OA10043A - Oxazole derivatives - Google Patents

Description

1 0043 1

CROSS REFERENCE ΤΟ RELATED APPLICATION

This application is a continuation-in-part of pendingapplication U.S. Serial No. 07/453,548 filed December 20, 1989.

BACKGROUND OF THE INVENTION

This invention generally pertains to heterocyclic carboncompounds having drug and bio-affecting properties and totheir préparation and use. In particular, the invention isconcerned with oxazole dérivatives characterized by Formulas Iand II, infra., which are inhibitors of blood platelet aggre-gation.

The following Chemical literature and patents areillustrative of related oxazole prior art known to applicant. D.L. Aldous, et al., J. Org. Chem., 25, 1151 (1960)describe the chemistry of styryloxazoles of the formula

Ph

Ph

CH=CH wherein R is hydrogen, p-methoxy, o-hydroxy and 3,4- methylendioxy.

Brown, U.S. Patent 3,578,671 describes a class ofoxazole-2-polycarbon aliphatic monocarboxylic acids arylatedat the 4- and/or 5-position in the oxazole ring of the formula 1 0043

2 3 in which each of the substituents R and R is a member of thegroup consisting of unsubstituted phenyl, naphthyl, thienyland furyl radicals and phenyl radicals substituted by substi-tuents selected from the group consisting of halogen, loweralkyl, lower alkoxy, nitro and trifluoromethyl radicals; andwherein Rx is selected from the group consisting of carboxy-alkyl- and carboxylalkenyl radicals each containing from 2 to5 carbon atoms and the amides, hydroxamic acid dérivatives,lower alkyl esters and lower alkanoyloxy-lower-alkyl estersthereof. The compounds of U.S. 3,578,671 include the clinical- ly effective anti-inflammatory agent known generically as2 3 1 oxaprozin (R = R = phenyl, R = (CH2

Meanwell, et al., U.S. Patent 4,775,674 describes a sériés of 2,3-dihydro-2-oxo-lH-imidazo[4, 5-b]quinolinyl etherdérivatives of the formula

H

wherein inter alia R^ and R2 are hydrogen, and ”alk-Y" analkanoic acid and ester residue. The compounds of U.S. Patent4,701,459 hâve cyclic AMP phosphodiesterase inhibitor activityand are useful as inhibitors of blood platelet aggregationand/or as cardiotonic agents.

Lautenschlager, et al., U.S. Patent 4,460,598 issuedJuly 17, 1984 describe a serres of triphenylimidazol-2-yloxy-alkanoic acids having the formula 2 ,7 R'

R

4 R'

o-(CH2)n-cooR ,5 1 0043 1 2 3 4 5 6 wherein R , R , R , R , R and R each are H, halogen, alkyl,7

alkoxy and trifluoromethyl; n is an integer of 1 to 10 and R is H, alkali métal ions, alkyl or benzyl group. The compoundsof U.S. Patent 4,460,598 are reportedly useful in the treat-ment of thromboembolie, inflammatory and/or atheroscleroticdisease in man. A particularly preferred member of the sériés T 6 7 wherein R to R° is hydrogen, n is 7 and R is sodium (identi- fied in the art as octimibate sodium) has been described aspossessing anti-aggregator activity and is under clinicaldevelopment as an antihyperlipidemic agent.

SUMMARY OF THE INVENTION

In its broadest aspect, this invention is concerned withoxazole dérivatives having Formula I and Formula II

(I)

wherein R, R^, R^, X, Y, and n are defined below which areinhibitors of adenosine diphosphate and collagen-inducedaggregation of human platelet-rich plasma and are particularlyuseful as inhibitors of mammalian blood platelet aggregation. 1 (II) 1 0043

Another embodiment of the invention relates to thealkali métal salts of carboxyllc acids of Formula X (R ishydrogen) and Formula II (R£ is hydrogen). A further embodi-ment concerns pharmaceutical compositions comprised of aFormula I or II compound combined with at least one pharmaceu-tically acceptable excipient. Yet another embodiment relatesto a method for inhibiting blood platelet aggregation in amammal which comprises administering a therapeutically effec-tive amount of a compound of Formula I or an alkali métal saitthereof where R is hydrogen or a Formula II compound or analkali métal sait thereof where R^ is hydrogen to a mammal inneed of such treatment.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to inhibitors of mammalian bloodplatelet aggregation OF Formula I

N — (CH2)nCO2RCi wherein n is 7-9 and R£ is hydrogen or lower alkyl; or when Ris hydrogen, the alkali métal sait thereof.

The compounds of the instant invention are furthercharacterized by Formula II

wherein R^ is phenyl or thienyl; R2 is hydrogen, lower alkyl or together with CO2 istetrazol-l-yl; X is a divalent connecting group selected from the groupconsisting of CÏ^Ci^, CH=CH, and CI^O; Y is a divalent connecting group attached to the 3- or 4-phenyl position selected from the group consisting ofOCH2, CH2CH2 and CH=CH, or when R2 is hydrogen, an alkali métal sait thereof. 1 0043

It is understood that as used herein limitations ofFormula I and II are defined as follows.

The term "lower alkyl" refers to a branched or un-branched saturated hydrocarbon Chain containing from 1-4carbon atoms; specifically, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary butyl, and tertiary butyl.

The term "Lower alkanol" dénotés an alcohol having 1-4carbon atoms defined by "lower alkyl".

The Symbol "Ph" represents phenyl.

The term "alkali métal salts" comprehends the alkalimetals and most preferably sodium and potassium.

When the "divalent connecting group X is Ci^O", carbonis covalently bonded to the oxazole and oxygen is covalentlybonded to the substituted phenyl grouping.

When the "divalent connecting group Y is OCl·^", oxygenis covalently bonded to phenyl and carbon is covalently bondedto the carboxylic function.

According to the présent invention, the compoundscharacterized by Formula I, as defined above, are obtained bya process comprising: (a) hydrolyzing a compound of Formula Ia

Ph

(CH2)nCO2R (ia) wherein n is 7-9 and Ra is lower alkyl to the correspondingacid, or (b) esterifying a compound of Formula 1^

wherein n is 7-9 with a lower alkanol, or

(c) reacting a keto ester of Formula III 1 0043

(II!)

(CH,) C09R wherein n is 7-9 and R is hydrogen or lower alkyl with ammo-nium acetate to form the corresponding oxazole, or

(d) decarboxylating a substituted malonic acid ofFormula IV

PH

COjH (IV)

C0,H wherein n is 6-8.

Scheme 1 below illustrâtes the foregoing process.Scheme 1 HO2C(CH2)nC02Râ

Ph

HO,C(CH,) C0,H i. i. η c

Ph 0H(V)

(IIIa) H3,C(CH2)nCH2ar

Ph^ 1) 0El

Ph 0 (CH2)nCH28r (IIIC) 1 0043

In general, oxazole ring formation is conventionallyaccomplished by treating a keto ester with an excess ofammonium acetate in acetic acid at reflux température. Theketo esters (IIIa'^'c) are obtained by esterifying benzoinwith an appropriately substituted carboxylic acid. For exam-ple, keto ester (IIla) is obtained by coupling benzoin (V) andthe half ester of the dicarboxylic acid HC^CÎ Ci^ ^CC^R3 wheren is 7-9 and Ra is lower alkyl using 1,3-dicyclohexylcarbodi-imide in the presence of a catalytic amount of 4-dimethyl-aminopyridine according to the procedure of H. H. Wasserman,et al., Tetrahedron, 37, 4059-4064 (1981). Purification is not a required and the keto ester (III ) treated with an excess ofammonium acetate in acetic acid at reflux température providesoxazole (Ia). Hydrolysis of the ester functionality withaqueous hydroxide provides the corresponding acid (I13). 8 100 43

Alternatively, oxazole (I*3) can be prepared by treating keto ester IIIe, where n is 5-8, with ammonium acetate and acetic acid to provide the oxazole bromide intermediate (VI, n=6-8). Treating this intermediate with a 3-fold excess of dimethylmalonate and potassium t-butoxide in tetrahydrofuran (THF) at reflux in the presence of a catalytic quantity of 18-Crown ether-5 provides the methyl ester of (IV) which is saponified to diacid (IV) and thermally decarboxylated to giveb b (I;. Estérification of (I) is accomplished conventionally byheating the acid (± ) in a lower alkanol in the presence ofconcentrated sulfurie acid.

Another approach to the préparation of (I*3) involvesestérification of benzoin (V) with a three-fold excess of thedicarboxylic acid HO2C( CH2 ) CC^H where n is 7-9 in the pre-sence of a slight excess of 1,3-dicyclohexyl-carbodiimide anda catalytic amount of 4-dimethylamino-pyridine in methylenedichloride to provide the keto ester (III*3). Treatment of thecrude keto ester (IIi ) with ammonium acetate under standardconditions affords the oxazole acid (I, which is separatedfrom by-products by column chromatography.

Alkali métal salts of Formula I carboxylic acids areconventionally prepared by dissolving the acid in methanolwith a molar équivalent of an alkali base such as sodiummethoxide and precipitating the sait or removing the solvent.

According to the présent invention, the compoundscharacterized by Formula II

wherein R^ is phenyl or thienyl; R2 is hydrogen, lower alkyl or together with CO2 istetrazol-1-yl; is a divalent connecting group selected from the groupconsisting of CH2CH2, CH=CH and CH2O; and

X 1 0043

Y is a divalent connecting group selected from the groupconsisting of OCl·^, C^CI^ and CH=CH are obtained by a process comprising:

a wherein is lower alkyl and R^, X and Y are as defined above to the corresponding acid; or

(b) esterifying a compound of Formula II

wherein R^, X and Y are as defined above with a loweralkanol; or

(c) reducing a compound of Formula III

wherein R^, R2 and Y are as defined above, to provide acompound of Formula IV

wherein R^, R2 and Y are as defined above, alkylating a

compound of Formula V 1 0043 (V) 10

OH

(0 N

wherein and X are as defined above and OH is attachedto the 3 or 4 phenyl position with BrCH2CO2R2 wherein Ris lower alkyl to provide a compound of Formula VI

(VI) wherein R2 is lower alkyl, R^ is as defined above, and Xis CH2H2, CH=CH; or (e) alkylating a 3 or 4 substituted phenyl of Formula

VII

YaC02R2 (VII) â â

wherein Y is CH2O or CH2CH2 and R2 is lower alkyl withan oxazole of Formula VIII

(VIII)

wherein R^ is phenyl or thienyl to provide a compound ofFormula IX

wherein R^ and RJ, are as defined above and Ya is CH2O or CH2CH2 10043 11

(f) reacting the trifluoromethanesulfonate ester of acompound of Formula X

CH2™2

0H (X) wherein R^ is phenyl or thienyl and OH is attached to a

the 3 or 4 phenyl position with H2C=CHCC>2R2 wherein Ris lower alkyl to provide a compound of Formula XI (0 ΓΊ

(XI) wherein R^ is phenyl or thienyl and R2 is

(g) reacting a compound of Formula XII lower alkyl.

(XII) wherein R^ is phenyl and the formyl grouping is attach-ed to the 3 or 4 phenyl position with the trimethyl- g g

phosphonate dérivative of CH2CO2R2 wherein R2 is loweralkyl to provide a compound of Formula XIII

CH2O

(XIII) wherein R^ and R2 are as defined above,

(h) reacting a compound of Formula XIV 1 0043

0CH2C02R2 12

OCH (XIV)

wherein R2 is lower alkyl and the side chain is attachedto the 3 or 4 phenyl position with a phosphonate oxazoleof Formula XV

(XV)

wherein R^ is phenyl or thienyl to provide a compound ofFormula XVI ll (XVI) CO s

wherein R^ is phenyl or thienyl and R® is(i) treating a compound of Formula XVII lower alkyl,

Ph

Y-CN (XVII)

wherein X and Y are as defined above with tri-n-butyltinazide to provide a tetrazole of Formula XVIII

Ph (XVIII)

Ph

H wherein X and Y are as defined above.

The following schemes for préparation of représentativecompounds of Formula XI illustrate the foregoing process. 1 0043 13

Scheme 2

(8) (9) 1 0043

Scheme 3 14

(10) OCH—,

OCH2CO2R (CH 0) P-—-->

^-CH2P0(0CH3)2 (il)

OCH2cn2R (7) (12)

Scheme 4 15 10 15 20

(18) 25 30

(19) 10043

ch2po(och3)2

CO2CH3/NaH

SX

V

35 (17) 1 0043

Scheme 5

Xo„ 15 16 (21)

(25) (26) 1 0043 17

Scheme 6

BrCH2C02CH3 k2co3/ch3cn

HC1/CH3OH

(31) 1 0043

Scheme 7 18

Th^_^· N

(32)

CH

Th

Th

Th'

(36) OH'

1) n-Buli/THF 2) Br, VCH3>3 (CH3>2 8rCH2C02CH3 k3cq3/ch3cn o co2ch3

Th

Th

Th „

Th^-0 > C(CH ) I 3 3

Si(CH3)2

n-Bu.NF/THF

Ι—ΟΗ

= Th (37)

Scheme 8 1 0043 19

Scheme 2 depicts préparation of Formula II compoundsderived from phenylpropionic and cinnamic acids. Alkylation ofthe sodium sait of a hydroxyphenylpropionic acid (2 ) orhydroxycinnamic acid (3) with desylbromide (1) followed byoxazole formation provided phénols (4) and ( 5) which werealkylated with a 2-bromoalkanoic acid ester to give esters (6)and (7), respectively. Subséquent hydrolysis with aqueousalkali provided the corresponding acids (8) and (9)· The satu-rated compounds (6) and (8) were synthesized from the unsa-turated precursors (7) and (9) by way of hydrogénation, pre-ferably catalytic, which also could be carried out at thephenolic stage as shown. 1 0043 20

Scheme 3 depicts an alternate approach to the prépara-tion of esters (7) involving coupling of the dimethylphos-phonate (11) prepared from bromide (10) via an Arbuzov reac-tion described by D.C. Schroeder, et al., J. Org. Chem. 27,1098-1101 (1952) with a functionalized aldéhyde (12). ProtonNMR data indicated that the unsaturated compounds were predo-minantly, if not exclusively, of the trans configuration.

Scheme 4 depicts préparation of Formula II compoundsincorporating an oxygen atom in the linkage between the aryland oxazole rings. Bromination of 4,5-diphenyl-2-methyloxazoleaccording to a modification of the procedure of D.L. Aldous,et al., J. Org. Chem. 25, 1151-1154 (1960) using N-bromosucci-nimide in carbontetrachloride at reflux in the presence of2,2'-azobis(2-methylpropionitrile) provided bromide (13).Alkylating the hydroxy benzaldehyde (14) with bromide (13) inthe presence of potassium carbonate in refluxing acetonitrileproduced aldéhyde (15) which was converted to ester (16) byway of the Wadsworth-Emmons modification of the Wittig reac-tion according to W.S. Wadsworth, Org. Reactions, 25, 73-253(1978). Conventional alkaline hydrolysis of ester (16) gavecarboxylic acid (17). Saturated ester (18) and acid (19)were synthesized by alkylating the ester of 3-hydroxyphenyl-propionic acid (20) in the presence of potassium carbonate andsubséquent hydrolysis.

Scheme 5 depicts the préparation of compounds of FormulaII wherein the connecting radical Y is "CI^CI^” and X isCh^CI^ or CH=CH. The triflate (22) was synthesized from theoxazole phénol (21) by treatment with trifluoromethanesulfonicanhydride in pyridine. Reacting the trifluoromethanesulfonateester (22) with ethyl acrylate in the presence of a Pd cata-lyst afforded cinnamic ester (23). Base-induced hydrolysis of(23) gave acid (26). Catalytic hydrogénation of the cinnamicester (14) provided saturated ester (24) which was convertedto acid (25) under aqueous alkaline conditions.

Scheme 6 illustrâtes the préparation of compounds ofFormula II when the "X connecting group" is CH^O and the"Y-side Chain connecting group" is OCI^. Resorcinol mono-acetate (27 ) was alkylated with methyl bromoacetate to give 10043 21 (28) which was dissolved in methanolic hydrogen chloridesolution to provide phénol (29). Alkylation of phénol (29 )with bromide (10) provided the oxazole ester (30) which washydrolyzed to carboxylic acid (31) using aqueous hydroxidesolution.

Scheme 7 illustrâtes the préparation of compounds ofFormula II wherein the two phenyl rings are replaced bythiophene rings in the two possible regio-isomeric forms. The2-methyl-4,5-(2- or 3-thienyl) oxazole dérivatives (32) wereobtained by the method of D. Davidson, et al., J. Org. Chem. 2, 328-334 (1937) from 2- or 3-thiophene carboxaldehyde.Metalation of (32) using n-butyllithium followed by benzylbromide (33) provided oxazoles (34). The phenolic protectinggroup dimethyl(1,1-dimethylethyl)silane was removed usingn-butylammonium fluoride to furnish phénols (35). Conventionalalkylation with methyl bromoacetate gave esters (36) whichwere hydrolyzed to carboxylic acids (37) with aqueous hydro-xide solution.

Scheme 8 illustrâtes préparation of compounds of FormulaII wherein the carboxylic acid moiety is replaced with thetetrazole heterocycle. Treatment of phénol (21) with bromo-acetonitrile and potassium carbonate gave nitrile (38) whichwas converted to the tetrazole (39) with tn-n-butyltin azide.

Alkali métal salts of Formula II carboxylic acids areconventionally prepared by dissolving the acid in a suitablesolvent such as methanol, adding a molar équivalent of analkali base such as sodium methoxide, and precipitating thesait or removing the solvent.

As stated above, the compounds of Formula I and Formu-la II hâve pharmacological properties which make them particu-larly useful as inhibitors of blood platelet aggregation.

Platelet aggregation is considered part of a complexphysiological mechanism for formation of a thrombus in thevascular System. Thromboembolie phenomena, i.e., the formationof thrombi, are involved in hemostasis and a number of disea-sed States in mammals including thrombophlebitis, phlebothrom-bosis, cérébral thrombosis, coronary thrombosis and retinalvessel thrombosis. An increase in propensity for platelet 1 0043 22 aggregation, sometimes referred to as platelet adhesiveness,is observed following parturition, surgical operations such ascoronary artery bypass surgery, organ transplant, angioplasty,prosthetic heart valve implants to name a few and in ischaemicheart disease, artherosclerosis, multiple sclerosis, intra-cranial tumors, thromboembolism, and hyperlipemia; refer to A.Poplawski, et al., J. Artherosclerosis Research, 8, 721(1968). Thus, the compounds of the invention which hâveantithrombogenic (inhibit blood platelet aggregation) areuseful in prévention or treatment of conditions involvingplatelet aggregation and thrombosis such as the above. Theinstant compounds are also considered to hâve antimetastaticpotential in view of their platelet inhibition properties.

The pharmacological properties of the instant compoundscan be demonstrated by conventional in vitro and in vivobiological tests such as the following.

IN VITRO INHIBITION OF HUMAN PLATELET AGGREGATION

The aggregometer method of Born, C.V.R., J. Physiol,(London), 1962, 162, 67-68, as modified by Mustard, J.F., etal., J. Lab. Clin. Med. 1964, 64, 548-599 was used to assessthe in vitro activity of the various compounds as to theinhibition of adenosine diphosphate (ADP) and collagen-inducedplatelet aggregation. The human volunteer donor's arm iscleansed with 70% ethyl alcohol. A stérile 20 ml syringe andneedle are used to withdraw 20 ml of blood. The blood isimmediately added to a test tube containing 3.8% sodiumcitrate to prevent clotting (1 part citrate to 9 parts blood).

Platelet rich plasma (PRP) was separated by centrifu-gation for 10 minutes at 1000 rpm (140xg) from citrated (3,8%)human blood. Ail glassware used for préparation of PRP isSilicon treated. ADP in final concentration of 0.5 mcg/ml or0.05 ml of a collagen suspension prepared according to themethod described by Evans, G., et al., J. Exp. Med., 1968, 128, 877-894 was used to induce aggregation. The variouscompounds tested were dissolved in dimethylsulfoxide (DMSO) sothat 5 mcl added to the platelet rich plasma would yield thedesired test concentration. Vehicle control trials were doneand compared with aggregation induced in platelet rich plasma 10043 23 containing various concentrations of the test compounds. Dose response curves were obtained and Inhibitor Concentration ( ICr-„ ) values calculated or the percent inhibition atou 32 mcg/ml noted. In this test, the IC^g values for dipyrida-mole, a clinically useful antithrombogenic agent, are512 mcg/ml vs. ADP and 245 mcg/ml vs collagen. Results aregiven in Tables I, II and III hereinafter for various FormulaI and II compounds and related prior art compounds.

TABLE I

Inhibition of Human PlateletAggregation of Formula I Compounds J (CH2)nCO2R 0 vs ADP vs. Collagen Example n R mg/ml % mg/ml % 1 8 CH3 32 2 32 83 2 8 H 2.5 50 1.4 50 3 7 CH3 32 0 4 7 H 32 4 11 50 (a)* 2 H 32 16 32 36 (a) 3 H 32 0 (a) 1 H 32 0 (a) U.S . Patent 3, 578, 671 * Oxaprozin It is évident that the acids of Formula I (Examples 2 and 4) are active whereas the short Chain acids of U. S.3,578,671 are essentially inactive against ADP-induced aggre-gation of human platelets. As for the esters (Examples 1 and3) corresponding to Examples 2 and 4, they are relatively weakanti-aggregators in vitro but serve as pro drugs in vivo wherethey are readily hydrolyzed to the active acids. 1 0 0 43 24

TABLE II

Inhibition of Human Platelet Aggregationof Formula II Compounds Wherein R^is Phenyl

Ex. Ring Position X Y Rp vs/ADP mcg/ml (%) vs.Collagen mcg/ml (%) 5 3 CH^CHj, 0CH2 CH3 0.29 (50) 0.25 (50) 6 3 CH?CHp 0CH2 H 0.49 (50) 0.12 (50) 7 4 CH?CH? 0CH2 ch3 7-4 (50) 2.9 (50) 8 4 ΟΗ?ΟΗ? 0CH2 H 3-7 (50) 1.6 (50) 9 3 CHpCH? CH=CE C2H5 32 (26) 10 3 ΟΗ?ΟΗ? CH=CH H 0.3 (50) 11 3 CHpCH? CHpCH., C2H5 32 (35) 12 3 CH-jCH? ch?ch3 H 6.5 (50) 13 3 CH=CH och2 ch3 3-1 (50) 0.2 (50) 14 3 CH=CH och2 H 5-3 (50) 0.39 (50) 15 4 CH=CH och2 ch3 15 16 4 CH=CH och2 H 4.05 21 3 ch2o CH=CH ch3 32 (3) 32 (6) 22 3 ch2o CH=CH H 5-5 (50) 1.8 (50) 23 4 ch2o CH=CH ch3 32 (19) 32 (7D 24 4 ch2o CH=CH H 32 (24) 32 (73) 17 3 ch2o CH^CH^ CH3 32 (0) 32 (47) 18 3 ch2o CH-jCH? H 32 (24) 32 (89) 19 4 ch2o CH^CH,, CH3 32 (29) 24 (50) 20 4 CH20 CH?CH? H 20 (50) 5 (50) 25 3 CH2° och2 ch3 1.9 (50) 26 3 CH20 och2 H 0.27 (50) 1 0043 25

TABLE III

Inhibition of Human PlateletAggregation of Thienylated Oxazoles

IN VIVO INHIBITION OF BIOLASER INDUCED THROMBOSIS

The laser induced thrombosis method is a modification ofthe technique developed by Sanders, A.G., et al. in Brlt. J.Exp. Pathol., 1954, 35, 331 and Grant, L., et al. in Proc.

Soc. Exp. Biol. Med. , 1965, 119, 1123. A detailed descriptionof this method has been described by Fleming, J.S., et al. inPlatelets and Thrombosis, A. Scriabine and S. Sherry, eds.,Baltimore, Univ. Park Press, pp. 247-262, 1974 and is herebyincorporated by reference.

Briefly, Lucite ear chambers were chronically implantedin adult, English lop-ear rabbits. The animais were condi-tioned to lie quietly in the supine position. Localizedmicrovascular injury was induced by focusing a single rubylaser beam through a microscope into the lumen of a vessel10-60 mcm in diameter. This evoked the formation of a smallthrombus consisting of platelets accumulated around a core ofone or two damaged red cells. Thrombus area was determined asa product of two perpendicular measurements made by using amicrometer eye piece. The mean thrombus area (mcm2) obtainedfor 10 trials in each rabbit served as a control value. Thetest compound was administered orally and post-dose trials 10043 26 were performed at selected times. Phartnacological activity wasevaluated by comparing pre- and post-dose mean thrombus areas.

In the above biolaser model of thrombosis, the compoundof Example 6 exhibited 53% inhibition of thrombosis at an oraldose of 10 mg/kg, 38% inhibition at 3 mg/kg and 23% inhibitionat 1 mg/kg body weight.

The dosage employed in the therapeutic methods of theinstant invention will vary with the form of administration,the particular compound chosen, the subject being tested andthe effect desired. Suitable effective doses in animais rangefrom 0.1-50 mg/kg body weight orally and from 0.05-10 mg/kgbody weight parenterally (generally characterized as subcuta-neous, intramuscular, and intravenous injection). It iscontemplated that the effective unit dose in man will rangefrom 1 to 100 mg and preferably from 0.5 to 20 mg administeredone to three times a day. In accordance with conventionalclinical practice, the effective dose can be determined byadministering a Formula I or II compound at a dosage substan-tially less than the dose of the compound which is thought tobe effective and then increasing the dosage in small incré-ments until the desired effect is achieved.

In carrying out the instant therapeutic methods, theactive ingrédient of Formula I or II or alkali métal salts ofFormula I and II carboxylic acids are preferably administeredwith a pharmaceutically acceptable carrier and such composi-tions constitute part of the instant invention. Suitabledosage forms for oral use are tablets, dispersible powders,granules, capsules, syrups and élixirs. Examples of parentéralforms are solutions, suspensions, dispersions, émulsions, andthe like. The compositions for oral use may contain one ormore conventional adjuvants, such as sweetening agents,flavoring agents, coloring agents and preserving agents, inorder to provide a composition of suitable pharmaceuticalelegance. Tablets may contain the active ingrédient in admix-ture with conventional pharmaceutical acceptable excipientsincluding inert diluents such as calcium carbonate, sodium 10043 27 carbonate, lactose and talc; granulating and disintegratingagents such as starch and alginic acid; binding agents such asstarch, gelatin and acacia and lubricating agents such asmagnésium stéarate, stearic acid and talc. The tablets may beuncoated or coated by known techniques to delay disintegrationand absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. Similarly,suspension, syrups and élixirs may contain the active ingré-dient in admixture with any of the conventional excipientsutilized for the préparation of such compositions such assuspending agents (e.g., methylcellulose, tragacanth, andsodium alginate), wetting agents (e.g., lecithin, polyoxy-ethylene stéarate) and preservatives such as ethyl-p-hydroxy-benzoate. Capsules may contain the active ingrédient alone oradmixed with an inert solid diluent such as calcium carbonate,calcium phosphate and kaolin. The injectible compositions areformulated as known in the art and may contain appropriatedispersing or wetting agents and suspending agents identicalor similar to those mentioned above.

The following examples are given by way of illustrationand are not to be construed as limiting the invention in anyway inasmuch as many variations of the invention are possiblewithin the spirit of the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS

In the following examples, ail températures are given indegrees Centigrade. Melting points were recorded on a Thomas-Hoover capillar melting point apparatus and are uncorrected.Proton magnetic résonance ( H-NMR) spectra were recorded on aBruker AM 300, Bruker WM 360 or Varian Gemini spectrometer.

Ail spectra were determined in CDCl^ or DMSO-dg unless other-wise indicated and Chemical shifts are reported in delta unitsdownfield from the internai standard tetramethylsilane (TMS)and interproton coupling constants are reported in Hertz (Hz).Splitting patterns are designated as follows: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet; br, broad peak;and dd, doublet of doublet. 10 0 43 28 EXAMPLE 1

Methyl 4,5-diphenyl-2-oxazolenonanoate

Ph

Ph % .0^ (CH2)8C02CH3 A mixture of 4,5-diphenyl-2-oxazole nonanoic acid(800 mg, 2 mmol), methanol (20 ml) and concentrated sulfuricacid (2 drops) was heated to reflux. After 2 hours, the sol-vent was evaporated and the residue partitioned between CH2C12and water. The organic phase was separated, washed with satu-rated NaHCOg solution, dried over sodium sulfate and concen-trated in vacuo to leave an oil. Chromatography on a column ofsilica gel using a mixture of hexanes and diethyl ether (4:1)as eluent gave methyl 4,5-diphenyl-2-oxazolenonanoate (800 mg,96%).

Anal. Calcd. for C25H29NO3: C, 76.70; H, 7.47; N, 3.58.Found: C, 76.61; H, 7.84; N, 3.94%. 1H-NMR (CDC13) delta: 1.20 to 1.50 (8H, m), 1.64 (2H,quintet, J=7Hz), 1.87 (2H, quintet, J=7Hz), 2.32 (2H, t,J=7.5Hz), 2.87 (2H, t, J=7.5Hz), 3.67 (3H, s), 7.20 to 7.50(6H, m) and 7.60 to 7.80 (4H, m). EXAMPLE 2 4, 5-Piphenyl-2-oxazolenonanoic Acid

Ph

Ph

2-[7-(4,5-Diphenyl-l-oxazolyl)heptyl]propanedioic acid(4.50 g, 10 mmol) was heated with stirring at 150°C. After2 hours, the flask was cooled and the residue triturated witha mixture of hexane and diethyl ether (1:1) to give a whitesolid. Crystallization from aqueous isopropyl alcohol afforded4,5-diphenyl-2-oxazolenonanoic acid (3.15 g, 87%) m.p. 83-85°C.

Anal. Calcd. for C24H27NO3: C, 76.37; H, 7.22; N, 3.72.Found: C, 76.37; H, 7.21; N, 3.66%. 1 0043 29 1H-NMR (DMSO-d5) delta: 1.10 to 1.40 (8H, m), 1.46(2H, m), 1.71 (2H, m), 2.15 (2H, t, J=7Hz), 2.76 (2H, t, J=7Hz), 7.20 to 7.45 (6H, m), 7.45 to 7.65 (4H, m) and 11.99(1H, bs). EXAMPLE 3

Methyl 4,5-d.iphenyl-2-oxazoleoctanoate

H jT {CMjîyCÛjCMj

Ph"0 A mixture of benzoin (6.00 g, 28 mmol), azelaic acidmonomethyl ester (7.17 g of 92% pure matériel, 32 mmol), 1,3-dicyclohexylcarbodiimide (7.00 g, 34 mmol), 4-dimethylamino-pyridine (catalytic amount) and dichloromethane (120 ml) wasstirred at room température. After 16 hours, the mixture wasfiltered and the solvent evaporated. Ammonium acetate (10.90 g,141 mmol) and acetic acid (150 ml) were added to the residueand the mixture heated at reflux for 65 minutes before beingcooled and diluted with water. The mixture was extracted withdiethyl ether, the combined extracts driad over sodium sulfateand concentrated in vacuo. The residual oil was chromatogra-phed on a column of silica gel using a mixture of hexanes anddiethyl ether (7:3) as eluent to give methyl 4,5-diphenyl-2-oxazole-octanoate (8.24 g, 77%) as an oil.

Anal. Calcd. for C24H27NO3: C, 76.37; H, 7.22; N, 3.72.Found: C, 76.25; H, 7.28; N, 4.05%. 1H-NMR (CDC13) delta: 1.10 to 1.35 (6H, m), 1.45 (2H,quintet, J=7Hz), 1.67 (2H, quintet, J=7Hz), 2.12 (2H, t,J=7.5Hz), 2.66 (2H, t, J=7.5Hz), 3.47 (3H, s), 7.05 to 7.25(6H, m), and 7.35 to 7.55 (4H, m). EXAMPLE 4 4,5-Dlphenyl-2-oxazoleoctanoic Acid

(CH^COjH 1 0043 30 A mixture of methyl 4,5-diphenyl-2-oxazole-octanoate(7.00 g, 18.5 mmol), 5N sodium hydroxide solution (7.42 ml),water (100 ml) and methanol (20 ml) was heated on a steam bathfor 45 minutes. After stirring at room température for 75 mi-nutes, the mixture was diluted with water (150 ml), heated ona steam bath for 10 minutes and then allowed to stir overnightat room température. The mixture was heated to reflux for 1hour, cooled, acidified with 2N hydrochloric acid solution andextracted with The combined extracts were dried over sodium sulfate and concentrated in vacuo to give an oil thatcrystallized. Recrystallization from a mixture of diethylether, Cl^C^ and hexanes furnished 4,5-diphenyl-2-ozazole-octanoic acid (5.25 g, 77%), m.p. 70-73°C.

Anal. Calcd. for C^H^NOg: C, 76.01; H, 6.94; N, 3.86.Found: C, 75.87; H, 6.94; N, 4.16%. 1H-NMR (CDC13) delta: 1.20 to 1.45 (6H, m), 1.54 (2H,quintet, J=7Hz), 1.75 (2H, quintet, J=7Hz), 2.23 (2H, t,J=7.5Hz), 2.76 (2H, t, J=7.5Hz), 7.10 to 7.35 (6H, m), 7.40 to7.60 (4H, m) and 11.74 (1H, bs). EXAMPLE 5

Methyl 2-[3- [2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate

Ph

Ph

CHjCH

och2cp2ch3 A mixture of methyl 3[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phénol (3.41 g, 10 mmol), potassium carbonate (1.52 g, 11 mmol), potassium iodide (catalytic amount), methyl bromo-acetate (1.68 g, 11 mmol) and acetonitrile (32 ml) was stirredat reflux under an atmosphère of nitrogen. After 90 minutes,the mixture was cooled, filtered and concentrated to leave anoil which was subjected to chromatography on a column of silicagel. Elution with a mixture of hexanes, ethyl acetate andtriethylamine (75:25:1) afforded methyl 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate (3.59 g, 86%) as a viscousoil. 10043 31

Anal. Calcd. for <-26H23NO4: 75.54·, H, 5.61; N, 3.39.

Found: C, 75.57; H, 5.67; N, 3.41%. 1H-NMR (CDC13) delta: 3.14 (4H, s), 3.76 (3H, s), 4.60(2H, s), 6.75 (1H, dd, J=8Hz, J’=2.5Hz), 6.90 (1H, d, J=8Hz ),7.15 to 7.40 (7H, m) and 7.50 to 7.75 (4H, m). EXAMPLE 6 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetlc Acid

Ph

Ph

OCH2cn2H A mixture of methyl 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy]acetate (2.25 g, 5.5 mmol), 3N sodium hydroxidesolution (5.5 ml) and methanol (50 ml) was heated to reflux ona steam bath. After 5 minutes, the mixture was cooled, themethanol evaporated and the residue diluted with water.

Warming provided a solution which was diluted with IN hydro-chloric acid solution to pH 3 to give an oily precipitate. Themixture was extracted with CH2C12 and the organic extractswashed twice with water and once with saturated sodium chlo-ride solution. Concentration, after drying over sodium sul-fate, left a pale yellow solid which was recrystallized twicefrom a mixture of hexanes and CH2C12 (2:1) to give 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]phenoxy]acetic acid (1.74 g,80%), m.p. 153.3-154.5°C.

Anal. Calcd. for C25H21NO4: C, 75.18; H, 5.30; N, 3.51.Found: C, 75.15; H, 5.35; N, 3.30%. 1H-NMR (DMSO-d6) delta: 3.12 (4H, m), 4.64 (2H, s), 6.73(1H, dd, J=8Hz, J'=2Hz), 6.88 (2H, m), 7.20 (1H, t, J=8Hz),7.30 to 7.50 (6H, m), and 12.98 (1H, bs).

Sodium métal (0.58 g, 25 mg/atom) was dissolved inmethanol (10 ml) and 1 ml of this solution diluted with metha-nol (20 ml). 2-[3-[2—(4,5-diphenyl-2-oxazolyl]-ethyl]phenoxy]-acetic acid (100 g, 2,5 mmol) was added and the mixturestirred at room température for 18 hours. Evaporation of thesolvent left a beige solid, sodium 2-[3-[2-(4,5-diphenyl-2-oxazolyl]ethyl]phenoxy]acetate (1.06 g, 100%) m.p. 278-280°C. 10043 32

Anal. Calcd. for C25 H20NO4Na· 0.2HQ: C, 70.65; H, 4.84; N, 3.30. H20, 0.85 . Found: C, 70.46 ; H, 4.75; N, 3.23; h2°. 0.68%. 1H-NMR (D20) delta : 2.55 (4H, bs), 4.19 (2H, s). 6.20 (1H, d, J=7.5Hz), 6.45 to 6.70 (5H, m), 6.79 (1H, t, J =7.5Hz), 6.90 to 7.30 (7H, m). EXAMPLE 7

Methyl 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate

Ph N

T A mixture of 4-[2—(4,5-diphenyl-2-oxazolyl)ethyl]phénol(6.00 g, 17 mmol), methyl bromoacetate (2.96 g, 1.83 ml, 19 mmol)

Z potassium carbonate (2.91 g, 21 mmol), potassium iodide (cata-lytic amount) and acetonitrile (80 ml) was stirred at reflux.After 1 hour, the mixture was cooled, filtered and the solventremoved to leave a crystalline solid that was triturated withhexanes and filtered to give methyl 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate (7.27 g, 100%). An analyticalsample was obtained by recrystallizing a 2.25 g batch frommethanol to give 1.70 g of pure material which had m.p. 122-125°C.

Anal. Calcd. for C2&amp;H23NO4: C, 75.53; H, 5.61; N, 3.39.Found: C, 75.30; H, 5.86; N, 3.39%. 1H-NMR (CDC13) delta: 3.11 (4H, s), 3.77 (3H, s), 4.60(2H, s), 6.84 (2H, d, J=8.5Hz), 7.18 (2H, d, J=8.5Hz), 7.20 to7.50 (6H, m), and 7.60 to 7.80 (4H, m). EXAMPLE 8 2-[4-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic Acid

A mixture of methyl 2-[4-[2-(4,5-diphenyl-2-oxazolyl]-ethyl]phenoxy]acetate (5g, 12 mmol), 5N sodium hydroxide 1 0043 33 solution (7.26 ml) and methanol (100 ml) was heated on a steambath for 45 minutes. The solution was concentrated in vacuodiluted with water and 2N HCl solution and a white solid fil-tered off. Recrystallization from methanol gave 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (2.88 g, 59%),m.p. 147-149-0.

Anal. Calcd. for C25H21NO4: C, 75.17; H, 5.30; N, 3.51.Found: C, 75.03; H, 5.50; N, 3.44%. 1H-NMR (DMSO-d6) delta: 3.11 (4H, bs), 4.68 (2H, s), 6.90 (2H, bs), 7.24 (2H, d, J=6Hz), 7.30 to 7.90 (10H, m) and13.10 (1H, bs). EXAMPLE 9

Ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy-2- propenoate

Ph

A mixture of 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenyl-trifluoromethane sulfonate (11.8 g, 25 mmol), ethyl acrylate(5.01 g, 50 mmol), triethylamine (10.12 g, 100 mmol) palladiumII acetate (0.28 g, 1.25 mmol) 1,3-bis-(diphenylphosphine)-propane (0.52 g, 1.25 mmol) and DMF (100 ml) was stirred at90°C under an atmosphère of nitrogen. After 2 hours and 6hours additional palladium II acetate (0.28 g, 1.25 mmol) and1,3-bis-(diphenylphosphine)propane (0.52 g, 1.25 mmol) wereadded. After 22 hours, the mixture was diluted with water andextracted with ethyl acetate. The combined extracts were washedthree times with water and once with saturated sodium chloridesolution, dried over sodium sulfate and concentrated. Theresidual oil was chromatographed on a column of silica gelusing a mixture of hexanes and ethyl acetate (3:1) as eluentto give ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyljphenyl-2-propenoate (9.37 g, 88%) as an oil.

Anal. Calcd. for C28H25NO3: C, 79.41; H, 5.96; N, 3.31.Found: C, 79.20; H, 6.21; N, 3.45%. 1 0043 34 1H-NMR (CDClg) delta: 1.31 (3H, t, J = 7Hz ), 3,17 (4H, m)4.24 (2H, q, J=7Hz), 6.41 (1H, d, J=16Hz), 7.20 to 7.50 (10H, m) and 7.50 to 7.80 (5H, m). EXAMPLE 10 3-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenyl]-2-propenoic acid hydrate hexane solvaté

Ph

H

Z A mixture of ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]phenyl]-2-propenoate (1.50 g, 3.5 mmol), 3N sodium hydro-xide solution (3.5 ml) and methanol (100 ml) was heated on asteam bath. After 25 minutes the mixture was cooled, concen-trated, diluted with water and made pH=l with dilute hydro-chloric acid solution. The mixture was extracted three timeswith The combined extracts were washed with saturated

NaCl solution, dried over sodium sulfate and the solvent eva-porated. The residual oil was chromatographed on a column ofsilica gel using a mixture of chloroform and methanol (9:1) aseluent to give 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenyl]-2-propenoic acid (1.40 g, 100%) as the hydrated hexane solvatéafter recrystallization from a mixture of hexanes and (3:1), m.p. 114-115°C.

Anal. Calcd. for Co,Hni N0_.0.6C,H.. . 0.2H_0: C, 78.88; H- 26213 614 2 6.67; N, 3.11; 1^0, 0.70. Found: C, 78,54; N, 6,86; N, 3.04; H20, 0.21%. 1H-NMR (CDC13) delta: 0.86 (3H, t, J=7Hz), 1.25 (4H, m3.19 (4H, s) 6.44 (1H, d, J=16Hz), 7.25 to 7.70 (14H, m) and7.75 (1H, d, J=16Hz). EXAMPLE 11

Ethyl 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzenepropanoate

Ph

10043 35 A solution of ethyl 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]phenyl-2-propenoate (1.02 g, 2.4 mmol) in ethyl acetate(50 ml) was hydrogenated over 10% palladium on charcoal (0.06 g )at 35 psi. After 27 hours, the mixture was filtered, concen-trated and the residue subjected to chromatography on a columnof silica gel using a mixture of ethyl acetate and hexanes(9:1) as eluent. Elution gave ethyl 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzene propanoate (0,92 g, 90%) as an oil.

Anal. Calcd. for Ο28Η2?ΝΟ3: C, 79.04; H, 6.40; N, 3.30.Found: C, 79.12; H, 6.72; N, 3.30% 1H-NMR (CDC13) delta: 1.22 (3H, t, J=7Hz), 2.59 (2H, t,J=8Hz), 2.93 (2H, t, J=8Hz), 3.14 (4H, s), 4.11 (2H, q, J=7Hz), 7.00 to 7.50 (10H, m) and 7.50 to 7.70 (4H, m). EXAMPLE 12 3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]benzenepropanoic acid

A mixture of ethyl 3-[2—(4,5-dipheny1-2-oxazolyl )ethyl] -benzenepropanoate (1.85 g, 4.3 mmol), 3N sodium hydroxidesolution (4.4 ml) and methanol (100 ml) was heated on a steambath. After 20 minutes the mixture was concentrated, dilutedwith water and IN hydrochloric acid solution to pH=l andextracted with CH2C12. The combined extracts were dried oversodium sulfate and the solvent evaporated to leave a whitesolid. Recrystallization from a mixture of hexanes and CH2C12gave 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzenepropanoic acid(1.58 g, 91%) m.p. 119-120’C.

Anal. Calcd. for C^H^NO.^ C, 78.57; H, 5.84; N, 3.53.Found: C, 78.61; H, 5.96; N, 3.31%. ^H-NMR (CDC13) delta: 2.64 (2H, t, J=8Hz), 2.93 (2H, t,J=7Hz), 3.14 (4H, s), 7.05 to 7.50 (10H, m) and 7.50 to 7.75(4H, m). 1 0043 EXAMPLE 13

Methyl [3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenoxy]acetate 36

CH=CH

Sodium métal (260mg, llmg atom) was dissolved in metha-nol (50 ml) and dimethyl [(4,5-diphenyl-2-oxazolyl)methyl]-phosphonate (3.89 g, 11 mmol) added followed by methyl(3-formylphenoxy)acetate (2g, 10 mmol). The mixture wasstirred at room température for 20 minutes before beingconcentrated and diluted with 2N HCl solution. The mixture wasextracted with CH2CI2, the organic phase dried over sodiumsulfate and the solvent evaporated to leave a yellow oil. Thiswas combined with the crude material from a reaction performedon 2 g of the phosphonate and 985mg of aldéhyde and chromato-graphed on a column of silica gel. Elution with a mixture ofhexanes and diethyl ether (3:2) furnished methyl [3-[2-(4,5-diphenyl-2-oxazolylJethenyl]phenoxy]acetate as the diethylether solvaté (2.92 g, 46%) after recrystallization fromdiethyl ether, m.p. 79-82°C.

Anal. Calcd. for C2gH21NO4.0.3C4H1Q0: C, 75.34; H, 5.58;N, 3.23. Found: C, 75.35; H, 5.47; N, 3.17%. 1H-NMR (CDC13) delta: 1.26 (1.25H, t, J = 7Hz ), 3.53 (0.75H, q, J=7Hz), 3.88 (3H, s), 4.73 (2H, s), 6.94 (1H, dd,J=7.5Hz, J'=2Hz), 7.06 (1H, d, J=16Hz), 7.14 (1H, t, J=2Hz), 7.20 to 7.55 (8H, m), 7.60 (1H, d, J=16Hz), and 7.70 to 7.90(5H, m ). EXAMPLE 14 [3-[2-(4,5-Diphenyl-2-oxazolyl)ethenyl]phenoxy]acetic Acid

Ph

Ph

CH=CH

1 0043 37 A mixture of methyl [3-[2-(4,5-diphenyl-2-oxazolyl)ethe-nyl]phenoxy]acetate (1.00 g, 2.5 mmol), 5N sodium hydroxidesolution (2 ml) and methanol (15 ml) was heated on a steambath for 10 minutes before being concentrated. Dilution withwater and 2N HCl solution gave a yellow solid which was combin-ed with the crude product from a reaction performed on 1.46 gof ester using 3 ml of 5N NaOH in 40 ml methanol. Recrystalli-zation from éthanol gave [3-[2-(4,5-diphenyl-2-oxazolyl)-ethenyl]phenoxy]acetic acid (1.70 g, 70%), m.p. 213-215°C.

Anal. Calcd. for C2gHigNO4: C, 75.56; H, 4.82; N, 3.53.Found: C, 75.37; H, 4.87; N, 3,43%. 1H-NMR (DMSO-d6 delta: 4.75 (2H, s), 6.90 (1H, m), 7.20to 7.70 (13H, m) and 13.02 (1H, bs). EXAMPLE 15

Methyl [4-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenoxy]acetate

OCH2CO2CH3

Sodium métal (570mg, 25mg atom) was dissolved in metha-nol (50 ml) and dimethyl [(4,5-diphenyl-2-oxazolyl)methyl]-phosphonate (7.80 g, 22 mmol) added. The mixture was stirredfor 10 minutes before adding (4-formylphenoxy)acetate (4.00 g,20 mmol). After stirring at room température for 1 hour, themixture was diluted with water and a yellow solid filtered offand air dried to give crude product (3.80 g, 44%). This wascombined with 3.50 g from a previous experiment and recrystal-lized twice from methanol to afford analytically pure methyl[4- [2-(4,5-dipheny1-2-oxazoly1)ethenyl]phenoxy] acetate, m.p.122-123’C

Anal. Calcd. for C26H21NO4: C' 75*90; H' S·1^; N, 3.41.Found: C, 76.00; H, 5.16; N, 3.44%. 1H-NMR (DMSO-d6) delta: 3.70 (3H, s), 4.85 (2H, s), 6.97(2H, d, J=10Hz, 7.08 (1H, d, J=13.5Hz), 7.30 to 7.55 (6H, m),and 7.55 to 7.80 (7H, m). 10043 EXAMPLE 16 [4-[2-(4,5-Diphenyl-2-oxazolyl)ethenyl3phenoxy3acetic Acid 38

A mixture of methyl [4-[2-(4,5-diphenyl-2-oxazolyl)-ethenyl]phenoxy]acetate (2.00 g, 5 mmol), 5N sodium hydroxidesolution (2.90 ml), water (40 ml) and methanol (10 ml) washeated on a steam bath to give a solution. The mixture wascooled, diluted with 2N hydrochloric acid solution to pH = 1and filtered. Recrystallization from éthanol gave [4-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]acetic acid (1.34 g, 69%), m.p.223-225°C.

Anal. Calcd. for C25H19NO4: C' 75-56; H' 4·82'* 3.53.

Found: C, 75.47; H, 4.79; N, 3,55%. 1H-NMR (DMSO-d6) delta: 4.74 (2H, s), 6.95 (2H, d,J=8.5Hz), 7.08 (1H, d, J=16Hz), 7.20 to 7.50 ( 6H, m), 7.50 to7.70 (5H, m), 7.69 (2H, d, J=8.5Hz), and 13.08 (1H, br).EXAMPLE 17

Methyl 3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl)propa- noate

Ph P h'

CO2CH3 A mixture of 2-bromomethyl-4,5-diphenyloxazole (10.00 g,3 mmol), methyl 3-(3-hydroxyphenyl)propanoate (5.73 g, 3 mmol)potassium carbonate (4.83 g, 3.5 mmol) potassium iodide (cata-lytic amount) and acetonitrile (150 ml) was stirred at refluxtempérature. After 30 minutes, the mixture was filtered,concentrated in vacuo and the residual oil chromatographed on 1 0043 39 a column of silica gel. Elution with a mixture of hexanes anddiethyl ether (3:1) furnished methyl 3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]propanoate (10.34 g, 78%) as an oil.

An analytical sample was prepared by subjecting a 4 g sampleto chromatography under the conditions described above tofurnish pure matériel as an oil.

Anal. Calcd. for ^26^23^41 C, 75.53; H, 5.61; N, 3.39.Found: C, 75.11; H, 5.60; N, 3.33%. 1H-NMR (CDClg) delta: 2.63 (2H, t, J=8Hz), 2.95 (2H, t,J=8Hz), 3.65 (3H, s), 5.19 (2H, s), 6.80 to 7.05 (3H, m), 7.20to 7.55 (7H, m) and 7.60 to 7.80 (4H, m). EXAMPLE 18 3-[3-[(4,5-Dlphenyl-2-oxazolyl)methoxy]phenyl]propanoic acid

Ph

A mixture of methyl 3-[3-[(4,5-diphenyl-2-oxazolyl)-methoxy]phenyl]propanoate (6g, 14.5 mmoï), 5N sodium hydroxidesolution (8.7 ml) and methanol (150 ml) was heated to refluxon a steam bath. After 20 minutes the mixture was concentrat-ed, diluted with water (200 ml) and 2N hydrochloric acid solu-tion to pH-1. After filtration and drying in air overnight,the solid was recrystallized from a mixture of hexanes andCH2CI2 to give 3—[3—[(4,5-diphenyl-2-oxazolyl)-methoxy]phenyl]-propanoic acid (4.15 g, 71%), m.p. 118-120°C.

Anal. Calcd: for ^25Η21Νθ4.0.llï^O: C, 74.84; H, 5.33; N, 3.50; H20, 0.45. Found: C, 74.49; H, 5.31; N, 3.31; H20, O. 05%. 1H-NMR (CDC13) delta: 2.67 (2H, t, J=8Hz), 2.95 (2H, t,J=8Hz), 5.22 (2H, s), 6.80 to 7.00 (3H, m), 7.15 to 7.50(7H, m), 7.55 to 7.80 (4H, m) and 10.71 (1H, br). 10043 EXAMPLE 19

Methyl 3-[4-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]propa- noate 40

Ph

Reaction of 2-bromomethyl-4,5-diphenyloxazole and methyl3-(4-hydroxyphenyl)propanoate according to the procedure ofExample 17 provided the title compound, m.p. 92-95’C.

Anal. Calcd. for C26H23N04.0.3H20: C, 74.56; H, 5.68; N,3.35; H20, 1.29. Found: C, 74.37; H, 5.81; N, 2.81; H20, 0.13.EXAMPLE 20 3-[4-[(4,5-Diphenyl-2-oxazolyl)methoxy]phenyl]propanoic Acid co2h

Methyl 3-[4-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]-propanoate was hydrolyzed with aqueous sodium hydroxideaccording to the procedure of Example 18 to provide the titlecompound, m.p. 124-127’C.

Anal. Calcd. for C25H21NO4: C' 75·18'' H> 5.30; N, 3.51.Found: C, 74.73; H, 5.38; N, 3.49. EXAMPLE 21

Methyl 3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]-2-pro- penoate

Ph

10043 41

Sodium hydride (2.57 g of a 60% disp, 64 mmol) was washedwith hexanes, covered with dimethylether (250 ml) and trimethylphosphonoacetate (10.71 g, 9.52 ml, 59 mmol) added portionwise.The mixture was stirred for 15 minutes and a solution of3-[(4,5-diphenyl-2-oxazolyl)methoxy]benzaldehyde (19.00 g, 53 mmol) in dimethylformamide (50 ml) added in one portion.

The mixture was stirred for 30 minutes to give an amber solu-tion before being diluted with water and extracted with CH2C12·The combined extracts were dried over sodium sulfate and thesolvent evaporated to leave an oil that crystallized upontrituration with a mixture of hexanes and diethyl ether togive methyl 3-[3—(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]-2-propenoate (27.20 g, 78%). An analytical sample was preparedby recrystallizing 1.40 g from ^PrOH to give 0.85 g of purematerial m.p. 88-90°C.

Anal. Calcd. for C26H21NO4: C, 75.90; H, 5.15; N, 3.41

Found: C, 75.80; H, 5.18; N, 3.43%. 1H-NMR (CDC13) delta: 3.85 (3H, s), 5.27 (2H, s), 6.49 (1H, d, J=16Hz), 7.10 to 7.55 (10H, m) and 7.60 to 7.80(5H, m). EXAMPLE 22 3-[3-[(4, 5-Diphenyl-2-oxazolyl)methoxy]phenyl]-2-propenolc acid

Ph

A mixture of methyl 3-[3-[(4,5-diphenyl-2-oxazolyl )-methoxy]phenyl]-2-propenoate (3g, 7.2 mmol), 5N sodium hydro-xide solution (4.40 ml) and methanol (60 ml) was heated toreflux. After 30 minutes, the mixture was cooled, concentra-ted, diluted with water and acidified to pH=l with 2N hydro-chloric acid solution. A yellow solid was filtered off and 1 0043 42 recrystallized from a mixture of hexanes and CH^Cl^ to give3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]-2-propenoicacid (2.25 g, 77%), m.p. 145-147°C.

Anal, calcd. for C25HigN04·0·1H2O: C, 75.22; H, 4.85; N,3.51; H2O, 0.45. Found: C, 74.94; H, 4.86; N, 3.42; H20, 0.11%. 1H-NMR (CDCl3/DMSO-d6) delta: 5.24 (2H, s), 6.46 (1H, d,J=16Hz), 7.09 (1H, dd, J=8Hz J'=2Hz) 7.17 (1H, d, J=8Hz), 7.25(1H, d, J=2Hz), 7.30 to 7.50 (7H, m) and 7.60 to 7.80 (5H, m).EXAMPLE 23

Methyl 3-[4-[(4,5-diphenyl-2-oxazolyl)methoxyjphenyl]-2-pro- penoate

Reaction of trimethyl phosphonacetate and 4-[(4,5-diphenyl-2-oxazolyl)methoxy]benzaldehyde according to theprocedure of Example 21 provided the title compound, m.p.159-161°C.

Anal. Calcd. for c26H21NO4·0 *3H2O: C, 74.92; H, 5.23; N,3.37; H20, 1.30. Found: C, 74.96; H, 5.04; N, 3.35; H20, 0.03.EXAMPLE 24 3-[4-(4,5-Diphenyl-2-oxazolyl)methoxy]phenyl]-2-propenoic Acid

Methyl 3-[4-(4,5-diphenyl-2-oxazolyl )methoxy]phenyl]-2-propenoate was hydrolyzed with aqueous sodium hydroxideaccording to the procedure of Example 22 to provide the titlecompound, m.p. 205-207°C.

Anal. Calcd. for c25Hi9NO40·1H20: C, 75.22; H, 4.85; N,3.51; H20, 0.45. Found: C, 75.14; H, 4.86; N, 3.47; H20, 0.20. EXAMPLE 25

Methyl [3- [ ( 4,5-diphenyl-2-oxazolyl )methoxy] phenoxy]acetate 43 100 43

0CH2C02CH3 A mixture of 2-bromomethyl-4,5-diphenyloxazole (6.68 g,21 mmol), methyl (3-acetoxyphenoxy)acetate (3.87 g, 21 nunol),potassium carbonate (3.52 g, 25 mmol), potassium iodide (cata-lytic amount) and acetonitrile (125 ml) was stirred at reflux.After 40 minutes, the mixture was cooled, filtered and thesolvent evaporated to leave an oil. Chromatography on a columnof silica gel using a mixture of hexanes and diethyl ether(3:1) as eluent furnished hydrated methyl[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenoxy]acetate (6.45 g, 72%) as an oil.

Anal. Calcd. for c25H21N05*0‘2H20: C, 71.66; H, 5.15; N,3.35; H90, 0.86. Found: C, 71.56; H, 5.49; N, 3.44; H„O, 0.60%. 1H-NMR (CDC13) delta: 3.77 (3H, s), 4.61 (2H, s), 5.17(2H, s) 6.55 (1H, dd, J=8Hz J'=2Hz), 6.65 (1H, m), 6.72 (1H,dd, J=8Hz, J'=2Hz), 7.20 (1H, t, J=8Hz), 7.30 to 7.50 (6H, m),and 7.50 to 7.70 (4H, m). EXAMPLE 26 [3-[ ( 4,5-Diphenyl-2-oxazolyl)methoxy]phenoxy]acetic Acid

A mixture of methyl [3-[(4,5-diphenyl-2-oxazolyl)me-thoxy]phenoxy]acetate (5.85 g, 14 mmol), 5N sodium hydroxidesolution (8.45 ml) and methanol (100 ml) was heated to reflux.After 10 minutes, the mixture was cooled, the solvent evapo-rated and the residue diluted with water and 2N HCl solution 1 0043 44 to pH=l. A yellow solid was filtered off and recrystallizedfrom a mixture of chloroform, diethyl ether, methanol andhexanes to give hydrated 3-[(4,5-diphenyl-2-oxazolyl)methoxy]-phenoxy]acetic acid (2.70 g, 47%), m.p. 133-135°C.

Anal. Calcd. for c24Hi9N°5·0·6H2O: C, 69.93; H, 4.94;H, 3.40; H2O 2.62. Found: C, 69,61; H, 4.79; N, 3.35; H20,0.21%. 1H-NMR (DMSO-d6) delta: 4.47 (2H, s), 5.29 (2H, s), 6.54(1H, d, J=8Hz), 6.68 (2H, m), 7.20 (1H, t, J=8Hz ), 7.30 to 7.80 (14H, m). EXAMPLE 27

Ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenylJ-2-pro- penoate

Reaction of 3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phe-nyltrifluoromethane sulfonate obtained by reaction of tri-fluoromethanesulfonic anhydride with 3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phénol according to the procedure of Example37 and ethyl acrylate analogously to the procedure of Example9 provides the title compound. EXAMPLE 28 3-[3-[2-(4,5-Diphenyl-2-oxazolyl)etheny1] phenyl]-2-propenoic

Acid

Hydrolysis of ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethenyl]phenyl]-2-propenoate with sodium hydroxide analogouslyto the procedure of Example 10 provides the title compound. 1 0043 EXAMPLE 29

Methyl [3-[2-[4,5-di(3-thienyl)-2-oxazolyl]ethyl]phenoxy]- acetate 45

A mixture of 3-[2-[4,5-d±(3-thienyl)-2-oxazolyl]ethyl]-phénol (2.00 g, 5.6 mmol), methyl bromoacetate (1.04 g, 6.8 mmol )

Z potassium carbonate (0.94 g, 6.8 mmol), potassium iodide (cata-lytic amount) and acetonitrile (100 ml) was stirred at refluxunder an atmosphère of nitrogen. After 15 hours, the mixturewas cooled, filtered and concentrated and the residue subject-ed to chromatography on a column of silica gel. Elution with amixture of hexanes and ethyl acetate (7:2) gave methyl [3-[2-[4,5-di(3-thienyl)-2-oxazolyl]ethyl]phenoxy]acetate (1.95 g, 80%) as an oil.

Anal. Calcd. for C22H19NO4S2: C, 62.10; H, 4.51; N, 3.30. Found: C, 62.39; H, 4.64; N, 3.37%. 1H-NMR (CDC13) delta: 3.10 (4H, s), 3.78 (3H, s), 4.60(2H, s), 6.74 (1H, dd, J=8Hz, J'=2.5Hz), 6.81 (1H, br), 6.89(1H, d, J=8Hz), 7.10 to 7.40 (5H, m), and 7.50 to 7.70 (2H,m). EXAMPLE 30 [3-[2-[4,5-Di(3-thienyl)-2-oxazolyl]ethyl]phenoxy]acetic acid

A mixture of methyl [3-[2-[4,5-di(3-thienyl)-2-oxazolyl]-ethyl]phenoxy]acetate (1.40 g, 3.3 mmol), 3N sodium hydroxide 1 0043 46 solution (3.3 ml) and methanol (50 ml) was heated on a steambath for 20 minutes. The solvent was evaporated, the residuediluted with water and IN HCl solution until pH=l and extract-ed with CH2CI2. The combined extracts were dried over sodiumsulfate and concentrated to give a beige solid. Recrystalli-zation from a mixture of hexanes and CH2CI2 (5:3) affordedhydrated [3-[2-[4,5-di(3-thienyl)-2-oxazolyl]ethyl]phenoxy]-acetic acid (1.16 g, 85%), m.p. 154-156°C.

Anal. Calcd. for c2iHi7NO4S2.0.4H20: C, 60.25; H, 4.29; N, 3.35; H2O, 1.72. Found: C, 60.11; H, 4.20; N, 3.26; H20,1.06%. 1H-NMR (DMSO-d6) delta: 3.06 (4H, m), 4.61 (2H, s), 6.72(1H, dd, J=8Hz, J'=2.5Hz), 6.87 (2H, m), 7.17 (1H, t, J=8Hz), 7.25 (2H, m), 7.60 to 7.90 (4H, m), and 13.03 (1H, br).EXAMPLE 31

Methyl [3-[2-[4,5-di(2-thienyl)-2-oxazolyl]ethyl]phenoxy]- acetate

Reaction of 3-[2-[4,5-di(2-thienyl)-2-oxazolyl]ethyl]-phénol with bromoacetate according to the procedure of Example29 provided the title compound. EXAMPLE 32 [3-[2-[4,5-Pi(2-thienyl)-2-oxazolyl]ethyl]phenoxyacetle Acid 0

OCH^CO^H 47

Hydrolysis of methyl [3-[2-[4,5-di(2-thienyl)-2-oxazo-lyl]ethyl]phenoxy]acetate with aqueous sodium hydroxideprovided the hydrated title compound, m.p. 105.5-107°C.

Anal. Calcd. for C21H17N04S2.0.3H20: C, 60.51; H, 4.26N, 3.36; H20, 1.29. Found: C, 60.40; H, 4.29; N, 2.95; H20, 1.26. EXAMPLE 33

Préparation of Scheme I Intermediates (33-1) 2-Oxo-l,2-diphenylethyl-8-bromooctanoate

Ph

Ph A mixture of benzoin (10 g, 47 mmol), 8-bromooctanoic acid(11.57 g, 52 mmol), 1,3-dicyclohexylcarbodiimide (11.66 g, 57 mmol), 4-dimethylaminopyridine (catalytic amount) anddichloromethane (250 ml) was stirred at room température underan atmosphère of nitrogen. After 17 hours, the mixture wasfiltered and concentrated to leave an oil which was chroma-tographed on a column of silica gel. Eluting with a mixture ofhexanes and diethyl ether (9:1) afforded 2-oxo-l,2-diphenyl-ethyl-8-bromooctanoate (18.43 g, 93%). A 1 g sample was re-chromatographed providing analytically pure material, m.p.58-62°C.

Anal. Calcd. for C^H^BrO^: C, 63.32; H, 6.04. Found: C, 63.39; H, 5.88%. 1H-NMR (CDC13) delta: 1.20 to 1.45 (6H, m), 1.67 (2H,quintet, J=7Hz), 1.82 (2H, quintet, J=7Hz), 2.46 (2H, m), 3.37(2H, t, J=7Hz), 6.86 (1H, s), 7.30 to 7.55 (8H, m), 7.92 (2H,d, J=7.5Hz). 48 1 0043 (33-2) 2-(7-Bromoheptyl)-4,5-diphenyloxazole

A solution of 2-oxo-l,2-diphenylethyl-8-bromooctanoate(16.0 g, 38 nunol), and ammonium acetate (14.8 g, 19.2 mmol) inacetic acid (240 ml) was heated at reflux. After 1 hour, themixture was poured onto water and extracted with (3x).

The combined extracts were washed with water, dried oversodium sulfate and concentrated in vacuo to leave an oil.Chromatography on a column of silica gel using a mixture ofhexanes and diethyl ether (9:1) as eluent afforded 2-(7-bromo-heptyl)-4,5-diphenyloxazole (13.20 g, 86%). A 1 g sample wasrechromatographed under identical conditions to provideanalytically pure material as an oil.

Anal. Calcd. for C22H24BrN0: C' 66,34; H, 6.08; N, 3.52.Found: C, 66.36; H, 6.07; N, 7.38%. 1H-NMR (CDC13) delta: 1.30 to 1.60 (6H, m), 1.80 to 1.95(4H, m), 2.84 (2H, t, J=7.5Hz), 3.38 (2H, t, J=7Hz), 7.20 to 7.40 (6H, m) and 7.50 to 7.80 (4H, m). (33-3)

Dimethyl 2-[7-(4,5-diphenyl-2-oxazolyl)heptyl]propanedioate

Ph

Ph 0’

A mixture of 2-(7-bromoheptyl)-4,5-diphenyloxazole(10.00 g, 25 mmol), dimethyl malonate (9.95 g, 8.60 ml, 75 mmol), potassium tert-butoxide (8.44 g, 75 mmol), EighteenCrown 6 ether (catalytic amount) and tetrahydrofuran (200 ml) 49 10043 was heated to reflux under an atmosphère of nitrogen. After17.5 hours, the mixture was cooled, diluted with 2N hydro-chloric acid solution and extracted with CH2C12· The combinedextracts were dried over sodium sulfate and concentrated invacuo to leave an oil. Chromatography on a column of silicagel using a mixture of hexanes and diethyl ether (9:1) aseluent afforded dimethyl 2-[7-(4,5-diphenyl-2-oxazolyl)heptyl]-propanedioate (9.47 g, 83%) as an oil. An analytical sample(hydrated) was prepared by rechromatographing a 3.28 g sampleon silica gel using a mixture of hexane and diethyl ether(4:1) as the mobile phase.

Anal. Calcd. for C2?H31NO5.0.1 H20: C, 71.86; H, 6.97; N, 3.11; H20, 0.40. Found: C, 71.70; H, 7.26; N, 3.01; H20, O. 48%. 1H-NMR (CDC13) delta: 1.20 to 1.50 ( 8H, m), 1.70 to 1.90(4H, m), 2.80 (2H, t, J=7.5Hz), 3.33 (1H, t, J=7.5Hz ), 3.33(1H, t, J=7.5Hz), 3.68 (6H, s); 7.20 to 7.40 ( 6H, m), and 7.50to 7.70 (4H, m). (33-4) 2-[7-(4,5-Piphenyl-2-oxazolyl)heptyl1propanedioic Acid

A mixture of dimethyl 2-[7-(4,5-diphenyl-2-oxazolyl)-heptyl]propanedioate (6.00 g, 13 mmol), 5N sodium hydroxidesolution (13.4 ml), water (120 ml) and methanol (20 ml) wasstirred at room température. After 10 minutes the mixture washeated to reflux for 1 hour before adding water (80 ml) and 5NNaOH solution (13 ml). After a further 3 hours at reflux, themixture was cooled, acidified with 2N HCl solution and extrac-ted with diethyl ether. The combined extracts were dried oversodium sulphate and the solvent evaporated to leave a white 50 10 0 43 solid, 2—[7-(4,5-diphenyl-2-oxazolyl)heptyl]propanedioic acid(5.65 g, 100%). An analytical sample was prepared byrecrystallizing 1.15 g from a mixture of CH2C12, diethyl etherand hexane to give pure product (1.05 g), m.p. 115-117°C.

Anal. Calcd. for C25H2?NO5: C, 71.25; H, 6.46; N, 3.33.Found: C, 71.03; H, 6.49; N, 3.27%. 1H-NMR (DMSO-d6) delta: 1.10 to 1.45 (8H, m), 1.60 to1.85 (4H, m), 2.78 (2H, t, J=7.5z), 3.18 (1H, t, J=7.5Hz), 7.25 to 7.50 (6H, m), 7.50 to 7.60 (4H, m) and 12.64 (2H, br).EXAMPLE 34

Préparation of scheme 2 intermediates (34-1) 3-[3-Hydroxyphenyl)propionic acid

A solution of 3-hydroxycinnamic acid (20.00 g, 122 mmol)in methanol (200 ml) was hydrogenated over 10% palladium oncharcoal (1.25 g) at 45-50 psi using a Parr hydrogénationapparatus. After 4 hours, the mixture was filtered throughCelite and the solvent evaporated to leave a tan-colored solidwhich was used without further purification. 1H-NMR (CD30D) delta: 2.32 (2H, t, J=7.5Hz), 2.68 (2H,t, J=7.5Hz), 6.30 to 6.50 (3H, m), and 6.82 ( 1H, t, J = 8.5Hz).(34-2) 3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenol

Ph

Sodium métal (2.69 g, 0.12 g atom) was dissolved inabsolute éthanol (250 ml) and a solution of 3-(3-hydroxy-phenyl)propionic acid (19.38 g, 120 mmol) in absolute éthanol(125 ml) added. The mixture was heated briefly to reflux, 1 0043 51 cooled and concentrated sulfurie acid (5 drops) in absoluteéthanol (5 ml) added followed by 2-bromo-2~phenylacetophenone(32.11 g, 120 mmol). The mixture was stirred at reflux for5.75 hours, cooled and concentrated in vacuo. To the residuewas added glacial acetic acid (600 ml) and ammonium acetate(45.09 g, 0.58 mmol) and the mixture heated at reflux for10.5 hours. The cooled reaction mixture was partitionedbetween water and CH2C12, the organic phase separated, washedwith water (3x) and saturated NaCl solution. After drying oversodium sulfate, évaporation of the solvent left a golden-colored solid. Recrystallization from a mixture of hexanes andCH2C12 (2:1) afforded 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]-phénol (29.35 g, 73%), m.p. 146-147.5°C.

Anal. Calcd. for C2gH^gNO2.0.05H20: C, 80.70; H, 5.63; N, 4.10; H20, 0.26. Found: C, 80.45; H, 5.69; N, 3.92; H20, O. 11%. ^H-NMR (CDC13) delta: 3.05 (4H, m), 6.60 (2H, m), 6.68(1H, d, J=7.5Hz), 7.05 (1H, t, J=7.5Hz), 7.20 to 7.45 (6H, m)and 7.50 to 7.80 (5H, m). (34-3) 4-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phénol

Sodium métal (1.00 g, 43mg atom) was dissolved in étha-nol (125 ml) and 3-(4-hydroxyphenyl)propionic acid (6.04 g, 36 mmol) added to give a white precipitate. The mixture waswarmed briefly with stirring and concentrated H2SO^ (3 drops)added followed by 2-bromo-2-phenylacetophenone (1.00 g, 36 mmol). The mixture was heated at reflux for 2 hours, cooled,concentrated and diluted with water. The mixture was extractedwith CH2C12, the combined extracts dried over sodium sulfateand concentrated to give an oil which was dissolved in aceticacid (250 ml). Ammonium acetate (14.00 g, 180 mmol) was addedand the mixture heated to reflux. After 100 minutes, the solu- 1 0043 52 tion was cooled, diluted with water and extracted with CH2C12·The combined extracts were dried over sodium sulfate and thesolvent evaporated to leave a solid that was triturated with amixture of hexanes and diethyl ether and filtered to give 4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phénol (8.00 g, 64%). Ananalytical sample was prepared by recrystallizing 1.5 g from amixture of hexanes and CH2C12 to give 1.20 g of pure matériel,m.p. 142-144’C.

Anal. Calcd. for C23Hi9N04-°-01H20: C, 80.50; H, 5.64; N, 4.04; H90, 0.53. Found: C, 80.16; H, 5.80; N, 4.16; H„0, O. 06%. 1H-NMR (CDC13) delta: 3.30 (4H, m), 6.80 (2H, d,J=8.5Hz), 7.15 (2H, d, J=8.5Hz), 7.35 to 7.70 (6H, m) 7.20 to7.90 (4H, m) and 7.95 (1H, br). (34-4) 3-(2-(4,5-Diphenyl-2-oxazolyl)ethenyl]phénol

Sodium métal (1.68 g, 73mg atom) was dissolved in éthanol(160 ml) and 3-hydroxycinnamic acid (10 g, 6 mmol ) added. Afterstirring for 5 minutes, concentrated H2S04 (4 drops) was addedfollowed by 2-bromo-2-phenoxyacetophenone (16.76 g, 6 mmol)and the mixture heated to reflux. After 135 minutes, the mix-ture was cooled, diluted with water and extracted with CH2C12.The combined extracts were dried over sodium sulfate and concen-trated to leave an oil which was dissolved in acetic acid(110 ml). Ammonium acetate (23.47 g, 300 mmol) was added andthe mixture heated to reflux. After 75 minutes, the solutionwas cooled, diluted with water and extracted with CH2C12· Theorganic extracts were dried over sodium sulfate and the sol-vent evaporated to leave a khaki solid that was triturated 10043 53 with diethyl ether to give (10.80 g, 52%). Recrystallizationof a 1.5 g sample from éthanol gave 0.7 g of analytically pure3-[2—(4,5-diphenyl-2-oxazolyl)ethenyl]phénol, m.p. 201-203°C.

Anal. Calcd. for C23H17NO2: 81-40; H, 5.05; N, 4.13.

Found: C, 81.02; H, 4.94; N, 3.93%. 1H-NMR (DMSO-d6) delta: 6.77 (1H, d, J=7.5Hz), 7.00 to7.35 (4H, m), 7.35 to 7.50 (6H, m), 7.53 (1H, d, J=16Hz), 7.60to 7.70 (4H, m), and 9.58 (1H, s). EXAMPLE 35

Préparation of scheme 3 intermediate

Dlmethyl[(4,5-diphenyl-2-oxazolyl)methyl]phosphonate

Ph

0 ch2-p(och3)2

Ph A mixture of 2-bromomethyl-4,5-diphenyloxazole (26.72 g,85 mmol) obtained according to D.L. Aldous, et al., J. Org.Chem., 25, 1151 (1960), and trimethylphosphite (80 g, 84 ml, 645 mmol) was heated with stirring at 120°C under an atmos-phère of nitrogen. After 90 minutes, the excess trimethylphosphite was removed in vacuo and the residue chromatographedon a column of silica gel. Elution with a mixture of diethylether and methanol (49:1) afforded 6.13 g of a yellow solidand 18.90 g of an oil with identical TLC characteristics.Recrystallization of 1.3 g of the solid material from hexaneprovided analytically pure dimethyl [(4,5-dimethyl-2-oxazolyl)-methyl]phosphonate (1.15 g), m.p. 54-57°C.

Anal. Calcd. for C18H18NO4P: C, 62.98; H, 5.29; N, 4.09;Found: C, 62.88; H, 5.26; N, 4.00%. 1H-NMR (CDC13) delta: 3.48 (2H, d, J=21Hz), 3.81 (6H, d,J=llHz), 7.20 to 7.35 (6H, m) and 7.50 to 7.70 (4h, m). 10043 54 EXAMPLE 36

Préparation of Scheme 4 Intermediate 3-[(4,5-Diphenyl-2-oxazolyl)methoxy]benzaldehyde

A mixture of 2-bromomethyl-4,5-diphenÿloxazole (26.72 g,85 mmol) obtained according to D.L. Aldous, et al., J. Org.Chem., 2, 228-334 (1937), 3-hydroxybenzaldehyde (9.34 g, 76 mmol) potassium carbonate (12.92 g, 93 mmol), potassiumiodide (0.5 g) and dimethylformamide (250 ml) was stirred atÎIO’C. After 45 minutes, the mixture was cooled, diluted withwater and extracted with diethyl ether (3x ). The combinedextracts were washed with water (3x), dried over sodium sul-fate and concentrated in vacuo to give an oil which was chro-matographed on a column of silica gel. Elution with a mixtureof hexanes and diethyl ether (2:1) afforded 3-[(4,5-diphenyl- 2- oxazolyl)methoxy]benzaldehyde (21.16 g, 70%). An analyticalsample was recrystallized from a mixture of CH^C^ and hexanesand had m.p. 72-75’C.

Anal. Calcd. for C23H17NO3: C, 77.74; H, 4.83; N, 3.95;Found: C, 77.49; H, 4.90; N, 3.87%. 1H-NMR (CDC13) delta: 5.28 (2H, s), 7.30 to 7.80 (14H,m) and 9.99 (1H, s). EXAMPLE 37

Préparation of Scheme 5 Intermediate 3- [2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenyltrlfluoromethane sulfonate CH2CH2_^Z^-QSO2CF3

10043 55

Trifluoromethanesulfonic anhydride (16.55 g, 58 mmol) wasadded to a stirred solution of 3-[2 —(4,5-diphenyl-2-oxazolyl ) -ethyl]phénol (10.00 g, 29 mmol) in pyridine (60 ml) maintainedat 0°C. The mixture was allowed to stand in the refrigeratorovernight before being poured onto ice water and extractedwith diethyl ether (3x). The combined extracts were washedfour times with water, dried over anhydrous magnésium sulfateand concentrated to leave an oil. Chromatography on a columnof silica gel using a mixture of hexanes and ethyl acetate(17:3) gave 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenyltri-fluoromethane sulfonate (12.54 g, 90%) as an oil.

Anal. Calcd. for C24H18F3NO4S: C, 60.89; H, 3.84; N, 2.96; Found: C, 60.97; H, 3.93; N, 3.21%. 1H-NMR (CDC13) delta: 3.18 (4H, m), 7.10 to 7.50 (10H,m) and 7.50 to 7.70 (4H, m). EXAMPLE 38

Préparation of Scheme 6 Intermediate

Methyl (3-hydroxyphenoxy)acetate HO—

0CH2C02CH3 A mixture of resocirnol monoacetate (20.00 g, 0.13mol),methyl bromoacetate (21.14 g, 13.05 ml, 0.14mol), potassiumcarbonate (21.80 g, 0.16mol) and acetonitrile (350 ml) wasstirred at reflux. After 30 minutes, the mixture was filtered,and the solvent removed in vacuo to leave an oil which wasdissolved in methanol (350 ml). Concentrated hydrochloric acid(2 ml) was added and the mixture stirred at reflux. After20 minutes, the solution was concentrated, diluted with waterand extracted with CHjClj to give an oil which was distilledat reduced pressure to furnish methyl ( 3-hydroxyphenoxy)ace-tate, b.p. 154-180’C/l.5mm (15.98 g, 66%). 10043 56 EXAMPLE 39

Préparation of Scheme 7 Intermediate (39-1) 2-[2-[3-[dimethyl(1,1-dimethylethyl)siloxy]phenyl]ethyl]-4,5- di(3-thienyl)oxazole

S

S

n-Butyllithium (0.518 g, 8 mmol) in hexanes (3.24 ml)was added to a solution of diisopropylamine (0.82 g, 8 mmol)in dry tetrahydrofuran (20 ml) maintained at 0’C under anatmosphère of nitrogen. After 20 minutes, the mixture wascooled to -78°C and a solution of 2-methyl-4,5-di(3-thienyl )-oxazole (1.60 g, 6.5 mmol) obtained analogous to D. Davidson,et al., J Org. Chem, 2, 328-334 (1937) in tetrahydrofuran(10 ml) added dropwise to give a red-orange solution. Themixture was stirred at -78 °C for 2 hours before adding a solu-tion of [3-(bromomethyl)phenoxy]dimethyl( 1,1-dimethylethyl )-silane (2.44 g, 8 mmol) in tetrahydrofuran (5 ml). Afterstirring at -78°C for 4 hours, the mixture was poured ontosaturated ammonium chloride solution and extracted withdiethyl ether. The combined extracts were washed twice withsaturated ammonium chloride solution, once with saturated NaClsolution and dried over magnésium sulfate. The solvent wasevaporated and the residue chromatographed on a column ofsilica gel using a mixture of hexanes and ethyl acetate (19:1)as eluent to give 2-[2-[3-[dimethyl(1,1-dimethylethyl)siloxy]-phenyl]ethyl]-4,5- di(3-thienylJoxazole (1.33 g, 43%) as anoil. 1H-NMR (CDC13) delta: 0.14 (6H, s), 0.94 (9H, s), 3.09(4H, s), 6.70 (2H, m), 6.83 (1H, d, J=8Hz), 7.13 (1H, t,J=8Hz), 7.20 to 7.40 (4H, m) and 7.50 to 7.75 (2H, m). 1 0043 57 (39-2) 3-[2-[4,5-Di(3-thienyl)-2-oxazolyl]ethyl]phénol

HO

Tetra-n-butylammonium fluoride (2.98 g, 11 mmol) intetrahydrofuran (11.40 ml) was added to a solution of 2-[2-[3-[dimethyl(1,1-dimethylethyl)siloxy]phenyl]ethyl]-4,5-di-(3-thienyl(oxàzole (4.26 g, 9 mmol) in tetrahydrofuran(185 ml). The mixture was stirred at room température underan atmosphère of nitrogen. After 30 minutes, the mixture wasdiluted with diethyl ether and saturated ammonium chloridesolution. The organic phase was separated, washed twice withsaturated ammonium chloride solution and once with saturatedNaCl solution before being dried over sodium sulfate and con-centrated in vacuo. Chromatography of the residue on a columnof silica using a mixture of hexanes and ethyl acetate (3:1)as eluent gave 3-[2-[4,5-di(3-thienyl)-2-oxazolyl]ethyl]phenol(2.45 g, 76%). An analytical sample was prepared by recrystal-lizing 0.45 g from a mixture of hexanes and CI^C^ (2:1) andhad m.p. 143.5-145°C.

Anal. Calcd. for ^^9^^^5^2^2: ^4.57; H, 4.28; N, 3.97. Found: C, 64.65; H, 4.41; N, 3.89%. 1H-NMR (DMSO-d6) delta: 3.00 (4H, m), 6.58 (1H, dd,J=8Hz, J'=2Hz), 6.67 (2H, m), 7.07 (1H, t, J=8Hz), 7.25 (2h, m), 7.60 to 7.90 (4H, m) and 9.30 (1H, s). EXAMPLE 40 5-[[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]methyl-lH- tetrazole

î 0043 58 A mixture of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]-phenoxy]acetonitrile (1.60 g, 4.2 mmol) and tri-n-butyltinazide (1.45 g, 4.4 mmol) was stirred at 140°C under an at-mosphère of nitrogen. After 20 hours, the mixture was cooled, 5 diluted with ethyl acetate (300 ml) and IN HCl (200 ml) and the mixture stirred for 2 hours. The aqueous phase was removedand the organic phase added to 0.1M potassium fluoride solu-tion. After stirring overnight, the organic layer was separat-ed, washed with water and saturated sodium chloride solution, 10 dried over sodium sulfate and concentrated in vacuo. The resi-due was chromatographed on a column of silica gel using amixture of chloroform and methanol (10:1) as eluent to give5-[[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]methyl]-lH-te-trazole (1.18 g, 66%) after recrystallization from a mixture 15 of hexanes and CH2C12 m.p. 138.5 - 140°C.

Anal. Calcd. for C25H21N5°2: C' H> 5.00; N, 16.54.

Found: C, 70.83; H, 5.05; N, 16.49%. 1H-NMR (CDC13 + DMSO -d6) delta: 2.91 (4H, s), 5.13 (2H, s), 6.55 to 6.70 (3H, m), 6.90 to 7.20 (7H, m) and 7.30 to 20 7.50 (4H, m).

SUPPLEMENTAL DISCLOSURE

The compounds of the instant invention are additionallycharacterized by Formula XIX 25

Pli

(xix)

wherein n is 7-9 and R is hydrogen or lower alkyl; and FormulaXX ')

Ph._

Ph -L,

OCH2Cn?R (XX) z wherein the OCH2CO2R moiety is attached to the 3 or 4 phenylposition and R is hydrogen or lower alkyl. 35 10043 59

Formula XIX compounds are obtained by a process compris- ing:

(a) hydrolyzing a compound of Formula XXI

Ph

Ph S-(CH2)nCO2Ra (XXI) wherein n is 7-9 and R is lower alkyl to the correspon-ding acid, or (b) esterifying a compound of Formula XXIIPh

Ph

S-(CH2)nC02H (XXII) wherein n is 7-9 with a lower alkanol, or alkylating4,5-diphenyl-2(3H)oxazolethione with Br-(CH2 )wherein n is 7-9 and Ra is lower alkyl.

Formula XX compounds are obtained by a process compri- sing:

(a) hydrolyzing a compound of Formula XXIII

Ph

Ph (XXIII) wherein Ra is lower alkyl and the OCl^CC^R moiety isattached to the 3 or 4 phenyl position, or

(b) esterifying a compound of Formula XXIV

S-CH2- OCH2CD2H (XXIV) wherein the OCHzCC^H moiety is attachedposition with a lower alkanol, or to the 3 or 4 1 0043 60 (c) alkylating 4,5-d±phenyl-2(3H)-oxazolethione with 3- (bromomethyl)phenoxyacetate or 4-(bromomethylJphenoxy-acetate.

The compounds of Formula XIX and Formula XX hâve pharma-cological and pharmaceutical properties similar to those ofFormula I and II compounds. In vitro inhibition of humanplatelet aggregation test results for the compounds of Exam-ples 41-44 are given hereinafter.

TABLE IV 10

Inhibition of Human Platelet Aggregation of Formula XIX and XX compounds L5

Example 41 42 43 44 EXAMPLE 41 vs. ADPmcg/ml 32 32 4 % inhibition19505050

Methyl 8-[(4,5-dlphenyl-2-oxazolyl)thio]octanoate 20

s-(ch2)7co2ch3 25 Sodium hydride (0.71 g of a 60% disp., 18 mmol) was added to a stirred solution of 4,5-diphenyl-2( 3H)oxazolethione(4.05 g, 16 mmol) in dimethylformamide (50 ml) maintainedunder a nitrogen atmosphère. The mixture was stirred at roomtempérature for 15 minutes to give a suspension and methyl 30 8-bromooctanoate (3.83 g, 16 mmol) in DMF (10 ml) added drop-wise. After the addition was complété, the reaction mixturewas stirred at ambient température for 2.5 hours and at 50°Cfor 30 minutes. The reaction mixture was diluted with Et2O andH20 and stirred. The organic layer was separated, dried (MgSO^) 35 and concentrated to leave an oil which was chromatographed ona column of silica gel. Elution with a mixture of hexanes anddiethyl ether (initially 2:1, then 1:1 and finally 1:2) gave 1 0043 61 methyl 8-[(4,5-diphenyl-2-oxazolyl) thio)octanoate (4.40 g,67.2%) as a partial hydrate.

Anal. Calcd. for C2^H2yNOgS.0.3 fl^O: C,69.46; H, 6.70; N, 3.38. Found; C, 69.48; H, 6.88; N, 3.15. 1H-NMR (CDClg) delta: 1.26 to 2.33 (10H, m), 2.30 (2H,t), 3.24 (2H, t), 3.66 (3H, s), 7.31 (6H, m) and 7.60 (4H, m).EXAMPLE 42 8-[ ( 4,5-Dlphenyl-2-oxazolyl)thio]octanoic Acid

Methyl 3-[(4,5-diphenyl-2-oxazolyl)thio]octanoate (2.0 g,4.9 nunol) was dissolved in methanol ( 30 ml). A solution oflithium hydroxide monohydrate (0.41 g, 9.8 mmol) in water(8 ml) was added and the mixture heated to reflux for 1 hour.After cooling to room température, the methanol was removed invacuo, the residue diluted with water and acidified to aboutpH = 2 using dilute hydrochloric acid solution. The mixturewas extracted with EtOAc, the combined extracts dried overMgSO^ and concentrated. The residue was chromatographed on acolumn of silica gel using C^C^/MeOH (95/5) as eluent togive 8-[(4,5-diphenyl-2-oxazolyl)thio]octanoic acid (1.70 g,88%).

Anal. Calcd. for CnoH„cN0oS.0.4 Ho0: C,68.59; H, 6.46;

- zo Zo ο Z N, 3.48. Found: C, 68.84; H, 6.57; N, 3.23. 1H-NMR (CDC13) delta: 1.27-1.80 (10H, m), 2.26 (2H, t),3.18 (2H, t), 7.26 (6H, m,) and 7.48 (4H, m,). EXAMPLE 43

Methyl [3-[[(4,5-Diphenyl-2-oxazolyl)thio]methyl]phenoxy]- acetate

Ph

Ph 0'

1 0043 62 4,5-Diphenyl-2(3H)-oxazolethione (5.7 g, 22.8 mmol) wasdissolved in DMF (100 ml). Sodium hydride (1.0 g of a 60%dispersion, 25 mmol) was added and the mixture stirred under anitrogen atmosphère for 30 minutes. The clear solution wascooled to 0’C and a solution of methyl 3-(bromomethyl)phenoxyacetate (6.5 g, 25 mmol) in DMF (10 ml) added dropwise. Afterthe addition was complété, the suspension was stirred at 0°Cfor 1 hour and then at room température for 2 hours. The reac-tion mixture was diluted with Et2O and water (200 ml each) andstirred. The organic layer was separated, washed with water(2 x 20 ml), dried (MgSO^) and concentrated in vacuo. Thecrude material was purified by flash chromatography on silicagel using a mixture of hexane and diethyl ether (2:1) as eluentto give methyl [3-[[(4,5-diphenyl-2-oxazolyl)thio]methyl]-phenoxy]acetate (1.5 g, 13%) as an oil.

Anal. Calcd. for C25H21NO4S: C,68.75; H, 4.69; N, 3.62.Found: C, 68.39; H, 4.65; N, 3.58. 1H-NMR (CDC13) delta: 3.75 (3H, s), 4.40 (2H, s), 4.56(2H, s), 6.78 (1H, dd, J=8Hz, J'=2.5Hz) and 6.98-7.92 (13H,m). EXAMPLE 44 [3-[[(4,5-Diphenyl-2-oxazolyl)thio]methyl]phenoxy]acetic Acid

Methyl [3-[[(4,5-diphenyl-2-oxazolyl)thio]methyl]phenoxy]-acetate (1.1 g, 2.6 mmol) was dissolved in methanol (25 ml).Lithium hydroxide monohydrate (0.22 g, 5.1 mmol) was addedfollowed by the dropwise addition of water (5 ml). This mixtu-re was heated at reflux for 30 minutes, cooled to room tempe-rature and concentrated in vacuo. The residue was dissolved inwater (15 ml) and acidified to about pH = 2. The mixture wasextracted with methylene chloride (25 ml), the combined ex-tracts dried over MgSO4 and concentrated in vacuo. The residue 63 1 0043 was purified by chromatography on a column of silica gel usinga mixture of CI^C^ and MeOH (95:5) as eluent to give[3-[[(4,5-diphenyl-2-oxazolyl)thio]methyl]phenoxy]acetic acid(0.6 g, 56.4%), m.p. 136-137’C.

Anal. Calcd. for C'24H19NO4^: C,69.05; H, 4.59; N, 3.36.Found: C, 68.83; H, 4.64; N, 3.35. 1H-NMR (CDClg) delta: 4.41 (2H, s), 4.61 (2H), 6.82 (1H,dd, J=8.2Hz, J'=2Hz) and 7.03-7.64 (13H, m).

Claims (46)

10043

64 CLAIMS

1.- A compound of formula I (CH )nC02R where n is 7-9 and R is hydrogen or lower alkyl.

2.- The compound of claim phenyl-2-oxazolenonanoate. 1 which is methyl 4,5-di- 3.- The compound of claim oxazolenonanoic acid. 1 which is 4,5-diphenyl-2- 4.- The compound of claim phenyl-2-oxazoleoctanoate. 1 which is methyl 4,5-di- 5.- The compound of claim 1 which is 4,5-diphenyl-2-oxa zoleoctanoic acid.

6.- A compound of formula II

wherein R^ is phenyl or thienyl; R2 is hydrogen, lower alkyl or together with CO2 is tetra-zol-l-yl; X is a divalent connecting group selected from the groupconsisting of CH=CH, and CH^O; Y is a divalent connecting group attached to the 3 or 4phenyl position selected from the group consisting ofOCH2, CH2CH2 and CH=CH.

7. - The compound of claim 6 wherein R^ is phenyl.

8. - The compound of claim 6 wherein R^ is phenyl, X isCH2CH2 and Y is OCl^·

9. - The compound of claim 6 which is methyl 2-[3-[2-( 4, 5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate. 65 1 0043

10. - The compound of claim 6 which is 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid.

11. - The sodium sait of the compound of claim 10.

12. - The compound of claim 6 which is methyl 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate.

13. - The compound of claim 6 which is 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid.

14. - The compound of claim 6 which is ethyl 3-[3-[2-(4, 5-diphenyl-2-oxazolyl)ethyl]phenyl]-2-propenoate.

15. - The compound of claim 6 which is 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenyl]-2-propenoic acid hydratehexane solvaté.

16. - The compound of claim 6 which is ethyl 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzenepropanoate.

17. - The compound of claim 6 which is 3-[2—(4,5-diphenyl-2-oxazolyl)ethyl]benzenepropanoic acid.

18. - The compound of claim 6 which is methyl [3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenoxy]acetate.

19. - The compound of claim 6 which is [3-[2-(4,5-di-phenyl-2-oxazolyl )ethenyl]phenoxy]acetic acid.

20. - The compound of claim 6 which is methyl [4-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenoxy]acetate.

21. - The compound of claim 6 which is [4-[2-(4,5-di-phenyl-2-oxazolylJethenyl]phenoxy]acetic acid.

22. - The compound of claim 6 which is methyl 3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]propanoate.

23. - The compound of claim 6 which is 3-[3-[(4,5-di-phenyl-2-oxazolyl)methoxy]phenyl]propanoic acid.

24. - The compound of claim 6 which is methyl 3-[4-[(4,5-diphenyl-2-oxazolyl )methoxy]phenyl]propanoate.

25. - The compound of claim 6 which is 3-[4-[(4,5-di-phenyl-2-oxazolyl )methoxy]phenyl]propanoic acid.

26. - The compound of claim 6 which is methyl 3-[3-[(4,5-dipheny1-2-oxazoly 1 )methoxy]phenyl]-2-propenoate.

27. - The compound of claim 6 which is 3-[3-[(4,5-di-phenyl-2-oxazolyl)methoxy]phenyl]-2-propenoic acid.

28. - The compound of claim 6 which is methyl 3-[4-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]-2-propenoate. 10043 66

29. - The compound of claim 6 which is 3-[4-[(4,5-di-phenyl-2-oxazolyl)methoxy]phenyl]-2-propenoic acid.

30. - The compound of claim 6 which is methyl [3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenoxy]acetate.

31. - The compound of claim 6 which is [3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenoxy]acetic acid.

32. - The compound of claim 6 which is ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenyl]-2-propenoate.

33. - The compound of claim 6 which is methyl [3-[2-[4,5-di( 3-thienyl)-2-oxazolyl]ethyl]phenoxy]acetate.

34. - The compound of claim 6 which is [3-[2-[4,5-di(3-thienyl)-2-oxazolyl]ethyl]phenoxy]acetic acid.

35. - The compound of claim 6 which is methyl [3-[2-[4,5-di(2-thienyl)-2-oxazolyl]ethyl]phenoxy]acetate.

36. - The compound of claim 6 which is [3-[2-[4,5-di(2-thienyl)-2-oxazolyl]ethyl]phenoxy]acetic acid.

37. - The compound of claim 6 which is 5-[[3-[2-(4,5-di-phenyl-2-oxazolyl)-ethyl]phenoxy]methyl]-ΙΗ-tetrazole.

38. - The method for inhibiting blood platelet aggregationin a mammal which comprises administering a therapeuticallyeffective amount of a compound of claim 1.

39. - The pharmaceutical composition for inhibiting bloodplatelet aggregation comprising a therapeutically effectiveamount of a compound of claim 1 and a pharmaceutical carrier.

40. - The method for inhibiting blood platelet aggregationin a mammal which comprises administering a therapeuticallyeffective amount of a compound of claim 6.

41. - The pharmaceutical composition for inhibiting bloodplatelet aggregation comprising a therapeutically effectiveamount of a compound of claim 6 and a pharmaceutical carrier.

42. - A compound of formula XIX Ph

Ph (xix) wherein n is 7-9 and R is hydrogen or lower alkyl. 10043 67

43. - The compound of claim 42 which is methyl 8—[(4,5—diphenyl-2-oxazolyl)thio]octanoate.

44. - The compound of claim 42 which is 8-[(4,5-diphenyl-2-oxazolyl)thio]octanoic acid.

45. - The pharmaceutical composition for inhibiting bloodplatelet aggregation comprising a therapeutically effectiveamount of a compound of claim 42 and a pharmaceutical carrier.

46. - A compound of formula XX

wherein the OCi^CC^R moiety is attached to the 3 or 4 phenylposition and R is hydrogen or lower alkyl.

47. - The compound of claim 46 which is methyl [3—[[(4,5—diphenyl-2-oxazolyl)thio]methyl]phenoxy]acetate.

48. - The compound of claim 46 which is [3-[[(4,5-di-phenyl-2-oxazolyl)thio]methyl]phenoxy]acetic acid.

49. - The pharmaceutical composition for inhibiting bloodplatelet aggregation comprising a therapeutically effectiveamount of a compound of claim 46 and a phaimaceutical carrier.