IE913254A1 - 5-trifluoroacylamino-2-aryloxazoles - Google Patents

Abstract

A series of novel 5-trifluoroacylamino-2-aryl oxazoles and their pharmaceutically acceptable base addition salts are disclosed. These compounds are useful in therapy as aldose reductase inhibitors for the control of certain chronic diabetic complications. Methods for preparing these compounds from known starting materials are provided.

Description

-TRIFLUOROACYLAMINO-2-ARYL OXAZOLES Background of the Invention This invention relates to 5-trifluoroacylamino-2-aryl oxazoles. The compounds are useful for the control of certain chronic complications arising from diabetes mellitus (e.g., diabetic cataracts, retinopathy and neuropathy). The present invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treating complications arising from diabetes mellitus.

Past attempts to obtain new and better oral antidiabetic agents have, for the most part, involved an endeavor to synthesize new compounds that lower blood sugar levels. More recently, several studies have been conducted concerning the effect of various organic compounds in preventing or arresting certain chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy, etc. For instance, K. Sestanj et al. in U.S. Patent No. 3,821,383 discloses that certain aldose reductase inhibitors like 1,3-dioxo-lH-benz[d,e]iso25 quinoline-2 (3H)-acetic acid and some closely-related derivatives thereof are useful for these purposes even though they are not known to be hypoglycemic. These compounds function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for catalyzing the reduction of aldoses (like glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, retina, peripheral nervous system and kidney of diabetic subjects are prevented or reduced. As a result, these compounds control certain chronic diabetic complications, including those of an ocular nature, since it is already known in the art that the presence of polyols in the lens of the eye leads to cataract formation and concomitant loss of lens clarity. -2Aldose reductase inhibitors of the formula R1 nhcooch2c6h5 wherein R* is hydrogen, C,-C4 alkyl or phenyl and R2 is 10 hydrogen, C,-C4 alkyl, aralkyl or aralkenyl of 8 or fewer carbons, or phenyl optionally substituted by C,-C4 alkyl are referred to in Japanese Patent Application 77105, published October 14, 1987, of Rohto Pharmaceutical KK.

Summary of the Invention The present invention relates to compounds of the formula fir NHCOCF3 u and the pharmaceutically acceptable base addition salt 25 thereof, wherein Ar is naphthalenyl, 4-chloro-l-methoxynaphthalen-2-yl, pyridinyl, 6-chloropyridin-3-yl, 2-methylthiopyridin-3-yl, phenyl, nitrophenyl, hydroxyphenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, -chloro-2-nitrophenyl, bromophenyl, dibromophenyl, 5-bromo30 2-chlorophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl, trifluoromethylphenyl, C,-C4 alkylphenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, phenoxyphenyl, 0,-0,, alkoxyphenyl, 3,5-dibromo-2-methoxyphenyl, 3,5-di-iodo-2-methoxyphenyl, C3-C8 cycloalkyl-al35 koxyphenyl having up to three carbon atoms in the alkoxy moiety, phenylalkoxyphenyl or C,-C4 alkoxyphenylalkoxyphenyl -3each having up to three carbon atoms in the central alkoxy moiety, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, thienylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, thiazolylalkoxyphenyl or 4-methylthiazolylalkoxyphenyl each having up to three carbon atoms in the alkoxy moiety, benzoylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, Cj-C4 alkylthiophenyl, 2-chloro-5-methylthiophenyl, C,-C4 alkanesulfonylphenyl, or phenylalkylthiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic moiety; and R is hydrogen, C,-C4 alkyl, or C,-C4 alkylthioalkyl or Cj-C4 alkanesulfonylalkyl each having up to three carbon atoms in the linking alkyl moiety.

In a preferred embodiment of the invention, R is hydrogen or R is C,-C4 alkylthioalkyl or C,-C4 alkanesulfonylalkyl each having up to three carbon atoms in the linking alkyl moiety. More preferably, R is C,-C4 alkyl20 thioalkyl or C,-C4 alkanesulfonylalkyl and Ar is 4-methylthiazolylalkoxyphenyl having up to three carbon atoms in the alkyl moiety.

In another preferred embodiment of the invention, R is hydrogen and Ar is fluorophenyl, difluorophenyl, chloro25 phenyl, dichlorophenyl, bromophenyl, dibromophenyl, iodophenyl, di-iodophenyl, or tri-iodophenyl.

In another preferred embodiment of the invention R is hydrogen and Ar is C,-C4 alkoxyphenyl, C3-C8 cycloalkylalkoxyphenyl, phenylalkoxyphenyl, C,-C4 alkoxyphenylalkoxy30 phenyl, pyridinylalkoxypheny1, thienylalkoxyphenyl, 4-methylthiazolylalkoxyphenyl, or benzoylalkoxyphenyl or C1-C4 alkylthiophenyl, ci-c4 alkanesulfonylphenyl, phenylalkylthiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic moiety. -4In another preferred embodiment of the present invention, R is hydrogen and Ar is 2-naphthalenyl, 4-chloro-lmethoxynaphthalen-2-yl, 6-chloro-3-pyridinyl, 2-methylthiopyridin-3-yl, phenyl, 4-hydroxyphenyl, 5-chloro-2-nitro5 phenyl, 5-bromo-2-chlorophenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylpheny1, 3,5-dibromo-2-methoxyphenyl, 3,5-di-iodo-2-methoxyphenyl, 2-hydroxy-2-phenylethoxyphenyl or 2-chloro-5-methylthiophenyl.

Preferred compounds of the invention include the 10 following: N-[2-(4-chlorophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-5oxazolyl]-2,2,2-trifluoroacetamide N-[2-(3,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5-oxazolyl]2,2,2-trifluoroacetamide N-[2-(2,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoro20 acetamide N-[2-(2-bromophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-(4-(2-cyclohexylethoxy)phenyl)-5-oxazolyl]-2,2,2trifluoroacetamide N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2trifluoroacetamide N-[2-naphthalenyl-5-oxazolyl]-2,2,2-trifluoroacetamide N-[ 2- (4-chloro-l-methoxynaphthalen-2-yl) -5-oxazolyl] 2,2,2-trifluoroacetamide N-[ 2- (2-chloro-5-methylthiophenyl) -5-oxazolyl]-2,2,2trifluoroacetamide N-[2-(3,5-diiodo-2-methoxyphenyl)-5-oxazolyl]-2,2,2trifluoroacetamide Specific compounds of the invention include the following: -5N-[ 2-( 4- (trif luor omethyl) phenyl) -5-oxazolyl] -2,2,2trifluoroacetamide N-[2-(4-cyanophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-(2,3-dihydro[4H-l]benzopyran-6-yl)-5-oxazolyl]2,2,2-trifluoroacetamide N- [2 - (2,3-dihydrobenzofuran-5-y 1) -5-oxazolyl ] 2,2,2trifluoroacetamide N-[2-(3,4-methylenedioxyphenyl)-5-oxazolyl]-2,2,210 trifluoroacetamide N- [2 - (3,4-ethylenedioxypheny1-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-(naphthalen-l-y1-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-(1,2,3,4-tetrahydronaphthalen-5-yl)-5-oxazolyl]2,2,2-trifluoroacetamide N- [ 2-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-oxazolyl]2,2,2-trifluoroacetamide N-[2 - (4-methy1sulf inylphenyl)-5-oxazolyl]-2,2,20 2-trifluoroacetamide N-[2-(4-methy1sulfonylphenyl)-5-oxazolyl]-2,2, 2-trifluoroacetamide N-[2-(2-methoxy-l-(trifluoromethyl)naphthalen-5-yl)-5oxazolyl]-2,2,2-trifluoroacetamide The present invention also relates to a pharmaceutical composition for the treatment of chronic complications associated with diabetes comprising a compound of the formula I or a pharmaceutically acceptable base addition salt thereof in an amount effective to prevent or alleviate such chronic complications and a pharmaceutically acceptable carrier. Specific and preferred compositions of the present invention comprise the foregoing specific and preferred compounds.

The present invention also relates to a method for treating a diabetic subject to prevent or alleviate chronic complications arising in said subject, which comprises -6administering to said diabetic subject an amount of a compound of the formula I or a pharmaceutically acceptable addition salt thereof effective to prevent or alleviate such complications.

Detailed Description of the Invention The following reaction scheme illustrates the preparation of the compounds of the present invention. flrCOOH R H V In accordance with the process employed for preparing 30 the compounds of the present invention, an appropriately substituted carboxylic acid amide of formula IV or nitrile of formula V, wherein Ar and R are as previously defined, is converted by means of a reagent or reagent mixture which is a strong protonic acid into the title compounds of formula I. Such reagents which may be useful for this transformation may include trifluoroacetic acid/trifluoroIE 913254 -7acetic anhydride, polyphosphate ester, and the like and may be used in the presence or absence of a reaction-inert solvent. A mixture of trifluoroacetic acid/trifluoroacetic anhydride, without additional solvent, is preferred for this step. These reactions may be carried out at a temperature that is in the range of about -20°C up to the boiling point of the reagent or solvent employed, and is preferably conducted in the range of about 0°C to about 25°C.

Isolation of the desired product I may be effected by 10 quenching the reaction mixture, preferably with water or a water-ice mixture, followed by removal of the crude reaction product either by filtration of the resulting solid precipitate or by extraction of the reaction products into a suitable organic solvent which may subsequently be evaporated to provide said crude reaction products. Further purification may be accomplished by crystallization/ recrystallization from a suitable solvent system or by chromatographic methods.

The appropriately substituted carboxylic acid amide starting materials of formula IV are themselves readily prepared from the corresponding esters of formula III by treating the latter in a reaction-inert solvent with ammonia gas or aqueous ammonia. The reaction is carried out in an organic solvent such as lower alcohol, lower dialkyl ethers, Ν,Ν-lower dialkyl amides, or aromatic or nonaromatic hydrocarbons. A preferred solvent in this connection is methanol. In general, equimolar or excess amounts of the ammonia are employed, and the reaction is effected at a temperature in the range of about O’C to about the boiling point of the solvent employed for a period of about one hour to about 72 hours. In practice, the reaction is conducted using two to ten equivalents of ammonia at room temperature for a period of from 6 to 48 hours.

The preparation of the esters of formula III, used as the starting materials in the above discussion, are themselves readily prepared by a variety of methods reported -8in the scientific literature and familiar to those practiced in the art. For example, the reaction of a carboxylic acid chloride of formula II (prepared from a suitable arylcarboxylic acid by known methodologies) with a suitably substituted or unsubstituted amino acid ester can provide the desired ester intermediates of formula III in good yield. The reactions may be carried out in reaction-inert solvents such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc. in the presence or absence of a suitable base (acid scavenger) at temperatures of from about -78°C to about the boiling point of the solvent employed and for periods of from about one hour to about 72 hours. Preferably, the reaction is conducted in methylene dichloride, employing triethylamine as the base (acid scavenger) and stirring the reaction components for up to 8 hours within the temperature range of about 0°C to about 25°C. Other methods available to prepare said intermediates of formula III, reported in the chemical literature, include the reaction of an activated aromatic acid (e.g., an acid anhydride or mixed acid anhydride) with a suitable aminoacid or aminoacid ester, and the Schotten-Baumann benzoylation of a suitable aminoacid ester.

In a similar fashion, the suitable nitriles of formula V, described at the beginning of this section, may also be prepared starting with the appropriate aromatic acid, aromatic acid chloride or activated acid (e.g., mixed acid anhydride) and the appropriate amino-nitrile. Some of these intermediates useful to the present invention are described in the literature (e.g., J.-P. Fleury and A. Baysong, 0 Bulletin de la Societe Chimique de France, (19 6 9), 4102-4108; A.J. Crovetti, US Patent 3,457,294).

Finally, the starting materials required for preparing the compounds of formula II are either known compounds which are readily available commercially or they are described in the literature or else they can easily be synthesized by those skilled in the art starting from common chemical -9reagents and using conventional methods of organic synthesis. For instance, 4-chlorobenzoyl chloride is readily prepared from the known 4-chlorobenzoic acid, e.g. through the action of thionyl chloride in refluxing toluene.

Further purification can then be carried out by such means as silica gel column chromatography and the like, in addition to standard recrystallization procedures.

The reaction pressures of the foregoing reactions are generally not critical unless otherwise indicated. They will generally be about 0.5 to about 2 atmospheres, preferably ambient pressure (i.e. about one atmosphere).

The chemical bases which are used as reagents in this invention for the preparation of pharmaceutically acceptable base salts are those which form non-toxic base salts with the herein described N-[2-substituted-5-oxazolyl]-2,2,2trifluoroacetamide compounds such as, for example, N-[23,4-dichlorophenyl)-5-oxazolyl)-2,2,2-trifluoroacetamide. These particular non-toxic base salts include those derived from such pharmaceutically acceptable cations as sodium, potassium, calcium, magnesium, etc., as well as such pharmaceutically acceptable organic bases such as ethylenediamine, diethanolamine, etc. These salts can be prepared by treating the aforementioned N-[2-substituted-5-oxazolyl]2,2,2-trifluoroacetamide compound with a lower alkanolic solution of the desired metal alkoxide and then evaporating the resulting solution to dryness. Alternatively, they may also be prepared by treating the aforementioned 2,2,2-trifluoroacetamides with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. In either case, stoichiometric quantities of reagents should be employed to ensure completeness of reaction and maximum production of yields of the desired final salt product.

The compounds of the formula I and the pharmaceutically acceptable addition salts thereof (hereinafter also referred -10to as the active compounds of the present invention) are readily adapted to therapeutic use as aldose reductase inhibitors for the control of certain chronic diabetic complications, in view of their ability to reduce lens and peripheral nerve (e.g., the sciatic nerve) sorbitol levels in diabetic subjects. The active compounds of the present invention can be administered to affected mammals (including humans) by either the oral, topical or parenteral routes of administration. In general, these compounds are ordinarily administered in dosages ranging from about 0.50 mg to about 100 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.

These compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by the various routes previously indicated, and such administration can be carried out in either single or multiple dosages. More particularly, the active compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In general, the active compounds of the invention will be present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition to provide the desired unit dosage.

For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, -11together with binding agents such as polyvinylpyrrolidone, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include the high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral administration, solutions of the active compounds of the present invention may be prepared, taking into account the solubility of the compound or salt to be utilized. Thus, solutions in sesame or peanut oil or in aqueous propylene glycol or Ν,Ν-dimethylformamide as well as sterile aqueous solutions may be empoyed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds topically via an appropriate ophthalmic solution (e.g., 0.5-2.0%) applied dropwise to the eye.

The utility of the compounds of the present invention, as agents for the control of chronic diabetic complications, may be predicted by measuring their ability to (1) inhibit the enzyme activity of isolated aldose reductase; (2) reduce -12or inhibit sorbitol accumulation in the sciatic nerve and lens of acutely streptozotocinized (i.e., diabetic) rats; (3) reverse already-elevated sorbitol levels in the sciatic nerve and lens of chronic streptozotocin-induced diabetic rats; (4) prevent or inhibit galactitol formation in the lens of acutely galactosemic rats, and/or (5) delay cataract formation and reduce the severity of lens opacities in chronic galactosemic rats.

The following Examples illustrate the preparation of 10 the compounds of the present invention. All melting points are uncorrected.

Example 1 N-f 2-(4-chlorophenvl)-S-oxazolvll-2,2,2-trifluoroacetamide A. Methyl N-(4-chlorobenzovl)aminoacetic acid 15 A mixture of 7.8 g (0.05 mol) p-chlorobenzoic acid, 50 mL SOC12 and 50 mL toluene was refluxed for 1 hour, another 50 mL SOC12 was added, and heating was continued for another 1 hour. The homogenous solution was concentrated in vacuo and distilled as an azeotropic mixture with toluene (2 x 50 mL). The residue was suspended in 50 mL of CH2C12 and added to a solution of glycine methyl ester (prepared from glycine methyl ester hydrochloride (18.75 g, 0.15 mol) and 7.6 g (0.075 mole) triethylamine in 100 mL CH2C12 at O’C over approximately 10 minutes). After being warmed to 25°C and stirred for an additional 30 minutes, the solution was filtered and the filtrate was concentrated to a solid.

Crystallization from hot ethyl acetate/hexane produced the title compound, 7.6 g (67%), m.p. 113-114°C; MS(%): 229, 227, 195, 168, 155, 139 (100), 111.

B. 4-Chlorobenzoylaminoacetamide A solution of the title compound of Example IA (7.5 g, 0.033 mol) in 250 mL anhydrous methanol was treated with NH3 gas for 1 hour at 25°C, then stirred for another 48 hours at 25°C under N2. A white solid, 1.5 g (m.p. 193-195°C) was collected and a second crop (5.1 g, m.p. 188-190°C) was obtained by concentration of the filtrate. Both solids were -13identical by thin layer chromatography (TLC) (Rf 0.25, 1 CH3OH: 9 CH2C12) ; MS(%): 214, 212.

By a similar procedure, the following benzoylaminoacetamides (X, R, yield, m.p.) were prepared: Η, H, 89%, 182-183°C; (m.p. 183° - Journal of Pharm.

Society of Japan 58. 809-15 (1938), (C.A. 33, 17266) ; 2.4- dichloro, H, 94%; 3.5- dichloro, H, 91%; 4-(2-(4-methoxyphenyl)ethoxy), H, 88%, m.p. 198-200°C; 4-methoxy, H, 87%; 4-(1-methylcyclohex-l-yl)methoxy, H, 70%, m.p. 75-78°C; 4-phenylmethoxy, H, 78%, m.p. 205-206°C; 3,4-dichloro, H, 62%, m.p. 210-212°C; 2.6- dichloro, H, 96%, m.p. 240-242°C; 4-benzoylmethoxy, H, 76%, m.p. 140-142°C; 4-(2-pyridin-2-yl)ethoxy, H, 64%, m.p. 173-174°C; 4-(2-phenylethyl)thio, H, 99%, m.p. 148-150°C; 4-(2-(4-methylthiazol-5-yl)ethoxy), 2-methylthioethyl, 77%, m.p. 133-135eC.

Also prepared by the same method was 6-chloro pyridin30 3-yl-carbonylaminoacetamide, 64%, m.p. 199-2O1°C (from CHjOH) .

C. N-Γ 2 - (4-Chlorophenyl) -5-oxazolyIl-2 , 2 . 2 trifluoroacetamide A solution of 6.5 g (0.031 mol) of the title compound of Example IB in 60 mL trifluoroacetic acid, cooled to O’C, was treated dropwise with 65 g (0.031 mol) trifluoroacetic -14anhydride over a 35 minute period, allowed to warm to 25°C and stirred at that temperature for 3 hours. On concentration in vacuo, a syrup was obtained which was dissolved in 250 mL ethyl acetate, washed with H20, saturated NaHCO3, H20 and saturated NaCl. After drying (MgSOJ , the organic layer was concentrated in vacuo to a cream colored solid (8 g) . Recrystallization from ethyl acetate/petroleum ether gave the title compound (6.3 g, 70%), m.p. 144-146°C; MS(%): 292, 290, 235, 193, 165, 150, 139 (100), 123, 111; Anal.: Calculated for CnH6ClF3N2O2: C, 45.46, H, 2.09, N, 9.64. Found: C, 45.27, H, 2.07, N, 9.53.

By a similar procedure, the following compounds were prepared from the corresponding acetamides (recrystallization solvents indicated in parentheses): N-[2-(4-(2-phenylethoxy)phenyl)-5-oxazolyl)-2,2,2trifluoroacetamide, 79%, m.p. 143-144°C (ethyl ether); Anal.: Calculated for C,9H15F3N2O3: C, 60.69, H, 4.02, N, 7.45; Found: C, 60.52, H, 4.07, N, 7.40.

N- [ 2 - (4 - ((1-methylcyclohexyl) methoxy, phenyl) -5-oxazoly20 1]-2,2,2-trifluoroacetamide quarter hydrate, 82%, m.p. 126-129°C (ethyl ether: hexane); Anal.: Calculated for C19H21F3N2O3*3jH2O: C, 58.99, H, 5.66, N, 7.24; Found: C, 59.18; H, 5.63, N, 7.06.

N-[2-(4-methoxyphenyl)-5-oxazolyl]-2,2,2-trifluoro25 acetamide, 66%, m.p. 141-142°C (ethyl ether: hexane); Anal.: Calculated for C12H„F3N2O3: C, 50,39, H, 3.18, N, 9.80; Found: C, 50.34, H, 3.70, N, 9.71.

N-[2-(4-phenylmethoxyphenyl)-5-oxazolyl]-2,2,2trifluoroacetamide, 20%, m.p. 155-156°C (ethyl acetate: hexane); Anal.: Calculated for ClgHl3F3N2O3: C, 59.67, H, 3.62, N, 7.73; Found: C, 59.85, H, 3.64, N, 7.70.

N-[2-phenyl-5-oxazolyl]-2,2,2-trifluoroacetamide, 76% , m.p. 152-153°C (ethyl acetate: hexane); MS (%) : 256, 237, 201, 104 (100). Anal.: Calculated for C,,H7F3N2O2: C, 51.57, H, 2.76, N, 10.94; Found: C, 51.65, H, 2.80, N, 10.99.

N-[2-(3,4-dichlorophenyl)-5-oxazolyl]-2,2,2IE 913254 -15trifluoroacetamide, 56%, m.p. 125-126°C (CH2C12: hexane); Anal.: Calculated for C,,HjC12F3N2O2: C, 40.64, H, 1.55, N, 8.62; Found: C, 40.51, H, 1.60, N, 8.55.

N-[2-(4-(benzoylmethoxy)phenyl)-5-oxazolyl]-2,2,25 trifluoroacetamide, 57%, m.p. 185-186OC (ethyl acetate: hexane); MS (%) : 390, 271, 255, 239, 105 (100). Anal.: Calculated for C19H13F3N2O4: C, 58.46, H, 3.36, N, 7.18; Found: C, 58.16, H, 3.30, N, 7.09.

N-[2-(4-(2-pyridyl)ethoxy)phenyl)-5-oxazolyl]-2,2,210 trifluoroacetamide, 72%, m.p. 152-153°C (ethyl acetate); MS (%): 377, 152, 132, 106 (100) Anal.: Calculated for C,gHi4F3N3O3: C, 57.29, H, 3.74, N, 11.14; Found: C, 57.06, H, 3.74, N, 11.11.

N-[2-(3,4-(dichlorophenyl) -5-oxazolyl]-2,2,2-tri15 fluoroacetamide, quarter hydrate, 72%, m.p. 116-120°C (ethyl ether: hexane); Anal.: Calculated for c, 40.09, H, 1.68, N, 8.50; Found: C, 40.00, H, 1.58, N, 8.22.

N-[2-(2,6-dichlorophenyl) - 5-oxazolyl]-2,2,2-trifluoroacetamide, 54%, m.p. 155-156’C (ethyl acetate: petroleum ether); MS (%) : 324, 172 (100), 152, 135, 121, 108, Anal.: Calculated for C„HSC12F3N2O2: C, 40.64, H, 1.55, N, 8.62; Found: C, 40,58, H, 1.57, N, 8.90.

N - [ 2 - (3,5-dichloropheny1)-5-oxazolyl]-2,2,2-trifluoroacetamide hemihydrate, 90%, Anal.: Calculated for C„H5C12F3N2O2*^H2O: C, 39.55, H, 1.81, N, 8.39; Found: C, 39.64, H, 1.69, N, 8.00.

N-(2-(6-chloropyridin-3-y1)-5-oxazolyl]-2,2,2trifluoroacetamide, m.p. 144-145’C (ethyl hexane); Anal.: Calculated for C10HjC1F3N3O2: C, 41.18, H, 1.73, N, 14.41; Found: C, 41.48, H, 1.74, N, 14.80.

N-[2-(4-(4-(2-methoxyphenylethoxy)phenyl)-5-oxazolyl]2,2,2-trifluoroacetamide, 76%, m.p. 124-126°C (ethyl ether: hexane); Anal.: Calculated for C20Hj7F3N2O4: C, 59.11, H, 4.22, N, 6.89; Found: C, 59.38, H, 4.19, N, 6.87. -16N-[2-(4-(2-(4-methylthiazol-5-yl) ethoxy)phenyl) 4 - (2-methy 1th ioethyl-5-oxazolyl] -2,2,2-trif luoroacetamide, 77%, m.p. 100-101°C (ethyl acetate: hexane); MS (%) : 471, 246, 126 (100), 112, 99.

N- [ 2- (4- (2-pheny1ethy1thio)phenyl)-5-oxazolyl]-2,2,2trifluoroacetamide, 52%, m.p. 103-104°C (ethyl acetate: hexane), MS(%): 392, 301, 256, 178, 159, 149, 135, 121, 105 (100); Anal.: Calculated for ϋ19Η15Ε3Ν2Ο23: C, 58.15, H, 3.85, N, 7.14; Found: C, 57.76, H, 3.78, N, 6.99.

Example 2 N- Γ 2 - (3,5-Diiodo-2-methoxyphenyl) -5-oxazolyl 1-2,2,2-trifluoroacetamide A. N-(3,5-diiodo-2-methoxvbenzovl)aminoacetonitrile A mixture of 20 g (0.05 mol) 3,5-diiodosalicylic acid and 20 mL thionyl chloride in 50 mL CH2C12 was refluxed for 24 hours, cooled to 25®C and concentrated in vacuo. The resulting oil (22 g) , dissolved in 20 mL of benzene, was added to a solution of 4.6 g (0.05 mol)aminoacetonitrile hydrochloride in 35 mL H20 at 0-5 °C, and the resulting mixture was treated with 49 mL 2N NaOH dropwise to maintain a pH greater than 9. After another 3 0 minutes, a light purple solid was filtered, air dried, and recrystallized from ethanol to give the title compound as colorless crystals, 5.92 g (27%), m.p. 193-195°C; NMR (6, DMSO-d6) : 3.70 (s, 3H), 4.27 (d, 2H), 7.76 (d, IH), 8.23 (d, IH), 9.08 (t, IH).

By a similar procedure, the following benzoylamino acetonitriles were prepared (definition of X followed by yield and by melting point; recrystallization solvents indicated in parentheses): -175-bromo-2-chloro, 23%, m.p. 150-154°C (aqueous ethanol); -chloro-2-nitro, 47%, m.p. 152-155°C (ethanol) (French Patent 1,520,925 (Chem. Abstr., 71. 49623k (1969)), m.p. 161-163°C); -chloro-2-methyl, 64%, m.p. 168-172°C (ethanol); 2-phenoxy, 38%, m.p. 104-109°C (ethanol); 2-chloro-5-methylthio, 94%, m.p. 95-97°C; 2.5- diiodo, 60%, 180-183°C (ethanol); 2,3,5-triiodo, 57%, m.p. 270°C; 3.5- dibromo-2-methoxy, 63%, m.p. 135-137°C (ethanol); 2-fluoro, 73%, m.p. 58-60’C (aqueous ethanol); 2- bromo, 34%, m.p. 120-123°C (aqueous ethanol); 3- fluoro-4-methyl, 39%, m.p. 93-95°C (aqueous ethanol); Also prepared by the same procedure were: (name of compound followed by yield and melting point; recrystallization solvent indicated in parentheses).

N-(cyanomethyl)-naphthalene-l-carboxamide, 49%, m.p. 130-133°C (ethanol); N-(cyanomethyl)-4-chloro-l-methoxynaphthalene-2-carboxamide, 54%, m.p. 139-141°C, (ethanol) and N-(cyanomethyl)2-(methylthio)pyridine-3-carboxamide, 53%, m.p. 128-132°C (methanol: toluene). Β. Ν-Γ 2-(3,5-diiodo-2-methoxyphenvl)-S-oxazolvll25 2.2,2-trifluoroacetamide A mixture of 2.0 g (4.53 mol) of the title compound of Example 2A, 15 mL trifluoroacetic anhydride and 1.0 mL trifluoroacetic acid were stirred at 25°C for 4 hours. The resulting homogeneous solution was then poured over 150 mL ice water and the resulting precipitate was filtered, washed well with 5% aqueous NaHC03 and H20 and dried. Recrystallization from aqueous methanol gave the title compound, 2.1 g (86%), m.p. 160-163°C; NMR (5, DMSO-d6) : 3.78 (s, 4H) , 7.32 (s, 1H) , 8.13 (d, 1H) , 8.26 (d, 1H) ; Anal.: Calculated for C12H7F3I2N2O3: C, 26.79, H, 1.31, N, 5.21. Found: C, 26.69, H, 1.32, N, 4.99. -18By a similar procedure, the following 2,2,2-trifluoroacetamides were prepared (name of compound followed by yield and melting point; recrystallization solvents indicated in parentheses): N-[2-(2-bromophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide hydrate, 74%, m.p. 117-119°C (ethyl acetate: hexane); MS (%): 336 (45), 334 (39), 290 (3), 194 (13), 184 (100), 182 (9). Anal.: Calculated for CnH6BrF3N2O2*H2O: C, 37.42, H, 2.28, N, 7.93; Found: C, 37.29, H, 2.18, N, 7.65.

N - [ 2 - ( 5-bromo-2-chloropheny 1) -5-oxazolyl ] - 2,2,2 trifluoroacetamide, 78%, m.p. 128-130°C (CH2C12: hexane); MS(%): 372 (7), 370 (34), 368 (27), 230 (15), 220 (29), 219 (42), 218 (82), 217 (43), 216 (76), 191 (15), 153 (100); Anal.: Calculated for CnH5BrClF3N2O2: C, 35.75, H, 1.36, N, 7.58; Found: C, 35.49, H, 1.28, N, 7.31.

N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, 68%, m.p. 149-152°C (CH2C12 hexane) ; MS (%): 335 (1), 170 (26), 168 (100), 140 (36), 138 (87), 100 (26); Anal.: Calculated for CuHjC1F3N3O4: C, 39.36, H, 1.50, N, 12.52. Found: C, 39.12, H, 1.68, N, 12.32.

N- [2-(5-chloro-2-methylphenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, 69%, m.p. 101-104°C (ethyl acetate: hexane); Anal.: Calculated for C12H8C1F3N2O2: C, 47.30, H, 2.65, N, 9.20; Found: C, 47.46, H, 2.80, N, 9.01.

N-[2-(2-phenyloxyphenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, quarter trifluoroacetate, 83%, m.p. 115-117 °C (CH2C12: hexane); MS(%): 349 (6), 348 (16), 209 (21), 208 (100), 207 (65), 181 (37), 180 (48), 153 (22), 152 (32); Anal.: Calculated for C17H,,F3N2O3*\CF3CO2H: C, 55.78, H, 3.00, N, 7.43; Found: C, 55.63, H, 3.04, N, 7.40.

N-[2 - (2-chloro-5-methy1thiophenyl)-5-oxazolyl]2,2,2-trifluoroacetamide, 64%, m.p. 97-100°C (toluene); Anal.: Calculated for C12H8C1F3N2O2S: C, 42.81, H, 2.39, N, 8.32, Found: C, 43.20, H, 2.54, N, 8.17.

N-[2-(3-fluoro-4-methylphenyl)-5-oxazolyl]-2,2,2trifluoroacetamide, 73% m.p. 110-113°C (ethyl acetate: -19hexane), MS (%): 289 (30), 288 (66), 234 (17), 191 (18), 148 (32), 137 (87), 136 (100), 109 (60), 107 (32); Anal.: Calculated for C12HgF4N2O2: C, 50.01, H, 2.80, N, 9.72; Found: C, 49.77, H, 2.72, N, 9.36.

N-[2-(2-fluorophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, 68%, m;p. 160-163°C (toluene); MS(%): 275 (26), 274 (91), 219 (9), 153 (28), 134 (28), 123 (83), 122 (100), 107 (28); Anal.: Calculated for C„H6F4N2O2: C, 48.18, H, 2.21, N, 10.22; Found: C, 47.94, H, 2.10, N, 10.07.

N-[2-(2,5-diiodophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, 79%, m.p. 165-167OC (CH3OH*H2O) ; MS(%): 508 (42), 368 (12), 357 (49), 356 (65), 329 (22), 229 (37), 214 (20), 202 (50), 153 (100); Anal.: Calculated for C„H5F3I2N2O2*H2O: C, 25.12, H, 1.34, N, 5.33; Found: C, 25.10, 40.96, N, 5.13.

N- [ 2-(3,5-dibromo-2-methoxyphenyl)-5-oxazolyl]-2,2,2trifluoroacetamide, 62%, m.p. 139-141°C (toluene); MS(%): 446 (8), 444 (19), 442 (9), 331 (45), 305 (55), 303 (100), 301 (51), 276 (83), 198 (50), 196 (67); Anal.: Calculated for C12H7Br2F3N2O3: C, 32.46, H, 1.59, N, 6.31. Found: C, 32.28, H, 1.55, N, 6.23.

N-[ 2-(2,3,5-triiodophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, 80%, m.p. 200-202°C (CH3OH:H2O) ; MS(%): 635 (10), 634 (95), 483 (59), 482 (90), 455 (22), 438 (14), 355 (40), 328 (36), 201 (100), 153 (90); Anal.: Calculated for CUH4F3I3N2O2: C, 20.84, H, 0.64, N, 4.42; Found: C, 20.55, H, O. 74, N, 4.94.

N-[2-(2-(methylthio)pyridin-3-yl)-5-oxazolyl]-2,2,2trifluoroacetamide hydrate, 58%, m.p. 109-lll°C (CH3OH:H2O); MS(%) 304 (20), 303 (28), 190 (48), 163 (57), 162 (77), 152 (41), 136 (75), 135 (100); Anal.: Calculated for C,,HgF3N3O2S*H2O C, 41.12, H, 3.14, N, 13.08; Found: C, 40.68, H, 3.12, N, 12.83.

N-[2-(2-naphthalenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, 50%, m.p. 215-220’C (CH2C12:hexane) ; MS(%): 306 (61), 155 (80), 154 (100), 127 (40); Anal.: Calculated for -20C15H9F3N2O2: C, 58.83, H, 2.96, N, 9.15. Found: C, 58.84, H, 3.11, N, 8.96.

N-[2-(4-chloro-l-methoxynaphthalen-2-yl)-5-oxazolyl]2,2,2-trifluoroacetamide hydrate, 35%, m.p. 119-122°C (toluene); MS(%): 372, 370 (48), 229 (80), 202 (100); Anal.: Calculated for C16H10ClF3N2O3«H2O: C, 49.44, H, 3.11, N, 7.21; Found: C, 49.37, H, 3.38, N, 6.94.

Example 3 N-Γ2-(4-(2-(4-methvlthiazol-5-vl)ethoxy)phenyl)-4-(2-methy10 lsulfonylethyl)-5-oxazolvll-2,2,2-trifluoroacetamide A solution of N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxyphenyl) -4- (2-methylthioethyl) -5-oxazolyl]-2,2,2tr if luoroacetamide (0.500 g, 11 mmol) in 30 mL CH2C12 under N2 was cooled to -74 °C and treated with m-chloroperbenzoic acid (0.500 g, 22 mmol) and then allowed to warm to 25°C overnight. The reaction mixture was then washed (saturated NaHCO3, H2O, saturated NaCl) and dried (MgSO4) , and then filtered and concentrated in vacuo to obtain 0.60 g of tan gum, crystallized from ethyl acetate: hexane to a tan solid, 0.355 g. Recrystallization of this material from ethyl acetate: hexane gave the title compound, 0.220 g (40%), m.p. 153-154°C; MS(%): 503, 434, 424, 326, 245, 126, 99; Anal.: Calculated for C20H20F3N3O5S2: C, 47.71, H, 4.00, N, 8.35; Found: C, 47.71, H, 4.16, N, 8.00.

By a similar process, the following was also prepared: N-[2-(4-(2-phenylethylsulfonyl)phenyl)-5-oxazolyl]-2,2,2trifluoroacetamide, 62%, m.p. 209-210°C (CH3OH); MS(%): 408, 304, 247, 195, 179, 152, 125, 105 (100); Anal.: Calculated for C19H15F3N2O3S: C, 55.87, H, 3.70, N, 6.86; Found: C, 55.79, H, 3.60, N, 6.81.

Example 4 N-f2-f 4-Hydroxyphenvl)-5-oxazolvll-2,2,2-trifluoroacetamide A. 4-Γ (3,4,5,6-tetrahydro-2H-pyran-2-vl)oxvlbenzoic acid A mixture of 4-hydroxybenzoic acid (45 g, 0.33 mol), p-toluenesulfonic acid (5.0 g, 0.026 mol) and 3,4-dihydroIE 913254 -212H-pyran (50 mL, 0.55 mol) in 1000 mL ethyl ether was stirred at 25°C for 18 hours. A solid (12 g) was collected by filtration, while a second crop (36 g) was obtained by concentration of the filtrate to approximately 250 mL.

B· 2 ~ Γ4-(3,4,5,6-Tetrahydro-2H-pvran-2-yl)oxy) benzovlaminolacetamide, The title compound of Example 4A (44.4 g, 0.20 mol), glycine methyl ester hydrochloride (28.2 g, 0.225 mol) and triethylamine (31.4 mL, 0.225 mol) in 500 mL CH2C12 was cooled to 0°C and treated with 1-hydroxybenzotriazole hydrate (30.4 g, 0.225 mol). After 5 minutes, a solution of dicyclohexylcarbodiimide (46.5 g, 0.225 mol) in 250 mL CH2C12 was added and stirring was continued for 18 hours at 25°C. The reaction mixture was then filtered, the filtrate was washed with 250 mL of 10% citric acid, 250 mL 10% NaHCO3, and saturated NaCl and then dried over MgSO4. After evaporation of the solvent, the residue was dissolved in CH3OH and saturated with NH3 gas for 1 hour, left at 25°C for 24 hours and evaporated. The residue was triturated with CH30H: ethyl ether to give 20 g of crude 2-[4-(3,4,5,6-Tetrahydropyran2-yl)oxy benzoylamino]-acetamide. Another 5 g was recoverd from the triturate to give an overall yield of 45%.

C. Ν- Γ 2 - (4-Hydroxypheny1) - 5-oxazolvll-2,2,2-trifluoroacetamide A mixture of trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (70 mL) cooled to O’C was treated with the title compound of Example 4B (20 g, 0.072 mol) over 10 minutes, and the reaction mixture was then allowed to warm to 25°C for 2.5 hours. After concentration in vacuo. the residue was dissolved in 500 mL ethyl acetate, washed with 10% NaHCO3 and saturated NaCl, dried (MgSO4) , and evaporated. Chromatography on silica gel using ethyl ether: hexane (2:1) and then 100% ethyl ether gave 18 g of a brown oily solid. Trituration of the solid with ethyl ether: hexane gave 9 g of the title compound as a white solid, while the filtrate provided a further 5 g for a combined -22yield of 72%, m.p. 220°C (dec); Anal.: Calculated for CnH7F3N2O3: C, 48.54, H, 2.59, N, 10.29, Found: C, 48.19, H, 2.61, N, 10.23.

Example 5 Ν-Γ2-(4-cvclohexylethoxyphenvl)-5-oxazolyll2.2.2-trifluoroacetamide A solution of N-[2-(4-hydroxyphenyl)-5-oxazolyl]2,2,2-trif luoroacetamide (2.2 g, 8 mmol) in 100 mL dry dimethylformamide was cooled to 0°C and treated with NaH (0.48 g, 0.020 mol) under N2 in 3 portions. After 15 minutes, 2-cyclohexylethyl p-toluenesulfonate (3.4 g, 12 mmol) was added in one portion and the reactants were allowed to warm to 25°C. The reaction mixture was then slowly heated to approximately 100°C. After 4 hours, the mixture was cooled to 25°C, poured over ice water and extracted with CH2C12. The organic layer was washed with H20, dried (MgSO4) and concentrated to a brown syrup.

Chromatography on 300 g silica gel using 2:1 ethyl ether:hexane gave 2.2 g of a gum which was crystallized from ethyl ether:hexane (1:10) to provide the title compound as a white solid, 1.96 g (64%), m.p. 136-137’C; MS(%): 382, 272, 217, 175, 153, 132, 121, 69 (100); Anal.: Calculated for C19H21F3N2O3: C, 59.68, H, 5.54, N, 7.33. Found: C, 60.04, H, 5.54, N, 7.33.

Using a similar procedure, 2-(thien-2-yl)ethyl p-toluenesulfonate gave N-[2-(4-(thien-2-yl)ethoxyphenyl)-5-oxazolyl] -2 , 2 , 2-trif luoroacetamide quarter hydrate, 12% yield, m.p. 140-142°C (ethyl ether:hexane); Anal.: Calculated for Cl7H13F3N2O3S«*iH2O: C, 52.78, H, 3.52, N, 7.24; Found: C, 52.91, H, 3.55, N, 7.26.

Similarly, 2-(4-methyl-5-thiazolyl)ethyl p-toluenesulfonate gave N-[2-(4-(2-(4-methylthiazol-5-yl)ethyl)phenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide, 8% yield, m.p. 176-177’C (ethyl ether:hexane); Anal.: Calculated for C17H14F3NjO3S: C, 51.38, H, 3.56, N, 10.58; Found: C, 50.93, H, 3.53, N, 10.35. -23Example 6 N-Γ 2-(4-(2-Hvdroxy-2-phenvlethoxv)phenyl)-5-oxazolyl12,2,2-trifluoroacetamide hemihvdrate A. 4-(2-hydroxy-2-phenvlethoxv) -N-(carbamoylmethvl) 5 benzamide A mixture of 4-(benzoylmethoxy)-N-(carbamoylmethyl)benzamide (1.0 g, 3.0 mmol) and 50 mL CH3OH was treated with NaBH4 (0.116 g, 3 mmol) at 25°C under N2. After 1 hour, the resulting solution was concentrated in vacuo. the gum was dissolved in ethyl acetate and was washed with H20 and then with saturated aqueous NaCl. After drying (MgSO4) , the organics were concentrated to an oil which was crystallized from CH3OH: ethyl ether: hexane (1:5:2) to give the title compound as a white solid, 0.470 g (48%), m.p. 14O-145°C (dec). Β. N-Γ 2-(4-(2-Hvdroxv-2-phenvlethoxv)phenyl)-5oxazovl1-2,2,2-trifluoroacetamide hemihvdrate The title compound of Example 6A(0.47 g, 1.4 mmol) in 5 mL trifluoroacetic acid and 3.0 g trifluoroacetic anhydride was stirred at 25°C for 3 hours, concentrated in vacuo to a syrup and dissolved in ethyl acetate. The organics were washed with H20 and saturated NaCl and then dried (MgSO4) . Concentration in vacuo gave a tan gum, 0.60 g. The gum was dissolved in 10 mL CH3OH, treated with 0.10 g anhydrous K2CO3 and stirred for 1 hour at 25°C. After filtering and concentration of the filtrate, the gum was dissolved in ethyl acetate, washed with H2O and saturated aqueous NaCl, and then dried (MgSO4) . Concentration to a light yellow residue, followed by chromatography on silica gel with CH3OH: CH2C12 (5:95) gave the title compound as a white solid, 37%, m.p. 145-147®C; Anal.: Calculated for C19H15F3N2O4*^H2O: C, 56.86, H, 4.02, N, 6.98; Found: C, 57.21, H, 4.01, N, 6.72. Example 7 The title compounds of Examples 1-6 were tested for their ability to reduce or inhibit aldose reductase enzyme -24activity via the procedure of S. Hayman et al., as described in the Journal of Biological Chemistry. Vol. 240, p. 877 (1965) and as modified by K. Sestanj et al. in U.S. Patent No. 3,821,383. In each case, the substrate employed was partially purified aldose reductase enzyme obtained from human placenta. At a concentration of lO^M the compounds showed a percent inhibition of greater than 50%.

The title compounds of Examples 1-6 are tested for their ability to reduce or inhibit sorbitol accumulation in the sciatic nerve and lens of streptozotocinized (i.e., diabetic) rats in accordance with the procedure described in U.S. Patent No. 3,821,383. The amount of sorbitol accumulation in the sciatic nerve and lens of each test animal is measured 27 hours after the induction of diabetes.

The compound is then administered orally at 100 mg/kg at intervals of 4, 8 and 24 hours after the administration of streptozotocin. The results obtained in this manner are presented in terms of the percent inhibition (%) afforded by the test compound as compared to the case where no compound was administered (i.e., the control or untreated animal where sorbitol levels normally rise from approximately 50-100 mM/g tissue to as high as 400 mM/g tissue in the 27-hour test period).

Claims (19)

1. A 5-trifluoroacetylamino-2-aryloxazole compound of the formula: PC7840AVMF 15 or a pharmaceutically acceptable addition salt thereof, wherein Ar is naphthalenyl, 4-chloro-l-methoxynaphthalen-2-yl, pyridinyl, 6-chloropyridin-3-yl, 2-methylthiopyridin-3-yl, phenyl, nitrophenyl, hydroxyphenyl, fluorophenyl, difluoro20 phenyl, chlorophenyl, dichlorophenyl, 5-chloro-2-nitrophenyl, bromophenyl, dibromophenyl, 5-bromo-2-chlorophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl, trifluoromethylphenyl, C,-C 4 alkylphenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, phenoxy25 phenyl, C,-C 4 alkoxyphenyl, 3,5-dibromo-2-methoxyphenyl, 3,5-di-iodo-2—methoxyphenyl, C 3 -C g cycloalkyl-alkoxyphenyl having up to three carbon atoms in the alkoxy moiety, phenylalkoxyphenyl or C,-C 4 alkoxyphenylalkoxyphenyl each having up to three carbon atoms in the central alkoxy 30 moiety, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, thienylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, thiazolylalkoxyphenyl or 4-methylthiazolylalkoxyphenyl each having up to three carbon atoms in 35 the alkoxy moiety, benzoylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, C,-C 4 alkylthiophenyl, 2-chloro-5-methylthiophenyl, C,-C 4 alkanesulfonylphenyl, or phenylalkylthiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic 40 moiety; and R is hydrogen, C t -C 4 alkyl, or C,-C 4 -26alkylthioalkyl or C t -C 4 alkanesulfonylalkyl each having up to three carbon atoms in the linking alkyl moiety.

2. A compound as claimed in claim 1 wherein R is hydrogen, C,-C 4 alkylthioalkyl or C,-C 4 alkanesulfonylalkyl 5 each having up to three carbon atoms in the linking alkyl moiety.

3. A compound as claimed in claim 2 wherein Ar is

4. -methylthiazolylalkoxyphenyl having up to three carbon atoms in the alkyl moiety. 10 4. A compound as claimed in claim 3 wherein Ar is 2-(4-methylthiazol-5-yl)ethoxyphenyl and R is 2-methylthioethyl or 2-methanesulfonylethyl.

5. A compound as claimed in claim 2 wherein Ar is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, 15 bromophenyl, dibromophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl; C,-C 4 alkoxyphenyl, C 3 -C 8 cycloalkylalkoxyphenyl, phenylalkoxyphenyl, Cj-C 4 alkoxyphenylalkoxyphenyl, pyridinylalkoxyphenyl, thienylalkoxyphenyl, 4- methylthiazolylalkoxyphenyl, benzoylalkoxyphenyl; C,-C 4 20 alkylthiophenyl, C,-C 4 alkanesulfonylphenyl, phenylalkylthiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic moiety; 2- naphthalenyl, 4-chloro-l-roethoxynaphthalen-2-yl,

6. -chloro3- pyridinyl, 2-methylthiopyridin-3-yl, phenyl, 4-hydroxy25 phenyl, 5-chloro-2-nitrophenyl, 5-bromo-2-chlorophenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro2-methylphenyl, 3,5-dibromo-2-methoxyphenyl, 3,5-di-iodo2-methoxyphenyl, 2-hydroxy-2-phenylethoxyphenyl or 2-chloro5- methylthiopheny1. 30 6. A compound as claimed in claim 5 wherein Ar is 2-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 2,5-di-iodophenyl or 2,3,5-tri-iodophenyl.

7. A compound as claimed in claim 5 wherein Ar is 35 2-phenoxyphenyl, 4-methoxyphenyl, 4-[(l-methylcyclohexyl)methoxy]phenyl, 4-[2-(cyclohexyl)ethoxy]phenyl, 4-(phenylIE 913254 -27methoxy)phenyl, 4-(2-phenylethoxy)phenyl, 4-[2-(4-methoxyphenyl) ethoxy]pheny1, 4-(2-pyridin-2-ylethoxy)phenyl, 4- (thien-2-ylethoxy) phenyl,4-(4-methylthiazol-5-ylmethoxy) phenyl, 4-[2-(4-methylthiazol-5-yl)ethoxy]phenyl, 45 benzoylmethoxyphenyl; 4-(2-phenylethylthio)phenyl or 4-(2phenylethanesulfonyl)-phenyl.

8. A compound according to claim 1, where said compound is selected from: N - [ 2-(4-chlorophenyl)-5-oxazolyl]-2,2,2-trifluoro10 acetamide; N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-5oxazolyl]-2,2,2-trifluoroacetamide; N-[2-(3,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide; 15 N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5-oxazolyl]2,2,2-trifluoroacetamide; N-[2-(2,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide; N-[2-(2-bromophenyl)-5-oxazolyl]-2,2,2-trifluoro20 acetamide; N-[2-(4-(2-eyelohexylethoxy)phenyl)-5-oxazolyl]-2,2,2trifluoroacetamide; N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2trifluoroacetamide; 25 N-[ 2-naphthalenyl-5-oxazolyl] -2,2,2-trif luoroacetamide ; N- [2 - (4-chloro-l-methoxynaphthalen-2-yl)-5-oxazolyl] 2,2,2-trifluoroacetamide; N- [ 2-(2-chloro-5-methylthiophenyl)-5-oxazolyl]-2,2,2trifluoroacetamide; and 3 0 N- [ 2-(3,5-diiodo-2-methoxyphenyl)-5-oxazolyl]-2,2,2trifluoroacetamide.

9. A pharmaceutical composition for the treatment of chronic complications associated with diabetes comprising a pharmaceutically acceptable carrier and a compound as 3 5 claimed in any one of claims 1-8 in an amount effective to prevent or alleviate such chronic complications.

10. A compound as claimed in any one of claims 1-8, for use as a medicament.

11. A compound as claimed in any one of claims 1-8, for use in the treatment of diabetes to prevent or alleviate chronic complications 5 associated therewith.

12. Use of a compound as claimed in any one of claims 1-8 in the manufacture of a medicament for use in the treatment of diabetes to prevent or alleviate chronic complications associated therewith.

13. A compound of the formula I given and defined in claim 1 10 or a pharmaceutically acceptable addition salt thereof, which is any one of those specifically hereinbefore mentioned other than a compound as claimed in claim 8.

14. A process for the preparation of a compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable 15. Addition salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples.

15. A compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable addition salt thereof, whenever prepared by a process claimed in claim 14. 20

16. A pharmaceutical composition according to claim 9, substantially as hereinbefore described.

17. Use according to claim 10, substantially as hereinbefore described.

18. Use according to claim 11, substantially as hereinbefore 25 described.

19. Use according to claim 12, substantially as hereinbefore described.