JPH05506244A - 5-trifluoroacylamino-2-aryl oxazole - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 5-Trifluoroacylamino-2-aryl oxazole Background of the invention The present invention relates to 5-trifluoroacylamino-2-aryl oxazole. Ru. These compounds may be used to treat diabetes mellitus (e.g., diabetic cataracts, retinopathy, and It is useful in the control of certain chronic complications resulting from neuropathy. The present invention also provides Regarding the pharmaceutical composition comprising the above-mentioned compound, furthermore, Concerning the use of the above compounds in therapy.

Previous attempts to obtain new and more effective oral antidiabetic agents have mostly failed. This included synthesizing new compounds that lower blood sugar levels. In recent years, diabetes Halting the progression of certain chronic complications of diabetes, such as pathological cataracts, neuropathy, and retinopathy There have been several studies on the effects of various organic compounds in or prevention. It is being done. For example, US Pat. No. 382 (K. Sestanj et al.) No. 1383 describes 1,3-dioxo-IH-benz[d,e]inquinoline-2 Certain aldose reductase inhibitors, such as (3H) monoacetic acid, and Although some closely related derivatives are known to be hypoglycemic, If not, they are disclosed to be useful for the above purposes. these compounds works by inhibiting the activity of the enzyme aldose reductase; Aldose reductase is mainly used in the human body (glucose and galactose). (such as sorbitol and galactitol). It catalyzes the reduction reaction to form the corresponding polyol. Do it like this Therefore, galactitol in the lenses of patients with galactosemia and patients with diabetes of sorbitol in the human kidneys, peripheral nervous system, retina, and lens. Accumulation is suppressed and reduced. As a result, these compounds may cause chronic diabetes in the eye. It will control certain chronic diabetes complications, including complications. Because the eye level The presence of polyols in lenses can lead to cataracts and loss of lens transparency. This is because it is already known to be induced.

On October 14, 1987, an aldose reductase inhibitor consisting of the following chemical formula was discovered. It is described in Japanese Patent No. M 77105 of Rohto Pharmaceutical Co., Ltd., published on It is listed.

Here, Rl is water 5F! child, an alkyl group having 1 to 4 carbon atoms, or a phenyl group , and R2 are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and an aramyl group having 8 or less carbon atoms. alkyl group or aralkenyl group, or 1 carbon! From Ll to 4 alkyl groups It is a phenyl group which may be substituted.

Public administration! teaching The present invention relates to a compound represented by the following chemical formula, and relates to a pharmaceutically acceptable compound of this compound. The invention relates to base addition salts.

Here, Ar is naphthalenyl, 4-chloro-1-methoxynaphthalene-2-yl Nole, pyridinyl, 6-chloropyridine-3-ynole, 2-methylthioviridine -3-yl, phenyl, nitrophenyl, hydroxyphenyl, fluorophenyl ru, difluorophenyl, chlorophenyl, dichlorophenyl, 5-riσrho2 Nitrophenyl, bromophenyl, dibromophenyl, 5-bromo-2-chloro Lophenyl, iodophenyl, short phenyl, triiodophenyl, triphenyl fluoromethylphenyl, alkylphenyl having 1 to 4 carbon atoms, 3-7 fluoro-4 monomethylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methyl Phenyl, phenoxyphenyl, alkoxyphenyl having 1 to 4 carbon atoms, 3, 5 -dibromo-2-methoxyphenyl, 3,5-short-2-methoxyphenyl , carbon N13 to 8 cycloalkyl having up to 3 carbon atoms in the alkoxy moiety Kyl-alkoxyphenyl, each having up to 3 carbon atoms in the central alkoxy moiety alkoxyphenylalkoxyphenyl or phenyla having 4 to 4 carbon atoms Rukoxyphenyl, 2-hydroxy-2-phenylethoxyphenyl, alkoxyphenyl Pyridinylalkoxyphenyl, alkoxy having up to 3 carbon atoms in the chenylalkoxyphenyl having up to 3 carbon atoms in each alkoxy moiety thiazolylalkoxyphenyl or 4-methyl having up to 3 carbon atoms in Thiazolyl alkoxyphenyl, base having up to 3 carbon atoms in the alkoxy moiety ndzoylalkoxyphenyl, alkylthiophenyl from carbon tl to 4, 2 -Chloro-5-methylthiophenyl, flucansulfonyl having 1 to 4 carbon atoms phenyl or phenyl each having up to 3 carbon atoms in the central aliphatic part Alkylthiophenyl or phenylalkanesulfonylphenyl.

R is a hydrogen atom, alkyl having 1 to 4 carbon atoms, or each bonded alkyl moiety Alkylthioalkyl from 1 to 4 carbon atoms having up to 3 carbon atoms, or or alkanesulfonylalkyl having 1 to 4 carbon atoms.

In a preferred embodiment of the invention, R is a hydrogen atom or each C1-C4 alkyl having up to 3 carbon atoms in the bonded alkyl moiety It is thioalkyl or flucanesulfonylalkyl of up to 4 carbon atoms.

More preferably, R is alkylthioalkyl having 1 to 4 carbon atoms, or carbon It is alkanesulfonylalkyl of prime number 1 to 4, and Ar is in the alkyl part. 4-methylthiazolylalkoxyphenyl having up to 3 carbon atoms.

In another embodiment of the invention, R is a water atom and Ar is a fluorocarbon Phenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromov phenyl, dibromophenyl, iodophenyl, short phenyl, or It is iodophenyl.

In another embodiment of the invention, R is one hydrogen atom, and Ar has one or more carbon atoms. alkoxyphenyl up to 4, cycloalkylalkoxy having 3 to 8 carbon atoms Cyphenyl, phenylalkoxyphenyl, alkoxyf having 1 to 4 carbon atoms Phenyl alkoxyphenyl, pyridinyl alkoxyphenyl, thenyl alkoxy Cyphenyl, 4-methylthiazolylalkoxyphenyl, or benzoylua Lucoxyphenyl or alkylthiophenyl having 1 to 4 carbon atoms, carbon Flukanesulfonylphenyl of numbers 1 to 4, each up to 3 in the central aliphatic part phenylalkylthiophenyl or phenylalkylthiophenyl having carbon atoms of It is sulfonylphenyl.

In another embodiment of the invention, R is a hydrogen atom and Ar is 2-naphthalene. Rhenyl, 4-chloro-1-methoxynaphthalen-2-yl, 6-chloro-3-pyl Lysinyl, 2-methylthiopyridin-3-yl, phenyl, 4-hydroxyphenyl Nyl, 5-chloro-2-nitrophenyl, 5-bromo-2-chlorophenyl, 3 -Fluoro-4-methylphenyl, 2-chloro-5-methylphenyl, 5-chloro rho-2-methylphenyl, 3.5-dibromo-2-methoxyphenyl, 3.5- Short-2-methoxyphenyl, 2-hydroxy-2-phenylethoxyphene or 2-chloro-5-methylthiophenyl.

Preferred compounds of the present invention include the following.

N-[2-(4-chlorophenyl)-5-oxazinol]-2,2,2-trif fluoroacetamide N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxy)phene Nyl)-5-oxasilyl]-2,2,2-trifluoroacetamide N-[2 -(3,4-dichlorophenyl)-5-oxazinol]-2,2,2-triflu Oroacetamide N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5- oxazinol]-2,2,2-)lifluoroacetamide N-[2-(2,4- dichlorophenyl)-5-oxasilyl]-2,2,2-trifluoroacetoa Mido N-[2-(2-bromophenyl)-5-oxacylyl]-2,2,2-trif fluoroacetamide N-[2-(4-(2-cyclohexylethoxy)phenyl)-5-oxazino ]-2,2,2-trifluoroacetamide N-[2-(5-chloro-2-di trophenyl)-5-oxasilyl]-2,2,2-trifluoroacetamide N-[2-su7talenyl-5-oxacylyl]-2,2,2-trifluoroacetate toamide N-[2-(4-chloro-1-methoxynaphthalen-2-yl)-5-oxaN -[2-(3,5-short-2-methoxyphenyl)-5-oxasilyl J- 2,2,2-TrifluoroacetamideSpecial compounds of the present invention include: Things can be mentioned.

N-[2-(4-()lifluoromethyl)phenyl)-5-oxasilylco-2 ,2,2-trifluoroacetamide N-12-(4-cyanophenyl)-5- oxacylyl]-2,2,2-trifluoroacetamide N-[2-(2,3-dihydro[4F(-1]benzobilan-6-yl)-5- oxacylyl]-2,2,2-trifluoroacetamide N-(2-(2,3- dihydrobenzofuran-5-yl)-5-oxasilyl]-2,2,2-trif fluoroacetamide N-[2-(3,4-methylenedioxyphenyl)-5-o [xasilyl]-2,2,2-trifluoroacetamide N-[2-(3,4-ethylenedioxyphenyl)-5-oxasilyl]-2, 2,2-trifluoroacetamide N-[2-(naphthalen-1-yl-5-oxasilyl)-2,2,2-trif fluoroacetamide N-[2-(1,2,3,4-tetrahydronaphthalen-5-yl)-5-ox sacilyl]-2,2,2-trifluoroacetamide N-[2-(1,2,3, 4-tetrahydronaphthalen-6-yl)-5-oxasilyl]-2,2,2- Trifluoroacetamide N-[2-(4-methylsulfinylphenyl)-5 -oxazinol]-2,2,2-trifluoroacetamide N-[2-(4-methylsulfonylphenyl)-5-oxasilyl]-2,2, It consists of administering salt.

Noboru Goji pressure bearer Akirazu The reaction formula below shows 11IvL of the compounds of the invention.

QrCOOH-QrCOCl According to the methods used to prepare the compounds of the invention, appropriately substituted chemical a carboxylic acid amide of formula IV or a nitrile of formula V, where Ar and R are , as above, and this carboxylic acid amide or nitrile is a strong protic acid. With certain reagents or mixtures of reagents, it is converted to the title compound of Formula 1. this strange Such reagents useful for this purpose include trifluoroacetic acid/trifluoroacetic anhydride, May contain rephosphate esters, reaction-inert solvent may be present. It can also be used without the presence of Trifluoroacetic acid without added solvent /trifluoroacetic anhydride mixtures are preferred for this step. these reactions at temperatures ranging from approximately -20°C to the boiling point of the reagent or solvent used. It can be carried out at temperatures ranging from about 0°C to about 25°C. be called.

Isolation of the desired product is preferably accomplished by terminating the reaction with water or an ice-water mixture. and then filtration of the resulting solid precipitate or extraction of the reaction product with a suitable organic solvent. This is done by doing the following. Note that this solvent was used in order to obtain the crude reaction product. It is then evaporated. Further purification can be achieved by crystallization/recrystallization from a suitable solvent system. It can be carried out by chromatography or by chromatographic methods.

An appropriately substituted carboxylic acid amide starting material of formula IV can be It is easily prepared from the corresponding ester, and this ester is oxidized with ammonia in an inert solvent. Prepared by treatment with gas or aqueous ammonia solution. reaction is low alcohol, lower dialkyl ether, N%N-lower dialkylamide, or It is carried out in an organic solvent such as an aromatic or non-aromatic hydrocarbon. In this case it is preferable A good solvent is methanol. Generally, equimolar or excess amounts of ammonia are used. and the reaction is carried out for about 1 hour at a temperature ranging from about 0°C to about the boiling point of the solvent used. It will be held for approximately 72 hours. In practice, the reaction consists of 2 to 1 O equivalents of ammonia. for 6 to 48 hours at room temperature.

The ester of formula III used as starting material above has not been reported in the scientific literature. , are easily made by various methods known to those skilled in the art. For example, formula I The carboxylic acid chloride of I (prepared from the appropriate aryl carboxylic acid by known methods) by the reaction of the amino acid ester with an appropriately substituted or unsubstituted amino acid ester. The desired ester intermediate of formula III can be obtained in good yield by be. This reaction is effective for halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc. reaction in an inert solvent in the presence or absence of a suitable base (acid scavenger). for about 1 hour at a temperature from about -78°C to about the boiling point of the solvent used. It can be carried out for about 72 hours. Preferably, this reaction In chloromethane, using triethylamine as a base (acid scavenger) The process is carried out at a temperature ranging from about 0° C. to about 25° C. with stirring for up to 8 hours.

Other methods available for the preparation of said intermediates of formula III are reported in the chemical literature. of an activated aromatic acid (e.g. anhydride or mixed anhydride) Reaction with an appropriate amino acid or amino acid ester, and reaction with an appropriate amino acid ester. The Schotten-Bau benzoylation of the Schotten-Bau mann benzoylation).

Similarly, the appropriate nitriles of formula V listed at the beginning of this section are also suitable. aromatic acids, aromatic acid chlorides or activated acids (e.g. mixed acid anhydrides) and a suitable amino-nitrile. These useful for the present invention Some of the intermediates of aysong, Bulletin de Ia 5ociete Chimi France, (1969), 4102-4108; A, J.

Crovetti, US Pat. No. 3,457,294).

Finally, the starting materials necessary for the preparation of the compound of formula II are as described in the above-mentioned literature. or from commercially available known compounds or common chemical reagents. It is a compound that can be easily synthesized by a person skilled in the art using organic synthesis. for example, 4-Chlorobenzoyl chloride is easily converted from the known 4-chlorobenzoic acid** prepared, for example, by the action of thionyl chloride under refluxing toluene. . Further purification can be achieved by silica gel column chromatography in addition to the usual recrystallization methods. This can be done by means such as a fee.

The reaction pressure for the reaction is generally not critical unless otherwise specified. Generally, about 0 ．． 5 atm to about 2 atm, preferably normal pressure (i.e. about 1 atm) It is.

Used as a reagent in the present invention for the preparation of pharmaceutically acceptable base salts. For example, N-[2-3,4-dichlorophenyl)-5-oxa N-[2-substituted-5- with silyl]-2,2,2-trifluoroacetamide [oxazinol]-2,2,2-trifluoroacetamide compound and It forms toxic base salts. These special non-toxic base salts are sodium , pharmaceutically acceptable cations such as potassium, calcium, and magnesium. as well as pharmaceutically acceptable drugs such as ethylenediamine and jetanolamine. Contains those derived from organic bases. These salts are based on the N-[2-substituted -5-oxasilyl]-2,2,2-trifluoroacetamide compound as desired. with a lower alkanolic solution of the metal alkoxide and concentrate the resulting solution. PA is possible by drying. Alternatively, these may also be referred to in 2.2 above. ．． Aqueous solution of 2-trifluoroacetamide with the desired pharmaceutically acceptable cation by treating the solution with a solution and concentrating the resulting solution to dryness, preferably under reduced pressure. It can be prepared as follows. In either case, ensure completeness of the reaction and achieve the desired maximum To maximize the yield of final salt product, stoichiometric amounts of reagents should be used. be.

The compound of formula 1 and its pharmaceutically acceptable additive salts (hereinafter referred to as active compounds of the present invention) compound) in diabetic patients and peripheral nerves (e.g. sciatica). Given that sorbitol levels can be reduced (sugar), some chronic sugar Applied for therapeutic use as an aldose reductase inhibitor for the control of urinary complications. It will be done. The active compounds of the invention can be administered orally or topically to sick mammals (including humans). Alternatively, it can be administered parenterally. Generally, the body of the patient being treated The forces that inevitably vary depending on the severity, situation, and particularly the chosen route of administration; The compound will typically be administered at a dosage of about 0.5 mg to about 100 mg/kg of body weight per day. Administered in dosages in the mg range.

These compounds alone or in combination with pharmaceutically acceptable carriers It can be administered by the various routes mentioned above. Such administration may include one or more It is possible to do it separately. In particular, the active compounds of the invention may be used in a variety of different ways. i.e., in combination with various pharmaceutically acceptable inert carriers. tablets, capsules, lozenges, pastilles, hard candies, powders, sprays liquid, aqueous suspension, injectable solution, elixir (el ix i rs ), can be administered in the form of syrup, etc. Such carriers are solid diluents , or containing fillers, sterile aqueous media, and various non-toxic organic solvents, etc. . Generally, the active compounds of the invention will be present in about 0.0% of the total composition. 5% to about 90% by weight present in such form at concentration levels in the range of % to the desired unit dosage and sweeteners or flavors, colorants or dyes, and, if desired, emulsifiers or (4) Restore the already elevated sorbitol level in the body and the Preventing or inhibiting galactitol formation in lenses of ectosemizkraft; and/or (5) chronic galactosemic ratS) to reduce lens opacity and delay cataract formation. It is possible to predict by measuring the possibilities.

The following examples illustrate xi of the compounds of the invention. All melting points are uncorrected. It is something.

Conflict! N-2-4-chlorophenyl-5-oxasilyl-222-) 50m A mixture of L toluene was refluxed for 1 hour and an additional 50 mL of SO ester salt acid salt (18.75 g, O, 15 mol) and triethylamine (7° ethyl acetate). Crystallization from L/hexane yielded the title compound, 7.6 g (67%), mp. 113-114°C; MS (%): 229.227.195.168.155.1 39 (100) and 111 were obtained.

melting point) was prepared.

2.4-dichloro, Hl 94%; 4-phenylmethoxy, H178%, mp 205-206°C; 3,4-dichloro , H262%, melting point 210-212°C; 4-(2-pyridin-2-yl)nidoxy H164%, mp 173-17 ethyl, 77%, mp 133-135°C.

C,N-2-4-chlorophenyl-5-oxasilyl-22 by the same method The following compounds were prepared from the corresponding a7doamides: H14.02, N, For 7.45, the measured value is C160,52, H14,07, for 7.24 , the measured values are C159,18, N15.63, N, 7.06°N-[2-(4-method) Toxyphenyl)-5-oxazinol]-2,2,2-triple oacetamide 66%, melting point 141-142°C (ethyl ether:hexane); analytical value: C12H,,F,N,O,ToL Theoretical value: C,50,39,N13.18,N , 9.80, the measured values are C,50,34,N13.70,N,N-[2- (4-phenylmethoxyphenyl)-5-oxazinol]-2,2,2-trif fluoroacetamide, 20%, mp 155-156°C (ethyl acetate:hexane) :Analytical value" Theoretical value as 1lH1IF3N101 2C159,67,N13 ．． 62, N, 7.73, the measured values are C, 59, 85, N13, 64, N, 7.70° N-[2-phenyl-5-oxasilyl]-2,2,2-trifluoroacetoa MS (%): 256.237.201.104 (100), analysis value: C, , H, F, N, Theoretical value as O□: C, 51,57, N12.76, N, 10.94 The measured values are C151,65, N12.80, N, 10.99°N-[2-(3 ,4-dichlorophenyl)-5-oxasilyl]-2,2,2-trifluoroa Cetamide, 56%, mp 125-126°C (dichloromethane:hexane); min Analytical values: C,, H, Cl□F, theoretical values as N20□: C, 40, 64, Hl l, 55. N, 8.62, the measured value is C, 40,5L H, l.

60, N, 8.55° N-[2-(4-(benzoylmethoxy)phenyl>-5-oxasilyl]-2 , 2,2-trifluoroacetamide, 57%, melting point 185-186°C (acetic acid ethyl chill: hexane); MS (%): 390.27L 255.239.105 (1 00); Analysis value: Theoretical value as C19H1SFIN204: C, 58, 46, For N13.36, N,7.18, the measured values are C,58,16, H,3,30 ,N.

N-[2-(4-(2-pyridyl)ethoxy)phenyl)-5-oxazinorco -2,2,2-trifluoroacetamide, 72%, melting point 152-153°C (vinegar MS (%): 377.152.132.106 (100); Analysis ([:C,,H,4F,N,O,ToL Theoretical value: C157,29,N13. For 74,N,11.14, the measured value is C,57,06,H,3,74,N, 11. Il.

N-[2-(3,4-(dichlorophenyl)-5-oxasilyl]-2,2,2 -Trifluoroacetamide quarter hydrate, 72%, melting point 116-120℃ ( Ethyl ether: hexane); Analysis value: C,, H, CI□F, N, 02・1/ Theoretical values as 4H,O: C140.09, Hll, 68, N, 8.50 The measured values are C, 40,00, H, 1, 5B, N, 8.22°N-[2-<2. 6-dichlorophenyl)-5-oxasilyl]-2,2,2-trifluoroacetate Toamide, 54%, mp 155-156°C (ethyl acetate dipetroleum ether); MS (%): 324.172 (100), 152.135.121.108, analysis Value: C,, H, Cl, F, N, O, t7) Theoretical value: C, 40, 64, H ,1,55,N,8.62, the measured value is C140,58,H,1,57, N, 8.90° N-[2-(3,5-dichlorophenyl)-5-oxazinol]-2,2,2- Trifluoroacetamide hemihydrate, 90%, analytical values: C,, H, CI .

F, N, O, ・l / 2 Theoretical value as H, O: C, 39, 55, H, 1 ,81,N18.39, the measured value is C,39,64,H,1,69,N, 8.00゜N-[2-(6-chloropyridin-3-yl)-5-oxazinorco -2,2,2-trifluoroacetamide, melting point 144-145°C (ethylhexyl Analytical value: C1゜H, CI　F, N, O, Theoretical value: C141,1 8, Hll,73,N,14.41, the measured value is C141,48,H,1 ,74,N,14°80° N-[2-(4-(4-(2-methoxyphenylethoxy)phenyl)-5-o [xasilyl]-2,2,2-trifluoroacetamide, 76%, melting point 124- 126°C (ethyl ether:hexane): Analysis value: C1°H,, F, N, 04 and The measured value is 20, 59.11 SH, 4, 22, N, 6.89. is C159,3g, H,4,19, N16.87゜N-[2-(4-(2-(4 -methylthiazol-5-yl)ethoxy)phenyl)-4-(2-methylthio Ethyl-5-oxasilyl]-2,2,2-trifluoroacetamide, 77% , melting point 100-101°C (ethyl acetate:hexane); MS (%): 471, 2 46, 126 (1 (ton, l) 12, 99°N-[2-(4-(2-F) Theoretical value as phenylethylthio)phenyl)-5-oxasilyS: C158, 15, N13.85, N, 7.14, the measured value is C157,76, N13 ．． 78, N, 6.99° N-2-35-short-2-methoxyphenyl-5-oxasilyl-222 −) Refluoroacetamide A, N-35-short-2-methoxybenzoyl aminoacetonide (22 g) in 35 mL of water at 0-5°C (0° (S, 3I(), 4. 27 (d, 2H), 7. 76 (d, IH), 8.2 3(d,1)(),9.08(t,IH) was obtained as colorless crystals.

The following benzoylaminoacetonitrile was prepared by a similar method (Xl j order, X, yield, and melting point; recrystallization solvent in parentheses): 5-promol 2-chloro , 23%, melting point 150-154°C (ethanol aqueous solution); 5-chloro-2-nitro, 47%, melting point 152-155°C (ethanol) (temple) Patent! No. 1,520,925 (Mika K Bustollto 71.49623k ( 1969)), mp 161-163°C); 5-chloro-2-methyl, 64%, mp 161-163°C); Point 168-172°C (ethanol); 2-phenoxy, 38%, melting point 104-1 09°C (ethanol); 2-chloro-5-methylthio, 94%, melting point 95-97 °C: 2.5-short, 60%, 180-183 °C (ethanol); 2.3.5 -Triiodo, 57%, melting point 270°C: 3.5-dibromo-2-methoxy, 63 %, melting point 135-137°C (ethanol); 2-fluoro, 73%, melting point 5 g-60°C (ethanol aqueous solution; 2-fluoro) Mo, 34%, melting point 120-123°C (ethanol aqueous solution); 3-fluoro-4- Methyl, 39%, melting point 93-95°C (ethanol aqueous solution); by the same method, The following compounds were prepared (sequentially, compound name, yield, melting point; recrystallization solvent in parentheses). ).

N-(cyanmethyl)-naphthalene-1-carboxamide, 49%, mp 13 0-133℃ (ethanol); N-(cyanomethyl)-4-chloro-1-methoxynaphthalene-2-carboxy Amide, 54%, mp 139-141'C (ethanol) and N-(cyanometallic) methyl)-2-(methylthio)pyridine-3-carboxamide, 53%, mp 1 2g-132°C (methanol:toluene).

B, N-2-35-short-2-methoxyphenyl-5-oxacyl -2 2 2-) Lifluoroacetamide Title compound of Example 2A (2.0 g (4.53 mol)), 15 mL of trifluoroacetic anhydride, and 1. OmL's The trifluoroacetic acid mixture was stirred at 25° C. for 4 hours. The resulting homogeneous solution The liquid was then poured into 150 mL of ice water, and the resulting precipitate was filtered to contain 5% Washed with aqueous sodium bicarbonate solution and water, and dried. Methanol aqueous solution? The title compound (2.1 g, 86%) was obtained by recrystallization. Its physical properties are Melting point 160-163°C; NMR (δ, DMSO-d,): 3.7 g (s, 4H ), 7.32 (s, IH), 8.13 (d, IH), 8.26 (d, I H); Analytical value 'Cl2H7j3 engineering 2N203 and theoretical value 2C126,7 9, Hll, 3LN, 5.21, and the measured value is C126,69, H, 1,32 , N, was 4.99.

By a similar method, 2.2.2-trifluoroacetamide was prepared (sequentially , compound name, yield, and melting point; recrystallization solvent is in parentheses).

N-[2-(2-bromophenyl)-5-oxacylyl]-2,2,2-trif fluoroacetamide hydrate, 74%, melting point 117-119°C (ethyl acetate:hexyl MS (%): 336 (45), 334 (39), 290 ( 3), 194 (13), 184 (100), 182 (9): Analysis value: C,,H,Br　F3N.

Theoretical value as 02 H, O: C, 37, 42, N12.28, N17.93 Yes, the measured values are C137,29, N12.18, N, 7.65°N-[2-(5 -bromo-2-chlorophenyl)-5-oxazinol]-2,2,2-triflu Oroacetamide, 78%, mp 128-130°C (dichloromethane:hexane) ); MS (%): 372 (7), 370 (34), 368 (27 ), 230 (15), 220 (29), 219 (42), 218 (82 ), 217 (43), 216 (76), 191 (15), 153 (1 00); Analytical value: C,, H, BrCIF, N, Theoretical value as O□: C135, 75, H, 1,36, N, 7.58, and the measured value is C135,49, Hll, 28, N, 7.31°N-[2-(5-chloro-2-nitrophenyl)-5-o [xasilyl]-2,2,2-trifluoroacetamide, 68%, melting point 149- 152°C (dichloromethane:hexane); MS (%): 335 (1), 1 70 (26), 168 (100), 140 (36), 138 (87 ), 100 (26); Analysis value: C11H5CI F 3N, theory as 04 Values: C, 39, 36, H, 1, 50, N, 1'2. 52, and the measured value is C1 39,12, H, 1,68, N, 12.32°N-[2-(5-chloro-2-methyl tylphenyl)-5-oxasilyl]-2,2,2-trifluoroacetamide , 69%, melting point 101-104°C (ethyl acetate:hexane); analytical value: Cl2 H, CI F, N, O, and Lte 17) Theoretical value: C147.30, N12.65, N, 9.20, and the measured values are C147,46, H,2,80, N19.01° N-[2-(2-phenyloxyphenyl)-5-oxazinol]-2,2,2 -Trifluoroacetamide, 1/4 trifluoroacetate, 83%, melting point 1 15-117°C (dichloromethane:hexane); MS (%): 349 (6 348 (16L 209 (21), 208 (100), 207 (6 5), 181 (37), 180 (4g), 153 (22), 152 (32); Analysis value 2C,,H11F3N20S・1/4CF3C02H Theoretical value: C155.78, N13°00SN, 7.43, and the measured value is C15 5,63,H,3,04,N,7゜N-[2-(2-chloro-5-methylthiophyl) phenyl)-5-oxasilyl]-2,2,2-trifluoroacetamide, 64 %, melting point 97-100°C (toluene); analysis value: C,,H,CI　F3N,0 2S and the theoretical values: C, 42.81, N12.39, N, 8.32, and the measured The fixed values are C,43,20,N12,54,N,N-[2-(3-fluoro-4-methane) tylphenyl)-5-oxasilylco-2,2,2-trifluoroacetamide , 73%, melting point 110-113°C (ethyl acetate:hexane; MS (%): 289 (30), 288 (66), 234 (17), 191 (1g), 148 (32), 137 (87), 136 (100), 109 (60) , 107 (32); Analysis value: C12H, F4N, ○, theoretical value: C 50,01, N12,80, N, 9.72, and the measured value is C149,77, H ,2,72,N,9.36° N-[2-(2-fluorophenyl)-5-oxasilyl]-2,2,2-tri Fluoroacetamide, 68%, mp 160-163°C (toluene); Mo(4 8), 163 (57), 162 (77), 152 (41>, 136 (7 5), 135 (100); Analysis value: C,, H, F, N, 02S -H, O and Theoretical value: C141,12, H, 3,14, N, 13.08, and the measured value (YoC,40,68,N12.96,N,9.15, and the measured value is C,58, 84, H, 3, 11, N.

Theoretical value: C, 49, 44, H, 3, l 11N, 7.21, and the measured value 1 is C, 49°37, N13.38, N, 6.94° Cleaned and dried (magnesium sulfate). then), filtered and vacuum When concentrated, 0.60 g of yellowish brown gummy material was obtained, and ethyl acetate: Crystallization from hexane gave 0.355 g of a tan solid. this Recrystallization from ethyl acetate:hexane yielded 0.220 g (4 0%) obtained. Its physical properties are: melting point: 153-154°C; MS (%): 503. 434.424.326.245.126.99: Analysis value: Cyo H211F, N Theoretical values for , O, S: C, 47,71, H, 4,00, N, 8.35. The measured values were C, 47,7LH14,16, N, S, OO.

The following compounds were prepared by a similar method. N-[2-(4-(2-phenyl) ethylsulfonyl)phenyl)-5-oxasilyl]-2,2,2-trifluoro Roacetamide, 62%, melting point 209-210°C (methanol); MS (%): 408.304.247.195.179.152.125.105 (100 ); Theoretical value as analytical value 'c,, H,, F, N, o, s: C155,87, N 53.70, N, 6.86, and the measured value is C, 55,79, H, 3,60, N , 6.81゜cross five earth N-2-4-hydroxyphenyl-5-oxazinol-2,22-to1fur Oro Seto Mido A, 4-3456-tetrahydro-2H-bilan-2-yl 4- and drooxybenzoic acid (45 g, 0°3 3 mol), p-)luenesulfonic acid (5.0 g, 0.026 mol) and 3.4 A mixture of -dihydro-2H-bilane (50 mL, 0.55 mol) was added at 25°C to Stirred for 8 hours. A solid (12g) was collected by filtration, a second collection (36g ) was obtained by concentrating the filtrate to about 250 mL.

B, 2-4-3456-tetrahydro-2H-bilan-2-yloxybenzo Triethyl acetamide in 500 mL of dichloromethane Min (31.4 mL.

0.225 mol), the title compound of Example 4A (44.4 g, 0.20 mol), and glycine methyl ester hydrochloride (28.2 g, 0.225 mol) at 0°C. Cooled and added 1-hydroxybenzotriazole hydrate (30.4 g, 0.225 mol). After 5 minutes, dicyclohexylcarbodiimide (46,5 g, 0.225 mol) in dichloromethane (>250 mL) was added, and 25 Stirring was continued for 18 hours at °C. The reaction mixture was then filtered and the filtrate was L of 10% citric acid, 250 mL of 10% sodium bicarbonate water, and saturated food Washed with brine and dried over magnesium sulfate. After concentrating the solvent, the residue is methane. Rule! saturated with ammonia gas for 1 hour and at 25°C for 24 hours. Left alone and concentrated. The residue was titrated with methanol:ethyl ether. Then, 20 g of crude 2-[4-(3,4,5,6-tetrahydrobilane-2 -yl)'oxybenzoylaminoco-acetamide was obtained. 5 more grams was recovered with a titration value of 1, giving a total yield of 45%.

, +(, N-2-4-hydroxyphenyl-5-oxasilyl-222-+ Refluoro Seto Mido Triple oleoacetic acid (<lOOmL) and anhydrous trifluoroacetic acid were incubated at 0°C. A mixture of Ml (70 mL) was mixed with the title compound of Example 4B (20 g, 0.072 mol). was processed for 10 minutes. The reaction mixture was then warmed to 25°C for 2.5 hours. I was caught. After concentration in vacuo, the residue was dissolved in 500 mL of ethyl acetate and diluted with 10% charcoal. Washed with sodium hydroxide solution and saturated saline solution and dried with magnesium sulfate. and concentrated. Silica gel column was washed with ethyl ether:hexane (2:1). 100% ethyl ether and then flushed with 100% ethyl ether. Filtration yielded 18 g of brown oily solid. Ethyl ether: drops using hexane The titration yielded 9 g of the title compound as a white solid, and an additional 5 g was obtained from the titration solution. The total yield was 72%. Physical properties are melting point 220℃ (dec): min. Analysis value "Theoretical value as IIH-7 FINIO1: C, 48, 54, N12.5 9, N, 10.29, and the measured value is C, 48, 19, H, 2, 6L N, 10 ．． 23゜1 fish l N-2-4-cyclohexylethoxyphenyl-5-oxasilyl-222- ) Refluoroacetamide N-[2-(4-hydroxyphenyl) in anhydrous di/thylformamide, 100 mL )-5-oxasilyl]-2,2,2-trifluoroacetamide (2,2g , 8 mol) was cooled to 0°C and added with sodium hydride (0.48 g, 0.020 mol) was treated in three portions under a nitrogen atmosphere. In one of them, after 15 minutes, 2-s Chlorhexylethyl p-)luenesulfone) (3.4 g, 12 mmol) was added and the temperature was raised to 25°C. The reaction mixture is then gradually heated to about 100°C. heated up to. After 4 hours, the mixture was cooled to 25°C, poured into ice water, and diluted. Extracted with chloromethane. The organic layer was washed with water and dried (magnesium sulfate ) and concentrated to give a brown syrup. 2:1 ethyl ether chromatography on a 300 g silica gel column using hexane. Incidentally, 2.2 g of gummy substance was obtained, and ethyl ether:hexane (1: 1.96 g (6 4%) was obtained.

Its physical properties are melting point: 136-137°C: MS (%): 382.272.217. 175.153.132.121.69 (100); Analysis value: C1, Hl, F , N20. Theoretical values: C159.68, H, 5.54, N, 7.33. The measured values were C, 60,04, N15.54, N, 7.33° using the same method. From 2-(Checy 2-yl)ethyl p-toluenesulfonate, N-[ 2-(4-(Theen-2-yl)ethoxyphenyl)-5-oxazinol]-2 , 2,2-trifluoroacetamide l/4 hydrate was obtained with a yield of 12%. , its physical properties are melting point, 140-142℃ (ethyl ether:hexane); analytical value : C,, H,, F, N, O, S -1/4 Hlo and theoretical value: C15 2,78, H, 3,52, N, 7.24, and the measured value is C, 52,91, N1 3.55, N, 7.26° 1117m, 2-(4-methyl-5-thiazolyl)ethyl p-)ruens From sulfonate, N-[2-(4-(2-(4-methylthiazol-5-yl) ethyl)-phenyl)-5-oxasilyl]-2,2,2-trifluoroacetate The amide was obtained in a yield of 8%, and its physical properties were as follows: melting point, 176-177°C (ethyl Ether: hexane); Analytical values: C,, H, 4F, N, O, S and theoretical values: C151,38, N13,56, N, 10.58, and the measured value is C150,9 3, N13゜53, N, 10.35゜ Fork plate l N-'2- 4- 2-hydroxy-2-phenylethoxy phenyl-5- Oxazinol-222-) refluorocetamido 1/2A, 4-2-hydro Roxy-2-phenylethoxy-N-carbamoylmethyl-benzamide 4-(benzoylmethoxy)-N-(carbamoylmethyl)-benzamide (1 , 0 g, 3.0 mmol) and 50 mL of methanol was mixed with NaBH4 (0,116 g, 3 mmol) at 25° C. under nitrogen atmosphere.

After 1 hour, the resulting solution was concentrated in vacuo and the gummy material dissolved in ethyl acetate. The solution was washed with water and then with saturated saline. Drying (magnesium sulfate After (m), the organic matter is concentrated to an oil, and methanol dinityl ether:hexyl The title compound was crystallized from San (1:5:2) as a white solid. 0.470g (48%) was obtained, melting point was 140-145°C (dec) .

B, N-2-4-2-hydroxy-2-phenylethoxy phenyl-5-oxy sazoyl-222-) refluorocetomide 123, trifluoro of Og The title compound of Example 6A (0,47 g, 1.4 mmol) was stirred at 25 °C for 3 h and concentrated to syrup in vacuo. and dissolved in ethyl acetate. Organic matter is washed with water and saturated saline. , dried (magnesium sulfate). When concentrated in vacuo, a yellow-brown gummy substance 0.60 g was obtained. This gummy material was dissolved in 10 mL of methanol. , treated with 0.10 g of anhydrous potassium charcoal and stirred for 1 hour at 25°C. filter After concentrating the filtrate by filtration, the resulting gummy material was dissolved in ethyl acetate and diluted with water and The solution was washed with saturated saline and dried (magnesium sulfate). When concentrated , a bright yellow residue was obtained using methanol:dichloromethane (5:95). When subjected to silica gel column chromatography, the title compound was found as a white solid. 37% of the product was obtained as a compound with a melting point of 145-147°C: analytical value 2C,,H,,F,N , 04-1/2H, Theoretical value as O: C, 56,86, H, 4,02, N, 6 ．． 98, and the measured values are C157.21, N14.01. N, it was 6.72 .

X Todoroki Modified by the literature (ournat of Biolo 1cal precision) It was a produced aldose reductase. At a concentration of 10-'M, the compound showed percent inhibition greater than 50%.

Diabetic tozoto according to the method described in US Pat. No. 8,382,1383 Orally at 4,8, and 24 hour intervals after administration of Percent inhibition conferred by test compound compared to untreated animals) Expressed in percentage.

5-trifluorosylmino-2-aryloxazole Novel 5-trifluor Ooacylamino-2-aryloxazoles and their pharmaceutically acceptable properties A base addition salt is disclosed. These compounds may be associated with certain types of chronic diabetes. It is useful in treatment for controlling complications and as an aldose reductase inhibitor. this Methods of preparing these compounds from known starting materials are provided.

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Claims (1)

[Claims] 1. 5-trifluoroacylamino-2-arylox represented by the following chemical formula It is a sasol compound or a pharmaceutically acceptable addition salt of this compound, and has mathematical formulas, chemical formulas, tables, etc.▼I Here, Ar is naphthalenyl, 4-chloro-1-methoxynaphthalene-2- stomach pyridinyl, 6-chloropyridin-3-yl, 2-methylthiopyridin-3-yl, phenyl, nitrophenyl, hydroxyphenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, 5-chloro-2-yl Trophenyl, bromophenyl, dibromophenyl, 5-bromo-2-chlorophenyl phenyl, iodophenyl, diiodophenyl, triiodophenyl, trifluoro romethylphenyl, alkylphenyl having 1 to 4 carbon atoms, 3-fluoro-4-methyl tylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl phenyl, phenoxyphenyl, alkoxyphenyl having 1 to 4 carbon atoms, 3,5-di Bromo-2-methoxyphenyl, 3,5-diiodo-2-methoxyphenyl, a cycloalkyl-alkoxyphenyl of 3 to 8 carbon atoms, each having up to 3 carbon atoms in the alkoxy moiety; alkoxyphenylalkoxyphenyl of 1 to 4 carbon atoms, each having up to 3 carbon atoms in the central alkoxy moiety; or Phenylalco xyphenyl, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxyphenyl with up to 3 carbon atoms in the alkoxy moiety, thienylalkoxyphenyl with up to 3 carbon atoms in the alkoxy moiety, each with 3 carbon atoms in the alkoxy moiety 4-methylthiazolylalkoxyphenyl or thiazolylalkoxyphenyl having up to 3 carbon atoms, phenyl having up to 3 carbon atoms in the alkoxy moiety ndzoylalkoxyphenyl, alkylthiophenyl having 1 to 4 carbon atoms, 2-chloro-5-methylthiophenyl, alkanesulfonyl phenyl having 1 to 4 carbon atoms, or each with up to 3 carbon atoms in the central aliphatic part phenyl alkanesulfonylphenyl or phenylalkylthiophenyl; R is a hydrogen atom, alkyl of 1 to 4 carbon atoms, or 1 to 4 carbon atoms, each having up to 3 carbon atoms in the bonded alkyl moiety; Alkanesulfonylalkyl up to or alkylthioalkyl having 1 to 4 carbon atoms, provided that Ar is When trophenyl, R is not a hydrogen atom. 2. R is a hydrogen atom, each having up to 3 carbon atoms in the bonded alkoxy moiety, alkanesulfonylalkyl having 1 to 4 carbon atoms or alkylthioalkyl having 1 to 4 carbon atoms; A compound according to item 1. 3. A compound according to claim 2, wherein Ar is 4-methylthiazolyl alkoxyphenyl having up to 3 carbon atoms in the alkoxy moiety. 4. The compound according to claim 3, wherein Ar is 2-(4-methylthiazol-5-yl)ethoxyphenyl, and R is 2-methylthioethyl or 2-methanesulfonylethyl. 5, Ar is fluorophenyl, difluorophenyl, chlorophenyl, dichloro lophenyl, bromophenyl, dibromophenyl, iodophenyl, diiodophenyl phenyl, triiodophenyl; alkoxyphenyl having 1 to 4 carbon atoms, cycloalkylalkoxyphenyl having 3 to 8 carbon atoms, phenyl alkoxyphenyl Nyl, alkoxyphenylalkoxyphenyl having 1 to 4 carbon atoms, pyridinyl alkoxyphenyl, thienyl alkoxyphenyl, 4-methylthiazolyl alkoxyphenyl Lucoxyphenyl, penzoylalkoxyphenyl; alkoxyphenyl having 1 to 4 carbon atoms Kylthiophenyl, alkanesulfonylphenyl having 1 to 4 carbon atoms, each phenylalkanesulfonylphenyl having up to 3 carbon atoms in the central aliphatic part. 2-naphthalenyl, 4-chloro-1-methoxynaphthalen-2-yl, 6-chloro-3-pyridinyl, 2-methylthiophenyl; Opyridin-3-yl, phenyl, 4-hydroxyphenyl, 5-chloro-2-nitrophenyl, 5-bromo-2-chlorophenyl, 3-fluoro-4-methyl phenyl, 2-chloro-5-methylphenyl, 5- is chloro-2-methylphenyl, 3,5-dibromo-2-methoxyphenyl, 3,5-diiodo-2-methoxyphenyl, 2-hydroxy-2-phenylethoxyphenyl, or 2-chloro-5-methylthiophenyl , a compound according to claim 2. 6, Ar is 2-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl phenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl 6. A compound according to claim 5 which is lorophenyl, 2-bromophenyl, 2,5-diiodophenyl or 2,3,5-triiodophenyl. 7, Ar is 2-phenoxyphenyl, 4-methoxyphenyl, 4-[(1-methoxyphenyl) tylcyclohexyl)methoxy]phenyl, 4-[2-(cyclohexyl)eth xy]phenyl, 4-(phenylmethoxy)phenyl, 4-(2-phenyletho) xy)phenyl, 4-[2-(4-methoxyphenyl)ethoxy]phenyl, 4-(2-pyridin-2-ylethoxy)phenyl, 4-(thien-2-ylethoxy) xy)phenyl, 4-(4-methylthiazol-5-ylmethoxy)phenyl, 4-[2-(4-methylthiazol-5-yl)ethoxy]phenyl, 4-ben The compound according to claim 5, which is zoylmethoxyphenyl; 4-(2-phenylethylthio)phenyl or 4-(2-phenylethanesulfonyl)-phenyl. 8. The compound is N-[2-(4-chlorophenyl)-5-oxazolyl]-2,2,2-triph fluoroacetamide; N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxy)phenylene N-[2-(3,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluor Oroacetamide; N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide; N-[2-(2,4-dichlorophenyl) )-5-oxazolyl]-2,2,2-trifluoroacetate Amide; N-[2-(2-bromophenyl)-5-oxazolyl]-2,2,2-trif fluoroacetamide; N-[2-(4-(2-cyclohexylethoxy)phenyl)-5-oxazoli ]-2,2,2-trifluoroacetamide; N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-naphthalenyl-5-oxazolyl]-2,2,2-trifluoroacetate; toamide; N-[2-(4-chloro-1-methoxynaphthalen-2-yl)-5-oxazo [lyl]-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; A compound according to claim 1. 9. A pharmaceutical composition for treating chronic complications associated with diabetes. 12. A pharmaceutical composition comprising: a compound according to claim 1 in an amount effective to provide relief or relief; and a pharmaceutically acceptable carrier. 10. A method for treating a diabetic patient for preventing or alleviating chronic complications associated with diabetes, wherein the compound according to claim 1 is administered to the diabetic patient to prevent or alleviate chronic complications, etc. A method of treating a diabetic patient comprising administering an amount effective to 11. A method for preparing a compound represented by the following chemical formula, including ▲mathematical formula, chemical formula, table, etc.▼I Here, Ar is naphthalenyl, 4-chloro-1-methoxynaphthalene-2-y pyridinyl, 6-chloropyridin-3-yl, 2-methylthiopyridin-3-yl, phenyl, nitrophenyl, hydroxyphenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, 5-chloro-2-yl Trophenyl, bromophenyl, dibromophenyl, 5-bromo-2-chlorophenyl phenyl, iodophenyl, diiodophenyl, triiodophenyl, trifluoro romethylphenyl, alkylphenyl having 1 to 4 carbon atoms, 3-fluoro-4-methyl tylphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl phenyl, phenoxyphenyl, alkoxyphenyl having 1 to 4 carbon atoms, 3,5-di Bromo-2-methoxyphenyl, 3,5-diiodo-2-methoxyphenyl, a cycloalkyl-alkoxyphenyl of 3 to 8 carbon atoms, each having up to 3 carbon atoms in the alkoxy moiety, alkoxyphenylalkoxyphenyl of 1 to 4 carbon atoms, each having up to 3 carbon atoms in the central alkoxy moiety, or Phenylalco xyphenyl, 2-hydroxy-2-phenylethoxyphenyl, pyridinylalkoxyphenyl with up to 3 carbon atoms in the alkoxy moiety, thienylalkoxyphenyl with up to 3 carbon atoms in the alkoxy moiety, each with 3 carbon atoms in the alkoxy moiety 4-methylthiazolylalkoxyphenyl or thiazolylalkoxyphenyl with up to 3 carbon atoms, base with up to 3 carbon atoms in the alkoxy moiety ndzoylalkoxyphenyl, alkylthiophenyl having 1 to 4 carbon atoms, 2-chloro-5-methylthiophenyl, alkanesulfonyl phenyl having 1 to 4 carbon atoms, or each with up to 3 carbon atoms in the central aliphatic part phenyl alkanesulfonylphenyl or phenylalkylthiophenyl; R is a hydrogen atom, alkyl of 1 to 4 carbon atoms, or 1 to 4 carbon atoms, each having up to 3 carbon atoms in the bonded alkyl moiety; Alkanesulfonylalkyl up to or alkylthioalkyl having 1 to 4 carbon atoms, provided that Ar is When trophenyl, R is not a hydrogen atom: A compound with the following chemical formula, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ IV or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ V Here, Ar and R are A reactively inert solution similar to that defined above. A reactant or reactant mixture that is a strong protic acid in the presence of a solvent or without a solvent. a compound of formula I, comprising reacting with a compound of formula I to form a compound of formula I and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt thereof. Methods for preparing compounds. 12. R is a hydrogen atom, each having up to 3 carbon atoms in the bonded alkyl moiety, C1-C4 alkanesulfonylalkyl or C1-C4 alkylthioalkyl The method according to paragraph 11. 13. The method of claim 12, wherein 13, Ar is 4-methylthiazolylalkoxyphenyl having up to 3 carbon atoms in the alkoxy moiety. 14, Ar is 2-(4-methylthiazol-5-yl)ethoxyphenyl and R is 2-methylthioethyl or 2-methanesulfonylethyl, The method according to claim 13. 15, Ar is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl Lorophenyl, bromophenyl, dibromophenyl, iodophenyl, diiodophenyl, triiodophenyl; alkoxyphenyl having 1 to 4 carbon atoms, carbon Cycloalkylalkoxyphenyl, phenylalkoxyf with prime numbers 3 to 8 phenyl, alkoxyphenylalkoxyphenyl having 1 to 4 carbon atoms, pyridi Nyl alkoxyphenyl, thienyl alkoxyphenyl, 4-methylthiazolyl alkoxyphenyl, penzoyl alkoxyphenyl; alkylthiophenyl, alkanesulfonylphenyl of 1 to 4 carbon atoms, each phenylalkanesulfonylphenyl having up to 3 carbon atoms in the central aliphatic part. phenyl or phenylalkylthiophenyl; 2-naphthalenyl, 4-chloro-1-methoxynaphthalen-2-yl, 6-chloro-3-pyridinyl, 2-methyl Thiopyridin-3-yl, phenyl, 4-hydroxyphenyl, 5-chloro-2-nitrophenyl, 5-bromo-2-chlorophenyl, 3-fluoro-4-methy Ruphenyl, 2-chloro-5-methylphenyl, 5-chloro-2-methylphenyl 3,5-dibromo-2-methoxyphenyl, 3,5-diiodo-2-methoxyphenyl Cyphenyl, 2-hydroxy-2-phenylethoxyphenyl, or 2-chloro 13. The method of claim 12, wherein rho-5-methylthiophenyl. 16, Ar is 2-fluorophenyl, 4-chlorophenyl, 2,4-dichloro Phenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl 16. The method of claim 15, wherein the chlorophenyl, 2-bromophenyl, 2,5-diiodophenyl or 2,3,5-triiodophenyl. 17, Ar is 2-phenoxyphenyl, 4-methoxyphenyl, 4-[(1-methylcyclohexyl)methoxy]phenyl, 4-[2-(cyclohexyl)ethyl] toxy]phenyl, 4-(phenylmethoxy)phenyl, 4-(2-phenylethyl) phenyl, 4-[2-(4-methoxyphenyl)ethoxy]phenyl, 4-(2-pyridin-2-ylethoxy)phenyl, 4-(thien-2-ylethoxy)phenyl, phenyl, 4-(4-methylthiazol-5-ylmethoxy)phenyl, 4-[2-(4-methylthiazol-5-yl)ethoxy]phenyl, 4-benyl 16. The method according to claim 15, wherein the methoxyphenyl methoxyphenyl is methoxyphenyl. 18, Ar is 4-(2-phenylethylthio)phenyl or 4-(2-phenyl 16. The method of claim 15, wherein the compound is nylethanesulfonyl)phenyl. 19. The compound of formula I is N-[2-(4-chlorophenyl)-5-oxazolyl]-2,2,2-triph fluoroacetamide; N-[2-(4-(2-(4-methylthiazol-5-yl)ethoxy)phenylene N-[2-(3,4-dichlorophenyl)-5-oxazolyl]-2,2,2-trifluor Oroacetamide; N-[2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide; N-[2-(2,4-dichlorophenyl) )-5-oxazolyl]-2,2,2-trifluoroacetate Amide; N-[2-(2-bromophenyl)-5-oxazolyl]-2,2,2-trif fluoroacetamide; N-[2-(4-(2-cyclohexylethoxy)phenyl)-5-oxazoli ]-2,2,2-trifluoroacetamide; N-[2-(5-chloro-2-nitrophenyl)-5-oxazolyl]-2,2,2-trifluoroacetamide N-[2-naphthalenyl-5-oxazolyl]-2,2,2-trifluoroacetate; toamide; N-[2-(4-chloro-1-methoxynaphthalen-2-yl)-5-oxazo [lyl]-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; 19. A method according to any one of claims 11-18.