methoxyphenyl-3-~-methylbenzoylbenzofuran.
2-p-Methosyphenyl-3-~-methylbenzoylbenzofuran (4.9 g., 0.014 mQl.) was combined with 50 g. of freshly dis-tilled pyridine hydrochloride and the mixture was heated at 1~0-190 for 4.5 hours. The hot mixture was poured with stirring onto an ice-5% aqueous hydrochloric . .

105367;~
acid mixture and the precipitate formed W8S extracted into etherO The ether solution was dried (MgS04) and concentrated under reduced pressure to give 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuranO
To a solution of 0O177 gO (7~7 g~-atom) of sodium dissclved in 25 ml~ of dry methanol was added a solution of 2.4 g, (7~3 mmol.) of 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuran in 75 ml. of toluene and 10 mlO
of methanolA The mixture was refluxed for 15 minutes, then the methanol was removed by distillatlon~ A solution of 1~15 g. (7.7 Z~L~O1.) of 3-diethylaminopropyl chloride in 25 mlO of toluene was then added and the resulting mixture was refluxed for six hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give the title compound.
The title compound was dissolved in dry ether and an etheral solution of hydrochloric acid was added to precipitate the benzofuran hydrochloride saltO The ether was decanted and the crude salt was dissolved in chloroform and chromatographed on silica with chloroform and chloroform containing 10% methanol ~s the eluant to give 2-r4'-~3-diethylaminopropoxy)phenyl~-3-(4'-methylbenzoyl)benzofursn hydrochloride, m.p. 84-87o 3-BenzoYl-2-[~'-(2-diethYlaminoethoxy)phenyl]benzofuran ~ tel benzoyl chloride was substituted in the procedure of ~xample 1 for P-toluic acid chlozide, 3-benzoyl-2-~-methoxyphenylbenzofursn was obtainedO
Demethylation of 3-benzoyl-2-P-methoxyphenylbenzo-furan followed by reaction of the 3-benzoyl-2-~-hvdro~y~h~nyl-benzofuran thus obtained with 2-diethylaminoethyl chloride accordIng to ;he proce~u-e or Ex~mple 1 gave the ~tle compound.
3-~enzoyl-2-~4'-(2-diethylaminoethoxy)phenyl~benzo-furan was conver~ed to the corresponding hydrochloride as described in Examp'e 1, C27H2_No3.HCl.~20 Calculated 69._0 c, 6.46~, ~. 99N; Found 69 . 43C, 6. 58 H, 2. 95N.

orobenzoyl)-2-~4'-(2-diethYlaminoethoxv~P~en~l?-benzofur~n Reaction of P-chlorobenzoyl chloride wIth 2-p-methoxyphenylbenzofuran gave 3-P-chlorobenzoyl-2-p-methoxyphenylbenzofuran.
Demethylation of 3-P-chlorobenzoyl-2-P-methoxy-phenylbenzofuran followed by reaction of the 3-P-chloro-benzoyl-2-P-hydroxyphenylbenzofuran thus obtained w~th lS 2-diethylaminoe~hyl chloride according to the procedure of Example 1 gave the title compound.
The corresponding hydrochloride of 3-(4'-chlorobenzoyl)-2-[4'-(2-diethylaminoethoxy)phenyl;benzofu.-an wa8 prepared as described in the procedure of Example 1, ?.0 m.p~ 155-165.

3-~4'-ChlorobenzoYl)-2-r4'-(3-diethYlamino~roPoxy)phen benzofuran When 3-P-chlorobenzoyl-2-p-hydroxyphenylbenzofur&n .S wa~ reac,ed with 3-diethylaminopropyl chlor~de by t~e procedure of Example 1, ~he title compound was obt~inedO
The corresponding hydrochloric acid salt of 3-(4'-chlorobenzoyl)-2-[4'-(3-d~ethyl~minopropo~y)phenyl~-benzofuran was prep~red as descr~bed in the procedure cf 3() Ex~mple 1, m.p. 90-94.

1 EXA~21E 5 3-~-Anisoyl-2-~4 ? _ ( 3-dlethylaminopropoxy~phenyl]ben7~ur~n ~ . . .
A solution of 4~9 g. (00023 molO) of 2-~-hydroxyphenylbenzofuran ln 75 mlO of toluene and 5 mlO
of methanol wac added to a sodium methoxide solutlon prepared by d~ssolving 0O5~ gO (00023 gO-atom~ cf sodiu~
in 25 ml~ of methanol. The mixt~re was refluxed ~or i5 minutes, then the methanol was removed by distillatlon snd 3.48 g. (0.023 mol.) of diethylaminopropyl chlorid~ w~s added and the resulting reaction mixture was refluxed ~or four hours. The mixture was filtered and the flltrate concentrated under reduced pr2ssu~e to give 2-~4'-~3-diethy~aminopropoxy)phenyllbenzofura~, m.p. 86-88.
To a ~olution of 1.02 g. (0.006 mol~) of D-anlsoyl chloride in 75 ml. of methylene chloride was added 2.0 g. (6.2 mmol.) of the hydrochloride salt of 2-t4'-(3-diethylaminopropoxy)phenyl~benzofuran~ The reaction mixture was cooled to 0, 3.3 ml. (0u024 1~) of stannic chloride was added snd the resulting ~ixture ?0 was stirred for 10 minutes at 0 then for 2.75 hours at 25. The mixture was then poured into water and stlrred vigorously. The layer~ were separated and the organ~c phase was washed with 10% aqueouQ sodium carbonate solution and water, dried (Mg~04) and concentrated to gi~e _S the tiele compound as an oil.
The hydrochloric acid salt of 3-p-anisoyl-2-t~ ~
(3-diethylaminopropox~phenyl~enzofuran was prepared as ~escri~ed in Example 1, C29R3lNo4-~
Calculated: 70.51 C, 6.;3 H, 2.84N;
3(1 FOUND: 70.26 C, 6.73 H, 2. 92N.

1~53673 2-[4'-(3-Diethylaminopropoxy)phenyl]-3-(3',5'-dimethylbenzoyl)-benzofuran -To a suspension of 2.0 g. (6.2 mmol.) of the hydro-chloride salt of 2-[4'-(3-diethylaminopropoxy)phenyl]benzo-furan in 10 ml. of nitrobenzene was added a solution of 1.84 g. (13.9 mmol.) of aluminum chloride in 20 ml. of nitrobenzene~
The solution was cooled to 0 and 1.24 g. (7.4 mmol.) of 3,5-dimethylbenzoyl chloride was added. The reaction mixture was stirred at 0 for 30 minutes then at 25 for 1.5 hours, after which time it was poured into water and the nitrobenzene was removed by steam distillation. The aqueous solution was ex-tracted with ether, ~ade alkaline with aqueous sodium carbon-ate solution and again extracted with ether. The ethereal solution was dried (MgSO4) and concentrated to give the title compound.
Addition of an ether solution of hydrochloric acid to a solution of the title compound in e~her gave the corre~
sponding hydrochloride salt as an oil which was purified by column chromatography and crystallized from ethyl acetate, m.p. 130-138.

.
2-[4'-(2-Diethylam_n eth~xy~phenyl]-3-(3~5~-dimeth benzoyl)benzofuran To a cooled (0) solution of 14.0 g. (0.105 mol.) of aluminum chloride in 100 ml. of nitrobenzene was added 11.2 g. ~0.05 mol.) of 2-p-methoxyphenylbenzofuran followed immediately by 10.0 g. (0.06 mol.) of 3,5-dimethylbenzoyl chloride. The reaction mixture W8S stirred at 0 for 12 min-utes (until the red color began to turn reddish-brown) then poured into water. The aqueous 1053~;73 l mlxture was steam di~tilled to remove nitrobenzene and the residue was dissolved in methylene chloride~ The methylene chloride solution was washed with aqueous sod~um carbonate and saturated sodium chloride solution, dried (MgS04) and concentrated at reduced pressure to gi~e a residue whlch was purified by column chromatography tc give 2-p-methoxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran which was then crystallized from ethanol~
2-p-Methoxyphenyl-3-(3',5'-dimethylbenzoyl)~
() benzofuran was demethylated to 2-p-hydroxyphenyl-3-(3',5'-dlmethylbenzoyl)benzofuran with pyridine hydrochloride as described in Example 1.
2-p-Hydroxyphenyl-3-(3',5'-dimethylbenzoyl)-benzofuran (5.25 g., 15.3 mmol.~ wa~ dissolved in 200 mlO
of dry acetone and 10.5 g. (0.076 mol~) of potassium carbonate and 2.10 g. (15.3 mmolO) of 2-diethylaminoethyl chloride were added. The reaction mixture was refluxed for three hours, then it was cooled and filteredO The filtrate was concentrated at reduced pressure to give the title 7 compound as an oil.
The title compound was dis~olved in dry ether to which solution was added an ether solution of hydrochloric acid to give the corresponding hydrochloric acid ~alt9 mOpO 155-157.

3-(3'.5'-Dichlorobenzoyl)-2-[4'-(2-diethYlaminoethoxY)-phenYl]benzofuran A solution of 13.4 g. t0.07 mol.) of 3,5-dichlorobenzoic acld and 10.7 g. (0.09 m~l~) of thionyl 3(~ chloride in 60 ml. of methylene chloride was refluxed on a steam bath for two hours. Concentration under reduced lOS3673 1 pressure and distillat~on of the residue gave 3,5-dichl~robenzoyl chloride.
Substltution of 3,5~dichlorobenzoyl chlorlde in the procedure of Example 7 for 3,5-dimethylbenzoyl chloride folklwed by demethylation of the 3-(3'95'-dichlorobenzoyl~
2-p~methoxyphenylbenzofuran as described above gave 3 (3',5'~
dichlorobenzoyl)-2-p-hydroxyphenylbenzofuran.
Treatment of 3-(3',5'-dichlorobenzoyl)-2~p-hydroxyphenylbenzofuran with 2~diethylaminoethyl chloride 1() according to the procedure of Example 7 gave the title compound.
The title compound wa~ converted to the corres-ponding hydrochloride salt as previously described, mOp. 165-168.

~;4'-(2-DimethYlaminoethoxY)phenyll-3-(3l.5'-dimethYl~
benzoyl)ben~ofuran Reaction of 2-~-hydroxyphenyl-3-(3'95'-dimethyl benzoyl)benzofuran with 2-dimethylaminoethyl chloride b~
~ ~he procedure described in Example 7 gave the title compound.
The title compound was converted to the corres~
pcnding hydrochloric acid salt as described in Example 7 m.pO 132-135.

2-14'-(2-DiethYlaminoethoxy)PhenYl]-3-(3',4',5~-trimethyl~
benzoYl)benzofuran By using 3,4,5-trimethylbenzoyl chloride, prepared from treatment of 3,4,5-trimethylbenzoic acid 3~) with thionyl chloride as de~cribed hereinabove, in ~la~e of 3,5-dimethylbenzoyl chloride in the procedure of lOS3673 Example 7, the title compound was ultimately obtained.
Treatment of the title compound with an ethereal solution of hydrochlorid acid as described in Example 7 gave the corresponding hydrochloride salt, m.p. 171-173.

2-[4l-(2-Diethylaminoethoxy)phenyl~-3-(3~5~-dimethoxyben-zoyl)benzofuran A mixture of 10.5 g. (0.05 mol.) of 2-~-hydroxy-phenylbenzofuran and 47 g. (0.25 mol.) of 1,2-dibromoethane in 200 ml. of 3-pentanone containing 46 g. (0.3 mol.) of potassium carbonate was heated at 100 for 12 hours. The mixture was filtered while hot and the solid remaining was washed with hot acetone. The o~mbined filtrate and washings were concentrated to give 2-[4'-(2-bromoethoxy)phenyl]benzo-furan.
To a mixture of 2.93 g. (0.022 mol.) of aluminum chloride and 2.21 g. (0.011 mol.) of 3,5-dimethoxybenzoyl chloride in 50 ml. of nitrobenzene at 0 was added 3.19 g.
(0.010 mol.) of 2-[4'-(2-bromoethoxy)phenyl]benzofuran. The reaction mixture was stirred for one hour then poured into water. The nitrobenzene was steam distilled from the aqueous mixture and the residue was extracted with chloroform. The extract was dried (MgSO4) and concentrated under reduced pressure to give, after chromatography, 2-[4'-(2-bromoethoxy)-phenyl~-3-(3',5'-dimethoxybçnzoyl~benzofuran.
A solution of 1.59 g. (3.3 mmol.) of 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethoxybenzoyl)benzofuran and 8 ml. of diethylamine in 100 ml. of ethanol was refluxed for 18 hours. The reaction mixture was concentrated under re-duced pressure and 10% aqueous sodium hydroxide and ether were added to the residue. The mixture was shaken until complete dissolution and the layers were separated. The ether layer was dried (MgSO4~ and concentrated under reduced pressure to give the title compound.
Treatment of a solution of the title compound with an ether solution of hydrochloric acid as described in the procedure of Example 1 gave the corresponding hydrochloric acid salt, m.p. 163-165.

2-~4'-(2-Diethylaminoethoxy)phenyl]-3-(3',5'-dimethyl-4'-methoxybenzoyl)benzofuran When an equivalent amount of 3,5-dimethyl-4-methoxy-benzoyl ch~oride, prepared from 3,5-dimethyl-4-methoxybenzoic acid and thionyl chloride as previously described, was sub-stituted in the procedure of Example 11 for 3,5-dimethoxy-benzoyl chloride, 2-[4'-(2-bromoethyxy)phenyl]-3-(3',5'-di-methyl-4'-methoxybenzoyl)benzofuran was obtained.
Reaction of 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethyl-4'-methoxybenzoyl)benzofuran with diethylamine as described in Example 11 gave the title compound.
The title compound was converted to the correspond-ing hydrochloride salt by the procedure of Example 1, m.p.
130-133.

3-(3'~5'-Dimethylbenzoyl)-2-I4'-(2-di-n-propylaminoethoxy~-phenyl]benzofuran Substitution of an equivalen~ amount of 3,5-dimethylbenzoyl chloride for 3,5-dimethoxybenzoyl chloride in the procedure of Example 11 gave 2-~4'-(2-bromoethoxy)-phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran.

10536'73 Reaction of 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran with di-n-propylamine as described in Example 11 gave the title compound.
The title compound was converted to the correspond-ing hydrochloride salt by the procedure of Example 1, m.p.
158-160.
EXAMP~E 14 When an equivalent amount of a substituted benzoic acid listed below:
p-bromobenzoic acid _-fluorobenzoic acid 3,5-dibromobenzoic acid 2,3-difluorobenzoic acid 2,3,5-trichlorobenzoic acid is used as a starting material in Example 8 in place of 3,5-dichlorobenzoic acid, there are obtained the following benzo-furans:
3-~-bromobenzoyl-2-p-methoxyphenylbenzofuran 3-_-fluorobenzoyl-2-p-methoxyphenylbenzofuran 3-~3',5'-dibromobenzoyl)-2-~-methoxyphenylbenzofuran 3-(2',3'-difluorobenzoyl)-2-p-methoxyphenylbenzofuran 3-(2',3',5'-trichlorobenzoyl)-2-p-methoxyphenylbenzofuran.
Demethylation of the above listed 2-_-methoxyphenyl benzofurans with pyridine hydrochloride followed by reaction of the 2-~-hydroxyphenyl benzofurans thus formed with 2-diethylaminoethyl chloride as described in Example 1 gives the following compounds of this invention:
3-(4'-bromobenzoyl)-2-[4'-(2-diethylaminoethoxy)phenyl]-benzofuran 2-14'-(2-diethylaminoethoxy)phenyl]-3-(3'-fluorobenzoyl)-benzofuran ~053673 3-(3',5'-dibromobenzoyl)-2-[4'-(2-diethylaminoethoxy)-phenyl]benzofuran 2-[4'-(2-diethylaminoethoxy)phenyl]-3-(2',3'-difluoro-benzoyl)benzofuran 2-[4'-(2-diethylaminoethoxy)phenyl]-3-(2',3',5'-tri-chlorobenzoyl)benzofuran.

2-[4'-(2-Diethylaminoethoxy)benzyl]-3-(3',5'-dimethylbenzoyl)-benzofuran To 11.0 g. (0.09 mol.) of salicylaldehyde in 30 ml.
of dry methanol was added 5.1 g. (0.09 mol.) of potassium hydroxide dissolved in 50 ml. of methanol. The solution was refluxed for 10 minutes and 20.5 g. (0.09 mol.) of a-bromo-~-methoxyacetophenone dissolved in 50 ml. of warm methanol was added dropwise but rapidly over a 10 minute interval. The resulting solution was refluxed for one hour, then filtered and concentrated. The residue was dissolved in ether and the ether soluton was washed with water. The aqueous washings were extracted twice with ether and the ethereal extracts were combined, reduced in volume, refluxed with decolorizing carbon, filtered, dried (MgSO4) and concentrated to give 2-(4'-methoxybenzoyl)benzofuran which was recrystallized from isopropanol, m.p. 93-94.
Hydrazine hydrate (28.0 g., 0.42 mol.) is added to a solution of 38.1 g. (0.16 mol.) of 2-(4'-methoxybenzoyl)-benzofuran in 400 ml. of ethanol and the reaction mixture is refluxed overnight. The solution is concentrated, chloro-form is added and the chloroform solution is washed with saturated aqueous sodium chloride, dried (~gSO4) and concen-trated to yield the corresponding hydraxone. T~e hydrazone ~OS3~73 is dissolved in lO0 ml. of dry dimethyl sulfoxide and added dropwise over a four hour interval to a slurry of 36.4 g.
(0.32 mol.) of potassium t-butoxide in lO0 ml. of dry dimethyl sulfoxide. The reaction mixture is poured into 500 ml. of water and the aqueous solution is extracted with chloroform.
The extracts are washed with water, dried (MgSO4) and con-centrated under reduced pressure to give 2-(4'-methoxybenzyl)-benzofuran which is purified by chromatography.
Substitution of an equivalent amount of 2-(4'-methoxybenzyl)benzofuran in the procedure of Example 7 for 2-~-methoxyphenylbenzofuran followed by the subsequent syn-thetic steps described therein gives the title compound.

2-[2~-(3-Diethylaminopropoxy)benzyl]-3 (4'-methylbenzoyl)-benzofuran 2-(2'-Methoxybenzyl)benzofuran is prepared as de-scribed in the procedure of Example 15 by the use of ~-bromo-o-methoxyacetophenone as a starting material in place of ~-br`omo-~-methoxyacetophenone.
Substitution of an equivalent amount of 2-(2'-methoxybenzyl)benzofuran in the procedure of Example 1 for 2-p-methoxyphenylbenzofuran followed by the subsequent syn-thetic steps ~escribed therein gives the title compound.
EXAMP~E 17 2-~3'-(2-Diethylaminoethoxy~phenyl]-3-(3',5'-dimethylbenzoyl)-benzofuran When an equivalent amount of 2-m-methoxyphenylben-zofur~n was used as a starting material in the procedure of Example 7 in place of 2-_-methoxyphenylbenzofuran, 2-_-meth-oxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran was obtained.

Demethylation of 2-m-methoxyphenyl-3-(3',5'-di-methylbenzoyl)benzofuran followed by reaction of the 2-m-hydroxyphenyl-3-t3',5'-dimethylbenzoyl)benzofuran thus formed with 2-diethylaminoethyl chloride as described in Example 7 gave the title compound which was converted to the correspond-ing hydrochloride salt as described hereinabove, m.p. 156-158.

5-Chloro-2-~4'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-di-methylbenzoyl)benzofuran Substitution of an equivalent amount of 5-chloro-2-p-methoxyphenylbenzofuran for 2-~-methoxyphenylbenzofuran in the procedure of Example 7 followed by the subsequent syn-thetic steps described therein gave the title compound as the final product.
The title compound was converted to the correspond-ing hydrochloride salt by procedures described hereinabove, m.p. 161-162.

4-Chloro-2-[4'-(2-diethylaminoethyoxy)benzyl]-3-(3',5'-di-methylbenzoyl)benzofuran When an equivalent amount of 6-Ghlorosalicylaldehyde is used as a starting material in the procedure of Example 15 in place of salicylaldehyde and the product 4-chloro-2-(4'-methoxybenzoyl)benzofuran is reduced with hydrazine hydrate, 4-chloro-2-(4'-methoxybenzyl)benzofuran is obtained.
Substitution of an equivalent amount of 4-chloro-2-(4'-methoxybenzyl)benzofuran in the procedure of Example 7 ~or 2-~-methoxyphenylbenzo~uran followed ~y the subsequent synthetic steps described therein gives the title compound as the final product.

6-Chloro-2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran To a stirred solution of 13.88 g. tO.105 mol.) of _-ethynylanisole in 500 ml. of ethanol is added a solution of 20.0 g. (0.105 mol.) of cuprous iodid~ in aqueous ammonia.
The reaction mixture is stirred for 15 minutes and the pre-cipitate formed is collected by filtration and washed with copious amounts of water, ethanol and ether to give cuprous p-methoxyphenylacetylide.
A flask containing 2.14 g. (0.011 mol.) of cuprous ~-methoxyphenylacetylide in 80 ml. of dimethylformamide is thoroughly flushed with nitrogen. A solution of 2.28 g.
(0.011 mol.) of 2-bromo-5-chlorophenol in 20 ml. of dimethyl-formamide is added under nitrogen and the reaction mixture is stirred and warmed at 120 for 24 hours. The mixture is then filtered and the filtrate is concentrated in vacuo.
The residue is dissolved in chloroform, refiltered and the filtrate is washed with water and concentrated to give 6-chloro-2-_-methoxyphenylbenzofuran.
Substitution of an equivalent amount of 6-chloro-2-p-methoxyphenylbenzofuran in the procedure of Example 7 followed by the subsequent synthetic steps of demethylation and reaction of the product with 2-diethylaminoethyl chloride as described therein gives the title compound.

Reaction of a substituted phenol listed below:
2-bromo-6-ethylphenol 2-bromo-4-fluorophenyl 2-bromo-4-methylphenol with cuprous p-methoxyphenylacetylide according to the procedure described in Example 20 gives the following sub-stituted 2-p-methoxyphen~lbenzofurans:
7-ethyl-2-p-methoxyphenylbenzofuran

5-fluoro-2-~-methoxyphenylbenzofuran 5-methyl-2-_-methoxyphenylbenzofuranr Substitution of a 2-_-methoxyphenylbenzofuran listed above in the procedure of ~xample 7 for 2-_-methoxy-phenylbenzofuran followed by the synthetic steps of demethyl-ation of the substituted 2-p-methoxyphenyl-3-(3',5'-dimethyl-benzoyl)benzofuran and treatment of the product thus formed with 2-diethylaminoethyl chloride as described therein gives the following compounds of this invention:
7-ethyl-2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran 2-[4'-(2-diethylaminoethoxy)phenyl]-5-fluoro-3-(3',5'-dimethylbenzoyl)benzofuran 2-[4'~2-diethylaminoethoxy)phenyl]-5-methyl-3-(3',5'-dimethylbenzoyl)benzofuran, m.p. 146-148 (HCl Salt).

Use of a benzoyl chloride listed below, prepared from treatment of the corresponding substituted benzoic acid with thionyl chloride as described in Example 8:
3,5-diethylbenzoyl chloride 4-n-propylbenzoyl chloride 4-t-butylbenzoyl chloride 3,5-di-t-butylbenzoyl chloride as a starting material in place of 3,5-dimethylbenzoyl chlor-ide in the procedure of Example 7 gives, as final products, the following compounds of this invention:
2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-diethyl-benzoyl)benzofuran, m.p. 174-176 (HCl salt).

2-[4'-(2-diethylaminoethoxy)phenyl]-3-(4'-n-propyl-benzoyl)benzofuran 3-(4'-t-butylbenzoyl)-2-[4' (2-diethylaminoethoxy)-phenyl]benzofuran 3-(3',5'-di-t-butylbenzoyl)-2-[4'-(2-diethylamino~
ethoxy)phenyl]benzofuran.
EXAMP~E 23 Use of a benzoyl chloride listed below, prapared from treatment of the corresponding substituted benzoic acid with thionyl chloride as described in Example 8:
3,4-diethoxybenzoyl chloride 3-_-propoxybenzoyl chloride 4-n-butoxybenzoyl chloride 3,5-di-t-butoxybenzoyl chloride 3,4,5-trimethoxybenzoyl chloride 2,5-dimethoxy-4-methylbenzoyl chloride as a starting material in place of 3,5-dimethoxybenzoyl chloride in the prodedure of Example 11 gives, as final products, the following compounds of this invention:
3-(3',4'-diethoxybenzoyl)-3-[4'-(2-diethylaminoethoxy)-phenyl]benzofuran 2~[4'-(2-diethylaminoethoxy)phenyl]-3-(3'-n-propoxy-benzoyl)benzofuran 3-(4'-n-butoxybenzoyl)-2-[4'-(2-diethylaminoethoxy)-phenyl]benzofuran 3-(3',5'-di-t-butoxybenzoyl)-2-[4l_(2-diethylaminoeth-oxy)phenyl]benzofuran 2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',4',5'-tri-methoxybenzoyl ! benzofuran 2-[4'-(2-diethylaminoethoxy)phenyl]-3-(2',5'-dimethoxy-4'-methylbenz~yl)benzofuran.
- ~9 ~

When 2-l4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimeth-oxybenzoyl)benzofuran is reacted with N-methylethylamine or N-methylpropylamine by the procedure described in Example 11, 3-(3',5'-dimethoxybenzoyl)-2-[4'-(2-N-methylethylaminoethoxy)-phenyl]benzofuran and 3-(3',5'-dimethoxybenzoyl)-2-t4'-(2-N-methylp00pylaminoethoxy)pheyl]benzofuran are prepared, re-spectively.
EXAMPL~ 25 3-Benzoyl-2-[4'-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-benzofuran To a mixture of 1.6 g. (0.04 mol.) of sodium hy-droxide and 3.7 g. (0.012 mol.) of 3-benzoyl-2-p-hydroxy-phenylbenzofuran was added with stirring 10.2 g. (0.11 mol.) of epichlorohydrin. The reaction mixture was refluxed for 1.5 hours, then it was cooled and extracted with methylene chloride. The extrac~ was dried (MgSO4) and concentrated to give a residue which, after chromatography, gave 3-bonzoyl-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran.
3-~enzoyl-2-[4'-(2,3-epoxypropoxy)phenyl]benzo-furan (1.9 g., 5.2 mmol.) was dissolved in 30 ml. of freshly distilled isopropylamine and the mixture was heated in a stainless steel pressure bomb at 100 for 4.5 hours. The contents of the bomb were concentrated under reduced pressure to give the title compound. The title compound was dissolved in ether and an ethereal solution of hydrochloric acid was added to precipitate the corresponding hydrochloride salt, m.p. 53-59.
EXAMPLE 2~
2-[4'-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-3-(4'-methylbenzoyl)benzofuran A mixture of 2.0 g. (6.1 mmol.) of 2-p-hydroxy-phenyl-3-~-methylbenzoylbenzofuran, 2.6 g. (0.019 mol.) of epibromohydrin and 3.0 g. (0.021 mol.) of potassium carbonate in 100 ml. of dry acetone was refluxed for 12 hours. After cooling, the reaction mixture was fil~ered and the filtrate was concentrated to give 2-[4'-(2,3-epoxypropoxy)phenyl]-3-(4'-methylbenzoyl)benzofuran.
Substitution of an equivalent amount of 2-[4'-(2,3-epoxypropoxy)phenyl]-3-(4'-methylbenzoyl)benzofuran in the procedure of Example 25 for 3-benzoyl-2-r4'-(2,3-epoxy-propoxy)phenyl]benzofuran gave the title compound. The title compound was converted to the corresponding hydrochloric acid salt as described in the previous example, m.p. 65-75.

3-(4'-Chlorobenzoyl)-2-[4'-(2-hydroxy-3-isopropylamino-propoxy)phenyl]benzofuran When an equivalent amount ~f 3-p-chlorobenzoyl-2-~-hydroxyphenylbenzofuran was reacted with epibromohydrin as described in the procedure of Example 26 and the product 3-(4'-chlorobenzoyl)-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran thus formed was treated with isopropylamine as described in the procedure of Example 25, the title compound was obtained.
The title compound was converted to the correspond-ing hydrochloride salt by treatment with an ethereal solution of hydrochloric acid as previously described~ m.p. 177-183.

3-(3'-Chlorobenzoyl)-2-[4'-(2-hydroxy-3-isopropylamino-propoxy)phenyl]benzofuran Treatment of 3-m-chlorobenzoyl-2-~-hydroxyphenyl-benzofuran with epibromohydrin as described in Example 26 ~053673 followed by reaction of the 3-(3'-chlorobenzoyl)-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran with isopropylamine as de-scribed in Example 25 gave the title compound.
Addition of ethereal hydrochloric acid solution to a solution of the t~tle compound in ether gave the correspond-ing hydrochloric acid s~lt, m.p. 167-172.

3-(4~- hlorobenzoyl)-2-[3~-(2-hydroxy-3-isopr~pylaminopr poxy)phen~l]benzofuran When 2-_-methoxyphenylbenzofuran was acylated with p-chlorobenzoyl chloride and the product was demethylated with pyridine hydrochloride according to the procedure de-scribed in Example 1, 3-p-chlorobenzoyl-2-m-hydroxyphenyl-benzofuran was obtained.
Substitution of an equivalent amount of 3-p-chloro-benzoyl-2-m-hydroxyphenylbenzofuran in the procedure of Ex-ample 26 in place of 2-p-hydroxyphenyl-3-~-methylbenzoyl-benzofuran with subsequent opening of the epoxy compound thus formed with isopropylamine as previously described gave the title compound.
The title compound was converted to the correspond-ing hydrochloride salt as described hereinabove, m.p. 53-60.

2-[4~-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-3-(3~5 dimethylbenzoyl)benzofuran When an equivalent amount of 2-p-hydroxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran was substituted in the pro-cedure of Example 26 for 2-p-hydroxyphenyl-3-_-methylbenzo~l-benzofuran and the epoxy compound thus formed was opened with isopropylamine as previously described, the title compound was obtained.

The title compound was converted to the correspond-ing hydrochloride salt as described hereinabove, m.p. 154-157.

2-[4'-t2-Dimethylaminoethoxy)phenyl]~3-(3',4',5'-trimethyl-benzoyl)benzofuran 2-p-Hydroxyphenyl-3-(3',4',5'-trimethylbenzoyl)-benzofuran (5.4 g., 15.3 mmol.) was dissolved in 200 ml. of dry acetone and 10.5 g. (0.076 mol.) of potassium carbonate and 2.10 g. (15.3 mmol.) of 2-dimethylaminoethyl chloride were added. The reaction mixture was refluxed for three hours, then it was cooled and filtered. The filtrate was concentrated under reduced pressure to give the title com-pound.
The title compound was dissolved in dry ether to which solution was added an ether solution of hydrochloric acid to give the corresponding hydrochloric acid aalt, m.p.
197-198.

2-[4l-(3-Dimethylaminopropoxy)phenyl]-3-(3',5'-dimethyl-benzoyl)benzofuran Treatment of 2-p-hydroxyphenyl-3-(3',5'-dimethyl-phenyl)benzofuran with potassium carbonate and 3-dimethyl-aminopropyl chloride in dry acetone by the procedure described in Example 31 gave the title compound.
The title compound was converted to the correspond-ing hydrochloric acid salt as described hereinabove, m.p.
103-106.

2-Benzoyl-3-[4~-(3-diethylaminopropoxy)phenyl]benzofuran Acylation of 3-p-methoxyphenylbenzofuran with benzoyl chloride and stannic chloride in methylene chloride as described in Example 1 for the preparation of 2-p-meth-oxyphenyl-3-p-methylbenzoylbenzofuran gives 2-benzoyl-3-_-methoxyphenylbenzofuran.
2-Benzoyl-3-_-methoxyphenylbenzofuran is demethyl-ated with pyridine hydrochloride as previously described to give 2-benzoyl-3-p-hydroxyphenylbenzofuran, which upon reac-tion with 3-diethylaminopropyl chloride as described in Example 1, gives the title compound.

3-[4'-(2-Diethylaminoethoxy)phenyl~-2-(3 '-r5 '-dimethylbenzoyl)-benzofuran When 3-p-methoxyphenylbenzofuran is acylated with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 1, 3-p-methoxyphenyl-2-(3',5'-dimethylbenzoyl)-benzofuran is obtained.
Demethylation of 3-p-methoxyphenyl-2-(3',5'-dimethylbenzoyl)benzofuran followed by reaction of the 3-p-hydroxyphenyl-2-(3',5'-dimethylbenzoyl)benzofuran thus formed with 2-diethylaminoethyl chloride as described in Example 1 gives the title compound, m.p. 108-110 (HCl salt).

2-Benzoyl-3-~4'-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-benzofuran Substitution of an equivalent amount of 2-benzoyl-3-p-hydroxyphenylbenzofuran -n the procedure of Example 26 for 2-~-hydroxyphenyl-3-p-methylben7oylbenzofuran with sub-sequent opening of the epoxy compound thus obtained with iso-propylamine as described hereinabove gives the title com-pound, m.p. 53-59 (HCl salt) 3-[4'-(2-Diethylamlnoethoxy?benzyl]-2-(3',5'-dimethylbenzoyl)-benzofuran To a solution of the Grignard reagent prepared from 4.27 g. (0.14 g.-atom) of magnesium turnings and 31.0 g.
(0.13 mol.) of 4-iodoanisole in 50 ml. of ether was added dropwise a solution of 10.0 g~ (0.07 mol.) of 3-cyanobenzo-furan in 150 ml. of ether. The reaction mixture was stirred at 25 for 17 hours, then 30 ml. of water was added followed by a mixture of 20 ml. of sulfuric acid and 40 ml. of water.
Additional amounts of the acid solution were added to dissolve the preoipitate that formed in the reaction mixture. The mixture was poured into 500 ml. of water and the aqueous so-lution was extracted with chloroform. The extracts were dried (MgSO4) and concentrated in vacuo to give 3-(4'-meth-oxybenzoyl)benzofuran which was purified by chromatography on alumina with chloroform, m.p. 89-90 (hexane-benzene).
Hydrazine hydrate (28.0 g., 0.5 mol.) is added to a solution of 40.4 g. (0.16 mol.) of 3-(4'-methoxybenzoyl)-benzofuran in 400 ml. of ethanol and the reaction mixture is refluxed overnight. The solution is concentrated in vacuo, chloroform is added and the chloroform solution is washed with saturated aqueous sodium chloride, dried (MgSO4) and concen-trated to yield the corresponding hydrazone. The hydrazone is dissolved in 100 ml. of dry dimethyl sulfoxide and added dropwise over a four hour interval to a slurry of 36.4 ~
(0.32 1.) of potassium t-butoxide in 100 ml. of dry dimethyl '' ~- "' ~ .

~053673 sulfoxide. The reaction mixture is poured into 500 ml. of water and the aqueous solution is extracted with chloroform.
The extracts are washed with water, dried (MgSO4) and concen-trated to give 3-~-methoxybenzylbenzofuran.
Acylation of 3-p-methoxybenzylbenzofuran with 3,5-dimethylbenzoyl chloride and stannic chloride in methylene chloride according to the procedure described in Example l gives 3-_-methoxybenzyl-2-(3',5'-dimethylbenzoyl)benzofuran.
Demethylation of 3-~-methoxybenzyl-(3',5'-dimethyl-benzoyl)benzofuran with pyridine hydrochlor~de as described above followed by reaction wf the 3-p-hydroxybenzyl-2-(3',5'-dimethylbenzoyl)benzofuran thus obtained with 2-diethylamino-ethyl chloride as described in Example 1 gives the title compound.

3-[4'-(2-Hydroxy-3-isopropylaminopropoxy)benzyl]-2-(3~5 dimethylbenzoyljbenzofuran Substitution of an equivalent amount of 3-p-hydroxybenzyl-2-(3',5'-dimethylbenzoyl)benzofuran in the pro-cedure of Example 26 for 2-~-hydroxyphenyl-3-p-methylbenzoyl-benzofuran with subsequent opening of the epoxy compound thus obtained with isopropylamine as described hereinabove gives the title compound.

2-[4'-(2-Diethylaminoetho~y)phenyl]-5-methoxy-3-(3~,5 dimethylbenzoyl)benzofuran A mixture of 27.7 g. (0.1 mol.) of ~-bromo-~-(2-chloroethoxy)acetophenone, 12.4 g. (0.1 mol.) of p-methoxy-phenol and 13.8 g. (0.1 mol.) of potassium carbonate in 75 ml. of dry acetone is refluxed with stirring for 16 hours.

~ - 3~ -lOS3673 After cooling, the reaction mixture is poured into 500 ml.
of water. The product is collected and dissolved in chloro-form and the chloroform solution is washed with water, dried (MgSO4) and concentrated to give ~-(2-chloroethoxy)-~-(p-methoxyphenoxy)acetophenone.p-(2-Chloroethoxy)-~-(p-methoxyphenoxy)acetophenone (14.4 g., 0.045 mol.) is added to 90 g. of polyphosphoric acid preheated to 130 and the reaction mixture is vigorously stirred for 12 hours. ~he mixture is poured into 800 ml. of water and the aqueous phase is extracted three times with ether. The extracts are combined, washed with water, satu-rated aqueous sodium bicarbonate solution - 36a -1 and saturated aqueous sodium chloride solution and dried ~MgS04)~ Removal of the solvent gives 2-[4'-(2-chloro-ethoxy)phenyll-5-methoxybenzofuranO
Acylation of 2-[4' (2-chloroethoxy)phenyl]-5 methoxybenzofuran with 3~5-dimethylbenzoyl chlorlde as ~escri.bed in the procedure of Example 11 gives 2-~4~g2~
chloroethoxy)phenyl]-5-methoxy-3-(3',5'-d~methylbenzoyl)-benzofuran.
Reaction of 2-[4'-(2-chloroethoxy)phenyl~5~
]() methoxy-3-(3',5'-dimethylbenzoyl)benzofuran with di.ethylamine by the procedure of Example 25 gives the title compoundO

When an equivalent amount of a phenol listed below~
4-bromophenol 154-n-butoxyphenol 4-t-butylphenol 4-nitrophenol a,a90-trifluoro-p-cresol i8 substituted in the procedure of Example 38 for p~metho~y~
- phencl and the resulting P-(2-chloroethoxy)-~-6ubstituted phenoxyacetophenone is reacted with polyphosphoric acid as described therein, there are obtained the following 2-[4'-(2-chloroethoxy)phenyl-5-substituted benzofurans~
2-[4'-(2-chloroethoxy)phenyl]-5-bromobenzofuran ~~2-[4'-(2-chloroethoxy)phenyl]-5-n-butoxybenzofuran 2-[4'-(2-chloroethoxy)phenyl~-5-t-butylbenzofuran 2-[4'-(2-chloroethoxy)phenyl]-5-nitrobenzofuran 2-14'-(2-chloroethoxy)phenyl]-5-trifluoromethylbenzcfuranO
Acylation of a 5-substituted benzofuran listed 3~above with 3,5-dime~hylbenzoyl chloride as described i~
the procedure of Example 11 followed by treatment of the l acylated benzcfuran product thus obtained wlth diethylamine by the prcceiure cf Example 25 gives the following compoullds of this lnvent:i.on 5-bromo~2. ~4l~(2-diethylaminoethoxy)phenyl]-3-(3'~5'~dimethy1.benzoyl)benzo~uran 5-n-butoxy~2~4 7 C ~2~dlethyl8mi.noethoxy~phenyll-3-(3'~5' d~methylbenzoyl)benzofuran 5-n-butyl 2-[4'-(2-diethylaminoethoxy)phenyl~-3-(3',5'-dimethylbenzoyl)benzofuran 2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',5~-dimethylbenzoyl)-5-nitrobenzofuran 2-[4'-(2-d~ethylaminoethoxy)phenyl]-3O(3~,5'-dimethylbenzoyl)-5-trifluoromethylbenzofuranO

Substitutlon of an equivalent amount of 2-m-hydroxyphenyl-3-(3' 9 5'-dimethylbenzoyl)benzofuran in the procedure of Example 26 for 2~p~hydroxyphenyl-3-p-methyl-benzoylbenzofuran followed by opening of the epcxy compound thus formed with isopropylamine as described in Example 25 ?.0 gives 2-13'-~2-hydroxy-3-isopropylamlnopropoxy)phenyl~-3-(3',5'-dimethylbenzoyl)benzcfuranO
In a similar manner9 2-L2'-(2-hydroxy-3-isopr aminopropoxy)phenyl]-3-(4'~methylbenzoyl)benzofuran ~s prepared when 2-o-hydroxyphenyl-3-(4'-methylbenzoyl)benzofuran 2~ is used as the ~tarting materialO

2-(4'-Chlorobenzoyl)-3-[4 r _ ( 2~hydroxy-3-isopropylaminopropoxy)~
phenyl]benzo ~
When 3-P-methoxyphenylbenzofuran was acylated with p-chlorobenzoyl chloride a~ described in the procedur~ of Example l, 2~-chlorobenzoyl-3-p~methoxyphenylbenzofuran was obtained.

lOS3673 Demethylation o 2-p-chlorobenzoyl-3-p-methoxy-phenylbenzofuran as previosly described followed by substi-tution of the 2-p-chlorobenzoyl-3-p-hydroxyphenylbenzofuran thus formed in the procedure of Example 26 for 2-_-hydroxy-phenyl-3-p-methylbenzoylbenzofuran with subsequent opening of the epoxy compound thus obtained with isopropylamine as described hereinabove gave the title compound, which was con-verted to the corresponding hydrochloride salt by the pro-cedure described in Example 1, m.p. 198-202.

3-(3',5'-Dimethylbenzoyl)-2-[4'-(2-N-piperidinoethoxy)phenyl]-enzofuran A. Reaction of 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran with piperidine as described in Example 11 gave the title compound.
The title compound was converted to the correspond-ing hydrochloride salt by the procedure of Ex~mple 1, m.p.
192-194.
B. An aqueous solution of 2--N-piperidinoethyl chloride hydrochloride was made basic by addition of aqueous sodium hydroxide solution. The solution was extracted with ether and the extract was dried (MgSO4) and concentrated to give 2-N-piperidinoethyl chloride.
3-(3',5'-Dimethylbenzoyl)-2-_-hydroxyphenylbenzo-furan (1.2 g., 35 mmol.) was dissolved in 50 ~1. of 3-penta-none and 2 g. of potassium carbonate and a little potassium iodide were added. 2-N-Piperidinoethyl chloride (0.6 g., 4 mmol.) was added and the reaction mixture was refluxed for 12 hours. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound as an oil which was dis-solved in ether and converted to the corresponding hydro-chloride salt by addition of an ethereal solution of hydro-chloric acid.

3-(3',5'-Dimethylbenzoyl)-2-[~'-(3-N-piperidinopropoxy)-phenyl]benzofuran A mixture of 3.0 g. of 3-(3',5'-dimethylbenzoyl)-2-~-hydroxyphenylbenzofuran, 5 g. of potassium carbonate and 25 ml. of 1,3-dibromopropane in 100 ml. of 3-pentanone was heated at 100 for 12 hours. The reaction mixture was fil-tered and the filtrate was evaporated. The residue was dis-solved in hot ethanol from which solution precipitated 2-~4'-(3-bromopropoxy)phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran, m.p. 102-104.

Substitution of 2-[4'-(3-bromopropoxy)phenyl]-3-(3!,5'-dimethylbenzoyl)benzofuran in procedure A of Example 42 in place of 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethyl-benzoyl)benzofuran gav~ the title compound.
The title compound was converted to the correspond-ing hydrochloride salt by the pro~edure of Example 1, m.p.
188~190.

3-(3',5'-Dimethylbenzoyl)-2-[4'-(2-N-morpholinoethoxy)phenyl]
benzofuran Use of morpholine in place of piperid~ne in pro-cedure A of Example 42 gave the title compound.
The title compound was converted to the correspond-int hydrochloride salt by the procedure of Example 1, m.p.
171-173.

3-(3',5'-Dimethylbenzoyl)-2-(4'-~2-N-(4-methylpiperazino)-ethoxy]phenyl)benzofuran Substitution of N-methylpiperazine for piperidine in procedure A of Example 42 gave the title compound.
The title compound was converted to the correspond-ing hydrochloride salt by the procedure of Example 1, m.p.
175-178.
Similarly, 3-(3'j5'-dimethylbenzoyl)-2-(4'-[2-N-(4-ethyl-, 4-propyl- and 4-butylpiperazino)ethoxy]phenyl) benzofuran are prepared by use of the corresponding N-(lower alkyl)-piperazine in place of N-methylpiperazine.

3-(3',5'-Dimethylbenzoyl)-2-[4'-(2-N-pyrrolidinoethoxy)phenyl]-benzofuran Use of pyrrolidine in procedure A of Example 42 in place of piperidine gave the title compound.

The title compound was converted to the correspond-ing hydrochloride salt by the procedure of Example 1, m.p.
160-163.

3-(3'!5'-Dimethylbenzoyl)-2-[4'-(2-N-perhydroazepinoethoxy) phenyl]benzofuran Substitution of perhydroazepine in procedure A of Example 42 for piperidine gave the title compound.
The title compound was converted to the correspond-ing hydrochloride salt by the procedure of Example 1, m.p.
174-177.

Acylation of a 5-substituted benzofuran listed below, prepared as described hereinabove:
2-[4'-(2-chloroethoxy)phenyl]-5-methoxybenzofuran 2-[4'-(2-chloroethoxy)phenyl]-5-bromobenzofuran 2-14'-(2-chloroethoxy)phenyl]-5-n-butoxybenzofuran 2-[4'-(2-chloroethoxy)phenyl]-5-t-butylbenzofuran 2-14'-(2-chloroethoxy)phenyl]-5-nitrobenzofuran 2-14'-(2-chloroethoxy)phenyl]-5-trifluoromethyl-benzofuran with 3,5-dimethylbenzoyl chloride as described in the pro-cedure of Example 11 followed by treatment of the acylated benzofuran product thus obtained with piperidine by procedure A of Example 42 gives the following compounds of this inven-tion, respectively:
3-(3',5'-dimethylbenzoyl)-5-methoxy-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran 5-bromo-3-(3',5'-dimethylbenzoyl)-2-[4'-(2-N-piper-idinoethoxy)phenyl]benzofuran 5-_-butoxy-3-(3',5'-dimethylbenzoyl)-2-[4l-(2-N-piperidinoethoxy)phenyl]benzofuran 5-t-butyl-3-(3',5'-dimethylbenzoyl)-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran 3-(3',5'-dimethylbenzoyl)-5-nitro-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran 3-(3',5'-dimethylbenzoyl)-2-[4'-(2-N-piperidino-ethoxy)phenyl]-5-trifluoromethylbenzofuran.

When a substituted benzofuran listed below:
5-chloro-3-(3',5'-dimethylbenzoyl)-2-p-hydroxy-phenylbenzofuran 4-chloro-3-(3',5'-dimethylbenzoyl)-2-_-hydroxy-phenylbenzofuran

6-chloro-3-(3',5'-dimethylbenzoyl)~2-_-hydroxy-phenylbenzofuran

7-ethyl-3-(3',5'-dimethylbenzoyl)-2-_-hydroxy-phenylbenzofuran 5-fluoro-3-(3',5'-dimethylbenzoyl)-2-_-hydroxy-phenylbenzofuran 5-methyl-3-(3',5'-dimethylbenzoyl)-2-_-hydroxy-phenylbenzofuran is used in procedure ~ of Example 42 in place of 3-(3',5'-dimethylbenzoyl)-2-p-hydroxyphenylbenzofuran, the following compounds of this invention are obtained, respectively:
5-chloro-3-(3',5'-dimethylbenzoyl)-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran 4-chloro-3-(3',5'-dimethylbenzoyl)-2-l4'-(2-N-piperidinoethoxy)phenyl]benzofuran 6-chloro-3-(3',5'-dimethylbenzoyl)-2- I 4'-~2-N-piperidinoethoxy)phenyl]benzofuran 3-13',5'-dimeihylbenzoyl)-7-ethyl-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran 3-(3',5'-dimethylbenzoyl)-5-fluoro-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran 3-(3',5'-dimethylbenzoyl)-5-methyl-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran.

Reaction of a hydroxyphenyl benzofuran listed below, prepared as described hereabove;
2-_-hydroxyphenyl-3-~-methylbenzoylbenzofuran 3-benzoyl-2-_-hydroxyphenylbenzofuran 3-~-chlorobenzoyl-2-_-hydroxyphenylbenzofuran 3-(3',5'-dichlrobenzoyl)-2-p-hydroxyphenylbenzo-15 furan 2-p-hydroxyphenyl-3-(3',4',5'-trimethylbenzoyl)-benzofuran 3-~-bromobenzoyl-2-~-hydroxyphenylbenzofuran 3-m-fluorobenzoyl-2-_-hydroxyphenylbenzofuran 3-(3',5'-dibromobenzoyl)-2-_-hydroxyphenylbenzo-furan 3-(2',3'-difluorobenzoyl)-2-_-hydroxyphenylbenzo-furan 3-(2',3',5'-trichlorobenzoyl)-2-_-hydroxyphenyl-benzofuran 2-(2'-hydroxybenzyl)-3-(4'-methylbenzoyl)benzofuran 3-(3',5'-diethylbenzoyl)-2-hydroxyphenylbenzofuran 2-~-hydroxyphenyl-3-(4'-_-propylbenzoyl)benzofuran 3-(4'-t-butylbenzoyl)-2-~-hydroxyphenylbenzofuran 3-(3',5'-di-t-butylbenzoyl~-2-_-hydroxyphenylbenzo-furan ~ - 44 -with 2-N-piperidinoethyl chloride by procedure B o~ Example 42 gives the following compounds of this invention, respec-tively:
3-(4'-methylbenzoyl)-2-[4'-(2-N-piperidinoethoxy)-phenyl]benzofuran 3-benzoyl-2-[4'-(2-N-piperidinoethoxy)phenyl]benzo-furan 3-(4'-chlorobenzoyl)-2-[4'-(2-N-piperidinoethoxy)-phenyl]benzofuran 3-(3',5'-dichlorobenzoyl)-2-[4'-(2-N-piperidino-ethoxy)phenyl]benzofuran 2-[4'-(2-N-piperidinoethoxy)phenyl]-3-(3',4',5'-trimethylbenzoyl)benzofuran 3-(4'-bromobenzoyl)-2-t4'-(2-N-piperidinoethoxy)-phenyl]benzofuran 3-(3'-fluorobenzoyl)-2-t4'-(2-N-piperidinoethoxy)-phenyl]benzofuran 3-(3',5'-dibromobenzoyl)-2-~4'-(2-N-piperidinoeth~
oxy~phenyl~benzofuran 3-(2',3'-difluorobenzoyl)-2-[4'-(2-N-piperidino-ethoxy)phenyl]benzofuran 2-[4'-(2-N-piperidinoethoxy)phenyl]-3-(2',3',5l-trichlorobenzoyl)benzofuran 3-(4'-methylbenzoyl)-2-[2~--(2-N-piperidinoethoxy)-phenyl]benzofuran 3-(3',5'-diethylbenzoyl)-2-t4'-(2-N-piperidino-ethoxy)phenyl]benzofuran 2-[4'-(2-N-piperidinoethoxy)phenyl]-3-(4'-n-propyl-benzoyl)benzofuran - 44a -1 3-(4'-t-butylbenzoyl)-2-[4'-(2-N-piperidinoethoxy)-phenyllbenzofuran 3-(3~C5!~:di~t butylbenzoyl~-2-[4'-(2-N-piperidino-ethoxy)phenyl]benzofuran~

3-p-Anisoyl-2~[4~(2 N piperidinoethoxy)phenyl]benzofuran When pDanisoyl chloride and 2-[4'-(2-bromoethoxy)-phenyl]benzofuran are reacted by the procedure described in Example 11 and the 2-[4'-(2-bromoethoxy)phenyl]-3-p-anisoylbenzofuran thus obtained is treated with piperidine as described in Example 11, the title compound is obtained.

Reaction of a benzofuran listed below, prepared as in Examples 11, 12 and 23:
2-[4'-(2-bro ethoxy)phenyl]-3-(3',5'-dimethoxy-benzoyl)benzofuran 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethyl-4'-methoxybenzoyl)benzofuran 2-[4'-(2-bromoethoxy)phenyl]-3-(3',4'-diethoxy-?O benzoyl)benzofuran 2-[4'-(2-bro ethoxy)phenyl~-3-(3'-n-propoxybenzoyl)-benzofuran 2-[4'-(2-bromoethoxy)phenyl]-3-(4'-n-butoxybenzoyl)-benzofuran 2S 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-di-t-butoxy-benzDyl)benzofuran 2-[4'-(2-bromoethoxy)phenyl]-3-(3',41,5'-trimethoxy-benzoyl)benzofuran 2-[4'-(2-bromoethoxy)phenyl]-3-(2',5'-dimethoxy-4'-methylbenzoyl)benzofuran with piperidine as described in the procedure of Example 11gi~es the following compounds, respectively:

1 3-(3'95t-dimethoxybenzoyl)-2-~4'-(2~N-piper~dino-ethoxy)phenyl]benzofuran 3-(3' 9 5~-dlmethyl-4'-methoxybenzoyl)-2-[4'-(2-N-piperidinoethoxy)phenyl]benzofuran 3-~3~,4' dlet~oxybenzoyl)-2-[4' (2 N7piperidino-ethoxy)phenyl]benzofur~n 2-141-(2~N piperidinoethoxy)phenyl]-3-(3'-_-propoxybenzoyl)benzofuran 3-(4'-n-butoxybenzoyl)-2-[4'-(2-N-piperidino-ethoxy)phenyl]benzofuran 3-(3' 9 5'-di-t-butoxybenzoyl)-2-[4'-(2-N-piperidino ethoxy)phenyl]benzofuran 2-14'-(2-N-piperidinoethoxy)phenyl]-3-(3',4',5'-trimethoxybenzoyl)benzofuran 3-(2',5~-dimethoxy-4'-methylbenzoyl)-2-14~-(2-N-piperidinoethoxy)phenyllbenzofuranO

Reaction of the following hydroxyphenyl benzofur~ns prepared hereinabove~
?0 2-benzoyl-3-p-hydroxyphenylbenzofuran 3-p-hydroxyphenyl-2-(3',5'-dimethylbenzoyl)benzofuran 3-p-hydroxybenzyl-2-(3',5'-dimethylbenzoyl)benzofuran with 2-N-piperidinoethyl chloride as described in procedure B
of Example 42 gives the compounds of thi~ invention listed 2~ below:
2-benzoyl-3-14'-(2-N-piperidinoethoxy)phenyl]benzofuran 2-(3',5'-dimethylbenzoyl)-3-[4'-(2-N-piperidinoethoxy)-phenyl]benzofuran 2-(3',5'-dimethylbenzoyl~-3-14'-(2-N-piperidinoethoxy)-benzyl]benzofuran.

Opening of ~he epoxide function of the substituLed benzofurans listed belowO
3-benzoyl-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran 2-[41 ~293~epoxypropoxy)phenyl~-3~(4l-methylbenzoyl)~
benzofuran 3 (4Y-chlcrobenzoyl)-2-[4Y-(2,3-epoxypropoxy)o phenyl]benzofuran 3-(3'-chlorobenzoyl)-2-[4'-(2,3-epoxypropoxy)-phenyl]benzofuran 3-(4'-chlorobenzoyl)-2-[3'-(2,3-epoxypropoxy)-phenyl]benzofuran 2-[4'-(2,3-epoxypropoxy)phenyl]-3-(3',5'-dimethyl-benzoyl)benzofuran 2-benzoyl-3-[4'-(2,3-epoxypropoxy)phenyljbenzofuran 3-[4'-(2,3-ep~xypropoxy)benzyl]-2-(3',5'-dimethyl-benzoyl)benzofuran with piperidine according to the procedure described in Example 25 gives the following compounds of this invention, ?O respectively:
3-benzoyl-2-~4'-(2-hydroxy-3-N-piperidinopropoxy)~
phenyl]benzofuran 2-[4'-(2-hydroxy-3-N-piperidinopropoxy)phenyl]-3-(4'-methylbenzoyl)benzofuran 3-(4'-chlorobenzoyl)-2-[4'-(2-hydroxy-3-N-piperidinc-propoxy)phenyl]benzofuran 3-(3'-chlorobenzoyl)-2-[4'-(2-hydroxy-3-N~piperidino-propoxy)phenyl]benzofuran 3-(4'-chlorobenzoyl)-2-[3'-(2-hydroxy-3-N-piperidino-propoxy)phenyl]benzofuran lOS3673 1 3-(3~5~-dLmethyl.benzoyl)-2 [4'-(2hydroxy-3-N-piperidlnopropoxy)phenyl~benzofuran 2-benzoyl-3-~4'~(2-hydroxy-3 N-piperidinopropoxy)~
phenyl]benzofuran 2 (319~'~dimethylbenzcyl)~3 ~41 (2~hydroxy 3~N~
piperidinopropoxy)benzyl~benzofuranO

By using morpholine9 N-methylpiperazine9 pyrrolidine or perhydroazepine in the proredures of Examples 48, 52 and 54 in place of piperidine, the corres-ponding 2-N-morpholinoethoxy, 2-N-(4-methylpiperazino)ethoxy 2-N-pyrrolidinoethoxy, 2-N-perhydroazepinoethoxy, 2-hydroxy-3-N-morpholinopropoxy, 2-hydroxy-3-N-(4-methylpiperarino)-propoxy9 2-hydroxy-3-N-pyrrolidinopropoxy9 and 2-hydroxy-3-N-perhydroazepinopropoxy benzofurans are respectively obtained~
EXAMP_LE 56 Additlon of an ethereal solution of oxalic acid to a solution of 2-[4'-(3-diethylaminopropoxy)phenyl]~3-(4'~
methylbenzoyl)benzofuran in ether gives the oxalate salt~
The correcponding hydrochloride salt may be prepared from the oxalate salt by passage of a solution of 2-[4'-(3-diethylaminopropoxy)phenyl]-3-(4'-methylbenz~
benzofuran oxalate in ethanol through an Amberlite IRA-401 chloride ion exchange column.
~S In a similar manner9 other acid addition salts may be prepared.

1053~o~73 .
In~redients A unts 2-[4'-(2-Diethylaminoethoxy)phenyl]-3-(3' 9 5~-dimethylbenzcyl~benzofuran100 mg O
Calcium su'lfate dihydra te 150 mgO
Sucrose 25 mgO
Starch 15 mgO
Talc 5 mg.
Stearic acid 3 mgO
lO The sucroseg calcium sulfate dihydrate and 2-[4~-(2-diethyl-aminoethoxy)phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran are thoroughly mixed and granulated with 10~ gelatin ~olutionO The wet granules are screened9 dried and then mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

In~redients Amounts 2-[4'-(2-Diethylaminoetho~y)phenyl~-3 (3',5'-dimethylbenzoyl)benzofuran150 mg.
Magnesium stearate 5 mg.
Lactose 100 mg.
The ingredients are mixed and filled into a hard gelatin capsule O
Similarly; the other substituted benzofurans disclosed herein may be formulated into tablets and capsules 2S by the procedures of E~amples 57 and 58~

The compositions prepared as in Examples 57 and 58 are administered orally to a sub~ect in need of coronary vasodilator activity within the dose ranges given hereabove~

1 ~XAl~PLE 59 2~ 3-Dfethylaminopropoxy3phenyl~-3-(3'~5'-dimethylbenzoyl)-benzofuran Reaction of 2-_-hydroxyphenyl-3-~3',5'-dlmethylbenzoyl~benzofuran wlth 3-diethylaminopropyl chloride as described in ~he procedure of Example 7 gave the title compound which was converted to the corresponding hydrochloride salt as described hereinabove9 mOp. 114-121o 2 ~ ~4 1 ~ (2 -Diethylaminoethoxy~phenyl~--3- (2 1 ~ 5 1 -dimethylbenzoyl)-benzofuran 295-Dimethylbenzoyl chloride was prepared from reaction of 2,5-dimethylbenzoic acid and thionyl chloride ~s described in Example 8~
Substitution of an equivalent amount of 2,5-dimethylbenzoyl chloride in the procedure of Example 7 for 3,5-dimethylbenzoyl chloride followed by demethylation of 2-p-methoxyphenyl- 3~ (21 ~ 51 -dimethylbenzoyl)benzofuran and reaction of the product thus formed with 2-diethylaminoethyl chloride as described therein gave the title compound.
The title compound was converted to the corres-ponding hydrochloride salt as previously described, m.pO
150-153 ~

2-[4'-(3-Dimethylaminopropoxy~phenyl]-3-(3l~5'-dimeth~lbenzoyl) benzofuran . _ Reaction of 2-p-hydroxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran with 3-dimethylaminopropyl chloride according to the procedure described in Example 7 gave the title compound~

1 The title compound w~s conv~rted to the correspondlng hydrochloric acid salt as described in Example 7~ m~p~ 14~-150o 3-(3',5'-~ieth~Lbenzoy~ 4'.-~2-N-p~rrolidinoethoxy)phenyll-benzofuran Acylation of 2-t4'-(~-bromoethoxy~phenyl~benzofuran with 3,5-diethylbenzoyl chloride as described herei~above gave 2-[4'-(2-bromoethoxy~phenyl~-3-(3',5'-diethylbenzoyl~-benzofuran.
Reaction of 2-[4'-~2-bromoethoxy)phenyl]-3-(3',5'-diethylbenzoyl)benzofuran with pyrrolidine as described in Example 11 gave the title compoundr The title compound was converted to the correspoading hydrochloride salt by the procedure of Example 1, m~p. 157-159o ~OS3673 ~ n additlon, this invention includes the benzothiophene compounds corresponding tO the benzofurans of formula I and represented by the following structural formula R2 ~ ~ (CH2)n'R3 X'lrI
or a pharmaceutically acceptable acid addition salt thereof, in which the terms Rl, R2 9 R3 and n are defined as in formula 1 Preferred compounds of formula XIII are 2-r4'-(2-diethylaminoethoxy)phenyl~-3-(3',5'-dimethylbenzoyl)benzo-lS thiophene, 5-chloro-2-[4'-(2-diethylaminoethoxy)phenyll-3-(3'~5'-dimethylbenzoyl)benzothiophene and 3-[4'-(2-diethylaminoethoxy)phenyl~-2-(3',5'-dimethylbenzoyl)benzo-thiophene~

The compounds of formula XIII have coronary vssodilator activity and are useful in the treatment of angina pectorisO The compounds may also be useful as hypotensive agents. Administration and formulation of these compounds are as described above for the corresponding compounds of formula I.

The benzothiophenes of formula XIII are prepared by methods similar to those used to prepare the benzofurans of formula I described above and illustrated in Schemes 1 and 2 Preferably, a methoxyphenyl or methoxybenzyl benzothiophene is acylated as previously described to give a methoxyphenyl- or methoxybenzyl-benzoyl benzothiophene which is then demethylated to the corresponding hydroxy compoundO Reaction of the hydroxyphenyl- or hydroxybenzyl-benzoyl benzothiophene with d s~bsti~uted aminoaLkyl halide or tosylate~ a dlhaloalkane fo~lowed b~ treatment of the produce formed with an amine of the formula R4R5NH where R4 and ~5 are defined as above o~ with an epihalohy~rin ~ollowzd by ring cpening with an amine ~R4R5NH) g~ves the benzothiophene compounds of formula XIII~
The methoxyphenyl or methoxybenzyl substituted benzothiophene nuclei are either known to the art or are prepared by methods sim~lar to those used to prepare the corresponding benzofuran nucleiO For example, these starting materials are prepared by addition of a phenyl magnesium halide to a cyanobenzothiophene followed by hydrolysis and reduction of the produet with a reducing agent such as hydrazine hydrate or by reaction of a substituted thiophenol with a-bromo-p-methoxyacetophenone with subsequent cyclization of the product thus formed, for example by treatment with polyphosphorlc acidO
o Whe~ -C-Rl is in the 3-position and R6 is hydrogen, the benzothiophenes corresponding to formula XIII are prepared as shown in Scheme 4 by reaction of a substituted thiophenol with a bromomethyl chloroalkoxyphenyl or benzyl ketone followed by cyclization of the intermediate formed.
The following examples illustrate the invention but are not to be construed as limiting the scope thereofO

2-[4'-(2-Diethylaminoethoxy)phenyl~-3-(3'.5'-dimethylbenzoYl)-benzothiophene W~en 2-p-methoxyphenylbenzothiophene was acylated with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 19 3-~3',5'-dimethylbenzoyl~-2-(4'-methoxyphenyl)-ben~oth~ophene was cbtained.
Demethylation of ~-~3',5'-dimethylbenzoyl)-2-(4'-methoxyphenyl)benzothiophene with pyridine hydrochloride as previously descrlbed followed by reaction of the 3-(3',5'-dimethylbenzoyl)-2-~4'-hydroxyphenyl)benzothiophene thus formed with 2-diethylaminoethyl chloride 9 also as described above, gave the title compound, mOp~ 138-142~

2-[4'-(2-Dieth~laminoethoxy)phenyl~-3-(3'~5'-dimethylbenzorl)-benzothiophene When 2-p-methoxyphenylbenzothiophene was acylated with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 1, 3-(3',5'-dimethylbenzoyl)-2-(4'-methoxyphenyl)-benzothiophene was obtainedO
Demethylation of 3-(3',5'-dimethylbenzoyl)-2-(4'-methoxyphenyl)benzothiophene with pyridine hydrochloride as previously described followed by reaction of the 3-(3',5'-dimethylbenzoyl-2-(4'-hydroxyphenyl)benzothiophene thus formed with 2-diethylaminoethyl chloride, also as described above, ga~re the title compound, m pO 138-142 3-[4~-(2-Dieth~laminoethoxy)phenyl]-2-(3~5'-dimethylbenzoyl~-benzothiophene A solution of lloO g~ (O~l molO) of thiophenol and 2209 g. (Ool molO) of a-bromo-p-methoxyacetophenone in 40 ml.
of pyridine is refluxed for four hours. Water is added to the reaction mixture and the solution is extracted with methylene c~loride. The extract is washed with water, dried and evaporated to dryness to give ~-methoxy-a-phenylthioacetophenone.

1 ~-Methoxy-~-phenylthioacetophenone (S0O gO~ 0002 mol ~s heated with 35 gO of polyphosphoric acid and 25 ml. of phosphoric acid at 90-~20 until the reaction is determined to be complete by thin layer chromatography~ ~he mixture is poured into ice-wAter and this mixture is ex~rac~ed with ether, E~aporation of the solven~ gives 3-p-metho2yphenylbenzothio-phenec 3-p-Methoxyphenylbenzothiophene is acylAted with 3,5-dimethylbenzoyl chlor~de as previously described to give 2-(3~,5~-dimethylbenzoyl)-3-p-methoxyphenylbenzothiophene.
Demethylation with pyridine hydrochloride followed by reaction of the hydroxy compuund thus formed with diethylaminoethyl chloride as described above gives the title compound.

S-Chloro-2-14'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-dimethyl-benzoyl)benzothiophene When p-chlorothiophenol is substituted in the procedure of Example 38 for p-methoxyphenol, p-(2-chloroethox~-a-(~-chlorophenoxy)acetophenone i8 obtained.
~ Cyclizstion of p-~2-chloroethoxy)--(p-chlorophenoxy)-acetophenone with polyphosphoric acid as described in Example 38, followed by acylation of the product thus formed with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 11 gives 5-chloro-2-~4'-~2-chloroethoxy~phenyll-3-(3',5'-dimethylbenzoyl)benzothiophene.
Reaction of 5-chloro-2-[4'-~2-chloroethoxy)phenyl-3-(3',5'-dimet~ylbenzoyl)benzothiophene with diethylamine by the procedure of Example 25 gives the title compound.

10536~3 3-(3' 5'-Dimethylbenzoyl~-2-~4'-(2-N-piperidinoethoxy)phenyl~-q benzothiophene Reaction of 3-(3',5'-dimethylbenzoyl)-2-(4'-hydroxy-phenyl~benzothiophene and 2-N-piperidinoethyl chloride acccrding to the proccdure described in Example 42-B gives the title compound~

Ingredient 8 AmoURtS
10 5-Chloro-2-l4'-(2-diethylamino-ethoxy)phenyl]-3-(3',5'-di~ethyl-benzoyl)benzothiophene 150 mg Mhgnesium stearate 5 mg.
Lactose 100 mg.
The ingredients are mixet and filled into a hard gelatin capsule.

Claims (23)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula:

or a pharmaceutically acceptable acid addition salt thereof, in which:
R1 is phenyl, halophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, di-lower alkylphenyl, tri-lower alkylphenyl, lower alkoxyphenyl, di-lower alkoxyphenyl, tri-lower alkoxyphenyl, lower alkyl-di-lower alkoxyphenyl or lower alkoxy-di-lower alkylphenyl;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, nitro or trifluoromethyl;

R3 is ;

R4 is hydrogen, methyl, ethyl or propyl and R5 is methyl, ethyl or propyl or R4 and R5 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, N-(lower alkyl)piperazine, morpholine or perhydroazepine ring;
R6 is hydrogen or hydroxy;
m is 0 or 1 when R6 is hydrogen and 1 when R6 is hydroxy;

n is 0 or 1; and Z is oxygen or sulfur;
comprising converting a compound of the formula:

where R2, n and Z are defined as above, to an intermediate selected from the following formulas:

, (a) , (b) or (c) (d) where R1, R2, R4, R5, n and Z are defined as above;
R1' is phenyl, halophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, di-lower alkylphenyl or tri-lower alkylphenyl;
p is 2 or 3; and X is halo;
and then, to prepare compounds in which R6 is hydrogen, acylating intermediate (a) or its corresponding acid addition salt with an acid chloride of the formula where R1 is defined as above; treating intermediate (b) with an amine of the formula R4R5NH where R4 and R5 are defined as above;
or reacting intermediate (c) with a compound of the formula R4R5N-(CH2)p-Y where R4, R5 and p are defined as above and Y is halo or a leaving group such as tosyl or mesyl; or, to prepare compounds in which R6 is dydroxy, reacting intermediate (d) with an amino of the formula R4R5NH
where R4 and R5 are defined as above; and optionally converting the product to a pharmaceutically acceptable acid addition salt.

2. A process according to claim 1 in which intermediate (a) or its corresponding acid addition salt is acylated with an acid chloride of the formula , where R1 is defined as in claim 1, at from about 0°C. to about 25°C.

3. A process according to claim 1 in which intermediate (b) is treated with an amine of the formula R4R5NH, where R4 and R5 are defined as in claim 1, in a solvent such as refluxing ethanol.

4. A process according to claim 1 in which intermediate (c) is reacted with a compound of the formula R4R5N-(CH2)p-Y, where R4, R5, p and Y are defined as in claim 1, in the presence of base.

5. A process according to claim 1 in which intermediate (d) is reacted with an amine of the formula R4R5NH, where R4 and R5 are defined as in claim 1, under pressure at about 25°C. to about 125°C.

6. A process according to claim 1 in which Z is oxygen.

7. A process according to claim 1 in which Z is sulfur.

8. A process according to claim 6 in which R4 is hydrogen, methyl, ethyl or propyl and R5 is methyl, ethyl or propyl.

9. A process according to claim 6 in which R1 is chlorophenyl, 3,5-dimethylphenyl, 3,4,5-trimethylphenyl, 3,5-dimethoxyphenyl or 3,5-dimethyl-4-methoxyphenyl; R2 is hydrogen or chloro; n is 0; R3 is ;

R4 and R5 are ethyl or together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring and m is 0.

10. A process according to claim 9 in which R4 and R5 are ethyl.

11. A process according to claim 4 for preparing 2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-dimethylbenzoyl)-benzofuran comprising reacting 2-(4'-hydroxyphenyl)-3-(3',5'-dimethylbenzoyl)benzofuran with 2-diethylaminoethyl chloride.

12. A process according to claim 4 for preparing 5-chloro-2-[4'-(2-diethylaminoethoxy)phenyl]-3-(3',5'-dimethyl-benzoyl)benzofuran comprising reacting 5-chloro-2-(4'-hydroxyphenyl)-3-(3',5'-dimethylbenzoyl)benzofuran with 2-diethylaminoethyl chloride.

13. A compound of the formula:

or a pharmaceutically acceptable acid addition salt thereof, in which:
R1 is phenyl, halophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, di-lower alkylphenyl, tri-lower alkylphenyl, lower alkoxyphenyl, di-lower alkoxyphenyl, tri-lower alkoxyphenyl, lower alkyl-di-lower alkoxyphenyl or lower alkoxy-di-lower alkylphenyl;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, nitro or trifluoromethyl;

;

R4 is hydrogen, methyl, ethyl or propyl and R5 is methyl, ethyl or propyl or R4 and R5 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, N-(lower alkyl)piperazine, morpholine or perhydroazepine ring;
R6 is hydrogen or hydroxy;
m is 0 or 1 when R6 is hydrogen and 1 when R6 is hydroxy;
n is 0 or 1; and Z is oxygen or sulfur, when prepared by the process of claim 1 or any obvious chemical equivalent thereof.

14. A compound according to claim 13 in which R6 is hydrogen, when prepared by the processes of claims 2 or 3 or any obvious chemical equivalent thereof.

15. A compound according to claim 13 in which R6 is hydrogen and R1 is phenyl, halophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, di-lower alkylphenyl or tri-lower alkylphenyl, when prepared by the process of claim 4 or any obvious chemical equivalent thereof.

16. A compound according to claim 13 in which R6 is hydroxy, when prepared by the process of claim 5 or any obvious chemical equivalent thereof.

17. A compound according to claim 13 in which Z
is oxygen, when prepared by the process of claim 6 or any obvious chemical equivalent thereof.

18. A compound according to claim 13 in which Z
is sulfur, when prepared by the process of claim 7 or any obvious chemical equivalent thereof.

19. A compound according to claim 13 in which Z is oxygen, R4 is hydrogen, methyl, ethyl or propyl and R5 is methyl, ethyl or propyl, when prepared by the process of claim 8 or any obvious chemical equivalent thereof.

20. A compound according to claim 13 in which Z is oxygen, R1 is chlorophenyl, 3,5-dimethylphenyl, 3,4,5-trimethyl-phenyl, 3,5-dimethoxyphenyl or 3,5-dimethyl-4-methoxyphenyl; R2 is hydrogen or chloro; n is 0; R3 is ;

R4 and R5 are ethyl or together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring and m is 0, when prepared by the process of claim 9 or any obvious chemical equivalent thereof.

21. A compound according to claim 13 in which Z is oxygen, R1 is chlorophenyl, 3,5-dimethylphenyl, 3,4,5-trimethyl-phenyl, 3,5-dimethoxyphenyl or 3,5-dimethyl-4-methoxyphenyl; R2 is hydrogen or chloro; n is 0; R3 is ;

R4 and R5 are ethyl, when prepared by the process of claim 10 or any obvious chemical equivalent thereof.

22. The compound 2-[4'-(2-diethylaminoethoxy)-phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran, when prepared by the process of claim 11 or any obvious chemical equivalent thereof.

23. The compound 5-chloro-2-[4'-(2-diethylaminoethoxy)-phenyl]-3-(3',5'-dimethylbenzoyl)benzofuran, when prepared by the process of claim 12 or any obvious chemical equivalent thereof.