|Publication number||USRE40667 E1|
|Application number||US 11/653,830|
|Publication date||17 Mar 2009|
|Filing date||16 Jan 2007|
|Priority date||21 Jul 1989|
|Also published as||CA2021546A1, CA2021546C, DE1061073T1, DE69033840D1, DE69033840T2, DE69034153D1, DE69034153T2, EP0409281A1, EP0409281B1, EP1061073A1, EP1061073B1, US5273995|
|Publication number||11653830, 653830, US RE40667 E1, US RE40667E1, US-E1-RE40667, USRE40667 E1, USRE40667E1|
|Original Assignee||Warner-Lambert Company Llc|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (101), Non-Patent Citations (99), Classifications (16), Legal Events (2) |
|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.
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.
BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
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.
DETAILED DESCRIPTION OF THE INVENTION
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:
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.
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%
- 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.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3808254||10 Jun 1971||30 Apr 1974||Syntex Corp||Resolution-racemization of alpha-amino-alpha-phenylacetonitrile|
|US3965129||15 May 1975||22 Jun 1976||Hoffmann-La Roche Inc.||Optical resolution of organic carboxylic acids|
|US3983140||12 May 1975||28 Sep 1976||Sankyo Company Limited||Physiologically active substances|
|US4072698||2 Dec 1976||7 Feb 1978||The Upjohn Company||Optically active acids with ketone or aldehyde catalyst|
|US4137322||31 Oct 1977||30 Jan 1979||Sankyo Company Limited||ML-236B carboxylic acid derivatives and their use as antihyperlipemic agents|
|US4139555||11 May 1977||13 Feb 1979||Bayer Aktiengesellschaft||Recovery of (1-S)-2-oxo-bornane-10-sulphonate|
|US4171359||12 Apr 1978||16 Oct 1979||Smithkline Corporation||Dopaminergic activity|
|US4192872||31 Mar 1978||11 Mar 1980||Smithkline Corporation||Anti -parkinsonism activity|
|US4231938||15 Jun 1979||4 Nov 1980||Merck & Co., Inc.||Antilipemic agents; fungistats|
|US4281132||24 Oct 1978||28 Jul 1981||John Wyeth & Brother Limited||Hypotensive|
|US4282155||5 Aug 1980||4 Aug 1981||Merck & Co., Inc.||Antihypercholesterolemic compounds|
|US4293496||5 Aug 1980||6 Oct 1981||Merck & Co., Inc.||6(R)-[2-(8-Hydroxy-2,6-dimethylpolyhydronaphthyl-1)-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones|
|US4319039||11 Aug 1980||9 Mar 1982||Merck & Co., Inc.||Preparation of ammonium salt of hypocholesteremic fermentation product|
|US4342761||20 Oct 1980||3 Aug 1982||John Wyeth & Brother Limited||Piperidine derivatives|
|US4342767||16 Jun 1980||3 Aug 1982||Merck & Co., Inc.||Hypocholesteremic fermentation products|
|US4346227||5 Jun 1981||24 Aug 1982||Sankyo Company, Limited||In treatment of hypercholesteremia|
|US4374829||17 Feb 1981||22 Feb 1983||Merck & Co., Inc.||Aminoacid derivatives as antihypertensives|
|US4374844||30 Oct 1981||22 Feb 1983||Schering Corporation||Bactericides|
|US4375475||11 Feb 1981||1 Mar 1983||Merck & Co., Inc.||Substituted pyranone inhibitors of cholesterol synthesis|
|US4444784||18 Dec 1980||24 Apr 1984||Merck & Co., Inc.||Antihypercholesterolemic compounds|
|US4450171||14 Jun 1982||22 May 1984||Merck & Co., Inc.||Antihypercholesterolemic compounds|
|US4474971||29 Sep 1982||2 Oct 1984||Sandoz, Inc.||Anticholesterol agents, atherosclerosis|
|US4495103||2 Mar 1983||22 Jan 1985||Sumitomo Chemical Company, Ltd.||Intermediate for synthesis of antibiotic and antitumor agent|
|US4555511||19 Jan 1984||26 Nov 1985||Boehringer Ingelheim Kg||Thieno [3,2,C]pyridines useful as antihypertensives|
|US4611067||31 Jan 1985||9 Sep 1986||Merck & Co., Inc.||Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein|
|US4613610||6 Jun 1985||23 Sep 1986||Sandoz Pharmaceuticals Corp.||Cholesterol biosynthesis inhibiting pyrazole analogs of mevalonolactone and its derivatives|
|US4647576||10 Dec 1984||3 Mar 1987||Warner-Lambert Company||Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis|
|US4681893||30 May 1986||21 Jul 1987||Warner-Lambert Company||Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis|
|US4697036||5 Apr 1985||29 Sep 1987||Zambon S.P.A.||Process for the preparation of optically active alpha-arylalkanoic acids and novel intermediates thereof|
|US4735958||22 Dec 1986||5 Apr 1988||Warner-Lambert Company||Antilipemic, anticholesterol agents|
|US4739073||4 Mar 1985||19 Apr 1988||Sandoz Pharmaceuticals Corp.||Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof|
|US4743450||24 Feb 1987||10 May 1988||Warner-Lambert Company||Angiotension converting enzyme inhibitors|
|US4775681||18 Jun 1987||4 Oct 1988||Warner-Lambert Company||Method of treating fungal infections with trans-6-[2-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones|
|US4786505||20 Apr 1987||22 Nov 1988||Aktiebolaget Hassle||Omeprazole, antisecretory agents|
|US4804679||6 Aug 1987||14 Feb 1989||Sandoz Pharm. Corp.||Inhibit cholesterol biosynthesis|
|US4847306||11 Apr 1988||11 Jul 1989||Merck & Co., Inc.||Antihypercholesterolemic compounds|
|US4851427||15 Oct 1986||25 Jul 1989||Sandoz Pharm. Corp.||Pyrrole analogs of mevalonolactone, derivatives thereof and pharmaceutical use|
|US4853230||20 Apr 1987||1 Aug 1989||Aktiebolaget Hassle||Subcoated; enteric coating;|
|US4864038||10 Jun 1988||5 Sep 1989||Merck & Co., Inc.||Antihypercholesterolemic compounds|
|US4866090||7 Jan 1988||12 Sep 1989||Merck & Co., Inc.||3-hydroxy-3-methylglutaryl-coenzyme a antihypercholesterolemic agents|
|US4870187||23 Aug 1988||26 Sep 1989||Bristol-Myers Company||Antilipemic, atherosclerosis|
|US4897490||18 Feb 1988||30 Jan 1990||Bristol-Meyers Company||Antihypercholesterolemic tetrazole compounds|
|US4898868||8 Jul 1988||6 Feb 1990||Hoechst Aktiengesellschaft||Anticholesterol agents; lactone or free acid form|
|US4898949||18 Feb 1988||6 Feb 1990||Bristol-Myers Company||Treatment of hyperlipemia, atherosclerosis|
|US4906624||2 Aug 1988||6 Mar 1990||Warner-Lambert Company||6-(((Substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis|
|US4939159||8 Mar 1989||3 Jul 1990||Sandoz Pharm. Corp.||Azaindole derivatives useful as cholesterol biosynthesis inhibitors|
|US4940727||6 Oct 1988||10 Jul 1990||Merck & Co., Inc.||Novel HMG-CoA reductase inhibitors|
|US4950775||11 Oct 1985||21 Aug 1990||University Of California||Antihypercholesterolemic compounds and synthesis thereof|
|US4962115||28 Nov 1989||9 Oct 1990||Janssen Pharmaceutica N.V.||Stimulate motility of gastrointestinal system|
|US4963538||13 Mar 1989||16 Oct 1990||Merck & Co., Inc.||Anticholesterol agent|
|US4968689||17 Jan 1989||6 Nov 1990||Bayer Aktiengesellschaft||Certain 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|
|US4976949||29 Jan 1990||11 Dec 1990||The University Of Michigan||Controlled release dosage form|
|US4978791||25 Jun 1985||18 Dec 1990||Lonza Ltd.||Substituted P,P'-methylene-bis-aniline|
|US4992462||7 Apr 1988||12 Feb 1991||Bayer Aktiengesellschaft||Inhibitor of HMG-CoA reductase|
|US5001255||1 Jul 1988||19 Mar 1991||Sandoz Pharm. Corp.||Idene analogs of mevalonolactone and derivatives thereof|
|US5003080||1 Feb 1989||26 Mar 1991||Warner-Lambert Company||Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis|
|US5004651||24 Jan 1989||2 Apr 1991||Abbott Laboratories||Of estropipate and tromethamine|
|US5006530||17 Jan 1989||9 Apr 1991||Bayer Aktiengesellschaft||Certain 7-[2,6-diisopropyl-4-phenyl-5-lower alkoxymethyl-pyrid-3-yl]-3,5-dihydroxy-6-enoates and derivatives useful for treating circulatory diseases|
|US5024999||13 Apr 1989||18 Jun 1991||Nissan Chemical Industries Ltd.||Anti-hyperlipidemia, anti-atherosclerosis agents|
|US5026708||12 Sep 1988||25 Jun 1991||Nissan Chemical Industries Ltd.||Antilipemic, antilipolytic, anticholesterol agents|
|US5030447||31 Mar 1988||9 Jul 1991||E. R. Squibb & Sons, Inc.||Pharmaceutical compositions having good stability|
|US5045321||13 Feb 1987||3 Sep 1991||Takeda Chemical Industries, Ltd.||Antiulcer compound lansoprazole or omeprazole with magnesium and/or calcium salt; tablets or granules|
|US5055484||8 Jul 1988||8 Oct 1991||Hoechst Aktiengesellschaft||7(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|
|US5061722||12 Jan 1989||29 Oct 1991||Hoechst Ag||Hypotensive agents; e.g. ramipril|
|US5093132||31 Aug 1990||3 Mar 1992||Takeda Chemical Industries, Ltd.||Stabilized pharmaceutical composition and its production|
|US5097045||9 Oct 1990||17 Mar 1992||Warner-Lambert Company||Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis|
|US5124482||14 Nov 1991||23 Jun 1992||Warner-Lambert Company||Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis|
|US5149837||12 Feb 1992||22 Sep 1992||Warner-Lambert Company||1,3-Dioxane intermediate|
|US5151433||22 Nov 1988||29 Sep 1992||Hoechst Aktiengesellschaft||Stabilized medicinal substances, a process for the preparation thereof, and stable medicinal formulations|
|US5208258||17 Apr 1990||4 May 1993||The Regents Of The University Of California||Antihypercholesterolemic compounds and synthesis thereof|
|US5216174||1 Jun 1992||1 Jun 1993||Warner-Lambert Co.||Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis|
|US5245047||16 Feb 1993||14 Sep 1993||Warner-Lambert Company||Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis|
|US5273995||26 Feb 1991||28 Dec 1993||Warner-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|
|US5280126||6 May 1993||18 Jan 1994||Warner-Lambert Company||Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis|
|US5354772||24 Nov 1993||11 Oct 1994||Sandoz Pharm. Corp.||Indole analogs of mevalonolactone and derivatives thereof|
|US5378729||4 Jun 1991||3 Jan 1995||Research Corporation Technologies, Inc.||Diamide derivatives|
|US5969156 *||8 Jul 1996||19 Oct 1999||Warner-Lambert Company||Crystalline [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)|
|US6087511||16 Jul 1996||11 Jul 2000||Warner-Lambert Company||Process 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)|
|US6121461||26 Jul 1999||19 Sep 2000||Warner-Lambert Company||Form 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)|
|US6274740||7 Sep 2000||14 Aug 2001||Warner-Lambert Company||Dissolving crystal form in solvent; drying|
|US6605729||28 Jun 2002||12 Aug 2003||Warner-Lambert Company||Crystalline 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 *||6 Jun 2003||5 Dec 2006||Warner-Lambert Company, Llc||Crystalline 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 *||25 May 2006||26 Oct 2006||Aeri Park||Crystalline 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|
|CA1161380A1||11 Jun 1980||31 Jan 1984||George Albers-Schonberg||Hypocholesteremic fermentation products and process of preparation|
|CA1268768A1||7 May 1987||8 May 1990||Bruce D. Roth||Trans-6-¬2-(3- or 4-carboxamido-substituted pyrrol- 1-yl)alkyl|-4-hydroxypyran-2-one inhibitors of cholesterol synthesis|
|CA1304080C||19 Jun 1986||23 Jun 1992||Isao Hayakawa||Optically active pyridobenzoxazine derivatives and intermediates thereof|
|CA1330441C||7 Feb 1989||28 Jun 1994||Donald Eugene Butler||Process for trans-6-[2-(substituted-pyrrol-1-yl) alkyl] pyran-2-one inhibitors of cholesterol synthesis|
|CA2021546A1||19 Jul 1990||22 Jan 1991||Warner 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|
|CA2465565A1||29 Apr 2004||12 Dec 2004||Warner-Lambert Company Llc||Pharmaceutical compositions of atorvastatin|
|DK171588B1|| ||Title not available|
|EP0024348A1||14 Aug 1980||4 Mar 1981||Merck & 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|
|EP0114027A1||22 Nov 1983||25 Jul 1984||Sandoz Ag||Analogs of mevalolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals|
|EP0171588A1||5 Jul 1985||19 Feb 1986||Lonza Ag||Chain-lengthening or cross-linking agent|
|EP0211416A2||1 Aug 1986||25 Feb 1987||Merck & Co., Inc.||Novel HMG-CoA reductase inhibitors|
|EP0221025A1||21 Oct 1986||6 May 1987||Sandoz Ag||Heterocyclic analogs of mevalonolactone and derivatives thereof, processes for their production and their use as pharmaceuticals|
|EP0232997A1||22 Jan 1987||19 Aug 1987||Merck & Co., Inc.||Antihypercholesterolemic compounds|
|EP0247633A1||29 May 1987||2 Dec 1987||Warner-Lambert Company||Trans-6-[2-(3- or 4-Carboxamido-substituted pyrrol-1-yl)-alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis|
|EP0251625A2||22 Jun 1987||7 Jan 1988||Merck & Co., Inc.||Novel HMG-CoA reductase inhibitors|
|EP0259086A2||25 Aug 1987||9 Mar 1988||Merck & Co., Inc.||Prodrugs of antihypercholesterolemic compounds|
|1||Alberts Am.J.Cardiology vol. 62, 10J-15J (1988).|
|2||Alberts Proc Natl Acad Sci USA Jul. 1980;777(7):3957-61.|
|3||Amin et al., J. Pharmacology 46:13 (1993).|
|4||Ariėns et al. Cholinergic and Anticholinergic Drugs: Do they act on common receptors?, Ann NY Acad Sci, vol. 144, pp. 842-868 (1967).|
|5||Ariėns Stereochemistry and Biological Activity of Drugs, 11-53, 89-102, 161-185 (1983).|
|6||Ariėns Stereochemistry, a Basis for Sophisticated Nonsense in Pharmacokinetics and Clinical Pharmacology, Eur. J. Clin. Pharmacol., vol. 26, pp. 663-668 (1984).|
|7||Ariėns, Chirality in bioactive agents and its pitfalls, TIPS, Elsevier Science Publishers B.V., Amsterdam, pp. 200-205 (1986).|
|8||Ariėns, E.J. "Implications of the Neglect of Stereochemistry in Pharmacokinetics and Clinical Pharmacology", Drug Intelligence and Clinical Pharmacy, (Oct. 1987), vol. 21, 827-829.|
|9||Ariėns, E.J., "Stereochemistry in the Analysis of Drug-Action. Part II", Medicinal Research Reviews, (1987), vol. 7, No. 3, 367-387.|
|10||Ariėns, E.J., "Stereochemistry: A Source of Problems in Medicinal Chemistry", Medicinal Research Reviews, (1986), vol. 6, No. 4, 451-466.|
|11||Audebert Direct Resolution of Enantiomers in Column Liquid Chromatography, J. Liquid Chromatography, vol. 2, No. 8, 1063-1095 (1979).|
|12||Banitt, 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.|
|13||Banker, Rhodes, eds., Modern Pharmaceutics, 3rd Edition, Marcel Dekker, Inc.: New York, 1996.|
|14||Berge et al. Pharmaceutical Salts, J. Pharm. Sci., vol. 66(1):1-19 (1977).|
|15||Braun, M et al., Tetrahedron Lett., 25, 5031-5034 (1984).|
|16||Brophy et al., Statin wars following coronary revascularization-Evidence based clinical practice? Can. J. Cardiol. 22(1): 54-58 (2006).|
|17||Brown, 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.|
|18||Burger Medicinal Chemistry, Chapter 7, pp. 81-107 (1970).|
|19||Burlinson, Tablets and Tabletting, William Heinemann medical Books Ltd. : London, 1968.|
|20||Canadian 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).|
|21||Carey et al. "Advanced Organic Chemistry", 2nd Ed., Chapter 2 and p. 75 (1984).|
|22||Casy, A.F. Stereochemistry and Biological Activity. Medicinal Chemistry, Wiley: New York, 1970.|
|23||Chapter 1-Selling to Everyone High Cholesterol. In Moynihan R. and Cassels A., Selling Sickness, Avalon Publishing Group: 2005, pp. 1-21.|
|24||Chemist'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.|
|25||CI-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.|
|26||Collet et al. Optical Resolution by Direct Crystallization of Enantiomer Mixtures, Chemical Reviews, vol. 80, No. 3, 215-230 (1980).|
|27||Conant et al. The Chemistry of Organic Compounds, A Year's Course in Organic Chemistry, 4th ed. Macmillan, New York, 1954, p. 234.|
|28||Consenus Conference. Lowering Blood Cholesterol to Prevent Heart Disease. JAMA 253: 1080-2086 (1985).|
|29||Cook Enantioselective Drug Analysis, Pharmacy International, vol. 6, No. 12, pp. 302-305 (1985).|
|30||Decamp Chirality, 1989, 1:2-6.|
|31||Defendants' Trial Exhibit 319 from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US. District Court, District of Delaware, 03-209-JJF.|
|32||Defendants' Trial Exhibit 321 from Pfizer, Inc et al, v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.|
|33||Defendants' 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.|
|34||Defendants' Trial Exhibit 3325 from Pfizer, Inc. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.|
|35||Defendants' Trial Exhibit 3325A from Pflizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.|
|36||Demerson 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).|
|37||Dietschy 1, CSI IC50 values, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.|
|38||Dietschy 2, COR IC50 values, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited, et al., US District Court, District of Delaware, 03-209-JJF.|
|39||Dietschy 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.|
|40||Dietschy 4, AICS data, from Pfizer, Inc et al. v. Ranbaxy Laboratories Limited. et al., US District Court, District of Delaware, 03-209-JJF.|
|41||Documents compiled by the World Health Organization's Department of Essential Drugs & Medicines Policy published as http://www.drugpromo.info/read-reviews.asp?id=4 and http://www.drugpromo.info/read-reviews.asp?id=5.|
|42||Dotsevi, 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.|
|43||Dugan, 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.|
|44||Dujovne et al., The Lovastatin-Niacin Trial: Adverse Events. Arteriosclerosis and Thrombosis 11: 1458a (1991).|
|45||Eliel et al., Section 3-1-Compounds with One Asymmetric Carbon Atom, Stereochemistry of Carbon Compounds, McGraw-Hill Book Company, Inc. (1962).|
|46||Eliel et al., Section 4-4-Resolution of Racemic Modifications, Stereochemistry of Carbon Compounds, McGraw-Hill Book Company, Inc. pp. 47-74 (1962).|
|47||Eliel et al., Stereochemistry of Organic Compounds, Wiley, New York, 1994, pp. 329-331, and remainder of Section 7-3.|
|48||Endo, 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.|
|49||Endo, 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.|
|50||Endo, J Med Chem., 28: 401-405 (1985).|
|51||English translation of Austrian decisions invalidating Austrian Patent No. 207 ,896.|
|52||Fodor 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).|
|53||Fodor et al., Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: 2003 update. CMAJ 168(9): 921-924 (2003).|
|54||Frolich 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).|
|55||Frost, P.H. et al., Lipid Metabolism. In PA Fitzgerald, Ed., Handbook of Clinical Endocrinology, 2nd Edition, Appleton and Lange, 1991.|
|56||Frost, P.H. et al., Lovastatin-Niacin Comparative Trial. JACC 19, 374A, 1992.|
|57||Frost, 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).|
|58||Gennaro, Remington's Pharmaceutical Sciences, 18th Ed., Mack Printing Company: Easton, Pennsylvania, 1990.|
|59||Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, Feb. 1987.|
|60||Hall and Roush, J. Org. Chem., 47: 4611-4621 (1982).|
|61||Havel et al., A multicenter study of mevinolin (lovastatin) in treatment of heterozygous familial hypercholestolemia. Annals Int. Med. 107: 609 (1987).|
|62||Havel, 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).|
|63||Illingworth, D.R. et al., Comparative effects of lovastatin and niacin in primary hypercholesterolemia: A prospective trial. Arch. Intern. Med. 154: 1586-1595 (1994).|
|64||Kibbe, A.H., ed., Handbook of Pharmaceutical Excipients, 3rd Ed., Pharmaceutical Press: London, 2000.|
|65||Lachman et al., Proformulation, The Theory and Practice of Industrial Pharmacy, 3rd Edition, Lea & Febiger: Philadelphia, 1986.|
|66||Letter 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.|
|67||Lieberman et al., eds. Pharmaceutical Dosage Forms Tablets, 2nd Edition (vol. 1), Marcel Dekker: New York, 1989.|
|68||Lipitor advertising placed in the Canadian Medical Association Journal, from 1997 to 2005.|
|69||Lovastatin Study Group III. A multicenter comparison of lovastatin and cholestyramine in the therapy of severe primary hypercholesterolemia. JAMA 260: 359 (1988).|
|70||Lovastatin Study Groups I through IV. Lovastatin 5-year safety and efficacy study. Arch. Intren. Med. 153: 1079-1087 (1993).|
|71||Manuel et al., The 2003 Canadian Recommendations for Dyslipidemia Management: Revisions are Needed. CMAJ 172: 1027-1032 (2005).|
|72||National Cholesterol Education Program Guideline III (2004 Update).|
|73||NHLBI News Release May 15, 2001, http://www.nhlbi.nih.gov/new/press/01-05-15.htm.|
|74||Parke-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.|
|75||Rawlins, Bentley's Textbook of Pharmaceutics, 8th Ed., Bailliere Tindall: London, 1977.|
|76||Report 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).|
|77||Results 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.|
|78||Roth 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).|
|79||Roush and Gillis, J. Org. Chem., 47: 4825-4829 (1982).|
|80||Seeman, P. Drug Receptors. Kalant H. et al. eds., Principles of Medical Pharmacology, 4thEdition, University of Toronto Press: Toronto, 1985.|
|81||Sit et al, J. Med. Chem., 33:2982 (1990).|
|82||Sit 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).|
|83||Stein et al., The Lovastatin-Niacin Trial: Effects on Lipoproteins. Arteriosclerosis and Thrombosis 11: 1458a (1991).|
|84||Stein, 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).|
|85||Stinson Chemical and Engineering News, 70, Sep. 28, 46 (1992).|
|86||Stinson Chemical and Engineering News, 71, Sep. 27, 38 (1993).|
|87||Stinson, Chemical and Engineering News, 70(39): 46-79 (1992).|
|88||Stinson, Chemical and Engineering News, 71(39): 38-64 (1993).|
|89||The Cholestrol Myth, Atlantic Monthly, Sep. 1989.|
|90||The Merck Index, 10th Edition (1983), entry 5949: N-Methylglucamine, pp. 870-871.|
|91||The Merck Index, 12th Edition (1996), entry 897: Atorvastatin, p. 146.|
|92||Transcript 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.|
|93||Trial transcripts taken on Jul. 18 to 22, 2005 and Jul. 25, 2005 in Ranbaxy (UK) Limited v. Warner-Lambert Company, HC-04C 02167.|
|94||Underberg et al., J. Pharm. Biomed Anal. 8(8-12): 681-683 (1990).|
|95||Warner-Lambert Company Notices of Application court files T-507-05, T-1128-05.|
|96||Warner-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.|
|97||Warner-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.|
|98||Warner-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.|
|99||Wazana, A., JAMA 283(3): (373-380 (2000).|
| || |
|U.S. Classification||514/422, 548/517, 514/423, 548/537|
|International Classification||A61K31/35, A61P43/00, C07D405/06, C07D207/416, C07D207/34, C07D207/327, A61P3/06, A61K31/40|
|Cooperative Classification||C07D207/34, C07D405/06|
|European Classification||C07D207/34, C07D405/06|
|17 Aug 2010||DC||Disclaimer filed|
Effective date: 20100708
|5 May 2009||CC||Certificate of correction|