OXO-ANALOGS OF MEVINOLIN-LIKE ANTIHYPERCHOLESTEROLEMIC AGENTS

Abstract: Mevinolin-like compounds of the structural formula: are disclosed wherein: R¹ is, e.g., hydrogen or C₁₋₄alkyl; E is -CH₂CH₂, -CH=CH-, or -(CH₂)₃-; and Z is wherein X is -O-or-NR⁹ wherein R⁹ is hydrogen or C₁₋₃alkyl; R⁷ is C₂₋₈alkyl; and R⁸ is hydrogen or -CH₃; wherein R¹⁰, R¹¹ and R¹² are independently, e.g., hydrogen, halogen or C₁₋₄alkyl; wherein n is 0-2 and R¹⁴ is halo or C₁₋₄alkyl; or wherein the dotted lines represent possible double bonds there being 0, 1 or 2 double bonds; m represents 1, 2 or 3; and R¹⁵ is methyl, hydroxy, C₁₋₄alkoxy, oxo, or halo. Those compounds are potent HMG-CoA reductase inhibitors possessing one less asymmetric centre.

Description: TITLE OF THE INVENTION OXO-ANALOGS OF MEVINOLIN-LIKE ANTIHYPER CHOLESTEROLEMIC AGENTS SUMMARY OF THE INVENTION This invention is concerned with novel compounds of structural formula I: EMI1.1 wherein Z is a variety of mono- and bi-carbocyclic moieties with various substituents well known to those skilled in the art of 3-hydrox-3-methyl- glutaryl Coenzyme A (HMG-CoA) reductase inhibitors useful in the treatment of familial hypercholesterolemia, hyperlipemia and atherosclerosis. The invention is also concerned with novel processes for the prepsration of the novel compounds; pharmaceutical formulations comprising a novel compound as active sngredient; and a method of treating familial hypercholesterolemia, hyperlipemia, and atherosclerosis. BACKGROUND OF THE INVENTION Over the past several years a number of structurally related antihypercholesterolemic agents acting by inhibition of HMG-CoA reductase have been reported in the patent literature and elsewhere. The compounds have varied from the natural fermentation products, compactin and mevinolin, EMI2.1 Compactin (R2-H) Mevinolin (R2=CH 3 to di- and tetrahydro derivatives thereof; to analogs with different esters in the 8-position of the polyhydronaphthalene moiety, to totally synthetic analogs, wherein the polyhydronaphthalene moiety is replaced by substituted mono- and bicyclic aromatics, and biphenyls. But in all instances the active compound included a 4-hydroxytetrahydropyran-2-one ring or the corresponding 315-dihydroxy acid, or derivatives thereof, formed by opening the pyranone ring such as: EMI3.1 4-hydroxytetrahydropyran-2-one 3,5-dihydroxy-acid In all of these compounds the 3,5-dihydroxy acid or corresponding lactone moiety is present and the particular stereochemistry depicted is essential for manifestation of the optimum enzyme inhibitory activity. Now with the present invention there are provided compounds structurally related to those lactones and dihydroxy acids that do not have the 5-hydroxy functionality, do not form a lactone ring, and are incapable of stereochemical variation at the 5-position of the acid because the 5-carbon is not asymmetric. On the contrary, the 5-carbon carries an oxo function which greatly facilitates the total synthesis of active compounds in that by eliminating one asymmetric center it is unnecessary to separate diastereoisomers or to conduct a stereoselective synthesis to obtain optimum enzyme inhibitory activity. It is believed that structures I are reduced in situ to generate the "active" inhibitors of structure II or Ila. The active compounds of this invention are useful in either the racemic form or as the 3(R)-isomer. Those compounds produced by total synthesis are obtained initially as racemates, but may be resolved by standard methods into 3(R)- and 3(S)-isomers. Compounds of Structure I which are synthesized starting from natural fermentation products such as mevinolin and its analogs are obtained as the optically pure 3(R)-isomers. DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention have structural formula: EMI4.1 wherein R1is 1) hydrogen, 2) C14alkyl, 3) 2,3-dihydroxypropyl, 4) alkali metal cation, such as Na , or K , or S) - ammonium of formula NR3R4-R5R6 wherein R3 R4, R5 and R6 are independently hydrogen or C1-4alkyl or two of R3 R4, R5 and R6 are joined together to form a 5 or 6-membered heterocycle such as pyrrolidino or piperidino with the nitrogen to which they are attached; E is - CH2CH2-, -CH=CH-, or (CH2)3-; ; and Z is 1) EMI5.1 wherein the dotted lines represent all of the possible oxidation states of the bicyclic system such as naphthalene, dihydro-, tetrahydro-, hexahydro-, octahydro-, and decahydronaphthalene; X is -O- or # NR9 wherein R9 is H or C1-3alkyl; R7 is C28alkyl; and R is H or -CH3; ; EMI5.2 wherein R10, R11 and R12 are independently a) hydrogen, b) halogen, such as bromo, chloro or fluoro, c) C1-4alkyl, d) halo-C1-4alkyl, e) phenyl either unsubstituted or substituted with one or more of i) C1-4alkoxy, ii) C1-4alkyl, iii) C2 8alkanoyloxy, or iv) halo-C1-4alkyl, v) halo, such as bromo, chloro or fluoro, f) OR wherein R13 is i) hydrogen, ii) C1-8alkanoyl, iii) benzoyl, iv) phenyl, v) halophenyl, vi) phenyl-C1-3alkyl, either unsubstituted or substituted with one or more of halogen, C1-4alkoxy, C1-4alkyl or halo-C1-4alkyl, vii) Cl¯galkyl, viii) cinnamyl, ix) halo-C1-4alkyl, x) allyl, xi) C3-6cycloalkyl-C1-3alkyl, xii) adamantyl-C13alkyl, EMI6.1 wherein n is 0-2, and R14 is halo such as chloro, bromo or fluoro, or C1-4 alkyl, and EMI6.2 wherein the dotted lines represent possible double bonds there being 0, 1 or 2 double bonds; m represents 1, 2 or 3; and R15 is 1) methyl, 2) hydroxy, 3) C14 alkoxy, 4) oxo or 5) halo. Preferred embodiments of the novel compounds are those in which: R1 is hydrogen, an alkali metal cation or an ammonium cation; E is -CH=CH- or -CH2CH2-; and Z is EMI7.1 wherein EMI7.2 is 2-methylbutyryl or 2,2dimethylbutyryl; EMI7.3 wherein R10, R11 and R12 are independently a) halogen, b) C14alkyl, c) halo-C1-4alkyl, d) phenyl with 1 to 3 substituents selected from halo, C1-4alkyl or C1-4alkoxy, e) OR13, wherein R13 is i) phenyl, ii) halophenyl, iii) phenyl substituted with 1-3 substituents selected from halogen, and C14alkyl, iv) phenyl-C1-3 alkyl, either unsubstituted or substituted with one or more of halogen, C1-4 alkoxy, C1-4 alkyl or halo-C1-4 alkyl; or EMI8.1 wherein n is 0, 1 or 2 and R14 is methyl and the ring system is naphthalene or 5,6,7,8tetrahydronaphthalene. One novel process for preparing the novel compounds of this invention is particularly useful when starting with compounds with a pre-formed 4-hydroxytetrahydropyran-2-one moiety or the corresponding 3,5-dihydroxy acid and is illustrated as follows: EMI9.1 wherein R16 is C1 4alkyl, especially methyl. After protecting the 4-hydroxyl of the lactone with a dimethyl-tert-butylsilyl group and preparing an alkyl ester by known procedures, the resulting 5-hydroxy of the open-chain acid is oxidized to the ketone. Suitable oxiding agents include: pyridinium chlorochromate in a chlorinated alkane such as methylene chloride or chloroform at about 0 to about 250C for about 1 to 4 hour; oxalyl chloride in dimethylsulfoxide at about -700 to about -400C for about 0.25 to 0.5 hours; trifluoroacetic anhydride in dimethylsulfoxide at about -700 to -400C for about 0.25 to 0.5 hour; and pyridinium dichromate in dimethyl formamide at 0 to 250C for 1 to 8 hours. The silyl ether group is then hydrolyzed by treatment with acetic acid and tetrabutylammonium fluoride in tetrahydrofuran. A related procedure is available for preparing compounds of this invention wherein E represents -CH2-CH2-. It obviates the need for protection of the 3-hydroxy group before oxidizing the 5-hydroxy and is represented as follows: EMI10.1 In the first step the dihydroxy compound is treated with activated manganese dioxide in a chlorinated hydrocarbon such as chloroform, methylene chloride, 1,2-dichloroethane or the like at about 00C to 400C preferably at ambient temperature for about 15 to 30 hours. The 5-oxo compound produced is then treated with tri-n-butyltin hydride and tetrakis(triphenylphosphine)palladium(0) in an ethereal solvent such as ether, THF, l,2-dimethoxyethane or the like, at about ambient temperature for about 15 to 30 hours. Alternatively-, if the 3-hydroxy-5-oxocarboxylic acid moiety is being synthesized, the 5-oxo group is realized directly by a process which is another embodiment of this invention and which is exemplified as follows: EMI10.2 The nitro compound is treated with a C1 alkyl 3-butenoate, preferably methyl 3-butenoate, and an aromatic isocyanate such as p-toluoyl isocyanate, p-chlorophenyl isocyanate, phenyl isocyanate or the like, preferably the latter, and a bit of triethylamine as a catalyst in an inert organic solvent such as toluene, benzene, xylene, or the like at about 15 to 300C, preferably about room temperature for about 5 to about 24 hours. The resulting isoxazoline is reduced catalytically with palladium on carbon, platinum oxide or the like in an inert organic solvent such as a C1¯3alkanol, acetic acid or the like containing a little water in the presence of boric acid at about 15 to 300C and about 1-2 atmospheres of hydrogen pressure for about 1 to 6 hours. The ester resulting from either of the foregoing synthetic schemes is readily saponified to the corresponding carboxylic acid salt by treatment with aqueous alkali such as potassium, or sodium hydroxide to form the potassium or sodium salt respectively or with a quaternary ammonium hydroxide of formula HONR 3R4R5R6 wherein none of the R groups is hydrogen to form the quaternary ammonium salt. Acidifying any of these salts with a mineral acid results in the formation of the free carboxylic acid. The acids are readily converted back to salts by treatment with the appropriate base or to esters by treatment with a C1 alkanol in the presence of a catalytic amount of an acid such as hydrogen chloride at about 50 to 1000C for about 3 to 6 hours. The previously described salts are converted back to esters by treatment with an alkyl halide such as 2,3-dihydroxypropyl iodide in an aprotic solvent such as N,N-dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide at about 25 to 1000C for about 18 to 36 hours. Those compounds, wherein Z is of the subtype (4), i.e., in which the polyhydronaphthalene moiety is substituted with hydroxy or oxo, halo or alkoxy are prepared from the corresponding substrate in which the 5-oxo group of the heptenoic acid is already in place. The processes, as applied to the 5-hydroxy analogs or the corresponding lactones, are disclosed in EP application 76601, British patents 2,111,052 and 2,075,013, EP application 74222, and Japanese published applications J58010572 and J57155995. Using those processes there are produced the following EMI12.1 Double Bonds ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ R7 3,4:4a,5 l-methylpropyl 6-OH 3,4:4a,5 l,l-dimethylpropyl 6-OH 4,4a l-methylpropyl 3-OH, 5-OH 4,4a l,l-dimethylpropyl 3-OH, 5-OH 4,4a:5,6 l-methylpropyl 3-OH 4,4a:5,6 l,l-dimethylpropyl 3-OH - l-methylpropyl 6-OH - l,l-dimethylpropyl 6-OH - l-methylpropyl 3-OH - l,l-dimethylpropyl 3-OH 4,4a l-methylpropyl 6-OH 4,4a l,l-dimethylpropyl 6-OH 4,4a l-methylpropyl 3-OH 4,4a l,l-dimethylpropyl 3-OH 4a,5 l-methylpropyl 6-OH 4a,5 l,l-dimethylpropyl 6-OH 4a,5 l-methylpropyl 3-OH 4a,5 l,l-dimethylpropyl 3-OH 4,4a l-methylpropyl 3-OH, 5=0 4,4a l,l-dimethylpropyl 3-OH, 5=0 4,4a l-methylpropyl 3=0, 5=0 4,4a l,l-dimethylpropyl 3=0, 5=0 - l-methylpropyl 3-OH, 5-OH - l,l-dimethylpropyl 3-OH, 5-OH 4,4a l-methylpropyl 3-C1, 5-C1 4,4a l,l-dimethylpropyl 3-C1, 5-C1 4,4a l-methylpropyl 3-OCH3, 5-OH 4,4a l,l-dimethylpropyl 3-OCH3, 5-OH 4,4a l-methylpropyl 3-OC2H5, 5-OH 4,4a l,l-dimethylpropyl 3-OC2H5, 5-OH 4,4a l-methylpropyl 3-OC4Hg, 5-OH 4,4a l,l-dimethylpropyl 3-OC4Hg, 5-OH 4,4a l-methylpropyl 6-CH3, 3-OH, 5-OH 4,4a l,l-dimethylpropyl 6-CH3, 3-OH, 5-OH The novel pharmaceutical composition of this invention comprises at least one of the compounds of formula I in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated in a classical manner utilizing solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations. A typical capsule for oral administration contains active ingredient (25 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by asceptically placing 25 mg of a water soluble salt of sterile active ingredient into a vial, asceptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 ml of physiological saline, to produce an injectable preparation. The novel method of treating atherosclerosis, familial hypercholesterolemia, or hyperlipemia of this invention comprises administration of an effective antihypercholesterolemic amount of a compound of Formula I to a patient in need of such treatment. The dose to be administered depends on the unitary dose, the symptoms, and the age and the body weight of the patient. A dose for adults is preferably between 20 and 2,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day. The compounds of this invention also have useful antifungal activities. For example, they may be used to control strains of Penicillium sp., Aspergillus niger, Cladosporium sup., Cochliobolus miyabeorus and Helminthosporium cynodnotis. For those utilities they are admixed with suitable formulating agents, powders, emulsifying agents or solvents such as aqueous ethanol and sprayed or dusted on the plants to be protected. This invention can be illustrated by the following examples. EXAMPLE 1 7-[2(S),6(R)-Dimethyl-8(S)-(2(S)-methylbutyryloxy)- 1,2,6,7,8,8a(R)-hexahydro-l(S)-naphthyll-3(R)-hydroxy- 5-oxoheptanoic acid Step A: Preparation of 6(R)-[2-(8(S)-(2(S)-methyl butyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8, 8a(R)-hexahydronaphthyl-l(S))-ethyl]-4(R)- (dimethyl-tert-butylsilyloxy) -3,4,5, 6-tetra- hydro-2H-pyran-2-one Mevinolin (4.04 g, 0.01 mol) was dissolved in 25 ml of dry dimethylformamide (DMIF) and treated with 2.7 g (0.04 mol) of imidazole and 3 g (0.02 mol) of dimethyl-tert-butylsilyl chloride, and the solution was stirred under nitrogen overnight. The mixture was poured into 200 ml of ether, washed with 2 X 50 ml of water, 1 X 25 ml of 1N hydrochloric acid, 1 X 25 ml of saturated aqueous sodium carbonate and 2 X 50 ml of brine, dried over MgSO4 and concentrated to dryness. The residue was chromatographed on a "Still" column of silica gel (6.0 X 17.7 cm, 230-400 mesh) by elution with 45% ether in hexane (V/V) collecting 20 ml fractions. The fractions containing the product (21-52) were combined and concentrated to dryness to give 5.2 of oil. Step B: Preparation of Methyl 7-[2(S), 6(R)-Dimethyl 8(S)-(2(S)-methylbutyryloxy)-1,2,6,7,8,8a(R) hexahydro-1(S)-naphthyl]-3(R)-(tert-butyldi methylsilyloxy)-5(R)-hydroxyheptanoate The silyl ether from Step A (1.03 g, 0.002 mol) was dissolved in 10 ml of methanol, treated with 2 ml of 1N aqueous sodium hydroxide and the mixture was stirred for 2 hours at room temperature. The methanol was evaporated under reduced pressure and the residue was freed of water by azeotropic distillation of 4 X 10 ml of toluene. The solid residue was dissolved in 5 ml of dry DMF, treated with 300 lull, (0.68 g, 0.0048 mol) of methyl iodide and the mixture was stirred overnight at room temperature. The mixture was poured into 100 ml of ether and washed with 20 ml of water and 20 ml of brine, dried (MgSO4) and concentrated to dryness to give 1.0 g of residue (contained DMF). This material was chromatographed on a "Still" column of silica gel (6.0 X 17.7 cm, 230-400 mesh) by elution with 45% ether in hexane (V/V) collecting 20 ml fractions. Fractions 32-50 containing the major component were combined and concentrated to dryness to give 576 mg of oily product. Step C: Preparation of Methyl 7-[2(S), 6(R)-Dimethyl 8(S)-(2(S)-methylbutyryloxy)-1,2,6,7,8,8a(R) hexahydro-l (S) -naphthyl] -3(R) - (tert-butyldi- methylsilyloxy)-5-oxoheptanoate The ester from Step B (586 mg, 0.001 mol) was dissolved in 10 ml of methylene chloride and cooled to OOC. Pyridine chlorochromate (0.56 g, 0.0026 mol) was added and the stirred mixture was allowed to warm spontaneously over 2 hours. Additional pyridine chlorochromate (224 mg, 0.001 mol) was added and stirring was continued another hour. The methylene chloride was evaporated in vacuo. The residue was suspended in 5 ml. ether, placed on top of a 4 X 40 cm column of silica gel (70-230 mesh) and eluted with 40% ether in hexane (V/V) collecting 15 ml fractions. Fractions 10-23 were combined and concentrated to 130 mg. of oily product. Step D: Preparation of Methyl 7-[2(S), 6(R)-Dimethyl 8(S)-(2(S)-methylbutyryloxy)-1,2,6,7,8,8a(R)- hexahydro-l (S) -naphthyl] -3(R) -hydroxy-5-oxo- heptanoate The silyl ether from Step C (230 mg, 0.00024 mol) was dissolved in 5 ml of tetrahydrofuran (THF) and treated with 54 lil, (0.057 9, 0.00095 mol) of acetic acid and 710 l (1M in THF, 0,00071 mol) of tetrabutylammonium fluoride (Bu4N F) and the mixture was stirred overnight at room temperature. Another 57 1ll of acetic acid and 710 'k1 of Bu4N F were added and stirring was continued an additional 24 hours. The mixture was poured into 100 ml of ether and washed with 1 x 5 ml of 1N hydrochloric acid, 1 x 10 ml of saturated aqueous sodium bicarbonate and 2 x 10 ml of brine and dried (MgSO4). Concentration to dryness gave 120 mg of an oil. The oil was chromatographed on a "Still" column of silica gel (1.5 x 17.7 cm, 230-400 mesh) by elution with 5% acetone in methylene chloride (v/v) collecting 5 ml fractions. Fractions 12-20 containing the product were combined and concentrated to dryness to give 53 mg of solid (m.p. 64-66 C). Recrystallization of a sample from hexane gave material with m.p. 67-680C. Analysis for C25H3806 (434.55): Calc: C, 69.09; H, 8.81. Found: C, 69.30; H, 9.38. Step E: Preparation of 7-[2(S) ,6(R)-Dimethyl-8(S)- (2(S)-methylbutyryloxy)-1,2,6,7,8,8a(R)-hexa hydro-l (S) -naphthyl] -3(R) -hydroxy-5-oxohept- anoic acid The ester from Step D (43 mg, 0.0001 mol) was dissolved in 5 ml of methanol and treated with 2 ml of 0.1N sodium hydroxide (0.0002 mol) and stirred overnight at room temperature. The methanol was evaporated in vacuo and the residue was acidified with 1N hydrochloric acid and extracted with ether. The ether extract was washed with 3 x 10 ml of brine and dried over MgSO4. Concentration to dryness provided 36 my of solid which after recrystallization from ether/hexane had m.p. 102-1030C. Analysis for C24H3606 (420.53): Calc: C, 68.54; H, 8.63. Found: C, 68.57; H, 8.88. Employing the procedure substantially as described in Example 1, Steps A through E, but substituting for the mevinolin used in Step A, equimolar amounts of the lactones described in Table I there are produced the corresponding 5-oxocarboxylic acids, salts, and esters also described in Table I in accordance with the following reaction scheme: : EMI19.1 TABLE I EMI20.1 EMI20.2 <tb> R8 <SEP> R8 <SEP> X <SEP> a <SEP> b <tb> 2(S)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> double <tb> 2(S)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> single <tb> 2(R)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> single <tb> acetyl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2(S)-methylbutyryl <SEP> H <SEP> 0 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> H <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> H <SEP> 0 <SEP> single <SEP> single <tb> 2,2-dim$thyLbutyryl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 2-methyl-2-ethylbutyryl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 2-methylbutyryl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 4-fluorobenzoyl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 4-fluar-opheylacety1 <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 4-tert-butylbenzoyl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> acetyl <SEP> -CH3 <SEP> NH <SEP> double <SEP> double <tb> acetyl <SEP> -CH3 <SEP> NCH3 <SEP> single <SEP> single <tb> 202-dimethylbutyryl <SEP> -CH3 <SEP> NCH3 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> NH <SEP> double <SEP> double <tb> EMI21.1 R10 R11 R12 6-(4-fluoro-3-methylphenyl)- 2-methyl 4-methyl 6-(4-fluorophenyl)- 2chloro chloro 6-(4-chlorophenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl)- 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl)- 2-methyl 4-methyl 6-(3,5-dimethylphenyl)- 2-chloro 4-chloro 6- (3,4-dichlorophenyl) - 2-methyl 5-methyl 6-(4-fluorophenyl)- 2-methyl 4-methyl 6-(4-fluoro-3-methylphenyl)- 2-methyl 4-chloro 6-(4-fluorobenzyloxy) 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl) 2-chloro 4-methyl EMI21.2 n R14 ¯¯¯¯¯¯¯¯¯¯¯¯¯ 1 2-methyl naphthyl 0 - naphthyl 2 2,6-dimethyl naphthyl 1 2-methyl 5,6,7,8-tetra hydronaphthyl EXAMPLE 2 7-(4'-Fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl)-3 hydroxy-5-oxoheptanoic acid Step A: Preparation of Methyl 3-(4'-Fluoro-3,3',5- trimethyl-[1,1'biphenyl]-2-yl)-propionate A solution of 1.716 g (13 mmol) of dimethyl malonate in 5 ml of DMF was added dropwise to a stirred suspension of sodium hydride (50% oil dispersion, 0.624 g, 13 mmol) in 15 ml of DMF and stirring was continued under nitrogen for 0.5 hour. The mixture was treated with ice bath cooling, with a solution of 3.1 g (11.8 mmol) of 2-chloromethyl-4' fluoro-3,3',5-trimethyl-l,l'-biphenyl in 10 ml of DMF. The resulting mixture was stirred at 0 C for 10 minutes, at room temperature for 0.5 hour, and heated on a steam bath for 1 hour. Sodium chloride (0.759 g, 13 mmol) and 0.234 ml (13 mmol) of water were added to the reaction mixture and it was heated at reflux for 16 hours. The reaction mixture was cooled, poured into cold water and extracted with ether twice. The combined extracts were washed with dilute hydrochloric acid, dried over MgSO4, filtered and concentrated to dryness in vacuo to give 3.42 (11.38 mmol, 96%) of the desired product as a brown oil which was used -directly in the next step without purification. nmr (CDCl3) s :2.27 (6H, a methyl singlet and a methyl doublet), 2.3 (2H, m), 2.34 (3H, s), 2.9 (2H, m), 3.60 (3H, s), 6.84 (H, bs), 7.1-7.2 (4H, m). Step B: Preparation of 3-(4'-fluoro-3,3',5-trimethyl Il,l'-biphenyl]-2-yl)propanol A solution of 3.42 g (11.4 mmol) of the ester from Step A in 25 ml of ether was added dropwise to a stirred suspension of 0.38 g (10 mmol) of lithium aluminum hydride in 75 ml of ether at OOC under nitrogen. After completion of the addition, the mixture was stirred at room temperature for 15 minutes, refluxed for 1 hour, cooled in ice and treated with successive additions of 0.4 ml of water, 0.35 ml of 20% (w/v) aqueous sodium hydroxide and 1.1 ml of water. The resulting mixture was stirred at OOC for 0.5 hour, treated with anhydrous MgSO4, stirred for 15 minutes and filtered. The filtrate was concentrated in vacuo to give 3.08 g (11.3 mmol) (99%) of pale yellow oily product which was used directly in the next step without purification. nmr (CDCl3)S :1.45-1.7 (2H, m), 2.25 (6H, s), 2.33 (3H, s), 2.45 -2.7 (2H, m), 3.45 (2H, t, J=6Hz), 6.85 (H, bs), 6.95-7.2 (4H, m). Step C: Preparation of 2-(3-Bromopropyl)-4'-fluoro 3,3'r5-trimethyl-l,l'-biphenyl A solution of 1.08 g (4 mmol;) of PBr3 in 10 ml of ether was added dropwise to a stirred solution of 3.08 g (11.3 mmol) of the alcohol from Step B in 40 ml of ether at 0 C. The mixture was stirred at room temperature for 1 hour, refluxed for 0.5 hour, cooled to room temperature, poured into ice water and extracted with ether. The extract was washed with water and saturated aqueous sodium bicarbonate, dried over MgSO4, filtered and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel (230-400 mesh) by elution with methylene chloride/hexane (1:3, v/v). Combination and evaporation of the appropriate fractions gave the desired bromide as a pale yellow oil, (1.9 g, 5.67 mmol, 48% overall Steps A, B and C). nmr (CDCl3) & : 1.7-2.0 (2H, m), 2.27 (6H, a methyl singlet and a methyl doublet), 2.35 (3H, s), 2.55-2.8 (2H, m), 3.23 (2H, t, J=6Hz), 6.85 (H, bs), 6.95-7.2 (4H, m). Step D: Preparation of 4'-Fluoro-3,3',5-trimethyl 2-(3-nitropropyl)-l,l'-biphenyl A solution of 1.90 g (5.66 mmol) of the bromopropyl compound from Step C in 5 ml of ether was added to a stirred suspension of 1.31 g (8.5 mmol) of silver nitrite in 5 ml of ether at OOC. The resulting mixture was stirred under nitrogen at 0 C for 7 hours, warmed to room temperature and stirred for an additional 16 hours. Another 1.0 g of silver nitrite was added and stirring was continued for another 20 hours. The reaction mixture was filtered and the filtrate was concentrated to leave a residue which was purified by flash chromatography on silica gel (230-400 mesh) by elution with methylene chloride/ hexane (1:4, v/v) to give, first, the recovered starting bromide, then the desired product, (0.64 g, 2.12 mmol, 78%). nmr (CDC13)s :1.8-2.2 (2H, m), 2.30 (6H, a methyl singlet and a methyl doublet), 2.33 (3H, s), 2.5-2.7 (2H, m), 4.18 (2H, t, J=6Hz), 6.88 (H, bs), 7.0-7.2 (4H, m). IR (neat) 1550, 1500 cm1. Step E: Preparation of Methyl 3-12-(4'-fluoro-3,3',5- trimethyl[l,l'-biphenyl]-2-yl)ethyl]-4,5-di- hydro-5-isoxazoleacetate A solution of 0.1 g (1.0 mmol) of methyl 3-butenoate and 0.174 ml (1.6 mmol) of phenyl isocyanate in I ml of toluene was added with stirring to a solution of 0.240 g (0.8 mmol) of the nitropropyl compound from Step D and 2 drops of triethylamine in 1 ml of toluene. The resulting mixture was stirred at room temperature for 3 hours. Additional quantities of methyl 3-butenoate (0.1 ml), triethylamine (0.1 ml) and phenyl isocyanate (0.15 ml) were added successively and stirring was continued overnight (18 hours). The mixture was filtered and the filtrate was concentrated in vacuo to a residue which was purified by flash chromatography on silica gel (230-400 mesh), first being eluted with methylene chloride to remove the impurities. Continued elution with acetone/methylene chloride (1:50, v/v) gave the desired product (0.218 g, 0.57 mmol, 71%) as a pale viscous oil. nmr (CDC13)t: 2.28 (6H, s), 2.32 (3H, s), 2.2-3.0 (6H, m), 3.70 (3H, s), 4.6-5.0 (H, m), 6.85 (H, bs), 7.0-7.2 (4H, m). IR (neat) 1735 cm 1. Analysis calculated for C23H26FNO3: C 72.04; H, 6.83; N, 3.65. Found: C, 72.35; H, 6.99; N, 3.88. Step F: Preparation of Methyl 7-(4'-fluoro-3,3',5 trimethyl-[l,l'-biphenyl]-2-yl)-3-hydroxy-5- oxoheptanoate A mixture of 0.1 g (0.26 mmol) of the isoxazoline from Step E, 50 mg of 10% palladium on carbon catalyst and 48 mg (0.78 mmol) of boric acid in 3 ml of methanol and 0.3 ml of water was stirred under hydrogen (1 atmosphere) at room temperature for 2.5 hours. The mixture was filtered and the filtrate was poured into brine and extracted with ether. The ethereal extract was washed with 5% (w/v) aqueous sodium bicarbonate solution, dried (MgSO4), filtered and evaporated to dryness to give 92 mg (0.23 mmol, 89%) as a pale yellow oil. nmr (CDC13) s: 2.30 (6H, a methyl singlet and a methyl doublet), 2.33 (3H, s) , 2.35-2.5 (6H, m) , 2.75-2.85 (2H, m), 3.30 (H, d), 3.70 (3H, s), 4.37 (H, m), 6.83 (H, bs), 6.95-7.1 (4H, m). IR (neat) 3450, 1710 cm 1 Step G: Preparation of 7-(4'-fluoro-3,3',5-trimethyl- [1,1'-biphenyl]-2-yl)-3-hydroxy-5-oxoheptanoic acid Employing the procedure substantially as described in Example 1, Step E, the ester from Step G of this Example 2 is saponified to the subject 5-keto acid. Employing the procedure substantially as described in Example 2, Steps A through G, but substituting for the chloromethylbiphenyl employed in Step A thereof, equimolar amounts of the chloromethyl compounds described in Table II, there are produced the 5-keto esters, salts and acids also described in Table II in accordance with the following reaction sequence: : EMI27.1 TABLE II EMI28.1 R10 R11 R12 6-(4-fluorophenyl)- 2-chloro 4-chloro 6-(4-chlorophenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl)- 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl)- 2-methyl 4-methyl 6-(3,4-dimethylphenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl)- 2-methyl 5-methyl 6-(4-fluorophenyl)- 2-methyl 4-methyl 6- (4-fluoro-3-methylphenyl) - 2-methyl 4-chloro 6-(4-fluorobenzyloxy) 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl)- 2-chloro 4-methyl EMI28.2 n R14 1 2-methyl naphthyl 0 - naphthyl 2 2,6-dimethyl naphthyl 1 2-methyl 5,6,7,8-tetra hydronaphthyl EXAMPLE 3 7-(2,4-Dichlorophenyl)-3-hydroxy-5-oxoheptanoic acid Step A: Preparation of Methyl 7-(2,4-Dichlorophenyl)- 3-hydroxy-5-oxo-6-heptenoate Activated manganese dioxide (40 g) was added to a solution of methyl 7-(2,4-dichlorophenyl)-3,5dihydroxy-6-heptenoate (6.8 g, 21.3 mmol) in chloroform (600 mL) and the black suspension was vigorously stirred at ambient temperature for 20 hours. After filtration and evaporation of the solvent the residual amber oil (4.5 gr 1 major spot on TLC with Rf 0.61 on Whatman MK6F silica using CHC13-MeOH; 19:1 as eluent) was chromatographed on a Still column to obtain the product (3.9 g, 58%) as a pale yellow oil which solidified on standing, m.p. 77-790C; NMR (CDC13) :2.57 (2H, d, J=6Hz, -CH2CO2-), 2.93 (2H, d, J=6Hz, -CH2-CO-), 3.70 (3H, s, -CO2CH3), 4.4-4.8 (H, m, -CH(OH)-), 6.67 (H, d, J=16 Hz, =CH-CO), 7.1-7.7 (3H, m. ArH), 7.93 (H, d, J=16 Hz, =CH). Analysis for C14H14Cl204. Calcd.: C, 53.02; H, 4.45. Found: C, 53.25; H, 4.50. Step B: Preparation of Methyl 7-(2,4-Dichlorophenyl) 3-hydroxy-5-oxoheptanoate Tributyltin hydride (450 pL, 1.7 mmol) was added dropwise over 1-1/2 hours to a stirred solution of the ene-one ester from Step A (320 mg, 1 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) in dry THF (5 mL) at ambient temperature under N2. After standing at 200C overnight the light-brown solution was distributed between water (100 mL) and ether (150 mL). The organic layer was separated and washed with water (2 x 100 mL), dried and evaporated. The residual oil (1 major spot on TLC with Rf 0.39 vis-a-vis 0.35 for the starting ene-one ester on Whatman MK6F silica using CHC13-MeOH; 99:1 as eluent) was chromatographed on a Still column to obtain the product (260 mg, 81%) as a pale amber gum; NMR (CDC13) J :2.5-2.525 (2H, m, -CH2CO2-), 2.57-2.73 (2H, m, -COCH2C(OH)-), 2.77 (2H, t, J=7.5 Hz, AR-CH2CH2CO-), 2.98 (2H, t, J=7.5 Hz, Ar-CH2CH2CO-), 3.71 (3H,;s, -OO2CH3), 4.45-4.51 (H, m, -CH(OH)-). Analysis for C14Hl6Cl204 Calcd.: C, 52.68, H, 5.05. Found: C, 52.47; H, 5.20. Step C: Preparation of 7-(2,4-dichlorophenyl)-3 hydroxy-5-oxoheptanoic acid Employing the procedure substantially as described in Example 1, Step E, the ester from Step B of this Example 3 is saponified to the subject 5-oxo acid.

Claims: WHAT IS CLAIMED IS 1. A compound of structural formula: EMI31.1 wherein: R1 is 1) hydrogen, 2) C1-4alkyl, 3) 2,3-dihydroxypropyl, 4) alkali metal cation, or + 3 4 5 6 5) ammonium of formula R R R wherein R3 R4 R5 and R6 are independently hydrogen or C1 4alkyl or two of R , R4 R5 and R6 are joined together to form a 5- or 6-membered heterocycle with the nitrogen to which they are attached; E is -CH2CH2, -CH=CH-, or -(CH2)3-; and Z. is EMI32.1 wherein X is -O- or -NR9 wherein R9 is hydrogen or C1-3alkyl; R7 is C2-8alkyl; and is hydrogen or -CH3; EMI32.2 wherein R10, R11 and R12 are independently a) hydrogen, b) halogen, such as bromot chloro or fluoro, c) C1-4alkyl, d) halo-C1-4alkyl, e) phenyl either unsubstituted or substituted with one or more of i) C1-4alkoxy, ii) C1-4alkyl, iii) C2-8alkanoyloxy, iv) halo-C1-4alkyl, or v) halo, f) OR13 wherein R13 is i) hydrogen, ii) C2-8alkanoyl, iii) benzoyl, iv) phenyl, v) halophenyl, vi) Phenyl-C1-3alkyl, either unsubstituted or substituted with one or more of halogen, C1-4alkoxy, C14alkyl or halo-C1-4alkyl, vii) C19alkyl, viii) cinnamyl, ix) halo-C1-4alkyl, x) allyl, xi) C3-6cycloalkyl-C1-3alkyl, or xii) adamantyl-C13alkyl; EMI33.1 wherein n is 0-2 and R14 is halo or C1-4 alkyl; and EMI33.2 wherein the dotted lines represent possible double bonds there being 0, 1 or 2 double bonds; m represents 1, 2 or 3; and R15 is 1) methyl, 2) hydroxy, 3) C1-4 alkoxy, 4) oxo, or 5) halo. 2. The compound of Claim 1 wherein: is hydrogen, an alkali metal cation or an ammonium cation; E is -CH-CH- or -CH2CH2-; and z is EMI34.1 wherein EMI34.2 is 2(5)-methylbutyryl or 2,2-dimethylbutyryl; EMI34.3 wherein R10, R11 and R12 are independently a) halogen, b) C1-4alkyl, c) halo-C1-4alkyl, d) phenyl with 1 to 3 substituents selected from halo, C1-4alkyl or C1-4alkoxy, e) OR13, wherein R13 is i) phenyl, ii) halophenyl, or iii) phenyl substituted with 1-3 substituents selected from halogen and C1-4alkyl, iv) phenyl-C1-3 alkyl, either unsubstituted or substituted with one or more of halogen, C1-4 alkoxy, C14 alkyl or halo-C1-4 alkyl; or EMI35.1 wherein n is 0, 1 or 2, and R14 is methyl, and the ring system is naphthyl, or 5,6,7, 8-tetrahydronaphthyl. 3. The compound of Claim 2 selected from: EMI35.2 EMI36.1 <tb> <SEP> 0 <tb> <SEP> 711 <tb> <SEP> R <SEP> C- <SEP> R8 <SEP> X <SEP> a* <SEP> b <tb> <SEP> o <tb> <SEP> R71c- <SEP> 8 <SEP> X <SEP> a* <SEP> b <tb> 2tS)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> double <tb> 2(S)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> single <tb> 2(R)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> O <SEP> single <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> single <tb> acetyl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2(S)-methylbutyryl <SEP> H <SEP> 0 <SEP> double <SEP> double <tb> 2(S)-methylbutyryl <SEP> H <SEP> 0 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> H <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> H <SEP> 0 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 2-methyl-2-ethyl- <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> <SEP> butyryl <tb> 2-methylbutyryl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 4-f <SEP> luorobenzoyl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 4-fluorophenyl- <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> <SEP> acetyl <tb> 4-tert-butylbenzoyl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> acetyl <SEP> -CH3 <SEP> NH <SEP> double <SEP> double <tb> acetyl <SEP> -CH3 <SEP> NCH3 <SEP> single <SEP> single <tb> 2,2-dimethyl-butyryl <SEP> -CH3 <SEP> NCH3 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> NH <SEP> double <SEP> double <tb> * When a=single bond, the rings are trans-fused. EMI37.1 R10 Rll R12 6-(4-fluoro-3-methylphenyl)- 2-methyl 4-methyl 6-(4-fluorophenyl)- 2chloro chloro 6-(4-chlorophenyl)- 2-chloro 4-chloro 6- (3,4-dichlorophenyl) 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl) 2-chloro 4chloro 6-(3,4-dichlorophenyl) 2-methyl 4-methyl 6-(3,5-dimethylphenyl)- 2-chloro 4-chloro 6- (3,4-dichlorophenyl) - 2-methyl 5-methyl 6-(4-fluorophenyl) 2-methyl 4-methyl 6-(4-fluoro-3-methylphenyl)- 2-methyl 4-chloro 6-(4-fluorobenzyloxy) 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl)- 2-chloro 4-methyl EMI37.2 EMI38.1 <SEP> 0 <tb> n <SEP> 1" <tb> 1 <SEP> 2-methyl <SEP> naphthyl <tb> naphthyl <tb> 2 <SEP> 2,6-dimethyl <SEP> naphthyl <tb> 1 <SEP> 2-methyl <SEP> 5,6,7,8-tetra <tb> <SEP> hydronaphthyl <tb> 4 . An antihypercholesterolemic pharmaceutical composition comprising a pharmaceutical carrier and an effective antihypercholesterolemic amount of a compound as claimed in Claim I. 5. The formulation of Claim 4 wherein the antihypercholesterolemic compound is as claimed in Claim 2. 6. The formulation of Claim 5 wherein the antihypercholesterolemic compound is as claimed in Claim 3 7. A process for the preparation of a compound of structural formula: EMI39.1 wherein: RÚ is 1) hydrogen, 2) C1-4alkyl, 3) 2,3-dihydroxypropyl, 4) alkali metal cation, or 5) ammonium of formula NR R4R5R6 wherein R3, R4, RS and R6 are independently hydrogen or C1-4alkyl, or two of R , R , R and R are joined together to form a 5- or 6-membered heterocycle with the nitrogen to which they are attached; E is -CH2CH2, -CH=CH-, or -(CH2)3-; and 2 is EMI39.2 wherein X is -O- or ,NR9 wherein is hydrogen or C1-3alkyl; R7 is C2-8alkyl; and R8 is hydrogen or -CH3; EMI40.1 wherein R10 R11 and R12 are independently a) hydrogen, b) halogen, such as bromo, chloro or fluoro, c) C1-4alkyl, d) halo-C1-4-alkyl, e) phenyl either unsubstituted or substituted with one or more of i C1-4alkoxy, ii C1-4alkyl, iii) C2-8alkanoyloxy, or iv) halo-C1-4alkyl, v) halo, f) OR13 wherein R13 is i) hydrogen, ii) C2-8alkanoyl, iii) benzoyl, iv) phenyl, v) halophenyl, vi) phenyl-C1-3-alkyl, either unsubstituted or substituted with one or more of halogen, C1-4alkoxy, C1-4alkyl or halo-C1-4alkyl, vii) C1-9alkyl, viii) cinnamyl, ix) halo-C1-4alkyl, x) allyl, xi) C3-6cycloalkyl-C1-3alkyl, or xxi) adamantyl-C1-3alkyl; EMI41.1 wherein n is 0-2 and R14 is halo or C14 alkyl, which comprises treating a compound of structural formula: : EMI41.2 wherein R16 is C1 4alkyl, with an oxidizing agent to produce the compound of structural formula: EMI41.3 followed by desilylation to produce the compound of structural formula: EMI42.1 followed by treatment with alkali to @@@@@@@ produce the product wherein R16 is an alkali metal cation, followed by acidification to produce the compound wherein R16 is a hydrogen ion. CLAIMS FOR THE CONTRACTING STATE AT WHAT IS CLAIMED IS: 1. A process for the preparation of a compound of structural formula: EMI43.1 wherein: R1 is 1) hydrogen, 2) C1-4alkyl, 3) 2,3-dihydroxypropyl, 4) alkali metal cation, or 5) ammonium of formula NR R4R5R6 wherein R , R4, R5 and R6 are independently hydrogen or C1-4alkyl, or two of R3, R4, R5 and R6 are joined together to form a 5- or 6-membered heterocycle with the nitrogen to which they are attached; E is -CH2CH2, -CH=CH-, or -(CH2)3-; and 2 is EMI43.2 wherein X is -O- is or # NR9 wherein R9 is hydrogen or C1-3alkyl, R7 is C2-8alkyl; and R8 is hydrogen or -CH3; EMI44.1 wherein R10, R11 and R12 are independently a) hydrogen, b) halogen, such as bromo, chloro or fluoro, c) C1-4alkyl, d) halo-C1-4-alkyl, e) phenyl either unsubstituted or substituted with one or more of i C1-4alkoxy, ii C1-4alkyl, iii) C2-8alkanoyloxy, or iv) halo-C1-4alkyl, v) halo, f) OR13 wherein R13 is i) hydrogen, ii) C2-8alkanoyl, iii) benzoyl, iv) phenyl, v) halophenyl, vi) phenyl-Cl¯3alkyl, either unsubstituted or substituted with one or more of halogen, C1-4alkoxy, C1-4alkyl or halo-Cl¯4alkyl, vii) C1-9alkyl, viii) cinnamyl, ix) halo-Cl¯4alkyl, x) allyl, xi) C3-6cycloalkyl-C1-3alkyl, or xxi) adamantyl-C1-3alkyl; ; EMI45.1 wherein n is 0-2 and R14 is halo or C1-4 alkyl, which comprises treating a compound of structural formula: EMI45.2 wherein R16 is C1-4alkyl, with an oxidizing agent to produce the compound of structural formula: EMI45.3 followed by desilylation to produce the compound of structural formula: EMI46.1 followed by treatment with alkali to produce the product wherein R16 is an - alkali metal cation, followed by acidification to produce the compound wherein R16 is a hydrogen ion. 2. The process of Claim 1 wherein: R1 is hydrogen, an alkali metal cation or an ammonium cation; E is -CH=CH- or -CH2CH2-; and z is EMI46.2 wherein EMI46.3 is 2(S)-methylbutyryl or 2,2-dimethylbutyryl; EMI46.4 wherein R10, R11 and R12 are independently a) halogen, b) C1-4alkyl, c) halo-C1-4alkyl, d) phenyl with 1 to 3 substituents selected from halo, C1-4alkyl or C1-4alkoxy, e) OR13, wherein R13 is i) phenyl, ii) halophenyl, or iii) phenyl substituted with 1-3 substituents selected from halogen and C1-4alkyl; or iv) phenyl-C13 alkyl, either unsubstituted of substituted with one or more of halogen, C1-4 alkoxy, C14 alkyl, or halo-C1-4 alkyl; or EMI47.1 wherein n is 0, 1 or 2, and R14 is methyl and the ring system is naphthalene or 5,6,7,8-tetrahydronaphthalene. 3. The process of Claim 2 for the preparation of a compound selected from: EMI48.1 <tb> <SEP> H <tb> <SEP> R <tb> <SEP> o <SEP> Wo <tb> <SEP> R7 <SEP> + <SEP> x <SEP> / <tb> <SEP> + <SEP> CE3 <tb> <SEP> 1 <SEP> 3 <tb> <SEP> O <SEP> Rs <tb> <SEP> R78- <SEP> R <SEP> X <SEP> a* <SEP> b <tb> 2(S)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> double <tb> 2(S)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> single <tb> 2(R)-methylbutyryl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> O <SEP> single <SEP> double <tb> 2,2-dim-thFlbutyryl <SEP> -CH3 <SEP> 0 <SEP> single <SEP> single <tb> acetyl <SEP> -CH3 <SEP> 0 <SEP> double <SEP> double <tb> 2(S)-methylbutyryl <SEP> H <SEP> 0 <SEP> double <SEP> double <tb> 2(S)-methylbutyryl <SEP> B <SEP> 0 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> H <SEP> 0 <SEP> double <SEP> double <tb> 2, <SEP> 2-dimethylbutyryl <SEP> B <SEP> 0 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 2-methyl-2-ethyl- <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> <SEP> butyryl <tb> 2-methylbutyryl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 4-fluorobenzoyl <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> 4-fluorophenyl- <SEP> -CH3 <SEP> NH <SEP> single <SEP> single <tb> <SEP> acetyl <tb> 4-tert-butylbenzoyl <SEP> rH3 <SEP> NH <SEP> single <SEP> single <tb> acetyl <SEP> -CH3 <SEP> NH <SEP> double <SEP> double <tb> acetyl <SEP> -CH3 <SEP> NCH3 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> INCH3 <SEP> single <SEP> single <tb> 2,2-dimethylbutyryl <SEP> -CH3 <SEP> NH <SEP> double <SEP> double <tb> * When <RTI ID=48.1> single bond, the rings are trans-fused. EMI49.1 R1 R11 R12 6-(4-fluoro-3-methylphenyl)- 2-methyl 4-methyl 6-(4-fluorophenyl)- 2-chloro 4-chloro 6-(4-chlorophenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl) 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl 2-chloro 4-chloro 6-(3,4-dichlorophenyl) 2-methyl 4-methyl 6-(3,5-dimethylphenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl)- 2-methyl 5-methyl 6-(4-fluorophenyl) 2-methyl 4-methyl 6-(4-fluoro-3-methylphenyl)- 2-methyl 4-chloro 6-(4-fluorobenzyloxy) 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl) 2-chloro 4-methyl EMI49.2 EMI50.1 <tb> <SEP> 14 <SEP> % <tb> nR14 <tb> 1 <SEP> 2-methyl <SEP> naphthyl <tb> 0 <SEP> - <SEP> naphthyl <tb> 2 <SEP> 2,6-dimethyl <SEP> naphthyl <tb> 1 <SEP> 2-methyl <SEP> 5,6,7,8-tetra <tb> <SEP> hydronaphthyl <tb> 4. A process for the preparation of a compound of formula EMI50.2 where in R1 is 1) hydrogen, 2) C1-4alkyl, 3) 2, 3-dihydroxypropyl, 4) alkali metal cation, or + 5) ammonium of formula NR3R4R5R6 wherein R3, R4, R5 and R6 are independently hydrogen or C1-4alkyl or two of R3, R4, R5 and R6 are jointed together to form a 5- or 6-membered heterocycle with the nitrogen to which they are attached; ; E is -CH2CH-, or -(CH2)3-, and Z is EMI51.1 wherein R10, R11 and R12. are independently a) hydrogen, b) halogen, such as bromo, chloro or fluoro, c) C1-4alkyl, d) halo-C1-4alkyl, e) phenyl either unsubstituted or substituted with one or more of i) C1-4alkoxy, ii) C1-4alkyl, iii) C2-8alkanoyloxy, iv) halo-C1-4alkyl, or t) halo, f) OR13 wherein R13 is i) hydrogen, ii) C2-8alkanoyl, iii) benzoyl, iv) phenyl, v) halophenyl, vi) phenyl-C1-3alkyl, either unsubstituted or substituted with one or more of halogen, C1-4alkoxy, C1-4alkyl or halo-C1-4alkyl, vii) C1 galkyl, viii) cinnamyl, ix) halo-C1-4alkyl, x) allyl, xi) C3¯6cycloalkyl-Cl¯3alkylf or xii) adamantyl-C1-3alkyl; ; EMI52.1 wherein n is 0-2, and R14 is halo, or C1-4 alkyl which comprises reacting the compounds EMI52.2 to produce the compound of structural formula: EMI52.3 followed by catalytic reduction to produce the desired compound wherein -1 is R16; followed by treatment with alkali to produce the product wherein R1 is an alkali metal cation, followed by acidification to produce the compound wherein R1 is a hydrogen ion. 5. The process of Claim 4 wherein: is hydrogen, en alkali metal cation or an ammonium cation; E is -CH2CH2-: and Z is EMI53.1 wherein R10, R11 and R12 are independently a) halogen, b) C1-4alkyl, c) halo-C1-4alkyl, d) phenyl with I to 3 substituents selected from halo. C1-4alkyl or C1-4alkoxy, e) OR , wherein it13 is i) phenyl, ii) halophenyl, or iii) phenyl substituted with 1-3 substituents selected from halogen and C1-4alkyl; or iv) phenyl-C1-3 alkyl, either unsubstituted or substituted with one or more of halogen, C1-4 alkoxy, C1.4 alkyl, or halo-C1-4 alkyl; or EMI54.1 wherein n is 0, 1 or 2, and R14 is methyl and the ring system is naphthalene or 5,6,7,8-tetrahydronaphthalene, 6. The process of Claim 5 for preparation of a compound selected from: EMI54.2 R10 R11 R12 6- (4-fluoro-3-methylphenyl) - 2-methyl 4-methyl 6-(4-fluorophenyl)- 2-chloro 4-chloro 6- (4-chlorophenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl) 2-chloro 4-chloro 6- (4-fluoro-3-methylphenyl) 2-chloro 4-chloro 6-(3,4-dichlorophenyl) 2-methyl 4-methyl 6-(3,5-dimethylphenyl)- 2-chloro 4-chloro 6-(3,4-dichlorophenyl)- 2-methyl 5-methyl 6- (4-fluorophenyl) 2-methyl 4-methyl 6-(4-fluoro-3-methylphenyl)- 2-methyl 4-chloro 6-(4-fluorobenzyloxy) 2-chloro 4-chloro 6-(4-fluoro-3-methylphenyl) 2-chloro 4-methyl EMI55.1 <tb> and <tb> <SEP> .1 <SEP> 0 <tb> <SEP> ii <tb> <SEP> 0 <tb> <SEP> *4)l <tb> <SEP> n <SEP> R14 <SEP> X <tb> <SEP> 1 <SEP> SII1hyl <SEP> Alphthy <tb> <SEP> O <SEP> Alphthy <tb> <SEP> 2 <SEP> ' <SEP> LR{14 <SEP> U <SEP> 2,6-dimethyl <SEP> nspthyl <tb> <SEP> 1 <SEP> 2-methyl <SEP> oephthyl <tb> <SEP> 1 <SEP> 2,6-dimethyl <SEP> nephthyi <tb> <SEP> bydronsptathyl <tb> 7. A process for the preparation of O compound of structural formula EMI55.2 wherein Z is as defined in Claim 1, which comprises treating a compound of structural formula: EMI55.3 with activated manganese dioxide to produce the compound of structural formula: EMI56.1 followed by treatment with tri-n-butyltin hydride and tetrakis (triphenylphosphine)palladium (0).

Inventors: HOFFMAN, WILLIAM F., LEE, TA JYH, STOKKER, GERALD E.
Applicants: MERCK & CO. INC.
Application year: 1984
Main classification: C07C59
IPC codes: C07C67, A61K31, A61P3, C07C69, C07F7, C07C51, C07C233, A61P9, C07D261, C07C59, C07C33, C07C205