This invention relates to novel azolidines of Formula I below which have demonstrated oral antihyperglycemic activity in diabetic db/db and ob/ob mice, animal models of non-insulin dependent diabetes mellitus (NIDD or Type II diabetes). The

Formula I compounds or pharmaceutical compositions thereof are therefore useful in treating hyperglycemia in mammals having non-insulin dependent diabetes mellitus.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urinary output and elevated blood glucose levels. There are two major subclasses of diabetes mellitus. One is the insulin-dependent diabetes mellitus (IDDM or Type I), formerly referred to as juvenile onset diabetes since it was evident early in life, and non- insulin dependent diabetes mellitus (NIDDM or Type II), often referred to as maturity-onset diabetes. Exogenous insulin by injection is used clinically to control diabetes but suffers from several drawbacks. Insulin is a protein and thus cannot be taken orally due to digestion and degradation but must be injected. It is not always possible to attain good control of blood sugar levels by insulin administration. Insulin resistance sometimes occurs requiring much higher doses of insulin than normal. Another shortcoming of insulin is that while it may control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, or cardiovascular disorders.

Orally effective antihyperglycemic agents are used to reduce blood glucose levels and to reduce damage to the nervous, retinal, renal or vascular systems through mechanisms affecting glucose metabolism. Such agents act in a variety of different mechanisms including inhibition of fatty acid oxidation, α-glycosidase inhibition, antagonism of 0C2- receptors and 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 thiazolidinediones of which ciglitazone is the prototype. Ciglitazone suppresses the symptoms of diabetes - hyperglycemia, hypertriglyceridemia and hyperinsulinemia [Diabetes 21, 804-10 (1983)].

Still another class of antihyperglycemic agents are the N-arylalkyl-N-hydroxy ureas and the 2-(arylalkyl)-[l,2,4]oxadiazolidine-3,5-diones. The published PCT patent application WO 92/03425 discloses compounds of the formula:

or

where R ¹ and R ² are independently H, C ₁ -C ₉ alkyl, C ₃ -C ₇ cycloalkyl, 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, 2238-2240 (1993).

SUMMARY OF THE INVENTION

The novel compounds useful in the treatment of hyperglycemia are represented by the following formula:

wherein:

R ¹ is Ci-Cό alkyl, C3-C8 cycloalkyl, thienyl, furyl, pyridyl,

where R ¹⁰ is hydrogen, -C6 alkyl, fluorine, chlorine, bromine, iodine, C1-C6 alkyoxy, trifluoroalkyl or trifluoroalkoxy; R ² is hydrogen or C1-C6 alkyl; X is O or S; n is 1 or 2;

where R ³ is hydrogen, Ci-Cό alkyl, halogen, C ₁ -C6 alkoxy, trifluoroalkyl or trifluoroalkoxy;

where R ⁴ is hydrogen, C1-C6 alkyl, allyl, C6-C10 aryl, C6-C10 aryl-

(CH2)i-6-, fluorine, chlorine, bromine, iodine, trimethylsilyl or C3-

C8 cycloalkyl;

R ⁵ is hydrogen, -Cό alkyl, C6-C10 aryl, or Ce-Cio aryl-

(CH ₂ )i-6-; m is O, 1, or 2;

R ⁶ is hydrogen or Ci-Cβ alkyl;

R ⁷ is hydrogen or Cj-Cό alkyl;

R ⁸ and R ⁹ are seleced independently from hydrogen, Ci-Cβ alkyl, 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 thereof.

The term -C6 alkyl means a alkyl group consisting of from one to six carbon atoms which may be a straight or branched chain. The term C]-C6 alkoxy means an O-Cj- C(_ alkyl group where the -C6 group is as defined above. The term C6-C10 aryl 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 CF3-(CH2)θ-2- and the term trifluoroalkoxy is an O-trifluoroalkyl group where trifluoroalkyl is as defined above.

Compounds of Formula I may 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 may be isolated as a solvate or hydrate which is considered to have the pharmacological properties of the active compound.

The preferred compounds are those of Formula la below

la

where:

R ¹⁰ is hydrogen, -Cό alkyl, fluorine, chlorine, bromine, iodine, Ci-Cό alkoxy, trifluoroalkyl or trifluoroalkoxy; n is 1 or 2;

where m is 0, 1 or 2;

R ⁴ , R ⁵ , R ⁶ , and R ⁷ are independently hydrogen or Cj-C ₆ alkyl;

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 therof.

The most preferred componds of this invention are those of Formula lb

lb wherein:

R ¹⁰ is hydrogen, CF ₃ — , CF O— , CF ₃ CH ₂ 0— or Cl- n is 1 or 2;

wherein m is 0 or 1;

R ⁴ , R ⁵ , R ⁶ , and R ⁷ are independently hydrogen, methyl or ethyl;

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 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)-[l,2,4]oxadiazolidine-3,5-dione,

(Z)-2-(3- { 3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy] -phenyl } -pent-2- enyl)-[l,2,4]oxadiazolidine-3,5-dione,

2-(3- { 3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]- phenyl } -but-2-enyl)- [l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(3- { 3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy ]-phenyl }-but-2- enyl)-[l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(3-{3-[5-methyl-2-(4-trifluoro-ethoxy-phenyl)-oxazo l-4-ylmethoxy]-phenyl}-but-2- enyl)-[l,2,4]oxadiazolidine-3,5-dione,

(E)-2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl ]-but-2-enyl}- [l,2,4]oxadiazolidine-3,5-dione,

(Z)-2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl ]-but-2-enyl}- [l,2,4]oxadiazolidine-3,5-dione,

(E)-2- { 3-[3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl } -but-2-enyl)- [l,2,4]oxadiazolidine-3,5-dione,

2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzofuran -5-yl]-but-2-enyl}- [l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-methyl-3-{4-[5-methyl-2-(4-trifluoromethyl-pheny l)-oxazol-4-ylmethoxy]- phenyl}-allyl)-[l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-ethyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl )-oxazol-4-ylmethoxy]-phenyl}- allyl)-[l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(l-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-pheny l)-oxazol-4-ylmethoxy]- phenyl}-allyl)-[l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(3-{3-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmeth oxy]-phenyl}-l-methyl-allyl)- [ 1 ,2,4]oxadiazolidine-3 ,5-dione,

(E)-2-(2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-ylmethoxy]- phenyl}-but-2-enyl)-[l,2,4]oxadiazolidine-3,5-dione,

(Z)-2-(2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-pheny l)-oxazol-4-ylmethoxy]- phenyl } -but-2-enyl)-[ 1 ,2,4]oxadiazolidine-3,5-dione,

(E)-2-(l-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-pheny l)-oxazol-4-ylmethoxy]- phenyl } -but-2-enyl)-[ 1 ,2,4]oxadiazolidine-3,5-dione,

2-[3-(4-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol- 4-ylmethoxy]-phenyl}-allyl)- [l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol -4-ylmethoxy]-phenyl)- cyclopropylmethyl)-[l,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-methyl-2-{3-[5-methyl-2-(4-trifluoromethyl-pheny l)-oxazol-4-ylmethoxy]- phenyl}-cyclopropylmethyl)-[l,2,4]oxadiazolidine-3,5-dione,

(E, E)-2- { 5-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl } -hexa-2,4-dienyl)- [l,2,4]oxadiazolidine-3,5-dione,

(Z, E)-2-{5-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl}-he xa-2,4-dienyl)- [l,2,4]oxadiazolidine-3,5-dione,

2-[3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl-oxazol-4 -yl]-ethoxy}-phenyl)-propyl-2- ynyl)-[l,2,4]oxadiazolidine-3,5-dione,

2-{ l-methyl-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl] -propyl-2-ynyl}- [l,2,4]oxadiazolidine-3,5-dione,

(E)-5-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethyl]-phenyl] -but-2-enyl}-oxazolidine-2,4- dione,

(E)-5-[3-(3-{5-methyl-2-[4-(2,2,2,-trifluoro-ethoxy)-phen yl]-oxazol-4-ylmethoxy}- phenyl)-but-2-enyl]-oxazolidine-2,4-dione,

(E)-5-(3- { 3-[5-methyl-2-(trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy] -phenyl } -but-2- enyl)-oxazolidine-2,4-dione,

(E)-5-(3- { 3-[2-(5-methyl-2-phenyl)-oxazol-4-yl)-ethoxy]-phenyl } -but-2-enyl)-oxazolidine- 2,4-dione,

(E)-5-{3-[3-(5-methyl-2-phenyl)-oxazol-4-ylmethoxy]-pheny l}-but-2-enyl)-thiazolidine- 2,4-dione, and

(E)-5-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazo l-4-ylmethoxy]-phenyl}-but-2- enyl)-thiazolidine-2,4-dione.

DETAILED DESCRIPTION OF THE INVENTION

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

II

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

III

These synthetic transformations are more fully described in the following reaction schemes

T -xii.

Scheme I outlines the synthesis of a Formula II intermediate where A is phenyl and B is an olefinic linking group as shown under Formula I.

Scheme I.

The terms R ¹ — R ⁵ , X, n, and m are as defined previously.

Scheme II illustrates the synthetic sequence for preparing a Formula I compound from the intermediate VIII.

Scheme II.

The terms R ¹ — R ⁵ , X, n, and m are as defined previously.

When R is halogen the compounds of the present invention can be prepared according to Scheme UI.

Scheme III

wherein R*, R^, R3, χ_ _an d n are as defined above; R ⁴ is halogen.

When R" is alkyl the compounds of the present invention can be prepared according to Scheme IV

Scheme IV

wherein Rl, R-~, R3, R4, R5, R6 ₅ χ _{t n anc} j _{m are as} d _e f _m ed above.

Scheme V outlines the synthesis of an intermediate where B is cyclopropylmethyl from an intermediate of Formula VIII where m is 0. Scheme V

wherein R , R^, R3, χ _? and n are as defined above; R ⁴ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl.

Scheme VI outlines the synthesis of a Formula II intermediate where B is propynyl.

Scheme VI

, C ₆ H ₅ CH ₃

wherein Rl, R^, R3, R6, X, and n are as defined above

Scheme VII outlines the reactions used to prepare Formula I compounds where Z is CH and Y is O or S from an intermediate of Formula VIII.

Scheme VII

wherein R ¹ , R ² , R , R5, R6, X, n and m are as defined above; R ⁴ is hydrogen, alkyl, allyl, aryl, aralkyl, trimethylsilyl, cycloalkyl; Y is O or S.

Preparation of a Formula I compound where A is benzofuran-2,5-diyl, Y is O and Z is N is shown in Scheme VIII.

Scheme VIII

wherein R , R-~, R--, x and m are as defined above; R ⁴ is hydrogen, alkyl, allyl, aryl, aralkyl, trimethylsilyl, cycloalkyl.

The starting heterocyclic intermediates of the formula V can be prepared according to standard literature procedures. For example, 4-(l'-hydroxyethyl)-5-R ² -2-phenyloxazoles and thiazoles where R ² is hydrogen or C1-C6 alkyl can be prepared according to Scheme IX (European Patent EP 0177353A2).

Scheme IX

LiAlH ₄

The starting heterocyclic intermediates of the formula IV can be prepared by known methods conventional in the art (Heterocyclic Compounds 34, 1979 and Heterocvclic Compounds 45. 1986). The 2-phenyl-4-chloromethyl-5-methyloxazoles 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.

5 Scheme XI

X = O or S

Intermediate of the formula VII can be prepared either from the commercially l o available phenols of formula IX or according to the synthetic Scheme XII.

Sche e xii

15 VII

The following examples are included for illustrative purposes and are not intended to limit the disclosure of this invention in any way. The reagents, intermediates, or

chemicals used herein are either commercilly available or can be readily synthesized using standard laboratory procedures known to those skilled in the art.

Example 1

(E)-2-(3-(3-r5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol -4-ylmethoxy1- phenyll-pent-2-envP-ri .,2.41oxadiazolidine-3.5-dione

Step a) 3-r5-methyl-2-(-4-trifluoromethyl-phenyl -oxa ol-4-ylmethoxy)- henzaldehvde

A mixture of 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (5.25 g, 19.1 mmol), 3-hydroxylbenzaldehyde (2.33 g, 19.1 mmol), potassium carbonate (3.77 g, 27.3 mmol) and dimethylformamide (50 mL) was stirred at 80°C for 3 hours. The mixture was then poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO Evaporation and crystallization from ethyl ether/hexane, gave a yellow solid (4.47 g, 65% yield, m.p. 104-105°C).

Analysis for: C19H14F3NO3

Calc'd: C, 63.16; H, 3.91; N, 3.88 Found: C, 62.84; H, 3.97; N, 3.87

Step b) l -l3- r5 -m eth yl -2 -(4-t rifl u oromet h yl - ph en vπ -oxa zol -4- ylmethoxy1-phenyl)-propan-I -one

Ethylmagnesium bromide (1 l.lmL, 33.24 mmol) was added dropwise in to 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 quenched with aqueous NH4CI, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSOφ 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 MgSOφ Evaporation and crystallization from ethyl ether/hexane (after cooling to 0 °C), gave a white solid (9.6 g, 74% yield, m.p. 73-74 °C).

Analysis for: C3gH3 ₆ N2θ9 Calc'd: C, 64.78; H, 4.66; N, 3.60

Found: C, 64.63; H, 4.60; N, 3.91

Step c) (E)-3.n- r5-Meth yl-2-(4-f ri fhιorometh yl - phen vn-oxa zo1-4- ylmethoxy1-phenyl)-pent-2-enoic acid ethyl ester

Triethylphosphonoacetate (8.67 ml, 43.1 mmol) was added dropwise in to a cold (0 °C) suspension of sodium hydride (1.24 g, 41.5 mmol) and toluene (200ml). After the addition, the mixture was stirred for 1 hour, and then l-{3-[5-methyl-2-(4-trifluoromethyl- phenyl)-oxazol-4-ylmethoxy]-phenyl}-propan-l-one (8.5 g, 21.85 mmol) in THF (20 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 hours, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSθ4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 8/1) gave the trans-isomer (white solid, 5.5 g, 55% yield, m.p. 85-86°C), and the cis-isomer (clear oil, 2.8 g28% yield). a) Analysis for: C25H24F3NO4 (trans-isomer)

Calc'd: C, 65.35; H, 5.27; N, 3.05 Found: C, 65.25; H, 5.42; N, 3.01

b) Analysis for: C25H24F3 O4 (cis-isomer) Calc'd: C, 65.35; H, 5.27; N, 3.05

Found: C, 65.11; H, 5.31; N, 3.00

Step d) fE -3-f3-r5-Methyl-2-(4-triflιι romethyl-phenvn-oxa7θl-4- ylmethoxyl-phenylT-pent-2-en-l -ol

Di-isobutyl aluminum hydride (1.0M in THF, 25.05 ml, 25.05 mmol) was added dropwise in to a cold (-50°C) solution of (E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy] -phenyl }-pent-2-enoic acid ethyl ester (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, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/

EtOAc 3/1), gave a clear oil (3.8 g, 91% yield).

Analysis for: C23H22F3NO3 Calc'd: C, 66.18; H, 5.31; N, 3.36

Found: C, 65.88; H, 5.41; N, 3.26

Step e) fE)-N-tert-Butoxycarbonyloxy- 3-l3-r5-methvI-2-(4- trifluoromethyl-phenyl -oxazol-4-ylmethoxyl-phenyl>-pent-2-enyl)- carhamic acid tert-hutvl ester

Diisopropylazodicarboxylate (1.98 ml, 10.07 mmol) in THF (15 ml) was added dropwise n to a cold (-20°C) solution of (E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-phenyl }-pent-2-en- l-ol (3.5 g, 8.39 mmol) in THF (30 ml), triphenylphosphine (2.64 g, 10.07 mmol) and tert-butyl N-(t -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 MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/

EtOAc 7/1) gave a clear oil (5.1 g, 96% yield).

Analysis for: C33H39F3N2O7 x 0.5 H2O Calc'd: C, 61.77; H, 6.24; N, 4.37

Found: C, 61.58; H, 6.46; N, 4.60

Step f) (E)-N-(3-(3-r5-Methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- ylmethoxy1-phenyl)-pent-2-enyl)-hvdroxylamine

A mixture of (E)-N-tert-butoxycarbonyloxy-3-(3- {3-[5-methyl-2-(4-trifluoromethyl- phenyl)-oxazol-4-ylmethoxy]-phenyl}-pentyl-2-enyl)-carbamic acid tert-butyl ester (5.0 g, 7.9 mmol), CH2CI2 (100 ml), and trifluoroacetic acid (10 ml) was stirred at room temperature for 8 h. The volatiles were removed in vacuo, and the residue taken in ethylether/water. It was basified to pH = 9-10 with NaOH (2N), and the organic layer separated and washed with water and brine. The organic extracts were dried over MgSO4. 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: C23H23F3N2O3

Calc'd: C, 63.88; H, 5.36; N, 6.48 Found: C, 63.63; H, 5.27; N, 6.48

Step g) (E -2-(3-(3-r5-methyl-2-(4-trifluoromethyl-Dhenvn-oxazol-4- vlmethoxvl-nhenvl)-pent-2-envl -π .2.41oxadiazolidine-3.f>-dione

N-(Chlorocarbonyl)isocyanate (0.37 ml, 4.63 mmol) was added dropwise to a cold (-5°C) mixture of (E)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-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 poured into HCl (IN) and extracted with EtOAc. The organic extracts were dried over MgSθ4. Evaporation and purification by flash chromatography on acid washed (5% H3Pθ4/MeOH) silica gel (hexane/ EtOAc 3/1) gave a white solid (1.48 g, 64% yield, mp 66-67°C).

Analysis for: C25H22F3N3O5 Calc'd: C, 59.88; H, 4.42; N, 8.38 Found: C, 59.83; H, 4.37; N, 8.28

Example 2

(E)-2-(3-f3-r5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol -4-ylmethoxyl- phenyl)-pent-2-enyl)-ri _< 2.41oxadiazolidine-3,5-dione

Step a) fZ 3-π-r5-Methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- ylmethoxyl-phenyl)-pent-2-en-l -ol

Di-isobutyl aluminum hydride (l.OM in THF, 10.89 ml, 10.89 mmol) was added dropwise in to a cold (-50°C) solution of (Z)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-phenyl}-pent-2-enoic acid ethyl ester (2.0 g, 4.35 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 quenched with acetone (dropwise addition), methanol, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSθ4. 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: C23H22F3NO3 Calc'd: C, 66.18; H, 5.31; N, 3.36 Found: C, 65.85; H, 5.12; N, 3.15

Step b) (ZVN-(3-(3-r5-Methyl-2-f4-triflιιoromethyl-phenvn-oxazol-4 - ylmethoxyl-phenyl)-pent-2-en yl)-hvdroxylamine

Diisopropylazodicarboxylate (0.68 ml, 3.45 mmol) in THF (10 ml) was added dropwise n to a cold (-20°C) solution of (Z)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-phenyl}-pent-2-en-l-ol (1.2 g, 2.87 mmol), THF (20 ml), triphenylphosphine

(0.9 g, 3.45 mmol) and tert-butyl N-(t -butoxy-carbonyloxy) carbamate (0.8 g, 3.45 mmol). After the 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 CH2C12 (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 taken in ethylether/water. It was basified to pH = 9-10 with NaOH (2N), and the organic layer separated and washed with water and brine. The organic extracts were dried over MgSO4.

Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 1/1, and MeOH/EtOAc 1/10), gave a white solid (3.0 g, 82% yield, m. p. 72-73 °C).

Analysis for: C23H23F3N2O3

Calc'd: C, 63.88; H, 5.36; N, 6.48

Found: C, 63.74; H, 5.34; N, 6.26

Step c) (Z -2-(3-l3-r5-methyl-2-(4-trifluoromethyl-phenyl -oxazol-4- ylmethoxy1-phenyl)-pent-2-enyl)-ri .2.41oxadiazolidine-3.5-dione

N-(Chlorocarbonyl)isocyanate (0.12 ml, 1.5 mmol) was added dropwise to a cold (-5°C) mixture of (Z)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]- phenyl} -pen t-2-enyl)-hydroxylamine (0.65 g, 1.5 mmol) in THF (10 ml). The mixture was stirred for 30 minutes, then poured into HCl (IN) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4/MeOH) silica gel (hexane/ EtOAc 2/1) gave a white solid (0.48 g, 64% yield, mp 126-127°C). Analysis for: C25H22F3N3O5

Calc'd: C, 59.88; H, 4.42; N, 8.38 Found: C, 60.03; H, 4.55; N, 8.03

Exam le 3

fE)-2-(3-(3-r5-methyl-2-(4-trifluoromethyl-phenvh-oxazol- 4-ylmethvπ- phenyl)-but-2-enyl)-ri*,2.41oxadiaxolidine-3,5-dione

Step a) 4,5-Dimeth yl-2-(4-trifluorometh yl- phen yl)-oxazole N -oxi d e hvdrochloride

HCl gas (21.2g, 58.1mmol) was bubbled via syringe into a 0°C solution of 4- trifluoromethylbenzaldehyde (50g, 28.7mmol), 2,3-butanedione monoxime (26.40g, 26.1mmol), and EtOAc (105ml). The reaction was stirred at 5°C for 3 h. Ice cold ether (575ml) was then added, and the resultant precipitate was filtered, washed with ether, and dried at 25°C for 16 h to give the product as a white solid (54.79g, 71% yield, mp 149- 159°C).

Analysis for: C12 H1 1CIF3NO2 Calc'd: 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-phenyl)-oxazole

In to a 5°C solution of 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole N-oxide hydrochloride (1 13.71g, 387.5 mmol) in CHCI3 (560ml), was added phosphorus oxychloride (39.4ml, 422.4 mmol) in CHCI3, dropwise over 15 min. The reaction was refluxed for 2.5 h, then cooled to 5°C, poured into ice water, and basified with NaOH (IN). The organic layer was dried over MgSO4. Evaporation and recrystallization from ether/hexane, gave a yellow solid (30.0g, 28% yield, mp 84-85°C).

Analysis for: C12H9CIF3NO Calc'd: C, 52.29; H, 3.29; N, 5.08 Found: C, 52.54; H, 3.20; N, 4.92

Step c) I-l3-r5-methyl-2- ⁽ 4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxyl-phenyll-ethanone

A mixture of 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (24.3g, 88.2 mmol), 3-hydroxyacetophenone (10. Og, 73.5 mmol), and potassium carbonate (13.2 g, 95.6 mmol), was stirred at 70°C for 16 h. The reaction was poured into water, acidified

with HCl (IN), and extracted with EtOAc. The organic extracts were dried over MgSO4. 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: C20H 16F3NO3 Calc'd: C, 63.99; H, 4.29; N, 3.73

Found: C, 63.86; H, 4.30; N, 3.64

Step d) (E)-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvπ-oxazol-4- ylmethoxyl-phenyll-but-2-enoic acid ethyl ester

In to a 0°C mixture of sodium hydride (4.27 g, 142.6 mmol) and toluene (500ml), was added triethylphosphonoacetate (29.79 ml, 150.1 mmol) via syringe. The reaction was stirred for 1 hour, and then l-{ 3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-phenyl}-ethanone (28.15 g, 75.1 mmol) in THF (150 ml) was added dropwise. The reaction mixture was stirred at room temperature for 16 h, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. 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: C24H23F3NO4 Calc'd: C, 64.57; H, 5.19; N, 3.14

Found: C, 64.81; H, 5.01; N, 3.13

Step e) (Ε -3-l3-f5-methyl-2-(4-trifluoromethyl-phenvπ-oxazol-4- ylmethoxyl-phenvU-but-2-en-l -oI

Di-isobutyl aluminum hydride (l.OM in THF) (219.2 ml, 219.2 mmol) was added, by syringe, to a -25°C solution of 3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-phenyl}-but-2-enoic acid ethyl ester (24.42 g, 54.8 mmol) in THF (300 ml). The reaction was warmed to 0°C and stirred for 1.5 h. It was poured into ice water, acidified with HCl (2N), stirred for 45 min, then extracted with EtOAc. The organic extracts were dried over MgSO4. 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: C22H18F3NO3 Calc'd: C, 65.83; H, 4.52; N, 3.49

Found: C, 65.78; H, 4.53; N, 3.45

Step f) (E)-N-tert-ButoxycarhonvIoxy-3-(3-r5-methyl-2-(4- trifluoromethyl-phenyl)-oxazol-4-ylmethoxyl-phenyl)-but-2-en yl -carhamic acid tert-hutvl ester

In to a -20°C solution of 3- {3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-phenyl}-but-2-en-l-ol (3.1 g, 7.69 mmol) in THF (50 ml), was added triphenylphosphine (2.42 g, 9.23 mmol) and tert-butyl N-(tert-butoxy-carbonyloxy) carbamate (2.15 g, 9.23 mmol). Diethylazodicarboxylate (1.45 ml, 9.23 mmol) in THF (10 ml) was then added via syringe, and the reaction was stirred for 1 h at 0°C. The reaction was poured into water, and extracted with EtOAc. The organic extracts were dried over MgSO4. 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: C32H37F3N2O7 Calc'd: 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-f5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxylphenyl ⁾ -but-2-envP-hvdroxylamine

Trifluoroacetic acid (20 ml) was added in to a solution of (E)-N-tert-butoxycarbonyloxy-3- 3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmetho xy]-phenyl}-but-2-enyl)- carbamic acid tert-butyl ester (4.5 g, 7.28 mmol) and CH2CI2 (40 ml). The reaction mixture was stirred at room temperature for 8 h. The volatiles were removed in vacuo, and the residue taken in ether/water. It was basified to pH = 9-10 with NaOH (2N), and the organic layer separated and washed with water and brine. The organic layer was dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/

EtOAc 1/1 and MeOH/EtOAc 1/10), gave a clear oil (2.70 g, 88% yield).

Analysis for: C22H21F3N2O3 Calc'd: C, 63.15; H, 5.06; N, 6.70

Found: C, 63.34; H, 4.79; N, 6.53

Step h) fE)-2-f3-f3-r5-methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- ylmethyll-phenyl)-but-2-envπ-π .2.41oxa diazolidine-3.5-dione

N-(Chlorocarbonyl)isocyanate (0.548 ml, 6.22 mmol) was added dropwise to a -5°C mixture of N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylme thoxy]-phenyl}-

but-2-enyl)-hydroxylamine (2.6 g, 6.22 mmol) in THF (25 ml). The mixture was stirred for 30 min, then poured into HCl (IN) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 / MeOH) silica gel (hexane/ EtOAc 3/1), gave a white solid (1.85 g, 61% yield, m l36-138°C).

Analysis for: C24H20F3N3O5

Calc'd: C, 59.14; H, 4.13; N, 8.62

Found: C, 58.95; H, 3.92; N, 8.77

Exam l 4

(E)-2-(3-(3-r5-methyl-2-(4-trifluoromethoxy-phenvπ-oxazo I-4-ylmethoxy1- phenyl)-but-2-enyπ-ri .2.41oxadiazolidine-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 145-146°C.

Analysis for: C24H20F3N3O6 Calc'd: C, 57.26; H, 4.00; N, 8.35 Found: C, 57.26; H, 3.94; N, 8.22

Example 5

(E)-2-r3-(3-(5-methvl-2-r4-(2. 2. 2-trifluoro-ethox v)- phen yll-oxazol-4- ylmethoxy)-phenyl)-but-2-enyll-π .2.41oxadiazoIidine-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 145-146°C.

Analysis for: C25H22F3N3O6

Calc'd: C, 58.03; H, 4.29; N, 8.12 Found: C, 58.05; H, 3.28; N, 8.30

Example 6

(E -2-(3-r3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy -phenyll-hut-2-enyl)- π .2.41oxadiazolidine-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 131-132°C.

Analysis for: C23H21N3O5 Calc'd: C, 65.86; H, 5.05; N, 10.02

Found: C, 65.89; H, 5.10; N, 9.87

Example 7

(Z)-2-(3-r3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy1-phenvn -but-2-enyl>- ri.2.41oxadiazolidine-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: C23H21N3O5

Calc'd: C, 65.86; H, 5.05; N, 10.02 Found: C, 65.83; H, 5.18; N, 9.97

Example 8

⁽ E -2- ⁽ 3-n-r2-f5-meth yl-2-phenyl-oxazo)-4-yl )-ethoxy1-phenyl)-but-2- enyl)-π .2.41oxadiazolidine-3.5-dione

The title compound was prepared in substantially the same manner as described in Example 2. The required l-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-etha none was prepared according to the following procedure. The title compound was obtained as a white solid, m.p. 142-143°C.

Analysis for: C24H23N3O5 Calc'd: C, 66.50; H, 5.35; N, 9.69 Found: C, 66.18; H, 5.41; N, 9.48

Preparation of l -(4-r2-(5-methyl-2-phenyl-oxazol-4-vh-ethoxyl-phenyl)- ethanone

Diethylazodicarboxylate (20.7 mL, 131.6 mmol) in THF (35 mL) was added dropwise in to a cold (0°C) solution of 4-(2'-hydroxy-ethyl)-5-methyl-2-phenyloxazole (25.0 g, 123.0 mmol), triphenylphosphine (34.5 g, 131.6 mmol), and 3'-hydroxyacetophenone (18.0 g, 131.6 mmol) and THF (180 mL). The mixture was allowed to come to room temperature and stirred for 48 hours. Then, it was poured into H ₂ O, 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 (30.5 g, 77% yield, m.p. 70-71°C).

Analysis for: C ₂₀ H ₁₉ NO ₃

Calc'd: C, 74.75; H, 5.96; N, 4.36

Found: C, 74.70; H, 6.15; N, 4.28

Example 9

(E)-2-{3-r2-(5-methyl-2-phenyl-oxazol-4-ylmethyll-benzofu ran-5-yll-but- 2-envπ-f l .2.41oxadiazolidine-3.5-dione

Step a) I -r2-(5-me h yl-2-phenyl-oxazol-4-yl eth vP-ben ofuran-5-yll- ethanol

Methyl magnesium choride (4.2 ml, 12.62 mmol) was added in to a cold (0°C) solution of 2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-carbald ehyde (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 min, and at room temperature for 30 min, then poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 2/1) gave a yellow solid (3.75 g, 88% yield, p 103-105°C).

Analysis for: C21H19NO3

Calc'd: C, 75.66; H, 5.74; N, 4.20 Found: C, 75.35; H, 5.80; N, 4.11

Step b) l -f2-(5-methyl-2-phen yl -oxazol-4-ylmeth yl)-benzofuran-5-yll- ethanone

Freshly prepared Jones' Reagent (6.5 mL, 10.51 mmol) was added dropwise in to a cold (10°C) solution of l-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]- ethanol

(3.5g, 10.51 mmol) and acetone (50 mL). After 30 min, the mixture was poured into water, and extracted with ethyl ether/EtOAc : 1/1. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/

EtOAc 2/1), gave a yellow solid (3.4 g, 97% yield, mp 108-109°C). Analysis for: C21H17NO3

Calc'd: C, 76.12; H, 5.17; N, 4.23 Found: C, 76.38; H, 5.13; N, 4.09

Step c) (E)-3-r2-(5-methyl-2-phenyl-oxazol-4-yImethvπ-benzofuran-5- yl1-but-2-enoic acid ethyl 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: C25H23NO4 Calc'd: C, 74.80; H, 5.77; N, 3.49

Found: C, 74.68; H, 5.75; N, 3.40

Step d) (E)-3-r2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5- yll-but-2-en-I -ol

The title compound was prepared in substantially the same manner as described in Example 3, step e, and was obtained as a white solid, m.p. 119- 121 °C.

Analysis for: C23H21 NO3 Calc'd: C, 76.86; H, 5.89; N, 3.90 Found: C, 76.71; H, 5.87; N, 3.77

Srep e) (E)-I -hvdroxy-l -(3-r2-(5-methyl-2-phenvI-oxazoI-4-ylmethyl - benzofuran-5-yl1-but-2-envn-urea

Diethylazodicarboxylate (2.56 mL, 16.3 mmol) was added dropwise in to a cold (-20°C) mixture of (E)-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5- yl]-but-2-en-l-ol (4.5 g, 12.5 mmol), triphenylphosphine (4.27 g, 16.3 mmol), N,O-bis(carbo- phenoxy)hydroxylamine (4.45 g, 16.3 mmol) and THF (100 mL) . After stirring for 30 minutes at -20°C, the mixture was allowed to come to 0°C and stirred for 2 hours. Then, it was poured into H2O and extracted with EtOAc. The organic extracts were dried over MgSO Evaporation gave a yellow oil (6.5), which was placed in a pressure vessel. Anhydrous ammonia (20 mL) was condensed in the vessel. The mixture was stirred at -5

°C to -10 °C for 3 hours and then at room temperature 18 hours. The excess ammonia was allowed to escape in to an acidic solution and the residue was recrystallized from ethyl ether/acetone, to give a white solid (2.5 g, 48% yield, m.p. 111-113 °C).

Analysis for: C24H23N3O4 Calc'd: C, 69.05; H, 5.55; N, 10.07

Found: C, 68.66; H, 5.36; N, 9.83

Step f) (E - l -Methoxycarbonyloxy- l -(3-r2-(5-methyl-2-phenyl-oxazol-4- ylmethyP-benzofuran-5-yl1-but-2-enyl)-urea

Sodium hydride (0.3 g, 10.0 mmol) was added portionwise in to a cold (0 °) solution of (E)-l-hydroxy-l-(3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)- 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 lhour, poured in to dioxane (50 mL)/MaOH (2N, 5 mL) solution and after 10 minutes acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporatuion and purification by flash chromatography on silicagel

(hexane/EtOAc 2/1), gave a yellow solid (1.72 g, 79% yield, m.p. 65-67 °C).

Analysis for: C26H25N3O6 Calc'd: C, 65.68; H, 5.30; N, 8.84

Found: C, 65.94; H, 5.06; N, 8.83

Step g) (E)-2-(3-r2-(5-methyl-2-phenyl-oxazol-4-ylmethyll-benzofuran - 5-yl1-but-2-enyl)-π .2.41oxadiazolidine-3.5-dione

Sodium hydride (76 mg, 2.52 mmol) was added portionwise in to a cold (0 °) solution of E)-N-carbamoyl-N-methoxycarbonyloxy-3-[2-(5-methyl-2-phenyl- oxazol-4-ylmethyl)- benzofuran-5-yl]-but-2-enyl-amine (1.2 g, 2.52 mmol) and DMF (10 mL). The reaction mixture was stirred for 30 minutes and then poured into water (10 mL), acidified with HCl (2N) and extrated with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from ethyl ether, gave a yellow solid (0.72 g, 65% yield, m.p. 163- 165).

Analysis for: C25H21N3O5

Calc'd: C, 67.71; H, 4.77; N, 9.47 Found: C, 67.79; H, 4.56; N, 9.39

Example IQ

rE -2-(2-methyl-3-l4-r5-methvI-2-(4-trifluoromethvI-phenvπ-oxa zol-4- ylmethoxyl-phenyl)-allv1)-ri .2,41oxadiazolidine-3,5-dione

Step a) (E -2-methyl-3-(3-r5-methvI-2-(4-trιfiuoromethyl-phenyl)- oxazol-4-ylmethoxyl-phenyl)-acrylic acid ethyl ester

Triethyl 2-phosphonopropionate (2.64 ml, 1 1.08 mmol) was added dropwise in to a cold (0 °C) suspension of sodium hydride (0.31 g, 10.52 mmol) and toluene (50ml). After the addition, the mixture was stirred for 1 hour, and then 3-[5-methyl-2-(-4-trifluoromethyl- phenyl)-oxazol-4-ylmethoxy)-benzaldehyde (2.0 g, 5.54 mmol) in THF (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 hours, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 8/1) gave a clear oil (2.2 g, 89% yield).

Analysis for: C24H22F3NO4 Calc'd: C, 64.71; H, 4.98; N, 3.14 Found: C, 64.82; H, 4.99; N, 2.93

Step b) (EV2-methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn- oxazol-4-ylmethoxyl-phenyl)-prop-2-en-l -ol

The title compound was prepared in substantially the same manner as described in Example 3, step e, and was obtained as a white solid, m.p. 90-91°C.

Analysis for: C22H20F3NO3 Calc'd: C, 65.50; H, 4.99; N, 3.47 Found: C, 65.40; H, 5.12; N, 3.33

Step c) (E)-2-methvI-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn- oxazol-4-ylmethoxyl-allyl)-hvdroxylamine

The title compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a yellow oil.

Analysis for: C22H21F3N2O3

Calc'd: C, 63.15; H, 5.06; N, 6.69 Found: C, 62.82; H, 4.99; N, 6.64

Step d) (E -2-(2-methyl-3-(4-r5-meth yl -2-(4-trifluorometh yl-phenvn- oxazol-4-ylmethoxy1-phenyl)-aIlvπ-ri .2.41ox diazolidine-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: C24H20F3N3O5

Calc'd: C, 59.14; H, 4.13; N, 8.62 Found: C, 59.20; H, 3.95; N, 8.57

Example 11

fE)-2-r2-ethyl-3-(3-r5-methyl-2-f4-triflιιoromethyl-phe nvn-oxazol-4- ylmethoxyl-phenyl)-allvπ-π ,2.41oxadiazolidine-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, mp 124-125°C.

Analysis for: C25H22F3N3O5 Calc'd: C, 59.88; H, 4.42; N, 8.38 Found: C, 59.94; H, 4.40; N, 8.34

Example 12

2-(l -Methyl-3-l3-r5-methyl-2-(4-trifluoromethyl-phenvπ-oxazol-4 - ylmethoxyl-phenyl>-allvπ-π .2.41oxadiazolidine-3.5-dione

Step a) 3-r5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxyl - benzaldehvde

The title compound was prepared in substantially the same manner as described in examplel, stepa, and was obtained as a yellow solid, mp 104-105°C.

Analysis for: C 19H 14F3NO3 Calc'd: C, 63.16; H, 3.91; N, 3.88 Found: C, 62.84; H, 3.97; N, 3.87

Step b) (E -4-(3-r5-Methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- ylmethoxyl-phenvI)-but-3-en-2-one

A solution of sodium hydroxide (1.13g, 28.25 mmol) in water (15 mL), was added to a mixture of 3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy] -benzaldehyde (6.0g, 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 (IN), stirred for 10 min, then extracted with EtOAc. The organic extracts were dried over MgSO4- Evaporation and purification by flash chromatography on silica gel (EtOAc 4/1) gave a white solid (4.6 g, 69% yield, mp 84-84°C).

Analysis for: C22H18F3NO3 Calc'd: C, 65.83; H, 4.52; N, 3.49 Found: C, 65.74; H, 4.41; N, 3.52

Step c) (E -4-l3-r5-Methyl-2-(4-tπfluoromethyl-phenvπ-oxazol-4- vlmethoxvl-phenvl)-hut-3-en-2-ol

Sodium borohydride (.389g, 10.22 mmol) was added to a -20°C solution of (E)-4-{3-[5- methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phen yl}-but-3-en-2-one (4.1g, 10.22 mmol), cerium trichloride (3.81g, 10.22 mmol), methanol (150 mL), and THF (30 mL). The reaction was stirred for 30 min, then poured into water, acidified with HCl (2N), an extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 2/1), gave a white solid (3.7g, 89% yield, mp 48-50°C). Analysis for: C22H20F3NO3

Calc'd: C, 65.50; H, 4.99; N, 3.47 Found: C, 65.78; H, 5.07; N, 3.58

Step d) rE1-N-f l -Methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-ρhenvn- oxazol-4-ylmethoxyl-phenyl)-allvπ-hydro ylamine

The title compound was prepared in substantially the same manner as described in Example 1, step b, and was obtained as a white solid, m.p. 118-120°C.

Analysis for: C22H21F3N2O3 Calc'd: C, 63.15; H, 5.06; N, 6.69 Found: C, 62.72; H, 5.04; N, 6.59

Step e) 2-(l -methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvπ-oxazol- 4-ylmethoxyl-phenyl)-aHvO-ri .2.41oxadiazolidine-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, mp 119-121°C.

Analysis for: C24H20F3N3O5 Calc'd: C, 59.14; H, 4.13; N, 8.62 Found: C, 59.00; H, 3.96; N, 8.82

Example 13

(E)-2-(3-l3-r2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmeth oxyl-phenyl)- l-methyl-allyl)-ri .2.41oxadiazolidine-3.5-dione

The title compound was prepared in substantially the same manner as described in Example 12, and was obtained as a white solid, mp 172-174°C.

Analysis for: C23H20CIN3O5 . Calc'd: C, 60.86; H, 4.44; N, 9.26 Found: C, 60.92; H, 4.39; N, 9.17

Example 14

rE .2-(2-methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn-oxaz ol-4- ylmethoxyl-phenyl)-but-2-en yl -ri .2.41oxadiazoIidine-3.5-dione

Step a) (E -2-methyl-3-(3-I5-methvI-2-(4-trifluoromethyl-phenyl)- oxazol-4-ylmethoxy1-phenyl)-but-2-enoic acid ethyl ester.

(Z -2-methvI-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn- oxazol-4-ylmethoxy1-phenyl)-but-2-enoic acid ethyl ester

The title compounds was prepared in substantially the same manner as described in Example 1, step c, and were obtained as white solids. (trans-) Analysis for: C25H24F3NO4

Calc'd: C, 65.35; H, 5.26; N, 2.3.05 Found: C, 66.74; H, 5.39; N, 2.84

(cis-) Analysis for: C25H24F3NO4 Calc'd: 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-f3-r5-methyl-2-(4-trifluoromethyl-nhenvn- oxazol-4-ylmethoxyl-phenyl)-but-2-en-l -ol

The title compound was prepared in substantially the same manner as described in Example 2, step a, and was obtained as a white solid, m.p. 115-116°C.

Analysis for: C23H22F3NO3 Calc'd: C, 66.18; H, 5.31; N, 3.56 Found: C, 66.04; H, 5.32; N, 3.49

Step c) fE -N-(2-Methyl-3-(3.r5-methyl-2-(4-trifluoromethyl-phenvn- oxazol-4-ylmethoxyl-phenyl)-but-2-enyl )-hvdrox via mine

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. 115-116°C.

Analysis for: C23H23F3N2O3 x 1 H2O Calc'd: 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-r5-methyl-2-(4-trifluoromethyl-phenvn- oxazol-4-ylmethoxyl-phenyl ⁾ -but-2-enyl -ri .2.41oxadiaxoIidine-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: C25H22F3N3O5 Calc'd: C, 59.88; H, 4.42; N, 8.38 Found: C, 59.79; H, 4.33; N, 8.16

Example 15

(Z -2-(2-methvI-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn-oxaz ol-4- ylmethoxyl-phenyl)-but-2-envI)-ri.2.41oxadiazolidine-3.5-dio ne

The title compound was prepared in substantially the same manner as described in Example 13, and was obtained as a white solid, m.p. 144-145°C.

Analysis for: C25H22F3N3O5

Calc'd: C, 59.88; H, 4.42; N, 8.38

Found: C, 59.69; H, 4.45; N, 8.37

Example 16

(E -2-(l-methyl-3-l3-r5-methyl-2-(4-trifluoromethyl-phenyl)-oxa zol-4- ylmethoxy1-phenvl)-hut-2-envI)-π .2.41oxadiazolidine-3.5-dione

Step a) (E)-3-l3-r5-Methyl-2-(4-trifluoromethyl-phenvπ-oxazol-4- ylmethoxyl-phenvD-but-2-enal

In to a solution of (E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylm ethoxy]- phenyl }-but-2-en-l-ol (21.48 g, 53.3 mmol) in CH2CI2 (500 ml), was added manganese dioxide (27.8 g, 319.8 mmol), and the reaction was stirred at room temperature for 60 h.

The mixture was filtered through solka floe. Evaporation and purification by flash

chromatography on silica gel (hexane/EtOAc 7/1), gave a light yellow solid (17.68 g, 82% yield, m.p. 145-146°C).

Analysis for: C22H18F3NO3

Calc'd: C, 65.83; H, 4.52; N, 3.49 Found: C, 65.78; H, 4.53; N, 3.45

Step b) (E)-4-(3-r5-Methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- vlmethoxv1-phenvl)-pent-3-en-2-oI

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-ylm ethoxy]- phenyl}-but-2-enal (16.68 g, 41.6 mmol) in THF (200 ml). The reaction was stirred at 0- 5°C for 25 min, then poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSθ4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 4/1), gave a yelllow solid (5.85 g, 33% yield, m.p. 45-47°C).

Analysis for: C23H22F3NO3 Calc'd: C, 66.18; H, 5.31; N, 3.36 Found: C, 65.97; H, 5.24; N, 3.34

Step c) (E)-N-(l -Methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn- oxazol-4-ylmethoxyl-phenyll-but-2--envπ-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: C23H23F3N2O3 Calc'd: C, 63.88; H, 5.36; N, 6.48 Found: C, 63.48; H, 5.33; N, 5.08

Step d) (E)-2-π -methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn- oxazol-4-ylmethoxyl-phenvI)-but-2-enyl)-π .2.41oxadiazolidine-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 (0.31 g, 27% yield, mp 55-56°C).

Analysis for: C25H22F3N3O5 Calc'd: C, 59.88; H, 4.42; N, 8.38 Found: C, 60.14; H, 4.49; N, 8.32

Example 17

(Ε)-2-(3-(4-r5-Methyl-2-(4-trifluoromethyl-phenvh-oxazol -4-ylmethoxyl- phenyl)-allvπ-ri .2,41oxadiazolidine-3.5-dione

Step a) (E -3-(3-r5-methyl-2-(4-trifluoromethyl-phenvπ-oxazol-4- ylmethoxyl-phenvD-acrylic ethyl ester

Triethylphosphonoacetate (4.38 ml, 22.06 mmol) was added dropwise in to a cold (0 °C) suspension of sodium hydride (0.59 g, 19.74 mmol) and toluene (lOOmL). After the addition, the mixture was stirred for 1 hour, and then 3-[5-methyl-2-(-4-trifluoromethyl- phenyl)-oxazol-4-ylmethoxy)-benzaldehyde (5.7 g, 15.79 mmol) in THF (20 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 5/1), gave a white solid (6.3 g, 93% yield, m.p. 79-80 °C). ^'

Analysis for: C23H18F3N3O5 Calc'd: C, 64.03; H, 4.67; N, 3.25 Found: C, 64.25; H, 4.63; N, 3.16

Step b) (E -l3-r5-Methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- ylmethoxy1-phenyl)-prop-2-en-l -ol

The title compound was prepared in substantially the same manner as described in Example 1, step d, and was obtained as a white solid, m.p. 117-118°C. Analysis for: C21H1 F3NO3

Calc'd: C, 64.78; H, 4.66; N, 3.59 Found: C, 64.60; H, 4.54; N, 3.65

Step c) fE -N-f3-l3-r5-methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- ylmethoxylphenyll-aHvπ-hvdroxylamine

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: C21H19F3N2O3 Calc'd: C, 62.37; H, 4.73; N, 6.93 Found: C, 62.17; H, 4.71; N, 6.79

Step d) (E -2-(3-M-r5-methyl-2-f4-trifluoromethyl-phenvn-oxazol-4- ylmethoxyl-phen yll-aIlvπ-ri .2.41oxadiazolidine-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. 179-181°C.

Analysis for: C23H18F3N3O5 Calc'd: 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-r5-methyl-2-(4-trifluoromethyl-phenyO-oxazol- 4-ylmethoxy1- phenyl)-cyclopropylmeth l)-π .2.4>oxadiazolidine-3.5-dione

(E)-2-(2-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol -4-ylmethoxy]-phenyl}- cyclopropylmethyl)-[l,2,4]oxadiazolidine-3,5-dione

Step a) (E -2- 3-r5-Methyl-2-(4-trifluoromethyl-phenvh-oxazol-4- ylmethoxyl-phenyll-cvclopropyP-methanol

Chloroiodomethane (3.37 mL, 46.28 mmol) was added dropwise in to a cold (0 °C) solution of diethyzinc (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-ylmet hoxy]- phenyl }-prop-2-en-l-ol (4.5 g, 11.57 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred for 1 hour, quenched with aqueous NH4CI 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 MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane /EtOAc 3/2), gave a clear oil (2.8 g, 80% yield).

Analysis for: C22H20F3NO3 Calc'd: C, 65.50; H, 5.00; N, 3.47

Found: C, 65.36; H, 5.12; N, 3.43

Step b) (E)-N-(2-l3-r5-methyl-2-(trifluoromethyl-phenvn-oxazol-4- ylmethoxyl-phenvπ-cvclopropylmethvπ-hvdroxylamine

The tide compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a clear oil.

Analysis for: C22H21F3N2O3 Calc'd: C, 63.15; H, 5.06; N, 6.69 Found: C, 62.90; H, 5.07; N, 6.66

Step c) (E)-2-(2-(3-r5-methyl-2-(4-trifluoromethyl-phenvn-oxazol-4- ylmethoxy1-phenyl>-cvclopropylmethyl)-ri .2.4loxadiazolidine-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: C24H20F3N3O5 Calc'd: C, 59.14; H, 4.14; N, 8.62 Found: C, 59.27; H, 3.99; N, 8.78

Example 19

(E -2-(2-methvI-2-(3-r5-methyl-2-(4-trifluoromethoxy-phenyl)-ox azol-4- ylmethoxy1-phenyl)-cvclopropyImeth yl -π .2.4)oxadiazolidine-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: C25H22F3N3O6 Calc'd: 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-r3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phen vπ-hexa-2.4- dienyl)-ri .2.41oxadiazolidine-3.5-dione

Step a) (E.E)-5-(3-r5-Methyl-2--phenyl-oxazol-4-vImethoxy1-phenyl)- hexa-2.4-dienoic acid ethyl ester

Lithium bis(trimethylsilyl)amide (45.12 mL, 45.12 mmol) was added dropwise in to a cold solution fo triethyl 4-phosphonocrotonate (10.0 ml, 45.12 mmol) in THF (200 mL). After stiring for 1 hour, l-(3-[5-methyl-2~phenyl-oxazol-4-ylmethoxy]-phenyl)-ethanone (12.0 g, 39.1 mmol) in THF (50 mL) was added dropwise. The reaction mixture was allowed to come to room temperature and stirred for 24 hours. Then, it was quenched with aqueous NH4C1, poured into water, acidified with HCL (2N), and extracted with EtOAc. The organic extracts were dried over MgSθ4. Evaporation and purification by flash chromatography on silica gel (hexane/EtOAc 8/1), gave a yellow oil (9.6 g, inseparable mixture of cis- and trans- isomers).

Analysis for: C25H25NO4 x 0.25 H2O Calc'd: C, 73.62; H, 6.26; N, 3.43 Found: C, 73.69; H, 5.86; N, 3.44

Step b) ⁽ E.E ⁾ -5-r3- ⁽ 5-Methyl-2"Phenyl-oxazol-4-ylmethoxy1-phenyl)- hexa-2.4-dien-l .ol

Di-isobutyl aluminum hydride (l.OM in THF, 55.83 ml, 55.83 mmol) was added dropwise in to a cold (-50°C) solution of (E,E)-5-(3-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]- phenyl)-hexa-2,4-dienoic acid ethyl ester(7.5 g, 18.61 mmol, mixture of 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, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 4/1), gave the trans- (4.9 g), and the cis- (1.7 g) isomers as yellow oils.

(trans-) Analysis for: C23H23NO3

Calc'd: C, 76.43; H, 6.41; N, 3.88 Found: C, 76.25; H, 6.36; N, 4.03

(cis-) Analysis for: C23H23NO3

Calc'd: C, 76.43; H, 6.41; N, 3.88 Found: C, 75.98; H, 6.21; N, 3.69

Step c) fE.E -N-(5-r3-(5-MethvI-2--phenyl-oxazol-4-ylmethoxyl-nhenvn- hexa-2.4-dienyl -hvdroxylamine

The tide compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a light yellow oil.

Analysis for: C23H24N2O3 Calc'd: C, 73.38; H, 6.43; N, 7.44

Found: C, 73.41 ; H, 6.45; N, 7.20

Step d) (E. E -2-f5-r3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy -phenyll- hexa-2.4-dien yl ⁾ -π .2.41oxa diazolidine-3.5-dione

The tide compound was prepared in substantially the same manner as described in Example 2, step c, and was obtained as a white solid, m.p. 151-152 °C.

Analysis for: C25H23N3O5 Calc'd: C, 67.40; H, 5.20; N, 9.43 Found: C, 67.70; H, 5.28; N, 9.35

Example 21

(Z. E)-2-(5-r3-(5-methyl-2-phenyl-oxazol-4-vImethoxy -phenyll-hexa-2.4- dienyl)-ri .2.41oxadiazoIidine-3.5-dione

The title compound was prepared in substantially the same manner as described in Example 20, and was obtained as a white solid, m.p. 117-118 °C.

Analysis for: C25H23N3O5 Calc'd: C, 67.40; H, 5.20; N, 9.43

Found: C, 67.32; H, 5.21; N, 9.32

Example 22

2-(l-methyl-3-P-r5-methyl-2-(4-trifluoromethyl-phenvπ-ox azol-4- ylmethoxy1-phenyl)-prop-2-vnvP-ri .2,41oxadiazolidine-3.5-dione

Step a) 4-(3-Ethvnyl-phenoxymethvπ-5-methyl-2-(4-trifluoromethyl- phenvD-oxazole

(Bromomethyl)triphenylphosphoniu bromide (21.2 g, 48.61 mmol) was added portionwise to a -78°C mixture of potassium-tert-butoxide (10.9 g, 97.23 mmol) in THF (200 mL). The mixture was stirred for 2 h, then 3-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-ylmethoxy]-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 quensched with aqueous NH4CI , poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. 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: C20H14F3NO2 x 0.25 H2O Calc'd: C, 66.39; H, 4.01; N, 3.87

Found: C, 66.67; H, 3.75; N, 4.15

Step b) 4-(3-r5-methyl-2-(4-trifluoromethyl-phenyl -oxazoI-4- ylmethoxy1-phenyl)-but-3-vn-2-ol

Lithium bis(trimethylsilyl)amide (10.5 mL, 10.5 mmol) was added to a cold (0°C) solution of 4-(3-ethynyl-phenoxymethyl)-5-methyl-2-(4-trifluoromethyl-ph enyl)-oxazole (3.0 g, 8.77 mmol) in THF (100 mL). After 1 h at 0°C, acetaldehyde (0.59 mL, 10.5 mmol) was added dropwise. The mixture was stirred for 30 min, then quenched with aqueous NH4CI, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel(hexane/ EtOAc 4/1) gave a yellow solid (2.1 g, 59% yield, m.p. 86-87°C). Analysis for: C22H1 F3NO3

Calc'd: C, 65.83; H, 4.52; N, 3.49 Found: C, 65.89; H, 4.38; N, 3.36

step c) N-(l -Methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-phenvn-oxazol- 4-ylmethoxyl-phenyl)-prop-2-vnyl -hvdroxylamine

The title compound was prepared in substantially the same manner as described in Example 2, step b, and was obtained as a light yellow solid, m.p. 110-112°C.

Analysis for: C22H19F3N2O3 Calc'd: C, 63.46; H, 4.60; N, 6.73 Found: C, 66.71; H, 4.56; N, 6.69

Step d) 2-(l -methyl-3-(3-r5-methyl-2-(4-trifluoromethyl-phenyl -oxazol- 4-ylmethoxyl-phenyll-prop-2-vnyl)-π .2.41oxadiazolid ine-3.5-dione

The tide compound was prepared in substantially the same manner as described in Example 1, step g, and was obtained as a white solid, m.p. 84-86°C.

Analysis for: C24H18F3N3O5 Calc'd: C, 59.38; H, 3.74; N, 8.66 Found: C, 59.38; H, 3.50; N, 8.56

Example 23

2-{l-methyl-3-r3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-p henyll-prop-2- vnyl)-ri .2.41oxadiazolidine-3.5-dione

The tide compound was prepared in substantially the same manner as described in Example 21, and was obtained as a white solid, m.p. 55-57°C.

Analysis for: C23H19N3O5 x 0.25 H2O

Calc'd: C, 65.40; H, 4.01; N, 9.95 Found: C, 65.20; H, 4.36; N, 10.23

Example 24

(E -5-0-r3-(5-methyI-2-phenyl-oxazol-4-ylmethyl1-phenyll-hut-2- enyl)- oxazolidine-2.4-dione

Step a) ⁽ E ⁾ -4-r3- ⁽ 3-Chloro-l -methyl-propenyl)-phenoxymethvπ-5- methyl-2-phenyl-oxazole

3-[3-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-but-2 -en-l-ol (10.0 g, 29.85 mmol) in ether (50 mL) was added to a cold(0°C) suspension of phosphorus oxychloride (9.31 g, 44.77 mmol), calcium carbonate (4.47 g, 44.77 mmol), 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 MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 5/1) gave a clear oil (9.1 g, 86% yield).

Analysis for: C21H20CINO2 Calc'd: C, 71.28; H, 5.70; N, 3.96 Found: C, 71.42; H, 5.71; N, 3.88

Step b) ⁽ E ⁾ -5-(3-r3-f5-methyl-2-phenyl-oxazol-4-ylmethyll-phenyll -but- 2-enyl)-oxazolidine-2.4-dione

Tert-butyl lithium (17.5 mL, 29.7 mmol) was added dropwise in to a rapidly stirred cold (- 78°C) solution of lithium chloride (3.6 g, 84.84 mmol) and oxazolidine-2,4-dione (1.43 g, 14.14 mmol) in THF (90 mL). The mixture was stirred at -78°C for 30 minutes, then gradually warmed to 0°C. After recooling to -78°C, (E)-4-[3-(3-chloro-l-methyl- propenyl)-phenoxymethyl]-5-methyl-2-phenyl-oxazole (5.0 g, 14.14 mmol) in THF (5 mL) was added 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 NH4CI, poured into water, acidified with HCl, and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/ EtOAc 3/1), gave a white solid (3.5 g, 59% yield, m.p. 138-139°C).

Analysis for: C24H22N2O5 Calc'd: C, 68.89; H, 5.30; N, 6.69

Found: C, 68.49; H, 5.29; N, 6.71

Example 25

(E -5-r3- -(5-methyl-2-r4-(2. 2. 2-trifluoro-ethoxy - phenvIl-oxazol-4- ylmethoxy)-phenvπ-but-2-enyll-oxazolidine-2,4-dione

The title compound was obtained in substantially the same manner as described in Example 24, and was obtained as a white solid, m.p. 120-121°C.

Analysis for: C26H23F3N2O6 Calc'd: C, 60.46; H, 4.49; N, 5.42

Found: C, 60.62; H, 4.47; N, 5.18

Example 26

(E)-5-(3-l3-r5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazo l-4-ylmethoxy1- phenyl)-but-2-enyl)-oxazolidine-2.4-dione

The tide compound was obtained in substantially the same manner as described in Example 24, and was obtained as a white solid, m.p. 105-106°C. Analysis for: C25H21F3N2O6

Calc'd: C, 59.76; H, 4.21; N, 5.58

Found: C, 59.92; H, 4.12; N, 5.54

Example 27

(E)-5-(3-l3-r2-(5-methyl-2-phenyl-oxazol-4-vn-ethoxyl-phe nvI)-but-2- enyl -oxazolidine-2.4-dione

The tide compound was obtained in substantially the same manner as described in Example 24, and was obtained as a white solid, m.p. 100-101°C.

Analysis for: C25H24N2O5

Calc'd: C, 69.43; H, 5.59; N, 6.48 Found: C, 69.59; H, 5.89; N, 6.16

Example 2

fE -5*-f3-r3-(5-methyl-2-phenvI-oxazol-4-ylmethoxy -phenvn-hut-2-enyl)- thiazolidine-2.4-dione

Butyl lithium (16.6 mL, 41.58 mmol) was added dropwise in to a cold (-78°C) solution of thiazolidine-2,4 -dione ( 2.31 g, 19.8 mmol) and THF (80mL). 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 recooling to -78°C, 4-[3-(3-chloro-l-methyl-propenyl)- phenoxymethyl]-5-methyl-2-phenyl-oxazole (7.0 g, 19.8 mmol) in THF (15 mL) was added all at once. 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 NH4CI, poured into water, acidified with HCl, and extracted with EtOAc. The organic extracts were dried over MgSθ4. Evaporation and purification by flash chromatography on acid washed (5% H3Pθ4/MeOH) silica gel (hexane/ EtOAc 3/1), gave a white solid (2.9 g, 33% yield, m.p. 48-49°C).

Analysis for: C24H22N2O4S x 0.25 H2O

Calc'd: 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-r5-methyl-2-(4-trifluoromethoxy-phenyπ-oxazo l-4-ylmethoxy1- phenyl ⁾ -but-2-enyl ⁾ -thiazolidine-2,4-dione

The tide compound was obtained in substantially the same manner as described in Example 27, and was obtained as a light yellow solid, m.p. 50-51°C.

Analysis for: C25H21F3N2O5S

Calc'd: C, 57.91; H, 4.08; N, 5.40 Found: C, 57.57; H, 4.16; N, 5.30

Pharmacology

Determination of Blood Glucose Lowering in db/db Mice.

On the morning of Day 1, 35 mice [male diabetic db/db (C57BL/KsJ) mice (Jackson

Laboratories), 2-7 months of age and 50-70 g] were fasted for 4 hours, weighed and a baseline blood sample (15-30 μl) was collected from the tail-tip of each mouse without anesthesia, and placed directly into a fluoride-containing tube, mixed and maintained on ice. Food was then returned to the mice. The plasma was separated and levels of glucose in plasma determined by the Abbott VP Analyzer. Because of the variable plasma glucose levels of the db/db mice, 5 mice having the most extreme (i.e., highest or lowest) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent mean plasma glucose levels (N=6 for 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 the ad libitum fed mice. On the morning of Day 4, the mice were weighed and food removed, but water was available ad libitum. Three hours later, a blood sample was collected and then the mice were given the fourth administration of drug or vehicle. Blood samples were collected again from the unanesthetized mice at 2 and 4 hrs after drug administration. The plasma was separated and levels of glucose in plasma was determined by the Abbott VP Analyzer.

For each mouse, the percent change of its plasma glucose level on Day 4 (mean of the 2 and 4 hr samples) from respective level before drug administration (Day 1 baseline sample) is determined as follows: mean of 2 and 4 hr samples (Day 4) _~ _ Baseline Sample (Day 1) ^{x IUυ}

Analysis of variance followed by Dunnett's multiple comparison (one-sided) 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 dosage administered, if the difference of the plasma glucose level has a p<0.05.

The actual difference between the mean percent change of the vehicle and drug-treated groups is shown in Table 1. The positive control, ciglitazone produces a 18 to 34% decrease in plasma glucose levels at 100 mg/kg/day x 4 days, p.o.

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 pharmacologic profile of McN- 3495 [N-(l-methyl-2-pyrrolidinylidene)-N'-phenyl-l-pyrrolidine-ca rboximidamide], 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 nephropathy by 2-tetradecylglycidate in the diabetic mouse (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, diabetic Chinese hamsters, and normal and streptozocin-diabetic rats. Diabetes 32: 830-838.

5. 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 Blood Glucose Lowering Effect in ob/ob mice

The non-insulin-dependent diabetic syndrome can be typically characterized by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance. The genetically obese-hyperglyce ic ob/ob mouse exhibits many of these metabolic abnormalities and is thought to be a useful media to search 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 into 4 groups of 10 mice. The mice are housed 5 per cage and are maintained on normal rodent chow with water ad libitum. The mice receive test compound daily. The test compound is suspended in 0.5 mL of 0.5% methyl cellulose and is administered by gavage (dissolved in drinking water) or admixed in the diet. The dose of compound given ranges from 2.5 to 200 mg/kg/day. Body weight of fed animals is measured at the beginning of each week and doses for the entire week are calculated using this weight and are expressed in terms of the active moiety of the compound. Control mice receive vehicle only. On the morning of Days 4, 7 or 14 two drops of blood (approximately 50 μl) are collected into sodium fluoride containing tubes either from the tail vein or after decapitation. For those studies in which the compound is administered daily by gavage, the blood samples are collected four hour after compound administration. The plasma is isolated by centrifugation and the concentration of glucose is measured enzymatically on an Abbott V. P. Analyzer and the plasma concentration 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 mean plasma glucose of the vehicle treated mice. Analysis of variance followed by Dunnett's Comparison Test (one tailed) is used to estimate the significant difference between the plasma glucose values from the control group and the individual compound treated groups. The results are presented in Table II.

The diabetic db/db (C57BL/KsJ) mouse exhibits many metabolic abnormalities that are associated with non-insulin dependent diabetes mellitus (Type II) in humans. The

animals are obese, glucose intolerant and have fasting hyperglycemia which is sometimes accompanied by a paradoxical hyperinsulinemia (1). Furthermore, the db/db mouse will eventually develop some of the long-term complications that have been associated with diabetes mellitus (1). In spite of these commonalities, the acute administration of sulfonylureas (even at extremely high doses) will not reduce the hyperglycemia of the db/db mouse (2). The ability of a few other hypoglycemic agents to be effective in this species suggest that the other agents have mechanism of action which are different from that of the sulfonylureas (2,3,4,5). Such compounds, therefore, are more likely to be efficacious in the population of type II diabetic patients that do not respond to sulfonylurea therapy.

Table II

References:

1. Brichard, S., Bailey, C. and Henquin, J.: Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes 39: 1326-1332, 1990.

2. Chang, A., Wyse, B., Gilchrist, B., Peterson, T. and Diani, A.: Ciglitazone, a new hypoglycemic agent. I. Studies in ob/ob and db/db mice, diabetic Chinese hamsters, and normal and streptozoticin-induced diabetic rats. Diabetes 32: 830-838, 1983.

3. Coleman, D.: Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14: 141-148, 1978.

4. Heding, L. G.: Determination of total serum insulin (IRI) in insulin-treated diabetic patients. Diabetologia 8: 260-266, 1972.

Pharmaceutical Composition

Based on the results of the pharmacological assay, the compounds of this invention are useful in the treatment of hyperglycemia in diabetes mellitus. The compounds may be administered neat or with a pharmaceutical carrier to a mammal in need thereof. The pharmaceutical carrier may be solid or liquid and the active compound shall be a therapeutically effective amount.

A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which 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 shape and size desired. 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 in 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 solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening 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, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). 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 otiier pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compound can also be administered orally either in liquid or solid composition form.

Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. A dosage range of from 0.1 to 200 mg/kg/day is contemplated, with a preferred dosage of from 0.1 to 100 mg/kg/day. Due to uncertainty in relating laboratory mouse study data to otiier mammals, the degree of hyperglycemia, and the compound selected, the dosages used in the treatment of non-insulin dependent diabetes mellitus must be subjectively determined by a physician or veterinarian according to standard medical or veterinary practice.