SE503210C2 - Phosphorus-containing HMG-CoA-Reductase Inhibitor, New Intermediates and Methods - Google Patents

Abstract

Compounds which are useful as inhibitors of cholesterol biosynthesis and thus as hypocholesterolemic agents have the structure including salts thereof, wherein R is OH, lower alkoxy or lower alkyl; R is H or alkyl; X is -O- or -NH-; n is 1 or 2 Z is a hydrophobic anchor, such as wherein the dotted lines represent optional double bonds. New intermediates used in preparing the above compounds, e.g. compounds in which the OH group is silane blocked, pharmaceutical compositions containing such compounds and a method for using such compounds to inhibit cholesterol biosynthesis are also provided.

Description

503 210 wherein E represents a direct bond, a C 1-3 alkylene bridge or a vinylene bridge and the various Rs represent a plurality of substituents.

The activity reported in the British patent is less than 1% of that of compactin.

U.S. Pat. 4,375,475 to Willard et al. Disclose hypocholesterolemic and hypolipemic compounds having the structure H O š wherein A is H or methyl; E is a direct bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or -CH = CH-; R 1, R 2 and R 3 are each selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, phenyl, phenyl substituted with halogen, C 1-4 alkoxy, C 2-8 alka-haloalkyl and OR 4, wherein R 4 is C 1-4 alkyl, C 1-9 -alkyl, cannamyl, C 1-4 haloalkyl, allyl, α-α-alkyl-C phenyl C 1-3 alkyl, wherein in each of the substituents are selected from halogen, C 1-4 alkoxy, C 1-4 alkyl or C 1-4 haloalkyl; and corresponding dihydroxy acids which are obtained from the hydrolynoyloxy, C 1-4 alkyl or C 1-4 H, C 2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl, 1-3 alkyl, adamantyl-C 1-3 alkyl or substituted tical opening of the lactone ring and the pharmaceutically acceptable only the salts of said acids and C 1-4 alkyl and phenyl, di- 1-3 methylamino- or acetylamino-substituted C 1-4 alkyl esters 1-3 of the dihydroxy acids; wherein all the compounds are enantiomers with a 4R configuration in the tetrahydropyran group of the trans-racemate shown in the above formula.

WO 84/02131 (PCT / EP83 / 00308) (based on US-P-443 668, filed November 22, 1982 and US-P-548,850, filed November 4, 503,210, 1983) in the name of Sandoz AG , refers to heterocyclic analogs of mevalonolactone and derivatives thereof having the structure wherein one of R and RO is and the other is primary or secondary C 1-6 alkyl, C 3-6 cycloalkyl or phenyl- (CH 2) m -r 4 C 1-4 alkyl, C 1-4 trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, wherein R is hydrogen, alkoxy, (except t-butoxy), R 5 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, alkyl, C alkoxy, fluorine or chlorine and R is hydrogen, 1-2 C1-2 m is 1, 2 or 3, with the proviso that both R 5 and R 5a must be hydrogen when R 4 is hydrogen, R 5a must be hydrogen when R 5 is hydrogen, no more more than one of R 4 and R 5 is trifluoromethyl, not more than one of R 4 and R 5 is phenoxy and not more than one of R 4 and R 5 is benzyloxy, R 2 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy (except t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R 3 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, with the proviso that R 3 must be hydrogen when R 2 is hydrogen, not more than one of R 2 and R 3 is tri fluoromethyl, not more than one of R 2 and R 3 is phenoxy and not more than one of R 2 and R 3 is benzyloxy.

X is - (CH) n- or -CH = CH- (n = 0, 1, 2 or 3), 2 sus 210 4 R e _ 5 4 3 2 1 Z ar -cH-cH -c-cH -cooH * I | Wherein R is hydrogen or C 1-4 alkyl in free acid form or in form 6 1-3 of a physiologically hydrolyzable and acceptable ester or a .alpha.-lactone thereof or in salt form.

GB 2162-179-A relates to naphthyl analogs of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure Me HG wherein R 1 = 1-3C alkyl; Z is a group of the formula Z1 or Z2; -CHCH CHCH COOR Å 2. 2 7 OH OH (zl) (22) R = H, a hydrolyzable ester group or a cation. 7 European patent no. 164 698-A relates to the preparation of lactones useful as anti-hypercholesterolemic agents by treating an amide with an organic sulfonyl halide RSSOZX, after which the protecting group Pr is removed. 503 210 5 * l O 5 * fl Pro '3 4 R sozx H0 - 0 H NR R ._._._;> H ~ OH Q I az åz R vari X = halogen; Pr = a carbinol protecting group; R = H or CH 3; R 3, R 4 = H, 1-ac alkyl or phenyl- (1-3c alkyl), wherein the phenyl group is optionally substituted with 1-3C alkyl, 1-3C alkoxy or halogen; R 2 = a group of formula (A) or (B): (B) 6 = H or OH; R R = H or CH 3; a, b, c and d = optional double bonds; R 7 = phenyl or benzyloxy, the ring being optionally substituted on each occasion with 1-3C alkyl or halogen; R8, R9 = 1-3C alkyl or halogen; R 5 = 1-3C alkyl, phenyl or mono- or di- (1-3C alkyl) phenyl.

Anderson, Paul Leroy, discloses in German Offenlegungsschrift 505 210 DE 3,525,256 naphthyl analogs of mevalonolactones having the structure H OH 7 I '-CHCH2CHCH2CO2R OII OH OH Q Ql I _ l U _ l 7 _ wherein R is alkyl, Z , Q 7 R - H or a hydrolysable ester group useful as inhibitors of cholesterol biosynthesis and in the treatment of arteriosclerosis.

WO 8402-903 (based on U.S. Application No. 460,600, filed January 24, 1983) filed in the name of Sandoz AG, relates to mevalonolactone analogs useful as hypolipoproteinemic agents having the structure wherein the two groups Ro together form a radical with Formula 8 SC = C 1 -C 2 C or - (CH 2) 4 - 505 210 \ J wherein R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy (except t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R 3 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, provided that not more than one of R 2 and R 3 is trifluoromethyl, not more than one of R 2 and R is phenoxy and not more than one of R 2 and R 3 is benzyloxy, is hydrogen, C 1-6 alkyl, fluorine, chlorine or benzyloxy, is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy R 5 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R 5a provided that no more than one of R 4 and R 5 is tri- is hydrogen, C 1-2 alkyl, C 1-2 alkyl oxy, fluorine or chlorine, and fluoromethyl, not more than one of R and R is phenoxy and not more than one of R 4 and R 5 is benzyloxy, CH H 2 (2) q X is - (CH) - C = C 2 '' / \ - (CH 2) q H wherein n is 0, 1, 2 or 3 and both q is 0 or H 1 is 0 and the other is 1, Z is Re 5 4 3 2 1 -CH-CH -C -CH -COOH II | 2 | OH OH wherein R 6 is hydrogen or C 1-3 alkyl, with the general proviso that -X-Z and the R 4 bearing the phenyl group are in the position of each other; in free acid form or in the form of a physiologically hydrolysable and acceptable ester or a β-lactone thereof or in salt form.

European patent application no. l27 848-A (Merck & Co., Inc.) relates to derivatives of 3-hydroxy-5-thia-acaryl-alkanoic acids having the structural formula 503 210 8 H0 0 fr, S (0) | Il E I Z wherein Z is ne | H4 “l Rz ÛÛ R3 RS n is 0, 1 or 2; E is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH = CH-CH 2 -; or -CH 2 -CH = CH-7 R 1, R 2 and R 3 are, e.g. hydrogen, chlorine, bromine, fluorine, C1-alkyl, phenyl, substituted phenyl or OR7, wherein R7 is e.g. hydrogen, C 2-8 alkanoyl, benzoyl, phenyl, substituted phenyl, C 1-9 alkyl, C 1-4 haloalkyl, allyl, cycloalkyl-C 1-6 alkyl, adamantyl-C 1-3 alkyl or phenyl-C 1-3 alkyl; R 4, R 5 and R are hydrogen, chlorine, bromine, fluorine or C 1-3 alkyl; and X is e.g. hydrogen, C 1-3 alkyl, a cation derived from an alkali metal amyl, 1-3 metal or is ammonium.

These compounds have antihypercholesterolemia activity due to their ability to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and antifungal activity.

French patent application no. 2,596,393 A filed April 1, 1986 (Sanofi SA) relates to 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives comprising salts thereof, which are useful as hypolipidemic agents and have the formula R 2 I R 10 OC-CH 2 -C-CH 2 -P OH wherein R 1 and R 2 = H, ar aralkyl; R 3 and R 4 = H, lower alkyl or or aralkyl.

These compounds are stated to give higher glyceride and phospholipid levels European patent application no. 142 503 210 O OR | l // 3 OR4 lower alkyl or optionally substituted- optionally substituted aryl reduction in cholesterol, tri- or meglutol. 146-A (Merck & Co., Inc.) relates to mevinolin-like compounds of the structural formula) r-; and HO OR 1 "OEZ wherein R 1 is eg hydrogen or C 1-4 alkyl; E is -CH 2 CH 2, -CH = CH- or - (CH 2 Z is 1) RV / Lë GQ wherein X is -O- or -NR 9 , R 7 is C 1-4 alkyl; and 2-8 wherein R 9 is CH or hydrogen or C 1-4 alkyl; 1 - H 3 R 3 is hydrogen or CH 3; 2) R 19 R 11 R 12 wherein R 10, R 11 and R 12 are independently for example, hydrogen, halogen or C 1-4 alkyl; 1-4 3) ae According to the present invention there are provided phosphorus-containing compounds which inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and thus are useful as hypocholesterolemic agents and includes the following compounds of the formula IQH "'co Rx I R'1,"' ° H2'§ '° H2' zx on 1 (? H2) nz comprising salts thereof, wherein R is OH, lower alkoxy or lower alkyl; R 'is H or lower alkyl; X is -O- or -NH-; n is 1 or 2; Z is a hydrophobic anchor.

Invention V also includes pharmaceutically acceptable salts thereof. The term "hydrophobic anchor" as used herein refers to a lipophilic group which, when attached to the HMG-like upper side chain of the molecule by the appropriate bypass (moiety ("X"), binds to a hydrophobic pocket of the enzyme which is not used in the binding of the substrate HMG COA, and results in an improved potency over compounds wherein Z = H.

The terms "salt" and "salts" refer to basic salts formed with inorganic and organic berries. Such salts include ammonium salts, alkali metal salts such as lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as amine-like salts, e.g. dicyclohexylamine salt, benzatin, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids such as arginine, lysine and the like. The non-toxic, pharmaceutically acceptable salts are preferred although other salts are also useful, e.g. when isolating or purifying the product.

Examples of hydrophobic anchors that may be included in the present invention include, but are not limited to, R 2 R 2 R 2 R 2 R 2 R 2 R 2 R 3 or R 3 R 2 R 3 alkyl ns 'Rs, s R q R 6 q Rs 3 1 I o alkyl alkyl Rs, 115's' m fi a) RS R q Q 6 116 R \ IO o aikyl alkyl 5 RGQ) R5 RS (R6a) q R (q or à § 1 alkyl R 5 - (aöa) q 503 210 13 wherein RF, R 2, R "and R" may be the same or different and each is independently selected from H, halogen, lower alkyl, haloalkyl, phenyl, Ch -alkyl-substituted phenyl or ORY, wherein RY is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl or Ch; - alkyl-substituted phenyl-lower alkyl.

When Z is, R 5 and R f are the same or different and are H, lower alkyl or OH; and one of R? and Ry is present when the carbon to which it is attached is attached by a double bond.

O R 0 is lower alkyl-3, such as or phenyl-CH 2 -; R 'is lower alkyl, hydroxy, oxo or halogen; q is 0, 1, 2 or 3, and R 7 is H or lower alkyl.

Thus, the compounds of formula IO u RP-CH ¿2 o ön l (912 »nz X -g fl- CH2-COZR and 503 210 14 O ll na np-cnz: fn ön WH X: ca-caz-cozn 2) n The term "lower alkyl" or "alkyl" as used herein separately or as part of another group includes both straight or branched chain hydrocarbon chains containing 1 to 12 carbon atoms in the normal chain, preferably 1 to 7 carbon atoms, such as methyl , ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branches the chain isomers thereof, and the like as well as such groups comprising a halogen substituent such as F, Br, Cl or I or CF 3, tuent, an alkyl aryl substituent, a halaryaryl substituent, an alkoxy substituent, an aryl substituent and a cycloalkyl substituent cycloalkyl substituent, hydroxy and alkylamino substituent, an alkanoylamino substituent, an aryl-carbonylamino substituent, a nitro substituent, a cyano substituent, a thiol substituent or an alkylthio substituent.

The term "cycloalkyl" as used herein, separately or as part of another group, includes saturated cyclic hydrocarbon groups containing 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl , cyclodecyl and cyclododecyl, and wherein any group may be substituted with 1 or 2 halogen atoms, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2 arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups; 1 or 2 cyano groups, 1 or 2 thiol groups and / or 1 or 2 alkylthio groups. The terms phenyl, naphthyl, substituted phenyl or substituted naphthyl include groups wherein the substituent on either the phenyl or naphthyl group may be 1, 2 or 3 lower alkyl groups, halogens (C1, Br or F), 1, 2 or 3 lower alkoxy groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy groups, 1, 2 or 3 benzoyloxy groups, 1, 2 or 3 haloalkyl groups, 1, 2 or 3 halophenyl groups, 1, 2 or 3 allyl groups , 1, 2 or 3 cycloalkylalkyl groups, 1, 2 or 3 adamantylalkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoylamino groups, wherein the aryl group preferably contains 3 substituents.

The term "lower alkoxy" or "alkoxy" as used herein, separately or as part of another group, includes any of the above lower alkyl or alkyl groups attached to an oxygen atom. The term "alkanoyl" as used herein as part of another group, refers to lower alkyl attached to a carbonyl group.

The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, iodine and CF3, with chlorine and fluorine being preferred.

Preferred are those compounds of formula I which have the following structure 11 R o ca H cs 'lt / V 2 \\ 2 \\ \ § g / CO22 * / x 5' C112 on z wherein R is OH, OLi; Rx is Li or H; X is O or NH; and Zaf 2a wherein R 1 is phenyl comprising an alkyl and / or halo substituent; or R 1 is benzyloxy comprising a halo substituent; R 2 and R 2a are the same and are halogen or lower alkyl; Z may also preferably be 66, wherein R 1 and R 2 have the just above definition with 503 210 17 with respect to the compound of formula II, or R 6, wherein R 5 is R is H, CH 3 or OH and R 6 is | °.

CH 2 C / 3 CH / ”H 3 R or (substituted) phenylmethyl, wherein R is H or CH 3.

The compounds of formula I according to the invention can be prepared according to the following reaction sequence and description thereof. 503 210 l8 - .n> fl xox fi m mumm fi um> mm um:: O H om n om .f q Hæx fl m wumm fi uw> mm um: Hæx fi æ mumm fi H am N mm 1. <> -F q c fi cx fi m. w m ^ m = U.U %% ¶ \ suwuwwuowmom f è = o o ~ =. ~> H ~> x ~ m ~ cu | ~ = o | = w | ~ = u | M | um N ~ M n _ w _ fi u = u _ ~ m «m || . = u .. ~> H m w m. u Ü fi ox fi m wnmw fi m.

= A / = Mw fifl w ~> xHm wHmm ~ n mm. = cø fi uxøøun> x ~ ø ~ OU | N: U | U | N: U | H m .mzuv u | $ @ \ §ämo \ Éßwnå dm = wu ~> x ~ m ~ ou | ~ = u- = w | ~ = u | @ «@ zf -HMM _ _. NA: Uvun fi mo o. ~> Xo. @ | @ Zm = @ w 503 210 l9 ~> mmwu mzwu mm \ _ = UU | fi w ~> x- ~ ou ~ = u | = w | ~ = u | @ -onm ._ o ^ mc fl uw «m fl Hwummv _:« fl «u> m ~ f ^ H> x fi m wumw fi n nav UUQIIOQM .mo m .ß v fl> 503 210 20 ÖH w = * ~ = w. : m «xm ~ ou | ~ = o | = m | ~ = o | 4 | m _ o fl xox fi m wuwm fi ww fifl w fi æx fl m wumw fi u oz.

HH> mmwu m = @ o /// N _ frö fi fä .: §w. _ _ w x ~> x ~ @ ~ ou ~ = u «= w- ~ = u | & | um ¶ _ o \ I .m> HGuu> :. cmxo fi ø. |: O .N Amc fi cv fl mwmmuwum H ~> | ~> ~ @ m. m = a. = oou ~ = u .mz «. @ = @ o | = v. ~ @ <: a;%. m = ~ u. \. <> / -: N no Éo fl uxwwuwmc flfi ceovï: xx A: Ena .N Amc fi c fi åïfäv wømv N fi owzu uf fi uøu. As can be seen from the above reaction sequence, compounds of formula I can be prepared by subjecting iodide A to an Arbuzov reaction by heating iodide α? HS O-E1-C (CH3) 3 C6H5. cH2-c-cnz-cozalkyl H and phosphonite / phosphite III III Ra-P (Oalkyl) 2 wherein Ra is lower alkyl or lower alkoxy, using standard Arbuzov conditions and phosphinate / phosphonate IV II formation procedures. Phosphinate / Phosphonate IV is a novel compound and as such part of the present invention.

Phosphinate / phosphonate IV is then subjected to a phosphorus ester cleavage by treating a solution of compound IV in an inert organic solvent such as methylene chloride, sequentially with bis (trimethylsilyl) trifluoroacetamide (BSTFA) and trimethylsilyl bromide under an inert atmosphere such as argon to form the phosphinic acid VA, wherein Ra in IV is lower alkyl, i.e. 5Û3 210 22 O.

In VA lower alkyl ~% -CH2-QH-CH2-CO2alkyl oH ö s'-c CH ,, f '~ ë (3): C655 sas or phosphonic acid VB (wherein Ra in IV is lower alkoxy), i.e. Compounds VA and VB are novel intermediates and as such form part of the present invention. o ll vs Ho-§-cnz-ga-ca on 2-Cozalkyl -0 Il Si-CKCH) / \ H 33i Cans Cs s.

When phosphonic acid VB is obtained, it is esterified by treating VB in dry pyridine with alcohol VC RbOH (wherein Rb is lower alkyl) and dicyclohexylcarbodiimide and the resulting reaction mixture is stirred under an inert atmosphere such as argon, to form the phosphonon monoalkyl ester VI VI Rbo_1_CH2-gH-CH2CO2alkyl. OH OII I s'-c ca) /, / Q å 3 3 C655 Cs s Ester VI or phosphinic acid VA is then dissolved in an inert organic solvent such as methylene chloride, benzene or tetrahydrofuran (THF) and treated with trimethylsilyldiethylamine and stirred under a inert atmosphere, such as argon; the mixture is evaporated and then dissolved in methylene chloride (or other appropriate inert organic solvents). The resulting solution is cooled to a temperature in the range of about 0 to about 25 ° C, treated with oxalyl chloride and then evaporated to give crude phosphonochloride. The phosphonochloride is dissolved in inert organic solvent such as methylene chloride, benzene, pyridine or THF; the solution is cooled to a temperature in the range of from about -20 ° C to about 0 ° C and treated with ä Z- (CH -XH 2) n using a molar ratio of VA: § of in the range of about 0.5: 1 to about 3: 1 and preferably from about 1: 1 to about 2: 1, followed by triethylamine and catalytic 4-dimethylaminopyridine (DMAP) to give adduct VII. 0 c "VII R -? - CH2 - EH-CH2-CO2alkyl in f" (fn fl n / si-cwa fi g Z CGHS C6Hs where RC is lower alkyl or lower alkoxy.

Compound VII is subjected to silyl ether cleavage by treating VII in an inert organic solvent, such as tetrahydrofuran, with glacial acetic acid and tetrabutylammonium fluoride to give ester VIII VIII. R - 503 210 24 i.e. wherein Rx is alkali metal or H by treatment with a strong base, such as lithium hydroxide, in the presence of dioxane, tetrahydrofuran or other inert organic solvents, under an inert atmosphere such as argon, at 25 ° C, using a molar ratio of base ester VIII of in the range from about 1: 1 to about 1.1: 1 to form the corresponding alkali metal salt O VIIIA R-å-CH2-gH-CH2-CO2 alkali metal § OH (QH Z 2) n wherein R is lower alkyl or lower alkoxy.

Compound VIIIA is then treated with strong acid such as HCl to give the corresponding acid VIIIB O VIIIB R-å-CH2-QH-CH2-COZH ¥ OH (ç fi Z 2) n The ester VIII, wherein R is lower alkoxy, can be converted to corresponding dialkali metal salt by treating the ester VIII with strong base at 50-60 ° C using a molar ratio of base ester VIII of in the range of from about 2: 1 to about 4: 1 to form VIIIC ON - V111c alkali metal-Q-CH2-gH -CH 2 -CO 2 alkali metal il: ön (? H 2) n Z 503 210 The di-alkali metal salt VIIIC can then be converted to the corresponding acid, wherein R is OH by treatment with strong acid such as HCl to give VIIID o 1 VIIID Ho-å -cH2-çn-ca kön ca <| 2 z 2-COZH) n The iodide starting material é can be prepared from the bromide 9 OH I Br-CH2-CH-CH2 10 Cozalkyl (prepared using procedures described in Tetrahedron Lett go, 2951 (1985)), which is dissolved in solution dimethylformamide (DMF) with imidazole and 4-dimethylaminopyridine and wherein the resulting solution no one is treated with t-butyldiphenylsilyl chloride under an inert atmosphere such as argon to form the silyl ether E 2+ // 9655 osi-c (cn 3) 3 Q Br-CH 2 -CH-CH CO alkyl 2 2 A solution of the silyl ether 2 in an inert organic solvent such as methyl ethyl ketone or DMF is treated with sodium iodide under an inert atmosphere such as argon, to form iodide A.

The starting compound E g z- (cn2) n-xn 503 210 26 can be prepared as described below, depending on the definition of Z and X.

Compounds of formula B, wherein Z is R 1, R 2 and Z is 0, i.e. compounds of the structure R 1 E z R a (cnz) n-one Rz can thus be prepared by treating the aldehyde E R 2 R (c1a2) n_1-c1 = 10 Rz with a reducing agent such as lithium aluminum hydride or [[11 sodium borohydride.

The compounds of formula B, wherein Z is R 1, R 2 and X is n, i.e. compounds with the structure 503 210 27 R 1 ä: 2 R a C 32) n_NH 2 R 2 can be prepared by oxidation of the aldehyde E by treatment of E in solution with acetone with, for example, Jones reagent to form the acid E | W 2 - R a '(CH 2) n - 1 COOH which in suspension with methylene chloride is treated with oxalyl chloride to give the corresponding acid chloride which is dissolved in an inert organic solvent such as tetrahydrofuran and treated with a mixture of concentrated ammonium hydroxide in tetrahydrofuran to give an amide having the structure R1 IQ n Rza (ca -NH 2) n-1 '° 2 The amide § is then reduced to the corresponding amide §2 by treating Q with a reducing agent such as lithium aluminum hydride.

The starting compounds of formula E, wherein Z is 505 210 zs Rs' RS g 4! | I} lk l (R6a) q a Y -NH-, i.e. compounds having the structure and X is 0 or wherein X is 0, are described by C.H. Heathcock et al., J. Org. Chem. 29, ll90 (1985). Compounds of formula H ', wherein X is NH, can be prepared by reductive amination of If-u (prepared as described by C. H. Heathcock et al, supra) of Q with ammonium acetate and sodium cyano- by treatment such as methanol. borohydride in the presence of an alcohol solvent, The starting compound of formula E, wherein Z is 503 210 R2a R1 I C) | :: š} - R2b R2 and X are 0, i.e. compounds having the structure R2â 1 E (cnz) n-oa ß Om, 2b R2 N are described in WO 8402-903-A and GB 2 l62 l79A, both filed in the name Sandoz AG.

The starting compounds of formula B, wherein Z is R 2a R 1 R 2b R 2 and X is NH, i.e. compounds of the structure R 2a R 1 E 1 ae R 2b R 2 can be prepared by reductive amination of the aldehyde 9 R 2a R 1 9 QJ) (C 32) n-1 ° H ° 2 R 2b 503 210 by treatment of 9 with ammonium acetate and sodium cyanoborohydride in the presence of an alcohol solvent, such as methanol.

The compounds of the invention may be prepared as racemic mixtures and may later be cleaved to give the preferred S isomer. However, the compounds of the invention can be prepared directly in the form of their S-isomers as described herein and in the working examples set forth below.

The compounds of the invention are inhibitors of 3-hydroxydimethyl-glutaryl-coenzyme A (HMG-COA) reductase and are thus useful for inhibiting the cholesterol biosynthesis demonstrated by the following test. l) Rat liver HMG-CoA reductase Rat liver HMG-CoA reductase activity is measured using a modification of the method described by Edwards (Edwards, P.A. et al., J. Lipid Res. 20:40, 1979). Rat liver microsomes were used as the enzyme source and the enzyme activity was determined by measuring the transfer of the 14 C-HMG-CoA substrate to 14 C-mevalonic acid. a. Preparation of Microsomes Levers are removed from 2-4 cholestyramine-reared, decapitated, Sprague Dawley rats and homogenized in phosphate buffer A (potassium phosphate, 0.04 M, pH 7.2; KCl, 0.05 M; sucrose, 0, 1 M; EDTA, 0.03 M; aprotinin, 500 KI units / ml). The homogenate is spun at 16,000 x g for 15 minutes at 4 ° C. The supernatant is removed and centrifuged a second time under the same conditions. The other 16,000 x g supernatant is spun at 100,000 x g for 70 minutes at 4 ° C. Pelletized microsomes are resuspended in a minimal volume of buffer A (3-5 ml per liver) and homogenized in a glass / glass homogenizer. Ditiotreitol is added (10 mM) and the preparation is aliquoted, quick-frozen in acetone / dry ice and stored at -80 ° C. The specific activity of the first microsomal preparation was 0.68 nmol mevalonic acid / mg protein / minute.

Asos 210 31 b. Enzyme analysis The reductase is analyzed in 0.25 ml, which contains the following components at the indicated final concentrations: 0.04 M potassium phosphate, pH 7.0 0,05 M KCl 0,10 M sucrose 0,03 M EDTA 0,01 M dithiothreitol 3.5 mM NaCl 1% dimethylsulfoxide 50-200 μg microsomal protein 100 μm 14c- / DL / HMG-cOA (δ, o5 uci, 30-so mci / mmol incubated at 37 ° C. Under the conditions described, the enzyme activity increases linearly up to 300 pg microsomal protein per reaction mixture and is linear with respect to the incubation time up to 30 minutes.The standard incubation time selected for drug studies is 20 minutes, resulting in 12-15% transfer of HMG-CoA substrate to the mevalonic acid product./DL- / HMG-CoA substrate was used at 100 μM, twice the concentration required to saturate the enzyme under the conditions described.NADPH was used in excess in an amount of 2.7 times the concentration required for at t achieve maximum enzyme rate.

Standardized assays for the evaluation of inhibitors were performed according to the following procedure. Microsomal enzyme is incubated in the presence of NADPH at 37 ° C for 15 minutes. DMSO vehicle with or without test compound is added and the mixture is further incubated for 15 minutes at 37 ° C. The enzyme assay is initiated by the addition of 14 C-HMG-COA substrate. After 20 minutes of incubation at 37 ° C, the reaction is stopped by adding 25 μl of 33% KOH. 3H-mevalonic acid (0.05 uCi) is added and the reaction mixture is allowed to stand at room temperature for 30 minutes. 50 μl of 5N HCl is added to lactonize the mevalonic acid.

Bromophenol blue is added as a pH indicator to monitor an adequate decrease in pH. Lactonization is allowed to continue for 30 minutes at room temperature. The reaction mixture is centrifuged for 15 minutes at 2800 rpm. The supernatants are layered on 2 g of AG 1-X8 anion exchange resin (Biorad, format form), poured into 0.7 cm (id) glass columns and eluted with 2.0 ml of H 2 O. The first 0.5 ml are discarded and the next 1.5 ml are collected and counted for both tritium and carbon 14 in 10.0 ml Optiffluoroscintillation fluid. The results are calculated as nmol of mevalonic acid produced per 20 minutes and corrected to 100% recovery of tritium. Drug effects are expressed as 150 values (the concentration of drug that provides a 50% inhibition of enzyme activity) derived from composite dose-response data with the 95% confidence interval indicated. Transfer of drugs in lactone form to their sodium salts is accomplished by solubilizing the lactone in DMSO, adding a 10-fold molar excess of NaOH and allowing the mixture to stand at room temperature for 15 minutes. The mixture is then partially neutralized (pH 7.5-8.0) using 1N HCl and diluted in the enzyme reaction mixture. 2) Cholesterol Synthesis in Freshly Isolated Rat Hepatocytes Compounds that demonstrate activity as inhibitors of HMG-CoA reductase are evaluated for their ability to inhibit 14C-acetate incorporation into cholesterol in fresh isolated rat hepatatocyte suspensions using methods originally described by Capuzzi et al. (Capuzzi, D.M. and Margolis, S., Lipids, §: 602, 1971). Isolation of rat hepatatocytes Sprague Dawley rats (180-220 g) are anesthetized with Nembutol (50 mg / kg). The abdomen is opened and the first branch of the portal vein is closed. Heparin (100-200 units) is injected directly into the abdominal vena cava. A single occlusive suture is placed on the distal section of the portal vein and the portal vein is cannulated between the suture and the first bifurcated vein. The liver is rinsed at a rate of 20 ml / minute with preheated (37 ° C) acidified buffer A (HBSS without calcium or magnesium containing 0.5 mM EDTA) after separation of the vena cava to allow drainage of the effluent. The liver is further purified with 200 ml of preheated buffer B (HBSS containing 0.05% bacterial collagenase). After rinsing with buffer B, the liver is separated and decapsulated in 60 ml of Waymouth's medium, allowing free cells to be distributed in the medium. Hepatocytes are isolated by low speed centrifugation for 3 minutes at 50 x g at room temperature. Pelleted hepatocytes are washed once in Waymouth's medium, counted and analyzed for viability by tryptane blue exclusion. These hepatocyte-enriched cell suspensions routinely show 70-90 6 viability. b. 14C Acetate Incorporation into Cholesterol Hepatocytes are resuspended at 5 x 10 6 cells per 2.0 ml in incubation medium (1M) / 0.02 M Tris-HCl (pH 7.4), 0.1 M KCl, 3.3 mM sodium citrate , 6.7 mM nicotinamide; 0.23 mM NADP, 1.7 mMN glucose-6-phosphate /.

The test compounds are routinely dissolved in DMSO or DMSO: H 2 O (1: 3) and added to 1M. The final DMSO concentration in IM is 31.0% and has no significant effect on cholesterol synthesis.

The incubation is initiated by adding 14 C-acetate (58 mCi / mmol, 2 uCi / ml) and placing the cell suspensions (2.0 ml) in 35 mm tissue culture dishes, at 37 ° C for 2.0 hours. After incubation, the cell suspensions are transferred to glass centrifuge tubes and spun at 50 x g for 3 minutes at room temperature. Cell pellets are resuspended and lysed in 1.0 ml H 2 O and placed in an ice bath.

Lipids are extracted mainly as described by Bligh, E.G. and W.J. Dyer, Can. J. Biochem. and Physiol., eel:; 9ll, 1959.

The lower organic phase is removed and dried under a stream of nitrogen and the residue is resuspended in (100 μl) chloroform: methanol (2: 1). The total sample is stained on silica gel (LK6D) thin layer plates and developed in hexane ethyl ether acetic acid (75: 25: 1). The plates are scanned and counted using a BioScan automated scanning system. Radiolabelling in the cholesterol peak (RF 0.28) is determined and expressed in total calculations per peak and as a percentage of the marker in the total lipid extract. The cholesterol peaks in control cultures routinely contain 800-1000 cpm and 9-20% of the marker is present in the total lipid extract; results compatible with Capuzzi et al. indicates 9% extracted markers in cholesterol.

Drug effects (% inhibition of cholesterol synthesis) are determined by comparing the% marker in cholesterol for control and drug-treated cultures. Dose response curves are constructed from composite data from two or more studies and the results are expressed as I50 values with a 95% confidence interval. 3) Cholesterol synthesis in human skin fibroblasts Compounds that selectively favor greater inhibitory activity in liver tissue would be an attribute of a cholesterol synthesis inhibitor. Therefore, these compounds are also tested for their activity as inhibitors of cholesterol synthesis in cultured fibroblasts in addition to evaluating cholesterol synthesis inhibitors in hepatocytes. a. Human skin fibroblast cultures Human skin fibroblasts (passages 7-27) are grown in Eagles' minimal essential medium (EM) containing 10% fetal calf serum. For each experiment, strain cultures are trypsonized to disperse the cell monolayer, counted and coated in 35 mm Tissue Culture Wells (5 x 10 5 cells / 2.0 ml). The cultures are incubated for 18 hours at 37 ° C in 5% CO 2/95% humidified room air. Cholesterol biosynthetic enzymes are induced by removing serum-containing medium, washing the cell monolayers and adding 1.0 ml of EM-containing 1.0% fatty acid-free bovine serum albumin and incubating the cultures for an additional 24 hours. b. šíC-Acetate incorporation into cholesterol-induced fibroblast cultures are washed with EMEM (Earle's 100 minimal essential medium). The test compounds are dissolved in DMSO 503 210 or DMSO: EM (1: 3) (final DMSO concentration in cell cultures 1.0%), added to the cultures and the cultures are pre-incubated for 30 minutes at 37 ° C in 5%. C02 / 95% humidified room air. After preincubation with drugs, / l-14C / Na-acetate (2.0 uCi / ml, 58 mCi / mmol) are added and the cultures are re-incubated for 4 hours. After incubation, the culture medium is removed and the cell monolayer (200 pg cell protein per culture) is scraped in 1.0 ml H 2 O. Lipids in the lysed cell suspension are extracted into chloroform-methanol as described for hepatocyte suspensions. The organic phase is dried under nitrogen and the residue is resuspended in chloroform-methanol (2: 1) (100 μl) and the total sample is stained on silica gel (LK6D) thin layer plates and analyzed as described for hepatocytes.

Inhibition of cholesterol synthesis is determined by comparing the percentage of marker in the cholesterol peak from control and drug-treated cultures. The results are expressed as ISO values and are derived from composite dose-response curves from two or more experiments. A 95% confidence interval for the I50 value is also calculated from the composite dose-response curves.

A further aspect of the present invention is a pharmaceutical composition consisting of at least one of the compounds of formula I together with a pharmaceutical vehicle or a diluent. The pharmaceutical composition may be formulated using conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type suitable for the mode of administration.

The compounds may be administered orally, for example in the form of tablets, capsules, granules or powders or they may be administered parenterally in the form of injectable preparations, these dosage forms containing from 1 to 2000 mg of active compound per dose, for use in treatment. . The dose to be administered depends on the unit dose, the symptoms and the age and body weight of the patient.

The compounds of formula I may be administered in a manner similar to known compounds proposed for use in inhibiting cholesterol biosynthesis such as lovastatin, in mammalian species such as humans, dogs, cats and the like. Thus, the compounds of the invention may be administered in an amount of from about 4 to 2000 mg in a single dose or in the form of individual doses from 1 to 4 times per day, preferably 4 to 200 mg in divided doses of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4 times daily or in delayed release form.

The following working examples illustrate preferred embodiments of the present invention. Unless otherwise indicated, all temperatures are expressed in ° C. Evaporation chromatography was performed on either Merck 60 or Whatmann LPS-I silica gel. Reverse phase chromatography was performed on CHP-20 MCI gel resin provided by Mitsubishi, Ltd.

Example 1 (S) -4 - /// 4'fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / methoxy / methoxyphosphinyl / -3-hydroxy-butanoic acid, monolithic salt A. N- (2,4-Dimethylbenzylidene] benzenamine Ref. Merck U.S. Patent No. 4,375,475, page 39 A solution of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich, 6.97 mL, 50 mmol) and distilled aniline (Aldrich, 4.56 mL, 50 mmol) in dry toluene (80.0 mL) was refluxed for 3.0 hours under argon in a flask equipped with a Dean-Stark apparatus.

The mixture was cooled, then evaporated in vacuo to a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mm Hg, 160-180 ° C) to give 8.172 g (78.1%) of the desired title benzeneimine as a pale yellow oil which crystallized on standing to a lower melting solid. substance. TLC (4: 1) hex-acetone, RF = 0.67 and 0.77 (geometric isomers), U.V. and Iz. 503 210 37 B N / + OCCH 8 3 _ CBS _¿ 2 Ref: Merck U.S. Pat. 4 375 475, p. A mixture of part A-benzeneimine (6.0 g; 28.7 mol) in glacial HOAc (144 ml) was treated with palladium (II) acetate (6.44 g, 28.7 mmol) and the clear red homogeneous solution refluxed under argon for one hour. The resulting cloudy mixture was filtered hot through a packed 1/2 "bed of Celite in 900 mL of H 2 O. Precipitated orange solid was collected by filtration and dried in vacuo at 65 ° C over P 2 O 5 for 16.0 hours to give 10, 627 g (85.5%) of the desired titanium-palladium complex as an orange solid, m.p. 194-196 ° C. (Literary melting point of a recrystallized analytical sample = 203-205 ° C.) c. 4'-fluorine. 3,3 ', 5-Trimethyl / 1,1'-biphenyl / -2-carboxylic acid (1) Bromo / 4-fluoro-3-methylphenyl / magnesium Ref. Merck U.S. Patent No. 4,375,475, p. 37 and 38 Title Part C (1) The Grignard reagent was prepared by adding 5-bromo-2-fluorotoluene (22.5 g, 60.9 mmol, Fairfield Chemical Co.) dropwise at a rate sufficient to maintain the reaction. at reflux to stirred magnesium turnings (1.35 g, 55.4 mmol, 8.0 eq.) in dry Et 2 O (70.0 mL). The reaction was initiated in an ultrasonic device. After the bromide addition was complete, the mixture was stirred in a ti under argon at room temperature, refluxed for 15 minutes and then allowed to cool to room temperature. 503 210 38 (2) 4'-Fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-carboxaldehyde In a second flask, a mixture of the Part B dipalladium complex (3.0 g, 6.92 mmol) and triphenylphosphine (14.52 g, 55.4 mmol, 8.0 eq.) In dry benzene (100 mL) at room temperature under argon for 30 minutes. Freshly prepared and filtered (glass wool plug) Part C (1) Grignard reagent was then added in one portion using a cannula to this solution and the mixture was stirred for 1.5 hours at room temperature under argon. 6.0N HCl (35 mL) was added, the mixture was stirred for an additional hour at room temperature, then filtered through packaged Celite (1/2 "bed). The filtrate was extracted with Et 2 O (250 mL), the extract was washed with brine (2 x 100 mL) , dried over anhydrous MgSO 4 and evaporated in vacuo to give 13.35 g of a viscous orange oil which crystallized on standing.The crude orange solid was purified by evaporative chromatography on silica gel (700 g) eluting with hexane, followed by (95 : 5) hexane-Et 2 O. The product fractions were evaporated to give 1.507 g (89.9%) of the desired title aldehyde as a light yellow solid, m.p. 72 DEG-75 DEG C. (Literature reported melting point = 73 DEG-74 DEG C.) TLC: (95 : 5) Hex-Et 2 O, Rf = 0.40, UV and PMA.

D. 4'-Fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-methanol A cooled (0 ° C, ice bath) solution of dry Et 2 O (15.0 mL) was treated with LiAlH 4 ( 259 mg, 6.82 mmol, 0.55 eq.) And the gray suspension was treated dropwise over 15 minutes with a solution of part C-aldehyde (3.0 g, 12.4 mmol) in dry Et ).

The mixture was stirred at room temperature under argon for 30 minutes, then cooled again to 0 ° C and quenched by subsequent dropwise addition of 260 .mu.l of H 2 O, 260 .mu.l of 15% NaOH and 780 .mu.l of H 2 O. The suspension was diluted with EtOAc, filtered through anhydrous Na 2 SO 4 over packed Celite (1/4 "bed) and the colorless filtrate evaporated in vacuo to give 2.99 g (98.8%) of a white solid. The solid with cold hexane and drying in vacuo gave 2.467 g (81.6%) of the desired title alcohol as a white solid, m.p. 102 DEG-103 DEG C. TLC: (9: 1) Hex-EtOAc, Rf = 0.24. UV and PMA 503 210 39 E. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy [-4- (hydroxymethoxyphosphinyl) -butanoic acid, methyl ester (1) (S) -4-bromo -3-hydroxybutanoic acid, methyl ester (1) (a) / R- (Rx, Rx) / - 2,3,4-trihydroxybutanoic acid, calcium salt, hydrate Ref. Carbohydrate Research 12, pp. 301-304 (1979).

Calcium carbonate (50 g) was added to a solution of D-iso-ascorbic acid (44.0 g, 250 mmol) in H 2 O (625 mL), the suspension was cooled to 0 ° C (ice bath) and treated portionwise with 30% H 2 O 2 (100 mL). The mixture was stirred at 30-40 ° C (oily) for 30 minutes. Darco (10 g) was added and the black suspension was heated on a steam bath until the evolution of O 2 ceased.

The suspension was filtered through Celite, evaporated in vacuo (bath temperature 40 ° C). The residue was taken up in H 2 O (50 mL), heated on a steam bath and CHBOH was added until the solution became cloudy. The gum-like precipitated solid was collected by filtration and air-dried to give 30.836 g (75.2%) of the desired calcium salt as a powdered white solid. TLC (7: 2: 1) iPrOH-NH 4 OH-H 2 O, Rf = 0.19, PMA. (1) (b) / S- (Rx, Sx) / - 2,4-dibromo-3-hydroxybutanoic acid, methylene Ref. Bock, K. et al., Acta Scandinavica (B) 31, p. 341-344 (1983) Part (1) (a) calcium salt (30 g) was dissolved in 30-32% HBr in acetic acid (210 ml) and stirred at room temperature for 24 hours. Methanol (990 ml) was then added to the brown solution and stirred overnight. The mixture was evaporated to an orange oil, taken up in CH 3 OH (75 ml), refluxed for 2.0 hours and evaporated. The residue was partitioned between EtOAc (100 mL) and H was washed with H 2 anhydrous Na 2 SO 4 crude dibromide as a bright orange oil. TLC (1: 1) EtOAc-Hex, Rf = 0.69, UV and PMA. The organic phase O (2x) and brine were then dried over and evaporated to give 22.83 g (90.5%) of 503 210 40 (1) (c) (S) -4-bromo-3-hydroxybutanoic acid , methyl ester Ref. same as for the preparation according to (1) (b) An argon-rinsed solution of the dibromide (20.80 g, 75.4 mmol) and anhydrous NaOAc (2.1.0 g) in EtOAc (370 mL) and glacial HOAC (37 mL) were treated with 5% Pd / C (1.3 g) and the black suspension was stirred under H 2 (1 atm.) while monitoring H 2 uptake. After 2.0 h, H 2 uptake was complete, the mixture was filtered through Celite, the filtrate was washed with saturated NaHCO 3 and brine, then dried over anhydrous MgSO 4 and evaporated to give crude dibromoester as a brown oil. The crude oil was combined with another batch (starting from 36.77 g of the dibromide) and vacuum distilled to give 25.77 g (61.3%) of the desired title bromine ester as a clear oil, b.p. 79-80 ° C ( 1.0 mm Hg). TLC (Izl) EtOAc-Hex, Rf = 0.44, PMA.

Analysis: Calculated for C 5 H 9 O 3 Br: C 30.48 H 4.60 Br 40.56 Found: C 29.76 H 4.50 Br 39.86 (2) (S) -4-bromo-3 - // (1, 1-dimethylethyl) -diphenylsilyl / oxy / butanoic acid, methyl ester A solution of Part E (1) -bromohydrin (4.0 g, 20.4 mmol), imidazole (6.94 g, 5.0 eq.) and 4-dimethylaminopyridine (4-DMAP) (12 mg, 0.005 eq.) in dry DMF (40 mL) was treated with t-butyldiphenylsilyl chloride (5.84 mL, 1.1 l eq.) and the homogeneous mixture was stirred overnight under argon at room temperature. The mixture was partitioned between 5% KHSO and EtOAc, the 4 organic fi was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 and evaporated to give 9.32 g (100%) of crude silyl ether as a clear viscous oil. TLC (3: 1) Hex-EtOAc, Rf silyl ether = 0.75, U.V. and PMA. (3) (S) -4-Iodo-3 - [(1,1-dimethylethyl) -diphenylsilyl] oxy] -butanoic acid, methyl ester A solution of the crude part E (2) bromide (9.32 g , 201 mmol) 503 210 41 in methyl ethyl ketone (60 ml, dried over 4Å sieves) was treated with sodium iodide (105.0 g, 100.5 mmol, 5.0 eq.) And the yellow suspension was refluxed for 5.0 hours under argon. .

The mixture was cooled, diluted with EtOAc, filtered and the filtrate was washed with dilute NaHSO 3 until colorless, and brine, then dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 10.17 g of a yellow oil. The crude oil was purified by flash chromatography on silica gel (600 g) eluting with (3: 1) hexane-CH 2 Cl 2. The product fractions were combined and evaporated to give 7.691 g (74.2%, total yield for both steps) of the desired title iodide as a clear colorless viscous oil. TLC (3: 1) Hex-EtOAc, product. Rf = 0.75, U.V. and PMA. (Note: product iodide spots with starting bromide). (4) (S) -4- (Diethoxyphosphinyl) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] butanoic acid, methyl ester A solution of the iodide (7.69l g) in triethylphosphite (20 ml) dissolved - heated at 155 ° C (oil bath) for 3.5 hours under argon. The mixture was cooled and the excess phosphite was distilled off in vacuo (0.5 mm H 2 O 75 °) to give a yellow oil (ß-8.0 g). The crude oil was purified by evaporative chromatography on silica gel (400 g) eluting with (4: 1) hexane-acetone. The product fractions were evaporated to give 3.222 g (41.1%) of the desired title phosphonate as a clear, colorless viscous oil. TLC (1: 1) Hexacetone, Rf = 0.51, U.V. and PMA. An additional 2.519 g (61, 1% corrected yield) of the starting part (3) iodide was recovered. (5) (S) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] -4-phosphonobutanoic acid, methyl ester A solution of the part (4) -phosphonate (9.85 g, 20.0 mmol) in dry CH 2 Cl 2 (60 mL) was treated sequentially with bistrimethylsilyltrifluoroacetamide (BSTFA) (5.3l mL, 32.0 mmol, 1.6 eq) and trimethylsilyl bromide (TMSBr) (6.60 mL, 50.0 mmol , 2.5 eq.) And the clear mixture was stirred overnight under argon at room temperature. 5% KHSO 4 (30 mL) was added and the mixture was extracted with EtOAc. The aqueous phase was saturated with NaCl and re-extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give crude title phosphonic acid as a viscous oil. TLC (7: 2: 1) iPrOH-NH OH-H O, Rf = 0.30, U.V. 4 2 and PMA. (6) (s) -3 - // <1,1-dimethylethyl) diphenyls11yl / ox1 / -4- (hyaroxymethoxyphosphinyl) -butanoic acid, methyl ester Part (5) -orene phosphonic acid (-20.0 mmol) in dry pyridine (25 mL) was treated with dried CH 3 OH (over 3 Å sieves, 1.62 mL, 40.0 mmOl, 2.0 eq.) and dicyclohexylcarbodiimide (DCC) (4.54 g, 22.0 mmol, 1.0 eq.) and the resulting white suspension was stirred under argon at room temperature overnight. Pyridine was removed in vacuo, then azeotroped with benzene (2 x 15 mL). The residual oil was dissolved in EtOAc, filtered and washed with 1.0 HCl and brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 8.272 g of crude title ester as an oil containing a small amount of precipitated dicyclohexylurea (DCU). . TLC (7: 2: 1) iPrOH-NH -OH H O, Rf = 0.60, U.V. and PMA. 4 2 F. (S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -methoxyphosphinyl] -3-t-butyldiphenylsilyloxybutanoic acid, methyl ester Part E-crude phosphonic acid monomethyl ester (6.595 g, 14.7 mmol) was dissolved in dry CH 2 Cl 2 (30 mL), treated with distilled trimethylsilyldiethylamine (5.60 mL, 29.4 mmol, 2.0 eq.) and stirred under argon at room temperature for one hour. The mixture was evaporated in vacuo, 1 month with benzene (1 x 30 ml) and dried in vacuo. The light yellow viscous oil was dissolved in dry CH 2 Cl 2 (30 mL) and DMF (dried over 4Å sieves, 2 drops), the clear solution was cooled to -10 ° C (salt / ice bath) and treated dropwise via syringe with distilled oxalyl chloride (1, 41 ml, 16.2 mmol, 1.1 l eq.). Strong gas evolution was clear and the solution became darker yellow in color. The mixture was stirred under argon at -10 ° C for 15 minutes, then allowed to stir at room temperature for one hour. The mixture was evaporated in vacuo, evaporated with benzene (1 x 30 ml) and dried in vacuo to give crude phosphonochloridate as a yellow oil. To a solution of the crude phosphonochloridate (14.7 mmol) in dry CH 2 Cl 2 (10 mL) was added dropwise a solution of Part D-biphenyl alcohol (2.06 g, 8.43 mmol) in dry pyridine (15 mL). ml) and the resulting mixture was stirred at room temperature under argon for 16 hours. The mixture was evaporated to dryness and the residue partitioned between 5% KHSO 4 and EtOAc. The organic phase was washed with saturated NaHCO 3 then poured over anhydrous Na 2 SO 4 and evaporated in vacuo to give 8.290 g of brown oil. The crude product was purified by brine, flash evaporation chromatography on silica gel (370 g) eluting with (70:30) hexane-acetone. Product fractions were combined and evaporated to give 3.681 g (66%) of the desired title phosphonate as a pale yellow oil. TLC (3: 2) hexane-acetone, Rf = 0.59, U.V. and PMA.

G. (S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A mixture of The F-silyl ether (1.03 g, 1.66 mmol) in dry THF (20.0 mL) was treated with glacial acetic acid (380 mL, 6.64 mmol, 4.0 eq.) and a 1.0 M tetrabutylammonium fluoride solution ( 4.98 ml, 4.98 mmol, 3.0 eq.) And the clear yellow solution was stirred overnight at room temperature under argon. The mixture was partitioned between cold H 2 O and EtOAc, the organic phase was washed with saturated NaHCO 3 free Na 2 SO 4 and evaporated to a viscous yellow oil (1.174 g). and brine, dried over water- The crude oil was purified by evaporative chromatography on silica gel (47 g) eluting with (85:15) CH 2 Cl 2 -acetone.

Product fractions were evaporated to give 679 mg (93.1%) of the desired title alcohol as a clear viscous oil. TLC (1zl) hexane-acetone, Rf = 0.41, U.V. and PMA.

H. (S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / methoxy / methoxyphosphinyl / -3-hydroxy-butanoic acid, monolithic salt A solution of the Part G methyl ester (84 mg, 0.420 mmol) in dioxane (5.0 mL) was treated with 1.0 N LiOH (0.50 mL, 1.2 eq.) And the mixture was stirred at room temperature under argon for 3 h - mar. The mixture was diluted with H 2 O, filtered through a 0.4 μm polycarbonate membrane and evaporated in vacuo. The residue was dissolved in H 2 O (75 mL), frozen and lyophilized. The 2 crude acid was dissolved in a minimal amount of H 2 O and chromatographed on a 100 mL bed of CHP-20 resin eluting with an H 2 O / CH 3 CN linear gradient system. The product fractions were evaporated, dissolved in H 2 O (50 mL), filtered through 0.4 μm polycarbonate membrane and lyophilized to give 174 mg (89.1% by weight of the hydrate) of the desired title monolithium salt as a white solid. TLC (7: 2: 1) iPrOH-NH OH-H O, Rf = 0.58, U.V. OCh PMA. Analysis: calculated for C 21 H 25 O 6 PFLi + 1.95 mol H 2 O (molecular weight 465.46): C 54.19 H 6.26 F 4.08 P 6.65 Found: C 54.19 H 6.21 F 4 29 P 6.43 1 H NMR (400 HMZ): δ 1.74-2, ppm (za, m, -Po (ocH 3) (3H, d, aromatic methyl, to fluorine JHF2.2 Hz) 2.35-2.62 (2H, m, -§§2CO2Li) 2.46 (3H, s, aromatic methyl) 3.57 & 3, 63 (3H, 2 doublets, -OP (OCH 3) -, 2 diastereomers, JH_p = 10.3 Hz) 4.28 (1H, m, -CH CH (OH) C fi CO Li) (za, m, Phggzoa 6.87-7.25 (SH, m, aromatic H) Example 2 (S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,1' -biphenyl / -2-yl / -methoxy / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A solution of Example 1-diester (374 mg, 0.853 mmol) in dioxane (8.0 mL) was treated with 1.0N Li , 6 ml, 3.0 eq.) And heated at 5000 (oil bath) for 5.0 hours under argon.

A white precipitate was clear. The mixture was diluted with H 2 O and filtered. The aqueous solution was extracted once with Et 2 O, filtered through a 0.4 μm polycarbonate membrane and concentrated in vacuo. The crude product was chromatographed on CHP-20 resin (100 mL bed) eluting with a H 2 O / CH 3 CN linear gradient system. Product fractions were evaporated in vacuo, taken up in H 2 O (50 mL), filtered through a 0.4 μm polycarbonate membrane and lyophilized to give 260 mg (67.1% by weight of hydrate) of the desired title lithium salt as a white solid. TLC (7: 2: 1). PrOH-NH 4 OH-H 2 O, Rf = 0.47, U.V. and PMA.

Analysis: calculated for C 2 OH 22 O 6 PFLi 2 + 1.77 mol H 2 O: C 52.88 H 5.67 F 4.19 P 6.82 Found: C 52.88 H 5.26 F 4.24 P 6.43 1 H NMR ( 400 MHz, CD OD): 3 o H δ 1.69 ppm (za, m. -0Pg§2CH (OH) -) 2.30 (3H, S, aromatic methyl) 2.31 (3H, d, aromatic methyl) 2-33 (3H, S, aromatic methyl) 4.22 (1H, m, -Q§ (OH) CH2-) O 4.75 (2H, m, Ph§§2Og-) I _ 6.86-7.23 (SI-I, m, aromatic proton) Example 3 (3S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / methoxy / methylphosphinyl / -3-hydroxybutanoic acid, monolithium salt A. (S) -4 - [(chloro) methylphosphinyl] -3- [(1,1-dimethylethyl / diphenylsilyl] oxy] butanoic acid, methyl ester The title phosphine chloridate compound is prepared as described in Example 6, Part B, 503 210 46 B. (38) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl- / 1,1'-biphenyl / -2-yl / methoxy / methylphosphinyl / -3-t-butyldiphenylsilyloxybutanoic acid, methyl ester A cooled (0 ° C, ice bath) solution of the Part A phosphinochloridate (^ / 2.2 mmol) and Example 1, Part C (2) the biphenyl alcohol (429 mg, 2.2 mmol, 1, 0 eq.) In dry CH Cl (10 mL) treated es with Et 3 N (425 μL, 3.04 mmol, 1.4 rpm?) and 4-DMAP (27 mg, 0.22 mmol) and the orange solution was stirred at room temperature overnight under argon. The mixture was partitioned between 5% KHSO 4 and EtOAc, the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated to give 1.1 g of an orange oil. The crude oil was purified by evaporative chromatography on LPS-1 silica gel (44 g ) eluting with (1: 1) EtOAc: hexane. Product fractions were combined and evaporated to give 298 mg (21%) of the desired coupled title product as a light yellow oil. Also 460 mg (67% corrected yield) of starting example 1, part C (2) the biphenyl alcohol was recovered. TLC (1: 1) EtOAc: Hex, Rf = 0.18 U.V. and PMA.

C. (3S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / methoxy / methylphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the Part B silyl ether (298 mg, 0.46 mmol) in dry THF (6.0 mL) was treated with glacial HOAC (10 μl, 1.84 mmol, 4.0 eq.) and 1.0 M in THF solution of tetrabutylammonium fluoride (1.43 ml, 3.1 eq.) and the resulting solution was stirred overnight under argon at room temperature. The mixture was partitioned between cold H 2 O and EtOAc, the organic phase was washed with saturated NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 and evaporated to a yellow oil (273 mg). The crude oil was purified by evaporative chromatography on LPS-1-silica gel (11 g) eluting with (3: 2) hex-acetone. Product fractions were combined and evaporated to give 150 mg (80%) of the desired title alcohol as a viscous oil. TLC (1: 1) Hex: acetone, Rf = 0.23, U.V. and PMA. 503 210 47 D. (35) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -methoxy / methylphosphinyl] -3-hydroxybutanoic acid monolithium salt A solution of part C-methyl ester (150 mg, 0.367 mmol) in dioxane (3.0 mL) was treated with 1.0 N LiOH (0.44 mL, 1.2 eq.) and the resulting white suspension was stirred at room temperature. under argon for 2 hours. The mixture was diluted with H 2 O, filtered through a 0.4 μm polycarbonate membrane and evaporated in vacuo to a colorless glass.

The crude product was taken up in a minimal amount of H 2 O and chromatographed on HP-20 (100 mL bed) eluting with an H 2 O / CH 3 CN linear gradient. Product fractions were evaporated, taken up in H 2 O (50 mL), filtered through a 0.4 μm polycarbonate membrane and lyophilized to give 130 mg (79% by weight of hydrate) of the desired title lithium salt as a white solid. TLC (8: 1: 1) CH Cl -CH OH-HOAC, 2 2 3 Rf = 0.52, U.V. and PMA.

Analysis: calculated for C 21 H 25 O 5 FL 2 P + 1.73 mol H (molecular weight 445.49): C 56.61 H 6.44 F 4.26 P 6.94 Found: C 56.67 H 6.26 F 4.31 P 7 43 H1 NMR (400 MHz) = δ 6.49 ppm (3H, d, -0g (CH3) -, JH_P = 14.7 Hz) δ 1.83-2.0 (za, m, 3f (ca3> g§2- > 2.27-2.40 (2H, m, §§2CO2Li) 2.30 (6H, s, 2 aromatic acetyl groups) 2.44 (3H, s, aromatic ethyl) 4.26 (15, m, -cH2g§ (oH) CH2co2Li) f? 4.87 (23, m, Argg2oP (cH3) -) 6.90-7.20 (SH, m, aromatic H) 503 210 48 Example 4 (S) -4 - /// 2,4-dichloro-6 - [(4-fluorophenyl) methoxy] - phenyl / methoxy / methoxyphosphinyl / -3-hydroxy-butanoic acid, monolithic salt A. 2,4-dichloro-6- (4-fluorophenylmethoxy) -benzaldehyde (Ref .: J. Med. Chem., 1986, 22, 167) A solution of 13.77 g (72.5 mmol) of 4.6 + dichloro-2-hydroxybenzaldehyde in 100 ml of DMF was stirred and 22.02 g (87 mmol) of K 2 CO 3 were added. This mixture was heated to 70 ° C for 60 minutes. , then 1.1 ml of 4-fluorobenzyl bromide was added.

The resulting solution was stirred at 70 ° C for 3.5 hours, then poured onto ice water (1.1 liters), filtered and washed with H 2 O and recrystallized from Et 2 O / petroleum ether. Yield: 17.88 g (83%) of off-white crystals, melting point lov-losoc.

B. 2,4-Dichloro 6 - [(4-fluorophenyl) -methoxy] -benzenemethanol Cold (0 ° C, ie bath) dry Etzo (158 mg, 4.16 mmol, 0.6 eq.) And the gray suspension 4 was treated dropwise with a solution of Part A aldehyde (2.06 g, 6.93 mmol) in 10 mL of dry THF. The mixture was warmed to room temperature and stirred for one hour under argon. The mixture was cooled again to 0 ° C (ice bath) and quenched by subsequent dropwise addition of H 2 O (160 .mu.l), 15% NaOH (160 .mu.l) and H 2 O (475 .mu.l). Precipitated salts were removed by filtration through anhydrous Na 2 SO 4 over packed Celite (1/4 "bed).

The clear filtrate was evaporated to give 2.052 g (98.9%) of crude alcohol as white crystals. A decomposition with cold hexane gave 1.892 g (91.2%) of pure title alcohol as a white crystalline solid, m.p. 72-73 ° C.

TLC (4: 1) hex-acetone, Rf = 0.31, U.V. and PMA.

Analysis: calculated for C 14 H 11 O 2 Cl F (molecular weight 301, 142): 2 C 55.84 H 3.68 Cl 23.42 F 6.31 Found: C 55.97 H 3.71 Cl 23.42 F 6.30 503 210 49 C. (S) -4 - /// 2,4-Dichloro-6 - [(4-fluorophenyl) methoxy / phenyl / methoxy] methoxyphosphinyl] -3-t-butyldiphenylsilyloxy-butanoic acid, methyl ester A solution of Example 1, Part E (6) The methyl ester (M3.84 mmol) in dry CH 2 Cl 2 (10 mL) was treated with distilled trimethylsilyldiethylamine (1.46 mL, 7.68 mmol, 2.0 eq.) and the resulting The solution was stirred at room temperature for argon for 0.1 hour. The mixture was evaporated in vacuo, evaporated with benzene (1 x 20 ml) and dried in vacuo to give crude silylated phosphonic acid monomethyl ester as a colorless oil.

A solution of the crude ester (3.84 mmol) in dry CH 2 Cl 2 (10 mL) of stirred DMF (1 drop) was cooled to -10 ° C (salt, ice bath) and treated dropwise with distilled oxalyl chloride (368 mL). 4.22 mmol, 1.1l eq.). Gas evolution was evident from the clear yellow mixture. The mixture was stirred at room temperature under argon for one hour, evaporated in vacuo, evaporated with benzene (2 x 20 ml) to give crude phosphonochloridate as a viscous yellow oil.

The crude phosphonochloridate (~ ~ 3.84 mmol) in dry CH 2 Cl 2 (10 mL) at 0 ° C (ice bath) was treated with Part B alcohol (1.5 g, 3.84 mmol, 1.0 eq.) Followed by Et 3 N ( 805 μl, 5.76 mmol, 1.5 eq.) And 4-DMAP (47 mg, 0.384 mmol, 0.1 eq.) And the brown mixture was stirred overnight at room temperature under argon. The mixture was partitioned between 5% KHSO 4 and EtOAc, the organic phase was washed with brine, dried over anhydrous Na SO 2 4 oil. The crude product was purified by evaporation chromatography and evaporated to give 3.197 g of a dark brown silica gel graphic (160 g) eluting with (7: 3) hex-EtOAc. Product fractions were combined and evaporated to give 594 mg (2.1%) of the desired title phosphonate as a yellow oil. An additional 688 mg (52.4% corrected yield) of the starting portion B alcohol was recovered. TLC (1zl) hex-hacetone, Rf = 0.29, U.V. and PMA. 503 210 50 D. (S) -4 - /// 2,4-Dichloro6- [(4-fluorophenyl) methoxy] phenyl / methoxy] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A solution of the part C-silyl ester (578 mg, 0.788 mmol) in dry THF (8 mL) was treated with glacial HOAC (180 μL, 3.2 mmol, 4NF in THF (2.36 mL, 2.36 mmol, 3.0 eq.) And the obtained bright yellow solution (4.0 eq.) followed by 1.0 M solution of n-Bu was stirred overnight under argon at room temperature. The mixture was poured into cold H 2 O and extracted with EtOAc (2x).

The organic phase was washed with saturated NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 and evaporated to give 625 mg of a yellow oil. The crude product was purified by flash chromatography on evaporating silica gel (31 g) eluting with (7: 3) hexane-acetone. Product fractions were combined and evaporated to give 339 mg (86.9%) of the title alcohol as a clear colorless viscous oil.

TLC (1zl) hex-acetone, Rf = 0.25. U.V. and PMA.

E. (S) -4 - /// 2,4-Dichloro-6 - [(4-fluorophenyl) methoxy / phenyl] -methoxy] -methoxyphosphinyl] -3-hydroxy-butanoic acid, monolithium salt A solution of part D-phosphonate (132 mg, 0.267 mmol) in dioxane (2.5 mL) was treated with 1.0N LiOH (0.32 mL, 1.2 eq.) And the mixture was stirred under argon at room temperature for 4.0 hours. A white precipitate was noted. The mixture was diluted with H 2 O, filtered and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on HP-20 resin (100 mL bed) eluting with an H 2 O / CH 3 CN linear gradient system.

Product fractions were combined and evaporated, taken up in H 2 O, filtered through a 0.4 μm polycarbonate membrane and lyophilized to give 108 mg (79% by weight of hydrate) of the desired title lithium salt as a white solid.

TLC (20: 1: 1) CH 2 Cl 2 -CH 3 OH-HOAC, Rf = 0.41, U.V. OCh PMA.

Analysis: calculated for C (molecular weight 51.72): C 44.59 H 4.10 Cl 13.86 F 3.71 P 6.05 Found: C 44.22 H 4.09 Cl 13.91 F 3.72 P 6.11.

O7Cl2Fli P + 1.42 mol H2O 19H1s 2 503 210 51 H1 NMR (400 MHz): δ δ 1.98-2.11 ppm (2H, m, OP (OCH3) §§2CH (0H) - 2 26-2-45 ppm (2H, m, -cH (oH) gg2co2Li) 3.63 & 3.62 (3H, 2 doublets, 2 diastereomers, β1 (OCH3) CH2-, JH? -11 Hz) 4-23 (1H, m, ( -cH2gg (on) cH2co2Li) 5.16 (za, s, F-Phggzo) 5-24 (2H. d, Arggzor, JHP = ez Hz) 7.13-7.53 (6H, m, aromatic fl Example 5 (3S) -4- / // 2,4-Dichloro-6 - [(4-fluorophenyl) -methoxy] phenyl / methoxy / hydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt A mixture of Example 4, Part D-diester (210 mg, 0.424 mmol ) in dioxane (4.0 ml) was treated with 1.0N LiOH (1.3 ml, 3.0 eq.) and the colorless solution was heated to 50 ° C (oil bath) under argon for 3.5 hours. After 15 minutes, the mixture was diluted with H 2 O, filtered and the filtrate was evaporated in vacuo The residue was dissolved in a minimal amount of H 2 O and chromatographed on HP-20 resin (100 mL bed) eluting with an H 2 O / CH 3 CN linear product fractions were combined and evaporated . The residue was taken up in H 2 O (50 mL), filtered through a 0.4 μm polycarbonate membrane and lyophilized to give 175 mg (81% by weight of hydrate) of the desired title lithium salt as a white solid.

TLC (8: 1: 1) CH 2 Cl 2 -CH 3 OH-HOAC, Rf = 0.07, U.V. And PMA.

Analysis: calculated for C 18 H 16 O 7 Cl 2 FL 12 P + 1.70 mol H 2 O (molecular weight 509.62): C 42.42 H 3.84 F 3.73 Cl 13.91 P 6.08 Found: C 42.46 H 3.90 F 3 .93 Cl 13.42 P 5.66. 503 210 sz HINMR (400 mm: i), δ δ 1.73-1.92 ppm (2H, m, -OP (OLi) -CH 2 CH (OH) - 2.27 (m, da, -cr 2.39 (m, dd, -cH (oH) g 2 co 2 Li, JHH = 4.4 H 2) 4.26 (in, m, cnzgwrncnzcozni) 5.08 (za, s, F-Ph-cnzoar) 7.03-7.53 (GH, m, aromatic H) 6 (3S) 4 // 2,4-dichloro-6 - [(4-fluorophenyl) methoxy] phenyl] methoxy] methylphosphinyl] -3-hydroxybutanoic acid, methyl ester A. (S) -3 - // (1, 1-Dimethylethyl) diphenylsilyl / -oxy / -4- (ethoxymethylphosphinyl) -butanoic acid, methyl ester A mixture of Example 1, Part E (3) -iodide (4.68 g, 9.18 mmol) in methyldiethoxyphosphine (Strem Chemicals (5.0 g, 36.7 mmol) was heated to 100 ° C (oil bath) for 2.5 hours, then at 150 ° C for a further 3 hours under argon. A white precipitate formed slowly in the yellow solution. was distilled in vacuo (0.5 mm Hg) and the crude product was purified by evaporative chromatography on silica gel eluting with (65:35) hexane-acetone, product fractions were combined and evaporated to give 1.590 g (38%) of the desired de tite The phosphine ester (mixture of diastereomers) as a clear viscous oil. TLC (3: 2) hex-acetone, Rf (2 diastereomers) = 0.19 and 0.22, U.V. and PMA.

B. (33) -4- [2,4-Dichloro-6 - [(4-fluorophenyl) methoxy] phenyl] methoxy] methylphosphinyl] -3-t-butyldiphenylsilylbutanoic acid, methyl ester A solution of the Part A phosphine ester (605 mg, 1.3 mmol) in dry CH 2 Cl 2 (6.0 mL) was treated with bis (trimethylsilyl) trifluoroacetamide (BSTFA) (280 μL, 1.05 mmol, 0.8 eq.) And trimethylsilyl bromide ( TMSBr) (210 μl, 1.57 mmol, 1.2 eq.) And the resulting solution were stirred at room temperature under argon overnight. 5% KHSO 4 (15 mL) was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give crude phosphinic acid as a colorless oil.

A solution of the crude phosphinic acid (1.3 mmol) in dry CH 2 Cl 2 (6.0 mL) was treated with distilled trimethylsilyldiethylamine (270 μL, 1.44 mmol, 1.1 l eq.) And the clear mixture was stirred at room temperature under argon for 1.0 hour. The mixture was evaporated in vacuo, evaporated with benzene (1 x 15 ml) and dried in vacuo.

A cooled (0 ° C, ice bath) solution of the crude silylated phosphinic acid (/ / 1.3 mmol) in dry CH 2 Cl 2 (6.0 mL) and DMF (1 drop) was treated dropwise via syringe with distilled oxalyl chloride (130 μl). , 1.44 mmol, l, l eq.). Gas evolution was clear.

The mixture was stirred at room temperature under argon for one hour, then evaporated in vacuo, evaporated with benzene (2 x 15 ml) and dried in vacuo to give crude phosphinochloridate as a yellow oil.

A cooled (0 ° C, ice bath) solution of phosphinochloridate (= »1.3 mmol) and Example 1, Part E (6) alcohol (392 mg, 1.3 mmol) in dry CH 2 Cl 2 (6.0 mL) was treated with Et 3 N (275 μL, 1.97 mmol, 1.5 eq;) and 4-DMAP (16 mg, 0.13 mmol, 0.1 eq.) and the resulting yellow mixture was stirred under argon at room temperature overnight. The mixture was partitioned between 5% KHSO 4 and EtOAc, the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated to give 908 mg of crude product as a dark yellow oil. The crude product was purified by evaporative chromatography on silica gel (45 g) eluting with (3: 2) hex-EtoAc. Product fractions were combined and evaporated to give 266 mg (28.3%) of the desired title product as a clear, colorless oil. 97 mg (57%, corrected yield) of the starting alcohol was also recovered. 505 210 54 C. (3S) -4 - // 2,4-Dichloro-6 - [(4-fluorophenyl) methoxy / phenyl / methoxy] methylphosphinyl] -3-hydroxybutanoic acid, methyl ester 275 mg, 0.38 mmol) in dry THF (6.0 mL) was treated with glacial HOAC (90 μL, 1.55 mmol, 4.0 eq.) And a 1.0 M solution in THF of tetrabutylammonium fluoride (1.2 ml, 3.1 eq.). The resulting solution was stirred overnight under argon at room temperature. The mixture was partitioned between cold H 2 O and EtOAc, the organic phase was washed with saturated NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 and evaporated to give 258 mg of a yellow oil. The crude product was purified by evaporative chromatography on LPS-1 silica gel (8 g) eluting with (1zl) hexane-acetone. Product fractions were combined and evaporated to give 142 mg (77%) of the desired title alcohol as a clear colorless oil.

TLC (1zl) hexane-acetone, Rf = 0.20, U.V. and PMA.

D. (3S) -4 - // 2,4-Dichloro-6 - [(4-fluorophenyl) methoxy / phenyl / methoxy] methylphosphinyl] -3-hydroxybutanoic acid, monolithic salt A solution of the Part C methyl ester (142 mg, 0.296 mmol) in dioxane (3.0 mL) was treated with 1.0N LiOH (0.36 mL, 1.2 eq.) And the resulting white suspension was stirred under argon at room temperature for 2.0 hours. The mixture was diluted with H 2 O, filtered through a 0.4 μm polycarbonate membrane and the filtrate evaporated in vacuo.

The crude product was dissolved in a minimal amount of H 2 O and chromatographed on a 100 mL bed of HP-20 resin eluting with an H 2 O / CH 3 CN linear gradient. Product fractions were combined, filtered through a polycarbonate membrane and lyophilized to give 93 mg (63% by weight of hydrate) of the desired title lithium salt as a white solid. was combined and evaporated. The residue was taken up in H TLC (8: 1: 1) CH 2 Cl 2 -CH 3 OH-HOAC, Rf = 0.51, U.V. And PMA.

Analysis: Calculated for C 19 H 19 O 7 Cl 2 FL 2 P + 1.38 mol H 2 O (molecular weight 495.94): C 46.01 H 4.42 F 3.83 Cl 14.30 P 6.24 Found: C 46.10 H 4.49 F 3 , 82 Cl 14.32 P 6.43 503 210 55 H1 NMR (400 MHz) =? - a 1.53 ppm (sn, d. -OP (gg3) cH2-, Jà_P = ~ 14.6 Hz) and 1.87-2.10 (2H , m, -oP (ocH3) gg2-) 2.27 (in, dd, -cH (oH) gg2co2Li, JH_H = s.4 Hz, JH_P = 1.1 az) 2.38 (1H, dd, -cH (oH) gg2co2L1, JH_H = 4.7 Hz, JH_P = 1.1 Hz) 4.29 (in, m, -cH2g§ (oH) cH2co2Li) s.16 + s.1s (45, m, Arggzopoch s = Phg§2o \ -) 7.11-7.52 (6H, aromatic SK Example 7 (S) -4- / 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl-2-yl / methyl / amino / methoxyphosphinyl / -3 hydroxybutanoic acid, monolithic salt A. 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-carboxylic acid A solution of Example 1, part C (2) -aldehyde (1.0 g, 4.13 mmol) in acetone (10.0 ml) at 0 ° C (ice bath) was treated dropwise with 8.0 N Jones reagent (4.1 ml, excess) and the resulting brown-green suspension was stirred overnight under argon at Excess oxidant was destroyed by the addition of isopro panol (10.0 ml) and precipitated chromium salts were removed by filtration through a 1/4 "pad of Celite.

The filtrate was evaporated, taken up in EtOAc, washed with 1.0N HCl (2x), saturated NHCl (2x) and brine, then dried over anhydrous Na 2 SO 4 and evaporated to give 1.01 g of a green solid with melting point l53-145 ° C.

The crude acid was purified via the dicyclohexylamine salt. To a solution of the crude acid in EtOAc (5.0 mL) was added dicyclohexylamine (DCHA) (823 μl, 1.0 eq.). The solution was diluted with hexane and the precipitated crystalline salt was collected to give 997 mg (55% from aldehyde, m.p. 181-183 ° C) of the desired product as an off-white crystalline DCHA salt. 503 210 56 The free title acid was regenerated from the DCHA salt by partitioning the salt between 5% KHSO 4 and EtOAc. The organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 554 mg (52% from the aldehyde) of the desired title acid. TLC (9: 1) CH 2 Cl 2 -CH 3 OH, Rf = 0.37, U.V. and PMA.

B. 4'-Fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-carboxamide A suspension of part A acid (554 mg, 2.4 mmol) in dry CH 2 Cl 2 (6.0 ml) and dry DMF (1 drop) at 0 ° C (ice bath) were treated dropwise via syringe with distilled oxalyl chloride (205 μl, 2.35 mmol, 1, 1 eq.) and the clear yellow solution was stirred under argon at room temperature for one hour. . The mixture was evaporated in vacuo, evaporated with benzene (2x) and dried in vacuo to give crude acid chloride as a yellow oil.

A cooled (0 ° C, ice bath) mixture of THF (3.0 mL) and concentrated NH 4 OH (2.0 mL, excess) was treated dropwise with a THF solution (3.0 mL) of the crude acid chloride and the the bright orange solution was stirred at room temperature under argon for 0.1 hour. The mixture was partitioned between H 0 and 2 EtOAc, the organic phase was washed with saturated NaHCO H O 3 2 2504 and evaporated to give 528 mg (96.1%) of crude amide as a light brine, then dried over anhydrous Na orange solid. A recrystallization from EtOAc-hexane gave 435 mg (79.1%) of purified title amide as light yellow needles, m.p. 97-198 ° C. TLC (Izl) Et 2 O-acetone, Rf = 0.83, U.V. and PMA.

C. 4'-Fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-methanamine A cooled (0 ° C, ice bath) solution of dry THF (5.0 ml) was treated with a solid LiAlH 4 (125 mg, 3.3 mmol) and the gray suspension were treated dropwise over 5 minutes with a solution of the Part B amide (424 mg, 1.65 mmol) in THF (5.0 mL). The resulting suspension was stirred at room temperature under argon for 2.5 hours, then refluxed for 45 minutes. The mixture was cooled to 0 ° C (ice bath) and quenched with subsequent dropwise addition of 125 ul of H 2 O, 125 ul of 15% NaOH and 375 ul of 2 503 210 57 H 2 O. Precipitated aluminum salts were removed by filtration through anhydrous Na 2 SO 4 over packed Celite. The clear filtrate was evaporated in vacuo to give the crude amine as a clear oil. TLC (7: 3) Et 2 O-acetone, Rf = 0.60, U.V. and PMA. The amine was purified as the HCl salt.

A solution of the crude amine (δ, 65 mmol) in absolute EtOH (8.0 mL) was treated with concentrated HCl (152 μl, 1.82 mmol) and the mixture was stirred at room temperature under argon for 15 minutes. The mixture was evaporated in vacuo to a white crystalline solid. The solid was decomposed with cold Et 2 O, collected by filtration and dried in vacuo to give 426 mg (92.4%) of title amine-HCl as fine white crystals.

D. (S) -4 - //// 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / methyl / amino / methoxyphosphinyl / -3-t butyldiphenylsilyloxy-butanoic acid, methyl ester A solution of Example 1, Part E (6) -methyl ester ('2.0 mmol) in dry CH 2 Cl 2 silyldiethylamine (758 μL, 4.0 mmol, 2.0 eq.) and the clear (5.0 ml) treated with distilled trimethyl mixture was stirred at room temperature under argon for one hour. The mixture was evaporated in vacuo, evaporated with benzene (1 x 15 ml) and dried in vacuo.

A cooled (0 ° C) solution of the crude silyl phosphonate in dry CH 2 Cl 2 (7.0 mL) and DMF (1 drop) was treated dropwise with distilled oxalyl chloride (192 μL, 2.2 mmol, 1.1 eq.). Gas evolution was evident from the clear yellow mixture. The solution was stirred at room temperature for one hour, evaporated in vacuo, evaporated with benzene (2 x 15 ml) and dried in vacuo to give the crude phosphonochloride as a yellow, viscous oil.

A cooled (0 ° C) solution of the phosphonochloridate and part C-biphenylamine.HCl (416 mg, 1.49 mmol) in dry CH 2 Cl 2 (10 mL) was treated with Et 3 N (641 μL, 4.6 mmol, 2.3 eq.) and 4-DMAP (24 mg, 0.2 mmol, 0.1 eq.) and the clear yellow mixture was stirred overnight at room temperature under argon. The mixture was partitioned between 5% KHSO 4 and EtOAc, the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 1.19 g of a yellow oil. The crude product was purified by evaporative chromatography on silica gel (60 g) eluting with (7: 3) hexane-acetone. Product fractions were evaporated to give 588 mg (59.5%) of the desired title phosphonamide as a pale yellow, viscous oil.

TLC (7: 3) hexane-acetone, Rf = 0.20, U.V. and PMA.

E. (S) -4 - //// 4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl) -2-yl] methyl-amino] -methoxyphosphinyl] -3-hydroxybutanoic acid , methyl ester A solution of the Part D silyl ether (588 mg, 0.888 mmol) in dry THF (1.0 mL) was treated with glacial HOAC (203 μL, 3.55 mmol, 4.0 eq.) and a 1.0 M solution in THF of tetrabutylammonium fluoride (2.66 mL, 2.66 mmol, 3.0 eq.) and the resulting solution was stirred overnight under argon at room temperature. The mixture was poured into cold H 2 O and extracted with EtOAc. The organic phase was washed with saturated NaHCO 3 and brine, then dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 605 mg of an orange dye. The crude product was purified by evaporative chromatography on silica gel (36 g) eluting with (1: 1) hexane-acetone. Product fractions were combined and evaporated to give 196 mg (50.4%) of the desired title alcohol as a light orange oil.

TLC (1zl) hexane-acetone, Rf = 0.16, U.V. and PMA.

F. (S) -4 - //// 4'-fluoro-3,3',5-trimethyl / 1,1'-biphenyl / -2-yl / methyl / amino / methoxyphosphinyl / -3-hydroxybutanoic acid, monolithic salt A solution of the Part E diester (105 mg, 0.240 mmol) in dioxane (2.0 mL) was treated with 1.0N LiOH (288 μL, 1.2 eq.) and the white suspension was stirred under argon at room temperature. for 20, was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed on HP-20 resin (100 mL bed) eluting with an H 2 O / CH 3 CN linear gradient. Product fractions were combined and evaporated in 4.0 hours. The mixture was diluted with H des. The residue was taken up in H 2 O (50 mL), filtered through a 0.4 μm polycarbonate membrane and lyophilized to give 70 mg of 503 210 59 (62.7% by weight of hydrate) the desired title lithium salt as a white solid. TLC (20: 1: 1) CH 2 Cl 2 -CH 3 OH-HOAC, Rf = 0.19, U.V. And PMA.

Analysis: calculated for C 21 H 26 NO 5 PPl 1 + 2.41 mol H 2 O (molecular weight 472.75): C 53.35 H 6.57 N 2.96 F 4.02 P 6.55 Found: C 53.35 H 6.52 N 2 , 98 F 4.05 P 6.59 H1 NMR (400 MHz): δ 1.79-1.97 ppm (ZH, m, -g (OCH3) §§2-) 2.26-2.44 ppm (ZH, m, -CH CO Li 2.29 (3H, s, aroalphatic methyl) 2.31 (3H, d, aromatic methyl to fluorine JHF = 1.4 Hz) 2-47 (33, aromatic methyl) 3.46 & 3.50 (3H, 2 doublets, 2 diastereomers = 10.5 Hz) «a 3.96 (ZH, m, -PhCH2NHP (OCH3) - 4.17 (1H, m, (-CH2§§ (OH) CH2CO2Li) 5-34'7-21 (53, m, aromatic protons Examples 8 to 20 Following the procedures set forth above and described in the foregoing working examples, the following additional compounds can be prepared: O H u H den co Rx R'É '° 2 °; 2 2 03 503 210 60 n OH CH3 ll.

OH 12.

Li -o czas, 2 9 13. C4H9O 503 210 61 Ex. n; '_ RZ n X Rx 14.: san 1 NH: H3 2 cz fl s cn, 3 15. ox c 1-1 -cH 2 o ox 2 s, c = osoa CH:: H3 16. oNa F _ @ _ CH _0 2 o H 2 C33 17. c fl3 o F _ @ _ CH _O 1 NH 2-1 2 1 ca Ho 3 503 210 62 Ex.

C33 18.

Li HO 19.

H C30 20. 503 210 63 Example 21 (S) -4- (diisopropyloxyphosphinyl) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / butanoic acid, methyl ester Example 1, part E (3) -iodide ( 45.1 mmol, 21.70 g) was stirred under high vacuum for 30 minutes. Freshly distilled triisopropyl phosphite (0.45l mol, 93.92 g, 113.37 ml) was added in one portion and the reaction mixture was stirred under argon and heated in a 155 ° C oil bath for 16.5 hours. The mixture was then cooled to room temperature. Excess triisopropyl phosphite and volatile reaction products were removed by short-range distillation (10 mm Hg) followed by Kugelrohr distillation (0.50 mm Hg, 10 ° C, 8 hours). The product was further purified by evaporation chromatography (95 mm diameter column, 6 "/ Merck silica gel, 6/3 / l hexane / acetone / toluene eluent, 2" / min. Flow rate, 50 ml fractions) to give 17.68 g (33.96 mmol, 75% yield) of the title isopropyl phosphonate as a clear viscous oil.

TLC: silica gel Rf = 0.32 (6: 3: 1 hexane / acetone / toluene). 1HNmmmm (270 MHz, cDc13) δ 7.70-7.65 (m, 4H) 7.45-7.35 (m, 6H) 4.57-4.44 (N, 3H) 3.59 (S, 3H) 2.94 and 2.88 (2Xd, 1H J = 3.7 H2 ) 2.65 and 2.60 (2Xd, 1H J = 7.4 H2) 2.24-1.87 (Series of m, ZH) 1.19 and 1.12 (2Xd, 12H J = 6.3 Hz) 1.01 (s, 93) 'Example 22 (S) -4 - (hydroxymethoxyphosphinyl) -3 - [(1,1-dimethylethyl) -diphenylsilyl] -oxy / butanoic acid, methyl ester, dicyclohexylamine (Izl) salt The isopropyl phosphonate from Example 21 (30.5 mmol, 10.66 g) was stirred under argon at room temperature in 80 ml of dry CH Cl. This solution was treated dropwise (5 minutes) with bistrimethylsilyltrifluoroacetamide (BSTFA) (32.8 mmol, 8.44 g, 8.71 ml), followed by dropwise addition (10 minutes) of trimethylsilyl bromide (50 minutes). TMSBr) (51, 3 mmol, 7.84 g, 6.75 mL). After stirring at room temperature for 20 hours, the reaction mixture was quenched with 200 ml of 5% aqueous KHSO 4 and stirred vigorously for 15 minutes. The aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, washed once with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was azeotroped twice with 50 ml of toluene.

The precipitate that formed was suspended in toluene and filtered. The filtrate was concentrated and the azeotrope / filter procedure was repeated. The resulting filtrate was evaporated in vacuo and then pumped under high vacuum for 5 hours. The resulting viscous clear oil was stirred under argon at room temperature in 50 ml of dry pyridine. This solution was treated in one portion with dicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g) followed by the addition of methanol (41.0 mmol, 1.3l g, 1.67 mL). After stirring at room temperature for 20 hours, the reaction mixture was filtered through a pad of Celite into a sintered glass funnel.

The celite was washed with ethyl acetate and the combined filtrates were evaporated in vacuo. The residue was redissolved in ethyl acetate and washed twice with 5% aqueous KHSO 4 and once with brine. The organic extract was washed over Na 2 SO 4, filtered, the filtrate was concentrated and azeotroped twice with toluene, suspended in toluene and filtered. The resulting filtrate was concentrated again, azeotroped, filtered and the filtrate evaporated in vacuo and placed under high vacuum for 6 hours to give the phosphonate monoester as a clear viscous oil (10.2 g, 100% yield). TLC: silica gel, Rf = 0.50 (7: 2: 1 nPrOH / NH 4 OH / H 2 O). The phosphonate monoester / 1.21 g was pumped under high vacuum for 4 hours to give 1.66 g (2.57 mmol) / dissolved in 10 ml of dry ethyl ether and treated dropwise with dicyclohexylamine (2.65 mmol, 0.481 g, 0.528 ml). The resulting homogeneous solution sedimented at room temperature for 7 hours and gave a significant crystal formation. The mixture was stored at -20 ° C for 16 hours and then warmed to room temperature and filtered. The crystals were washed with cold dry ethyl ether and then pumped under high vacuum over P 0 for 18 hours. The crystals were then pumped under high vacuum at 45 ° C for 4 hours to give 503 210 65 1.25 g (1.98 mmol, 77% yield) of the tite1-dicyclohexylamine salt as a white powdered solid, mp 155-165 ° C. TLC: silica gel, Rf = 0.57 (20% MeOH / CH 2 Cl 2 H NMR: (270 MH, CDCl 3) 2) δ 7.71-7.65 (m, 4H) 7.40-7.32 (m, 6H) 4.02 (m, 1H ) 3.52 (s, 3H) 3.28 and 3.22 (m, 1H) 3.11 (d, 3H J = 11 Hz) 2.77-2.64 (m, ZH) 2.62-2.56 (m, 1H) 1.92-1.08 (Series of m, 22H ) 1.00 (S, 9H) Mass Spec: (FAB) .632 (M&H) + IR: (KBr) 3466-3457 (broad) 3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633 , 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051, 820 CM-1 Analysis: Calculated for C 22 H 31 O 6 PS 6 N 2.22 Found: C 64.51 H 8.49 N 2.18

Claims (7)

A compound which inhibits the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, having the structure 0 ll x __ __ _c RFCHzEHCH2 Qf ¥ OH (F Z n Z and its salts, wherein R is OH, lower alkoxy or lower alkyl and Rx is H or lower alkyl; X is -O- or -NH-; n is 1 or 2, Z is a hydrophobic anchor, which is I 2 32a R 1 3 R. ßß 2b 2 R 1 R 2a or R 5 O alkyl I * S QQ SR 6a (R) q wherein the dotted lines represent optional double bonds, wherein R 1, R 2, R 2a and R 2b may be the same or different and are H, halogen, lower alkyl , haloalkyl, phenyl, C 1-4 alkyl-substituted phenyl or ORY, wherein Ry is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl- lower alkyl or C 1-4 alkyl-substituted phenyl-lower alkyl, wherein when Z is R 5 and R 5 'are the same or different and are H, lower alkyl or OH, one of R 5 and R 5' being present when the carbon to which it is attached ä r connected to a double bond; O R 6 is alkyl-g- or phenyl-CH 2 -; R 6 is lower alkyl, hydroxy, oxo or halogen and q is 0, 1, 2 or 3; wherein Rx is hydrogen or lower alkyl in free acid form or in the form of a physiologically hydrolyzable and acceptable ester in salt form. A compound according to claim 1, wherein X is -O-, R is alkoxy and Z is 2a 505 210 w A compound according to claim 1, wherein X is -NH-, R is alkoxy and (CH 2) n is CH and Z is 2! R2a A compound according to claim 2 named (S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / methoxy / methoxyphosphinyl / -3-hydroxy-butanoic acid, methyl ester or its monolithium salt, (S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / - methoxy / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt, (3S) -4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / methoxy / methylosphinyl / -3-hydroxybutanoic acid, monolithium salt, (S) -4 - /// 2,4-dichloro-6 - [(4-fluorophenyl) -methoxy] -phenyl] -methoxy / -methoxyphosphinyl / -3-hydroxybutanoic acid, monolithium salt, M3S-4 - /// 2,4-dichloro-6 - [(4-fluorophenyl) -methoxy] phenyl / methoxy / hydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt, (3S) (- 4 - // 2 4-Dichloro-6 - [(4-fluorophenyl) -methoxy] -phenyl] -methoxy] -methylphosphinyl / -3-hydroxybutanoic acid, or its methyl ester, or (S) -4 - //// 4'-fluorophenyl 3,3 ', 5-trimethyl / 1,1'-biphenyl-2-yl / methyl / amino / methoxyphosphinyl / -3-hydroxybutanoic acid monolithium salt, A hypocholesterolemia or hypolipemia composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier therefor. (f) 505 210 A compound having the structure 0 a u - R 1 -C 82 - (HTCH 2 -CO 2 alkylalkyl gsi-cwna) 3 wherein Ra is lower alkyl or lower alkoxy, comprising all stereoisomers thereof. A compound having the structure 0 Ra 2a-cnz-en-CH 2 -cozalkyl C 58 85 C 635 wherein Ra is lower alkyl or OH, comprising all stereoisomers thereof.