MXPA96005520A

MXPA96005520A - New azolidindions as agents antiglicemi

Info

Publication number: MXPA96005520A
Application number: MXPA/A/1996/005520A
Authority: MX
Inventors: Sotiorios Malamas Michael; Gunawan Iwan
Original assignee: American Home Products Corporation
Priority date: 1994-05-18
Filing date: 1996-11-12
Publication date: 1998-02-01

Abstract

This invention relates to novel compounds, which have demonstrated oral antihyperglycemic activity in ob / ob and db / db diabetic mice, animal models in non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes). These compounds have the formula (I), wherein: R1 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, thienyl, furyl, pyridyl, (a) or (b) wherein R10 is hydrogen, alkyl of 1 to 6 atoms of carbon, fluorine, chlorine, bromine, iodine, alkyloxy, from 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy, R2 is hydrogen or alkyl of 1 to 6 carbon atoms, X is 0SS; n is 0.1, 2; is (c) or (d); wherein R3 is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; B is (e), (f) or (g), where R4 is hydrogen, alkyl of 1 to 6 carbon atoms, allyl, aryl of 6 to 10 carbon atoms, aryl of 6 to 10 carbon atoms- (CH2) 1-6, fluorine, chlorine, bromine, iodine, trimethylsilyl or cycloalkyl of 3 to 8 carbon atoms, R5 is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy, B is (e), (f) or (g), where R4 is hydrogen , rent ilo of 1 to 6 carbon atoms, allyl, aryl of 6 to 10 carbon atoms, aryl of 6 to 10 carbon atoms- (CH2) 1-6, fluorine, chlorine, bromine, iodine, trimethylsilyl or cycloalkyl of 3 to 8 carbon atoms R5 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms or aryl of 6 to 10 carbon atoms- (CH2) 1-6-; m is O, 1 or 2; R6 is hydrogen or alkyl of 1 to 2; to 6 carbon atoms, R7 is hydrogen or alkyl of 1 to 6 carbon atoms, R8 and R9 is independently selected from alkyl hydrogen of 1 to 6 carbon atoms, fluorine, chlorine, bromine or iodine; Y is O or S; Z is N or CH when Y is O and Z is CH when Y is S, or a pharmaceutically acceptable salt of the same

Description

- < - NEW AZOLIDINDIONS AS ANTI-GLYCEMIC AGENTS FIELD OF THE INVENTION This invention relates to novel azolidins of the subsequent Formula I, which have demonstrated oral antihyperglycemic activity in diabetic db / db and ob / ob mice, animal models of non-insulin-dependent diabetes mellitus (NIDDM or diabetes or Type 10). II). Therefore, the compounds of Formula I or pharmaceutical compositions thereof are useful in the treatment of hyperglyceraia in mammals having diabetes mellitus not dependent on insulin.

BACKGROUND OF THE INVENTION Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urine output and elevated glucose levels. in the blood. There are two main subclasses of diabetes mellitus. One is insulin-dependent diabetes mellitus (IDDM or Type I), formerly referred to as early onset diabetes since it was evident in the first years of life, and non-insulin-dependent diabetes mellitus (NIDDM REF: 23448; • / or Type II), frequently referred to as diabetes at the onset of maturity. Exogenous insulin is used clinically by injection to control diabetes, but it suffers from several drawbacks. The Insulin is a protein and in this way it can not be taken orally, due to digestion and degradation, but it must be injected. It is not always possible to achieve good control of blood sugar levels by administering insulin. Sometimes, Insulin resistance occurs requiring much higher doses of insulin than normal. Another deficiency of insulin is that while this can control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, or cardiovascular disorders. Orally effective anti-perglycemic agents are used to reduce blood glucose levels and reduce damage to the nervous systems, retinal, renal or vascular through mechanisms that affect the metabolism of glucose. Such agents act in a variety of different mechanisms including the inhibition of fatty acid oxidation, the inhibition of alpha-glycosidase, the antagonism of alpha ^ -25 receptors and the inhibition of gluconeogenesis. Two classes of compounds have predominated: the biguanides as represented by phenformin and the sulfonylureas as represented by tolbutamide (Orinase). A third class of compounds, which has shown antihyperglycemic activity are the thiazolidinediones of which the ciglitazone is the prototype. Ciglitazone suppresses the symptoms of diabetes - hyperglycemia, hypertriglyceridemia, and hyperinsulinemia [Diabetes 32, 804-10 (1983)].

Still another class of antihyperglycemic agents are the N-arylalkyl-N-hydroxy ureas and the 2- (arylalkyl) - [1,4,4] oxadiazolidine-3,5-diones. The published PCT patent application WO 92/034-25 describes compounds of the formula: - TO - wherein R 1 and R 2 are independently H, alkyl 1 to 9 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, etc. or R 1 and R 2 together are carbonyl, which have utility as hypoglycemic or hypocholesteremic agents. The hypoglycemic properties of these compounds in ob / ob mice are discussed by Goldstein et al. J. Med. Chem. 36, 2238-22? 0 (1993).

BRIEF DESCRIPTION OF THE INVENTION The novel compounds useful in the treatment of hyperglycemia are represented by the following formula: wherein: R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, thienyl, furyl, pyridyl, wherein R 10 is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; R 2 is hydrogen or alkyl of 1 to 6 carbon atoms; X is 0 or S n is 1 or 2 where R is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; where R is hydrogen, alkyl of 1 to 6 carbon atoms, allyl, aryl of 6 to 10 carbon atoms, aryl of 6 to 10 carbon atoms- (CH) -i? -, fluorine, chlorine, bromine, iodine, trimethyl-J- '10 silyl or cycloalkyl of 3 to 8 carbon atoms; R is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms or aryl of 6 to 10 carbon atoms- (CH?) -. , -, 'm is 0, 1 or 2; R is hydrogen or alkyl of 1 to 6 carbon atoms; n R is hydrogen or alkyl of 1 to 6 carbon atoms; R 8 and R 9 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine or iodine; 25? is 0 or S; ~ * ~ Z is N or CH when Y is 0 and Z is CH when Y is S; or a pharmaceutically acceptable salt thereof. The term alkyl of 1 to 6 carbon atoms means an alkyl group consisting of one to six carbon atoms, which may be a straight or branched chain. The term "C 1 -C 6 alkoxy" means an O-alkyl group of 1 to 6 carbon atoms where the group of 1 to 6 carbon atoms is as defined above. The term aryl of 6 to 10 carbon atoms means phenyl, 1-naphthyl or 2-naphthyl and may be optionally substituted by one to three substituents as listed above according to commercial availability or synthetic means. The term "trifluoroalkyl" means a group _ having the formula CFO- (CH2) Q_2- and the term "trifluoroalkoxy" is an O-trifluoroalkyl group where trifluoroalkyl is as defined above. The compounds of Formula I can be transformed into, or isolated as, pharmaceutically acceptable salts of alkali metals or alkaline earth metals, such as a sodium, potassium, lithium or calcium salt. It will also be recognized by those skilled in the art that the active compound or salt thereof can be isolated as a solvate or hydrate, which is considered to have the pharmacological properties of the active compound. Preferred compounds are those of the Formula below the wherein: R is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; n is 1 or 2; B «j í '6 where is 0, 1 or 2; R, R, R and R are independently hydrogen or alkyl of 1 to 6 carbon atoms; And it is 0 or S; 5 Z is N or CH when Y is 0 and Z is CH when Y is S; or a pharmaceutically acceptable salt thereof. The most preferred compounds of this invention are those of Formula Ib Ib wherein: R10 is hydrogen, CF3 ~, CF-0-, CF3CH20- or CI-; 20 n is 1 or 2; where m is 0 or 1; I tZ. rj T, R, R and R are independently hydrogen, methyl or ethyl; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when And it's S; or a pharmaceutically acceptable salt thereof. The most preferred compounds of the invention are the following: (E) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-enyl) - [1, 2.4 -Joxadiazolidin-3, 5-dione, (Z) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-enyl) - [1, 2, 4 ] oxadiazolidin-3, 5-dione, 2- (3- [3-C5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethyl] -phenyl] -but-2-enyl) - [1,4] oxadiazolidin-3, 5-dione, (E) -2- (3- [3- [5-Methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1,, 4 ] oxadiazolidin-3, -dione, (E) -2- (3- [3- [5-methyl-2- (4-trifluoro-ethoxy-f-enyl) -oxazol-4-ylmethoxy] -phenyl] -but -2-enyl) - [1,2,4-oxadiazolidin-3,5-dione, (E) -2- [3- [3- (5-ethyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl] -but-2-enyl] - [1, 2, 4] oxadiazolidin-3 , 5-dione, (Z) -2- [3- [3- (-methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] - , "~ but-2-enyl] - [1, 2, 4] oxadiazolidin-3, 5-dione, 10 (E) -2- [3- [3- [2- (5-methyl-2-phenyl- oxazole-4-H) -ethoxy] -phenyl] -but-2-enyl) - [1, 2, 4-] oxadiazolidin-3, 5-dione, 2- [3- [3- (5-methyl-2-f-enyl-oxazol-4-ylmethoxy] -benzofuran-15-yl] -but-2-enyl] - [1,4] oxadiazolidin- 3, 5-dione, (E) -2- (2-methyl-3- [4 - [5-methyl-2- (4-trifluoromethyl-f-enyl) -oxazol-4-yl-p-ethoxy] -phenyl] -alyl) - [1, 2, 4] oxadiazolidin-3,5-dione, 20 (E) -2- (2-ethyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole- 4-ylmethoxy] -phenyl] -alyl) - [1,2-, 4-ioxadiazolidin-3, 5-dione, ^ (E) -2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -alyl) - [1,4,2] oxadiazolidin-3,5-dione, (E) -2- (3- [3- [2- (4-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -phenyl] -1-methyl-allyl) - [1 , 2,4] oxadiazolidin-3,5-dione, (E) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1 , 2,4-oxadiazolyl-O-din-3,5-dione.

(Z) -2- (2-methyl-3- [3- [5-methyl-2- (-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1, 2,4] oxadiazolidin-3, 5-dione, 15 (E) -2- (1-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole-4 -ylmethoxy] -phenyl] -but-2-enyl) - [1,4-oxadiazolidin-3, 5-dione, 2- [3- (4- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -allyl) - [1,4,4-oxadiazolidin-3, 5-dione, (E) -2- (2- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -cyclopropylmethyl) - [1,4] oxadiazolidin-25 3,5-dione, (E) -2- (2-methyl-2- (3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl) -cyclopropylmethyl) - [1, 2,.] Or a-diazolidin-3, 5-dione, (E, E) -2- [5- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] -hexa-2,4-dienyl) - [1,2,4] oxadiazolidin -3, -diona, (Z, E) -2- [5- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] -hexa-2,4-dienyl) - [1,2,4] oxadiazolidin -3, 5-dione, 2- [3- (4- [2- [5-methyl-2- (-trifluoromethyl-phenyl-oxazol-4-yl] -ethoxy] -phenyl) -propyl-2-ynyl) - [1, 2, 4-] oxadiazolidin-3,5-dione, 2- [1-methyl-3- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl] -propyl-2-ynyl- [1,4] oxadiazolidin-3, 5 -Diona, (E) -5- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethyl] -phenyl] -but-2-enyl] -oxazolidin-2,4-dione, (E) -5- [3- (3- [5-Methyl-2- [4- (2,2,2-trifluoro-ethoxy) -phenyl] -oxazole-4-methoxy] -phenyl) -but- 2-enyl] -oxazolidin-2,4-dione, -u - (E) -5- (3- [3- [5-methyl-2- (trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl ] -but-2-enyl) -oxazolidin-2,4-dione, (E) -5- (3- [3- [2- (5-Methyl-2-phenyl) -oxazol-4-yl) -ethoxy] -phenyl] -but-2-enyl) -oxazolidin-2, 4 --Diona, (E) -5- [3- [3- (5-Methyl-2-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) -thiazolidin-2,4-dione, and (E) -5- (3- [3- [5-Methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) -thiazolidin-2, 4 - Diona.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the invention of the Formula I can be prepared from intermediates of formula II below, wherein the variables n, R 1, R 2, X, A and B are as previously defined.

II The oxadiazolidinediones of Formula I are prepared from an intermediate of Formula II by first converting to a hydroxylamine followed by reaction with N- (chlorocarbonyl) isocyanate or by converting the alcohol of Formula II to an N-hydroxyurea, which is reacted with methyl chloroformate to give an oxadiazolidinedione of Formula I. The oxazolidinediones and thiazolidinediones of Formula I are prepared by converting the intermediate of Formula II to the halide of Formula III below, followed by the reaction with 2. , 4-oxazolidinedione or 2,4-thiazolidinedione.

C! III These synthetic transformations are described more fully in the following reaction schemes I-XII.

Scheme I summarizes the synthesis of an intermediate of the Formula II where A is phenyl and B is an olefinic linking group as shown below in Formula I.

Scheme I The terms R 1 -R5, X, n and m are as previously defined. Scheme II illustrates the synthetic sequence for preparing a compound of Formula I of intermediate VIII.

Scheme II The terms R 1 -R5, X, n and are as 2Q define previously. When R '* is halogen, the compounds of the present invention can be prepared according to Scheme III.

Scheme III wherein R 1, R 2, R 3, X and n are as defined above; R ^ is halogen. When R is alkyl, the compounds of the present invention can be prepared according to Scheme IV.

Scheme III 1 _J "3 / £ - where R, R, R, R, R, X, n and m are as defined above Scheme V summarizes the synthesis of an intermediate where B is cyclopropylmethyl of an intermediate of the Formula VIII where m is 0. f- Scheme V wherein R 1, R 2, R 3, X and n are as defined above; R is hydrogen, alkyl, aryl, aralkyl, cycloalkyl. Scheme VI summarizes the synthesis of an intermediate of Formula II where B is propynyl.

Scheme VI • 1 9 ^ where R, R, R, R, X and n are as defined above. Scheme VII summarizes the reactions used to prepare the compounds of Formula I, wherein Z is CH and Y is 0 or S from an intermediate of Formula VIII.

Scheme VII "1 Q C" wherein R, R, R, R, R, X, n and m are as defined above: R is hydrogen, alkyl, allyl, aryl, aralkyl, trimethylsilyl, cycloalkyl; 0 or S. The preparation of a compound of the Formula Wherein A is benzofuran-2, 5-diyl, Y is 0 and Z is N, is shown in Scheme VIII.

Scheme VIII-1, - f wherein R 1, R 2, R 5, x and m are as defined above; R is hydrogen, alkyl, allyl, aryl, aralkyl, trimethylsilyl, cycloalkyl. The initial heterocyclic intermediates 5 of Formula V can be prepared according to normal literary procedures. For example, the 2- 4- (1'-hydroxyethyl) -5-R-2-phenyloxazoles and triazoles where R 2 is hydrogen or alkyl of 1 to 6 carbon atoms, can be prepared according to Scheme IX (European patent EP 0177353A2).

Scheme IX r * ~ The initial heterocyclic intermediates of formula IV can be prepared by methods known conventionally in the art (Heterocyclic Compounds - »1979 and Heterocyclic Compounds 45, 1986). The 2-phenyl-4-chloromethyl-5-methyl-oxazoles can be prepared according to the reaction sequence shown in Scheme X.

Scheme X The intermediate 4-chloromethyl-2-phenyloxazoles or thiazoles can be prepared according to the reaction shown in Scheme XI.

Scheme XI X = Oo S The intermediate of formula VII can be prepared from either the commercially available phenols of formula IX or according to Synthetic Scheme XII.

Scheme XII The following examples are included for illustrative purposes and are not intended to limit the description of this invention in any way. The reagents, intermediates or chemicals used are either commercially available or can be easily synthesized using standard laboratory procedures known to those skilled in the art.

Use 1 / - 10 (E) -2- (3- [3- [5-methyl-2- (-trif luoromethyl-f-enyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-enyl) - [1 , 2, 4- J oxadiazolidin- 3. -dione Step a) 3- [5-methyl-2 - (- 4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy) benzaldehyde ^? .- A mixture of 4-chloromethyl-5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole (5.25 g, 19.1 mmol), 3-hydroxybenzaldehyde (2.33 g, 19.1) was stirred at 80 ° C. mmol), potassium carbonate (3.77 g, 27.3 mmol) and dimethylformamide (50 mL), for 3 hours. The mixture was then poured into H ?0, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO,. The evaporation and crystallization of Ethyl ether / hexane gave a yellow solid (4.47 g, 65% yield, m.p., 104-105 ° C). Analysis for: C. qH-, .F-NO.-, Calculated: C, 63.16; H, 3.91; N, 3.88 Found: C, 62.84; H, 3-97; N, 3.87 Step b) 1 - [3- [5-Methyl-2- (-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -propan-1 -one Ethylmagnesium bromide (11.1 mL, 33.24 mmol) was added dropwise in a cold (0 ° C) solution of 3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy) - benzaldehyde (12.0 g, 33.24 mmol) and THF (50 mL). After stirring for 30 minutes, the reaction mixture was rapidly cooled with aqueous NH.C1, emptied into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation gave a yellowish oil (13.0 g), which was dissolved in acetone (200 mL). The mixture was cooled to 5 ° C and freshly prepared Jones Reagent (40 mL) was added dropwise. After the addition, the mixture was stirred for 30 minutes, poured into water and extracted with EtOAc. The organic extracts were dried over MgSO,. Evaporation and crystallization from ethyl ether / hexane (after cooling to 0 ° C) gave a white solid (9.6 g, 74% yield, mp 73-74 ° C). Analysis for: Calculated: C, 64.-78; H, 4-.66; N, 3.60 Found: C, 64.63; H, 4.60; N, 3.91 Step c) Ethyl ester of (E) -3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazoyl-4-ylmethoxy-3-phenyl] -pent-2-enoic acid ester Triethylphosphonoacetate was added dropwise (8.67 ml, 4-3.1 mmol) to a cold (0 ° C) suspension of sodium hydride (1.24 g, 41.5 mmol) and toluene (200 ml). After the addition, the mixture was stirred for 1 hour, and then 1 - [3- [5-methyl-2- (4-trifluoromethyl-1-phenyl) -oxazol-1-methoxy] -phenyl] -propan was added dropwise. -1-one (8.5 g, 21.85 mmol) in THF (20 ml). The reaction mixture was stirred at room temperature for 24 hours, emptied into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 8/1) gave the trans isomer (white solid, 5. 5 g, yield 55, mp 85-86 ° C) and the isomer cis (light oil, 2.8 g, 28% yield). a) Analysis for: (trans isomer) Calculated: C, 65.35; H, 5.27; N, 3.05 Found: C, 65.25; H, 5.4-2; N, 3.01 b) Analysis for: (cis isomer) Calculated: C, 65.35; H, 5.27; N, 3.05 Found: C, 65.11; H, 5.31; N, 3.00 Step d) (E) -3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) - '' 'oxazol-4-ylmethoxy] -phenyl] -pent-2-en-1 -ol Aluminum diisobutyl hydride (1.0M in THF, 25.05 ml, 25.05 mmol) was added dropwise to a cold (-50 ° C) solution of ethyl ester of (E) -3- [3- [5- methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-enoic acid (4-6 g, 10 mmol) in THF (100 mL) and ethyl ether (100 mL) . The reaction was warmed to 0 ° C and stirred for 1 hour. The reaction mixture was quenched with acetone (dropwise addition), methanol, emptied into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 3/1) gave a clear oil (3.8 g, yield 91). Analysis for: Cp HppF NO., Calculated: C, 66.18. H, 5.31; N, 3.36 Found: C, 65.88; H, 5-41; N, 3.26 Step e) Ter-butyl ester of (E) -N-tert-butoxy-carbonyloxy- (3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] phenyl] -pent-2-enyl) -carbamic Diisopropylazodicarboxylate (1.98 ml, 10.07 mmol) in THF (15 ml) was added dropwise to a cold (-20 ° C) solution of (E) -3- [3- [5-methyl-2-trifluo -methyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-en-1-ol (3.5 g, 8.39 mmol) in THF (30 ml), triphenylphosphine (2.64- g, 10.07 mmol) and N - tert-Butyl (tert-butoxy-carbonyloxy) carbamate (2.35 g, 10.07 mmol). After the addition, the mixture was stirred for 1 hour, poured into water, and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 7/1) gave a clear oil (5.1 g, 96% yield). Analysis for: C ^ oH nFo ^ O, -, x 0.5 H20 Calculated: C, 61.77; H, 6.24; N, 4.37 Found: C, 61.58; H, 6.4.6; N, 4.60 / * - Step f) (E) -N- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent- 2-enyl) -hydroxylamine A mixture of (E) -N-tert-butoxycarbonyloxy-3- (3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) - tert-butyl ester) was stirred at room temperature. oxazol-4-ylmethoxy] -phenyl] -pentyl-2-enyl) -carbamic acid (5.0 g, 7.9 mmol), CH2C12 (100 mL), and trifluoroacetic acid (10 ml), for 8 hours. The volatiles were removed in vacuo, and the residue taken in ethyl ether / water. This was basified to pH = 9-10 with NaOH (2N), and the organic layer was separated and washed with water and brine. The organic extracts were dried over MgSO,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 1/1, and MeOH / EtOAc 1/10), gave a clear oil (3-0 g, 88% yield) . Analysis for: Cp HpoF N O.-, 20 Calculated: C, 63.88; H, 5-36; N, 6.48 Found: C, 63.63; H, 5.27; N, 6.8 Step g) (E) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-enyl) - [1, 2,4] oxa-25 diazolidin-3, 5-dione ri "t" N- (chlorocarbonyl) isocyanate (0.37 ml, 0.63 mmol) was added dropwise to a cold mixture (-5 ° C). C) of (E) -N- (3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxa-zol-4-ylmethoxy] -phenyl] -pent-2-enyl) - hydroxylamine (2.0 g, 4.63 mmol) in THF (20 ml). The mixture was stirred for 30 minutes, then it was emptied into HCl (1H) and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by »- chromatography with flash evaporation in gel silica (H ^ PO, 3% / MeOH) washed with acid gave a white solid (1.48 g, yield 64.%, mp 66-67 ° C), Analysis for: C eH ^ pF-N- .OR,. Calculated: C, 59.88; H, 4.4-2; N, 8.38 15 Found: C, 59.83; H, 4-.37; N, 8.28 Example 2 (E) -2- (3- [3- [5-methyl-2- (-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-pent-2-enyl) - [1, 2, 4 -] oxadiazolidin-3, 5-dione Step a) (Z) -3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-en-1-ol- '* Aluminum diisobutyl hydride (1.0M in THF, 10.89 ml, 10.89 mmol) was added dropwise to a cold solution (-50 ° C) of ethyl ester of acid.

(Z) -3- [3- [5-Methyl-2- (-trifluoromethyl-phenyl) -oxazol-5-4-ylmethoxy] -phenyl] -pent-2-enoic (2.0 g, 4-.5 mmol) in THF (30 ml) and ethyl ether (30 ml). The reaction was warmed to 0 ° C and stirred for 1 hour. The reaction mixture was rapidly cooled with acetone (addition . drop by drop), methanol, was poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 3/1) gave a white solid (1.65 g, 91% yield, m.p. 88-89 ° C). Analysis for: C o H F NO- Calculated: C, 66.18 H, 5.31; N, 3.36 Found: C, 65.85; H, 5.12; N, 3.15 Step b) (z) -N- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phene-1) -oxazol-4-ylmethoxy] -phenyl] -pent-2-enyl ) -hydroxylamine Diisopropylazodicarboxylate (0.68 ml, 3-45 mmol) in THF (10 ml) was added dropwise to a cold (-20 ° C) solution of (Z) -3- [3- [5-methyl-2 - (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -pent-2-en-1-ol (1.2 g, 2.87 mmol), THF (20 ml), triphenylphosphine (0.9 g, 3 -4-5 mmoles) and N- (tert-butoxy-carbonyloxy) tert-butyl carbamate (0.8 g, 3.45 mmol). After addition, the mixture was stirred for 1 hour, poured into water, and extracted with EtOAc. Evaporation gave a yellowish oil (1.7 g), which was dissolved in CH Cl (30 mL), and treated with trifluoroacetic acid ", (3.0 mL). After stirring at room temperature for 8 hours, the volatiles were removed in vacuo, and the residue was taken up in ethyl ether / water. This was basified to pH = 9-10 with NaOH (2N), and the organic layer was separated and washed with water and with brine. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc -y, / 1> and MeOH / EtOAc 1/10) gave a white solid (3.0 g, 82% yield). , mp 72-73 ° C). Analysis for C H F N O, 20 Calculated: C, 63.88; H, 5-36; N, 6.48 Found: C, 63.74; H, 5.34; N, 6.26 Step c) (Z) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phe-ni1) -oxa-ol-4-ylmethoxy] -phenyl] -pent-phenyl ) - [, 2,4] oxa-diazolidin-3, 5-dione N- (chlorocarbonyl) isocyanate (0.12 ml, 1.5 mmol) was added dropwise to a cold mixture (-5 ° C) of (Z) -N- (3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxa-zol-4-ylmethoxy] -phenyl] -pent-2-enyl) -hydroxylamine (0.65 g, 1.5 mmol) in THF (10 mL). The mixture was stirred for 30 minutes, then it was emptied into HCl (1H) and extracted with EtOAc. The organic extracts were dried over MgSO,. Evaporation and purification by flash chromatography on silica gel (H, P0, 3% / MeOH) washed with acid gave a white solid (0.48 g, 64% yield, mp 126-127 ° C) . Analysis for: OprHppF Calculated N-Or: C, 59.88; H, 4-42; N, 8.38 Found: C, 60.03; H, 4-55; N, 8.03 Example 3 (E) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethyl] -phenyl] -but-2-enyl) - [1, 2, 4 ] oxadiazolidin-3 > 5-dione Step a) 4,5-Dimethyl-2- (4-trifluoromethyl-phenyl) -oxazole N-oxide hydrochloride HCl gas (21.2 g, 58.1 mmol) was bubbled through a syringe in a 0 ° C solution of 4-trifluoromethylbenzaldehyde (50 g, 28.7 mmol), 2,3-butanedione monoxime (26.40 g, 26.1 mmol), and EtOAc (105 mL). The reaction mixture was stirred at 5 ° C for 3 hours. Then ice-cooled ether (575 ml) was added, and the resulting precipitate was filtered, washed with ether and dried at 25 ° C for 16 hours to give the product as a white solid (54-79 g> yield of 71%, mp 149-159 ° C Analysis for: C, ^ -jCIF-NO, -, Calculated: C, 49-08; H, 3.77; N, 4-77 Found: C, 49.48; H, 3.81; N, 4.88 Step b) 4-Chloromethyl-5-methyl-2- (4-trifluoromethyl-phe nyl) -oxazole It was added to a solution at 5 ° C of 4,5-dimethyl-2- (4-trifluoromethyl-phenyl) -oxazole N-oxide hydroxide (113.71 g, 387.5 mmol) in CHCl 2 (560 ml), oxychloride phosphorus (39.4 ml, 422.4 mmol) in CHC1--, drop by drop for 15 minutes. The reaction was refluxed for 2.5 hours, then cooled to 5 ° C, emptied into ice water, and basified with NaOH (1N). The organic layer was dried over MgSO ,. Evaporation and recrystallization from ether / hexane gave a yellow solid (30.0 g, yield 28%, m.p. 84-85 ° C). Analysis for: C- | gHnOlFoNO Calculated: C, 52.59; H, 3.29; N, 5.08 Found: C, 52.54; H, 3.20; N, 4.92 Step c) 1- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxa-zol-4-ylmethoxy] -phenyl] -ethanone A mixture of 4-chloromethyl-5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole (24.3 g, 88.2 mmol), 3-hydroxyacetophenone (10.0 g, 73-5 mmol) and carbonate was stirred at 70 ° C. of potassium (13.2 g, 95.6 mmol) for 16 hours. The reaction was evacuated in water, acidified with HCl (1N) and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 9/1) gave an off white solid (20.14 g, 60% yield, mp 90-91 ° C). Analysis for: 020 ^ 16 3 ^ 3"" Calculated: C, 63.99; H, 4-29; N, 3.73 Found: C, 63.86; H, 4-30; N, 3.64 Step d) Ethyl ester of (E) -3- [3- [5-methyl-2-5 (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enoic acid ester To a mixture at 0 ° C of sodium hydride (4 «27 g, 142.6 mmol) and toluene (500 ml), or trifluorophosphonoacetate (29.70 ml, 150.1 mmol) was added via syringe. The reaction was stirred for 1 hour, and then 1- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -ethanone (28.15 g, 75.1 mmole) in THF (150 ml). The reaction mixture was stirred at room temperature for 16 h, emptied in water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 20/1) gave a white solid (24-42 g, 73% yield, mp 91-92 ° C). Analysis for: p / Hp F-NO, Calculated: C, 64-57; H, 5-19; N, 3-U Found: C, 64-81; H, 5-01; N, 3-13 Step e) (E) -3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-en-1- ol Aluminum di-isobutyl hydride (1.0M in THF) (219.2 ml, 219.2 mmol) was added via syringe to a solution at -25 ° C of ethyl 3- [3- [5-methyl-2-ethyl ester. - (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl) -but-2-enoic (24-42 g, 54-8 mmol) in THF (300 mL). The reaction was heated to 0 ° C and stirred for 1.5 hours. This was poured into ice water, acidified with HCl (2N), stirred for 45 minutes, then extracted with EtOAc. The organic extracts were dried over MgSO,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 3/1) gave a light yellow solid (17.68 g, 82% yield, mp 145-146 ° C). Analysis for: Calculated: C, 65.83; H, 4-52; N, 3-49 Found: C, 65.78; H, 4.53; N, 3-45 Step f) Ter-Butyl Ester of (E) -N-tert-butoxy-carbonyloxy-3- (3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) -carbamic It was added to a solution at -20 ° C of 3-3-> 5- • * "methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-en-1 -ol (3.1 g, 7.69 mmol) in THF (50 ml), triphenylphosphine (2.42 g, 9.23 mmol) and N- (tert-butoxy-carbonyloxy) tert-butyl carbamate (2.15 g, 9.23 mmoles). Then diethylazodicarboxylate (1.45 ml, 9.23 mmol) in THF (10 ml) was added via syringe, and the reaction was stirred for 1 hour at 0 ° C. The reaction was poured into water and extracted with EtOAc. The organic extracts were dried over MgSO ,. The IO evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 6/1) gave a light yellow oil (4 * 69 g, 98% yield). Analysis for: CopH yF.-jNpOr, 15 Calculated: C, 62.13; H, 6.03; N, 4-53 Found: C, 62.17; H, 6.12; N, 4.67 Step g) (E) -N- (3- [3- [5-methyl-2- (4-trifluoromethyl-phene-1) -oxazol-4-ylmethoxy] phenyl] -but-2-enyl) -hydroxylamine Trifluoroacetic acid (20 ml) was added to a solution of (E) -N-tert-butyl-butoxycarbonyloxy-3-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -butyl ester) -oxazo1-4-ylmethoxy] -phenyl] -but-2-enyl) -carbamic acid (4.5 g, 7.28 mmol) and CH ^ Cl (40 ml). The reaction mixture was stirred at room temperature for 8 hours. The volatiles were removed in vacuo, and the residue was taken up in ether / water. This was basified to pH = 9-10 with NaOH (2N), and the organic layer was separated and washed with water and brine. The organic layer was dried over MgSO,. Evaporation and purification by flash chromatography on silica gel (1/1 hexane / EtOAc and 1/10 MeOH / EtOAc) gave a clear oil (2.70 g, 88% yield). Analysis for: Calculated: C, 63.15; H, 5.06; N, 6.70 Found: C, 63-34; H, 4-79; N, 6.53 Step h) (E) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phe nyl) -oxazol-4-ylmethyl] -phenyl] -but-2-enyl) - [ 1, 2,4] oxadi-azolidin-3, 5-dione N- (chlorocarbonyl) isocyanate (0.548 ml, 6.22 mmol) was added dropwise to a mixture at -5 ° C and N- (3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) ) -oxazol-4-ylmethoxy] -phenyl] -but-enyl) -hydroxylamine (2.6 g, 6.22 mmol) in THF (25 ml). The mixture was stirred for 30 minutes, then emptied into HCl (IN) and extracted with EtOAc. The organic extracts were then dried over MgSO,. Evaporation and purification by the 4 < * '- flash chromatography on silica gel (H-PO, 5% / MeOH) washed with acid (Hexane / EtOAc 3/1), gave a white solid (1.85 g, 61% yield, mp 136-75). 138 ° C). 5 Analysis for: C2 and Hp-.F .-. N .-. Oj- Calculated: C, 59-U; H, 4-13; N, 8.62 Found: C, 58.95; H, 3-92; N, 8.77 Example 4 -O (E) -2- (3- [3- [5-methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1 , 2,4] oxadiazolidin-3, -dione 1 The title compound was prepared in substantially the same manner as described in Example 3, and was obtained as a white solid, m.p. 145- 146 ° C. Analysis for: 20 Calculated: C, 57.26; H, 4-00; N, 8.35 Found: C, 57.26; H, 3-94; N, 8.22 Example 5 (E) -2- (3- [3- [5-Methyl-2- [4- (2,2,2-trifluoro-ethoxy) -phenyl] -25-oxazol-4-ylmethoxy] -pheni!] - but -2-enyl] - [, 2, 4] oxadiazo-lidin-3,5-dione The title compound was prepared substantially in the same manner as described in Example 3, and was obtained as a white solid, m.p. 145-146 ° C. Analysis for: C2-rH22F ~ 0 ¿Calculated: C, 58.03; H, 4.29; N, 8.12 Found: C, 58.05; H, 3.28; N, 8.30 Example 6 (E) -2- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl] -but-2-enyl) - [1,4,4] oxadiazolidin-3, 5 -diona The title compound was prepared in substantially the same manner as described in Example 3, and was obtained as a white solid, m.p. 131-132 ° C. Analysis for: Calculated: C, 65.86; H, 5.05; N, 10.02 Found: C, 65.89; H, 5.10; N, 9.87 Example 7 (Z) -2- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] -but-2-enyl] - [1,4] oxadiazolidin-3, 5 -dione The title compound was prepared in substantially the same manner as described in Example 3, and was obtained as a white solid, mp 118-119 ° C. Analysis for: Calculated: C, 65.86; H, 5.05; N , 10.02 Found: C, 65.83; H, 5.18; N, 9.97 Example 8 (E) -2- (3- [3- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl] -but-2-enyl) - [1,2,4-Oxadiazolidin] -3, 5-dione The title compound was prepared in substantially the same manner as described in Example 2. 1- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -fe-nil ] -ethanone required was prepared according to the following procedure. The title compound was obtained as a white solid, m.p. 142-143 ° C. Analysis for: 2, H2 N 0? Calculated: C, 66.50; H, 5.35; N, 9.69 Found: C, 66.18; H, 5-41; N, 9-48 Preparation of 1- [4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl] -ethanone * "" 'Diethyl azodicarboxylate was added dropwise (20.7 mL, 131.6 mmol) in THF (35 mL) in a cold (0 ° C) solution of 4- ('-hydroxy-ethyl) -5-methyl-2-phenyloxazole (25.0 g, 123.0 mmol), triphenylphosphine (34.5 g, 131.6 moles), and 3 '-hydroxyacetophenone (18.0 g, 131.6 mmol) and THF (180 mL). The mixture was allowed to come to room temperature and was stirred for 48 hours. Then, it was emptied in H O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO 2. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 5/1) gave a white solid (30.5 g, 77% yield, mp 70-71 ° C). Analysis for: C2QH-.QNO-3 15 Calculated: C, 74-75; H, 5.96; N, 4-36 Found: C, 74-70; H, 6.15; N, 4.28 Example 9 (E) -2- [3- [2- (5-Methyl-2-phenyl-oxazol-4-ylmethyl] -benzofur-5-yl] -but-2-enyl] - [1, 2, 4] oxa-iazolidin-3, 5-dione Step a) 1 - [2- (5-Methyl-2-phenyl-oxazol-4-ylmethyl) -benz0-furan-5-yl] -ethanol Methyl magnesium chloride (4.2 ml, 12.62 mmol) was added to a cold solution (0 ° C) 2- (5-methyl-2-phenyl-oxazol-4-yl ethyl) -benzofuran-5-carbaldehyde (prepared according to EP 0 428 312 A2, 4-0 g, 12.62 mmol) and THF (20 ml). The reaction was stirred at 0 ° C for 20 minutes, and at room temperature for 30 minutes, then it was poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 2/1) gave a yellow solid (3.75 g, 88% yield, mp 103-105 ° C). Analysis for: C2-.H-.gNO.-. Calculated: C, 75.66; H, 5.74; N, 4.20 Found: C, 75.35; H, 5.80; N, 4.11 Step b) 1- [2- (5-methyl-2-phenyl) -oxazol-4-ylmethyl) -benzo-furan-5-yl] -β-tannone A reagent was added dropwise.

Jones freshly prepared (6.5 mL, 10.51 mmol) to a cold (10 ° C) solution of 1- [2- (5-methyl-2-phenyl-oxazol-4-ylmethyl) -benzofuran-5-yl] -ethanol ( 3.5 g, 10.51 mmol) and acetone (50 ml). After 30 minutes, the mixture was emptied in water, and extracted with ethyl ether / EtOAc: r'r ": 1/1. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography. on silica gel (hexane / EtOAc 2/1), gave a yellow solid (3.4 g, 5. yield 97, mp 108-109 ° C.) Analysis for: C -jH-, "NO-, Calculated: C , 76.12; H, 5.17; N, 4.23 Found: C, 76.38; N, 5.13; N, 4.09 Step c) Ethyl ester of (E) -3- [2- (5-methyl-2-phenyl-oxazol-4-ylmethyl) -benzofuran-5-yl] -but-2-enoic acid ester The title compound was prepared in substantially the same manner as described in Example 3, step d, and was obtained as a white solid, m.p. 81-83 ° C. Analysis for: ^ '25 ^ '^ L Calculated: C, 74.80; H, 5-77; N, 3-49 Found: C, 74-68; H, 5.75; N, 3-40 20 Step d) (E) -3- [2- (5-Methyl-2-phenyl-oxazol-4-ylmethyl) -benzofuran-5-yl] -but-2-en-ol The title compound was prepared substantially in the same manner as described in Example 3, step e, and was obtained as a white solid, m.p. 119-121 ° C. Analysis for: C oH -iNO-, Calculated: C, 76.86; H, 5.89; N, 3.90 Found: C, 76.71; H, 5.87; N, 3.77 Step e) (E) -1-hydroxy-1- (3- [2- (5-methyl-2-phenyl-oxazol-4-ylmethyl) -ben-ofuran-5-yl] -but-2-enyl) - urea Diethylazodicarboxylate was added dropwise (2.56 mL, 16.3 mmol) to a cold mixture (-20 ° C) of (E) -3- [2- (5-methyl-2-phenyl-oxazol-4-ylmethyl-benzofuran-5-yl] -but -2-en-1-ol (4.5 g, 12.5 mmol) triphenylphosphine (4.27 g, 16.3 mmol), N, 0-bis (carbophenoxy) hydroxylamine (4-45 g, 16.3 mmol) and THF (100 mL). After stirring for 30 minutes at -20 ° C, the mixture was allowed to reach 0 ° C and stirred for 2 hours, then it was drained in H ?O and extracted with EtOAc, the organic extracts were dried over MgSO 4. The evaporation gave a yellow oil (6.5), which was placed in a pressure vessel Anhydrous ammonia (20 mL) was condensed in a vessel The mixture was stirred at -5 ° G at -10 ° C during 3 hours and then at room temperature for 18 hours.The excess ammonia was allowed to escape in an acidic solution and the residue was recrystallized from ether / acetone, to give a white solid (2.5 g, 48% yield, mp 111 -113 ° C) Analysis for: C2, H2 -, N ~ 0. Calculated: C, 69-05; H, 5-55; N, 10.07 Found: C, 68.66; H, 5.36; N, 9.83 Step f) (E) -1-O-oxycarbonyloxy-1- (3- [2- (5-methyl-2-phenyl-oxazol-4-ylmethyl) -benzofuran-5-yl] -but-2-enyl) - urea Sodium hydride (0.3 g, 10.0 mmol) was added portion-wise to a cold (0 °) solution of (E) -1-hydro-xi-1 - (3- [2- (5-methyl-2-phenyl) -oxazol-4-yl ethyl) -benzofuran-5-yl] -but-2-enyl) urea (1.9 g, 4-55 mmol) and THF (20 mL). After stirring for 1 hour, methyl chloroformate (1.6 mL, 18.2 mmol) was added dropwise. The reaction mixture was stirred for 1 hour, was poured into a solution of dioxane (50 mL) / MaOH (2N, mL) and after 10 minutes it was acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 2/1) gave a yellow solid (1.72 g, 79% yield, m.p. 65-67 ° C). Analysis for 2) H2cN 0 ^) > r Calculated: C, 65.68; H, 5.30; N, 8.84 Found C, 65.94; H, 5.06; N, 8.83 Step g) (E) -2- [3- [2- (5-Methyl-2-phenyl-oxazol-4-ylmethyl] -5-benzofuran-5-yl] -but-2-enyl] - [1, 2] , 4] oxadiazolidin-3, 5-dione Sodium hydride (76 mg, 2.52 mmol) was added portion-wise to a cold (0 °) solution of E) -N-carba-10-moyl-N-methoxycarbonyloxy-3- [- (5-methyl-2-phenyl) -oxazol-4-ylmethyl) -benzofuran-5-yl] -but-2-enylamine (1.2 g, 2.52 mmol) and DMF (10 mL). The reaction mixture was stirred for 30 minutes and then emptied into water (10 mL), acidified with HCl (2N) and extracted with EtOAc.

The organic extracts were dried over MgSO ,. Evaporation and crystallization from ethyl ether gave a yellow solid (0.72 g, 65% yield, m.p. 163-165). Analysis for: 20 Calculated: C, 67.71; H, 4-77; N, 9.47 Found: C, 67.79; N, 4-56; N, 9-39 EXAMPLE 10 (E) -2- (2-methyl-3- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) - - ^ oxazol-4-ylmethoxy] -phenyl] -alyl) - [1, 2, 43-oxadiazolidin-3, 5-dione Step a) Ethyl ester of (E) -2-methyl-3- [3- [5- 5 methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl-ethoxy] -phenyl] -acrylic acid ester Triethyl 2-phosphonopropionate (2.64 ml, 11.08 mmol) was added dropwise to a suspension.

Cold (0 ° C) of sodium hydride (0.31 g, 10.52 mmol) and toluene (50 ml). After the addition, the mixture was stirred for 1 hour, and then 3- [5-methyl-2- (-4-trifluoromethylphenyl) -oxazol-4-ylmethoxy) -benzaldehyde (2.0 g, 5.54 g) was added dropwise. mmoles) in THF (10 ml). The The reaction mixture was stirred at room temperature for 24 hours, emptied into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts. dried over MgSO ,. Evaporation and purification by evaporation chromatography instant silica gel (hexane / EtOAc 8/1) gave a clear oil (2.2 g, 89% yield) - Analysis for: Calculated: C, 64-71; H, 4-98; N, 3-14 Found: C, 64-82; H, 4-99; N, 2-93 ^ Step b) (E) -2-methyl-3- [3- [5-methyl-2- (4-trifluoromethylphenyl) -oxazol-4-ylmethoxy] -phenyl] -prop-2-en -1-ol The title compound was prepared substantially in the same manner as described in Example 3, step e, and a white solid, m.p. 90-91 ° C Analysis for: Calculated: C, 65.50; H, 4-99; N, 3-47, * - 10 Found: C, 65-40 H, 5.12; N, 3.33 Step c) (E) -2-methyl-3- [3- [5-methyl-2- (4-trifluoromethylphenyl) -oxazol-4-ylmethoxy] -alyl) -hydroxylamine The title compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a yellow oil. J Analysis for: 0 & ? ^ ^ 2 ^ Calculated: C, 63.15; H, 5.06; N, 6.69. 20 Found: C, 62.82; H, 4-99; N, 6.64 Step d) (E) -2- (2-methyl-3- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -alyl) - [1, 2,4] oxadiazolidin-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 1, step h, and was obtained as a white solid, mp. 144-146 ° C. Analysis for: C2, H2 F-N-0Í. Calculated: C, 59.14; H, 4-13; N, 8.62 Found: C, 59.20; H, 3.95; N, 8.57 Example 11 (E) -2- (2-Ethyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -alyl) - [1, 2.4 ] oxadiazolidin-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 10, and was obtained as a white solid, m.p. 124-125 ° C. Analysis for: C2.rH22F N.5Or Calculated: C, 59.88; H, 4-42; N, 8-38 Found: C, 59-94; H, 4-40; N, 8-34 Example 12 2- (1-Methyl-3- (3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -allyl) - [1,2,4] oxadiazolidin-3 , 5-dione Step a) 3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -benzaldehyde The title compound was prepared in substantially the same manner as described in Example 1, step a, and was obtained as a yellow solid, m.p. 104-105 ° C Analysis for: C.QH. , F ~ N0, Calculated: C, 63.16; H, 3.91; N, 3.88 Found: C, 62.84; H, 3-97; N, 3-87 Step b) (E) -4- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-3-en-2-one A solution of sodium hydroxide (1.13 g, 28.25 mmol) in water (15 mL) was added to a mixture of 3- [5-methyl-2- (4-rifluoromethyl-phenyl) -oxazol-4-yl-methoxy] ] -benzaldehyde (6.0 g, 16.62 mmol) and acetone (100 mL). The reaction was stirred for 1 hour, and the excess acetone was removed in vacuo. The residue was acidified with HCl (1N), stirred for 10 minutes, then extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (EtOAc 4/1) gave a white solid (4.6 g, yield 69, p.f. 84-84 ° C). Analysis for: C22H-10F -. NO-3 Calculated: C, 65.83; H, 4.52; N, 3-49 Found: C, 65.74; H, 4.41; N, 3-52 Step c) (E) -4- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-3-en-2-ol Sodium borohydride (.389 g, 10.22 mmole) was added to a solution of -20 ° C of (E) -4- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-) ylmetoxy] -phenyl] -but-3-en-2-one (4-1 g, 10.22 mmol), cerium trichloride (3.81 g, 10.22 mmol), methanol (150 mL), and THF (30 mL). The reaction was stirred for 30 minutes, then it was poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 2/1) gave a white solid (3-7 g, 89% yield, mp 48-50 ° C). Analysis for: Calculated: C, 65.50; H, 4-99; N, 3-47 Found: C, 65.78; H, 5.07; N, 3-58 Step d) (E) -N- (1-Methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -alyl ) -hydroxylamine The title compound was prepared substantially in the same manner as described in Example 1, step b, and was obtained as a white solid, m.p. 118-120 ° C. Analysis for: F N20-, Calculated: C, 63.15; H, 5.06; N, 6.69 Found: C, 62.72; [E, 5.04; N, 6.59 Step e) 2- (1-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -alyl) - [1,2,4] oxadiazoli-din-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 2, step c, and was obtained as a white solid, m.p. 119-121 ° C. Analysis for: 2 / H2QF.2_N .-, 0, - Calculated: C, 59.14; H, 4-13; N, 8.62 Found: C, 59-00; H, 3-96; N, 8.82 Example 13 (E) -2- (3- [3- [2- (4-Chloro-phenyl) -5-methyl-oxazol-4-iimethoxy-3-phenyl] -1-methyl-allyl) - [1,2,4] oxadiazolidin -3, 5-dione The title compound was prepared substantially in the same manner as described in Example 12, and was obtained as a white solid, m.p. 172-174 ° C. Analysis for: C2 -. H2QCl .3O, - Calculated: C, 60.86; H, 4-44; N, 9.26 Found: C, 60.92; H, 4-39; N, 9.17 Example 14 (E) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -but-2-enyl) - [1, 2, 4] oxadiazoli-din-3, 5-dione Step a) Ethyl ester of (E) -2-methyl-3- (3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enoic acid ester , Ethyl (Z) -2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enoic acid ethyl ester The title compounds were prepared substantially in the same manner as described in Example 1, step c, and were obtained as white solids, (trans-) Analysis for: Calculated: C, 65.35; H, 5.26; N, 2.3.05 5 Found: C, 66.74; H, 5.39; N, 2.84 (cis-) Analysis for: 2-rH2, F-, N0, Calculated: C, 65.45; H, 5.26; N, 3.05 Found: C, 65.45; H, 5.29; N, 2.80 Step b) (E) -2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-en-1 -ol The title compound was prepared substantially in the same manner as described in Example 2, step a, and was obtained as a white solid, mp. 115-116 ° C. Analysis for: Calculated: C, 66.18; H, 5-31; N, 3.56, 20 Found: C, 66.04; H, 5.32; N. 3-49 Step c) (E) -N- (2-Methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-but-2-enyl) -hydroxylamine The title compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a white solid, mp. 115-116 ° C. Analysis for: Cj? ^ F ^ 0 1 H? 0 Calculated: C, 61.33; H, 5.55 N, 6.22 Found: C, 61.34 H, 5.57; N, 5.84 Step d) (E) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -but-2-enyl ) - [1, 2,43-oxadiazolidin-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 2, step c, and was obtained as a white solid, m.p. 152-153 ° C. Analysis for: C2CH22F Calculated N2OC: C, 59-88; H, 4-42; N, 8.38 Found: C, 59.79; H, 4-33; N, 8.16 Example 15 (Z) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -but-2-enyl) - [1 , 2,43-oxadiazoli-din-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 13, and was obtained as a white solid, mp. 144-145 ° C Analysis for: Calculated: C, 59.88; H, 4-42; N, 8.38 Found: C, 59.69; H, 4-45; N, 8.37 Example 16 (E) -2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl] - [1 2,43-oxadiazoli-din-3, 5-dione Step a) (E) -3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enaI It was added to a solution of (E) -3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-methoxy-3-phenyl] -but-2-en-1-ol ( 21.48 g, 53-3 mmol) in CH2C12 (500 mL), manganese dioxide (27.8 g, 319-8 mmol), and the reaction was stirred at room temperature for 60 hours. The mixture was filtered through a loose solka mass. Evaporation and purification by flash chromatography on silica gel r-V, (hexane / EtOAc 7/1), gave a light yellow solid (17.68 g, 82% yield, mp 145-146 ° C). Analysis for: O ^ H 8F-0- Calculated: C, 65.83; H, 4-52 N, 3-49 5 Found: C, 65-78; H, 4.53; N, 3.45 Step b) (E) -4- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy 3-phenyl-3-pent-3-en-2-ol Methyl magnesium bromide (3.0M in ether) (13-9 ml, 41-4 mmol) was added to a 0 ° C mixture of (E) -3- [3- [5-methyl-2- (4 -trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-but-2-enal (16.68 g, 41.6 mmol) in THF (200 mL). The reaction was stirred at 0-5 ° C for minutes, then it was poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 4/1) gave a solid yellow (5.85 g, yield 33, m.p. 45-47 ° C).

Analysis for: C23H22F O3 Calculated: C, 66.18 H, 5.31; N, 3-36 Found C, 65.97; H, 5.24; N, 3.34 J 'Step c) (E) -N- (1-Methyl-3- [3- [5-methyl-2- (4-tri-loromethyl-1-phenyl) -oxazol-4-yl-ethoxy] -phenyl] -but-2-enyl) - hydroxylamine The title compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a clear oil. Analysis for: 2 H2 F N2O3"Calculated: C, 63.88; H, 5.36; N, 6.48. 10 Found: C, 63-48; H, 5.33; N, 5.08 Step d) (E) -2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2- enyl3- [, 2,43-oxadiazolidin-3, 5-dione The title compound was prepared substantially in the same manner as described in Example 2, step c, and was obtained as a white solid (0.31 g. , yield 27%, mp 55-56 ° C) 20 Analysis for: C25H22F N-OC Calculated: C, 59.88; H, 4-42; N, 8.38 Found: C, 60.14; H, 4-49; N , 8.32 Using 17 (E) -2- (3- [4- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-allyl) - [1,2,4-oxadiazolidin-3, 5- diona Step a) Ethyl ester (E) -3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-acrylic) Triethylphosphonoacetate (4.38 ml, 22.06 mmoles) in a cold (0 ° C) suspension of sodium hydride (0.59 g, 19.74 mmol) and toluene (100 mL). After the addition, the mixture was stirred for 1 hour, and then 3- Í 5-methyl-2- (4-trifluororaethyl-phenyl) -oxazol-4-ylmethoxy) -ben-zaldehyde (5.7 g, 15.79 g) was added dropwise. mmoles) in THF (20 ml). The reaction mixture was stirred at room temperature for 1 hour, emptied into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 5/1) gave a white solid (6.3 g, yield 93%, m.p. 79-80 ° C). Analysis for: C2 H-jgF-N-0c Calculated: C, 64.03; H, 4-67; N, 3.25 Found: C, 64.25; H, 4-63; N, 3.16 Step b) (E) - [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -prop-2-en-1 -ol The title compound was prepared substantially in the same manner as described in Example 1, step d, and was obtained as a white solid, m.p. 117-118 ° C. Analysis for: C21H..gF3? 3 Calculated: C, 64.78; H, 4.66; N, 3.59 Found: C, 64.60; H, 4.54; N, 3.65 Step c) (E) -N- (3- [3- [5-methyl-2- (4-trifluoromethyl-phe nyl) -oxazol-4-ylmethoxy] phenyl-3-allyl) -hydroxylamine The title compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a white solid, m.p. 128-130 ° C. Analysis for: C2- »H .. gF-NgOo Calculated: C, 62.37; H, 4.73; N, 6.93 Found C, 62.17; H, 4-71; N, 6.79 Step d) (E) -2- (3- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-allyl) - [1, 2,4] ozadiazoli-din -3, 5-dione The title compound was prepared in substantially the same manner as described in Example 1, step g, and was obtained as a white solid, mp. 179-181 ° C. Analysis for: C2 H., 0F3N3OC Calculated: C, 58.35; H, 3.83; N, 8.88 Found: C, 58.47; H, 3.70; N, 8.86 Example 18 (E) -2- (2- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-J-phenyl] -cyclopropylmethyl) - [1,4,4-oxazolidin-3] , 5-dione (E) -2- (2- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-cyclopropylmethyl) - [1, 2, 43-oxadiazoli-din-3, 5 -diona Step a) (E) -2- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl-ethoxy] -phenyl] -cyclopropyl) -methanol Chloroiodomethane (3.37 mL, 46.28 mmol) was added dropwise to a cold (0 ° C) solution of diethyl zinc (23.14 mL, 23.14 mmol) and dichloroethane (40 mL). After stirring for 10 minutes, (E) - [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-prop-2-enyl) was added dropwise. l-ol (4.5 g, 11.57 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 1 hour, quenched with NH, aqueous Cl 4 and allowed to come to room temperature. After 15 minutes, it was poured into water and extracted with ethyl ether. The organic extracts were dried over MgSO,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 3/2) gave a clear oil (2.8 g, 80% yield). Analysis for: Calculated: C, 65.50; H, 5.00; N, 3.47 Found: C, 65-36; H, 5-12; N, 3-43 15 Step b) (E) -N- (2- [3- [5-methyl-2- (trifluoromethyl-phenyl) - »_ oxazol-4-ylmethoxy] -phenyl-3-cyclopropyl ethyl) - hydroxylamine The title compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a clear oil. Analysis for: C22H21F N2O0 Calculated: C, 63.15; H, 5.06; N, 6.69. 25 Found: C, 62.90; H, 5.07; N, 6.66 Step c) (E) -2- (2- [3- [5-Methyl-2- (4-trifluoromethyl-phe nyl) -oxazol-4-yl-ethoxy-3-phenyl-3-cyclopropylmethyl) - [, 2 , 43-oxadiazolidin-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 1, step g, and was obtained as a white solid, m.p. 126-128 ° C. Analysis for: 2, H2 F-N_0C Calculated: C, 59-U H, 4-14; N, 8.62 Found: C, 59.27; H, 3.99; N, 8.78 EXAMPLE 19 (E) -2- (2-Methyl-2- [3- [5-methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-cyclopropylmethyl) - [1, 2,4Joxa -diazolidin-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 17, and was obtained as a white solid, m.p. 42-43 ° C. Analysis for: Calculated: C, 58.03 H, 4-28; N, 8.12 Found: C, 57.69; H, 4-32; N, 8.09 ^ Example 20 (E, E) -2- [5- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl-3-hexa-2,4-dienyl] - [1,4] oxadiazolidin- 3,5-dione 5 Step a) Ethyl ester of (E, E) -5- (3- [5-methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] -hexa-2,4-dienoic acid ester Lithium bis (trimethylsilyl-lysyl) amide (45.12 mL, 45.12 mmol) was added dropwise to a cold solution of triethyl 4-phosphonocrotonate (10.0 mL, 45.12 mmol) in THF (200 mL). After stirring for 1 hour, 1- (3- [5-methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl) -ethanone (12.0 g, 39.1 mmol) in 15 THF (50 mg) was added dropwise. mL). The reaction mixture was allowed to come to room temperature and stirred for 24 hours. Then it was rapidly cooled with aqueous NH.C1, emptied into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 8/1) gave a yellow oil (9.6 g, inseparable mixture of the cis and trans isomers). Analysis for C25H25N0 ^ x 0.25 H20 5 Calculated: C, 73.62; H, 6.26; N, 3.43 Found: C, 73.69; H, 5.86; N, 3.44 Step b) (E, E) -5- [3- (5-Methyl-2-phenyl-oxazol-4-ylmeto-xi] -phenyl) -hexa-2,4-dien-1-ol Aluminum di-isobutyl hydride (1.0M in THF, 55.83 ml, 53.88 mmol) was added dropwise to a cold (-50 ° C) solution of ethyl ester of (E, E) -5- (3- [ 5-methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl) -hexa-2,4-dienoic acid (7.5 g, 18.61 mmol, mixture of the cis and trans isomers), THF (100 ml) and ethyl ether ( 100 mL). The reaction was warmed to 0 ° C and stirred for 1 hour. The reaction mixture was quenched with acetone (dropwise addition), methanol, emptied into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 4/1), gave the trans isomer (4 * 9 g) and the cis isomer (1.7 g) as yellow oils. (trans) Analysis for C23H2 NO3 Calculated: C, 76.43; H, 6.415 N, 3.88 Found: C, 76.25; H, 6.36; N, 4-03 (cis) Analysis for: C23H23NO., Calculated: C, 76.43; H, 6.41; N, 3.88 Found: C, 75.98; H, 6.21; N, 3.69 Step c) (E, E) -N- (5- [3- [5-Methyl-2-phenyl-oxazol-4-yl-methoxy-3-phenyl) -hexa-2,4-dienyl) - hydroxylamine The title compound was prepared substantially in the same manner as described in Example 2, step b and was obtained as a light yellow oil. Analysis for: 23H2 N2O-3 r - Calculated: C, 73.38; H, 6.43; N, 7.44. 10 Found: C, 73.41; H, 6.45; N, 7.20 Step d) (E, E) -2- [5- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl-3-hexa-2,4-diethyl-3- [1, 2, 43oxadiazoIidin-3, 5- dione 15"-> The title compound was prepared in substantially the same manner as described in Example 2, step c was obtained as a white solid, mp 20 151-152 ° C. Analysis for: O ^ J ^^ - ^ - t- Calculated: C, 67.40; H, 5.20; N, 9-43 Found: C, 67.70; H, 5.28; N, 9.35 f 'E p p e x (Z, E) -2- [5- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl] -hexa-2,4-dienyl 3- [1, 2,43-oxadiazolin-3 , 5-dione 5 The title compound was prepared in substantially the same manner as described in Example 20, and was obtained as a white solid, mp. 117-118 ° C. 10 Analysis for: Calculated: C, 67.40; H, 5.20; N, 9-43 Found: C, 67.32; H, 5.21; N, 9-32 EXAMPLE 22 2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-prop-2-ynyl) - [1, 2 , 43-oxadiazolidin-3, 5-dione Step a) 4- (3-Ethynyl-phenoxymethyl) -5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole Bromide (trifluoromethyl) triphenylphosphonium bromide (21.2 g, 48.61 mmol) was added portionwise to a mixture. to -78 ° C potassium-tert-butoxide (1 0.9 g, 97.23 mmoles) .r's in THF (200 mL). The mixture was stirred for 2 hours, then 3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-benzaldehyde (11.7 g, 32.41 mmol) in THF (50 mL) was added dropwise. ). The mixture was stirred for 1 hour at -78 ° C, then at room temperature for 2 days. The reaction mixture was rapidly cooled with NH, C1 aqueous, was poured into water, acidified with HCl 4 (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 8/1) gave a white solid (7.5 g, 67% yield, mp 62-64 ° C). Analysis for: C20H -, ^ F3 02 x 0.25 H20 Calculated: C 66.39; H, 4.01; N, 3.87. 15 Found C, 66.67; H, 3.75; N, 4.15 Step b) 4- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxa-zol-4-ylmethoxy] -phenyl-3-but-3-in-2-ol Lithium bis (trimethylsilyl) amide was added (10.5 mL, 10.5 mmol) was added to a cold (0 ° C) solution of _ (3-ethynyl-phenoxymethyl) -5-methyl-2- (4-trifluoromethyl-phenyl) oxazole (3.0 g, 8.77 mmol) in THF ( 100 mL). After 1 hour at 0 ° C, acetal-25-dehyde (0.59 mL, 10.5 mmol) was added dropwise. The mixture was stirred for 30 minutes, then cooled with NH, aqueous C1, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 4/1) gave a yellow solid (2.1 g, yield 59, mp 86-87 ° C) Analysis for: Calculated: C , 65.83; H, 4-52; N, 3-49 10 Found: C, 65.89; H, 4-38; N, 3.36 Step c) N- (1-Methyl-3- [3- [5-methyl-2- (4-tri-loromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -prop-2-ynyl) -hydroxyl-amine The title compound was prepared substantially in the same manner as described in Example 2, step b, and was obtained as a light yellow solid, mp. 110-112 ° C. 20 Analysis for: Calculated: C, 63.46; H, 4.60; N, 6.73 Found: C, 66.71; H, 4.56; N, 6.69 Step d) 2- (1-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-prop-2-ynyl) - [1 2,43-oxadiazolidin-3, 5-dione The title compound was prepared in substantially the same manner as described in Example 1, step g, and was obtained as a solid, m.p. 84-86 ° C.

Analysis for: C2, H-.gF3 -0f. Calculated: C, 59.38; H, 3.74; N, 8.66 Found: C, 59.38; H, 3-50; N, 8.56 Example 23 2- [1-methyl-3- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl] -prop-2-ynyl- 3- [1,4-oxadiazolidin-3,5-dione] The title compound was prepared substantially in the same manner as described in Example 21, and was obtained as a white solid, m.p. 55-57 ° C. Analysis for: C2 H19 305 x 0.25 HgO Calculated: C, 65.40; H, 4-01; N, 9.95 Found: C, 65.20; H, 4-36; N, 10.23 E emplo 24 (E) -5- [3- [3- (5-Methyl-2-phenyl-oxazpl-4-ylmethyl-3-phenyl-3-but-2-enyl] -oxazolidin-2,4-dione Step a) (E) -4- [3- (3-Chloro-1-methyl-propenyl) -phenoxymethyl-3-methyl-2-phenyl-oxazole 3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl-3-but-2-en-1-ol (10.0 g, 29.85 mmol) in ether (50 mL) was added to a suspension. cold (0 ° C) of phosphorus oxychloride (9.31 g, 44.77 mmole), calcium carbonate (4.47 g, 44.77 mmole), and ether (300 mL). After 30 minutes, the reaction mixture was poured into water. The organic layer was separated, washed with water and brine. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 5/1) gave a clear oil (9.1 g, 86% yield). Analysis for: C21H2QCINO2 Calculated: C, 71.28; H, 5.70; N, 3-96 Found: C, 71.42; H, 5.71; N, 3.88 Step.b) (E) -5- [3- [3- (5-Methyl-2-phenyl-oxazoI-4-ylmethyl-3-phenyl] -but-2-enyl-3-oxazolidin-2,4-dione Tert-butyllithium (17.5 L, 29.7 mmol) was added dropwise to a rapidly stirred cold (-78 ° C) solution of lithium chloride (3.6 g, 84.84 mmol) and oxazolidin-2,4-dione (1.43 g, 14-U mmoles) in THF (90 mL). The mixture was stirred at -78 ° C for 30 minutes, then gradually warmed to 0 ° C. After cooling again to -78 ° C, (E) -4- [3- (3-chloro-1-methyl-propenyl) -phenoxymethyl] -5-methyl-2-phenyl-oxazole (5.0 g, 14.14) was added. mmoles) in THF (5 mL) all at once. After stirring for 10 minutes at -78 ° C, the mixture was gradually warmed to room temperature, and allowed to stir for 5 hours. Then, the reaction mixture was quenched with aqueous NH, C1, emptied in water, acidified with HCl and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (hexane / EtOAc 3/1) gave a white solid (3.5 g, yield 59%, mp 138-139 ° C). Analysis for: Calculated: C.68.89; H, 5.30; N, 6.69 Found: C, 68.49; H, 5.29; N, 6.71 f Example 25 (E) -5- [3- (3- [5-Methyl-2- [4- (2,2,2-trifluoro-ethoxy) -phenyl] -oxazol-4-ylmethoxy-3-phenyl) -but-2 -enyl] -oxazolidin-2,4- 5 dione The title compound was prepared in substantially the same manner as described in Example 24, and was obtained as a white solid, m.p. 10 120-121 ° C. Analysis for: Calculated: C, 60.46; H, 4-49; N, 5-42 Found: C, 60.62; H, 4-47; N, 5-18 Example 26 ^ (E) -5- (3- [3- [5-Methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-but-2-enyl) -oxazolidin-2,4-dione The title compound was prepared in substantially the same manner as described in Example 24, and was obtained as a white solid, m.p. 105-106 ° C. Analysis for: Cgc ^ -jF ^ O ^ 25 Calculated: C, 59.76; H, 4-21; N, 5.58 Found: C, 59.92; H, 4-21; N, 5.54 Example 27 (E) -5- (3- [3- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy-3-phenyl] -but-2-enyl) -oxazolidin-2,4-dione The title compound was prepared in substantially the same manner as described in Example 24, and was obtained as a white solid, m.p. 100-101 ° C. Analysis for: Calculated: C, 69-43; H, 5.59; N, 6.48 Found: C, 69.59; H, 5.89; N, 6.16 Example 28 (E) -5- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl-3-but-2-enyl] -thiazolidin-2,4-dione Butyl lithium (16.6 mL, 41.58 mmol) was added dropwise to a cold solution (-78 ° C) of thiazolidin-2,4-dione (2.31 g, 19.8 mmol) and THF (80 mL). The mixture was stirred at -78 ° C for 15 minutes, then gradually warmed to 0 ° C and stirred for 30 minutes to complete the dianion formation. After re-cooling to -78 ° C, 4- [3- (3-chloro-1-methyl-propenyl) -phenoxymethyl-3-methyl-2-p-en-oxazole (7.0 g, 19.8 mmol) in THF was added. (15 mL), everything insta. After stirring for 30 minutes at -78 ° C, the mixture was gradually warmed to room temperature, and allowed to stir for 2 hours. Then, the reaction mixture was quenched with aqueous NH, C1, emptied in water, acidified with HCl, and extracted with EtOAc. The organic extracts were dried over MgSO ,. Evaporation and purification by flash chromatography on silica gel (H3PO, 5% / MeOH) washed with acid (hexane / EtOAc 3/1), gave a white solid (2.9 g, 33% yield). , mp 48-49 ° C). Analysis for: x 0.25 H20 Calculated: C, 65.68; H, 5.13; N, 6.38 Found: C, 65.72; H, 5.19; N, 6.45 Example 29 (E) -5- (3- [3- [5-Methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-but-2-enyl) -thiazolidin-2,4-dione The title compound was prepared substantially in the same manner as described in Example 27, and was obtained as a light yellow solid, m.p. 50-51 ° C. Quantity for: Calculated: C, 57.91; H, 4.08; N, 5-40 Found: C, 57.57; H, 4.16; N 5-30 Pharmacology Determination of the Blood Glucose Decrease in Mice db / db.

On the morning of day 1, 35 mice [male diabetic db / db mice (C57B1 / KsJ) (Jackson Laboratories), 2-7 months old and 50-70 g] were fasted for 4 hours, weighed and collected a reference blood sample (15-20 μl) from the tip of the tail of each mouse without anesthesia, and placed directly into a tube containing fluorine, mixed and kept on ice. The feed was then returned to the mice. Plasma was separated and plasma glucose levels were determined by the Abbott VP Analyzer. Since the variable plasma glucose levels of the db / db mice, 5 mice having more extreme (ie higher or lower) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned in 7 groups of glucose levels in the average plasma, equivalent (N = 6 per vehicle and N = 4 for each drug group). On the afternoon of days 1, 2 and 3, the vehicle, control or test drugs were administered (p.o.) to mice fed ad libitum. On the morning of day 4, the mice were weighed and the feed was removed, but the water was available ad libitum. Three hours later, a blood sample was collected and then the mice were given the fourth administration of the drug or vehicle. Blood samples are collected again from the unanesthetized mice at 2 and 4 hours after the administration of the drug. Plasma was separated and plasma glucose levels were determined by the Abbott VP Analyzer. For each mouse, the change in percent of its plasma glucose level on day 4 (average of the 2 and 4 hour samples) from the respective level prior to drug administration (day 1 reference sample was determined as follows: average of the samples of 2 and 4 hours (day 4) x 100 Reference Sample (day l) The variation analysis followed by Dunnett's multiple comparison (on one side) will be used to estimate the degree of statistical significance of the difference between the vehicle control group and the individual drug treated groups. A drug will be considered active, at the specific dose administered, if the difference in the level of glucose in the plasma has a p < 0.05. The current difference between the change in average percent of the vehicle and groups treated with drug is shown in Table 1. The positive control, the ciglitazone produces a decrease of 18 to 34% in plasma glucose levels to 100 mg / kg / day x 4 days, po Table 1 (lates db / db Dose Compound% Change Example No. m k p.o. in glucose 1 100 -76 2 100 -78 3 100 -71 4 100 -45 5 100 -47 6 100 -33 7 100 -50 9 100 -47 10 100 -47 11 100 -30 12 100 -50 16 100 -20 18 100 -38 21 50 -32 24 100 -23 25 100 -49 References: 1. Coleman, D.L. (1982) Diabetes-obesity syndromes in mice. Diabetes 31 (Suppl 1); 1-6; 2. Tutwiler, G.F., T. Kirsch, and G. Bridi (1978). A pharmacological profile of McN-3495 [N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidin-carboximidamide], a new orally effective hypoglycemic agent. diabetes 27: 856-857. 3. Lee, S.M., G. Tutwiler, R. Bressler, and C.H. Kircher (1982). Metabolic control and prevention of 2-tetradecylglicidate nephropathy in diabetic mice (db / db). Diabetes 31: 12-18. 4. Chang, A. Y., B. W. Wyse, B.J. Gilchrist, T. Peterson and R. Diani (1983) Ciglitazone, a new hypoglycemic agent. 1. Studies in ob / ob and db / db mice, Chinese diabetic hamsters, and normal and and streptozocin-diabetic rats. Diabetes 32-830-838.

. Hosokawa, T., K. Ando and G. Tamura (1985). An ascochlorin derivative, AS-6, reduces insulin resistance in the genetically obese diabetic mouse, db / db. Diabetes 34: 267-274- Determination of the Effect that Decreases Blood Glucose in Ob / ob Mice The non-insulin-dependent diabetic syndrome can typically be characterized by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia, and insulin resistance. The obg / ob hyperglycemic, genetically obese mouse exhibits many of these metabolic abnormalities and is thought to be a useful means of searching for hypoglycemic agents to treat NIDDM (Coleman, 1978). Male or female ob / ob mice (C57B1 / 6J), ages 2 to 5 months (10 to 65 g), of a similar age are randomized according to plasma glucose in 4 groups of 10 mice. The mice are housed 5 per cage and kept in rodent feed, normal with water ad libitum. The mice receive the test compound daily. The test compound is suspended in 0.5 mL of 0.5% methylcellulose and administered by priming (dissolved in drinking water) or mixed in the diet. The dose of given compound varies from 2.5 to 200 mg / kg / day. The body weight of fed animals is measured at the beginning of each week and the doses for the whole week are calculated using this weight and are expressed in terms of the active portion of the compound. Control mice receive only the vehicle. On the morning of days 4, 7 or 14, two drops of blood (approximately 50 μl) are collected in tubes containing sodium chloride, either from the vein of the tail or after decapitation. For those studies in which the compound is administered daily by priming, the blood samples are collected for four hours after administration of the compound. The plasma is isolated by centrifugation and the glucose concentration is measured enzymatically in an Abbott V.P. Analyzer and the concentration in the plasma of insulin is determined by radioimmunoassay (Heding, 1972). For each mouse, the percentage change in plasma glucose on day 4, 7 or 14 is calculated relative to the average plasma glucose of the mice treated with the vehicle. The variation analysis followed by the Dunnett's Comparison Test (one tail) is used to estimate the significant difference between the glucose values in the plasma of the control group and the groups treated with the individual compound. The results are presented in Table II.

The diabetic mouse db / db (C57BL / KsJ) exhibits many metabolic abnormalities that are associated with diabetes mellitus not dependent on insulin (Type II) in humans. The animals are obese, glucose intolerant and have rapid hyperglycemia that is sometimes accompanied by paradoxical hyperinsulinemia (1). In addition, the db / db mouse will eventually develop some long-term complications that have been associated with diabetes mellitus (1). Despite the fact that these groups or communities, the acute administration of sulfonylurea (even in extremely high doses) will not reduce the hyperglycemia of the db / db mouse (2). The ability of a few hypoglycemic agents to be effective in this species suggests that the other agents have mechanisms of action that are different from those of the sulfonylureas (2,3,4,5). Therefore, such compounds are more likely to be effective in the population of type II diabetic patients who do not respond to sulfonylurea therapy.

Table II Dose Compound% Change% Change% Example No. mg / kg p.o. of insulin glucose 4 100 -39 -82 6 100 -39 -76 7 100 -30 -75 100 -36 -28 11 100 -32 -91 References: 1. Brichard, S., Bailey, C. and Henquin, J.: Marked improvement of glucose homoestasis in diabetic ob / ob mice given in oral vanadate. Diabetes 39: 1326-1332, 1990. 2. Chang, A., yse, B., Gilchrist, B., Peterson, T. and Diani, A .: Ciglitazone, a new hypoglycemic agent. I. Bacteria in ob / ob and db / db mice, diabetic Chinese hamsters and normal diabetic rats and streptozoticin inducers. Diabetes 32: 830-838, 1983. 3. Coleman, D.: Obese and diabetes: Two mutant genes that cause diabetes-obesity syndromes in mice.

Diabetology 14: 141-148, 1978. 4- Heding, L. G .: Determination of insulin in total serum (IRI) in diabetic patients treated with insulin. Diabetology 8: 260-266, 1972.

Pharmaceutical composition Based on the results of the pharmacological test, the compounds of this invention are useful in the treatment of hyperglycemia in diabetes mellitus. The compounds can be administered pure or with a pharmaceutical carrier to a mammal in need thereof. The pharmaceutical carrier can be solid or liquid and the active compound must be a therapeutically effective amount. A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, dispersing agents, fillers, glidants or sliders, compression stockings -Auxiliaries, binders or tablet disintegrating agents; It can also be an encapsulation material. In the powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets, preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used when preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, dulcificadores, flavoring agents, dispersing agents, crosslinking agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, eg cellulose derivatives, as preferred solution of sodium carboxymethyl cellulose), alcohols (including monohydric alcohols and poly-hydric, for example glycols) and their derivatives, and oils (for example, fractionated coconut oil and arachis oil (alkaloid isolated from peanuts)). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or another pharmaceutically acceptable impeller. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be given intravenously. The compound can also be administered orally, either in the form of a liquid or solid composition. Preferably, the pharmaceutical composition is in unit dosage form, for example as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, eg, packaged powders, fras-quitos, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form be, for example, a capsule or tablet itself, or this be the appropriate number of any such composition in package form. A dosage range from 0.1 to 200 mg / kg / day is contemplated, with a preferred dose from 0.1 to 100 mg / kg / day. Due to the uncertainty regarding the study data of the laboratory mouse or other mammals, the degree of hyperglycemia, and the selected compound, the doses used in the treatment of non-insulin-dependent diabetes mellitus should be determined subjectively by a physician. or veterinarian according to normal medical or veterinary practice.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

1 . A compueto in accordance with formula I below characterized in that: R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, thienyl, furyl, pyridyl, where R is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; R is hydrogen or alkyl of 1 to 6 carbon atoms; X is 0 or S; n is 1 or 2; Wherein R is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; where R is hydrogen, alkyl of 1 to 6 carbon atoms, allyl, aryl of 6 to 10 carbon atoms, aryl of 6 to 10 carbon atoms- (CH2) - • _ -, fluorine, chlorine, bromine, iodine, trimethylsilyl or cycloalkyl of 3 to 8 carbon atoms; R is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, or aryl of 6 to 10 carbon atoms- (CH2) -, _6-! m is 0, 1 or 2; R is hydrogen or alkyl of 1 to 6 carbon atoms; n R is hydrogen or alkyl of 1 to 6 carbon atoms; R 8 and R 9 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine or iodine; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when And it's S; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that it has the formula wherein: R is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; n is 1 or 2; where m is 0, 1 or 2; R are independently hydrogen or alkyl of 1 to 6 carbon atoms; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when And it's S; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2, characterized in that it has the formula Ib Ib wherein: R 10 is hydrogen, CF 3 -, CF-0-, CF 3 CH 20 -C 1 -; n is 1 or 2; where m is 0 or 1; they are independently hydrogen, methyl or ethyl; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when And it's S; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3, characterized in that it is selected from the group consisting of: (E) -2- (3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-) ylmetoxy] -phenyl-3-pent-2-enyl) - [1, 2, 43-oxadiazolidin-3, 5-dione, (Z) -2- (3- [3- [5-methyl-2- (4-rifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -pent-2-enyl) - [1,2,4-oxadiazolidin-] 3, 5-dione, 2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethyl] -phenyl-3-but-2-enyl) - [1,4,4] oxadiazolidin-3, 5-dione, (E) -2- (3- [3- [5-Methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-but-2-enyl) - [1, 2,43-oxadiazolidin] -3,5-diona, (E) -2- (3- [3- [5-Methyl-2- (4-trifluoro-ethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1, 2 , 4] oxadiazolidin-3, 5-dione, (E) -2- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl-3-but-2-enyl-3- [1,4-oxadiazolidin-3,5-dione] (Z) -2- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy-3-phenyl-3-but-2-enyl] - [1,2-43-oxadiazolidin-3,5-dione] , (E) -2- [3- [3- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy-3-phenyl-3-but-2-enyl) - [1,2,43-oxadiazolidin] -3, 5-dione, 2- [3- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy-3-benzofuran-5-yl] -but-2-enyl] - [1,2-43-oxadiazolidin-3,5-dione] , (E) -2- (2-methyl-3- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-enyl] -alyl) - [1,2,4-Oxadiazolidin] -, 3,5-dione, 10 (E) -2- (2-ethyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl-ethoxy] -phenyl] -alyl) - [1, 2, 43-oxadiazolidin-3, 5-dione, 15 (E) -2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazo-1-4-yl-ethoxy] -phenyl] -alyl) - [1, 2 , 4] oxadiazolidin- / ^ 3,5-dione, (E) -2- (3- [3- [2- (4-Chloro-phenyl) -5-methyl-oxazol-4-ylmetho-20? I] -phenyl] -1-methyl-allyl) - [1 , 2,4] oxadiazolidin-3,5-dione, (E) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1 , 2,4] oxadiazolidin-3,5-dione. (Z) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1 , 2, 43-oxadiazoli-din-3, 5-dione, (E) -2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-but-2-enyl) - [1, 2, 43-oxadiazoli-din-3, 5-dione, 2- [3- (4- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -alyl) - [1,2,4-oxadiazolidin-3,5-dione] , (E) -2- (2- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] cyclopropylmethyl) - [1,2,4] oxadiazolidin-3, 5-dione, (E) -2- (2-Methyl-2- (3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl) -cyclopropylmethyl) - [1, 2.4 ] oxa-diazolidin-3, 5-dione, (E, E) -2- [5- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] -hexa-2,4-dieni] - [1,4] oxadiazolidin -3, 5-dione, (Z, E) -2- [5- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] -hexa-2,4-dienyl) - [1,2,4] oxadiazolidin -3, 5-dione, 2- [3- (4- [2- [5-methyl-2- (4-trifluoromethyl-phenyl-oxazol-4-yl-3-ethoxy-3-phenyl) -propyl-2-ynyl) - [1, 2,4] oxadiazolidin-3, 5-dione, 2- [1-methyl-3- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl] -propyl-2-ynyl- [1,4] oxadiazolidin-3,5-dione , (E) -5- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethyl] -phenyl] -but-2-eny1] -oxazolidin-2,4-dione, (E) -5- [3- (3- [5-Methyl-2- [4- (2,2,2-trifluoro-ethoxy) -phenyl] -oxazol-4-ylmethoxy] -phenyl) -but-2 -enyl] -oxazolidin-2,4-dione, (E) -5- (3- [3- [5-Methyl-2- (trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-but-2-enyl) -oxazolidin-2,4-dione, (E) -5- (3- [3- [2- (5-Methyl-2-phenyl) -oxazol-4-yl) -ethoxy-3-phenyl] -but-2-enyl) -oxazolidin-2,4- diona, (E) -5- [3- [3- (5-Methyl-2-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-but-2-enyl) -thiazolidin-2,4-dione, and (E) -5- (3- [3- [5-Methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-but-2-enyl) -thiazolidin-2,4-dione.

5. A method of treating hyperglycemia of non-insulin-dependent diabetes mellitus in mammals, characterized in that it comprises administering to them a therapeutically effective amount of a compound of the formula I wherein: -I R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, thienyl, furyl, pyridyl, where R is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkyloxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; 2 R is hydrogen or alkyl of 1 to 6 carbon atoms; X is 0 or S; n is 1 or 2; where R is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; where R is hydrogen, alkyl of 1 to 6 carbon atoms, allyl, aryl of 6 to 10 carbon atoms, aryl of 6 to 10 carbon atoms- (CH2) 1, fluorine, chlorine, bromine, iodine, trimethylsilyl or cycloalkyl of 3 to 8 carbon atoms; R- is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, or aryl of 6 to 10 carbon atoms- (CH 2) 1 _ -; m is 0, 1 or 2; R is hydrogen or alkyl of 1 to 6 carbon atoms; R 7 is hydrogen or alkyl of 1 to 6 carbon atoms; R 8 and R 9 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, or iodine; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when And it's S; or a pharmaceutically acceptable salt thereof.

6. A method of treatment according to claim 5, characterized in that the compound used has the formula wherein: R is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; where m is 0, 1 or 2; i c L r and R, R, R and R are independently hydrogen or alkyl of 1 to 6 carbon atoms; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when And it's S; or a pharmaceutically acceptable salt thereof.

7. A treatment method according to claim 6, characterized in that the compound used has the formula Ib, Ib , 1 I0u is hydrogen, CF3-, CF30-, CF ^ CHgO-cy-; n is 1 or 2; where m is 0 or 1; r r and R, R, R and R are independently hydrogen, methyl or ethyl; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when And it's S; or a pharmaceutically acceptable salt thereof.

8. A method of treatment according to claim 7, characterized in that the compound used is selected from the group consisting of: (E) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-pent-2-enyl) - [1,2,4-oxadiazolidin-3] , 5-dione, (Z) -2- (3- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -pent-2-enyl) - [1, 2, 43-oxadiazolidin- 3, 5-dione, 2- (3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethyl-3-phenyl-3-but-2-enyl) - [1, 2,43 oxadiazolidin-3, 5-dione, (E) -2- (3- [3- [5-me-il-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy-3-phenyl] -but-2-eni1) - [1, 2, 43 oxadiazolidin-3, 5-dione, (E) -2- (3- [3- [5-Methyl-2- (4-trifluoro-ethoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl] -but-2-enyl) - [1, 2 , 43-oxadiazolidin-3, 5-dione, (E) -2- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl-3-but-2-enyl-3- [1,4-oxadiazolidin-3,5-dione] (Z) -2- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl] but-2-enyl-3- [1,2-43-oxadiazolidin-3,5-dione] (E) -2- [3- [3- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy-3-phenyl] -but-2-enyl) - [1, 2, 43-oxadiazolidin- 3, 5-dione, 2- [3- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy-3-benzofuran-5-yl] -but-2-enyl] - [1, 2, 43-oxadiazolidin-3, 5-dione, (E) -2- (2-methyl-3- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-allyl) - [1,2,4-oxadiazolidin-3] , 5-dione, (E) -2- (2-Ethyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-allyl) - [1,2,4-oxadiazolidin-3] , 5-dione, (E) -2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-allyl) - [1,2,4-oxadiazolidin-3] , 5-dione, (E) -2- (3- [3- [2- (4-chloro-phenyl) -5-methyl-oxazol-4-ylmeto-xi] -phenyl] -1-methyl-allyl) - [1, 2 , 43-oxadiazolidin-3, 5-dione, (E) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazo-1-4-ylmethoxy-3-phenyl-3-) but-2-enyl) - [1, 2, 4] oxadiazoli-din-3, 5-dione. (Z) -2- (2-methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazo-1-4-yl-ethoxy-3-phenyl-3-but-2-enyl) - [1 , 2,43-oxadiazoli-din-3, 5-dione, (E) -2- (1 -methyl-3- [3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-but-2-enyl) - [1, 2 , 4] oxadiazoli-din-3, 5-dione, 2- [3- (4- [4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] -allyl) - [1,4,2-oxadiazolidin-3, 5-dione, (E) -2- (2- [3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl] cyclopropylmethyl) - [1, 2, 43-oxadiazolidin-3, 5 diona, (E) -2- (2-Methyl-2- (3- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazo-1-4-ylmethoxy] -phenyl) -cyclopropylmethyl) - [1, 2,43-oxa] -diazolidin-3, 5-dione, (E, E) -2- [5- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethoxy] -phenyl-3-hexa-2,4-dienyl) - [1, 2, 43-oxadiazolidin-3, 5-dione, (Z, E) -2- [5- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy-3-phenyl-3-hexa-2,4-dienyl) - [1,2,4-oxadiazolidin] -3, 5-dione, 2- [3- (4- [2- [5-Methyl-2- (4-trifluoromethyl-phenyl-oxazol-4-yl] -ethoxy] -phenyl) -propyl-2-ynyl) - [1, 2, 4] oxadiazolidin-3, 5-dione, 2- [1-methyl-3- [3- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl] -propi1-2-inyl- [1, 2,43-oxadiazolidin-3,5-dione, (E) -5- [3- [3- (5-Methyl-2-phenyl-oxazol-4-ylmethyl-3-phenyl-3-but-2-enyl] -oxazolidin-2,4-dione, (E) -5- [3- (3- [5-Methyl-2- [4- (2,2,2-trifluoro-ethoxy) -phenyl-3-oxazo-1-4-ylmethoxy-3-phenyl) -but-2- enyl3-oxazolidin-2,4-dione, (E) -5- (3- [3- [5-Methyl-2- (trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy-3-phenyl-3-but-2-enyl) -oxazolidin-2,4-dione, (E) -5- (3- [3- [2- (5-Methyl-2-phenyl) -oxazol-4-yl) -ethoxy-3-phenyl-3-but-2-enyl) -oxazolidin-2,4-dione , (E) -5- [3- [3- (5-Methyl-2-phenyl) -oxazol-4-ylmethoxy] -phenyl-3-but-2-enyl) -thiazolidin-2,4-dione, and '* ( E) -5- (3- [3- [5-Methyl-2- (4-trifluoromethoxy-phenyl) -oxazol-4-ylme-oxy-3-phenyl-3-bu-2-enyl) -thiazolidin-2,4-dione.

9. A pharmaceutical composition for the treatment of hyperglycemia in mammals, characterized in that it comprises a pharmaceutical carrier and a therapeutically effective amount of a compound having the formula: 10 Wherein: R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, thienyl, furyl, pyridyl, - | or wherein R is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkyloxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; 2 R is hydrogen or alkyl of 1 to 6 carbon atoms; X is 0 or S n is 1 or 2 where R 3 is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; where R is hydrogen, alkyl of 1 to 6 carbon atoms, allyl, aryl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms- (CH?) 1? -, fluorine, chlorine, bromine, iodine, trimethylsilyl or cycloalkyl of 3 to 8 carbon atoms; R5 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms or aryl of 6 to 10 carbon atoms -CH) "-, m is 0, 1, or 2; R is hydrogen or alkyl; R 7 is hydrogen or alkyl of 1 to 6 carbon atoms; R 8 and R 9 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine or iodine; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when Y is S; or a pharmaceutically acceptable salt thereof. SUMMARY OF THE INVENTION This invention relates to novel compounds, which have demonstrated oral antihyperglycemic activity in ob / ob and db / db diabetic mice, animal models in non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes). These compounds have the formula (I), wherein: R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, thienyl, furyl, pyridyl, (a) or (b) where R is hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, iodine, alkyloxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; R is hydrogen or alkyl of 1 to 6 carbon atoms; X is 0 or S; n is 0, 1 or 2; A is (c) or (d); where R is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl or trifluoroalkoxy; B is (e), (f) or (g), where R is hydrogen, alkyl of 1 to 6 carbon atoms, allyl, aryl of 6 to 10 carbon atoms, aryl of 6 to 10 carbon atoms- (CH2 ), fluorine, chlorine, bromine, iodine, trimethylsilyl or cycloalkyl of 3 to 8 carbon atoms; R is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms or aryl of 6 to 10 carbon atoms- (CH 2) -1 - »m is 0, 1 or 2; R is hydrogen or alkyl of 1 to 6 carbon atoms; R is hydrogen or alkyl of 1 to 6 a. Carbon atoms; R8 and Q R are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine or iodine; And it is 0 or S; Z is N or CH when Y is 0 and Z is CH when Y is S; or a pharmaceutically acceptable salt thereof. - "- (X (*) --TCÍ (b)