WO1992005163A1

WO1992005163A1 - 5-trifluoroacylamino-2-aryl oxazoles

Info

Publication number: WO1992005163A1
Application number: PCT/US1991/005172
Authority: WO
Inventors: David A. Clark; Harry R. Howard
Original assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Priority date: 1990-09-17
Filing date: 1991-07-29
Publication date: 1992-04-02
Anticipated expiration: 1993-03-17
Also published as: JPH0667915B2; IE913254A1; FI931157L; PT98981A; FI931157A0; JPH05506244A; FI931157A7; CA2090857A1; EP0549600A1

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

5-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 anti- diabetic 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 l,3-dioxo-lH-benz[d,e]iso- guinoline-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. Aldose reductase inhibitors of the formula

wherein R¹ is hydrogen, Cj- alkyl or phenyl and R² is hydrogen,- C^ , alkyl, aralkyl or aralkenyl of 8 or fewer carbons, or phenyl optionally substituted by Cj- , 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

NHCOCF-

and the pharmaceutically acceptable base addition salt thereof, wherein Ar is naphthalenyl, 4-chloro-l-methoxy- naphthalen-2-yl, pyridinyl, 6-chloropyridin-3-yl, 2-methyl- thiopyridin-3-yl, phenyl, nitrophenyl, hydroxypheny1, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl,

5-chloro-2-nitrophenyl, bromophenyl, dibromophenyl, 5-bromo- 2-chlorophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl, trifluoromethylphenyl, Cj-Q, alk lphenyl, 3-fluoro-4-methyl- phenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, phenoxyphenyl, C,-C₄ alkoxyphenyl , 3,5-dibromo-2-methoxy- phenyl, 3,5-di-iodo-2-methoxyphenyl, C₃-C₈ cycloalkyl-al- koxyphenyl having up to three carbon atoms in the alkoxy moiety, phenylalkoxyphenyl or Cι-C₄ alkoxyphenylalkoxyphenyl each having up to three carbon atoms in the central alkoxy moiety, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxy- phenyl having up to three carbon atoms in the alkoxy moiety, thienylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, thiazolylalkoxyphenyl or 4-methylthia- zolylalkoxyphenyl each having up to three carbon atoms in the alkoxy moiety, benzoylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, C.-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 Cj-C₄ alkylthioalkyl or Cι~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_t-C₄ alkylthioalkyl or Cι~C₄ alkanesul¬ fonylalkyl each having up to three carbon atoms in the linking alkyl moiety. More preferably, R is C,-C₄ alkyl- thioalkyl or C,-C₄ alkanesulfonylalkyl and Ar is 4-methyl- thiazolylalkoxyphenyl 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, chloro- phenyl, dichlorophenyl, bromophenyl, dibromophenyl, iodo- phenyl, di-iodophenyl, or tri-iodophenyl.

In another preferred embodiment of the invention R s hydrogen and Ar is C--C₄ alkoxyphenyl, C₃-C₈ cycloalkyl- alkoxyphenyl, phenylalkoxyphenyl, C,-^ alkoxyphenylalkoxy- phenyl, pyridinylalkoxyphenyl, thienylalkoxyphenyl, 4-methylthiazolylalkoxyphenyl, or benzoylalkoxyphenyl or C-.-C. alkylthiophenyl, Cτ_-C₄ alkanesulfonylphenyl, phenylalkylthiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic moiety. In another preferred embodiment of the present inven¬ tion, R is hydrogen and Ar is 2-naphthalenyl, 4-chloro-l- methoxynaphthalen-2-yl, 6-chloro-3-pyridinyl, 2-methylthio- pyridin-3-yl, phenyl, 4-hydroxyphenyl, 5-chloro-2-nitro- phenyl, 5-bromo-2-chlorophenyl, 3-fluσro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-m thylphenyl, 3,5-di- bromo-2-methoxyphenyl, 3,5-di-iodo-2-methoxyphenyl, 2-hy- droxy-2-phenylethoxyphenyl or 2-chloro-5-methylthiophenyl.

Preferred compounds of the invention include the following:

N-[2-(4-chlorophenyl)-5-oxazolyl]-2,2,2-trifluoro- acetamide

N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxy)phenyl) -5- oxazolyl]-2,2,2-trifluoroacetamide N-[2-(3,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoro¬ acetamide

N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5-oxazolyl]- 2,2,2-trifluoroacetamide

N-[2-(2,4-dichlorophenyl)-5-oxazolyl]-2,2 ,2-trifluoro- acetamide

N-[2-(2-bromophenyl)-5-oxazolyl]-2 , 2 ,2-trifluoro¬ acetamide

N-[2-(4-(2-cyclohexylethoxy)phenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide

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]-2,2,2- trifluoroacetamide

N-[2-(3,5-diiodo-2-methoxyphenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide

Specific compounds of the invention include the following: -o-

N-[2-(4-(trifluoromethyl)phenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide

N-[2-(4-cyanσphenyl)-5-oxazolyl]-2,2,2-trifluoro¬ acetamide N-[2-(2,3-dihydro[4H-1]benzopyran-6-yl)-5-oxazolyl]- 2,2,2-trifluoroacetamide

N-[2-(2,3-dihydrobenzofuran-5-yl) -5-oxazolyl]2,2,2- trifluoroacetamide

N-[2-(3, -methylenedioxyphenyl)-5-oxazolyl]-2,2,2- trifluoroaσetamide

N-[2-(3 ,4-ethylenedioxyphenyl-5-oxazolyl]-2,2 ,2-tri- fluoroacetamide

N-[2-(naphthalen-l-yl-5-oxazolyl]-2 , 2 ,2-trifluoro¬ acetamide N-[2-(l,2,3,4-tetrahydronaphthalen-5-y1)-5-oxazolyl]- 2,2,2-trifluoroacetamide

N-[2-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-oxazolyl]- 2,2,2-trifluoroacetamide

N-[2- (4-methylsulfinylphenyl) -5-oxazolyl] -2,2,- 2-trifluoroacetamide

N-[2- (4-methylsulfonylphenyl) -5-oxazolyl] -2,2,- 2-trifluoroacetamide

N-[2-(2-methoxy-l-(trifluoromethyl)naphthalen-5-yl)-5- oxazolyl]-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 administering 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 prepara¬ tion of the compounds of the present invention. flrCOOH- flrCOCl

III

0 flr

In accordance with the process employed for preparing 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/trifluoro- acetic 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 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, N,N-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 0°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 in 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 arylcar- boxylic 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 hydro¬ carbons, 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^βC. 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, Bulletin de la Societe Chimiσue de France. (1969) , 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 reagents and using conventional methods of organic synthesis. For instance, 4-chlorobenzoyl chloride is readily prepa ed from the known 4-chlorobenzoic acid, e.g. through the acrion 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]-2,2,2- trifluoroacetamide compounds such as, for example, N-[2- 3 ,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 ethylene- diamine, 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-tri- fluoroacetamides 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 to 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 yarious 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, together 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 N,N-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 (l) inhibit the enzyme activity of isolated aldose reductase; (2) reduce or 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 the compounds of the present invention. All melting points are uncorrected.

Example 1 N-r2-(4-chlorophenyl)-5-oxazolvn-2.2.2-trifluoroacetamide A. Methyl N-(4-chlorobenzoyl)aminoacetic acid A mixture of 7.8 g (0.05 mol) p-chlorobenzoic acid, 50 mL S0C1₂ and 50 mL toluene was refluxed for 1 hour, another 50 mL SOCl₂ 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 0°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 1A (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 identical by thin layer chromatography (TLC) (R_f 0.25, 1 CH₃0H: 9 CH₂C1₂) ; MS(%): 214, 212.

By a similar procedure, the following benzoylamino- acetamides (X, R, yield, m.p.) were prepared:

H, H, 89%, 182-183°C; (m.p. 183° - Journal of Pharm. Society of Japan 58. 809-15 (1938) , (CA. 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-(l-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. 133-135°C.

Also prepared by the same method was 6-chloro pyridin- 3-yl-carbonylaminoacetamide, 64%, m.p. 199-201°C (from CH₃OH) .

C. N-r2-f4-Chlorophenγl)-5-oxazolyl1-2.2.2- tr if luoroacetamide

A solution of 6.5 g (0.031 mol) of the title compound of Example IB in 60 mL trifluoroacetic acid, cooled to 0^βC, was treated dropwise with 65 g (0.031 mol) trifluoroacetic anhydride 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 L ethyl acetate, washed with H₂0, saturated NaHC0₃, H₂0 and saturated NaCl. After drying (MgS0₄) , 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

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 (recrystal¬ lization solvents indicated in parentheses) : N-[2-(4-(2-phenylethoxy)phenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide, 79%, m.p. 143-144°C (ethyl ether) ; Anal.: Calculated for Ci₉H₁₅F₃N₂0₃: 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-oxazoly- 1]-2,2,2-trifluoroacetamide quarter hydrate, 82%, m.p. 126-129°C (ethyl ether: hexane); Anal.: Calculated for C₁₉H₂ιF₃N₂0₃ ^»» H₂0: 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-trifluoro- acetamide, 66%, m.p. 141-142°C (ethyl ether: hexane); Anal.: Calculated for Cι₂H₁₉F₃N₂0₃: 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]-2,2,2- trifluoroacetamide, 20%, m.p. 155-156°C (ethyl acetate: hexane); Anal.: Calculated for Cι₈Hι₃F₃N₂0₃: 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_nH₇F₃N₂0₂: 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]-2,2,2- trif luoroacetamide, 56%, m.p. 125-126°C (CH₂C1₂: hexane) ; Anal.: Calculated for C_nH₅Cl₂F₃N₂θ₂: 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, 2,2- trif luoroacetamide, 57%, m.p. 185-186°C (ethyl acetate: hexane); MS (%) : 390, 271, 255, 239, 105 (100). Anal.:

Calculated for C₁₉H₁₃F₃N₂0₄ : 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]-2,2,2- trifluoroacetamide, 72%, m.p. 152-153°C (ethyl acetate); MS

(%) : 377, 152, 132, 106 (100) Anal.: Calculated for C_lgH,₄-

F₃N₃0₃: 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-tri- f luoroacetamide, quarter hydrate, 72%, m.p. 116-120°C (ethyl ether: hexane); Anal.: Calculated for C_HH₅Cl₂F₃N₂0₂*»i{H₂0: 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-tri- f luoroacetamide, 54%, m.p. 155-156 °C (ethyl acetate: petroleum ether) ; MS (%) : 324, 172 (100), 152, 135, 121,

108, Anal.: Calculated for C_πH₅Cl₂F₃N₂0₂ : C, 40.64, H, 1.55, N,

8.62; Found: C, 40,58, H, 1.57, N, 8.90.

N-[2- (3 , 5 -dichlorophenyl) -5-oxazolyl] -2,2, 2-tri- f luoroacetamide hemihydrate, 90%, Anal.: Calculated for C_πH₅Cl₂F₃N₂0₂ ^»»%H₂0: C, 39.55, H, 1.81, N, 8.39; Found: C, 39.64, H, 1.69, N, 8.00.

N-[2- (6-chloropyridin-3-yl) -5-oxazolyl] -2 ,2,2- tr if luoroacetamide, m.p. 144-145°C (ethyl hexane); Anal.: Calculated for C₁₀H₅ClF₃N₃O₂ : 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-trif luoroacetamide, 76%, m.p. 124-126°C (ethyl ether: hexane); Anal.: Calculated for C₂₀Hι₇F₃N₂O₄ : C, 59.11, H, 4.22, N, 6.89; Found: C, 59.38, H, 4.19, N, 6.87. N-[2- (4- (2- (4-methylthiazol-5-yl) ethoxy) phenyl) - 4- (2-methylthioethyl-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-phenylethylthio)phenyl) -5-oxazolyl] -2 , 2,2- tr if luoroace amide, 52%, m.p. 103-104°C (ethyl acetate: hexane), MS(%) : 392, 301, 256, 178, 159, 149, 135, 121, 105 (100); Anal.: Calculated for C₁₉H₁₅F₃N₂0₂S : C, 58.15, H, 3.85, N, 7.14; Found: C, 57.76, H, 3.78, N, 6.99. Example 2

N-r2-f3.5-Diiodo-2-methoxyphenyl)-5-oxazolyl]-2.2.2-tri- fluoroacetamide

A. N- (3.5-diiodo-2-methoxybenzoyl)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 30 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. 193-195⁰C; NMR (δ , 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) :

5-bromo-2-chloro, 23%, m.p. 150-154°C (aqueous ethanol) ;

5-chloro-2-nitro, 47%, m.p. 152-155°C (ethanol) (French Patent 1,520,925 fChem. Abstr.. 71. 49623k (1969)), m.p. 161-163°C) ;

5-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^βC (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-carbox- amide, 54%, m.p. 139-141°C, (ethanol) and N-(cyanomethyl)- 2-(methylthio)pyridine-3-carboxamide, 53%, m.p. 128-132°C (methanol:toluene) .

B. N-T2-(3.5-diiodo-2-methoχyphenyl)-5-oxazolyl1- 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 (ό^", DMS0-d₆) : 3.78 (s, 4H) , 7.32 (s, IH) , 8.13 (d, IH) , 8.26 (d, IH) ; Anal.: Calculated for Cι₂H₇F₃I₂N₂0₃: C, 26.79, H, 1.31, N, 5.21. Found: C, 26.69, H, 1.32, N, 4.99. By a similar procedure, the following 2,2,2-tri- fluoroacetamides 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-trifluoro¬ acetamide 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 C_uH₆BrF₃N₂0₂*»H₂0: C, 37.42, H, 2.28, N, 7.93; Found: C, 37.29, H, 2.18, N, 7.65. N-[2-(5-bromo-2-chlorophenyl) -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 C_uHjBrClF₃N₂0₂: 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-tri- f luoroacetamide, 68%, m.p. 149-152°C (CH₂C1₂ hexane) ; MS (%) : 335 (1), 170 (26), 168 (100), 140 (36), 138 (87), 100 (26); Anal.: Calculated for C_UH₅C1F₃N₃0₄ : 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-tri- f luoroacetamide , 69%, m.p. 101-104 °C (ethyl acetate: hexane); Anal.: Calculated for C₁₂H₈C1F₃N₂0₂: 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-trif luoro¬ acetamide, 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_πF₃N₂0₃ ^«» CF₃Cθ₂H: C, 55.78, H, 3.00, N, 7.43; Found: C, 55.63, H, 3.04, N, 7.40.

N-[2- (2-chloro-5-methylthiophenyl) -5-oxazolyl] - 2, 2, 2 -trif luoroacetamide, 64%, m.p. 97-100°C (toluene); Anal.: Calculated for Cι₂H₈ClF₃N₂θ₂S : C, 42.81, H, 2.39, N, 8.32, Found: C, 43.20, H, 2.54, N, 8.17. N-[2-(3-f luoro-4-methylphenyl) -5-oxazolyl] -2 ,2,2- trif luoroacetamide, 73% m.p. 110-113°C (ethyl acetate: hexane) , MS (%) : 289 (30), 288 (66), 234 (17), 191 (18), 148 (32), 137 (87), 136 (100), 109 (60), 107 (32); Anal.: Calculated for Cι₂H_gF₄N₂0₂: C, 50.01, H, 2.80, N, 9.72; Found: C, 49.77, H, 2.72, N, 9.36. N- [ 2- (2-f luorophenyl) -5-oxazolyl ] -2 , 2 , 2-trif luoro¬ acetamide, 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_nH₆F₄N₂0₂: 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-trif luoro¬ acetamide, 79%, m.p. 165-167°C (CH₃OH*H₂0) ; MS(%): 508 (42), 368 (12), 357 (49) , 356 (65), 329 (22), 229 (37), 214 (20), 202 (50) , 153 (100) ; Anal.: Calculated for C_nH₅F₃l₂N₂0₂*»H₂0: 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 ,2,2- trif luoroacetamide, 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 C₁₂H₇Br₂F₃N₂0₃: 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-trif luoro¬ acetamide, 80%, m.p. 200-202°C (CH₃OH:H₂0) ; MS(%) : 635 (10), 634 (95), 483 (59) , 482 (90), 455 (22), 438 (14) , 355 (40) , 328 (36), 201 (100), 153 (90) ; Anal.: Calculated for C_πH₄F₃I₃N₂0₂: C, 20.84, H, 0.64, N, 4.42; Found: C, 20.55, H, 0.74, N, 4.94.

N-[2- (2- (methylthio) pyridin-3-yl) -5-oxazolyl] -2 ,2,2- trifluoroacetamide hydrate, 58%, m.p. 109-lll°C (CH₃OH:-^' H₂0) ; MS(%) 304 (20) , 303 (28) , 190 (48), 163 (57), 162 (77), 152 (41), 136 (75), 135 (100); Anal.: Calculated for C_nH_gF₃N₃0₂S^»»H₂0 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-trif luoro¬ acetamide, 50%, m.p. 215-220°C ( CH₂C1₂: hexane ) ; MS(%) : 306 (61) , 155 (80), 154 (100), 127 (40); Anal.: Calculated for Cι₅H₉F₃N₂0₂: 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 -trif luoroacetamide hydrate, 35% , m.p . 119-122 °C (toluene) ; MS (%) : 372 , 370 (48 ) , 229 (80) , 202 (100) ;

Anal. : Calculated for C₁₆Hι₀ClF₃N₂O₃-»H₂O : C, 49 .44 , H, 3 . 11 , N,

7.21; Found: C, 49.37, H, 3.38, N, 6.94.

Example 3 N-r2-(4-f2-(4-methylthiazol-5-yl)ethoxy)phenyl)-4-C2-methv- lsulfonylethyl)-5-oxazolyll-2.2.2-trifluoroacetamide

A solution of N-[2-(4-(2-(4-methylthiazol-5-yl)- ethoxyphenyl) -4-(2-methylthioethyl) -5-oxazolyl]-2,2,2- trifluoroacetamide (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 NaHC0₃, H₂0, saturated NaCl) and dried (MgS0₄) , 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]-2,2,2- trifluoroacetamide, 62%, m.p. 209-210°C (CH₃OH) ; MS(%): 408, 304, 247, 195, 179, 152, 125, 105 (100); Anal.: Calculated for C₁₉H_l5F₃N₂0₃S: C, 55.87, H, 3.70, N, 6.86; Found: C, 55.79, H, 3.60, N, 6.81.

Example 4 N-T2- (4-Hydroxyphenyl)-5-oxazolyll-2.2.2-trifluoroacetamide A. 4-r (3.4,5.6-tetrahvdro-2H-pyran-2-yl)oxylbenzoic acid A mixture of 4-hydroxybenzoic acid (45 g, 0.33 mol), p-toluenesulfonic acid (5.0 g, 0.026 mol) and 3,4-dihydro- 2H-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-r4-f3.4.5.6-Tetrahydro-2H-pyran-2-yl) oxy) benzoylamino1acetamide.

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% NaHC0₃, and saturated NaCl and then dried over MgS0₄. After evaporation of the solvent, the residue was dissolved in CH₃0H 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-Tetrahydropyran- 2-yl)oxy benzoylamino]-acetamide. Another 5 g was recoverd from the triturate to give an overall yield of 45%.

C. N-f2- (4-Hydroxyphenyl)-5-oxazolyl]-2.2.2-tri- fluoroacetamide A mixture of trifluoroacetic acid (100 mL) and tri¬ fluoroacetic anhydride (70 mL) cooled to 0°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% NaHC0₃ and saturated NaCl, dried (MgS0₄) , 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 yield of 72%, m.p. 220°C (dec); Anal.: Calculated for C_uH₇F₃N₂0₃: C, 48.54, H, 2.59, N, 10.29, Found: C, 48.19, H, 2.61, N, 10.23.

Example 5 N-r2- (4-cyclohexylethoxyphenyl)-5-oxazolyl1-

2.2.2-trifluoroacetamide A solution of N-[2-(4-hydroxyphenyl)-5-oxazolyl]- 2,2,2-trifluoroacetamide (2.2 g₇ 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 (MgS0₄) 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 C₁₉H₂ιF₃N₂0₃: 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-tolu¬ enesulfonate gave N-[2-(4-(thien-2-yl)ethoxyphenyl)-5-oxa¬ zolyl]-2,2,2-trifluoroacetamide quarter hydrate, 12% yield, m.p. 140-142°C (ethyl ether:hexane) ; Anal.: Calculated for C₁₇H₁₃F₃N₂0₃S^» H₂0: 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-toluene¬ sulfonate gave N-[2- (4- (2- (4-methylthiazol-5-yl) ethyl) - phenyl) -5-oxazolyl ] -2 , 2 , 2-trif luoroacetamide, 8% yield, m.p. 176-177°C (ethyl ether : hexane ) ; Anal. : Calculated for C₁₇H₁₄F₃N₃0₃S : C, 51.38 , H, 3.56 , N, 10.58 ; Found: C, 50.93 , H, 3.53 , N, 10.35. Example 6

N-r2-(4-f2-Hvdroxy-2-phenylethoxy)phenyl)-5-oxazolyl]-

2.2.2-trifluoroacetamide he ihydrate

A. 4- (2-hvdroxy-2-phenylethoxy)-N- (carbamoylmethyl)- benzamide

A mixture of 4-(benzoylmethoxy)-N-(carbamoylmethyl)- benzamide (1.0 g, 3.0 mmol) and 50 mL CH₃0H 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 (MgS0₄) , the organics were concentrated to an oil which was crystallized from CH₃0H: ethyl ether: hexane (1:5:2) to give the title compound as a white solid, 0.470 g (48%), m.p. 140-145^QC (dec) .

B. N- [ 2 - (4-f2-Hvdroxy-2-phenylethoxy)phenyl) -5- oxazoyll-2.2.2-trifluoroacetamide hemihydrate

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 H_zO and saturated NaCl and then dried (MgS0₄) . Concentration in vacuo gave a tan gum, 0.60 g. The gum was dissolved in 10 mL CH₃0H, treated with 0.10 g anhydrous K₂C0₃ and stirred for 1 hour at 25°C. After filtering and concentration of the filtrate, the gum was dissolved in ethyl acetate, washed with H₂0 and saturated aqueous NaCl, and then dried (MgS0₄) . Concentration to a light yellow residue, followed by chromatography on silica gel with CH₃0H: CH₂C1₂ (5:95) gave the title compound as a white solid, 37%, m.p. 145-147°C; Anal.: Calculated for ^ci₉ ^Hi5^F3^N ₂°₄ ^#%^H ₂ ^{0: 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 activity 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 10"*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

CLAIMS 1. A 5-trifluoroacetylamino-2-aryloxazole compound of the formula:

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, difluoro- phenyl, chlorophenyl, dichlorophenyl, 5-chloro-2-nitro¬ phenyl, bromophenyl, dibromophenyl, 5-bromo-2-chlorophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl, trifluoromethy1- phenyl, C,-C₄ alkylphenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, phenoxy- phenyl, Cι-C₄ alkoxyphenyl, 3,5-dibromo-2-methoxyphenyl, 3,5-di-iodo-2-methoxyphenyl, C₃-C₈ cycloalkyl-alkoxyphenyl having up to three carbon atoms in the alkoxy moiety, phenylalkoxyphenyl or C,-C₄ alkoxyphenylalkoxyphenyl each having up to three carbon atoms in the central alkoxy moiety, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxy- phenyl having up to three carbon atoms in the alkoxy moiety, thienylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, thiazolylalkoxyphenyl or 4-methylthia- zolylalkoxyphenyl each having up to three carbon atoms in the alkoxy moiety, benzoylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, 0,-0, 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, Cj-C₄ alkyl, or C_j-C₄ alkylthioalkyl or Cj-Q, 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, Cι-C₄ alkylthioalkyl or C,-C₄ alkanesulfonylalkyl 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.

4. A compound as claimed in claim 3 wherein Ar is 2-(4-methylthiazol-5-yl)ethoxyphenyl and R is 2-methylthio- ethyl or 2-methanesulfonylethyl.

5. A compound as claimed in claim 2 wherein Ar is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl; C_j-C₄ alkoxyphenyl, C₃-C₈ cycloalkyl- alkoxyphenyl, phenylalkoxyphenyl, 0,-0, alkoxyphenyl- alkoxyphenyl , pyridinylalkoxyphenyl, thienylalkoxyphenyl, 4-methylthiazolylalkoxyphenyl, benzoylalkoxyphenyl; C_j-Q_t alkylthiophenyl, Cj-C₄ alkanesulfonylphenyl, phenylalkyl¬ thiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic moiety; 2-naphthalenyl, 4-chloro-l-methoxynaphthalen-2-yl, 6-chloro- 3-pyridinyl, 2-methylthiopyridin-3-yl, phenyl, 4-hydroxy- phenyl, 5-chloro-2-nitrophenyl, 5-bromo-2-chlorophenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro- 2-methylphenyl , 3,5-dibromo-2-methoxyphenyl, 3,5-di-iodo- 2-methoxypheny1, 2-hydroxy-2-phenylethoxyphenyl or 2-chloro- 5-methylthiophenyl. 6. A compound as claimed in claim 5 wherein Ar is 2-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 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 2-phenoxyphenyl, 4-methoxypheny1, 4-[ (l-methylcyclohexyl)- methoxy]phenyl, 4-[2-(cyclohexyl)ethoxy]phenyl, 4-(phenyl- methoxy)phenyl, 4-(2-phenylethoxy)phenyl, 4-[2-(4-methoxy- phenyl)ethoxy]phenyl, 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, 4- benzoylmethoxyphenyl; 4-(2-phenylethylthio)phenyl or 4-(2- phenylethanesulfonyl)-phenyl.

8. A compound according to claim 1, where said compound is selected from:

N-[2-(4-chlorophenyl)-5-oxazolyl]-2,2,2-trifluoro- acetamide;

N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxy)phenyl) -5- oxazolyl]-2,2,2-trifluoroacetamide;

N-[2-(3,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoro¬ acetamide; N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5-oxazolyl]- 2,2,2-trifluoroacetamide;

N-[2-(2,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoro¬ acetamide;

N-[2-(2-bromophenyl)-5-oxazolyl]-2,2,2-trifluoro- acetamide;

N-[2-(4-(2-cyclohexylethoxy)phenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide;

N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide; 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]-2,2,2- trifluoroacetamide; and N-[2-(3,5-diiodo-2-methoxyphenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide.

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

10. A method for treating a diabetic subject to prevent or alleviate chronic complications associated with diabetes arising in said subject, which comprises administering to said diabetic subject an amount of a compound as claimed in claim 1 effective to prevent or alleviate such complications.

11. A process for the preparation of a compound having the formula:

wherein Ar is naphthalenyl, 4-chloro-l-methoxy- naphthalen-2-yl, pyridinyl, 6-chloropyridin-3-yl,

2-methylthiopyridin-3-yl, phenyl, nitrophenyl, hydroxyphenyl , fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, 5-chloro-2 -nitrophenyl, bromophenyl, dibromophenyl, 5-bromo-2-chlorophenyl, iodophenyl, di-iodophenyl, tri- iodophenyl, trif luoromethylphenyl, C'_ι~C₄ alkylphenyl, 3-f luoro-4-methylphenyl,

2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, phenoxy- phenyl, Cj-C₄ alkoxyphenyl , 3,5-dibromo-2-methoxyphenyl, 3,5-di-iodo-2-methoxyphenyl, C₃-C₈ cycloalkyl-alkoxyphenyl having up to three carbon atoms in the alkoxy moiety, phenylalkoxyphenyl or Cj-C₄ alkoxyphenylalkoxyphenyl each having up to three carbon atoms in the central alkoxy moiety, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxy- phenyl having up to three carbon atoms in the alkoxy moiety, thienylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, thiazolylalkoxyphenyl or 4-methylthia¬ zolylalkoxyphenyl each having up to three carbon atoms in the alkoxy moiety, benzoylalkoxyphenyl having up to three carbon atoms in the alkoxy moiety, C,-C₄ alkylthiophenyl, 2-chloro-5-methylthiophenyl, Cι~C₄ alkanesulfonylphenyl, or phenylalkylthiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic moiety; and

R is hydrogen, Cj-C₄ alkyl, or Cj-C₄ alkylthioalkyl or C_j-C₄ alkanesulfonylalkyl each having up to three carbon atoms in the linking alkyl moiety, comprising reacting a compound of the formula

0 R 0 R

IV flr I CONH, or flr A IΛ CN

H H

wherein Ar and R are as defined above with a reagent or reagent mixture which is a strong protonic acid in the presence or absence of a reaction-inert solvent to form a compound of formula I, and, if desired, converting a compound of formula I to a pharmaceutically acceptable salt thereof.

12. A process as claimed in claim 11 wherein R is hydrogen, C^Q, alkylthioalkyl or Cj-C₄ alkanesulfonylalkyl each having up to three carbon atoms in the linking alkyl moiety.

13. A process as claimed in claim 12 wherein Ar is 4-methylthiazolylalkoxyphenyl having up to three carbon atoms in the alkyl moiety.

14. A process as claimed in claim 13 wherein Ar is 2-(4-methylthiazol-5-yl)ethoxyphenyl and R is 2-methylthio- ethyl or 2-methanesulfonylethyl.

15. A process as claimed in claim 12 wherein Ar is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl, C_j-C₄ alkoxyphenyl, C₃-C₈ cycloalkyl- alkoxyphenyl, phenylalkoxyphenyl, Cι-C₄ alkoxyphenyl- alkoxyphenyl, pyridinylalkoxyphenyl, thienylalkoxyphenyl, 4-methylthiazolylalkoxyphenyl, benzoylalkoxyphenyl; ^-Q, alkylthiophenyl, C_!-C₄ alkanesulfonylphenyl, phenylalkyl¬ thiophenyl or phenylalkanesulfonylphenyl each having up to three carbon atoms in the central aliphatic moiety; 2-naphthalenyl, 4-chloro-l-methoxynaphthalen-2-yl, 6-chloro- 3-pyridinyl, 2-methylthiopyridin-3-yl, phenyl, 4-hydroxy- phenyl, 5-chloro-2-nitrophenyl, 5-bromo-2-chlorophenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro- 2-methylphenyl, 3,5-dibromo-2-methoxypheny1, 3,5-di-iodo- 2-methoxypheny1, 2-hydroxy-2-phenylethoxyphenyl or 2-chloro- 5-methylthiophenyl.

16. A process as claimed in claim 15 wherein Ar is 2-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl , 2-bromophenyl, 2,5-di-iodophenyl or 2,3,5-tri-iodophenyl.

17. A process as claimed in claim 15 wherein Ar is 2-phenoxyphenyl, 4-methoxypheny1, 4-[ (l-methylcyclohexyl)- methoxy]phenyl, 4-[2-(cyclohexyl)ethoxy]phenyl, 4-(phenyl- methoxy)phenyl, 4-(2-phenylethoxy)phenyl, 4-[2-(4-methoxy- phenyl)ethoxy]phenyl, 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, 4-benzoyl- methoxyphenyl.

18. A process as claimed in claim 15 wherein Ar is 4-(2-phenylethylthio)phenyl or 4-(2-phenylethanesulfonyl)- phenyl.

19. A process according to any of the preceding claims 11-18 wherein said compound of the Formula I is selected from:

N- [ 2 - ( 4 -chlorophenyl ) -5-oxazolyl ] -2 , 2 , 2 -trif luoro¬ acetamide ;

N- [ 2- ( 4 - ( 2 - ( 4-methylthiazol-5-yl) ethoxy) phenyl ) -5- oxazolyl] -2 , 2 , 2-trif luoroacetamide; N- [2- (3 , 4-dichlorophenyl) -5-oxazolyl] -2 , 2 , 2-trif luoro¬ acetamide; N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5-oxazolyl]- 2,2,2-trifluoroacetamide;

N-[2-(2,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluoro¬ acetamide; N-[2-(2-bromophenyl)-5-oxazolyl]-2,2,2-trifluoro¬ acetamide;

N-[2-(4-(2-cyclohexylethoxy)phenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide;

N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide;

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]-2,2,2- trifluoroacetamide; and

N-[2-(3 ,5-diiodo-2-methoxyphenyl)-5-oxazolyl]-2,2,2- trifluoroacetamide.