ORAL HYPOGLYCEMIC AGENTS

Background ς__ _l__ Invention

This invention relates to C-substituted pentacycloazoles containing heteroatoms in the 2, 3 and 5 positions of the pentacycloazole ring and N-substituted pentacycloazoles containing nitrogen atoms in either the 2 and 4 positions or in the 3 position of the pentacycloazole ring.

Ellingboe et al . state in the J. Med. Chem.. Vol. 36, pages 2485-2493 (1993), which is hereby incorporated by reference, that drugs currently available for the control of the hyperglycemia associated with type 2 (non-insulin dependent) diabetes mellitus possess significant liabilities or efficacy limitations and that considerable effort has been directed toward the development of novel, orally active antihyperglycemic drugs. They also state that many of these new compounds incorporate a relatively acidic heterocycle which serves as the pharmacophore responsible for antihyperglycemic activity, such as thiazolidine-2,4-dione, tetrazole and oxazolidine-2, -dione rings. In an earlier paper, J. Med. Chem. Vol. 35, pages 1176-1183 (1992), which is hereby incorporated by reference, Ellingboe et al .

described a number cf antihyperglycemic agents, which contain an acidic 2K-1.2. 2 . Ξ-oxathiadiazoie 2-oxide ring, appended via a methylene bridge to numerous aromatic systems. Kangi et al . E.?. 177, 353, which is hereby incorporated by reference, disclose antihyperglycemic thiazoiidine pharmacophore appended via a methyiene bridge to suitable aromatic systems. The general object cf this invention is to provide new antihyperglycemic compounds based on new pharmacophores. Other objec s appear hereinafter. In one aspect, this invention s an antihyperglycemic compound selected from tne group ccns sting 2-substitutes pentacycloazole pnarmacopncre containing hetercatoms m the 2,2 and Ξ position cf the pentacycloazole ring and u-substituted pentacycloazole pharmacophore containing nitrogen atoms in a position selected from the group consisting of the 2 and 4 positions cf the pentacycloazole ring and the 3 position of the pentacycloazole ring.

In a second aspect, this invention is an antihyperglycemic composition comprising a pharmaceutically acceptable carrier, diluent or excipient and an effective amount cf an antihyperglycemic compound selected frcm tne group consisting C-suostituted pentacycloazole pnarmacopncre containing heteroatoms m the 2,3 and 5 position cf the pentacycloazole ring and N-alkyl substituted pentacycloazole pharmacophore containing nitrogen or other hetero atoms n a position selected from the group consisting of the 2 and 4 positions cf the pentacycloazole ring and the 3 position cf the pentacycloazole ring. In a third aspect, this invention is a method of reducing the hypergiycemia associated with non-insulin dependent diabetes ellitus which method comprises oraliy administering to a mammal, such as a human, a therapeutic

dose of an antihyperglycemic compound selected from the group consisting C-substituted pentacycloazole pharmacophore containing heteroatoms in the 2.3 and 5 position of the pentacycloazole ring and N-substituted pentacycloazole pharmacophore containing nitrogen atoms in a position selected from the group consisting of the 2 and 4 positions of the pentacycloazole ring and the 2 position of the pentacycloazole ring.

We have now found that the objects of this invention can be attained with antihyperglycemic compounds having a 2-suost tuted pentacycloazole pharmacophore containing neteroatcms m the 2, 2 and Ξ position of the pentacycloazole ring cr an M-al yi-substituted pentacycloazole pnarmacophore (where the alkyl group has 1 to 12 carbon atoms; containing nitrogen atoms in both the 2 and 4 positions or in the 3 position cf the pentacycloazole ring wherein the pentacycloazole ring is linked to a suitable aromatic system utilized with pharmacophores responsible for antihyperglycemic activity by an aliphatic group of 1 to 2 carbon atoms and a carbon atom of said aliphatic group is bonded directly to the pentacycloazole ring. Our studies have snown that other things being equal . many other compounds containing different pentacycloazole moieties, _acκ the antihyperglycemic activity cf the compounds of this invention. Further, it appears that if the pentacycloazole moiety is linked to the same aromatic system by an lsomeπc aliphatic group having no carbon atom bonded to the pentacycloazole ring, the compound lacks antihyperglycemic activity. For example, when a -CH2-S- linker was employed, the compound was inactive when the "£-" part of the linker was bonded to a C-pentacycloazole moiety and active when the "CH -" part cf the linker was bonded to a C-pentacycloazoie moiety. Likewise, when the pharmacophore was bonded directly

to the aromatic moiety without an aliphatic linking group, the compounds were inactive.

While Mullican ec al . m the J. Med. r em..

Vol. 26, pages 1090-1099 (1993) disclose a C-subscituted- 2,3, 5-triazole linked through methyiene to a 4-hydroxy-3, 5- dibutylphenyi moiety at page 1091 and Eoschelli et al. in j. Med. "h i-n.. Vol. 25, pages 1802 to 1810 (1993) disclose a C- substituted pentacycloazole containing heteroatoms in the 2,3 and 5 position linked through methyiene to a dichlorophenyiaminophenyi group moiety at page 1804, neither article descrices or suggests that the compounds have antihyperglycem c activity. Further, to the best of our knowledge neither the 4-hydroxy- , 5-dibutylphenyl moiety nor the dichloropnenyiamincphenyl group have been used with pharmacophores responsible for antihyperglycemic activity.

The compounds of this invention can be represented by the structure

Ar-(G; _n _ ₁ -(CH ₂ ) _m - ₁ -CH ₂ Z

The bond of attachment to Z is assigned number 1 as described m tne following schematic structure formula (I):

where each 0 is independently C, N, 0, or S as described in the followmc definition of Z.

Z is a C-suostituted pentacycloazole containing heteroato s m the 2, 3 and 5 positions of the pentacycloazole ring or an N-suoscituted (N at position 1) pentacycloazole containing N atoms m either the 2 and 4 positions or in the 2 position cf the pentacycloazole ring; G is oxygen or sulfur; and n are whole numbers ranging from 1 to 2; and Ar is a suitable aromatic system.

In somewhat greater detail, Z can have any of the structures inclusive cf double oond tautomeπc forms as follows:

wherein X_ is 0 or £; ∑2 s -SE; and each R is independently selected from K, methyl, ethyl, propyi and butyl. Ar can be any suitable aromatic system utilized with other pharmacophores responsible for antihyperglycemic activity such as those disclosed in the aforesaid Ellingboe ec -, articles; the aforesaid Kangi ≡c al . E . P . 177, 353; Momose z a- , m Ch° . ? *-"-. °-j lJ .. Vol. 29, No. 5 at pages 1440 to 1445 ^■ .1991); Canteilo ec al . E.P. 415605; Clark ec aJ. U.S. 4,791,125; Kees U.S. 5,183,825; Goldstein ec al . WO 93/00343; Hmdley E.P. 306,228 ail of which are hereby incorporated by reference. Accordingly, the aromatic systems can range from simple dihydronaphthaienε moieties in U.S. 5,183,825 to aromatic rings linked to heterocylic rings.

The preferred aromatic systems can be represented by the structure:

Y- (CH2> _p - t'G') -Ar ^' -

wherein Ar' is a divalent arylene moiety, such as phenylene, methyl substituted phenyiene, ohlorophenyiene, etc.; G" is 0 or Ξ; and Y is a cycioalkyl ring, such as methylcyclohexyl, a substituted or unsubstituted aryl group or a heterocyclic such as 2-phenyi-4-oxazolyl; p is a number from 1 to 6. An illustrative Ar ^■ group is shown in formula (II):

As s demonstrated in the Examples, the various C- subst tuted pentacycloazole compounds of this invention can be prepared by routine techniques. For example, C- substituted 2, 2 , 5-trιazoles can be prepared by reacting

o

(1) ArCH ₂ C ^• 0 CH ₃ hydrazme hydrate followed by cyclization with an isocyanate or

(2) ArCH ₂ C ^■ CH- 3-alk 1 semicarbazide methane sulfonic acid salt or

O

(3) ArOH ErCH;COCH _; followed by hydrazine hydrate and then cyclized with an isocyanate or

(4) ArOH N,N-dimethyl thiocarbamyl chloride

thermally rearranged, hvdrolyzed, followed y BrCK;COCH- and then cyclization with an isocyanate, or

O

(5) ArCH-CH-COCH- hydrazme hydrate followed by cyclization with an isocyanate, etc .

A C-substituted 2,3-d azole can be prepared by reacting ArCK2C02?. + Hydrazine hydrate followed by cyclization with CSi .

A C-suostituted 2,5-dιazoie can be prepared by reacting ArCH^CN - CH3OK - KC1 to form ArC (=NH2 )OCH3 ⁺ Cl- followed by Na m CH3OH to form an amidoxime and then treating with carbonyidiimidazole .

A C-suostιtuted-1, 3 , -oxathιazoiιn-5-one can be prepared by converting

ATCHTCOCHT

to tne amiαe :J . θ eα cy cycization with chlorocarocny εuifenyi cnicride.

A C-≤uostituted 2 , 2, 4-thιadιazoim-5-one can be prepared cy reacting ArC (=NH2 ) OCH3 ⁺ Cl~ described above with sodium hydride and cyciizmg with chlorocarbonylsulfeπyl chloride.

A N-substituted azole can be prepared either by reaction route (1) or (2) below:

( 1 ) Reacting A.rCHO with semicaroazide hydrochloride followed by reduction with boron πydr de and cyciizmg with caroonyidiimidazole or;

(2 ⁾ Reacting ArCH2NH2 with sodium cyanate and cyciizmg with diechyl oxylate.

The compounds of this invention and salts thereof exhibit excellent blood-glucose and blood-lipid lowering actions m mammals (e.g. , mouse, rat, dog, cat, monkey, horse, and human oemgs) , and show a low degree of toxicity in terms cf been acute and supacuce toxicities. Therefore, the compounds and salts tnereof are of vaiue to human beings

for the treatment of hyperiipemia, diabetes and their complications.

The compounds cf this invention are generally compounded with "pharmaceutically acceptable" carriers, diluents or excipients, which are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, cf course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about C.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention. Preferably the pharmaceutical formulation is in unit dosage form. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of active ingredient in a unit dose cf composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that t may be necessary to make routine variations to the dosage depending en the age and condition of the patient. The dosage will also depend on the route of administration. The compound can be administered by a variety of routes although oral is greatly preferred.

Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeucically effective amount cf the compounds cf the invention together with a pharmaceutically acceptable carrier or diluent therefor. In making the compositions cf the present mventicn. the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a

carπer which may be the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form cf tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration. For the pnarmaceutical formulations any suitable carrier known m the art can ce used. In sucn a formuiaticr., tne carrier may oe a soiid, liquid, or mixture cf a solid and a liquid. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or ciπdmg agents, for example, geiatm or acacia, and lubricating agents sucn as magnesium stearate, stearic acid, or talc. 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 binding properties in suitable proportions and compacted in the shape and size desired. The powders and taolets preferably contain from about 1 to about ?9 weight percent of the active ingredient which is novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl

cellulose, sodium carboxymethyi cellulose, low melting waxes, and cocoa butter. Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. Tne active ingredient can be dissolved cr suspended in a Ξ pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture cf both.

The active ingredient can also oe dissolved in a suitable organic solvent, for instance aqueous prcpylene glycol. Other compositions can be made by dispersing the G finely divided active ingredient n aqueous starch cr sodium carboxymethyi cellulose solution cr m a suitable oil.

Tne following Examples illustrate t e preparation cf ccmocun s cf tne invention unless ctnerv:ιse indicated ¹ .

SXAKPLES

General Experimental Method:

Melting points are uncorrected. Thin Layer Chromatography was performed on silica plates. Reactions were conducted under an atmosphere of nitrogen. NMR spectra were obtained in CDCI3 unless noted otherwise. Flash column chro atographies were performed over Siθ2-

2- 2-Phenyl-4-oxazolyi )ethanol was prepared as described Example 12 Part A.

Example I

Preparation of: -Methyl -5- [4- ( (2- (2-phenyl-4-oxazolyl ) ethoxy Jphenyl ) - methyl] 1,2, 4-trιazoiin-3-one.

Part a Preparation of:

Methyl 4- [2- (2-phenyl-4-oxazolyl ) ethoxyljphenyl acetate.

A stirred solution of 9.46 g 2- '2-phenyl-4- oxazolyϋ etnanol , 3.34 g methyl ' -hydrcxyphenyl) acetate, 13.10 g. tπphenyi phospn e and ^" 5 mL anhydrous THF (tetrahydrcfuran; was treated dropwise with 7.9 mL diethyl 5 azodicarooxylate over 15 minutes, allowing the temperature to rise spontaneously to 40-50 "C. The reaction was stirred at ambient temperature fcr 48 hours, treated with 2 mL of 30% H θ2. and evaporated vacuo. The residue was extracted with boiling Et2θ (ethyl etherj , contacted with 75 mL of 10 brine and dried over MgSθ4. Af er removal of the drying agent, tne solvent was evaporated, tne residue onromatograpneo. e uting with ethy.. acεtate-nexane . The product crystallized from ethyiacetate-hexane to provide 14.8 g (88%! , of a wnite solid mp 47-48"C. 15 Anal. Cal . for C ₂ θHι NO4 : C, 71.20; K, 5.68; N,

4.15; Found: C, 71.43; H, 5.66; N, 4.07. IR 1734 cm ^-1 ; NMR 5 3.15 (t, 2H) , 3.6 (ε, 3H) , 3.7 (s, 2H) , 4.3 (t, 2H) , 6.9

(d, 2H, (7.2 (d, 2H) . 7.5 (m, 4H) , 7.8 (s, 1H) ; MS:m/e 337.

Preparation of:

4- [2-2 ^' 2-pneny_-4-oxazoiyi > -ethoxyj nenyi acetyl hydrazine.

CO HNH-

A stirred solution of 2.3 g cf methyl 4- 2-(2- phenyl- -oxazoiyD etnoxyjphenyl acetate and 20 mL cf MeOH was treated with 2.4 mL cf 80% hydrazine hydrate, 0.5 gm cf NaOMe and heated to reflux for 0.5 hour, during which time a

copious precipitate formed. The cooled mixture was filtered and the white solid washed with MeOH and dried to provide 2.86 gm (86%) of product mp 163-165"C.

Anal. Cal. for C19K19M3O3: C, SI . 64 ; K, 5.68 ; N,

5 12.46. Found: IP. 1643 cm ^-1 . MS/m/e 32 1 . IMP. 1.6 delta

(broad m, 2H) , 3.1 (t, 2H) , 3.5 (s, 2K) , 4.3 (t, 2ή' ) , 6.9 (d, 2H) , 7.2 (d, 2K) , 7.5 (m, 4H, 7.8 (s, IK! .

Part C C Preparation of:

4-Methyl-5- [4- ( ^; 2 - (2-phenyl-4-oxazolyl) etncxyjphenyi 1methyl] -

1,2, 4-trιazoiin-3 -one .

Tne intermediate prepared m Exampl 1 Part E was suspended in 30 L cf TKF ( etrahydrofuran, , treated with 0.4 mL of methyl isocyanate and the stirred mixture heated to reflux for 2 hours. The mixture was cooled, diluted with

Et2θ and filtered. The resulting white powder (0.97 gm, mp

191-194 'O was added to a solution prepared from 0.5 gm of Na metal and 25 mL of MeOK. The resulting solution was heated to reflux under an atmosphere of nitrogen for 5 hours, cooled and acidified with IN HCi . The resulting precipitate was collected by filtration, washed with KτO and dried.

Recrystalli∑atio from THF-iPrOK provided 0.82 gm (36%) of product, mp 164-167'C. Anal. Cal. for C21H20N4O3 • C, 67.01; H, 5.36; N,

14.82. Found: C, 66.75; H, 5.19; N, 14.63. Ir: 3302, 3072, 2933, 2854, 1691 cm ^-1 . Ms: m/e 3 ^" £. NMR 1.7 (broad s, IK, exchanges with D20) , 2.1 (s, 3H) , 3.15 (t.2K) , 3.85 (s.2K) , 4.3 (t, 2H) , 6.9 (d,2KΪ , 7.2 (d,2K) , 7.5 ιm,4K), 7.8 (s, 1H) .

Example 2

Preparation of: -Ethyl-5- [4- ( (2- (2-phenyl- -oxazoiyl ) ethoxy)phenyl j ethvl] 1,2, 4-trιazoiin-3-one .

A suspension of 1.5 gm cf the intermediate prepared

10 as in Example I Part E was suspended in 30 mL of THE, treated with 0.4 mL cf ethyl isocyanate and refluxed for 2 hcurs . The mixture was cooled, diluted with Et2<2- and filtered. The white solid was collected, washed with Et2θ and added to a solution prepared from 1.4 gm cf 85% KOH and 100 mL cf MeOH.

15 The resulting solution was heated to reflux for 24 hcurs, at which time TLC (thin layer chromatcgraphy) showed complete consumption cf starting material. The cooled solution was acidified with IN KCl and the resulting precipitate collected by filtration. Recrystallization from ETOAc (ethyl acetate)

20 provided 0.89 gm (51%) of product as white needles mp 139- 140 ^* C.

Anal. Cal. for C22 ^H 22 ^N 4°2 ^{: c} < 67.68; H, 5.58; N, 12.2=. Found: C, 67.40; H, 5.73; i:, 14.40. Ir: 1690cm ^"1 .

MS . e 39! NM? delta 1.05 (t jr. ,' i.l ( 2K) , 3.5 (1,

-) ^** ; bD (S, ΔΓ. 4.3 (t, 2K) , (c, 2K) , ^• .2 (c, :κ) , ^■

'-., Δ ^• - IK) .

Mel-hnri 7

Part A. Preparation of:

3-Ethyl semicarbazide ethanesul omc acid salt.

A stirred solution cf 25 gm ter -butyl carbazate in 200 mL CHCI5 under nitrogen was treated dropwise over 0.5 hours with 16.5 mL ethyi isocyanate. The solution was stirred at room temperature 27 hours, treated with H2O and the layers were separated. The aqueous layer was extracted with three 100 L portions cf CHCI3 and the combined extracts were washed with brine, dried with Na2S04 _; and filtered. Removal cf the solvent vacuo was followed by dissolution of the residue m 2Ξ0 m cf dry THE. The resulting solution was treated dropwise with 22 mL cf methane sulfomc acid over 0.5 hour. The resulting mixture was stirred at ambient temperature for 26 hours, during which time a precipitate formed. The solid was filtered and washed with THE and Et2θ to provide 24.2 gm (86%) cf the salt mp 115-118 "C.

NMR: delta 1.04 (t, 3H) , 2.37 (s, 3H) , 3.10 (q, 2h), 7.08 (t, 1H), 3.59 (s, 1H) , 9.76 (broad s, 2K) > MS: m/e

Da -f " ^**

To a solution prepared from 6.32 gm cf ::a metal and 200 mL of MeOH were added 2.95 gm of the salt from Method 2

^* 5E; Example 2 Part A and 5 gm cf the intermediate prepared as in Example 1, Part A. The resulting mixture was refiuxed for 100 hr, cooled and evaporated in vacuo. The residue was treated with 200 mL 221 HCl and extracted with three 100 mL portions cf ETOAc. The combined extracts were washed with H2O, brine, dried with a2≤θ , filtered, and the solvent removed m vacuo. Chromatography cf the residue over silica produced 1.5 gm (26%) cf product identical to the material prepared m Method 1.

Examnle 3

Preparation of:

4-β-Butyi-5- [4- ( (2- ;2-phenyl-4-oxazoiyl)ethoxy)phenyl) methyl]l,2,4-trιazoiin-3-one.

A suspension of 1.6 gm cf the intermediate prepared as in Example 1 Part E in 40 mL of THF was treated with 0.8 mL of n-butyi isocyanate and heated to reflux for 2 hours. The cooled mixture was diluted with E 2θ and filtered. The white powder (1.9 gm, mp 172-175'O was added to a solution prepared from 2.8 gm 85% KOH and 20 mL of MeOH and the resulting solution refiuxed for a total of 48 hours. The cooled solution was acidified with IN HCl and the soft white powder collected c ^' filtration, washed with KTO and dried.

Recryscaiiicaticr. from ι-?rOH-Hexane provided 1.21 gm (51%) of product mp 120-122 ^* C. Anal.: Cal. for C2 H26N O3. C, 68.88; H, 6.26; N,

13.39. Found: C, 68.63; H, 6.42; N, 12.82. MS: m/e 418. IR: 3401. 3063, 3063, 1702 cm ^-1 . NMR: 0.9 !t, 3H) , 1.3 ( , m, 2H! , 1.45 (m, 2H) , 1.7 (broad s, 1H, exchanges with D2O) ,

3.1 :t, 2K!, 2.5 it, 2H) , 3.85 is, 2H) , 4.3 (t, 2H) , 6 . 9 (d, 2H!, ".2 id. 2H) , ".5 (m, 4H), 7.8 (s, 1H).

Example £

Preparation cf:

4 -Methyl -5-[4-('2- 2- pheny 1 - 4 - oxazolyl ) ethoxy ι phenyi ) methyl] 1,2, 4-trιa∑oim-3 -thione.

• - - *- - - - - - -

The intermediate prepared as Example 1 Part 1 2.48 gm; and 0.30 gm of 4-mechyI thiosemicarbazide were added to a solution prepared from 0.72 gm of Ma metal and 20 mL of MeOH. The resulting yellow solution was refluxed for 2 hours, cooled and acidified with IN HCl. The resulting white precipitate was collected, washed with HτO and dried. Recrystallizaticn from THF-K->0 and from EtOAc provided 0.82 or 4-metnvi- [ 2-pnenyi-4 ^• oxazolyl ecncxy; ^■ -methyl3 -1.2, -triazcim-j-thione. mp

189-190 ^, C.

Anal. : Cal. for C2iH2θW θ2 ^£: -• 64.27; H, 5.14; !J. 14.27. Found Z. 64.41; H, 5.22; 11, 14.00. IR: 3099, 3042. 2939. 2878 1574 cm" ¹ . MS: m/e 392. NMR: delta 3.1 ! . 2H) , 2.25 is 3H), 4.0 is, 2K) , 4.3 < ^" c, 2H) , 6.9 id, 2K) ,

>d, 2H) , ".5 i , 4H) , 7.8 (ε, 1H)

A stirred suspension cf 1.25 gm cf the intermediate prepared as m Example 1 Part B m 20 mL cf THE was treated

with 0.7 gm of methyl lsothiocyanate and heated to reflux for 1 hour. The precipitate which formed cr. cooling was filtered and washed with ether. This solid (1.44 gm, mp 175-177'C) was added to a solution prepared from 0.3 gm of Na metal and 25 mL cf MeOH and the resulting solution refluxed for 2 hours. The cooled solution was acidified with 1 N KCl and the resulting precipitate collected. P.ecrystaili∑ation from ETOAc provided 1.2 gm (76%) of 4-methyl-5- [ - ^{( (} 2- (2-phenyl-4- oxazol l > ethoxy)phenyl)methyl] -1, 2 , 4-trιazoiin-3-thione. mp. 189-19C"C, identical to that prepared m Example 4 Method 1.

Example 5

Preparation cf:

1 (3 ) K-5- [4- ( (2- ;2-pnenyl-4-oxazolyl ) ethoxy j phenyl ) - methyl] 1,2, 4- trιazolιn-3 -thione

Thiosemicarbazide (1.90 gm; and 2.0 gm of the intermediate prepared as in Example 1 part A were added to a solution prepared from 0.6 gm of Ma metal and 20 mL cf 1- PrO . The resulting mixture was heated to reflux fcr 2 hours and kept at room temperature overnight . The cooled mixture was acidified with IN KCl and the solid filtered. Recrystallicatior. from THF-MeOK provided 1.2 gm (53 ; of product as a white solid o 228-230A.

Anai.. Cal. for C20H18N4O2S: C, 63.47; H, 4.79; N, 14.8C. Founα: 2, £2."2; K, 4.85; N, 14.78. I?.: 3096, 3029, 2928, 2877, 1609 cm ^"1 . MS: m/e 27S. NMR: delta 2 . 2 (t, 2H) , 4.0 'croad s, 2H excnanges with D2O) , 4.3 (t, 2H) , 6.9 (d, 2H), ".2 (a, 2H) , ".5 (m, 4H) , 7.8 (s, IK) .

Example 6

Preparation of:

3-Methyitnιo-4-metnyi-5- [ - ( (2- (2-pnenyl-4- oxa∑oiyi' ecncxy pnenyi;metnyi]1, 2 , 4-triazcime.

A stirred suspension of 2.42 gm cf the intermediate prepared as n Example 1 Part B 40 L THE was treated with 2.1 gm cf methyl isothiccyanate and refluxed for 2 nours . The reaction mixture was cooied and tne solid fiitereα ana wasned witn E 2l- This solid was t en added to a solution prepared from 1.5 gm of Na metal and SO mL of MeOH and the resulting solution refluxed for 2 hours. The solution was allowed to cool with protection from atmospheric oxygen and treated with 5 L of CH3 . The resulting mixture was kept at room temperature overnight, treated with H2O and extracted with tnree 125 mL portions cf EtOAc . The combineα extracts were wasned witn H2O, brine, dried over MgSθ and evaporated to provide an cil wnicn solidified en standing. Crystallization from EtOAc-nexane with the aid of

decolorizing carbon provided 1.62 gm (56% ⁾ cf the product as glittering flakes mp 110-112 ^" C.

Anal. : Cal. for C ₂ 2---22 ^N 4 ⁰ 2 ^{£ :} < 65.00 K, 5,45; N, 13.7S. Found: 2, 64.61; K, 5.44; II, 13.5r. I?.: 2914, 1550 cm" ¹ . MS: m/e 406. NMR: delta 2.7 (s, 3K) , 2.1 (t, 2H) , 3.3 (s, 3H) , 4.15 (s, 2K) , 4.3 (t, 2H) , 6.9 (d, 2H) , 7.2 (d, 2H) , 7.5 tm, 4K! , 7.8 is, 1H ⁾ .

Example 7 ^p reparation or: 4-Methvl-5 - [ 4- i 2- {2-phenyi-4-oxazolyl ) ethoxy; phenyl ) 2 ^* oxaethvl ] 1 , 2 , 4 - :rιazolin-3 -one .

Preparation cf;

5- [ (2- -etho:*ryphenyl ) ] benzyl ether

stirred solution cf 38. / gm 4-benzyioxv-phenol,

.4 cm _l er.J choschine, 27.4 gm 2- (2-phenyl-4-

oxazoiyl)ethanol and 200 mL THE was treated dropwise with 25 gm of diethyl azodicarboxyiate over .23 hours, allowing the temperature tc rise spontaneously to 50-60 'C. The solution was kept at room temperature for 72 hours, treated with 2 mL cf 30% H2 2 and the solvent removed in vacuo. The solid residual mass was dissolved in 350 mL of boiling EtOH and allowed tc cool slowly. The white crystals which precipitated were filtered and washed with small portions of EtOH to provide 29.1 gm (75%) cf needles mp 108-112"C. Anal: Cal. for C24H21NO3 ; C, 77.61; H, 5.70; N,

2.7". Founc: ^~ . ^~ ".25; K, 5.75; 11. 2.50.MS: m/e 271.

Par

Preparation c : 4- [2- . -phenyl- -oxazclyl)ethoxy] phenol.

A solution of the intermediate prepared in Example 7 Part A in 240 mL ETOH/280 mL THF was hydrogenated with 4 gm of 5% Pd/C at room temperature overnight with an initial hydrogen pressure of 60 psi (412.7 KPa) . A.fter removal of the catalyst by filtration, the solvents were removed in vacuo and the residue crystallized from i-PrOH to provide 24.7 gm ι£2%) mp 1"1-276 ^* C.

Anal. : Cal. for A7H 5 O3 : Z . ^" 2.58; H, Ξ.2S; N,

4.9S. Found: Z , 72.21; H, 5.40; N, 5.01. MS: m/e 281.

Preparation of:

Methyl 0-4- [2- 12-phenyl- -oxazolyl) ethoxyjphenylglycciic acid hydrazide. A stirred solution of 5.40 gm cf the intermediate from Example " Part E in 75 mL cf methyl ethyl ketone was treated with 4 mL of methyl bromoacetate, 1.2 gm powdered KI, 11.I gm powdered K2CO and heated to reflux for 4 hours. The

cooled mixture was diluted with H2 , brine, dried over MgS04, filtered, and evaporated to provide an cil which solidified on trituration with hexane, p 62-66"C. A solution of 2.36 gm of this solid in 25 L MeOH was treated with 2 mL of 85% 5 hydrazine hydrate. 0.2 gm cf NaOMe and refluxed 1 hour, during which time a thick precipitate formed. The cooled mixture was filtered and the solid washed with MeOH and E 2θ to provide 2.20 gm (93%) of white powder mp 151-154 ^* .

Anal.: Cal. for C19K2 _. CN3O : C, 64.53; H, 5.42; N, 0 11.89. Found: :, 64.71; H, 5.64; N, 11.70. MS: m/e 352.

Da r-f — - —- m

A stirred suspension cf 1.46 gm cf the intermediate from Example ~ Part Z 20 mL THE was treated with 1 mL 5 methyl isocyanate and refluxed for 1 hour. The cooled mixture was diluted with E 2θ and filtered. The fine white powder was washed with E 2θ; mp 180-132 "C. This solid was added tc a solution prepared from 2.9 gm of 85% KOH/30 mL MeOH and the resulting solution refluxed 4 hours. An C additional 1.8 gm of 85% KOH was added and the mixture refluxed an additional 2 hours, kept at room temperature overnight and acidified with 2N HCl. The solid ootamed by filtration was wasned with H and dried to provide 0.94 gm

(58%) of 4-metnyi-5- [4- ( (2- (2-phenyl-4-oxazoiyl ) ethoxy) - phenyl! 2-oxaethyi; 1,2, 4-tπazoiin-3-one mp I2~-140'C.

Anai.: Cal. for C2iH20 ^N 4°4 ^{: c} * 64.23; H, 5.14; N, 14.2". Found: C, 64.48; H, 5.27; I.\ 14.04. MS: m/e 392. IR:1712, I6S5 cm ^"1 . NMR.. ^* delta 3.1 :t, 2K) , 2.25 (s, 3H) , 4.3 :t, 2H) , 4.9 is, 2H), 6.9 (d, 2H) , ^" .2 id, 2H) , 7.5 '.m, 4H) , 7.9 is, IK), 9.5 (broad s, IK, exchanges with D20) .

Example

Pr epar a 11 on of:

4 -Methyl -5- [4- ( ;2- (2-phenyi-4-oxazoIyl > ethoxy J phenyl) 2* thiaethyi 31,2, 4-trιazoim-3 -one.

Preparation of:

N,N-Dιmechyl 4- [2- (2-pnenyi-4-oxazolyl ) ethoxy] - phenylthionocarbamate.

A stirred mixture of 15.5 gm of the intermediate prepared as in Example 7 Part B and 50 mL DMF was treated with 2.8 gm cf 60% NaH/oii. Gas evolution occurred and was allowed to proceed at autogenous temperature for 0.25 hours. The resulting dark mixture was treated with ^" .0 gm N,N-

Dimetnyl tniccarDamoyi chloride and stirred for 2 hours. The mixture was treated with ice and tne thick curdy solid filtered. The solid was wasned with H2O, hexane and recrystailized from CH2Cl2"hexane ⁽ decolorizing carbon) to provide 13.3 gm (90%) of white flakes mp 111-113 ^* C.

Anal. : Cal. for C ₂ oH20 ^N 2°3 ^S: - 65. 0; K, 5.47; N, 7.60. Found: Z, 65.26; H. 5.50; N, 7.59. MS: m/e 368.

- ^p "τ-ι- a

Preparation of

N,N-Dιmethyl 4- [2- '2-phenyl-4-oxazolyl) etnoxy] - phenyithioicarcamate.

A stirred mixture of 4.15 gm of the intermediate from Example 8 Part A and 15 mL cf tεtragiyme was heated to reflux for a total of 17 hours and cooled. The dark solid mass was treated with hexane, heated to boiling, cooled and filtered. The tan flakes were washed thoroughly with hexane and dried to provide 3.58 gm (88%), mp 123-132 "C. Anal.. ^* Cal. for C oH20 ^N 2°3 ^{s : z} • 65.20; H, 5.47;

: , ^" .50. Founα: :. 54.97; H, 3.50; I.\ ^" .52.

Daai-"---- -

Preparation of: Methyl S-4-[2- 12-pnenyl- -oxazolyl) ethoxyjphenyithioglycolic acid hydrazide.

A stirred mixture of 3.4 gm of the intermediate prepared in Example 2 Part B, 50 mL MeOH and 15 mL 2N NaOH was refluxed for 6 hours, cooled and acidified to pH4 with HOAc. The mixture was extracted with three 125 mL portions of EtOAc. The extracts were washed with H2O, brine, dried over MgSθ4 , filtered, and evaporated. The residuai oil was dissolved m 30 L of metnyl ethyl ketone, the solution treated with 1.5 mL cf methyl bromoacetate, 4,5 gm powdered K2CO3, 0.5 gm powdered KI and refluxed 2 hours. The cooled mixture was diluted with H2O and extracted with three 50 mL portions of EtOAC. The extracts were washed with H2O, brine, dried over gSθ , filtered, and evaporated to provide 4.5 gm of a semi-solid oil. A solution of 2.7 gm cf this oil m 25 m MeOH was treated with 2 mL 85% hydrazine hydrate, 2.1 gm NaOMe and refiuxed 1 hour. The solution was kept at room temperature overnight, diluted with KoO and tne resulting precipitate filtered. The solid was washed with H2O, dried

and recrystallized from i-PrOH-hexane tc provide 2.92 gm (69% overall) cf nearly white powder mp 113-121'C.

Anal.: Cal. for 2, 61.77; K, 5.18;

N, 11.37. Found: C, 61.71; H, 5.2C; , 11.12. MS: m/e

p-rt P

A stirred suspension of 1.2 gm cf the intermediate from Example 8, Part C in 20 L TKF was treated with 1 mL of methyl isocyanate and the resulting solution stirred at ambient temperature fcr 2 hours. The solvent was removed by evaporation and the residue dissolved in 25 m MeOK. The solution was treated with 2.3 gm cf £5% E2K and heated tc reflux for ^" hours. The mixture was kept at roc temperature overnight, heated just to boiling tc redissoive a small amount of solid and acidified with 5.1 HCl. The hot mixture w s treated with ice, diluted with K2O and the resulting solid filtered. The solid was washed with HTO and recrystallized from i-PrOH-hexane tc provide 0.47 gm (35%) of 4-methyl-5- [ (2- (2-phenyl- -oxazolyl ) ethoxyphenyl) 2- thiaethyl] 1,2, 4-triazoiin-3-one mp 120-132 "C.

Anal. : Cal. for 21K20 O3S: Z , £1.75; K, 4.94; r:. 13."2. Found: C, £1.99; K, 5.00; V. , 13.42. MS: ir. e 408. IP.: 1725 1577 cm ^"1 . NMR: delta 3.1 (t, 2H) , 3.3 is, 3H) , 3.8 is, 2H) , 4.3 (t, 2H), 6.9 (d, 2K ^' , 7.2 (c, 2H) , 7.5 (m, 4H! , 7.8 (s, IK) , 8.7 (broad s, IK, exchanges with D2O) .

Example 8A

This Example prepares ε compound outside the scope cf the invention (contrast to compound prepared m Example 8, supra. ) . PreDaration cf:

4-Methyl-5- [4- ( (2- (2-phenyl-4-oxazoiylJ ethoxy)phenyl) -1- thiaethyl] 1,2, 4-triazolin-3-thione

CH

Preparation cf:

Methyl 4- [2- (2-phenyl- -oxazolyl ' -etnoxy] benzoate.

A stirred solution of 14.2 g 2- ⁽ 2-phenyl-4- oxazolyi) ethanol, 11.45 g methyl 4-hydroxybenzoate, 19.67 g triphenylphosphine and 150 mL THF was treated dropwise with diethyl azodicarboxylate (11.8 mL) over .5 hours allowing the temperature to rise spontaneously to 50-60"C. The reaction mixture was stirred at ambient temperature 24 hours, treated with 3 mL cf 30% H2C2 and evaporated in vacuc. The residue was dissolved m 250 L EtOAc, the solution was successively treated with 2N NaOK, H2O, brine, dried over MgSC , and filtered. After removal cf the solvent the residue v/as chromatographed over silica. The product was recrystallized from TKF/hexane tc provide 23.66 g (97%) cf white flakes mp 100-102'C.

Anal.: Cal. for C19H17NO : C, 70.53; H, 5.30; N, 4.32. Found: C, 70.83; H, 5.33; 17 4.49.1?.: 1707 cm ^"1 . ( , 2HCi , 6.9 id, 2h) , 7.5 tm, 4K , 7.8 ⁽ s, lh ⁾ , 8.0 ιτ„ 3H) .

* —- - -^ •

SUβsn UTE SHEET (JU£ »

Preparation of:

4-[2- (2-Phenyl- -oxazolyl i -ethoxy]phenyimεthanol.

A solution cf 4.4 g of the intermediate prepared as in Example 8A, Part A 50 mL THF was added dropwise to a stirred suspension of 2.7 g LiAlH4 in 50 mL THF over 1 hour. The mixture was stirred an additional 1 hour and treated dropwise with 2 mL H2O/8 mL THF, 4 mL %N NaOH, 8 mL H2O, stirred and filtered. The white powder was washed with THF.

The combined filtrate and washings were dried with K2CO3 and the solvent evaporated to provide an cii which solidified on scratch c. P.ecryscaiiizaticr. from TKF-hexane produced 4.02 g (98%) cf fluffy powder mp 95-9 ^* C.

Anai. : Cal. for C13H17NO3 : C, "3.20; H. 5.80; N,

4.74. Found: Z , 72.01; K, 5.82; N. 4.51. IR: 2526,

Part ?

A stirred mixture of 1.40 g of the intermediate prepared as in Example 8A, Part B, 1.30 g 1-methyl-l, 3, 4- triazoie-2 , 5-dithione and 20 mL i-PrOH was treated with 2.4 mL 48% HBr and heated to reflux for 2 hours. The cooled mixture was diluted with H2O and filtered. The resulting white powder was washed with H2O and filtered. The resulting white powder was washed with H2O and recrystallized from THF/i-PrOH to provide 1.55 g (82%) of 4-Methyl-5- [4- ( (2- (2- phenyl-4-oxazolyl)ethoxy;phenyl) -1-thiaethyl]1,2, -triazolin- 3-thione mp 173-175'C as fluffy white needles.

Anal.: Cal. for C21H20N4O2S2 : C, 59.41; H, 4.75; N, 13.20; S. 25.10. Found: C, 59.59; H, 4.80; N. 12.22; S, 14.81. MS: m/e 424. NMR: (DMSO-d6» • delta 3.1 (t, 2H) ,

3.35 :s. 2r.) , 4.2 (t, 2K) , 4.25 (s, 2H) , 6.9 (d, 2H) , 7.2 (d, 2H) , ~.5 i , 3H) , 7.6 (s, 1H) , 8.0 (m, 2H) .

Example

Preparation of : -Methyl -5 - ( ( 2 - ( 2 -phenyl - -oxazolyl ) ethoxy / phenyl ) -2 - ethyl ] 1 , 2 , 4 -tπazoiin-3 -one .

Preparation of: 4- [2- (2-?henyl-4-oxazolyl)ethoxy]phenyl-3-propanoιc acid hydrazide.

A stirred solution of 15.15 gm 2- (2-phenyl-4- oxazolyDethanol, 14.42 gm methyl 4-hydroxydihydrocinnamate, 20.98 gm triphenyi phosphme and 200 mL anhydrous THF was treated dropwise with 12.6 mL diethyl azodicarboxylate over 15 minutes, allowing tne temperature to rise spontaneously to 50-6 ' Z . The solution was stirred at ambient temperature for 48 hours, treated with 2 mL 30% H2O2 and evaporated in vacuo.

The residue was dissolved m 250 mL of EtOAC and the solution washed successively with 211 NaOH, H2O, brine and dried over MgSθ4. After removal cf solvent the residue was chromatographed over silica to provide 21.93 gm (78%) of ester p 47-48'C. A solution of 3.51 gm of ester 25 mL of MeOH was treated with 4 mL 85% hydrazine hydrate, C.l gm !JaOMe and refluxed 2 hours. -The cooled mixture was diluted with K--C and the solid filtered. The solid was washed with

H2O and dried tc provide 3.4 gm '97%) of product p 144- 145'C.

Anal. : Cal. for C20K21N3O2 ^: -• 58.36; H, 6.02; N, 11.96. Found: Z , 68.40; H, 6.06; N, 11.84. MS: m/e 351.

^p "^ °

A sampie of 4.04 gm cf the hydrazide prepared in Example 9 Part A was suspended m 40 L THF and treated with 0.6 mL cf methy.. isocyanate. The mixture was refluxed 1 hour, oooieα, diluted with Et2θ and filtered. The wmte solid

.2.5 gm, p l£6-i£3'2 was added to a solution prepared from 1.6 gm of Na rneta. and 25 mL cf MeOH and the resulting soluticn refluxed for 6 hours. The cooied solution was acidified with 2N HCl and the resulting white solid filtered, washed with H2O and dried. Recrystallization from i-PrOH provided 1.7 gm (50%) cf -methyl-5- [4- ( (2- (2-phenyl-4- oxazolyD ethoxy) -phenyl) -2-ethyl] 1,2, 4-trιazoiin-3-one mp

127-129'C. Anal.: Cal. for 22H2 N4O3 : C, 67.68; K, 5.68; N,

14.35. Founα: Z , 57.55; H, 5.69; N, 14.5 ^" . MS: m/e 390. NMR: deita 2.~5 t, 2K! , 2.95 t. 2H) , 2.05 ε, 2H) , 2.1 (t. 2H), 4.3 t, 2H: , 6.9 d, 2H), ".2 la, 2K) , ^" .5 ιm, 4H! , ".8 (s, 1H) , 9.3 ibroad s, 1H, exchanges with D2O) .

Example

This Example prepares a compound outside the scope of the invention (contrast to compound prepared m Example 9, supra. ; . Preparation of:

4-Methyi-5- [4- (2- (2-phenyl-4-oxazolyl) ethoxy ιpnenyl 1,3,4- triazoiin-3-thione.

^a —r - r -- * 1 - • •

Preparation of:

4- [2- ' ^' 2 -PhenvJ-4-oxazolyl.' ethoxy]benzoylhydrazine.

A stirred solution cf 2.22 g of zhe intermediate prepared as i Example £A, Part A m 40 mL MeOH was treated with 5 L cf 82% hydrazine hydrate. 0.1 g NaOMe and heated tc reflux for 2 hours. The cooled mixture was diluted with H20 and filtered. The white solid was washed with H20 and dried to provide 2.00 g (97%) of hydrazide mp 157-159'C.

Part B

A stirred mixture cf 1.89 g of the intermediate prepared as m Example 9A Part A in 40 mL THF was treated with 1.06 g methyl isothiccyanate and heated to reflux for 1 hour. the res -tmg solution was kept at room temperature 12 nours and evaporated in vacuc. The residue was boiled with EtOH, cooled and filtered. The white solid was washed with Ξt2θ and added to a solution prepared from 0.64 g Na metal/25 mL MeOK. The resulting mixture was heated to reflux 3 hours, cooled and treated with 100 mL 2N HCl. The resulting precipitate was filtered, washed with H2O and recrystallized from THF/i-PrOH to provide 2.12 g (91%) cf 4-Methyi-5- [4- (2- .2 -phenyi - 4 ) ethoxy;phenyl] 1,2, 4-tπazciin-2-thione rr.o 1ΞS-19C" .

Anal.: Cal. for C20Hl8N4θ2≤: C. 63.47; H, 4.79; N, 14.80. Found: 2, 53.45; K. 4.88; N, 14.79. IR: 2120, 1610 cm ^" -. MS: m/e 272. NMR: delta 2.1 (t, 2K) , 2.7 (s, 3H, 4.4 ;t, 2H, 7.1 (d, 2H) , ".5 (m, 3n) , 7.6 (d, 2H) , 7.65 (s, 1H) , 3.0 (m, 2H) .

Example UQ.

Preparation of: -Methyl-5- [4- ( (2- (2-phenyl-4-oxazolyl) ethoxy ιphenyl) -2- ethyl] 1.2, 4-tπazoiin-2-thione.

A suspension of 1.75 gm of the intermediate prepared as m Example 9 Part A and 25 mL THF was treated with 0.2 gm methyl isothiocyanate and refluxed 1 hour. The resulting solution was kept at room temperature 12 hours, and diluted with hexane. The resulting solid was filtered, washed with hexane and recrystallized from EtOH tc give 1.34 gm of white powder mp 142-144 ^* C. This powder was added to a solution prepared from 0.7 gm Na metal and 20 mL MeOH and refluxed for 2 hours. The cooied solution was acidified with 2N HCl, diluted with H2O and stirred at room temperature overnight. The solid was filtered, washed with HT , dried and recrystallized from THF-i-PrOH to provide 1.14 gm (56%) of 4-methyl-5-[4- ( (2- (2-phenyl- -oxazolyl!ethoxyjphenyl) -2- ethyl] 1,2, 4-tπazolin-3-thione mp 152-154"C.

Anal.: Cal. for C22H22 ^N °2 ^£: -• 65.00; K, 5. 5; N, 13.78. Found: Z , 64.71; H, 5.44; N, 13.65. y.S : m/e 406. NMR: deita 2."5 !t, 2H) , 2.9 (t, 2H) , 2.0 :t, 2K) , 2.1 (t, 2H) , 2.4 (s, 3H) , 4.9 (s, IK. exchanges with D2O) , 6.9 (d,

2H) , ".2 (d, 2H) , ~.5 im. 4H) , 7.8 (s, 1H) .

Example 11

Preparation of:

5- [4- ( ;2- (2-phenyl-4-oxazolyl) -ethoxy/phenyl )methyl]1,2,4- oxadιazciιn-3-thione.

A stirred suspension of 3.37 g cf the intermediate prepared as m Example 1 Part B, 0.84 g 83% KOH and 30 mL EtOH was treateα witn 0.6 mL CΞ2 and heated to reflux 8 nours . The mixture was Kept at room temperature overnight, the solvent evaporated vacuo and the residue treated with IN HCl. The white solid was filtered, washed with H2O and dried. Chromatcgraphy over silica followed by several recrystaiiizations from TKF-hexane provided 1.D7 gm (28% of product mp 194-197 ^* C.

Anal. : Cal. for C20 ^H 17 ^N 3°3 ^S: > 63.31; H, 4.52; N, 21.0". Found: C, 63.60; H, 4.82; N, 1080. MS: m/e 379. IE: 1525 c . NMR: delta 2.1 :t, 2H) , 4.05 is, 2H) , 4.3 .t, 2K), 5.9 (d, 2H) , ".2 (d, 2H) , ".5 ιm, 4H) , 7.8 (s, 1H) .

^■ 35*

Example 11A

This Example prepares a compound outside the scope of the invention ιcontrast to compound prepared in Example 11, supra. ) .

Preparation of:

5- [4- ^; 2- (2-Phenyl- -oxazolyl) -ethoxy]phenyl-1, 3 , -oxadιazole-

2-thione.

A stirred mixture of 4.05 g of the intermediate prepared as in Example 9A, Part A and 75 mL MeOH was treated with 1 mL carbon disulfide, 4.0 g of KOH and heated to reflux for 12 hours. An additional 1 mL carbon disulfide was added and refi xing continued for an additional 24 hours. The mixture was stirred at ambient temperature for 26 hours, neutralized with HOAc and concentrated. The residue was chromatcgraphed to provide 1.73 g (38% of white powder mp 229-231"C) .

Anal..* Cal. for C19H15N3O3S: C, 62.45; H, 4.12; N,

11.5C. Found: 2, 62.65; K, 4.41; II. 11.22. IP.: 2878, 1614 cm ^"1 . MS: m/e 365. NMR: delta 3.1 (t, 2H) , 3.4 (broad s, iκ, exchanges with D2O) , 4.4 (t, 2HO, 7.15 (d, 2H) , ".5 (m, 3H) , ".8 (d, 2K), 8.0 <m, 2H) , 9.1 (s, 1H) .

-36*

Example 12

Preparation of:

5- [ (4- (2- i2-Phenyl-4-oxazolyl:etnoxy;phenyl/methyl] 2,4* trιazoiιn-3-one.

o----. r--r--

-reoar ti:

To an ice-cooled suspension of 5.87 g (0.155 mol) of L1AIH4 m 700 mL of E 2θ was added a solution of 35.53 g ; 0.154 mol) cf ethyl 2-phenyl- -oxazoieacecate m 300 mL of E 2θ over a 1.5 hour period. The temperature cf the reaction during tne addition was Kept oeiow 15 ^* 2. After otirrmg for 2 nours at 25'2 tne reaction was decomposed cy tne aαdition of 15 mL cf ΞtOAo and 33.5 mL of H2O. The mixture was filtered througn anhydrous Na2≤θ4 and concentrated in vacuo to leave 28.1 g of oil. Distillation cf the crude cil gave 2- (2-phenyl-4-oxazolyl) ethanol 122.52 g, 81%, op 120- 122 ^* C ' .05-.06 mm/ as an oil whicn solidified en standing. Elemental analysis for Calcd. : 2, 69.83; H, 5.86;

7.40 ounα: 69.78; H, 5.90; N, 7.49,

-37-

Part B Preparation of:

CN

To a solution -•" ^■ g mol) cf product of

Example 12 Part 4.82 g (.0363 mol) p-hydroxyoenzyl nrtriie and 8.20 z ..02. ^" id tπpnenyiphosphine m 85 mL cf freshly distii_ed THE a: 2 was added 4.70 mL diethvi azodicarccxyiate over a 15 minute period. The reaction mixture was stirred at 23 ^* C for 16 hours and then treated with 1.5 L cf 20% H2O2 followed by 100 mL of E C. The organic layer was washed successively with IN NaOH and H2O. After drying over anhydrous a2S©4 and filtering the solvent ι - was removed. Addition cf E 2θ precipitated triphenyiphosphine oxide which was removed by filtration. The residue after removal of the solvent was chromatographed on silica. Ξlution with CK2CI2 gave 4- [2- (2- phenyloxazolyl ! ethoxyjphenyl-acecon: :πie '5.46 c, 665 mo

31-83'C: .

Elemental analysis for 0H15 2O , Zalcά . : C ,

74.98; K, 5.30; N, 9.20. Found: C, 75.08; H, 5.38; N, 8.98.

Part

--reDaracicn or

(-NH;)OCH;.- cr

-M-o-t--'•-->n"* "- ••

A solution cf 1.0 g .3.29 m oi ' of product of Example 12 Part 3 and 0.146 L of anhydrous MeOH m 10 mL of CH2CI2 at O'C was saturated with gaseous KCl and kept for 20 hours m the ccld. The reaction mixture was evaporated to dryness m vacuo to ieave 1.2 g of 4- [2- ^' 2-pnenyl-4- oxazoiyD etnoxyj benzeneetnammidic acid metnyi ester nydrccnioride as a white solid, p 122-184 'C.

NMR CDCI3 : delta 2.227 't. 2H) , 4.000 ,s, 2H) ,

4.25 ^" s, 2K' 4.22" t, 2K ¹ , 6.912 d. 2H) , ^" .259 ^r d, 2H) , ^~ .542--.549 - , 2K , ^~ . "59 z , IK , 2.229 o, 2K, , 11.790 :Dr.s. 1H' , 12. "22 'br.s. , 1H) .

Morr"--<" ~

A stirred mixture of 7.8 g of nitrile from Example 12 Part B and 80 L cf MeOH was cooled to O'C and gaseous HCl was introduced for 1 hour until dissolution occurred. Anhydrous Ξt2C ("00 L) was added and the resultant cii was washed with E 2θ and solidified en standing leaving crude 4-

[2- 2-pnenyl- -oxazolyl 1 etnoxyj -oenzeneethanimi ic acid met. ^■* . ^• /_ ester r.yαrcchJ cπde .

D-ir- *- Preparation of Example 12:

A mixture of 5.3 g of im oethεr product cf Example

12 Part 2 Method 1, 1.75 g of semicarbazide HCl, 100 mL cf

Pi' 'pyπdme' and 130 mL cf DMF aimet yi formamide/ was refluxed for 5 hours. After cooi g, K2 was added and the mixture was evaporated vacuo and crystallized from a mixture of MεOK-K^O and wasned with CH2CI leaving 1.21 g cf

5-[>4- 2- 2-phenyl- -oxazolyl ) ethoxy/pner.yi/methyl] -1,2,4- tπazclm-2-one as a white solid '20%, mo 222-229'C) .

Elemental analysis for C20H13N4O , Calcd. : C, 66.29; H, 5.01; IJ, 15.46. Found: C, 66.14; H, 5.11; N, 15.41. FD-MS m/e 352; NMR (DMSO-d6) : delta 2.944 ;t, 2H) , 3.585 :s. 2H) , 4.195 it, 2H) , 5.870 ⁽ d, 2H) , 7.113 (d, 2H) , 7.464-7.482 :m, 3H) , 7.898 - 7.928 (m, 2H) , ^" .983 (s, 1H) , 11.104 (s, 1H) , 11.198 (s, 1H) .

Example 13

Preparation cf:

- ^• - [ ⁽ 4- i2 - ^' 2-Phenyl -4-oxazolyl ) ethoxy; phenyl 1 methyl] 2 , 3 , 4- oxadiaooiir.-2 -one .

15 A solution of 1.4 xnL of phenyl chiorcformate in 20 mL of CH2C12 was added to a stirred mixture of 3.45 g of hydrazide from Example 1 Part E, 1.5 L of Fy and 800 mi of CH2CI2 at 15 '2. After stirring for two days at 25 ^" 2, 630 mL cf solvent was removed and the mixture was otirred for 2T anotπer five αayo . Methyiene chloride was added tc bring the total voiume to 500 L and the reaction was washed successively with aqueous NaHCθ3 , aqueous 5% citric acid, H2O and dried over anhydrous Na2≤θ4. Evaporation cf the solvent after filtration left 4.9 g of residue which was -5 chromaccgraphed cr. 120 g of silica. Ξlution with 1-2% MeOH in CH2CI2 gave 2.9 g of a mixture cf intermediate phenoxycarbonyi hydrazide and product 1, 2 , 4-oxadιazol-2-one. Further eiution with 2% MeOH in CH2CI2 provided 1.2 g of recovered starting hydrazide.

The 1.9 g of the above mixture was dissolved in 175 mL of EtOH and treated with 30 ml cf IN KaOH for 2.5 hours at 25 ^* C. After acidification with aqueous KCl, the solvent was removed and the residue was dissolved m CHCI3 , washed with K2O and brine and dried over anhydrous Na2Sθ . Removal of the solvent left 2.0 g of white solid v/hich was recrystallized from 50 mL cf MeOH to give 1.3 g of 5- [(4- (2- (2-phenyl- -oxazolyl) -ethoxyjphenyl /methyl] 1, 3 , -oxadiazolin- 2-one (56%, mp 142-144'C) .

Elemental analysis for 2G ^H 17 ^!>I 3° ■ Calcd. : C,

00. 1 1 T ^* 56. Found: £5.84, H, 4.90, N,

11.34. FD-MΞ: J ; NMF. (DMΞ2 : delta (t, 2K) , 2.799 ^■ . s, 2K ^' 4.20 £ . Q~ ? ⁷ .155 (α, 2K; , 7.463- 7.423 ιm, 3Ki , .905 7 Q ^' ιm, 2κ: !3 (s, IK) , 12.072 (br.s, 1H) .

Example 14

Preparation of:

3- [ (4- (2- (2-Phenyl- -oxazolyl) ethoxy)phenyl)methyl] 1,2,4- oxadiazolin-5-one.

Part A Preoar tion o :

) K IHOH

To a cooled ( O ' Z ) solution cf 0.38 g of Na in 80 mL of anhydrous MeOH was added 2.57 g cf NH2 ^{0H κ} -- followed by a solution cf the i inoecher of Example 12 Part C Method 2 in 100 mL of annydrous MeOH. The reaction mixture was allowed to warm to 25'C and was stirred for 18 hours. The residue, after removal of solvent, was partitioned between 200 mL of H2O and "00 L cf EtOAc. The solid was removed by filtration and washed with H2O and EtOAc. The combined organic phases were wasned with H2O and ccm ined with the solid. After removal of tne solvent, tne residue was recrystallized from MeOH. Tne filtrate was dil tεα with EC2O and tne resulting solid was filtered to give 4.14 g of crude N-hydroxy-4- [2- (2- phenyi- -oxazolyl) etnoxy]benzεneεthanimidamide. FD-MS: m/e 337.

Part

Preparation cf Example 14:

A mixture of 4.06 g of the amidoxime from Examplε 14 Part A, 150 mL cf THF and 1.98 g cf carbonyldiimidazole was heated at reflux for 7 hours, cooled to 25 "C, and stirred anotnεr 1*5 hours. The solvent was removεd m vacuo. The residue was cissoived m 600 mL of EtOAc, washed with H O and dried ever annydrous Na2≤0 . The residue, obtained after filtration and evaporation cf the solvent, was recrystallized from EtOH tc give 3.11 g of 3- [ (4- (2- (2-phenyl-4- oxazolyl) ethoxy:phenyl) -methyl] 1.2.4-oxadιazolin-5-one (71%, mp 154.5-15 ^" .5 ^* C) .

Elemental analysis for C20H1--N3O , Calcd. : Z , 66.11; K, 4."2; N, 11.56. Found: C, 66.22; H, 4.77; N, 11.34. NMR CMSO-dόi : delta (t. 2H) , 2.747 is, 2K) , 4.210 (t, 2K) , -5.906 ,d, 2H) , 7.167 (d, 2H) , ^" .464-7.483 ' , 3H) , 7.905-~.929 i , 2H) , ".988 is, 1H) , 12.232 (br.ε, IH) .

^■ 42 -

Example 15 Preparation of:

5- [ (4- (2- (2-phenyl- -oxazolyl) etnoxy/phenyl/methyl]1, 3,4* cxathiazolin-2-one

.-reDa:

CK-JCO H-

A solution of 0.5 g of methyl ester of Example 1 Part A, 50 mL cf MeOH, 2.2 g of NH C1 and 40 mL cf NH4OH was stirred at

25 'C for 43 hours with brief, intermittent warming at 5 'C. The MeCK was partially removed, and tne reaction mixture was diluted with H-2. The solid precipitate was filtered, washed with H and dried to give 4- (2- (2-phenyl-4-oxazolyl) ethoxy) - phenyiacetamide 3.39 g, 82%, mp 130-182.5 "O .

Elemental analysis for Cτ_gK _] _gN2C' , Calcd. : C,

70.79; K. 5.63; II, 8.69. Found: Z , "0.54; K, 5.72; K . 8.50. FD-MS: m/e 222; NMR !DMSO-d6) : delta 2.968 It, 2K) , 2.250 :s, 2H) , 4.214 t, 2K) , 5.768 (br.s, IK) , 5.865 ,d, 2H) , ^" .250 ,d, 2H) . ~.254 (br.s, IK), ^" .492- ^" .504 i , 2K) , ^" .928- ^" .954 ,.-., 21-n , 2.003 z . IK) .

*Da ^ζ ---—rt-- —n

Preparation cf Example 15:

To a stirred mixture of 2.6 g of amide of Example 15 Part A and 200 mL of toluene at 82 "C was added dropwise 1.05 mL of chlorocarbonyisulfenyi chloride. The reaction was heated fcr 7 hours at 82 'C and stirred an additional 18 hours at 25 "C. The voiatiles were removed in vacuc, and the residuε was partitioned between CHZ∑2 and H2C . The layers were separated and the aqueous layer was extracted with CHCI3. The combined organic layers were evaporated and onrcmatograpned on 5 ^" σ of silica. Ξlution with 0.5% MeOH m CK2CI gave 1. ^" g solid wnicr. was recrysca_lιzed from a mixture of acetone and E 2θ to give 1.4 g cf 5-[(4-(2-(2- pher.y_.-4-oxazolyl . -ethoxyJphenyl:methyl]1, 2 , 4-oxathιazolin-2- one (29%, mp 122-105'c; .

Elemental analysis fcr C20 15N2O4S. Calcd. : C,

63.15; K, 4.24; II, 7.36. Found: C, 63.01; K, 4.28; N, 7.31. FD-MS: m/e 380; NMR (CDCI3 : : delta 2.962 :t. 2H) , 3.938

(s, 2K) . 4.223 t, 2H) , 6.918 (d, 2HJ , ".203 ,d, 2H) , 7.459- ".503 ,ιr„ 3H) , ~.909-".938 i , 2H) , ".998 < _ . 1H) .

Example 16

Preparation cf:

2- [ (4- .2- (2-phenyl-4-oxazolyl) ethoxy/phenyi)methyl]1,2,4- thιadιazoiin-5-σne.

Part .-.

PreDaratic of

To a mixture of 4- (2- ^■ 2-phenyl-4- oxazoiyi: ethoxy: benzεne-ethanimidic acid methyl ester hydrocniorioe of Example 12 Part Z , ontamed from 20. C g of nitπ_e Ξxa p. 12 Part Ξ, 2.5 g of IZr.± Z- and 220 mL of anhydrous MeOH was added 100 L of annydrous NH OH saturated with NK . The reaction mixture was stoppered and stirred at

25 "C fcr 15 hours. The voiatiles were removed in vacuo and the solid was treated with H2O and with MeCN and driεd to leave 21.4 g cf 4- (2- (2-phenyl- -oxazolyl) - ethoxy/benzεneethanimidamide hydrochioride, mp 137-19 'C. A 4.94 g portion of soiid was dissolved in 50 mL cf refluxing MeOH, filtered, and diluted with 80 mL cf MeCN. Most cf the MeOH was evaporated and the solution was cooied and allowed to crystallize. Filtration gave 4.45 g of 4- ^■ 2- - ^' 2-phenyi-4- cxazcly. et oxy: cenzenεεtnani idamide nydrocrJonde as a white solid after washing with E 2θ, mp 191-193 'C.

Elemental analysis for , Calcd. : C,

53.77 'J ; IJ, 11, Found: C, 53.49 N, 11.71,

- -*- ^- ~

Preparation of Example 16:

To a stirred suspension cf 1.9 g cf 60% NaH in mineral oil and 440 mL cf freshly distilled THF was added 17.0 g of soiid crude imidamide hydrochioride of Example 16

-45-

Part A. The mixture was stirred for 2.5 hours at 25'C and 25.0 g of άiiscprcpyiethyi amme was added followed by 3.70 mL of chiorocaroonyis ifenyi chloride. After stirring for 18 hours, the reaction mixture was poured into h ^* 2θ and extracted with EtOAc. The EtOAc layer was washed with H2O, brine and dried over anhydrous Na2≤θ . After filtrtion and evaporation of the solvent, the dark oil was chromatographed en 220 g of silica. Ξluticn with 1% MeOH in CH2CI2 afforded 8.2 g of soiid which was recryεtalli∑εd twice from a mixture cf CH2CI2 n and hexanes to give 7.40 g cf 2- f (4- (2- (2-phenyi-4- oxazciyi etnoxy ^• pner.y- -metnyi 1, 2, 4-thιadιazciιn-5-one 41%,

Ξlεmencai anaivsis or C20«J7 ^N °3 - ■ Caic . : C

63.31, K, 4.52, N, 11.07. Found: C, 53.10; H, 4.61; N.

11.07. FD-MS: m/e 379; NMR (DMSO-d6) : delt 2.991 (t, 2H),

3.746 (9s. 2H) , 4.223 (t, 2H) . 5.908 (d, 2H) , .172 (d, 2H) ,

.924- / . ;Ό / <m, 3H) S.002 (s. 1H), 12.823 (br.s 1H)

Example _J_

Preparation of:

1-[ (4- (2- . ^' 2-Phenyi- -oxazolyl )ethoxy/phenyl/methyl]1,2,4- trιazoiidm-2 , 5-dione.

P≤rr, ■-. Preparation oi

To a solution cf 72.7 g of alcohol product of Example 9A, Part A, 47.9 cf 4-hydroxyoenzaidehyde, 104 g triphen.Jcnospnine and 450 mL of anhydrc ε THF at -5'C was added ^~ r g cf dιetr.y_ azcdiearecxyiate over a 20 minute period. The tεmperat re was maintained at O'C. The cooling bath was removεd and tne reaction mixture was stirred for 20 hours at 25 'C. After tne addition of 5 mL cf 30% H2O2 the reaction mixture was diiutεd with 1.2 L of EtiO. washed with 1 N NaOH and H2O and dried over Na2≤θ . The solvent was removed and the residue was dissolved in 1 L of E 2θ and cooled to O'C. The solid which precipitatεd (P^PO) was removed by filtration and tne filtrate was concentrated to 600 L and cooled to O'C. The precipitate was filtered and recrystallized twice from acetonε/H2θ to give 4- (2- (2-phenyi- -oxazciiJ ' etnoxy ^■ -oenzaidehyde (23. g, mp 92-97'C . .An additional 22.6 cf product '.total yield 61.5 g, 54%) was obtained from filtrates.

Elemental analysis fcr C 8H25NO3 , Calcd. : C,

73.71; H, 5.15; N, 4.77. Found: C, 73.84; H, 5.34; N, 5.02. FD-M≤: m/e 292. NMR !DMSO-dc): delta 2.006 :t, 2H) , 4.354 (t, 2K! . ".120 < ά . 2H) , 7.453-7.485 ιm.3K). 7.817 (d, 2H) , ".902-~.922 im, 2K) , S.013 !ε, 1H) , 9.820 *s, 1H) .

-47-

Part

A mixture of 20.0 g of aldehyde from Example 17 Part A, 8.29 g of semicarbazidε hydrochioride, 8.14 g of NaOAc and 150 mL of H2O was heated fcr 0.75 hours at 100"C with occasional swirling. The neterogenous mixture was

54 hours. The solid was fiiterεd and washed with H2O, refluxeα with 500 mL of MeOH and filtered hot leaving 21.3 g of 4- (2- ⁽ 2 -pnenyi- -oxazolyl ) ethoxy)benzaldehyde semicarbazone (39%, m.p. 221-226'C) .

Elemental analysis fcr £19^5^03, Calcd. : C,

55.13; H, 5.18; N, 15,99. Found: C, 64.91; H, 5.20; N, 15.73.

"eparation or:

CH: NHNKCONH-

A mixture of 26.1 g cf semicarbazonε cf Example 17 Part Ξ m 500 mL cf THF was trεatεd with 298 mL cf a IN BH*-* m soiutioi After stirπnα fcr hours at 25 'C the solution was slowly poured into 500 mL cf MeOH. The reaction mixture was evaporated in vacuo to drvness. The solid was

created twice with 600 mL of MeOH by refluxing and evaporating the voiatiles. The residue was then diluted with 400 mL of MeOH, cooled to C'C and filtered leaving 22.4 g N*--- [4- (2- (2-phenyi-4-oxazolyl ! ethoxy;phenyijmetnyisemicarbazide (85%, mp 192-196'C! .

Elemental analysis fcr •' - • 64.76; H, 5."2; , 15.90. Found: Z , 64.58; H. 5.67; N, 15.64. NMR DMSO-dδ) : delta 2.951 .t, 2H) , 2.655 id, 2H) , 4.203 it, 2K), 4.822 (br.s, 1H> , 5.722 (br.s, 2H) , 5.856 (d, 2H), 7.207 d. 2H), 7.468-7.485 ,m, 3H) , ~.902-~. 32 ιm, 2H) , ^~ .993 Ξ , IK..

Preparation of Example 17: A mixture of 11.9 g cf semicarbazide from Example

17 Part C, S.10 g of carbonyidiimidazoie, 0.5 mL cf triethylamine and 400 mL cf anhydrous DMF was stirred at 25 'C for 4 days, diluted with 1 L of H2O and filtered. The filtrate was evaporated. The residue was treated with 100 mL of MeOH and the solid was filterεd and dried to give 2.43 g of 1- [ (4- (2- ^' 2-pnenyi-4-oxazolyl) ethoxy j phε J:methyl] 1,2, 4- trιazoiιdιn-2 , Ξ-dione ' 271 . mp 222.5-230 "C! .

Ξiementa. analysis fcr ~20-"*J 8A * Za±zz . : Z , £3.49; H, 4.80; IJ, 14.81. Found: Z , 63 .24 ; H. 4.87; :;, 14.80. FD- MS: m/e 372, ^* NMR (DMSO-d6i : delta 2.975 (t, 2H) , 4.225 (t, 2H) , 4.418 ε, 2K) , 5.928 (d, 2h) , ^" .151 (d, 2h0, ^" .488- ^" .504 (m, 3H) , ".925- ^" . 51 ( , 2H) , 10.2 (br.s, 1H) , 10.9 ibr.ε, 1H) .

Example H

Preparation cf :

I- [ (4- (2- 12-Phenyi-4-oxazolyl/ ethoxy/pnenyi jmetnyi] 1,3- dιazciidin-2 , , 5-trione.

ar a

Preparation o:

To a 12.89 g of 60% dispersion cf NaH in mineral oil, washed

10 three times with hexaneε, was added 100 mL of anhydrous DMF. The stirred suspension was cooled to 10"C and a solution of 52.1 g of alcohol from Example 9A Part A in 150 mL of anhydrous DMF was added dropwise. One hour after the completion cf the addition, a solution of 27.59 g cf para- fluoro-benzcnitrile 100 mL cf anhydrous DMF (dimethylformamideJ was added siowiy while keeping the reaction mixture at 15-20'2. The reaction temperature was increased to 40"C whiie the mixture stirred for 4 hours. After the third hour, an additional 1.05 g of 60% NaH

20 dispersion was added. The reaction was allowed to stay at 25"C for 15 hours and was then diluted slowly with 880 mL of H20. The precipitate which formed was filtered, washed with 1 L cf H20 followed by 1 L of hexanes and dried to give 71.8 g of 4- (2- :2-phenyi- -oxazolyl) ethoxy)benzonitriie (90%, mp

")=; U4.6-i!5'C: .

-50-

Par g

Preparation of.

A solution of 12.34 g of nitrile from Example 18 Part A m 80 mL cf anhydrous THF was added to a stirred suspension cf 1.70 g cf lithium aluminum hydride m 110 mL cf ≤nnyαrc Ξ THF oooied to 12 ^* 2 over a 5 mm period. Stirring at 10 'C was continued fcr 1.5 hours and then at 25 "C for 20 hours. The reaction mixture was decomposed by the sequential addition of 1.8 mL of H2θ, 1.3 mL of 5N NaOH and 6.3 ml of H2O. The slurry was filtered and the solid was washed with THF. The combined filtrates were evaporated and the residue was dissolved in 500 mL of EtOAc. The solution was washed with H2O and brine, dried over anhydrous Na2Sθ , and filtered. Evaporation of the solvent left 12.4 g of amine which was taken up in MeOH and converted to the HCl salt by treatment with a solution of HCl in Et2C. The residue, after evaporation of tnε voiatiles, was crystallized from a mixture of 60 mL of MeOH and 250 mL cf EtOAc. After filtration, the solid was washed with EtOAc and dried to give 11.4 g of 4- [ (2- (2-phenyl- -oxazolyl) ethoxy) -benzene]methyl amine hydrochioride (90%, mp 198-206 ^* 0. FD-MS: m/e 294; NMR (DMSO-d6) : delta 2.963 (t, 2H) , 3.8^9 ,d, 2K) , 4.239 (t, 2H) , 6.958 (d, 2H) , 7.360 (d, 2H) , ~.46S-~.4S8 (m, 3H) , 7.905-7.930 (m, 2H) , ".997 (s, lh) , 8.2": ibr.s, 3H) .

Pa ⁱ r ^" Preparation of

CH-JNHCONHT

A mixture cf 10.3 g of frεε amine cf example 18 Part E 120 mL of H20, 120 mL of MeOH and 7.0 L cf 5N HCl was stirred until the amine dissolved and 2.27 g of sodium cyanate was added. The reaction mixture was ^• .-. ^• armed to 50 '2 and then allowed to cool to 25 "C. After 2.5 hours, the mixture was cooled an ice bath and filtered. The solid was washed with H20 and recrystallized from 250 mL of EtOH and 250 mL of H20 to give 6.05 g cf N-4- (2- (2-phenyl-4- oxazolyl) ethoxy) -bεnzenemethyl urea (61%, mp 191-196'C) . Elemental analysis for C19H19N3O3 , Calcd. : C,

67.64 K. 5.68; N, 12.45. Found: C, 67.59; H, 5.75; N,

12.16 FD-MS: m/e 337; NMR (DMSO-d6i : delta 2.946 it, 2H) ,

4.040 id, 2h), .195 t, 2H) , 5.425 (s, 2H) , 5.261 (t, 1H) ,

6.862 id, 2H) , .113 d. 2HO, 7.464-7.485 i , 3K) . ".902- - a n ..-, 2h! , .986 s, 1H) .

Preparation cf Example 18:

To a solution of 0.38 g of Na in 100 mL of anhvdrc s MeOH at Q ' Z was added g of thε substituted urea of Example IS Part C. After several minutes of stirring, 2.0 mL cf diethyl oxalate was added. The cooling bath was removed and the reaction mixture was stirred for four days. Aftsr thε addition cf 3 mL cf 3N HCl and H20, the mixture was filtered. The solid v/as washed with H20 and recryscaiiized

form 65 mL of THF and 75 mL of H20 tc give 3.28 g of l-[(4- (2- (2-phenyl-4-oxazolyl)ethoxy: -phenyi/methyl] 1, 3-dιazoiidin- 2,4,5-5-trιone (63%, mp 217-222 'C ) .

Elemental analysis for C21H17N3O5, Calcd. : C, 64.45; K, 4.38; N, 10.74. Found: C, 64.72; H, 4.52; N,

10.59. NMR (DMSO-d6) : delta 2.946 ,t, 2H) , 4.216 (t, 2H) , 4.510 (d, 2H) , 5.882 J , 2HO, ^" .209 id, 2H) , 7.464-7.482 (m, 3H), 7.898-".927 (m, 2H) , ".984 s, IK). 12.011 (s, 1H) .

Example n

Preparation cf:

4 - lscpropiJ - r - ■ ^' 4- .2- 2-pnenyi-4- oxazciyi ' etnoxy ^• pnenyijmetnyi] 1.2, 4-trιazolm-3-one.

A suspension of 4.0 gm cf tne intermediate prepared as in Example 1 Part 3 was suspended m 20 mL of THF, treated with 1.2 g cf iso-propyl isocyanate and refluxed for 2 hours. The mixture was cooled, diluted with Et20 and filtered. The white solid ,2.1g) was collectεd, washεd with Et20 and added to a solution prepared from 4.19 gm cf 85% KOH and 100 mL of MeOH. The resulting solution was neatεd to reflux for 7 days, at whicr. time TLC εnowed complete consumption of starting material. The cooled soiuticn was acidified with IN KCl and tne resulting precipitatε coilεctεd by filtration. Purification was effected by sequεntiai cnromatography on

silica gel columns, elutmg with EtOAc and 30:1 CHCI3/MeOH, respectively to provide 1.5 g (52%) of 4-ιsopropyl-5- [4- ( (2- (2-phenyl-4-oxazolyl) etnoxy: phenyi )methyl] 1,2.4-trιazoiin-3- one as white needles, mp 140-143 'C.

Anal. Cal. for C23H24N4O3: C, 68.30; H, 5.98; N. 13.85. Found: Z , 68.31; H, 6.10; N, 13.88. IR: 1685cm ^"1 . MS: m/e 404. NMR: 1.3 (d, 2H) , 3.09 (t, 2H) , 3.84 is. 2H) , 4.01 (septet, IK). 4.28 (t, 2H) , 6.9 (d, 2H) , 7.12 (m, 3H) , 7.57 is, IK), 3.03 (m, 2H) , 9.35 (s, IK, exchanges with D2O) .

Example 20

^reparation 01 :

4 -n-Propyi - 5 - [ 4 - •. ^■ 2 - ' 2 -phenyl - -oxazolyl ) ethoxy ) phenyl ) - methyl ] 1 , 2 . - trιazoiιn-2 -one .

A suspension cf 2.0 gm of the termediatε prεpared as in Example 2 Part E was suspended in 30 mL of THF, treated with 1.01 g of n-propyi isocyanate and refluxed for 2 hours. The mixture was cooled, diluted with Et2θ and filtered. The white solid (3.3 g) was collected, washed with EC20 and added to a solution prepared from 4.38 gm of 85% KOH and 100 mL of MeOH. The resulting solution was heated to reflux for 48 hours, at which time TLC showed complete consumption of starting material. The cooled solution was acidified with IN KCl and the resulting precipitate collected by filtration.

Purifioation was effectεd by chromaccgraphy on silica gel, elutmg with CHCI3 to provide 2.2 g (72% ⁾ of 4-n-propyl-5-[4- ( (2- (2-phenyi-4-oxazolyl: ethoxy/phenyijmethyl]1,2,4- triazoiin-3-one as whitε needles, mp 121-132 'C.

Anal. Cal. fcr C23H24N4O3: 2. 63.30; H, 5.98; N, 13.85. Found: Z , 68.25; K, 6.13; N, 13.87. IP.: 1694cm" ¹ . MS: m/e 404. NMR: 0.72 It, 3H) , 1.31 (m, 2H) , 3.0 (t, 2H) , 3.34 ( , 4H) , 3.84 (ε, 2K) , 4.25 (t, 2H) , 5.92 (d, 2K) . 7.17 (d, 2K) , -.54 im, 3K) , 7.97 ur,, 2H) , 3.02 s, 1H) , 11.45 is, IK) , exchanges with D2O) .

Example 21 Preparation of:

2-Methyl-4-ethyi-5- [4- ( (2- (2-phenyl-4- oxazciyi) etnoxy:phenyi :methyl] 1,2, 4-tπazoiin-3-one.

A stirred solution of 1.0 gm cf the intermediate prepared in Example 2, Part A in 75 mL cf DMF under 2 was treated one portion with .06 gm of 60% cf NaH/oil and the resulting mixture allowed to react for 15 minutes. After addition cf 0.54 gm cf CH3I, the mixture was kept at ambient te pεrature fcr 1 hour, poured onto ice and extracted with 100 ml EtOAc. The EtOAc solution was washed with H2O. dried with Na?S2j and evapcrated. The solid residue was chromatcgraphed ovεr silica iεlution with 2% MεOH CKCI3

^• -33-

to provide 0.7 gm (67%) cf 2-methyl- -ethyl-5- [4- ( (2- (2- phenyi-4-oxazolyl) ethoxyJphenyi;methyl 1.2 , 4-tπazolin-3-one as colorless needles, mp 128-130'C.

Anal.: Cal. for C23H24N4O3 : C, 58.30; H, 5.98; N, 13.85. Found: 2, 68.09; H.m 5.38; N, 14.00. Ms: m/e 404. IR: 1690cm ^"1 . NMR: delta 1.0 't, 3H) , 3.07 (t, 2H) , 3.25 (s, 2H) , 3.2 -q. 2H) , 4.26 (t, 2K) , 5.88) d, 2h) , 7.12 (d, 2H) , -.43 im, 2H) , 7.55 (s, 1H) , 3.02 ( , 2H) .

10 ExampA

Tr.is Example prepares a compound outside the scope of tne invention contract to compound prepared m Example 21, εuυra...

Preparation of:

4-Phenyi-5- (4- •: (2- (2-pnenyi- -oxazolyl) ethoxy)phenyl) - methyl] 1, 2, 4-trιa∑olin-3-one.

20

A suspension of 3.0 gm cf the intermediate prepared as in Example 1 Part B was suspended 30 mL cf THF, treated with 1.4 g of phenyi isocyanate and refluxed fcr 2 hours. The mixture was cooled, diluted with Et2θ and filtered. The

TC white soiid (2.8 g) was collected, washed with E 2θ and added to a solution prepared from 2.37 gm of 85% KOH and 100 mL of MeOK. The resuitinα solution was heated to reflux for 7

days, at whi,ςh time TLC showed complete consumption of starting mateπa.. Thε cooiεd solution was acidified with IN HCl and the resulting precipitate collected by filtration. Purification was effectεd by rεcrystaiiizaticn from MeOH tc provide 1.3 g (43%) cf product as whitε needleε , mp 179- 181'C.

Ana-. Cal. fcr 026^22^ 03* C, 71.22; K, 5.06; N, 12.78. Found: Z, 71.11; H, 5.14; II, 12.97. IE: 1 ⁷ 19c ^"1 . MS: /e 423. NMR: 2.97 <c, 2K) , 2. ^" 3 is, 2K) , 4.19 (t, 2H) , £.73 d. 2h! . 5.25 id. 2h) . ^" .22 (dd, 2K; , 7.44 im. 2H) , ⁷ .53 , 2r... ^" .? ^" m, 2K) , 2.02 ≤, Ih), ll. ^~ l s, IK, excnangeε ^• .*. ^• ! tn 232..

Compounds were tested fcr antihyperglycemic activity according to the protocol described A.M. Gill and T.T. Yen, "Effects of Ciglitazonε on Endogenous Plasma Islet Amyloid Polypeptidε and Insulin Sensitivity m Obese-Diabetic Viable Yellow Mice" Life Ξciencεs 43, 703-712 (1991; . The mice used m these tests were obese-diabetic viable yellow mice form the mored Lilly colony. Thεy were housed m transparent p-astio cages v;ιth bedding. Pur a Formu_a Chow 5008 '.product of Pur a Mills Inc., 717 South Hickory St., Fond Du Lac, '.."I 54935-5517 USA) and water were available ad libitum. The ambient temperature cf the animal room was 25 'C and lights were en from 0600 to 1800.

To study the εffects cf the candidate compounds, twelve male ooeεe-diabetic viable yellow (VY) mice were divided into two groups for each candidate compound. One grcup was fed mesh or repeiietized Purma 5006 Chow and one group was fed tne same enow 1mammal food) containing thε indicated amount of candidate compound as set forth below m

thε Table. 3ody weight and food consumption were monitored and blood samples collected befcrε the experiment was initiated and after 14 days of treatment. In tne Table, the blood glucose levels of mice givεn thε tεst compounds are reported as a percentage of thε initial value as compared to untreated controls cr. day 14 cf treatment. Reductions cf the initial values by less than 20% are regarded as inactive. The dose is the percεnc of compound incorporated into the feed imesh or repεiiεtized.. The corresponding data for ciαlitazone are included for comparison.

_______

are comparative Examples to show criticaiity of structure control experiment