IE921815A1 - New oxazole derivatives and their preparation and use - Google Patents

Abstract

New derivatives of oxazole of general formula (I) in which R is a hydrogen atom or an alkyl (1 or 2C) radical, R1 and R2 are identical or different and represent hydrogen or halogen atoms, or alkyloxy radicals whose alkyl part contains 1 to 4 straight- or branched-chain carbon atoms and n is 3 to 6, as well as their salts, when they exist their isomers and their mixtures, and their preparation. These products are synthetic intermediates, some of them also having an anti-inflammatory activity.

Description

THIS INVENTION relates to oxazole derivatives and their preparation and use.

The oxazole derivatives of formula: in which R2 and R3 are identical or different and represent optionally substituted aryl radicals and R* is a saturated or unsaturated aliphatic acid radical containing 2 to 6 carbon atoms and their salts, esters and amides or the corresponding hydroxamic acids, have been described in Patent Application GB 1,206,403. These products possess anti-inflammatory activity.

The present invention provides, as new compounds, the oxazole derivatives of formula: in which: R is a hydrogen atom or an alkyl radical containing 1 or 2 carbon atoms, Rj and R2 are identical or different and represent hydrogen or halogen atoms, or alkyloxy radicals whose alkyl part contains 1 to 4 carbon atoms in a linear or branched chain and n equals 3 to 6, and their salts, and their isomers (if any).

The products according to the invention are intermediates for the preparation of new antagonists with respect to the effects of leukotriene B4 and 510 lipoxygenase. They themselves exhibit a 5-lipoxygenase inhibitory activity and, furthermore, some of them, in which n equals 5 or 6, also exhibit an antagonistic activity with respect to the effects of leukotriene B4.

In the formula (I) , when the radicals Rj and/or R2 represent halogen atoms, they may be chosen from fluorine, chlorine or bromide atoms. Preferably, they represent chlorine. The symbol n is between 3 and 6 but preferably is 4 or 5.

The hydroxylamine derivative of formula (I) may 20 be obtained by reducing an oxime of formula: in which R,, R2 R and n are defined as above.

(II) The reaction is carried out according to known methods which do not affect the rest of the molecule. The procedure is advantageously carried out in an acetic acid medium using a reducing agent such as, for example, an alkali metal cyanoborohydride at a temperature of between 5 and 50°C, according to the method described by G. W.

Gribble et al.. Synthesis, 856 (1977).

It is also possible to carry out the reduction according to the methods described by I.D.M. Herscheid et al,. , Tet. Lett., 51. 5143 (1978) or by M. W. Tijhuis et al.. Synthesis, 890 (1980).

The oxime of formula (II) may be prepared by reacting hydroxylamine with the corresponding ketone of formula: (HI) in which R,, R2, R and n are defined as above.

The reaction is generally carried out by reacting hydroxylamine hydrochloride in the presence of a base such as, for example, sodium hydroxide, a carbonate or a nitrogen-containing base (e.g. pyridine), in a wateralcohol medium (e.g. aqueous ethanol), at a temperature of between 2 0 and 80°C. - 4 The ketone of formula (III) for which R is a hydrogen atom, may be obtained by oxidation of the corresponding alcohol of formula: (IV) in which Rlz R2 and n are defined as above.

The oxidation may be performed by any known method which does not affect the rest of the molecule. In particular, the procedure is carried out in the presence of pyridinium chlorochromate in a chlorine-containing solvent (for example methylene chloride), at a temperature of between 0 and 20°C.

The alcohol of formula (IV) may be prepared by saponification of the ester of formula: in which R,, R2 and n are defined as above and Aik alkyl radical containing 1 to 4 carbon atoms in a branched chain. The saponification is carried out is an linear or in an alcoholic medium (e.g. methanol or ethanol) at a temperature of about 20°C, by reaction with concentrated ammonium hydroxide, dilute sodium hydroxide or an alkali metal carbonate.

The ester of formula (V) may be obtained from a brominated derivative of formula: (VI) by reaction with an alkali metal acetate in an acetic acid medium.

The brominated derivative of formula (VI) may be obtained by cyclisation of the ketoamide of formula: in which Rx, R2 and n are defined as above.

The procedure is carried out in the presence of a dehydrating agent such as, for example, phosphorus oxychloride, thionyl chloride, phosphorus tribromide, chlorosulphonic acid or in the presence of an arylsulphochloride (e.g. benzenesulphonyl chloride or tosyl chloride) in pyridine. The reaction is carried out with or without solvent, at a temperature of between 5 and 150°C. When the procedure is carried out in a solvent, the latter is advantageously cyclohexane, an aromatic solvent (e.g. toluene) or a chlorine-containing solvent (e.g. methylene chloride or 1,2-dichloroethane).

The brominated derivative of formula (VII) may be obtained by reacting an acid chloride of formula: Cl-CO- (CH2)n-CH2-Br (VIII) in which n is defined as above, with the hydrochloride salt of an amino ketone of formula: (IX) in which R, and R2 are defined as above.

The reaction is generally carried out in the presence of an excess amount of the acid chloride of formula (VIII), and a nitrogen-containing organic base such as pyridine or a tertiary amine (for example triethylamine, N-roethylmorpholine or Ν,Ν-dimethylaniline) or an alkali metal carbonate. The procedure is advantageously carried out in a chlorine-containing solvent (e.g. chloroform or methylene chloride), in an ether (e.g. ethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane) or in an - 7 aliphatic or aromatic hydrocarbon, at a temperature of between 5 and 120°C.

The hydrochloride salt of the amino ketone of formula (IX) may be prepared according to the methods described by: - G. Drefahl et al.. Ann. Chem., 589, 82 (1954) and J.

Prakt. Chem., 32, 307 (1966); - M.J. Hatch et al., J . Am. Chem. Soc., 75, 38 (1953); - H.O. House et al., J . Org. Chem., 28 . 307 v1963); or as described in the examples below.

The ketone of formula (III) for which R is an alkyl radical may be prepared from a j3-ketone ester of formula: in which R,, R2, R and n are defined as above.

The reaction is carried out in an acidic medium (for example hydrochloric acid), at a temperature of between 30 and 150°C.

The 0-ketone ester of formula (X) may be prepared 25 by reacting ethyl acetylacetate with a brominated derivative of formula: (XI) in which R,, R2 and n are defined as above.

The reaction is generally carried out in a solvent such as dimethylformamide using the sodiumcontaining derivative of ethyl acetylacetate as starting material, at a temperature of between 30 and 110°C.

The brominated derivative of formula (XI) may be prepared by analogy with the preparation of the brominated derivative of formula (VI).

The hydroxylamine derivatives of formula (I) for which R is a hydrogen atom, may also be obtained by alkylation of the sodium salt of alkyl 3-methyl-5-hydroxy4-isoxazolecarboxylate followed by an acid hydrolysis according to the method of G. DOLESCHALL, Tet. Lett., 28. 2993 (1987), using an oxazole derivative of formula (VI).

The condensation of the 4-isoxazolecarboxylate derivative with the product of formula (VI) is carried out in an organic solvent such as an amide (for example dimethylformamide), dimethylsulphoxide, dimethylacetamide or N-methyl25 pyrrolidone in the presence of potassium iodide for example, at a temperature of between 50 and 150°C.

Acid hydrolysis of the product thus obtained, of in which Rx, R2 and n are defined as above and Aik represents a linear or branched alkyl radical containing 1 to 4 carbon atoms, is advantageously carried out in solution in an acetic acid/concentrated hydrochloric acid mixture, at a temperature of between 90°C and the reflux temperature of the reaction mixture.

The products of formula (I) according to the invention are intermediates for the preparation of oxazole derivatives of formula: (XIII) in which R, Ru R2 and n are defined as for the formula (I), 25 and R3 represents an amino or alkyl radical containing 1 to carbon atoms in a linear or branched chain.

According to a feature of the invention, the - 10 oxazole derivatives of formula (XIII) are prepared from a hydroxylamine of formula (I) or its salt, either by reaction with an alkali metal cyanate or by acylation with a reactive derivative of an acid of formula: Rj-COOH (XIV) in which R3 is defined as above.

The treatment with an alkali metal cyanate leads to the oxazole derivatives of formula (XIII) in which R3 is an amino radical. The procedure is preferably carried out using potassium cyanate in an aqueous-organic medium, for example in a water-tetrahydrofuran mixture, at a temperature between 20°C and the reflux temperature of the reaction mixture.

The acylation leads to an oxazole derivative in which R3 is an alkyl radical. It may be carried out using any known method which does not affect the rest of the molecule, in particular using the corresponding acid chloride, in the presence of a base [e.g. a dilute alkaline base, a carbonate (for example potassium carbonate) or a nitrogen-containing organic base (especially a tertiary organic base such as for example triethylamine)], at a temperature of between 0 and 150°C, in a chlorinecontaining organic solvent (for example methylene chloride) or an ether (for example tetrahydrofuran or dioxane), in an ester (e.g. ethyl or isopropyl acetate) or in a ketone (for example acetone or butanone). It is also possible to carry out the procedure using an anhydride in solution in the - 11 corresponding acid, at a temperature of between 5 and 150°C, or optionally in the presence of a chlorinecontaining solvent, an ether (e.g. dioxane), pyridine, or in an aqueous medium in the presence of an inorganic base and then releasing the hydroxyl radical by treating with a base in a water-alcohol medium. The procedure is advantageously carried out in the presence of ammonium hydroxide in a water-methanol medium, at a temperature of about 2 0°C.

The products of formula (I) according to the invention and the products of formula (XIII) to which they lead, may be purified by crystallisation or by chromatography.

Where appropriate, the isomers of the products according to the invention may be separated according to the usual methods which do not alter the rest of the molecule. For example, they may be separated by chromatography on a chiral column.

The products according to the present invention may be converted to addition salts with acids according to the usual methods. The salts formed with inorganic acids (e.g. hydrochlorides, hydrobromides, sulphates, nitrates or phosphates) or with organic acids (e.g. succinates, fumarates, tartrates, oxalate, acetates, propionates, maleates, citrates, methanesulphonates, p-toluenesulphonates, isethionates, or with substituted derivatives of these compounds), may be mentioned as examples of acid - 12 addition salts.

The products of formula (XIII) may be converted into metallic salts by methods which are known per se.

These salts may be obtained by reacting a strong metallic base with a product according to the invention, in an appropriate solvent. The salt formed precipitates after optional concentration of the solution thereof and is separated by filtration, decantation or freeze-drying. The salts with alkali metals (sodium, potassium or lithium) may be mentioned as examples of pharmaceutically acceptable salts.

The oxazole derivatives of the invention are particularly useful given that they lead to products having an antagonist activity with respect to the effects of leukotriene B4 and an inhibitory activity with respect to the activity of 5-lipoxygenase.

Furthermore, the products of formula (I) themselves also exhibit inhibitory effects with respect to -lipoxygenase and some of them also have an antagonist activity with respect to leukotriene B4.

Leukotriene B4 is a potent mediator of inflammation, which is formed following the biotransformation of arachidonic acid via the 5lipoxygenase pathway. It contributes in particular to phenomena such as chemotaxis, cell activation, exocytosis of enzymes and also participates in immunological and tissue disorders. Given that anti-inflammatory agents do - 13 not necessarily possess this activity, the products according to the invention are particularly useful in the treatment of diseases involving this mediator.

The inhibitory property with respect to 55 lipoxygenase has been measured on a type I Rat Basophil Leukaemia sonicate (RBL) using a technique inspired by M.M. Steinhoff et al.. Biochem. Biophysica Acta, 618. 28 (1980) and B.A. Jakshik, J. Biol. Chem. 257, 5346 (1982), and/or on rat PMN (Polynuclear) derived from a peritoneal extrudate using a technique inspired by H. Safayhi et al., Biochem. Pharmacol., 34, 2691 (1985).

In these techniques, the products according to the invention proved active at concentrations of between 300 and 600 nM (IC50) .

The affinity for leukotriene B4 receptors has been demonstrated by measuring their effect on the binding of tritiated leukotriene B4, on human blood neutrophils according to a technique inspired by the method of Η. H.

LIN et al.. Prostaglandins, 28 837 (1984). In this technique the products tested proved active at Ki values of less than 500 nM (IC50) .

Moreover, the products according to the invention and the products of formula (XIII) possess the advantage of having a very low toxicity. Their toxicity (LDJ0) in mice is between 500 mg/kg and values greater than lg/kg orally.

The following Examples illustrate the present invention. - 14 Example 1 a) Ethyl 2-{6-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]hexyl}2.5- dihydro-3-methyl-5-oxo-4-isoxazolecarboxylate may be prepared as follows: 44 g of the sodium salt of ethyl 3-methyl-5hydroxy-4-isoxazolecarboxylate in suspension in 220 cm3 of dimethylformamide are heated, with stirring, with 97 g of 4.5- bis(4-methoxyphenyl)-2-(6-bromohexyl)oxazole and 2 g of potassium iodide, for 20 hours at 105°C, according to the method described by G. DOLESCHALL. After cooling, the solution containing sodium bromide in suspension is poured into 1 litre of water. The mixture is extracted with 500 cm3 of ethyl acetate. The organic phase is separated by decantation, washed with 4 times 100 cm3 of a saturated aqueous solution of sodium bicarbonate, with 3 times 100 cm3 of water and with 2 times 100 cm3 of a saturated aqueous solution of sodium chloride. After drying over magnesium sulphate, the solvent is evaporated under reduced pressure (5.2 kPa). The residue is chromatographed on a column with an inner diameter of 4.4 cm, containing 300 g of silica gel (50 to 200 μ). The column is eluted with 2 litres of diisopropyl ether and then with 1 litre of a diisopropyl ether-ethyl acetate mixture (80-20 by volume) and finally with 3 litres of diisopropyl ether-ethyl acetate (50-50 by volume) while collecting 250-cm3 fractions. The fractions from this last eluent mixture are pooled and concentrated to dryness. 101 g (86%) of ethyl 2-{6-[4,5-bis(4IE 921815 - 15 methoxyphenyl)-2-oxazolyl]hexyl}-2,5-dihydro-3-methyl-5oxo-4-isoxazolecarboxylate are thus obtained in the form of a yellowish oil which is directly used in the subsequent reaction.

Proton NMR spectrum (200 MHz, CDC13, 6 in ppm, J in Hz): 1.32 (t, J=7, -O-CH2-CH3) ; 2.47 (s, -CH3) ; 2.78 (t, J=7, -N=C-CH2-) ; 3.78 (2s, -OCH3) ; 3.83 (t, J=7, -CH2N<) ; 4.27 (q, J=7, -O-CH2-CH3) . b) 101 g of ethyl 2-{6-[4,5-bis(4-methoxyphenyl)-2oxazolyl]hexyl}-2,5-dihydro-3-methyl-5-oxo-4isoxazolecarboxylate in solution in 190 cm3 of pure acetic acid are heated, with stirring, with 380 cm3 of 6N hydrochloric acid, for 20 hours at 95°C.

The mixture is then adjusted to 60°C and then concentrated to dryness under reduced pressure (5.2 kPa). The residue is dissolved in 1 litre of water and the solution is washed with 0.5 litre of diethyl ether. The decanted aqueous solution is supplemented with 200 cm3 of 2N sodium hydroxide and extracted with 3 times 200 cm3 of diethyl ether. The pooled ethereal extracts are washed with 100 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and the solvent evaporated. The residue, in solution in 100 cm3 of dichloromethane, is salified by the addition of 14 g of - 16 anhydrous oxalic acid. The solution is concentrated to dryness under reduced pressure (5.2 kPa). The resulting solid, which is taken up in 300 cm3 of ethyl acetate, is drained, washed with 200 cm3 of diethyl ether and dried. 52 g (56%) of N-{6-[4,5-bis(4-methoxyphenyl)-2oxazolyl]hexyl}hydroxylamine acid oxalate are obtained in the form of a white powder with a melting point of 122°C. 4,5-Bis(4-methoxyphenyl)-2-(6-bromohexyl)oxazole may be prepared in the following manner: 223 g of 1,2-bis(4-methoxyphenyl)-2-(7bromoheptanamido)ethanone in 430 cm3 of toluene are heated, with stirring, with 222 g of phosphorus oxychloride, for 4 hours at 80°C. After concentrating under reduced pressure (6 kPa), the residue is supplemented with 500 cm3 of ice cold water and stirred with 1 litre of diethyl ether. The organic phase is decanted, washed with 3 times 300 cm3 of water, 2 times 100 cm3 of a saturated solution of sodium bicarbonate and 2 times 100 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (5.2 kPa). The residue is chromatographed on a column with a diameter of 4.4 cm, containing 300 g of silica gel (50 to 200 μ). The column is eluted with 2 litres of diisopropyl ether while collecting 200-cm3 fractions. The fractions between 0.5 litre and 2 litres are concentrated to dryness. 184.5 g (86%) of 4,5-bis(4-methoxyphenyl)-2-(6-bromohexyl)oxazole are thus obtained in the form of a yellowish oil - 17 which can be directly used in the subsequent reaction. Proton NMR spectrum (200 MHz, CDC13, δ in ppm, J in Hz): 2.84 (t, J=7.5, -N=C-CH2-) ; 3.42 (t, J=7, -CH2Br) ; 3.82 (2s, -OCH3) . 1,2-Bis(4-methoxyphenyl)-2-(7bromoheptanamido)ethanone may be prepared in the following manner: A solution of 99 g of pyridine in 125 cm3 of dichloromethane is added over 2 hours to a stirred suspension, cooled to 5°C, of 154 g of 2-amino-l,2-bis(4methoxyphenyl)ethanone hydrochloride (obtained according to G. DREFAHL and M. HARTMAN, Ann. Chem., 589, 82-90 (1954)) in 600 cm3 of dichloromethane containing 119.5 g of 715 bromoheptanoic acid chloride (prepared according to R.C. ELDERFIELD, et al.. Croat. Chem. Acta, 35, 85-91 (1963)). The mixture is stirred for 20 hours at room temperature. 150 cm3 of water are added and the organic phase is decanted and washed with 2 times 100 cm3 of N hydrochloric acid and then with water (2 times 60 cm3) . It is dried over magnesium sulphate, filtered and the solvent is evaporated under reduced pressure (0.2 kPa). 223 g (96%) of l,2-bis(4methoxyphenyl)-2-(7-bromoheptanamido)ethanone are obtained in the form of a yellowish oil which is directly used in the subsequent stage.

Proton NMR spectrum (200 MHz, CDC13, δ in ppm, J in Hz) : 2.22 (t, J=7.5, O=C-CH2-) ; 3.34 (t, J=7, -CH2-Br) ; 3.71 and 3.79 (2s, two -OCH3) ; 6.47 (d, J=7, -CO-CH-N); 7.05 (d, J=7, -CONH-); Example 2 N-{5-[4,5-bis(4-methoxyphenyl)-2oxazolyl]pentyl}hydroxylamine may be prepared according to the conditions defined in Example 1. 17.5 g of ethyl 2-{510 [4,5-bis(4-methoxyphenyl)-2-oxazolyl]pentyl}-2,5-dihydro-3 methyl-5-oxo-4-isoxazolecarboxylate in 100 cm3 of acetic acid are treated with 66 cm3 of 6N hydrochloric acid. The mixture is concentrated to dryness. After treatment, the crude reaction product is purified by chromatography on a column with a diameter of 3 cm, containing 80 g of silica gel (50 to 200 μ). The column is eluted with 2.3 litres of a diisopropyl ether-methanol mixture (95-5 by volume). The fractions between 1 and 2.3 litres are concentrated to dryness under reduced pressure (0.2 kPa). 8.2 g (64%) of N-{5-[4,5-bis(4-methoxyphenyl)-2 oxazolyl]pentyl}hydroxylamine are obtained in the form of colourless oil.

Proton NMR spectrum (250 MHz, CDC13, δ in ppm, J in Hz) : 2.85 (t, J=7.5, -N=C-CH2-) ; 25 2.96 (t, J=7, >N-CH2-) ; 3.84 (s, two -OCH3) ; 4 to 4.8 (mf, -OH). - 19 Ethyl 2-(5-(4,5-bis(4-methoxyphenyl)-2oxazolyl]pentyl}-2,5-dihydro-3-methyl-5-oxo-4isoxazolecarboxylate may be prepared according to Example 1.

A viscous residue is obtained, after treatment, from 34.5 g of 4,5-bis(4-methoxyphenyl)-2-(5bromopentyl)oxazole, 16 g of the sodium salt of ethyl 3methyl-5-hydroxy-4-isoxazolecarboxylate and 0.8 g of potassium iodide in 200 cm3 of dimethylformamide. It is chromatographed on a column with a diameter of 3.8 cm, containing 90 g of silica gel (50 to 200 μ). The column is eluted with 1.5 litres of a diisopropyl ether-ethyl acetate mixture (50-50 by volume) and then with 2.1 litres of ethyl acetate, while collecting 150-cm3 fractions. The pooled fractions of this last eluent are concentrated to 130 cm3 and supplemented with 3 00 cm3 of diisopropyl ether. The precipitate obtained is drained and dried, and 19 g (45%) of ethyl 2-(5-(4,5-bis(4-methoxyphenyl)-2-oxazolyl]pentyl}2,5-dihydro-3-methyl-5-oxo-4-isoxazolecarboxylate are obtained in the form of white crystals with a melting point of 127°C. 4,5-Bis(4-methoxyphenyl)-2-(5-bromopentyl)oxazole may be prepared in the conditions of Example 1. 37.5 g of 1,2-bis(4-methoxyphenyl)-2-(625 bromohexanamido)ethanone, 135 cm3 of toluene and 38 g of phosphorus oxychloride are heated. After treatment, 34.5 g (96%) of 4,5-bis(4-methoxyphenyl)-2-(5-bromopentyl)oxazole - 20 are isolated in the form of a viscous oil which is directly used in the subsequent stage.

Proton NMR spectrum (300 MHz, CDC13, δ in ppm, J in Hz) : 2.82 (t, J=7.5, -N=C-CH2) ; 5 3.41 (t, J=7, -CH2-Br) ; 3.79 (s, two -OCH3) . 1,2-Bis(4-methoxypheny1)-2-(6bromohexanamido)ethanone may be prepared as in Example 1.

A solution of 41.5 g of pyridine in 50 cm3 of dichloromethane is added over 50 minutes to 64.6 g of 2amino-l,2-bis(4-methoxyphenyl)ethanone hydrochloride (obtained according to G. DREFAHL and M. HARTMAN, Ann. Chem., 589, p.82-90 (1954)) in 250 cm3 of dichloromethane containing 47 g of 6-bromohexanoic acid chloride. The mixture is stirred for 20 hours at room temperature. 60 cm3 of water are added, and the organic phase is decanted and washed with 2 times 50 cm3 of N hydrochloric acid and then with water (2 times 30 cm3) . The solution is dried over magnesium sulphate, filtered and the solvent is evaporated under reduced pressure (0.2 kPa). The solid residue is recrystallised from a mixture of 80 cm3 of isopropanol and 1300 cm3 of diisopropyl ether. 84.9 g (90%) of l,2-bis(4methoxyphenyl)-2-(6-bromohexanamido)ethanone are obtained in the form of white crystals with a melting point of 93°C. - 21 Example 3 N-{6-[4,5-bis(4-chlorophenyl)-2oxazolyl]hexyl}hydroxylamine acid oxalate may be prepared according to the conditions defined in Example 1. 11 g of ethyl 2-(6-(4,5-bis(4-chlorophenyl)-2oxazolyl]hexyl}-2,5-dihydro-3-methyl-5-oxo-4isoxazolecarboxylate in 20 cm3 of acetic acid are treated with 40 cm3 of 6N hydrochloric acid. The mixture is concentrated to dryness. After treatment, the crude reaction product is purified by chromatography on a column with a diameter of 2 cm, containing 50 g of silica gel (50 to 200 μ). The column is eluted with 0.75 litre of a diisopropyl ether-ethyl acetate mixture (50-50 by volume) while collecting 25-cm3 fractions. The fractions between 0.25 and 0.75 litre are concentrated to dryness under reduced pressure (0.2 kPa). 6 g of a pale yellow oil are obtained. A solution of 1.35 g of oxalic acid in 20 cm3 of ethyl acetate is added to a solution of the oil in 30 cm3 of ethyl acetate. The expected salt is precipitated by the addition of 100 cm3 of diisopropyl ether. The solid is drained and dried. 5 g (50%) of N-{6-[4,5-bis(4chlorophenyl)-2-oxazolyl]hexylJhydroxylamine acid oxalate are obtained in the form of white crystals with a melting point of 165°C.

Ethyl 2—{6—[4,5-bis(4-chlorophenyl)-2oxazolyl]hexyl}-2,5-dihydro-3-methyl-5-oxo-4isoxazolecarboxylate may be prepared according to Example 1 - 22 From 13.5 g of 4,5-bis(4-chlorophenyl)-2-(6bromohexyl)oxazole, 6 g of the sodium salt of ethyl 3methyl-5-hydroxy-4-isoxazolecarboxylate and 1 g of potassium iodide in 80 cm3 of dimethylformamide. The product derived from the reaction is recrystallised from 150 cm3 of isopropyl acetate. 11 g (68%) of a white powder with a melting point of 115°C are obtained. 4,5-Bis(4-chlorophenyl)-2-(6-bromohexyl)oxazole may be prepared in the following manner: 18 g of 1,2-bis(4-chlorophenyl)-2-(7bromoheptanamido)ethanone in solution in 150 cm3 of toluene and 12.8 g of phosphorus tribromide are heated for 4 hours at 90°C. 150 cm3 of ethyl acetate, 150 cm3 of water and 100 cm3 of a 2N solution of sodium hydroxide are added at room temperature. The mixture is stirred and the organic phase is decanted. It is washed with 3 times 50 cm3 of water and 40 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure (5.2 kPa). The product of the reaction is chromatographed on a column with a diameter of 3 cm, containing 100 g of silica gel (50 to 200 μ). The column is eluted with 0.8 litre of a diisopropyl ether-hexane mixture (50-50 by volume), while collecting 50-cm3 fractions. The fractions between 0.5 and 0.8 litre are concentrated to dryness under reduced pressure (0.2 kPa). The oily residue obtained crystallises from 100 cm3 of petroleum ether. 13.5 g (78%) of white crystals with a melting point of 30°C are - 23 obtained. 1,2-Bis(4-chlorophenyl)-2-(7bromoheptanamido)ethanone may be prepared according to Example 1. g of pyridine in 12 cm3 of dichloromethane are added to 15.8 g of 2-amino-l,2-bis(4-chlorophenyl)ethanone hydrochloride (obtained according to G. DREFAHL et al., Ann. Chem., 589, 82-90 (1954)) in 100 cm3 of dichloromethane containing 12 g of 7-bromoheptanoic acid 10 chloride. The solid residue obtained is extracted and crystallised from 200 cm3 of diisopropyl ether. 19 g (80%) of white crystals with a melting point of 98°C are isolated.

Example 4 N-{5-[4,5-bis(4-chlorophenyl)-2oxazolyl]pentyl}hydroxylamine acid oxalate may be prepared in the following manner: g of ethyl 2-{5-[4,5-bis(4-chlorophenyl)-220 oxazolyl]pentyl}-2,5-dihydro-3-methyl-5-oxo-4isoxazolecarboxylate in solution in 50 cm3 acetic acid are heated, with stirring, with 100 cm3 of 6N hydrochloric acid, for 16 hours at 120°C. The mixture is adjusted to 60°C and then concentrated to dryness under reduced pressure (5.2 kPa). The residue is dissolved in 0.1 litre of water and the solution is washed with 0.1 litre of diethyl ether. The decanted aqueous solution is - 24 supplemented with 10 cm3 of 5N sodium hydroxide and extracted with 2 times 50 cm3 of diethyl ether. The pooled ethereal extracts are washed with 50 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and the solvent evaporated. The residue, in solution in 100 cm3 of diethyl ether, is salified by the addition of a solution of 2 g of oxalic acid in 20 cm3 of ethyl acetate. The salt obtained is drained and recrystallised from 100 cm3 of ethanol. 5.5 g (60%) of N10 {5-[4,5-bis(4-chlorophenyl)-2-oxazoly1]pentyl}hydroxylamine acid oxalate are obtained in the form of white crystals with a melting point of 145°C.

Ethyl 2—(5—[4,5-bis(4-chlorophenyl)-2oxazolyl]pentyl}-2,5-dihydro-3-methyl-5-oxo-415 isoxazolecarboxylate may be prepared according to Example 1. 8g of the sodium salt of ethyl 3-methyl-5-hydroxy-4isoxazolecarboxylate in suspension in 100 cm3 of dimethylformamide are heated, with stirring, with 15 g of 4,5-bis(4-chlorophenyl)-2-(5-bromopentyl)oxazole and 1 g of potassium iodide. The product derived from the reaction is recrystallised from 100 cm3 of isopropyl acetate and 10 g (55%) of a white powder with a melting point of 128°C, are obtained. 4,5-Bis(4-chlorophenyl)-2-(5-bromopentyl)oxazole may be prepared in the following manner: g of 1,2-bis(4-chlorophenyl)-2-(6bromohexanamido) ethanone in 100 cm3 of toluene, and 14.2 g - 25 of phosphorus tribromide are heated, with stirring, for 3 hours at 110°C. 100 cm3 of diethyl ether and 100 cm3 of a 2N solution of sodium hydroxide are added at room temperature. The mixture is stirred for 0.5 hour and the organic phase is decanted. It is washed with 3 times 50 cm3 of water, and 40 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure (5.2 kPa). The oily residue obtained crystallises from 100 cm3 of diisopropyl ether. 15 g (92%) of white crystals with a melting point of 92°C are obtained. 1,2-Bis(4-chlorophenyl)2-(6bromohexanamido)ethanone may be prepared according to Example 1: g of pyridine in 10 cm3 of dichloromethane are added to 15 g of 2-amino-l,2-bis(4-chlorophenyl)ethanone hydrochloride in 100 cm3 of dichloromethane containing 11.8 g of 6-bromohexanoic acid chloride. The solid residue is recrystallised from 150 cm3 of diisopropyl ether. 17.5 g (80%) of white crystals with a melting point of 105°C are isolated.

Example 5 N-[5-(4,5-diphenyl-2-oxazolyl)pentyl]25 hydroxylamine acid oxalate may be prepared according to the conditions defined in Example 1: 18.6 g of ethyl 2-[5-(4,5-diphenyl-2IE 921815 - 26 oxazolyl)pentyl]-2,5-dihydro-3-roethyl-5-oxo-4oxazolecarboxylate in solution in 40 cm3 of pure acetic acid are treated with 80 cm3 of 6N hydrochloric acid. The product of the reaction is treated as in Example 1. The residue in solution in 150 cm3 of dichloromethane, is salified by the addition of 3.1 g of anhydrous oxalic acid. The resulting solid is drained and dried. 10.65 g (64%) of N-[5-(4,5-dipheny1-2-oxazoly1) pentyl]hydroxylamine acid oxalate are obtained in the form of a white powder with a melting point of 139°C.

Ethyl 2-[5-(4,5-diphenyl-2-oxazolyl)pentyl]-2,5dihydro-3-methyl-5-oxo-4-isoxazolecarboxylate may be prepared according to Example 1: 13.6 g of the sodium salt of ethyl 3-methyl-515 hydroxy-4-isoxazolecarboxylate in 70 cm3 of dimethylformamide are heated with 25.2 g of 4,5-diphenyl-2(5-bromopentyl)oxazole and 0.7 g of potassium iodide, for 20 hours at 105°C. After treatment, the product obtained is chromatographed on a column with a diameter of 4.4 cm, containing 260 g of silica gel (50 to 200 μ). The column is eluted with 5 litres of a diisopropyl ether-ethyl acetate mixture (80-20 by volume) and then with 4.5 litres of a mixture, in equal parts (vol/vol), of diisopropyl ether and ethyl acetate, while collecting 250-cm3 fractions. The fractions from the last mixture are concentrated to dryness. 18.6 g (59%) of ethyl 2-[5-(4,5-diphenyl-2oxazolyl) pentyl]-2,5-dihydro-3-methyl-5-oxo-4IE 921815 - 27 isoxazolecarboxylate are obtained in the form of a yellowish oil which is directly used in the subsequent reaction.

Proton NMR spectrum (300 MHz, CDC13, 6 in ppm, J in Hz): 1.35 (t, J=7, -CH2-CH3) ; 2.55 (s, -CH3) 1 2.87 (t, J=7, -N=C-CH2-) ; 3.89 (t, J=7, -CH2-N) ; 4.31 )q( J=7, -COOCH2-CH3) . 4,5-Diphenyl-2-(5-bromopentyl)oxazole may be prepared according to Example 1. 50.5 g of l,2-diphenyl-2-(6bromohexanamido)ethanone in 130 cm3 of toluene are heated, with stirring, with 42.2 g of phosphorus tribromide for 4 hours at 110°C. After treatment, the product of the reaction is chromatographed on a column with a diameter of 4.4 cm, containing 200 g of silica gel (50 to 200 μ). The column is eluted with 3 litres of hexane and then with 4.5 litres of a diisopropyl ether-hexane mixture (10-90 by volume), while collecting 300-cm3 fractions. The pooled fractions from the last eluent mixture are concentrated to dryness under reduced pressure (5.2 kPa). 25.3 g (52%) of 4,5-diphenyl-2-(5-bromopentyl)oxazole are obtained in the form of a yellowish oil which is directly used in the subsequent reaction.

Proton NMR spectrum (300 MHz, CDC13, δ in ppm, J in Hz): 2.9 (t, J=7.5 , -N=C-CH2-) - 28 3.45 (t, J=7, -CH2-Br) . 1,2-Diphenyl-2-(6-bromohexanamido)ethanone may be prepared according to Example 1. .3 g of pyridine in 13 cm3 of dichloromethane 5 are added to 12.9 g of 2-amino-l,2-diphenylethanone hydrochloride in 63 cm3 of dichloromethane containing 11.7 g of 6-bromohexanoic acid chloride. After treatment, the product is recrystallised from 100 cm3 of diisopropyl ether. 15.1 g (74%) of white crystals with a melting point of 92°C are obtained.

Example 6 (R,S)-N-{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]2-heptyl}hydroxylamine may be prepared according to Example 7 below, as follows: A mixture of 11 g of 4,5-bis(4-chlorophenyl)-2(4-bromobutyl)oxazole in solution in 30 cm3 of dimethylformamide and the sodium-containing derivative of ethyl acetylacetate, obtained from 7.5 g of ethyl acetylacetate, in 40 cm3 of dimethylformamide, 1.4 g of 50% sodium hydride and 0.1 g of potassium iodide, is heated.

The product derived from the reaction is purified by chromatography on a column with a diameter of 3.8 cm, containing 200 g of silica gel (50 to 200 μ). The column is eluted with 3.6 litres of a mixture, in equal parts, of diisopropyl ether and hexane, while collecting 2OO-cm3 fractions. The fractions between 1.6 and 3.6 litres are - 29 concentrated to dryness. 8.2 g of a yellowish oil are obtained. The oil is heated in 90 cm3 of 5N hydrochloric acid and 45 cm3 of acetic acid. The product of the reaction is chromatographed on a column with a diameter of 3 cm, containing 120 g of silica gel (50 to 200 μ). The column is eluted with 1.5 litres of diisopropyl ether, while collecting 100-cm3 fractions. The fractions between 0.6 and 1.5 litres are concentrated to dryness. 6.2 g (89%) of a colourless oil are obtained. The oil is dissolved in 70 cm3 of ethanol, and a solution of 2.7 g of hydroxylamine hydrochloride in 6 cm3 of water, and 6.6 g of pyridine, are added. This mixture is refluxed for 6 hours. After treatment, 6.4 g of a pale yellow oil are obtained. The oil is dissolved in 70 cm3 of acetic acid and 1.4 g of sodium cyanoborohydride are added. The product of the reaction is chromatographed on a column with a diameter of 2 cm, containing 35 g of silica gel (50 to 200 μ). The column is eluted with 0.3 litre of diispropyl ether and then with 1.1 litre of a diisopropyl ether-methanol mixture (98-2 by volume), while collecting 100-cm3 fractions. Concentrating to dryness fractions of this last mixture gives 5.7 g (90%) of (R,S)-N-{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2heptyl}hydroxylamine in the form of white crystals with a melting point of 90°C. 4,5-Bis(4-chlorophenyl)-2-(4-bromobutyl)oxazole may be prepared according to the conditions defined in Example 7. - 30 11.2 g of pyridine in 12 cm3 of dichloromethane are added to a suspension of 20 g of 2-amino-l,2-bis(4chlorophenyl)ethanone hydrochloride in 150 cm3 of dichloromethane containing 13.5 g of 5-bromopentanoyl chloride. The solid residue obtained is recrystallised from 75 cm3 of diisopropyl ether. 20 g (71%) of l,2-bis(4chlorophenyl)-2-(5-bromopentanamido)ethanone are isolated in the form of white crystals with a melting point of 102°C. g of 1,2-bis(4-chlorophenyl)-2-(5bromopentanamido)ethanone in 150 cm3 of toluene are heated, with stirring, with 14.5 g of phosphorus tribromide, for 4 hours at 90°C. 100 g of ice, 150 cm3 of diethyl ether and 100 cm3 of a 2N solution of sodium hydroxide are added at room temperature. The mixture is stirred for 0.5 hour and the organic phase is decanted. It is washed with 3 times 50 cm3 of water and 40 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure (5.2 kPa). The reaction product is chromatographed on a column with a diameter of 3.8 cm, containing 200 g of silica gel (50 to 200 μ). The column is eluted with 1.8 litres of a diisopropyl etherhexane mixture (50-50 by volume), while collecting 150-cm3 fractions. The fractions between 0.6 and 1.8 litres are concentrated to dryness under reduced pressure (5.2 kPa). The solid residue is recrystallised from 100 cm3 of hexane. 11 g (57%) of 4,5-bis(4-chlorophenyl)-2-(4IE 921815 -31bromobutyl)oxazole are obtained in the form of a yellow powder with a melting point of 79°C.

Example 7 (R,S)-N-{7-(4,5-bis(4-methoxyphenyl)-2-oxazolyl]2-heptyl}hydroxylamine acid oxalate may be prepared in the following manner: A solution of 9.9 g of 7-[4,5-bis(4methoxyphenyl)-2-oxazolyl]-2-hydroxyiminoheptane in 110 cm3 of acetic acid is stirred at 10°C and 2.1 g of sodium cyanoborohydride are added over 20 minutes. After 2 hours at this temperature, the mixture is treated with 200 g of ice, 200 cm3 of 10 N sodium hydroxide and then extracted with 2 times 200 cm3 of diethyl ether. The pooled organic phases are washed with 4 times 50 cm3 of water and 40 cm3 of a saturated solution of sodium chloride and dried over magnesium sulphate. The solvent is evaporated under reduced pressure (5.2 kPa). The evaporation residue is chromatographed on a column with a diameter of 2 cm, containing 100 g of silica gel (50 to 200 μ). The column is eluted with a diisopropyl ether-methanol mixture (98-2 by volume) and then with 1.4 litres of a diispropyl ethermethanol mixture (95-5 by volume), while collecting 100-cm3 fractions. Evaporation of the fractions from this last mixture gives 7.7 g (85%) of (R,S)-N{7-[4,5-bis(4methoxyphenyl)-2-oxazolyl]-2-heptyl}hydroxylamine in the form of a viscous and colourless oil.

IE 921815 - 32 0.3 g of oxalic acid is added to a stirred solution of 1.4 g of the hydroxylamine derivative obtained above in 40 cm3 of dichloromethane. The resulting solution is concentrated under reduced pressure (5.2 kPa) and then the solid residue is dissolved in 50 cm3 of ethyl acetate. The salt formed is precipitated from a solution thereof, in ethyl acetate, by the addition of 100 cm3 of diispropyl ether. The solid is drained and dried. 1.4 g (82%) of (R,S)-N-{7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]-210 heptyl}hydroxylamine acid oxalate is obtained in the form of a white crystalline powder with a melting point of 90°C. 7-[4,5-Bis(4-methoxyphenyl)-2-oxazolyl]-2hydroxyiminoheptane may be prepared in the following manner: 21 g of pyridine in 25 cm3 of dichloromethane are added to a suspension of 36.7 g of 2-amino-l,2-bis(4methoxyphenyl)ethanone in 250 cm3 of dichloromethane containing 23.8 g of 5-bromopentanoyl chloride, according to the conditions defined in Example 1, and 47.2 g of a brownish oil are isolated. The oil is dissolved in 250 cm3 of toluene and the mixture is treated with 49 g of phosphorus oxychloride. The product derived from the reaction is chromatographed on a column with a diameter of 5.8 cm, containing 400 g of silica gel (50 to 200 μ). The column is eluted with 2.5 litres of diisopropyl ether, while collecting 250-cm3 fractions. The fractions between 1 and 2.5 litres are concentrated to dryness under reduced - 33 pressure (5.2 kPa). 33 g (75%) of 4,5-bis(4-methoxyphenyl)2-(4-bromobutyl)oxazole are obtained in the form of a yellowish oil.

Proton NMR spectrum (200 MHz, CDC13, ί in ppm and J in Hz) : 89 (t, J=7.5, -N=C-CH2-) ; 47 (t, J=7.5, -CH2-Br) ; 84 (s, two -OCH3) . g of the oxazole obtained above are dissolved in 30 cm3 of dimethylformamide and the solution is added to the sodium-containing derivative of ethyl acetylacetate which is obtained from 10 g of ethyl acetylacetate, in 40 cm3 of dimethylformamide, and 1.9 g of 50% sodium hydride. 0.1 g of potassium iodide is added to the mixture and the resulting mixture is heated for 10 hours at 8 0°C. The mixture is diluted with 150 cm3 of ice cold water at room temperature and extracted with 2 times 150 cm3 of diethyl ether. The pooled organic extracts are washed with 5 times 40 cm3 of water and 3 0 cm3 of a saturated solution of sodium chloride and dried over magnesium sulphate. The solvent is evaporated under reduced pressure (5.2 kPa). The residue is chromatographed on a column with a diameter of 3.8 cm, containing 280 g of silica gel (50 to 200 μ). The column is eluted with 2.5 litres of diisopropyl ether while collecting 100-cm3 fractions. The fractions between 1.2 and 2.5 litres are concentrated to dryness. 9.8 g of ethyl 6[4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-acetylhexanoate are obtained in the form of a yellowish oil. - 34 Proton NMR spectrum (200 MHz, CDC13, δ in ppm and J in Hz) : 1.27 (t, J=7, -CH2-CH3) ; 2.24 (s, -COCHj) ; 2.84 (t, J=7.5, -N=C-CH2-) ; 3.45 (t, J=7.5, -OCO-CH-CO); 3.84 (s, two -OCH3) ; 4.2 (q, J=7.5 , -O-CH2-CH3) .

The ethyl hexanoate derivative obtained in the above stage is dissolved in 100 cm3 of 5N hydrochloric acid and the mixture is refluxed for 3 hours with stirring. It is cooled and 150 cm3 of water are added and the resulting mixture is extracted with ethyl ether (2 times 150 cm3) .

The pooled organic extracts are washed with 4 times 50 cm3 of water and 50 cm3 of a saturated solution of sodium bicarbonate, dried over magnesium sulphate, filtered and concentrated to dryness. The evaporation residue is chromatographed on a column with a diameter of 3.8 cm, containing 160 g of silica gel (50 to 200 μ). The column is eluted with 2.7 litres of a diisopropyl ether-methanol mixture (98-2 by volume), while collecting 150-cm3 fractions. The fractions between 1.2 and 2.7 litres are concentrated to dryness and 7.5 g (90%) of 7-[4,5-bis(4methoxyphenyl)-2-oxazolyl]-2-heptanone are obtained in the form of a pale yellow oil.

Proton NMR spectrum (200 MHz, CDC13, δ in ppm and J in Hz) : 2.14 (s, -OC-CH3) ; 2.47 (t, J=7, -CH2-CO-) ; - 35 2.83 (t, J=7.5, -N=C-CH2-) ; 3.82 (s, two -OCH3) .

The heptanone obtained above is dissolved in 90 cm3 of ethanol containing 3.9 g of hydroxylamine hydrochloride in solution in 8 cm3 of water. The mixture is supplemented with 8.8 g of pyridine and then refluxed for 6 hours. After cooling, it is concentrated to dryness and 50 cm3 of water and 200 cm3 of diethyl ether are added. The ethereal phase is decanted and washed with 5 times 40 cm3 of water and 30 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure (5.2 kPa). 9 g of 7[4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-hydroxyiminoheptane are obtained in the form of a viscous oil which is used directly in the subsequent stage.

Proton NMR spectrum, mixture of the (E) and (Z) isomeric oximes (200 MHz, CDC13, & in ppm and J in Hz) : 1.86 and 1.88 (2s, -C-CH3 of the two isomers); 2.83 (t, J = 7.5, - N = C - CH2 -) ; 7.8 to 8.5 and 8.62 (2 mf, = N - OH of the two isomers).

Example 8 A solution of 1.5 g of hydroxylamine hydrochloride in 5 cm3 of water and 4 g of pyridine is added to a solution of 3.5 g of 6-[4-(4-chlorophenyl)-5-(4methoxyphenyl)-2-oxazolyl]hexanal in 50 cm3 of ethanol. The mixture is refluxed for 6 hours with stirring and it is - 36 concentrated to dryness under reduced pressure. 40 cm3 of water are added to the residue and the mixture is extracted with ethyl ether (2 times 50 cm3) , the pooled organic extracts are washed with 3 times 30 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness. The product of the reaction is chromatographed on a column with a diameter of 2.8 cm, containing 40 g of silica gel (50 to 200 μ). The column is eluted with 0.4 litre of diisopropyl ether while collecting 20-cm3 fractions. The fractions between 0.1 and 0.4 litre are concentrated to dryness. 3.3 g of a yellowish oil are obtained. The oil is dissolved in 50 cm3 of acetic acid and 1.5 g of sodium cyanoborohydride are added. The mixture is stirred for 2 hours at 10°C. It is treated at 0°C by the addition of 100 cm3 of 10 N sodium hydroxide and the mixture is extracted with 2 times 100 cm3 of diethyl ether. The pooled organic extracts are washed with 4 times 40 cm3 of water and dried over magnesium sulphate, filtered and concentrated under vacuum. 2.2 g of colourless oil are obtained and the oil is used as it is for the preparation of the product of Example of use 11. 6-[4-(4-Chlorophenyl)-5-(4-methoxyphenyl)-2oxazolyl]hexanal may be prepared in the following manner: 4.3 g of 6—[4—(4-chlorophenyl)-5-(425 methoxyphenyl)-2-oxazolyl]hexanol, in 70 cm3 of dichloromethane, and 3.6 g of pyridinium chlorochromate are stirred for 4 hours at 20°C. The precipitate is filtered on - 37 Clarcel and the filtrate is concentrated under vacuum. The oil obtained is chromatographed on a column with a diameter of 2 cm, containing 50 g of silica gel (50 to 200 μ). The column is eluted with 0.4 litre of diisopropyl ether while collecting 20-cm3 fractions. The fractions between 0.1 and 0.4 litre are concentrated to dryness. An oil is obtained which crystallises from 30 cm3 of hexane. 3.5 g (81%) of white crystals with a melting point of 60°C are obtained. 6-[4-(4-Chlorophenyl)-5-(4-methoxyphenyl)-210 oxazolyl]hexanol may be prepared in the following manner: g of pyridine in 5 cm3 of dichloromethane are added to a stirred suspension, cooled to 5°C, of 6.2 g of 2-amino-2-(4-chlorophenyl)-1-(4-methoxyphenyl)ethanone hydrochloride [G. DREFAHL, G. HEUBLEIN, K. FRITZSCHE and R.

SIEMANN, J. Prakt. Chem., 32, p 307 to 310, (1966)] in 50 cm3 of dichloromethane containing 4.9 g of 7-bromoheptanoyl chloride, according to Example 1. 8 g of a thick yellowish oil are isolated as described in Example 1. A solution thereof in 50 cm3 of toluene is treated with 3 g of phosphorus oxychloride. The product derived from the reaction is purified by chromatography on a column with a diameter of 2.8 cm, containing 150 g of silica gel (50 to 200 μ). The column is eluted with 0.5 litre of a mixture, in equal parts (vol/vol), of diisopropyl ether and hexane, while collecting 50-cm3 fractions. The fractions between 0.2 and 0.5 litre are concentrated to dryness. 7 g of a light yellow oil are obtained. The oil is dissolved in 100 - 38 cm3 of methyl ethyl ketone, and 3.1 g of potassium acetate and 0.05 g of tetraethylammonium bromide are added and the mixture is heated for 20 hours at 100°C. The mixture is cooled and the inorganic residue is drained and 5 concentrated under vacuum. The residue obtained is chromatographed on a column with a diameter of 2.5 cm, containing 50 g of silica gel (50 to 200 μ). The column is eluted with 0.7 litre of a mixture, in equal parts (vol/vol) of diisopropyl ether and hexane, while collecting 50-cm3 fractions. The fractions between 0.2 and 0.7 litre are concentrated to dryness and 6 g of a light yellow oil are obtained. The oil is dissolved in 50 cm3 of methanol and 25 cm3 of 33% ammonium hydroxide are added and the solution is stirred for 10 hours under reflux. It is concentrated under reduced pressure (5.2 kPa). The residue obtained is purified by chromatography on a column with a diameter of 2.5 cm, containing 50 g of silica gel (50 to 200 μ). The column is eluted with 0.2 litre of diisopropyl ether and then with 0.4 litre of ethyl acetate, while collecting 50-cm3 fractions. The eluates of this last solvent are concentrated to dryness and the oily residue is crystallised from 30 cm3 of hexane. 4.3 g (79%) of 6-[4-(4chlorophenyl)-5-(4-methoxyphenyl)-2-oxazolyl]hexanol are obtained in the form of white crystals with a melting point of 76°C. - 39 Example 9 38.1 g of ethyl 2-[6(4, 5-diphenyl-2-oxazolyl)hexyl]-2,5-dihydro-3-methyl-5-oxo-4-isoxazolecarboxylate in solution in 80 cm3 of pure acetic acid are treated with 160 cm3 of 6N hydrochloric acid, according to the conditions (time and temperature) defined in Example 1. The product of the reaction is extracted as in the example mentioned. The residue, in solution in 100 cm3 of dichloromethane, is salified by the addition of 6.4 g of anhydrous oxalic acid.

The resulting solid is drained and dried. 21.8 g (63%) of N-[6-(4,5-diphenyl-2-oxazolyl)hexyl]hydroxyl-amine acid oxalate are obtained in the form of a white powder with a melting point of 153 °C.

Ethyl 2-(6-(4,5-diphenyl-2-oxazolyl)hexyl]-2,515 dihydro-3-methyl-5-oxo-4-isoxazolecarboxylate may be prepared according to Example 1: 17.5 g of the sodium salt of ethyl 3-methyl-5hydroxy-4-isoxazolecarboxylate in 70 cm3 of dimethylformamide are heated with 33 g of 4,5-diphenyl-220 (6-bromohexyl)oxazole and 0.8 g of potassium iodide, for 20 hours at 1O5°C. After the treatment, the product obtained is chromatographed on a column with a diameter of 4.4 cm, containing 300 g of silica gel (50 to 200 μ). The column is eluted with 1 litre of diisopropyl ether and then with 1.5 litres of a mixture, in equal parts (vol/vol), of diisopropyl ether and ethyl acetate, while collecting 250cm3 fractions. The fractions from the last mixture are - 40 concentrated to dryness. 38.1 g of (93%) of ethyl 2-[6(4,5-diphenyloxazolyl)hexyl]-2,5-dihydro-3-methyl-5-oxo-4isoxazolecarboxylate are obtained in the form of a yellowish oil which is used directly in the subsequent reaction.

Proton NMR spectrum (2 50 MHz, CDC13, δ in ppm and J in Hz) : 1.33 (t, J=7, -CH2-CH3) ; 2.49 (s, -CH3) ; 2.83 (t, J=7.5, -N=C-CH2-) ; 3.84 (t, J=7 , >N-CH2-) ; 4.27 (q, J=7 , -COOCH2CH3) . 4,5-Diphenyl-2-(6-bromohexyl)oxazole may be prepared according to Example 6. 42.4 g of 1,2-diphenyl-2-(7-bromoheptan15 amido)ethanone in 100 cm3 of toluene are heated, with stirring, with 34.2 g of phosphorus tribromide, for 4 hours at 110°C. After the treatment, the product of the reaction is chromatographed on a column with a diameter of 4.4 cm, containing 300 g of silica gel (50 to 200 μ). The column is eluted with 2 litres of diisopropyl ether while collecting 200-cm3 fractions. The fractions between 0.4 and 2 litres are concentrated to dryness under reduced pressure (5.2 kPa). 33 g (81%) of 4,5-diphenyl-2-(6-bromohexyl)oxazole are obtained in the form of a yellowish oil which is used directly in the subsequent reaction.

Proton NMR spectrum (300 MHz, CDC13, δ in ppm and J in Hz): 2.86 (t, J=7, -N=C-CH2-) ; - 41 3.4 (t, J=7, -CH2-Br) . 1,2-Diphenyl-2-(7-bromoheptanamido)ethanone may be prepared according to Example 1. 39,7 g of pyridine in 50 cm3 of dichloromethane 5 are added to 49.4 g of 2-amino-l,2-diphenylethanone hydrochloride in 240 cm3 of dichloromethane containing 47.8 g of 7-bromoheptanoic acid chloride. After treatment, the product is recrystallised from 70 cm3 of isopropyl acetate. 42.4 g (52%) of white crystals with a melting point of 93°C are obtained.

The products according to the invention may lead to oxazole derivatives of formula (XIII) by carrying out the procedure as illustrated below in the examples of use.

EXAMPLE OF USE 1 A mixture of 15 g of N-{6-[4,5-bis(4methoxyphenyl)-2-oxazolyl]hexyl}hydroxylamine acid oxalate, .5 g of potassium cyanate, 61 cm3 of tetrahydrofuran and 6 cm3 of water, is refluxed for 4 hours. After cooling, 200 0 cm3 of water and 600 cm3 of ethylacetate are added. The organic phase is decanted, washed with 5 times 50 cm3 of water, 100 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to about 150 cm3. The solid formed is drained and dried. 8.9 g (65%) of N-{6-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]hexyl}N-hydroxyurea are obtained in the form of white crystals with a melting point of 127°C. - 42 EXAMPLE OF USE 2 N-{5-[4,5-bis(4-methoxyphenyl)-2oxazolyl]pentyl}-N-hydroxyurea maybe prepared in the following manner: 0.82 g of oxalic acid is added with stirring to a solution of 3.45 g N-{5-[4,5-bis(4-methoxyphenyl)-2oxazolyl]pentyl}hydroxylamine in solution in 18 cm3 of tetrahydrofuran and 2 cm3 of water, followed by 1.61 g of potassium cyanate, and the mixture is refluxed for 4 hours. After cooling, 20 cm3 of water and 100 cm3 of ethyl acetate are added. The organic phase is decanted, washed with 5 times 2 0 cm3 of water and 50 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated to dryness. The evaporation residue is chromatographed on a column with a diameter of 1.6 cm, containing 50 g of silica gel (50 to 200 μ). The column is eluted with 1.8 litres of ethyl acetate while collecting 100-cm3 fractions. The fractions between 0.5 and 1.8 litres are concentrated to dryness under reduced pressure (0.2 kPa). 1.15 g (30%) of N-{5-[4,5-bis(4-methoxyphenyl)-2oxazolyl]pentyl}-N-hydroxyurea are obtained in the form of a yellowish solid with a melting point of 60°C.

EXAMPLE OF USE 3 A mixture of 1.8 g of N-{6-[4,5-bis(4chlorophenyl)-2-oxazolyl]hexyl}hydroxylamine acid oxalate and 0.65 g of potassium cyanate in 10 cm3 of - 43 tetrahydrofuran and 1 cm3 of water is refluxed for 4 hours. After cooling, 30 cm3 of water and 100 cm3 of ethyl acetate are added. The organic phase is decanted, washed with 3 times 20 cm3 of water and 20 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure (5.2 kPa). The oil obtained crystallises from 25 cm3 of diethyl ether. The precipitate is drained and recrystallised from 12 cm3 of isopropyl acetate, and 1.1 g (67%) of N-{6-[4,5-bis(410 chlorophenyl)-2-oxazolyl]hexyl}-N-hydroxyurea are obtained in the form of white crystals with a melting point of 124°C.

EXAMPLE OF USE 4 (R,S)-N-{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]2-heptyl}-N-hydroxyurea may be prepared in the following manner: 2.6 g of (R,S)-N-{7-[4,5-bis(4-chlorophenyl)-2oxazolyl]-2-heptyl}hydroxylamine are dissolved in 50 cm3 of tetrahydrofuran containing 6.8 cm3 of N hydrochloric acid. 0.55 g of potassium cyanate is added to the solution and the mixture is stirred for 5 hours under reflux. After evaporating to dryness, 150 cm3 of diethyl ether and 30 cm3 of water are added. The ethereal solution is washed with 3 times 30 cm3 of water and 30 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness. The residue is chromatographed on - 44 a column with a diameter of 2 cm, containing 20 g of silica gel (50 to 200 μ). The column is eluted with 1.2 litres of ethyl acetate, while collecting 100-cm3 fractions. The fractions between 0.4 and 1.2 litres are concentrated to dryness, and 1.7 g of a colourless oil are obtained. The oil is crystallised from 30 cm3 of a diethyl etherdiispropyl ether mixture (35-65 by volume). 1.5 g (52%) of white crystals are obtained with a melting point of 125°C.

EXAMPLE OF USE 5 g of N-{6-[4,5-bis(4-methoxyphenyl)-2oxazolyl]hexyl}hydroxylamine acid oxalate in 100 cm3 of acetic acid containing 9.5 g of sodium acetate and 23 g of acetic anhydride, are stirred at 110°C for 3 hours. After cooling, 150 cm3 of water are added and the solution is stirred for 1 hour at 20°C and concentrated to dryness under reduced pressure (5.2 kPa). The organic-inorganic residue is dissolved in 200 cm3 of ethyl acetate and 50 cm3 of water, and the organic phase is separated and washed with 3 times 50 cm3 of water and 50 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness. The oily residue (23 g) is chromatographed on a column with a diameter of 2 cm containing 150 g of silica gel (50 to 200 μ). The column is eluted with 1 litre of diispropyl ether while collecting 50-cm3 fractions. The fractions between 0.15 and 1 litre are concentrated to dryness. 17 g (64%) of N-acetoxy-N-{6IE 921815 - 45 [4,5-bis(4-methoxyphenyl)-2-oxazolyl]hexyl}acetamide are obtained.

Proton NMR spectrum (250 MHz, CDC13, δ in ppm, J in Hz): 2 and 2.16 (2s, CH3CO-N-OCOCH3) ; 2.82 (t, J=7.5, -N=C-CH2-) ; 3.68 (t J=7, >N-CH2-) ; 3.82 (s, two -OCHj) .

The acetamide obtained above is dissolved in 200 cm3 of methanol containing 100 cm3 of 33% ammonium hydroxide. The mixture is stirred for 2 hours at 20°C.

After concentrating to dryness under reduced pressure, 50 cm3 of water are added and the mixture is extracted with diethyl ether (3 times 150 cm3) and the pooled ethereal solutions are washed with 100 cm3 of a saturated solution of sodium chloride. The solution is dried over magnesium sulphate, filtered and the solvent is removed. The evaporation residue is chromatographed on a column with a diameter of 2 cm containing 150 g of silica gel (50 to 200 μ). The column is eluted with 2.5 litres of ethyl acetate while collecting 50-cm3 fractions. The fractions between 1 and 1.5 litres are concentrated to dryness under reduced pressure (0.2 kPa). 10 g (64.5%) of N-{6-[4,5-bis(4methoxy-phenyl)-2-oxazolyl]hexyl}acetohydroxamic acid are thus obtained in the form of a yellowish oil.

Proton NMR spectrum (200 MHz, DMSO-d6, δ in ppm, J in Hz): 2 (s, -COCH3) ; 2.78 (t, J=7.5, -N=C-CH2-) ; - 46 3.5 (t, J=7.5, >N-CH2-) ; 3.79 and 3.81 (2s, two -OCH3) ; 9.7 (s, >N-OH).

EXAMPLE OF USE 6 g of isobutyryl chloride is added to the mixture, stirred at 0°C, of 4 g of N-{6-[4,5-bis(4methoxyphenyl)-2-oxazolyl]hexyl}hydroxylamine acid oxalate, 20 cm3 of 2N sodium hydroxide and 25 cm3 of dichloromethane.

After 2 hours at low temperature and 2 hours at 20°C, 100 cm3 of ethyl acetate are added and the organic phase is decanted, washed with 2 times 2 0 cm3 of water, 3 0 cm3 of N hydrochloric acid and 2 times 30 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, and the solvent is filtered and removed. The evaporation residue is chromatographed on a column with a diameter of 1.8 cm, containing 25 g of silica gel (50 to 200 μ). The column is eluted with 0.5 litre of diispropyl ether and then with 0.7 litre of a diisopropyl ether-ethyl acetate mixture (80-20 by volume), while collecting 50-cm3 fractions. The fractions from the last eluent mixture are pooled and concentrated to dryness under reduced pressure (2 kPa). 1.6 g (41%) of N-{6-[4,5-bis(4-methoxyphenyl)-2oxazolyl]hexyl}-N-hydroxyisobutyramide are obtained in the form of a yellowish oil.

Proton NMR spectrum (200 MHz, CDC13, δ in ppm, J in Hz) : 2.75 and 3.1 (2 mt, >CH- of the 2 rotamers) 2.85 (t, J=7.5, -N=C-CH2-) ; 3.65 (t, J-7.5, >N-CH2-); 3.83 (S, two -OCHj); 8.5 and 9.2 (2 mf N-OH of the two rotamers).

EXAMPLE OF USE 7 6.3 g of (R,S)-N-{7-[4,5-bis(4-methoxyphenyl)-2oxazolyl]-2-heptyl}hydroxylamine in 50 cm’ of acetic acid containing 6.2 g of acetic anhydride are stirred at llO’C for 3 hours. After cooling, 50 cm3 of water are added and the solution is stirred for 1 hour at 20°C and concentrated to dryness under reduced pressure (5.2 kPa). The organic residue is dissolved in 200 cm3 of diethyl ether and 50 cm3 of water and the organic phase is separated and washed with times 50 cm3 of water and 30 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness. The oily residue (7.5 g) is chromatographed on a column with a diameter of 3 cm, containing 80 g of silica gel (50 to 200 μ) . The column is eluted with 1.5 litres of a diisopropyl ether-methanol mixture (98-2 by volume) while collecting 100-cm3 fractions. The fractions between 0.6 and 1.5 litres are concentrated to dryness and 7 g (92%) of N-acetoxy-N-{7[ 4,5-bis (4 -methoxyphenyl) -2-oxazolyl) -2 -heptyl} acetamide are obtained in the form of a colourless oil.

Proton NMR spectrum (300 MHz, CDC13, S in ppm and J in Hz at 300’K): - 48 1.18 (d, J=7, -CH3) ; and 2.17 (2s, CH3CO-N-OCOCH3) ; 2.82 (t, J=7.5, -N=C-CH2-) ; 3.85 (s, two -OCH3) ; 4.5 (mt, >N-CH<). 6.6 g of the acetamide obtained above are dissolved in 50 cm3 of methanol containing 20 cm3 of 33% ammonium hydroxide. The mixture is stirred for 2 hours at 20°C. After evaporating to dryness under reduced pressure, cm3 of water are added and the mixture is extracted with diethyl ether (2 times 150 cm3) and the pooled ethereal solutions are washed with 4 times 4 0 cm3 of water and 30 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness.

The oily residue is chromatographed on a column with a diameter of 3 cm, containing 90 g of silica gel (50 to 200 μ). The column is eluted with 1.2 litres of ethyl acetate while collecting 100-cm3 fractions. The fractions between 0.3 and 1.2 litres are concentrated to dryness under reduced pressure (0.2 kPa) and 5.7 g (94%) of (R,S)-N-{7[4,5-bis(4-methoxyphenyl)-2-oxazolyl] -2heptyl}acetohydroxamic acid are obtained in the form of a colourless oil.

Proton NMR spectrum (400 MHz, DMSO-d6, 6 in ppm and J in Hz): 1.03 (d, J=7, -CH3) ; 1.98 (s, -COCH3) ; - 49 2.77 (t, J=7.5, -N=C-CH2-); 3.77 and 3.8 (2s, two -OCH3); 4.43 (mt, >N-CH<); 9.3 (S, >N-OH).

EXAMPLE OF USE θ 1.45 g of N-{6-[4,5-bis(4-chlorophenyl)-2oxazolyl]hexyl}hydroxylamine are heated in 55 cm3 of acetic acid containing 1.5 g of acetic anhydride, according to Example of use 5. By carrying out the procedure as described in Example of use 5, a yellowish oil is obtained. It is chromatographed on a column with a diameter of 2 cm, containing 30 g of silica gel (50 to 200 μ) . The column is eluted with 0.4 litre of a mixture, in equal parts, of diisopropyl ether-ethyl acetate, while collecting 25-cm3 fractions. The fractions between 0.15 and 0.4 litre are concentrated to dryness under reduced pressure. The residue obtained (1.3 g) is dissolved in 20 cm3 of methanol containing 5 cm3 of 33% ammonium oxide. After stirring and treatment, the residue obtained is chromatographed on a column vith a diameter of 2 cm, containing 15 g of silica gel (50 to 200 μ). The column is eluted with 0.3 litre of ethyl acetate, while collecting 20-cm3 fractions. The fractions between 0.1 and 0.3 litre are concentrated to dryness under reduced pressure (0.2 kPa) and the oily residue is crystallised from 20 cm3 of hexane. 0.8 g (67%) of N-{6-[4,5-bis(4-chlorophenyl)-2IE 921815 -50oxazolyl]hexyl}acetohydroxamic acid is obtained in the form of white crystals with a melting point of 78°C.

EXAMPLE OF USE 9 2.5 g of N-{5-[4,5-bis(4-chlorophenyl)-2oxazolyl]pentyl}hydroxylamine acid oxalate in 50 cm’ of acetic acid containing 3.2 g of acetic anhydride are stirred at 110°C for 3 hours, according to Example of use 7. After the treatment, an oily residue is obtained which is chromatographed on a column with a diameter of 2 cm, containing 20 g of silica gel (50 to 200 μ). The column is eluted with 0.3 litre of a diisopropyl ether-ethyl acetate mixture (50-50 by volume), while collecting 20-cm3 fractions. The fractions between 0.1 and 0.3 litre are concentrated to dryness. The residue obtained (2 g) is dissolved in 50 cm3 of methanol containing 10 cm3 of 33% ammonium hydroxide. The mixture is stirred for 2 hours at 20eC. After treatment, as in Example of use 7, the oily residue is chromatographed on a column with a diameter of 2 cm, containing 20 g of silica gel (50 to 200 μ). The column is eluted with 0.2 litre of ethyl acetate while collecting 20-cm3 fractions. The fractions between 0.1 and 0.2 litre are concentrated to dryness under reduced pressure (0.2 kPa). 1.5 g (82%) of N-{5-[4,5-bis(4-chlorophenyl)-225 oxazolyl]pentyl}acetohydroxamic acid are obtained in the form of a light yellow oil.

Proton NMR spectrum (250 MHz, CDC13, ί in ppm and J in Hz - 51 at 340βΚ): 2.04 (s, >N-CO-CH3); 2.91 (t, J=7.5, -N=C-CH2-) ; 3.7 (t, J=7, >N-CH2-) .

EXAMPLE OF USE 10 2.9 g of N-acetoxy-N-{7-[4,5-bis(4-chlorophenyl) 2-oxazolyl]-2-heptyl]acetamide are stirred in 60 cm3 of methanol containing 10 cm3 of 33% ammonium hydroxide, according to Example of use 7. The product of the reaction is extracted as in Example of use 7 and it is crystallised from 100 cm3 of diisopropyl ether. 2.2 g (83%) of (R,S)-N{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2heptyl}acetohydroxamic acid are obtained in the form of crystals with a melting point of 100eC.

N-acetoxy-N-{7-(4,5-bis(4-chlorophenyl)-2oxazolyl]-2-heptyl}acetamide may be prepared as follows: An oily residue is obtained, after extraction, from 3 g of (R,S)-N-{7-[4,5-bis(4-chlorophenyl)-220 oxazolyl]-2-heptyl}hydroxylamine, prepared according to Example of use 4, in 30 cm3 of acetic acid containing 3 g of acetic anhydride. It is chromatographed on a column with a diameter of 2 cm, containing 40 g of silica gel (50 to 200 μ). The column is eluted with 0.4 litre of diisopropyl ether and then with 0.8 litre of a diisopropyl ethermethanol mixture (98-2 by volume), while collecting 100-cm3 fractions. The pooled fractions from the last eluent - 52 mixture are concentrated to dryness. 3 g (83%) of Nacetoxy-N-{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2heptyl}acetamide are obtained in the form of a colourless oil which is used in the subsequent reaction.

Proton NMR spectrum (250 MHz, CDC13, δ in ppm and J in Hz at 333°K): 1.16 (d, J=7, -CH3) ; 2.01 and 2.21 (2s, CH3-CO-N-OCOCH3) ; 2.83 (t, J=7.5, -N=C-CH2-) ; 4.55 (mt, >N-CH<).

EXAMPLE OF USE 11 The oil obtained in Example of use 6 is dissolved in 20 cm3 of acetic acid with 4.3 g of acetic anhydride.

The solution is heated for 2 hours at 100eC. It is concentrated to dryness under reduced pressure at 60°C. 50 cm3 of water and 100 cm3 of diethyl ether are added to the residue and the mixture is stirred for l hour and decanted.

The organic extracts are washed with 4 times 30 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness. The oil obtained is chromatographed on a column with a diameter of 2 cm, containing 30 g of silica gel (50 to 200 μ). The column is eluted with 0.4 litre of a mixture, in equal parts, (vol/vol) of diisopropyl ether and ethyl acetate, while collecting 20 cm3 fractions. The fractions between 0.2 and - 53 0.4 litre are concentrated to dryness. An oil which crystallises from 30 cm3 of diisopropyl ether is obtained. 2.2 g (82%) of N-acetoxy-N-{6-[4-(4-chlorophenyl)-5-(4methoxypheny1)-2-oxazolyl]hexyl}acetamide are obtained in the form of white crystals with a melting point of 80°C. cm3 of 33% ammonium hydroxide are added to a solution of 1.4 g of N-acetoxy-N-{6-[4-(4-chlorophenyl)-5(4-methoxyphenyl)-2-oxazolyl]hexyl}acetamide in 40 cm3 of methanol. The mixture is stirred for 2 hours at 20eC. After evaporation under reduced pressure, 10 cm3 of water are added to the residue and the mixture is extracted with ethyl acetate (2 times 40 cm3). The pooled organic extracts are washed with 3 times 30 cm3 of water and 20 cm3 of a saturated solution of sodium chloride. The solution is dried over magnesium sulphate, filtered and concentrated to dryness. The oily residue obtained crystallises from 30 cm3 of diisopropyl ether. 1 g (78%) of N-{6-[4-(4chlorophenyl)-5-(4-methoxyphenyl)-2oxazolyl)hexyl}acetohydroxamic acid is obtained in the form of white crystals with a melting point of 74eC.

EXAMPLE OF USE 12 g of N-[6-(4,5-diphenyl-2-oxazolyl)hexyl]hydroxylamine acid oxalate are treated with 50 cm3 of acetic acid and 5.4 g of acetic anhydride, according to the conditions defined in Example of use 5. After treatment, the product is chromatographed on a column with a diameter - 54 of 2 cm, containing 25 g of silica gel (50 to 200 μ). The column is eluted with 0.24 litre of a diisopropyl etherethyl acetate mixture (65-35 by volume), while collecting 20-cm3 fractions. The fractions between 60 and 240 cm3 are concentrated to dryness. The residue (3.5 g) is dissolved in 50 cm3 of methanol containing 10 cm3 of 3 3% ammonium hydroxide and then the mixture is stirred for 2 hours at 20°C. After treatment, the product is chromatographed on a column with a diameter of 2 cm, containing 20 g of silica gel (50 to 200 μ). The column is eluted with 0.24 litre of ethyl acetate while collecting 20-cm3 fractions. The fractions between 0.1 and 0.24 litre are concentrated to dryness under reduced pressure (0.2 kPa). 1.9 g (70%) of N-[6-(4,5-diphenyl-2-oxazolyl)hexyl]acetohydroxamic acid are thus obtained in the form of a yellowish oil.

Proton NMR spectrum (300 MHz, CDC13, & in ppm and J in Hz): 2.1 (s, -COCH3); 2.85 (mt, -N=C-CH2-); 3.62 (mt, N-CH2-) ; 8.6 and 9.4 (2mf, >N-OH of the two rotamers).

EXAMPLE OF USE 13 g of N-[6-(4,5-diphenyl-225 oxazolyl)hexyl]hydroxylamine acid oxalate in solution in 30 cm3 of tetrahydrofuran and 30 cm3 water containing 1.85 g of potassium carbonate are treated with 0.83 g of isobutyryl - 55 chloride diluted in 2 cm1 of tetrahydrofuran, according to the conditions (time and temperature) defined in Example of use 6. The product of the reaction, which is isolated according to the Example of use 8 mentioned, is chromatographed on a column with a diameter of 1.6 cm, containing 20 g of silica gel (50 to 200 μ). The column is eluted with 0.2 litre of dichloromethane and then with 0.7 litre of a dichloromethane-methanol mixture (90-10 by volume), while collecting 50-cmJ fractions. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 1.9 g (66%) of N-(6-(4,5diphenyl-2-oxazolyl) hexyl] -N-hydroxyisobutyramide are obtained in the form of a yellowish oil.

Proton NMR spectrum (200 MHz, CDC13 plus a few drops of CD3OD-d4, 6 in ppm and J in Hz) : (d, J=6.5, -CH-(CH3)2); 2.75 (t, J-7.5, -N»C-CH2-); 3.06 (mt, >N-CO-CH<); 3.5 (t, J*7, >N-CHj-) .

EXAMPLE OF USE 14 g of N-[5-(4,5-diphenyl-2-oxazolyl)pentyl]hydroxylamine acid oxalate are stirred in 50 cm1 of acetic acid containing 3.8 g of acetic anhydride, at 11O*C for 3 hours, according to Example of use 7. After treatment, the oil obtained is chromatographed on a column with a diameter of 2 cm, containing 20 g of silica gel (50 to 200 μ) . The - 56 column is eluted with 0.85 litre of ethyl acetate, while collecting 50-cm3 fractions. The fractions between 0.15 and 0.85 litre are concentrated to dryness. The residue (2.5 g) is dissolved in 50 cm3 of methanol containing 10 cm3 of 33% ammonium hydroxide and then the mixture is stirred for 2 hours at 20°C. After treatment, according to Example of use 7 , the oily residue is chromatographed on a column with a diameter of 2 cm, containing 20 g of silica gel (50 to 200 μ). The column is eluted with 0.6 litre of ethyl acetate, while collecting 50-cm3 fractions. The fractions between 0.1 and 0.6 litre are concentrated to dryness under reduced pressure (0.2 kPa). 1.4 g (63%) of N[5-(4,5-diphenyl-2-oxazolyl) pentyl ] acetohydroxamic acid are obtained in the form of a colourless oil.

Proton NMR spectrum (200 MHz, DMSO-d6 plus a few drops of CDjCO OD-d,(, S in ppm and J in Hz) : 1.98 (s, >N-COCHj) ; 2.84 (t, J=7.5, -N=C-CH2-) ; 3.52 (t, J=7, >N-CH2-) .

The present invention also provides pharmaceutical compositions consisting of a product of formula (I), or a pharmaceutically acceptable salt thereof, optionally combined with any other compatible product which may be inert or physiologically active, and especially with one or more pharmaceutically acceptable diluents or adjuvants. The compositions of the invention may be used - 57 parenterally, orally, rectally or topically.

Tablets, pills, powders or granules may be used as solid compositions for oral administration. In these compositions, the active product according to the invention is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch. These compositions may also comprise substances other than diluents, for example a lubricant such as magnesium stearate.

Emulsions, solutions, suspensions, syrups and 10 elixirs containing inert diluents such as water or paraffin oil, which are pharmaceutically acceptable, may be used as liquid compositions for oral administration. These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavouring products.

The compositions for parenteral administration may be sterile solutions which are aqueous or non-aqueous, suspensions or emulsions. Propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, and organic esters for injection, for example ethyl oleate, may be used as solvent or vehicle. These compositions may also contain adjuvants, in particular wetting, emulsifying or dispersing agents. Sterilisation may be performed in a number of ways, for example by means of a bacteriological filter, by incorporating sterilising agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which - 58 are dissolved at the time of use in sterile water or in any other sterile medium for injection.

The compositions for rectal administration are suppositories or rectal capsules which may contain, in addition to the active product, excipients such as cocoa butter or Suppocire.

The compositions for topical administration may be for example creams, ointments or lotions.

In human therapy, the products of the invention may be particularly useful in the treatment of diseases of inflammatory origin. They may therefore prove very useful in osteoarticular pathology in the treatment of arthritis, rheumatoid polyarthritis, spondylarthritis, gout, arthrosis, chondrocalcinosis, as well as in other inflammatory pathologies affecting the lungs, the digestive tracts (ulcerative colitis, hepatic inflammation, cirrhosis, colon diseases, Crohn's disease), the skin (psoriasis, herpes, acne, erythema, eczema, dermatitis), the eyes, the nasal tracts, the buccal cavity and the teeth. They may also be used in the treatment of nasal and bronchial allergies (asthma). The products according to the invention may also be useful in the treatment of inflammations linked to the seating of implants, by improving their compatibility with the surrounding tissue.

They may also play a role in immunoregulation (autoimmune diseases), ischemia and reperfusion (cardiac in particular). - 59 These products also exert a beneficial effect in the treatment of hypothermia and pain.

The dosage depends on the desired effect and on the duration of treatment. For an adult, it is generally between 500 mg and 2 g per day orally. Generally, the doctor will determine the dose which he judges to be most appropriate, according to age, weight and all the other factors which are specific to the individual to be treated.

The following Example illustrates a composition according to the invention.

EXAMPLE Tablets having the following composition are 15 prepared by the usual technique: - N-{6-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]hexyl}-Nhydroxylamine acid oxalate..................... 100 mg - starch...................................... 332 mg - silica...................................... 120 mg - magnesium stearate.......................... 12 mg ,E 921815

Claims (13)

filADH

1. An oxasole derivative of formula: * is e hydrogen ate* or an alkyl radical containing 1 or a cartoon atoms, R, and *

2. Are identical or different and represent hydrogen or halogen atone, or alkyloxy radicals whose alkyl part contains l to 4 carbon atone in a linear or branched chain and n equals 3 to 6, and their salts and their isonere (if any), and mixtures thereof. a. An oxasole derivative according to claim l which is N-(6-[4 f 5-bie(4-methoxyphenyl)-2axasolyl]hexyl}hydroxylamine or a salt thereof.

3. An oxazole derivative according to claim l which le (R,e)-N-(7-(4,5-bis(4-methoxyphenyl)-2-oxaxolyl]2-heptyl)hydroxylamine or a salt thereof.

4. An oxasole derivative according to claim ι Which ie N-(B-[4,9-bie(4-ohlorophenyl)-2oxasolyl]pentyl)hydroxylanine or a salt thereof.

5. An oxasole derivative according to claim x - βι which ia H-[6-(4,5-diphenyl-2-oxaiolyl] hexyl]hydroxylaaine or a salt thereof.

6. Method of preparing an exaiole derivative according to clain l, which ooepriaea reducing an oxiae of forvulat in whiob Rj, Hg, H, and n are defined ae in olaln 1, by any known Method vhiah does not affect the rest of the nolecule, and optionally converting the product obtained into its salt.

7. Method of preparing an oxazole derivative according to clain 1, in which R is a hydrogen atom, which coatpriaea alkylating the aodiua salt of an alkyl 3-aathyl5-hydroxy-4-laoxazolecarboxylate vith an oxazole derivative of foraulat (CH 2 ) n -CB 2 -Br in which R,, Rj and n are aa defined in olaia 1, and then hydrolyaing the product obtained of formula *E 921815 in which Rg and n are defined ae in olaia l and Aik represent* a linear or branched alkyl radical containing 1 to 4 carbon atone, in an aaidic medium, and optionally converting the product obtained into its ealt.

8. use of a product according to olaia 1, for the preparation of an oxacole derivative of formula: in which R, R 1 , ftg and n are ae defined in elain l, and x, represents an amino or alkyl radical containing 1 to 4 carbon atoas in a linear or branched chain, and their salts and their isomers (if any) and mixtures thereof.

9. A pharmaceutical composition comprising at least one oxazole derivative according to any one of claims 1 to 5, in association vith one or mors compatible and pharmaceutically acceptable diluents or adjuvants.

10. An oxazole derivative according to olaia l substantially aa described in any one of the foregoing Examples. - 63 11. Method according to dal* 6 or 7 substantially ae hereinbefore described.

11.

12. An oxazole derivative according to olein 1 Vhen prepared by e Method aa claimed in any of claims t, 7 or

13. A coapoeition according to elaim 9 eubetentially ae hereinbefore described.