WO1993010778A1

WO1993010778A1 - Inhibition of angiogenesis with pyridinyloxazole-2-ones

Info

Publication number: WO1993010778A1
Application number: PCT/US1992/009261
Authority: WO
Inventors: Paul S. Wright; Alan J. Bitonti
Original assignee: Merrell Dow Pharmaceuticals Inc.
Priority date: 1991-12-02
Filing date: 1992-10-29
Publication date: 1993-06-10
Also published as: AU2915392A; IL103899A0

Abstract

This invention is directed to pyridinyloxazole-2-ones which are useful in inhbiting angiogenesis in patients having cancer. The pyridinyloxazole-2-ones act to inhibit protein kinase C and thereby modulate angiogenesis.

Description

I HIBITION OF ANGIOGENESIS WITH PYRIDINYLOXAZO E-2-ONES This invention relates to the use of certain pyridinyloxazole-2-ones as inhibitors of angiogenesis.

BACKGROUND OF THE INVENTION

Angiogenesis, the formation of new blood vessels, is a developmental process in organogenesis and is limited in human adults to the female reproductive cycle and to wound healing. Nearly every other neovascularization event in adults is pathological as in solid tumor growth, diabetic retinopathy, and various inflammatory diseases.

Tumor promoting phorbol esters have been shown to promote endothelial cell differentiation in vitro as evidenced by capillary tube formation on collagen gels. These phorbol esters can also stimulate angiogenesis in the chick chorioallantoic membrane and rabbit cornea assays. Protein kinase C (PKC) activation is one of the primary effects of phorbol ester treatment of cells. S.R. Doctrow, et al., Protein Kinase C Activators Suppress Stimulation Of Capillary Endothelial Cell Growth By Angiogenic Endothelial Mitogens , J . Cell Biol . , 104 ( 3 ) , 679-687 ( 3/1987 ) , showed that tumor promoting esters selectively inhibit growth factor stimulated pro¬ liferation of bovine adrenal capillary endothelial cells . Recently , I . Daviet , et al . , Involvement Of Protein Kinase C In The Mitogenic And Chemotaxis Effects Of Basic Fibroblast Growth Factor On Bovine Cerebral Cortex Capillary Endothelial Cells , FEBS Letters , 259(2) , 315-317 (1990), have shown that down regulation of PKC by prolonged treatment with phorbol esters or inhibition of protein kinases with staαrosporine prevents the itogenic and chemotactic effect of basic fibroblast growth factor on bovine cerebral capillary endothelial cells. These studies suggest that modulation of PKC activity plays an important role in the proliferative response of specific vascular endothelial cells to growth factors and overall in neovascularization. Virtually all solid tumors are highly vascularized and the activation of neovascularization appears to occur prior to overt tumor formation in a subset of the preneoplastic nodules. The switch to an angiogenic phenotype may well be a crucial and general stage in solid tumor development (see J. Kandel, E. Bossy-Wetzel, F. Radvanyl, M. Klagsburn, J. Folkman, and D. Hanahan, Neovascularization is Associated with a Switch to the Export of bFGF in the Multistep Development of Fibrosarcoma, Cell, 66, 1095- 1104 (September 20, 1991)).

The oxazolone 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, which has been shown to inhibit PKC and cyclic AMP dependent protein kinase (PKA) activity, relaxes smooth muscle contracted with phorbol esters. Here we show that this protein kinase inhibitor can inhibit capillary tube formation by vascular endothelial cells on basement membrane preparations and neovascularization in developing chick embryos.

SUMMARY OF THE INVENTION The present invention is directed to the use of certain pyridinyloxazole-2-ones of the formula

R2 R

wherein

R is selected from the group consisting of C₂-C₆ alkyl and phenyl wherein the phenyl ring is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C₃.-C₄ alkyl and C₁-C₄ alkoxy;

R¹ is selected from the group consisting of hydrogen, Ci-Cβ alkyl, and phenyl wherein the phenyl ring is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C₄ alkyl and C₁-C₄ alkoxy; and

R2 is a 2-, 3-, or 4-pyridyl group wherein the pyridyl group is optionally substituted with one or two substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C₄ alkyl, C₁-C4 alkoxy,

C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfon- yl, cyano, carboxy, carb(Cι-Cs)alkoxy, carbamido, (Cι~

CsJalkanoylamino, imidazolyl, nitro and trifluoromethyl or wherein the pyridyl group is optionally substituted with a phenyl group which is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C₄ alkyl, and C₁-C₄ alkoxy; and the pharmaceutically-acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION This invention concerns the use of the compounds of Formula I as agents effective in inhibiting angiogenesis.

As used herein, the terms "C₁-C₃ alkyl", "C₁-C₄ alkyl", and "C-.-C- alkyl" mean straight or branched chain alkyl groups having from one to three, from one to four, or from one to six carbon atoms respectively, and include such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like,^" as well as vinyl, allyl, propenyl, butenyl, butadienyl, isopropenyl, and the like. The term "C₁-C₄ alkoxy" means alkoxy groups having from one to four carbon atoms, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. When R or Ri is "optionally substituted phenyl", the one,, two or three substituent(s) can be located at any available position on the phenyl ring.

The expression "a pharmaceutically acceptable acid addition salt" is intended^"to apply to any nontoxic organic or inorganic acid addition salt of the base compounds. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acids and acid metal salts such as sodium onohydrogen .orthophosphate and potassium hydrogen sulfate. Illustra¬ tive organic acids which form suitable salts include the mono, di, and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy- benzoic, phenylacetic, cinnamic, salicylic, and 2-phenoxy- benzoic acids. Other organic acids which form suitable salts are the sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. These salts and the base compounds can exist in either a hydrated or a sub¬ stantially anhydrous form. The acid salts are prepared by standard techniques such as by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvent containing the appropriate acid and isolating by evaporating the solution, or by reacting the free base in an organic solvent in which case the salt separates directly or can be obtained by concentration of the solu¬ tion. In general the acid addition salts of the compounds of this invention are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, demon¬ strate higher melting points and an increased solubility.

Illustrative examples of the compounds of this inven¬ tion include compounds of Formula I wherein the R groups are designated as follows:

As is true for most classes of therapeutically effec¬ tive compounds, certain subclasses and certain species are especially effective and are preferred over others. In this instance, those compounds of Formula I wherein R2 is optionally substituted 2-, 3-, or 4-pyridinyl are pre¬ ferred. Also preferred are compounds wherein R is hydrogen or a Ci-Cβ alkyl. Most preferred are the compounds wherein R2 is an unsubstituted 2-, 3-, or 4-pyridinyl group, R is propyl and Ri is hydrogen. The most preferred compound of this invention is 4-propyl-5-(4-pyridinyl)-2(3i_T)-oxazolone.

The preparation of the 2-, 3-, or 4-pyridinyloxazole-2- ones of this invention is known in the art. See for example, United States Patent Number 4,698,353. The preparation of those compounds not specifically taught in the art can be readily accomplished by the skilled artisan.

In essence, the compounds of this invention can be prepared by reacting a compound of formula 2

wherein Ri and R₂ are as defined above with a cyanate in dimethylformamide to form the corresponding isocyanate which undergoes cyclization under the reaction conditions to yield the desired formula 1 product.

NC=0

Another procedure involves cyclizing a hydroxy ketone of structure 4

wherein Ri and R₂ are as defined above by reaction with a cyanate or salt in the presence of an acid. ια

The bromo ketones of formula 2 are either known in the art or can be readily prepared by standard techniques. For example the des-bromo analog of a structure 2 compound can be treated with bromine. Where the group adjacent to the carbon to be bro inated is a hydrogen or a (C₁-C₅) alkyl

15 group, a radical initiator can be used to promote the bromination. Suitable initiators include iron metal and N- bromosuccinimide. The bromination can also be accomplished by the addition of concentrated hydrobromic acid, typically 48% aqueous hydrobromic acid, to a solution containing des- 0 bromo compound. The structure (4) hydroxy ketones can also be readily prepared in any suitable manner. For example, a structure 2 bromo ketone can be allowed to react with an acetate salt, preferably potassium acetate, to form the corresponding acetoxy ketone which upon treatment with an 5 acid, such as hydrochloric acid, yields the desired structure (4) compound.

The compounds wherein R is Cj.-Ce alkyl or optionally substituted phenyl are produced by subsequent reaction of 0 the compound of Formula 1 wherein R is hydrogen with sodium hydride and the appropriate alkyl iodide or phenylalkyl iodide in tetrahydrofuran according to procedures well known in the art. 5 The compounds of this invention are useful both in the free base form and as salts. The term "pharmaceutically- acceptable salt" means any organic or inorganic addition salt of the base compounds of Formula I which are rela- tively nontoxic and innocuous to a patient at concentra¬ tions consistent with effective activity so that the side effects ascribable to the salt do not vitiate the bene¬ ficial effects of the base compounds of Formula I. These salts are included within the scope of this invention. Such salts include alkali metal salts, such as sodium and potassium salts and alkaline earth metal salts, such as calcium and magnesium salts; and the like. Also salts with organic and inorganic acids can be prepared, such as, for example, those formed with the following acids: hydrochlo- ric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, ascorbic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, ita- conic, fumaric, benzenesulfonic and toluenesulfonic. The nontoxic, physiologically acceptable salts are preferred, although other salts are also useful, for example, in isolating or purifying the product.

The salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze drying, or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin. EXPERIMENTAL PROCEDURES

Cell Culture. Human umbilical vein endothelial cells (HUVEC) and growth medium were obtained from Clonetics, and used for experiments up through passage 5. For measurement of proliferation, HUVEC were plated at 5 x 104 cells per well on 12-well cluster plates and 1 μCi/ml [3H]thymidine was added. The next day, the compounds were added to the cultures at the indicated concentrations for 24 hours. The cells were washed twice with phosphate-buffered saline (PBS), then 10% trichloroacetic acid was added and left on the cultures for 15 minutes on ice. After removal of the acid from the cultures, the cells were solubilized from the well with 1 N sodium hydroxide, then neutralized, and the (counts per minute (CPM)) incorporated were quantitated using liquid scintillation counting. HUVEC cultures on Matrigel (Collaborative Research) were prepared as described here briefly. Twenty four well cluster plates were coated with 250 μl of undiluted Matrigel, and 5.5 x 104 HUVEC were seeded per well. HUVEC were either pretreated for 24 hours or coincubated with the compounds to test their effects on tube formation. The cultures were observed and photographed the next day with a Zeiss IM inverted microscope equipped with Hoffman modulation optics, then quantitatively scored for tube formation as follows: ++++, complete tube formation; +++, nearly com¬ plete, some single cells; ++, about 50% tube formation; +, limited tube ^"formation, mostly dispersed cells; or, -, no tube formation. TABLE 1

Effect of Protein Kinase Inhibitors On [3H]Thymidine Incorporation Into Endothelial Cell DNA

*The 10, 50, and 100 μM levels correspond to the addition of 0.1, 0.5, and 1.0%, respectively, for assessment of % control values.

Protein Kinase Assays: Larger scale HUVEC cultures were harvested and crude extracts were assayed for PKC and PKA activities using commercially available enzyme assay systems (GIBCO BRL) . Briefly, these assays measure calcium and phospholipid dependent phosphorylation of the N- terminal synthetic peptide from myelin basic protein and cAMP dependent Kemptide phosphorylation with [gamma-32p]ATP by PKC and PKA respectively.

TABLE 2 Effect Of Oxazolones Of HUVEC cAMP-Dependent Protein Kinase (PKA), Protein Kinase C (PKC), And Tube

Formation Of Matrigel

Yolk Sac Neovascularization: Fertilized chicken eggs (Spafas, Inc.) were cracked on day 3 and the embryos placed on plastic wrap slings. The next day, silicone rings containing test compounds or vehicle mixed 1:1 with 1% methylcellulose were placed on the yolk sac membrane. Neovascularization inside the rings was observed and scored either as inhibited (development of a vascular zone or marked decrease in microvessel density) or uninhibited (no decrease or a minimal decrease in microvascular density) .

TABLE 3

Effect of Kinase Inhibitors On Yolk Sac Neovascularization

^♦Inhibition of yolk sac neovascularization (embryonic chick) in the presence or absence of the compounds was assessed qualitatively as vascular zones in the membrane yolk sac as described in EXPERIMENTAL PROCEDURES. The compounds were added as 1 % DMSO solution atthe indicated amounts per test.

The term "patient" used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice.

The amount of the oxazolone derivative of formula 1 to be administered can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of deve¬ lopment of the tumor to be treated, and the particular oxazolone derivative selected. The amount of a oxazolone derivative of formula 1 effective to inhibit angiogenesis in patients having cancer will generally range from about 15 mg/kg to 500 g/kg. A unit dosage may contain from 25 to 500 mg of the oxazolone derivative, and can be taken one or more times per day. The oxazolone derivative can be administered with a pharmaceutical carrier using conven¬ tional dosage unit forms either orally or parenterally.

The preferred route of administration is oral adminis- tration. For oral administration the oxazolone derivative can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions. The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and cornstarch. In another embodiment the compounds of this invention can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents in¬ tended to assist the breakup and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow of tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or mag¬ nesium, calcium, or zinc stearate, dyes, coloring agents, and flavoring agents intended to enhance the esthetic qualities of the tablets and make them more acceptable to .the patient. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent, or emulsifying agent.

The oxazolone derivatives of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-l,3-dioxolane-4- methanol, ethers such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addi¬ tion of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutically adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-β-aminopropionates, and 2- alkylimidazoline quaternary ammonium salts, as well as mixtures. The parenteral compositions of this invention will typically contain from about 0.5 to about 25% by weight of the oxazolone derivative of formula 1 in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irri¬ tation at the site of injection, such compositions may contain a nonionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. The surfactant can be a single com¬ ponent having the above HLB or can be a mixture of two or more components having the desired HLB. Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

For topical administration, the compounds can incorporated into a suitable topical carrier using techniques well known in the art. Examples of suitable topical carriers include oleaginous bases such as white petrolatum, absorption bases such as hydrophilic petrolatum, emulsion bases^' such as lanolin, and water soluble bases such as polyethylene glycol ointment. The topical carrier may also contain preservatives, buffers, etc., as are known in the art.

Topical administration may also be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Some suitable transdermal de- vices are described in U.S. Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894.- These devices generally contain a backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces. The following specific examples are presented to illu¬ strate the synthesis of the compounds of this invention, but they should not be construed as limiting the scope of this invention in any way.

EXAMPLE 1 4-Ethyl-5(4-Pyridinyl)-2( 3H)-Oxazolone

First, l-hydroxy-2-(4-pyridyl)butan-2-one (26.4 g, 0.16 mol) was dissolved in 350 ml of 2N HC1. Potassium cyanate (38.9 g, 0.48 mol) was added portionwise to this solution over a period of one hour with stirring. After the addition was complete, concentrated hydrochloric acid was added until the pH of the solution was one. After an additional hour the reaction mixture was made basic by addition of sodium bicarbonate solution and the resulting mixture was stirred overnight. The resulting solid precipitate was collected and recrystallized twice from 50% aqueous ethanol to yield the title compound (14.4 g, 47% of theoretical yield), m.p. 287°-289°C (dec).

Using the procedure above but using l-(hydroxy)-l-( - pyridyl)pentan-2-one or l-(hydroxy)-l-(4-pyridyl)-propan-2- one instead of l-hydroxy-l-(4-pyridyl)butan-2-one results in 4-propyl-5(4-pyridinyl)-2(3JF_T)-oxazolone, m.p. 257°-259°C (dec.) or 4-methyl-5(4-pyridinyl)-2(3H)-oxazolone, m.p. >310°C.

EXAMPLE 2 4-Ethyl-5-(2-Pyridyl)-2( 3H)-Oxazolone

Potassium cyanate (35.4 g, 0.44 mol) was added to a solution of 2-hydroxy-l-(2-pyridyl)butan-l-one (31 g, 0.15 mol) in 250 ml of 2N HC1 diluted with 300 ml of water. After 1 hour the acidity was adjusted (pH = 1) with concentrated hydrochloric acid and then allowed to stir overnight. The mixture was made basic by addition of aqueous sodium bicarbonate. The resulting gummy precipi¬ tate was chromatographed on silica gel and recrystallized twice from 50% aqueous ethanol to give the title compound, m.p. 196°-197^βC (dec).

In a manner substantially similar to that of Examples 1 and 2, the compounds 4-phenyl-5(4-pyridinyl)-2(3i_T)oxazolone (m.p. >300°C) and 4-propyl-5-(2-phenylpyridin-4-yl)-2(3i_T.)- oxazolone (m.p. 202-204°C) were prepared.

EXAMPLE 3 A tablet is prepared from:

4-propyl-5(4-pyridinyl)-2 ( 3_*H)-oxazolone 250 mg starch 40 mg talc 10 mg magnesium stearate 10 mg

EXAMPLE 4 A capsule is prepared from:

4-ethyl-5(4-pyridin)yl-2(32_T)-oxazolone 400 mg talc 40 mg sodium carboxymethylcellulose 40 mg starch 120 mg

EXAMPLE 5

A tablet is prepared from:

4-methyl-5(3-pyridinyl)-l-(3i_r)-oxazolone 250 mg starch 40 mg talc 10 mg magnesium 10 mg EXAMPLE 6 A capsule is prepared from:

4-phenyl-5(2-pyridinyl)l-(3__T)-oxazolone 400 mg talc 40 mg sodium carboxymethyl cellulose 40 mg starch 120 mg

It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.

Claims

WHAT IS CLAIMED IS:

1. A method of inhibiting angiogenesis in a patient having cancer which comprises administering to the patient an amount of a compound of the formula I effective to inhibit angiogenesis

wherein

R is selected from the group consisting of Z-₂.--Z- alkyl and phenyl wherein the phenyl ring is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C alkyl and C₁-C₄ alkoxy; Ri is selected from the group consisting of hydrogen, C₃.-C₆ alkyl, and phenyl wherein the phenyl ring is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C₄ alkyl and C₃.-C₄ alkoxy; and R2 is a 2-, 3-, or 4-pyridyl group wherein the pyridyl group is optionally substituted with one or two substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₃.-C₄ alkylsulfonyl, cyano, carboxy, carb(Cι-Cs)alkoxy, carbamido, (C₁-C₅)alkanoylamino, imidazolyl, nitro and trifluoromethyl or wherein the pyridyl group is optionally substituted with a phenyl group which is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C₄ alkyl, and C₁-C₄ alkoxy; or a pharmaceutically-acceptable salt thereof.

2. A method of Claim 1 wherein R2 is an optionally substituted 2-, 3-, or 4-pyridyl group.

3. A method of Claim 2 wherein R is C₂-C6 alkyl.

4. A method of Claim 3 wherein the compound is 4- propyl-5(4-pyridinyl)-2( 3H)-oxazolone.