PT98981A - METHOD FOR THE PREPARATION OF 5-TRIFLUORO-ACYLAMINO-2-ARYL-OXAZOLES - Google Patents

Description

Description relating to the patent of PFIZER INC. (USA), (inventors: David A. Clarr and Harry R. Howard, residents of the United States), to " PROCESS FOR THE PREPARATION OF 5-TRI-FLUOROACYLIMINO-2-ARYL-OXAZO-LOS " .

The present invention relates to 5-trifluoro-acylamino-2-aryl-oxazoles. These compounds are useful for the control of certain chronic complications caused by diabetes mellitus (e.g., diabetic cataracts, retinipathy and neuropathy). The present invention also relates to pharmaceutical compositions containing said compounds and to the use of such compounds for the treatment of complications caused by diabetes mellitus.

Previous attempts to obtain novel and improved oral antidiabetic agents have in most cases involved a goal for the synthesis of novel compounds which lower blood sugar levels. More recently, several studies have been conducted on the effect of various organic compounds on the prevention or sus- pension of certain chronic complications of diabetes, such as ca-. diabetic retinopathy and neuropathy, etx .. For example, 1 N. t

K. Sestanj et al. in U.S. Patent 3,821,383 disclose that certain aldose reductase inhibitors such as 1,3-dioxo-1H-benz [d, e] isoquinoline-2 (3H) -acetic acid and some of its further derivatives are useful for these purposes although no hypoglycemic event has occurred. These compounds function by inhibiting the activity of the aldose reductase enzyme, which is primarily responsible for aldose reduction catalysis (such as glucose and galactose) to give the respective polyols (such as sorbitol and galactitol) in the human body. In this way, unwanted accumulations of galactopic in the lens of galactosemic and sorbitol patients in the lens, retina and peripheral nervous system and in the kidney of diabetic patients are avoided or reduced. As a result, these compounds bind to certain chronic complications of diabetes, including those of an ophthalmic nature, since it is known in the prior art that the presence of polyols in the lens causes cataracts to form and the concomitant loss of clarity thereof.

In Japanese Patent Application 77105, published October 14, 1987, from Hohto Pharmaceutical KK, alluded reductase inhibitors of formula

R

TST

NHCOOCELC, Hc 2 6 5 1 2 2 wherein R 1 is hydrogen, C 1 -C 4 -alkyl or phenyl and R 2 is hydrogen, C 1 -C 4 -alkyl, aralkyl or aralkenyl having 8 or fewer carbon atoms, or phenyl optionally substituted by

-C? C?

Summary of the Invention The present invention relates to compounds of the invention.

formula: R

Ar -NHCOCF 3

I

and the pharmaceutically acceptable acid addition salts thereof wherein Ar is naphthalenyl, 4-chloro-1-methoxy-2-naphthalenyl, pyridinyl, 6-chloro-3-pyridinyl, 2-methyl-3-thiopyridinyl, phenyl, diphenyl, hydroxyphenyl, hydroxyphenyl, hydroxyphenyl, difluorophenyl, difluorophenyl, chlorphenyl, dichlorophenyl, 5-chloro-2-nitrophenyl, bromophenyl, dibromophenyl, 5-bromo-2-chlorophenyl, iodophenyl, diiodophenyl, triiodophenyl, trifluoromethylphenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, phenoxyphenyl, C1 -C4 -alkoxyphenyl, 3,5-dibromo -2-methoxyphenyl, 3,5-diiodo-2-methoxyphenyl, cycloalkyl-C--C--alkoxyphenyl having a maximum of three carbon atoms in the central moiety of alkoxy, phenylalkoxyphenyl or C1- phenylalkoxyphenyl in each case having a maximum of three carbon atoms in the central moiety of alkoxy, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxyphenyl having a maximum of three carbon atoms in the alkoxy, thiazolylalkoxyphenyl or 4-methyl moiety in each case having a maximum of three carbon atoms in the alkoxy, benzoylalkoxyphenyl moiety having a maximum of three carbon atoms in the alkoxy, C1 -C4 alkylthiophenyl, 2-chloro-5-methylthiophenyl, C1 -C4 alkanesulfonylphenyl or phenylalkylthiophenyl or phenylalkanesulfonylphenyl in each case having a maximum of three carbon atoms in the aliphatic central moiety; and R3 is hydrogen, C1 -C4 -alkyl or C1 -C4 -alkylthioalkyl or C1 -C4 -alkanesulfonyl in each case having a maximum of three carbon atoms in the alkyl moiety of Link.

In a preferred embodiment of the present invention, R 2 is hydrogen or C 1 -C 4 -alkylthioalkyl or C 1 -C 4 -alkylsulfonylalkyl in each case having a maximum of three carbon atoms in the linking alkyl moiety . Particularly preferred, R is C 1 -C 4 -alkylthioalkyl or C 1 -C 4 -alkanesulfonylalkyl and Ar 4 -methylthiazolylalkoxyphenyl having a maximum of three carbon atoms in the alkyl moiety.

In another preferred embodiment of the present invention, R is hydrogen and Ar is fluorophenyl, di

fluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, iodophenyl, di-iodophenyl or tri-iodophenyl.

In another preferred embodiment of the present invention, R 2 is hydrogen and Ar is C 1 -C 4 -alkoxy-phenyl, C 1 -C 6 -cycloalkyl-alkoxyphenyl, phenylalkoxyphenyl, C 1 -C 4 -alkoxyphenylalkoxyphenyl, pyridinylalkoxyphenyl, thienylalkoxyphenyl, 4-methylthiazolylalkoxyphenyl or benzoylalkoxyphenyl or C1 -C4 -alkylphenyl, C1 -C4 -alkanesulfonylphenyl, phenylalkylthiophenyl or phenylalkanesulfonylphenyl in each case having a maximum of three carbon atoms in the central aliphatic.

In another preferred embodiment of the present invention, R is hydrogen and Ar is 2-naphthalenyl, 4-chloro-methoxy-2-naphthalenyl, 6-chloro-3-pyridinyl, 2-methyl-3-thiohpyridinyl, phenyl , 4-hydroxyphenyl, 5-chloro-2-nitrophenyl, 5-chloro-2-nitrophenyl, 5-bromo-2-chlorophenyl, 3-fluoro-4-methylphenyl, chloro-2-methylphenyl, 3,5-dibromo-2-methoxyphenyl, 3,5-diiodo-2-methoxyphenyl, 2-hydroxy-2-phenylethoxyphenyl or 2-chloro-5-methylthiophenyl.

Preferred compounds of the present invention include the following: N- [2- (4-chlorophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (4- (2- (4-methyl-5-thiazolyl) -ethoxy) -phenyl) -5-oxazolyl] -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-trifluoroacetamide; N- [2- (2-bromophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; 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-oxazolyl] -2,2,2-trifluoroacetamide, 4 τ

N- [2- (4-chloro-1-methoxy-2-naphthalenyl) -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.

Specific compounds of the present invention include the following: N- [2- (4- (trifluoromethyl) phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (4-cyanophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide;

N- [2- (2,3-dihydro- [4H-1] -6-benzopyranyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (2,3-dihydro-5-benzofuranyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (3,4-methylenedioxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (3,4-ethylenedioxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (1-naphthalenyl-5-oxazolyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (1,2,3,4-tetrahydro-5-naphthalenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide;

N- [2- (1,2,3,4-tetrahydro-6-naphthalenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (4-methylsulfinyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (4-methylsulfonylphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; and N- [2- (2-methoxy-1- (trifluoromethyl) -5-naphthalenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide. The present invention also relates to a pharmaceutical composition for the treatment of chronic complications associated with diabetes containing a compound of formula I or a pharmaceutically acceptable base addition salt thereof in an amount effective to prevent or alleviate these complications.

The specific and preferred compositions of the present invention contain the specific and preferred compounds discussed above. The present invention also relates to a method for the treatment of a diabetic patient in order to avoid or alleviate the chronic complications that such patient may suffer comprising administering to said diabetic patient an amount of a compound of formula I or a pharmaceutically acceptable addition salt thereof effective to prevent or alleviate said complications.

DETAILED DESCRIPTION OF THE INVENTION The following reaction scheme illustrates the preparation of the compounds of the present invention: - ArCOCl

ArCOOH

H III

• II \

0 R

''

H V

H o

6

IR

According to the process used for the preparation of the compounds of the present invention, an amine of the formula IV or a nitrile of the formula V of an appropriately substituted carboxylic acid, wherein Ar and R have the abovementioned meanings, by means of a reagent or a mixture of reagents which is a strong protonic acid, into the title compounds of the formula I. Said reagents which may be useful for this transformation may include trifluoroacetic acid / trifluoroacetic anhydride, polyphosphates and the like and may be used in the presence or absence of an inert solvent towards the reactants. For this phase a mixture of trifluoroacetic acid / trifluoroacetic anhydride without additional solvent is preferred. These reactions may be carried out at a temperature in the range of from about -20 ° C and the boiling point of the reagent or solvent used, and is preferably conducted at a temperature in the range of from about 0 ° C to about 25 ° C.

The insulation of the desired product I can be effected by quenching the reaction, preferably with water or a mixture of water and ice, and then separating the crude reaction product from the resulting solid precipitate by filtration or extraction of the reaction products into a organic solvent which can then be evaporated to give the said crude reaction products. It may further be purified by crystallization / recrystallization from a suitable solvent system or by chromatographic methods.

The appropriately substituted carboxylic acid amides of formula IV may be readily prepared from the corresponding esters of formula III by treating them in a solvent which is inerted with the reaction medium with ammonia gas or aqueous ammonia. The reaction is carried out in an organic solvent such as, for example, a lower alcohol, lower dialkyl ethers. Ν, Ν-lower dialkylamines or hydrocarbons

aromatic or non-aromatic. A preferred solvent for this purpose is methanol. Generally, amounts of ammonia or ammonia are used in excess or equimolar and the reaction is carried out at a temperature from about 0 ° C to about the boiling point of the solvent used for a period of from about one hour to about 72 hours. In practice, the reaction is conducted using two to ten equivalents of ammonia or ammonia at room temperature for a period of 6 to 48 hours.

The esters of formula III used as raw materials in the foregoing process are readily prepared by various methods described in the scientific literature and familiar to those skilled in the art. For example, reaction of a carboxylic acid chloride of formula II (prepared from a suitable arylcarboxylic acid by known methods) with an ester of a substituted or unsubstituted amino acid may give the desired intermediate esters of formula III in good yield . The reactions may be carried out in solvents inert to the reaction medium such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., in the presence or absence of a suitable base (acid acceptor) at temperatures from about- 78 ° C to about the boiling point of the solvent used and for periods from about 1 hour to about 72 hours. Preferably, the reaction is run in methylene dichloride employing triethylamine as the base (acid acceptor) and stirring the reaction components for up to 8 hours at a temperature from about 0øC to about 25øC. Other methods available for the preparation of said intermediates of formula III described in the chemical literature include reacting an activated aromatic acid (for example an acid anhydride or a mixed anhydride) with an appropriate amino acid or ester of a suitable amino acid and the benzoylation of Schotten-Baumann from an ester of an appropriate amine acid.

Similarly, suitable nitriles of formula V * described at the beginning of this section may also be pre. from the aromatic acid, the acid chloride of

active acid (for example mixed anhydride) and the appropriate amino nitrile. Some of the intermediates useful for the present invention are described in the literature (for example J.P. Pleury and A. Baysong, Bulletin of the Societe Chiquique de France, (1969), 4102-4108, AJ Crovetti, US Pat. 457-294).

Finally, the raw materials necessary for the preparation of the compounds of the formula II are known compounds which are available commercially or are described in the literature or may be readily synthesized by those skilled in the art from ordinary chemical reagents using known methods of synthesis organic. For example, 4-chlorobenzoyl chloride can be readily prepared from 4-chlorobenzoyl acyl, which is a known product, for example by the action of thionyl chloride in refluxing toluene. The product obtained may be purified by methods such as silica gel column chromatography or the like, in addition to standard recrystallization procedures.

The working pressures of the foregoing reactions are not generally critical, unless otherwise indicated. They will generally range from about 0.5 to about 2 atmospheres, preferably using atmospheric pressure (i.e., about one atmosphere).

The bases which are used as reagents in the present invention for the preparation of pharmaceutically acceptable base salts are those which form non-toxic base salts with the unsubstituted N- [5-oxazolyl] -2,2,2-trifluoroacetamides described in 2, such as N- [2,3,4-dichlorophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide. Such non-toxic salts with bases include the pharmaceutically acceptable derivatives of sodium, potassium, calcium, magnesium, etc., as well as pharmaceutically acceptable organic bases such as ethylenediamine, diethanolamine, etc. These salts can be prepared by the addition of a pharmaceutically- By treatment of the compound N- [5-oxazolyl] -2,2,2-trifluoro-. acetamide derivative thereof with a lower alkanolic solution of the desired metal alkoxide and evaporating the resulting solution thereafter. Alternatively, they may also be prepared by treating said 2,2,2-trifluoroacetamides with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution, preferably under reduced pressure. In any case stoichiometric quantities of the reactants should be employed to ensure that the reaction is complete and that the maximum yields of the desired final salt are reached.

The compounds of formula I and their pharmaceutically acceptable addition salts (hereinafter also referred to as active ingredients of the present invention) are readily adapted to therapeutic use as aldose re-ductase inhibitors for the control of certain chronic complications of diabetes , taking into account their ability to reduce levels of sorbitol in the lens and peripheral nerves (eg the sciatic nerve) in diabetic patients. The active compounds of the present invention may be administered to affected mammals (including humans) via oral, topical or parenteral administration. In general, these compounds are usually administered at dosages in the range of from about 0.50 mg to about 100 mg per kilogram of body weight per day, although variations in the function of weight and condition of the patient occurring there necessarily occur. and the particular route of administration chosen.

These compounds may be administered alone or in combination with pharmaceutically acceptable carrier substances by the various routes previously indicated, and this administration may be carried out in single or multiple dosages. More in particular, the active compounds of the present invention may be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carrier substances in the form of tablets, capsules, lozenges, troches, candies , powders, sprays, aqueous suspensions, solutions 10

injectables, elixirs, syrups, etc. The carrier substances to be considered include solid or extenders, sterile aqueous media and various non-toxic organic solvents. In general, the active compounds of the present invention should be present in the dosage forms at concentration levels of from about 0.5% to about 90% by weight of the total composition in order to provide the desired dosage unit.

For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be used together with various disintegrants such as starch and preferably potato or manioc starch, alginic acid and detergents complex silicates, together with binders such as for example polyvinylpyrrolidone, gelatin or acacia. In addition, the use of lubricants is often very useful for the preparation of tablets, for example magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be employed as solid diluents in soft gelatin capsules or hard; the preferred materials for this purpose also include the high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweeteners or flavorings, colorants or pigments and, if desired, emulsifiers and / or suspenders as well as, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations of these agents.

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 used. Thus, solutions in sesame or peanut oil or in aqueous propylene glycol or N, N-dimethylformamide may be employed as well as sterile aqueous solutions. These aqueous solutions may be suitably buffered if necessary and the liquid diluent is first rendered isotonic with sufficient saline or fluctuation. These particulate aqueous solutions

are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injections. In these cases, the sterile aqueous media employed are all readily obtainable by standard techniques well known to those skilled in the art. In addition, it is possible to administer the compounds in an appropriate ophthalmic solution (for example 0.5 to 2.0%) applied as eye drops. The utility of the compounds of the present invention as agents for combating chronic diabetic complications can be predicted by measuring their ability to (1) inhibit the enzymatic activity of aldose alone reductase, (2) reduce or inhibit the accumulation of solbitol in the sciatic nerve and in the lens of acutely streptozotocinized (ie, diabetic) rats; (3) reversing already high levels of sorbitol in the nervitic and crystalline rats of chronic diabetes induced by streptozotocin; (4) preventing or inhibiting the formation of ga-lactitol in the lens of acute galactosemic rats and / or (5) delaying the formation of cataracts and reducing the severity of lens opacification in chronic galactosemic rats.

The following examples are intended to illustrate the preparation of the compound of the present invention. The melting points indicated are not corrected.

Example 1 N- [2- (4-chlorophenyl) -5-oxazolyl-2,2,2-trifluoroacetamide A. Methyl N- (4-chlorobenzoyl) aminoacetate

A mixture of 7.8 g (0.05 mol) of p-chlorobenzoic acid, 50 ml of SOCl and 50 ml of toluene was refluxed for one hour, a further quantity of 50 ml of SOCl 2 and heating was continued for another hour. The homogenous solution was concentrated under vacuum and distilled. in azeotrope with toluene (2 x 50 ml). Suspended 12

The residue was dissolved in 50 ml of CH2 Cl2 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) of triethylamine in 100 ml of CH2 Cl2 at 0 ° C for about 10 minutes). After heating to. 25 ° C and stir for a further 30 minutes, the solution was filtered and the filtrate was concentrated to a solid. Crystallization from hot ethyl acetate / hexane afforded the title compound, 7.6 g (67%), m.p. 113-114 ° C; MS (%): 229, 227, 195, 168, 155, 139, (100), 111. B. Chlorobenzoylaminoacetamide

A solution of the title compound of Example 1A (7.5 g, 0.033 mol) in 250 ml of anhydrous methanol was treated with gaseous NH 3 for one hour at 25øC, then stirred for another 48 hours at 48ø Under nitrogen. A white solid, 1.5 g (mp 193-195) was obtained, and a second fraction (5.1 g, mp 188-190 ° C) was obtained by concentrating the filtrate. The two fractions were the same by thin layer chromatography (TLC) (Rf 0.25, 1 CH 3 OH: 9 CH 2 Cl 2); MS (%): 214, 212.

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

The R

Δ, H, 89%, 182-183 ° C; (mp 183 ° C - Journal of Pharm. Society of Japan 58, 809-15 (1938), (CA 33, 17266), 2,4-dichloro, H, 94%, 3.5-dichloro, H, 2- (4-methoxyphenyl) ethoxy), H, 88%, mp 198-200 ° C, 4-methoxy, H, 87%, 4- (1-methyl-1-cyclohexyl) methoxy), H , 70%, mp 75-78 ° C; 13

4-phenylmethoxy, Η, 78%, m.p. 205-206 ° C; 3,4-dichloro, H, 62%, m.p. 210-212 ° C; 2,6-dichloro, H, 96%, δ, 240-242 ° C; 4-benzoylmethoxy, H, 76%, m.p. 140-142 ° C; 4- (2-pyridinyl-2) -ethoxy, H, 64%, m.p. 173-174 ° C; 4- (2-phenylethyl) thio, H, 99%, m.p. 148-150 ° C; 4- (2- (4-methylthiazolyl-5) -ethoxy), 2-methylthioethyl, 77%, m.p. 133-135 ° C;

Also prepared by the same method was 6-chloro-3-pyridinylcarbonylaminoacetamide, 64%, m.p. 199-201 ° C (from CH3 OH). C. N- [2- (4-chlorophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide

A solution of the title compound of Example 1B (6.5 g, 0.031 mol) in trifluoroacetic acid (60 ml) cooled at 0 ° C was treated dropwise with 65 g (0.031 mol) of trifluoroacetic anhydride a period of 35 minutes, warmed to 25 ° C and stirred at this temperature for 3 hours. Concentration in vacuo gave a syrup which was dissolved in 250 ml of ethyl acetate, washed with Et2 O, saturated NaHCO3, H2 O and saturated NaCl. After drying (MgSO 4), the organic layer was concentrated under vacuum to a beige solid (8 g). Recrystallization from ethyl acetate / petroleum ether afforded the title compound (6.3 g, 70%), m.p. 144-146 ° C; MS (%): 292, 290, 235, 193, 165, 150, 139, (100), 123, 111;

Analysis: Calculated for Câ, â,Hâ,,Clâ,ƒFâ,,â,ƒCâ, ...: C, 45.46; H, 2.09; N, 9.64 Found: C, 45.27; H, 2.07; N, 9.53.

The following compounds were prepared from the corresponding acetamides (recrystallization solvents are indicated in parentheses): N- [2- (4- (2-phenylethoxy) phenyl) -5-oxazolyl] -2 , 2,2-trifluoroacetamide, 79%, mp 143-144 ° C; (ethyl ether); Calc'd for: C, 60.69; H, 4.02; N, 7.45. Found: 14

C, 60.42, Η, 4.07, N, 7.40. N- [2- (4 - ((1-methylcyclohexyl) methoxy) phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide, one quarter hydrate, 82%, mp 126-129ø W? ethyl ether: hexane);

Analysis: Calculated for C 19 H 21 F 3 N 2 O 3 · 1/414: 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-trifluoroacetamide, 66%, m.p. 141-142 ° C; (ethyl ether: hexane);

Analysis: Calculated for C 24 H 31 N 3 O 3 ú2O: 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 ether: hexane);

Calc'd for C 13 H 13 N 2 O 3: 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 ether: hexane); MS (%): 256, 237, 201, 104, (100). Analysis: Calculated for C 19 H 19 F 2 N 2 O 2: 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-trifluoroacetamide, 56%, m.p. 125-126 ° C; (CH 2 Cl 2: hexane);

Analysis: Calculated for C 11 H 25 N 2 F 3 N 2 O 2: C 40.64, H 1.55, N 8.62. Found: C 45.51, H 1.60, N 8.55. N- [2- (4-benzoylmethoxy) -phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide, 57%, m.p. 185-186 ° C; (ethyl acetate: hexane); MS (%): 390, 271, 255, 239, 105 (100).

ANALYSIS: Calculated for: Found: 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).

Analysis: Calculated for: H 4 F 3 N 3 O 3: C 57.29, H 3.74, N 11.14; Found: C 57.06, H 3.44, N 11.11. N- [2- (3,4- (dichlorophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide, one fourth hydrate, 72%, mp 116-120 ° C; (ethyl acetate: hexane) ;

Analysis: Calculated for C 15 H 12 Cl 2 F 3 N 2 O 2 · 1 / 4H 2 O: 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,

Analysis: Calculated for C H HH C ^N ^O F: 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-trifluoroacetamide hehydrate, 90%,

Analysis: Calculated for Câ, â,,HCl: F₂N0O · 1 / 2Hâ,ƒOâ,,O: 523222 C 39.55, H 1.81, N 8.39;

Found: C 39.64, H 1.69, N 8.00. N- [2- (6-chloro-3-pyridinyl) -5-oxazolyl] -2,2,2-trifluoroacetamide, m.p. 144-145 ° C; (ethyl acetate: hexane);

Analysis: Calculated for C g gH-ClClFN ^N₂O: 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%, mp 124-126 ° C; (ethyl ether: hexane ) Analysis: Calculated for C 20 H 17 F 3 N 2 O 4: C 59.11, H 4.22, N 6.89;

Found: C 59.38, H 4.19, N 6.87. N- [2- (4- (2- (4-methyl-5-thiazolyl) ethoxy) phenyl) -4- (2-methylthioethyl-5-oxazolyl] -2,2,2-trifluoroacetamide, 77% , mp 100-101 ° C (ethyl acetate: hexane), MS (%), 471, 246, 126 (100), 112, 99. N- [2- (4- (2-phenylethylthio) phenyl ) -5-oxazolyl] -2,2,2-trifluoroacetamide, 52%, mp 103-104 ° C; (ethyl acetate: hexane): MS (%): 392, 301, 256, 178, 135, 121, 105 (100);

Analysis: Calculated for: C 58.15, H 3.85, N 7.14; . Found: C 57.76, H 3.78, N 6.99. 16

Example 2 N- [2- (3,5-diiodo-2-methoxyphenyl) -phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide A. N- (3,5-diiodo-2 -ethoxyethoxybenzoyl) aminoacetonitrile

A mixture of 20 g (0.05 mol) of 3,5-diiodosalicylic acid and 20 ml of thionyl chloride in 50 ml of CH 2 Cl 2 was refluxed for 24 hours, cooled to 25øC and concentrated in vacuo. The resulting oil, dissolved in 20 ml of benzene, was added to a solution of 4.6 g (0.05 mol) of aminoacetonitrile hydrochloride in 35 ml of H2 O at a temperature of 0 to 5 ° C, and the resulting mixture was stirred with 49 ml of 2 N NaOH dropwise to maintain the pH above 9. After a further 30 minutes a light purple solid was filtered, air dried and recrystallized from ethanol, yielding the title compound as colorless crystals, 5.92 g (27%), mp 193-195 ° C; NMR (δ, DMSO-D6): 3.70 (s, 3H), 4.27 (d, 2H), 7.76 (d, 1H), 8.23 (d, 1H), 9.08 (t, 1H).

By a similar procedure the following benzoylaminoacetonitriles were prepared (definition of X followed by the yield and melting point; recrystallisation 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 (Chem Abstr., 71, 49623 (1969)), m.p. 161-363 ° C); 5-chloro-2-methyl, 64%, m.p. 168-172 ° C (ethanol); 2-phenoxy, 38%, m.p. 104-109 ° C (ethanol); 17

2-chloro-5-methylthio, 38%, m.p. 104-109 ° C; 2,5-diiodide, 60%, m.p. 180-183 ° C (ethanol); 2.3.5 triiodo, 57%, m.p. 270 ° C; 3,5-dibromo-2-methoxy, 63%, m.p. 135-137 ° C (ethenol); 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).

They also prepared by the same procedure; (name of compound followed by yield and melting point; recrystallization solvent indicated in parentheses). N- (cyanomethyl) -naphthalene-1-carboxamide, 49%, m.p. 130-133 ° C (ethanol); N-Cyanomethyl-4-chloro-1-methoxynaphthalene-1-carboxamide, 54%, mp 139-141 ° C (ethanol) and N- (cyanomethyl) -2-methylthio) pyridine-3-carboxamide, 33%. P. f. 128-132 ° C (methanol, toluene). B. N- [2- (3,5-diiodo-2-methoxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide

A mixture of 2.0 g (4.53 mol) of the title compound of Example 2A, 15 ml of trifluoroacetic anhydride and 1.0 ml of trifluoroacetic acid at 25 ° C for 4 hours was stirred. The resulting homogeneous solution was then poured into 150 ml of ice water and the resulting precipitate was filtered, washed well with 5% aqueous NaHCO 3 and H2 O, and dried. Recrystallization from aqueous methanol gave the title compound 2.1 g, (86%), m.p. 160-163 ° C; NMR (Î', DMSO-D6): 3.78 (s, 4H), 7.32 (s, 1H), 8.13 (d, 1H), 8.26 (d, 1H);

Analyze; Calculated for C 12 H 7 F 3 I 2 N 2 C> 3; 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-trifluoroacetamides (name of the compound followed by the yield and melting point: recrystallisation solvent shown in parentheses) were prepared: N- [2- ( 2-bromophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide hydrate, 74%, mp 117-119 ° C (ethyl acetate: hexane); MS (%): 336 (45), 334 (39), 290 (3), 184 (100), 182 (9).

Analysis: Calculated for C 19 H 28 BrF 3 N 2 O 2 • H 2 O; 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 (CH2 Cl2: hexane); MS (%): 372 (7), 370 (34), 368 (27), 230 (15), 220 (29), 219 (42), 218 (82), 217 (43) 191 (15), 153 (100);

Analysis: Calculated for Câ, â, H Hâ, â, Br BrFâ,,â, ... Nâ, ...: 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 (CH2 Cl2: hexane); MS (%): 335 (1), 170 (26), 168 (100), 140 (36), 138 (87), 100 (26);

Analysis: Calculated for C 24 H 19 F 3 N 3 O 4: 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); Analysis: Calculated for C 21 H 12 ClF 2 N 2 O 2: 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, one quarter trifluoroacetate, 83%, m.p. 115-117 ° C (CH2 Cl2: hexane); MS (%): 349 (6), 348 (16), 206 (21), 208 (100), 207 (65), 181 (37), 180 (48), 153 (22), 152 (32);

Calc'd for C 20 H 18 F 3 N 3 O 3 · H 2 O: Calc'd: 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-trifluoroacetamide, 64%, m.p. 97-100 ° C (toluene);

Analysis: Calculated for C 12 H 19 ClF 3 N 2 O 2 S: 19

C 42.81, Η 2.39, N 8.32;

Found: C 43.20, H 2.54, N 8.17. N- [2- < 3-fluoro-4-methylphenyl) -5-oxazole] -2,2,2-trifluoroacetamide, 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);

Analysis: Calculated for C 12 H 8 F 4 N 2 O 2: C 50.01, H 2.80, N 9.72,

Found: C 49.77, H 2.72, N 9.36.

N- [2- (2-trifluorophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide, 68%, m.p. 160-163 ° C (toluene); MS (%): 275 (26), 274 (91), 219 (9), 153 (2.8), 134 (28), 123 (83), 122 (100), 107 (28).

Calc'd for C 13 H 16 F 4 N 2 O 2: 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. 165-167 ° C (CH3 OH * H2 O); MS (%): 508 (42), 368 (12), 357 (49), 356 (65), 329 (22), 229 (37), 214 (20), 202 (50), 153 (100);

Analysis: Calculated for C 19 H 13 F 3 F 2 = 2 · 20: C 25.12, H 1.34, N 5.33;

Found: C 25.10, H 40.96, N 5.13.

N- [2- (3,5-dibromo-2-methoxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide, 62%, m.p. 139-141 ° C (toluene); MS (%): 446 (51), 444 (19), 442 (9), 331 (45), 305 (55), 303 (100), 301 (51), 276 (83), 198 196 (67);

Analysis: Calculated for C 21 H 25 Br 2 F 3 N 2 C 3: 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 (CH3 OH: H2 O); MS (%): 635 (10), 634 (95), 483 (59), 482 (90), 455 (22), 438 (14), 355 (40), 328 (36), 153 (90);

Calc'd for C 12 H 14 F 3 N 3 O 2: 20

C 20.84, δ 0.64, N 4.42;

Found: C 20.55, H 0.74, N 4.94. N- [2- (2- (methylthio) -3-pyridinyl) -5-oxazolyl] -2,2,2-trifluoroacetamide hydrate, 58%, mp 109-111 ° C (CH3 OH: ); MS (%): 304 (20), 303 (28), 190 (48), 163 (57), 161 (77), 152 (41), 136 (75), 135 (100);

Calc'd for 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 (CH3 Cl2: hexane); MS (%): 306 (61), 155 (80), 154 (100), 127 (40).

Analysis: Calculated for C j jHFgF ^N₂O: C 58.83, H 2.96, N 9.15; Found: C 58.84, H 3.11, N 8.96. N- [2- (4-chloro-1-methoxy-2-naphthalenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide hydrate, 35%, m.p. 119-122 ° C (toluene); MS (%): 372, 370 (48), 229 (80), 202 (100);

Analysis: Calculated for C gHH₂ gClFâ,,Nâ,,Oâ,

Found: C 49.44, H 3.11, N 7.21; C 49.37, H 3.38, N 6.94.

Example 3 N- [2- (4- (2- (4-methyl-5-thiazolyl) ethoxy) phenyl) -4- (2-methylsulfonyl-ethyl) -5-oxazolyl] -2,2,2- trifluoroacetamide

A solution of N- [2- (4- (2- (4-methyl-5-thiazolyl) ethoxyphenyl) -4- (2-methylthioethyl) -5-oxazolyl] -2,2,2-trifluoroacetamide (0.500 g, 11 mmol) were dissolved in 30 ml of CH2 Cl2 under N2 and treated with m-chloroperbenzoic acid (0.5 g, 22 mmol) and then The reaction mixture was then washed with saturated NaHCO 3 (10%, saturated NaCl) and dried (MgSO 4), then filtered and concentrated in vacuo, yielding 0.60 g of a brown gum, crystallized from acetate,

ethyl acetate: hexane to give a brown solid, 0.355 g. Recrystallization of this product from ethyl acetate: hexane afforded the title compound, 0.220 g (40%), m.p. 153-154 ° C; MS (%): 503, 434, 424, 326, 245, 126, 99;

Analysis: Calculated for C20 H20 F3 O3 S2: C 47.71, H 4.00, N 8.35;

Found: C 47.71, H 4.16, N 8.00.

By a similar procedure, the following was also prepared: N- [2- (4- (2-phenylethylsulfonyl) phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide, 62%, mp 209- 210 ° C (CH 3 O); MS (%): 408, 304, 247, 195, 179, 152, 105 (100);

Analysis: Calculated for C 19 H 15 F 3 N 2 O 3 S: C 55.87, H 3.70, N 6.86;

Found: C 55.79, H 3.60, N 6.81.

Example 4 N- [2- (4-hydroxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide A. 4 - [(3,4,5,6-Tetrahydro-2H-2-pyranyl) oxy] benzoic 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-2 H -pyran (50 ml, 0.55 mol) in 1000 ml of ethyl ether at 25øC for 18 hours. The solid formed (12 g) was collected by filtration to give a second fraction (36 g) by concentration of filtered to approximately 250 ml B. 2- [4- (3,4,5,6-Tetrahydro-2H-2-pyranyl) oxy) benzoylamino] acetamide

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 of CH 2 Cl 2 and treated with 1-hydroxybenzo [2, 4,

triazole (30.4 g, 0.225 mol). After 5 minutes, a solution of dicyclohexylcarbodiimide (46.5 g, 0.225 mol) in 250 ml of CH 2 Cl 2 was added and stirring 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 of 10% NaHCO3 and saturated NaHCO3 and then dried over MgSO4. After evaporation of the solvent, the residue was dissolved in CH 2 OH and saturated with NH 2 gas for one hour, allowed to stand at 25 ° C for 24 hours and evaporated to dryness. The residue was triturated with CHâ,ƒOH: ethyl ether to give 20 g of 2- [4- (3,4,5,6-tetrahydro-2-pyranyl) oxy) benzoylamino] acetamide . Another 5 g was recovered from the comminuted product, obtaining in overall yield of 45%. C. N- [2- (4-hydroxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide

A mixture of trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (70 mL) cooled at 0 ° C was treated with the title compound of Example 4B (20 g, 0.072 mol) for 10 minutes, and then The reaction mixture was allowed to warm to 25 ° C for 2.5 hours. After concentration in vacuo, the residue was dissolved in 500 ml of ethyl acetate, washed with saturated NaHCO 3 and NaCl, dried (MgSO 4) and evaporated to dryness. Chromatography on silica gel using ethyl ether / hexane (2: 1) followed by 100% ethyl ether gave 18 g of an oily brown solid. Trituration of the solid with ethyl ether hexane afforded 9 g of the title compound as a white solid, yielding from the filtrate plus 5 g in 72% yield, mp 220øC (dec.). ; Calc'd for C 48.54, H 2.59, N 10.29;

Found: C 48.19, H 2.61, N 10.23.

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

A solution of N- [2- (4-hydroxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide (2.2 g, 8 mmol) was cooled to 0 ° C in dry dimethylformamide (100 mL) and treated with NaH (0.48 g, 0.020 mol) under a 3 portions atmosphere. 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 warmed to about 100 ° C. After 4 hours, the mixture was cooled to 25 ° C, poured into ice-water and extracted with 1% Cl. The organic layer was washed with H2 O, dried (MgSO4) and concentrated to a brown syrup. Chromatography through 300 g of silica gel using ethyl acetate: hexane (2: 1) gave 2.2 g of a gum which was recrystallized from ethyl ether / hexane (1:10) to give the title compound -amide as a white solid, 1.96 g (64%), mp 136-137 ° C; MS (%): 382, 372, 217, 175, 153, 132, 121, 69 (100);

Analysis: Calculated for C 19 H 21 F 3 N 2 O 3: C 59.68, H 5.54, N 7.33;

Found: C 60.04, H 5.54, N 7.33.

Using a similar procedure from 2- (2-thienyl) ethyl p -toluenesulfonate there was obtained N- [2- (4- (2-thienyl) ethoxyphenyl) -5-oxazolyl] 2-trifluoroacetamide, one fourth of hydrate in 12% yield, mp 140-142 ° C (ethyl ether: hexane);

Calc'd for: 1/41% C: 52.78; H, 3.52; N, 7.24;

Found: C 52.91, H 3.55, N 7.26.

In a similar manner from 2- (4-methyl-5-thiazolyl) ethyl p-toluenesulfonate there was obtained N- {2- (4- (2- (4-methoxy-5-thiazolyl) ethyl ) -phenyl) -5-oxazolyl] -2-2-2-trifluoroacetamide in 8% yield, mp 176-177 ° C (ethyl ether: hexane)

Calc'd for: C 51.38, H 3.56, N 10.50; Found: C 50.93, H 3.53, N 10.35. 24

Example 6 N- [2- (4- (2-hydroxy-2-phenylethoxy) -phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide hemihydrate A. 4 - [(2-hydroxy- 2-phenylethoxy) -N- (carbamoylmethyl) benzamide

A mixture of 4- (benzoylmethoxy) -N- (carbamoylmethyl) benzamide < 1.0 g, 3.0 mmol) and 50 mL CH 2 OH was treated with NaBH 4 (0.116 g, 3 mmol) at After one hour, the resulting solution was concentrated under vacuum, the gum was dissolved in ethyl acetate and washed with H2 O and then with saturated NaCl. After drying (MgSO 4), the organic phase was concentrated to an oil which was crystallized from CH 2 OH: ethyl ether hexane (1: 5: 2) to give the title compound as a white solid of a white solid, 0.470 g (48%), mp 140-145Â ° C (dec.). B. N- [2- (4- (2-hydroxy-2-phenylethoxy) -phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide hemihydrate

The title compound of Example 6A (0.47 g, 1.4 mmol) in 5 mL of trifluoroacetic acid and 3.0 g of trifluoroacetic anhydride was stirred at 25 ° C for 3 hours, concentrated vacuum to a syrup consistency and dissolved in ethyl acetate. The organic phase was washed with Et2 O and saturated NaCl, then dried (MgSO4). By concentration in vacuo a light brown gum weighing 0.60 g was obtained. The gum was dissolved in 10 ml CH 2 OH, treated with 0.10 g K 2 CO 3 and stirred for 1 hour at -25 ° C. After filtration and concentration of the filtrate, the gum was dissolved in ethyl acetate, washed with H2 O and saturated NaCl, and then dried (MgSO4). Concentration to the state of a light yellow residue followed by silica gel chromatography with CH3 OH: CH2 Cl2 (5:95) provided the title compound as a white solid, 37%, mp 145 DEG- 147 ° C. . Analysis: Calculated for C 19 H 19 F 3 N 4 O 4 • 1 / 2H 2 O: 25

C 56.86 / Η 4.02, N 6.98; Determined; C 57.21, H 4.01, N 6.72.

Example 7

The title compound of Examples 1 to 6 was tested for its ability to reduce or inhibit the activity of the aldose reductase enzyme by the procedure of S. Hayman et al., As described in the Journal of Biological Chemistry, Vol. 240, p. 877 (1965) and with the modification of K. Sestanj et al. in U.S. Patent 3,821,383. In both cases, the substrate employed was partially purified aldose reductase enzyme obtained from human placenta. At a concentration of 10 M the compounds showed a percentage of inhibition greater than 50%.

The title compounds of Examples 1 to 6 are assayed for evaluation of their ability to reduce or inhibit the accumulation of sorbitol in the sciatic nerve and luteal nerve of streptozotocinised (i.e., diabetic) rats in accordance with the procedure described in U.S. Pat. No. 3,821,383. The amount of srbrbitol accumulation in the sciatic nerve and lens in each experimental animal is measured 27 hours after the induction of diabetes. The compound is then administered orally at 100 mg / kg at 4, 8 and 24 hour intervals after streptozotocin administration. The results obtained in this way are presented in terms of percentage inhibition (%) of each test compound as compared to the case where no compound was administered (i.e., white from untreated animals in which sorbitol levels typically range from about 50 to 100 mM / g tissue to values as high as 400 mM / g tissue in the 27 hour test period). 26

Claims (1)

A process for the preparation of a compound of the formula wherein Ar is naphthalenyl, 4-chloro-1-methoxy-2-naphthalenyl, pyridinyl, 6-chloro-3-pyridinyl, 2-methyl-3-thiopyridinyl, phenyl, nitrophenyl, hydroxyphenyl, trifluorophenyl, difluorophenyl, chloro nyl, dichlorophenyl, 5-chloro-2-nitrophenyl, bromophenyl, dibromophenyl, 5-bromo-2-chlorophenyl, iodophenyl, diiodophenyl, triiodophenyl, trifluoromethylphenyl, C1-4 alkylphenyl, 4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, phenoxyphenyl, C1-4 alkoxy-phenyl, 3,5-dibromo-2-methoxyphenyl, 3,5 2-methoxyphenyl, C 1 -C 6 -cycloalkyl-alkoxyphenyl having a maximum of three carbon atoms in the central moiety of alkoxy, phenylalkoxyphenyl or C 1 -C 4 -alkoxyphenylalkoxyphenyl in each case with a maximum of 3 carbon atoms in the central moiety of alkoxy, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxyphenyl having a maximum of three carbon atoms in the alkoxy, thienylalkoxyphenyl moiety having a maximum of three carbon atoms in the alkoxy moiety, azolylalkoxyphenyl or 4-methylthiazolylalkoxyphenyl in each case having a maximum of three carbon atoms in the alkoxy, benzoylalkoxyphenyl moiety having a maximum of three carbon atoms in the alkoxy, C1 -C4 alkylthiophenyl, 2-chloro-5 phenylthio, C1-4 alkanesulfonylphenyl or phenylalkylthiophenyl or phenylalkanesulfonylphenyl in each case having a maximum of three carbon atoms in the aliphatic central moiety; and R é is hydrogen, C1 -C4 -alkyl or C1 -C4 -alkylthioalkyl or C1 -C4 -alkanesulfonyl in each case having a maximum of three carbon atoms in the A compound of the formula: Wherein Ar and R are as defined above with a reagent or a mixture of reagents which is a strong protonic acid in the presence or absence of an inert solvent towards the reactants such that forming a compound of formula I and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt thereof. A process according to claim 1, characterized in that R is hydrogen, C1 -C4 -alkylthioalkyl or C1 -C4 -alkylsulfonyl in each case having a maximum of three carbon atoms in the alkyl. A process according to claim 2, wherein Ar is 4-methylthiazolylalkoxyphenyl having a maximum of three carbon atoms in the alkyl moiety. A process according to claim 3, Ar is 2- (4-methyl-5-thiazolyl) ethoxyphenyl and R is 2-methylthioethyl or 2-methanesulfonylethyl. A process according to claim 2, characterized in that Ar is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, iodophenyl, di-iodophenyl, tri-iodophenyl; C 1 -C 4 alkoxy-C 1 -C 6 -cycloalkyl-alkoxyphenyl, phenylalkoxyphenyl, C 1 -C 4 -alkoxyphenylalkoxyphenyl, pyridinylalkoxyphenyl, thienylalkoxyphenyl, 4-methylthiazolylalkoxyphenyl, benzoylalkoxyphenyl; C1 -C4 alkylthiophenyl, C1 -C4 alkanesulfonylphenyl, phenylalkylthiophenyl or phenylalkanesulfonylphenyl in each case having a maximum of three carbon atoms in the aliphatic central moiety; 2-naphthalenyl, 4-chloro-1-methoxy-2-naphthalenyl, 6-chloro-3-pyridinyl, 2-methyl-3-thiopyrimidinyl, phenyl, 4-hydroxyphenyl, 5-chloro-2-nitrophenyl, 5 2-chlorophenyl, 3-fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl, 3,5-dibromo-2-methoxyphenyl, 3,5-diiodo 2-methoxyphenyl, 2-hydroxy-phenylethoxyphenyl or 2-chloro-5-methylthiophenyl. A process according to claim 5, characterized in that A is 2-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6- dichlorophenyl, 2-bromophenyl, 2,5-diiodophenyl or 2,3,5-triiodophenyl. Method according to claim 5, According to the present invention, there is provided a compound of the formula wherein Ar is 2-phenoxyphenyl, 4-methoxyphenyl, 4 - [(1-methylcyclohexyl) -methoxy] -phenyl, 4- [2- (cyclohexyl) -ethoxy] -phenyl, 4- (phenylmethoxy) ) -phenyl, 4- (phenylethoxy) -phenyl, 4- (2-pyridin-2-ylethoxy) -phenyl, 4- (thienyl-2-ylethoxy) -phenyl, 4- (4-methyl-5-thiazolomethoxy ) -phenyl, 4- [2- (4-methyl-5-thiazolyl) -ethoxy] -phenyl or 4-benzoylmethoxyphenyl. A process according to claim 5, characterized in that Ar is 4- (2-phenylethyl) -phenyl or 4- (2-phenyl-ethanesulfonyl) -phenyl. A process as claimed in any one of the preceding claims wherein said compound of formula I is selected from: N - [(2- (4-chlorophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (4- (2- (4-methyl-5-thiazolyl) -ethoxy) -phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (4- (2-hydroxy-2-phenylethoxy) -phenyl) -5-oxazolyl] -2,2,2-tri N- [2- (2,4-dichlorophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (2-bromophenyl) -5-oxazolyl] -2,2-trifluoroacetamide; , 2-trifluoroacetamide, N- [2- (4- (2-cyclohexylethoxy) phenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (5-chloro-2-nitrophenyl N- [2-naphthalenyl-oxazolyl] -2,2,2-trifluoroacetamide; N- [2- (4-chloro-1-methoxy-2- naphthalenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; N- [2-chloro-5-methylthiophenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide; and N- [2- (3,5-diiodo-2-methoxyphenyl) -5-oxazolyl] -2,2,2-trifluoroacetamide. The claimed applicant is the priority of the U.S. application filed September 17, 1990, under the number 583,425. Lisbon, September 16, 1991 31