NO760539L - - Google Patents

Description

"Procedure for the preparation of a pharmaceutical preparation with hypolipidemic activity"

The invention relates to pharmaceutical preparations which have bypolypidemic activity, eg in particular preparations comprising phenoxyallyl compounds.

Occlusive vascular diseases are characterized by the accumulation of lipids (especially cholesterol, triglycerides and phospholipids) in the interior of large arteries. These lesions occlude the vessel and result in ischemia in the organ supplied by the artery. Prolonged or sudden ischemia that occurs in this way is a major cause of death in many countries. It has been shown that increased lipid levels, e.g. of cholesterol in the blood is associated with an increased frequency of coronary artery disease and heart attack. There is thus a need for a drug that effectively reduces serum lipid levels. :

In the applicant's BRD-Off.skrift 2439458, a pharmaceutical preparation is described which comprises one or more pharmaceutically acceptable carriers together with a compound of formula (I):

where: R^ is a carboxylic acid group or a group that can be converted into a carboxylic acid group in the human body;

R 2 is a hydrogen atom, a lower alkyl group or a lower alkoxy group;

Rg is one hydrogen or halogen atom, or a lower alkyl or lower alkyl group;

R 1 is a hydrogen or halogen atom, or a phenyl, lower alkyl, lower carboxyl, halogen-lower alkyl, nitro or carboxyl ester group; or R^ and R^ together form the remainder of a benzene ring;

Z is oxygen or sulfur;

X is a straight or branched lower alkylene, lower alkyleneoxy, lower alkylenethio or lower alkylenecarbonyl group;

q is zero or an integer from 1-12 j" and one of m and n is zero and the other 1.

The applicant has found a class of substituted phenoxy (or phenylthio)-allyl compounds, individual members of the class having useful hypolipidemic activity.

Although certain benzene derivatives such as are substituted with alkenyloxy or alkenylthio groups are described to be i

possessing pharmacological activity, usually anti-inflammatory or analgesic properties (see, e.g., Belgian Patents Nos. 621,225 and 718,573, French Patents Nos. 1,580,970, 2,054,532 and 2,108,943, and US Patent Nos. 3,586,713 and 3,824,277), the applicant is not aware of any literature that suggests the specific class of allyl oxy- and: allyl thiobenzenes referred to here or that such compounds may possess hypolipidemic activity.

Accordingly, the invention provides a pharmaceutical preparation comprising at least one pharmaceutically acceptable carrier, together with a compound of formula (II)s

2 3 4

where one of the groups R , R and R represents eh.group

1 and the remaining groups 2 3 4 hydrogen; -(CH,) R , and the remaining groups R , R and R are hydrogen;

R is a carboxylic acid group or a pharmaceutically acceptable non-toxic salt, an ester, an amide or hydrazide of a carboxylic acid group; an alkyl group which is optionally substituted with one or more hydroxyl or lower alkoxy groups; cyano-, formyl-, acyl-, carboxyl-substituted acyl group or tetrazole group;

q is zero or an integer from 1 to 12;

Z is oxygen or sulfur; and 5 5 7 R , R and R are independently hydrogen or a lower alkyl group.

As used herein, the adjective "lower" means that the alkyl portion of the group to which it belongs contains 1-6 carbon atoms.

Suitable lower alkyl groups for R 5 , R 6 and R 7 in formula (II) include methyl, ethyl and straight and branched propyl and biethyl groups. R is preferably hydrogen. 6 7 A compound with R - and R -groups which are for-. different and the corresponding compound with these groups in-r the yield, - will of course be geometric isomers of each other. It is to be understood that the invention includes both such cis and trans isomers as well as mixtures thereof.

If the group R 1 is a salt of a carboxylic acid group, suitable salts include metal salts, e.g. aluminum salts, alkali metal salts such as sodium or potassium, alkaline earth metal salts, e.g. of. calcium or magnesium, and ammonium or substituted ammonium salts, e.g. those with lower alkylamino,.e.g. triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-_

(2-hydroxyethyl)amine, cycloalkylamines, e.g. bicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, N-benzyl-/3-phenethylamine, dehydroabi-ethylamine, N,N'-bis-dehydroabiethylethylenediamine, or bases of the pyridine type , e.g. pyridine, collidine or quinoline.

Preferred salts are sodium and potassium salts.

Suitable ester groups include alkyl, aryl and aralkyl esters, e.g. C-^^Q straight-chain or branched alkyl esters. Lower alkyl and lower aralkyl esters are preferred, e.g. methyl, ethyl, straight and branched propyl, butyl, pentyl, hexyl and benzyl esters.

,;• Suitable alkyl groups for the group R1 include straight chain and branched C1_20 alkyl groups, preferably lower

alkyl groups, especially methyl. Any such alkyl group may be substituted at any position with a hydroxy-. or lower alkoxy group.

Preferred such substituted alkyl groups include hydroxymethyl, methoxymethyl, ethoxymethyl.

Suitable acyl groups include alkanoyl groups, preferably lower alkanoyl, e.g. acetyl.

A particularly useful group of compounds for use in the preparations according to the invention is represented by formula (III):

16 7

where R, R, R and q are as defined with respect to formula. (II).

So that. for a compound to have maximum potential as a hypolipidemic agent it must significantly lower serum lipid levels: and have little or no effect on growth, liver weight and liver lipid. Among compounds of formula (III), such a combination of parameters is best satisfied when either R"*" is a carboxylic acid group or a salt, or an ester thereof when q is zero; or R"*" is methyl, hydroxymethyl or a carboxylic acid group or a salt or ester thereof when q is an integer from 1 to 12.

Another group of compounds which have good hypolipidemic activity and are applicable in the preparations according to the invention are represented by formula (IV): 16 7' where R , - R , R and q are as defined above with regard to formula (II) .

Preferred compounds of formula (i) include those wherein q is zero and R 1 is a carboxylic acid group or a salt or ester thereof.

A further subclass of compounds which are useful for incorporation into the preparations according to the invention, when formula (I)s

6

where R , Z and R are as defined with respect to formula (II), r is an integer from 1 to 12, and R 8 is a lower alkyl group.

The whole number r can preferably be from 2 to 6.

Preferably r is equal to 2 when R 1 is a carboxylic acid group or a salt or an alkyl ester thereof.

The preparations can be prepared for administration by any route, although oral administration is preferred. The preparations can be in the form of tablets, capsules, powders, granules, throat lozenges or liquid preparations, e.g. oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dose form and may contain conventional drug carriers, e.g. binders, e.g. syrup, gum acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g.

lactose, sugar, corn starch, calcium phosphate, sorbitol or glycyrrhizin; tablet lubricants, e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide; crumbling agents, e.g. potato starch; or acceptable wetting agents, e.g. sodium lauryl sulfate. The tablets can be coated by methods well known in normal pharmaceutical practice. Oral liquid preparations can be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, e.g. suspending agents, e.g. sorbitol, syrup, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat, emulsifiers, e.g. lecithin, sorbitan monooleate, or gum acacia; non-aqueous carriers (which may include edible oils), e.g. almond oil, fractionated coconut oil, oily esters, e.g. glycerol, propylene glycol or ethyl alcohol; preservatives, e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid and, if desired, conventional flavoring or coloring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa butter or other glyceride.

For parenteral administration, liquid unit dose forms are prepared using the compound and a sterile carrier, water being preferred. The connection kah, depending on it

carrier and concentration used, either suspended or dissolved in water for. injection and filter are sterilized before filling into a suitable glass container or ampoule and sealing. Advantageously, such auxiliaries as a local anaesthetic, preservative and buffering agents can be dissolved in the carrier. To improve stability, the preparation can be frozen after filling in the glass container and the water removed under vacuum. The dry, lyophilized powder is then sealed in the glass container, and a lidded glass container with water for injection is provided for reconstitution of the liquid before use. Parenteral suspensions are prepared in essentially the same way, with the exception that the compound is suspended in the carrier instead of being dissolved, and that sterilization cannot be carried out by filtration. The compound can be sterilized by prior exposure to ethylene oxide

suspension in the sterile carrier. Advantageously, a surfactant or wetting agent is included in the preparation to facilitate uniform distribution of the compound.

The preparations can contain from 0.1 to 99% by weight, preferably 10-60% by weight, of the active material, depending on the drainage method. If the preparations comprise unit doses, each unit will preferably contain from 50 mg to ljgav of the active ingredient. The dose used for the treatment of an adult person will preferably vary from 100 mg to 5 g per day, e.g. 1500 mg per day, depending on the route and frequency of administration.

Also included within the scope of the invention is. a method for regulating or reducing serum lipid levels in mammals including humans, and this method comprises administering to the mammal one or more compounds of formula (II) above. Oral administration is preferred.

Some of the compounds of formula (II) are new compounds. Thus, the invention also provides compounds of formula (II) above, where either: 2 7 i) q is zero, one or two, R is cyan and R to R and r Z are as defined with respect to formula (II)s

-or

ii) q is an integer from 2 to 12, R 1 is a carboxylic acid group or a pharmaceutically acceptable non-toxic salt, an ester, an amide or hydrazide

thereof, an alkyl group which is optionally substituted with one or more hydroxyl or lower alkoxy groups, a cyano-, formyl-r, acyl-J or 2 7 carboxyl-substituted acyl group; and Z and R to R are as defined with respect to formula (II) with . except that when Z is oxygen and q is two, then R 1 is not a carboxylic acid group.

A class of new compounds has the formula:

where R is a lower alkyl group or a carboxylic acid ester group, s is an integer from 2 to 6 and R 6 and R 7 are as defined with respect to formula (II).

Specific new compounds include the following: ethyl 3-[4-(3-methyl-but-2-enyloxy)phenyl]-propionate; 4-(but-2-enyl-1-oxy)-benzyl ethyl ether; ethyl 3-(4'-(but-2-enyl-1-oxy)-phenyl J-propionate; ethyl 2-(but-2-enyl-1-oxy)-benzoate; ethyl 4-(but-2-enyl-1-oxy)-phenylacetate; 4-(but-2-enyl-1-oxy)-benzonitrile; 2-(but-2-enyl-1-oxy)-acetophenone; . 3-(but-2-enyl-1-oxy)-acetophenone; 4-(but-2-enyl-1-oxy)ethylbenzene; iso-propyl-3-[4(but-2-enyl-1-oxy)-phenyl]-propionate; 4-14'-(but-2-enyl-1-oxy)-phenyl]-butan-2-one; ethyl 2-(but-2-enyl-1-thio)-benzoate; benzyl 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate; n-hexyl-3-14'-(but-2-enyl-1-oxy)-phenyl J-propionate; 3-14'-(but-2-enyl-1-oxy)-phenyl N-propionic acid; 4'-(but-2-enyl-1-oxy)-benzoic acid; sodium 3-[4<*->(but-2-enyl-1-oxy)-phenyl]-propionate; sodium 4'-(but-2-enyl-1-oxy)-benzoate; 3- t 4'-(but-2-enyl-1-oxy)-phenyl]-propionoylhydrazide; 4-(but-2-enyl-1-oxy)-acetophenone; ethyl 4-(but-2-enyl-1-thio)-benzoate; ethyl 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate; ethyl-3-[4'-(hept-2-enyl-1-oxy)-phenyl]-propionate The compounds according to the invention can be prepared by reacting a compound of formula (VI):

with eh compound of formula (VII)s

where one of the groups P or Q is -ZH [where Z is defined with respect to formula (II)] or a reactive derivative thereof, and the 2 3 4 5 6 other is an easily displaceable group, and where R , R , R R , R

7

and R is as defined with respect to formula (II) above, and optionally then conversion of the group R 1 within the substituent

2 3 4 1 -

R , R or R to another such group R .

The resulting product of formula (II) can then be combined with a pharmaceutically acceptable carrier to produce the new preparations according to the invention.

Reactive derivatives of the -ZH group include salts and other derivatives that increase the nucleophilicity of the Z atom.

By an "easily displaceable group" is meant an atom or group which is displaceable at a nucleophilic center (eg the lone pair of electrons on a hydroxyl-oxygen or alkoxide ion). Such groups include halides, e.g. I, Br or Cl; pseudo-halides, e.g.. the azido group N2~;; active esters, e.g. the groups O.SOjCH^O.CO.OC^H,.; compounds produced in situ by dehydrating agents, e.g. carbodiimides or carbonyl diimidazoles,. phosphorus pentachloride, phosphoryl chloride*thio chloride, phosphorus pentoxide or sulfuric acid; or other such good trailing groups.

For the preparation of compounds where Z is oxygen, the group -ZH is a hydroxyl group. If the hydroxyl compound used in the above condensation reaction is in the form of a salt, it is generally in the form of the sodium or potassium salt.

.When the condensation reaction uses a salt as one of the reactants, the salt is preferably produced by means of a

strong base, e.g. sodium hydride, sodium amide, or a sodium alkoxide or sodium methoxide. Suitable solvents for the reaction include dimethylformamide or dimethylsulfoxide (especially when using sodium hydride or sodamide or base), methanol (when using sodium methoxide) and ethanol (when using sodium ethoxide).

Alternatively, the free hydroxyl group in compound (VI) or (VII) can be used, and the method is then carried out in the presence of an acid acceptor, e.g. a tertiary organic base, e.g. pyridine, triethylamine or N-methylpyrrolidine; or potassium carbonate (in acetone as solvent).

For the preparation of compounds of formula (II) wherein

Z is sulfur, . the group -ZH is a thiol group. Such a group can be used in the above-mentioned condensation either as the free thiol or as a salt thereof.

It may be preferable to modify the group R^" within the substituents R 2 , R 3 and/or R 4 after the condensation reaction rather than before. Thus, it is preferred, in the preparation of compounds of formula (II) where R^ includes an amide or an carboxylic acid group, first to prepare the corresponding compound with a carboxylic acid ester group and then to convert such group to carboxylic acid group or amide in a conventional manner. It may be noted that some of the compounds where R is an alkyl ester are difficult to hydrolyze to the corresponding carboxylic acid group, and the it is often convenient to prepare the benzyl ester by the above-mentioned condensation, as the ester is more easily hydrolysed.

Likewise, if the group R contains a hydroxyl group, it may be advantageous to first protect it by forming an easily hydrolyzable ester which can be removed after the condensation reaction.

Alternative methods for preparing compounds, where R<1> contains an ester group, include esterification of the free acid or its salt or another reactive derivative of the acid, or transesterification of a compound having another ester group. Esterification can be carried out in any conventional manner, e.g. by reacting the free acid (a) with the relevant alcohol in the presence of a catalyst, e.g. a strong acid, dry hydrogen chloride or p-toluenesulfonic acid; or

(b) with the appropriate halide or sulfate of the alcohol in the presence of dimethylsulfoxide and calcium carbonate or with the halide in the presence of hexamethylphosphoramide, or (c) by phase transfer catalysis methods with the halide and/or sulfate of the alcohol in aqueous and/or organic solution in the presence of a quaternary

ammonium salt, eg* tetrabutylammonium bisulphate or halide or benzyltrimethylammonium halide.

The formation of compounds (II) where R3" is an ester can also be carried out by conventional transesterification methods, e.g. reaction of an ester with the relevant other alcohol in the presence of a catalyst, e.g. the sodium salt of the alcohol, or dry hydrogen chloride . where R^- is a group of formula-:

where R^. is the hydrocarbon residue of an alcohol or phenol. . Compounds where R"*" contains a carboxylic acid group can also be prepared by the acid- or base-catalyzed hydrolysis of the corresponding compound of formula (II) where R''" is selected from:

å) the carboxylic acid amide group:

b) the nitrile group (-C=N):

c) the esterified carboxylic acid group.

Hydrolysis of amides can be carried out using

a mineral acid as a catalyst, preferably hydrochloric or sulfuric acid. Base-catalyzed hydrolysis can be carried out using an alkali metal or alkaline earth metal hydroxide, e.g. sodium or potassium hydroxide. The hydrolysis reaction is usually carried out in aqueous solution, and fairly strict reaction conditions are preferred, e.g. reflux cooling for several hours. The desired compound can be isolated in the form of the free acid by neutralization of the resulting reaction mixture or in the form of the appropriate base addition salt (e.g. the sodium salt if sodium hydroxide was used) or in the form of the acid addition salt

.(eg the hydrochloride if HCl was used). Alternatively, the free acid can be converted to any desired salt by standard methods. Upon hydrolysis of a compound where R^" is a nitrile group, ammonia is released, and therefore the preferred catalyst is an acid that will bind aramonia, e.g. a hydrogen -halide, e.g. HCl or HBr. If base-catalyzed hydrolysis is used, ammonia is liberated and the acid will be obtained as an alkali salt or, after neutralization, as the free acid. For hydrolysis of an esterified carboxylic acid group, the process preferably involves hydrolysis with a strong base, e.g. sodium hydroxide. The esterified carboxylic acid groups R* can be e.g. lower alkoxycarbonyl groups, e.g. methoxycarbonyl or tert-butoxycarbonyl groups. The remarks previously made regarding salts of the resulting free acid, is also suitable in this case.

A further method for preparing compounds of formula (II) where s}~ is a carboxylic acid group, comprises carbonation of a compound of formula (II); where R"*" is a group of formula:

-MX

followed by hydrolysis, where M is magnesium, calcium or lithium,

and X is chlorine, bromine or iodine. Such reagents are of course well known in the field and can be prepared by known methods. Carbonization is preferably carried out using gaseous carbon dioxide, but solid carbon dioxide may occasionally be used. Hydrolysis of the intermediate product that forms after carbonization can be carried out simply by adding water.

Compounds of formula (II) where R is a hydroxymethyl group can be prepared by reduction of the compound where R 1 is a formyl or ester group, e.g. with sodium borohydride.

Compounds where R<1>contains one carboxyl group

can be produced by oxidation of the corresponding precursor of formula (II) where R1 is selected from:

a) formyl; b). methyl; c) hydroxymethyl; d) acyl.

Examples of the reagents that can be used to effect such boxidations include respectively: a) basic silver oxide or concentrated nitric acid; b) acid sodium or potassium dichromate; c) manganese dioxide followed by basic sulfur dioxide; . d) a hypohalite. The acyl group can be an acetyl- group (CH^CO). The hypohalide reactant is preferably sodium hypohalide which can be generated. in situ in aqueous solution by reacting sodium hydroxide with a mixture of iodine and potassium iodide.

The desired free acid can be isolated and converted into

any desired salt by known methods.

Compounds of formula (II) where R and R are both hydrogen, and in a cis configuration, can be prepared by hydrogenation of the corresponding acetylene of formula (VIII):

Catalytic hydrogenation can often be used in the presence of palladium on barium sulphate.

Compounds according to the invention can also be prepared by reacting a compound of formula (IX) or (X) with a compound of formula (XI) or reacting a compound of formula (XII) with a compound of formula (XIII) or (XIV). where the symbols R 2 - R 7 and Z are as defined with respect to formula (II), and Ra» Rtø °9“ Rcer are the same or different and each is lower alkyl, aryl or aralkyl.

The reaction is usually carried out in an inert solvent, e.g. in dimethylformamide, at a temperature of from approx. 10 to approx. 100°C. Under these conditions, the reaction proceeds smoothly over a period of from a few minutes to a few hours, and the product can be isolated by any of the usual techniques, e.g. solvent evaporation or anti-solvent precipitation followed by filtration. In many cases the reaction can be carried out in a solvent in which the product is insoluble, and in such cases the precipitated solid can be collected by filtration. Purification of the product can take place by any of the usual chromatographic or recrystallization techniques.

During the preparation of the starting materials (IX), (X), (XI), (XII), (XIII) or (XIV), and above all the final product (II), it may be desirable to protect any particularly reactive groups that are present. Thus, free carboxylic acid groups are preferably protected by esterification. Free amino groups can be protected using the groups known for the purpose of peptide synthesis.

The following examples illustrate the invention.

In these examples, the products that can exist as geometric isomers are a mixture of cis and trans isomers unless otherwise specified.

Example 1

Ethyl- 3-[ 4-(( 3- methyl- but- 2- enyloxy)- phenyl)]- propionate

Sodium (1.6 g, 0.07 m) was dissolved in 50 ml of absolute ethanol with protection against atmospheric humidity. To this was added a solution of ethyl 3-(4-hydroxyphenyl)-propionate (9.7 g, 0.05 mol) in absolute ethanol (25 ml), and the mixture was stirred for 30 minutes at room temperature. 1-Bromo-3-methyl-but-2-ene (6.7 g, 0.05 mol) in absolute ethanol (25 mL) was added dropwise to the stirred solution, and the mixture was refluxed with stirring for 6 h . The mixture was cooled, the inorganic salts filtered and washed with 30 ml of cold ethanol and the filtrate evaporated. The evaporation residue was dissolved in 150 ml of dichloromethane. washed 2 times with 100 ml of 5% sodium hydroxide solution <g>, once with 100 ml of water, dried over anhydrous magnesium sulfate so that 8.0 l g of crude product was obtained. This was distilled to give ethyl 3-14-((3-methyl-but-2-enyloxy)-phenyl)]-propionate (5.0 g, 38%) which boils at 178-182°C (3mm ).

Free potassium carbonate (lo g»0i'O7 m) bl©suft.$eatiéxt in BO ml -aasefeo»^ ^yl^3»{4^l3iy^-?oi^phenyl)^iE©piotiafe (å»2 o( u5 ra) was added and the mixture undisturbed vad^omtempeiratur åens t^os-l-feE^Eitaattt-S-røa (£,6S 0*05 at) , o^l^st in 40 ml of acetoa» bi« added dropwise. The mixture was boiled under reflux with stirring for 4 hours, cooled to room temperature, filtered through a strainer of solvent and vacuum. The residue was refluxed at 100°C and washed twice with lOO ml S% x^triafiihy^eoxydl^aiiftf, once with lOO ml of water and dried over anhydrous magiiesianrattlfat. Filtration and foréarapation of the solvent rö'råprøaaSttefc (8.37 g}.. S«tt^.bl© fi@sfeill.Wt -«ttdtt. raAowHCte ,ts|4dc slilft *t mn fi&k traas.-et^l-a*t4'-{bat-2-^ «oyl«l*^£^ {6,199, SOSS) s«ssi Icfcker v®é l$3~iS§°C

Example 31

3- 14'-(but^ 2-enyl-1-oxy)-phenyl1- propionic acid

Ethyl 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate (48 g, 0.194 m) was dissolved in 100 ml of absolute alcohol, and a solution of sodium hydroxide, (10 g„ 0 .25 m) in lOO ml of water was added. The mixture was refluxed for 18 hours, cooled and extracted twice with 100 ml of dichloromethane. The aqueous layer was acidified with 1056 hydrochloric acid and the product filtered and dried under vacuum at 65°G. Crystallization from 20% aqueous ethanol gave 3-[4(but-2-eryyl-1-oxy)-phenyl]-propionic acid (27.36 g, 64%) melting at 107-108°C.

Example 32

4'-(but-2-enyl-1-oxy)-benzoic acid was prepared by the method according to Example 31, crystallized white from 30% aqueous ethanol; yield 81%, m.p. 173-175°C.

Example 33

Sodium - 3- 14'-(but-2-enyl-1-oxy)-phenyl]- propionate

3^1,4'-(but-2-enyl-1-oxy)-phenyl]-propionic acid (4.40 g, 0.02 m) was suspended in 20 mL of water, and sodium bicarbonate (1.68 g; 0 .02 m) in 10 ml of water was added. The mixture was heated on a steam bath for 1 hour and the water removed under vacuum. The last traces of water were removed by azeotropic distillation with ethanol and then the residue was triturated with acetone. The acetone suspension was filtered and the product dried under vacuum at 60°C to give analytically pure sodium 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate (4.26 g, 88% ) which melts at 284-285°C.

Example 34

Sodium 4'-(but-2-eny-yl-oxy)-benzoate was prepared by the method described in Example 33; dividend; 88%, m.p. >3p0°C.

Example 35

3-[4'-(but-2-enyl-1-oxy)-phenyl]- propionoyl hydrazide

Ethyl 3-[4<*->(but-2-enyl-1-oxy)-phenyl]-propionate (5. g, 0.02 m) was dissolved in absolute ethanol, hydrazine (20 mL of 40% solution ) was added and the mixture boiled under reflux for 6 hours - The mixture was allowed to stand at room temperature overnight and was then diluted with 100 ml of water. The solid product was filtered off, dried under vacuum at 60°C and crystallized from ethanol to give 3rl4<*->(but-2-enyl-1-oxy)-phenyl]-propionoylhydrazide (4.33 g, 93 %) which melts at 125-127°C.

Example 36

5-14'-(but-2-enyl-1-oxy)-phenyl]- tetrazole

4-(but-2-enyl-1-oxy)-benzonitrile (8.65 g, 0.05 ra), sodium azide (3.75 g, 0.051 m) and ammonium chloride. (7.5 g, 0.15 m ) was mixed in dry dimethylformamide and heated at 115 C with stirring for 36 hours. The mixture was cooled to room temperature, the solvent removed under vacuum, the residue suspended in 100 ml of water and acidified to pH 2 using concentrated hydrochloric acid. The product was filtered off, dried and crystallized from absolute ethanol to give 5-14'-(but-2-enyl-1'-oxy)-phenyl]-tetrazole (8.32 g, 77%) which melts at 214-216C.

Example 37

Methyl-3-[4(but-2-enyl-1-oxy)-phenyl]- propionate

Ethyl 3-14<*->(but-2-enyl-1-oxy)-phenyl]-propionate (5.0 g, 0.02 m) was dissolved in a solution of 0.5 g sodium in 150 ml methanol. The mixture was refluxed for 5 hours, cooled and the solvent removed under vacuum. 50 ml of water was added to the residue and the product extracted 2 times with 50 ml of midichloromethane. The organic extracts were dried (MgSO 4 ) and evaporated to give the crude methyl ester (4.94 g). This was distilled so that methyl-3-14,-(but-2-enyl-1-oxy)-fertyl]-propionate was obtained (4.48 g, 96%) which boils at 142-145°C (0 .3 mm).

Example 38

4-(but-2-enyl-1-oxy)-acetophenone

4-Hydroxyacetophenone (13.6 g, 0.1 m) was dissolved in

50 ml of dry dimethylformamide in a 3-necked flask equipped with stirrer, dropping funnel and condenser with calcium chloride drying tube. Sodium hydride (3.0 g, of an 80% suspension in paraffin, 0.1 m) was added portionwise with stirring and was stirred at 50°C until the reaction ceased. The mixture was cooled to room temperature and a solution of l-bromo-but-2-ene (13.5 g, 0.1 m) dissolved in 20 ml of dimethyl formamide was added dropwise with stirring. The mixture was stirred for 2 hours at room temperature, 1 hour on a steam bath, cooled to room temperature and then added to 100 ml of ice water. The product was extracted with ether (2 x 100 ml), washed twice with 100 ml of 5% sodium hydroxide solution, once with 100 ml of water, dried over MgSO 4 and evaporated. The product was distilled to give 4-(but-2-enyl-1-oxy)-acetophenone (10.43, 55%); which boils at 149-152°C (1.5 rm).

Example 39

4-(but-2-enyl-1-oxy)-benzaldehyde was prepared by the method described in example 38; yield: 61%,

bp: 124-126°C at 0.9 mm.

Example 40

Trans-ethyl-4-(but-2-enyl-1-thio)-benzoate

Diethyl-4,4'-dithiobisbenzoate (8.30 g, 0.023 m) was dissolved in 275 mL of absolute ethanol at room temperature, and sodium borohydride (1.83 g, 0.048 m) was added to the stirred solution, which was then stirred at room temperature for 90 minutes during which time the solution turned yellow. A solution of traris-1-bromo-but-2-ene (6.21 g, 0.046 µm) in 20 mL of ethanol was added and the mixture stirred at room temperature for 3 hours. After this time, the solvent was removed under reduced pressure, the residue was dissolved in ether, washed with 50 ml of 10% aqueous sodium carbonate, 100 ml of water and

100 ml of brine, dried over MgSO4 and evaporated to give a pale yellow oil which crystallized on standing. Crystallization from 40-60° gasoline gave trans-ethyl-4-(but-2-enyl-1-thio)-benzoate (4.60 g, 43%) as colorless small leaves. Temp. 41-42 C.

Example 41

(a) Ethyl-3-[4'-(but-2-vinyl-1-oxy)-phenyl]- propionate

... Sodium (2.4 g, 0.104 m) was dissolved in 80 ml of absolute ethanol under protection from atmospheric moisture, and until the solution became. added a solution of ethyl 3-(4-hydroxyphenyl)-propionate (20.6 g", 0.106 m) in ethanol (20 mL). The mixture was stirred at room temperature for 30 min and treated dropwise with a solution of but-2 -ynyl methanesulfonate (12.5g, 0.08m) in ethanol (20ml) The mixture was refluxed for 3h with stirring, cooled, filtered and the solvent removed under vacuum.

The product was diluted with 100 ml of water, extracted with ether, washed twice with 100 ml of 5% sodium hydroxide solution, once with 100 ml of water, dried over MgSO 4 and evaporated to give the crude product (19 g). Distillation of the product gave ethyl 3-[4'-(but-2-ynyl-1-oxy)-phenyl]-propionate (8.66 g, 44%) boiling at 162-166°C (2 mm).

(b) cis-ethyl-3-(4'-(but-2-enyl-1-oxy)-phenyl]-propionate

Ethyl-3-t4'-(but-2-ynyl-1-oxy)-phenyl]-propionate (4.1 g, 0.0167 m) in methanol (30 ml) in the presence of 5% palladium on bariura -sulfate (0.15 g) and quinoline (0.35 ml) were hydrogenated at atmospheric pressure until exactly one equivalent of hydrogen (375 ml) had been absorbed. The catalyst was filtered from below

vacuum, the solvent evaporated and the product dissolved in 50 ml of ether. The ether solution was washed 2 times with 50 ml of 5% hydrochloric acid,

once with 50 ml of saturated sodium bicarbonate solution and once with 50 ml of water, dried over MgSO 4 and evaporated. The crude product was distilled to give cis-ethyl-3-14'-(but-2-enyl-1-oxy)-phenyl3-propionate (3.43 g, 83%) which boils at 146-150°C (1 .5 mm).

Example 42.

Similar to Example 41, there was prepared": (a) Ethyl-3-14'-(hept-2-ynyl-1-oxy)phenyl]-propionate; (yield:

61%, kp. 176°C at 1.6 mm).

(b) cis-ethyl-3-[4'-hept-2-enyl-1-oxy)-phenyl]-propionate; (yield: 94%, bp. 182-184° at 2.5 mm).

Example 43

4-[3-methyl-but-2-enyl-1-oxy]-benzyl alcohol

4-(3-Methyl-but-2-enyl-1-oxy)-benzaldehyde (7.6 g, 0.04 m) was dissolved in 100 mL of ethanol, sodium borohydride (0.4 g, 0.012 m) was added and the mixture boiled under reflux for 1 hour. The mixture was cooled, the solvent removed under vacuum, the product dissolved in 100 ml of dichloromethane, washed with 100 ml of water, dried over MgSO 4 and evaporated to give 5.92 g of crude product. Pure 4-[3-methyl-but-2-enyl-1-oxy]-benzyl alcohol (2.3 g, 3%), m.p. 42°C, was obtained by chromatography on silica gel in dichloromethane.

Biological data

The hypocholesterolemic and/or hypotriglyceridemic effects of various compounds according to the invention were shown in the following experiments: Groups of 8 male albino rats (C.F.Y. strain), weight to- approached 150 g, was given one powdered, commercial to- common diet ("Oxoid") to which compounds were added in an amount of 0.25%. These diets were fed in 7

days. The rats were then killed, and their total serum cholesterol and triglyceride were measured by Technicpn Auto analyzers.

Table 1 shows the results expressed as percent cholesterol reduction and percent triglyceride reduction compared to control samples.

Claims (2)

1. Process for preparing a compound of formula: 2 3 4 R 1 where one of the groups R , R and R represents a group -(CH0) R 2 3 4 q and the remaining groups R , R and R are hydrogen; Z is oxygen or sulfur; R~*, R and R are independently hydrogen or a lower alkyl group; and either (i) q is zero, one or two and R is cyano; or (ii) q is an integer from 2 to 12, and R"*" is a carboxylic acid group or a pharmaceutically acceptable non-toxic salt, an ester, an amide or hydrazide thereof, an alkyl group which is optionally substituted with one or more hydroxy or lower alkoxy groups; a cyano-, formyl-, acyl-, or carboxyl-substituted acyl group; under the proviso that when Z is oxygen, and q is 2, then R is not a carboxylic acid group, characterized by :(A) reaction of a compound of formula (VI): with a compound of formula (VII ): where one of P or Q is -ZH (where Z is as defined in claim 13) or a reactive derivative thereof, and the other is an easily displaceable group; or (B) reacting a compound of formula (IX) or (X) as defined here, with a compound of formula (XI) as defined here, or reacting a compound of formula (XII) as defined here, with a compound of formula (X III ) or (XIV) as herein defined; and (C) after step (A) or step (B) possibly converting one group into another group R1. 2.. Method as stated in claim 1., characterized in that Z is oxygen. 3. Method as stated in claim 1 or 2, characterized in that R <5> is hydrogen. 4.. Process as stated in claim 1 for the preparation of a compound of formula: where R is a lower alkyl group or a carboxylic acid ester-6 7 group; s is an integer from 2 to 6, and R and R are like those veneered in claim 13. 5.. Method as stated in claim 1 for the production of a compound selected from: ethyl 3-[4-(3-methyl-but-2-enyloxy)phenyl]-propionate; 4-(but-2-enyl-1-oxy)-benzyl ethyl ether; ethyl 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate; ethyl 2-(but-2-enyl-1-oxy)-benzoate; ethyl 4-(but-2-enyl-1-oxy)-phenylacetate; 4-(but-2-enyl-1-oxy)-benzonitrile; 2-(but-2-enyl-1-oxy)-acetophenone; 3-(but-2-enyl-1-oxy)-acetophenone; 4-(but-2-enyl-1-oxy)-ethylbenzene; iso-propyl-3-[4<1-(but-2-enyl-1-oxy)-phenyl]-propionate; 4-[4'-(but-2-enyl-1-oxy)-phenyl]-butan-2-one; ethyl 1-2-(but-2-enyl-1-thio)-benzoate; benzyl 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate; n-hexyl-3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate; 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionic acid; 4'-(but-2-enyl-1-oxy)-benzoic acid; sodium 3-[4<1-(but-2-enyl-1-oxy)-phenyl]-propionate; sodium 4'-(but-2-enyl-1-oxy)-benzoate; 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionoyl hydrazide; 4-(but-2-enyl-1-oxy)-acetophenone; ethyl 4-(but-2-enyl-1-thio)-benzoate; ethyl 3-[4'-(but-2-enyl-1-oxy)-phenyl]-propionate; ethyl 3-[4'-(hept-2-enyl-1-oxy)-phenyl]-propionate. K. Process for the preparation of a compound of formula (II) where R"*" is a carboxylic acid ester group, characterized by: a) esterification of the corresponding compound of formula (II) wherein R"*" is a carboxylic acid group; or b) transesterification of the corresponding compound of formula (II) where R"'' is a different, esterified carboxylic acid group; or c) alkanolysis of a compound of formula (II ) where R 1 is a nitrile group (-C sN); or d) hydrolysis of a compound of formula (II) where R is an iminoether group of formula: where R is the hydrocarbon residue of an alcohol or phenol. ?• Process for the preparation of a compound of formula (II) where R^ is a carboxylic acid group, characterized by : a) oxidation of the corresponding precursor having formula (II) where R is selected from: formyl; methyl; hydroxymethyl; and -acyl; or b) acid- or base-catalyzed hydrolysis of the corresponding compound of formula (II) wherein R<1> is selected from: carboxylic acid amide group; nitrile group; esterified carboxylic acid group; c) carbonization of a compound of formula (II ) where R is a group of formula: -MX followed by hydrolysis, wherein M is magnesium, calcium or lithium, and X is chlorine, bromine or iodine. 8. Process for producing a compound of formula (II) where R is a hydroxymethyl group, characterized by reduction of the compound of formula (II) where R<1> is a formyl or carboxylic acid ester group. 9.. Process for the preparation of a compound of formula (II) where R^ and R<6> are both hydrogen and in cis configuration, characterized by hydrogenation of a compound of formula (VIII): 2 3 4 7 where R , R , R , R and Z are as defined in claim 1.. 10. Intermediate of formula (VIII): where R <2> , R <3> , R <4> , R <7> and Z are as defined in claim 1.