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Publication numberUSRE40667 E1
Publication typeGrant
Application numberUS 11/653,830
Publication dateMar 17, 2009
Filing dateJan 16, 2007
Priority dateJul 21, 1989
Also published asCA2021546A1, CA2021546C, DE1061073T1, DE69033840D1, DE69033840T2, DE69034153D1, DE69034153T2, EP0409281A1, EP0409281B1, EP1061073A1, EP1061073B1, US5273995
Publication number11653830, 653830, US RE40667 E1, US RE40667E1, US-E1-RE40667, USRE40667 E1, USRE40667E1
InventorsBruce Roth
Original AssigneeWarner-Lambert Company Llc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
[R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US RE40667 E1
[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-((1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl)]-1H-pyrrole-1-heptanoic acid or (2R-trans)-5-(4-fluoro-phenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide; and pharmaceutically acceptable salts thereof.
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1. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid or (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide; or pharmaceutically acceptable salts thereof.
2. A compound of claim 1 which is [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
3. A compound of claim 1 which is (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
4. The monosodium salt of the compound of claim 2.
5. The monopotassium salt of the compound of claim 2.
6. The hemicalcium salt of the compound of claim 2 [R-(R*,R*)]- 2 -( 4 -fluorophenyl)-β,δ-dihydroxy- 5 -( 1 -methylethyl)- 3 -phenyl- 4 -[(phenylamino)-carbonyl]- 1H-pyrrole- 1 -heptanoic acid.
7. The N-methylglucamine salt of the compound of claim 2.
8. The hemimagnesium salt of the compound of claim 2.
9. The hemizinc salt of the compound of claim 2.
10. The 1-deoxy-1-(methylamino)-D-glucitol mixture with the compound of claim 2.
11. A pharmaceutical composition for treating hypercholesterolemia comprising a hypocholesterolemic effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
12. A method of inhibiting cholesterol synthesis in a human suffering from hypercholesterolemia comprising administering a compound of claim 1 in unit dosage form.
13. A pharmaceutical composition for treating hypercholesterolemia comprising a hypocholesterolemic effective amount of the hemicalcium salt of [R-(R*,R*)]- 2 -( 4 -fluorophenyl)-β,δ-dihydroxy- 5 -( 1 -methylethyl)- 3 -phenyl- 4 -[(phenylamino)-carbonyl]- 1H-pyrrole- 1 -heptanoic acid and a pharmaceutically acceptable carrier.
14. A method of inhibiting cholesterol synthesis in a human suffering from hypercholesterolemia comprising administering to said human the hemicalcium salt of [R-(R*,R*)]- 2 -( 4 -fluorophenyl)-β,δ-dihydroxy- 5 -( 1 -methylethyl)- 3 -phenyl- 4 -[(phenylamino)-carbonyl]- 1H-pyrrole- 1 -heptanoic acid in unit dosage form.

Notice: More than one reissue application has been filed for the reissue of Pat. No. 5,273,995. U.S. application Ser. No. 11/973,897, filed on Oct. 10, 2007, is a continuation reissue of U.S. application Ser. No. 11/653,830 (the instant application), filed on Jan. 16, 2007, which is a reissue of U.S. application Ser. No. 07/660,976, filed Feb. 26, 1991, now U.S. Pat. No. 5,273,995.

This is a continuation of U.S. application Ser. No. 07/384,187 filed Jul. 21, 1989, abandoned.


Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamides are among compounds of U.S. Pat. No. 4,681,893 having usefulness as inhibitors of cholesterol biosynthesis. The compounds therein broadly include 4- hydroxypyran-2-ones and the corresponding ring-opened acids derived therefrom.

It is now unexpectedly found that the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide; that is [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, provides surprising inhibition of the biosynthesis of cholesterol.

It is known that 3-hydroxy-3-methylglutaryl 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-Hydroxy-3-methylglutaryl-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)-6-[2-(2,4-dichlorophenyl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyranone having a positive rotation. Further, the absolute configuration for the β-hydroxy-δ-lactone moiety common to mevlnolin of the formula (1a)

apparently is required for inhibition of HMG-CoA reductase. This is reported by Lynch et al. in “Synthesis of an HMB-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.


Accordingly the present invention provides for compounds consisting of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-((1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (compound of formula I), pharmaceutically acceptable salts thereof and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (the lactone form of the heptanoic acid or compound of formula II).

The present invention also relates to a pharmaceutical composition, useful as a hypocholesterolemic agent, comprising a hypocholesterolemic effective amount of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its pharmaceutically acceptable salts of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide acid; and a pharmaceutically acceptable carrier. Further, the present invention is also a method of treating mammals, including humans, suffering from hypercholesterolemia by administering to such mammal a dosage form of the pharmaceutical composition described above.


The pharmaceutically acceptable salts of the invention are those generally derived by dissolving the free acid or the lactose; 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. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine and the like. 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 the cationic exchange resin (H+resin) and evaporating the water.

The most preferred embodiment of the present invention is [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, hemicalcium salt.

Generally, the compounds I and II of the present invention may be prepared by the processes described in U.S. Pat. No. 4,681,893 which is incorporated by reference therefor, or (2) synthesizing the desired chiral form beginning from 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:

The “trans racemate” of Scheme 1 means a mixture of the following:

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 screen that is disclosed in U.S. Pat. No. 4,681,893 which is now also incorporated by reference therefor. The CSI data of the compound I, its enantiomer the compound II and the racemate of these two compounds are as follows:

Compound (micromoles/liter)
[R—(R*R*)] isomer 0.0044
[S—(R*R*)] isomer 0.44
Racemate 0.045

Accordingly, the present invention is the pharmaceutical 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. Pat. 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. The compounds of the present invention utilized in the pharmaceutical method 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 pharmaceutically 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.


285 ml 2.2M 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(+)-2-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 −10° 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 3 L flask equipped with reflux condenser, and overhead stirrer. When this is completed, the MgBr2 suspension is cooled to −78° C. and the enolate solution (dark brown) is cannulated into the suspension within 30 minutes. Stirring is continued for 60 minutes at −78° C. 150 g 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide in 800 ml THF absolute was added dropwise over 30 minutes; then stirred for 90 minutes at −78° C., then quenched with 200 ml AcOH at −78° C. This is removed to a cool bath, 500 ml of H2O is added and the mixture concentrated in vacuo at 40°-50° C. 500 ml of 1:1 EtOAc/Heptane is added to the yellowish slurry and filtered. The filtrate is washed extensively with 0.5N HCl, then several times with H2O and finally with EtOAc/Heptane (3:1) that was cooled with dry ice to −20° C. The light brown crystalline product (Example 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 material and recrystallized from EtOAc/Hexane. 33 g of 1B shows the following: HPLC: 97.4:2.17 of the R,S to S,S isomers. 28.5 g of 1C shows the following: HPLC:95.7:3.7. The combined 1B and 1C is recrystallized from CHCl3 MeOH 10:1; 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: 71.56:25.52.

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.

1D is recrystallized from CHCl3/MeOH to yield the product 1H.

All mother liquor is combined, concentrated then the residue is dissolved in hot CHCl3/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 CHCl3/Heptane 3:1 yields 33.7 g of product 1I.

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

The mother liquor of 1K is crystallized to yield 6.3 g of product 1L.

1I, 1K and 1L is combined and recrystallized from CHCl3/Heptane to yield 48 g.

The combined mother liquor of 1I, 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


162 g (0.206M) of the combined products 1F, 1G, 1H and 1L 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:

This product is added to 500 ml H2O 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 Et2O/Heptane to yield:

73.9 g first crop; white crystals

8.2 g second crop; white crystals.

The crystals provide the following data:

m.p. 125°-126° C., αD 20=4.23° (1.17M, 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


77 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 2.2M 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 30 minutes). This mixture is stirred 30 minutes at −40° C., then 140 ml 2.2M of n-butyl lithium is added over 20 minutes. When addition is complete, 81 g of the product of Example 2 in 500 ml absolute THF is added as quickly as possible without allowing the temperature to rise above −40° C. Stirring is continued for four hours at −70° C. The reaction mixture is then quenched with 69 ml glacial acetic 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, NaHCO3 (saturated), and finally with brine. The organic layer is dried over anhydrous MgSO4, filtered and the 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


73 g crude product of Example 3 is dissolved in 500 ml absolute THF and 120 ml triethyl borane is added, followed by 0.7 t-butylcarboxylic acid. The mixture is stirred under a dry atmosphere for 10 minutes, cooled to −78° C. and 70 ml methanol is added and followed by 4.5 g sodium borohydride. The mixture is again stirred at −78° C. for six hours. Then poured slowly into a 4:1:1 mixture of ice/30% H2O2/H2O. This mixture is stirred overnight then allowed to warm to room temperature.

CHCl3 (400 ml) is added and the mixture is partitioned. The water layer is extracted again with CHCl3. The organic extracts are combined and washed extensively with H2O until no peroxide could be found. The organic layer is dried over MgSO4, 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 H2O, and extracted with Et2O twice. The aqueous layer is acidified with 1N HCl and extracted with EtOAc three times. The combined organic layers are washed with H2O. 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 10 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 CHCl3 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 (98.5:1.5) yields 13.2 g.

C: 73.31
H: 6.15
N: 5.18


Preparation of 2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H/-pyrrole-3-carboxamide

The product of Example 4 is recrystallized from EtOAc/Hexane. Fraction 1 yields 8.20 g of 4A. The another liquor yields 4.60 g of 4B, HPLC of 4B shows 100% of the product to be the [R-(R*R*)] isomer. 4A is recrystallized to yield 4.81 g of 4C. 4B is chromatographed on silica gel in CHCl3/2-propanol to yield 4.18 g colorless foam of 4D showing αD 23+24.53° (0.53% in CHCl3). 4C is recrystallized and the mother liquor of 4C is to yield 2.0 g.HPLC which indicates 100% of the R-trans isomer 2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.


Preparation of diastereomeric α-methylbenzylamides

A solution of the racemate, trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, (30 g, 55.5 ml) in (R)-(+)-α-methylbenzylamine (575 ml, 4.45 mol, 98% Aldrich) is stirred overnight at room temperature.

The resulting solution is then diluted with ether (2 l) and then washed exhaustively with 2M HCl (4×500 ml), water (2×500 ml) and brine (2×500 ml). The organic extract is then dried over MgSO4, filtered and concentrated in vacuo to yield 28.2 g of the diastereomeric α-methylbenzylamides as a white solid; m.p. 174.0°-177°. The α-methylbenzylamides are separated by dissolving 1.5 g of the mixture in 1.5 ml of 98:1.9:0.1 CHCl3:CH3OH:NH4OH (1000 mg/ml) and injecting onto a preparative HPLC column (silica gel, 300 mm×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 41 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.


Preparation of 2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide

To an ethanolic solution (50M) of diastereomer 1 of Example 6, [3R-[3R*(R*),5R*]]-2-(4-fluorophenyl)-[β],[δ]-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-N-(1-phenylethyl-1H-pyrrole-1-heptanamide, (hydroxy centers are both R) (1 g, 1.5 mmol) is added 1N NaOH (3.0 ml, 3 mmol). The resulting solution is heated 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 6N HCl. The resulting acidic solution is extracted with ethyl acetate. The organic extract is washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. This residue is redissolved in toluene (100 ml) and heated to reflux with azeotropic removal of water for three hours. This is cooled to room temperature and concentrated in vacuo to yield 1.2 g of a yellow semi-solid. Flash chromatography on silica gel eluting with 40% EtOAc/Hexane gives 0.42 g of a white solid which still contains impurities. This is rechromatographed to give 0.1 g of essentially pure R,R, enantiomer, 2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, as a white foam. HPLC shows this material to be 94.6% chemically pure [α]D 23:0.51% in CHCl3=25.5°. The peak at room temperature=53.46 minutes is tentatively assigned to an unknown diastereomer resulting from the 2% (S)-(−)-α-methylbenzylamine present in the Aldrich α-methylbenzylamine.


Preparation of 2S-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide-(S,S enantiomer of the compound prepared in Example 5

Carrying out the procedure described in Example 7 on diastereomer 2 afforded 0.6 g of a foamy solid which was flash chromatographed on silica gel. Elution with 50% EtOAc/Hexane gave 0.46 g of essentially pure S,S, enantiomer 2S-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, as a white foam. HPLC showed this material to be 97.83% chemically pure. [α]D 23=0.51% in CHCl3=−24.8%.


Hydrolysis of chemical lactone of formula II

To a room temperature, solution of the lactone in THF is added a solution of sodium hydroxide in water. The mixture is stirred for two hours HPLC:99.6% (product); 0.34 to (starting lactone). The mixture is diluted with 3 L water, extracted with ethyl acetate (2×1 L) and acidified to pH×4 by addition of 37 ml of 5N hydrochloric acid. The aqueous layer is extracted with 2×1.5 L portions of ethyl acetate. The combined ethyl acetate extracts are washed with 2×1 L 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.


Calcium Salt from Sodium Salt and/or Lactone

Dissolve one mole lactone (540.6 g) in 5 L of MeOH; after dissolution add 1 L H2O. 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, 0.98 eq.).

The above procedure is shown as follows:

Upon completion of hydrolysis, add 10 L H2O, then wash at least two times with a 1:1 mixture of EtOAc/Hexane. Each wash should contain 10 L each of EtOAc/Hexane. If sodium salt is pure, add 15 L of MeOH. If it is impure and/or contains color, add 100 g of G-60 charcoal, stir for two hours and filter over supercel. Wash with 15 L MeOH. Perform a wt/vol % on the reaction mixture, by HPLC, to determine the exact amount of salt in solution.

Dissolve 1 eq. or slight excess CaCl2.2H2O (73.5 g) in 20 L H2O. Heat both reaction mixture and CaCl2 solution to 60° C. Add CaCl2 solution slowly, with high agitation. After completion addition, cool slowly to 15° C. and filter. Wash filter cake with 5 L H2O. 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:


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 (0.106M) 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.

    • H2O=0.47% (KF)
    • HPLC: MeOH, H2O, THF (40; 550; 250)
      • Econosil: C18, 5 μ, 25 CM
      • 256 nm: 1.0 ml/min.
      • 6-81 min.: 98.76%
    • Opt. Ret.: [α]·b=−10.33° (c=1.00, MeOH)
    • Residual Solvents: CH2CH=0.26%
    • Titrations:
      • HClO4 (0.1N)=203.8%
      • Bu4NOH (0.1N)=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 1-deoxy-2-(methylamino)-D-glucitol complex of the compound of formula I.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3808254Jun 10, 1971Apr 30, 1974Syntex CorpResolution-racemization of alpha-amino-alpha-phenylacetonitrile
US3965129May 15, 1975Jun 22, 1976Hoffmann-La Roche Inc.Optical resolution of organic carboxylic acids
US3983140May 12, 1975Sep 28, 1976Sankyo Company LimitedPhysiologically active substances
US4072698Dec 2, 1976Feb 7, 1978The Upjohn CompanyResolution of aminonitriles
US4137322Oct 31, 1977Jan 30, 1979Sankyo Company LimitedML-236B carboxylic acid derivatives and their use as antihyperlipemic agents
US4139555May 11, 1977Feb 13, 1979Bayer AktiengesellschaftRecovery of (1-S)-2-oxo-bornane-10-sulphonate
US4171359Apr 12, 1978Oct 16, 1979Smithkline CorporationBenz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines
US4192872Mar 31, 1978Mar 11, 1980Smithkline Corporation6-Halo-3-lower alkyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines
US4231938Jun 15, 1979Nov 4, 1980Merck & Co., Inc.Hypocholesteremic fermentation products and process of preparation
US4281132Oct 24, 1978Jul 28, 1981John Wyeth & Brother LimitedPiperidino ureas and thioureas
US4282155Aug 5, 1980Aug 4, 1981Merck & Co., Inc.Antihypercholesterolemic compounds
US4293496Aug 5, 1980Oct 6, 1981Merck & Co., Inc.6(R)-[2-(8-Hydroxy-2,6-dimethylpolyhydronaphthyl-1)-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones
US4319039Aug 11, 1980Mar 9, 1982Merck & Co., Inc.Preparation of ammonium salt of hypocholesteremic fermentation product
US4342761Oct 20, 1980Aug 3, 1982John Wyeth & Brother LimitedPiperidine derivatives
US4342767Jun 16, 1980Aug 3, 1982Merck & Co., Inc.Hypocholesteremic fermentation products
US4346227Jun 5, 1981Aug 24, 1982Sankyo Company, LimitedML-236B Derivatives and their preparation
US4374829Feb 17, 1981Feb 22, 1983Merck & Co., Inc.Aminoacid derivatives as antihypertensives
US4374844Oct 30, 1981Feb 22, 1983Schering CorporationStable derivatives of (5R,6S,8R)-6-hydroxyethyl-2-ethylthiopenem-3-carboxylic acids
US4375475Feb 11, 1981Mar 1, 1983Merck & Co., Inc.Substituted pyranone inhibitors of cholesterol synthesis
US4444784Dec 18, 1980Apr 24, 1984Merck & Co., Inc.Antihypercholesterolemic compounds
US4450171Jun 14, 1982May 22, 1984Merck & Co., Inc.Antihypercholesterolemic compounds
US4474971Sep 29, 1982Oct 2, 1984Sandoz, Inc.(Tetrahydropyran-2-yl)-aldehydes
US4495103Mar 2, 1983Jan 22, 1985Sumitomo Chemical Company, Ltd.Preparation of optically active 4-demethoxydaunomycinone
US4555511Jan 19, 1984Nov 26, 1985Boehringer Ingelheim KgThieno [3,2,C]pyridines useful as antihypertensives
US4611067Jan 31, 1985Sep 9, 1986Merck & Co., Inc.Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein
US4613610Jun 6, 1985Sep 23, 1986Sandoz Pharmaceuticals Corp.Cholesterol biosynthesis inhibiting pyrazole analogs of mevalonolactone and its derivatives
US4647576Dec 10, 1984Mar 3, 1987Warner-Lambert CompanyTrans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis
US4681893May 30, 1986Jul 21, 1987Warner-Lambert CompanyTrans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
US4697036Apr 5, 1985Sep 29, 1987Zambon S.P.A.Process for the preparation of optically active alpha-arylalkanoic acids and novel intermediates thereof
US4735958Dec 22, 1986Apr 5, 1988Warner-Lambert CompanyTrans-6-[2-[2-(substituted-phenyl)-3- (or 4-) heteroaryl-5-substituted-1H-pyrrol-1-yl]-ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one inhibitors of cholesterol biosynthesis
US4739073Mar 4, 1985Apr 19, 1988Sandoz Pharmaceuticals Corp.Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof
US4743450Feb 24, 1987May 10, 1988Warner-Lambert CompanyStabilized compositions
US4775681Jun 18, 1987Oct 4, 1988Warner-Lambert CompanyMethod of treating fungal infections with trans-6-[2-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones
US4786505Apr 20, 1987Nov 22, 1988Aktiebolaget HasslePharmaceutical preparation for oral use
US4804679Aug 6, 1987Feb 14, 1989Sandoz Pharm. Corp.Erythro-(E)-7-(3'-C1-3alkyl-1'-(3",5"-dimethylphenyl)naphth-2'-yl)-3,5-dihydroxyhept-6-enoic acids and derivatives thereof
US4847306Apr 11, 1988Jul 11, 1989Merck & Co., Inc.Antihypercholesterolemic compounds
US4851427Oct 15, 1986Jul 25, 1989Sandoz Pharm. Corp.Pyrrole analogs of mevalonolactone, derivatives thereof and pharmaceutical use
US4853230Apr 20, 1987Aug 1, 1989Aktiebolaget HasslePharmaceutical formulations of acid labile substances for oral use
US4864038Jun 10, 1988Sep 5, 1989Merck & Co., Inc.Antihypercholesterolemic compounds
US4866090Jan 7, 1988Sep 12, 1989Merck & Co., Inc.Novel HMG-CoA reductase inhibitors
US4870187Aug 23, 1988Sep 26, 1989Bristol-Myers CompanyAntihypercholesterolemic tetrazol-1-yl compounds
US4897490Feb 18, 1988Jan 30, 1990Bristol-Meyers CompanyAntihypercholesterolemic tetrazole compounds
US4898868Jul 8, 1988Feb 6, 1990Hoechst Aktiengesellschaft3-demethyl-4-fluoromevalonic acid derivatives, a process for the preparation thereof, pharmaceutical products based on these compounds, the use thereof, and intermediates
US4898949Feb 18, 1988Feb 6, 1990Bristol-Myers CompanyIntermediates for the preparation of antihypercholesterolemic tetrazole compounds
US4906624Aug 2, 1988Mar 6, 1990Warner-Lambert Company6-(((Substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4939159Mar 8, 1989Jul 3, 1990Sandoz Pharm. Corp.Azaindole derivatives useful as cholesterol biosynthesis inhibitors
US4940727Oct 6, 1988Jul 10, 1990Merck & Co., Inc.Novel HMG-CoA reductase inhibitors
US4950775Oct 11, 1985Aug 21, 1990University Of CaliforniaAntihypercholesterolemic compounds and synthesis thereof
US4962115Nov 28, 1989Oct 9, 1990Janssen Pharmaceutica N.V.Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives
US4963538Mar 13, 1989Oct 16, 1990Merck & Co., Inc.5-oxygenated HMG-CoA reductase inhibitors
US4968689Jan 17, 1989Nov 6, 1990Bayer AktiengesellschaftCertain 2,6-diisopropyl-4-(4-fluoro-phenyl)-3,5-bis-dimethyl-3',5'-dihydroxy-hept-6-enoate-pyridine derivatives useful for treating lipoproteinaemia and arteriosclerosis
US4976949Jan 29, 1990Dec 11, 1990The University Of MichiganControlled release dosage form
US4978791Jun 25, 1985Dec 18, 1990Lonza Ltd.Substituted P,P'-methylene-bis-aniline
US4992462Apr 7, 1988Feb 12, 1991Bayer AktiengesellschaftSubstituted pyrroles
US5001255Jul 1, 1988Mar 19, 1991Sandoz Pharm. Corp.Idene analogs of mevalonolactone and derivatives thereof
US5003080Feb 1, 1989Mar 26, 1991Warner-Lambert CompanyProcess for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
US5004651Jan 24, 1989Apr 2, 1991Abbott LaboratoriesStabilizing system for solid dosage forms
US5006530Jan 17, 1989Apr 9, 1991Bayer AktiengesellschaftCertain 7-[2,6-diisopropyl-4-phenyl-5-lower alkoxymethyl-pyrid-3-yl]-3,5-dihydroxy-6-enoates and derivatives useful for treating circulatory diseases
US5024999Apr 13, 1989Jun 18, 1991Nissan Chemical Industries Ltd.Pyrazolopyridine type mevalonolactones useful as pharmaeuticals
US5026708Sep 12, 1988Jun 25, 1991Nissan Chemical Industries Ltd.Pyrimidine type mevalonolactones
US5030447Mar 31, 1988Jul 9, 1991E. R. Squibb & Sons, Inc.Pharmaceutical compositions having good stability
US5045321Feb 13, 1987Sep 3, 1991Takeda Chemical Industries, Ltd.Stabilized pharmaceutical composition and its production
US5055484Jul 8, 1988Oct 8, 1991Hoechst Aktiengesellschaft7(1h-pyrrol-3-yl)-substituted 3,5-dihydroxyhept-6-enoic acids, 7-(1h-pyrrol-3-yl)-substituted 3,5-dihyroxyhept-anoic acids, their corresponding delta-lactones and salts, their use as medicaments and pharmaceutical products and intermediates
US5061722Jan 12, 1989Oct 29, 1991Hoechst AgCis, endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, a process for their preparation, agents containing these compounds and their use
US5093132Aug 31, 1990Mar 3, 1992Takeda Chemical Industries, Ltd.Stabilized pharmaceutical composition and its production
US5097045Oct 9, 1990Mar 17, 1992Warner-Lambert CompanyProcess for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5124482Nov 14, 1991Jun 23, 1992Warner-Lambert CompanyProcess for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5149837Feb 12, 1992Sep 22, 1992Warner-Lambert CompanyProcess for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5151433Nov 22, 1988Sep 29, 1992Hoechst AktiengesellschaftStabilized medicinal substances, a process for the preparation thereof, and stable medicinal formulations
US5208258Apr 17, 1990May 4, 1993The Regents Of The University Of CaliforniaAntihypercholesterolemic compounds and synthesis thereof
US5216174Jun 1, 1992Jun 1, 1993Warner-Lambert Co.Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5245047Feb 16, 1993Sep 14, 1993Warner-Lambert CompanyProcess for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5273995Feb 26, 1991Dec 28, 1993Warner-Lambert Company[R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5280126May 6, 1993Jan 18, 1994Warner-Lambert CompanyProcess for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5354772Nov 24, 1993Oct 11, 1994Sandoz Pharm. Corp.Indole analogs of mevalonolactone and derivatives thereof
US5378729Jun 4, 1991Jan 3, 1995Research Corporation Technologies, Inc.Amino acid derivative anticonvulsant
US5969156 *Jul 8, 1996Oct 19, 1999Warner-Lambert CompanyCrystalline [R- (R*,R*)]-2-(4-Dfluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
US6087511Jul 16, 1996Jul 11, 2000Warner-Lambert CompanyProcess for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)
US6121461Jul 26, 1999Sep 19, 2000Warner-Lambert CompanyForm III crystalline [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US6274740Sep 7, 2000Aug 14, 2001Warner-Lambert CompanyProcess for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethy)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US6605729Jun 28, 2002Aug 12, 2003Warner-Lambert CompanyCrystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US7144915 *Jun 6, 2003Dec 5, 2006Warner-Lambert Company, LlcCrystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
US20060241169 *May 25, 2006Oct 26, 2006Aeri ParkCrystalline forms of [R-(R*.R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
AU601981B2 Title not available
AU621874B2 Title not available
CA1161380A1Jun 11, 1980Jan 31, 1984George Albers-SchonbergHypocholesteremic fermentation products and process of preparation
CA1268768A1May 7, 1987May 8, 1990Bruce D. RothTrans-6-¬2-(3- or 4-carboxamido-substituted pyrrol- 1-yl)alkyl|-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
CA1304080CJun 19, 1986Jun 23, 1992Isao HayakawaOptically active pyridobenzoxazine derivatives and intermediates thereof
CA1330441CFeb 7, 1989Jun 28, 1994Donald Eugene ButlerProcess for trans-6-[2-(substituted-pyrrol-1-yl) alkyl] pyran-2-one inhibitors of cholesterol synthesis
CA2021546A1Jul 19, 1990Jan 22, 1991Warner Lambert Co(r-(r*r*))1-2-(4-fluorophenyl)beta ’-dihydroxy-5-(1-methylethyl-3-phenyl-4-((phenylamino) carbonyl)-1h-pyrrole-1-heptanoic acid, its lactone form and salts thereof
CA2465565A1Apr 29, 2004Dec 12, 2004Warner-Lambert Company LlcPharmaceutical compositions of atorvastatin
DK171588B1 Title not available
EP0024348A1Aug 14, 1980Mar 4, 1981Merck & Co., Inc.Substituted 6-Phenethyl-and phenylethenyl-3,4,5,6-tetrahydro-4-hydroxytetraydropyran-2-ones in the4-R trans stereoisomeric forms and the corresponding dihydroxy acids, process for preparing and pharmaceutical composition comprising them
EP0114027A1Nov 22, 1983Jul 25, 1984Sandoz AgAnalogs of mevalolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals
EP0171588A1Jul 5, 1985Feb 19, 1986Lonza AgChain-lengthening or cross-linking agent
EP0211416A2Aug 1, 1986Feb 25, 1987Merck & Co., Inc.Novel HMG-CoA reductase inhibitors
EP0221025A1Oct 21, 1986May 6, 1987Sandoz AgHeterocyclic analogs of mevalonolactone and derivatives thereof, processes for their production and their use as pharmaceuticals
EP0232997A1Jan 22, 1987Aug 19, 1987Merck & Co., Inc.Antihypercholesterolemic compounds
EP0247633A1May 29, 1987Dec 2, 1987Warner-Lambert CompanyTrans-6-[2-(3- or 4-Carboxamido-substituted pyrrol-1-yl)-alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
EP0251625A2Jun 22, 1987Jan 7, 1988Merck & Co., Inc.Novel HMG-CoA reductase inhibitors
EP0259086A2Aug 25, 1987Mar 9, 1988Merck & Co., Inc.Prodrugs of antihypercholesterolemic compounds
Non-Patent Citations
1Alberts Am.J.Cardiology vol. 62, 10J-15J (1988).
2Alberts Proc Natl Acad Sci USA Jul. 1980;777(7):3957-61.
3Amin et al., J. Pharmacology 46:13 (1993).
4Ariėns et al. Cholinergic and Anticholinergic Drugs: Do they act on common receptors?, Ann NY Acad Sci, vol. 144, pp. 842-868 (1967).
5Ariėns Stereochemistry and Biological Activity of Drugs, 11-53, 89-102, 161-185 (1983).
6Ariėns Stereochemistry, a Basis for Sophisticated Nonsense in Pharmacokinetics and Clinical Pharmacology, Eur. J. Clin. Pharmacol., vol. 26, pp. 663-668 (1984).
7Ariėns, Chirality in bioactive agents and its pitfalls, TIPS, Elsevier Science Publishers B.V., Amsterdam, pp. 200-205 (1986).
8Ariėns, E.J. "Implications of the Neglect of Stereochemistry in Pharmacokinetics and Clinical Pharmacology", Drug Intelligence and Clinical Pharmacy, (Oct. 1987), vol. 21, 827-829.
9Ariėns, E.J., "Stereochemistry in the Analysis of Drug-Action. Part II", Medicinal Research Reviews, (1987), vol. 7, No. 3, 367-387.
10Ariėns, E.J., "Stereochemistry: A Source of Problems in Medicinal Chemistry", Medicinal Research Reviews, (1986), vol. 6, No. 4, 451-466.
11Audebert Direct Resolution of Enantiomers in Column Liquid Chromatography, J. Liquid Chromatography, vol. 2, No. 8, 1063-1095 (1979).
12Banitt, E.H. et al., "Resolution of Flecainide Acetate, N-(2-Piperidylmethyl)-2,5-bi5(2,2,2,-trifluoroethoxy)benzamide Acetate, and Antiarrhythmic Properties of the Enantiomers", J. Med. Chem. (1986),29:299-302.
13Banker, Rhodes, eds., Modern Pharmaceutics, 3rd Edition, Marcel Dekker, Inc.: New York, 1996.
14Berge et al. Pharmaceutical Salts, J. Pharm. Sci., vol. 66(1):1-19 (1977).
15Braun, M et al., Tetrahedron Lett., 25, 5031-5034 (1984).
16Brophy et al., Statin wars following coronary revascularization-Evidence based clinical practice? Can. J. Cardiol. 22(1): 54-58 (2006).
17Brown, A.G. et al., "Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium brevicompactum", J. Chem. Soc. Perkin I, (1976) 1165-1170.
18Burger Medicinal Chemistry, Chapter 7, pp. 81-107 (1970).
19Burlinson, Tablets and Tabletting, William Heinemann medical Books Ltd. : London, 1968.
20Canadian Consenus Conference on Cholestrol. Final Report, Canadian Consenus Conference on the Prevention of Heart and Vascular Disease by Altering Serum Cholesterol and Serum Lipoprotein Factors. CMAJ 139: 111-63 (1988).
21Carey et al. "Advanced Organic Chemistry", 2nd Ed., Chapter 2 and p. 75 (1984).
22Casy, A.F. Stereochemistry and Biological Activity. Medicinal Chemistry, Wiley: New York, 1970.
23Chapter 1-Selling to Everyone High Cholesterol. In Moynihan R. and Cassels A., Selling Sickness, Avalon Publishing Group: 2005, pp. 1-21.
24Chemist's Binder of Biological Data, identified as DTX 552, in Pfizer, Inc et al., v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
25CI-981 IND submitted to the FDA, identified as DTX 326 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
26Collet et al. Optical Resolution by Direct Crystallization of Enantiomer Mixtures, Chemical Reviews, vol. 80, No. 3, 215-230 (1980).
27Conant et al. The Chemistry of Organic Compounds, A Year's Course in Organic Chemistry, 4th ed. Macmillan, New York, 1954, p. 234.
28Consenus Conference. Lowering Blood Cholesterol to Prevent Heart Disease. JAMA 253: 1080-2086 (1985).
29Cook Enantioselective Drug Analysis, Pharmacy International, vol. 6, No. 12, pp. 302-305 (1985).
30Decamp Chirality, 1989, 1:2-6.
31Defendants' Trial Exhibit 319 from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US. District Court, District of Delaware, 03-209-JJF.
32Defendants' Trial Exhibit 321 from Pfizer, Inc et al, v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
33Defendants' Trial Exhibit 3323, "Data Provided to Patent Office in '995 Specification and Data from Experiment 107," from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited et al., US District Court, District of Deleware, 03-209-JJF.
34Defendants' Trial Exhibit 3325 from Pfizer, Inc. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
35Defendants' Trial Exhibit 3325A from Pflizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
36Demerson et al. Resolution of Etodolac and Antiinflammatory and Prostaglandin Synthetase inhibiting Properties of the Enantiomers, J. Med. Chem., vol. 26, No. 12, 1778-1780 (1983).
37Dietschy 1, CSI IC50 values, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
38Dietschy 2, COR IC50 values, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
39Dietschy 3, IC50 values (nM) for head-to-head CSI and COR screens, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
40Dietschy 4, AICS data, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited. et al., US District Court, District of Delaware, 03-209-JJF.
41Documents compiled by the World Health Organization's Department of Essential Drugs & Medicines Policy published as and
42Dotsevi, C. et al., "Chromatographic Optical Resolution through Chiral Complexation of Amino Ester Salts by a Host Covalently Bound to Silica Gel", J. Am. Chem. Soc., (1975), 97:1259-1261.
43Dugan, R.E. et al., "Factors Affecting the Diurnal Variation in the Level of beta-Hydroxy-beta-Methylglutaryl Coenzyme A Reductase and Cholestrol-Synthesizing Activity in Rat Liver", Archiv. Biochem. Biophys., (1972), 152:21-27.
44Dujovne et al., The Lovastatin-Niacin Trial: Adverse Events. Arteriosclerosis and Thrombosis 11: 1458a (1991).
45Eliel et al., Section 3-1-Compounds with One Asymmetric Carbon Atom, Stereochemistry of Carbon Compounds, McGraw-Hill Book Company, Inc. (1962).
46Eliel et al., Section 4-4-Resolution of Racemic Modifications, Stereochemistry of Carbon Compounds, McGraw-Hill Book Company, Inc. pp. 47-74 (1962).
47Eliel et al., Stereochemistry of Organic Compounds, Wiley, New York, 1994, pp. 329-331, and remainder of Section 7-3.
48Endo, A. et al., "Biochemical Aspect of HMG CoA Reductase Inhibitors", Adv. in Enzyme Regulation, Proceedings of the 28 Symposium on Regulation of Enzyme Activity and Synthesis in Normal and Neoplastic Tissues held at Indiana University School of Medicine, Indianapolis, Indiana, (Oct. 2 and 3, 1988), vol. 28, pp. 53-64.
49Endo, A. et al., "Inhibition of Cholesterol Synthesis in vitro and in vivo by ML-236A and ML-236B, Competitive Inhibitors of 3-Hydroxy-3-methylglutaryl- Coenzyme A Reductase", Eur. J. Biochem., (1977), 77:31-36.
50Endo, J Med Chem., 28: 401-405 (1985).
51English translation of Austrian decisions invalidating Austrian Patent No. 207 ,896.
52Fodor et al., for the Working Group on Hypercholesterolemia and Other Dyslipidemias: Recommendations for the Management and Treatment of Dyslipidemia. CMAJ 162 (10): 1441-1447 (2000).
53Fodor et al., Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: 2003 update. CMAJ 168(9): 921-924 (2003).
54Frolich et al., Rationale for and Outline of the Recommendations of the Working Group of Hypercholesterolemia and Other Dyslipidemias: Interim Report. Can. J. Cardiol. 14 (supp. A): 17A-21A (1998).
55Frost, P.H. et al., Lipid Metabolism. In PA Fitzgerald, Ed., Handbook of Clinical Endocrinology, 2nd Edition, Appleton and Lange, 1991.
56Frost, P.H. et al., Lovastatin-Niacin Comparative Trial. JACC 19, 374A, 1992.
57Frost, P.H. et al., Rationale for use of non-high-density lipoprotein cholestrol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholestrol screening and assessment of risk and therapy, Am. J. Cardiol. 81: 26B-31B (1998).
58Gennaro, Remington's Pharmaceutical Sciences, 18th Ed., Mack Printing Company: Easton, Pennsylvania, 1990.
59Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, Feb. 1987.
60Hall and Roush, J. Org. Chem., 47: 4611-4621 (1982).
61Havel et al., A multicenter study of mevinolin (lovastatin) in treatment of heterozygous familial hypercholestolemia. Annals Int. Med. 107: 609 (1987).
62Havel, R.J. et al., The role of non-high-density lipoprotein cholesterol in evaluation and treatment of lipid disorders. J. Clin. Endocrinology and Metabolism 85: 2105-2108 (2000).
63Illingworth, D.R. et al., Comparative effects of lovastatin and niacin in primary hypercholesterolemia: A prospective trial. Arch. Intern. Med. 154: 1586-1595 (1994).
64Kibbe, A.H., ed., Handbook of Pharmaceutical Excipients, 3rd Ed., Pharmaceutical Press: London, 2000.
65Lachman et al., Proformulation, The Theory and Practice of Industrial Pharmacy, 3rd Edition, Lea & Febiger: Philadelphia, 1986.
66Letter dated Dec. 2, 2005 from Taylor Wessing to L. Caswell attaching expert reports of Dr. Newton dated May 27, 2005 and Jun. 17, 2005 that were filed in Ranbaxy (UK) v. Warner-Lambert Company, HC-04C 02167, and said reports.
67Lieberman et al., eds. Pharmaceutical Dosage Forms Tablets, 2nd Edition (vol. 1), Marcel Dekker: New York, 1989.
68Lipitor advertising placed in the Canadian Medical Association Journal, from 1997 to 2005.
69Lovastatin Study Group III. A multicenter comparison of lovastatin and cholestyramine in the therapy of severe primary hypercholesterolemia. JAMA 260: 359 (1988).
70Lovastatin Study Groups I through IV. Lovastatin 5-year safety and efficacy study. Arch. Intren. Med. 153: 1079-1087 (1993).
71Manuel et al., The 2003 Canadian Recommendations for Dyslipidemia Management: Revisions are Needed. CMAJ 172: 1027-1032 (2005).
72National Cholesterol Education Program Guideline III (2004 Update).
73NHLBI News Release May 15, 2001,
74Parke-Davis Memo re: Lead Compound Pharmacological Profile for CI-981 (PD 134298-38A) to Mr. H.F. Oberkfell and Mr. J. Peroni from Newton and Roth, dated Sep. 28, 1989, identified as DTX 4 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
75Rawlins, Bentley's Textbook of Pharmaceutics, 8th Ed., Bailliere Tindall: London, 1977.
76Report on the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch. Intern. Med. 148: 36-69 (1988).
77Results of the National Cholesterol Education (NCEP) Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II Survey and Implications for Treatment under Recent NCEP Writing Group Recommendations.
78Roth et al., Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J. Med. Chem. 34(1): 357-366 (Jan. 1991).
79Roush and Gillis, J. Org. Chem., 47: 4825-4829 (1982).
80Seeman, P. Drug Receptors. Kalant H. et al. eds., Principles of Medical Pharmacology, 4thEdition, University of Toronto Press: Toronto, 1985.
81Sit et al, J. Med. Chem., 33:2982 (1990).
82Sit et al., Synthesis, Biological Profile, and Quantitative Structure Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem.33: 2982-2999 (1990).
83Stein et al., The Lovastatin-Niacin Trial: Effects on Lipoproteins. Arteriosclerosis and Thrombosis 11: 1458a (1991).
84Stein, E.A. et al., Efficacy and tolerability of low-dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial. J. Cardiovasc. Pharmacol. Therapeut. 1: 107-116 (1996).
85Stinson Chemical and Engineering News, 70, Sep. 28, 46 (1992).
86Stinson Chemical and Engineering News, 71, Sep. 27, 38 (1993).
87Stinson, Chemical and Engineering News, 70(39): 46-79 (1992).
88Stinson, Chemical and Engineering News, 71(39): 38-64 (1993).
89The Cholestrol Myth, Atlantic Monthly, Sep. 1989.
90The Merck Index, 10th Edition (1983), entry 5949: N-Methylglucamine, pp. 870-871.
91The Merck Index, 12th Edition (1996), entry 897: Atorvastatin, p. 146.
92Transcript of evidence given by Dr. Scallen in US trial of Prizer, Inc., et al. v Ranbaxy Laboratories Limited wt. al., Court file No. 03-209-JJF, on Dec. 3, 2004.
93Trial transcripts taken on Jul. 18 to 22, 2005 and Jul. 25, 2005 in Ranbaxy (UK) Limited v. Warner-Lambert Company, HC-04C 02167.
94Underberg et al., J. Pharm. Biomed Anal. 8(8-12): 681-683 (1990).
95Warner-Lambert Company Notices of Application court files T-507-05, T-1128-05.
96Warner-Lambert Pharmaceutical Research Report No. RR-740-02620, Acute Inhibition of Cholesterol Synthesis in the Rat by the Calcium Salts (Racemic and Chiral) of CI-971, dated May 31, 1989, identified as DTX 11 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
97Warner-Lambert/Parke-Davis memo to Oberkfell and Pieroni from Newton and Roth re: PD 134298-38A Product Profile A for HMG-Co-A Reductase Inhibitor, Jun. 1, 1989, identified as DTX 142 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
98Warner-Lambert/Parke-Davis Pharmaceutical Research Report RR-740-01682, CSI (Cholesterol Synthesis Inhibitors): A Rapid Screen for Inhibitors of Cholesterol Synthesis in Crude Microsomal Preparations from Rat Liver, dated May 3, 1985, identified as DTX 271 in Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.
99Wazana, A., JAMA 283(3): (373-380 (2000).
U.S. Classification514/422, 548/517, 514/423, 548/537
International ClassificationA61K31/35, A61P43/00, C07D405/06, C07D207/416, C07D207/34, C07D207/327, A61P3/06, A61K31/40
Cooperative ClassificationC07D207/34, C07D405/06
European ClassificationC07D207/34, C07D405/06
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