IE44414B1 - Phenoxyacetic aci derivatives - Google Patents

Abstract

The invention provides a process for the preparation of 4-keto-phenoxyacetic acids, their reduced derivatives and their oximes, as well as their pharmaceutically acceptable alkali or amine addition salts, the compounds being of the formula: in which A represents 0 to 5. one of Z1 and Z2 represents H and the other OH or Z1 and Z2 taken together represent an oxygen atom or the group NOH, and X1 and X2 are the same or different and each represents a hydrogen or a halogen atom, or a methyl group, with the proviso that the benzene nucleus is never substituted by two halogen atoms in ortho-position with respect to one another.

Description

The present invention relates to 4-keto-phenoxyacetic acids, their reduced derivatives and their oximes as well as the pharmaceutically acceptable alkali metal, alkaline earth metal or amine salts of these acids, their preparation and their therapeutic use as uricosuric non-diuretic agents.

The compounds according to the invention are those of the following general formula (I) X. ‘2 in which A represents 0 or S, one of and Z2 represents H and the other OH or and Z2 taken together represent an oxygen atom or the group NOH, and X^ and X2 are the same or different and each represents a 15 hydrogen or a halogen atom, or a methyl group, with the proviso that the benzene nucleus is never substituted by two halogen atoms in ortho- position with respect to one another.

Certain dihalogenated compounds of this type have been described in British Patent Specification No. 1,323,328? these are uricosuric agents but above all powerful diuretic agents. However, in the treatment of certain conditions. for example gout, it is necessary to administer medicaments which are exclusively uricosuric, any associated diuretic effect being unwanted and, indeed, damaging. In addition, it is known that numerous diuretics currently used have a hyperuricemic effect, which necessitates the simultaneous administration of uricosurics in the treatment of certain cardiovascular illnesses and the compounds of formula I have a certain importance in this therapeutic area.

The compounds of formula I can be prepared by reacting, in an alkaline medium, a phenol of the formula II (II) in which A, X^ and X2 have the meanings given above, with a compound of the formula XCf^COOR (III), in which X represents a halogen atom and R represents a hydrogen atom or an alkyl group. The compound so obtained is saponified when it is an ester (R = alkyl), and in appropriate cases a chemical reduction of the ketone function is carried out with the object of obtaining the corresponding alcohol, or the ketone can be reacted with hydroxylamine to obtain the oxime.

The ketones of the formula I (Z^ and = 0) can also be prepared by a Friedel Crafts type reaction between a heterocyclic acid chloride of the formula COCl (IV) - 4 and a phenol ether of the formula in which X^, X2 and A have the meanings given above and R* represents a hydrogen atom, a COOH or COOR group, R being an alkyl group.

When the reaction is carried out with a methylether (V, R' = H), the compound of formula I is obtained by using a process known per se, which is demethylation by aluminium chloride or pyridine hydrochloride, followed by reaction of the phenol in an alkaline medium with a haloacetic acid (particularly chloro- or bromoaoetic acid) or an alkyl ester thereof followed, if necessary, by a hydrolysis reaction.

When a compound of formula V wherein R‘ represents a COOR group is used, the ester obtained is hydrolysed to give a compound of fonnula I.

When the compounds of the formula X carry on the benzene nucleus in the ortho- position to the ether function at least one halogen substituent it is preferable to carry out the Friedel Crafts reaction on anisole, to demethylate the ether so obtained, and then to halogenate the benzene nucleus of the 4-keto phenol by the action of Cl., Br or 2 X2 before preparing the phenoxy acetic acid ether.

The alcohols of the formula I (Z^ = H and Z2 = OH) are prepared according to the invention by the chemical reduction of a corresponding ketone of the formula I.

A ketone in the form of an alkali metal pr alkaline earth metal salt thereof in, for example, an alcoholic solution, may be reduced by the action of sodium borohydride. Alternatively, the corresponding ketone in the form of an ester thereof in solution in isopropanol may be reduced by the action of aluminium isopropylate. Reduction provides the two optical isomers in equal quantities.

The oximes Of the formula I (Z^ and Z2 = NOH) are prepared according to the invention by reacting a corresponding ketone with hydroxylamine. Conveniently this may be effected by the action of hydroxylamine hydrochloride on the ketone in solution in pyridine. The oximes are generally obtained in the form of a mixture of their two stereoisomers. The relative proportions of these two isomers of the carbimino group can be determined, for example, by nuclear magnetic resonance spectroscopy.

The salts of the compounds of formula I may be prepared by the action on the aoid in solution in, for example, an alcohol or a ketone, of an alkali or alkaline earth metal hydroxide or a pharmaceutically acceptable amine.

The following Examples illustrate the invention.

The compounds mentioned have been subjected to analytical study (elementary analysis, potentiographic titrationjI.R. and N.M.R. spectra) and they are characterised by their melting points determined upon a Kofler bench.

Example 1. 4-(2-Thenoyl)-2,6-dimethyl-phenoxyacetic acid A) (2-Thienyl) (3,5-dimethyl-4-methoxyphenyl)ketone Into a solution of 60 g of 2,6-dimethyl-anisole and 62.7 g of the chloride of 2-thiophene-carboxylic acid in 250 ml of anhydrous methylene chloride there was introduced 44*ί4 - 6 over 3Q minutes 58.5 g of aluminium chloride while maintaining the temperature at about 10°C. The reaction medium was brought to the reflux temperature of the solvent for 2¾ hours, then poured onto one kg of crushed ice mixed with 150 ml of concentrated hydrochloric acid. The organic phase was decanted, the aqueous phase extracted with methylene chloride, and the organic phase washed with an aqueous solution of sodium hydroxide, then vzith water. After drying and evaporation of the solvent, 110 g of an oil was isolated which vzas distilled under reduced pressure to give 89 g of ketone. Boiling point (14 mm Hg) = 225°C.

B) (2-Thienyl) (3,5-dimethyl-4-hydroxyphenyl)ketone A mixture of 20 g of the ketone obtained according to A) and 46 g of pyridine hydrochloride were kept for 6 hours at 180°C and then poured onto iced water. The mixture was extracted with ethyl ether, then with an aqueous solution of sodium hydroxide. After acidifying the solution, the phenol was extracted in ethyl ether, the solvent evaporated and the residual oil distilled to give 17 g of pure phenol. Boiling point (0.15 m Hg) = 185°C - m.pt. = 50°C.

C) Ethyl 4-(2-thenoyl)-2,6-dimethylphenoxyaeetate There was kept for 3 hours at 60°C a solution in 150 ml of dimethylformamide of 10 g of the phenol obtained according to B), 3 g of potassium hydroxide and 9 g of ethyl bromoacetate. The mixture was filtered, the solvent evaporated, the residue dissolved in ethyl ether, and the impurities extracted in a basic aqueous solution. After concentration of the solvent, 11.2 g of the ester were obtained which melted at 89°C.

D) 4-(2-Thenoyl)-2,6-dimethylphenoxyacetic acid g of the ester obtained according to c) were dissolved in 150 ml of aqueous ethanol (50/50) containing 444 1 4 2.7 g of sodium hydroxide; the solution was kept for 3 hours at 95°C, the ethanol evaporated under reduced pressure and the aqueous phase acidified. 9.4 g of the acid precipitated - m.pt. = 115°C.

Example 2 . 4-(2-Thenoyl)-2,3-dimethyl-phenoxyacetic ac id A) (2-thienyl) (2,3-dimethyl-4-methoxyphenyl)ketone This compound was prepared in 86% yield by using in step A) of Example 1 the chloride of 2-thiophene-earboxylic acid and 2,3-dimethyl-anisole.

B) (2-Thienyl) (2.3-dimethyl-4-hydroxyphenyl)ketone 123 g of the preceding ether were dissolved in 1300 ml of benzene and there was introduced into the solution over a period of 1 hour 30 minutes, 133 g of aluminium chloride. The mixture was kept for 5 hours at its reflux temperature and then poured onto a mixture of ice and hydrochloric acid. The phenol was extracted in ether and purified by' dissolving in an aqueous solution of sodium hydroxide from whichjWas precipitated by acidification There was obtained 67 g of the product melting at 144°C.

C) Ethyl 4-(2-thenoyl)-2,3-dimethyl-phenoxyacetate Into a solution of sodium ethylate prepared by the action of 2.3 g of sodium on 200 ml of ethanol, there was introduced 23.2 g of the phenol of step B), 14.9 g of sodium iodide and 13.5 g of ethyl chloroacetate. The mixture was kept under reflux for 8 hours, the hot solution filtered and the solvent evaporated, the phenol which had not reacted being eliminated from the residue by extraction in an aqueous sodium hydroxide solution. There was thus isolated, after drying, 22.15 g of pure acetate in the form of an oil. - - 8 D) 4-(2-Thenoyl)-2,3-dimethyl-phenoxyacetic acid This compound was obtained by hydrolysis of its ethyl ester in aqueous ethanol in the presence of potassium hydroxide. After recrystallisation in benzene or 1,2dichloroethane, the pure acid melted at 134°C.

Example 3. 4-Γ(2-Thienyl)hydroxymethyl]-2,3-dimethylphenoxyacetic acid There was poured into 5 ml of an 0.2N sodium hydroxide solution containing 0.8 g of sodium borohydride, a solution of 8.15 g of 4-(2-thenoyl)-2,3-dimethyl-phenoxyacetic acid and 2.1 g of sodium hydroxide in 75 ml of water. After 12 hours of stirring at ambient temperature the solution was acidified by the addition of acetic acid and then hydrochloric acid. The precipitate was isolated and then recrystallised in an acetone/water (50/50) mixture. There was thus obtained 7g of the acid which melted at 154°C.

Example 4. 4-(2-furoyl)-2,6-dibromo-phenoxyacetic acid A) (2-Furyl) (3,5-dibromo-4-hydroxyphenyl)ketone There was introduced into a solution of 28 g sodium acetate and 6 ml methanol 19 g of (2-furyl); (4-hydroxyphenyl) ketone (m.pt. = 164°C) prepared according to the method described in Example 1 A) and B), and then there was introduced dropwise 11 ml of bromine dissolved in 14 ml of acetic acid. After 2 hours stirring at ambient temperature the mixture was poured into three volumes of water and the precipitate isolated. After recrystallisation in dichloroethane there was obtained 22 g of the di bromophenol melting at 164°C.

B) Ethyl 4-(2-furoyl)-2,6-dibromo-phenoxyacetate There was kept under reflux for 6 hours 300 ml of methylethylketone containing 21 g of the phenol of step A), 15 g of potassium carbonate and 18 g of ethyl bromoacetate. After hot filtration, the solvent was evaporated and the solid recrystallised in ethanol. 21 g of the ester were obtained which melted at 114°C.

C) 4-(2-furoyl)-2.6-dibromo-phenoxyacetic acid This compound was obtained by hydrolysis of its ester from step B) in aqueous ethanol (50/50) in the presence of potassium carbonate with 90% yield. It melted at 167°C.

Example 5. 4-Γ(2-furyl)hydroxymethyl)-2,6-dibromo-phenoxyacetic acid A) Isopropyl 4-f(2-furyl)hydroxymethyl]-2,6-dibromophenoxyacetate. g of ethyl 4-(2-furoyl)-2,6-dibromo-phenoxyacetate and 9.8 g of aluminium isopropylate were dissolved in 300 ml of isopropanol and the mixture was kept for 20 hours at 82°C with distillation off of the acetone as it formed.

The solvent was then evaporated and the mixture poured into iced water. The precipitate formed was discarded and the final product extracted in ethyl ether. After drying, the solvent was removed and the solid product was recrystallised in isopropyl ether. 5.5 g of the ester were thus obtained which melted at 119°C.

B) 4^|(2-furyl)hydroxymethyl)-2,6-dibromo phenoxyacetic acid.

This acid was obtained by hydrolysis with potassium carbonate in aqueous ethanol of the isopropyl ester of step A). it melted at 136°C.

Example 6. ir Γ(2-thienyl)hydroxyiminomethyl 1 -2,6-dimethylphenoxyacetic acid - 10 4 g of 4-(2-thenoyl)-2,6-dimethylphenoxyacetic acid and 4 g of hydroxylamine hydrochloride were dissolved in 30 ml of pyridine and the mixture was kept for 3 hours at reflux. The mixture was then poured into an N aqueous solution of hydrochloric acid and the oxime extracted in ethyl ether. The remaining solid, after evaporation of the solvent, was a mixture of the two isomers of the oxime and melted at 152°C.

Example 7. 4-(2-Thenoyl)-2,6-diiodo-phenoxyacetic acid A) (3,5-Diiodo-4-hydroxyphenyl) (2-thienyl) ketone and (3-iodo-4-hydroxyphenyl) (2-thienyl) ketone Into a solution of 50 g of (4-hydroxyphenyl) (2thienyl) ketone, in 400 ml of a 3% aqueous solution of sodium hydroxide there was introduced slowly 76.2 g of iodine and 104 g of potassium iodide in solution in 400 ml water. After 12 hours stirring, the precipitate was removed, and then a 5% aqueous solution of sodium bisulphite introduced until the pH was acid. The precipitate which appeared was isolated. It contained the mono and diiodo phenols which could be separated due to their differences in solubility in chloroform. There was thus obtained after recrystallisation in ethanol, 14 g of the (3,5-diiodo-4-hydroxyphenyl) (2-thienyl) ketone which melted at 158°C and 40.2 g of (3-iodo-4-hydroxyphenyl) (2-thienyl) ketones m.pt. = 190°C (recrystallisation in aqueous dioxane (50/50)).

B) Ethyl 4-(2-thenoyl)-2,6-diiodo-phenoxyacetate The sodium salt of (3,5-diiodo-4-hydroxyphenyl) (2-thienyl) ketone was prepared from 13.65 g of the phenol and 2 g of sodium methylate in methanol. The mixture in solution was poured into 100 ml of dimethylformamide, the methanol removed and 6.2 g of ethyl bromoacetate were introduced. After 12 hours at ambient temperature, there was introduced into the medium 3 volumes of water and the mixture extracted with ethyl ether. The ethereal phase was washed with aqueous sodium hydroxide solution, then with water, dried, and the solvent removed. The ester was recrystallised in 95% aqueous ethanol.

There was obtained 9 g of ester which melted at 93°C.

C) 4-(2-Thenoyl)-2,6-diiodo-phenoxyacetic acid This was prepared starting from its ester with 90% yield by hydrolysis in aqueous ethanol in the presence of l^COg. It melted at 160°C.

Example 8. 4-(2-Thenoyl)-2-iodo-phenoxyacetic acid A) Ethyl 4-(2-,thenoyl)-2-iodo-phenoxyacetate This compound was prepared by using the method described in Example 7 B). It melted at 123°C after recrystallisation in ethanol.

B) 4-(2-Thenoyl)-2-iodo-phenoxyacetic acid This was prepared by hydrolysis of its ethyl ester with 97% yield. It melted at 164°C.

Example 9. 4-(2-Thenoyl)-2-bromo-phenoxyacetic acid A) Ethyl 4-(2-thenoyl)-2-bromo-phenoxyaeetate This ester was prepared with 95% yield by reaction of ethyl bromoacetate with (3-bromo-4-hydroxyphenyl) (2-thienyl) ketone. The product was an oil.

B) 4-(2-Thenoyl)-2-bromo-phenoxyacetic acid This acid was obtained by hydrolysis in a basic medium of its ethyl ester. It melted at 180°C.

The following Table I lists the structural formula and melting point of each of the compounds of the above Examples 1 to 9, together with structural formulae and metling points for additional Examples 10 to 23 of compounds prepared in like manner.

TABLE I TABLE I (Continued) TABLE I (Continued) - 15 TABLE I (Continued) - 16 TABLE I (Continued) - 17 TABLE I (Continued) The compounds of the invention have been subjected to different pharmacological tests which have revealed in particular their value as uricosuric agents. The following results illustrate this property.

The uricosuric activity was studied on lots of 5 rats weighing 250 to 280 g. The compounds of the invention were administered to the animals orally in doses of from 5 to 200 mg/kg. One hour after this administration and anaesthesia with ether, the animals received an intravenous - 18 3 injection of 1 cm of an aqueous 1% solution of phenol red. Samples of blood were taken 15, 30, 45 and 60 minutes after this injection and the quantity of blood phenol red measured This method is described by H. C. SCARBOROUGH and G. R. MCKINNEY in J. Med. Pharm. Chem. 5. 175 (1962) and E. KREPPEL in Med. Exptl. 1 285 (1959).

All the compounds of the invention diminish the speed of elimination of phenol red in the rat at the dosages mentioned and can thus be considered specifically uricosuric agents. In the following Table II there are set out the results obtained with the administration of certain of the compounds as well as with the administration of benziodarone, a uricosuric agent currently used in human therapy.

Since in addition the LDg0 of all the compounds of the invention, determined by the method of C. I. BLISS Quart. J. Pharm. Pharmacol. 2 192-216 (1938) is orally greater than 1000 mg/kg, it can be seen that the therapeutic index of the compounds of formula I and of their salts permit their use in human therapy in daily doses of from 10 mg to 1 g.

The compounds of the invention can be administered orally or parenterally, optionally in association with known vehicles such as excipients or diluents, for example, in the form of gelatine capsules, tablets or solutions.

Thus, the invention includes a pharmaceutical composition, which composition comprises a compound of formula I or a pharmaceutically acceptable alkali metal, alkaline earth metal or amine addition salt thereof, together with a pharmaceutically acceptable vehicle. Η Η Μ £ Η Ο W β Η Φ fl £ § *β Ρ fl Ο Η β Ο Ο rt •Η Ρ Ρ β β Ο Φ Ο Ρ Φ Φ Μ Ρ η Ρ &4> •Η U > β •Η Φ Ρ Μ U Φ fl Ψί Φ ϋ Η •rl μ χ: ο -Μ οι ·Η Ο 5 •Η Ό S Μ o 02 X X, 10 ο r-l cn in Ol in in o ω co oo M p 10 CS cs I** 0* ft in 10 Tf in CQ H Φ P P β rd + + + + + + + a. + + + + M4 -Η + fl ε in fl φ X X X 3* 10 10 cn co r> Tf Ol o o m tn 10 CQ P Φ P M-l <Ρ § •Η CO Ρ 10 + rM + σ\ + in + ω + cn + o i—l + ω + 10 + O H + CQ + m 4 fl ε O fl φ X. ft CO Tf π 10 00 tn σ» ft ft CQ o p Ρ ω CO Tf o 10 co H r* m Tf CS Ol in Φ V g + + + H + + r-l + + 4 1—1 + + •rl + + 4 fl fi in fl ip ft r* ft co cn CO cn Ol m CD CO β Ρ 10 CD co H m 00 10 m tn 10 Tf CQ Φ +> β β + + + H + + + + + + + + + •ri + fl fi Οι < b> fi οι 0OOOWOWOOOOOQ inOOmNViciOininOino Η Η tt) rd & ι-1 pH ft H H CS Φ β M fl •ϋ o •H N β Φ Λ / statistically non-significant results. 4444 4

Claims (14)

1. A compound of the general formula in which A represents 0 or S, one of Z^ and Z^ represents H and the other OH or and Z 2 taken together represent an oxygen atom Or the group NOH, and and X 2 are the same or different and each represents a hydrogen or a halogen atom, or a methyl group, with the proviso that the benzene nucleus is never substituted by two halogen atoms in ortho-position with respect to one another, or a pharmaceutically acceptable alkali metal, alkaline earth metal or amine salt thereof.

2. A compound according to claim 1 in which represents H and Z 2 represents OH.

3. A compound according to claim 1 in which Z^ and Z 2 together represent an oxygen atom.

4. A compound according to claim 1 in which Z^ and Z 2 together represent the group NOH.

5. 4-(2-Thenoyl)-2,6-dibromo-phenoxyacetic acid, its oxime dr the corresponding alcohol or a pharmaceutically acceptable alkali metal, alkaline earth metal or amine salt thereof.

6. 4-(2-Thenoyl)-2-iodo-phenoxyacetic acid, its oxime or the corresponding alcohol.

7. 4-(2-Thenoyl)-2,6-diiodo-phenoxyacetic acid, its oxime or the corresponding alcohol.

8. A compound according to claim 1 specifically disclosed in any one of Examples 1 to 6, 9, 10, 12, 14, 16 to 20 or 23.

9. A process for preparing a compound as claimed in claim 1 wherein and Z 2 represent oxygen, which process comprises reacting, in an alkaline medium, a phenol of the formula II in which A, X^ and X 2 are as defined in claim 1, with a compound of the formula XCH/OOR in which X represents a halogen atom and R represents H or an alkyl group, the compound thus obtained being saponified in the case where R is alkyl.

10. A process for preparing a compound as claimed in claim 1 wherein Ζ χ and Z 2 together represent the group NOH, which process comprises reacting the corresponding compound of formula I wherein Z^ and Z 2 together represent oxygen with hydroxylamine.

11. A process for preparing a compound as claimed in claim 1 wherein Z^ is H and Z 2 is OH, which process comprises reducing the corresponding compound of formula I wherein Z^ and Z 2 together represent oxygen. - 22

12. A process for preparing a compound as claimed in claim 1 substantially as hereinbefore described with reference to the specific Examples.

13. A compound as claimed in claim 1 when prepared 5 · by a process according to any one Of claims 9 to 12.

14. A pharmaceutical composition, which composition comprises a compound according to any one of claims 1 to 8 together with a pharmaceutically acceptable vehicle.