ANTIATHEROSCLEROTIC AND ANTITHROMBOTIC 2-AMINO-6-PHENYL-4H-PYRAN-4-ONES

Abstract: This invention relates to compounds of formula (I), which are useful as antiatherosclerotic agents and inhibitors of cell proliferation for the treatment of proliferative diseases. In addition, various compounds of formula (I) are useful inhibitors of platelet aggregation.

Description: A TIATHEROSCLEROΉC AND ANTΠΉROMBOΉC 2-AMINO-6-PHENYL- H-PYRAN-4-ONES BACKGROUND OF THE INVENTION The present invention is directed toward 2-amino-6-phenyl-4H-pyrano-4-ones which are pharmacologically active compounds. They have been shown to be inhibitors of cell proliferation in fibroblasts and therefore may be useful for the treatment or prevention of atherosclerosis as well as proliferative diseases. The compounds of the subject invention are further useful in the prevention or treatment of thrombotic diseases as they have been shown to inhibit ADP-induced platelet aggregation. Atherosclerosis in mammals is a disease characterized by the deposition of atherosclerotic plaque on arterial walls. While atherosclerosis exhibits many varied forms and consequences, typical consequences of atherosclerotic diseases include angina pectoris, myocardial infarction, stroke and transient cerebral ischemic attacks. Other forms of atherosclerotic diseases include certain peripheral vascular diseases and other ischemias (e.g., bowel and renal). Medical science now recognizes that certain forms of atherosclerosis may be preventable or reversible. Agents capable of preventing or reversing atherosclerosis are characterized as exhibiting antiatherosclerotic activity. Since serum lipids have a recognized association with atherogenesis, an important class of antiatherosclerotic agents are those with serum lipid-modifying effects. Serum lipids implicated in atherogenesis include serum cholesterol, serum triglycerides, and serum lipoproteins. With respect to serum lipoproteins, at least three different classes of these substances have been characterized; high density lipoproteins (HDL's), low density lipoproteins (LDL's), and very low density lipoproteins (VLDL's). HDL's are often referred to as alphalipoproteins, while LDL's and VLDL's are referred to as betalipoproteins. The enhancement of HDL levels (hyperalphalipoproteinemic activity) is postulated to have direct antiatherosclerotic effects. See Eaton, R.P., J. Chron. Dis 31:131-135 (1978). In contrast, agents which reduce serum LDL's and serum VLDL's (hypobetalipoproteinemic agents) are also associated with antiatherogenic effects. See Haust, M.D., "Reaction Patterns of Intimal Mesenchyme to Injury and Repair in Atherosclerosis", Adv. Exp. Med. Biol. 43:35-57 (1974), which postulates that serum LDL is a factor in atherosclerotic lesion formation. Numerous animal models have been developed for assessing antiatherosclerotic activity. Principal among these are models for assessing hypolipoproteinemlc activity in the rat and antiatherosclerotic activity in the Japanese quail. For a description of the operation of the hypobetalipoproteinemic rat model, refer to the known methods of Schurr, P.E., et al., "High Volume Screening Procedure for Lypobetalipoproteinemia Activity in Rats", Adv. Exp. Med. Biol. 67: Atherosclerotic Drug Discovery, pp. 215-229, Plenum Press (1975). For a description of the Japanese quail model, see Day, C.E. et al., "Utility of a Selected Line (SEA) of the Japanese Quail (Corturnic Corturnix japonica) for the Discovery of New Anti-Atherosclerosis Drugs", Laboratory Animal Science 27:817-821 (1977). While various compounds are known to have antiproliferative and antiplatelet activity the subject compounds are structurally unique. Chem. Ber.. 109(11), 3497-3504 (1976) reports a 6- (dimethylamino)-2,3-diphenyl-4H-pyran-4-one which has a diphenyl substituted pyrone ring. SUMMARY OF THE INVENTION The present invention is directed toward compounds of Formula I (shown in the Formulas sheet, below) which are useful in association with a pharmaceutical carrier as a medicament in d e prevention or treatment of a ierosclerosis or thrombotic diseases. In addition, various compounds of me Formula I are useful inhibitors of cell proliferation and/or platelet aggregation. In one aspect, this invention is represented by compounds of Formula I or pharmaceutically acceptable salts thereof wherein X is hydrogen, C!-C 5 alkyl, or a halogen atom; Y is selected from d e wherein R and R 10 , being the same or different, are selected from the group consisting of (a) hydrogen, preferably R9 and RJ Q are not both hydrogen; (b) Cι-C 12 alkyl; (c) phenyl optionally substituted wiΛ one, 2 or 3 C1-C4 alkyl, C r C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl); (d) -(CH2) q phenyl wherein phenyl is optionally substituted with one, 2 or 3 C j ^ alkyl, C j -C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl), (e) -(CH^pyridinyl or (f) wherein Rg and R 10 , taken togedier with N, form a saturated or unsaturated heterocyclic amine ring selected from die group consisting of: (aa) 4-morpholine optionally substituted widi one or two members selected from the group consisting of C j ^ alkyl, C j *^ alkoxy, halo or trifluoromethyl, (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C C^ alkyl, C C4 alkoxy, halo or trifluoromethyl, (cc) 3-amino-l-pyrrolidine, (dd) 1-pyrrolidine optionally substituted with one or two members selected from the group consisting of 0^4 alkyl, C-f^ alkoxy, halo, OH, -CH 2 OH, or trifluoromethyl, (ee) 1-piperidine optionally substituted with one or two members selected from me group consisting of C r C 4 alkyl, Cγ L alkoxy, halo, trifluoromemyl, -(CH^qOH, -CO 2 H, -CO 2 CH 3 -CO 2 CH 2 CH 3 or phenyl (wherein phenyl is optionally sub- stituted with one, 2 or 3 C r C 4 alkyl, C C 4 alkoxy, halo or trifluoromemyl), (ft) l-piperazine,4-methyl-l-piperazine,4-(cycloC 3 -C 6 alkyl)-l-piperazine,4-phenyl-l- piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C^-C^ alkoxy, halo or trifluoromethyl) or 4-pyridinyl-l-piperazine optionally substituted with one or two members selected from the group consisting of C j -^ alkyl, C r C 4 alkoxy, halo, OH, trifluoromethyl, -CH 2 OH, -CO 2 H, -CO 2 CH 3 or - CO 2 CH 2 CH 3 , and (gg) thiazolidine, thiazolidine-4-carboxylic acid, pipecolimc acid, p-piperazinaceto- phenone, 1-piperazine, 1-methylpiperazine, 4-phenyl-l,2-3,6-tetrahydropyridine, proline, tetrahydrofurylamine, l-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4- tetrahydroisoquinoline or imidazole; R j , R 2 , R 3 , R4 and R 5 are independendy selected from die group consisting of: hydrogen, Ci-Cg alkyl, -(CH^phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C j -C^ alkyl, C^ alkoxy, halo, OH, trifluoromethyl or -CO^C^ lkyl)), -(CH^naphthyl, -CH=CH-phenyl (wherein phenyl is optionally substituted witii one, 2 or 3 C1-C4 alkyl, ^-€4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -CH 2 -CH=CH 2 , -CH=CH-CH 3 , -O-CH 2 -CH=CH 2 , -CβC-phenyl (wherein phenyl is optionally substituted wititi one, 2 or 3 C j -C4 alkyl, C-t-C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -©(CH^p N-methylpiperdin-S-yl), -O-(CH 2 )pNR 9 R 10 , -O-CH 2 CH(0CH 3 )2, -O-(CH2)pOR 15 (wherein R 15 is selected from C^ alkyl, -(CH^phenyl (phenyl optionally substituted wiύi one, 2 or 3 C j ^ alkyl, ^^4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -(CH2) n pyridin-yl or -(CH2)ppiperidin-l-yl), -(CH^OMCH^Rg, -(CH^C^CKCH^, -(CH) n C(O)O-(CH 2 ) p NR 9 R 10 , NO j , -CHCH^nCCOHCH^Rg, -©-(CH^C^O^CH j )^, -O-(CH 2 ) n C(O)-(CH 2 ) I1 NR 9 R 10 , -NRgRiQ, ^(R j XCH^CCOHCH^ ^, N(R 9 )(CH 2 ) n C(O)-(CH 2 ) n NR 9 R 10 , -OCH(nBu)phenyl, alkyl, C^ alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -O-(CH2) n pyridine, ^(CH^QOMCH^pyridine, -©-(CH^C^CKCH^yridine, -OtCH^C^-N^XCH^pyridine, -O-(CH 2 ) n quinoxal inyl, -O-(CH2) n quinolinyl, -O-(CH2) n naphthyl, -©-(CH^OMCH^naphthyl, -O CH j ^CCO CH j J^a hth i, -©-(CH^C^NR^CH^naphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH j X j -OH, (CH^qOC^Rg, -(CH 2 ) q OC(O)-NR 9 R 10 , -(1-cyclohexyl- lH-tetrazol-S-y C j -^ alkoxy, -(l-^ j -Csalky -lH-tetrazol-S-y C j ^ alkoxy, -(l-(phenyl)-lH-tetrazol-5-yl) C-^ alkoxy (wherein phenyl is optionally substituted with one, 2 or 3 CγC^ alkyl, C-*^ alkoxy, halo, OH, trifluoromethyl or -CO^C j -dalkyl)), -(l-φyridiny -lH-tetrazol-S-y C^ alkoxy, -(l-(l-phenylethyl)-lH-tetrazol-5-yl)C 1 -C4 alkoxy, -C r C 4 alkoxyl; n is 0-5 (preferably 0 or one); p is 2-5 (preferably 2 or 3); and q is 1-5 (preferably 1 or 2). In another aspect, this invention is represented by compounds of Formula II (shown in the Formulas sheet, below) as defined above or pharmaceutically acceptable salts thereof. The compounds of Formula I are useful in the inhibition of cell proliferation and tiierefore are useful in the treatment of diseases whose mechanism of action is the proliferation of cells. Detailed Description of the Invention The present invention is directed toward compounds of Formulas I and II as defined above and which are pharmaceutically useful for treating atherosclerosis, and thrombotic proliferative diseases. The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating me minimum and maximum number of carbon atoms in die moiety, i.e., die prefix C j - Cj indicates a carbon atoms content of the integer "i" to die integer "j" carbon atoms, inclusive. Thus, C j -C 3 alkyl refers to alkyl of 1-3 carbon atoms, inclucive, or methyl, ethyl, propyl, and isopropyl. Witfi respect to me above, C j -04 alkyl is metiiyl, ethyl, propyl, or butyl, including isomeric forms diereof. Similarly, C^Cg alkyl is mediyl, ethyl, propyl, butyl, pentyl, hexyl, and isomeric forms thereof. The term "halo" includes fluoro, chloro, bromo and iodo. Examples of C j -Cg alkylthiomemyl are metiiyltfiiomethyl, ethylthiomediyl, propyl thiomethyl, butylthiomethyl, pentylthiomethyl, hexylthiomethyl, and heptylthiomediyl, and isomeric forms diereof. Examples of C j -C alkoxymethyl are me oxy methyl, ethoxymediyl, propoxymethyl, butoxymemyl, pentoxymeύiyl, butoxymethyl, pentoxymethyl, hexoxymemyl, and heptoxymeύiyl, and isomeric forms diereof. Examples of heterocylic amines corresponding to heterocyclic amine rings according to -NR RjQ are: 4-morpholine, 4-phenyl- 1 -piperazine, 4-(2-pyridinyl)- 1 -piperazine, 2,6-dime yl-4-morpholine, 1-pyrrolidine, 4-methyl-l -piperazine, 1-piperidine, 4-phenyl- 1 -piperidine thiazolidine, 3-piperidine methanol, 2-piperidine me anol, pipecolic acid, 3-piperidine ethanol, 2-piperidine edianol, 1-piperazine propanol, p-piperazinoacetophenone, 4-phenyl-l,2,3,6-tetrahydropyridine, 4-phenylpiperidine, proline, l-(3-hydroxy)pyrrolidine, tetrahydrofurylamine, pyrrolidimedianol, 3-pyrroline, thiazolidine-4-carboxylic acid, diiomorpholine, nipecotamide, 2-methylpiperidine, 3-methylpiperidine, 4-medιylpiperidine, N-methylpiperazine, 1 -methylhomopiperazine, 1-acetylpiperazine, N-carboethoxypiperazine, 3-medιylpiperazine-2-carboxylic acid, 2-methylpiperazine, 2,3,5,6,-tetramethylpiperazine, 1,4-dimethylpiperazine, 2,6-dimedιylpiperazine, 2-methyl-l-phenylpiperazine, l-(l-phenylethyl)piperazine, 1 -(2-pyrazinyl)piperazine, 1-cyclopropylpiperazine, 1 -cyclobutylpiperazine, 1 ,2,3 ,4-tetrahydroisoquinoline, imidazole, homopiperdine, or pharmaceutically acceptable salts and hydrates diereof. Examples of -OζCH-^pCN-methylpiperdin-S-yl) include: (2-(N-methylpiperdin-3-yl)ed yl)oxy, (3-(N-methylpiperdin-3-yl)propy)loxy, (4-(N-methylpiperdin-3-yl)butyl)oxy. Examples of -O-(CH 2 )pNR9R 10 include: (2-(l -piperidinyl)edιyl)oxy, (2-(4-morpholinyl)etiιyl)oxy, (2-( 1 -pyrrol idinyI)etiιyl)oxy , (3-(N-methylpiperazinyl)propyl)oxy, (4-(N-ethyl-N-phenylamino)butyl)oxy, (5-(diethylamino)pentyl)oxy, (2-(4-benzylpiperazinyl)ethyl)oxy, and (3-(N,N-diisopropyl)propyl)oxy. Examples of O-(CH2)pOR 15 include: (2-medιoxyethyl)oxy, (3-butoxypropyl)oxy, (4-phenoxybutyl)oxy, (2-benzyloxyetiιyl)oxy, (2-(2-(l-piperidinyl)ethoxy)ethyl)oxy, and (3-(3-picolylmethoxy)propyl)oxy. Examples of -(CH^pyridinyl include: 2-pyridyl, 3-pyridylmemyl, and 4-pyridylethyl. Examples of -(CH^piperdinyl include: 1-piperidinyl, 1-peiperidinylmedιyl, 2-(l-piperidinyl)edιyl, and 3-(l -piperidinyl)propyl . Examples of -(CH2)qNR9R 10 include: (l-piperidinyl)methyl, 2-(4-morpholinyl)emyl, 3-(l-pyrrolindinyl)propyl, and 4-(l-piperazinyl)butyl. Examples of include: acetyl, acetylmediyl, mediylacetylmediyl, mediylacetylethyl, phenylacetyl, phenylacetylmethyl, 2-(phenylacetyl)edιyl, 2-pyridylacetyl, 3-pyridylacetylmethyl , 3-(t-butylacetyl)propyl, and 4-(ed ylacetyl)butyl. Examples of -(CH2) n C(O)O-(CH 2 ) n R 9 include: carbomethoxy, carbomethoxymethyl, 2-(carbomedιoxy)ethyl , carbophenylmethoxy, carbophenylmethoxymethyl, 2-(carbo(3-pyridyl)methoxy)edιyl, carboethoxymethyl, and 3-(carbopropoxy)propoxy. Examples of -(CH 2 ) n C(O)O-(CH 2 ) p NR 9 R 10 include: -C(O)O-(CH 2 ) 2 N(ethyl) 2 , -(CH^C^O-^H^N^H^φhenyl), -(CH^C^O-tCH^Cl-pyrrolidine), -(CH 2 ) 3 C(O)O-(CH 2 ) 2 (l-piperidinyl), and -(CH^C^CKCH^^morpholinyl). Examples of -(CH 2 ) n C(O)(CH 2 ) I1 NR 9 R 10 include: -C(O)(li)yτrolidine), -(CH^C^XCH^Cl-piperidine), and -(CH 2 ) 3 C(O)(CH 2 )(4-morpholine). Examples of -O-(CH 2 ) n C(O)-(CH 2 ) n R 9 include: -CKCH^C OMCH^CH*}), -0-C(0)-(CU_) 2 (CR^. -O-(CH 2 ) 3 C(O)-(CH 2 )phenyl, -O-(CH 2 ) 2 C(OHCH 2 ) 3 (2-pyridyl), -O-(CH 2 )C(O)-(CH 2 ) 2 (3-pyridyl), and -O-CCH^CCOJ-CCH^Ct- utyl). Examples of -©-(CH^C^O-^H^Rg include: -O^CHJX OJCKCHJXCHJ), -O-(CH 2 ) 2 C(O)O-(CH 2 ) 3 (phenyl), and Examples of -O-(CH 2 ) n C(O)-(CH 2 ) n NR 9 R 10 include: -O-tCH^CCDMCH^N CH^, -O-C(O)-(CH2)(l-pyrrolidine), -O-(CH2)C(O)-(l-piperidine), -O-(CH 2 ) 2 C(O)-(CH 2 )(l-N-methylpiperazine), -CKCH^C OMCH^-morpholine), -CKCH^C OMCH^cyclohexylamine), -O-(CH 2 ) 2 C(O)-(CH 2 ) 3 (t-butylamine), -O-(CH2)C(O)-(CH 2 ) 2 (l-phenylethylamine), -O-(CH 2 )C(O)-(CH 2 ) 2 (aniline), -CKCH^C OMCH^ L-phenylalanine ethyl ester), and -O-(CH 2 ) 2 nC(O)-(CH 2 ) 3 (3-pyridylamine). Examples of include: -N(CH 3 )C(O)-(CH 3 ), -N(H)(CH2)C(O)-(CH2) 2 (3-pyridyl), and -N(CH 3 )(CH 2 ) 3 C(O)-(CH2)(CH 3 ). Examples of include: -N(H)-(CH2)C(O)O-(CH 3 ), -N(H)-(CH2) 2 C(O)O-(CH 2 )(benzyl), -N(H)-(CH 2 ) 2 C(O)O-(CH 2 )(3-pyridyl), and -N(CH 3 )-(CH 2 )C(O)O-(CH2) 2 (t-butyl). Examples of include: -N(H)(CH 2 )C(O)-(CH 2 )N(CH 3 ) 2 , -N(H)C(O)-(CH 2 )(l-pyrrolidine), -N(H)(CH 2 ) 2 C(O)-(CH 2 ) 2 (l-piperidine), and -N(CH 3 )(CH 2 )C(O)-(CH2) 2 (4-mo holine). Examples of -O-(CH 2 ) n phenyl include: 2-(4-trifluoromethylphenyl)eύιoxy, 4-chlorophenoxy, 4-fluorophenylmethoxy, 3-(4-methoxyphenyl)propoxy, 4-(2-methyl-4-fluorophenyl)butoxy, 2-(2-methoxyphenyl)ethoxy, 3-meύιoxyphenylmethoxy, 4-carbomethoxyphenylmethoxy, 2-(3 ,4-dichlorophenyl)ethoxy , 4-edioxyphenylmedioxy, 3-(4-nitrophenyl)propoxy, 4-t-butylphenylmedιoxy, 4-benzyloxyphenylmethoxy, and 2-(3-triflouromethylphenyl)ethoxy. Examples of -©-(CH^ jj pyridin include: 2-pyridyloxy, 3-pyridylmedιoxy, and 2-(4-pyridyl)ethoxy. Examples of include: -O(CH 2 )C(O)-(CH 2 )(2-pyridine), -O(CH2) 3 C(O)-(CH 2 )(3-pyridine), and -O(CH 2 ) 2 C(O)-(CH 2 ) 3 (4-pyridine). Examples of include: -O(CH 2 )C(O)O-(CH 2 )(2-pyridine), -O(CH 2 ) 3 C(O)O-(CH2)(3-pyridine), and -O(CH2) 2 C(O)O-(CH 2 ) 3 (4-pyridine). Examples of -©(CH^C^-N^^H^pyridine include: -O(CH 2 )C(O)-N(CH 3 )(CH 2 )(2-pyridine), -O(CH 2 ) 2 C(O)-N(CH 3 )(CH 2 )(3-pyridine), and -©(CH^C^-NφenzylXCH^Φ-pyridine). Examples of -O CH^ Q quino alinyl include: 2-quinoxalinyloxy, 2-quinoxalinyImethoxy, and 2-(2-quinoxalinyl)edιoxy. Examples of -O-(CH 2 ) n quinolinyl include: 2-quinolinyloxy, 2-quinolinylmedιoxy, and 2-(2-quinolinyl)edιoxy. Examples of -O-(CH- 2 ) n pyrazinyl include: 2-pyrazinyloxy, 2-pyrazinylmedιoxy, and 2-(2-pyrazinyl)ed oxy. Examples of -O-(CH 2 ) n naphthyl include: 1-naphthyloxy, 2-naphthylmethoxy, and 2-(l -naphthyl)ethoxy . Examples of include: -CKCH^C OMCH-aXl-naphthyl), -O-(CH 2 ) 2 C(O)-(CH 2 )(2-naphthyl), -O-C(O)-(CH2)(l-naphthyl), and -O-(CH2)2C(O)-(CH2)2(2-naphthyl). Examples of -©-(CH^C^O-^H^naphthyl include: -O-(CH 2 )C(O)O-(CH 2 )(l-naphthyl), -O-(CH 2 ) 2 C(O)O-(CH 2 )(2-naphthyl), -O-C(O)O-(CH 2 )(l-naphthyl), and -O-(CH 2 )2C(O)O-(CH 2 ) 2 (2-naphthyl). Examples of -O-(CH 2 ) n C(O)NR 9 -(CH 2 ) n naphthyl include: -O-(CH2)C(O)N(H)(CH 2 )(l-naphthyl), -O-(CH 2 )C(O)N(CH 3 )(CH 2 ) 2 (2-naphthyl), and -CKCH^C OJNφenzylXCH^ -naphthyl). Examples of -(CH^-OH include: hydroxyme iyl, hydroxyediyl and hydroxybutyl. Examples of (CH^qOCζOJRg include: (CH2)OC(O)methyl, (CH2) 2 OC(O)ethyl, (CH2) 3 OC(O)phenyl, (CH2)4OC(O)(3-pyridyl), and (CH2)OC(O)thiophene. Examples of -(CH^qOC^-NRgR j o include: -(CH2) 2 OC(O)-N(ethyl) 2 , -(CH2) 3 OC(O)-(l-pyrrolidine), -(CH 2 ) 4 OC(O)-(l-piperidine), and -(CH^OC^-N-benzylamine. Examplesof-(l-cyclohexyl-lH-tetrazol-5-yl)C 1 -C 4 alkoxy,-(l-(C 1 -C 5 alkyl)-lH-tetrazol-5- yl)C j -C4 alkoxy include: -(l-cyclohexyl-lH-tetrazol-5-yl)methoxy, -(l-cyclohexyl-lH-tetrazol-5-yl)ethoxy, -(l-(methyl)-lH-teu * azol-5-yl)methoxy, -(l-(cyclopropyl)-lH-tetrazol-5-yl)ethoxy, -(l-(l-tert-butyl)-lH-tetrazol-5-yl)propoxy, and -(l-(cyclopenyl)-lH-tetrazol-5-yl)methoxy. Examples of -(l-φheny^-lH-tetrazol-S-y C j ^ alkoxy (wherein phenyl is optionally substituted with one, 2 or 3 C!-C 4 alkyl, C-*-C alkoxy, halo or trifluoromethyl) include: -(l-(phenyl)-lH-tetrazol-5-yl)methoxy, -(l-(phenyl)-lH-tetrazol-5-yl)ethoxy, -(l-(4-methoxyphenyl)-lH-tetrazol-5-yl)methoxy, and -(1 -(4-fluorophenyl)- lH-tetrazol-5-yl)propoxy . Examples of -(l-φyridiny -lH-tetrazol-S-y C^ alkoxy or -(l-(l-phenylethyl)-lH- tetrazol-S-y C j ^ alkoxy include: -(l-(2-pyridinyl)-lH-tetrazoI-5-yl)medιoxy, -(l-(3-pyridinyl)-lH-tetrazol-5-yl)edιoxy, -(l-(4-pyridinyl)-lH-tetrazol-5-yl)propoxy, -(l-(l-phenyIet yl)-lH-tetrazol-5-yl)medιoxy, and - l-(l-phenyledιyl)-lH-tetrazol-5-yl)edιoxy. The tertiary amines and aromatic heterocyclic amines of d e subject specification and claims include die N-oxides thereof. Pharmaceutically acceptable salts means salts useful for administering die compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate malate, succinate, tartrate, citric acid and d e like. These salts may be in hydrated form. Various compounds of Formula I are potent inhibitors of cell proliferation and are contemplated as useful in e treatment of proliferative diseases such as cancer, rheumatoid arthritis, psoriasis, pulmonary fibrosis, scleroderma, cirrhosis of the liver and for the improved utilization of artificial prosthetic devices such as arterial grafts. These agents may also be useful in the prevention or treatment of obstruction or restenosis of arteries by subsequent administration of drug in cases such as by-pass surgery, coronary by-pass surgery, balloon angioplasty (and odier procedures directed at re-establishing patency in occluded or partly occluded vessels, i.e adierectomy, laser or ultrasonic procedures), transplants, and post-tiirombotic re-stenosis. The compounds of Formula I are active as inhibitors of cell proliferation as shown in Table 1 by the test procedure described in Pledger W.J., Stiles CD., Antniades H.N., Scher CD., (Proc. Nad. Acad. Sci (USA) (1977). In addition, various compounds of Formula I are also inhibitors of ADP induced platelet aggregation and are useful in die prevention or treatment of thrombotic diseases and related complications by, for example, inhibition or reversal of platelet aggregation, or platelet adhesion or blood coagulation. Most compounds of Formula I are active as inhibitors of platelet aggregation as shown in Table 1 by the test procedure described in Born, G.R., Cross M.J., J. Physiol., 168, p. 178 (1963). Accordingly, in using compounds of Formula I for d e prevention or treatment of atherosclerotic disease or d rombotic diseases, an oral route of administration, either by conventional oral dosage forms or by mixture with food, represents me preferred metiiod of tiieir systemic administration. Alternatively, however, these compounds may be administered by odier convenient routes of administration whereby systemic activity is obtained. These other routes of administration would include rectal, vaginal, subcutaneous, intramuscular, intravenous, and like routes. In using compounds of Formula I for use in angioplasty, an oral route of administration represents the preferred me od of their systemic adminstration. Alternatively, however, diese compounds may be administered by o er convenient routes of administration whereby systemic activity is obtained. The patient or animal being treated must be given periodic doses of d e drug in amounts effective to reduce serum and/or arterial cholesterol, and reduce arterial atheroscl erotic lesion size (as determined by angiogram, ultrasound, NMR, etc.); or, by die inhibition or reversal of platelet aggregation, platelet adhesion or blood coagulation; or, by preventing arterial occlusion in vascular trauma associated wiύi procedures such as by-pass grafts, coronary by-passes, angioplasty, post- thrombotic re-stenosis and transplants. Such effective dosages are readily determined by methods known in the art. For example, small daily doses of the drug ( e.g., 0.01-200 mg/kg) may be administered initially widi higher succeeding doses until levels of serum and/or arterial cholesterol are favorably affected. By this regimen, a compound of Formula I is administered initially at doses as low as about 0.01 mg/kg per patient per day, wid increasing doses up to about 200 mg/kg per patient per day. In d e event me antiatherogenic response in a patient being treated at a dose of 200 mg/kg per day is insufficient, higher doses are also utilized to die extent patient tolerance permits further increases in dose. While die preferred dosage regimen is with single daily dosing of patients, also preferred for obtaining more uniform serum levels of drug are multiple dosages per day (e.g., up to 4-6 times daily). Accordingly, when 4 daily doses of drug are to be administered, each such dose may be about 50 mg/kg per patient per dose, or higher depending on tolerance. Similar doses are employed in hon-human mammals, e.g. 0.01-200 mg/kg/day. The compounds of the subject invention can be prepared as shown in the four Schemes, below. In die first Scheme I, benzoylacetone was treated with boron trifluoride edierate to provide an 82% yield of die corresponding complex. Treatment of this complex with 4-morpholine dichloromethylene iminium chloride afforded a 2.5% yield of d e desired compound along widi an equivalent recovery of carboxamide byproduct. This same chemistry can be applied using 4'-acetyloxyacetophenone. Formation of die boron difluoride complex (43%) followed by treatment widi 4-morpholine dichloromemylene iminium chloride gives a mixture of byproduct and die desired compound (as an equimolar mixture of the acetates and d e corresponding phenols). In Scheme π, the intermediate compound is prepared by d e coupling of lithio acetoxymorpholine and ethyl phenylpropiolate in 27% yield (unoptimized). Cyclization is then accomplished widi trifluoroacetic acid to afford the subject compounds in about a 69% yield. The ready availability of phenylpropiolates and acetoxyamines (two steps from the corresponding benzaldehyde) makes this a general method for d e synthesis of 6-aryl-2-amino-4-pyrones. Compounds of me subject invention can also be prepared by a another means of syntiiesis, generally following Scheme JJ. For example, 4-Phenylmethoxybenzaldehyde is reacted with carbon tetrabromide and triphenylphosphine to afford dibromoolefin which upon treatment with n-butyl lidiium and med yl chloroformate gave the phenyl propiolate. Reaction of die first compound with lithioacetoxymorpholine affords die product in an 81 % yield. Optimal cyclization conditions for the product were found to be 15% trifluoroacetic acid in mediylene chloride producing d e aminopyrone in 72% yield. In some situations die use of trifluoroacetic acid as solvent is required to afford proper product in sufficiendy high yields. In yet another approach to prepare compounds of die subject invention, Scheme III begins with a phenyl propiolate reacted wid acetyl-med ylphenyl sulfoxide to produce die desired intermediate compound. The intermediate is then warmed in methanol to yield die desired 4- pyrone. Pummerer rearrangement widi acetic anhydride at 110°C gives an intermediate which is reduced (NaBH 4 ) to an alcohol which is tosylated (TSC1) to give a tosylate. The tosylate is displaced widi an amine to yield die subject compound 6-phenyl-2-methylamino-4-pyrone. The foregoing Schemes provide a general explanation of successful procedures for preparing the subject compounds which are described in further detail in die individual examples. The compounds of die invention were tested for biological activity and die individual results are reported in Table 1, Biological Data. The data collected shows the antiprolifeative assay results measured in EC50 (uM) and percent inhibition at d e maximum concentration tested. Only Compound 14 exhibited no measurable antiproliferation or inhibition activity but still a novel compound. Also, reported is die percent inhibition of platelet aggregation at lOug/ml and 30 ug/ml concentrations. Typical examples of the subject compounds are identified by structure in Table 2, below. Table 1 : Biological Data Antiproliferative Assay Data Inhibition of Platelet Aggregation i Inhibition (%) 10 ug/ l 30 ug/ml 54 66 77 72 30 88 34 36 20 0 96 73 20 8 12 9 13 25 H -N O H H H H H Table 2. Compound Identification - continued Compound Y R, R, R, R« 20 H -N O H H -CH,-N N-CH, H H 22 H -N^b H H H H 23 H - 3 H H 24 H • H H 25 H -NH, H H EXAMPLE 1: 2-C4-Hydroxyphenyl ' )-6-(4-moφholinyl')-4H-pyran-4-one (Compound 1). 4'-Hydroxyacetophenone (lOg, 73.4 mmole) was suspended in 200 ml dichlorometiiane in a 500 ml one neck round bottom flask under nitrogen at 0°C The supension was treated widi diisopropylethylamine (14.7ml, 84.5 mmole) followed by acetyl chloride (6.0ml, 84.5 mmole) in I X 50ml dichloromethane slowly dropwise. The reaction mixture was stirred 30 minutes at (PC and tiien for 1 hour at room temperature. The mixture was washed widi 1 X 100ml 10% hydrochloric acid and die organics were dried over magnesium sulfate. The dried organics were conentrated in vacuo to a yellow oil. The oil was distilled via kugelrohr (high vacuum, 165°C) to give 12.25g (94%) of 4'-acetoxy-acetophenone as a white solid. Melting Point: 47-49°C 4'- Acetoxy-acetophenone (lOg, 56.2 mmole) was dissolved in acetic anhydride (10.6ml, 112.2 mmole) in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0°C and boron trilfuoride gas was bubbled into the reaction mixture until it was saturated. The reaction was stirred 1 hour at room temperature and was poured into 600 ml diethyl ether. The orange precipitate was collected, washed widi fresh diediyl ether, and was dried to afford 6.6g (43%) of a boron difluoride complex. Melting Point: 130-132°C The 4'-Acetoxy-benzoylacetone-boron difluoride complex (4.02g, 15 mmole) was combined widi 4-moφholine phosgeniminium chloride (3.7g, 18 mmole) in 50ml 1,2-dichloroethane in a 100ml one neck round bottom flask under nitrogen. The reaction mixture was heated to 80PC for 6 hours and was cooled to room temperature. The dichloroed ane was removed in vacuo and die residue was dissolved in 50 ml acetonitrile in a 100 ml one neck round bottom flask. The solution was diluted widi 5 ml water and d e reaction mixture was stirred overnight at room temperature. The acetonitrile was removed in vacuo and die aqueous residue was diluted widi 30 ml methanol and 15 ml 2N sodium hydroxide. The reaction mixture was stirred for 3 hours at room temperature. The methanol was removed in vacuo and diepH of die aqueous residue was adjusted to 5 with 10% hydrochloric acid (pH meter). The mixture was extracted wi 4 X 25 ml dichloromethane followed by 4 X 20 ml dichloromemane. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a semisolid residue. The crude material was chromatographed over 68 g silica gel (230-400 mesh) eluting with 60-80% acetone/ethyl acetate for die first 144 fractions while collecting 9 ml fractions. Fractions 141-213 were combined and concentrated to afford 281 mg (4.9%) of 3-carboxamido-pyrone as a tan solid. Fractions 276-302 were eluted widi 80% acetone/ediyl acetate + 5% methanol and were combined and concentrated to afford lOOmg (2.4%) of Compound 1 as an off white solid. H-NMR (CDC13,TMS): d 3.43(m,4H,CH2); 3.84(m,4H,CH2); 5.42(d,J=2Hz,lH,CH); 6.42(d,J=2Hz,lH,CH); 6.94(d,2H,ArH); 7.53(d,2H,ArH); 9.41(bs,lH,OH) ppm. TLC (silica gel-60, F-254): Rf = 0.26, 10% methanol/dichloromethane. Melting Point: > 250°C Infrared (v max, mineral oil): 2926, 2602, 1649, 1549, 1508, 1450, 1425, 1248, 1174, 841 cm-1. Mass Spectrum: Calculated for C15H15NO4: 273.1001, Found: 273.1004. EXAMPLE 2: 2-(4-Mθφholinyl-6-('4-(phenylmetfιoxy ' )phenyl ' )-4H-pyran-4-one (Compound 2). 2-Moφholinyl-6-(4-hydroxyphenyl)-4-pyrone(85mg, 0.31 mmole), as prepared in Example 1 , was suspended in 5 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated successively widi potassium carbonate (249mg, 1.8 mmole) and benzyl bromide (0.050ml, 0.42 mmole). The reaction mixture was stirred at 65°C for 4 hours. The reaction was cooled to room temperature and d e acetonitrile was removed in vacuo. The residue was washed widi 1 X 25ml dichloromemane and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo to a yellow solid. The solid was chromatographed over 6 g silica gel (230-400 mesh) eluting widi 3% med anol/dichloromethane and collecting 3 ml fractions. Fractions 12-18 were combined and concentrated to afford 74mg (66%) of Compound 2 as a pale yellow solid. H-NMR (CDC13,TMS): d 3.42(m,4H,CH2); 3.84(m,4H,CH2); 5.13(s,2H,CH2); 5.42(d,J=2Hz,lH,CH); 6.46(d,J=2Hz,lH,CH); 7.04(d,2H,ArH); 7.26-7.45(m,5H,ArH); 7.60(d,2H,ArH) ppm. NMR (CDC13): d 44.92; 65.93; 70.19; 90.48; 108.22; 115.37; 124.02; 127.06; 127.45; 128.26; 128.73; 136.23; 159.21; 160.88; 163.37; 180.34 ppm. TLC (silica gel-60, F-254): Rf = 0.35, 10% methanol/dichloromethane. Melting Point: 202.5-203.5°C Infrared (v max, mineral oil): 2925, 1647, 1600, 1564, 1512, 1406, 1258, 1221, 1119 cm-1. Ultraviolet (v max, ethanol): 227, 257, 287, 299, 322 nm. Mass Spectrum: Calculated for C22H21NO4: 363.1470 Found: 363.1476. EXAMPLE 3: 2-C4-Moφho1iny1 , )-6-phenyl-4H-pyran-4-one (Compound 3). A flame dried 500ml diree neck round bottom flask under nitrogen was charged widi 140 ml dry tetrahydrofuran and diisopropylamine (23.9ml, 170.3 mmole). The solution was cooled to 0°C, was treated widi butyllidiium (115ml, 178.7 mmole), and was stirred 30 minutes. The mixture was treated with acetyl moφholine (9ml, 77.4 mmole) in 30 ml dry tetrahydrofuran and die reaction was stirred 30 minutes at 0°C Ediylphenyl propiolate (12.8ml 77.4 mmole) in 30 ml dry tetrahydrofuran was added slowly dropwise to die reaction mixture at (PC. The reaction was stirred 3 hours at 0°C and was quenched widi 30 ml water. The yellow precipitate was collected and washed successively with water, methanol, and diediyl edier to afford 5.4g (27%) of acetylenic ketoamide. Melting Point: > 300°C. Acetylenic ketoamide (760mg, 2.95 mmole) was dissolved in 10 ml trifluoroacetic acid in a 50 ml one neck round bottom flask under nitrogen. The reaction mixture was warmed to 60°C for 20 hours and was cooled to room temperature. The trifluoracetic acid was removed in vacuo and die residue was diluted widi 20 ml dichloromemane. The mixture was extracted widi 1 X 20 ml 1:1 saturated sodium chloride/2N sodium hydroxide. The aqueous layer was back extracted with 3 X 20 ml dichloromemane. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a dark brown semisolid residue. The residue was chromatographed over 68g silica gel (230-400 mesh) eluting with 3% methanol/dichloromethane and collecting 12 ml fractions. Fractions 27-36 were combined and concentrated to afford 525mg (69%) of Compound 3 as a tan solid. H-NMR (CDC13.TMS): d 3.44(m,4H,CH2); 3.84(m,4H,CH2); 5.46(d,J=2Hz,lH,CH); 6.54(d,J=2Hz,lH,CH); 7.45-7.50(m,3H,ArH); 7.62-7.69(m,2H,ArH) ppm. C-NMR (CDC13): d 44.66; 65.70; 90.32; 109.30; 125.23; 128.89; 130.75; 131.13; 158.95; 163.25; 179.88 ppm. TLC (silica gel-60, F-254): Rf = 0.46, 10% methanol/dichloromethane. Melting Point: 136.5-137.5°C Infrared (v max, mineral oil): 2926, 1651, 1601, 1578, 1565, 1402, 1229, 1029, 792 cm-1. Mass Spectrum: Calculated for C15H15NO3: 257.1052, Found: 257.1053. Analysis: Calculated for C15H15NO3: C.70.02; H,5.88; N,5.44; Found: Q69.99; H,5.74; N,5.59. EXAMPLE 4: 2-(4-Mθφholinyl-6-('4-fphenylmethoxy ' )phenyl)-4H-pyran-4-one (Compound 2). Carbon tetrabromide (78. lg, 235.6 mmole) and triphenylphosphine (123.5g, 471.2 mmole) were combined in 460ml dichloromemane in a flame dried 1000 ml tiiree neck round bottom flask under nitrogen at 0°C The mixture was stirred 1 hour at 0°C and was treated portionwise with 4-benzyloxybenzaldehyde (25g, 117.8 mmole). The reaction was stirred 30 minutes at 0°C and was washed successively widi 1 X 100 ml water and 1 X 100 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were poured into 3 liters hexane. The supernatant was collected and die residue was dissolved in a minimum amount of dichloromemane. This solution was also poured into 3 liters hexane and the process was repeated one more time. The combined supernatants were filtered mrough a 125 ml plug of silica gel (230-400 mesh) in a 600 ml coarse filter runnel. The plug was washed widi 1 liter 15% ediyl acetate/hexane and die combined eluents were concentrated in vacuo to provide 38.2g (89%) of 2-(4-Benzyloxyphenyl)- 1,1-dibromo-edιene as a white solid. Melting Point: 97-98°C The dibromo-olefm (20g, 54.3 mmole) was dissolved in 200 ml dry tetrahydrofuran in a flame dried 500 ml three neck round bottom flask under nitrogen. The solution was cooled to -78°C and was treated slowly dropwise with butyllithium (70 ml, 108.6 mmole). The reaction was stirred lh at -78°C followed by 1 hour at 0°C. The mixture was cooled to -78°C and was treated widi memyl-chloroformate (4.6 ml, 60 mmole). The reaction mixture was stirred for 20 minutes at -78°C and dien for 1.5 hours at 0°C The reaction was quenched with 1 X 100 ml 1:1 saturated ammonium chloride/saturated sodium chloride. The layers were separated and d e aqueous layer was washed widi 2 X 100ml diediyl ether. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a red oil. The oil was crystallized and dien recrystallized from hexane to provide 9.2 g (75%) of medιyl-4-benzyloxyphenyl-propiolate as orange tinged flakes. Melting Point: 78°C Acetyl moφholine (3.99 ml, 34.5 mmole) was dissolved in 30ml dry tetrahydrofuran in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution was cooled to OPC and was treated slowly dropwise widi lidiium diisopropylamide (23 ml, 34.5 mmole). The reaction mixture was stirred 30 minutes at 0°C and was susequently added slowly dropwise via cannula to a solution of the previously prepared propiolate (3.9 g, 17.2 mmole) in 40 ml dry tetrahydrofuran in a flame dried 250 ml diree neck round bottom flask under nitrogen. The reaction was stirred 1 hour at 0°C and was quenched widi 100 ml water which resulted in die immediate solidification of die mixture. The mixture was diluted widi water and the solid was collected. The solid was washed widi diediyl edier and was dried to afford 5.06 g (81%) of acetylenic ketoamide (Moφholine-5-(4-benzyloxyphenyl)-3-oxo-pent-4-ynamide) as a pale yellow solid. Melting Point: 282-285°C The acetylenic ketoamide just prepared (363mg, 1.0 mmole) was suspended in 5 ml dichloromethane in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated with 1 ml trifluoroacetic acid and was stirred 1.5 hour at room temperature. The mixture was diluted widi 25 ml dichlorometiiane. The mixture was washed widi 1 X 20 ml 2N sodium hydroxide and the organics were dried over magnesium sulfate. The organics were concentrated in vacuo to give 287 mg of a brown solid. The solid was recrystallized from ethyl acetate to afford 223 mg (61%) of Compound 2 as a pale solid. H-NMR (CDCI3,TMS): d 3.41(m,4H,CH2); 3.83(m,4H,CH2); 5.12(s,2H,ArCH2); 5.42(d,J=2Hz,lH,CH); 6.45(d,J=2Hz,lH,CH); 7.03(d,2H,ArH); 7.30-7.45(m,5H,ArH); 7.60(d,2H,ArH) ppm. C-NMR (CDC13): d 44.76; 65.79; 70.04; 90.32; 108.06; 115.23; 123.86; 126.91; 127.32; 128.12; 128.59; 136.09; 159.05; 160.73; 163.22; 180.14 ppm. TLC (silica gel-60, F-254): Rf = 0.28, 8% memanol/dichloromemane. Melting Point: 205.4-206°C Infrared (v max, mineral oil): 2925, 1647, 1600, 1564, 1512, 1406, 1252, 1230, 1119 cm-1. Ultraviolet (v max, ethanol); 227, 256, 286, 299, 322 nm. Mass Spectrum: Calculated for C22H21NO4: 363.1469, Found: 363.1470. Analysis: Calculated for C22H21NO4: C,72.71; H,5.82; N,3.85. Found: C,72.53; H,5.99; N.3.90. Following die general procedure of Example 4, but starting with die appropriate benzaldehyde, the following products can be prepared: 2-(4-moφholinyl)-6-(3-φhenylmethoxy)phenyl)-4H-pyran-4-one (Compound 15), mp 170.5-171.5°C; 2-(3-hydroxyphenyl)-6-(4-moφholinyl)-4H-pyran-4-one (Compound 16), mp 255.5-256°C EXAMPLE 5: 2-(4-Hydroxyphenyl -6-f4-moφholinyl ' )-4H-pyran-4-one (Compound 1). 2-Mθφholinyl-6-(4-benzyloxyphenyl)-4-pyrone (2.6 g, 7.15 mmole), which was prepared as in Example 4, was suspended in 50 ml metiianol in a 100 ml one neck round bottom flask under nitrogen. The suspension was treated successively widi 10% palladium on carbon (910 mg) and cyclohexene (3.9 ml, 38.5 mmole). The reaction mixture was heated at 60°C for 1.5 hours and was filtered hot dirough a celite plug. The celite filter cake was washed well widi 250 ml hot methanol. The filtrate was concntrated in vacuo to a crude solid. The solid was recrystallized from medianol to afford 1.6 g (82%) of Compound 1 as a white crystalline solid. H-NMR (d6DMSO): d 3.38(m,4H,CH2); 3.71(m,4H,CH2); 5.36(d,J=2Hz,lH,CH); 6.43(d,J=2Hz, 1H); 6.86(d,2H,ArH); 7.69(d,2H,ArH); 10.17(bs, lH,OH) ppm. C-NMR (dόDMSO): d 46.14; 67.03; 90.94; 108.24; 117.55; 123.26; 128.91; 160.29; 161.71; 164.55; 180.29 ppm. TLC (silica gel-60, F-254): Rf = 0.26, 10% methanol/dichloro- methane. Melting Point: >250°C Infrared (v max, mineral oil): 2925, 2537, 1647, 1612, 1564, 1511, 1447, 1425, 1246, 1174, 1120 cm-1. Ultraviolet (v max, ethanol): 227, 257, 286, 298, 325 nm. Mass Spectrum: Calculated for C15H15NO4: 273.1001, Found: 273.1000. EXAMPLE 6: 2-(4-(3.3-Dimethyl-2-oxobutoxy phenyn-6-f4-morphoIinyn-4H-pyran-4-one (Compound 4). 2-Mθφholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273mg, 1.0 mmole) was suspended in 7 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated successively widi potassium carbonate (829 mg, 6.0 mmole) and 1- bromo-3,3,3-trimedιylacetone (336 ul, 2.5 mmole). The reaction mixture was heated at 60°C for 6 hours and was cooled to room temperature. The acetonitrile was removed in vacuo and die residue was washed widi 1 X 25 ml dichloromemane. The insoluble material was removed by filtration and die filtrate was concentrated in vacuo to a red oil. The oil was chromatographed over 18 g silica gel (230-400 mesh) eluting with 3% medianol/dichloromediane and collecting 5 ml fractions. Fractions 28-42 were combined and concentrated to afford 144 mg of a puφle solid. The solid was recrystallized from ethyl acetate to provide 125 mg (33%) of Compound 4 as a puφle solid. H-NMR (CDC13,TMS): d 1.47(s,9H,CH3); 3.42(m,4H,CH2); 3.84(m,4H,CH2); 4.96(s,2H,CH2); 5.42(d,J=2Hz,lH,CH); 6.44(d,J=2Hz,lH,CH); 6.92(d,2H,ArH); 7.59(d,2H,ArH) ppm. C-NMR (CDC13): d 26.21; 43.06; 44.75; 65.78; 90.32; 114.95; 124.41; 126.93; 158.87; 160.01; 163.21; 180.06; 208.72 ppm. TLC (silica gel-60, F-254): Rf = 0.53, 10% methanol/dichloromethane. Melting Point: 181-182.5°C. Infrared (v max, mineral oil): 2925, 1720, 1644, 1605, 1566, 1508, 1408, 1234, 829 cm-1. Ultraviolet (v max, etiianol): 226, 256, 286, 298, 321 nm. Mass Spectrum: Calculated for C21H25NO5: 371.1733, Found: 371.1734 Analysis: Calculated for C21H25NO5: C.67.91; H,6.78; N,3.77. Found: C,67.57; H,6.91; N,3.84. EXAMPLE 7: 2-(4-Mθφholinyl)-6-(4-( ' 3-pyridinylmemoxy ' )phenyl)-4H-pyran-4-one (Compound 5). 2-Moφholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 6 ml dimemylformamide in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated widi sodium hydride suspension (192 mg, 4.0 mmole) and die reaction mixture was warmed to 60°C for 40 minutes. The reaction was treated widi 3-picolyl chloride hydrochloride (492 mg, 3.0 mmole) and die mixture was stirred 2 hours at 6CPC. The reaction was poured into 50 ml 2N sodium hydroxide/ice and the mixture was extracted widi 4 X 20 ml dichloromethane. The combined organics were washed widi 4 X 25 ml 50% saturated sodium chloride and were dried over magnesium chloride. The dried organics were concentrated in vacuo to a yellow solid. The crude material was recrystallized twice from ethyl acetate to provide 229 mg (62%) of Compound 5 as a golden crystalline solid. H-NMR (CDC13,TMS): d 3.42(m,4H,CH2); 3.85(m,4H,CH2); 5.15(s,2H,ArCH2); 5.43(d,J=2Hz,lH,CH); 6.45(d,J=2Hz,lH,CH); 7.04(d,2H,ArH); 7.29-7.36(m,lH,ArH); 7.61(d,2H,ArH); 7.78(m,lH,ArH); 8.61(m,lH,ArH); 8.71(m,lH,ArH) ppm. NMR (CDC13): d 44.88; 65.90; 67.70; 90.44; 108.34; 115.29; 123.60; 124.43; 127.13; 131.80; 135.29; 148.99; 149.72; 158.99; 160.39; 163.35; 180.19 ppm. TLC (silica gel-60, F-254): Rf = 0.34, 10% methanol/dichloromethane. Melting Point: 207.5-209.5°C Infrared (v max, mineral oil): 2925, 1647, 1597, 1561, 1509, 1408, 1254, 1236, 1176, 1014 cm-1. Ultraviolet (v max, ethanol): 226, 256, 286, 298, 321 nm. Mass Spectrum: Calculated for C21H20N2O4: 364.1423, Found: 364.1428 Analysis: Calculated for C21H20N2O4: C.69.22; H,5.53; N.7.69, Found: C,68.84; H,5.68; N,7.67. EXAMPLE 8: 2-('4-Moφholinyπ-6-f4-(2-pyridinylmemoxy')phenyl')* H-pyran-4-one (Compound 6). 2-Mθφholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 6 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated with sodium hydride suspension (192 mg, 4.0 mmole) and die reaction mixture was warmed to 55°C for 40 minutes. The reaction was treated widi 2-picolyl chloride hydrochloride (492 mg, 3.0 mmole) and die mixture was stirred 4hours at 55°C The reaction was poured into 50 ml 2N sodium hydroxide/ice and the precipitated solid was collected, washed widi water and diediyl edier and was dried (188 mg). The crude material was recrystallized from ethyl acetate to give 123mg (34%) of Compound 6 as an off-white solid. H-NMR (CDC13.TMS): d 3.42(m,4H,CH2); 3.84(m,4H,CH2); 5.26(s,2H,ArCH2); 5.42(d,J=2Hz,lH,CH); 6.45(d,J=2Hz,lH,CH); 7.06(d,2H,ArH); 7.24-7.28(m,lH,ArH); 7.50(d,lH,ArH); 7.60(d,2H,ArH); 7.74(m,lH,ArH); 8.62(m,lH,ArH) ppm. C-NMR (CDC13): d 44.76; 65.78; 70.69; 90.34; 108.16; 115.23; 121.25; 122.78; 124.11; 126.95; 136.81; 149.26; 156.29; 158.95; 160.36; 163.22; 180.09 ppm. TLC (silica gel-60, F-254): Rf = 0.34, 10% methanol/dichloromethane. Melting Point: 200-201°C Infrared (v max, mineral oil): 2925, 1649, 1598, 1563, 1513, 1407, 1261, 1248, 1222, 1191, 1117 cm-1. Ultraviolet (v max, ethanol): 226, 256, 280, 286, 298, 321 nm. Mass Spectrum: Calculated for C21H20N2O4: 364.1423; Found: 364.1429. EXAMPLE 9: 2-f4-Morpholinvn-6-ff4-f2-n-piperidinvnethvnoxy')Dhenvn-4H-pyran-4-one (Compound 7). 2-Moφholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 8 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated successively with potassium carbonate (829 mg, 6.0 mmole) and N- chloroediyl-piperidine (466 ul, 3.0 mmole) and the reaction mixture was warmed at 70°C for 5 hours. The acetonitrile was removed in vacuo and die residue was washed widi 1 X 25 ml dichloromethane. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to an amber oil. The oil was crystallized from diediyl ether and was recrystallized twice from ethyl acetate to provide 147mg (38%) of Compound 7. H-NMR (CDC13.TMS): d 1.38-1.67(m,6H,CH2); 2.31-2.58(m,4H,CH2); 2.79(t,J=6Hz,2H,CH2); 3.42(m,4H,CH2); 3.85(m,4H,CH2); 4.15(t,J=6Hz,2H,CH2); 5.42(d,J=2Hz,lH,CH); 6.45(d,J=2Hz,lH,CH); 6.98(d,2H,ArH); 7.60(d,2H,ArH) ppm. C-NMR (CDC13): d 24.01; 25.79; 44.76; 54.97; 57.62; 65.78; 66.14; 90.29; 107.95; 114.92; 123.59; 126.84; 159.13; 160.89; 163.22; 180.15 ppm. TLC (silica gel-60, F-254): Rf = 0.27, 10% medianol/dichloromediane. Melting Point: 141.5-142.0°C Infrared (v max, mineral oil): 2925, 1654, 1606, 1568, 1511, 1407, 1366, 1253, 1235, 1193, 1121 cm-1. Ultraviolet (v max, ethanol): 226, 256, 286, 299, 322 nm. Mass Spectrum: Calculated for C22H28N2O4: 384.2049; Found: 384.2041. EXAMPLE 10: 2-(4-Mθφho1invD--6-(4-(2-quinolinylmethoxy ' )phenyl ' )-4H-pyran-4-one (Compound 8). 2-MoφholinyI-6-(4-hydoxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 8 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated successively widi potassium carbonate (829 mg, 6.0 mmole) and 2- chloromethyl-quinoline (533 mg, 3.0 mmole). The reaction mixture was stirred at 70°C overnight. The acetonitrile was removed in vacuo and die residue was washed widi 1 X 25 ml dichloromemane. The insoluble material was removed by filtration and die filtrate was concentrated in vacuo to a yellow solid. The crude material was washed widi diediyl edier and was recrystallized from ethyl acetate to give 377 mg (91%) of Compound 8 as an orange solid. H-NMR (CDC13 MS): d 3.40(m,4H,CH2); 3.82(m,4H,CH2); 5.44(s,2H,ArCH2); 5.45(d,J=2Hz,lH,CH); 6.45(d,J=2Hz,lH,CH); 7.09(d,2H,ArH); 7.55-7.66(m,4H,ArH); 7.76(m,lH,ArH); 7.74(d,lH,ArH); 8.10(d,lH,ArH); 8.21(d,lH,ArH) ppm. C-NMR (CDC13): d44.75; 65.77; 71.30; 90.27; 108.02; 115.33; 118.89; 124.11; 126.66; 126.99; 127.50; 127.63; 128.75; 129.89; 137.16; 147.36; 156.87; 158.98; 160.40; 163.20; 179.99 ppm. TLC (silica gel-60, F-254): Rf = 0.47, 10% methanol/dichloromethane. Melting Point: 222.5-223.5°C Infrared (v max, mineral oil): 2924, 1643, 1602, 1561, 1507, 1454, 1249, 1178, 1118, 831 cm-1. Ultraviolet (v max, ethanol): 205, 228, 256, 285, 295, 303, 309, 317, 326 nm. Mass Spectrum: Calculated for C25H22N204: 414.1579; Found: 414.1588. EXAMPLE 11: 2-f4-Morphol inyl)-6-(2-(phenylmethoxy phenvI)-4H-pyran-4-one (Compound 9). 2-Bromophenol (6.7 ml, 57.8 mmole) was dissolved in 200 ml acetonitrile in a 500 ml one neck round bottom flask under nitrogen. The solution was treated successively potassium carbonate (32 g, 231 mmole) and benzyl bromide (6.9 ml, 57.8 mmole). The reaction mixture was stirred for 6 hours at room temperature. The insoluble salts were removed by filtration and die filtrate was concentrated in vacuo to a pale oil. The oil was taken up in 100 ml diediyl edier and the mixture was washed successively wid 2 X 25 ml IN sodium hydroxide and 1 X 25 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were concentrated in vacuo to give 14.8 g (97%) of 2-benzyloxy-bromobeπzene as a pale oil. 2-Benzyloxy-bromobenzene (5 g, 19 mmole) and trimethylsilyl-acetylene (3.4 ml, 24 mmole) were combined in 50 ml degassed triediylamine in a 100 ml one neck round bottom flask under nitrogen. The solution was treated successively with bis ( riphenylphosphine) palladium dichloride (533 mg, 0.76 mmole) and cuprous iodide (72 mg, 0.38 mmole) and die reaction was heated to 80°C for 3 hours. The mixture was cooled to room temperature and die volatiles were removed in vacuo. The black residue was washed widi diethyl ether and die insoluble material was removed by filtration. The filtrate was concentrated in vacuo to a dark brown oil. The oil was dissolved in 30 ml methanol in a 100 ml one neck round bottom flask under nitrogen. The solution was treated with 1 X 10 ml 2N sodium hydroxide and die reaction mixture was stirred 1 hour at room temperature. The reaction was treated widi DARCO and was filtered tiirough celite. The filtrate was concentrated in vacuo to an aqueous residue. The residue was extracted widi 3 X 20 ml diediyl ether and die combined organics were dried over magnesium sulfate. The organics were concentrated in vacuo to provide a crude yellow oil (3.32g). The oil was chromatographed over 120 g silica gel (230-400 mesh) eluting with 1% ediyl acetate/ hexane and collecting 16 ml fractions. Fractions 80-86 were combined and concentrated to afford 786 mg (20%) of 2-benzyloxyphenyl acetylene as a yellow oil. 2-Benzyloxyphenyl acetylene (760 mg, 3.65 mmole) was dissolved in 12 ml dry tetrahydrofuran in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to -78°C and was treated slowly dropwise widi butyllidiium (2.3 ml, 3.65 mmole). The reaction mixture was stirred 30 minutes at -78°C, was warmed to 0°C for 30 minutes, and was recooled to -78°C The reaction was treated with methyl chloroformate (0.50 ml, 6.47 mmole) and the mixture was warmed to 0°C for 30 minutes. The reaction was diluted widi 50 ml diediyl edier and was quenched widi 1 X 20 ml 1:1 saturated ammonium chloride/saturated sodium chloride. The layers were separated and the aqueous layer was washed widi 2 X 20 ml diethyl edier. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a crude yellow oil. The oil was chromatographed over 42 g silica gel (230-400 mesh) eluitng widi 8% ethyl acetate/hexane and collecting 9 ml fractions. Fractions 30*48 were combined and concentrated to afford 620 mg (62%) of mefhyl-(2-benzyloxyphenyl)-propioplate as a yellow oil. Acetyl moφholine (546 ul, 4.72 mmole) was dissolved in 10 ml dry tetrahydrofuran in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0^C and was treated slowly dropwise widi lidiium diisopropylamide (3.2 ml, 4.72 mmole). The mixture was stirred 30 minutes at 0°C and was treated widi methyl-2-benzyloxyphenyl propiolate (600 mg, 2.25 mmole) in 2 ml dry tetrahydrofuran. The reaction mixture was stirred for 1 hour at 0°C and was diluted widi 10ml water. The volatiles were removed in vacuo and die residue was crystallized from diediyl ether/metiianol (20:1). The tan solid was collected, was washed widi dieώyl ether, and was dried to afford 500 mg (61 %) of moφholine-5-(2-Benzyloxyphenyl)-3-oxo-pent-4-ynamide as a tan solid. Melting Point: 224-227°C Acetylenic ketoamide, just prepared above, (480 mg, 1.32 mmole) was dissolved in 5 ml trifluoroacetic acid in a 25 ml one neck round bottom flask under nitrogen. The reaction mixture was stirred 2 hours at room temperature and was poured into 50 ml 2N sodium hydroxide. The mixture was extracted wi i 4 X 25 ml dichloromethane and the combined organics were dried over magnesium sulfate. The organics were concentrated in vacuo to a dark yellow oil. The oil was chromatographed over 18 g silica gel (230-400 mesh) eluting widi 3% medianol/dichloromediane and collecting 4 ml fractions. Fractions 21-32 were combined and concentrated to afford 227mg (47%) of Compound 9 as a yellow solid. H-NMR (CDC13,TMS): d 3.30(m,4H,CH2); 3.69(m,4H,CH2); 5.17(s,2H,ArCH2) 5.55(d,J=2Hz,lH,CH); 6.71(d,J=2Hz,lH,CH); 7.06(m,2H,ArH); 7.30-7.44(m,6H,ArH) 7.53(m,lH,ArH) ppm. C-NMR (CDC13): d 44.64; 65.72; 70.51; 90.04; 113.20; 113.53; 120.97 127.08; 128.14; 128.62; 129.06; 131.87; 135.99; 156.39; 157.79; 163.46; 180.01 ppm. TLC (silica gel-60, F-254): Rf = 0.47, 10% methanol/dichloromethane. Melting Point: 112.5-113°C Infrared (v max, mineral oil): 2923, 1643, 1600, 1561, 1454, 1411, 1244, 1119 cm-1. Ultraviolet (v max, ethanol): 210, 245, 270, 281, 309 nm. Mass Spectrum: Calculated for C22H21NO4: 363.1470; Found: 363.1466 Analysis: Calculated for C22H21NO4: C,72.71; H,5.82; N,3.85; Found: C,72.78; H,6.01; N,4.08. Following die general procedure for Example 11, but starting with die appropriate bromobenzene, there are prepared die following products: 2-(4-0ιydroxymedιyl)phenyl)-6-(4-moφholinyl)-4H-pyran-4-one (Compound 17), mp 258- 259.5°C; 2-(4-moφholinyl)-6-(4-(l-piperidinylmethyl)phenyl)-4H-pyran-4-one (Compound 18), mp 194-195.5°C; 2-(4-moφholinyl)-6-(4-(l-pyrrolidinylmedιyl)phenyl)-4H-pyran-4-one(Compound l9),mp 168-169.5°C; 2-(4-((4-methyl-l-piperazinyl)methyl)phenyl)-6-(4-morpholinyl)-4H-pyran-4-one (Compound 20), mp 161.5-163°C; 2-(4-((2-(hydroxymethyl)-l-piperidinyl)medιyl)phenyl)-6-(4-moφholinyl)-4H-pyran-4-one (Compound 21), mp 160.5-161.5°C. EXAMPLE 12: 2-(2-Hydroxyphenyl')-6-(4-moφholinyn-4H-pyran-4-one (Compound 10). 6-((2-Benzyloxy)-phenyl)-2-moφholinyl-4-pyrone (lOOmg, 0.275 mmole) was dissolved in 5 ml methanol in a 10 ml one neck round bottom flask under nitrogen. The solution was treated widi 10% palladium on carbon (100 mg) and cyclohexene (1 ml, 15 mmole) and die reaction mixture was heated to reflux for 30 minutes. The reaction was filtered hot dirough celite and die filter cake was washed well widi fresh hot medianol. The filtrate was concentrated in vacuo to a yellowish crude solid. The solid was recrystallized from methanol to afford 34 mg (45%) of Compound 10 as a white crystalline solid. H-NMR (d6DMSO): d 3.36(m,4H,CH2); 3.68(m,4H,CH2); 5.36(d,J=2Hz,lH,CH); 6.66(d,J=2Hz,lH,CH); 6.88-6.98(m,2H,ArH); 7.26-7.3 l(t,lH,ArH); 7.60(d,lH,ArH); 10.5(bs,lH,OH) ppm. C-NMR (dόDMSO): d 46.11; 67.03; 90.91; 114.47; 118.56; 119.33; 121.09; 129.55; 133.32; 157.59; 157.78; 164.74; 180.32 ppm. TLC (silica gel-60, F-254): Rf = 0.33, 10% memanol/dichloromediane. Melting Point: > 250°C Infrared (v max, mineral oil): 2925, 2855, 1638, 1567, 1544, 1445, 1400, 1234, 1126, 763 cm-1. Mass Spectrum: Calculated for C15H15NO4: 273.1001; Found: 273.0999 Analysis: Calculated for C15H15NO4: C,65.92; H,5.53; N,5.12; Found: C,65.93; H,5.60; N,5.39. EXAMPLE 13: 2-(4-Mθφholinyl -6-(4-((l-phenylpentyDoxy phenyl **4H-pyran-4-one (Compound 11). Dibromo-olefin from Example 4 (20 g, 54 mmole) was dissolved in 250 ml dry tetrahydrofuran in an oven dried 500 ml three neck round bottom flask under nitrogen. The solution was cooled to -78°C and was treated dropwise widi butyllitiiium (80 ml, 128 mmole). The reaction was stirred 40 minutes at -78°C and was warmed to 0°C for 1 hour. The reaction was recooled to -78°C and was treated widi me yl chloroformate (4.95 ml, 64 mmole). The reaction mixture was stirred overnight as die cooling bath expired. The mixture was quenched widi 1 X 50 ml 1 : 1 saturated ammonium chloride/saturated sodium bicarbonate. The terahydrofuran/hexane was removed in vacuo and die residue was extracted with 4 X 50 ml ethyl acetate. The combine organics were dried over magnesium sulfate and were concentrated in vacuo to a reddish oil. The oil was chromatographed over 600 g silica gel (230-400 mesh) eluting widi 10% ethyl acetate/hexane and after a 2000 ml forerun collecting 75 ml fractions. Fractions 1-12 were combined and concentrated to afford 6.4 g (37%) of butylated benzyloxyphenyl propiolate methyl- (4-αbutylbenzyloxy)-phenylpropiolate as a white solid. Fractions 15-38 were combined and concentrated to provide 4.5 g (35%) of 4-benzyloxyphenyl propiolate as a white solid. Melting Point: 45-47.5°C Acetyl moφholine (2.43ml, 21 mmole) was dissolved in 30 ml dry tetrahydrofuran in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution was cooled to 0°C and was treated slowly dropwise widi lidiium diisopropylamide (14 ml, 21 mmole). The reaction was stirred 30 min at 0 C and was treated widi phenyl propiolate, prepared above, (3.22 g, 10 mmole) in one lot. The reaction mixture was stirred 1 hour at 0°C The mixture was diluted widi 50 ml water and the organic volatiles were removed in vacuo, The precipitated solid was collected and was washed successively widi water and diediyl edier. The solid was dried in vacuo overnight at 40°C to provide 3.3g (79%) of moφholine-5-((4-α-Butylbenzyloxy)-phenyl)-3-oxo-pent-4- ynamide as a yellow solid. Melting Point: 271-273°C The acetylenic ketoamide, prepared above, (1.23 g, 3.0 mmole) was dissolved in 18 ml 15% trifluoroacetic acid/dichlorome ane in a 50 ml one neck round bottom flask under nitrogen. The solution was stirred 15 minutes at room temperature and die reaction mixture was poured into saturated sodium bicarbonate. The mixture was extracted widi 3 X 25 ml dichloromethane. The combined organics were dried over magnesium sulfate and were concnetrated in vacuo to a yellow paste. The aqueous layer was filtered to collect die precipitated product which was washed widi water and diediyl edier and was recrystallized from methanol to afford 451 mg (55%) of the phenol. The yellow paste was chromatographed over 18 g silica gel (230-400 mesh) eluting widi 4% medianol/dichloromediane and collecting 5 ml fractions. Fractions 21-26 were combined and concentrated to provide 41 mg (3%) of Compound 11 as a yellow solid. H-NMR (CDC13,TMS): d0.90(t,3H,CH3); 1.29-1.57(m,4H,CH2); 1.79-1.89(m,lH,CH); 1.97-2.09(m,lH,CH); 3.46(m,4H,CH2); 3.82(m,4H,CH2); 5.13(dd,lH,ArCH); 5.74(bs,lH,CH); 6.53(d,lH,CH); 6.92(d,2H,ArH); 7.24-7.39(m,5H,ArH); 7.50(d,2H,ArH) ppm. C-NMR (CDC13): d 13.98; 22.49; 27.83; 38.35; 45.04; 65.80; 80.77; 89.05; 105.03; 116.50; 122.34; 125.86; 127.28; 127.78; 128.72; 141.28; 160.72; 161.30; 163.42; 178.47 ppm. TLC (silica gel-60, F-254): Rf = 0.39, 10% methanol/dichloromethane. Melting Point: 185-186°C Infrared (v max, mineral oil): 2925, 1646, 1605, 1563, 1507, 1452, 1417, 1254, 1178, 1118, 830 cm-1. Ultraviolet (v max, ethanol): 228, 257, 288, 300, 322 nm. Mass Spectrum: Calculated for C26H29NO4: 419.2096; Found: 419.2103. Analysis: Calculated for C26H29NO4: C.74.44; H,6.97; N.3.34; Found: C.74.56; H,7.22; N,3.70. EXAMPLE 14: 2-(4-hydroxyphenvn-6-(4-moφholinylmedιyl)-4H-pyran-4-one (Compound 14). Phenylacetylmethyl sulfoxide (5.65g, 31 mmol) was dissolved in 60ml THF in a flame dried 3-neck flask under nitrogen. The solution was cooled to -78°C and treated dropwise widi lidiium diisopropylamide (41 ml, 62 mmol, 1.5 M in THF/heptane). The mixture was stirred 20 minutes at -78°C, followed by 30 minutes at 0°C and recooled to -78°C Mediyl 4-benzyloxyphenyl propiolate (3.5g, 15.5 mmol) was added and d e reaction was stirred at -78°C for 30 minutes and then at 0°C for 30 minutes. The mixture was quenched widi 50 ml water and the THF was removed in vacuo. The orange precipitate was collected and washed widi water and ether. The solid was dried overnight in vacuo to give 4.77g (74%) of die diketone, mp. >300°C The diketone (4.77g, 11.45 mmol) was dissolved in 230 ml of methanol and stirred at room temperature for 28 hours. The methanol was removed in vacuo and die solid residue was dissolved in mediylene chloride and filtered dirough a plug of celite. The filtrate was concentrated in vacuo to a tan solid. The solid was chromatographed over 200g of silica gel, eluting widi 4% methanol/methylene chloride and collecting 60ml fractions. Fractions 14-25 were combined and concentrated to afford 2.99g (63%) of die pyrone sulfoxide as a tan solid, mp. 155-156°C The pyrone sulfoxide (840mg, 2 mmol) was suspended in 6ml of acetic anhydride under nitrogen. The mixture was heated to 105°C for 4 hours, poured into 10ml water and shaken vigorously. The mixture was diluted widi 10ml of saturated NaCl and extracted 4x20ml methylene chloride. The combined organics were dried over magnesium sulfate and concentrated to a dark oil. The oil was chromatographed over 32g of silica gel eluting widi 55% etiiyl acetateMiexane to afford 769mg of a dark oil. Crystallization from ether afforded 679mg (74%) of the acetoxysulfide pyrone as a tan solid, mp. 117-119°C The acetoxysulfide pyrone (1.12g, 2.44 mmol) was suspended in 20ml methanol under nitrogen. The mixture was cooled to 0°C, treated widi 450mg of sodium borohydride, and warmed to room temperature. The addition of sodium borohydride was repeated tiiree times and die mixture was concentrated to dryness. The residue was diluted with 50ml of 10% HC1 and die insoluble material was collected, washed widi water and edier and dried in vacuo at 40°C to provide 688mg (91%) of die pyrone alcohol, mp. 166-167°C The pyrone alcohol (173mg (0.56 mmol) was suspended in 5ml of chloroform under nitrogen. The mixture was cooled to 0°C and treated wid triethylamine (0.117ml, 0.84 mmol), tosyl chloride (160mg, 0.84 mmol) and dimemylaminopyridine 7mg, 0.06 mmol). The reaction was warmed to room temperature and stirred 2h. The mixture was diluted wid 20ml of metiiylene chloride and washed widi 10ml saturated sodium bicarbonate, 10ml 5% HC1, and 10ml of saturated NaCl. The organics were dried over magnesium sulfate and concentrated to a green oil. The oil was crystallized from 1:1 ether/hexane to provide 188mg of a mixture of the pyrone tosylate and pyrone chloride as a green solid. The mixture of the pyrone tosylate and pyrone chloride (188mg) was dissolved in 2ml moφholine under nitrogen. The mixture was stirred 1 hour at room temperature and die moφholine was removed in vacuo at 40°C The residue was washed widi 10ml IN NaOH and die insoluble material was collected. The solid was washed widi water and edier to give 150mg. The crude material was recrystallized from ethylacetate to give 145mg (71%) Compound 14 as amber flakes, mp. 162.5-163.5°C Following the general procedure for example 15, mere are prepared die following products: 2-(4-moφholinyl)-6-(3-(phenylmethoxy)phenyl)-4H-pyran-4-one(Compound 15, mp 170.5- 171.5°C; 2-(3-hydroxyphenyl)-6-(4-moφholinyl)-4H-pyran-4-one (Compound 16), mp255.5-256°C EXAMPLE 15 2-(4-Fluorophenyl')-6-(4-moφholinyn-4H-pyran-4-one (Compound 22). Compound 22 was prepared according to Scheme 2 where the phenylmemoxy group was substituted widi a fluoride. Melting Point 214-215°C. EXAMPLE 16 2-(4-Moφholinvn-6-4-(l-pyrrolidinyl phenyl-4H-pyran-4-one (Compound 23). Compound 23 was prepared as in Example 15 where the fluorine was then replaced widi a pyrrolidine by direct substitution. Melting Point 279°C EXAMPLE 17 2-(4-Moφholinyl')-6-4-(l-piperidinyl')phenyl-4H-pyran-4-one (Compound 24). Compound 24 was prepared as in Example 15 with the fluorine being replaced widi a piperidine by direct substitution. Melting Point 260-262 °C EXAMPLE 18 2-(4-Aminophenyl)-6-(4-moφhoIinyl)-4H-pyran-4-one (Compound 25). The subject compound was prepared following Scheme IV as follows. A solution of acetylacetylmoφholine (3.42 g, 20 mmol) in 20 ml of tetrahydrofuran was treated widi sodium hydride (0.8 g, 20 mmol, 60% in oil) and stirred at room temperature for 30 minutes. The mixture was cooled to 0°C, treated widi n-butyl lithium in hexane (12.9 ml, 20 mmol, 1.6M) and stirred for 30 minutes. The mixture was treated widi 1.51 g (10 mmol) of metiiyl 4- aminobenzoate, stirred 1 hour at 0°C and 1 hour at room temperature. The mixture was quenched widi 3.1ml of trifluoroacetic acid and die volatiles were removed in vacuo. The residue was chromatographed over 150g of silica gel, eluting with 4% methanol/ methylene chloride to afford 0.80 g (28%) of die intermediate tricarbonyl compound, mp = 167-168°C The tricarbonyl compound (0.94 g, 3.26 mmol) was dissolved in 6.5 ml of concentrated sulfuric acid and heated at 70°C for 40 min. The mixture was allowed to cool, added slowly to excess sodium bicarbonate in water. The insoluble material was collected, washed widi water and dried. The solid was recrystallized from e yl acetate/methanol to afford 0.64 g (72%) of the title compound, Melting Point: 257.5-259.5°C FORMULAS Syndwaia of 2-Ami_«>-6-Pb ny H-Pyτaa--4-onei Scheme* 3. H 2 0 IV 1. Nal 2. nBuLi

Claims: CLAIMS 1. A compound of Formula I or pharmaceutically acceptable salts diereof, wherein: X is hydrogen, 0-^5 alkyl, or a halogen atom; Y is selected from the group consisting of -(CH2) n NR9R 10 wherein R and RJ , are independently selected from the group consisting of (a) hydrogen; (b) -C- β alkyl; (c) phenyl optionally substituted widi one, 2 or 3 C j ^ alkyl, C1-C4 alkoxy, halo, OH, trifluoromemyl or -CO 2 (C 1 -C 4 alkyl); (d)-(CH2) q phenyl wherein phenyl is optionally substituted widi one, 2 or 3 C1-C4 alkyl, C-^ alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl); (e) -(CH2) n pyridinyl; or (f) wherein R and RJ Q , taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-moφholine optionally substituted widi one or two members selected from the group consisting of C j ^ alkyl, C j -C4 alkoxy, halo or trifluoromethyl (bb) 4- iomoφholine optionally substituted widi one or two members selected from the group consisting of C j -C 4 alkyl, C j -C 4 alkoxy, halo or trifluoromethyl (cc) 3-amino-l -pyrrol id ine, (dd) 1-pyrτolidine optionally substituted widi one or two members selected from the group consisting of C j ^ alkyl, Cy ^ alkoxy, halo, OH, -CH 2 OH, or trifluoromemyl (ee) 1-piperidine optionally substituted widi one or two members selected from the group consisting of C j -C 4 alkyl, C -C^ alkoxy, halo, trifluoromethyl, -(Q^qOH, -CO 2 H, -CO2CH3 -CO2CH2CH3 or phenyl (wherein phenyl is optionally sub¬ stituted widi one, 2 or 3 C j -C4 alkyl, C j -C 4 alkoxy, halo or trifluoromediyl), (ft) 1-piperazine, 4-methyl-l -piperazine, 4-(cycloC 3 -C 6 alkyl)- 1-piperazine, 4- phenyl- 1-piperazine (wherein phenyl is optionally substituted widi one, 2 or 3 C j - C 4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-l-piperazine optionally substituted widi one or two members selected from e group consisting of C!-C 4 alkyl, C-^ alkoxy, halo, OH, trifluoromethyl, -CH 2 OH, -CO 2 H, - CO 2 CH 3 or -CO 2 CH 2 CH 3 , and (gg) diiazolidine, dιiazolidine-4-carboxylic acid, pipecolinic acid, p-piperazinaceto- phenone, 1-piperazine, 1-medιylpiperazine, 4-phenyl-l,2-3,6-tetrahydropyridine, proline, tetrahydrofurylamine, l-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4- tetrahydroisoquinoline or imidazole; R j , R 2 , R3, R4 and R5 are independently selected from the group consisting of: hydrogen, -Cg alkyl, -(CH2) n phenyl (wherein phenyl is optionally substituted widi one, 2 or 3 C-rC4 alkyl, C j ^ alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -(CH2) n naphthyl, -(CH2) n pyridinyl, -(CH-^qNR^o, -CH=CH-phenyl (wherein phenyl is optionally substituted widi one, 2 or 3 γ- ^ alkyl, C^ alkoxy, halo, OH, trifluoromemyl or -CO 2 (C 1 -C 4 alkyl)), -CH2-CH = CH 2 , -CH=CH-CH 3 , -O-CH 2 -CH=CH 2 , -CβC-phenyl (wherein phenyl is optionally substituted widi one, 2 or 3 C-^^ alkyl, C^ alkoxy, halo, OH, trifluoromemyl or -CO 2 (C 1 -C 4 alkyl)), -OtCH-^pO^-metiiylpiperdin-S-yl), -O-CH 2 CH(0CH 3 ) 2 , -O-tCH-^pOR^ (wherein R 15 is selected from ^-C ζ alkyl, -(CH 2 ) n phenyl (phenyl optionally substituted widi one, 2 or 3 C j ^ alkyl, C 1 -C alkoxy, halo, OH, trifluoromethyl or -CO 2 (C r C 4 alkyl)), -(CH^pyridin-yl or -(CH^ppiperidin-1-yl), -(CH^OMCH^Rc,, -(CH^C^CKC^Ro, -(CH) n C(O)O-(CH 2 ) p NR 9 R 10 , -(CH 2 ) n C(O)(CH 2 ) n NR 9 R 10 , NO 2 , -O^CH^CCOHCH^Rg, -O-CCH^C^O-CCH^Rg, -O-(CH 2 ) n C(O)-(CH 2 ) n NR 9 R 10 , -NR9R 10 , -N(R 9 )(CH 2 ) n C(OHCH 2 ) II R 10 , -N^-tCH^C^O-^H^R jQ , N(R 9 )(CH 2 ) n C(O)-(CH 2 ) n r--JR 9 R 1 o, -OCH(nBu)phenyl, -O-(CH2) n phenyl (wherein phenyl is optionally substituted widi one, 2 or 3 C C 4 alkyl, C r C 4 alkoxy, halo, OH, trifluoromemyl or -CO 2 (C 1 -C 4 alkyl)), -O-(CH 2 ) n pyridine, -O(CH 2 ) n C(O)-(CH 2 ) n pyridine, -©-(CH^C^O-tCH^pyridine, -O(CH 2 ) n C(O)-N(R 9 )(CH 2 ) n pyridine, -O-(CH2) n quinoxal inyl , -O-(CH2) n pyrazinyl, -O-(CH2) n naphthyl, -O-(CH 2 ) n C(O)O-(CH 2 ) n naphthyl, -O-tCH^C^NR^CH^naphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH^-OH, (CH^OCCORg, -(l-cyclohexyl-lH-tetrazol-5-yl)C r C 4 alkoxy, -(l^Ci-CsalkylJ-lH-tetrazol-S-y Ci^ alkoxy, -(l-(phenyl)-lH-tetrazol-5-yI) 0^4 alkoxy (wherein phenyl is optionally substituted with one, 2 or 3 C C alkyl, C j ^ alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -(l-(pyridinyl)-lH-tetrazol-5-yl)C r C 4 alkoxy, -(l-(l-phenylethyl)- lH-tetrazol-5-yl)C r C 4 alkoxy, -C j -C 4 alkoxyl; n is 0-5; p is 2-5; and q is 1-5. 2. The compound of Claim 1 wherein X is hydrogen. 3. The compound of Claim 1 wherein Y is (CH^^-moφholine where n is 0 or 1. 4. The compound of Claim 3 wherein R lt R 2 , R and R 5 are hydrogen. 5. The compound of Claim 1 which is a) 2-(4-hydroxyphenyl)-6-(4-moφhol inyl)-4H-pyran-4-one; b) 2-(4-moφholinyl)-6-(4-(phenylmemoxy)phenyl)-4H-pyran-4-one; c) 2-(4-moφholinyl)-6-phenyl-4H-pyran-4- ne; d) 2-(4-(3,3-dimethyl-2-oxobutoxy)phenyl)-6-(4-moφholinyl)-4H-pyran-4-one; e) 2-(4-moφholinyl)-6-(4-(3-pyridinylmedιoxy)phenyl)* H-pyran-4-one; f) 2-(4-Mθφholinyl)-6-(4-(2-pyridinylmemoxy)phenyl)-4H-pyran-4-one; g) 2-(4-Mθφholinyl)-€-((4-(2-(l-piperidinyl)ethyl)oxy)phenyl)-4H-pyran-4-one; h) 2-(4-Mθφholinyl)-6-(4-(2-quinolinylmemoxy)phenyl)-4H-pyran-4-one; i) 2-(4-Moφholinyl)-6-(2-(phenylmedιoxy)phenyl)-4H-pyran-4-one; j) 2-(2-Hydroxyphenyl)-6-(4-moφhol inyl)-4H-pyran-4-one; k) 2-(4-Moφholinyl)-6-(4-((l-phenylpentyl)oxy)phenyl)-4H-pyran-4-one; l) 2-(4-moφholinylmedιyl)-6-(4-(phenylmethoxy)phenyl)-4H-pyran-4-one; m) 2-(4-(phenylmethoxy)phenyl)-6-(l-piperidinylmethyl)-4H-pyran-4-one; n) 2-(4-hydroxyphenyl)-6-(4-moφholinylmemyl)-4H-pyran-4-one; o) 2-(4-moφhol inyl)-6-(3-(phenylmedιoxy)phenyl)-4H-pyran-4-one; p) 2-(3-hydroxyphenyl)-6-(4-moφholinyl)-4H-pyran-4-one; q) 2-(4-(hydroxymethyl)phenyl)-6-(4-moφholinyl)-4H-pyran* -one; r) 2-(4-moφholinyl)-6-(4-(l -piperidinylmedιyl)phenyl)-4H-pyran-4-one; s) 2-(4-moφholinyl)-6-(4-(l-pyrrolidinylmethyl)phenyl)-4H-pyran-4-one; t) 2-(4-((4-methyl-l-piperazinyl)memyl)phenyl)-6-(4-moφholinyl)-4H-pyran-4-one; u) 2-(4-((2-(hydroxymedιyl)- 1 -piperidinyl)memyl)phenyl)-6-(4-moφhol inyl)-4H-pyran-4- one; v) 2-(4-fluorophenyl)-6-(4-moφhol inyl)-4H-pyran-4-one; w) 2-(4-Moφholϊnyl)-6-4-(l-pyrrolidinyl)phenyl* H-pyran-4-one; x) 2-(4-Mθφholinyl)-6-4-(l-piperidinyl)phenyl-4H-pyran-4-one; or y) 2-(4-Aminophenyl)-6-(4-moφholinyl)-4H-pyran-4-one. 6. A compound of Formula II or pharmaceutically acceptable salts diereof, wherein: X is hydrogen, C1-C5 alkyl, or a halogen atom; R 1? R 2 , R 3 , R 4 and R5 are independently selected from die group consisting of: hydrogen, Ci-Cg alkyl, -(CH^phenyl (wherein phenyl is optionally substituted widi one, 2 or 3 C1-C4 alkyl, ^-€4 alkoxy, halo, OH, trifluoromethyl or -CO^C-^alk l)), -(CH^naphthyl, -(CH^NRpR^, -CH=CH-phenyl (wherein phenyl is optionally substituted wi one, 2 or 3 C j -C4 alkyl, C-^ alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -CH 2 -CH = CH 2 , -CH=CH-CH 3 , -O-CH 2 -CH=CH 2 , -CβC-phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C!-C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -O CH.pXN-methylpiperdin-S-yl), -O-CH 2 CH(0CH 3 )2, -O^CH-^pOR j s (wherein R 15 is selected from C^ alkyl, -(CH^henyl (phenyl optionally substituted widi one, 2 or 3 C C^ alkyl, C j -C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)), -(CH-^CCOHCH^Rg, -(CH^C^O-^H^Rg, -(CH^C OXCH^NR^o, NO 2 , -CKCH 2 ) B C(OHCH 2 ) Il R9, -O-(CH 2 ) n C(O)-(CH 2 ) n NR 9 R 10 , -NR9R 10 , -N(R 9 )(CH 2 ) n C(OHCH 2 ) n R 1 o, N(R 9 )(CH 2 ) I1 C(OHCH 2 ) ll NR 9 R 1 o, -OCH(nBu)phenyl, -O-ζCH^nphenyl (wherein phenyl is optionally substituted widi one, 2 or 3 C-^- i -©-(CH^quinoxalinyl, -O-(CH2) n quinolinyl, -©-(CH-^ jj pyrazinyl, -O-(CH2) n naphthyl, halo (fluoro, chloro, bromo, iodo), -OH, -(CH 2 ) q -OH, -(l-cyclohexyl-lH-tetrazol-S-y Cj-C.^ alkoxy, -(H - salkylHH-tetrazol-S-y -^ alkoxy, -(l-(phenyl)-lH-tetrazol-5-yl) C j ^ alkoxy (wherein phenyl is optionally substituted widi one, 2 or 3 γ-C 4 alkyl, C j -C alkoxy, halo, OH, trifluoromediyl or -CO 2 (C 1 -C 4 alkyl)), -(l-φyridiny -lH-tetrazol-S-y Ci-C,^ alkoxy, -(l^l-phenylethy -lH-tetrazol-S-y^C j ^ alkoxy, - 1-C4 alkoxyl; n is 0-5; p is 2-5; and q is 1-5. 7. The compound of Claim 6 wherein X is hydrogen. 8. The use of a compound of Claim 1 for die manufacture of a medicament for inhibiting cell proliferation in the treatment of proliferative diseases.

Inventors: MORRIS JOEL, MORRIS, JOEL
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P7, A61P9, C07D309, C07D405