IE922227A1 - Benzofuran derivatives - Google Patents

Abstract

The invention relates to compounds represented by general formula I below, pharmacologically acceptable salts of the same and pharmaceutical compositions containing them, <IMAGE> in which R1 represents hydrogen, halogen or alkyl, R2 represents alkoxy carbonyl, aralkyloxycarbonyl, carboxy, hydroxyalkyl or acyloxyalkyl, Y represents >CHOH, >CHOZ, >CO or >CH2, and Z represents acyl. The pharmaceutical compositions according to this invention are effective for the prevention and treatment of arteriosclerosis, ischaemic heart disease, cerebral infarcts and stenosis after PTCA operations. [PT100667A]

Description

----, ~ vx^jnpciny organised under the Kisshoin Nishinosho Monguchicho, Minami-ku, Ky fi - 1 Benzofuran Derivatives The present invention relates to benzofuran derivatives, their preparation and pharmaceutical compositions containing them.

Lipoprotein, or Lp(a), was first found in the blood of patients suffering from arteriosclerosis and is believed to be a fatal factor for arteriosclerosis. Today, it is known as a kind of liprotein having apoprotein B-100 (the same as in the LDL molecule) at the centre to which apoprotein (a) is bonded, (cf. Gendai Iryou, vol.22, no.7, 1990).

Lp(a) is detected only in primates including human being. Therefore, it is difficult to investigate by animal experiments using rodents and the like, whereby the investigation of its behaviour in animals has been delayed.

Lp(a) has the same fundamental structure as plasminogen and, accordingly, Lp(a) is believed to participate in the inhibition of decomposition of fibrin in blood resulting in the inhibition of the dissolution of thromboses.

Lp(a) is distributed in areas where arteriosclerosis may take place in higher concentrations than other areas whereby Lp(a) is presumed to directly participate in arteriosclerosis. In addition, the concentration of Lp(a) in blood is not affected by conventional hypolipemic drugs and arteriosclerosis is observed even in the people with low lipid level. Consequently, the relation between Lp(a) and arteriosclerosis is believed to be important. - 2 It is known that the Lp(a) of patients suffering from arteriosclerosis and hyperlipemia does not lower in the blood by a diet therapy. It is known that high Lp(a) concentration in blood is dominated and decided by genetic factors. As a result it may be concluded that Lp(a) is directly related to arteriosclerosis and is based upon the inhibitory action of dissolution of thrombosis.

Since it is likely that Lp(a) is a lipoprotein which accelerates arteriosclerosis, there have been attempts to prevent those disease by curing diseases with high Lp(a) concentration in blood (cf. Arteriosclerosis, vol.10, no.5, pages 672-679, 1990). Nicotinic acid has been known as a substance which lowers the concentration of Lp(a) in the blood though it gives adverse reactions such as flushing and, moreover, the main action is not particularly satisfactory.

It is known that, besides the lowering action of Lp(a) concentration, substances which lower the lipid concentration in blood are useful for the therapy of arteriosclerosis. Accordingly, it is presumed that, if there is a substance which lowers the Lp(a) concentration and also lowers the lipid level in blood, such a substance would be useful in the therapy of the above-given diseases.

It has now been found, in accordance with the present invention, that certain benzofuran derivatives, as hereinafter defined, possess activity to reduce the level of Lp(a) in the blood. - 3 According to the invention, therefore, these are provided, as new compounds, benzofuran derivatives, and salts thereof, of the formula: in which r7 is a hydrogen or halogen atom or an alkyl group; R2 is an alkoxycarbonyl, an alkyloxycarbonyl, carboxy, hydroxyalkyl or acyloxyalkyl group; and Y is a group - CH0H-, -CH0Z-, -CO- or -CH2_ (in which Z is an ayl group) .

When Rl is a halogen atom it may be a fluorine, chlorine, bromine or iodine atom; and when an alkyl group it may be a Cj _ c7 straight or branched alkyl group such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, iso-hexyl, n-heptyl or isoheptyl group. When R2 is alkoxycarbonyl the alkyl moiety may be as for R^ above.

When R2 is an aralkyloxycarbonyl group it preferably has 8 to 14 carbon atoms and examples include benzyloxycarbonyl, 2- methylbenzyloxycarbonyl, 3-methylbenzyloxycarbonyl, 4-methyIbenzyloxycarbonyl, phenethyloxycarbonyl, 3- phenylpropoxycarbonyl, 1-naphthylmethoxycarbonyl, 2- naphthylmethoxycarbonyl, 2-(l-naphthyl)-ethoxycarbonyl and 3- (l-naphthyl)propoxycarbonyl groups . - 4 Preferred examples of R2, when a hydroxyalkyl group, are straight chain or branched groups having 1-7 carbon atoms, such as, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3- hydroxypropyl, 1-hydroxypropyl, 4-hydroxybutyl, 1-hydroxybutyl, -hydroxypentyl, 1-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyhexyl, 7-hydroxyheptyl and 1-hydroxyheptyl groups. Preferred acyloxyalkyl groups are O-acyl derivative of the above hydroxyalkyl, to be preferred acyl groups having with 1 to 11 carbon atom(s), such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, sec-valeryl, benzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4- methylbenzoyl, 1-naphthoyl and 2-naphthoyl groups. The preferred acyl group expressed by Z is similarly one with 1 to 11 carbon atom(s), examples being as above.

When R2 is a carboxy group the compounds may be used in the free form or in the form of pharmacologically-acceptable salts, e.g. alkali metal salts such as sodium salts and alkaline earth metal salts such as calcium salts.

In addition to the compounds which mentioned in the Examples, examples of compounds of the invention include the following compounds : -tert-Butyl-2-[2-(3-carboxyphenoxy)-l-hydroxye thyl] benzofuran; -tert-Butyl-2-[2-(2-carboxyphenoxy)-l-hydroxye thyl] benzofuran; - 5 5-tert-Butyl-2- [1-( l-hydroxy-2-(4-hydroxymethylphenoxy) ethyl]benzofuran; -tert-Butyl-2-[l-hydroxy-2-(3-hydroxymethylphenoxy)ethyl] benzofuran; 2-[2-(4-Ethoxycarbonylphenoxy)-1-hydroxyethyl]-5-fluorobenzofuran; -Chloro-2-[l-hydroxy-2-(3-propyloxycarbonylphenoxy) ethyl] benzofuran; - Bromo-2-[l-hydroxy-2-(4-isopropyloxycarbonylphenoxy) ethyl] benzofuran; 2-[2-(3-Butoxycarbonylphenoxy)-1-hydroxyethyl]-5-iodobenzofuran; 2- [2-(3-tert-Butoxycarbonylphenoxy)-1-hydroxyethyl]-5-methylbenzofuran; 6- Ethyl-2-[l-hydroxy-2-(2-pentyloxycarbonylphenoxy)ehtyl] benzofuran; 2- [2-(4-Hexyloxycarbonylphenoxy)-1-hyd roxye thyl]-5-propylbenzofuran; 2-] 3-(3-Heptyloxycarbonylphenoxy)-1-hydroxyethyl]-5-isopropylbenzofuran; -Butyl-2-[hydroxy-2-(4-hydroxymethylphenoxy)-ethyl] benzofuran; 2-[1-Hydroxy-2-[ 2-( 1-hydroxyethyl) phenoxy ]e thyl ] -6-pentylbenzofuran; - 6 5- Hexy1-2-[ 1 -hydroxy-2- [4-(3-hydroxypropyl) phenoxy 3 -ethyl ] benzofuran; 6- Heptyl-2-[l-hydroxy-2-(4-( 1-hydroxypropyl) -phenoxy] ethyl] benzofuran; 2- [ 1 -Hydroxy-2-[2-(4-hydroxybutyl) phenoxy] ethyl] -benzo furan; 6-Fluoro-2- ί l-hydroxy-2- [4-( 1-hydroxybutyl) phenoxy ] -ehtyl ] benzofuran; 2-[1-Hydroxy-2-[4-(2-hydroxyethyl)phenoxy] ethyl] -6-methylbenzofuran; -Chloro-2-11 -hydroxy-2- [4-( 1-hydroxypentyl) -phenoxy] ethyl ] benzofuran; -Bromo-2-[ l-hydroxy-2-[3-( 1 -hydroxyhexyl)phenoxy] -ethyl] benzofuran; 2-[l-Hydroxy-2-[2-(6-hydroxyhexyl)phenoxy] ethyl]-5-propylbenzofuran; - Isopropyl-2-[ l-hydroxy-2-[4-( 7-hydroxyheptyl)-phenoxy] ethyl]benzofuran; 6- tert-Butyl-2-[l-hydroxy-2-[4-(l-hydroxyheptyl)-phenoxy] ethy1]benzofuran; -tert-Butyl-2-[2-(4-carboxyphenoxy) ethyl] benzo fur an; -tert-Butyl-2- [2-(4-methoxycarbonylphenoxy) ethyl] benzo furan; 2- [ 2 - (4-Hyd roxyme thyl phenoxy) e thyl ] -5-i s opropylbenzo f ur an; 2- [2-(4-Acetoxymethyl phenoxy) ethyl ]-5-cblorobenzof uran; 2-[l-Acetoxy-2-(4-methoxycarbonyl phenoxy) ethyl] -5-ter t-butyl benzofuran; - 7 2-[ l-Acetoxy-2-(4-carboxyphenoxy)ethyl] -5-tert-butylbenzofuran; 2-[l-Benzoyloxy-2-(4-methoxycarbonylphenoxy)ethyl] -5-tertbutylbenzofuran; 2-[l-Benzoyloxy-2-(4-carboxyphenoxy)ethyl] -5-tert-butylbenzo furan; -tert-Bu tyl-2-[2-(4-methoxycarbonylphenoxy)-1-propionyloxyethyl]benzofuran; -tert-Butyl-2-[2-(4-carboxyphenoxy)-l-propionyloxyethyl] benzofuran; -tert-Butyl-2-[l -butyryl oxy-2-(4-methoxycarbonylphenoxy) ethyl]benzofuran; -tert-Butyl-2-[ 1 -butyryloxy-2-(4-carboxyphenoxy) -ethyl ] benxofuran; -tert-Butyl-2-[2-(4-methoxycarbonylphenoxy)-l-( 1-naphthoyloxy)ethyl]benzofuran; -tert-Bu tyl-2- [2-(4-carboxyphenoxy) -1 -(1 -naphthoyloxy) ehty1]benzo furan; -tert-Bu tyl-2-[2-(4-methoxycarbonylphenoxy) -1-( 2-naphthoyloxy) ethyl]benzofuran; -tert-Butyl-2-[2-(4-carboxyphenoxy)-l-(2-naphthoyloxy) ethyl]benzofuran; -tert-Butyl-2-(4-hydroxymethylphenoxyacetyl)-benzofuran; 2-(4-Acetoxymethylphenoxyacetyl)-5-tert-butylbenzofuran; and 2- [ 1 -Acetoxy-2-(4-acetoxymethylphenoxy) ethyl ] -5-tert-butylbenzofuran. - 8 Compounds in accordance with the invention may be produced by the following reaction scheme:vChem-3" [la] Base -> Reduction ·*> Acylating agent Wolff-Kishner Reduction (Reaction 1) (Reaction 2) Cib] (Reaction 3) Del R1 [H] (Reaction 4) - 9 wherein R^, R2 and Z are as defined above and X is a halogen atom on an alkylsulfonyloxy or arylsulfonyloxy group.

Thus, a compound (II) is reacted with a compound (III) in the presence of a base to give a compound (la) (Reaction 1).

The compound (la) is then reduced to give a compound (Ib) (Reaction 2). The compound (Ib) is then O-acylated to give a compound (Ic) (Reaction 3). The compound (la) may be subjected to Wolff-Kishner reduction to give a compound (Id) (Reaction 4).

The reaction of a compound (II) with a compound (III) (Reaction I) is usually conducted in an aprotic solvent (e.g. polar solvents such as acetonitrile and Ν,Ν-dimethylformamide; ethers such as tetrahydrofuran and diethyl ether; halogenated hydrocarbons such as chloroform and methylene chloride; and hydrocarbons such as benzene, toluene and n-hexane) in the presence of a base (e.g. potassium carbonate, sodium carbonate, pyridine and triethylamine) at a temperature of from -20°C to 100°C. The reaction time may vary depending upon the nature of compounds (II) and (Ill) and also upon the reaction temperature but, usually, 30 minutes to 24 hours will suffice the preferred amount of compound (III) per 1 mole of compound (II) is from 1 to 1.2 moles.

When compound (la) used as a starting material and the method in Reaction 2 differs, then compounds (Ib) with different structures are obtained. As hereunder, Reaction 2 will be discussed in the order of the structure of R2 in compound (Ib) . - 10 (1) When R2 is alkoxycarbonyl, aralkyloxycarbonyl or acyloxyalkyl; an ester (R2 = alkoxycarbonyl, aralkyloxycarbonyl or acyloxyalkyl) is used as compound (la) and, as a reducing agent, a metal hydride complex (e.g. sodium borohydride or sodium cyanoborohydr ide) or diborane or the like or the compound (la) same as above (excluding the case where R2 is benzyloxycarbonyl) is used followed by catalytic hydrogenation to give a compound (lb). When a metal hydride complex or diborane or the like is used, the reaction is suitably conducted at a temperature of -20°C to 100°C in a suitable solvent such as polar solvent (e.g. water, methanol, ethanol, isopropanol, Ν,Ν-dimethylformamide or dimethyl sulfoxide) provided that sodium borohydride or sodium cyanoborohydride is used while, when diborane is used, the solvent used is an ether type solvent (e.g. tetrahydrofuran, diethyl ether or diethylene glycol dimethyl ether).

The reaction time may vary depending upon the nature of the compound (la) and the reducing agent and also upon the reaction temperature but, usually, 30 minutes to 24 hours will suffice. The amount of the reducing agent may vary depending upon its type but, preferably, it is 0.5-2.4 moles per mole of the compound (la).

When catalytic hydrogentation is adopted, the hydrogenation is carried out at ambient temperature and ordinary pressure in a suitable solvent such as alcoholic solvent (e.g. methanol, ethanol, etc); aqueous alcoholic solvent; or ether type solvent (e.g. dioxane or tetrahydrofuran) in the presence of a catalyst such as palladium/ - 11 carbon, platinum oxide, ruthenium/carbon or Raney nickel. Depending upon the type of the compound (la) or the catalyst used, the reaction may be conducted with cooling or heating or under pressure. The reaction time may very depending upon the nature of the compound (Ia) or the catalyst but, usually, it will be from 30 minutes to 24 hours. The amount of the catalyst may vary depending upon its type though, preferably, it is 1-20% to the amount of the compound (la). (2) When R2 is carboxy, i.e. when a carboxylic acid is used as compound (Ia), a metal hydride complex (e.g. sodium borohydride or sodium cyanoborohydride) is used as reducing agent and the reaction may be carried out in the same manner as in the case of (1) wherein the metal hydride complex is used or where catalytic hydrogenation is employed, in the same manner as in the case of (1) wherein catalytic hydrogenation is employed.

When a benzyl ester (R2 is benzyloxycarbonyl) is used as the compound (la), the reaction may be same as in the case of (1) wherein catalytic hydrogenation is carried out. (3) When a hydroxyalkyl compound (R2 is hydroxyalkyl) is used as compound (la), a metal hydride complex (e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or lithium trimethoxyaluminum hydride, diborane or the like is used as reducing agent or the same compound (la) (except the case where R2 is hydroxymethyl) as above is used followed by a catalytic reduction to give compound (lb). - 12 When an ester (R2 is aikoxycarbonyi, aralkyloxycarbonyl or acyloxyalkyl) is used as compound (Ia), a metal hydride complex (e.g. lithium aluminum hydride or lithium trimethoxyaluminum hydride) is used as a reducing agent.

When a carboxylic acid (R2 is carboxy) is used as a compound (la), a metal hydride complex (e.g. lithium aluminum hydride or lithium trimethoxyaluminum hydride), diborane or the like is used as a reducing agent.

The compound (lb) may also be manufactured starting from the oxoalkyl compound (la) (R2 is oxoalkyl) [obtained by the reaction of a compound (il) with the compound (ill) wherein R2 is oxoalkyl] in accordance with the Reaction (1) in the same manner as when a hydroxyalkyl compound (R2 is hydroxyalkyl) is used.

When a metal hydride complex or diborane or the like is used, the reaction is carried out at -20°C to 100°C using a suitable solvent e.g. an ether type solvent such as tetrahydrofuran, diethyl ether or diethylene glycol dimethyl ether when lithium aluminum hydride or lithium trimethoxyaluminum hydride is used, or when sodium borohydride, sodium cyanoborohydride or diborane are used, the solvent is the same as that used in the case of a metal hydride complex or diborane in (1) above.

The reaction time may vary depending upon the types of the compound (Ia) and the reducing agent and also upon the reaction temperature but, usually, 30 minutes to 24 hours will suffice. The amount of the reducing agent may vary depending upon its type but, - 13 preferably, it is 0.5 to 2.4 moles to one mole of the compound (Ia).

When compound (Ib) is acylated, in Reaction 3, using an acylating agent or compound (Ib) is dehydrated/condensed using a suitable carboxylic acid and condensing agent, the compound (Ic) is obtained .

When an acylating agent such as a carboxylic acid anhydride (e.g. acetic anhydride, propionic anhydride and benzoic anhydride) or carboxylic acid halide (e.g. acetyl chloride, propionyl chloride or benzoyl chloride) is used, (Ib) is reacted at -20 to 100°C in the presence of a base (e.g. potassium carbonate, sodium carbonate, pyridine or triethylamine) in the presence or absence of an aprotic solvent such as a polar solvent (e.g. acetonitrile or Ν,Ν-dimethylformamide), ether type solvent (e.g. tetrahydrofuran or diethyl ether), halogenated hydrocarbon (e.g. chloroform or methylene chloride) or hydrocarbon (e.g. benzene, toluene or n-hexane).

The reaction time may vary depending upon the type of the compound (Ib) or the acylating agent as well as the reaction temperature but, usually, it is 30 minutes to 24 hours. The preferred amount of the acylating agent per mole of compound (Ib) is 1 to 1.2 moles. When a compound (Ib) wherein R2 is hydroxyalkyl is used, the use of 2 or more moles of acylating agent to the compound (Ib) gives the compound (Ic) wherein R2 is acyloxyalkyl.

When a condensing agent (e.g. N,N-dicyclohexylcarbodimide, 2-chloro-N-methylpyridinium iodide or triphenylphosphine and carbon tetrachloride) is used, compound (Ib) is reacted with a suitable - 14 carboxylic acid (e.g. acetic acid, propionic acid or benzoic acid) in the above aprotic solvent at a temperature of -20 to 100°C.

The reaction time may vary depending upon the type of the carboxylic acid and condensing agent used as well as the reaction temperature but, usually, it is 30 minutes to 24 hours. Preferred amount of the carboxylic acid and the condensing agent per mole of compound (lb) is 1 to 1.2 moles.

When compound (lb) wherein R2 is hydroxyalkyl is used, the use of 2 or more moles of carboxylic acid and condensing agent gives the compound (Ic) wherein R2 is acyloxyalkyl. The compound (la) may also be manufactured by oxidation of a compound (lb) with a suitable oxidizing agent (e.g. permanganate, manganese dioxyde, chromic acid, N-halocarboxylic amide, dimethylsulfoxyde and the like).

When a compound (la) wherein R2 is carboxy or hydroxyalkyl is heated at 150-250°C with hydrazine monohydrate and a base (e.g. sodium hydroxide or potassium hydroxide) in diethylene glycol, the compound (Id) wherein R2 is carboxy or hydroxyalkyl is obtained.

When a compound (la) wherein R2 is alkoxycarbonyl or aralkyloxycarbonyl is used, the reaction may be effected in the same way as above to give the compound (Id) wherein R2 is carboxy.

When a compound (la) wherein R2 is acyloxyalkyl is used, the reaction may be effected in the same way above to give the compound (id) wherein R2 is hydroxyalkyl.

The compound (Id) wherein R2 is alkoxycarbonyl or aralkyloxycarbonyl is obtained by esterifying the compound (Id) wherein R2 is carboxy. - 15 The compound (Id) wherein R2 is acyloxyalkyl is obtained by reacting the compound (Id) wherein R2 is hydroxyalkyl in the same manner as in Reaction 3.

When a compound (lb) or a compound (Ic) is subjected to catalytic hydrogenation, the compound (Id) (excluding the case wherein R2 is hydroxymethyl orlbenzyloxycarbonyl) may also be manufactured.

The preferred solvent is an alcoholic solvent (e.g. methanol, ethanol, propanol or isopropanol) or an ether type solvent (e.g. tetrahydrofuran or dioxane).

The reaction is usually carried out under a pressure of 2-8 atm., and accelerated by adding an acidic catalyst such as acetic or hydrochloric acid.

The compound of the present invention (I) wherein R2 is carboxy may also be manufactured by hydrolysis of the ester (R2 is alkoxycarbonyl or aralkyloxycarbonyl) prepared as hereinabove. Such hydrolysis is carried out in a solvent such as water, methanol, ethanol or a mixture thereof in the presence of a base such as potassium carbonate, sodium hydroxide or potassium hydroxide at the temperature of 0-150°C or, preferably, 20-100°C. The amount of the alkali per mole of the ester (R2 is alkoxycarbonyl or aralkyloxycarbonyl) is 1-5 moles or, preferably, 2-3 moles.

This hydrolysis reaction may also be conducted in the presence of a mineral acid (e.g. hydrochloric acid, hydrobromic acid or sulfuric acid) in a suitable solvent (e.g. aqueous methanol, - 16 aqueous ethanol or other aqueous alcohol or acetic acid) at room temperature to 80°C. The amount of acid per mole of the ester (R2 is alkoxycarbonyl or aralkyloxycarbonyl) is 0.1-10 moles or, preferably, 0.2-3 moles.

The compound (I) of the present invention wherein R2 is alkoxycarbonyl or aralkyloxycarbonyl may also be manufactured by esterification of the carboxylic acid (R2 is carboxy) obtained as hereinabove.

Such esterification reaction can be carried out conventionally such as by the use of diazomethane, alcohol with acid (e.g. hydrochloric acid, suluric acid, p-toluenesulfonic acid, etc.) or thionylchloride with alcohol.

When the compound (I) of the present invention prepared as such is a free caboxylic acid (R2 = carboxy), the compound may be converted to a salt by conventional means by reaction with pharmacologically-acceptable bases. For example, an alkali metal salt can be manufactured by hydrolysis of an ester (R2 is alkoxycarbonyl or aralkyloxycarbonyl) in alcohol or in aqueous alcohol using sodium hydroxide or potassium hydroxide.

Alternatively, the carboxylic acid (R2 is carboxy) may be treated with one equivalent of sodium hydroxide, potassium hydroxide, metalic sodium, etc. preferably in an alcoholic solvent whereupon the corresponding alkali metal salt is prepared.

In the case of alkaline earth metal salts, the alkali salt prepared as above is dissolved in water and an equivalent amount of - 17 calcium chloride or the like is added thereto whereupon the corresponding alkali earth metal salts can be prepared.

The compound (I) prepared as such, or a salt thereof, can be isolated/purified from the reaction mixture by conventional isolating/purifying methods such as, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography or thin layer chromatography.

Some of the compounds (I) of the invention have two or more stereoisomers due to asymmetric carbon atom(s) and such isomers and a mixture thereof are also covered by the present invention.

Among compounds (I) of the present invention, optically active compounds due to an asymmetric carbon substituted with a hydroxyl group may be manufactured by an asymmetric reduction of (la) using a catalyst such as rhodium complex or ruthenium complex utilizing an asymmetric ligand such as MCCPM, BINAP or BPPFOH. In such a reaction, an optical (R) or (S) isomer can be freely obtained by a suitable selection of the antipode of the asymmetric ligand.

A reduction enzyme may also be used in the asymmetric reduction. In that case, (R) or (S) optical isomers may be freely manufactured by suitable selection of the enzyme.

Alternatively, a racemic mixture is reacted with an optically active resolution reagent (e.g. cis-benzamidocyclohexanecarbonyl chloride, trans-benzamidocyclohexanecarbonyl chloride, trans-cyclohexanedicarboxylic acid anhydride, etc.), the resulting diastereomer is separated by means of fractional crystallization or chromatography - 18 and then hydrolyzed to give the above optically active substances. When the resulting diastereomer is a carboxylic acid, the diastereomer may be further treated with a suitable base to afford diastereomer salt with good crystallinity.

Further, the above optical isomers may also be manufactured by subjecting a racemic mixture to a high performance liquid chromatography using an optically active column such as CHIRALCEL OD or CHIRALCEL OF.

The optical active substance wherein R2 is carboxy may also be prepared by treating the racemic mixture with optically active base (e.g. brucine, quinine or a-methylbenzylamine) by utilizing its acidity and by separating the resulting diastereomer by means of fractional crystallization followed by treating with an acid.

The starting material of formula (II) may be prepared in accordance with the following scheme: Ghem-4 wherein R^ and X are as defined above.

The starting material (VII) in the above route is known or may be manufactured in conventionally. - 19 The compound (VII) is dissolved in an alcoholic solvent such as methanol or ethanol and is reacted with chloroform and aqueous solution of alkali hydroxide (e.g. sodium hydroxide or potassium hydroxide) at 50-80°C to give the compound (VI).

The reaction time may vary depending upon the type of the compound (VII) and reaction temperature but, usually, 30 minutes to 5 hours will be suitable. The preferred amount of the alkali hydroxide per mole of the compound (VII) is 2 to 10 moles.

Then, the compound (VI) and haloacetone (e.g. chloroacetone, bromoacetone or iodoacetone) are reacted in accordance with the reaction of the compound (II) with the compound (III) whereupon the compound (V) is prepared.

Then, the resulting compound (V) is reacted with halogen (e.g. bromine, chlorine or iodine) in a suitable solvent (e.g. chloroform, carbon tetrachloride, diethyl ether or N,N-dimethylformamide) at the temperature of -20 to 80°C to give a compound (II) (X is halogen).

The reaction time may vary depending upon the type of the compound (V) used and also upon the reaction temperature but, usually, 30 minutes to 24 hours will be suitable. Preferred amount of the halogen per mole of the compound (V) is 0.9 to 1.2 moles.

The compound (ll) wherein X is alkylsulfonyloxy or arylsulforiyloxy may be manufactured by conventional methods starting from the compound (II) wherein X is halogen prepared as hereinabove. - 20 The other starting material (III) is known or may be manufactured in accordance with known methods.

The compounds of the present invention are effective for the therapy of the diseases wherein the concentration of Lp(a) in blood is high and also of the diseases caused thereby. Besides the above pharmacological action, the compound of the present invention exhibits a lowering action of lipid concentration in blood.

Thus, the pharmaceutical composition of the present invention is effective for the prevention and therapy of the arteiosclerosis caused by hyperlipemia and, further, is applicable to the therapy of the following symptoms, namely, cardiac infarction, coronary diseases including restenosis after PTCA treatment, angina pectoris and ischemic heart diseases caused by coronary diseases, cerebral infarction including cortical branch and perforator branch farctions and thrombosis as well as arteriosclerosis caused by that.

Compounds which lower the lipid concentration in the blood are known but, none having a 2-(l-hydroxy-2-phenoxyethyl)benzofuran 2-(phenoxyacetyl)benzofuran structure have been reported.

When the compounds of the present invention are given as drugs, they are given as they are or in a form of pharmaceutical compositions containing, for example, 0.1-99.5% or, preferably, 0.5-90% of the compound together with a pharmaceutically-acceptable, nontoxic and inert carrier to animals, including human beings.

Suitable carriers are solid, semisolid and liquid diluents, fillers and other auxiliary agents used for pharmaceutical - 21 preparations. The pharmaceutical compositions are preferably administered in unit dosage form. The pharmaceutical compositions of the present invention may be administered via vein, mouth, tissue, local part (e.g. via skin) or rectum. Needless to say, a dosage form suitable for the administration route will be chosen. Oral administration is particularly preferred.

The dose as a pharmaceutical composition for therapy of diseases of high Lp(a) concentration in blood is preferably assessed by taking the state of the patients (e.g. age and body weight), administration route, type and degree of the diseases, etc. into consideration but, usually, the common dose of the effective amount of the compound is 50-600 mg/day or, preferably, 100-300 mg/day per person.

In some cases, the dose may be less than the above or, in some cases, more than the above range may be necessary. It is also possible to give the compound twice or thrice daily by dividing the daily dose into two or three.

The same or similar dose may be applied for prevention and for therapy of arteriosclerosis and others.

Oral administration may be carried out using a solid or liquid unit dosage form such as, for example, a powder, diluted powder, tablet, sugar-coated agent, capsule, granule, suspension, liquid, syrup, drop, sublingual agent, or the like.

Powders may be manufactured by making the active substance into a suitably fine size. Diluted powders may be manufactured by - 22 making the active substance into a suitably fine size followed by mixing with similarly fine pharmaceutical carrier such as, for example, starch, mannitol and other edible carbohydrates and others. If necessary, seasonings, preservatives, dispersing agents, colouring agents, perfumes, etc. may be mixed therewith.

Capsules may be manufactured by filling the above-mentioned powder or diluted powder or the granules into capsules made, for example, of gelatin. It is also possible that lubricants or fluidizing agents (e.g. colloidal silica, talc, magnesium stearate, calcium stearate and solid polyethylene glycol) be mixed with the powders followed by filling. The addition of disintegrating agents or solubilizing agents such as, for example, carboxymethyl cellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose, sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate, etc. is effective in improving the effectiveness of the drug when the capsules are taken.

Further, the fine powder may be suspended/dispersed in vegetable oil, polyethylene glycol, glycerol or surface active agent followed by packing with gelatine sheet to give soft capsules.

Tablets may be prepared by preparing a powder mixture by adding diluents, making it into granules or slugs, adding disintegrating agents or lubricants thereto and making into tablets. The powder mixture may be prepared by mixing the suitably powdered substance with the above diluents and bases and, if necessary, mixed with binders (e.g. carboxymethylcellulose sodium, methylcellulose, - 23 hydroxypropylmethylcellulose, gelatine, polyvinylpyrrolidone, polyvinyl alcohol, etc.), dissolution-retarding agents (e.g. paraffin), reabsorbing agents (e.g. quaternay salts) and adsorbers (e.g. bentonite, kaolin, dicalcium phosphate, etc.). The powder mixture may be firstly wetted with a solution of binders (such a syrup, starch paste, gum arabic or cellulose) or aqueous solution of polymer, stirring/mixture and drying followed by pulverizing to give granules. Instead of making powder the granules as such, the powder may be first tableted and the resulting slub of incomplete shape is pulverized to give granules .

The granules prepared as such may be mixed with lubricants (such as stearic acid, stearates, talc, mineral oil, etc), so that adhesion to each other can be prevented. The lubricated mixture prepared as such is then tableted. The tablet prepared as such may be coated with a film or with sugar.

Alternatively, the drug may be directly tableted after mixing with flowing and inert carrier without the step of preparing granules or slugs. Transparent or semitransparent protective coating comprising closed shellac coating, the coating of sugar or polymar material or a brush coating comprising wax may be used as well.

Other types of preparations for oral use such as, for example, solutions, syrups, elixirs, etc. may be also made into unit dosage form wherein certain amount of a drug contains certain concentration of the drug. Syrups may be prepared by dissolving the compound in a suitable aqueous solution with a flavour. Elixirs are - 24 manufactured using alcoholic and nontoxic carriers. Suspensions are manufactured by dispersing the compound into nontoxic carrier. If necessary, solubilizing agents or emulsifiers (e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters), preservatives, flavouring agents (e.g. peppermint oil and saccharine) may be added thereto.

If necessary, the unit dosage form for oral administration may be made into microcapsules. Such form may be coated or embedded in polymers or in wax so that the delivery time can be elongated or sustained released action may be resulted.

Administration into tissue may be carried out by a liquid unit dosage form for hypodermic, intramuscular or intravenous injection (such as, for example, solution or suspensions). They may be manufactured by suspending or dissolving certain amount of the compound into an appropriate nontoxic liquid carrier (such as an aqueous or oily medium) followed by subjecting the suspension or solution to sterilization. In order to make the injection solution isotonic, nontoxic salt or salt solution may be added thereto. Further, stabilizers, preservatives, emulsifiers or the like may be also used.

Rectal administration can be carried out using suppositories or the like which may be prepared by dissolving or suspending the compound in a low-melting and water-soluble or water-insoluble solid such as polyethylene glycol, cacao butter, semisynthetic fat/oil (e.g. Witepsol [trademark]), higher esters (e.g. myristyl palmitate) and a mixture thereof. - 25 In order that the invention may be well understood, the following examples are given by way of illustration only.

Reference Example. 2-Bromoacety1-5-tert-butylbenxofuran.

Step 1: 5-tert-Butylsalicylaldehyde. 4- tert-Butylphenol (180.3 g) was dissolved in 95% ethanol; a solution of 345.6 g of sodium hydroxide in 800 ml of water was added thereto and, with stirring, 229.2 g of chloroform was dropped thereinto keeping the reaction temperature at 65-75°C. After completion of the dropping, the reaction temperature was kept at 7O-75°C and the mixture stirred for 1 hour. After cooling the reaction mixture, it was poured into dilute hydrochloric acid and the resulting oil was extracted with 1.5 litres of ether. The extract was washed twice with water, dried over anhydrous madnesium sulfate and concentrated in vacou. The residue (220 g) was dissolved in 1.1 litres of isopropyl ether, the solution was extracted with 1.1 litres of 3% aqueous solution of sodium hydroxide and then extracted with 550 ml of a 1% aqueous solution of sodium hydroxide. The aqueous layer was neutralized with concentrated hydrochloric acid, the resulting oil was extracted with ethyl acetate, the extract was twice washed with water, dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue was distilled in vacuo to give 97.45 g of a oil, b.p. 129-135°C/5 mmHg.

Step 2: 2-Acetyl-5-tert-butylbenxofuran - tert-Butylsalicylaldehyde (163 g) was dissolved in 1.5 litres of acetonitrile; 252.5 g of anhydrous potassium carbonate was - 26 added and 84.6 g of chloroacetone was dropped into the mixture with stirring at room temperature. After completion of the dropping, insoluble matter was filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate followed by twice washing with water. The ethyl layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized by adding isopropyl ether thereto followed by filtering to give 120.5 g of crystals, m.p. 99-101°C.

Step 3: 2-Bromoacetyl-5-tert-butylbenzofuran. 2-Acetyl-5-tert~butylbenzofuran (86.5 g) was dissolved in 800 ml of ether and, with stirring at room temperature, 63.9 g of bromine was dropped thereinto. When crystals started to separate, the reaction mixture was cooled with ice water. After completion of the dropping, the mixture was stirred for 30 minutes, the reaction mixture was poured into ice water and ethyl acetate was added thereto until the crystals were dissolved. The organic layer was washed with water three times, dried over anhydrous magnesium sulfate, concentrated in vacuo and n-hexane was added to the residue to crystallize followed by filtration to give 100.1 g of crystals, m.p. 100-102°C.

In accordance with the same manner as the Reference Example, the following compounds were manufactured: 2-Bromoacetyl-5-chlorobenzofuran 2-Broraoacetyl-5-ieopropylbenzofuran and 2-Bromoacetylbenzofuran - 27 Example 1. 5-tert-Butyl-2-(4-methoxycarbonylphenoxyacetyl) benzo furan and 5-tert-butyl-2-[l-hydroxy-2-(4-me thoxycarbonylphenoxy) ethyl]benzofuran. 1) 5-tert-Butyl-2-(4-methoxycarbonylphenoxyacetyl)-benzofuran.

Methyl p-hydroxybenzoate (7 2.1 g) was dissolved in 800 ml of acetonitrile, 65.54 g of anhydrous potassium carbonate was added and, with stirring at room temperature, a solution of 140 g of 2-bromoacetyl-5-tert-butylbenzofuran in 1,000 ml of acetonitrile was dropped thereinto over 2 hours. After completion of the dropping, the mixture was stirred for 2 hours, the reaction mixture was poured into aqueous hydrochloric acid and the resulting crystals were collected by filtration followed by washing with water. The crystals were then dissolved in ethyl acetate, washed twice with water, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and ether was added to the residue followed by filtering to give 124 g of crystals, m.p. 148-150°C.

IR (GBr) cm-1: 2940, 1700, 1600, 1545, 1510 ) 5-ter t-Butyl-2- [ l-hydroxy-2- ( 4-me thoxycarbonylphenoxy ) ethyllbenxofuran. -tert-Butyl-2-(4-methoxycarbonyIphenoxyacetyl) benzo furan (124 g) was suspended in 980 ml of methanol and, with cooling with ice and stirring, 30 g of sodium borohydride was added thereto little by little. After stirring for 2 hours, 8.8 g of sodium borohydride was added and the mixture was stirred at room temperature for 4 - 28 hours. The reaction mixture was poured into 10 litres of ice water (acidified with hydrochloric acid) and the resulting crystals were collected by filtration. The crystals were dissolved in chloroform, the solution was washed twice with water and the chloroform layer was dried over anhydrous magnesium sulfate followed by concentrating in vacuo to give 120.1 g of crystals, m.p. 110-112°C.

Elementary Analysis for ¢22^2405: Calcd: C 71.72%, H 6.57% Found: C 71.59%, H 6.43% In the same manner as in Example 1, the following compounds were manufactured in Examples 2 and 3.

Example 2. 5-Chloro-2-(4-methoxycarbonylphenoxy-acetyl) benzofuran and 5-chloro-2-[l-hydroxy-2-(4-methoxycarbonylphenoxy) ethyl]benzofuran. 1) 5-Chloro-2-(4-methoxycarbonylphenoxyacetyl)-benzo furan. m.p. 145-147°C. IR (KBr) cm-1: 1710, 1695, 1600, 1560. 2) 5-Ch loro-2-[ l-hydroxy-2-(4-me thoxycarbony lphenoxy) ethyl] benzofuran. m.p. 100-103°C. Elementary Analysis for C^gH|5C105: Calcd: C 62.35%, H 4.36% Found: C 62.22%, H 4.57% Example 3. 5-Isopropyl-2-(4-methoxycarbonylphenoxyacetyl) benzo furan and 2-[l-hydroxy-2-(4-methoxycarbonylphenoxy) ethyl] -5isopropylbenzofuran. - 29 1) 5-Isopropyl-2-(4-methoxycarbonylphenoxyacetyl)-benzofuran. m.p. 95-97°C. IR (KBr) cm-1: 2950, 1705, 1695, 1600, 1510. 2) 2- [l-Hydroxy-2-(4-raethoxycarbonylphenoxy)ethyl]-5-isopropry 1 benzo fur an. m.p. 7O-72°C. Elementary Analysis for ^2ΐΗ22θ5· Calcd: C 71.17%, H 6.26% Found: C 71.32%, H 6.15% Example 4. 5-tert-Butyl-2-[2-(4-carboxyphenoxy)-l-hydroxyethyl]benzofuran. -tert-Butyl-2-[ 1 -hydroxy-2-(4-methoxycarbonyl phenoxy)-ethyl ] benzofuran (112 g) obtained as in Example 1 was dissolved in 1.5 litres of methanol, a solution of 24.3 g of sodium hydroxide dissolved in 400 ml of water was added thereto and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo, ice water was added to the residue and the mixture was acidified with concentrated hydrochloric acid to give crystals. The crystals were collected by filtration and dissolved in ethyl acetate, the solution was washed with water and dried over anhydrous magnesium sulfate followed by concentrating in vacuo whereupon the residue is crystallized. This was dried and recrystallized from acetonitrile to give 88.3 g of crystals, m.p. 175-177°C.

Elementary Analysis for 02ΐΗ22θ5· Calcd: C 71.17%, H 6.26% Found: C 71.03%, H 6.46% - 30 Example 5. 2-[2-(4-Carboxyphenoxy)-l-hydroxyethyl] -5-chlorobenzofuran.

Following the procedure of Example 4, -chloro-2-[l-hydroxy-2- (4-methoxycarbonyl phenoxy)-ethyl] benzo furan obtained in Example 2 was processed to give crystals, m.p. 157-159°C.

Elementary Analysis for C17H23CIO5.

Calcd: C 61.36%, H 3.94% Found: C 60.85%, H 4.10% Example 6. 2-[2-(4-Carboxyphenoxy)-l-hydroxyethyl]-5-isopropylbenzofuran. 2-[l-Hydroxy-2-(4-methoxycarbonyl phenoxy)ethyl]-5-isopropylbenzofuran obtained as in Example 3 was treated by the same method as in Example 4 to give crystals, m.p. 148-150°C.

Elementary Analysis for C20H2QO5.

Calcd: C 70.58%, H 5.92% Found: C 70.39%, H 5.76% Example 7. 2-[2-(4-Carboxyphenoxy)-l-hydroxyethyl]-benzofuran. 2- [ 1 -Hydroxy-2-(4-methoxycarbonylphenoxy)ethyl ] benzo-furan prepared by the same method as in Example 1 was treated by the same method as in Example 4 to give crystals, m.p. 153-155°C.

Elementary Analysis for C17H14O5.

Calcd: C 68.45%, H 4.73% Found: C 68.67%, H 4.59% - 31 Example 8. 2-[2-(4-Carboxyphenoxy)-l-hydroxyethyl]-5-isopropylbenzofuran sodium salt.

Metallic sodium (2.3 g) was dissolved in 200 ml of ethanold and 35.7 g of 2-[2-(4-carboxyphenoxy)-l-hydroxyethyl]-5-isopropylbenzofuran obtained as in Example 6 was dissolved therein. The reaction solution was concentrated in vacuo and acetone was added to the residue whereupon crystals were obtained. The crystals were collected by filtration and recrystallized from ethanol to give 26.5g of crystals, m.p. 305°C (decomposition) Elementary Analysis for C2oH^gNa05.1/2 H20.

Calcd: C 64.69%, H 5.43% Found: C 64.82%, H 5.27% Example 9. 2-[2-(4-Carboxyphenoxy)-l-hydroxyethyl]-5-isopropylbenzofuran calcium salt. 2- [2-(4-Carboxyphenoxy) -1-hydroxyethyl] -5-isopropylbenzofuran sodium salt (37.1 g) was dissolved in 300 ml of water. A solution of 5.55 g of calcium chloride dissolved in 50 ml of water was added to the solution. The crystals which separated out were collected by filtration and washed with water and then with acetone to give 34.6 g of crystals, m.p. not lower than 300°C.

Elementary Analysis for C^Q^gCaO^Q. 2H2O.

Calcd: C 63.65%, H 5.61% Found: C 63.48%, H 5.77% IR (KBr) cm-1: 3340, 2950, 1600, 1540 - 32 Example 10: 2-[ l-Hydroxy-2-(4-hydroxymethylphenoxy)-ethyl]5-isopropylbenzofuran.

Step 1: 5-Isopropyl-2-(4-f ormylphenoxyacetyl) benzo furan. p-Hydroxybenzaldehyde (12.2 g) was dissolved in 200 ml of N,N-dimethylformamide; 13.8 g of anhydrous potassium carbonate was added and, with stirring at room temperature, 28.1 g of 2-bromoacetyl-5-isopropylbenzofuran was added thereto over 30 minutes. The mixture was stirred at room temperature for 2 more hours. The reaction mixture was poured into an aqueous solution of hydrochloric acid and the resulting crystals were collected by filtration and washed with water. The crystals were then dissolved in ethyl acetate, the solution was washed with water and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo whereupon the residue was crystallized. To the crystals was added ether to give 18.1 g of crystals.

Step 2: 2-[ 1-Hydroxy-2-(4-hydroxymethylphenoxy)ethyl ]-5isopropylbenzofuran.

-Isopropyl-2-(4-formylphenoxyacetyl)benzofuran (18.1 g) was dissolved in 200 ml of methanol. Sodium borohydride (2 g) was added thereto with stirring and cooling with ice and the mixture was stirred for 1 hour. The reaction mixture was poured into an aqueous solution of hydrochloric acid and the crystals which separated out were collected by filtration followed by recrystallizing from ethyl acetate/n-hexane to give 16.5 g of crystals, m.p. 98-100°C.

Elementary Analysis for C2o822®4· - 33 Calcd: C 73.60%, H 6.79% Found: C 73.45%, H 6.68% Example 11. (+)-5-tert-Butyl-2-[2-(4-carboxyphenoxy)-lhydroxyethyl]benzofuran. -tert-Butyl-2-[1-hydroxy-2-(4-methoxyearbonylphenoxy)ethyl]benzofuran (4.16 g) obtained as in Example 1 was suspended in 30 ml of toluene; 1.7 g of triethylamine was added, then 3.0 g of (+)-cis-2-benzamidocyclohexanecarbonyl chloride was dropped thereinto at room temperature with stirring and the mixture was stirred for 18 hours. The mixture was further stirred at 80°C for 1.5 hours, the reaction mixture was poured into ice water, the mixture was extracted with ethyl acetate, the extract was washed with an aqueous solution of sodium hydroxide followed by washing with water, dried over anhydrous magnesium sulfate and concentrated to give a dark brown oil. Methanol (25 ml) was added to the oil, the mixture was heated to dissolution and cooled to give 1.26 g of crystals. Recrystallization from methanol gave 760 mg of white crystals, m.p. 147-148°C.

The resulting crystals were heated to reflux for 1.5 hours in a mixture of 40 ml of methanol and 11 ml of a 2% aqueous solution of sodium hydroxide, the reaction mixture was concentrated, the residue was dissolved in water, the solution was neutralized with hydrochloric acid, extracted with ethyl acetate, the extract was washed with 5% aqueous solution of potassium acetate and then with water, dried over anhydrous magnesium sulfate, concentrated and the - 34 residue was recrystallized from acetonitrile to give 283 mg of white crystals, m.p. 133-135°C. Elementary analysis for θ21^22θ5: C 71.17, H 6.26; Found: C 70.97, H 6.45. IoC]D = +1.98° (MeOH, c = 1.00).

Example 12. (-)-5-tert-Butyl-2-[2-(4-carboxyphenoxy)-lhydroxyethyl]benzofuran.

The same operations as in Example 11 were conducted using (-)-cis-2-benzamidocyclohexanercarbonyl chloride to give crystals, m.p. 134-136°C. Elementary analysis for ¢2^2205: θ 71.17, H 6.26; Found: C 71.07, H 6.38. k/.]D = -1.90° (MeOH), c = 1.00).

Example 13. 2-(4-Benzyloxycarbonylphenoxyacetyl)-5-tertbutylbenzofuran.

The same operations as in Example 1 were conducted to give the crystals, m.p. 153-155°C. IR (KBr) cm’1; 2940, 1695, 1600, 1505.

Example 14. 5-tert-Butyl-2-(4-carboxyphenoxyacetyl)-benzofuran. 2-(4-Benzyloxycarbonylphenoxyacetyl)-5-tert-butyl-benzofuran (1 g) obtained as in Example 13 was suspended in 15 ml of acetic acid and 2 ml of 47% hydrobromic acid and the mixture was stirred at 60°C for 15 hours. The reaction mixture was cooled, poured into ice water, the mixture was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, concentrated in vacuo, ether was added to the residue and the mixture was filtered followed by recrystalizing from acetonitrile to give 510 mg of crystals, m.p. 209.5-211°C. Elementary analysis for c21H20°5: c 71-58, H 5.72; Found: C 71.38, H 5.65. - 35 Example 15. 5-tert-Butyl-2-[2-(4-carboxyphenoxy)-l-hydroxyethyl]benzofuran sodium salt.

The same operations as in Example 8 were conducted using 5-ter t-bu ty 1-2- [2-( 4-carboxyphenoxy)-l-hydroxye thyl] benzo furan obtained in Example 4 to give crystals, m.p. not lower than 300°C. Elementary Analysis for C2iH2iNaO5·1/4^2θ· θ 66.22, Η 5.69; Found: C 66.22, H 5.66 IR (KBr) cm1: 2950, 1600, 1590, 1540.

Example 16. 2-[l-Acetoxy-2-(4-acetoxymethylphenoxy)ethyl]-5isopropylbenzofuran. 2-[l-Hydroxy-2-(4-hydroxymethylphenoxy)ethyl]-5-isopropylbenzofuran (10 g) obtained as in Example 10 was dissolved in 100 ml of pyridine, 20 ml of acetic anhydride was added, the mixture was stirred at room temperature for 24 hours, the reaction mixture was poured into ice water and the crystals separated therefrom were filtered, dried and recrystallized from methanol to give 7.3 g of crystals, m.p. 74-76°C. Elementary analysis for 0214112505: C 70.23, H 6.38; Found: C 70.46, H 6.14.

Example 17. 2-[l-Acetoxy-2-(4-carboxyphenoxy)-ethyl]-5isopropylbenzofuran. 2-[1-Hydroxy-2-(4-hydroxymethylphenoxy)ethyl]-5-isopropylbenzofuran (10 g) was dissolved in 100 ml of pyridine, the mixture was stirred at room temperature for 24 hours with 10 ml of acetic anhydride, poured into ice water, the mixture was acidified with concentrated hydrochloric acid and the crystals separated out therefrom were filtered, dried and recrystallized from ethyl acetate/ - 36 n-hexane to give 8.2 g of crystals, m.p. 135-137°C. Elementary analysis for C22H22O6: c &9.09, H 5.79; Found: C 68.86, H 5.93.

Example 18. 5-tert-Butyl-2-[2-(4-carboxyphenoxy)ethyl] benzofuran.

Diethylene glycol (10 ml) and 285 mg of hydrazine monohydrate were added to 5-tert-butyl-2-(4-carboxyphenoxyacetyl)benzofuran (1 g) obtained as in Example 14 and the mixture was stirred at 90°C for 40 minutes. Potassium hydroxide (398 mg) was added to the mixture and then heated at 120°C for 2 hours with stirring and further heated at 180-190°C for 3 hours. The reaction mixture was poured into aqueous solution of hydrochloric acid and the crystals separated out therefrom were filtered to give 0.86 g of crystals. Elementary analysis for 02χΗ22θ4: C 74.53, H 6.55; Found: C 74.36, H 6.68. Mass spectrum mt; 338.

Pharmacological tests. (1) Activity for lowering total cholesterol (TC) in serum using normal rhesus monkeys.

Test Method: Male rhesus monkeys of 2-5 years age (body) weight: 3.0-6.4 kg; Experiment No.) or male rhesus monkeys of 2-6 years age (body weight: 3.5-8.0 kg; Expt. Nos. 2, 3 and 4) were subjected to the experiments. During the experiment, solid feed (manufactured by Oriental Yeast) was given at a dose of 150 g once daily. Each group consisted of 2 to 6 monkeys. The substance to he tested was in a form of a suspension in 0.5% methylcellulose solution. The suspension was given orally using a rubber probe at a - 37 dose of 30, 50 or 100 mg/kg for seven days [Expt. Nos 1 and 2(2)] or for 28 days (Expt. Nos. 2(1), 3 and 4). Blood was taken from saphena in lower limbs one week and immediately before the administration and also 7, 14, 21 and 28 days after the administration of the suspension whereby serum TC was measured, the change in serum TC was calculated from the expression (ATC - BTC) / BTC x 100.

In the expression, ATC is the TC after administration of the substance tested while BTC is that before the administration (average of those one week and immediately before the administration). The results are given in Table 1 wherefrom it is clear that the compounds of the present invention exhibit a lowering action for serum TC.

Table 1. Experi- Substance Dose Numbers TC Change Rate (%) ment Used (mg/kg) of after Number (Example No.) Animals 7 14 21 28dys 1(1) (Control 1(2) Example 6 100 2(1) (Control) 2(2) Example 10 100 7 -42 -1374 -32* - 38 3(1) (Control) -8 -5 -8 -11 3(2) Example 8 50 3 -31** -31 -44* -51* 4(1) (Control) 1 I 1 4(2) Example 9 30 3 -19** -34** -29** -24** 4(3) Bezafibrate 100 3 -13* -10 3 -7 * and ** mean that significant differences were noted at the risk of 5% and 1%, respectively. 2) Serum TC lowering activity in normal crab-eating macaques.

Test Method: Male crab-eating macaques (body weight: 2.5-6.6 kg) were subjected to the experiments. During the experiment period, the feed (manufactured by Oriental Yeast) containing 0.1% (Expt. No.) or 0.3% (Expt. No. 2) of the compound of Example 4 was given once daily at 35 g/kg for 5 weeks (0.1%) or for 8 weeks (0.3%). Usual feed for monkeys was given to the control group. Blood was taken immediately before the administration and 1, 2 and 5 weeks after the administration in the case of 0.1% mixed feed or, in the case 0.3% mixed feed, immediately before and 2, 4, 6 and 8 weeks after the ,E 922227 - 39 administration. All operations for taking blood were conducted prior to giving the feed and the serum TG was calculated from the expression (ATC - BTC) / BTC x 100.

In the expression, ATC is the TC after administration of the substance tested and BTC is the TC immediately before that. The results are given in Tables 2 and 3 wherefrom it is clear that the compound of the present invention exhibits a serum TC lowering action. Table 2. Concn of Experi- Substance the Subst- Numbers TC Change Rate(%) ment Used ance in of after Number (Example No.) the Feed Animals 1 2 5 weeks 1(1) (Control) - 5 6 14 2 1(2) Example 4 0.1% 7 16 _18** -31** ** means that significant difference was noted at the risk of 1% Table 3. Concn of Experi- Substance the Subst- Numbers TC Change Rate(%) ment Used ance in of after Number (Example No.) the Feed Animals 2468 weeks 2(1) (Control) 6 1 -5 -7 -3 2(2) Example 4 0.3% 3 -32* -46** -42* -37* * and ** means that significant difference were noted at the risk of 5% and 1%, respectively. 3) Acute Toxicity: Mice of ddY-strain (7 weeks age; four mice per group) were fasted overnight, the compound of Example 4 of the present invention suspended in 0.5% methylcellulose solution was orally administered at 2 g/kg and the general symptoms until 3 hours after that and those until one week thereafter were checked. No animals tested died and no abnormal symptoms were noticed. 4) Influence of the compounds of the present invention on LP(a). - 41 Five to six crab-eating monkeys (male; body weight ranging 5-9 kg) as one group were fed and, to the group administered with the test sample, the feed containing 0.3% of this invention compound (that of Example 4) was fed while, to the control group, the usual feed was given. The Lp(a) concentrations in the plasma were measured by the following method at the initiation of the administration, 13 weeks thereafter and 5 weeks after completion of the administration.

Method of measuring the Lp(a) values: Commercially-available kit manufactured by Biopool Co, was used. In accordance with the procedures as given in the kit, PET buffer and sample buffer were prepared. To 20 /ul of the plasma was added 1 ml of sample buffer and to 10 or 20 /ul of the resulting diluted liquid was further added 1.01 ml or 1 ml of the sample buffer to that the liquid diluted to an extent of 5202 times or 2601 times was prepared. In accordance with the steps as instructed by the kit, each 20 /ul of the diluted sample was added to each well and measurement was conducted by duplicate. The results were calculated from the working curve prepared from the data obtained for the standard human Lp(a) in the kit. - 42 Table 4.

Action of the Compound of this Invention (Example 4) for Lowering Lp(a) in Plasma in Crab-Eating Monkeys Group Numbers _Plasma Lp(a) (mg/dl) of the Immed.after 13 weeks 5 weeks after CornAnimals administration thereafter pletion of Admin.

Control 6 Administered Group 5 71.5 + 11.1 59.1+19.3 71.3+12.8 73.2 + 8.5 9.2+ 1.2* 60.1+ 7.9 *: p < 0.05 (tested to the control by means of Student's test) Values are given as average + S.E.

) Activity of the compounds of the present invention to lipid biosynthesis by tissue slices of liver of rats: Test method: Krebs-Ringer-Bicarbonate solution (1 ml) containing 1 mM of ^^-acetic acid and 10 /ug/ml of the test substance was added to 100 mg of liver slice of rat, the air was replaced with a mixed gas (oxygen: carbon dioxide = 95:5) and incubation was conducted at 37°C for 2 hours. After completion of the reaction, 15% ethanolic solution of potassium hydroxide was added and saponification was conducted at 75°C for 2 hours. A part of the - 43 saponified solution was subjected to a protein measurement. Residual saponified solution was extracted with petroleum ether and the radioactivity of the extract was measured to determine the cholesterol synthesizing activity. The aqueous layer was acidified with 6N hydrochloric acid, extracted with petroleum ether and the radioactivity of the extract was measured to determine fatty acid synthsizing activity. The values after calculating the mole numbers (nmol/mg) of the ^C-acetic acid incorporated into each extract per cellular protein (nmol/mg protein).

The results are given in Table 5 wherefrom the inhibitory action for fatty acid synthesis and for cholesterol synthesis of the compounds of the present invention is clear Table 5.

Compound Amount Fatty Acid Synth. Cholesterol Synth. Given Added _(X)__(%) (Ex. No.) (/ug/ml) Expt.1 Expt.2 Expt.1 Expt.2 Control - 100 100 100 100 Example 4 10 20 12 41 27 Example 11 10 12 18 35 24 Example 12 10 16 14 33 27 - 44 6) Activity to lipid biosynthesis of tissue slices of liver of rate (part 2): The activity of the present invention compound was measured by the same manner as above 5). The amount of incorporated 14c_acetic acid in moles (nmol/mg) was calculated and then expressed in terms of percentage to the control value. The results are given in Table 6 wherefrom it is clear that the compounds of the present invention exhibit inhibitory action for fatty acid synthesis and for cholesterol synthesis.

Table 6.

Compound Amount Fatty Acid Cholesterol Given Added Synthesis Synthesis (Ex . No .) (/ug/ml) (%) (%) Control - 100 100 Example 4 10 29 61 Example 14 10 32 64 Example 17 10 33 66 Manufacturing Example 1. Tablets for oral use. - 45 Prescription: Each tablet (180 mg) contains The compound of Example 4 100 mg Lactose 45 mg Corn starch 20 mg Hydroxypropylcellulose of low degree of substitution 9 mg Partially-hydrolyzed polyvinyl alcohol 5 mg Magnesium stearate 1 mg The above ingredients exc< apt polyvinyl alcohol and magnesium : were homogeneously mixed and subjected to wet tableting using an aqueous solution of polyvinyl alcohol as a binder to give granules. They were mixed with magnesium stearate and the mixture was made into tablets for oral use in a form of 8 mm diameter and 180 mg weight per tablet.

Manufacturing Example 2. Hard capsules.

Prescription: Each capsule (285 mg) contains The compound of Example 4 100 mg Lactose 107 mg Microcrystalline cellulose 10 mg Magnesium stearate 3 mg The above ingredients were homogeneously mixed and each 220 mg of the mixture was filled in a capsule (No.2 size) using a capsule filling machine whereupon hard capsules (each capsule weighed 285 mg) were prepared.

,E 922227 - 46 Manufacturing Example 3. Granules.

Prescription: Each one gram of the granules contain: The compound of Example 4 100 mg Lactose 790 mg Hydroxypropylcellulose of low degree of substitution 70 mg Hydroxypropylcellulose 40 mg The above ingredients were homogeneously mixed, kneaded and granulated using a granulating machine to give granules (each granule was with 0.7 mm diameter).

Claims (11)

1. Benzofuran derivatives expressed and pharmacologically-acceptable salts thereof, of the formula:- wherein is a hydrogen a halogen atom or an alkyl group; is an aikoxycarbonyl, aralkyloxycarbonyl, carboxy, hydroxyalkyl or acyloxyalkyl group; Y is >CHOH, >CHOZ, >C0 or >CH2; and Z is an acyl group.

2. A pharmaceutical composition containing a composition as claim 1 together with a pharmaceutical carrier or diluent

3. A pharmaceutical composition as claimed in Claim 2 for therapy of a disease caused by a high lipoprotein (a) concentration in the blood.

4. A pharmaceutical composition as claimed in Claim 2 for the therapy of arterio-sclerosis.

5. A pharmaceutical composition as claimed in Claim 2 for the therapy of ischemic heart disease.

6. A pharmaceutical composition as claimed in Claim 2 for the therapy of cerebral infarction.

7. A pharmaceutical composition as claimed in Claim 2 for the therapy of restenosis after a PTCA operation. - 48

8. A compound as claimed in Claim 1, substantially as hereinbefore described and exemplified.

9. A pharmaceutical composition according to Claim 2, substantially as hereinbefore described.

10. A process for preparing a compound as claimed in Claim 1, substantially as hereinbefore described and exemplified .

11. A compound as claimed in Claim 1, whenever prepared by a process claimed in Claim 10.