CYCLIC LACTAMS FOR CHOLESTEROL AND ATHEROSCLEROSIS CONTROL

Abstract: Cyclic lactams of formula (I), where R is hydrogen or C1 to C6-alkyl; X is oxygen or bivalent sulfur; Y is hydrogen or C1 to C6-alkyl; or -XY taken together represents hydrogen or C1 to C6-alkyl; or -XY is part of a double bond between the 5- and 6-position carbon atoms of the ring when R2 is also part of that double bond; R1 is hydrogen or C1 to C6-alkyl; R2 is part of the double bond between the 5- and 6-position lactam ring carbon atoms when -XY is also part of that same double bond and R3 is hydrogen, C1 to C6-alkyl or phenyl, or R2 and R3 are independently selected from the group consisting of hydrogen, C1 to C6-alkyl or phenyl; R4 and R5 are independently selected from the group consisting of hydrogen, C1 to C6-alkyl or phenyl, and when one of R4 and R5 is phenyl, the other is hydrogen; or R4 and R5 are taken together with the carbon to which they are bonded to complete a spiro-cycloalkyl ring having from 4 to 6 methylene carbon atoms; R6 and R7 are independently hydrogen, C1 to C6-alkyl or phenyl, and when one of R6 and R7 is phenyl, the other is hydrogen, and wherein R3 and R6 can be taken together to form a -(CH2)n-bridge ring forming connections where n is 2 or 3 across the lactam ring; provided that (I) when -XY and R2 form a double bond between the ring carbon atoms in the 5- and 6-positions, R1 is hydrogen and R3 is hydrogen, C1 to C6-alkyl or phenyl, (II) when X is oxygen or bivalent sulfur, Y is hydrogen or C1 to C6-alkyl; and (III) when -XY is taken together they represent hydrogen or C1 to C6-alkyl; are effective as drugs in warm-blooded animal patient to lower total cholesterol to treat atherosclerotic conditions and/or to alter the HDL/LDL ratio toward an increase in HDL cholesterol or toward a lower LDL cholesterol, or both, relative to the HDL/LDL ratio in a sample of the patient's blood before such treatment began.

Description: CYCLIC LACTAMS FOR CHOLESTEROL AND ATHEROSCLEROSIS CONTROL INTRODUCTION This invention relates to the use of certain cyclic lactam compounds as drugs for treating atherosclerotic conditions. for lowering total cholesterol in blood fractions and/or for treatment to beneficially alter the relative distribution and ratios of circulating high density (HDL) and low density (LDL) lipoprotein bound cholesterol fractions in the blood and arteries of valuable, warmblooded animal patients, including humans, and to some of such compounds as new compounds per se. More particularly, this invention provides the use of a below defined class of cyclic lactam compounds, termed 2-(lH)-pyridinone and 2-piperidone derivative compounds which we have discovered to have useful ranges of drug activity to treat atherosclerosis, to control total cholesterol, and/or to beneficially alter the ratio of HDL/LDL lipoprotein bound cholesterol in the blood of warm-blooded animals. BACKGROUND OF THE INVENTION The deposition of lipids within the arterial wall is thought to be a causative event in the development of atherosclerosis. The blood plasma lipoproteins, and particularly the low density lipoproteins (LDL), are probably the major source of cholesterol that accumulates in an atherosclerotic lesion. One of the most outstanding and earliest appearing biochemical changes associated with atherogenesis is the increase in cholesterol esterification within the arterial wall and the subsequent deposition and accumulation of cholesterol esters. This increased sterol esterification results from a stimulation of acyl-CoA:cholesterol acyltransferase (ACAT). The increase in arterial cholesterol esterification tends to parallel disease severity and contributes significantly to the total amount of lipid that accumulates in the atheromatous tissue. Recently, Bell and Schaub demonstrated that under conditions of experimental atherosclerotic development in rabbits, chloropromazine (an arterial ACAT inhibitor) reduced arterial cholesterol ester deposition by 53% and reduced total arterial cholesterol by 40%. In an effort to find anti-atherosclerotic drug candidate compounds, we have synthesized and tested a wide variety of compounds in our standard laboratory animal test, involving a cholesterol fed quail (SEA Japanese quail). Quail were chosen because of their small size, hardiness and susceptibility to the development of atherosclerosis during cholesterol feeding. We have searched for compounds which are effective to lower beta-lipoprotein (LDL) cholesterol in normal quail, are active as ACAT inhibitors or which are inhibitors of platelet aggregation, but also which are active in altering the HDL/LDL cholesterol ratio in blood fractions toward an increase in HDL cholesterol, or lower LDL cholesterol, or both, and/or a lowering of total cholesterol in the patient's blood, relative to HDL/LDL cholesterol ratios in that patient before treatment with the drug compounds of this invention. INFORMATION DISCLOSURE STATEMENT Other cholesterol lowering agents are known. For example, lovastatin, sold under the trademark MevAcore, is described in the Phvsicians' Desk Reference0, (PDR),-42nd Edition (1988), pages 13651367. It is a polycyclic compound that is not similar to the compounds described for use according to this invention. In addition, the following U.S. patents describe compounds which are said to be useful to- treat atherosclerosis or as anti-hyperlipemia drugs: Inone et al 3,864,343 discloses l-phthalazone derivatives having di-nitrogen ring systems; Carney 3,895,032 discloses an (cyclic tert-aminophenoxy)alkanoic acids for hypolipidemic drug use. Nadelson 4,000,307 discloses alkanoyl isoindolenylmethylphenones as hypolipidemic agents. Hall et al 4,395,471 discloses the use of a variety of cyclic imides, diones and partially reduced diones to treat diseases associated with increased serum cholesterol or triglycerides. Hall et al 4,689,326 discloses the use of 3,4,5,6-dibenzohomopiperidine and certain deviatives thereof for controlling hyperlipidemia. Ienaga et al 4,683,240 discloses the use of certain imidazolidinetrione derivatives as having hypolipidemic effects. None of these references disclose the compounds described herein or the ability to alter the HDL/LDL cholesterol ratios which are properties of the compounds disclosed for use according to this invention. Other references disclosing lactam compounds similar to the compounds described for use according to this invention, although not for the use of our invention include: Published U.K. patent application GB 2 162 180A which discloses 2-pyridone derivatives which are disclosed as being intermediates for insecticides and pharmaceuticals, although there is no disclosure of for what pharmaceutical compounds or drug use. Clauson-Kaas et al U.S. patent 2,748,142 discloses N-hydroxy-2pyridone derivative compounds to treat animals infected with certain organisms susceptible to such compounds. There is also a suggestion that the pyridones can be converted to the corresponding piperidone, by hydrogenation in the presence of Raney nickel, but does not disclose for what purpose that should be done. Derwent Abstract references to related lactam compounds include the following abstracts to the indicated patent application or issued patent publications: 86-030694/045 British 2 162 180A (cited, supra). 85-116682/20 D.C. 1770-095A discloses some 6-substituted- 5,5- dimethyl-2-piperidones as intermediates for plastics and pharmaceuticals. 84-250979/41 D.E. 1670-570-A discloses 3,3-dialkyl-2-piperidone production from the corresponding 4-cyano-butyraldehyde. The products are said to be pharmaceutical or intermediates. 84-219976/36 D.E. 1670-521-A discloses the production of some 2piperidone ring compounds said to be useful as pharmaceutical or as intermediates for plastic production. 43495Y/25 Belgium 849,625 discloses a generic formula IV lactam compounds which are said to be useful antistatic agents in the textile industry and as intermediates for polymers and a-aminodicarboxylic acids. 65313A/37 Belgian 864,683 discloses the use of omega-alkoxylactams as chemical intermediates to form dialkoxycarbocylic acid derivatives, which end products are said to be intermediates for making prostaglandin analog compounds, as sexual attractants and antioxidants. 87-200482/29 Great Britain 2185-478-A discloses some tetrahydropyridinrone compounds (lactams) useful for treating acute and chronic viral hepatitis, liver intoxication, hypoxia or amnesia. 78359A/44 Belgian 866,482 (U.S. equivalent 4,234,488) discloses some cyclic enamide compounds said to be useful as chemical intermediates. 52440A/29 Japan 3065-897 discloses some benzo(a)quinolizines prepared from some 4-oxobenzo-(a)quinolizines which starting materials have a modified lactam linkage in the polycyclic reactant. 71-37117S/22 DE1958424-A discloses 6- (p-hydroxyphenyl) -2- piperidones as intermediates in the preparation of plastics and as stabilizers for oxidation-sensitive plastics. 84-062583/10 U.S. patent No. 4,432,979A discloses 5-(6-membered heteroaryl ring including two nitrogen)-2-pyridone compounds as cardiotonic drugs. 83-820802/47 Belgian 896,678 discloses 5- or 6-aryl-3-(cyano, amido or amino)-2-pyridones as cardiotonic agent drugs. 83-772314/39 to EP 89,022A discloses 5-alkanoyl-6-alkyl-2-(lH)pyridinone derivatives as cardiotonic drugs. 27760K/12 EP 74,091 discloses 6-phenyl-2-(lH)pyridinone as cardiotonic drugs, and 86-068955/10 WO 8601-202-A discloses 2-pyridone derivative compounds as cardiotonic drugs. In addition, the following chemical publications disclose hydroxy or alkoxy lactam compounds: J. C. Hubert et al. Tetrahedron, 31, pp. 1437-41 (1975) discloses some 5-ethoxy-l-methyl-2-piperidinone, and the 5-hydroxy-lmethyl-2-piperidinone, but no cholesterol HDL/LDL altering properties are disclosed therein. T. Shono et al., J. Orz. Cham., 50, No. 17, pp. 3244-45 (1985) discloses 6-methoxy.2-piperidinone and some related compounds but no drug utility is disclosed for such compounds. OBJECTS OF THE INVENTION It is an object of this invention to provide a new use for a group of 3,4-dihydro-2-pyridinone and 2-piperidinone derivative compounds as active drug ingredients for treating a warm-blooded animal patient in need of treatment to lower total serum cholesterol, to alleviate symptoms of atherosclerosis, to alter the HDL/LDL ratio of cholesterol fractions in blood serum fractions and in arterial vessels of such animals toward elevating the HDL portion, lowering the LDL portion of cholesterol fractions of blood serum or both. It is another object of this invention to provide a group of new compounds within this above group of 3,4-dihydro-2-pyridinones and 2piperidinone derivative compounds, some of which have advantageous chemical and physical properties, relative to closely related structural compounds, to favor them for development toward pharmaceutical drug formulations in effective dosage forms, useful to treat warm-blooded animal patients to alleviate the hypercholesteremic and its related medical and veterinary conditions. SUMMARY OF THE INVENTION Briefly, one aspect of this invention provides a process pr method for treating a valuable warm-blooded animal patient to lower the total cholesterol content and/or to beneficially alter the distribution of high density lipoprotein-bound cholesterol (HDL) relative to the amount of low density lipoprotein-bound cholesterol (LDL) circulating in the blood or in the arteries of such warmblooded animal patient which comprises administering to said patient a lactam compound of formula I (see the General Structural Formula sheets, infra) wherein R is hydrogen or C1 to C6-alkyl; X is oxygen (-0-) or bivalent sulfur (-S-); Y is hydrogen or C1 to C6-alkyl, or -XY taken together represent hydrogen or C1 to C6-alkyl, or -XY is part of a double bond between the 5- or 6-position carbon atoms of the ring when R2 is also part of that double bond; ; R1 is hydrogen or C1 to C6-alkyl; R2 is part of the double bond between the 5- and 6-position lactam ring carbon atoms when -XY is part of that same double bond, and R3 is hydrogen, C1 to C6-alkyl or phenyl; or R2 and R3 are independently selected from the group consisting of hydrogen, C1 to C6-alkyl and phenyl, R4 and R5 are independently selected from the group consisting of hydrogen, C1 to C6-alkyl, or phenyl, and when one of R4 and R5 is phenyl, the other is hydrogen; or R4 and R5 are taken together with the carbon to which they are bonded to complete a spiro-cycloalkyl ring having from 4 to 6 methylene carbon atoms therein; ; R6 and R7 are independently selected from the group consisting of hydrogen and C1 to C6-alkyl, or phenyl and when one of R6 or R7 is phenyl, the other is hydrogen; and wherein R3 and R6 can be taken together to form a -(CH2)n bridge ring forming connections where n is 2 to 3, across the lactam ring, provided that (I) when -XY and R2 form a double bond between the ring carbon atoms in the 5- and 6- positions, R1 is hydrogen and R3 is selected from the group consisting of hydrogen, C1 to C6-alkyl and phenyl; and (II) when X is oxygen or bivalent sulfur, Y is hydrogen or C1 to C6-alkyl and (III) when -XY are taken together they represent hydrogen or C1 to C6-alkyl; and (III) when -XY are taken together they represent hydrogen or C to C6-alkyl; in an amount effective to lower the total cholesterol content or to alter the HDL/LDL ratio toward an increase of the HDL cholesterol or toward a lowering of the LDL cholesterol, or both, relative to the HDL/LDL ratio in a sample of that patient's blood before such treatment began. Three subgroups of the formula I lactam compounds, all useful for the same HDL/LDL cholesterol altering, cholesterol lowering and/or anti-atherosclerotic drug use purpose, are set forth hereinafter in the detailed description. Another aspect of this invention provides a group of specific new compounds, within the above Formula I definitions, which have the same valuable cholesterol lowering, anti-atherosclerosis and/or HDL/LDL cholesterol-altering property, although not all to the same degree. The compounds believed to be new include 1,4-dimethyl-6-ethoxy-2-piperidinone, 1,4-dimethyl-3,4-dihydro-2-pyridinone, 6-hydroxy-1,4-dimethyl-2-piperidinone, 9-hydroxy-8-methyl-8-azaspiro[4.5] -decan-7-one, 8-methyl-8-azaspiro[4.5]decan-9-ene-7-one, 9-ethoxy-8-methyl-8-azaspiro[4/5] -decan-7-one, 6-hydroxy-1 ,4,4-trimethyl-2-piperidinone, 6-hydroxy- 1,3,3 - trimethyl-2-piperidinone, 1,3,3-trimethyl-3,4-dihydro-2-pyridinone, 3,4-dihydro-1-methyl-3-phenyl-2(1H)-pyridinone, and 4hydroxy-l,3,8,8-tetramethyl-3-azabicyc1o3.2.1]octan-2-one. DETAILED DESCRIPTION OF THE INVENTION Subgroups of compounds within formula I for the drug use of this invention include (a) compounds of formula II (see the General Structural Formula pages) wherein R is hydrogen or C1 to C6-alkyl; R1 and R3 are hydrogen; R4 and R5 are independently selected from the group consisting of hydrogen and C1 to C6-alkyl and phenyl, or R4 and R5 are taken together with the carbon to which they are bonded to complete a spiro cycloalkyl ring having from 4 to 6 methylene carbon atoms therein; and R6 and R7 are hydrogen, C1-C6 alkyl or phenyl. Examples of such compounds include: l-methyl-3,4-dihydro-2-pyridinone, l,4-dimethyl-3 ,4-dihydro-2-pyridinone, 8-methyl-8-azaspirot4.5]decan-9-ene-7-one, l,3,3-trimethyl-3,4-dihydro-2-pyridinone, and 1-methyl-3-phenyl-3 ,4-dihydro-2(lH) -pyridinone, (b) compounds of the formula (III) wherein R is C1 to C6-alkyl; X is oxygen or bivalent sulfur; Y is hydrogen or C1 to C6-alkyl; R1 is hydrogen; R2 and R3 are each hydrogen, C1-C6 alkyl or phenyl; R4 is C1 to C6-alkyl and R5 is hydrogen; or R4 and R5 are taken together with the carbon to which they are bonded to complete a spiro cycloalkyl ring having from 4 to 6 methylene carbon atoms therein; and R6 and R7 are each hydrogen, C1 to C6-alkyl or phenyl. Examples of such compounds include: 6-ethoxy-l-methyl-2-piperidinone, 6-hydroxy-l-methyl-2-piperidinone, 6-ethoxy-1,4-dimethyl-2-piperidinone, 6-hydroxy-1,4-dimethyl-2-piperidinone, 9-hydroxy-8-methyl-8-azaspiro[4.5] -decan-7-one, 9-ethoxy-8-methyl-8-azaspiro[4.5] -decan-7-one, 6 -hydroxy- 1,4,4- trimethyl- 2 -piperidinone, 6-hydroxy-1,3,3-trimethyl-2-piperidinone, and (c) compounds of the formula (IV) wherein R is C1 to C6-alkyl; X is oxygen or bivalent sulfur; Y is hydrogen or C1 to C6-alkyl; R1 is hydrogen; R2 is hydrogen or C1 to C6-alkyl; R4 and R5 are hydrogen or methyl; R7 is hydrogen or C1 to C6-alkyl, n is 2 or 3. An example of such a compound is 4-hydroxy-1,3,8,8-tetramethyl 3-azabicyclo(3 .2ioctan-2-one. Of the compounds described and claimed as being within the scope of this invention, the following compounds are considered to be within a group of lead compounds, from which group one or more compounds may be selected for advanced testing for the use of this invention: 6-hydroxy-1,4-dimethyl-2-piperidinone, 1,4-dimethyl-2-piperidinone, 9-hydroxy-8-methyl-8-azaspiro[4.5]decan-7-one, 6-hydroxy-1 , 4 ,4-trimethyl-2-piperidinone, 6-hydroxy-1,3,3-trimethyl-2-piperidone, 3,4-dihydro-1-methyl-3-phenyl-2(1H)-pyridinone, 6 -ethoxy- 1,4- dimethyl- 2-piperidinone. The various compounds which are the active drug compounds for use in the method of lowering total cholesterol content or for altering the relative distribution of circulating high density (HDL) and low density lipoprotein-bound (LDL) cholesterol in blood serum in the invention described herein, in general, can be made by known chemical process steps starting with substituted or non-substituted glutaric acid anhydrides. Scheme I (on the accompanying process flow sheets, hereinafter) outlines a general process for preparing these compounds. Thus, referring to Scheme I, the substituted (where any of R1 to R6 is other than hydrogen or unsustituted (all of R1 or R6 are hydrogen) formula 5 glutaric acid anhydride compound can be treated with the selected primary amine, e.g., a C1 to C3-alkylamine such as methylamine, as a concentrated solution of the amine in water, say 30% to 45% V/V concentration followed by heating the mixture sufficiently to effect an imidation reaction, say 150 to 275"C., to obtain the N-substituted-piperidindione (imide) compound 6 in good yield. This resulting imide compound 6 intermediate can be isolated) or treated in its reaction mixture) and then reduced and etherified by known methods, e.g., by the sodium borohydride/ethanol or thioethanol imide reduction method of Speckamp [Hubert, J.C., Wynberg, J.P.B.A. and W.N. Speckamp, W.N., TETRAHEDRON, 31 (1975), pp. 1437-41] to convert the imide compound 6 to the corresponding alkyl ether compounds 7 after workup in acidic ethanol in good yields (60% to 85%). Other alkanols or thioalkanols can be used to make the other ether compounds. Exceptions to this imide reduction method were attempts to reduce tricyclic aza-dione compounds such as 1,6,8,8-tetramethyl [3.2.2] -6-aza-cycloocta-5,7-dione which was unreactive under these conditions. Other methods for reducing these compounds were used. See below. Also, reduction of substituted piperidin-2,6-dione compounds 6 such as the 3-phenylpiperidin-2,6-dione or the 3,3-dimethylpiperidin2,6-diones are separable by silica gel chromatography procedures to afford the desired ethyl ether, 1,5,5-trimethyl-6-ethoxy-2-piperidi- none 7 where R7 is ethyl and smaller amount of the useful ether compound, l,3,3-trimethyl-6-ethoxy-2-pyridinone. The 3-phenylsubstituted imides gives inseparable mixtures which require further heat treatment with toluene and p-toluene-sulfonic acid (TsOH) to yield the separatable desired l-methyl-3-phenyl-3,4-dihydro-2pyridinone and the l-methyl-5-phenyl - 3, 4-dihydro -2 -pyridinone type compounds, 8. The N-alkyl-6-alkyloxy-2-piperidinones 7 and the enamides 8 are all, in general, active as anti-atherosclerotic drug compounds in standard laboratory animal tests, but some are preferred over others. The chemical process can be carried further to hydrolyze the 6-alkoxy or 6-alkylthio ether type compounds 7 to the corresponding 6-hydroxyor 6-mercapto- N-alkyl-2-piperidinone compounds (hydroxy or mercapto lactam compounds) 9. This can be done by several known methods, e.g., by mixing the selected 6-alkoxy- or 5-alkylthio ether compound 7 with water and acetic or other equivalent acid to remove the alkyl group and to form the 6 hydroxy or 6 -mercapto 9 compound which can be recovered from the reaction mixture by concentration, extraction of the residue into an appropriate solvent such as methylene chloride, and silica gel column chromatography procedures, collecting appropriate fractions and evaporation of the diluent liquids. Methods for preparing the compounds which are the active drug compounds for use according to this invention are further exemplified by the following detailed examples. For brevity, these examples use common shorthand chemical terms Temperatures are in degrees Celsius unless otherwise indicated. The letter h means hours, the letter bnum where a num subscript is used means a boiling point at the indicated number of millimeters mercury pressure, e.g., b10 80it. means the product boiled at 800C; at 10 millimeters mercury pressure. The terms 1H NMR (CDC13, 6) means proton nuclear magnetic resonance spectra in delta scale units, IR means infrared spectrum analysis, MS means mass spectrum analayis, HC1 means hydrogen chloride, often in a solvent such as ethanol, which is indicated by the term "ethanolic He'1", Prep-Pak (SiO2) means a trademark (Waters and Assoc.) type of commercially available silica gel used in chromatography procedures to purify or separate different compounds often mixed in oily residue product mixtures. Diluent or solvent mixture numbers, e.g., 85/15, are in parts by volume, V/V, unless otherwise indicated. TsOH means p-toluenesulfonic acid, EtOH means ethanol or ethyl alcohol, KOH means potassium hydroxide, CH2C12 means methylene chloride, 13C NMR (CDC13, ppm) means carbon 13 nuclear magnetic resonance spectrum analysis in parts per million scale units, EtOAc means ethyl acetate, a common solvent, CH3NH2 means methylamine, H20 means water, AcOH means acetic acid, Et2O means diethyl ether, DMF means N,N-dimethylformamide, a common solvent, CH3I means methyl iodide, HI RES MS means high resolution mass spectral analysis, TLC means thin layer chromatography analysis procedures, Et3N means triethylamine, MgSO4 means a common organic liquid drying form of magnesium sulfate. SYNTHESIS OF REPRESENTATIVE COMPOUNDS Example 1. l-Methyl-3,4-dihydro-2-pyridinone. l-Methylglutarimide. Glutaric anhydride (20 g., 0.176 mol) was added to methylamine 40% in H20, 75ml) at 0 C. The solution was stirred for 15 minutes then heated to remove water by distillation. The pot was further heated to 220"C. for one hour. The pot was cooled. The residue was vacuum distilled to give the subtitled compound (A) (13.8 g., 62%), b10 800c. 1H NMR:(CDC13, 6): 1.94 (p*, J - 7Hz, 2H, CH2), 2.67 (t, J - 7Hz, 4H, COCH2), 3.10 (s, 3H, NCH3). IR (mull): 2859, 1669, 1417, 1298, 1113, 1045 cm'l, MS for C6HgNO2: m/e(rel.int.): 127 (M+, 100), 99(32), 71(16), 70(23), 55(16). Analysis for C6HgNO2: Calc: C, 56.68; H, 7.13; N, 11.02; Found: C, 56.43; H, 7.13; N, 11.00. *p - pentuplet B. l-Methyl-6-ethoxy-2-piperidone. Sodium borohydride (11.38 g., 0.3 mol) was added to a 11 g., 167 mol portion of the 1-methylglutarimide from Step A at hereinabove in ethanol (750 mL) at -100C. Ethanolic 2N HC1 was added to the solution at a rate of 1 mL per hour. After six hours ethanolic 2N HC1 was added until the solution reached pH 3. The reaction was allowed to stand overnight at room temperature. The solution was recooled to 0 C. and neutralized with 1% ethanolic KOH. The solution was filtered and the filtrate concentrated in vacuo. The residue was extracted with chloroform (4 x 125 mL). The extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give the subtitled piperidone (12.6 g., 94%). An analytical sample was prepared by chromatography on a Waters Prep 500A silica gel column eluting with an EtOAc/hexane mixture, 85/15, V/V. Concentration of the appropriate fractions give analytically pure subtitled compound as a coloress oil. SiO2 TLC: Rf - 0.35, EtOAC. 1H NMR (CDC13, 6): 1.20 (t, J 7HZ, 3H, CH3), 1.47-2.50 (m, 6H, CH2), 2.97 (s, 3H, NCH3), 3.54 (q, J - 7Hz, 2H, OCH2), 4.50-4.64 (m, 1H, OCH). IR (mull): 3367 (H20), 2954, 1628, 1491, 1399, 1332 cm-l MS for C8H15N02: m/e (rel.int.): 157(M +, 8), 129(20), 112(100), 100(13). Analysis for C8H15N02: Calc: C, 61.12; H, 9.62; N, 8.91; Found: C, 61.23; H, 9.56; N. 8.92. Corrected for 1.19% H20. C. l-Methyl-3,4-dihydro-2-pyridinone. The step B piperidinone (10 g., 63.7 mmol), TsOH (0.16g.) and benzene (300 mL) were heated to reflux. The flask was equipped with a Dean-Stark trap filled with 4A molecular sieves. After five hours the solvent was removed in vacuo. The residue was vacuum distilled bulb to bulb to give the titled -2-pyridinone, (4.7 g., 66.46) b40 950C. SiO2 TLC: Rf - 0.70, ETOAc. 1H NMR:(CDCL3, 6) 2.16-2.75 (m, 4H, CH2), 3.10 (s, 3H, NCH3), 5.08-5.34 (m, 1 H, CH2-CH) 6.02-6.20 (m, 1 H, NCH). IR (mull): 3470 (H20), 2942, 1660, 1442, 1391, 1373, 1326 cm-1, MS for C6H9NO: m/e(rel.int): 112(M+, 32), 101(52), 73(52), 55(34). Analysis for C6HgNO: Calc: C, 64.84; H, 8.16; N, 12.60; Found: C, 64.81; H, 8.27; N, 12.35. Corrected for 1.36% H2O. Example 2. 1,4-Dimethyl-6- 1,4-Dimethyl-6-ethoxy-2-piperidinone. A. 1,4-Dimethylglutarimide. 4-Methylglutaric anhydride (25 g., 0.19 mol) was added to methyl amine, 40% in H20 (100 mL) at -10 C. The solution was allowed to warm to room temperature for 0.5 hours, then heated to distill off H20. The solution was further heated to 220"0. After 0.5 hours no more H20 evolution was noted. The solution was cooled and the residue distilled bulb to bulb to give the subtitled compound (14.0 g., 51%)b101050C. 1H NMR(CDC13, 6): 1.03 (d, J - 7Hz, 3H, CH3CH), 2.09-3.03 (m, 5H, CH2, CH), 3.20 (s, 3H, NCH3). IR(neat): 2962, 1723, 1675, 1419, 1301, 1116 cm'l, MS for C7H11N02: (m/e, rel.int.): 141(M+, 100), 112(27), 100(20), 69(28), 56(79). Analysis for C7H11N02: Calc.: C, 59,56; H, 7.85; N, 9.92; Found: C, 59,80; H. 8.04; N, 9.57. B. 1,4-Dimethyl-6-ethoxy-2-piperidinone. Sodium borohydride (11.4 g., 0.3 mol) was added to imide from part A (10 g., 70.9 mmol) in EtOR (750 mL) at -5'G. 2 N HC1 in EtOH was added to the solution at a rate of 1.2 mL/h. Ater five hours 2N HC1 was added until pH 3 was obtained. After stirring for one hour the solution was neutralized with 1% KOH in EtOH. The solution was filtered and the filtrate concentrated in vacuo. The residue was extracted with CH2C12 (6x100 mL). The extracts were combined, dried (HgSO4), filtered and concentrated in vacuo to give the titled 2piperidinone as a colorless oil (11.4 g., 94.0%). A sample of the titled product (3.4 g.) was chromatographed on a Prep-Pak (5i02) eluting with EtOAc. Combining the appropriate fractions gave analytically pure titled compound (3.0 g.). Si02 TLC: Rf - 0.35, EtOAc. 1H NMR(CD2Cl2, 6): 0.94 (d, J 7Hz, 3H, CH3CH), 1.15 (t, J - 7Hz, 3H, CH3CH2), 1.30-2.55 (m, 5H, CH2, CHCH3) 2.86 (s, 3H, NCH3), 3.30-3.67 (m, 2H, OCH2), 4.50-4.67(m, 1H, CHO). 13C NMR(CD2C12,ppm): 170.2, 88.8, 64.2, 41.1, 35.9, 33.3, 23.4, 21.4, 15.6. IR(neat): 2955, 1653, 1458, 1327, 1099cm'1 MS for C17N02: (m/e, rel.int.): 171(M+, 8), 129(11), 127(9), 126(100), 101(10), 88(7). Analysis for C9H17N02: Calc: C, 63.23; H, 9.87; N, 8.19; Found: C, 63.21; H, 10,21; N, 8.14. Example 3 1,4-Dimethyl-3,4-dihydro-2-pyridinone. The piperidinone from Example 2, part B (8.0 g, 46.8 mmol) in benzene (270 mL) with TsOH(0.15g) was heated to reflux. The flask was equipped with a Dean-Stark tube filled with 4A molecular sieves. After 24 hours the solvent was removed in vacuo. The residue was distilled bulb to bulb to give the titled compound as a colorless liquid (3.0g,52%)b5095"C. Si02TLC: Rf - 0.7, EtOAc. 1H NMR(CD2C12, & : 1.06(d, J - 7HZ, 3H, CH3CH), 2.00-2.70 (m, 3H, CH2, CHCH3), 3.00 (s, 3H, NCH3), 5.04 (dd, J - 3HZ, 7HZ, 1H, CHCH-CH), 6.05(dd, J - 1HZ, 7HZ, NCH). 13C NMR(CD2C12,ppm): 169.5, 130.2, 112.5, 40.0, 33.7, 27.8, 20.5. IR:(neat): 3423(H20), 2959, 1669, 1456, 1376, 1262cm-1. HI RES MS for C6H1lNO:(m/e, rel.int.): Calc: 125.0841, Found: 126,0834, 125 (M+, 51), 111(7), 110(100), 82(29),68(15). Analysis for C6H11NO: Calc: C, 67.17; H, 8.86; N, 11.19; Found: C, 66.76; H, 9.87; N. 10.64. Example 4 6-Hydroxy-1,4-dimethyl-2-Piperidinone. A. By reduction of 1,4-dimethylglutarimide. A 30.0 g (2.3 mmole) portion of the 1,4-dimethylglutarimide prepared as described, for example, in Example 2, part A hereinabove, at -780C in CH2C12 (600 mL), was treated with a 425 mL (425 mmole) portion of lithium triethylborohydride (Super Hydride) to obtain the titled compound, m.p. 79 -83 C. 1,4-Dimethyl-6-ethoxy-2-piperidinone. Sodium borohydride (11.4 g. 0.3 mol) was added to (10 g., 70.9 mmol) of the 1.4-glutarimide from part A in EtOH (750 mL) at -5 C. 2N HC1 in EtOH was added to the solution at a rate of 1.2 mL./h. After 5h 2N HC1 was added until pH 3 was obtained. After stirring for one hour the solution was neutralized with 1% KOH in EtOH. The solution was filtered and the filtrate concentrated in vacuo. The residue was extracted with CH2C12 (6x100mL). The extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give the titled compound as a colorless oil (11.4g, 94.0*). A sample of the 6-ethoxy compound (3.4 g.) was chromatographed on a Prep-Pak(Si02) silica gel column eluting with EtOAc. Combining the appropriate fractions gave analytically pure 1,4-dimethyl-6-ethoxy-2-piperidinone (3.0 g), SiO2TLC: Rf - 0.35,EtOAc. H-RMR(CD2C12,6): 0.94(d, J - 7Hz, 3H, CH3CH), 1.l5(t, J - 7Hz, 3H, CH3CH2), 1.30-2.55 (m, 5H, CH2, CHCH3) 2.86 (s, 3H, NCH3), 3.30-3,67 (m, 2H, OCH2), 4.50-4.67 (m, 1H, CHO). 13CNMR(CD2Cl2,ppm): 170.2, 88.8, 64.2, 41.1, 35.9, 33.3, 23.4, 21.4, 15.6. IR(neat): 2955, 1653, 1458, 1327, 1099 cm71. MS for C9H17N02: (m/e, rel.int.): 171(M+, 8), 129(11), 127(9), 126 (100), 101(10), 88(7). Analysis for C9H17N02: Calc: -C, 63.23; H, 9.87; N, 8.19; Found: C, 63.21; H, 10.21; N, 8.14. Then a 13.0 g. (76 mmole) portion of this 1,4-dimethyl-6ethoxy-2-piperidinone is hydrolyzed in aqueous acetic acid (pH-4) to obtain the 6-hydroxy compound. ExamDle 5 6-Hydroxy-1,3,3-trimethyl-2-piperidinone. A 1,3, 3-Trimethyl-2 , 6-piperidinedione. 3,3-Dimethylglutaric anhydride (25.0 g, 0.176 mol) was added to 40% CH3NH2 in H20 (150 mL). The solution temperature was kept between 10- and 15 e C. Following the addition the solution was allowed to warm to room temperature. After 18 hours the H20 was removed in vacuo. The residue was heated to 200 C. and the formed H20 was removed by distillation. The pot residue was distilled under vacuum bulb to bulb (90"C, 0.6 mm) to yield the subtitled imide (14.9 g, 55%): mp 47-50"C (Lit. mp 48-50 C)FN; 1H NMR (CDC13)E 1.34 (s, 6 H, C(CH3)2, 1.85 (t, 2 H, J-6Hz, CCH2), 2.77 (t, 2 H, J-6Hz, OCCH2), 3.16 (s, 3H, NCH3); IR(mull)2926, 1716, 1667, 1457, 1305, 1112, 637 cm'l; MS for C8H13N02, m/e (relative intensity) 155 (M+, 88), 127(94), 126(22), 70(100). FN: Hall, Jr., H.K., J. Orz. Chem., (1964), 29, 335-3138. B. 1,5,5-Trimethyl-6-ethoxy-2-piperidinone (A) and 1,3,3-Trimethyl6-ethoxy-2-piperidinone (B). Sodium borohydride (16.0 g, 0.42 mol) was added to the subtitled imide from part A hereinabove (14.2 g, 91.6 mmol) in EtOH (1.3L) at -10 C. 2N HC1 in EtOH was added at a rate of 1.4 mL/h to the solution. After 20 hours the solution was cooled to -30 C. and the pH adjusted to 3 with 2N HC1 in EtOH. After stirring at 20 hours at -10 C the pH was brought to 7 by the addition of 18 KOH in EtOH. The solution was filtered and the filtrate concentrated in vacuo. The residue was taken up on CH2C12 and filtered and the filtrate concentrated in vacuo. The residue was chromatographed on an SiO2 PrepPAK silica gel column eluting with 3/2 V/V EtOAc/hexane. The appropriate fractions were combined and concentrated in vacuo. The mixed fractions were rechromatographed on an SiO2 PrepPAK silica gel column (3/2 EtOAc/hexane) and the appropriate fractions were combined and concentrated in vacuo to afford starting imide (1.7 g, 12.0%) ether (B) (3.5 g., 20.7%) and regioisomer ether (A) (6.70 g.; 39.5%). Data for (B): 1H NMR (CDCL3)S 1.22 (t, 3 H, J - 6 Hz, CH2CH3), 1.29 (s, 6 H, C(CH3)2), 1.37-1.50 (m, 1H, CH2), 1.83-2.09 (m, 3 H CH2), 2.95 (s, 3 H NCH3), 3.42-3.60 (m, 2 H, OCH2), 4.48-4.52 (m, 1 H OCH): 13C NMR (CDC13) ppm 176.7, 88.8, 63.3, 38,3, 33.6, 31.0, 27.6, 26.9, 24.1, 15.4; IR(neat) 2967, 1650, 1304, 1112, 1063, 632 cm-l; MS for C10H19N02, m/e (relative intensity) 185 (M+, 5), 156 (6), 140 (100), 127 (15), 112 (21), 88 (17). Anal. Calcd for C10H19N02: C, 64.83; H, 10.34; N, 7.56; Found: C, 62.99; H, 9.45; N, 7.90. TLC (SiO2) Rf - 0.41 3/2, EtOAc/hexane. Data for (A): 1H NMR (CDC13)E 0.99 (s, 3 H, CCH3), 1.04 (s, 3 H, CCH3), 1.22 (t, 3 H, J - 7 Hz, CH2CL3), 1.27-1.41 (m, 1 H, OCCH2CH2), 1.94-2.18 (m, 1 H, OCCH2C2), 2.35-2.45 (m, 2 H, OCCH2), 3.03 (s, 3 H, NCH3), 3.52-3.83 (m, 2 H, OCH2), 4.00 (d, 1H, J - 1.7 Hz, OCH); 13C NMR (CDC13) ppm 170.7, 97.7, 67.0, 35.6, 35.0, 29.0, 28.9, 26.0, 23.8, 15.5; IR (neat) 2976, 1653, 1479, 1398, 1073, 1038, 992 cm-l; MS for C10H19N02, m/e (relative intensity) 185 (M+, 25), 156 (94), 140 (100), 129 (49), 101 (46). Anal. Calcd for C1OH19N02: C, 64.83; H, 10.34; N. 7.56; Found: C, 64.43; H, 10.67; N, 7.57. TLC (SiO2) Rf - 0.26, 3/2, EtOAc/hexane. C. 1,3,3-Trimethyl-6-hydroxy-2-piperidinone Ethyl ether (B) from part B hereinabove (2.90 g, 15.7 mmol) was dissolved in H20 (50 mL) which had been adjusted to pH 4 with AcOH at room temperature. After 20 h the solvent was removed in vacuo. The residue was chromatographed on an 5i02 PrepPAK silica gel column eluting with EtOAc. The appropriate fractions were combined and chromatographed in vacuo to afford the titled compound (2.30 g, 92.9%); mp 84-850C.; 1H NMR (CDC13)E 1.21 (s, 3 H, CCH3), 1.24 (s, 3 H, CCH3), 1.48-1.58 (m, 1 H, CCH2), 1.81-2.20 (m, 3 H, HOCCH2, CCH2), 2.99 (s, 3 H, NCH3), 3.80 (d, 1 H, J - 7.0 Hz, OH), 4.92 (m, 1 H, NCH); 13C NMR (CDC13) ppm 176.9, 81.9 38.2, 32.9, 30.8, 27.6, 27.4, 26.9, 20.8; (mineral oil mull) 3235, 2924, 1603, 1462, 1306, 1009 cm 1; MS for C8H15N02, m/e (relative intensity) 157 M+, 47), 70 (46) 60 (30), 56 (100). Anal. Calcd for C8H15N02: C, 61.12; H, 9.62; N, 8.91; Found: C, 61.49; H, 9.87; N. 8.93. The ethyl ether (A) from part B hereinabove was also hydrolyzed in similar manner. Examole 6 9-Hydroxy-8-methyl-8-azaspiro[4.5]decan-7.one. A. 7,9-Dioxo-8-methyl-[4.5]-8-azaspirocyclodecane. The 7,9-dioxo-8-oxaspirodecane(glutaric anhydride derivative) (25.0 g, 0.149 mol) was added 40% CH3NH2 in H20 (150 mL) at 50C. Following the addition the solution was warmed to room temperature. After stirring overnight the solution was concentrated in vacuo. The residue was heated at 220"C. until no more water distilled. The pot residue was then distilled bulb to bulb (by 7 lO5eC.) to afford the subtitled compound (22.8 g, 84.4%): mp 53-54C: 1H NMR (CDCL3)E 1.341.42 (m, 4 H, CH2), 1.54-1.67 (m, 4H, CH2), 2.47 (s. 4H, OCCH2), 3.00 (s, 3 H, NCH3); 13C NMR (CDCl3) ppm 172.6, 44.9, 39.7, 37.8, 26.4, 24.3; IR (mineral oil mull) 2960, 1720, 1673, 1457, 1300, 1118, 633 cm-l; MS for C10H15N02, m/e (relative intensity) 181 (100), 152 (42), 82 (43), 81 (44), 67 (90). Anal. Calcd for C10H15N02: C, 66.27; H, 8.34; N, 7.73; Found: C, 66.61; H, 8.25; N, 7.67. B. 9-Ethoxy-8-methyl-8-azaspirot4/5]decan-7-one. Sodium borohydride (8.73 g, 0.23 mol) was added to a solution of the 7,9-dioxo-8-methyl-[4.5]-8-azaspirocyclodecane from part A hereinabove (9.0 g, 49.7 mmol) in EtOH (500 mL) at -10 C. 2N HCl in EtOH was added at a rate of 1.0 mL/h to the reaction. After 20 hours the solution was adjusted to pH 3 by the addition of 2N HCl in EtOH at -40"C. The solution was warmed to -15 C and after 6 hours the pH was adjusted to 7 with 1% KOH in EtOH. The solution was filtered and the filtrate concentrated in vacuo. The residue was taken up in CH2C12 and filtered and the filtrate concentrated in vacuo. The residue was chromatographed on an PrepPAK 5i02 silica gel column eluting with 3/1 V/V EtOAc/hexane. The appropriate fractions were combined and concentrated in vacuo to yield some of the starting material (1.07 g, 11.9%) and the subtitled product compound (8.41 g, 80.1%); 1H NMR (CDC13)E 1.24 (t, 3 H, J - 7.0 Hz, CH3), 1.38-1.70 (m, 8 H, CH2), 1.84-201 (m, 2 H, CHCH2), 2.27-2.31 (m, 2 H, OCCH2), 2;95 (s, 3 H, NCH3), 3.53 (q, 2 H, J - 7.0 Hz, OCH2), 4.58 (t, 1 H, J 5.5 Hz); IR (neat) 2950, 1657, 1433, 1397, 1065 cm-l; MS for C12H21 N02. m/e (relative intensity) 211 (M+, 4), 166 (100), 129 (21), 109 (43), 101 (23). Anal. Calcd for C12H21N02: C, 68.21; H, 10.02; N, 6.63. Found: C, 67,93; H, 10.22; N. 6.53. TLC (SiO2) Rf - 0.30, 3/1 EtOAc/hexane. C. 9-Hydroxy-8-methyl-8-azaspiro[4. 5]decan-7-one. The 9-ethoxy-8-methyl-8-azaspiro[4.5]decan-7-one from part B hereinabove (3.0 g, 14.2 mmol) and H20 (75 mL), which had been adjusted to pH 4 with AcOH were stirred together at room temperature. After 18 hours the solvent was removed in vacuo. The residue was taken up in CH2C12, dried (MgS04), filtered and concentrated in vacuo. The residue was recrystallized from Et2O to afford the titled compound (2.0 g). The mother liquors were chromatographed on an SiO2 PrepPAK silica gel column eluting with EtOAc. Concentration in vacuo of the appropriate fractions yielded an additional 0.14 g of the titled product compound (2.14 g, 82.3%): mp 87-890C; 1H NMR (CDC13)E 1.40-1.82 (m, 9 H, CH2), 2.10-2.22 (m, 1 H, CHCCH2), 2.32 (s, 2 H, OCCH2), 3.01 (s, 3 H, NCH3), 3.52 (d, 1 H, J - 8.8 Hz, OH), 4.86-4.94 (m, 1 H, CH); IR (mull) 3154, 2925, 1609, 1324, 1054, 609 cm¯1; MS for C10H17N02, m/e (relative intensity) 183 (M+, 52), 182 (27) 101 (83), 81 (16), 73 (82), 60 (100). Anal. Calcd for C10H17N02: C, 65.54; H, 9.35; N, 7.64; Found: C, 65.24; H, 9.78; N, 7.49. TLC (SiO2) Rf - 0.36, EtOAc. ExamDla 7 8-Methyl-8-azaspiro[4.5]decan-9-ene-7-one. The 9-ethoxy-8-methyl-8-azaspiro[4.5]decan-7-one, prepared as described in Example 6, part B hereinabove, (3.0 g, 14.2 mmol) was added to a refluxing solution of toluene (150 mL) and TsOH (0.30 g). After 5 min Et3N (10 mL) was added. The solution was cooled and concentrated in vacuo. The residue was chromatographed on an SiO2 PrepPAK column eluting with 1/1 V/V hexane/EtOAc. The appropriate fractions were combined and concentrated in vacuo to yield the titled compound product (2.03 g, 86.6%): 1H NMR (CDC13)E 1.51-1.73 (m, 8 H, CH2), 2.42 (s, 2 H, OCCH2), 3.06 (s, 3 H, NCH3), 5.07 (d, 1 H, J 8.1 Hz, NCHC), 5.91 (d, 1 H, J - 7.5 Hz, NCH); IR (neat) 2953, 1675, 1656, 1368, 1272, -1014, 721 cm-l; HI RES MS for C10H15NO1 Calcd: 165.1153; Found: 165.1148; m/e (relative intensity) 165 (M+, 54), 136 (45) 123 (100), 108 (18), 94 (42). Anal. Calcd for CloHlsNO: C, 72.69; H, 9.15; N, 8.48; Found: C, 72.56; H, 9.29; N. 8.39. (Corrected for 1.22% H20). Example 8 6-Hydroxy-l,4,4-trimethyl-2-piperidinone. A. 1,4,4-Trimethyl-2,6-piperidinedione. The 4,4-dimethyl-2,6-piperidinedione (25.0 g, 0.177 mol) in DMF (150 mL) was added to a solution of sodium hydride (7,44 g, 0.186 mol, 60% oil dispersion) at 0 C over one hour. The solution was stirred an additional 1.5 hours followed by addition of CH3I (31.0 g, 0.219 mol). The solution was allowed to warm to room temperature. After 18 hours H20 (100 mL) and Et2O (200 mL) were added. The organic layer was removed and the aqueous portion extracted with Et2O (4x125 mL). The organic layers were combined and washed with H20 (2x100 mL) and brine (1x100 mL), The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Residual DMF was removed by placing the residue on a high vacuum pump at room temperature. After stirring overnight the oil solidified to provide the subtitled compound (20.7 g, 75.0%): mp 57-58 C (lit. mp 61-63"C)FN; 1H NMR (CDC13)6 1.07 (s, 6 H, C(CH3)2, 2.52 ;(s, 4 H, CH2), 3.13 (s, 3 H, NCH3); IR (mull) 2960, 1711, 1683, 1666, 1307, 1277, 1118, 617 cm 1; HI RES MS for C8H13N02, Calcd: 155.0946; Found: 155.0955. m/e (relative intensity) 155 (M+, 68), 126 (28) 83 (49), 70 (68), 55 (100). FN. Leonard, N.J. et al. J. Am. Chem. Soc., 79 (1957), 5279-5292. B. 6-Ethoxy-1,4,4-trimethyl-2-piperidinone. Sodium borohydride (16.9 g, 0.45 mol) was added to the 1,4,4trimethyl-2,6-piperidinedione from part A (15.0 g, 96.1 mmol) (starting compound) in EtOH (1.0 L) at -10 C. 2N HC1 in EtOH was added at a rate of 1.6 mL/h to the reaction. After 20 hours the solution was cooled to -400C. and the pH adjusted to 3 with 2N HC1 in EtOH. The solution was warmed to -150C. and after 5 hours the pH was adjusted to 7 with 1% KOH in EtOH. The solution was filtered and the filtrate was concentrated in vacuo. The residue was taken up in CH2C12 and filtered and the filtrate concentrated in vacuo. The residue was chromatographed on an SiO2 PrepPAK column eluting with 4/1 V/V EtOAc/hexane. The appropriate fractions were combined and concentrated in vacuo to afford the starting compound (2.38 g, 15.7%) and the subtitled product compound (12.11 g., 68%): 1H NMR (CDC13)6 0.98 (s, 3 H, CCH3), 1.08 (s, 3 H, CCH3), 1.24 (t, 3 H,J - 7.0 Hz, OCH2), 1.72 (dd, 1 H, J - 6.8, 11.0 Hz, CHCH2) 1.82-1.93 (m, 1 H, CHCa2), 2.21-2.23 (m, 2 H, OCCH2), 2.96 (s, 3 H, NCH3), 3.52 (q, 2 H, J -7.0 Hz, OCH2), 4.59 (dd, 1 H, J - 5.5, 6.6 Hz, CH); 13C NMR (CDC13) ppm 170.3, 87.8, 62.1, 46.0, 40.7, 31.1, 29.7, 27.3, 15.4; IR (neat) 2956, 1657, 1451, 1326, 1063 cm'l; MS for C10H19N02, m/e (relative intensity) 185 (M+, 4), 140 (100), 129 (22), 101 (31), 83 (90). Anal. Calcd for C10H19N02: C, 64.83; H, 10.34; N, 7.56. Found: C, 64.35; H, 10.34 N, 7.56. TLC (SiO2) Rf - 0.57, EtOAc. C. 6-Hydroxy-1,1,4-trimethyl-2-piperidinone. The 6-ethoxy-1,4,4-trimethyl-2-piperidinone from part B hereinabove (6.60 g, 35.6 mmol) and H20 (160 mL) which had been adjusted to pH 4 with AcOH were stirred at room temperature. After 20 hours the solvent was removed in vacuo. The residue was dissolved in CH2C12, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on an SiO2 PrepPAK column eluting with EtOAc to afford the titled compound (4.30 g, 76.4%): mp 56-580C; 1H NMR (CDC13)E 0.98 (3 H, CCH3), 1.08 (s, 3H, CCH3,), 1.63 (dd, 1H, J 7.5, 13.7 Hz, CHCH2), 1.97-2.11 (m, 1 H, CHCH2), 2.20 (s, 2 H, OCCH2), 2.99 (s, 3H, NCH3), 4.54 (d, 1 H, J - 8.6 Hz, OH), 4.87 (dt, 1 H, J - 8.3, 5.7, CH); 13C NMR (CDC13) ppm 170.4, 80.8, 45.9, 44.8, 30.0, 29.5, 28.0, 26.1: IR (mull) 3222, 2932, 1602, 1313, 1049, 668 cm'l; MS for CgHL5N02, m/e (relative intensity) 157 (M+, 58), 101 (76), 83(37), 73 (89), 60 (100). Anal. Calcd for CgH15N02: C, 61.12; H, 9.62; N, 8.91; Found: C, 61.08; H, 9.57; N, 8.87. TLC (SiO2) Rf - 0.33, EtOAc. Example 9 3,4-Dihydro-1 -methy1-3-phenyl- 2(1H) -pyridinone. A. 1-Methyl-3-phenyl-2,6-piperidindione. The anhydride, 3-phenylglutaric anhydride, (5.0 g, 26.3 mmol) was added to 40% CH3NH2 in H20 (50 mL) at 5 C. After the addition, the solution was warmed to room temperature and stirred overnight. The H20 was removed by evaporation and the residue was heated to 2400C. for five hours. The pot residue was distilled bulb to bulb (b1.2 11000) to give the subtitled compound as a yellow solid. The solid was washed with Et2O to afford the subtitled compound as a white solid (3.63 g, 67.9%): mp 97-99"G; 1H NMR (CDCl3)E 2.13-2.31 (m, 2 H, CH2), 2.63-2.83 (m, 2 H, CH2), 3.25 (s, 3 H, CH3), 3.84 (dd, 1 H, J - 6.7, 11.1 Hz, CH), 7.16-7.19 (m, 2 H, arom.), 7.26-7.40 (m, 3 H, arom.); 130 NMR (CDC13) ppm 173.6, 172.6, 138.1, 129.0, 128.1, 127.7, 48.7, 31.5, 36.9, 25.4,; IR (mineral oil mull) 2925, 1722, 1668, 1463, 1355, 1114, 704 cm-1: MS for C12H13N02, m/e (relative intensity) 203 (M+, 26), 146 (11), 117 (7), 104 (100). Anal. Calcd for C12H13N02: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.00; H, 6.05; N, 6.81. B. I-Methyl-3-phenyl-3 ,4-dihydro-2-pyridinone and 1-Methyl-5 phenyl-3 , 4-dihydro-2-pyridinone. Sodium borohydride (9.31 g, 0.246 mol) was added to a solution of 1-methyl-3-phenyl-2,6-piperidindione, prepared as in part A hereinabove, (13.4 g, 65.8 mmol) in EtOH (875 mL) at -10 C. 2N HC1 in EtOH was added at a rate of 1.0 mL/min to the solution. After 28 hours the solution was acidified to pH 3 with 2N HC1 in EtOH. After stirring for 72 hours at -10'C. the solution was neutralized with 1% KOH in EtOH. The solution was filtered and the cake washed with CH2C12. The filtrate was concentrated in vacuo. The residue was taken up in Et20 (300 mL) and filtered to remove solids. Concentration in vacuo of the filtrate gave 15.6 g of liquid residue. The residue (13.0 g) was added to a refluxing solution of toluene (1.2 L) and TsOH (1.3 g.). The solvent was allowed to distill off for eight minutes followed by addition of Et3N (25 mL). The solvent was removed in vacuo and the residue chromatographed on an Si02 PrepPAK column eluting with 15% V/V EtOAc/hexane. The mixed fractions were rechromatographed eluting with 1/1 V/V EtOAc/hexane. Combination of the appropriate fractions afforded l-methyl-3-phenyl-3,4-dihydro-2pyridinone main product (3.80 g, 30.8%) and l-methyl-5-phenyl-3,4dihydro-2-pyridinone byproduct (1.61 g, 13.8%): Data for the main product 1H NMR (CDC13)E 2.59-2.69 (m, 2 H, CH2), 3.13 (s, 3 H, NCH3), 3.75 (dd, 1 H, J - 7.6, 8.9 Hz), 5.21 (dt, 1H, J - 4.5, 7.6 Hz, NCHCH), 6.08 (dt, 1 H, J - 1.6, 7.6 Hz, NCH), 7.23-7.38 (m, 5 H, arom.); IR (neat) 2936, 1661, 1378, 1244, 761, 697 cm-l, MS for C12H13NO, m/e (relative intensity) 187 (M+, 73), 118 (100), 90 (33), 73 (41), 70 (35), 41 (39). Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48; Found: C, 76.99; H, 6.96; N, 7.46. Data for the byproduct 1H NMR (CDC13)E 2.62-2.83 (m, 4 H, CH2), 3.18 (s, 3 H, NCH3) 6.45 (t, 1 H, J - 1.4 Hz, NCH), 7.22-7.41 (m, 5 H, arom.); IR (mineral oil mull) 2927, 1687, 1669, 1642, 1453, 1381, 1214, 761 cm 1. MS for C12H13NO, m/e (relative intensity) 187 (M+, 100), 158 (17), 144 (68), 96 (14), 91 (11), 73 (75). Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48; Found: 76.88; H, 7.05; N, 7.38. Example 10 1,4-dimethyl-2-piperidinone. A solution of (9.03 g.; 0.063 mol) of 6-hydroxy-1,4-dimethyl-2piperidinone, obtainable, e.g., by the procedure of Example 15, in 90 ml. of acetic acid was hydrogenated over 0.90 g. of 10% W/W palladium carbon catalyst at a pressure of 50 pounds per square inch (psi) for six hours. The resulting solution was then filtered through a filter (Celite) pad, and the filter pad was washed with diethyl ether. The filtrate was concentrated in a vacuum atmosphere to remove the bulk of the acetic acid. The residue was taken up in a small amount of methylene chloride and the mixture was extracted with three 18-ml portions of saturated sodium bicarbonate in water solution. The organic liquid layers were separated from the aqueous phase, combined and dried with magnesium sulfate, filtered and concentrated in vacuo. Traces of solvent were removed from the liquid residue under high vacuum with stirring. The titled product was obtained as a colorless liquid, weighing 7.26 g. (90.6% yield): 1H NMR (CDC13, 6) 1.03 (d, 3H, J - 6.4 Hz CHC¯3), 1.40-1.61 (m, 1H, CH), 1.82-2.07 (m, 2H, CH2), 2.41-2.58 (m, 2H, O-CCH2), 2.96 (s, 3H, NCH3), 3.29-2.26 (m, 2H, NCH2); 13C NMR (CDCl3, ppm) 169.7, 49.1, 40.4, 34.4, 31.0, 28.2, 21.0; IR (neat) 3524 (1120), 2953, 2927, 1644, 1506, 1338, 605 cm-1, MS for C7H13NO, m/e (relative intensity) 127 (M+, 93), 126 (31), 84 (17), 69 (23), 57 (30), 44(100). Anal Calcd for C7H13NO: C, 66.11; H, 10.30; N, 11.01; Found: C, 65.95; H, 10.39; N, 10.98. Example 11 4-Hydroxy-l,3,8,8-tetramethyl-3-azabicyclo[3.2.1]octan-2- one. A. l,6,8,8-Tetramethyl-[3.2.1] -6-aza-cycloocta-5,7-dione. The (+) glutaric anhydride derivative precursor compound (41.1 g. 0.225 mol) was added portionwise to 40% CH3NH2 in water (200 mL) at 500. After the addition, the solution was warmed to room temperature for one hour followed by concentration in vacuo. The residue was heated to 200 C for one hour followed by bulb to bulb distillation of the residue (b1.0 1050 0) to afford the subtitled imide as a white crystalline solid (28.8 g, 65.6%): mp 48.5000.; 1H NMR (CDCl3)E 0.95 (s, 3 H, CCH3), 0.97 (s, -3--R, GCH3), 1.32 (s, 3 H, OCCCH3), t.72-1.81 (m, 1 H, CHCH2), 1.92 (t, 2 H, J - 9.0 Hz, CCH2), 2.14-2.26 (m, 1 H, CHCH2), 2.72 (d, 1 H, J - 8.4 Hz, OCCH), 3.07 (s, 3 H, NCH3); 13C NMR (CDCl3)# 178.6, 176.6, 56.5, 54.3, 44.3, 34.1, 25.9, 25.1, 21.8, 19.3, 14.0; IR (mineral oil mull) 2961, 1722, 1685, 1672, 1326, 1275, 1029 cm-1, MS for C11H17N02, m/e (relative intensity) 195 (99, M+), 180 (58), 138 (48), 126 (24), 123 (23), 110 (23), 95 (100). Anal. Calcd for CllHl7NO2: C, 67.66; H, 8.78; N, 7.17; Found: C, 67.38; H, 9.02; N, 7.20. B. 8-Hydroxy-l,5 ,5,7-tetramethyl- [3.2.1] -7-aza-bicyclooctane (A) and 6-hydroxy-1,5,5,7-[3.2.l]-7-aza-bicyclooctane (B). Diisobutylaluminum hydride (293 mL, 1.0 M in CH2C12) was added to a solution of the l,6,8,8-tetramethyl-3.2.1]-6-aza-cycloocta-5,7- dione, from part A hereinabove imide (14.3 g, 73.2 mmol) in CH2C12 (150 mL) at -78µC. After one hour the solution was poured slowly onto 5% H2S04 (200 mL). The solution was extracted with CH2C12 (3x100 mL). The organic extracts were combined, dried (MgS04), filtered and concentrated in vacuo to 10.7 g. The residue was chromatographed on an SiO2 PrepPAK eluting with 3/1 EtOAc/hexane. The appropriate fractions were combined and concentrated in vacuo. The mixed fractions were combined and rechromatographed on an SiO2 PrepPAK eluting with 3/1 EtOAc/hexane. The appropriate fractions were combined and concentrated in vacuo to separate and give the first titled compound (A) (5.07 g, 35.1%) and (0,71 g, 4.98): Data for compound (A): mp 93-104"C; 1H NMR (CDC13)E 0.92 (s, 3 H, CH3), 0.96 (s, 3 H, CH3), 1.10 (s, 3 H, CH3), 1.69-2.15 (m, 4 H, CH2), 2.66 (d, 1 H, J - 10.7 Hz, OH), 2.87 (s, 3 H, CH3), 0.96 (s, 3 H, CH3), 1.10 (s, 3 H, CH3), 1.69-2.15 (m, 4 H, CH2), 2.66 (d, 1 H, J - 10.7 Hz, OH), 2.87 (s, 3 H, NCH3), 4.84 (dd, 0.9 H, J - 5.3, 10.7 Hz, NCHO); in the same spectra signals attributed to the minor epimer were noted at 8 2.93 (s, NCH), 4.60 (d, J - 11.9 Hz, NCHO); 13C NMR (CDC13) ppm (major epimer) 177.1, 82.5, 51.6, 51.0, 43.4, 35.5, 29.3, 19.0, 18.8, 14.2; 13C NMR (CDC13) ppm (minor epimer) 176.3, 87.8, 52.7, 50.2, 42.1, 35.5, 31.6, 25.5, 23.9, 20.9, 13.8; IR (mineral oil mull) 3368, 2932, 1638, 1625, 1336, 1059 cm-l, MS for C11H19N02, m/e (relative intensity) 197 (M+, 61), 138 (32), 95 (77), 83 (58), 69 (100). Anal. Calcd for C11H19N02: C, 66.97; H, 9.71; N, 7.10; Found: C, 67.29; H, 9.89; N, 7.16. Data for compound (B): mp 105-l080C; 1H NMR (CDCl3)8 0.91 (s, 6 H, CH3), 1.01 (s, 3 H, CH3), 1.42-1.71 (m, 2 H, CH2), 1.91-2.17 (m, 2 H, CH2), 2.31 (d, 1 H, J - 10.9 Hz, OH), 2.35 (d, 1 H, J - 8.0 Hz, OCCH), 2.87 (s, 3 H, NCH3), 4.41 (d, 1 H, J - 10.2 HZ, NCHO); in the same spectra a signal attributed to the minor epimer was noted at 6 2.94 (s, NCH3); 13C NMR (CDC13) ppm 175.5, 87.7, 54.4, 48.7, 43.2, 29.0, 27.0. 25.7, 22.7, 18.0, 16.4; in the same spectra peaks attributed to the minor epimer were noted at ppm 82.5, 23.3, 20.8, 19.0, 18.8, 16.8; IR (mineral oil mull) 3165, 2924, 1614, 1321, 1065, 623 cm-l; MS for C11H19N02, m/e (relative intensity) 197(M+, 26), 138 (45), 114 (81), 95 (100), 69 (25). Anal. Calcd for C11H19N02: C, 66.97; H, 9.71; N, 7.10. Found: C, 66.89; H, 9.91; N, 7.10 Example 12 3,4-Dihydro-1,4,4-trimethyl-2(1H)-pyridinone. A. 1,4,4-Trimethyl-2,6-piperidinedione. 4,4-Dimethyl-piperidinedione (imide) (25.0 g, 0.177 mol) in DMF (150 mL) was added to a solution of sodium hydride (7.44 g, 0.186 mol, 60% oil dispersion) at 0 C over one hour. The solution was stirred an additional 1.5 hours followed by addition of CH3I (31.0 g, 0.219 mol). The solution was allowed to warm to room temperature. After 18 hours H20 (100 mL) and Et20 (200 mL) were added. The organic layer was removed and the aqueous portion extracted with Et2O (4x125 mL). The organic layers were combined and washed with H20 (2x100 mL) and brine (1x100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Residual DMF was removed by placing the residue on a high vacuum pump at room temperature. After stirring overnight the oil solidified to provide the subtitled compound (20.7 g, 75.0%): mp 57-68"C (Lit. mp 61-630C); 1H NMR (CDC13)6 1.07 (s, 6 H, C(CH3)2), 2.52 (s, 4 H, CH2), 3.13 (s, 3 H, NCH3); IR (mull) 2960, 1711, 1683, 1666, 1307, 1277, 1118, 617 cm 1; HI RES MS for C8H13N02, Calcd: 155.0946; Found: 155.0955. m/e (relative intensity) 155 (M+, 68), 126 (28), 83 (49), 70 (68), 55 (100). B. 6-Ethoxy-1,4,4-trimethyl-2-piperidinone. Sodium borohydride (16.9 g, 0.45 mol) was added to the imide 1,4,4-trimethyl-2,6-piperldinedione from part A hereinabove (15.0 g, 96.1 mmol) in EtOH (1.0 L) at -10'C. 2N HC1 in EtOH was added at a rate of 1.6 mL/h to the reaction. After 20 hours the solution was cooled to -40 C and the pH adjusted to 3 with 2N HC1 in EtOH. The solution was warmed to -150C and after five hours the pH was adjusted to 7 with 1% KOH in EtOH. The solution was filtered and the filtrate was concentrated in vacuo. The residue was taken up in CH2C12 and filtered and the filtrate concentrated in vacuo. The residue was chromatographed on an SiO2 PrepPAK column eluting with 4/1 V/V EtOAc/hexane. The appropriate fractions were combined and concentrated in vacuo to afford the dione starting material (2.38 g, 15.7%) and the subtitled ethyl ether (12.11, 68%); 1H, NMR (CDC13)E 0.98 (s, 3 H, CCH3), 1.08 (s, 3 H, CCH3), 1.24 (t, 3 H, J - 7.0 Hz, OCH2), 1.72 (dd, 1 H, J - 6.8, 11.0 Hz, CHCH2) 1.82-1.93 (m, 1 H, CHCH2), 2.21-2.24 (m, 2H, OCCH2), 2.96 (s, 3 H, NCH3), 3.52 (q, 2 H, J - 7.0 Hz, OCH2), 4.59 (dd, 1 H, J - 5.5, 6.6 Hz, CH); 13C NMR (CDC13) ppm 170.3, 87.8, 62.1, 46.0, 40.7, 31.1, 29.7, 27.3, 15.4; IR (neat) 2956, 1657, 1451, 1326, 1063 cm-l, MS for C10H19N02, m/e (relative intensity) 185 (M+, 4), 140 (100), 129 (22), 101 (31), 83 (90). Anal. calcd for C10H19N02: C, 64.83, H, 10.34; N. 7.56; Found: C, 64.35; H, 10.34 N, 7.56. TLC (SiO2) Rf - 0.57, EtOAc C. 3.4-Dihydro-1,4,4-trimethyl-2-(lH)-pyridinone. The 6-ethoxy-1,4,4-trimethyl-2-piperidinedione from part B hereinabove (3.0 g, 16.2 mmol) was added to a refluxing solution of toluene and TsOH (0.3 g). Et3N (10 mL) was added after seven minutes. The flask was cooled and the contents concentrated in vacuo. The residue was chromatographed on an Si02 PrepPAK column eluting with 5/3 V/V EtOAc/hexane. Combination and concentration in vacuo of the appropriate fractions afforded the titled compound (1.78 g, 89.3%) as a colorless liquid: 1H NMR (CDC13)E 1.07 (s, 6 H, C(CH3)2, 2.36 (s, 2 H, OCCH2), 3.07 (s, 3 H, NCH3), 4.97 (d, 1 H, J 7.5 Hz, NC11CH), 5.90 (d, 1 H, J - 8.1 Hz NCH); 13C NMR (CDC13) ppm 169.3, 128.2, 117.3, 46.1, 33.4, 31.9, 28.0; IR (neat) 2957, 1679, 1657, 1366, 1281, 1019, 724 cm¯1; HI RES MS for C8H13N0, Calcd: 139.0991; Found: 139.0997. m/e (relative intensity) 139 (25), 124 (100), 96 (9), 82 (11). Anal. Calcd for C8H13NO: C, 69.03; H, 9.41; N, 10.06; Found: C, 68.97; H, 9.39; N, 10.01. TLC (Si02) Rf - 0.68, EtOAc Example 13 9-Ethoxy-8-methyl-8-azaspiro-[4.5]decan-7-one. A. 7,9-Dioxo-8-methyl-[4.5]-8-azaspirocyclodecane. The commercially available 7,9-dioxo-[4.5]-8-oxaspirocyclo- decane, a glutaric acid anhydride derivative (25.0 g, 0.149 mol) was added 40% CH3NH2 in H20 (150 mL) at 5etc. Following the addition the solution was warmed to room temperature. After stirring overnight the solution was concentrated in vacuo. The residue was heated at 2200C until no more water distilled. The pot residue was then distilled bulb to bulb (by 7 1050C) to afford the subtitled compound (22.8 g, 84.48): mp 53-54 "C; 1H NMR (CDC13)E 1.34-1.42 (m, 4 H, CH2), 1.54-1.67 (m, 4 H, CH2), 2.47 (s, 4 H, OCCH2), 3.00 (s, 3 H, NCH3); 13C NMR (CDC13) ppm 172.6, 44.9, 39.7, 37.8, 26.4, 24.3; IR (mineral oil mull) 2960, 1720, 1673, 1457, 1300, 1118, 633 c-1; MS for C10H15N02, m/e (relative intensity) 181 (100), 152 (42), 82 (43), 81 (44), 67 (90). Anal. Calcd for C10H15N02: C, 66.27; H, 8.34; N, 7.73. Found: C, 66.61; H, 8.25; N, 7.67. B. 9-Ethoxy-8-methyl-8-azaspiro[4.5]decan-7-one. Sodium borohydride (8.73 g. 0.23 mol) was added to a solution of the 7,9-dioxo-8-methyl-[4.5] -8-azaspirocyclodecane from part A hereinbove (9.0 g, 49.7 mmol) in EtOH (500 mL) at -10 C. 2N HC1 in EtOH was added at a rate of 1.0 mL/h to the reaction. After 20 hours the solution was adjusted to pH 3 by the addition of 2 N HCL in EtOH at -400C. The solution was warmed to -l50C and after six hours the pH was adjusted to 7 with 1% KOH in EtOH. The solution was filtered and the filtrate concentrated in vacuo The residue was taken up in CH2C12 and filtered and the filtrate concentrated in vacuo. The residue was chromatographed on an Si02 PrepPAK column eluting with 3/1 V/V EtOAc/hexane. The appropriate fractions were combined and concentrated in vacuo to yield some of the starting, unreacted imide (1.07 g, 11.9%) and the subtitled compound (8.41 g, 80.1%): 1H NMR (CDC13)E 1.24 (t, 3 H, J - 7.0 Hz, CH3), 1.38-1.70 (m, 7 H, CH2), 1.84-2.01 (m, 2 H, CHCH2), 2.27-2.31 (m, 2 H, OCCH2), 2.95 (s, 3 H, NCH3), 3.53 (q, 2 H, J - 7.0 Hz, OCH2), 4.58 (t, 1 H, J - 5.5 Hz); IR (neat) 2950, 1657, 1433, 1397, 1065 cm-l, MS for C12H21N02, m/e (relative intensity) 211 (?. 4), 166 (100), 129 (21), 109 (43), 101 (23). Anal. Calcd for C12H21N02: C, 68.21; H, 10.02; N, 6.63. Found: C, 67.93; H, 10.22; N, 6.53. TLC (Si02) Rf - 0.30, 3/1 V/V EtOAc/hexane. Example 14 1,3 ,3-Trimethyl-3 ,4-dihydro-2-pyridinone. Some l,3,3-trimethyl-6-ethoxy-2-piperidinone from Example 5, part B (3.7 g, 20.0 mmol) in toluene (5 mL) was added to a refluxing solution of toluene (175 mL) and TsOH (0.34 g). The solvent was removed by distillation for seven minutes followed by addition of Et3N (10 mL). The solution was cooled and the solvent removed in vacuo. The residue was chromatographed on an Si02 PrepPAK column eluting with 3/1 V/V EtOAc/hexane to afford the titled compound as a pale yellow liquid (1.35 g. 48.5%): 1H, NMR (CDC13)E 1.55 (s, 6 H, CCH3), 2.10 (dd, 2 H, J - 2.4, 14.7 Hz, CH2), 3.05 (s, 3 H, NCH3), 5.02-5.08 (m, 1 H, NCHCH), 6.00 (d, 1 H, J - 9.5 Hz, NCH); 13C NMR (CDCl3) ppm 175.2, 130,3, 104.3, 37.3, 35.6, 34.3, 24.9; IR (neat) 2965, 1665, 1387, 1319, 1236, 1023, 702 cm'l; MS for CgH13NO, m/e (relative intensity) 139 (M+, 100), 138 (65), 124 (25), 111 (13), 96 (34), 83 (30). Anal. Calcd for C8H13NO: C, 69.03; H, 9.41; N, 10.06; Found: C, 69.08; H, 9.40; N, 9.91. Example 15 Preparation of 6-hydroxy-l,4-dimethyl-piperidin-2-one. (Alternative method) To a flame dried 3-liter, 3-necked round bottom flask, equipped with an overhead stirrer and addition funnel, under a nitrogen atmosphere there was added 30.0 g (0.213 mol) of 1,4-dimethylglutarimide via a syringe and 600 ml. of dichloromethane via cannula. The resulting mixture was cooled to -78 C. Then 425 ml of lithium triethylborohydride was transferred to the addition funnel via a cannula. The lithium triethylborohydride1 was then added slowly to the 1,4-dimethylglutarimide/dichloromethane2 solution to form the titled compound. After 15 minutes of stirring the mixture to ensure reaction, a saturated solution of 300 ml of ammonium chloride in water was added to quench the reaction. The resulting mixture was allowed to warm to room temperature, and then the organic liquid layer was removed. The separate aqueous layer was washed three times with 300 mL portions of dichloromethane. The resulting organic liquid layers were combined, dried with magnesium sulfate, filtered and concentrated under vacuum to remove most of the solvent. The residue was chromatographed through a silica gel column, eluting with 5% V/V methanol in dichloromethane. The appropriate fractions of the eluate were combined and concentrated in a vacuum atmosphere to give the titled compound as a white solid, 26.2 g (86% yield): m.p. 79-83"C, 1H NMR (CDC13, 6): 1.03 (d, 3H, J - 6.4 HZ, CHCH3), 1.51-1.78 (m, 1H, CH2), 1.862.06 (m, 2H, CH2), 2.22-2.58 (m, 2H, CH2), 3.00 (s, 3H, NCH3), 4.60 (d, 1H, J - 7.0Hz, OH), 4.92-5.00 (m, 1H, OCH). IR (mull) 3210, 2927, 1627, 1610, 1318, 1056, 619 cm-l, Notes: 1. Lithium triethylborohydride must be stored and handled under nitrogen. 2. Lithium triethylborohydride reacts with dichlormethane at room temperature. Therefore, the reaction temperature should not exceed 40"C. 3. The byproduct of the reaction is triethylborohydride which is toxic. Example li 1,4,4-Trimethyl-3,4-dihydro-(1H)-pyridin-2-one. A 3.0 g (6.2 mmol) portion of 6-ethoxy-1,4,4-trimethylpiperidin- 2-one was added to a refluxing solution of toluene and 0.3 g of ptoluenesulfonic acid (TsOH). After seven minutes 10 mL of triethylamine was added. The reaction vessel flask was cooled and the contents concentrated in vacuo. The residue was chromatographed on a silica gel (PrepPak&commat;) column using a 5/3 V/V ethylacetate/hexane eluting mixture. Combination and concentration in vacuo of the appropriate fractions afforded the titled compound (1.78 g, 89.3%) as a colorless liquid: 1H NMR (CDC13)E 1.07 (s, 6 H, C(CH3)2), 2.36 (s, 2 H, OCCH2), 3.07 (s, 3 H, NCH3), 4.97 (d, 1 H, J - 7.5 Hz, NCHCH), 5.90 (d, 1 H, J - 8.1 Hz, NCH); 13C NMR (CDC13) ppm 169.3, 128.2, 117.3, 46.1, 33.4, 31.9, 28.0; IR (neat) 2957, 1679, 1657, 1366, 1281, 1019, 724 cm 1. HI RES MS for CgH13NO, Calcd: 139.0991; Found: 139.0997. m/e (relative intensity) 139 (25), 124 (100), 96 (9), 82 (11). Anal. Calcd for C8H13NO: C, 69.03; H, 9.41; N, 10.06. Found: C, 68.97; H, 9.39; N, 10.01. TLC (six2) Rf - 0.68, EtOAc. Example 17 6- (Ethylthio) -l ,4-dimethyl-2-piperidinone. A solution of the hydroxy lactam, 1,4-dimethyl-6-hydroxy-2piperidinone (5.0 g., 0.035 mol in CH2C12 (41 mL) was added to a solution of ethanethiol (26 mL, 0.35 mol) and TiC14 (0.40 mL, 3.5 mmol) which had been cooled to -200C.; it may be preferable to cool the ethanethiol to -20'C before adding the TiC14. The solution was stirred at -20 C. for four hours and then warmed to 0 C. Deionized water (7 mL) was added after 15 minutes. The organic layer was removed and the aqueous layer was washed with CH2C12 (7 mL). The organic layers were combined, washed with H20 (7 mL), dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed eluting with ethyl acetate. The appropriate fractions were combined and concentrated in vacuo. Solvent traces were removed from the residue under high vacuum. The colorless liquid titled product weighed 4.57 g (69.7%): 1H NMR (CDC13, 8) 1.01 (d, 3H, J - 6.4 Hz, CHCH3), 1.24-1.33 (m, 3H, CH2CH3), 1.76-2.10 (m, 3H, CHCH3 and CH2CHS), 2.30-2.54 (m, 2H, O-CCH2), 2.54-2.66 (m, 2H, SCH2), 2.542.66 (m, 2H, SCH2), 3.02 (s, 3H, NCH3), 4.40-4.45 (m, 1H, CHSCH2); 13C NMR (CDC13), ppm 170.0, 66.5, 40.3, 38.5, 34.0, 26.3, 24.1, 21.1, 15.1; IR (neat) 3493, 2956, 1652, 1455, 1392, 1282, 1250, 653 cm-l; MS for CgH17NOS m/e (relative intensity) 375 (40), 313(3), 189(9), 188(100), 126(43), 110(2),82(2), 69(94). Anal. Calcd for CgH17NOS: C, 57.72; H, 9.15; N, 7.48. Found: C, 57.23; H, 9.32; N, 7.75. The compounds described herein for use in the process of this invention are expected to be useful as the active drug ingredient in drug formulations used to treat a valuable warm-blooded animal patient including, humans, horses, dogs, cats, goats, pigs, and the like, for the reduction or prevention and control of atherosclerosis, for lowering serum cholesterol, for altering the relative distribution of circulating and esterified high density and low density lipo-protein-bound cholesterol fractions, and for the reduction of cholesterol in arterial tissues. The selected drug compound used in this invention can be administered orally or systemically, neat, but most usually in combination with one or more pharmaceutical composition ingredients in the form of tablets, hard or soft filled gelatin capsules and/or in sterile solutions, administered by sterile intramuscular or intravenous procedures. The effective dosage of one or more of these selected compounds will usually range from about 0.5 to about 50 mg. of drug compound per kilogram of body weight of the patient per day depending upon the drug compound selected, the patient body weight, the severity of the condition being treated, and other factors of concern to the patient's physician, until the HDL/LDL ratio in blood serum samples improves or until the atherosclerotic condition of the patient improves. A standard laboratory animal test to determine or to show in a preliminary way that the compounds are capable of reducing beta-lipoproteins and/or increase alpha-lipoproteins is the normocholesterolemic SEA Japanese quail test, where SEA means Susceptible to Experimental Atherosclerosis, can be described as follows: Methods and Materials: Male SEA Japanese quail, approximately four to six weeks of age, were reared at Miles Quail farm, Cobles, Michigan, U.S.A., from a colony of animals originally derived at The Upjohn Company, Kalamazoo, Michigan, U.S.A. Prior to drug testing, birds were randomly distributed into 10-15 groups of 10 quail each. They were housed individually in 10-cage units and fed a commercial diet (Purina Game Bird Layena, Ralton Purina Co., St. Louis, MO.) for seven days. Compounds (0.5 g for 50 mg/kg dose, 0.15 g for 15 mg/kg dose, 0.05 g for 5 mg/kg dose, etc.) were dissolved or dispersed in 50 ml of 95% ethanol and mixed with 1.2 kg of the diet. Control groups received diet mixed with ethanol alone, and positive control groups received diet mixed with l-propyl-2(1H)pyridone at 50 mg/kg. After one week on the diets, each bird was bled from the right jugular vein and serum samples were obtained after low speed centri fugation. Food intake was determined for each group by subtracting the weight of diet remaining at the end of the experiment from the weight of the starting diet. Beta and alpha lipoproteins were isolated from individual serum samples using PEG-8000 (polyethyleneglycol of about 8000 molecular weight) and glycine buffer, pH 9. Three hundred microliters of serum were mixed with 300 microliters of solution A (20 gram of PEG-8000 + 100 ml of glycine buffer, pH 9) using a Micromedic automatic pipette. Samples were allowed to stand at room temperature for 10 minutes and were centrifuged for 20 minutes at 2000 x g at 4-C. The resulting beta-lipoprotein pellet was dissolved in 300 microliters of solution B (10 ml Triton X-100 + 1000 ml distilled water). Cholesterol, triglycerides and total protein in alpha and beta lipoproteins were measured using Demand Autoanalyzer system Model AU 500 (Cooper Biomedical Inc.) and Standard Enzymatic reagents (Olympus Demand). All data were statistically analyzed using a one day classification design (G. W. Snedecor et al, "Statistitcal Method", ISU Press, Ames, IA (1969), pp. 258-296). All values were transformed to logarithms to achieve more homogenous within-group variances. The mean response for each test compound was compared with mean observed in the control animals and the LSD test (E. S. Pearson et al, Biometrika, 38 (1951), pp 112-130). Treated/control ratios of antilogts of the log means are presented. A P-value less than 0.004 is significantly different from control (g x 2000 means centrifugation at 2000 the force of gravity). The test results are presented in groups of tables for representative compounds used according to this invention. Data for the following compounds, in terms of ratios of the effect of test compound treated diet-fed quail to control diet-fed quails (T/C) for alpha-cholesterol (HDL), beta-cholesterol (LDL) and total cholesterol in the serum are provided in TABLE 1, attached hereinafter. Test Compound Number Compound Name 1. 6-Hydroxy-l-methyl-2-piperidinone 2 6-Ethoxy-1,4-dimethyl-2-piperidinone 3. 3,4-Dihydro-1,4-dimethyl-2(1H)pyridinone 4. 6-Hydroxy-1,4-dimethyl-2-piperidinone 5. 1,4-Dimethyl-2-piperidinone 6. 9-Hydroxy-8-methyl-8-azaspiro[4.5]decan-7-one 7. 8-Methyl-8-azaspiro[4.5]dec-9-en-7-one 8. 9-Ethoxy-8-methyl-8-azaspiro[4.5]decan-7-one 9. 6-Hydroxy-1,4,4-trimethyl-2-piperidinone 10. 6-Hydroxy-1,5,5-trimethyl-2-piperidinone 11. 6-Hydroxy-1,3,3-trimethyl-2-piperidinone 12. 3,4-Dihydro-1,3,3-trimethyl-2(1H)-pyridinone 13. 3,4-Dihydro-1-methyl-3-phenyl-2(1H)-pyridinone 14. 4-Hydroxy-1,3,8,8-tetramethyl-3-azacyclo[3.2.1]-octan-2-one 15. 6-Hydroxy-l-methyl-4-phenyl-2-piperidinone 16. 6-Ethylthio-1,4-dimethyl-2-piperidinone For example, looking at the data for compound 2 in Table 1, the data indicate that at a dosage of 50 mg./kg./day compound 2 lowered the beta-cholesterol (LDL) fraction approximately 30% (100-62-38), raised the alpha-cholesterol (HDL) fraction approximately 22% (100+22) and the total cholesterol content stayed even (1.00). Similarly, the data for compound 4 in Table 1 indicate that compound 4 lowered the beta cholesterol (LDL) fraction, raised the alphacholesterol (HDL) fraction and the total cholesterol fraction stayed even. In general it is desired to see the test drug compound diet (T) cause a lowering of the beta-cholesterol (LDL) content relative to the control diet group (C), indicated by a T/C number less than 1. The amount below 1 can be generally referred to as a percentage lowering by the treated group diet. It is also encouraging to see an increase (ratio) more than 100 in the T/C ratio for the alphacholesterol (HDL) content analysis but such an increase is not necessarily required for the test compound (T) to be of interest for further testing. It is also desirable to see the T/C ratio for the total cholesterol analysis for the given test compound be no higher than 1, indicating that the total cholesterol content in the test animal be no more in the drug treated animal, but preferably less than one than what appears in the control group animals for that test, that is, that the total cholesterol in the serum has not increased over the control. From the data in Table 1 for this group of test compounds, we believe these compounds used as a drug in a valuable animal and humans would lower blood serum LDL cholesterol (the beta fraction) and some of these compounds might also favor an increase in the HDL cholesterol (alpha fraction) Some of these compounds also effect a lowering of total cholesterol. So that, with the use of one or more of these compounds as a drug, we expect that these compounds would be useful to beneficially alter the total lipoprotein cholesterol distribution in the patient so that the body can more readily metabolize those lipoprotein cholesterol fractions in the body and thus prevent development of and/or reduce the presence of atherosclerotic lesions in the patient's arteries. Selected compounds are also tested in a more advanced eight-week quail test wherein the diet is intentionally increased in cholesterol content according to the following procedure: Adult, male, SEA Japanese quail were raised in gang cages on a commercial diet (Purina Game Bird Layena, Ralston Purina Company, St. Louis, MO) until five-six weeks of age. One hundred birds were randomly distributed into groups of 10 birds. These were housed individually in 10-cage units (Sani Battery unit B6010, Marsh Manufacturing, Garden Gover, CA) and fed a diet consisting of 48.258 each of yellow corn and soybean meal 0.5% NaCl, 2% cholesterol and 1% cholic acid. Drugs were mixed into the diet using a feed mixer (Hobart A-200) for 20 minutes. Two groups were controls and one group served as the positive standard. Birds in the latter group were treated with l-vinyl-2-pyrrolidinone. After eight weeks on the diet, the birds were bled via the right jugular vein and decapitated. The left and right brachiocephalic arteries and the thoracic aortas were removed in one piece and placed in saline. The aortas were cleaned free of blood, fat and adventitia, blotted dry, weighed and frozen. Frozen arteries were homogenized using a glass grinder in 2 ml of Solution A (hexane:isopropanol 3:2 V/V) and the homogenate was rinsed with 2 ml of the same solution. All homogenized samples were poured into 13 ml conical, glass test tubes. Then 3 ml of Solution B (solution A + 1.5* Triton X-100 surfactant) was added. The tubes were capped, mixed and left at room temperature overnight. Samples were then centrifuged at 2000 RPM for 30 minutes at 6"C. The clear solution was poured into another 13 ml conical, glass tube and the solvent was evaporated under nitrogen at 45"C. After all the organic solvent was evaporated, 450 p1 of Solution C (5% Triton X-100 surfactant in isopropanol V/V) was added to each tube, the tubes were capped, incubated in a water bath for 5-10 minutes at 450C and then mixed well. Total cholesterol, free cholesterol and triglycerides were run on Demand Autoanalyzer, Model AU 500 (Cooper Biomedical, Inc.) using standard enzymatic reagents (Olympus-Demand) with Triton X-100 added. Cholesterol ester was calculated as the difference between total cholesterol and free cholesterol. Serum samples were diluted 1:5 with saline. Lipids and total protein in serum were analyzed using the same methods as described previously for serum samples. Data were statistically analyzed as a one-way analysis pf variance. All values were transformed to logarithms to achieve more homogenous within-group variances. The mean response to each test compound was compared with the mean observed in the control animals using the least significant difference test. Results for compounds included within this invention in this above test are set forth in TABLE II parts (A) Serum Samples and (B) Artery Sample analyses. Looking at the data in Table IIA it can be seen, for example, that compound 4 lowers total serum cholesterol 59% (100-41 - 59) at a dose of 50 mg/kg/day. The other compounds shown in Table IIA (compounds &num;1, 2, 5, 10, 11 and 15) also caused decreases in total serum cholesterol; the range of decreases in total serum cholesterol was from 16% to 65%. It is desirable for these compounds to cause a decrease in total serum cholesterol, althought this effect is not considered to be essential in this test model. The data in Table IIB show that some of these compounds also decrease arterial levels of cholesterol and arterial weight. For example, compound 4 decreased free, esterified and total cholesterol in the artery as well as decreasing arterial weight 32% (100-68 32). Two of the compounds in Table IIB (&num;10 and &num;15) did not cause a significant decrease in arterial total cholesterol, but they did cause a significant decrease in arterial weight. In this assay it is preferable for a compound to decrease both arterial cholesterol and weight. However, a decrease in only arterial weight does indicate that the atherosclerotic lesion is smaller because of treatment with these compounds. From the data in Tables IIA and IIB we believe these compounds used as a drug in a valuable animal and humans would lower serum cholesterol and prevent the accumulation of cholesterol in arteries. So that by the use of one or more of these compounds as a drug, we expect that these compounds would be useful to prevent the development of and/or reduce atherosclerosis. This invention also relates to compositions containing a formula I compound as an active-ingredient in a pharmaceutical carrier. The compositions are useful in pharmaceutical dosage unit forms of the formula I compounds for systemic administration (oral, rectal and parenteral administration form) in therapy for treating and alle viating symptoms of atherosclerosis, elevated cholesterol levels and/or other than normal HDL/DL lipoprotein-bound cholesterol ratios, in blood serum fractions in humans and valuable animals, including dogs, cats and other commercially valuable and domestic animals. The term "dosage unit form" as used in this specification and in the claims refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing a çredetermined quantity for the essential active ingredient compound of this invention calculated to produce the desired effect, in combination with the required pharmaceutical means which adapt the said ingredient for systemic administration. The specification for the novel dosage unit forms of this invention are dictated by and directly dependent on the physical characteristics of the essential active ingredient and the particular effect to be achieved in view of the limitations inherent in the art of compounding such an essential active material for beneficial effects in humans and animals as disclosed in detail in this specification under exemplified embodiments, these being features of the present invention. Examples of suitable dosage unit forms in accordance with this invention are tablets, capsules, orally administered liquid preparations in suitable liquid vehicles, sterile preparations in suitable liquid vehicles for intramuscular and intravenous administration, sup positories and sterile dry preparations for the extemporaneous preparation of sterile injectable preparations in a suitable liquid vehicle. Suitable solid diluents or carriers for the solid oral pharmaceutical dosage unit forms are selected fron the group consisting of lipids, carbohydrates, proteins and mineral solids, for example, starch, sucrose, lactose, kaolin, dicalcium phosphate, gelatin, acacia, corn syrup, corn starch, talc and the like. Capsules, both hard and soft, are filled with compositions of the selected formula I compound or salt thereof ingredients in combination with suitable diluents and excipients, for example, edible oils, talc, calcium carbonate and the like and also calcium stearate. Liquid preparations for oral administration are prepared in water or aqueous vehicles which advantageously contain suspending agents, for example, methylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol and the like. In the case of injectable forms, the injectable formulation must be sterile and must be fluid to the extent that easy syringeabiliity exists. Such preparations must be stable under the conditions of manufacture and storage, and ordinarily contain in addition to the basic solvent or suspending liquid, preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and the like. In many cases, it is preferable to include osmotically active agents, for example sugars or sodium chloride in isotonic concentrations. Carriers and vehicles include vegetable oils, ethanol, polyols, for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like. Any solid preparations for subsequent extemporanoues preparation of sterile injectable preparations are sterilized, preferably by exposure to a sterilizing gas, for example, ethylene oxide. The aforesaid carriers, vehicles, diluents, excipients, preservatives, isotonic agents and the like constitute the pharmaceutical means which adapt the preparations for systemic administration. The pharmaceutical dosage unit forms are prepared in accordance with the preceding general description to provide from about 0.5 mg to about 50 mg of the essential active ingredient per dosage unit form, for administration to the patient one or more times per day, or slowly but continuously by intravenous drip methods in severe cases, depending upon the medical condition being treated, the age and weight of the patient and other factors of concern to the patient or his or her physician. TABLE I Normal Ouail Lipoprotein Assav Compound Dose T/C (p Value) T/C (p Value) T/C (p value) Number (mg/kg/day) Alpha Chol. Beta Chol. Total Chol. 1 50.0 1.30(0.002) 082(0.011) 1.17(0.021) 50.0 1.01(0.411) 0.72(0.037) 0.90(0.178) 2 5.0 1.02(0.264) 0.88(0.142) 0.97(0.459) 15.0 0.97(0.460) 0.77(0.021) 0.89(0.098) 50.0 1.22(0.003) 0.62(0.000) 1.00)0.397) 3 5.0 1.20(0.006) 0.98(0.489) 1.13(0.024) 15.0 1.25(0.002) 0.78(0.042) 1.09(0.046) 50.0 1.19(0.009) 0.65(0.001) 1.01(0.354) 4 50.0 1.23(0.022) 0.55(0.000) 1.00(0.369) 5.0 0.86(0.017) 0.92(0.301) 0.88(0.010) 15.0 0.86(0.022) 0.81(0.038) 0.84(0.002) 50.0 0.98(0.382) 0.63(0.000) 0.88(0.012) 5 50.0 1.07(0.257) 0.67(0.003) 0.95(0.282) 6 50.0 1.09(0.136) 0.93(0.318) 1.03(0.265) 50.0 1.17(0.039) 0.74(0.003) 1.05(0.382) 7 50.0 0.98(0.475) 0.61(0.000) 0.86(0.023) 50.0 0.89(0.059) 0.67(0.005) 0.79(0.001) 8 50.0 1.16(0.006) 0.72(0.005) 1.03(0.083) 9 50.0 1.19(0.098) 0.51(0.000) 0.98(0.305) 5.0 1.07(0.285) 0.80(0.027) 0.97(0.305) 15.0 1.06(0.294) 0.76(0.017) 0.96(0.227) 50.0 1.22(0.032) 0.53(0.000) 0.98(0.314) 5.0 1.28(0.007) 0.98(0.365) 1.17(0.029) 15.0 1.13(0.141) 0.68(0.001) 0.97(0.308) 50.0 1.37(0.002) 0.92(0.128) 1.21(0.011) 10 50.0 1.06(0.140) 0.56(0.000) 0.89(0.083) 5.0 1.09(0.169) 0.92(0.245) 1.03(0.314) 15.0 0.88(0.126) 0.73(0.010) 0.82(0.016) 50.0 1.02(0.462) 0.67(0.001) 0.89(0.071) 11 50.0 1.11(0.188) 0.60(0.000) 0.90(0.034) 5.0 0.86(0.092) 0.76(0.008) 0.84(0.025) 15.0 0.99(0.391) 0.81(0.111) 0.93(0.171) 50.0 0.90(0.190) 0.59(0.000) 0.80(0.006) Normal Ouail LiDoDrotein Assav (continued) Compound Dose T/C (p Value) T/C (p Value) T/C (p value) Number (mg/kg/day) Aloha Chol. Beta Chol. Total Chol. 12 50.0 1.13(0.132) 0.60(0.001) 0.97(0.367) 13 50.0 1.36(0.004) 0.82(0.045) 1.19(0.023) 14 50.0 1.13(0.059) 0.63(0.000) 0.98(0.415) 5.0 0.92(0.L79) 0.094(0.324) 0.95)9.066) 15.0 0.80(0.032) 0.085(0.092) 0.83(0.016) 50.0 0.89(0.062) 0.66(0.001) 0.82(0.001) 15 50.0 .06(0.208) 0.84(0.141) 0.98(0.498) 16 50.0 0.92(0.192) 0.63(0.000) 0.87(0.011) TABLE IIA DATA FOR COMPOUNDS DEMONSTRATING ANTI-ATHEROSCLEROTIC ACTIVITY (SERUM SAMPLES) Table I T/C (p Value) Compound Dose Tot. Chol. Number (mg/kg/day) 4 5.0 0.66(0.017) 15.0 0.73(0.049) 50.0 0.41(0.000) 100.0 0.56(0.001) 11 50.0 0.75(0.114) 5 50.0 0.68(0.028) 10 15 50.0 0.84(0.164) 1 50.0 0.68(0.028) 2 50.0 0.35(0.000) TABLE IB DATA FOR COMPOUNDS DEMONSTRATING ANTI-ATHEROSCLEROTIC ACTIVITY (ARTERY SAMPLES) Cmpd. Dose T/C (p Value) T/C (p Value) T/C (p Value) T/C (p Value) No. (mg/ Free Chol. Ester. Chol. Tol. Chol. Weight kg/day) 4 5.0 0.55(0.005) 0.90(0.458) 0.69(0.074) 0.65(0.000) 15.0 0.59(0.074) 0.87(0.487) 0.70(0.402) 0.71(0.001) 50.0 0,28(0.000) 0.46(0.014) 0.36(0.000) 0.68(0.000) 100.0 0.32(0.000) 0.55(0.000) 0.42(0.000) 0.70(0.000) 11 50.0 0.28(0.000) 0.62(0.004) 0.38(0.000) 0.65(0.000) 5 50.0 0.26(0.000) 0.39(0.000) 0.32(0.000) 0.63(0.000) 10 50.0 0.61(0.059) 1.25(0.133) 0.82(0.476) 0.81(0.042) 5 50.0 0.72(0.028) 1.40(0.105) 1.04(0.488) 0.84(0.034) 1 50.0 0.44(0.000) 0.97(0.398) 0.63(0.007) 0.69(0.001) 2 50.0 0.51(0.000) 0.40(0.000) 0.47(0.000) 0.74(0.000) GENERAL STRUCTURAL FORMULAE EMI41.1 GENERAL STRUCTURAL FORMULAE (CONTINUED) EMI42.1 PROCESS SCHEME I FOR MAKING EMI43.1

Claims: CLAIMS 1. A process for using a lactam compound of the formula EMI44.1 wherein R is hydrogen or CL to C6-alkyl; X is oxygen (-0-) or bivalent sulfur (-S-); Y is hydrogen or C1 to C6-alkyl, or -XY taken together represents hydrogen or C1 to C6-alkyl, or -XY is part of a double bond between the 5- and 6- position carbon atoms of the ring when R2 is also part of that double bond; R1 is hydrogen or C1 to C6-alkyl; R2 is part of the double bond between the 5- and 6-position lactam ring carbon atoms when -XY is part of that same double bond, and R3 is hydrogen, C1 to C6-alkyl or phenyl; or R2 and R3 are independently selected from the group consisting of hydrogen, C1 to C6-alkyl and phenyl; R4 and R5 are independently selected from the group consisting of hydrogen, C1 to C6-alkyl, or phenyl, and when one of R4 and R5 is phenyl, the other is hydrogen; or R4 and R5 are taken together with the carbon to which they are bonded to complete a spiro-cycloalkyl ring having from 4 to 6 methylene carbon atoms therein; R6 and R7 are independently selected from the group consisting of hydrogen and C1 to C6-alkyl or phenyl, and when one of R6 and R7 is phenyl, the other is hydrogen; and wherein R3 and R6 can be taken together to form a bridge ring forming connections where n is 2 or 3 across the lactam ring; ; provided that (I) when -XY and R2 form a double bond between the ring carbon atoms in the 5- and 6- positions, R1 are hydrogen, and R3 is selected from the group consisting of hydrogen, C1 to C6-alkyl and phenyl; (II) when X is oxygen or bivalent sulfur, Y is hydrogen or C1 to C6-alkyl; and (III) when -XY are taken together they represent hydrogen or C1 to C6-alkyl; to prepare a medicament useful for lowering the total cholesterol content or to alter the distribution of high density lipoprotein-bound cholesterol (HDL) relative to the low density lipoprotein-bound cholesterol (LDL) circulating in the blood of a warm-blooded animal patient. 2. A process according to claim 1 wherein the lactam compound of formula I is a compound of the formula EMI45.1 where in R is hydrogen or C1 to C6-alkyl; R1 and R3 are hydrogen; R4 and R5 are independently selected from the group consisting of hydrogen, C1 to C6-alkyl and phenyl, or R4 and R5 are taken together with the carbon to which they are bonded to complete a spiro cycloalkyl ring having from 4 to 6 methylene carbon atoms therein; R6 and R7 are hydrogen. 3. A process according to claim 1 wherein the lactam compound of formula I is a compound of the formula EMI46.1 wherein R is C1 to C6-alkyl; X is oxygen or bivalent sulfur; Y is hydrogen or C1 to C6-alkyl; R1 is hydrogen; R2 and R3 are each hydrogen; R4 is C1 to C6-alkyl and R5 is ydrogen, and R6 and R7 are each hydrogen 4. A process according to claim 1 wherein the lactam compound of formula I is a compound of the formula EMI46.2 where in R is C1 to C6-alkyl; X is oxygen or bivalent sulfur; Y is hydrogen or C1 to C6-alkyl; R1 is hydrogen; R2 is hydrogen or C1 to C6-alkyl; R4 and R5 are hydrogen or methyl; R7 is hydrogen or C1 to C6-alkyl, n is 2 to 3; 5. A process according to claim 2 wherein the lactam compound is selected from the group consisting of l-methyl-3,4-dihydro-2-pyridinone, 1,4-dimethyl-3,4-dihydro-2-pyridinone, 8-methyl-8-azaspiro[4.5]decan-9-ene-7-one, l,3,3-trimethyl-3,4-dihydro-2-pyridinone, and l-methyl-3-phenyl-3,4-dihydro-2(1H)-pyridinone. 6. A process according to claim 3 wherein the lactam compound is selected from the group consisting of 6-ethoxy-l-methyl-2-piperidinone, 6-hydroxy-l-methyl-2-piperidinone, 6-ethoxy-1,4-dimethyl-2-piperidinone, 6-hydroxy-1,4-dimethyl-2-piperidinone, 9-hydroxy-8-methyl-8-azaspiro[4/5]-decan-7-one. 9-ethoxy-8-methyl-8-azaspiro[4.5]-decan-7-one, 6-hydroxy-1,4,4-trimethyl-2-piperidinone, 6-hydroxy-1,5,5-trimethyl-2-piperidinone, and, 6-hydroxy-1,3,3-trimethyl-2-piperidinone. 7. A process according to claim 4 wherein the lactam compound of formula IV is 4-hydroxy-l,3,8,8-tetramethyl-3-azabicyclo[3.2]octan-2.one. 8. A compound selected from the group consisting of 1,4-dimethyl-6-ethoxy-2-piperidinone, 1,4-dimethyl-3,4-dihydro-2-pyridinone, 6-hydroxy-1,4-dimethyl-2-piperidinone, 9-hydroxy-8-methyl-8-azaspiro[4.5]-decan-7-one, 8-methyl-8-azaspiro[4/5]decan-9-ene-7-one, 9-ethoxy-8-methyl-8-azaspiro[4.5] -decan-7-one, 6-hydroxy-1,4,4-trimethyl-2-piperidinone, 6-hydroxy-1,3,3-trimethyl-2-piperidinone, l,3,3-trimethyl-3,4-dihydro-2-pyridinone, 3,4-dihydro-1-methyl-3-phenyl-2(1H)-pyridinone, and 4-hydroxy-l,3,8,8-tetramethyl-3-azabicyclot3.2.l]octan-2-one, 9. A compound according to claim 8 which is l,4-dimethyl-6-ethoxy- 2-piperidinone. 10. A compound according to claim 8 which is 1,4-dimethyl-3,4dihydro-2-pyridinone. 11. A compound according to claim 8 which is 6-hydroxy-1,4-dimethyl2-piperidinone. 12. A compound according to claim 8 which is 9-hydroxy-8-methyl-8 azaspuri[4.5]decan-7-one. 13. A compound according to claim 8 which is 8-methyl-8-azaspiro [4.5]decan-9-ene-7-one. 14. A compound according to claim 8 which is 9-ethoxy-8-methyl-8azaspiro[4.5]-decan-7-one. 15 A compound according to claim 8 which is 6-hydroxy-1,4,4trimethyl-2-piperidinone. 16. A compound according to claim 8 which is 6-hydroxy-1,3,3trimethyl-2-piperidinone. 17. A compound according to claim 8 which is 1,3,3-trimethyl-3,4- dihydro-2-pyridinone. 18. A compound according to claim 8 which is 3,4-dihydro-l-methyl-3phenyl-2(1H)-pyridinone. 19. A compound according to claim 8 which is 4-hydroxy-1,3,8,8 tetramethyl-3-azabicyclo[3.2,1]octan-2-one.

Inventors: SPILMAN CHARLES H, THOMAS EDWARD W, SPILMAN, CHARLES, H., THOMAS, EDWARD, W.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P9, C07D211, C07D221