IE45905B1 - Substituted furan and thiophen alkyl ketones - Google Patents

Abstract

Compounds of the following general structure are useful as antirhinovirus agents: wherein Y Is a bond, oxygen or divalent sulfur; X is oxygen or sulfur; R is a straight or branched hydrocarbon chain having from 6 to 20 carbon atoms and is saturated or unsaturated having from 1 to 4 double bonds when R has from 10 to 20 carbon atoms and l or 2 double bonds when R has from 6 to 9 carbon atoms; and R, is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms; with the proviso that when Y is a bond the R-Y group is attached at the 4- or 5- position of the heterocycltc ring.

Description

This invention relates to substituted furan and thiophene alkyl ketones which are useful as anti-rhinovirus agents. Some of these compounds are hovel.

Compounds of the formula wherein Y is oxygen or sulphur and R is saturated hydrocarbyl of 10 to 20 carbon atoms or unsaturated hydrocarbyl of 10 to 20 carbon atoms and having from one to 4 double bonds, are disclosed as intermediates in the preparation of hypolipidemic agents in Belgian Patent Specification No. 842,969 and British Patent Specification No. 1,496,307.

Compounds of the formula II wherein Y and R are as defined above, are also disclosed 15 as intermediates in the preparation of hypolipidemic agents, in British Patent Specification No. 1,417,103.

According to a first aspect of the present invention, a pharmaceutical composition comprises a compound of the formula 4S905 R-Y / COR.

III wherein X is oxygen or sulphur; R^ is alkyl of one to 4 carbon atoms; and Y and R are as defined above, in association with a pharmaceutically acceptable carrier which is a solid or a sterile liquid.

A second aspect of the present invention provides compounds of formula III in which R^ is alkyl of 2 to 4 carbon atoms.

Illustrative examples of straight or branched saturated hydrocarbon groups which R may represent are tetradecyl,3,7-dimethyloctyl, 2,4-diethylnonyl, 1-methylundecyl, pentadecyl, hexadecyl, heptadecyl, 3-methyloctadecyl, nonadecyl and didecyl.

Illustrative examples of straight of branched unsaturated hydrocarbon groups containing one to 4 double bonds which R may represent are lo-undecenyl, 9,12-octadecyldienyl, 3,7,11 - trimethyl - 2,6,10 - hexadecyltrienyl, 3,7 - dimethyl - 2,6 - octadienyl, 5,9 - dimethyl - 2,4,8decatrienyl, 4,6 - dimethyloct - 3 - enyl, 1,2,5,9 - tetramethyl - 2,4,8 - dicatrienyl and 11 - didecenyl.

Illustrative examples of straicjht or branched lower alkyl groups of from one to 4 carbon atoms which R^ may represent are methyl, ethyl, n-propyl·, isopropyl, n-butyl and tert-butyl.

In the compounds of the invention, the RY group may be attached to any of the 3-, 4- and 5-positions of the furan or thiophene ring, but it is preferably attached at - 4 4590S the 5-position.

In the compounds of formula III, Y is preferably oxygen. R^ is preferably straight chain, rather than branched chain, alkyl. X is preferably oxygen, R prefer ably has from 12 to 16 carbon atoms. Most preferably, R has 14 carbon atoms.

In the novel compositions of this invention, the compounds of formula III in which Rl is methyl are particularly preferred. illustrative examples of compounds of formula III are the following: methyl 2-(5- tetradecylthio)furyl ketone, ethyl 2-(5- dodecylthio)furyl ketone, n - propyl 2-(4- decylthio)furyl ketone, isopropyl 2-(3- undecylthio)furyl ketone, n - butyl 2 - (4 - tridecylthio)furyl ketone, tert - butyl 2-(5- octadecylthio)furyl ketone, methyl 2-(5- tetradecylthio)thienyl ketone, ethyl 2-(5- dodecylthio)thienyl ketone, n - propyl 2-(4- decylthio)thienyl ketone, isopropyl 2-(5- tetradecylthio)thienyl ketone, n - butyl 2-(3- pentadecy lthio)thienyl ketone, tert - butyl 2-(4- heptadecylthio)thienyl ketone, methyl 2-(5- octadecylthio)thienyl ketone, methyl 2-(5- tetradecyloxy)furyl ketone, ethyl 2-(5- dodecyloxy)furyl ketone, ethyl 2-(3- tridecyloxy)furyl ketone, n - butyl 2-(4- undecyloxy)thienyl ketone, tert - butyl 2-(3- didecyloxy)thienyl ketone, ethyl 2-(5- dodecyloxy)thienyl ketone, methyl 2-(5- tetradecyloxy)thienyl ketone, n - propyl 2-(5- pentadecyloxy)thienyl ketone. - 5 isopropyl 2-(3- hexadecyl)furyl ketone, n - butyl 2-(3- tridecyl)thienyl ketone, methyl 2-(5- tetradecyl)thienyl ketone, methyl 2-(5- tetradecyl)furyl ketone, ethyl 2-(5- dodecyl)furyl ketone, methyl 4 - (3,7 - dimethyloctyl) - 2 - furyl ketone, ethyl 5 - (2,4 - diethylnonyl) - 2 - thienyl ketone, methyl 5 - (2,4 - diethylnonylthio) - 2 - thienyl ketone, methyl 5 - (9,12 - octadecadienyl) - 2 - furyl ketone, - (3,7,11 - trimethyl - 2,6,10 - hexadecatrienyloxy)2 - furyl ketone, and ethyl 5 - (4,6 - dimethyloct - 3 - enylthio) - 2 - furyl ketone.

The compounds of formula III are useful as antirhinovirus agents. The rhinovirus genus, which is a member of the picornavirus family, contains over 100 different antigenic types, and is known to be responsible for many of the symptoms associated with respiratory infections. The name rhinovirus is indicative of the prominent nasal involvement seen in infections with these viruses resulting in syndromes characteristic of the common cold. Khinoviruses have been classified as serotypes 1 to 89 and subtypes IA (88, 89, 90) with at least 20 more types to be added to the classification. Experimental studies indicate that nasal mucosa is more susceptible to rhinovirus than is the lower respiratory tract. The symptoms of rhinovirus infection have also been produced experimentally by dropping small amounts of the virus on the conjunctiva, indicating that the dye is another site susceptible to infection. Developed rhinovirus infection is characterised by hyperemia and edema of the mucous membrane with exudation of serous and mucinous fluid. The - 6 nasal cavities are narrowed by thickening of the membrane and engorgement of the turbinates.

The compounds described herein have been found to be effective antiviral agents against numerous types of rhino5 virus rendering said compounds useful in treating the symptoms of a rhinovirus infection in hosts susceptible to said infections including humans and certain anthropoid apes such as the chimpanzee. It is known in the art that several test systems can be employed to measure antiviral activity against rhinovirus. For example, antirhinovirus activity can be measured using a plaque assay or tube test wherein the activity of the compound against virus challenge in a cell system is measured. Using a variety of test systems it was found that compounds of formula III are effective antirhinovirus agents when the test compound is given prior to, concurrently with or subsequent to virus challenge. The utility of the compounds described herein as antirhinovirus agents has been demonstrated in a variety of test systems. For example, using HeLa cell cultures to which a rhinovirus challenge of from 30 to 100 ΤΟΙΟ^θ is added concurrently with test compounds at a concentration of 4, 20 or 100 |ig/ml after which the cell cultures are incubated for 48 hours it was found upon microscopic examinations of the cell cultures that compounds of formula III markedly inhibit the cytopathic effect of the virus when compared to cell cultures containing virus challenge. For example, when the compound of Example 1 at a concentration of 4 p.g/ml was added to cell cultures together with a rhinovirus challenge of 100 TCID5Q the cyto30 pathic effect of virus was inhibited by 87% when compared to control. In a tube test system using HeLa cells it was found that the tissue culture ED^0 of the compound of 9 0 5 - 7 Example 1 is 0.3 (ig/ml.

In the treatment of symptoms of rhinovirus infection the compounds of formula III can be administered orally, topically, for example, intranasally, and parenterally, for example, intramuscularly. Topical administration is preferred. The compounds are administered preferably in the form of a pharmaceutical preparation to a host susceptible to rhinovirus infection either prior to or after invasion of virus or after onset of the infection. Por prophylactic treatment it is contemplated that an antirhinovirus effective amount of compound be administered for from about 1 to 5 days prior to anticipated exposure to virus and from about 5 to 10 days subsequent to exposure or from about 5 to about 15 days subsequent to exposure to rhinovirus. It is known that rhinovirus is readily transmitted from one susceptible host to another as commonly occurs, for example, among family members, in classrooms and in military populations. The compounds of general Formula I are also useful therapeutically in treating rhinovirus infections in that said compounds are effective in diminishing or blocking replication of the virus.

For prophylactic or therapeutic treatment of rhinovirus infection any antirhinovirus effective amount of a compound of formula III may be employed. For therapeutic treatment the amount of compound administered will vary depending primarily on the severity of the infection. For therapeutic or prophylactic treatment the amount of compound administered will vary from about 0.1 mg/kg to 15 mg/kg of body weight of the patient, that is, susceptible host. Preferably the amount of compound administered will vary from about 1 mg/kg to about 3 mg/kg. Typically a unit dose containing about 25 mg of compound administered 43905 - 8 from 1 to 6 times daily will achieve the desired effect.

The compound of formula III together with suitable pharmaceutical carriers can be in the form of solid unit dosage forms such as tablets, capsules, powders, or in the form of a suppository. The powders oan be administered orally or by insufflation. In the preparation of solid unit dosage forms it may be desirable to micronize the compound to be employed. In solid unit dosage forms the compounds can be combined with conventional carriers, for example, binders, such as acacia, corn starch or gelatin, disintegrating agents, such as, corn starch, potato starch or alkinic acid, lubricants, such as, stearic acid or magnesium stearate, and inert fillers, such as, lactose, sucrose or corn starch.

The compounds of formula III may also be administered as liquid suspensions or solutions using a sterile liquid, such as, an oil, or water with or without the addition of a pharmaceutically suitable surfactant or emulsifying agent for oral, topical or parenteral administration. A particu20 larly suitable mode of administration is a liquid formulation of the compounds applied directly to the nasal cavity, for example, in the form of a nose drop. For liquid prepara tions the compounds can be suitably formulated with fixed oils, such as, peanut oil, sesame oil, cottonseed oil or olive oil. Peanut oil and sesame oil are particularly useful in preparation of formulations for intramuscular injection. Such oils can also be employed in the preparation of formulations of the soft gelatin type and suppositories. In general, water, saline, aqueous dextrose and related sugar solutiohs and glycerols, such as, polyethylene glycol may be employed in the preparation of liquid formula4 ίϊϋ <) sj tions which may suitably contain suspending agents, such as, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose as well as buffers and preservatives.

Illustrative examples of suitable pharmaceutical formulations are set forth hereinbelow.

The ketone compounds of formula ill may be prepared by treating one equivalent of the corresponding carboxylic acid derivatives with two equivalents of an appropriate alkyllithium as generally described by Fieser and Fieser, Reagents for Organic Synthesis, J. Wiley and Sons, Ino., New York, p. 688 (1967). This reaction is suitably carried out in solvents, such as, ether, tetrahydrofuran, p-dioxane, dimethoxyethane or diethyleneglycol dimethylether at temperatures of from -10°C to the reflux temperature of the solvent for from 1/2 hour to 10 hours.

The ketone compounds of formula III may also be prepared by the reaction of alkyl magnesium bromide wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms, and the imidazolide derivative of an appropriate R—Y— substituted thiphene or furancarboxylic acid derivative wherein R and Y are as defined above. This reaction is carried out in solvents such as ether, tetrahydrofuran, dioxane, dimethoxyethane, or acetonitrile.

The reaction mixture is initially cooled to -10°C after which the temperature is elevated to from about 25°C to the reflux temperature of the solvent, and the reaction time varies from about 1/2 hour to 10 hours. The imidazolide derivative is obtained by treating an appropriately R““Y— substituted thiophene or furan carboxylic acid derivative with N,N' - carbonyldiimidazole or by treatment of the R—Y— substituted thiophene or furancarboxylic acid 4S90S chloride, obtained by treating the substituted carboxylic acid with thionyl chloride, with two equivalents of imidazole as generally described by H. A. Staab, Angew. Chem. Internat. Edit. .1 351 (1962).

The ketone compounds of formula III wherein the R—Y— substituent group is attached at the 5-pcs ition of the furan or thiophene ring may also be prepared by a Friedel - Crafts acylation of an appropriately R—Y— substituted thiophene or furan, wherein R and Y are as defined above with an acyl halide of the formula R^—COHal wherein hal is halogen, preferably chlorine or bromine, and is a straight or branched alkyl group of from 1 to 4 carbon atoms. This reaction is carried out in the presence of an acid catalyst, for example, borontrifluoride etherate, stannic chloride, zinc chloride, hydriodic acid or orthophosphoric acid and optionally in the presence of a solvent, for example, methylene chloride, nxtromethane or benzene. Suitable temperatures for this reaction vary from -20°C. to the reflux temperature of the solvent, and the reaction time varies from 30 minutes to 10 hours.

The R—Y— substituted thiophene derivative employed herein wherein Y represents sulphur can be obtained in the manner described by E. Profft, Chemiker-Zeitung, 82 298 (1958). The corresponding derivatives wherein Y represents oxygen can be prepared from 3 - thiolene - 2 - one (R. P. Hawkins, Journal Heterocyclic Chemistry, 11 (3) 291—4 (1974,) with a suitable alkyl halide, alkyl mesylate or alkyl tosylate in the presence of a base such as, for example, sodium hydride, potassium amide, potassium tertbutylate, sodium or potassium metal, potassium carbonate, sodium carbonate, triethylamine or pyridine, to yield the - 11 43995 - alkoxythiophene intermediate. This reaction may be carried out with or without a solvent. Suitable solvents include pyridine, benzene, xylene, chlorobenzene, ethers such as bis(2 - methoxyethyl)ether or anisole, dimethyl5 formamide, dimethylacetamide and hexamethylphosphoric triamide. The alkyl halide may be, for example, an alkyl chloride, an alkyl bromide or an alkyl iodide. The alkyl radical in the alkyl halide, the alkyl mesylate or the alkyl tosylate is R as defined above.

The R—Y— substituted furan derivatives employed herein can be obtained by thermodecarboxylaticn (above 150°C.) of an appropriately R—Y— substituted furoic acid by procedures known in the art.

The R—Y— substituted furan and thiophene carboxylic 15 acid derivatives used herein can be prepared by aromatic nucleophilic substitution as generally described in J.

March, Advanced Organic Chemistry; Reactions, Mechanism and Structure, McGraw Hill (1968), page 500, as outlined below.

COOH base acid COOH IV In the above reaction R, X and Y are as defined above and L represents a leaving group such as nitro, fluorine, 43905 chloride, bromine or iodine, the preferred leaving group being chlorine. The substituent group L on compounds of formula IV and the R—Y— group on compounds of formula V may be attached at the 3-, 4- or 5-position of the thiophene or furan ring.

The above reaction may be carried out with or without a solvent. Suitable solvents for the reaction include benzene, xylene, toluene, chlorinated hydrocarbon solvents such as chlorobenzene, ethers such as bis(2-methoxyethyl)ether, 1,2 - dimethoxyethane or anisole, dimethylformamide, dimethylacetamide, 1-methyl - 2 - pyrrolidone or pyridine. Preferred solvents are xylene and dimethylacetamide. Copper metal or a salt such as cuprous chloride may be optionally added to the reaction. Suitable bases for the reaction include sodium or potassium metal, sodium hydride, potassium amide, potassium tert-butyla te or other strong bases such as potassium carbonate, potassium hydroxide, sodium hydroxide and sodium carbonate. The temperature of the reaction varies from about 25°C to the reflux temperature of the solvent, and the reaction time varies from 1 hour to 7 days. Following completion of the reaction the earboxylate salt derivative is treated with a mineral or organic acid to give compounds of formula V.

Alcohols as represented by R—Y—H which find use in the above general reaction are commercially available or may be prepared by reduction of the corresponding carboxylic acid or aldehyde.

The thiophene carboxylic acid derivatives as represented by compounds of formula IV wherein X is sulphur may be prepared by several methods as described in the Chemistry of Heterocyclic Compounds, Thiophene and Its Derivatives, AS9 0 5 - 13 by H. D. Hartough, Interscience Publishers, Inc., New York pp. 379—381 (1952). The furoic acid derivatives as represented by compounds of formula IV wherein X is oxygen may be prepared by several methods as described in The Furans, by A. P. Dunlop and F. N. Peters, Reinhold Publishing Corp., pp. 80—169 (1953).

Examples 1 to 8 illustrate how compounds of formula III may be prepared. Examples 3, 5 and 7 illustrate the preparation of novel compounds of formula III.

Example 1 Methyl 2-(5-tetradecyloxy)furyl ketone (A) A mixture of 125.0 (0.652 mole) of 5 - bromo2 - furoic acid, 210.0 g (0.978 mole) of 1 - tetradecanol, 183.0 g (1.630 mole) of potassium ter t-butoxide and 250 ml of dimethylacetamide is heated with stirring. The tert-butanol formed in the reaction is allowed to distill off, then the mixture is heated to reflux with stirring for 48 hours. To'the cooled mixture is added 6 litres of ice-water, and the mixture is acidified with malonic acid. The resulting precipitate is collected dried and recrystallised twice from methanol to give 82.0 g (29%) of 5 - (tetradecyloxy) - 2 - furoic acid, M.P. 112—115°C (dec.).

(B) A mixture of 82.0 g (0.253 mole) of 5 - (tetradecyloxy) - 2 - furoic acid, 41,0 g (0.253 mole) of N,N'carbonyldiimidazole and 800 ml tetrahydrofuran is stirred at room temperature during which time carbon dioxide gas is evolved. The reaction mixture is cooled to 0°C to give imidazole, 50.0 g (0.134 mole) in 500 ml tetrahydrofuran is cooled in an ice bath. An equivalent amount of methyl magnesium bromide (50 ml of a 3 M solution in ether) is 4S90S - 14 slowly added over a 2 hour period to the stirred mixture.

The reaotion is stirred for an additional 3 hours then excess (500 ml) of 2N HCl is added and the product extracted into ether. The ether extract is separated, washed with water, dried over sodium sulfate, filtered and evaporated to dryness to give methyl 2-(5- tetradecyloxy)furyl ketone, M.P. 70—72°C.

EXAMPLE 2 Methyl 5 - (cis - 9 - octadecen - 1 - yloxy) - 2 - furyl ketone A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 121.0 g (0.45 mole) of cis-9-octadecenol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue recrystallized from hexane to give 5 - (cis - 9 - octadecen - 1yloxy) - 2 - furoic acid.

When in the procedure of Example 1(B) an appropriate amount of 5 - (cis - 9 - octadecen - 1 - yloxy) - 2furoic acid is substituted for 5 - (tetradecyloxy) - 2furoic acid, methyl 5 - (cis - 9 - octadecen - 1 - yloxy)2 - furyl ketone is obtained.

EXAMPLE 3 Ethyl 5 - (9,12,15 - octadecatrien - 1 - yloxy) - 2furyl ketone A mixture of 57.0 g (0.300 mole) of 5 - bromo-2furoic acid, 119.0 g (0.450 mole) of 9,12,15 - octadecatrienol, and 84 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off, and the - 15 mixture is refluxed at 110°C with stirring for 48 hours.

The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice-water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5 - (9,12,15 - octadecatrien - 1yloxy) - 2 - furoic acid.

When in the procedure of example 1(B) an appropriate amount of 5 - (9,12,15 - octadecatrien - 1 - yloxy) - 2furoic acid is substituted for 5 - (tetradecyloxy) - 2furoic acid, and an appropriate amount of ethyl magnesium bromide is substituted for methyl magnesium bromide, ethyl 5(9,12,15 - octadecatrien - 1 - yloxy) - 2 - furyl ketone is obtained.

EXAMPLE 4 Methyl 2-(5- tetradecyloxy)thienyl ketone (A) A mixture of 214 g (1.0 mole) of 1 - tetradecanol, 59 g (1.46 mole) of sodium hydride (59.5% in oil) and 3 1. of dried xylene is heated to reflux with stirring for two hours, then allowed to cool after which 75 g (0.46 mole) of 5 - chloro - 2 - thiophene carboxylic acid is added. The mixture is refluxed for 64 hours after which it is cooled and poured into a water-ice mixture, acidified with acetic acid and extracted with the addition of ether. The ether is evaporated, and the xylene layer extracted five times with water:strong ammonia solution (1:1). The combined aqueous extract is acidified with acetic acid. The solid obtained is crystallized twice from hexane to give 2-(5- tetradecyloxy)thiophenecarboxylic acid, M.P. 95—96°C. - 16 4590S (Β) A mixture of 86.1 g (0.253 mole) of 2 - (5tetradecyloxy)thiophene carboxylic acid, 41.0 g (0.253 mole) of N,N' - carbonyldiimidazole and tetrahydrofuran, is stirred at room temperature during which time carbon dioxide is evolved, then cooled to give N-[5 - tetradecyloxy) - 2 - thenoyl] imidazole. Tha N-substituted imidazole, 52.3 g (0.134 mole) in tetrahydrofuran is cooled in an ice bath. An equivalent amount of methyl magnesium bromide (50 ml of a 3 molar solution of ether) is slowly added over two hours to the stirred mixture.

The reaction is stirred for an additional three hours.

Then excess (500 ml) of 2N HCl is added and the product extracted into ether. The ether layer is separated, washed with water, dried over sodium sulfate, filtered, and evaporated to dryness to give 5 - (tetradecyloxy)2 - thienyl methyl ketone.

EXAMPLE 5 n - Propyl 5 - (cis - 9 - octadecenyloxy) - 2 - thienyl ketone When in the procedure of Example 4(A) an appropriate amount of cis - 9 - octadecanol is substituted for 1tetradeoanol 5 - (cis - 9 - octadecenyloxy) - 2 - thiophene carboxylic acid is obtained. When an appropriate amount of the thus obtained acid is substituted for 5 - tetra25 decyloxy - 2 - thiophenecarboxylic acid and an appropriate amount of n - propyl magnesium bromide is substituted for methyl magnesium bromide in the procedure of Example 4(Β), n-propyl 5 - (cis - 9-octadecenyloxy) - 2 - thienyl ketone is obtained. - 17 EXAMPLE 6 Methyl 2-(5- tetradecylthio)thienyl ketone A mixture of 18.6 g (0.090 mole) of 2-(5-bromo)~ thiophene carboxylic acid, 25.0 g (.109 mole) of 1tetradecanethiol and 500 ml of dried dimethylacetamide is stirred at room temperature after which 10.8 g (0.200 mole) of sodium methoxide is added. The mixture is heated, and the methanol formed is allowed to spill off. The mixture is refluxed for 24 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with 10% aqueous hydrochloric acid, filtered and the precipitate washed with water and dried. The solid obtained is crystallized from methanol then recrystallized from hexane to give 2-(5- tetradecylthio)thiophene carboxylic acid, M.P. 106—108°C.

To 17.8 g (0.05 mole) of 2 - (5 - tetradecylthio)thiophene carboxylic acid in tetrahydrofuran cooled in an ice bath is added 3.3 g (0.15 mole) of methyl lithium.

The mixture is allowed to warm up to room temperature, then treated with saturated ammonium chloride solution until neutral to litmus paper to give methyl 5 - (tetradecylthio) - 2 - thienyl ketone.

EXAMPLE 7 n - Butyl 2-(5- tetradecyloxy)thienyl ketone A mixture of 20.0 g (0.2 mole) of 3 - thiolen - 2one [R. T. Hawkins, J. Heterocyclic Chem., 11 291—4 (1974)] 65.5 g (0.2 mole) of 1 - bromo - 9,12,15 - octadeeatriene, and 4.8 g (0.2 mole) of sodium hydride in benzene is refluxed with stirring for 24 hours after which the solvent is removed, and the product distilled to give 2(9,12,15 - octadeeatrienyloxy)thiophene. 4S9°5 - 18 To 6.0 g of sodium amalgam in 100 ml of anhydrous ether at reflux temperature (36—39°C) under slight nitrogen pressure is added 34.7 g (0.10 mole) of 2 - (9, 12,15 - octadecatrienyloxy)thiophene in 50 ml of anhydrous ether over a four hour period. The mixture is refluxed an additional two hours. The mixture is cooled to room temperature and carbonated by adding freshly crushed dry ice after which 20 ml of ethanol is added dropwise followed by the addition of 50 ml of water. The aqueous solution is separated from the ether layer, filtered and acidified with hydrochloric acid to precipitate 5 - (9,12, - octadecatrien - 1 - yloxy) - 2 - thiophene carboxylic acid.

To 36.3 g (0.10 mole) of 5 - (9,12,15 - octadecatrien1 - yloxy) - 2 - thiophene carboxylic acid in anhydrous tetrahydrofuran is added 17.4 g (0.107 mole) of H,K'carbonyl - diimidazole. The mixture is stirred at room temperature until the evolution of carbon dioxide gas ceases after which the mixture is evaporated to dryness, and the residue extracted with anhydrous ether. The ether extract is evaporated to dryness to give N - [5 - (9,12, - octadecatrien - 1 - yloxy) - 2 - thenoyl] imidazole.

When an appropriate amount of the thus obtained imidazole is substituted for N - [5 - tetradecyloxy) - 2furoyl] - imidazole and an appropriate amount of n-butyl magnesium bromide is substituted for methyl magnesium bromide in the procedure of Example 1(B), n-butyl 2 - (5tetradecyloxy)thienyl ketone is obtained.

Example 8 When in the procedure of Example 4(A) appropriate amounts of 1 - decanethiol and 3 - chloro - 2 - thiophene 45995 - 19 carboxylic acid are substituted respectively for 1 - tetradecanol and 5 - chloro - 2 - thiophene carboxylic acid 2(3 - decylthio)thiophene carboxylic acid is obtained. When in the procedure of Example 4(B) an appropriate amount of 2-(3- decylthio)thiophene carboxylic acid is substituted for 2-(5- tetradecyloxy)thiophene carboxylic acid, methyl 2-(3- decylthio) - thienyl ketone is obtained.

Examples 9 to 14 illustrate compositions of the invention.

EXAMPLE 9 Solution Methyl 2-(5- tetradecyloxy)furyl ketone Alcohol Isopropyl Myristate Polyethylene Glycol 400 Purified Water qs ad 0.85 g 78.9 ml 5.0 g 10.0 g 100 ml Combine the alcohol, isopropyl myristate and polyethylene glycol 400 and dissolve the drug substance therein. Add sufficient purified water to give 100 ml.

EXAMPLE 10 Tablet Methyl 2-(5- dodecyloxy)furyl ketone Lactose Corn Starch For 1,000 g 1.216 kg 0.3 kg Mix the active ingredient, the lactose and corn starch uniformly. Granulate with 10% starch paste. Dry to a moisture content of about 2.5%. Screen through a No. 12 mesh screen. Add and mix the following: 459 0 5 Magnesium Stearate 0.015 kg Corn Starch qs ad 1.725 kg Compress on a suitable tablet machine to a weight of 0.115 g/tablet.

EXAMPLE 11 Soft Gelatin Capsule Methyl 2-(5- dodecyloxy)furyl ketone 0.25 kg Polysorbate 80 0.25 kg Corn Oil qs ad 25.0 kg Mix and fill into 50,000 soft gelatin capsules.

Example 12 An oil type composition for intramuscular injection is made up as follows: Ethyl 5-(9,12,11-octadecatrien1 - yloxy) - 2 - furyl ketone BHA, BHT aa Peanut Oil or Sesame Oil qs mg 0.1% w/v 0.1 ml Example 13 A suspension type composition for intramuscular injection, is made up as follows: Methyl 2-(5- tetradecyloxy)thienyl ketone micronized Sodium Carboxymethylcellulose Sodium Bisulphite Water for Injection, qs Example 14 A powder is made up from: mg 0.5% w/v 0.02% w/v 1.0 ml 9 9 5 - 21 Methyl 2-(5-tetradecyloxy)- % w/w furyl ketone l Silicon dioxide, anhydrous 0.5 Corn starch, lactose, fine powder aa qs 9 0 5

Claims (16)

1. A pharmaceutical composition, comprising a compound of the formula III 5 wherein X is oxygen or sulphur; Y is oxygen or sulphur? is alkyl of one to 4 carbon atoms? and R is saturated hydrocarbyl of 10 to 20 carbon atoms or unsaturated hydrocarbyl of 10 to 20 carbon atoms and having from one to 4 double bonds, in association with a pharmaceutically accep10 table carrier which is a solid or a sterile liquid.

2. A composition as claimed in claim 1 wherein, in the compound, X is oxygen.

3. wherein, A composition as claimed in claim 1 or claim 2 in the compound, Y is oxygen.

4. wherein, A composition as claimed in any preceding claim in the 'compound, R has from 12 to 15 carbon atoms.

5. A composition as claimed in claim 4 wherein, in the compound, R has 14 carbon atoms.

6. A composition as claimed in any preceding claim wherein, in the compound, R^ is ethyl, n-propyl or n-butyl.

7. A composition as claimed in any of claims 1 to 5 wherein, in the compound, R^ is methyl.

8. A composition as claimed in claim 1 wherein, in the compound, X and Y are each oxygen; R^ is methyl, ethyl, n-propyl or n-butyl; and R is saturated hydrocarbyl of 12 to 16 carbon atoms or unsaturated hydrocarbyl of 12 to 16 459 05 - 23 carbon atoms and having from one to 4 double bonds.

9. A composition as claimed in claim 8 wherein,in the compound, is methyl and R has 14 carbon atoms.

10. A composition as claimed in any preceding claim 5 wherein, in the compound, the R—Y— group is at the 5position.

11. A composition as claimed in claim 1 wherein the compound is methyl 2-(5- tetradecyloxy)furyl ketone.

12. A composition as claimed in claim 1 wherein the 10 compound is methyl 2-(5- dodecyloxy)furyl ketone.

13. A composition as claimed in claim 1 substantially as herein described with reference to any of Examples 9 to 14.

14. A compound of formula III as defined in claim 15. 1, with the proviso that R^ is not methyl.

15. A compound as claimed in claim 14 having the characteristics of any of claims 2 to 6.

16. A compound as claimed in claim 14 substantially as herein described with reference to any of Examples 3, 5 20 and 7.