IE85318B1 - (R-(R*R*))-2-(4-fluorophenyl)-á,d-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof - Google Patents

Abstract

ABSTRACT [R—(R*,R*)] — 2 — (4—f1u0ropheny1) -B,6—dihydroXy—5—((1—methylethy1)—3-phenyl—4- [(pheny1amino)-carboyn1]-1H—pyrrole-l—heptanoic acid or (2R—trans)—5—(4— fluoropheny1)—2—( 1—methy1ethy1—N, 4—dipheny1—l[2-(tetrahydro—4—hydroxy—6—oxo—2H— pyran—2—y1)ethy1]-1H-pyrrole-3—carboxamide; a process for their preparation and pharmaceutically acceptable salts thereof.

Description

PATENTS ACT, 1992 2004/0325 (R-(R*R*))(4—FLUOROPHENYL)-B,5-DTHYDROXY—b—(l— METHYLETHYLPHENYL-4((PHENYLAMTNO)-CARBONYL)-lH- PYRROLE-l—HEPTANOIC ACID, ITS LACTONE FORM AND SALTS THEREOF WARNER-LAMBERT COMPANY It is now unexpectedly found that the enantiomer having the R form of the ring-opened acid of trans—5-(4- fluorophenyl)(1-methylethyl)-N,4-diphenyl[2- tetrahydrohydroxyoxo-2g-pyranyl)ethyl] pyrrolecarboxamide; that is [R—(R*,R*)](4- fluorophenyl)-B,5-dihydroxy(1-methylethyl)-3—phenyl [(phenylamino)carbonyl]-lg-pyrroleheptanoic acid, provides surprising inhibition of the biosynthesis of cholesterol.

It is known that 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) exists as the 3R-stereoisomer. Additionally, as shown in the study of a series of 5-substituted 3,5-dihydroxypentanoic acids by Stokker et al., in "3-Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitors. 1. Structural Modification of 5-Substituted 3,5-Dihydroxypentanoic acids and Their Lactone Derivatives," J. Med. Chem. 1985, 28, 347-358, essentially all of the biological activity resided in the trans diastereomer of (E)[2-(2,4-dichlorophenyl)ethenyl]—3,4,5,6-tetrahydro—4— hydroxy-2H-pyranone having a positive rotation. Further, the absolute configuration for the B—hydroxylactone moiety common to mevinolin of the formula (la) O HO 3 O 0 CH3 1 a Of H3C‘ and compactin of the formula (lb) 0 HO O Of H‘ apparently is required for inhibition of HMG-CoA reductase.

This is reported by Lynch et al. in "Synthesis of an HMG-COA Reductase Inhibitor; A Diastereoselective Aldol Approach in Tetrahedron Letters, Vol. 28, No. 13, pp. 1385-1388 (1987) as the 4R, 6R configuration.

However, an ordinarily skilled artisan may not predict the unexpected and surprising inhibition of cholesterol biosynthesis of the present invention in view of these disclosures. l\) V.) I SUMMARY OF THE INVENTION Accordingly the present invention provides for compounds consisting of [R—(R*R*)]—2—(4—fluorophenyl)—B,é— dihydroxy—5—((l—methylethyl)—3—phenyl—4~[(phenylamino)— carbonyl]-lH—pyrrole—l—heptanoic acid (compound of formula I), and pharmaceutically acceptable salts thereof. suffering from hypercholesterolemia or hyperlipidemia.

DETAILED DESCRIPTION OF THE INVENTION The pharmaceutically acceptable salts of the invention are those generally derived by dissolving the free acid or the lactone; preferably the lactone, in aqueous or aqueous alcohol solvent or other suitable solvents with an appropriate base and isolating the salt by evaporating the solution or by reacting the free acid or lactone; preferably the lactone and base in an organic solvent in which the salt separates directly or can be obtained by concentration of the solution.

In practice, use of the salt form amounts to use of the acid or lactone form. The able salts within the scope of the invention are those pharmaceutically accept- derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 1-deoxy (methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine.

Preferably, the lithium, calcium, magnesium, aluminum and ferrous or ferric salts are prepared from the sodium or potassium salt by adding the appropriate reagent to a solution of the sodium or potassium salt, i.e., addition of calcium chloride to a solution of the sodium or potassium salt of the compound of the formula I will give the calcium salt thereof.

The free acid can be prepared by hydrolysis of the lactone form of formula II or by passing the salt through a cationic exchange resin (H + resin) and evaporating the water.

Generally, the compounds I and II of the present invention can be prepared by (l) resolving the racemate, that is prepared by the processes described in U.S. Patent No. or (2) synthesizing the desired chiral form beginning from ,681,893 which is incorporated by reference therefor, starting materials which are known or readily prepared using processes analogous to those which are known.

Specifically, resolution of the racemate may be accomplished as shown in Scheme I (where Ph is phenyl) as follows: ' Scheme 1 IO on on o /\/k)\)\ 3 pm R R S ‘ "1 mm N ° ° C33 u 5 21: R ‘ 0 " ‘T’ Step A + (cs: ‘"" I F trans racqmatg OH OH 0 H Pb ’”‘\/’i\»/£‘\¢’l\ N 5 5 N = Ph PhHN H CH3 ° R Step B ) Separate 2) Na0H V3) reflux in toluene no 0 aqwy O 0 O w @xiz*©X:z* h Ph CONHh Ph CONE? [R(R'R*) 1 isomer [S (R*R*) lisomer Naofi naoa C0733 CO7Na moon 08 ohm OH 1' F ©X:r‘ “ yh cgngph Pb Coflflh The "trans racemate” of Scheme 1 means a mixture of the following: H0 0 Ho 0 ‘C? O and F Ph CONHPh Ph CONHph "'1 Z $ —\mu [R (R*R*> J isomer [5 (R*R*) ]isomer The conditions of the Step 1 and 2 of Scheme 1 are generally as found in the Examples 6 and 7 hereinafter.

The chiral synthesis is shown in Scheme 2 (where Ph is phenyl) as follows: Scheme 2 F .M9“ CD ‘~‘ , 1. THF—80—-90°C 0‘ Ph 2 1hr X ' G 0 + O 0 2.Adm F 1.1 eq NaOMe 0 Ph OH M OH, -10 C e l6hrs ’ N/\)\/CO2” PhNHOC (4) % (3) 75% o "L\0Bu‘ 8 99 1. B(Et)3 , NaBH4 on 0 --~---——--------* Ph 2 . H202 -40°C N CO2But Shrs PhNHOC (5) 78% F on 1. NaOH Ph OH OH 2. T01. -H20‘* Ph ,» N,»\V/J\\//L\¢,CO2But -------> N O O “ PhNHOC H PhNHOC (7) 57% Generally, conditions for Scheme 2 are as shown in the Examples 1-5 hereinafter.

One of ordinary skill in the art would recognize variations in the Schemes 1 and 2 which are appropriate for the preparation of the compounds of the present invention.

The compounds according to present invention and especially according to the compound of the formula I inhibit the biosynthesis of cholesterol as found in the CSI U.S. Patent No. 4,681,893 which reference therefor. The CSI enantiomer the compound II and the racemate of these two compounds are as follows: screen that is disclosed in is now also incorporated by data of the compound I, its °50 Compound (micromoles/liter) [R-(R*R*)] isomer 0.0044 [S-(R*R*)] isomer 0.44 Racemate 0.045 Accordingly, the present invention is the pharmaceu- tical composition prepared from the compound of the formula I or II or pharmaceutically acceptable salts thereof.

These compositions are prepared as described in U.S.

Patent No. 4,681,893 which is, therefore, again incorporated by reference here.

Likewise, the present invention is a method of use as hypolipidemic or hypocholesterolemic agents. of the method The compounds present invention utilized in the pharmaceutical of this invention are administered to the patient at dosage levels of from 10 to 500 mg per day which for a normal human adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kg of body weight per day. The dosages may be preferably from 0.5 to 1.0 mg/kg per day.

The dosage is preferably administered as a unit dosage form. The unit dosage form for oral or parenteral use may be varied or adjusted from 10 to 500 mg, preferably from 20 to 100 mg according to the particular application and the potency of the active ingredient. The compositions can, if desired, also contain other active therapeutic agents.

Determinations of optimum dosages for a particular situation is within the skill of the art.

The compounds of the formula I and II and their pharma- ceutically acceptable salts are in general equivalent for the activity of the utility as described herein.

The following examples illustrate particular methods for preparing compounds in accordance with this invention.

These examples are thus not to be read as limiting the scope of the invention.

EXAMPLE 1 285 ml 2.2 M n-butyl lithium (in Hexane) is added dropwise to 92 ml diisopropylamine in 300 ml THF at 50—60°C in a 1000 ml 1 neck flask via dropping funnel and under nitrogen. The well stirred yellow solution is allowed to warm to about -20°C. Then it is cannulated into a suspension of 99 g S(+)acetoxy-1,1,2-triphenylethanol in 500 ml absolute THF, kept in a 2L-3 neck flask at -70°C. when addition is complete, the reaction mixture is allowed to warm to —l0°C over a period of two hours. Meanwhile, a suspension of 0.63 mol MgBr2 is prepared by dropping 564 ml (0.63 mol) of bromine into a suspension of 15.3 g of magnesium (0.63 mol) in 500 ml THF plus in 3L flask equipped When this is completed, the MgBr2 suspension is cooled to -78°C and the with reflux condenser, and overhead stirrer. enolate solution (dark brown) is cannulated into the suspension within 30 minutes. Stirring is continued for 60 150 g 5-(4-fluorophenyl)(l- minutes at -78°C. carboxamide in 800 ml THF absolute was added dropwise over minutes; then stirred for 90 minutes at -78°C, then quenched with 200 ml ACOH at -78°C. cool bath, 500 ml of H2 concentrated in vacuo at 40-50°C.

This is removed to a O is added and the mixture 500 ml of 1:1 EtOAc/Heptane is added to the yellowish slurry and filtered.

The filtrate is washed extensively with 0.5 N Hcl, then several times with H20 and finally with EtOAc/Heptane (3:1) that was cooled with dry ice to -20°C. The light brown crystalline product 1A is dried in vacuum oven at 40°C. The yield is 194 g.

The product 1A is recrystallized from EtOAc at -10°C to yield 100 g to yield product 1B and then recrystallized from acetone/pentane to yield 90 g to yield product 1C. The mother liquor is combined from the wash of the crude 33 g of 1B HPLC: 97.4:2.l7 of the R,S to S,S 28.5 g of 1C shows the following: HPLC:95.7:3.7.

The combined 1B and 1C is recrystallized from CHCl3 MeOH material and recrystallized from EtOAc/Hexane. shows the following: isomers. :1; providing a product 1F having a yield of 48.7 g of white crystal.

The mother liquor of the first aqueous wash is crystallized (EtOAc/Heptane) to yield product 1D of 21.4 g; HPLC: 7l.56:25.52.

The mother liquor of 1B and 1C is combined and recrystallized from CHCl3/MeOH/Heptane to yield 55.7 g white crystals of product 1G.

D is recrystallized from CHCl3/MeOH to yield the product lH.

All mother liquor is combined, concentrated then the residue is dissolved in hot CHC13/MeOH 10:1; put on a silica gel column; and eluted with EtOAc/Hexane 40:60. The material crystallized out on the column and the silica gel is extracted with CHCl3/MeOH and concentrated.

Recrystallization of the residue from CHCI3/Heptane 3:1 yields 33.7 g of product II.

The mother liquor of ll is recrystallized to yield 18.7 g of product 1K.

The mother liquor of 1K is crystallized to yield 6.3 g of product lL. ll, 1K and 1L is combined and recrystallized from CHCl3/Heptane to yield 48 g.

The combined mother liquor of II, 1K, and 1L is concentrated to yield 31 g of 1M.

The product 1F provides the following data.

Anal: 1F m.p. 229—230°C Calc. Found C: 77.84 77.14 H: 6.02 6.45 N: 3.56 3.13 These data are consistent with the formula F Ph Ph OH OH N Ph \ Ph PhNHCO EXAMPLE 2 g (0.206 M) of the combined products 1F, 1G, 1H and L of Example 1 are suspended in 800 ml Methanol/THF (5:3).

Cooled to 0°C and added to 11.7 g sodium methoxide. The mixture is stirred until everything is dissolved, then put in the freezer overnight. The reaction mixture is allowed to warm to room temperature, quenched with 15 ml HOAC, then concentrated in vacuo at 40°C to obtain expected product as follows: F OH Ph 9 N PhNHC This product is added to 500 ml H20 and extracted twice with EtOAc (300 ml). The combined extracts are washed with saturated NaHCO3, brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated. The residue is chromatographed on silica gel in EtOAc/Heptane (1:4) as eluent to yield 109 g colorless oil which is recrystallized from Etzo/Heptane to yield: .9 g first crop; white crystals 8.2 g second crop; white crystals.

The crystals provide the following data: m.p,.125-125°c, (130 .23° (1.17 M, CH3OH) Calc. Found C: 72.76 72.51 H: 6.30 6.23 N: 5.30 5.06 These data are consistent with the formula -13..

F Pb /’ OH N /W COZME X PhNHCO EXAMPLE 3 ml of diisopropylamine is dissolved in 250 ml THF in a 2000 ml three-neck flask equipped with thermometer and dropping funnel. The reaction mixture is kept under nitrogen. The mixture is cooled to —42°C and added to 200 ml 2.2 M of n-butyl lithium (in Hexane) dropwise over 20 minutes and stirred for 20 minutes before adding dropwise 62 ml of t-butylacetate, dissolved in 200 ml THF (over about minutes). This mixture is stirred 30 minutes at -40°C, then l40_ml 2.2 M of n-butyl lithium is added over 20 minuutes. when addition is complete, 81 g of the product of Example 2 in 500 ml absolute THF is added as possible without allowing the temperature to -40°C. reaction mixture is then quenched with 69 ml quickly as rise above at -70°C. The glacial acetic Stirring is continued for four hours acid and allowed to warm to room temperature. The mixture is concentrated in vacuo and the residue is taken up in EtOAc, washed with water extensively, then saturated NH4Cl, NaHCO layer is dried over anhydrous MgSO4, filtered and the (saturated), and finally with brine. The organic solvent evaporated. The NMR of the reaction is consistent with starting material plus product in about equal amounts plus some material on the baseline of the TLC. The material of the baseline of the TLC is separated from starting material and the product is extracted by acid/base extraction. The organic phase is dried and concentrated in vacuo to yield 73 g. The NMR and TLC are consistent with the formula F OH O O 1/ Ph /“\./l\v/fl\o/J\ N OtBu & PhNHCO EXAMPLE 4 g crude product of Example 3 is dissolved in 500 ml absolute THF and 120 ml triethyl borane is added, followed by 0.7 g t-butylcarboxylic acid. is stirred to -78°C and sodium -78°C for six Then poured slowly into a 4:1:l mixture of ice/30% H202/H20. warm to room temperature.

The mixture under a dry atmosphere for 10 minutes, cooled 70 ml methanol is added and followed by 4.5 g borohydride. The mixture is again stirred at hours.

This mixture is stirred overnight then allowed to CHC13 (400 ml) is added and the mixture is partitioned.

The water layer is extracted again with CHCI3. The organic extracts are combined and washed extensively with H20 until no peroxide could be found.

MgSO The organic layer is dried over 4, filtered and the solvent is evaporated.

The residue is treated by flash chromatography on silica gel, i.e. EtOAc/Hexane 1:3 to yield 51 g.

The product is dissolved in THF/MeOH and added to 100 ml in NaOH, then stirred for four hours at room temperature. The solution is concentrated at room temperature to remove organic solvent, added to 100 ml H20, -15.. and extracted with Et2O twice. The aqueous layer is acidified with l N HCl and extracted with EtOAc three times.

The combined organic layers are washed with H20. The organic layer is dried with anhydrous MgSO4, filtered, and the solvent evaporated. The residue is taken up in 2 liters of toluene and heated to reflux using a Dean-Stark trap for minutes.

The reaction mixture is allowed to cool to room temperature overnight. Reflux is repeated for 10 minutes and cooled for 24 hours.

The procedure above is repeated. The reaction is left at room temperature for the next 10 days, then concentrated to yield 51 g of colorless foam.

This product is dissolved in minimum CHCl and chromatographed on silica gel eluting with EtOAc/Heptane (50:50) to yield 23 g in pure material.

Chromatography on silica gel in CHCl3/2-propanol (98.5:l.5) yields 13.2 g.

Calc.

C: 73.31 H: 6.15 N: 5.18 EXAMPLE 5 Preparation of 2R-trans(4-fluorophenyl)-2—(l— methylethyl)-E,4-diphenyl[2-tetrahydro-4—hydroxy The product of Example 4 is recrystallized from EtOAc/Hexane. Fraction 1 yields 8.20 g of 4A. The mother liquor yields 4.60 g of 4B! HPLC of 4B shows 100% of the product to be the [R-(R*R*)] isomer. to yield 4.81 g of 4C. in CHCl3/2-propanol to yield 4.18 g colorless foam of 4D showing ag3 + 24.53° (O.53% in CHCI3). 4C is recrystallized A is recrystallized 4B is chromatographed on silica gel EXAMPLE 6 Preparation of diastereomeric a-methylbenzylamides A solution of the racemate, trans—(t)(4- (30 g, 55.5 ml) in (R)-(+)—a- methylbenzylamine (575 ml, 4.45 mol, 98% Aldrich) is stirred pyrrolecarboxamide, overnight at room temperature.

The resulting solution is then diluted with ether (2 l) and then washed exhaustively with 2 M HCl (4 x 500 ml), water (2 x 500 ml) and brine (2 x 500 ml). extract is then dried over MgSO4, filtered and concentrated The organic in vacuo to yield 28.2 g of the diastereomeric a-methylbenzylamides as a white solid; m.p. 174.0-177°. The a—methylbenzylamides are separated by dissolving 1.5 g of the mixture in 1.5 ml of 98:l.9:0.l CHCl3:CH3OH:NH4OH (1000 mg/ml) and injecting onto a preparative HPLC column (silica gel, 300 mm X 41.4 mm I.D.) by gastight syringe and eluting with the above solvent mixture. Fractions are collected by UV monitor. Diastereomer 1 elutes at minutes. Diastereomer 2 elutes at 49 minutes. Center cut fractions are collected. This procedure is repeated three times and the like fractions are combined and concentrated. Examination of each by analytical HPLC indicates that diastereomer 1 is 99.84% pure and diastereomer 2 is 96.53% pure. Each isomer is taken on separately to following Examples.

To an ethanolic solution (50 M) of diastereomer 1 of [3R-[3R*(R*),5R*]](4-fluorophenyl)—[B],[6]- dihydroxy(l-methylethyl)phenyl[(phenylamino) carbonyl]—N-(l-phenylethyl—lH-pyrroleheptanamide, (l g, 1.5 mmol) is added The resulting solution is heated Example 6, (hydroxy centers are both R) 1 N NaOH (3.0 ml, 3 mmol). to reflux for 48 hours.

The solution is cooled to room temperature and concentrated in vacuo. The residue is resuspended in water and carefully acidified with 6 N HCl. solution is extracted with ethyl acetate. .46 minutes is tentatively -carboxamide, as a white foam. be 94.6% chemically pure [a] peak at room temperature = assigned to an unknown diastereomer resulting from the 2% (S)—(-)—d—methylbenzylamine present in the Aldrich d-methylbenzylamine.

EXAMPLE 8 Preparation of 2S-trans-5—(4-fluorophenyl)(l- methylethyl)-3,4-diphenyl—l-[2-(tetrahydro—4—hydroxy—6- [M1233 = 0.51% in flash chromatographed on silica gel. pyrrole-3—carboxamide, as a white foam. material to be 97.83% chemically pure.

CHCI3 = -24.8%. 5 EXAMPLE 9 Hydrolysis of chemical lactone of formula II To a room temperature, solution of the lactone in THF The mixture is stirred for two hours HPLC:99.65% (product); 0.34 The mixture is diluted with 3L water, extracted with ethyl acetate (2 X 1L) and acidified to pH X 4 by addition of 37 ml of 5N hydrochloric acid. The aqueous layer is extracted with 2 X 1.5L portions of ethyl is added a solution of sodium hydroxide in water. to (starting lactone). acetate. The combined ethyl acetate extracts are washed with 2 X 1L of water, brine and dried, gave after filtration the ethyl acetate solution of the required face-acid. This solution is used directly in the fraction of the N-methylglucamine salt.

The ethyl acetate extracts from the brine-water were concentrated to give 15.5 g of an off-white solid. $7., EXAMPLE 10 Calcium Salt from Sodium Salt and/or Lactone Dissolve one mole lactone (540.6 g) in 5 L of MeOH; after dissolution add 1L H20. while stirring, add one equivalent NaOH and follow by HPLC until 2% or less lactone and methyl ester of the diolacid remains (cannot use an excess of NaOH, because Ca(OH)2 will form an addition of CaCl2). Charge NaOH as caustic (51.3 ml, 98 eq.) or as pellets (39.1 g, .98 eq.).

The above procedure is shown as follows: O N “"0!-i F \ / Ph ,0‘ .98 eq. NaOH 0 .N. —————————- H Ph Me0H, H20 : 1 m.m= M0.6g OH OH O 1 :1 Et0Ac, Hexane 0- + Wash Pb ‘c‘ O .N~ Ph Upon completion of hydrolysis, add 10 L H20, then wash at least two times with a 1:1 mixture of EtOAc/Hexane. Each wash should contain 10 L each of Et0Ac/Hexane. If sodium salt is pure, add 15 L of MeOH. contains color, add 100 g of G-60 charcoal, stir for two Wash with 15 L Me0H.

Perform a wt/vol % on the reaction mixture, by HPLC, to If it is impure and/or hours and filter over supercel. determine the exact amount of salt in solution.

Dissolve 1 eq. or slight excess CaCl2-2H20 (73.5 g) in L H20. Heat both reaction mixture and Caclz solution to 60°C.

Add CaCl2 solution slowly, with high agitation.

After complete addition, cool slowly to 15°C and filter. wash filter cake with 5 L H20. Dry at 50°C in vacuum oven.

Can be recrystallized by dissolving in 4 L of EtOAc (50°C) filtering over supercel, washing with 1 L EtOAc, then charging 3 L of hexane to the 50°C rxn solution.

The above procedure is shown as follows: (on on o ' Ca" m.w.- 1155.4 g 2 EXAMPLE 11 Treatment of Ethyl Acetate Solution of Free-acid of the Formula I with N—methylglucamine To a solution of the free-acid of the formula I (0.106 M) in ethyl acetate (3 L) is added a solution of N-methylglucamine (20.3 g, 0.106 m) in (1:1) water-acetone (120 ml, 120 ml) with vigorous stirring at room temperature.

Stirring is continued for 16 hours and the hazy solution concentrated in vacuo to ~ 250 mp. Toluene (1 L) is added and the mixture concentrated to a white solid ~ 100 g. The solid is dissolved in 1670 ml acetone and filtered into a three-neck flask equipped with a mechanical stirrer and thermostat controlled thermometer. The flask and filter is washed with 115 ml (1:1) water-acetone and the clear solution is cooled slowly. This provided a precipitate which is re-dissolved by heating back to 65°C. Addition of a further 20 ml of water followed by the washing gives a crystalline product which was isolated by filtration. The solids are washed with 1200 ml CH3Cl and vacuum dried at 255° to give a white solid. Analysis of this material indicates that it contains 4% amine as well as 0.4% residual acetone and 0.67% water. Analytical results are noted as follows: Melting point: 105-155°C (decomposition) Analysis Expected: C = 63.73; H - 6.95; N = 5.57; F2 = 9.53 Analysis Found: C = 62.10; H - 6.89; N - 5.34; F2 C = 61.92; H - 7.02; N = 5.38; F2 H20 = 0.47% (KF) HPLC: MeOH, H20, THF (40; 550; 250) Econosil: C18, 5u , 25 CM 256 nm: 1.0 ml/min. 6-81 min.: 98.76% Opt. Ret.: [a]-b = -l0.33° (c = 1.00, MeOH) Residual Solvents: CHZCH = 0.26% Titrations: HClO4 (0.1 N) = 203.8% Bu4NOH (0.1 N) = 98.5% Other salts prepared in a manner analogous to those processes appropriately selected from Examples 10 and 11 above may be the potassium salt, hemimagnesium salt, hemizinc salt or the l—deoxy(methylamino)-D-glucitol complex of the compound of formula I.

Claims (10)

1. [R-(R*,R*)](4-fluorophenyl)-fl,5—dihydroxy-S-(1- methylethyl)—3—phenyl[(phenylamino)carbony1]—1H-pyrrole—1— heptanoic acid and pharmaceutically acceptable salts thereof derived from bases selected form the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, 1—deoxy—2— (methylamino)—D—glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous hydroxide, ferric hydroxide, ammonium hydroxide, and organic amines.

2. The monosodium salt of the heptanoic acid of claim 1.

3. The monopotassium salt of the heptanoic acid of claim 1.

4. The N-methylglucamine salt of the heptanoic acid of claim 1.

5. The hemimagnesium salt of the heptanoic acid of claim 1.

6. The hemizinc salt of the heptanoic acid of claim 1.

7. The 1-deoxy(methylamino)-D—glucitol mixture with the heptanoic acid of claim 1.

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. Use of a compound of claim 1 for the preparation of a pharmaceutical composition useful for treating hypercholesteremia or hyperlipidemia.

10. A process for the preparation of a compound according to claim 1 to 6 which comprises A)l) treating a trans racemate of the formula “<3 trans racemate with a compound of the formula to obtain compounds of the formula I on OH 0 Ph N N H Ph R R = puma HY CH3 0 R + F OH OH 0 I Ph ’“\./i\./i\v/1\ N 3 5 N = Ph PhHN H CH3 0 2) treating the compounds with a strong base; 3) refluxing the product of step 2 and 4) treating separated product of step 3 to obtain [R—(R*,R*)]— 2-(4—f1uorophenyl)—B,5-dihydroxy—5—(l—methylethyl)phenyl—4— 5 [(phenylamino)carbonyl]—1H~pyrrole—l—heptanoic acid and pharmaceutically acceptable salts thereof or B)1l treating a compound of the formula (1) F Ph 0 ” ’“\o/1\ N H R Phuag O \‘M92+ 10 ' O o‘\‘ Pb,’ /\ f0 G 0 Ph Ph (2) in tetrahydrofuran for about an hour at from about -80 to —90°C and then treated with acetic acid to obtain the compound (3) F Ph /\}\/Hy,/'\K°“ PIINHOC 2) treating the compound (3) of the step 1 with a slight excess of sodium methoxide in methanol at about —10°C for up to 16 hours to obtain the compound of the formula (4) F Pb OH Z N/\/K/CO;Me \ PhNHOC M) 3) treating the compound of 4 of step 2 with a large excess of O- 4¢L\OBut at from about -30 to -40°C for up to 5 hours to obtain the compound of formula (5) Phfiflx (5) and 4) treating the compound 5 of step 3 with triethyl borane followed by sodium borohydride in methanol followed by the addition of hydrogen peroxide to obtain [R—(R*,R*)](4- fluorophenyl)—fi,6-dihydroxy—S—(1-methylethyl)phenyl—4— [(phenylamino)carbonyl]—lH—pyrrole—1—heptanoic acid as well as the pharmaceutically acceptable salts thereof.